Study of MTCT programme finds resistance in women on two doses of monotherapy
Polly Clayden, HIV i-Base
At this conference around fifty lectures, poster presentations and posters addressed the subject of mother to child transmission (MTCT) in resource-poor settings. Of these, however, only two presented programmes to reduce the chances of these children losing their mothers before they even learn to walk.
3-fold increase in resistance with 2 NVP monotherapy doses
Of the many studies using nevirapine monotherapy to reduce MTCT, the most alarming findings were reported in a late breaker poster from John Sullivan . In this study resistance was determined in a group of women receiving two doses of nevirapine – the second dose to offer additional prophylaxis during breastfeeding – compared to a group receiving ZDV/3TC (for seven days).
Genotyping at four to six weeks postpartum detected resistance in 74/111 (67%) of the women receiving nevirapine – largely the K103N and Y181C mutations (62% and 45% respectively). Additionally of the 40/111 HIV-positive infants born to women receiving nevirapine, 21 (53%) had detectable nevirapine resistance mutations at four to six weeks of age. Evaluation of paired mother and infant data suggested that in some cases nevirapine resistant virus could have been transmitted by breastfeeding. No detectable resistance was observed in the 37 women receiving the ZVD/3TC.
Dr Sullivan concluded that as this two maternal dose nevirapine regimen conferred a three-fold increase in selection frequency compared to a single maternal dose – as reported in HIV NET 012  – he recommended that ‘These results favour the use of single dose nevirapine or the seven-day ZDV/3TC regimens for the prevention (note: A more accurate description would be ‘reduction’ given the transmission rate) of MTCT.’
Transmission rates in advanced disease
Further data was presented from the HIVNET 012 trial looking at transmission rates stratified by CD4 and viral load . At the lowest CD4 counts (<=200) at 18 months transmission rates for women receiving nevirapine were 31.6% (vs. 54.9% for ZDV). The investigators concluded that ‘These data support the efficacy of the simple NVP two dose peripartum regimen including women with the most advanced HIV disease.’ No data to evaluate selection of resistance or maternal health in the women receiving these interventions were presented with these findings.
And the good news…
A protocol design from the WHO to be implemented beginning later this year was presented as a poster . The objective of this study is to assess the acceptability, safety and efficacy of HAART (ZDV, 3TC, NVP) to reduce MTCT during pregnancy and to maintain the mothers’ own health. The women participating in the study will be stratified into three groups by CD4 count:
- CD4 counts below 200 cells/mm3 or AIDS symptoms: all women will be provided with HAART through pregnancy, delivery, the breastfeeding period and beyond, as they require antiretroviral therapy for the management of their own HIV disease
- CD4 counts in the range 200 – 500 cells/mm3: randomisation to either short-course ZDV prophylaxis, or HAART for up to six months post-partum provided that mothers continue to breastfeed
- CD4 counts above 500 cells/mm3: ZDV short-course prophylactic regimen
Additionally, all women will receive infant feeding counselling according to WHO recommendations. Women and their infants will be followed for twp years from delivery. It is important to note that ZDV+3TC+NVP combination for six months currently costs ~200 USD, similar to infant formula. HAART and treatment of OIs will be provided to all study volunteers with AIDS and to those that develop AIDS during the study. HAART will also be provided to women’s partners and children who require treatment. First results from this protocol will be presented in 2004.
Finally the headline grabbing new programme MTCT-Plus attracted much attention at this conference and was described in an oral presentation by Dr Wafaa El Sadr . This initiative is led by Allan Rosenfield, dean of the Mailman School of Public Health, who asked in Durban ‘Where’s the M in MTCT?’ in a pithy keynote session that began by questioning the ethics of ’…preventative therapy [that] uses the woman’s body to confer treatment to the child but gives no benefit to the woman’.
MTCT-Plus, a joint venture between the Mailman and a coalition of private foundations, acknowledges that, although programmes for the reduction of MTCT have expanded in resource-poor settings, primarily through the use of nevirapine, the women receive nothing for their own or their families’ diseases. They explained that, ‘…this has resulted in an ethical dilemma, inconceivable suffering with millions of orphans struggling to survive without their mothers’.
The programme will expand on existing MTCT sites – including those administered by UNICEF, Médecins Sans Frontières and the WHO – with the establishment of 10-12 MTCT Plus sites in the first phase. It will provide sites with the resources for building multidisciplinary care teams, antiretrovirals, diagnostics and treatment for OIs, thus facilitating a transition from antenatal to ongoing family care. In addition the programme will offer comprehensive patient education and adherence support.
The clinical protocols for this initiative are being finalised and the project is expected to be operational as soon as possible and will be a $100 million dollar plus initiative over the next five years.
With such exciting news on the horizon the only worry is, going back to Dr Rosenfield’s own concerns raised in Durban, that following interventions such as those described earlier ‘…we may be increasing viral resistance to treatment. One thing we don’t want to do with MTCT is make the woman’s condition worse while reducing transmission’ so that a woman could already be disadvantaged due to her treatment history before she even begins MTCT-Plus. What we would like to see are, as Dr El Sadaa described ‘…not only healthy children but mothers that can watch their children grow’.
- Sullivan J. South African Intrapartum Nevirapine Trial: Selection of resistance mutations. XIV International AIDS Conference, Barcelona 2002. Abstract LbPeB9024
- Jackson JB, Mracna M, Guay L et al. Selection of nevirapine resistance mutations in Ugandan women and infants receiving NVP prophylaxis to prevent HIV-1 vertical transmission Program and Abstracts XIII International AIDS Conference Durban 2000. Abstract LbOr13
- Nakabiito C, Guay L A, P Musoke P- Ef fect of Nevirapine (NVP) for perinatal HIV prevention appears strong among women with advanced disease: Subgroup analyses of HIVNET 012. Program and Abstracts XIV International AIDS Conference Barcelona 2002. Abstract TuOrB1174
- de Vincenzi I, Gaillard P, Farley T – Impact of Highly Active Anti-Retroviral Treatment (HAART) during pregnancy and breastfeeding on Mother-to-Child HIV Transmission (MTCT) and mother’s health in developing countries. Program and Abstracts XIV International AIDS Conference Barcelona 2002. Abstract WePeB5953
- Rosenfield A, El-Sadr W, Rabkin, M. The MTCT Plus Program: A major initiative to provide care and treatment to HIV-infected women and their children. Program and Abstracts XIV International AIDS Conference Barcelona 2002 Abstract MoPeB3244