“All pregnant women eligible for antiretroviral therapy (ART) must have access to it, and countries must adopt more efficacious antiretroviral (ARV) regimens for preventing mother-to-child transmission (PMTCT) among pregnant women who do not yet require ART” — rather than simply using single dose nevirapine (sd-NVP) during labour, according to new guidelines issued this week by the World Health Organisation.
The ‘more efficacious’ regimen for PMTCT for pregnant HIV-infected women in resource-constrained settings who do not yet qualify for ART, consists of AZT from 28 weeks of pregnancy (or as soon as possible thereafter); during labour – AZT/3TC plus sd-NVP); and postpartum – AZT/3TC for seven days for women and sd-NVP and AZT for one week for infants. However, both ART and ARV regimens or is complicated significantly depending upon local constraints, when HIV test results become available for the pregnant woman and other maternal health matters (see Recommended ART and ARV prophylaxis regimens below).
But much more important than the precise ARV regimen used is the recognition by the guidelines that, to be most effective, PMTCT services must address maternal and child health holistically. These expanded PMTCT services, beginning with the routine HIV testing of all pregnant women and recent mothers, must be integrated into strengthened mother and child health (MCH) services and HIV programmes throughout the developing world in order to meet the goals of the recent Abuja Call to Action: “the elimination of HIV infection in infants and young children to pave the way towards an HIV-free and AIDS-free generation across the globe.”
Background
WHO first issued recommendations for the use of ARV drugs for PMTCT in 2000, and revised them in 2004 with the adoption of simplified and standardised regimens. However, the implementation of national PMTCT programmes has been slow, with less than 10% of pregnant women living with HIV having access to such services according to the 2006 UN Report on the Global AIDS Epidemic.
This is despite the fact that, in many resource constrained settings, PMTCT programmes have consisted of little more than screening pregnant women for HIV and offering sd-NVP to the mother during labour and to the child shortly after birth. But as capacity improves, programmes need to offer much more than that according to the new guidelines.
Since the original guidelines were published, considerable experience that has been accumulated on how best to scale up PMTCT and ART programmes. As a result, the revised guidelines now emphasise a more comprehensive approach to the prevention of HIV infection in infants and young children, which consists of four components:
1. primary prevention of HIV infection;
2. prevention of unintended pregnancies among women living with HIV;
3. prevention of HIV transmission from mothers living with HIV to their infants;
4. care, treatment and support for mothers living with HIV, their children and families.
Preserving the mother’s health
The woman’s health is the “overarching priority in decisions about ARV treatment during pregnancy.” The mother’s continued well-being is perhaps the most important determinant to the child’s survival as well.
According to the guidelines, every pregnant woman who tests HIV-positive must be assessed to determine whether she is eligible for ART, by staging her HIV disease according to WHO’s clinical staging system, and, where available, monitoring her CD4 cell counts. “Efforts should be made to include the CD4 cell count measurement in the essential package of care for pregnant women.” This is especially important for women without symptoms of disease (WHO stage I or II) who may however, have CD4 cell counts below 200. CD4 cell counts may also be an important factor in deciding which ART regimen to use.
WHO recommends that
- any woman with CD4 cell counts below 200 should be offered ART regardless of clinical stage
- women with stage III disease should be placed on ART if their CD4 cell counts are below 350
- all women with stage IV disease should be placed on ART irrespective of the CD4 cell count
also,
- where CD4 cell tests are not available, all women with stage III and IV disease should be put on ART.
In addition, women with HIV should be screened, and if necessary treated for TB infection or offered isoniazid prophylaxis, be given cotrimoxazole prophylaxis (if they are eligible), and provided with counselling and care relating to nutrition, infant feeding and psychosocial support. In areas where malaria transmission is common, women should have access to insecticide-treated nets, case management for malaria illness, if needed, or intermittent preventive treatment with at least three doses of sulfadoxine-pyrimethamine or daily cotrimoxazole prophylaxis.
Enhancing mother and child health services
The best way to mount this comprehensive attack upon MTCT is to integrate a set of key interventions into enhanced MCH systems to make sure “that women (i) have greater access to high-quality antenatal, labour, delivery and postpartum care, including counselling and support for infant feeding, and (ii) use existing services more frequently and earlier in pregnancy than is currently the case.”
The first key intervention, the routine offer of HIV testing as early in the pregnancy as possible, should be considered “an integral component of essential care during pregnancy.” Those who test negative should be provided with services to keep them that way, especially while they are pregnant or breastfeeding. For those women who test positive, other HIV care (including access to CD4 cell monitoring) and support services need to be integrated into MCH systems.
But getting women to utilise the MCH system is a challenge in many resource limited settings. For example, in some settings, many women do not access antenatal care or do not utilise delivery/maternity services. Thus, in order to make PMTCT programmes more effective, these MCH services must be improved, and”the sociocultural factors, conditions and circumstances that limit their uptake must be identified and addressed.
Recommended ART and ARV prophylaxis regimens
Since the previous WHO guidelines were published, more evidence has become available on the effectiveness of ART for PMTCT; the potential for resistance following sd-NVP prophylaxis among mothers and its implications for their future treatment options; better (though more complicated) ARV prophylaxis regimens; and the safety of specific ARVs in pregnant women. Furthermore, much more is known about how to use ARV in women with co-morbidities such as tuberculosis or severe anaemia.
As a result, the recommended ART or ARV prophylaxis varies significantly depending upon the situation.
ART
Nevirapine/AZT/3TC is generally the preferred regimen for pregnant women who need ART, and infants should be given AZT for 7 days after birth. However, there are some situations where this guidance is a bit tricky:
- Women with CD4 cell counts between 250-350. There are concerns about nevirapine-related toxicity, including hepatitis, in this population. The guidance recommends either using nevirapine and monitoring closely over the first twelve weeks, or using either an efavirenz-, a protease inhibitor- or a nucleoside-analogue based regimen, or delaying treatment until CD4 cells fall below 250 (using ARV prophylaxis for PMTCT). However, there are downsides to each alternative.
- Women with severe anaemia (Hb
- Women who require treatment for active TB. Since rifampicin and nevirapine can negatively interact, efavirenz-based regimens are the recommended first-line therapy for people with TB. However, since there are concerns about possible effects to the foetus, efavirenz-based ART should not be started until the second trimester of pregnancy. A nucleoside analogue-based regimen is also an alternative, though they are considered less potent.
- Women on methadone. Nevirapine can decrease blood levels of methadone so a 50–100% increases in the
daily methadone doses may be required to treat opiate withdrawal. Methadone could also increase AZT-related side effects.
- Women who are already on ART when they become pregnant should continue what they are doing, unless, they are still in their first trimester and on an efavirenz-based regimen. In such a case, nevirapine (at full dose) should be substituted for efavirenz with close monitoring of women who have CD4 cell counts above 250. Alternatively, a triple nucleoside or PI-based regimen could be used. However, the guidelines stress that efavirenz use in the first trimester is not an indication for abortion.
- When a woman receives less than four weeks of ART, four weeks of AZT is recommended for her infant rather than just one.
ARV prophylaxis
As already noted, the recommended regimen for PMTCT is:
- antepartum – AZT from 28 weeks of pregnancy (or as soon as possible thereafter)
- intrapartum – AZT/3TC plus sd-NVP); and
- postpartum – AZT/3TC for seven days for women and for infants sd-NVP (as soon as possible and up to 72 hours after birth) and AZT for one week
The length of time that a women receives AZT will depend upon when she is identified as being HIV-infected and guidance varies accordingly.
- If she receives at least four weeks of AZT, another recommendation (given a lower grading for a weaker evidence base) is that sd-NVP may be omitted in the mother (which may better preserve her future treatment options).
- If she receives less than four weeks of AZT before delivery, the infant’s AZT dose should be extended to four weeks.
- Whenever sd-NVP is used for PMTCT, the mother should always receive seven days of AZT/3TC to prevent resistance to nevirapine. If she receives sd-NVP during a false labour, she should not be given a second dose during labour as the second dose can greatly increase the likelihood of reistance.
- If delivery occurs less than two hours after taking sd-NVP, or the mother receives no ARVs for PMTCT prior delivery, the infant should be given sd-NVP immediately and AZT for four weeks.
The guidelines list the pros and cons of a number of alternative regimens as well as their evidence-base. In addition, the guidelines acknowledge that some settings “do not currently have the capacity to deliver the recommended prophylactic regimen to prevent MTCT, [and that] it may be necessary – as an absolute minimum – to implement the single-dose (mother and infant) nevirapine regimen.” However, this should be considered “a short-term interim measure while steps are being taken to enable more effective regimens to be delivered.”
Recommendations for women who have previously received sd-NVP for PMTCT
The guidelines stress that any woman who should be considered eligible for nevirapine or efavirenz-based antiretroviral therapy, although alternative regimens should perhaps be considered if ART is begun within six months of exposure.
Also, women who are pregnant can safely receive the same ARV regimen as they used for a previous pregnancy without loss of activity (although they should always be given the optimal recommended regimen).
Recommendations on ART during breastfeeding
Breastfeeding continues to be a major source of infection, undermining the use of PMTCT during pregnancy. At the same time, breastfeeding is usually the best option for feeding the child.
The use of antiretroviral drugs by breastfeeding could possibly reduce transmission, — and preliminary data show that this is indeed the case in women taking ART for their own health. Nonetheless, WHO believes that this is one area where the evidence base must be developed significantly before making any firm recommendations.
So the new guidelines state that the current WHO recommendations on breastfeeding is still in effect —irrespective of whether a woman is receiving ART.
The guidance states that when replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breastfeeding by mothers living with HIV is recommended, and that, otherwise, exclusive breastfeeding is recommended during the first months of life and should then be discontinued as soon as feasible.
Thus, when women are already on ART for their own health, the guidance states that they should continue taking their regimen, (and still wean their infants as soon as feasible), while for women who do not yet qualify for ART, taking ARVs simply to reduce transmission through breastfeeding is currently not recommended.
This in the area where the guidance is most likely to change, since recent studies suggest that infant HIV-free survival may be significantly higher in women on ART — and that finding safe and reliable replacement feeding can be virtually impossible in most resource-constrained settings.
The full guidelines document may be downloaded from the WHO website at http://www.who.int/hiv/pub/guidelines/pmtct/en/index.html