Adding Combivir to single dose nevirapine for reduction of MTCT significantly reduces resistance
Polly Clayden, HIV i-Base
Perhaps the most important data from this meeting was an interim analysis from the currently ongoing TOPS (Treatment Options Preservation Study, aka BI 1100.1413) presented as a late breaker by James McIntyre from the University of Witwatersrand, Johannesburg, South Africa. McIntyre described these preliminary findings as “causing quite a stir, certainly among the Africans.” 
The study was originally planned to enrol 300 treatment naïve women and their infants and randomises mothers and babies to one of three arms. Arm1 involves single dose nevirapine given to mothers at onset of labour and single dose to the baby. Arm 2 involves single dose nevirapine to mother and baby plus 4 days twice daily Combivir (zidovudine/lamivudine combined pill) to mother and baby starting during labour and within 24-72 hours of birth respectively. Arm 3 involves single dose nevirapine to mother and baby plus 7 days twice daily Combivir. Enrolment and informed consent is at 34 weeks and women are randomised in labour.
The objective is to determine whether adding either 4 or 7 days Combivir can reduce the occurrence of nevirapine resistance in treatment naïve HIV-positive pregnant women, which would in turn preserve their future treatment options.
At the time of this interim analysis 156 women had entered the trial and six week resistance data was available for 61 (18, 20, 23 mothers in the single dose nevirapine, single dose nevirapine plus 4 days Combivir and single dose nevirapine plus 7 days Combivir arms respectively). The women in each study arm were well matched at baseline (see below). All women in this analysis had Clade-C HIV-1 infection.
Table 1: Baseline characteristics (median) for 61 mothers in interim analysis
|Prior live births||1.0||1.0||1.0|
|Baseline HIV RNA (log)||4.62||4.15||4.54|
|Baseline CD4 count||298||317||299|
|Resistance at 6 weeks||53%||5%||13%**|
|Resistance at any time||9/18 (50%)||1/20 (5%)||3/23 (13%)|
** p=0.001 single-dose NVP to pooled CBV arms
The investigators reported that at 2 weeks, 57.1% of the mothers receiving single dose nevirapine had detectable nevirapine resistance vs 0% in either of the other two arms. At 6 weeks resistance was detected in 53.3%, 5.00% and 13.6% of mothers receiving single dose nevirapine, single dose nevirapine plus 4 days Combivir and single dose nevirapine plus 7 days Combivir respectively. They noted that 9/18 (50%), 1/20 (5%) and 3/23 (13%) of mothers from the three groups had detectable resistance at any time after baseline. Overall resistance was detected in 50% receiving single dose nevirapine and in 9.3% of those receiving nevirapine plus Combivir (p=0.001). The most frequently detected mutations at any time were the K103N and the Y181C. There was no resistance to either zidovudine or lamivudine.
Following these dramatic results, enrolment into the single dose nevirapine arm of the study was closed in June 2004. McIntyre explained: “The trial was originally powered expecting 20% resistance in the nevirapine arm but emerging data, notably Neil Martinson‘s Retrovirus report of 39%, suggest the real figure is much higher…” The trial is continuing with adjusted sample size (150 mothers in each arm) to compare 4 and 7 days of Combivir as the optimal duration of this supplementation is uncertain. 
The trial was not powered to look at efficacy but of the 68 evaluable infants, four were infected through intrauterine transmission and one peri- or post-partum in the single dose nevirapine alone group.
Prior to the presentation of these results, on 14 July, the WHO announced the publication of their new guidelines on preventing mother to child transmission of HIV . Key recommendations include:
i) Treatment for maternal disease if indicated
ii) Prophylaxis for MTCT if treatment not indicated or not available and described as follows:
- Zidovudine from 28 weeks of pregnancy plus single-dose nevirapine during labour and single-dose nevirapine and one-week zidovudine for the infant;
- Alternative regimens based on zidovudine alone, short-course zidovudine + lamivudine or single-dose nevirapine alone are also recommended.
The guidelines also acknowledge the issue of resistance: “Drug resistance linked to short-course regimens to prevent mother to child transmission that do not fully suppress the virus has been known since early 2000…Since these women are all expected to eventually require treatment, potential resistance has become a far greater concern.” Continuing: “New data being presented at the International AIDS Conference in Bangkok may offer a way of reducing resistance observed shortly after delivery and needs to be further assessed before any recommendation can be made to use this approach in programmes to prevent mother to child transmission.”
Tim Farley, from the WHO Department of Reproductive Health and Research explained: “We now have access to the full (McIntyre) data, this will be reviewed by the panel and we expect to issue a statement to accompany the guidelines. This appears to be a promising approach but it may be premature to make recommendations based on these preliminary results. Results from a similar study are expected in the next few months – a sub-study of DITRAME Plus – that also covers the nevirapine tail with Combivir. Those data are currently being analysed.”
Additionally the WHO will soon initiate their own study providing comprehensive care to HIV-positive pregnant women and assessing the safety and effectiveness of using combination antiretrovirals to reduce the risk of HIV transmission to the infant. The overall objective is to optimise the use of ARVs during pregnancy, delivery and the postpartum period in order to (a) preserve the health of the mother, (b) minimise the risk of MTCT, and (c) provide a safe alternative to replacement feeding.
Both the risk of MTCT and the risk of maternal AIDS or death are strongly associated with the maternal stage of HIV-disease. Transmission and progression risks are increased for women in advanced stages of HIV disease as measured by clinical stage, CD4+ cells count or viral load.
- Over 500 CD4 cells/mm3 the risk of maternal progression to AIDS is low, currently recommended short-course MTCT prophylaxis ARV regimens are highly effective and the risk of transmission during breastfeeding is very low. Therefore, a short-course MTCT prophylaxis ARV regimen and counselling on safer infant feeding practices appears sufficient for this group of women.
- By contrast, women with CD4 counts below 200 cells/mm3 have a high risk of rapidly progressing to AIDS and death, and of transmitting HIV to their child despite the use of short-course MTCT-prophylaxis ARV regimens. WHO recommends that such women be treated with long-term Highly Active Antiretroviral Therapy (HAART) for their own health. Starting HAART during pregnancy or lactation is likely to substantially reduce the risk of MTCT.
- The situation for women with CD4 counts between 200 and 500 cells/mm3 is much less clear: although triple-ARV combinations may help reduce MTCT rates, the well-known toxicity of antiretrovirals may offset their efficacy in MTCT reduction. Furthermore, a CD4 cell count of 200-500 cells/mm3 is not currently an indication for HAART in developing countries. Further research is needed to define the best MTCT-prevention strategy for this group.
The project divides women into three groups according to their disease stage assessed during late pregnancy.
- Women with CD4 counts below 200 cells/mm3 or who are clinically ill will be offered triple-ARV therapy for their own health and continued through pregnancy, delivery and as long as required.
- Women with CD4 counts above 500 cells/mm3 will be offered a short-course regimen consisting of zidovudine starting from 34-36 weeks plus single-dose nevirapine during labour (and possibly cover the nevirapine tail following these data).
- Women with intermediate CD4 counts (in the range 200–500 cells/mm3) will be randomised to receive the short-course or the triple-combination regimen which will be continued up to six months provided the mother chooses to breastfeed her infant.
All infants will receive single-dose nevirapine within 72 hours of birth.
The health of all women will be carefully monitored and any mother whose health deteriorates and requires ARV treatment will be offered treatment during the project. In order to ensure sustainability of the programme beyond the life of the project, partnerships are being built with existing or developing access to treatment programmes so that long-term care of the participants and their families can be assured.
The project is a partnership between the local and national MTCT and ARV access programmes and international agencies working to improve maternal health and MTCT-prevention programmes. It is due to start shortly in three sites in Africa – Bobo Dioulasso (Burkina Faso), Mombasa (Kenya) and Nairobi (Kenya) –supported by grants from the French Agence Nationale de Recherche sur le SIDA (ANRS), the Belgian Technical Cooperation and WHO, and the USA Centers for Disease Control and Prevention and National Institutes of Health, and respectively. Additional funds are being sought by the project team in order to extend the project to Durban (South Africa), Kigali (Rwanda) and Moshi (Tanzania). When complete a total of 2400 women and their infants will have been treated by the programme.
The results from the project will be very important in determining how to balance the risk and benefits of combination ARVs in pregnant women, and are expected to influence international and national guidelines, as well as being implemented in public sector and private sector maternal health and MTCT-prevention programmes.
- McIntyre J, Martinson N, Boltz V et al. Addition of short course Combivir (CBV) to single dose Viramune (sdNVP) for prevention of mother-to-child transmission of HIV-1 can significantly decrease the subsequent development of maternal NNRTI-resistant virus. XV Intl AIDS Conference, Bangkok. LbOrB09.
- Martinson M, Morris L, Gray G et al. HIV resistance and transmission following single-dose nevirapine in a PMTCT cohort. 11th CROI, 8-11 February 2004, San Francisco. Abstract 38.
- Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: guidelines on care, treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. WHO document.