Recent news at aidsmap.com

This edition of HIV & AIDS Treatment in Practice is a compilation of key news stories on HIV treatment in resource-limited settings published at www.aidsmap.com over the past six months.

It includes news stories on recent journal publications covering prevention of mother to child transmission, treatment for children, antiretroviral treatment, tuberculosis and opportunistic infections, and biomedical prevention.

This edition also includes an overview of the work of the Global HIV/AIDS Initiatives Network, a research network studying the impacts of global HIV/AIDS Initiatives on health systems, with a guide to recent publications.

Preventing mother to child transmission

Maternal death rate five times higher in women with HIV, South African audit shows

By Carole Leach-Lemens

Maternal mortality ratios in Johannesburg, South Africa in HIV-infected women are more than six times higher than in HIV-negative women despite integration of antiretroviral treatment into prenatal services, reported Vivian Black and colleagues in a five-year audit published in the August 2009 issue of Obstetrics and Gynecology.

If the United Nation’s Fifth Millennium Development Goal (MDG) of reducing maternal mortality by 20% by 2015 is to be reached the causes of maternal mortality as well as of preventable contributing factors need to be clearly understood.

The global maternal mortality ratio of 400 per 100,000 live births as estimated by the World Health Organization does not reveal the considerable regional variations.

In 2005, South Africa—a middle income country—had a ratio close to the global average but considerably higher than countries of similar gross domestic product per person, for example, Portugal and Brazil which had a ratio of 11 and 110 respectively.

Since 1998 HIV, an indirect cause of maternal mortality, has been the leading contributor to maternal mortality in South Africa, reversing previous declines seen in maternal mortality rates.

An audit of maternal deaths for the period 1996-1998 in Durban, South Africa showed facility-based maternal mortality rates for women with HIV to be 323 per 100,000 compared to 148 per 100,000 for those not infected - over two times higher. Co-infection with tuberculosis had a considerable impact on outcomes.

The authors noted that HIV prevalence among women attending antenatal clinics has remained steady at between 28% and 33% over the past four years.

The authors reviewed maternal deaths at a tertiary level facility in Johannesburg, Gauteng Province, for the five-year period from 2003 to 2007. Variables of interest included: deaths due to HIV, the patterns of these deaths and changes over time. Antiretroviral therapy became available in 2004 and was integrated into an existing programme for prevention of mother to child transmission (PMTCT) in the prenatal clinic of the hospital at the facility. The authors assess its impact on maternal mortality.

HIV testing and counselling is offered at the first prenatal visit and CD4 cell counts done for those who test positive. Eligibility for antiretroviral treatment is based upon a CD4 cell count <200 cells/mm³ or WHO clinical stage 4. Women receive the standardized ART regimen of stavudine, lamivudine and nevirapine, along with cotrimoxazole prophylaxis. Single-dose nevirapine (for both mother and infant) was given for prevention of mother to child transmission during the period under review, prior to the updating of South African guidelines.

Patient case files, birth registers, death certificates and mortality summaries were reviewed. Maternal death was defined as death of a woman at the facility during pregnancy or within 42 days of childbirth. No information was available for women who died at home or at another facility. Cause of death was determined through multidisciplinary clinical case discussions. Annual maternal mortality ratios were calculated and disaggregated by HIV status.

For the period 2003 to 2007 a total of 108 women died and had a mean age of 28.7 years. It was the first pregnancy for eleven percent, a third of the proportion of all women in their first pregnancy delivering at the hospital.

HIV test results were available for 72 % (76); almost 80% were HIV positive. The median CD4 cell count for 53 of HIV infected women who had the test was 72 cells/mm³ (interquartile range: 29-194 cells/mm³).

Only two of the HIV-infected women had begun antiretroviral therapy. The authors note this clearly demonstrates that missed opportunities for starting treatment persist.

Most deaths were associated with advanced HIV disease, the most common causes being tuberculosis (36%) and pneumonia (20%). Median CD4 count in women whose death was due to an HIV-related illness was 50 cells/mm³ compared to a median of 335 cells/mm³ in HIV-infected women who died of non-related HIV causes.

The authors argue that most of the HIV-related deaths could have been avoided if ART and cotrimoxazole prophylaxis had been started. In HIV-negative women or those of unknown status deaths were overwhelmingly due to obstetric causes with hypertension accounting for over 50%.

While the number of deaths over the five year period ranged from 15 to 25, the number of live births remained constant at around 7,000 per year.

The authors note that while coverage of HIV testing increased each year (women in 2007 were 3.4 times more likely to have a known HIV status (95% CI 3.2-3.6) than those in 2003) HIV testing and follow-up after diagnosis remained the most significant programmatic weakness.

The authors suggest that systematic evaluation of the processes of HIV testing and care for pregnant women could be useful and might include: “assessment of performance against predefined criteria and agreed targets, for example, routine provider-initiated HIV testing, provision of CD4 results at the second prenatal visit, a target time of three weeks from first visit to antiretroviral treatment initiation and active follow-up processes to ensure that women with advanced HIV disease are retained in care”. The authors highlight the use of mobile phone technologies as an effective means of follow-up in this setting.

While the numbers of women who began ART increased over time, with coverage in 2007 estimated at 59.2%, the maternal mortality ratio for HIV-infected woman was over six times higher than the ratio in HIV-negative women (776 versus 124 per 100,000), or 6.2 (95% confidence interval 3.6 - 11.4).

44.3% (95%CI 30.8-54.8%) of total deaths were due to HIV. The mortality rate among HIV-infected women who died of non HIV-related causes was 171/100,000, similar to that of HIV-negative women.

The authors note the importance of expansion of ART to two primary health facilities close to the hospital led by nurses and midwives. Advantages include ensuring high level coverage, bringing HIV care closer to the patient and potentially avoiding unnecessary referrals to tertiary care. They stress that integration of ART into prenatal care will help secure both the health of women as well as prevent transmission to newborns. Others factors the authors cite as barriers to uptake of prevention of mother to child transmission are: the framing of PMTCT itself as a paediatric issue, weak health systems, poor communication between health workers and pregnant women as well as the fear of stigma.

Nearly three-quarters of all deaths occurred in the week after childbirth, and the authors stress the importance of strengthening postnatal health services.

The authors note that statistically, maternal deaths are rare, which makes understanding the effects of new interventions difficult. Comparison of facility-based deaths with other institutions may not be feasible since a disproportionately higher number of difficult pregnancies are referred to them increasing the probabilities of a higher mortality rate. The authors note too that their findings may be the result of changes over time and not necessarily the introduction of ART.

They conclude “Although it was not possible to demonstrate that the integration of antiretroviral treatment within prenatal care services has reduced maternal deaths, provision of antiretroviral treatment into prenatal care remains an important strategy for reducing maternal deaths in high HIV-burden countries. Interventions, such as clinical audits, are required to target weaknesses in HIV treatment and care within maternal health services”.

Reference

Black V et al. Effect of human immunodeficiency virus treatment on maternal mortality at a tertiary center in South Africa: A 5-year audit. Obstetrics and Gynecology 114 (2), 292-299, 2009 (full text freely available here).

Low maternal vitamin D increases risk of HIV transmission to child and infant mortality

By Michael Carter

Low maternal vitamin D is associated with an increased risk of mother-to-child HIV transmission and child mortality, investigators report in the online edition of the Journal of Infectious Diseases.

“An increased risk of being HIV infected or of dying at birth was observed for children born to women with a low vitamin D level at baseline; a low maternal vitamin D level was also associated with HIV transmission via breast-feeding and with higher infant mortality during follow-up”, write the investigators.

It is already known that vitamin D levels can affect the functioning of the immune system and that maternal vitamin D levels have an impact on foetal growth. Furthermore, vitamin D supplementation has been shown to improve the outcome of tuberculosis therapy, which is significant in the context of HIV as tuberculosis is the single most important cause of illness and death in HIV-positive individuals.

There has, however, been little research into the impact of vitamin D levels in HIV-positive pregnant women and outcomes including adverse birth events, mother-to-child HIV transmission, infant death during the early months of life, or HIV transmission because of breastfeeding.

A study into the use of vitamin supplementation in HIV-positive women in Tanzania provided investigators with an opportunity to assess the importance of maternal vitamin D levels on such outcomes.

A total of 884 women were included in the researchers’ analysis. Most (80%) had asymptomatic HIV disease. Vitamin supplementation was initiated between weeks twelve and 27 of pregnancy. This did not, however, include vitamin D, levels of which were assessed at baseline.

No association was detected between vitamin D levels and adverse pregnancy outcomes such as premature delivery, or having a baby with a low birth weight, or that was small for its gestational age.

However, low baseline maternal vitamin D (below 32 ng/ml), was associated with a 49% increase in the risk of foetal death or HIV transmission at birth (95% CI, 7% - 109%), compared to the infants of mothers with sufficient vitamin D levels.

In addition, the infants of mothers with low vitamin D had a 50% increase in their risk of being HIV-infected at six weeks of age compared to the children of mothers with normal vitamin D (95% CI, 1.02-2.20).

After 24 months of follow-up, 30% of infants were HIV-positive. The children of mothers with insufficient vitamin D who were HIV-negative at six weeks of age had a two-fold increase in the risk of acquiring HIV from their mothers during breastfeeding than did infants whose mothers had adequate vitamin D (incidence rate ratio [IRR], 2.03; 95% CI, 1.08-3.82).

The overall rate of mother-to-child HIV transmission after 24 months was 46% higher in the infants of mothers with deficient vitamin D than it was in the children of mothers with normal levels of this vitamin.

Further analysis by the investigators showed that mothers with the lowest levels of vitamin D had the highest risk of mother-to-child transmission (p = 0.01), and that this risk decreased as maternal vitamin D increased.

Finally, the researchers found that low maternal vitamin D increased the risk of infant death during follow-up.

“Vitamin D is known to contribute to the development of the foetal immune system; a stronger immune system may be more resistant to HIV infection and may explain the decreased risk of mother-to-child transmission observed”, comment the investigators.

They continue, “this finding would also likely correlate with fewer infections and opportunistic illnesses during follow-up and, consequently, with decreased mortality. In addition, there is increasing evidence supporting the role of vitamin D in fighting tuberculosis; tuberculosis is one of the primary killers in HIV-infected populations.”

The investigators conclude that should vitamin D supplementation be shown to be effective in studies it “could prove to be a relatively simple and inexpensive method to lower mortality among children and to help prevent mother-to-child transmission of HIV as a adjunct to HIV therapy.”

Reference

Mehta S et al. Perinatal outcomes, including mother-to-child transmission of HIV, and child mortality and their association with maternal vitamin D status in Tanzania. J Infect Dis 200 (online edition), 2009.

Routine infant HIV testing acceptable and feasible at South African immunisation clinics

By Michael Carter

Routine HIV testing at infant immunisation clinics is feasible and acceptable, investigators from South Africa report in the online edition of AIDS. They found that most mothers agreed to HIV testing and that 7% of the infants of mothers who reported that they were HIV-negative were, in fact, infected with HIV.

Testing at the immunisation clinics allowed both the mothers and infants to be linked into antiretroviral treatment programmes.

Early initiation of HIV treatment in HIV-infected babies is associated with a significantly reduced risk of early death. World Health Organization guidelines therefore recommend that all babies with HIV should start antiretroviral therapy.

However, many infants are unable to benefit from HIV treatment because their infection remains undiagnosed.

To try and increase the detection of HIV infection in babies, investigators in the South African KwaZulu Natal, where 39% of women receiving antenatal care are HIV-positive, undertook a study to see how feasible and acceptable opt-out HIV testing was at infant immunisation clinics.

The study was conducted between November 2007 and February 2008. Mothers attending with infants aged six, ten and 14 weeks were offered opt-out tests by trained counsellors.

Infants and mothers found to be HIV-positive were referred to an antiretroviral treatment clinic.

A total of 646 mothers of infants attending the immunisation clinics were offered opt-out HIV tests by the counsellors. The median age of the infants was a little under eight weeks. Most (584, 90%) mothers consented to their baby being tested for HIV.

There was a very high level of HIV testing amongst the mothers, with 98% reporting that they had ever had a test. The use of single-dose nevirapine during labour was reported by 266 women, although only 233 reported that they were HIV-positive. Of the mothers who said that they were HIV-positive, approximately 70% said their infants received single-dose nevirapine.

Of the 584 mothers who agreed to have their infant tested for HIV, only 332 (57%) returned for the result. Of those who returned, 160 (48%) came back for their scheduled appointment, but approximately 80% of the other women returned within four weeks, often on the date of the next immunisation.

Mothers who reported being HIV-positive were more likely to return than mothers who believed themselves to be HIV-negative.

HIV infection was diagnosed in 247 (42%) of infants, a finding that accorded with the 38% rate of vertical HIV transmission in the province.

Amongst the women who reported being HIV-negative, 7% of their babies were found to be infected with HIV.

Most mothers (78%) said reported that they were comfortable with the offer of an opt-out HIV test for their baby. However, 5% of mothers said that the offer frightened them, and 2% said that it caused anxiety.

Furthermore, 2% of mothers said that they did not accept the offer of an HIV test because they needed more time to decide.

The main reasons for accepting a test were to confirm the HIV status of the infant (77%) and to access to antiretroviral therapy (55%). Over a quarter of women also said that the test result would help inform their infant feeding practices.

“Routine HIV testing of infants attending primary healthcare clinics for immunizations was acceptable and feasible”, write the investigators, “if implemented as the standard of care at primary health care clinics, more than half of infants and mothers would know their HIV status at about 6-10 weeks of age after which they could gain access to a continuum of care.”

Reference

Rollins N et al. Universal HIV testing of infants at immunization clinics: an acceptable and feasible approach for early infants diagnosis in HIV prevalence settings. AIDS 23 (online edition), 2009.

3% incidence of HIV in pregnant women shows importance of repeat HIV testing in pregnancy

By Michael Carter

A South African study has revealed that a significant number of women are being infected with HIV during pregnancy. In the June 19^th edition of AIDS, researchers report that 3% of women who had a negative HIV test result when first accessing antenatal services subsequently tested positive later in the pregnancy.

“Pregnant women continue to represent a vulnerable population, and HIV testing late in pregnancy or labor offers an additional opportunity to prevent mother to child transmission or prevent further horizontal transmission in the community as well as ensure continued care for women who seroconvert during pregnancy”, comment the investigators.

HIV prevalence amongst pregnant women in South Africa is estimated to be 28%. It is recommended that all women should be offered voluntary HIV testing and counselling when they first access antenatal services. However, repeat testing of women testing negative is rarely offered.

This practice means that infections at the time of the first visit may remain undetected because of low antibody levels and infections acquired during pregnancy will not be diagnosed unless a subsequent test is offered.

Investigators therefore offered a repeat HIV test to women using antenatal services at one rural and two urban clinics in Eastern Cape and Free State between July 2006 and April 2007. Their aim was to determine HIV incidence during pregnancy and its risk factors.

A total of 5233 pregnant women registered for antenatal care and 3742 (79%) accepted an HIV test. HIV prevalence amongst these women was 28%.

The investigators referred 2377 women who initially tested negative for a repeat HIV test between weeks 36 and 40 of pregnancy. A total of 1278 (53%) had such a test.

Of these women, 72 (3%) were HIV-positive. They were tested an average of 24 weeks after their initial screening for the virus, yielding an incidence rate of eleven per 100 person years.

There was a non-significant trend for a higher risk of HIV incidence for women attending the urban rather the rural clinics (risk ratio = 1.37; 95% CI: 0.86 to 2.17, p =0.182).

HIV was higher amongst women aged 25 to 29 (4%) and 30 to 40 (5%) than amongst those aged below 20 (2%). There was also a lower incidence rate (1%) amongst women who had received a tertiary education than those with lower levels of education (3%).

Single and divorced women had a higher incidence of HIV during pregnancy (3%) than married women (2%).

Only 40% of women used a condom during pregnancy. However, condom use did not differ between women who contracted HIV and those who did not.

The investigators conclude, “In light of the above findings, public health programs need revisiting to ensure that HIV retesting in pregnancy is implemented, reinforce the need for continued education on prevention during pregnancy and extend the use of female-controlled prevention methods such as microbicides when proven well tolerated and efficacious during pregnancy.”

Reference

Moodley D et al. High HIV incidence during pregnancy: compelling reason for repeat HIV testing. AIDS 23: 1255-59, 2009.

Treatment and care for children

Over 3000 children diagnosed with HIV in Lusaka after hospital introduces opt-out HIV testing

By Michael Carter

Implementing a policy of routine opt-out HIV testing led to the diagnosis of 3000 HIV infections in children admitted to hospital in Lusaka over an 18-month period, investigators report in a study published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“Increased HIV testing has been proposed as an important component of HIV prevention and a pathway to support universal access to antiretroviral therapy”, write the investigators. “This is particularly important for infants where the rate of disease progression is extremely rapid, the risk of early death is high, and antiretroviral therapy can decrease mortality significantly in the first year of life”, they add.

In an attempt to increase the number of diagnosed HIV-positive children in Lusaka, Zambia, investigators at the University Teaching Hospital implemented a policy of offering routine HIV counselling and testing to all children admitted as inpatients.

HIV prevalence amongst women attending antenatal services in Zambia is 25% and an estimated 28,000 infants are born each year in the country with HIV infection. The investigators therefore hypothesised that routinely offering HIV testing would identify large numbers of HIV-infected children.

A total of 15,670 children of unknown HIV status were admitted to the hospital as in-patients between January 2006 and June 2007. Of these, 13,239 parents/caregivers (85%) received counselling for testing of their child and 11,571 children (87%) had an HIV test.

In all, 3373 (29%) of children tested HIV-positive. Almost a third of children under six months of age were HIV-positive, as were 23% of children aged five and over. Nevertheless, two-thirds (69%) of children testing positive were under 18 months of age.

Children admitted to the malnutrition ward had the highest prevalence of HIV infection (36%). After adjusting for possible confounding factors, the investigators found that children admitted to the malnutrition ward (adjusted odds ratio [AOR], 16.7; 95% CI: 13.7-20.4) and the diarrhoea/rehydration ward (AOR, 8.2; 95% CI: 13.7-20.4) were significantly more likely to test HIV-positive than children admitted to other wards.

Approximately 4100 eligible children were not tested for HIV and 1668 (41%) received counselling but were not subsequently tested for the infection. The most common reason for not testing were the death of the child (44%), the refusal of the parent (12%) and early discharge (10%).

“Many of the categories represent missed testing opportunities: early discharge, absconded, and weekend admission. The majority of children in these categories received no counselling. In contrast, parental refusal and waiting for husband’s permission represent situations where counselling was performed, but the child was not tested”, note the authors.

As well as diagnosing over 3000 children, the investigators note secondary benefits of their programme of routine testing. “Parents and caregivers were offered HIV testing and, later in the programme, CD4 cell testing. HIV-positive adults were referred for care.” The investigators also write that parents were encouraged to bring other children in for HIV testing.

“We successfully implemented a routine HIV counselling and testing programme for hospitalized paediatric patients”, conclude the investigators, “we propose that this programme is particularly relevant in settings with generalised HIV epidemics and should be replicated as a highly feasible way to identify children in need of HIV care and antiretroviral treatment.”

Reference

Kankasa C et al. Routine offering of HIV testing to hospitalized pediatric patients at University Teaching Hospital, Lusaka, Zambia: Acceptability and feasibility. J Acquir Immunde Defic Syndr (online edition), 2009.

European study confirms that HIV treatment within three months of birth improves outcome for HIV-positive infants

By Michael Carter

HIV-infected infants who start HIV treatment within three months of birth have a significantly reduced risk of developing AIDS or dying, European investigators report in the March 13^th edition of AIDS. “Deferring treatment in infected infants is no longer an option,” write the investigators.

Without HIV treatment, approximately 20% of HIV-infected infants born in richer countries like the UK will develop AIDS or die in the first year of life. The introduction of combination HIV treatment in the mid 1990s lead to suggestions that starting HIV treatment soon after birth could reduce the risk of disease progression in infected children. There were, however, concerns about the pharmacokinetics of antiretroviral drugs in children, the lack of paediatric formulations and the risk of both short- and long-term side-effects.

Nevertheless, a number of non-randomised studies in richer countries demonstrated that HIV treatment before six months of age reduced the risk of disease progression, lowered viral load and strengthened the immune system.

Furthermore, a randomised study in South Africa involving 375 HIV-positive infants demonstrated clear advantages to starting HIV treatment within three months of birth, the risk of death being reduced by 76%.

European researchers therefore looked at medical records obtained from 13 cohorts in eleven European countries to determine the benefit of HIV-infected, symptom-free infants starting antiretroviral treatment before three months of age.

The children were born between 1996 and 2004. A total of 124 infants started treatment before three months of age (the early treatment group) and 86 did not (the deferred treatment group).

Of the infants who started HIV treatment early, four developed AIDS (three cases of encephalitis and one of wasting disease) and two died. HIV treatment was started within a year by 58 of the infants whose treatment was deferred. This included six children who did so because of the development of an AIDS-defining illness (three cases of encephalitis, one of PCP pneumonia, one of CMV and one serious recurrent bacterial infection). Of the 52 children who started treatment without having developed serious HIV-related illness, six subsequently developed AIDS (another three cases of encephalitis, two CMV, and one serious recurrent bacterial infection).

A total of 28 children had not received HIV treatment by their first birthday, and six AIDS-defining illnesses were reported amongst these infants.

Infants who started HIV treatment within three months of birth had a 2% risk of developing AIDS in their first year of life compared to a 12% risk for children who deferred treatment. Furthermore, infants taking early HIV treatment had a lower risk of developing AIDS within their first five years (5%) than children who deferred treatment (22%). These differences in risk were highly significant (p < 0.001).

Deferred treatment was associated with a hazard ratio (HR) of death of 5.0 (95% confidence interval [CI], 2.0 to 12.6, p = 0.001). This remained the case when the investigators took into account possible confounding factors such as year of birth, use of HIV treatment during pregnancy and delivery, mode of delivery, length of pregnancy, birth weight, CD4 cell percentage, use of PCP prophylaxis, and number of drugs in first antiretroviral combination.

There were significant differences in the characteristics of children in the cohorts included in the analysis. Taking these into account slightly reduced the hazard ratio of death for infants whose treatment was deferred (HR = 3.0, 95% CI, 1.2 to 7.9, p =0.021). However, restricting the analysis to infants who took triple HIV treatment consisting of either three nucleoside reverse transcriptase inhibitors (NRTIs) or two NRTIs plus the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune) strengthened the association between deferred treatment and poorer outcome (HR = 7.9, 95% CI, 2.3 to 27.6, p < 0.001).

“The benefit of systematic antiretroviral therapy before 3 months of age to avoid…rapid progression has been recently demonstrated in the South African controlled randomized trial. Our analysis confirmed that this is also the case in routine clinical practice in industrialized countries,” write the investigators.

They conclude, “antiretroviral therapy initiated before the age of 3 months has a dramatic effect on reducing progression to AIDS and death in high income countries.”

Reference

Goetghebuer T et al. Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants. AIDS 23: 597-604, 2009.

Antiretroviral treatment

d4T dose reduction does not result in poorer treatment outcomes in South African patients

By Keith Alcorn

The use of a reduced dose of d4T (stavudine), as recommended by the World Health Organization, did not reduce the likelihood of viral load suppression after six months in a large cohort of South African patients, researchers from the Aurum Institute of Health Research report in the August 24th edition of AIDS.

The use of d4T in first-line treatment has been phased out in the developed world due to toxicity, but in developing countries fixed-dose combinations containing d4T are still widely used due to the drug’s low cost compared to tenofovir or abacavir. In South Africa d4T remains a staple component of first-line treatment in the public health system, despite widespread calls for its use to be phased out.

The key toxicities associated with d4T are lipoatrophy (fat loss), hyperlactatemia and lactic acidosis, and peripheral neuropathy.

The drug was originally licensed at a dose of 40mg twice daily in adults weighing more than 60kg.

In 2007 the World Health Organization recommended that developing country treatment programmes should use a 30mg dose of d4T if it was not possible to phase out use of the drug. Their recommendation was based on a number of small studies which showed no negative effect of using a lower dose in adults weighing more than 60kg.

Adoption of the 30mg dose has been slow in some national programmes, and data are still lacking from an African population on the virological effects of initiating therapy with a lower dose of d4T.

Researchers at the Aurum Institute in Johannesburg analysed data from 618 patients enrolled in community-based HIV care programmes in South Africa who initiated treatment containing d4T between January 2006 and January 2008. All patients had been followed for at least six months after starting treatment, and weighed at least 60kg at baseline.

Of the eligible patients, 110 received a 30mg dose and 508 received a 40mg dose. Those receiving a 30mg dose were slightly more likely to receive nevirapine than efavirenz and to have WHO stage 4 HIV disease, and had significantly lower baseline CD4 counts (91 vs 115, p=0.0001). These differences were not a result of individualisation of treatment, say the investigators, but due to a change in guidelines during the period under study.

There was no significant difference after six months of treatment in the proportion of patients who had viral load below 400 copies/ml or 50 copies/ml (79% vs 81% and 60% vs 58% respectively). Multivariate analysis which adjusted for NNRTI agent, baseline viral load and weight showed no effect of dose on viral suppression.

The investigators say their findings provide additional evidence to support the WHO recommendation, but note that evaluation of long-term side effects according to dose is essential.

Reference

Hoffmann CJ et al. HIV suppression with stavudine 30mg versus 40mg in adults over 60kg on antiretroviral therapy in South Africa. AIDS 23 (13): 1784-1786, 2009.

Clinical officers and nurses make similar decisions to physicians on starting antiretroviral therapy in rural Uganda

By Roger Pebody and Carole Leach-Lemens

An analysis of decision-making by non-specialist physicians, clinical officers and nurses in Uganda has found that there is a high level of agreement in decisions on starting antiretroviral therapy.

The study, in the journal Human Resources for Health, contributes to the evidence base in support of task-shifting, and may ease concerns about a decrease in quality compared to current standards of care. It lends support to arguments for increased investment in training of nurses and clinical officers for the delivery of antiretroviral therapy in rural and semi-rural settings.

Rapid scale up of antiretroviral therapy has brought to light weaknesses in the health systems of developing countries. WHO estimates that over four million health workers are needed, and this shortage of medical doctors and other health workers trained to deliver HIV treatment and care has been identified as the most serious barrier to the sustained scale up of ART in resource-poor settings.

Task-shifting involves the delegation of healthcare tasks from more highly trained individuals to those with less training, and it has been increasingly employed as a way to help address the shortage of highly trained staff in many resource-limited settings.

Few countries in the developing world legally mandate non-physician clinicians to provide HIV treatment and care (exceptions include Malawi, Kenya, Ethiopia and Uganda). There is a reluctance to legalise task-shifting due to concerns about the capacity of the workers, as well as the quality of care provided.

Conversely this is a common and very successful practice in the developed world where non-physician clinicians (in particular nurse practitioners) play a central role in the treatment and care of HIV-positive patients.

Moreover the Integrated Management of Adolescent and Illnesses (IMAI) guidance, developed by the World Health Organization and partners, uses task-shifting to support a public health approach to treating HIV within government health systems. The target audience is principally healthcare workers providing clinical care at front-line health facilities. More than 30 countries, mostly in sub-Saharan Africa are currently using IMAI.

Ashwin Vasan and colleagues designed a study in which a non-physician first assessed the patient and made a recommendation on whether to start treatment, after which a physician repeated the procedure (without being aware of the initial recommendation). The study compares each worker's assessment, although all final clinical decisions were made by the physician.

Study sites were twelve district hospitals and subdistrict primary care clinics in Uganda. Sites were chosen based on their large HIV programmes, and staff were trained in the management of HIV through the Ministry of Health programme (an adaptation of generic WHO/IMAI protocols). Rural or semi rural sites were chosen to provide an accurate picture of decentralised ART care. Viral load testing was not available and access to CD4 cell counts was limited at all sites.

Healthcare workers were classified as:

• Physicians: those who had completed a six year medical school programme plus a one-year internship. Physicians were not usually HIV specialists.
• Clinical officers: those who had completed three years' pre-service education plus two years' internship.
• Nurses, who had completed between one and four years' formal nursing education.

The authors acknowledge that the variation in the level of training of Ugandan nurses is a limitation of the study. Moreover, the study did not record the number of years of work experience that each worker had.

The researchers used Kappa analysis to evaluate levels of agreement. Kappa is a statistical measurement of the degree of agreement between two observers, and which rates strength of agreement as ‘slight’ (0 to 0.2), ‘fair’ (0.2 to 0.4), ‘moderate’ (0.4 to 0.6), ‘substantial’ (0.6 to 0.8) or ‘almost perfect’ (0.8 to 1).

The 521 eligible patients were HIV-positive adults not currently on treatment.
Each patient was first assessed by either a clinical officer or a nurse, and then by a physician. The primary outcome in the study was the final recommendation on whether or not to start antiretroviral therapy.

In the clinical officer arm, agreement with physicians on starting therapy was almost perfect (Kappa 0.91), with 95% of decisions being the same (as opposed to 43% agreement which could be expected by chance alone).

Agreement between nurses and physicians was less consistent and was calculated to be at the top end of the moderate category (Kappa 0.59). A total of 78% of decisions were in agreement, as opposed to 46% which could be expected by chance alone.

Moreover, both nurses and clinical officers were both somewhat more likely than physicians to recommend an alternative to the standard d4T/3TC/nevirapine regime.

Nurses’ assessments of patients’ WHO clinical stage and TB status were both in substantial agreement with those of physicians. On the other hand, the assessments of clinical officers for both these items were only in moderate agreement with the doctors.

On a number of items, the agreement of both nurses and clinical officers with physicians was assessed as ‘fair’. This was the case for functional status (able to work, able to walk, etc.), opportunistic infection status, absolute exceptions to starting antiretroviral therapy immediately, and patient readiness to start therapy. However the authors note that a number of these variables are subjective in nature. Moreover in some cases there was a great deal of missing data.

Although nurses had higher agreement scores on some items than clinical officers, the authors focus their conclusions on the latter group because of the decisions concerning initiation of therapy. They say that there is “compelling evidence” that clinical officers should be allowed to initiate therapy.

The authors believe that their findings show that under routine conditions at rural health facilities, and without any targeted increase in training or supervision of healthcare workers beyond the national framework, there is agreement in the clinical judgement between different cadres of healthcare workers in terms of starting antiretroviral therapy.

Nonetheless, they also describe the study as a pilot, and argue that “these preliminary data warrant more detailed and multicountry investigation”.

Reference

Vasan A et al. Agreement between physicians and non-physician clinicians in starting antiretroviral therapy in rural Uganda. Human Resources for Health 7:75, 2009.

Uganda survey shows major ART training gaps for non-physicians

By Carole Leach-Lemens

A survey of health facilities providing antiretroviral treatment in Uganda has found that nearly two-thirds of those providing ART are not doctors, and report major gaps in training. Two out of every five of this group had received no training in starting patients on ART and two-thirds had not been trained in how to monitor patients on ART.

The findings were published in the August 23 edition of Human Resources for Health.

In self-assessment questionnaires seven percent of doctors, 42% of clinical officers, 35% of nurses and 77% of midwives thought their overall knowledge of ART was lower than “good”.

Task-shifting from physicians to nurses and clinical officers requires ongoing integrated trainings to ensure the correct use and monitoring of ART if toxicity and drug resistance are to be avoided and the success achieved to date in the management of HIV is to be maintained in resource-poor settings.

Access to ART continues to expand beyond urban centres into remote areas and task-shifting is widely acknowledged as a means to counter the challenge that the chronic shortage of healthcare personnel in resource-poor settings presents. Studies have demonstrated that in some cirumstances the quality of care provided by non-physician clinicians is equal to or better than that provided by clinicians.

The Infectious Diseases Institute (IDI) at Makerere University, Uganda together with the (Ugandan) Ministry of Health undertook a training needs assessment that focused on two of the World Health Organization’s recommendations for task-shifting in the promotion of access to HIV and other health care services:

• Recommendation Four: countries undertake or update a human resources analysis on the extent to which task-shifting is already taking place and
• Recommendation Nine: countries adopt a systematic approach to harmonised, standardised and competence-based training that is needs-driven and accredited.

A survey of health professionals and heads of antiretroviral therapy clinics from a stratified random sample of 44 of the country’s 205 accredited health facilities was undertaken. Six out of 12 catchment areas were chosen by a lottery method. The sample included six regional referral hospitals, 16 district hospitals and 22 health centres. Facilities were grouped as follows: ownership (government or non-governmental organisation and/or faith-based) and whether antiretroviral therapy was being provided.

A sample of health professionals was chosen in collaboration with the head of the ART clinic. Criteria included being present on the day the study team visited. Efforts were made to have at least one doctor, one clinical officer, one nurse and one midwife from each clinic.

Data collection involved self-administered questionnaires for individual health professionals and face-to-face interviews with the heads of the antiretroviral clinics.

Forty-three of the 44 facilities selected were included of which 38 provided ART and five (one district hospital and four health centres) did not.

Expansion of ART from urban clinics to district hospitals and primary care facilities is reflected in the numbers. Although regional referral hospitals provided ART to a higher proportion of people with HIV (45%) than district (33%) and health centres (17%) the authors suggest that over time these percentages may even out as care is transferred closer to accredited facilities near the patient’s home.

The sample comprised 265 clinicians: 34 doctors, 46 clinical officers, 124 nurses and 61 midwives. This distribution across professions was markedly different to the distribution of staff at ART clinics. Doctors were under-represented at all facilities, whereas nurses were over-represented at health centres and underrepresented at regional referral and district facilities. ART clinics at two district hospitals and two health centres had no doctors on staff.

ART tasks were performed by all staff interviewed. 64 percent of clinicians prescribing ART were clinical officers, nurses and midwives. The authors note that this task-shifting was in line with recommendations from experts and may well have contributed to increased access to ART.

The study revealed that training on starting and monitoring ART has not kept pace with task-shifting. Of those prescribing ART 35% had not been trained on starting ART and 49% had not been trained on the monitoring of ART. These percentages differed across health professions: 27% of doctors had no training on monitoring ART compared to 64% of other clinicians. Similarly 24% of doctors had no training on starting ART compared to 38% of clinical officers, 38% of nurses and 49% of midwives.

While higher percentages of doctors and clinical officers attended training on monitoring of ART and paediatric HIV care than nurses and midwives, a lower percentage of doctors and clinical officers attended training on voluntary counselling and testing than nurses and midwives.

Self-assessment of knowledge of ART also differed across professions and was closely related to training in starting and monitoring ART: Ratings were categorized as “excellent”, “very good” and “good” and were grouped together as “sufficient”. 75% of all respondents deemed their overall knowledge of HIV as sufficient and 40% rated their overall knowledge of ART as sufficient. 7% of doctors prescribing ART rated knowledge less than “good” compared to 48% of other clinicians.

Limitations noted by the authors include overrepresentation of certain professionals at some facilities and underrepresentation of others due to reliance on those present at accredited ART clinics on the day of the study.

The authors further note that of the 45 facilities in the sample two remote facilities were replaced by those easier to reach. Task-shifting and an absence of training, the authors believe, were more likely to occur in remote facilities so the sample may have underestimated the extent of task-shifting in addition to the associated ART training needs.

The authors suggest that this assessment provides an innovative method that can be replicated to inform ART trainings in the context of ongoing scale up and task-shifting. The authors conclude that “Training initiatives should be an integral part of the support for task-shifting and ensure that ART is used correctly and toxicity or drug resistance does not reverse the successes to date.”

Reference

Lutalo IM et al. Training needs assessment for clinicians at antiretroviral therapy clinics: evidence from a national survey in Uganda. Human Resources for Health 7:76, 2009.

 

Earlier treatment could be cost-effective for South Africa

By Keith Alcorn

Starting treatment at a CD4 count of 350 would be cost-effective in South Africa, with a maximum extra expenditure of $1.5 billion over five years if everyone eligible was treated, according to findings from a collaborative study by American and South African researchers published in the August 4th edition of the Annals of Internal Medicine.

South Africa’s Department of Health is currently considering a recommendation from the South African National AIDS Council (SANAC) to revise national guidelines so that people diagnosed with HIV infection can receive treatment once their CD4 counts fall below 350 cells/mm³.

This would bring the South African public sector into line with recommendations in the United States and Europe, and align the public sector with the recommendations of the South African HIV Clinicians Society, which are already followed by most private sector providers.

Earlier treatment has the potential to reduce deaths and illness, but only if individuals with HIV infection are tested and then initiated on treatment before experiencing a serious CD4 cell decline.

At a symposium during the International AIDS Society conference in Cape Town last month Dr Francois Venter, President of the South African HIV Clinicians Society, warned that South Africa was still failing to initiate treatment promptly in people diagnosed with very low CD4 counts. He said that the health system needed to address this issue urgently, and that current debates about earlier treatment were simply ignoring this question.

In their analysis, Rochelle Walensky and colleagues in the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International group used a computer-based model of HIV disease progression and 2006 South African health system costs, together with WHO estimates of the number of people infected with HIV, in order to assess the potential increase in treatment costs and gains in life expectancy if treatment guidelines were to recommend earlier HIV treatment for South Africans.

The full methodology of the study can be reviewed in the published journal article, which is freely available online.

Patients in the hypothetical cohort were assumed to have a baseline CD4 count of 375, and their disease course over the next five years was projected, together with the costs of providing care to those who either became eligible for treatment under current South African guidelines, or who required medical care as a result of falling ill due to HIV infection, or who died.

The study assumed that in people who received treatment according to different potential guidelines, 84% would achieve a viral load below 50 copies/ml after 48 weeks, with a mean CD4 cell increase of 184 cells within the same period. Of those who failed first-line treatment, 71% would be assumed to achieve undetectable viral load. These estimates were based on data from South African cohorts already receiving treatment.

They found that over a five-year period 4.7 million people in South Africa would become eligible for treatment if the CD4 count threshold was raised to 350, of whom 1.2 million are already judged to be eligible, with a further 1.6 million becoming eligible within one year. In years three, four and five, another 1.9 million people would become eligible, indicating that the impact of changing the guidelines could be felt very quickly by the health system.

However, not all these patients are likely to be identified. The researchers analysed the impact of three different levels of diagnosis and linkage to care. If 10% of people eligible for treatment under new guidelines actually started treatment the effect on deaths and illness would be modest (just 25,000 fewer deaths over a five-year period), and taking into account the reduced cost of treating opportunistic infections, health spending would rise by $142 million over five years.

If fifty per cent of those eligible were diagnosed and started treatment, around 600,000 deaths would be averted (a one-third reduction), while health spending would rise by a net $1.1 billion over five years.

One hundred per cent success in diagnosing and treating everyone eligible would avert around 1.5 million deaths and lead to additional health expenditure of $1.5 billion over five years, even taking into account the money saved through illness averted.

Current debates over earlier treatment in resource-limited settings also focus on the long-term financial sustainability of treating larger numbers of patients. Cost-effectiveness analysis can also demonstrate how changes in life expectancy and health service utilisation in people who receive treatment translate into long-term costs, and the extent to which the investment is affordable within a country’s own resources.

In the case of South Africa, the CEPAC International analysis shows that earlier treatment would be affordable within the framework endorsed by the World Health Organization for measuring the cost-effectiveness of new health interventions in developing countries. The incremental cost-effectiveness ratio is the ratio of the cost per life year saved by the intervention to GDP per capita. Where the ratio is less than 1, the investment represents very good value for money, and where it is less than 3, the investment is cost-effective.

If starting treatment at a CD4 count of 350 results in a superior outcome to treatment at 250, as a recent trial in Haiti has shown, earlier treatment is highly cost-effective for South Africa, with an incremental cost-effectiveness ratio of $1200 per life year saved compared to starting treatment at a CD4 count of 250 (South African GDP in 2006 was $5400).

However treatment advocates have criticised current levels of funding in South Africa, and say they are inadequate to meet current needs, let alone expanded demand for treatment.

Reference

Walensky RP et al. When to start antiretroviral therapy in resource-limited settings. Ann Int Med 151: 157-166, 2009.

IRIS responsible for low number of deaths in patients starting HIV treatment in Uganda

By Michael Carter

Immune reconstitution inflammatory syndrome (IRIS) is not a significant cause of death in patients initiating antiretroviral therapy in Uganda, investigators report in the September 15^th edition of Clinical Infectious Diseases, now available online. In a retrospective study, the investigators found that although 17% of patients died within the first three years of starting HIV treatment, only a small proportion of these deaths were attributable to IRIS.

"In our experience, the contribution of IRIS…to early mortality is limited," comment the investigators.

HIV treatment has been shown to be as effective in resource-limited settings as it is in developed countries. However, significant early mortality and loss to follow-up has been observed in patients starting antiretroviral therapy in a number of African countries. There has been little research into the conditions causing these deaths, nor has the contribution of IRIS to early mortality been well characterised.

After an individual starts HIV treatment, their immune system starts to improve and this can unmask sub-clinical infections, sometimes resulting in an inflammatory response that can cause unpleasant symptoms, illness, and – in rare cases – death.

Investigators from Kampala therefore undertook a retrospective study lasting three years that recorded mortality rates and the cause of death in 559 individuals who started HIV treatment for the first time between 2004 and 2005.

These patients had a median age of 38 years and 69% were women. At the time HIV treatment was started, the patients had advanced HIV disease, with 89% having an AIDS diagnosis, and the median CD4 cell count was 98 cells/mm³.  A third of patients had a body mass index (BMI) of 18 kg/m² or below and 36% had a haemoglobin level below 11 g/dl.

A total of 99 patients died during the three years of the study. As with other studies investigating deaths amongst patients starting HIV treatment in Africa, most deaths (80; 14% of the entire cohort) occurred during the year after HIV treatment was started (with 54, 73% of deaths, in the first three months). There was a significant fall in mortality thereafter (15 deaths in the second year and four in the third).

This provided a mortality rate of 17.9 per 100 person years in the first year after starting HIV treatment, 2.3 per 100 person years in the second year, and 1.2 per 100 person years in the third year.

Of the 80 deaths in the first year, 69 (86%) were HIV-related, with four being attributed to IRIS. All four cases were "unmasking events" including one case each of Cryptococcus meningitis, extra-pulmonary tuberculosis (TB), TB meningitis and a tumour in the brain.

Overall, TB and Cryptococcus were the most common causes of death, and almost two-third of the deaths attributed to TB occurred in individuals who had symptoms of the infection before initiating antiretroviral therapy.

In multivariate analysis that controlled for possible confounding factors, the baseline characteristics associated with both all-cause and HIV-related death were a CD4 cell count below 25 cells/mm³, a BMI below 18 kg/m², and a haemoglobin level below 8 g/dl.

"We observed a high mortality rate of 14% during the first year of therapy, particularly during the first three months," write the investigators. They note that many of these deaths were due to infections and "may have been preventable if the infrastructure for opportunistic infection screening was routinely available and patients were given prophylaxis treatment prior to antiretroviral therapy initiation".

They emphasise that few deaths could be attributed to IRIS, supporting "the view that, in most cases, IRIS is a self-limited clinical entity".

Reference

Castelnuovo B et al. Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis 49 (online edition), 2009.

Further evidence of needless treatment switches in absence of viral load testing

By Keith Alcorn

Further evidence has emerged that a substantial proportion of switches to second-line treatment in a resource-limited setting, triggered in the absence of viral load testing, are unnecessary and result in an avoidable inflation in drug costs as people switch to more expensive regimens.

The findings, published in the August 1^st edition of Clinical Infectious Diseases, are likely to lend further support to calls for viral load testing to be made more accessible in resource-limited settings to confirm cases of suspected treatment failure.

In well-resourced settings everyone receiving treatment undergoes regular viral load testing in order to detect viral rebound and the failure of treatment. Switches to new treatment take place if viral rebound is detected, since the existing regimen becomes ineffective - due to drug resistance - once viral rebound occurs.

In resource-limited settings, viral load testing is rarely available due to cost and lack of well-equipped laboratories.

Failure of first-line treatment can be detected only by monitoring the CD4 count for declines or looking for the development of clinical symptoms.

It had been widely assumed that CD4 counting would chiefly tend to result in delayed identification of large numbers of cases of viral rebound because of the time lag between viral rebound and subsequent loss of CD4 cells due to uncontrolled viral replication. It was feared that the major consequence would be that large numbers of patients would develop high-level resistance to some second-line drugs.

However research presented at the Conference on Retroviruses and Opportunistic Infections in February this year showed that treatment switches on the basis of CD4 counts were often unnecessary, because the patients often continued to have undetectable viral load despite a decline in CD4 count. The researchers who conducted the study, in Uganda, suggested that infections such as malaria could be causing temporary dips in CD4 count.

They also estimated that in a cohort of 125 patients who experienced CD4 declines, 107 would have been switched to more expensive second-line treatment, adding $75,000 in drug costs to the treatment programme’s budget.

Now, research from western Kenya has confirmed that the Ugandan observation is a common problem.

AMPATH, a service collaboration between Moi University and local clinics in the Eldoret region of western Kenya, carried out viral load tests on all patients receiving ART who had suspected immunologic signs of treatment failure (a CD4 cell decrease of at least 25% over the previous six months).

The retrospective study identified 149 patients who had suspected treatment failure. Of these 58% turned out still to have a viral load below 400 copies, and even among the subset of 42 who experienced a CD4 decline of more than 50% during the previous six months, 43% (18) still had a viral load below 400 copies, indicating that there was no need to switch treatment in those cases.

Among those with a CD4 cell count above 200 at the time of suspected treatment failure, two-thirds (66%) had a viral load below 400 copies, compared to 41% of those with a CD4 count below 100 cells/mm³

When misclassification was analysed according to CD4 cell percentage rather than absolute number it became clear that the highest risk of 'true' treatment failure occurred in those with a CD4 cell percentage below 10 (65% had viral load above 400 copies, compared to only 26% of those with a CD4 percentage between 20 and 29).

Logistic regression analysis showed that misclassification of treatment failure was more likely if the patient had a higher CD4 count, a shorter duration of treatment and a smaller decline in CD4 cell percentage.

“In our study, there was a high likelihood of failure if the patient had a CD4 cell count of <200 cells/uL and was on therapy for > 20 months; there was a low likelihood of failure of therapy if the patient had a CD4 count of <300 and >200 cells/uL and was on therapy for <12 months.”

At AMPATH clinics, viral load testing is now mandatory in all cases of suspected treatment failure, but, say the authors: “We recognize the fact that … selective virological monitoring may not be instantly achievable. These results suggest the need to reconsider recommendations on immunological monitoring in resource-limited settings.”

They suggest that use of CD4 percentages may improve the sensitivity of immunological monitoring for treatment failure, but say that their findings need to evaluated in other populations before generalised conclusions can be drawn.

They also note that a previous simulation study carried out by Professor Andrew Phillips, which found only modest benefit to viral load and CD4 monitoring when compared to clinical monitoring in resource-limited settings with regard to cost-effectiveness, was based on the assumption that misclassification of treatment failure occurred in no more than 19% of cases.

They note several limitations: the fact that they could not verify viral load and CD4 measures; an average delay of two months between CD4 count and viral load test; and a lack of information about seasonal variations in CD4 count or changes in CD4 count due to intercurrent illnesses such as malaria.

In an accompanying editorial, doctors from Kenya and South Africa say: “In 2008 Smith and Schooley referred to managing ART without viral load as “running with scissors”. The emerging data…suggest it is more akin to throwing these programs onto drawn swords.”

“The time has come to work towards the progressive introduction of appropriate viral load monitoring technology in these programs with the same sense of urgency and commitment as the world approached ART access. To do less is to abandon the early success of ART to global collapse.”

Reference

Kantor R et al. Misclassification of first-line antiretroviral treatment failure based on immunological monitoring of HIV infection in resource-limited settings. Clin Infect Dis 49: 454-462, 2009.

Sawe FE, McIntyre JA. Monitoring antiretroviral therapy in resource-limited settings: time to avoid costly outcomes. Clin Infect Dis 49: 463-464, 2009.

d4T toxicity risk seven-fold higher when started with TB treatment

By Keith Alcorn

In patients receiving treatment for TB, initiating antiretroviral treatment that contains d4T results in a greatly increased risk of d4T-related toxicity during the first two months of antiretroviral treatment, US and South African researchers report. They say that all TB patients should be screened for pre-existing neuropathy before starting antiretroviral treatment, and that alternatives to d4T should be considered for antiretroviral treatment (ART) alongside TB treatment.

The findings are published in the June 1^st edition of the journal Clinical Infectious Diseases by researchers from the University of North Carolina and the Clinical HIV Research Unit of the University of the Witwatersrand, Johannesburg.

First-line antiretroviral treatment regimens containing d4T (stavudine) remain the norm in many developing countries due to the low cost of fixed-dose combinations containing the drug.

However d4T has a number of serious potential toxicities including lactic acidosis, peripheral neuropathy and lipoatrophy. Lactic acidosis is life-threatening if early symptoms are not recognised, and nerve damage caused by the drug may exacerbate existing neuropathy caused by HIV, leading to irreversible, extremely painful, harm to the nerves in the feet and legs.

For many patients receiving TB treatment there is a need to initiate antiretroviral treatment either concurrently or after TB treatment has begun, due to a low CD4 count and the consequent high risk of further opportunistic illnesses. In South Africa at least 20% of people with HIV who start a course of TB treatment need to initiate antiretroviral treatment at the same time as TB treatment.

But TB treatment contains isoniazid, a drug also known to cause peripheral neuropathy.

This study was designed to examine the extent to which d4T use alongside TB treatment results in termination of d4T use and substitution with another drug, the most concrete marker of unacceptable toxicity available for measurement.

The researchers reviewed data on 7066 patients who initiated d4T-containing ART at the Themba Lethu clinic in Johannesburg between April 2004 and March 2007. Of this group, 1845 patients received treatment for active TB that coincided with the period of d4T treatment: 1272 were already receiving TB treatment when they began ART, 224 commenced TB treatment at the same time as ART and 349 required TB treatment after beginning ART.

Of all patients who initiated ART, regardless of TB history, 3.7% died, 17.7% were lost to follow-up and 17.3% (1219) switched from d4T to another drug (of whom 69% changed only d4T). The overall rate of substitution was 12.1 per 100 person years of follow-up, with the rate of substitution increasing with the duration of d4T treatment from 7.9 per 100 person years in months zero to six, to 18.1 per 100 person years beyond year one.

The analysis controlled for the effects of sex, age, previous history of peripheral neuropathy or TB, haemoglobin, body mass index, CD4 count, WHO disease stage and stavudine dosage on the risk of switching from d4T during TB treatment.

Among patients who received TB treatment, hazard ratios for d4T substitution compared to those who did not receive TB treatment were:

	Adjusted hazard ratio of substituting d4T (95% confidence interval in brackets)
	Months 0-2	Months 3-6	After month 6
Already on TB treatment when d4T started	3.18  (1.82 – 5.56)	2.51 (1.77-3.54)	1.19 (0.94-1.52)
Started TB treatment and ART at the same time	6.6  (3.03 – 14.37)	1.88 (0.87- 4.09)	1.07 (0.65 – 1.76)
Started TB treatment more than 2 months after ART	0.99 (0.46 – 2.12)	1.18 (0.61 – 2.25)	0.87 (0.28 – 2.73)

Forty-three per cent of single-drug d4T substitutions were due to peripheral neuropathy, 24% to lipodystrophy and 20% to lactic acidosis or symptomatic hyperlactataemia. The dose of d4T received did not appear to affect the risk of substitution. Patients who received TB treatment were more likely to switch due to peripheral neuropathy.

“Our results show that initiation of TB treatment and stavudine-based HAART within a 2-week window puts patients at a nearly 7-fold increased risk of stavudine substitution in the first 2 months of HAART,” the authors note.

They suggest that their results may, if anything, understate the frequency with which concomitant d4T and TB treatment is leading to serious peripheral neuropathy, due to the fact that South African patients receive vitamin B6 alongside isoniazid to reduce the risk of peripheral neuropathy. In addition, patients with peripheral neuropathy often receive amtriptyline to manage neuropathic pain.

Without these interventions, severe peripheral neuropathy could lead even more frequently to switches from d4T, they say.

The study was unable to assess the extent to which milder peripheral neuropathy is emerging as a result of concomitant TB and d4T treatment.

In South Africa at least 20% of people with HIV who start a course of TB treatment need to initiate antiretroviral treatment while taking isoniazid, highlighting the public health relevance of these findings. The authors say that screening for peripheral neuropathy is important in all patients receiving TB treatment and d4T, especially those who start TB treatment and d4T within a short time of each other. In addition, “where additional antiretroviral drugs are available,” they say, ”we may wish to reconsider the use of stavudine in first-line HAART for patients with ongoing or concurrent initiation of TB treatment.”

Further information
NAM’s electronic newsletter HIV & AIDS Treatment in Practice recently published an extensive clinical review on the management of peripheral neuropathy in people with HIV in resource-limited settings. Download the pdf here.

Reference

Westreich D et al. Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy. Clin Infect Dis 48:

HIV treatment should be started earlier in resource-limited settings, shows trial

By Michael Carter

A major clinical trial has shown that HIV-positive patients in resource limited countries are more likely to survive and experience less HIV disease progression if they start taking antiretroviral therapy when their CD4 cell count is between 350 and 200 cells/mm³, rather than waiting until their CD4 cell count falls to below 200 cells/mm³.

Interim analysis of the CIPRA HT 001 study, a randomised control trial being conducted in Haiti, showed that patients who started HIV treatment before their immune system had been severely damaged had better outcomes.

A total of 816 adults with CD4 cell counts between 300 and 250 were recruited to the study. Half were randomised to start HIV treatment immediately, the others waiting until their immune systems had weakened further or they developed an AIDS-defining illness. The combination of antiretroviral drugs used in the study was efavirenz, 3TC and AZT.

The study’s independent safety and monitoring board recommended that the trial should be stopped early after a planned interim analysis showed that only six patients who started antiretroviral therapy when their CD4 cell count was between 350 – 200 cells/mm³ died. (Patient recruitment began in 2005 but the median duration of follow-up is unspecified in the NIAID press release).

This compared to 23 deaths amongst individuals who started treatment later. Furthermore, twice as many individuals in the deferred treatment arm of the study developed tuberculosis, an AIDS-defining illness, than did patients who started HIV treatment before their immune systems were severely damaged by the virus.

In the light of these findings, the study’s monitoring board recommended that it should be terminated immediately and that all individuals in the deferred treatment arm should be offered anti-HIV drugs.

HIV treatment guidelines in industrialised countries, such as the UK, recommend that HIV treatment should be started when an individual’s CD4 cell count is around 350 cells/mm³. Starting treatment at this time has been shown to reduce the risk of developing both HIV-related and non-HIV-related illnesses.

However, in resource limited settings, where only 30% of eligible individuals are currently taking anti-HIV drugs, treatment is not started until a patient’s CD4 cell count falls below 200 cells/mm³ or they develop AIDS. HIV treatment is often started by individuals when their immune systems are severely weakened, meaning that in many cases they die before they have the opportunity to benefit from HIV treatment.

“The public health community now has evidence from a randomized, controlled clinical trial – the gold standard – that starting antiretroviral therapy between 200 and 350 cells/mm³ in resource-limited settings yields better health outcomes than deferring treatment”, said Dr Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, who sponsored the study.

High prevalence of lipodystropy amongst patients taking HIV treatment in Senegal: d4T sole risk factor

By Michael Carter

Approximately a third of patients starting antiretroviral treatment in Senegal developed moderate to severe lipodystrophy, with the use of d4T being the sole risk factor, investigators report in a study published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

Lipodystrophy, a disturbance in the way the body stores and processes fat, was first widely described as a potential side-effect of antiretroviral therapy in 1998. Its prevalence and possible causes have been well-described in industrialised countries, but there is little information about lipodystrophy in resource-limited settings.

Investigators from Senegal undertook a study to describe the prevalence and causes of body fat changes in people with HIV, and to assess the impact of HIV treatment on lipids. Their study was case controlled, with 189 patients treated with anti-HIV drugs for between four and nine years matched with an HIV-negative individual of the same age and sex.

Changes in subcutaneous fat were assessed by the patients’ physicians, and blood samples were taken to measure the levels of blood fats. Measurements of skin folds were also taken, as were waist circumferences and waist-to-hip ratio.

The patients had a mean age of 42 years and 60% were women. The mean duration of HIV treatment was approximately five and a half years.

Earlier research has shown that the drugs most associated with fat loss (lipoatrophy) are d4T (stavudine, Zerit) and AZT (zidovudine, Retrovir). The HIV treatment of 83 patients in the Senegalese study involved AZT, with 63 individuals taking therapy that included d4T.

Moderate-to-severe lipodystrophy was diagnosed in 31% of patients. This included 13% of patients who had fat loss, 15% with fat gain, and 3% with a combination of both. Women were more likely than men to experience body fat changes after starting HIV treatment (34% vs 26%), but the difference was not statistically significant.

However, when the investigators employed a broader definition of lipodystrophy, they found that almost two-thirds of patients (65%) had developed body fat changes to same extent, ranging from mild to severe. This included 18% with fat loss, 36% with fat gain, and 12% with both.

Lipodystrophy was also assessed using body measurements. Using this method, 50% of patients were found to have developed body fat changes after starting HIV treatment.

The investigators also found that HIV-positive patients weighed significantly less than the controls (mean 64kg vs 72kg, p < 0.001), and had a significantly lower body mass index (mean 22.5kg/m² vs 25.7kg/m², p < 0.001). Hip circumference was also lower in HIV-positive individuals (95cm vs 101cm, p < 0.001). Furthermore, mid-upper arm circumference was significantly lower in patients with HIV (28cm vs 31cm, p < 0.001), as were skin fold measurements at all the assessed body sites (p < 0.001).

Unsurprisingly, metabolic abnormalities were more common amongst the HIV-positive patients than the controls. Levels of fasting glucose (mean 4.86 mmol/l vs 3.60 mmol/l, p < 0.0001) were higher in the individuals taking HIV treatment, as were triglycerides (mean 1.03 mmol/l vs 0.79 mmol/l, p = 0.007). Furthermore, HDL cholesterol was lower in the patients with HIV (mean 1.33 mmol/l vs 1.22mmol/l, p = 0.008).

Next the investigators compared the metabolic profiles of the HIV-positive patients with and without body fat changes. This showed that patients with such changes had significantly higher triglycerides (p = 0.0005), total cholesterol (p = 0.007) and LDL-cholesterol (p = 0.04).

Finally, the investigators conducted analyses to identify possible risk factors for the development of lipodystrophy. The only significant risk factor revealed by these was treatment with d4T (p < 0.01).

After a year of d4T treatment, 22% of patients had developed body fat changes, increasing to 40% after three years and 50% after five years of treatment with the drug.

“Thirty-one percent of subjects had moderate-severe lipodystrophy, and the only independent significant risk factor was stavudine therapy”, comment the investigators.

Reference

Mercier S et al. Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4-to 9-year antiretroviral therapy in Senegal: A case-control study. J. Acquir Immune Defic Syndr (online edition), 2009.

Weight gain predictive of survival in Cambodians and Kenyans taking antiretroviral therapy

By Kelly Safreed-Harmon

A study published in the April 27^th issue of AIDS indicates that weight gain may be a reliable predictor of survival in underweight men and women starting antiretroviral therapy. The finding has broad implications because resource limitations in many developing countries preclude the use of laboratory monitoring to assess treatment effectiveness. If healthcare providers have some other means of identifying which patients are responding poorly to antiretroviral regimens, they may be able to intervene before those patients become dangerously ill.

The cohort study analysed mortality rates six and twelve months after the initiation of antiretroviral therapy. Study participants were being treated in Médecins Sans Frontières (MSF) programmes in Phnom Penh, Cambodia and Homa Bay, Kenya. The most striking finding was that people who had an initial body mass index (BMI) score of 18.5 kg/m² or less and experienced weight gains of 10% or less during the first three months of antiretroviral therapy were far more likely to die within the next three months than people who had comparable initial BMI scores but experienced greater weight gains.

The study population was comprised of 2451 Cambodian adults and 2618 Kenyan adults. MSF followed World Health Organization (WHO) recommendations for initiating antiretroviral therapy: people offered antiretrovirals had either a WHO stage 4 condition, a WHO stage 3 condition with a CD4 cell count of less than 350 cells/mm³, or a CD4 cell count of less than 200 cells/mm³.

All antiretroviral regimens consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). In Cambodia, 51% of study participants received 3TC (lamivudine, Epivir), d4T (stavudine, Zerit), and nevirapine (Viramune), while 47% received 3TC, d4T, and efavirenz (Sustiva). In Kenya, 86% of people received the nevirapine-containing regimen, and 9% received the efavirenz-containing regimen.

The study evaluated the prognostic value of weight gain using four categories of initial BMI scores: ≤17 kg/m²; >17 to ≤18.5 kg/m²; >18.5 to ≤20 kg/m²; and >20 kg/m². Individuals in the first two categories are considered underweight by international standards.

Mortality was analysed in relation to three levels of BMI increase at three months and six months: ≤5%; >5% to ≤10%; and >10%. Weight gain was found to be predictive of survival for study participants with initial BMI scores in the lower two quartiles, i.e., those who were underweight. People with an initial BMI score of ≤18.5 kg/m² and weight gain of ≤5% had a mortality rate ratio (MRR) of 6.3 when compared to those in the same initial BMI category with weight gain of >10% (95% confidence interval [CI], 3.0 – 13.1).

The MRR for people with an initial BMI score of ≤18.5 kg/m² and weight gain of >5% to ≤10% was 3.4 when compared to those in the same initial BMI category with weight gain of >10% (95% CI, 1.4 – 8.3).

When the researchers compared the prognostic value of weight gain in men and women, they found no significant differences. Nor were there differences between Kenyans and Cambodians; between people who started antiretroviral therapy at different disease stages or CD4 count levels; or between people using different antiretroviral regimens. All of this indicates that tracking weight over time can be an effective strategy in a wide range of antiretroviral recipients.

Weight gain was not predictive of survival for people whose initial BMI score was higher than 18.5 kg/m². This somewhat lessens the value of weight monitoring as a clinical management tool. However, given that many people in resource-limited settings do not begin treatment until relatively late in the course of HIV disease, low BMI scores at treatment initiation are not uncommon. Forty-six percent of Cambodian study participants and almost forty percent of Kenyan study participants had BMI scores of 18.5 kg/m² or less.

“Weight gain can be of great use in resource-limited settings, especially when decentralization of HIV care is required and access to well-trained physicians is limited,” the authors conclude. They go on to note that three possible reasons for an HIV-positive person’s failure to put on weight after initiating antiretroviral therapy are poor medication adherence, opportunistic infections, and insufficient nutritional intake. They advise assessing adherence and providing adherence counselling as warranted.

The authors express particular concern about the importance of screening for tuberculosis (TB) in antiretroviral non-responders, noting, “The experience from MSF in five countries showed a high incidence of TB under [antiretroviral therapy], and TB remains a leading cause of death in resource-limited settings.”

The authors stress that identifying antiretroviral non-responders by tracking weight should only be regarded as an interim solution. “Our results should not be interpreted as advocacy for minimal care and monitoring of patients taking ART in developing countries,” they write. “CD4 cell count and viral load remain the gold standards for patient monitoring, and everything should be done to make these tests available in resource-limited settings.”

Reference

Madec Y et al. Weight gain at three months of antiretroviral therapy is strongly associated with survival: evidence from two developing countries. AIDS 23: 853–861, 2009.

ARV roll-out in Ethiopia has reduced adult AIDS deaths by 50% in capital

By John Owuor

The roll-out of antiretroviral therapy has led to a decline of about 50% in adult AIDS deaths in Ethiopia's capital, Addis Ababa, over a period of five years, according the findings of a study published in the February 20^th edition of the journal AIDS.

The effectiveness of antiretroviral roll-out in sub-Saharan Africa has been widely reported as encouraging despite persistent concerns about universal access and adherence. However, there are still only limited data on its effects at a population level on deaths.

In Ethiopia, antiretroviral treatment was made freely available in public hospitals from October 2005. The investigators carried out the current study to find out what effect the availability of antiretroviral treatment had had on AIDS-related mortality.

The researchers used data from burial surveillance records and 'verbal autopsy' interviews. Burial surveillance was implemented in all Addis Ababa cemeteries in 2001 and records about 20,000 deaths per year. The surveillance is undertaken by cemetery clerks who receive regular training. They record a lay report of the cause of death as narrated by close relatives or friends of the deceased and other demographic details.

Verbal autopsies are post-mortem interviews conducted by researchers with close relatives or caretakers, about the signs and symptoms they witnessed during the terminal illness of the deceased. Causes of death described in the interviews were then confirmed through physicians’ review.

Two different physicians reviewed the verbal autopsies to assign cause of death to the described symptoms. Whenever the assigned cause of death by two physicians did not match, a third physician was used to review the verbal autopsy questionnaire. The data used in the current study were derived from 413 cases involving individuals aged 20 to 64 years. Physicians assigned causes of death, classified as either AIDS or non-AIDS deaths.

Epidemiological modelling was used by the investigators to determine mortality trends in the study population.

The investigators then compared projected deaths with observed numbers from burial surveillance.

To determine possible averted AIDS-related deaths, the investigators compared the estimated with the implied numbers of AIDS deaths in population projections. They estimated HIV prevalence using UNAIDS estimation and projections package (EPP 2007).

Results showed that the ratio of observed over projected deaths in adults peaked in 2001. However, between 2001 and 2005 the ratios dropped by about 11% (from 1.92 to 1.71) for women and 20% for men (from 1.80 to 1.44).This was a period when patients part-paid for treatment. The researchers attributed this average AIDS mortality drop of about 15% to treatment effect and noted that the drop was higher in men than women partly because of sex imbalances in access to healthcare financing.

The results further showed that between 2005 and 2007, there was a decline of about 25% for women (from 1.71 to 1.28) and 21% for men (from 1.44 to 1.13). The investigators attributed this drop of over 40% to free treatment, suggesting that treatment cost is an important factor in the decline of AIDS deaths.

To confirm whether the trends noted above resulted from reduced AIDS mortality, the investigators turned to the findings from the lay reports. They found a decline from 8467 deaths in 2001 to 4230 in 2007 (about 50%). The study further found that the decline was greater between 2005 and 2007 when treatment was free.

The researchers noted that the decline observed took place during a period when mortality was supposed to be very high. HIV infections in Ethiopia peaked in the late 1990s, demonstrating the impact of treatment. Assuming that the burial surveillance coverage was 85%, the scientists estimated a reduction of about 56% in AIDS deaths by 2007.

The 56% decline compared favourably with findings from São Paulo in Brazil, which reported a decline in AIDS deaths of about 65% between 1995 and 2002, noted the investigators. They further compared their findings to a New York study which showed a higher decline (63% in two years).

The researchers said that their findings demonstrate the effectiveness of treatment coverage on averting deaths in early phases of HIV care (long-term impact is not yet known). For Ethiopia and similar settings, the researchers said that the immediate worry is about short-term mortality because treatment coverage is still at its infancy (only 2% of adult patients are on second-line regimens in Addis Ababa).

The researchers also noted that their findings raise questions about whether and how the decline in mortality can be sustained, and whether improvements in access to antiretrovirals alone can achieve this goal. More proactive attempts to diagnose people earlier and initiate treatment earlier may be necessary in order to reduce death rates further, given the continued high risk of death during the first year of antiretroviral treatment in those who start treatment at lower CD4 cell counts in sub-Saharan Africa.

The investigators acknowledged that, even though their study was based on epidemiological models, model-based and observational estimates can be very different. The findings might have been limited further by shortcomings of burial surveillance such as under-reporting, said the scientists.

However, for adaptability to similar settings, the investigators noted that burial surveillance is logistically simple to implement because it uses existing structures and is usable in settings with no population-based data.

Reference

Reniers G et al. Steep decline in population-level AIDS mortality following the introduction of antiretroviral therapy in Addis Ababa, Ethiopia. AIDS, 23:511-518, 2009.

TB and opportunistic infections

Isoniazid and ARVs reduce TB risk by 90% in two South African clinics

By Carole Leach-Lemens

Isoniazid preventive therapy (IPT) combined with antiretroviral therapy (ART) reduced the risk of developing active tuberculosis (TB) in people with HIV by almost 90% compared with no treatment, a South African study has shown. Use of both interventions had a significantly greater impact on TB incidence than either intervention used alone, according to findings reported in the March 13^th edition of AIDS.

The researchers suggest that the data from this prospective cohort study supports the need for the provision of IPT together with the roll-out of ARVs as a cheap and cost-effective strategy against TB.

TB remains the leading opportunistic infection and cause of death for people infected with HIV in resource-poor countries. The World Health Organization recommends IPT for people infected with HIV in high-prevalence countries, but few countries have this policy in place. Isoniazid is taken once a day, either in a six-month course of treatment, or indefinitely in some settings, and can be initiated before an individual qualifies for antiretroviral therapy.

Results of a recent study in Brazil showed that while IPT and ART used alone are effective against TB, the combination of the two offers significantly greater protection. In sub-Saharan Africa, where the incidence of TB is considerably higher, data of this kind are lacking.

From 1 June 2003 until 31 December 2007 a total of 3868 HIV-infected adults receiving primary HIV care at two clinics, one in a large urban setting, the Perinatal HIV Research Unit (PHRU) in Johannesburg, and Tintswalo Hospital in a remote rural area of Mpumalanga province, were followed.

Both sites offered IPT for six months. At PHRU it was given following a positive tuberculin skin test (TST), whereas at Tintswalo no test was given. A government decision to stop providing isoniazid tablets meant that few people were on IPT.

Government guidelines required the provision of ART on diagnosis with WHO stage 3 (pulmonary tuberculosis) or 4 (extra-pulmonary tuberculosis) disease or CD4 counts of <200 cells/mm³ and began at the PHRU in 2004 and from 2005 at Tintswalo.

A diagnosis of tuberculosis was the primary outcome irrespective of where the diagnosis took place. The primary exposures of interest were receipt of IPT and/or ART.

Follow-up time was divided into 4 exposure categories:

• Patients having received neither IPT nor ART
• Patients who received IPT but not ART
• Patients who received ART without prior IPT; and
• Patients on ART who had received IPT and then ART.

Follow-up time began with the patient’s baseline cohort visit and ended at the first incidence of tuberculosis or at the last recorded clinic visit.

Of the total 3868 of HIV-infected adults with a minimum of two data-collection visits, 282 were excluded from the analysis because of missing CD4 counts and a further 838 due to a history of tuberculosis or recent diagnosis. Of the remaining 2778 patients, 80% were female and 76% from the urban setting.

The overall tuberculosis incidence rate was 6.2/100 person-years. Factors that put patients at an increased risk for tuberculosis included being male, from a rural area, over 30 years of age and having a CD4 count of <100.

Tuberculosis incidence for treatment-naive patients was 7.1/100 person-years (95% CI 6.2 to 8.2) and in comparison decreased by 27% in those who only got IPT (IR=5.2/100 person-years; IRR=0.73; 95% CI 0.44), and by 35% in those receiving only ART (IR=4.6/100 person-years; IRR=0.65; 95% CI 0.46 to 0.91) and by 85% (IR=1.1/100 person-years; IRR=0.15; CI 0.004 to 0.85) in those who had received IPT before getting ART.

In the final adjusted model similar trends to the incidence rate ratios emerged. While IPT alone did not result in a statistically significant reduction in risk compared to treatment-naive patients after adjustment for CD4 counts and other variables, living in a rural area and a CD4 count of <100 were linked with an increased risk.

Despite concerns raised about the failure to detect active TB in people given isoniazid preventive therapy in high-burden settings, selection for isoniazid resistance as a result of single-drug prophylaxis has not been an issue in studies to date.

Several limitations are noted by the authors. As with other studies, adherence to IPT is an issue, with only 59% of patients receiving 6 months of IPT.

While the sample of patients receiving both IPT and ART is relatively small, the authors believe that since follow-up in all groups was at least one year the results are convincing.

The observational nature of the study raises the possibility for bias.

Adjustment for possible confounders eliminates the suggestion that stronger patients survived long enough to receive IPT and then ART according to the authors.

The authors conclude that their findings support widespread implementation of isoniazid preventive therapy prior to antiretroviral therapy in high-burden countries. They suggest that IPT be given prior to ART when CD4 counts are above 300 cells/mm³ to reduce the risk of early diagnosis with TB following ART initiation.

Reference

Golub JE et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS, 23:631-636, 2009.

New drug for MDR-TB does well in trial

By Michael Carter

TMC207 is a safe and effective drug for the treatment of multidrug-resistant tuberculosis (TB), the results of a randomised, placebo-controlled trial published in the June 4^th edition of the New England Journal of Medicine have shown. Patients who received the drug were significantly more likely to have a negative culture result after eight weeks than patients who received standard second-line TB treatment.

The author of an editorial accompanying the study describes the development of the drug as “an important advance in the chemotherapy of tuberculosis.”

In 2006, there were over 9 million cases of TB diagnosed around the world and 1.7 million deaths because of the infection. Many patients with TB are also infected with HIV, and the infection is the leading cause of death amongst HIV-positive individuals around the world.

Treatment for TB consists of therapy with multiple drugs for at least six months. Multidrug-resistant strains of the infection (MDR-TB) have emerged that are resistant to the key first-line anti-TB drugs isoniazid and rifampicin. Furthermore, some strains of the infection, known as extensively drug-resistant TB (XDR-TB) have evolved with resistance to second-line drugs as well.

TMC207 is an investigational drug that belongs to a class of agents known as diarylquinolines. Test tube studies demonstrated that it had considerable activity against drug-resistant TB.

Investigators designed a Phase II, placebo-controlled trial involving patients with newly diagnosed, sputum smear-positive MDR-TB to assess TMC207’s safety, side-effects, pharmacokinetics, and antibacterial action.

The study involved 47 hospitalised patients aged between 18 and 65 years in South Africa. All the patients received a five-drug combination for the treatment of MDR-TB.

They were randomised on an equal basis to also receive either TMC207 (400mg daily for two weeks, followed by 200mg three times a week for six weeks) or a placebo.

Most of the patients (74%) were male, 55% were black and 13% were HIV-positive. Adherence was good with 97% of doses taken in both arms of the study.

An identical proportion of patients in both arms (87%) completed the study. There were no premature discontinuations due to side-effects. The profile of side-effects was similar in the two arms of the study, however the TMC207-treated patients were more likely than those taking the placebo to report nausea (26% vs. 4%, p = 0.04).

The majority of patients achieved the target steady-state plasma concentration of 600 ng/ml throughout the study.

Sputum became smear-negative significantly faster in patients treated with TMC207 in addition to their background therapy than those receiving the placebo. A negative culture was achieved by 48% of patients receiving TMC207 compared to only 9% of those taking the placebo.

Rates of negative smears for acid-fast bacilli at week four of the study were 77% for the TMC207 group and 57% for those receiving the placebo. At week eight this had increased to 84% for the patients taking TMC207 and 68% for patients taking the placebo.

“Our data present evidence that TMC207, in combination with a five-drug second-line regimen, had an acceptable side-effect profile; reduced the time to sputum-culture conversion in patients with newly-diagnosed, smear-positive, multidrug-resistant tuberculosis; and significantly increased the proportion of patients with negative sputum cultures after 8 weeks”, comment the investigators.

The authors of the accompanying editorial believes that both the drug and trial are “very encouraging.” However, he believes that the use of TMC207 is likely to be restricted to second-line TB therapy. This is because the available safety data are limited and “urgently need to be expanded.” Furthermore, the drug is metabolised using the P450 pathway, as is the important anti-TB drug rifampicin, raising the possibility of a negative interaction between the two drugs. Interactions with antiretroviral drugs such as efavirenz and nevirapine, also processed through this pathway, will be investigated by the drug's developer, Tibotec, a Johnson & Johnson company.

References

Diacon AH et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 360: 2397-2405, 2009.

Barry CE. Unorthodox approach to the development of a new antituberculosis therapy. N Engl J Med 360: 2466-67, 2009.

Half a million deaths from cryptococcal meningitis a year in people with HIV

By John Owuor

Researchers have estimated that there were about one million infections and half a million deaths from HIV-related cryptococcal meningitis worldwide in 2006. The findings published in the February 20^th edition of the journal AIDS also show that sub-Saharan Africa had the highest global burden of cryptococcal meningitis among people living with HIV.

The scientists (led by Benjamin J Park of the US Centers for Disease Control) did the study because although cryptococcal meningitis is one of the most widely reported HIV-related opportunistic infections, the global burden is unknown.

In regions with higher HIV burdens, particularly sub-Saharan Africa, cryptococcal meningitis has been reported to be on the increase (more than any other type of meningitis).

Studies from Zimbabwe, Rwanda, Central African Republic, Kenya and Tanzania have all shown increased incidence of cryptococcal meningitis as an AIDS-defining illness and a leading cause of AIDS mortality. Away from Africa, similar reports have emerged from India, Thailand and Asia-Pacific (see the December 2007 edition of HATIP, a clinical review on meningitis, for more information).

The investigators said that understanding the burden of cryptococcal meningitis is an important public health goal that would enable adequate planning and prioritisation of resources to enable effective prevention of the disease.

The investigators carried out a systematic review of all available literature published in English after 1996. Articles were selected if they used prospective or retrospective cohort study design, reported incidence among people living with HIV (PLHIV) or reported results which could allow calculation of incidence among PLHIV. The researchers found 19 studies which met eligibility criteria.

The scientists used the 2007 United Nations Programme on HIV/AIDS (UNAIDS) estimates for prevalence in adults and children as the global HIV estimates. They used median incidence rates from available studies to estimate region-specific cryptococcal incidence. For those regions where data were not available, the investigators imputed the rates using medians from regions of geographic proximity and similar economic development level.

The researchers estimated the regional cryptococcal burdens by multiplying the median incidence rate by the 2007 UNAIDS population prevalence estimate for each region. They then got the sum of all regional estimates to get the global burden of cryptococcal meningitis.

Due to variations in regional mortalities, the investigators estimated the deaths by using case-fatality rates from clinical trials conducted in high- and middle-income countries. They also reviewed case series, surveillance reports and reports on outcomes of cryptococcal meningitis and consulted with clinical experts. The scientists assumed a ten-week case-fatality rate of 9% among infected people in high-income countries and 55% for middle- and low-income countries, except sub-Saharan Africa where the estimate was 70%.

The investigators found cryptococcal incidence ranged from 4% to 12% per year in the the reports. They had at least one eligible report per region except for Eastern Europe and Central Asia, North Africa and the Middle East, and the Caribbean. The incidence for Eastern Europe and Central Asia, and North Africa and Middle East were estimated at 1.7% per year (the same as East Asia). For the Caribbean, the researchers assumed an incidence of 3.4% per year (the same as Latin America).

The scientists estimated 957,900 (range 371,700 to 1.54 million) cases of cryptococcal meningitis in 2006. Sub-Saharan Africa had the highest numbers of infection (720,000; range 144,000 to 1.3 million) followed by South and South-East Asia (120,000; range 24,000 to 216,000). Oceania had the fewest estimates (100 cases) followed by Western and Central Europe (500 cases). The researchers said these estimates of both infections and deaths will be useful for public health efforts to prevent, diagnose and treat the disease.

The researchers further estimated about 624,725 (range 124,956 to 1.2 million) cryptococcal meningitis deaths in 2006. Again sub-Saharan Africa had the highest (504,000; range 100,800 to 907,200) and Oceania had the fewest (9) death estimates.

When the scientists compared the death estimates for sub-Saharan Africa with other diseases other than HIV, they found that cryptococcal deaths were higher than tuberculosis (350,000), which has received greater public health attention, and were closely comparable to the childhood cluster diseases combined (530, 000), diarrhoeal diseases (708,000) and malaria (1.1million).

The researchers acknowledged that their estimates were restricted by limited availability of studies and the limitations of the available studies themselves. They also noted that provider-based cohort studies may be limited by incomplete follow-ups.

However, they felt the estimates were fairly accurate (particularly for sub-Saharan Africa) because their estimates are consistent with possible calculations from HIV-cohort and natural history studies which have reported that about 13 to 44% of AIDS deaths in the region result from cryptococcal meningitis.

Although most of the estimates in their study were determined prior to antiretroviral roll-out efforts, the researchers said the expansion of treatment is not likely to impact on the global burden soon because access to treatment is not yet universal and in some cases (such as South Africa) the rates of cryptococcal meningitis have actually gone up despite increased access to treatment.

Acknowledging that access to treatment can substantially reduce the disease among PLHIV, the scientists noted that the introduction of antiretroviral therapy has led to a drop in incidence of cryptococcal meningitis mainly in North America and Western Europe.

The researchers said their findings emphasise the growing and future need for attention to the problem in regions with higher HIV burden. They suggest the expansion of accurate and simple to implement diagnostic technologies, further research into the disease and expansion of treatment options .

In his commentary, Thomas S. Harrison of St. George’s, University of London, acknowledged that, despite study biases, there is little doubt that HIV-related cryptococcal mortality in Africa has been underestimated over the years..

He further said that the current study is important in stressing the need to address the problem of cryptococcal disease. Apart from fluconazole prophylaxis, he suggested pre-emptive fluconazole therapy for those who screen positive for cryptococcal antigen before starting antiretroviral treatment, suggesting that such strategy would prevent one third of cases that present after starting antiretroviral therapy.

He concluded that many patients in Africa simply present too late for current antifungal therapy to be effective. He also called for efforts to facilitate earlier diagnosis and treatment and trials to compare amphotericin B-based and oral antifungal regimens as well as to determine the best time to start anti-HIV treatment for those diagnosed with cryptococcal infection.

References

Harrison TS The burden of HIV-associated cryptococcal disease (Editorial comment). AIDS, 23:531-532, 2009

Park BJ et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS, 23: 525-530, 2009

Screening for cryptococcal antigens in HIV-positive cohort shows benefits of targeted pre-emptive strategy

By Lesley Odendal

Screening for cryptococcal antigens in HIV-positive patients before the initiation of antiretroviral therapy (ART) is a highly effective way of identifying those at risk of developing cryptococcal meningitis, researchers from South Africa have found.

Cryptococcal meningitis is one of the leading causes of death in ART patients who die during the first year of treatment, accounting for up to 20% of all deaths.

The majority of patients at risk of cryptococcal meningitis have detectable Cryptococcus antigen more than three weeks prior to developing meningitis, so a screening test could prevent many cases if patients are then able to receive prompt preventive treatment with the anti-fungal drug fluconazole, or with amphotericin B if a lumbar puncture shows evidence of central nervous system involvement.

Fluconazole has been shown to protect against the development of cryptococcal meningitis in people with low CD4 counts, whether they are taking ART or not, a randomised study in Uganda has shown.

If antigenaemia is left untreated, clinical disease may develop. Once ART is initiated, rapid restoration of pathogen-specific immune responses may cause the unmasking of subclinical disease, or it is possible that ART could lead to the clearance of asymptomatic infection. Screening for cryptococcal antigens would allow clinicians to treat pre-emptively prior to initiation of ART, according to factors such as baseline CD4 cell count.

Researchers from the University of Cape Town and St George’s, University of London, investigated the value of cryptococcal antigen screening in identifying patients who subsequently developed cryptococcal meningitis after commencing antiretroviral therapy.

The retrospective study, published in the April 1^st 2009 issue of Clinical Infectious Diseases, found that of 707 HIV-positive ART-naive cohort patients tested for cryptococcal antigenemia, 7% were positive. 91% of these cases had a CD4 cell count below 100 cells/mm³. Cryptococcal antigenemia also remained a strong independent risk factor for death.

Patients who were cryptococcal antigen-positive were found to have lower baseline CD4 cell counts, were more likely to have a history of cryptococcal disease and were more likely to develop new cases of cryptococcal meningitis during ART. During the first year of ART, 28% of those who tested positive for cryptococcal antigens developed new or relapse cases of cryptococcal meningitis a median of 35 days after starting ART, while no cases developed in 661 patients with negative cryptococcal antigen test results during the first year of follow up.

If relapse cases were excluded, the researchers say, 98 patients would need to be screened in this cohort to identify one case, but if screening was restricted to those with a CD4 count below 100 cells/mm³, the number that would need to be screened to identify one case would fall to 52, with a cost per identified case of $206.

An analysis of those patients with lower baseline CD4 cell count (below 100 cells/mm³) showed that 13% had a positive cryptococcal antigen screening result.

Multivariate analysis showed that cryptococcal antigenaemia remained a strong independent risk factor for death even after adjustments for CD4 cell count, viral load, age and sex were made. 34% of those who tested antigen-positive died during the first year of ART, compared to only 11% of the antigen-negative patients. Once adjusted, the risk of death was 3.2 times greater in the antigen-positive patients than in the antigen-negative patients.

The antigen test used (Meridian Cryptococcal Latex Agglutination System) were found to be both highly sensitive and specific.

The researchers suggest that prospective studies to test the benefits of antigen-based screening need to be conducted, especially in relation to the use of fluconazole prophylaxis at lower antigen titres. Further research is also needed to determine whether lumbar puncture to determine central nervous system involvement is always necessary in antigenaemic patients.

Cryptococcal antigen screening for patients with a CD4 cell count below 100 cells/mm³ would allow for a targeted pre-emptive strategy, avoiding clinical disease and death, the researchers conclude.

Reference

Jarvis JN et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clinical Infectious Diseases. 48: 856-862, 2009.

HIV-positive Rwandan women have a high prevalence of high-risk cervical HPV infection

By Michael Carter

Many HIV-positive women in Rwanda are infected with strains of human papilloma virus associated with a high risk of cervical cancer, investigators report in an article published in the online edition of the Journal of Infectious Diseases. Their study also showed that women with cancer-associated strains of human papilloma virus who had a low CD4 cell count were more likely to have cancerous or pre-cancerous cell changes in the cervix.

Over 80% of cases of cervical cancer occur in resource-limited settings. There is little information about the characteristics of women who are infected with human papilloma virus. Such information is needed if appropriate screening and prevention services are to be provided.

Rwanda experienced a genocidal conflict in 1994, meaning that there is little recent information on the prevalence of either HIV or cervical infection with human papilloma virus. Studies before 1994 showed that cervical cancer was the most common malignancy amongst Rwandan women, accounting for 22% of all cancers. Furthermore, research undertaken in 1992-93 found that 24% of HIV-positive women in Rwanda had pre-cancerous cervical lesions.

Investigators therefore undertook a study to determine the prevalence and type of human papilloma virus infection in HIV-positive and HIV-negative women in Rwanda. The research was also designed to identify the factors associated with a risk of human papilloma virus infection.

A total of 647 HIV-positive and 188 HIV-negative women from the Rwanda Women’s Interassociation Study and Assessment (RWISA) were included in the research. The women were recruited to the study in 2005. All were aged over 25 years and were present in Rwanda during the 1994 genocide. The HIV-positive women were antiretroviral-naive, although women were eligible for recruitment to the study if they had taken single-dose nevirapine to prevent mother-to-child HIV transmission. Blood tests and cervical samples were obtained and the women completed questionnaires to determine their risk factors for infection with human papilloma virus.

Regardless of age, the prevalence of human papilloma virus was higher in HIV-positive than HIV-negative women (25-34 years, 75% vs 29%; 35-44 years, 64% vs 7%; 45-54 years, 57% vs 13% [all p < 0.001]; and 55 years and above, 38% vs 0%, p = 0.02).

Furthermore, HIV-positive women of all ages were also significantly more likely to be infected with strains of human papilloma virus associated with cervical cancer (25-34 years, 50% vs 15%; 35-44 years, 43% vs 7%; 45-54 years, 33% vs 5%; and 55 years and above, 13% vs. 0%, all p < 0.001).

The investigators then restricted their analyses to HIV-positive women. They found that women with a CD4 cell count below 200 cells/mm³ were significantly more likely to be infected with a strain of human papilloma virus, other than HPV-16, associated with cervical cancer (p = 0.004). Furthermore, women with a CD4 cell count below 200 cells/mm³ were more likely than women with a CD4 cell count above 350 cells/mm³ to be infected with multiple strains of human papilloma virus (48% vs 24%).

A large proportion of HIV-positive women with human papilloma virus infection had abnormal cervical cells.

Almost all (91%) women with a CD4 cell count below 200 cells/mm³ and abnormal cervical findings were infected with human papilloma virus. By contrast, 49% of women with a CD4 cell count above 350 cells/mm³ infected with human papilloma virus had normal cervical cytology. Similar trends were seen when the investigators restricted their analysis to cancer-associated strains of human papilloma virus.

Finally the investigators examined risk factors for infection with human papilloma virus. Compared to women with a CD4 cell count above 350 cells/mm

³ those with a CD4 cell count below 200 cells/mm³ (OR, 4.0; 95% CI, 2.4-6.6) and between 201-349 cells/mm³ (OR, 1.8; 95% CI, 1.1-2.7) were more likely to have the infection. Eating meat every week, an indicator of greater wealth, was also identified as a risk factor, as was a history of two or more gynaecological infections (OR, 2.1; 95% CI, 1.4-3.2).

“HIV-seropositive Rwandan women in our study had high prevalences of infection with HPV (69%), carcinogenic HPV (46%), and multiple HPV types (35%), which in turn were associated with higher risks of abnormal cervical cytology findings”, write the investigators.

Women who had been raped were slightly less likely to have human papilloma virus infection. The investigators note that this finding may seem “counterintuitive” but write “our data indicate that many women who experienced genocidal rape over ten years before the study were subsequently abstinent or had very few partners, thus limiting their exposure to new HPV infections.”

The investigators conclude, “in the past decade, significant strides have been made in the prevention, detection, and treatment of cervical cancer. With ongoing research and commitment from global policy makers, such services can be provided to…highest-risk populations.” They are hopeful that the results of their study “will help guide cervical cancer prevention strategies in Rwanda”.

Reference

Singh DK et al. Human papillomavirus infection and cervical cytology in HIV-infected and HIV-uninfected Rwandan women. J Infect Dis 199: 1-9, 2009.

Biomedical prevention

The perils of success - what if the new prevention methods work?

By Gus Cairns

Within a couple of years’ time, we may know if two crucial new HIV prevention approaches will work. If they do, what then? Who will pay for them, who will use them, and will their use have a positive or negative impact on the epidemic? A debate at the International AIDS Society (IAS) Conference in Cape Town in July, sponsored by the IAS and the AIDS Vaccine Advocacy Coalition (AVAC) looked at how to prepare for microbicides and pre-exposure prophylaxis (PrEP).

To remind you, a microbicide is a substance that can be incorporated into a lubricant, gel or barrier such as a diaphragm that will stop HIV transmission during sex. And PrEP is the concept of HIV-negative people taking anti-HIV drugs in advance of sex (or needle-sharing) to prevent HIV.

Over the next three years or so, crucial trials of these new prevention methods will announce their results. In 2010, we’ll have results from the biggest microbicide trial to date, the Microbicides Development Partnership trial of PRO2000 gel, followed by results from a US trial, too small to produce a definitive result, of PrEP in gay men.

By 2011 we’ll know about tenofovir PrEP in Thai drug users, tenofovir/FTC PrEP in South American gay men, and tenofovir gel as a microbicide in South Africa. 2012 will offer PrEP results from men and women in Africa, and from a comparison trial of tenofovir as a microbicide and PrEP. And 2013 will see the end of HPTN052, a lengthy trial aiming for a definitive answer on whether treating everyone with HIV would stop onward transmission.

New prevention methods in HIV have had setbacks in the last few years, after the Merck HIV vaccine and a microbicide (cellulose sulphate) actually increased the risk of acquiring HIV. But following a promising result for the microbicide PRO2000 announced earlier this year, prevention advocates are daring to believe that positive results could be on their way. UNAIDS’ chief epidemiologist, Catherine Hankins, commented: “I’ve got more of my chips down for PRO2000 than I did. We need to anticipate success and plan a very careful communication strategy.”

Hankins was speaking at an AIDS Vaccine Advocacy Coalition (AVAC) seminar, which preceded the recent IAS conference in Cape Town and brought together leaders in HIV prevention technologies.

Carl Dieffenbach, director of the AIDS Division of the US National Institute of Allergies and Infectious Diseases (NIAID) laid out an apparently straightforward development strategy.

“The first thing we have to do is to prove that these concepts work,” he said. “Then, with the current agents, we have to develop alternative dosing schedules using pharmacological data to maximise adherence.”

This refers to the fact that PrEP and microbicide trials have featured continuous use of the products to try to get the most convincing result. But no one expects this is how people will use PrEP, let alone a microbicide, in real life.

Dieffenbach added, “We need to engage our partners in social marketing programmes that are also pieces of operational research. How are we going to market these products?”

“We also need to keep working on new agents,” he said. This was echoed by Yasmin Halima, the new director of the Global Campaign for Microbicides, who said: “I am really worried about the lack of a drug pipeline for PrEP. If tenofovir doesn’t work, we’re stuffed.”

Others responded that the original question of ‘proof of concept’ was not a simple one. What level of efficacy would be regarded as a success? The PRO2000 trial was powered to demonstrate a protective effect of 30%: its consistent use protected only three out of ten people exposed to HIV. Most panel members said that if the second trial demonstrated this, it would not be enough efficacy to take the product forward.

What would be enough? A straw poll indicated that most audience members would be happy with efficacy of 40 to 60% (roughly comparable to male circumcision), but some would want the product to stop at least four out of five infections (80% efficacy, comparable with real-world condom use).

Sharon Hillier, Director of the Microbicides Trials Network, defined this as the problem of the ‘partial yes’. She foresaw that people would need to use a variety of different prevention methods, rather than putting all their faith in one.

“We need to identify approaches that are going to be used by a wide variety of people,” she said, “which they are going to want to use and have available. We need …funders … willing to buy them and regulators willing to register them. We need to make sure our successes are not just clinical.”

She criticised what she called the hitherto ‘siloised’ approach in the field, with PrEP and microbicide researchers not co-ordinating research, and rectal microbicide development only slowly being incorporated. “We will need all of these approaches,” she said.

Stephen Becker of the Bill and Melinda Gates Foundation, which has been one of the prime private-sector sponsors of new prevention technologies for HIV, was concerned about the slow progress: “We can’t wait until clinical proof of concept has occurred,” he said. We need to investigate delivery channels, how we engage with policy makers, and how we will market these approaches now.”

He reminded delegates that the current trials of such novel concepts were not sufficient for registration purposes by regulators such as the US Food and Drug Administration. Successful trials might require novel regulatory processes.

Catherine Hankins and other delegates contrasted PrEP with microbicides. Although complementary, they may have to be prescribed and marketed in very different ways. Prophylaxis pills would always have to be prescribed and countries would need to consider strategies for PrEP availability.

“If we are certain PrEP will work, we need to strengthen the knowledge of countries as to where their next 1000 HIV cases are going to come from. For whom would PrEP be a useful product? Which groups do I give it to and in what way? To sex workers in exchange for a monthly HIV test? To gay men in exchange for counselling?”

Some countries’ experience of HIV drug side-effects might make PrEP unpopular: “If you are going to introduce it in a country with widespread experience of lipodystrophy related to the use of d4T, you will find widespread resistance to it.”

In contrast, some delegates said that they suspected that if PrEP trials came up with a positive result, widely publicised, a black-market culture would start. Morenike Ukpong of Nigeria’s New HIV Vaccine and Microbicide Advocacy Society said: “I tell you, if a result is announced at a conference, PrEP will be on the market in 24 hours.”

Professor Helen Rees, Executive Director of the Reproductive Health and HIV Research Unit (RHRU) at the University of Witwatersrand in South Africa, agreed: “If PrEP works, we can’t waste a lot of time debating registration, because people will vote with their feet and start to use it. There are several studies in Africa to show that people are secretly taking it already, with findings of drug in people’s blood and so on.”

She emphasised the urgency and importance of finding out if PrEP was safe and whether it would differently affect populations excluded from the trials such as pregnant women and adolescents. Like many delegates, she also stressed the urgent need to do trials of intermittent use (a study comparing intermittent versus continuous use in heterosexual couples has just begun in Uganda).

With microbicides, the potential still exists, especially if PRO2000 produces a positive result, that they could eventually be sold over the counter.

Dr Francois Venter, also of the RHRU, described himself as a microbicide sceptic. Delegates should not dismiss the effect of the public’s perception of “a lot of failed trials – the field is vulnerable. We do need varied prevention approaches, but this is an expensive approach. There is a lot of rhetoric around about how women are dying and need protecting: they do, but I’m sceptical about how in a country like South Africa, you decide who is high risk enough to need it, and how you tell them that. How are you going to ensure that people who go home deciding to have sex that night will use a microbicide?”

Delegates answered by citing microbicide acceptability studies. These showed that people liked microbicides: for the first time, we have an HIV prevention intervention that could potentially make sex more rather than less enjoyable.

Sharon Hillier commented: “Maybe if they’re going to make sex fun, people who don’t consider themselves at risk and who wouldn’t take a medicine might use a microbicide.”

She said it was important to find out how people thought. For instance, in one trial in Uganda, the microbicide had an unexpected double effect: firstly, women said it made sex fun and then, because of that, their male partners were more faithful. When the trial stopped, their men started looking for other girls. “Prevention interventions may have completely unexpected additional positive and negative effects,” she said.

Nonetheless, Francois Venter maintained, it was going to be an extremely hard job persuading funders to pay for approaches with only partial efficacy. It’s not just about whether these interventions will work and can be promoted ethically; can cash-strapped health systems pay for them?

Dr Yogan Pillay, Director of Strategic Health at South Africa’s Health Ministry, agreed, commenting that it was challenging enough “pay[ing] for the cost of HIV treatment today and paying for TB and opportunistic infections too. Don’t ask me to be on a panel discussing paying for PrEP!”

Pillay and others drew parallels between the new technologies and circumcision. Three conclusive randomised, controlled trials showing that circumcision prevented about 60% of infections in men had not translated into national programmes.

Patrick Ndase, regional physician for the Ugandan PrEP trial, said that partial efficacy had been a stumbling block of circumcision programmes. “We need to do convincing modelling studies of efficacy and cost-effectiveness so that these options become really attractive to people who are already trying to fund HIV or TB treatment. We need to cost this approach before it comes to our doorstep.”

“We need to be deciding what language we need to use with the ministries and the funders that is going to make them decide to support an approach with 50% efficacy.”

Yasmin Halima said that this was why an ongoing development pipeline for biomedical prevention was so important: we would not, in all likelihood, be able to stop at the first approach licensed and say it was good enough. Jim Rooney of the tenofovir manufacturers Gilead agreed, saying his company was looking at approaches such as a long-term injectable formulation of their new HIV drug rilpivirine (TMC278).

Zeda Rosenberg, Director of the International Partnership for Microbicides, summed up the feeling of the meeting. “We’re used to scepticism,” she said. “The sceptics used to say ‘it won’t work and women won’t use it’. Now they say ‘You won’t be able to fund and deliver it to the people who need it’. That’s progress!”

References

AVAC and IAS. The Promise and Perils of ARV-Based Prevention: A Dialogue of Optimism & Informed Scepticism. Non-commercial satellite meeting, 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, July 2009. See www.ias2009.org/pag/PSession.aspx?s=2392

 Perreau M et al. Activation of a dendritic cell-T-cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells. Journal of Experimental Medicine 205(12): 2717-2725. 2009.

Mesquita PMMO. Disruption of the epithelial barrier by cellulose sulfate: development of a model to assess microbicide safety. Microbicides 2008 Conference, Delhi, abstract AO10-415, 2008.

Antidepressants

Drug	Therapeutic Dose Range	Major side effects/drug interactions
Buproprion	50 to 400mg; divided doses	Side effects include anxiety/psychosis/seizures. Potential for interactions with PIs/NNRTIs: No effect on PI levels but ritonavir-boosted PIs expected to decrease bupropion levels. Coadministration with Kaletra significantly reduced levels but dose should not exceed recommended dose because ritonavir both induces and inhibits CYP2B6 hepatic enzymes that metabolise bupropion.  Efavirenz decreases bupropion exposure by 55%
Venlafaxine	37.5 to 300mg	Withdrawal associated with GI distress, headaches, anxiety. Blood pressure elevations in hypertensive patients. Potential interaction with PIs/NNRTIs. Decreased indinavir exposure
Citalopram	10 to 60mg (SSRI)	Potential interactions with PIs/NNRTIs: Citalopram unlikely to affect other drugs concentrations, but ritonavir-boosted PIs may increase citalopram concentrations.
Sertraline	25 to 200mg (SSRI)	Potential interactions with PIs/NNRTIs. Ritonavir may increase levels.
Fluoxetine	10 to 80mg (SSRI)	Long half life Potential interaction with PIs except nelfinavir. Ritonavir may increase fluoxetine concentrations. Cardiac and neurological events have been reported when coadministered. A decrease in fluoxetine dose may be needed.
Paroxetine	10 to 50mg q hs (SSRI)	Most sedating SSRI anticholinergic, may cause withdrawal Potential interactions with PIs (except nelfinavir). Ritonavir may increase paroxetine concentrations
Fluvoxamine	25 to 300mg (SSRI)	(Mainly used for OCD) Potential for interactions with PIs/NNRTIs: A CYP3A4 inhibitor
Mirtazapine	15 to 45mg	Some risk of haematologic problems (agranulocytosis, neutropenia) Significant potential for interactions with strong CYP3A4 inhibitors. NNRTIs may reduce mirtazapine concentrations
Nefazodone	50 to 400mg	Warning of potential for hepatic toxicity/liver failure. Potential interactions with PIs/NNRTIs. Ritonavir: may increase nefazodone concentrations. Cardiac and neurological events have been reported when coadministered.
Nortriptyline	50–150 mg q hs	Potential interaction with PIs except nelfinavir. Ritonavir may increase nortriptyline levels
Desipramine	100–300 mg q hs	Potential interaction with PIs. Standard ritonavir doses increased desipramine exposure but nelfinavir & Kaletra had no effect
Imipramine	50–300 mg q hs	Potential interaction with PIs: Ritonavir may increase levels
Clomipramine	150–250 mg q hs	Potential interaction with PIs. Ritonavir or ritonavir boosted PIs may increase clomipramine concentrations
Doxepin	75–300 mg q hs	Potential interaction with PIs. Ritonavir or ritonavir boosted PIs may increase doxepin concentrations
Duloxetine	20-30 mg bid	Sometimes used for chronic pain/neuropathy

Abbreviations: SSRI-selective serotonin reuptake inhibitors, q hs (before sleep).