The Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention took place July 19-22 in Cape Town, South Africa.
More than any other recent international conference, IAS 2009 was dominated by important research from sub-Saharan Africa that will have significant implications for the way that treatment and care are delivered in resource-limited settings.
This edition reproduces in full news coverage published during the conference by aidsmap.com, the official online news provider for the IAS 2009 conference.
Future editions of HATIP will be looking in more detail at some of the major topics of the conference, including:
- What will the results of studies on antiretroviral therapy during pregnancy and breastfeeding mean for frontline services and for women with HIV?
- What do the results of the DART study mean for treatment monitoring practices in resource-limited settings?
Preventing mother to child transmission
BAN study: Giving ART to mothers or ARV prophylaxis to infants during breastfeeding equally effective at reducing HIV transmission
by Theo Smart
Maternal antiretroviral therapy (ART) or infant prophylaxis during the time of breastfeeding are equally safe and effective in reducing post-natal mother-to-child transmission of HIV, Dr Charles Chasela of the University of North Carolina Project in Lilongwe, Malawi, reported to the Fifth International AIDS Society conference on Wednesday.
He presented the findings of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study as a late-breaker at IAS 2009 in Cape Town - making it the fifth major study at the conference evaluating ways to make it possible for an HIV-infected mother to breastfeed her infant without passing on HIV.
Breastfeeding in HIV
Breastfeeding is generally the best way of feeding a baby, but when the mother is HIV-positive there is a risk of vertical transmission of the virus to her infant. WHO guidelines recommend exclusive breastfeeding for HIV-infected women for the first six months of life unless replacement feeding is acceptable, feasible, affordable, sustainable and safe (AFASS) for them and their infants before that time.
Unfortunately, replacement feeding is rarely possible in resource-limited settings. Formula is expensive and reliable supplies are difficult to maintain in countries with limited infrastructure for transport and storage. Even when formula feed is freely provided it may not be culturally acceptable and often puts the mother at risk of having her HIV status disclosed involuntarily to her family and community and of being stigmatised.
Finally, the water to prepare it with may not always be safe or it may be difficult to keep the babies’ environment hygienic. As a result, some programmes have reported diarrhoea outbreaks.
Breastfeeding reduces diarrhoea-related morbidity and mortality. Even early weaning poses problems. In fact, in another presentation at the conference, Dr Ashraf Fawzy of Columbia University reported that diarrhoea and morbidity increased among uninfected infants of HIV-infected mothers in the Zambia Exclusive Breastfeeding Study (ZEBS). The effect was most pronounced in children who stopped breastfeeding earlier. What was worse? “Among children who weaned early, severe diarrhoeal morbidity and mortality continued to be higher between 6 and 18 months,” Dr Fawzy reported.
“Formula is not recommended in Malawi since it is expensive, and if used in the first six months, yields high infant mortality. Therefore, there is an urgent need for interventions to make breastfeeding safer for infants of HIV-infected women,” said Dr Chasela.
The BAN Study
So investigators from Malawi, the University of North Carolina and the US Centers for Disease Control (CDC) launched the BAN study, a randomised controlled trial to evaluate two interventions given to HIV-infected mothers or their infants during a 24-week period of exclusive breastfeeding.
To prevent mother-to-child transmission of HIV, all the mothers were treated with a single dose of nevirapine during labour, followed by a week of twice-daily treatment with 3TC and AZT. All the women participating in the study were given nutritional supplementation to prevent maternal depletion.
To be eligible for the study, all the mothers had a CD4 cell count above 250 cells/mm3 and the infants weighed at least 2 kg. Then within the first week after delivery, the mothers and their infants were randomised into one of three treatment arms:
- Maternal daily treatment with nevirapine (after they were switched to nelfinavir, then the protease inhibitor lopinavir/ritonavir) in combination with 3TC and AZT
- Infant nevirapine (NVP) that the mother administered to her infant through 28 weeks
- A control arm. No antiretroviral treatment, but nutritional support.
All the mothers breastfed for 24 weeks, followed by rapid weaning by 28 weeks. Weaning food Plumpy Nut was provided until week 48.
The study outcomes were HIV infection or death in infants at week 28 amongst those who were HIV-uninfected a week after birth.
Results
A total of 2367 HIV-positive mothers and their infants were included in the study: 851 were on maternal ART, 848 were randomised to infant NVP, and 668 to the enhanced control. Fewer women were in the enhanced control arm since randomisation to the control arm was stopped after March 2008 based on a Data Safety and Monitoring Board recommendation.
There were no statistical significant differences in age, body mass index, CD4 count, haemoglobin and infant birth weight at baseline.
Severe side-effects were rare. There were no significant differences in terms of grade three or four toxicities except for low neutrophil count in mothers on the maternal ART arm (this is a known side-effect of AZT). And out of the 848 infants on the infant NVP arm, there were 16 possible cases of NVP hypersensitivity that were mild and all were resolved when NVP was discontinued. There appeared to be one additional case of NVP hypersensitivity in a breastfeeding infant whose mother was receiving NVP.
According to Dr Chasela, there had been concerns about NVP hypersensitivity (reactions that includes rash, eosonophilia, sometimes liver toxicity and Stevens Johnson Syndrome), which has been well documented in NVP use in adults, usually within the first weeks of treatment, but there is less information on its use in infants.
HIV infection status was assessed by testing the infant at birth, 2, 12, 28 and 48 weeks by DNA PCR. Dried Blood Spots (DBS) were obtained at each visit and tested to narrow the window of transmission to less than four weeks. All positives were confirmed with a second specimen. The rate of mother-to-child transmission of HIV one week after delivery (before randomisation) was 5%.
“Using standard survival methods - both the infant NVP and maternal ART regimens significantly reduced 28 week HIV transmission, compared with the enhanced control arm,” said Dr Chasela.
At the end of the study, 6.4% of the infants in the control arm were HIV-positive. This was significantly higher (p = 0.003) than the 3% rate of mother-to-child transmission observed in the infants of mothers who took antiretroviral therapy during breastfeeding, and the 1.8% transmission rate seen in infants treated with nevirapine (p < 0.001).
The overall risk of HIV transmission or death was 7.6% for infants in the control arm, compared to 4.7% for the maternal HIV treatment arm (p = 0.03) and 2.9% for the nevirapine arm (p < 0.0001).
The study was not powered to directly compare the maternal and infant interventions, but there was some suggestion that HIV-free survival was lower among infants who were treated with NVP for 28 weeks (p = 0.07).
Implications
“The BAN results give global and national policy makers the choice of which interventions to implement: either maternal ART or infant NVP, based on the appropriateness of their particular setting,” said Dr Chasela.
Indeed, this was just one of five studies presented at IAS on interventions that could make breastfeeding safer for women with HIV and their infants. The first was a retrospective analysis of the DREAM cohort in Malawi and Mozambique, which found that giving ART during pregnancy and breastfeeding reduces the risk of a woman transmitting HIV to her infant to just 2%.
The other studies were all randomised controlled studies.
In the Mma Bana study in Botswana, there was about a half a percent risk of transmission during breastfeeding.
The PEPI-Malawi study was presented as a poster, and showed that extended antiretroviral prophylaxis of breastfeeding HIV-exposed infants for 14 weeks reduced postnatal transmission by 67% at age 14 weeks and 50% at age 9 months (Mofenson). However, continued transmission after 14 weeks suggested that infant prophylaxis needs to last at least as long as the mother continues to breastfeed.
Finally the Kesho Bora study used the same regimen as the BAN Study but commenced treatment between week 28 and 36 of pregnancy, rather than after delivery, and showed about a two percent risk of transmission during breastfeeding.
Taken together these findings have clear policy implications. Noting that transmission from women with CD4 counts of 200-350 cells/mm3 is still unacceptably high, Mofenson et al. wrote: Use of infant prophylaxis should be considered to reduce breast milk transmission risk in infants born to women with CD4 [cell counts] over 350, while women with CD4s [below] 350 should receive ART for their own health… which would be continued after breastfeeding cessation for maternal health.”
References
Chasela C et al. Both maternal HAART and daily infant nevirapine are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28 week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLBC103, 2009.
Fawzy A et al. Diarrhea morbidity and mortality increases with weaning prior to 6 months among uninfected infants born to HIV-infected mothers in Zambia. . 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUAC104, 2009.
Mofenson LM et al. Infant Extended Antiretroviral (ARV) Prophylaxis is Effective in Preventing Postnatal Mother-to-Child HIV Transmission at All Maternal CD4 Counts. . 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUPEC053, 2009.
Further information
A powerpoint presentation by Charles Chasela and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.
A powerpoint presentation by Ashraf Fawzy and a webcast of the conference session in which it was presented are also available on the IAS 2009 website here.
Kesho Bora study: Maternal ART during pregnancy and breastfeeding prevents more infections than short-course prophylaxis
by Keith Alcorn
Antiretroviral treatment for mothers started during pregnancy and continued throughout the breastfeeding period resulted in a significantly lower rate of mother-to-child HIV transmission when compared with the standard short-course regimen, investigators on the Kesho Bora study reported this week at the Fifth International AIDS Society conference in Cape Town.
The Kesho Bora study, conducted in Kenya, South Africa and Burkina Faso, found that antiretroviral treatment for the mother with a protease inhibitor-based regimen was significantly more effective than short-course treatment in which the mother took AZT from week 28 to 36 of pregnancy with AZT/3TC and single dose nevirapine at the onset of labour, and AZT/3TC for one week, while the infant received single dose nevirapine with one week of AZT/3TC, and was either formula fed or breastfed with weaning at 6 months.
The differing short-course regimens studied reflect variations in practice as a result of previous clinical trial results.
In the Kesho Bora study 824 pregnant women not currently eligible for antiretroviral treatment for their own health, with CD4 counts between 200 and 500 cells/mm3, were randomised to one of two regimens.
Women in the triple therapy group (n=413) received AZT/3TC and lopinavir/ritonavir (Kaletra) from the third trimester of pregnancy until six months postpartum, the point at which breastfeeding was recommended to cease.
Women in the short-course group received AZT (zidovudine) from week 28 to 36 of pregnancy until the onset of labour, when they received AZT/3TC and single dose nevirapine. They continued to take AZT/3TC for one week after delivery, an amendment introduced to the study in December 2007.
All infants received single dose nevirapine within 72 hours of delivery, and one week of AZT treatment was added from December 2007.
Women were counselled on the risk of transmission through breastfeeding and offered the choice of free formula for bottle feeding, or exclusive breastfeeding with weaning over a two-week period commencing at five and a half months. During the study 76 and 78% of mothers in the two study arms breastfed at some point, with around 45% in each arm breastfeeding exclusively during the first three months after delivery. The average duration of breastfeeding was 21 weeks.
Study recruitment began in June 2005 and the study was fully recruited by August 2008, with the result that the majority of births in the study occurred in the period before the December 2007 protocol amendment.
In the triple ART arm there were 402 live births, and infant HIV infections as measured by real-time PCR were detected in 1.8% at birth, 3.3% at six weeks, 4.9% at six months and 5.5% at one year. The reduction in the risk of transmission at one year was 42% when compared to the short-course regimen. A log rank test at 12 months showed this difference to be statistically significant (p = 0.039).
In comparison there were 411 live births in the short-course arm, and infant HIV infections were detected in 2.2% at birth, 4.8% at six weeks, 8.5% at six months and 9.5% at one year.
A difference in infant survival became apparent after six months: 6.3% of infants born to mothers in the triple therapy arm had died after 12 months of follow-up, compared to 10% of infants in the short-course arm, a reduction in risk of 37%. However a log rank test at 12 months did not show this difference to be statistically significant (p = 0.086).
Subgroup analysis showed that the reduction in HIV infection rate associated with the triple therapy regimen was statistically significant only in the group of mothers with baseline CD4 counts between 200 and 350 cells/mm3. In the infants born to these mothers there was a cumulative HIV infection rate of 5.5% by six months in the triple ART group and 10.5% in the short-course group, rising to 6.1 and 11.1% at 12 months (p = 0.044).
A significant difference was not detected in infants born to mothers with baseline CD4 counts between 350 and 500 cells/mm3, and there was no significant difference in HIV infections according to regimen in the infants of mothers who ever breastfed during the study (5.9% vs 10.2%, p = 0.064).
The study authors note that the biggest effect of triple ART was detected between six weeks and six months after delivery, and in mothers with CD4 counts between 200 and 350 cells/mm3, reinforcing the view that if earlier treatment is to be recommended in resource-limited settings, this group should be a priority. The median CD4 count in this study population was 335 cells/mm3.
The authors also noted that a small number of postnatal transmissions occurred after six months, the point at which breastfeeding was recommended to stop, indicating the importance of continuing ART until breastfeeding stops completely.
Analyses of adherence and the long-term impact of treatment on maternal health will take place, and full results of the study, with 12-month and 18-month follow-up on all participants, are expected in 2010.
References
Kesho Bora Study Group. Triple-antiretroviral prophylaxis during pregnancy and breastfeeding compared to short-ARV prophylaxis to prevent mother-to-child transmission of HIV-1: the Kesho Bora randomized controlled clinical trial in five sites in Burkina Faso, Kenya and South Africa. Fifth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLBPeC01, 2009
Chasela C et al. Both maternal HAART and daily infant nevirapine are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28 week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study. Fifth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLBC103, 2009.
Further information
A powerpoint presentation by Charles Chasela and a webcast of the conference session in which it was presented are available on the IAS 2009 website.
Mma Bana study: Mother-to-child transmission reduced below 1% in breastfeeding mothers who receive ART
by Keith Alcorn
Antiretroviral treatment during pregnancy and breastfeeding resulted in a mother-to-child transmission rate of less than 1% in a large randomised comparison of two triple combinations in women with CD4 counts above 200 cells/mm3, the Mma Bana study, presented this week at the Fifth International AIDS Society conference in Cape Town.
The study also showed that a triple-nucleoside analogue regimen containing abacavir is just as effective as a protease inhibitor-based regimen in a population of women with relatively low viral load (Trizivir has previously shown itself to be less effective than efavirenz-based ART in people with viral loads above 100,000 copies/ml, leading to its withdrawal from the list of recommended first-line regimens in the United States and Europe).
However it should be noted that women in this study were followed for a little less than nine months, which may not be long enough to evaluate the suitability of Trizivir as a long-term regimen for women in sub-Saharan Africa.
The Mma Bana study was a randomised comparison of the virologic efficacy and PMTCT (prevention of mother-to-child transmission) efficacy of two antiretroviral regimens taken during pregnancy and breastfeeding by women with CD4 counts above 200 cells/mm3.
The investigators randomised 560 HIV-positive pregnant women with CD4 cell counts above 200 cells/mm3 to start one of two antiretroviral regimens between weeks 26 and 34 of pregnancy. This treatment was continued until weaning six months after giving birth.
Women in the first arm were provided with a combination of drugs that comprised the three nucleoside reverse transcriptase inhibitors (NRTIs) 3TC, abacavir and AZT, dosed as Trizivir. Nevirapine-based ART is unsuitable for women with CD4 counts above 250 cells/mm3 due to an increased risk of liver toxicity, so alternative regimens need to be identified to enable treatment in pregnancy to be extended to women with higher CD4 counts.
Women in the other arm were treated with the protease inhibitor lopinavir/ritonavir (Kaletra) in combination with 3TC and AZT (dosed as Combivir).
Also included in the study were 170 women with a CD4 cell count below 200 cells/mm3. In accordance with treatment guidelines at that time, to protect their own health they started a combination of anti-HIV drugs consisting of nevirapine with 3TC and AZT between weeks 18 and 34 of pregnancy.
All mothers received supplemental AZT (zidovudine) during labour.
Infants received single dose nevirapine after delivery and one month of treatment with AZT (zidovudine).
Women in the randomisation arms had median CD4 counts of approximately 400 cells/mm3, and were enrolled to the study around week 27 of their pregnancy. Median viral loads were relatively low in the randomisation arm; 13,300 and 9100 copies in the Trizivir and Kaletra arms respectively, with only 15% of women having a baseline viral load above 100,000 copies/ml.
In the observational group receiving nevirapine-based ART the median CD4 cell count was 147 cells/mm3 and the median viral load 51,000 copies/ml. Thirty-seven per cent had baseline viral load above 100,000 copies/ml.
There were two main study outcomes: the proportion of women with a viral load below 400 copies/ml at delivery and throughout breastfeeding at months 1, 3 and 6; and the rate of mother-to-child transmission of HIV assessed at birth and then months 1, 3 and 6 of feeding. Data were also gathered on adverse events, including still births and the number of babies born prematurely or with a low birth weight.
At the time of birth, equal proportions of women taking triple NRTI treatment (96%), protease inhibitor-based therapy (93%) and treatment that included nevirapine (94%) had a viral load below 400 copies/ml. The median duration of treatment was 11 weeks in the randomisation arm, and 13 weeks in the observational arm.
Moreover, similar proportions of women maintained viral suppression throughout breastfeeding, regardless of the HIV treatment they were taking (92% vs 93% vs 95%).
The cumulative rates of mother-to-child transmission of HIV were equally low in all three groups of women (2% in the triple NRTI arm vs below 0.4% in the Kaletra group and 0.6% in the nevirapine group). This difference was not statistically significant.
The very small number of transmissions in the study occurred almost entirely in utero, in women who had high baseline viral loads and shorter than average periods on ART prior to delivery, and in some cases, a history of self-reported adherence problems. Insufficient viral suppression is likely to explain these cases of transmission, and indicates the need for ART to be initiated promptly in pregnancy in order to achieve rapid viral suppression before delivery.
Only two transmissions occurred during the breastfeeding period, in one case from a mother who had viral load below 50 copies/ml at months 1 and 3 and no evidence of adherence problems.
There was no difference in the number of babies born with a low birth weight between the arms of the study, although babies born to mothers in the Kaletra arm were more likely to be premature (p = 0.04).
Furthermore, there was a comparable rate of still births amongst the women treated with three NRTIs (3%) and those receiving a protease inhibitor (2%). However, 7% of the babies of mothers taking nevirapine were still births.
Side-effects causing a change of treatment were recorded in 2% of women taking both the triple NRTI treatment or the protease inhibitor-based treatment. Nevirapine-based treatment was associated with a much higher rate of treatment changes, with 11% changing because of side-effects.
Approximately 75% of women breastfed for over five months. Nearly all infants had been weaned six months after birth. Infant mortality during breastfeeding was 2% amongst women who took triple NRTI treatment, 3% amongst those taking a protease inhibitor, and 4% amongst those who started nevirapine-based therapy because they had a low CD4 cell count.
The mother-to-child transmission rate in the Mma Bana study is the lowest yet seen in any randomised study of antiretroviral treatment during pregnancy and breastfeeding, and despite the higher rate of drug substitution in the nevirapine arm, shows that in mothers with higher viral load and low CD4 counts, nevirapine-based ART is remarkably effective in preventing mother-to-child transmission.
Reference
Shapiro R et al. A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child transmission among breastfeeding women in Botswana (The Mma Bana Study). 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLLB101, 2009.
Further information
A webcast of the conference session in which this study was presented is available on the IAS 2009 website >here.
DREAM study: Extended prenatal ART protects against mother-to-child transmission of HIV at low and high CD4 levels
by Theo Smart
Antiretroviral therapy (ART) administered during pregnancy and breastfeeding reduces the risk of a woman transmitting HIV to her infant to just 2% by the time the child is six months of age – even without caesarean sections or formula feeding, according to a retrospective analysis of participants in the Drug Resource Enhancement against AIDS and Malnutrition (DREAM) programme in sub-Saharan Africa, presented this week at the International AIDS Society conference in Cape Town.
Without ART, even women with CD4 cell counts over 350 cells/mm3 were at high risk of transmitting the virus to their infants: “In our cohort, 37% of the transmissions that occurred were in this group with CD4 cell counts over 350,” said Professor Leonardo Palombi, of the University of Tor Vergata in Rome, who presented on behalf of the DREAM Programme.
But the benefit of ART was observed regardless of whether the mother had a low or high CD4 cell count when she went on treatment – and the longer that she was on treatment, the better. In fact, a shorter course of pre-delivery ART (less than 30 days) was strongly associated with HIV transmission and death at 1 month and between 1 and 6 months of age. Again, “this effect was also apparent in the women with higher CD4 cell counts,” said Prof. Palombi.
Going on ART during pregnancy was also associated with a dramatic reduction in adverse pregnancy outcomes, including a 70% reduction in the rates of spontaneous abortion and stillbirths, a 72% reduction in prematurity rates and a significant reduction in maternal mortality regardless of baseline CD4 cell counts. Toxicity was infrequent and mainly associated with AZT and d4T, even though there were concerns of nevirapine-related hypersensitivity in women with higher CD4 cell counts.
DREAM
The DREAM programme supports HIV care and treatment for around 75,000 adults and children in 10 countries within sub-Saharan Africa. Their approach to the prevention of mother-to-child transmission (PMTCT) is much closer to the norm in industrialised countries than the typical African PMTCT regimen (a short course of AZT monotherapy during late pregnancy, followed by single-dose nevirapine [sdNVP] as the woman goes into labour).
“In DREAM, we start as soon as possible and continue for at least six months while women are breastfeeding,” said Prof. Palombi. Women with CD4 cell counts below 350 cells/mm3 are deemed to need ART for their own health, and given nevirapine with either AZT/3TC or d4T/3TC as early as the 14th week of gestation and continuing for life (or treatment switch). Those with CD4 cell counts over 350 cells/mm3 are given the same regimen, starting from the 25th week of pregnancy, and continuing during breastfeeding and stopping after weaning (about six months after birth).
Since nevirapine has a long half-life, the women then continue to take a AZT/3TC ‘tail’ for three weeks to reduce the risk of becoming resistant to nevirapine. All infants are also given sdNVP within 72 hours of birth.
Participants in the programme also receive more intensive monitoring than is routinely available in their countries (with routine viral load, CD4 cell counts and toxicity monitoring).
Impact on vertical transmission
The retrospective analysis presented by Prof. Palombi involved a record review for 3148 live births among 3273 HIV-positive women enrolled in the programme in Malawi and Mozambique from July 2005 to December 2008.
Of the live births, at one month, 93 infants were lost to follow-up and seven had died (for a neonatal mortality rate of 0.23%) but 2994 infants were tested by bDNA (and testing was still pending for 54 at the time of analysis).
Out of the 2994 infants tested at one month, 22 have been confirmed as being HIV-positive (and five with positive results await confirmation), for an HIV transmission rate of 0.7%.
At month 6, 2120 of the children who were HIV negative at month 1 were again tested (another 642 are waiting to be tested, while between month 1 and 6, 143 have been lost to follow-up and 41 have died (for a 1-6 month mortality rate of 1.9%). At this timepoint, 15 more children have been confirmed to be positive, and 5 are waiting to be confirmed as positive.
The cumulative transmission rate at 6 months is between 1.4 and 1.9%, the cumulative mortality rate at 6 months is 2.1% and the loss to follow-up rate at six months is 7.5%. These are rates as low as typically reported in well-resourced countries – but again, these are breastfeeding women who would be more likely to transmit HIV if not on treatment.
Benefit associated with time on ART
Because of factors such as late diagnosis and presentation, not every women started treatment as per protocol. This enabled the researchers to detect an association between outcomes and length of time on ART.
At one month, there was a 0.9% transmission rate for infants whose mothers had received at least one dose of ART before delivery (these women had a viral load of 3.55 log) but a 5.1% transmission rate among infants whose mothers waited until delivery to begin ART (with a viral load of 4.51 log, p = 0.001). The one-month HIV-free survival rate for infants was 97.6%.
When infant outcomes were stratified according to maternal baseline CD4 level, pre-delivery ART use appeared to have an impact regardless of whether mothers had low or high CD4 cell counts. Among 1388 children of women whose baseline CD4 levels were below 350 cells/mm3, there was a 1.3% rate of HIV transmission or death with 30-plus days of maternal ART use (16 of 1231 infants) versus a 3.8% rate when maternal ART was used for 30 days or less (six of 157 infants) (odds ratio [OR] 0.33, confidence interval [CI] 0.12-0.86). Among 1533 children of women whose baseline CD4 levels were 350 cells/mm3 or higher, there was a 0.7% rate of either HIV transmission or death with 30-plus days of maternal ART use and a 2.0% rate with a shorter duration of maternal ART use (OR 0.33, CI 0.10-1.09).
In multivariate analysis, 30 days or less of pre-delivery ART was found to be associated with either infant death or HIV transmission at one month postpartum after adjusting for baseline viral load, CD4 cell count, haemoglobin and body mass index.
During the period of breastfeeding – between 1 to 6 months – the association between the length of time on ART pre-delivery was significantly associated with both HIV transmission on its own and the combined endpoint of transmission and death – again, this was apparent in both CD4 cell strata, but most pronounced in the women with lower CD4 cell counts.
Among the 990 children of women whose baseline CD4 levels were below 350 cells/mm3 who were tested for HIV at month 6, there was a 3.1% rate of HIV transmission or death with 30-plus days of maternal ART use (27 of 876 infants) but an 8.8% rate when maternal ART was used for 30 days or less (10 of 114 infants) (OR 0.33, CI 0.16-0.70).
Among 1105 children of women whose baseline CD4 levels were 350 cells/mm3 or higher, there was a 1.8% rate of either HIV transmission or death with 30-plus days of maternal ART use and a 2.1% rate with a shorter duration of maternal ART use (OR 0.81, CI 0.24-2.83).
In a multivariate analysis, both baseline maternal viral load and receiving 30 days or less of pre-delivery ART were found to be associated with either infant death or HIV transmission at 1-6 months postpartum after adjustments.
The six-month estimated HIV-free survival for the children of women who received less than 30 days of ART was 90.9%, while it was 96% in those who received extended therapy.
Finally, “the infant mortality rate and other parameters of infant health (such as birth weight, weight for age) were also positively affected by the approach,” said Prof. Palombi. “Breastfeeding under ART is a safe, feasible and acceptable choice in resource-limited settings where the health risks associated with no breastfeeding are extremely high.”
ART results in favourable pregnancy outcomes
The DREAM researchers also looked pregnancy outcomes (such as spontaneous abortion, stillbirth and prematurity), maternal mortality, toxicity and resistance to ARVs to determine how the approach impacted on the mother’s health.
Out of the 3273 pregnancies in the cohort, 42 died, for a maternal mortality rate of 1.2%. 3.1% of the pregnancies ended in stillbirth, 2.1% were spontaneous abortions (9 of these coincided with the mother’s death), and 19.1% of the infants were premature.
Of the entire cohort, 68 women received no ART, and 365 received less than 30 days of ART – and again, there were clear differences in outcomes. While only 5.2% of those on ART for more than 90 days had stillbirths, the rate was 26.5% in women who received no ART, and 7.1% in those who received ART for less than 30 days. The rate of stillbirth and abortion in those who received less than 30 days of ART was higher regardless of the CD4 cell count but those with CD4 cell counts below 200 cells/mm3 were most likely to have poor outcomes. Likewise, prematurity was strongly associated with shorter duration of ART – regardless of CD4 cell strata. And although the numbers were rather small, maternal mortality followed the same pattern.
ART-related adverse reactions were rather uncommon. Grade 3/4 anaemia was reported in 8.6% of subjects. Likewise, d4T-related peripheral neuropathy was observed in 6.9% of subjects – mostly after pregnancy. Nevirapine-related toxicity was less common. Grade 3/4 liver toxicity was observed in only 2.2% (one patient's LFT increased more than 5 times the upper limit of normal within six weeks of ART). There were 39 cases of Stevens-Johnson Syndrome (1.2%), while grade 3/4 rash was reported in 2.4% of the subjects.
Finally, no viral resistance has been detected among a substudy of 26 women who discontinued ART after weaning.
Limitations
Prof Palombi conceded that as a retrospective study, there is a potential for selection bias. Some in the audience pointed out that the better outcomes seen in the women who accessed ART earlier might simply be due to better access to care. However, Prof. Palombi doesn’t think this is likely – the various benefits are too consistently associated with longer ART across CD4 strata.
References
Marazzi MC et al. Extended use of highly active antiretroviral therapy (HAART) during pregnancy in Southern Africa is highly protective in HIV-1 prevention of mother-to-child-transmission (PMTCT) also in women with higher CD4 cell counts. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUC101, 2009.
Increased risk of HIV transmission in serodiscordant couples wishing to conceive
by Lesley Odendal
Harm reduction interventions to avoid HIV transmission in heterosexual, serodiscordant couples who wish to have children are urgently needed, according to Dr Sara Brubaker, from Kenya, as reported at the Fifth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town.
A study conducted in Kisumu, Kenya, found that HIV-serodiscordant couples, where one partner is HIV-infected and the other is not, continue to conceive despite knowledge of their serostatus. In this cohort, couples who conceived were at 80% increased risk of HIV transmission between the partners.
A large proportion of new HIV infections in sub-Saharan Africa occur in stable heterosexual partnerships.The Kenya AIDS Indicator Survey of 2007 showed that half of HIV-infected Kenyans have partners who are HIV-uninfected.
Prevention efforts have focused on couples-based HIV testing. Although couples studies in central Africa have shown that condom use increases when couples learn about their discordant status, these same studies had shown that 20 to 43% of couples continue to have unprotected intercourse despite knowledge of their serostatus. This behaviour is often motivated by the desire to have children.
A systematic review of factors influencing fertility desires in HIV-infected people showed the factors that positively influence the desire and intention to have children are young age, having few or no previous children and having access to antiretroviral treatment (ART).
Five hundred and thirty-two heterosexual HIV-serodiscordant couples were enrolled in the study. Forty-one (7.6%) of the HIV-uninfected partners seroconverted, at a rate of 4.6 per 100 person years. In 328 (61.7%) of the couples, the female was HIV-infected, compared to 204 (38.3%) where the male was HIV-infected. 95.3% of study participants were married to their partner.
There were 373 pregnancies during the study period (this number included men if their partner conceived) compared to 698 individuals who did not become pregnant.
A comparison of those who conceived and those who did not showed that 10.8% of individuals who conceived or whose partner conceived aquired HIV, compared to only 5.9% in those where no pregnancy occurred.
The relative risk of a partner aquiring HIV was 1.8 times greater in serodiscordant couples where pregnancy did not occur than in those where pregnancy did occur.
Individuals who conceived were significantly younger with a median age of 27 compared to 34 in those who did not become pregnant (p<0.01).
The study investigators could not assess intentionality or if the pregnancies were unplanned. Researchers suggested that rather than people acquiring HIV while attempting to become pregnant, they may acquire HIV because of possible increased susceptibility to HIV due to pregnancy.
An analysis of timing of pregnancy in relation to seroconversion showed that approximately 30% of seroconversions occurred six months before conception, 35% in the six months after conception and the remaining 35% were remote from conception.
A second study in Kenya, carried out among a cohort of 296 stable, HIV-discordant couples at Kenyatta National Hospital in Nairobi, already participating in a study of immune responses in exposed but uninfected partners, found a one-year cumulative pregnancy rate of 10.5%, with no difference in pregnancy rates between HIV-positive and uninfected women. This study did not evaluate HIV incidence.
The study found a particularly high rate of pregnancy in women below the age of 30 who wanted children: after 500 days of follow-up, 30% of this group had become pregnant, compared with fewer than 5% of women under 30 who did not want children. Women in the earlier stages of relationships were significantly more likely to become pregnant, with the incidence of pregnancy falling by 16% for each year the couple had been together by the time of recruitment to the study.
Implications for service delivery
Despite being unable to assess intentionality for pregnancy in the first cohort, if a portion of these pregnancies were intentional, these couples were risking HIV transmission in order to conceive. In high-income settings there are high-tech interventions such as sperm washing available that make conception for serodiscordant couples safe. However, even in free-at-the-point-of-care health systems like the United Kingdom, assisted conception procedures like sperm washing are charged for.
Antiretroviral treatment may also reduce the risk of transmission when it is fully suppressive, and some clinics, particularly in Switzerland and the United Kingdom, have already begun counselling couples about how to time unprotected intercourse in order to maximise the potential for conception once undetectable viral load has been achieved on treatment.They may also offer antiretroviral drugs to the uninfected partner as pre- and post-exposure prophylaxis, an approach to managing conception that would be feasible and affordable in settings where it is possible to measure viral load and provide results promptly.
Interventions and public health campaigns addressing the desire to have children in serodiscordant couples need to be designed and implemented in low-income settings in order to address this issue. As researchers from the University of Washington and Kenyatta National Hospital norte, it is not enough to say “avoid unprotected sex”.
References
Nattabi B et al. A systematic review of factors influencing fertility desires and intentions among people living with HIV/AIDS: implications for policy and service delivery. AIDS Behaviour, DOI 10.1007/s10461-00909537-y, March 2009.
Brubaker S et al. Pregnancy and HIV transmission among HIV discordant couples in a clinical trial in Kisumu. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract WELBC105, 2009.
Guthrie BL et al. Predicting pregnancy among HIV-1 discordant couples. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract LBPEC08, 2009.
Further information
A powerpoint presentation by Sara Brubaker and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.
Treatment and care for children
Large-scale paediatric treatment shows success in South-East Asia
by Carole Leach-Lemens
Long-term treatment success in children in both Thailand and Cambodia demonstrates the sustainability of paediatric antiretroviral therapy (ART) in resource-limited settings at clinic, district and provincial levels, as reported in studies by Michelle McConnell and Petros Isaakidis, respectively, at the Fifth IAS Conference on Pathogenesis, Treatment and Prevention, held in Cape Town.
An absence of documentation on the long-term outcomes of children on ART in resource-limited settings impedes effective management of HIV in children. A better understanding of outcomes will support earlier initiation of treatment as well as helping in the diagnosis of treatment failure, improving overall morbidity and mortality rates in children.
In Thailand, national antiretroviral treatment began in 2000. Michelle McConnell of the US Centers for Disease Control and colleagues from the Thai Ministry of Public Health reviewed outcomes for HIV-positive children, under 15 years of age, who began ART between 2000 and 2005 in district/community hospitals as well as at provincial (larger) hospitals. Eligibility criteria for ART included being under one year of age or having a CD4 percentage ≤ 20 or CDC clinical stage B or C. Follow-up data for patients were included through March 2007.
In Cambodia, Petros Isaakidis of Médecins sans Frontières and his Cambodian colleagues undertook a cross-sectional survey within a cohort study in two paediatric HIV-clinics. Three-year survival rates, as well as changes in CD4 counts and viral load, were evaluated to determine the risk factors for treatment failure. Assessment of viral load and viral genotyping for drug resistance were undertaken on children who had been on first-line treatment for at least two years.
In the national Thai programme, analysis included 3409 children at 327 hospitals of whom 20% began ART at a district/community hospital and 80% in the larger hospitals. The median age at the start of antiretroviral treatment was 7.3 years, weight for age z-score was -2.0 (IQR = 2.6 to 1.4) and CD4 percentage 5.0% (IQR =1.9 to 13.0%). Close to 75% were on nevirapine-based regimens and just over 20% on efavirenz-based treatment.
Approximately 10% (346) were lost to follow-up (defined as more than three months late for a clinic visit, cross-checked against the national death registry) and another 9% died (90% (274) of deaths were related to HIV). Median time to death was 3.6 months (IQR= 1.4 to 10.7). Of note, unlike Thailand, most resource-poor countries do not have national death registries limiting an understanding of the causes of HIV mortality.
Survival probability for one year and for five years was 0.93(95% CI: 0.93 to 0.94) and 0.88 (95% CI :0.86 to 0.90) respectively. Factors associated with survival included being in a district/community hospital, having a higher weight-for-age ratio at baseline and being at a better clinical stage.
In Cambodia, 57% of 1168 HIV-positive children registered at the two paediatric clinics began antiretroviral treatment between January 2003 and December 2007. Survival probabilities for one year, two years and three years were 0.95 (95% CI: 0.93 to 0.97), 0.93 (95% CI: 0.91 to 0.95) and 0.91 (95% CI: 0.88 to 0.93) respectively. The median duration of antiretroviral treatment was just over three years. Median CD4 count gains for children over the age of five were +304, +704 and +737 cells/mm3 at six months, two years and three years respectively.
An intention-to-treat analysis demonstrated an 85% virological success rate. 93.5% of 138 children who had been on ART for at least three years had an undetectable viral load. A CD4 count below 100 (threshold) at two years (24 months) and three years (36 months) was predictive of failure after month 24 and month 36 respectively. Of the 22 children with viral loads >1000 copies/ml, two met the World Health Organization criteria for failure. Resistance, primarily to 3TC (lamivudine, Epivir) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), was detected in 21 children. Orphan status did not affect outcome.
Long-term survival with good treatment outcomes in these two large cohorts of children demonstrates the sustainability of antiretroviral treatment programmes for children in resource-limited settings at the clinic, district and provincial levels. Earlier initiation, as well as routine viral load testing, is needed, with scale-up to support better outcomes that include timely and accurate diagnosis of treatment failure.
References
McConnell M et al. Survival rate following expansion of the national pediatric antiretroviral treatment program, Thailand, 2000-2005. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract 1715, 2009.
Isaakidis P High survival and treatment success sustained after up to three years of ART for children in Cambodia. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract 850, 2009.
Further information
Powerpoint presentations by Michelle McConnell and Petros Isaakidis and a webcast of the conference session in which they were presented are available on the IAS 2009 website (follow this link).
Risk factors for treatment failure in children: ritonavir and advanced disease strong predictors
by Carole Leach-Lemens
Ritonavir used alone as a third drug is a strong predictor of virologic failure in children receiving antiretroviral treatment, according to an analysis of data from the International Epidemiological Databases to Evaluate AIDS (leDEA) Southern Africa's paediatric antiretroviral cohorts, presented by Mary Ann Davies et al. at the Fifth IAS Conference on Pathogenesis, Treatment and Prevention, in Cape Town.
Advanced immunosuppression was also a predictor of treatment failure.
Fifty percent of children with virologic failure were not switched to second-line antiretroviral therapy (ART) and, for those who did receive second-line treatment, a delay of close to five months between failure and switching occurred.
As more children access antiretroviral treatment, a corresponding increase in the number of treatment failures will occur, requiring second-line treatment.
The absence of a definition of virologic failure in children, coupled with the lack of studies in resource-limited settings about treatment failure and outcomes of second-line treatment, severely handicap the effective management of HIV in children.
The World Health Organization does not recommend the use of routine viral load monitoring regarding decision-making on treatment failure. Viral load monitoring is suggested when CD4 counts and clinical criteria are conflicting. WHO suggests a viral load greater than 10,000 copies as indicative of treatment failure in adults. Thresholds for children have – as yet – not been defined.
However, levels of HIV RNA that are greater than 100,000 copies in children are associated with a higher mortality rate and suggest treatment should be switched.
To understand the probabilities of virologic failure in addition to the outcomes of second-line therapy, an analysis was undertaken of children under sixteen years of age who started combination therapy at leDEA Southern Africa sites and who received routine six-monthly virologic monitoring.
Failure was defined as two consecutive viral loads above 10,000 copies/ml more than five months after the start of antiretroviral treatment.
Among 5484 children, median follow-up was 16 months (IQR 6 to 29). 310 children had virologic failure and 146 were switched to second-line treatment; at three years cumulative probabilities were 11.4% (95% CI: 10.1 to 12.8) and 6.0% (95%CI: 5.0 to 7.2) respectively. The median time between failure and switch was 4.8 months (IQR 1.5 to 9.4).
Characteristics of children at the start of antiretroviral therapy and the corresponding association with virologic failure (where significant) included:
- being under 12 months of age (21%)
- having a viral load in excess of one million copies/ml (21%)
- being severely immunosuppressed, as defined by WHO (82% – adjusted hazard ratio 2.01 [1.20 to 3.36])
- being at WHO stage 3 or 4 (75%)
- ritonavir being used alone as a third drug (versus lopinavir/ritonavir or a non-nucleoside reverse transcriptase inhibitor) (7% – adjusted hazard ratio 2.69 [1.72 to 4.20]).
Survival and retention in care of children one year after switching to second-line therapy were 97.1% (95%CI: 91.9 to 99.1) and 88.7% (95% CI: 81.7 to 93.5) respectively. Fifty-five per cent had viral load suppression one year after switching to second-line therapy.
The authors noted that findings from this population may not be applicable to all South African cohorts, since the centres and clinics involved in the study are well-resourced. No good information was available on adherence or co-infection.
Ritonavir liquid, less frequently used in developed world settings, was in use due to the limited range of antiretroviral formulations suitable for young children. The study authors said that they were unable to determine whether the unpleasant taste of ritonovir liquid affected adherence and thus led to higher rates of virologic failure seen in ritonavir-treated children.
Fifty percent of children who had failed first-line treatment were not switched to second-line treatment, and the fifty percent who were switched experienced a considerable delay between the diagnosis of treatment failure and switching to second-line therapy.
References
Davies MA et al. Virologic failure and second-line antiretroviral therapy (ART) in children in South Africa: the international epidemiologic databases to evaluate AIDS (leDEA) Southern Africa collaboration. 5th IAS Conference on Pathogenesis, Treatment and Prevention, Cape Town, abstract 1759, 2009.
Further information
A powerpoint presentation by Mary-Ann Davies and a webcast of the conference session in which it was presented are available on the IAS 2009 website (follow this link).
Nevirapine-based treatment regimen for children previously exposed to single-dose nevirapine shown to be effective
By Lesley Odendal
Switching to nevirapine-based antiretroviral therapy (ART) as a treatment strategy for HIV-infected children previously exposed to single-dose nevirapine has the potential to maintain viral suppression in children, according to the data of the NEVEREST study presented by Dr Ashraf Coovadia at the Fifth IAS Conference on Pathogenesis, Treatment and Prevention in Cape Town.
The study aimed to examine the efficacy of switching from a protease inhibitor-based regimen for children to a non-nucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimen in children previously exposed to single-dose nevirapine (Viramune).
Current guidelines recommend initiating protease inhibitor-based regimens in infants previously exposed to single-dose nevirapine after delivery.
These regimens are more costly and have greater long-term toxicity than NNRTI-based regimens. Given that treatment options for HIV-infected children are limited, investigation into alternative regimens is necessary.
A total of 195 HIV-positive children under two years of age from the Rahima Moosa Mother and Child Hospital in Johannesburg were included in the study. All their mothers had taken nevirapine in an attempt to prevent mother-to-child transmission of HIV. The children were initiated on an antiretroviral regimen consisting of lopinavir/ritonavir in combination with d4T (stavudine, Zerit) and 3TC (lamivudine, Epivir).
After maintaining a viral load below 400 copies for at least three months with this combination, the children were randomised either to continue taking their existing treatment (99 children), or to replace lopinavir/ritonavir with nevirapine (96 children) There were no significant differences in the median ages, viral load or CD4 percentage of the two groups at baseline or at randomisation stage.
To monitor viral suppression of HIV post-randomisation, the children were followed for 52 weeks, during which period they had regular viral load tests with a lower limit of detection of 50 copies/ml.
56.2% of children who replaced lopinavir/ritonavir with nevirapine consistently had a viral load below 50 copies/ml for the 52 weeks compared to 42.4% of children who remained on lopinavir/ritonavir. This difference was statistically significant (p = 0.01).
However, a higher proportion of children treated with lopinavir/ritonavir than those switching to nevirapine maintained a viral load below 1000 copies/ml for the duration of the study (98% vs 80%, p = 0.007), suggesting that the difference in the proportion with viral load below 50 copies/ml may have been driven chiefly by viral load 'blips' resulting from poorer adherence to the protease inhibitor.
Patterns of viral suppression post-randomisation showed that in those children remaining on lopinavir/ritonavir, 42% sustained a viral load of less than 50 copies/ml, 55.5% had viral load between 50 and 1000 copies/ml and 2.1% had a viral load above 1000 copies/ml. This compared to 56%, 23.7% and 20.1% respectively in those who switched to nevirapine.
Factors predicting sustained viral suppression in the children who had switched to nevirapine were found to be having a viral load of less than 50 copies/ml at randomisation and no NNRTI mutations occurring before the initiation of treatment.
It was found that, in the children who had switched to nevirapine, 86.1% of those with a viral load of less than 50 copies/ml at randomisation had a sustained viral load suppression below 1000 copies/ml compared to 63.5% of those with viral load between 50 and 400 copies/ml (p<0.001).
Of those who had experienced no NNRTI mutations, 88% had sustained viral load suppression of less than 1000 copies/ml compared to only 55.3% in children where mutations had occurred (p=0.007).
The median CD4 percentage at 24 weeks was 30% in the children continuing with lopinavir/ritonavir, compared to 33.2% in those who had switched to nevirapine (p<0.001). CD4 percentage declined by 10% in 16.3% of those continuing with lopinavir/ritonavir compared to 3.2% of those who switched to nevirapine.
Two children taking nevirapine died as did two children remaining on lopinavir/ritonavir. Adherence to treatment as determined through medication reconciliation at 36 weeks post-randomisation was found to be 80% in those taking lopinavir/ritonavir and 86% in the children who switched to nevirapine although this difference was not found to be statistically significant.
The results suggest that NNRTI-based regimens for children need to be investigated further, and that a substantial proportion of children who develop resistance as a result of exposure to single-dose nevirapine are able to maintain viral suppression when treated with nevirapine after initial, or induction, treatment with a protease inhibitor.
Reference
Coovadia A et al. Randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract MoAB103, 2009.
Further information
A webcast of the presentation by Ashraf Coovadia is available on the IAS 2009 website (follow this link).
ART for mothers leading to decline in child deaths, KwaZulu Natal study finds
by Theo Smart
A major decrease in the childhood mortality rate in children under the age of two (U2CMR), observed between 2001 and 2006 in northern rural KwaZulu Natal, South Africa, was associated with the rollout of antiretroviral therapy (ART) in that region, according to a presentation made at IAS 2009 in Cape Town this week.
Although some of the benefit may have been due to the introduction of programmes to prevent vertical (mother to child) transmission in 2001, researchers found that it was most strongly associated with maternal access to ART.
“Maternal survival is critical for the health of young children,” said Dr James Ndirangu of the Africa Centre for Health and Population Studies.
Background
Globally, the reduction of child mortality is a major public health priority (and one of the Millenium Development Goals). However, in areas with a high prevalence of HIV, child mortality rates have increased for a number of reasons. Quite obviously, children who are HIV-infected are at a much greater risk of death, but maternal HIV infection also contributes to mortality even in HIV-negative children — especially if their mothers die.
Programmes to prevent mother to child transmission, and increasing access to ART, should hopefully have an impact on child mortality in these settings. In South Africa, PMTCT programmes, including infant feeding interventions, were first launched in 2001. The ART roll-out began in late 2004.
The investigators wished to establish the impact of programmes to prevent mother-to-child HIV transmission and HIV treatment for mothers on childhood mortality. They therefore examined mortality data for children aged under two years obtained between 2001 and 2006. These data were obtained from the Africa Centre Demographic Surveillance System, which was set up in 2000, in a largely rural area of northern Kwazulu-Natal, involving approximately 90,000 women. The Africa Centre began annual HIV surveillance in 2003.
The overall HIV prevalence in the cohort is 23% — 50% among women 24 to 29 years of age. Currently, there are over 9000 people on ART in the catchment area.
The fall in childhood mortality — and its causes
A total of 12,031 live births were included in the investigators’ analysis. Between 2001 and 2006, infant mortality declined from a peak of 86 per 1000 live births in 2001 to 37 per 1000 live births in 2006, a fall of 57%.
Post-neonatal mortality accounted for the largest decline, while neonatal mortality remained constant. Dr Ndirangu noted that after the rollout of ART, there was a statistically significant reduction in the cumulative risk of childhood mortality that becomes apparent after the first 100 days of life.
Dr Ndirangu showed an analysis of temporal changes in childhood mortality by clinic catchment areas within the region. This illustrated reductions in each district after PMTCT was implemented at the clinic, and then again, after the clinic began offering ART.
The researchers performed a multivariate analysis adjusting for maternal HIV, PMTCT availability and ART availability, that also adjusted for other factors that have been shown to be associated with child mortality, such as maternal age and education, child’s gender, multiple pregnancy, birth order, history of foetal and child death, delivery location, area of birth, household socio-economic factors (water and sanitation, electricity, household assets, distance to the health facility). In other words, the analysis excluded every other factor that the researchers could think of that may have contributed to the observed reduction in child mortality. For example, if there were improvements in the community’s socio-economic status, or health services, it would have helped reduce child mortality as well.
But it was clear that maternal HIV was a major risk factor for child mortality in this region.
“Children who are born to mothers known to be HIV-positive at the time of birth, were four times more likely to die compared to those born to HIV-negative mothers,” said Dr Ndirangu [with an adjusted hazard ratio [AHR] = 4.31, 95% confidence interval (CI) 3.09-6.01 p < 0.001)]. “While those women who didn’t know their HIV-status at birth who were HIV-negative before delivery but HIV-positive after delivery, their children were three times more likely to die compared to those who were born to HIV-negative mothers.” [AHR = 3.24, 95% CI 2.58-4.09, p <0.001).
According to the abstract, maternal death was associated with a modest increase in infant mortality, but this did not reach significance (AHR = 2.02, p = 0.076).
As to the impact of the availability of PMTCT and ART on mortality, the multivariate analysis indicated that children who were born when single-dose nevirapine (sdNVP) was available as PMTCT but before ART, were 15% less likely to die than those born at a time when there was no ART and no PMTCT, but this did not reach statistical significance.
However, among those who were born less than two years after the roll-out of ART began, there was a 34% decline in the risk of mortality [AHR = 0.66, 95% CI 0.55-0.79, p <0.001); while those who were born more than two years after the roll-out of ART began, had a 55% decline in child mortality [AHR = 0.45, 95% CI 0.32-0.64, p <0.001).
“Overall, U2CMR substantially declined in our area from 2001 and this is despite a continued high HIV prevalence and incidence in the area,” said Dr Ndirangu. On the basis of the multivariate analysis, much of the effect was due to maternal access to ART.
He added that they further modelled the impact of the interventions using locally informed assumptions about transmission and the impact of the interventions and concluded that almost a third (31%) of the fall in infant mortality seen during the period of the study could be attributed to maternal antiretroviral treatment. A further 8% was likely explained by programmes to prevent mother to child transmission.
Reference
Ndirangu J et al. A decline in early life mortality in a high HIV prevalence rural area of South Africa: associated with implementation of PMTCT and/or ART programmes? 5th International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeD105, 2009.
A webcast of James Ndirangu's presentation is available on the IAS 2009 website.
DART study
DART study shows HIV treatment without lab monitoring safe, effective in Africa
by Keith Alcorn
Antiretroviral treatment can be delivered safely without laboratory monitoring in sub-Saharan Africa, say the investigators of the DART study, presented this morning at the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town.
The study, coordinated by the United Kingdom’s Medical Research Council and sponsored by the UK Department for International Development and the Rockefeller Foundation, demonstrated only a small difference in rates of death and serious illness between patients randomised to receive laboratory monitoring and those who received clinical monitoring and so switched to second-line treatment only on the basis of clinical symptoms.
DART was designed to test whether a lack of laboratory monitoring would result in significantly worse treatment outcomes for people taking antiretroviral drugs in resource-limited settings. CD4 cell count monitoring is difficult in many resource-limited settings due to lack of laboratory infrastructure.
Researchers from Uganda, Zimbabwe and the United Kingdom found that the difference in outcomes only became apparent after the second year of treatment in the five-year study, leading them to conclude that clinical monitoring alone is feasible during the first two years of treatment, and that CD4 counts should be reserved for monitoring treatment beyond this point.
The results of the DART study are likely to stoke the growing controversy over the best way to monitor HIV treatment in resource-limited settings. In the past year, there have been growing calls to incorporate viral load monitoring into treatment programmes, both in order to detect failure of first-line treatment early and in order to determine whether patients apparently failing treatment on the basis of recent declines in CD4 count are genuine cases of treatment failure.
However, trial investigator Professor James Hakim of the University of Zimbabwe told delegates that it would be possible to treat up to one-third more patients with antiretroviral drugs if laboratory monitoring were limited to the use of CD4 counts after the second year of treatment.
Indeed, for the use of regular CD4 counting to be cost-effective in Uganda, one of the trial sites, the cost per test would have to come down to $3.80 per test, said Professor Charles Gilks of Imperial College, London. The current cost of each test, the trial investigators calculated, is near to $9.
The DART trial randomised 3316 adults in Uganda and Zimbabwe to clinically driven monitoring (CDM) or to laboratory and clinical monitoring (LCM). Individuals were eligible to join the trial if they had symptomatic HIV disease (World Health Organization stage 2, 3 or 4) and a CD4 cell count below 200 cells/mm3, with no prior experience of antiretroviral treatment and no clinical or laboratory abnormalities contraindicating treatment.
All participants received clinical and laboratory monitoring, but the results of CD4 and other blood tests were only returned to clinicians in respect of patients in the laboratory and clinical monitoring arm, except when a patient had a grade 4 laboratory abnormality such as severely elevated liver enzymes or severe anaemia: in this case those results would be supplied to clinicians in respect of patients in the clinical monitoring arm.
Three-quarters of participants in the study received a first-line regimen of AZT/3TC (dosed as Combivir, donated by Glaxo SmithKline) and tenofovir (Viread. The remainder received either Combivir plus nevirapine (Viramune) (16%) or Combivir plus abacavir (Ziagen) (9%).
A sub-study within DART, which recruited patients with a separate informed-consent procedure, compared first-line treatment with abacavir or nevirapine. Participants were assigned to nevirapine or abacavir by randomisation and dosing was double-blinded in order to assess the safety of the two drugs in a resource-limited setting. (Results of this randomised sub-study have been reported previously, and showed a trend towards fewer toxicity-related discontinuations during the first 24 weeks of the study in the abacavir group.)
Patients were switched to second-line treatment if they experienced a new WHO stage 4 clinical event in the clinical monitoring arm, and on the basis of CD4 declines or WHO stage 4 clinical events in the clinical and laboratory monitoring arm.
After just short of five years of follow-up (median 4.9 years), final analysis of the trial shows patients who received clinical monitoring alone were around 30% more likely to develop a new WHO stage 4 event or die, but the absolute difference in terms of numbers was so small that 130 people would need to receive CD4 monitoring for a year to prevent one additional death.
Overall, survival in the study was 'excellent', investigators said, with 87% of the clinical monitoring group and 90% of the laboratory and clinical monitoring group alive after five years of treatment. This survival record compares favourably with results from some treatment cohort studies in sub-Saharan Africa, although it is hard to draw direct comparisons due to different statistical methods used.
There were 459 new events or deaths in the clinical monitoring arm (28%) compared to 356 (22%) in the clinical and laboratory monitoring arm, an absolute difference of 1.7 events per 100 person years of follow-up (95%CI +0.87 to +2.54/100 PY). The hazard ratio was 1.31 [1.14 to 1.51], p=0.0001).
The study found no significant difference in rates of toxicity between the two arms, whether measured as time to first serious adverse event (HR=1.12[0.94 to 1.31];p=0.20), grade 4 toxicity (HR=1.08[0.97 to 1.20];p=0.18) or ART-modifying toxicity (HR=1.01[0.88 to 1.16];p=0.85).
Cost-effectiveness
A separate cost-effectiveness analysis, presented by Professor Charles Gilks of Imperial College on behalf of Antonietta Medina-Lara, assessed the median cost of treatment and monitoring for patients in each study arm. While the cost of first-line treatment was similar in the two arms ($1451 vs $1470), the cost of second-line treatment was lower in the clinical monitoring arm due to a lower rate of switching. CD4 monitoring was estimated to cost $175 year, but the more substantial expenditure was for laboratory toxicity monitoring, which amounted to $699 in the laboratory and clinical monitoring arm.
The researchers calculated the extra cost of the life-years gained by using the laboratory and clinical monitoring approach as opposed to clinical monitoring (the incremental cost-effectiveness ratio) by dividing the incremental average cost by the incremental average survival.
The researchers calculated that after statistical adjustment the incremental cost-effectiveness ratio of the laboratory and clinical monitoring arm was $9,016 per life-year gained.
“This is clearly way outside what would normally be considered to be cost-effective,” said Professor Gilks, pointing out that the WHO Commission on Macroeconomics and Health has proposed that any intervention with an incremental cost-effectiveness of more than three times GDP per capita would not be considered cost-effective. GDP per capita in Uganda is around $400 a year.
Even if the monitoring package was reduced to use of CD4 counts after the second year of therapy, the incremental cost-effectiveness ratio would be $2146, while inputting the lowest available costs into the model (as opposed to the actual health service costs accrued in the trial) would reduce the ratio to $1693.
The price of a CD4 test, including laboratory reagents and staff time, would have to fall to $3.78 or less for antiretroviral management with quarterly CD4 counting after the first year to be cost-effective, Professor Gilks said. If first - and second-line drug costs fell substantially when compared with the prices used in this study, the cost of CD4 counts would have fall even further to make their use cost-effective.
Dr Peter Mugyenyi of the Joint Clinical Research Centre in Uganda said that the results of the trial should not be used to downgrade spending on laboratories. “We need more support, not less support for laboratories, but the results of DART show where laboratory resources need to be optimally applied.”
Asked how the DART investigators would respond to calls for viral load monitoring to be made more widely available in resource-limited settings, Professor Gilks said that policy makers needed evidence about laboratory monitoring before making spending decisions.
“There is only one study – the Home Based AIDS Care study – which has looked at viral load and the results are still pending publication two years after the study was completed.
“If you have such a benefit from clinically driven monitoring alone and only a small extra benefit from CD4 counts, how much extra benefit would you get from more expensive viral load testing?” he asked.
References
Mugyenyi P et al. Impact of routine laboratory monitoring over 5 years after antiretroviral therapy (ART) initiation on clinical disease progression of HIV-infected African adults: the DART Trial final results. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract TuSS103, 2009.
Medina-Lara A et al. Cost effectiveness analysis of routine laboratory or clinically driven strategies for monitoring anti-retroviral therapy in Uganda and Zimbabwe (DART Trial). 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract TuSS104, 2009.
Antiretroviral treatment
Getting people onto treatment, not earlier treatment, must be priority, conference warned
by Keith Alcorn
Debates about whether to start treatment at a CD4 count of 350 in developing countries ignore the fact that current programmes are doing very badly at retaining patients in care after diagnosis or starting people on treatment before they become seriously ill, Dr Francois Venter, President of the South African HIV Clinicians Society told the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention on Monday.
Speaking during a conference symposium on when to start treatment, Dr Venter pointed out that the current average CD4 count at which patients start treatment in South Africa is 87 cells/mm3.
Despite a huge increase in the number of people who undergo HIV testing – up to one-quarter of South African adults took a test in the past year, according to 2009 research by the Human Sciences Research Council – the average CD4 count at which patients in his Johannesburg clinic start treatment has not moved above 80 to 100 cells since 2004, Dr Venter said.
“We are still doing a terrible job of retaining patients in care, and we need to start looking harder at retention in care,” he said. “Are you delivered into a package of care that looks after you [after diagnosis]?” he asked.
A large number of patients were dying while waiting for the results of diagnostic tests and while undergoing treatment-preparation counselling, or during acute opportunistic infections.
“Around half of patients in my practice start antiretroviral treatment during or just after treatment of an acute OI,” said Dr Venter, but clinicians still lack definitive information about the most appropriate time to start antiretroviral treatment in conditions such as cryptococcosis, the second most common opportunistic infection in southern Africa, and there is limited awareness of data from the recently halted SAPIT trial, which shows that antiretroviral treatment should not be delayed in TB patients until the completion of the TB treatment course.
He also expressed concern about the implications of recent findings on the inflammatory effects of HIV infection for developing countries. “Cardiovascular disease is not usually seen as an African problem, but death-certificate analysis in South Africa recently revealed that diabetes and hypertension were among the most frequent causes of death.”
Similarly, South Africa is seeing overlapping epidemics of HIV and obesity. Potent cardiovascular risks may lead to a high rate of cardiovascular disease in people with HIV, Dr Venter argued. He also drew attention to the high rate of liver disease and hepatitis virus infection in the developing world, to data showing that uncontrolled HIV replication exacerbates liver damage, and to the high frequency of kidney disease in African-Americans with advanced HIV infection (people of African origin appear to have a high risk of HIV-associated kidney damage).
“The thing that filled me with fear [looking at the data on inflammation and HIV] was renal disease. Kidney transplants, dialysis, even prophylactic drugs to deal with proteinuria are difficult to obtain and expensive in this region.”
However, the priority group for earlier treatment is pregnant women, said Dr Venter. “Treating mothers is much easier than treating children”, although implementation challenges such as defining the best antiretroviral regimen for use in pregnant women remain.
Eighty-four per cent of maternal deaths and 47% of postnatal infant infections occur at CD4 counts below 350, he noted.
“We could meet the Millenium Development Goal 5 on reducing maternal mortality by raising the threshold to 350 for pregnant women.”
However, one of the major obstacles to early treatment in the developing world is the current reliance on d4T (stavudine) in first-line treatment.
Dr Venter said that when he conducted an informal survey of colleagues treating large number of patients on when they would choose to start treatment, significant reservations about earlier treatment using d4T were expressed.
At a satellite meeting organised by Médecins sans Frontières, Dr Venter warned that activist demands for the better-tolerated drug tenofovir (Viread) to replace d4T in South Africa’s first-line regimen needed to be considered in the light of poor progress towards delivering treatment to those in urgent need. “A lot of our patients are dying without even having access to d4T.” He also warned that South Africa’s national treatment programme “is pretty much committed to staying with d4T for the next three to four years”.
He called for prospective research to quantify the effects of lower doses of d4T in the region, and Dr Graeme Meintjes of GF Jooste Hospital in Cape Town told the satellite meeting that the incidence of lactic acidosis and hyperlactataemia had fallen dramatically since the adoption of a 30mg adult dose of d4T in 2006.
Starting treatment in the developed world
In the developed world national US, British and European guidelines now concur that treatment should be recommended to all patients with CD4 counts below 350.
While US cohort data suggest benefits to starting treatment before the CD4 count falls below 500, another major cohort analysis did not find an additional benefit to starting treatment at CD4 counts above 400, and an international randomised trial called START is currently recruiting patients to determine whether starting treatment at a CD4 count above 500 results in less death and illness than starting at the currently recommended threshold.
Dr Jose Gatell of Hospital Clinic, University of Barcelona, highlighted that current European AIDS Clinical Society treatment guidelines state that antiretroviral treatment should be considered for all diagnosed patients.
He warned “We cannot wait until completion of the START study to make decisions.”
Even in resource-rich settings cost of earlier treatment is not going to be minor issue, said Gatell.
He cited modelling by his own team which showed that while delaying treatment until a CD4 count of 350 is reached might save 30% over five years when compared with treating before the CD4 count falls below 500, when considered over a 30-year timeframe the saving in medical costs attributable to delayed treatment fell to 13%.
But to achieve an extended period of healthy life, normalisation of CD4 counts needs to be achieved. Professor Gatell pointed to research showing that normalisation of CD4 counts for at least five years above 500 cells is necessary in order to eliminate the difference in mortality between people with HIV and the general population.
Nevertheless, a substantial proportion of patients continue to fail to reach this CD4 level with current treatment due to late initiation of treatment, he noted. Therefore all patients with a CD4 count below 350 should be offered treatment unless there is a specific contraindication.
Gatell also highlighted the need to consider chronic inflammation caused by viral replication in untreated patients with higher CD4 cell counts, which may lead to an excess of non-AIDS-defining serious illness in this population when compared with the general population.
Delays in starting treatment common in ART programmes
by Carole Leach-Lemens
Late initiation of antiretroviral treatment following diagnosis is contributing to the continuing high death rate among people who present with low CD4 counts in eight sub-Saharan African countries.
Data from South Africa show that more than half of people eligible for antiretroviral treatment (ART) at diagnosis waited at least 12 months to begin treatment, while data from eight African countries show that patients in rural areas, those identified with HIV outside a PMTCT programme and those who are not followed up when they miss appointments were most likely to start treatment at a very low CD4 count.
Earlier enrolment and better management leading to improved retention can play an important role in the linkage of diagnosis to antiretroviral treatment (ART) and care to improve mortality rates reported Ingrid Bassett and Denis Nash in two different studies presented at the Fifth International AIDS Society Conference on Pathogenesis, Treatment and Prevention in Cape Town.
In spite of World Health Organization guidelines recommending treatment initiation before the CD4 count falls below 200 cells/mm3, many continue to access care with low CD4 counts despite having been diagnosed some time before. Little is known about what happens to a patient after diagnosis and how programme factors can positively affect enrolment and retention in treatment and care.
Speaking at a conference symposium on when to start treatment, Dr Francois Venter, President of the South African HIV Clinicians’ Society told delegates that South Africa is doing very badly at retaining patients in care after diagnosis and starting people on treatment before they become seriously ill.
Data presented today from Durban show the extent of delays in initiating treatment and the extent to which patients are being lost to follow-up despite extensive uptake of HIV testing.
In a prospective study Ingrid Bassett and colleagues enrolled patients prior to HIV testing at two semi-private, partially government-subsidised, outpatient clinics in Durban, South Africa. McCloud serves a predominantly urban population and St. Mary’s a semi-rural one. Both offer comprehensive HIV care. Patients pay a fee for care.
The minimum observation time for patients included in the study was six months. CD4 counts ≤200cells/mm³ or an AIDS-defining condition determined antiretroviral eligibility. Patients were enrolled from November 2006 until October 2008 with follow-up until the end of June 2009.
Of the 3,401 patients screened 2,797 (82%) were tested. Of the 1,467 (52%) who tested positive 605 (41%) underwent CD4 count testing within 90 days of diagnosis. Of the 368 (61%) with a CD4 count <200cells/mm³) who met eligibility criteria for antiretroviral therapy, only 154 (42%) began antiretroviral treatment within twelve months.
Fifty per cent of those eligible waited 3.5 months or longer before starting ART. Fifteen per cent (216/1,467) of HIV-positive patients died during the study period and 21% (76/368) of the ART-eligible cohort died before starting ART. In spite of outreach 30% of pre-ART patients were not reached.
Limitations noted by the authors include the fact that sites may not be representative of public sector hospitals in South Africa.
The problems of late treatment initation is not confined to South Africa.
In a second study Denis Nash and colleagues reviewed PEPFAR data on median CD4 count at the start of antiretroviral treatment for the period January 2005 until October 2008 for a total of 1,690 cohorts (121,154 patients) at 267 sites in eight sub-Saharan countries (Ethiopia, Kenya, Lesotho, Mozambique, Nigeria, Rwanda, South Africa and Tanzania).
Cohorts represented patients who had begun antiretroviral treatment at a particular site every quarter.
Cohorts with median CD4 counts <111cells/mm³ at the start of treatment were categorised as low CD4 count. Information on cohorts was combined with that of programme level from semi-annual facility surveys from the same time period.
While the median CD4 count was 135 cells/mm³, it increased from 115 to 140cells/mm³ during the period under review. Taking into account calendar time, cohort size and country, programme level factors associated with low CD4 count included:
- Not being affiliated with a PMTCT programme resulting in a 4.4 higher risk of a low CD4 count at treatment initiation
- The programme being in a urban area.
Knowledge of HIV was not associated with having a low CD4 count when starting ART. However, knowledge of HIV and believing that having one sexual partner reduced risk let to a false sense of security and increased risks of late ART initiation.
Limitations noted by the authors include the fact that data on programme-level factors only indicate the availability of services and not the quality nor coverage.
References
Bassett I et al. Who starts ART in Durban, South Africa?...Not everyone who should! 5th IAS Conference of Pathogenesis, Treatment and Prevention, Cape Town, South Africa, abstract 1921, July 2009
Nash D et al. Program-level determinants of low CD4 count ART initiation in cohorts of persons aged ≥ 6 years initiating ART in 8 sub-Saharan countries. 5th IAS Conference of Pathogenesis, Treatment and Prevention, Cape Town, South Africa, abstract 1882, July 2009.
Further information
Powerpoint presentations by Ingrid Bassett and Denis Nash, and a webcast of the conference session in which they were presented are available on the IAS 2009 website here.
Innovative, cost-effective and patient-friendly methods for delivery of HIV care feasible in resource-limited settings
by Lesley Odendal
Innovative methods of delivery of HIV care using home-based care and nurse-initiated antiretroviral treatment (ART) are feasible and can have good treatment outcomes in resource-limited settings such as Uganda and Lesotho, delegates heard on Monday at the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, held in Cape Town.
The shortage of healthcare workers and health facilities in settings where HIV prevalence is high means that there is a need for creative solutions to delivering care to ensure that the largest possible number of people can be reached within the constraints of existing resources.
This means that models such as home-based care and nurse-led prescribing and monitoring of antiretroviral treatment are of particular interest, and good evidence of the effectiveness of such approaches is urgently needed.
In Uganda, a cluster randomised trial was conducted by The AIDS Support Organisation (TASO) in Jinja. Fourty-four clusters of patient groups of were randomised to receive either home-based HIV care (859 individuals in 22 clusters) or care at a healthcare facility (595 individuals in 22 clusters).
The home-based approach for access to HIV care is believed to be easier for patients and allowed for decongestion in the primary healthcare facilities.
In Lesotho, the international aid agency Médècins sans Frontiéres (MSF), in conjunction with the Lesotho health ministry, launched a project that allowed nurses to assume a high level of responsibility in the clinical management of HIV-positive patients, including the initiation of antiretroviral therapy in the Scott Hospital programme.
This approach meant that an increased number of patients could be started on ART despite staffing constraints and a lack of physicians.
In the TASO study in Uganda, antiretroviral therapy was initiated at the clinic. Individuals receiving home-based care were then provided with support and monitoring at home. This was done monthly by lay workers, who also delivered all ART and other necessary medication such as family planning and tuberculosis treatment and condoms. Every six months, this group of patients attended the clinic for a thorough check-up.
Individuals who were randomised to receive clinic-based care attended their clinic once a month for evaluation and to collect their antiretroviral drugs. All the patients received World Health Organization-approved fixed-dose antiretroviral combinations, and the study’s main outcome was the proportion of patients in each arm who experienced virological failure, defined as a sustained viral load above 500 copies/ml.
At baseline, 50% of individuals receiving home-based care and 41% of those receiving clinic-based care had severe immune suppression and a CD4 cell count below 100 cells/mm3. 14% of patients in both study arms experienced virological failure.
At the end of follow-up, 66% of patients in the home-based care group had an undetectable viral load compared to 65% of individuals who received clinic-based care. Similar CD4 count recovery and levels of adherence were reported in both groups.
While the differences in treatment outcomes in the patients appear negligible, the number of visits to the facility per patient differed significantly between those in the home-based care group (4.2 visits) and the facility-based group (7.2). The median cost to access care for patients also differed between the two groups with the cost for the home-based group being five times less than that of the facility-based group ($0.50 vs $2.50), rendering greater access to, and affordability of, services through the home-based care programme.
The Scott Hospital programme in Lesotho has a catchment area of 200,000 people, 35,000 of whom are infected with HIV and 10,000 of whom are in need of ART. The country has very limited healthcare resources with only five physicians and 62 nurses per 100,000 individuals.
A retrospective cohort analysis of the characteristics and outcomes of individuals in Lesotho who started nurse-prescribed HIV treatment over a two-year period between 2006 and 2008 showed that a total of 14,864 individuals (of whom 568 were children) were enrolled in HIV care in the region and 4347 of these started HIV treatment (of whom 282 were children). The vast majority (80%) of those initiating antiretroviral therapy did so in primary care, initiated by nurses. Additional capacity to treat patients was also generated through the appointment of HIV/TB lay counsellors who assisted in pre-ART counselling and patient education.
Key innovations included prescribing a regimen of tenofovir, 3TC and efavirenz at a CD4 count threshold of 350 cells/mm3. This was to facilitate easier monitoring of side-effects by nurses, since tenofovir is less toxic than d4T (stavudine), the more common component of first-line treatment in sub-Saharan Africa.
In 2006, 27% of individuals presenting for care had very advanced HIV disease as indicated by a CD4 cell count below 50 cells/mm3. This had decreased to 13% by 2008.
After two years, 80% of adults and 88% of children were still receiving care. The twelve-month mortality rate was described by the investigators as “highly satisfactory” at 9% for adults and 5% for children, indicating that nurse-initiated ART can have successful treatment outcomes and that a shortage of physicians should not be a barrier to providing ART to patients in resource-limited settings.
References
Jaffar S et al. The impact of home-based compared with facility-based HIV-care on virologic failure and mortality: a cluster randomised trial. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract MoAD101, 2009.
Cohen R et al. Nurse-driven, community-supported HIV/AIDS care and treatment: 2 year antiretroviral treatment outcomes from a primary care level programme in rural Lesotho. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract MoAD102, 2009.
Further information
A powerpoint presentation by Shabbar Jaffar and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.
Cost of ART delivery in Malawi affordable within WHO-recommended health budget
by Carole Leach-Lemens
Total additional costs for sustaining universal access in a high prevalence, extremely poor rural area of Malawi are well within budget guidelines set by the World Health Organization for a minimal basic health package, reported Mary Bemelmans in a study presented at the Fifth IAS Conference on Pathogenesis, Treatment and Prevention in Cape Town, South Africa this week.
A Ministry of Health and Médècins sans Frontières (MoH-MSF) supported HIV programme achieved universal access in Thyolo, a rural area of Malawi where poverty rates are ten times higher than the national average with an HIV prevalence rate of 21%.
Of the 14,101 people who started treatment in the programme close to 80% were alive and in care at the end of 2007 and currently 80% remain in care.
A “public health” approach has been integral to successful scale-up. Decentralisation of care along with the extensive use of task-shifting and the streamlining of patient flow together with high level community involvement were key to achieving rapid scale-up.
Between 2005 and the end of 2007 the mean CD4 count at treatment initiation rose from around 150 cells/mm3 to 250 cells/mm3, while the mean delay between diagnosis and treatment initiation fell from around 90 days to 40 days in the same period, due to the decentralisation of antiretroviral (ART) prescribing to primary health clinics and task-shifting of ART management to medical officers.
A retrospective cost-analysis of additional costs for HIV care and treatment for the period from 2005-2007 was undertaken.
Annual recurring costs amounted to €237, 67% (€158) of which was spent on antiretrovirals and a further 14% on other essential drugs. Human resources and general running costs accounted for 13%, with an additional 6% for laboratory expenses.
Drugs constitute the most significant cost. Human resource costs per patient declined over time due to task-shifting, from around €45 per patient per year in 2005 to €25 per person per year in 2007.
Universal access has been achieved in a high prevalence rural area of Malawi with a total population of 600,000 at an estimated annual cost per inhabitant of €3.20, said Matu Bemelmans.
Current national health expenditure per person is €13.20 per year. Achieving universal access to antiretroviral treatment cost “an additional €2.60 per person, well within the estimated minimal basic health package costs” [as determined by the World Health Organization], she concluded, but warned of potential for considerable cost increases over time due to the anticipated demand for alternatives to the current first-line treatment regimen, and for second-line antiretroviral treatment, which is currently twelve times more expensive than first-line treatment in Malawi.
Reference
Jouquet et al. Cost analysis of an ARV care programme reaching universal access in Thyolo, Malawi. Fifth International AIDS Society Conference on Pathogenesis, Treatment and Prevention, Cape Town, South Africa, abstract 3291, July 2009.
Further information
A powerpoint presentation by Marielle Bemelmans and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.
Care
Improved surveillance of cervical cancer recommended in populations with high HIV prevalence
by Lesley Odendal
Cervical cancer prevention guidelines may need to be reviewed to address the particular needs of HIV-infected women, due to poorer outcomes of treatment for precancerous cervical changes, data from a South African study suggest.
Priya Batra of Columbia University and colleagues from the University of Cape Town reported on a retrospective study evaluating the impact of HIV status of excisional treatment for cervical intraepithalial neoplasia (CIN), a human papillomavirus (HPV)-associated precursor lesion to cervical cancer at the Fifth International AIDS Society conference in Cape Town.
Once CIN has developed it can be detected in women through pap smears and easily treated by large loop excision of the transformation zone (LLETZ), a procedure where the HPV-induced cells in the lesion are excised by a large thin loop used to cut into the cervix encompassing the lesioned area.
The study aimed to evaluate the impact of HIV status on LETTZ outcomes. Annual incidence of CIN is four to five times greater in HIV-positive women.
778 women referred to Groote Schuur Hospital, the primary referral centre for women in the Western Cape in South Africa, who had undergone LLETZ for the treatment of CIN were included in the study. Medical records and pathology databases of patients were reviewed from 2006 to 2008. Patients were followed up to four months post-LLETZ procedure. 46.3% (360) of the women in the study were self-reported as HIV-positive and 51.7% (186) of these women were on antiretroviral therapy (ART) at the time of their first visit.
21.9% of all women undergoing LLETZ were lost to follow up at four months and these women were significantly more likely to be HIV-positive. 55.1% of the LLETZ specimens had one or both excision margins positive for residual CIN.
The study found that HIV-positive women had suboptimal treatment outcomes, with higher proportions of abnormal pap smears and positive margins four months after excision. There was no difference in severity of disease in the HIV-positive and HIV-negative women.
30.2% of the women had incomplete treatment with persistent cervical disease at four months after excision found through abnormal pap smears. Incomplete treatment was found to be associated with residual CIN at excision margins. It was also found to be significantly associated with positive HIV status (p<0.0001). Age, use of injectable progestin contraception and histological grade or severity of lesion were not associated with treatment outcome.
45% of HIV-positive women were incompletely treated by LETTZ, as compared to only 16.8% in HIV-negative women. This difference was found to be statistically significant. Among HIV-positive women, treatment failure occurred significantly more frequently among those women who were receiving ART, compared to 37.1% who were not receiving it (p=0.0335).
Although ART may appear to not be protective in this study, the investigators could not be sure of this finding as no data were available on duration of ART or the CD4 count of patients. ART use may also be a proxy measure for low CD 4 count as ART is initiated at less than 200 cells per mm3. This may also be due to ART initiation occurring after persistent infection of HPV, since it would not prevent genetic changes which lead to cervical cancer from occurring.
The findings of suboptimal LLETZ treatment outcomes in HIV-positive women replicate those of previous studies in many developed and developing settings. Findings of an unclear cervical benefit of ART in previous studies has also been mixed with some American and European studies suggesting that ART improves regression of CIN, while others have not shown any specific benefit in this case even when taking CD 4 levels into account.
The authors suggested that primary preventative interventions such as providing HPV vaccines in populations with high HIV prevalence need further investigation. Cervical cancer prevention guidelines may need to be revised to address the special needs of HIV-infected women and to achieve better population-wide screening coverage, they say.
Reference
Batra P et al. Excisional therapy outcomes for cervical intraepithelial neoplasia (CIN) in a South African population with high HIV prevalence. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeB103, 2009.
Further information
A powerpoint presentation by Priya Batra and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.
Anal cancer in men with HIV much more common in post-HAART era: could HPV vaccination help?
by Gus Cairns
The annual incidence of anal cancer amongst people with HIV has continued to increase in recent years and now stands at 128 cases per 100,000 or one case in 784 people, the Fifth IAS Conference was told on Wednesday by Nancy Crum-Cianflone of the US Infectious Disease Clinical Research Program. This is nearly 100 times the rate in the general population (1.4 per 100,000).
In a separate presentation, Stephen Berman of the Veterans Administration Healthcare System told the conference that findings from a study of HIV/HPV co-infected army veterans implied that up to 89% of men with HIV could potentially derive at least some benefit from one of the currently-licensed HPV vaccines and 53% substantial benefit, providing that HIV infection did not compromise the normal immune response to the vaccine.
In the first study, researchers investigated the incidence of anal cancer in HIV-positive individuals between 1985 and 2008. The figures were obtained from the U.S. Military Natural History Study, a cohort study which followed participants from 1985 till 2008.
A total of 4,901 HIV-infected participants, 55% with documented seroconversion dates, contributed 40,951 person years of follow-up. Researchers investigated the association between CD4 cell count, use of antiretroviral therapy, AIDS-defining illnesses and sexually transmitted infections, and the risk of developing anal cancer.
Anal cancer was diagnosed in 20 patients, all men and 55% Caucasian. At cancer diagnosis the patients’ median age was 42 years, with 40% of cases in men below 40.
The rate of cancer was five times higher in the post-HAART era than in the pre-HAART era with an annual incidence of 11 per 100,000 before 1996 and 55 per 100,000 from 1996-2008.
The incidence increased during the HAART era from 13.4 per 100,000 between 1996 and 2000 to 51 per 100,000 between 2001 and 2005 and 128 per 100,000 in 2006 to 2008.
The incidence of anal cancer was also considerably higher in people with longer duration of HIV infection. Up to 10 years post-infection the rate was 28 per 100,000, from 10-15 years it was 63 per 100,000 and in patients diagnosed for more than 15 years it was 348 per 100,000 - one case per 288 patients per year.
In multivariate analysis only AIDS diagnosis and nadir CD4 count were associated with anal cancer, with having had an AIDS-defining illness raising the risk 3.4 times and the risk decreasing by 15% for every 50 cells/mm3 higher CD4 nadir. Gonorrhoea was also marginally associated with anal cancer with a hazard ratio of 2.33 (p=0.08). Being on HAART was not protective against the development of the condition (p = 0.19).
Could the HPV vaccine help?
In another study of patients in members of former members of the armed forces, Dr Stephen Berman investigated infection with human papilloma virus (HPV) and its subtypes in 62 HIV-positive men, 90% of them gay and 90% on HAART with undetectable HIV.
“Little or no data has been published on the ability of HIV positive individuals to respond to [the quadrivalent HPV vaccine] Gardasil,” he commented. “Can they make an appropriate serological response, and which subgroups will not benefit?”
The study therefore took serological tests of study participants to see if they had antibodies to HPV types 16 and 18. These, the two most common ‘high risk’ varieties of HPV, cause 70% of cases of anal and cervical cancer, and the available HPV vaccines Gardasil and Cervarix produce a high level of protection against these strains for individuals who are not already infected with them. In addition Gardasil protects against infection with HPV types 6 and 11, which cause 95% of non-cancerous warts.
The patients also had an anal smear for precancerous cells and an anal screen for HPV DNA, which indicates actively reproducing virus. The patients were then given an initial dose of Gardasil.
The second and third doses of Gardasil were given at month two and month six, and tests taken again at month seven for antibodies to HPV, HPV DNA and precancerous cells.
Results showed that 34% of the men in the study had antibodies to HPV-16, 6.4% to HPV-18 and 3.2% to both. The majority of individuals (56.5%) therefore did not have antibodies to the two strains of HPV with the highest risk of anal and genital cancers.
Sixty-three per cent of men had HPV DNA (of any high-risk type) detectable in anal samples, and 22.6% of men had HPV DNA from types 16, 18 or both. This means that 40% of men had active infections with other high-risk types of HPV (although types other than 16 and 18 are associated with much slower progression to cancer).
Berman commented that the men with detectable DNA could either be men with relatively recent infection and a normal antibody response or men with prolonged infection and a delayed or non-existent antibody response. The latter are at most risk of developing cancer. In HIV negative people antibodies to the infecting subtype of HPV develop within 6-9 months of infection and then clear the infection from the body. This process is delayed and attenuated in people with HIV, which is the probable cause of the higher rates of anal cancer seen.
Twelve individuals had abnormal anal cells, six of whom had squamous intraepithelial lesions, or precancerous cells. Of the twelve, ten had detectable HPV DNA, three of whom had HPV-16, three were co-infected with HPV-16 and HPV-18, and four had types other than 16 or 18.
Of the 25 individual with antibodies to HPV-16, ten (40%) had detectable DNA from this strain detected in samples, in addition to three of the individuals who did not have antibodies to HPV-16, and two men without antibodies to HPV-18 had detectable DNA from this strain. Altogether 11% of patients had both antibodies to HPV16 or 18 and evidence of the genetic material of these strains, indicating a complete or ineffective antibody response.
In answer to a question, Berman commented that it was possible that giving such men the HPV vaccine might stimulate a much stronger response which might result in clearance of infection “but Merck (Gardasil’s manufacturers) have absolutely no data on the efficacy of giving their vaccine to people with an existing infection.”
Altogether, 53% of men had evidence of neither exposure nor infection with HPV-16 or HPV-18 and were therefore likely to derive substantial benefit from Gardasil as long as HIV infection does not impair the immune response, while another 35% had one of the strains and would therefore benefit at least from vaccination against the other one.
Becker commented that the proportion of men with antibodies to HPV16 was higher than reported previously. However since 40% of men had indications of active infections with subtypes other than HPV-16 or 18, second-generation polyvalent vaccines should be developed.
References
Crum-Cianflone N et al. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeB101, 2009.
Berman S et al. Seroprevalence of antibodies to HPV-16 and HPV-18, and correlation with the presence of HPV DNA and anorectal cytologic abnormalities in a cohort of HIV-positive men involved in a study of HIV-positive men receiving the quadrivalent HPV vaccine, Gardasil. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeB102, 2009.
Further information
Powerpoint presentations by Nancy Crum-Cianflone and Stephen Berman, and a webcast of the conference session in which they were presented are available on the IAS 2009 website here.
Aciclovir reduces disease progression and death in people with HIV by nearly 20 per cent
by Gus Cairns
HIV positive people given 400mg of aciclovir twice-daily as part of a trial to see if the drug reduced HIV transmission in serodiscordant couples were 17% less likely to progress to AIDS, to have to start antiretroviral therapy, or die, the Fifth IAS Conference was told on its final day. This effect was statistically significant (p=0.03).
This result came out of the Partners in Prevention Study, which failed to find that giving aciclovir to people with HIV reduced HIV transmission to their partners (Celum). But study investigator Dr Jairam Lingappa said that the drug might nonetheless have a role in delaying the initiation of HAART.
The Partners in Prevention study gave 400mg of aciclovir or placebo twice daily for 24 months to 3408 people, two-thirds of them women, who were the HIV- positive partners in a serodiscordant relationship. The average age of women in the study was 29 and of men 37, and the average CD4 count was 480 cells/mm3 in women and about 420 cells/mm3 in men.
Although aciclovir did not reduce HIV transmission, patients on aciclovir were 24% less likely to die from non-traumatic causes (i.e. not because of accidents or violence), though this was not statistically significant (p=0.29). They were 19% less likely to start HAART (p=0.06) or develop a CD4 count under 200 (p=0.05).
Gender, baseline CD4 or baseline viral load made no difference to progression, but there was a trend towards association with good adherence: people who took more than 90% of their doses were 23% less likely to progress to the composite endpoint than average, and people who took less than 90% were 11% more likely to progress (p=0.13).
Could HSV-2 suppression slow HIV disease progression in HIV-infected persons not eligible for ART by current national guidelines, Dr Lingappa asked?
Although the 17% reduction in progression observed was not spectacular, it might be combined with other inexpensive interventions such as co-trimoxazole (Septrin) PCP prophylaxis, which in studies reduced HIV mortality by 45%, and multivitamins, which reduced it by 27%. Based on these findings, aciclovir could delay median time to a CD4 count below 350 cells/mm3 by 6.3 months (28.8 versus 35.1 months).
Audience members commented that the proposal sat uncomfortably with the idea of getting as many people on HAART as possible in order to reduce transmission.
“You have an intervention which prolongs time off antiretroviral therapy but fails to suppress transmission,” said one.”Isn’t that a problem if all it does is prolong the period people are infectious?”
Another audience member criticised the exclusion of pregnant women from the study, since aciclovir has a very safe record in pregnancy, and pregnancy might be a good marker for unprotected sex.
“These findings support the concept of non-ART medications delaying HIV disease progression in HIV infected persons with high CD4 counts,” commented Dr Lingappa.
Additional data will be available from an ongoing trial of herpes suppression in people with CD4 counts between 300-400 which is being conducted in Rakai, Uganda. Further cost effectiveness analyses and modelling studies were also needed, he said.
References
Lingappa JL et al. Daily acyclovir delays HIV-1 disease progression among HIV-1/HSV-2 dually-infected persons: a randomized trial. . 5th conference on HIV Pathogenesis, Treatment and Prevention, Cape Town. Abstract WELBC102. 2009.
Celum C et al. Twice-daily acyclovir to reduce HIV-1 transmission from HIV-1 / HSV-2 co-infected persons within HIV-1 serodiscordant couples: a randomized, double-blind, placebo-controlled trial. 5th conference on HIV Pathogenesis, Treatment and Prevention, Cape Town. Abstract WELBC101, 2009.
Further information
A webcast of the conference session in which Jairam R Lingappa and Connie Celum presented is available on the IAS 2009 website here.
Nurse management of ART matches doctor care in South African trial
by Keith Alcorn
Monitoring of antiretroviral treatment by nurses resulted in outcomes just as good as those seen when patients are monitored by doctors in South Africa, a large randomised trial has shown.
The findings, presented on Wednesday at the Fifth International AIDS Society conference in Cape Town, are likely to reinforce calls to expand treatment capacity in South Africa by allowing nurses a much greater role in the management of patients receiving antiretroviral therapy.
Nurses and other cadres of medical staff below physician level are already taking substantial roles in staging patients for treatment and monitoring patients on treatment in several African countries, including Malawi and Ethiopia.
The policy, called task-shifting by the World Health Organization, is designed to maximise healthcare worker resources in settings where doctors are scarce.
The study was carried out by the Comprehensive International Programme for Research on AIDS in South Africa (CIPRA) an international partnership led by Professor Robin Wood of the University of Cape Town, and recruited patients at primary healthcare sites in two townships, Masiphumelele in Cape Town and Soweto in Johannesburg.
Patients were eligible to join the study if they had a CD4 count below 350 cells/mm3 or a prior AIDS-defining illness (excluding a single episode of bacterial sepsis or herpes zoster). Patients with newly diagnosed opportunistic infections were excluded, as were patients with more than six weeks of prior antiretroviral experience.
Treatment was initiated by a doctor before randomisation. The study enrolled and randomised 812 patients to receive care from either a doctor or a primary healthcare nurse after starting treatment with a first-line regimen of d4T, 3TC and either efavirenz or nevirapine.
Monitoring consisted of viral load and CD4 measurements, monitoring of clinical state for grade 3 and 4 adverse events associated with the study medications, assessment of clinical status, and measurement of height, weight and blood pressure.
Since neither doctors nor nurses had much experience of delivering antiretroviral therapy, all providers received lecture training in HIV management including toxicity and management of opportunistic infections, and instruction on the protocols in South African national treatment guidelines for monitoring and management of patients.
Patients received adherence and psychosocial support from lay community counsellors.
The primary outcome of the study was the emergence of treatment-limiting events: death, loss to follow-up, defaults on clinic appointments (included as a proxy for treatment adherence, since patients collected drugs at each scheduled visit), grade 3 or 4 toxicity that resulted in more than 42 days off treatment, or virologic failure, defined as either failure to achieve a viral load reduction of at least 1.5 log by week 12, or two consecutive viral load measurements above 1000 copies/ml after at least 24 weeks of treatment.
All the deaths and toxicity events were reviewed by an independent panel to ensure that they had been correctly assigned.
Results
There were no significant baseline differences between the two groups, although a slightly larger proportion of the group randomised to nurse care were women (73 vs 67%). Approximately two-thirds of patients had a CD4 count below 200 cells/mm3 at baseline and around 60% had symptomatic HIV disease or an AIDS-defining illness. Twenty per cent in each arm had been exposed to single-dose nevirapine for prevention of mother-to-child transmission.
After 96 weeks of follow-up there was no significant difference in outcomes between the two groups, whether analysed by all treatment-limiting events, by virologic failure, by time to loss to follow-up, by time to death or by time to treatment-limiting toxicity.
Overall the failure rate was 45%, but a large proportion of the events defined as failures were either missed clinic appointments or loss to follow-up (16.4%), or treatment-limiting toxicity (15.2%).
An analysis stratified by baseline CD4 count below 200 cells/mm3 and by viral load above 100,000 copies/ml similarly found no significant difference in outcome between the two modes of care, suggesting that more seriously ill patients did not do worse when monitored by a nurse rather than a doctor.
The only difference that emerged was a higher rate of reporting of grade 3 and 4 toxicities that resulted in dose alterations or drug switches by doctors. These were driven almost entirely by d4T (stavudine) and nevirapine (liver toxicity, hyperlactatemia and lipodystrophy).
Reference
Wood R et al. Nurse management is not inferior to doctor management of ARV patients: the CIPRA South Africa randomized trial. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract LBPE, 2009.
Hepatitis B vaccine scale-up and treatment of HIV/HBV co-infection present challenges
by Liz Highleyman
Hepatitis B vaccine coverage has increased dramatically in recent years, but some regions still lag behind and collaboration with broader health programmes would aid scale-up, according to a symposium presentation on viral hepatitis at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention last week in Cape Town, South Africa.
In the absence of timely vaccination, management of patients with HIV and hepatitis B co-infection presents challenges related to drug resistance and liver disease flare-ups.
Hepatitis B vaccination
Hepatitis B virus (HBV) is "extremely prevalent", according to Steven Wiersma, a medical officer with the World Health Organization (WHO) in Geneva, but it is not evenly distributed globally, with the highest rates in parts of Asia and Africa.
Of an estimated two billion people infected with HBV, of whom more than 350 million have chronic infection, about 88% live in areas with high (> 8%) or moderate (2 to 7%) prevalence. Hepatitis B is among the leading causes of mortality worldwide, accounting for more than 600,000 deaths annually.
While most people infected as adults clear HBV without treatment, those infected as infants or children – often through mother-to-child transmission in endemic areas – usually develop chronic disease. Over years or decades, chronic hepatitis B can lead to advanced liver fibrosis, cirrhosis and liver cancer. In fact, hepatitis is thought to be responsible for about half of all liver cancer cases.
Dr Wiersma said that, according to current WHO policy, all regions – not just those where hepatitis B has traditionally been considered endemic – should develop goals for widespread vaccination. Early life offers the best opportunities for prevention, and WHO recommends that all infants should receive the first dose of the vaccine within 24 hours of birth, with two follow-up doses, usually given one and six months later, to complete the series.
Several countries in Asia and Africa have achieved "dramatic" increases in hepatitis B vaccine coverage, Dr Wiersma said. As of 2007, more than 88% of WHO member countries had introduced HBV vaccination and 65% provided universal three-dose coverage for infants.
But some countries, he added, are "lagging". WHO estimates that more than 44 million babies still do not receive a full course of the vaccine, with the largest gap – 24 million infants – in India.
To improve vaccination rates, Dr Wiersma advocated more collaboration with maternal and child health programmes, including HIV treatment and prevention of mother-to-child transmission programmes and vitamin K distribution efforts. But the most commonly used hepatitis B vaccines present a logistical challenge in resource-limited settings because whilst they should be refrigerated, they can become ineffective if frozen.
Later in life, people who did not receive the hepatitis B vaccine as young children can still benefit from "catch-up" vaccination. Dr Wiersma said WHO is interested in integrating adult hepatitis B vaccination into HIV and sexually transmitted disease prevention and treatment programmes.
"It doesn’t take a lot of cost to make adult vaccination available," he said. With a price as low as US $0.42 per dose, he said advance seromarker screening to determine which individuals would benefit from the vaccine (that is, those who have not already been exposed to HBV) may not be cost-effective, and it may be better to just vaccinate everyone.
Dr Wiersma noted that experts believe age cohorts who receive three doses of the vaccine now will be protected for life, and are not expected to need booster shots later. Since vaccination prevents not only illness and death but also onward transmission, WHO considered hepatitis B "a primary candidate for elimination or eradication".
HIV/hepatitis B co-infection
While vaccination offers hope for a large decrease in hepatitis B in the future, many people today are co-infected with HIV and HBV, particularly in regions where both diseases are common. As Sharon Lewin from Monash University in Australia described in an overview of HIV/HBV co-infection at the same session, hepatitis B has an "enormous impact" on liver-related mortality, even amongst patients on effective combination antiretroviral therapy.
Co-infection presents some unique challenges, since drugs that are dually active against both HIV and HBV – including the widely-used tenofovir (Viread, also in the Truvada and Atripla combination pills – can trigger resistance in either virus if used improperly, and stopping them can lead to temporary worsening of liver disease known as 'flares'.
Discussing the management of HIV/HBV co-infection, Sanjay Bhagani from the Royal Free Hospital in London noted that many ART roll-out programmes in resource-limited countries do not test people for hepatitis B before starting dually active antiretroviral drugs, raising the risk of resistant HBV and potentially limiting future hepatitis B treatment options. This risk can be overcome by using two dually active drugs together, for example tenofovir plus either 3TC (Epivir) or FTC (Emtriva).
Treatment of hepatitis B in co-infected patients not receiving ART is also a challenge, since using these dually active drugs without a more potent antiretroviral agent (such as a protease inhibitor or NNRTI) can lead to HIV resistance mutations.
Few drugs are active against HBV but not HIV, and recent studies have shown that entecavir (Baraclude) and possibly telbivudine (Sevibo) have previously unrecognised anti-HIV activity. For this reason, many experts – and US HIV treatment guidelines – now recommend that HIV/HBV co-infected patients who need hepatitis B treatment should receive a full combination ART regimen that contains dually active drugs.
Along similar lines, Juan Pineda from Hospital Universitario de Valme in Seville, Spain, explained that whilst HIV/HBV co-infected patients should receive regular liver enzyme (ALT and AST) monitoring and liver cancer screening, they usually do not need liver biopsies, because they can be pre-emptively treated with dually active ART regardless of the extent of liver damage.
References
Wiersma S Scaling up global access to Hepatitis B vaccination. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeBS102, 2009.
Lewin S Pathogenesis of HIV-HBV co-infection. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeBS101, 2009.
Pineda JA Diagnosis and Monitoring of Hepatitis B and C co-infection. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeBS103, 2009.
Bhagani S Management of Hepatitis B and C co-infection. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeBS104, 2009.
Further information
Powerpoint presentations and a webcast of the conference session in which they were presented are available on the IAS 2009 website here.
Malaria cases fall with each year of HIV treatment in Ugandan patients
by Keith Alcorn
Antiretroviral treatment was associated with a 75% decline in the incidence of malaria over four years in DART study participants, Ugandan and UK-based researchers reported last week at the Fifth International AIDS Society conference in Cape Town.
People with HIV are at especially high risk of malaria when they have very low CD4 counts, and malaria may cause a decline in the CD4 count. Much of sub-Saharan Africa is affected by malaria, including many areas with a high HIV prevalence.
The DART study was a five-year comparison of clinical versus laboratory and clinical monitoring for the management of antiretroviral treatment in Uganda and Zimbabwe.
Since participants were reviewed for clinical symptoms whenever they attended three-monthly study visits, or when acutely ill, researchers were able to conduct a retrospective review of 1020 trial participants receiving care at the Entebbe trial site in Uganda to determine risk factors for the development of malaria during antiretroviral treatment.
Febrile illness suggestive of malaria was investigated in 638 patients (2013 episodes). In 68% of cases plasmodium falciparum, the causative agent of malaria, was detected in a peripheral blood film, and a total of 51% of patients at the site were diagnosed with malaria.
In the first year of antiretroviral treatment the incidence of malaria was 591 cases per 1000 person years of follow-up; by year four the incidence had declined to 153 cases per 1000 person years, a decline of almost 75%. Duration of treatment is likely to be a surrogate for improvement in immune status, although this study could not directly evaluate the association between immune reconstitution and risk of malaria.
The factors associated with a reduced risk of malaria were cotrimoxazole use (adjusted hazard ratio 0.40, 95% confidence interval 0.33-0.48, p<0.001) and secondary or tertiary education (AHR 0.70 and 0.55 respectively).
The risk of malaria was greatest in individuals with baseline CD4 counts below 10 (AHR not stated), the investigators reported.
The investigators say that malaria prevention efforts should be particularly targeted towards those patients with advanced immune suppression and low educational levels, both prior to antiretroviral treatment and during treatment. They also note that antiretroviral treatment could have an indirect effect over time on the burden of malaria in settings where malaria is a serious problem.
Reference
Kasirye R et al. Epidemiology of malaria in HIV-infected patients on ART in Uganda : a prospective cohort study. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract TuPDB104, 2009.
Further information
A powerpoint presentation by Ronnie Kasirye and a webcast of this conference session are available on the IAS 2009 website here.
Biomedical prevention
High-risk HPV infection raises HIV risk at least fourfold: HPV vaccine study suggested
by Gus Cairns
Infection with one or more of the cancer-causing subtypes of the human papilloma virus (HPV) multiplied the risk of acquiring HIV among young men in by 4.5-fold in a randomised controlled study of circumcision in South Africa.
Bertran Auvert, the principal investigator of the ANRS1265 circumcision trial in Orange Farm, South Africa, hinted that he was proposing a trial of one of the HPV vaccines as a method of reducing HIV infection.
The substudy of HPV infection collected swabs for DNA analysis from 1683 men and tested them for the presence of 13 of the high-risk, cancer-causing subtypes of HPV and 24 of the low-risk wart-forming ones. HPV samples were collected when the study terminated, 21 months after participants were circumcised.
Observed HPV prevalence was related to the risk of seroconversion during the study and the researchers also related it for the purposes of multivariate analysis to the participants’ age, education level, number of sexual partners, condom use, and whether they had TB or other sexually transmitted infections including herpes, gonorrhoea and chlamydia.
During the trial, two per cent of trial participants became infected with HIV, and 17.5% and 14.3% when tested were infected with at least one low-risk or high-risk strain of HPV respectively. The most common types of high-risk HPV were type 16 (3.5%) and 18 (3.1%).
Participants with at least one strain of HPV were 5.5 times more likely to acquire HIV than participants without high-risk HPV and were still 4.6 times more likely when this was adjusted by taking into account other factors influencing HIV infection.
This was associated exclusively with high-risk HPV infection. Participants with low-risk types of HPV were no more likely to acquire HIV than HPV-uninfected men (adjusted risk ratio 0.92) whereas men with high-risk HPV were four times more likely (adjusted risk ratio 3.8).
The likelihood of acquiring HIV increased dramatically in men with multiple subtypes of HPV. Auvert calculated that annual HIV incidence in men without HPV was less than one per cent, 3-4% in men with one or two types, 10% in men with three types and 21% in men with five types. Each infection with an additional high-risk type of HPV increased the likelihood of HIV acquisition by two-thirds.
Auvert commented that one possible limitation of his study was that because HPV infection was determined at the end of the study, HIV infection might predate HPV infection: however he commented that because HIV infections were by definition recent in this study, the men who caught HIV would not have suffered a significant amount of immune damage and should be no more vulnerable to HPV than average.
He quoted several other studies that found that high-risk HPV infection was associated with increased risk of HI infection (relative risk ranging from 1.7 to 3.5). Auvert also presented another study in a poster at the conference which showed that there was a 3.4-fold higher risk of HIV infection in female sex workers with high-risk HPV infection.
An audience member suggested that it might be worth funding a trial of one of the HPV vaccines as an HIV prevention measure and Auvert hinted that he was in talks with possible funders.
References
Auvert B et al. Is genital human papillomavirus infection associated with HIV incidence? 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract TUAC202, 2009.
Auvert B et al. High risk HPV infection is associated with HIV acquisition among South African female sex workers. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract TUPEC073, 2009.
Antiretrovirals and condoms will have more effect on HIV in South Africa than circumcision, model finds
by Gus Cairns
In preliminary results from a mathematical model set up by researchers from the British Columbia Centre for Excellence in HIV/AIDS, male circumcision was found to have a considerably lower impact than condom use or antiretroviral therapy (ART) coverage on new HIV infection rates and on death rates in men in South Africa.
Researchers seeking to assess the population-level impact of different HIV prevention strategies in South Africa have developed a mathematical model that identifies increased condom use and ART coverage as keys to reducing new HIV infections in that country. Using published data from 2003 to 2008 for calibration, the model compared simulated scenarios involving various levels of male circumcision, condom use and ART coverage up to 2025.
The simulations set male circumcision rates at 51% (current level), 75% and 90%; condom use rates at 14% (current level), 50%, 75%, 80% and 90%; and ART coverage at 21% (current level), 50%, 75%, 80% and 90% with a CD4 cell count of 200 cells/mm3 or lower as the primary criterion for initiating ART.
Condom efficacy with 100% use was set at 90% and the efficacy of circumcision in preventing new infections at 53%. The infectiousness of HIV-positive members of the population was set in six strata: primary infection (less than 12 weeks after infection); chronic infection with viral load under 1000; viral load between 1000 and 10,000; viral load from 10,000 to 100,000; viral load over 100,000; and late-stage disease.
Other assumptions in the current model included that 50% of infected people knew their serostatus and, for the purposes of this initial, simple version of the model, that the both the number of women infected with HIV and their infectiousness would remain the same; obviously in a more sophisticated model which includes both male and female infections, reductions in female infections and infectiousness would have a synergistic effect. The impact of ART, condoms and circumcision in women is currently being calculated.
Impacts on the heterosexual male population aged 15 to 49 were measured.
Presenter Viviane Lima told the conference that scaling condom use up from 14% (the current estimated level) to 50% and antiretroviral therapy coverage from 21% to 80% would result in an estimated 950,000 infections averted in men by 2019. Raising ART use to 50% and condom use to 80% would have a similar effect.
Raising both to 50% would result in 700,000 fewer infections. But raising circumcision rates from the current 51% of men circumcised to 90% would only add another 48,000 infections averted to this total.
Condom use and ART coverage, alone or in combination, were found to reduce new HIV infections by from 64% to 95% by 2025 and to reduce mortality by 10% to 34%. Circumcision brought about a 3% to 13% reduction in new HIV infections and a 2% to 4% reduction in mortality; according to Lima, its impact “was overshadowed when combined with the other interventions.
“We were surprised by how little effect it had,” she said.
The mathematical model is susceptible of a huge number of permutations. Forthcoming studies include testing the effect of different numbers of people coming forward for testing, drug resistance, different criteria for starting treatment, mother to child transmission, and many other variables.
Reference
Lima V et al. The combined impact of male circumcision, condom use and HAART coverage on the HIV-1 epidemic in South Africa: a mathematical model. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WECA105, 2009.
Further information
A powerpoint presentation by Viviane Dias Lima and a webcast of the conference session in which it was presented are available on the IAS 2009 website here
‘Treatment as prevention’ must not violate human rights, conference told
by Gus Cairns
The expansion of HIV testing programmes and the advocacy of universal testing and treatment of those who test positive as a means of prevention must not violate the human rights of target populations, the Fifth IAS Conference on HIV Pathogenesis, Treatment and Prevention was told on Monday in Cape Town.
Representatives from the organisations Human Rights Watch and the AIDS and Rights Alliance of Southern Africa (ARASA) told testing advocates to ensure that testing is not coercive, that it is linked to treatment provision and treatment education, that the peer counsellors who perform testing understand confidentiality and informed consent, and that those who test positive are not subjected to ostracism within their communities.
The background to a series of seminars and discussions on the way forward for ‘treatment as prevention’ was a political disagreement among the HIV advocacy and public health communities dating from last year.
In 2008, two mathematical models appeared in HIV journals showing that universal treatment of people who test positive for HIV would reduce the epidemic in the worst-affected countries by 90 to 95% by the year 2050.
The first, by Julio Montaner’s team (Lima) at the British Columbia Centre for Excellence in HIV/AIDS, found that two-thirds of infections in the province would be averted if all patients started treatment when their CD4 cell count was around 350 cells/mm3. (See this report.)
The second modelling exercise (Granich) was conducted by the World Health Organization and published in The Lancet last November. This model found that achieving the somewhat utopian goal of universal HIV testing and treatment for everyone diagnosed HIV-positive would reduce HIV incidence from 2% a year to 0.1% a year within ten years and would reduce prevalence by 95% by 2050. (See this report.)
This report caused considerable controversy. In April 2009, a Civil Society Consultation on ART for Prevention met in Johannesburg, convened by ARASA and attended by activists from Kenya, Tanzania, Uganda, Botswana, Mauritius, South Africa and Namibia. The delegates produced a statement which declared that they had “fundamental concerns about the assumptions on which the model is based, its shortcomings from a human rights perspective and its inattention to vulnerable and marginalised groups”.
“Given the flawed and optimistic assumptions on which the model is based,” this statement continued, “the authors’ argument that the benefits of eradicating AIDS outweigh the potential violations of individual rights that this may occasion is hard to accept.” The full document can be read here.
At the IAS Conference several meetings pitted advocates of 'the right to know' against advocates for a broader definition of civic health and safety.
Dr Julio Montaner introduced a ‘town hall meeting’ on the issue by saying that the idea of treatment as prevention was initially advanced because the Government of British Columbia was threatening to cap what it would pay for antiretrovirals. Montaner said he had brought up the dimension of the public health good of ARV's ability to reduce infectiousness and was told to go away and research it. “We did it as an additional justification for not rationing antiretrovirals,” he said.
In a plenary, WHO’s Reuben Granich emphasised that “all models are wrong, but some are useful”, but reiterated the theoretical benefits of universal testing and treatment. In particular, the initial huge cost of a universal testing and treatment programme would be overtaken by the cost of doing nothing and seeing a continued increase in global HIV prevalence by 2030.
At the town hall meeting he said that he wished that WHO had stressed the truly voluntary aspect of any proposed testing, with informed consent and no coercion or criminalisation of those who test positive.
Teguest Guerma, Associate Director of WHO's HIV/AIDS Department, told the town hall meeting that she would like to tackle "the perception that the WHO only supports public health rather than human rights".
She added: "We think that, along other human rights, it is a human right to know your status and to be able to access treatment.”
She emphasised that using antiretrovirals for prevention was not yet a WHO policy and the next step would be a meeting in November to explore what evidence was needed.
However, Joseph Amon, director of the Health and Human Rights Division at Human Rights Watch, told the meeting that 'the right to know' could not be equated with 'the right to live' in situations where testing programmes were at best inefficient. Knowing might not result in any positive outcome.
In situations where confidentiality was violated, it could also only too easily turn change from being 'the right to know' into 'the right of others to know' their neighbours’ HIV status, a demand which, coming as it did periodically from employers, healthcare workers, immigration officials, schools and others, had had to be consistently resisted from the start of the epidemic.
He added that people's right to know they had HIV was meaningless without an equal right to the health information they needed to make sense of knowing.
He criticised Granich’s model for building in unwarranted assumptions such as positing that HIV-positive Africans would have on average eight new sexual partners a year, sustained over ten years. “The problem with saying that testing is evidence-based prevention is actually a shortage of evidence, for instance that expanding testing actually does lead to expanded access to antiretrovirals.”
Michaela Clayton, Director of ARASA, expanded on this theme by giving as an example ‘Know Your Status’, the universal HIV testing programme initiated in Lesotho. ARASA had conducted an evaluation programme. They found, amongst other things, that:
- Lay counsellors were putting people under pressure to test by, for instance, coming into their homes
- Lay counsellors had little understanding of confidentiality and would disclose subjects’ test results to family members
- Counsellors had little training in obtaining informed consent
- There was little effort by counsellors to advise on strategies to remain HIV-negative
- There was no monitoring of referrals to care and treatment.
Professor Susan Kippax of the National Centre in HIV Social Research at the University of New South Wales in Australia emphasised the issue of deductive disclosure. She cited one Médecins Sans Frontières (MSF) project where locals told the researcher that they always know who was positive “because they get half an hour with the counsellor after the test, where the negative ones only get five minutes.” The researcher found that people thus deduced to have HIV were still being isolated and ostracised from communities. Joseph Amon added that people needed a variety of venues in which to test so that violations of confidentiality were less problematic.
Paula Akugizibwe of ARASA said that the legal framework often ‘boxed in’ the potential dream of universal access. It did this by there being, in most countries, a lack of constitutional recognition of the right to health. This resulted in a situation of “universal access for the mainstream and zero access for the margins”, as epitomised by situations such as the position of injecting drug users or men who have sex with men.
“Science is evolving faster that the legal human rights framework needed for successful interventions,” she said. “The over-medicalisation of HIV is one of the greatest failures in the management of the epidemic.”
Joseph Amon added that until scientists could understand the social stress of a woman who, for example, he had met in Zimbabwe, who was afraid to test because of fear of being thrown out by the husband she loved, and who had probably infected her, they would consistently fail to understand community and individual resistance to the idea of testing for all.
References
Lima VD et al. Expanded access to highly active antiretroviral therapy: a potentially powerful strategy to curb the growth of the HIV epidemic. J Infect Dis 198 (online edition), 2008.
Granich R et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. The Lancet (online publication, November 26 2008): doi:10.1016/S0140-6736(08)61697-9.
Montaner M Clinical principle of treatment as prevention; benefits of earlier treatment to the individual and the community. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, satellite presentation SUSAT0501, 2009.
Granich R HAART as Prevention. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, plenary presentation MOPL101. 2009.
Guerma T Treatment as prevention model; future public health planning and considerations. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, satellite presentation SUSAT0505, 2009.
Amon J Human Rights context of routine/standardized testing. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, satellite presentation SUSAT0502, 2009.
Clayton M Lesotho case example and regional perspectives from Southern Africa on HIV testing/human rights. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, satellite presentation SUSAT0503, 2009.
Kippax S Situating the biomedical in the real world: the need for social and political science. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, symposium presentation MOSS201, 2009.
Akugizibwe P Legal challenges and successes in overcoming HIV stigma and discrimination to expand uptake of services. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, symposium presentation MOSS203, 2009.
Further information
A powerpoint presentation by Reuben Granich and a webcast of the conference plenary session in which it was presented are available on the IAS 2009 website here.
Vaginal washing increases HIV infection risk; results for dry sex less clear-cut
by Roger Pebody
A meta-analysis of data on vaginal practices and HIV infection from ten African cohorts has found that both vaginal washing with soap and wiping the vagina with cloths, tissues or paper were associated with an increased risk of acquiring HIV, researchers reported at the Fifth International AIDS Society conference in Cape Town last week. The use of products to dry or tighten the vagina, often referred to as ‘dry sex’, did not however have a statistically significant association with HIV infection.
Globally, there is a wide variety of vaginal practices and products used by women to clean, tighten, dry or warm the vagina. Women’s efforts to change their genital environment can undermine the body’s innate defences against pathogens. In particular, vaginal practices have been linked to disruption of the vaginal epithelium and loss of lactobacilli (i.e. an increase in bacterial vaginosis, which is also associated with an increased risk of HIV infection).
In resource-limited settings with strong imbalances in power between men and women, women may be motivated to adopt vaginal practices which enhance men’s sexual pleasure in order to maintain economically essential relations with husbands or other sexual partners. Other reasons to engage in these practices include genital hygiene, self-treatment of vaginal discharge, and pregnancy prevention.
Partly because of the wide variety of vaginal practices in different communities, and because of differences in the way in which practices have been recorded by researchers, epidemiological studies have so far produced conflicting findings on whether vaginal practices are associated with an increased risk of women acquiring HIV.
An international team of researchers therefore took the data from ten previous studies, and conducted an individual patient data meta-analysis. Most meta-analyses involve combining the end results from a number of different studies, whereas the approach taken here involved re-coding and re-analysing the data for each individual who had participated in the ten separate studies. This allowed for vaginal practices to be recorded according to a standardised classification system and for new analyses to be carried out.
The analysis from ten cohorts in six sub-Saharan African countries includes 16,307 women, of whom 865 contracted HIV. Six cohorts were of women in the general population; four were of commercial sex workers or women working in high-risk settings. There was a wide variation in the prevalence of both vaginal practices and bacterial vaginosis in these cohorts.
Compared to women who had no vaginal practices or who cleaned the vagina with water alone, women who cleaned with soap had an increased risk of acquiring HIV. In multivariate analysis (which controlled for age, marital status and number of sexual partners - the only factors found to skew the result), the hazard ratio was 1.22 (95% confidence interval 1.00-1.49).
Women who used cloths, tissues or paper to wipe the vagina and remove moisture also had an increased risk of infection. In multivariate analysis, the hazard ratio was 1.41 (95% confidence interval 1.03-1.77). The researchers suggest that some items used intravaginally may be more harmful than others and could cause abrasions.
As the lower confidence interval for the last two factors was above 1.00, the results are considered statistically significant (i.e. unlikely to be produced by chance alone).
However in the case of the use of products to dry or tighten the vagina, the hazard ratio was 1.23 (95% confidence interval 0.97-1.56). The lower confidence interval of 0.97 means that this result is not statistically significant, but Matthew Chersich, presenting, said that the findings did suggest that these practices are harmful.
The researchers hypothesised that vaginal practices may cause an increase in bacterial vaginosis, which in turn leads to an increased risk of HIV acquisition. However, when bacterial vaginosis was added to the multivariate model, it did not substantially affect the results.
Matthew Chersich said that although the meta-analysis had attempted to re-classify previous studies’ data using a standardised classification, the questions used in the studies were often ambiguous. He called for more research which asked more precise questions about different practices and products. He also recommended evaluation of interventions encouraging women to switch to less harmful practices, such as washing with water alone.
Concentrating on the finding that washing with soap is associated with an increased risk of infection, he noted: “The effect size is modest, but as this is a very common practice, at a population level a small effect would have important implications”.
Reference
Chersich MF Association between intravaginal practices and HIV acquisition in women: individual patient data meta-analysis of cohort studies in sub-Saharan Africa. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUAC204, 2009.
Further information
A powerpoint presentation by Matthew Chersich and a webcast of this conference session are available on the IAS 2009 website here.