XIV International HIV Drug Resistance Workshop: preventing mother-to-child transmission

One message from PMTCT that has come through resoundingly clear is that administering a single dose of nevirapine (NVP, Viramune) can lead to drug resistance in both the mother and the child. This is because nevirapine may persist for up to 14-21 days in the mother’s body after a single dose. Dwindling drug levels create the ideal environment for the selection of drug-resistant viruses, which require only one mutation to occur for high-level nevirapine resistance to emerge. Although single dose nevirapine reduces the rate of HIV transmission, other strategies that supplement single dose nevirapine with zidovudine (Retrovir) or zidovudine/lamivudine result in lower rates of nevirapine resistance.

A second message is less emphatic but nevertheless an important development - if PMTCT is only about preventing HIV to the infant and not treating the mother, should we consider dosing only neonates for prevention? The data presented at this meeting seem to suggest so. In the meantime, methods for assessing patterns of resistance from PMTCT have been improved using refined techniques for resistance detection not only in blood but in breast milk where a significant number of transmissions occur.

Susan Eshleman from John Hopkins University in Baltimore showed that avoiding pre-delivery maternal NVP but providing only the infant with NVP and AZT can be effective. The study compared four arms:

• 1 - mother and infant given single dose NVP (the HIVNET 012 regimen)
• 2 - mother given single dose NVP and infants given single dose NVP and AZT BID for 7 days
• 3 - women presenting in late labour and given no NVP but infants receiving single dose NVP
• 4 - no NVP to women presenting in late labour but both receiving single dose NVP and AZT BID for 7 days

Resistance was measured 6-8 weeks following HIV infection in infants. Transmission rates reported were similar across all groups but lowest in Group 4 where NVP and AZT were administered only to the child. NVP resistance was also found to be lowest in this group compared to women and infants who had both received single dose NVP (87% versus 27%), with no detectable AZT resistance. This study confirms that combined NVP and short-course AZT may prove to be effective both as a prophylactic for HIV infection in the infant but also avoiding possible drug resistance in the mother. (1)

Nevirapine plus zidovudine/lamivudine (AZT/3TC, Combivir)

David Hall from Boehringer Ingelheim (BI) also confirmed that single dose NVP can be optimised by the addition of AZT/3TC. In their study in South Africa, they compared three arms:

• 1 - single dose NVP
• 2 - single dose NVP plus 4 days of AZT/3TC
• 3 - single dose NVP with 7 days CBV

300 mother-infant pairs are planned for this study of whom 226 have been enrolled. Arm 1 of the study was closed after an interim analysis. At weeks 2 and 6, resistance in the first group was higher (57%, 13% and 9% in the respective arms). No mutations associated with lamivudine or zidovudine were noted in either mother or child. Mutations noted in the mother were: K103N, Y188C, Y181C, V106M, A190G and V106A. In the infant cohort, resistance to single dose NVP was 78%, and 13% in the NVP plus 4 days of combivir. Surprisingly, no resistance was found in the women who received NVP plus 7 days AZT/3TC. Both the latter arms of the study remain open to date. Based on this study, the researchers conclude that the optimal duration of NVP with combined AZT/3TC needs to be established, although the efficacy of the latter regimen appears to be convincing.

A further analysis of this cohort from Sarah Palmer at HIV Drug Resistance Programme at the National Cancer Institute detected resistance using an allele-specific RT-PCR assay to quantify variants at 103N and 181C at very low frequencies (<0.1%). The study found that whilst these mutations were not detected by standard genotyping, which detects mutants that occur at minimum frequencies of 10-20% within a sample, they could be confirmed by the more sensitive method of analysis.

At week 6 for example, 75% of women receiving single dose NVP were found to have NNRTI resistance, significantly higher than the 50% reported by standard genotyping. Similarly, although no 103N or 181C mutations were found at week 6 in the combination arms, the allele-specific RT-PCR detected these mutations in 27% of women receiving NVP plus 4 days or 7 days Combivir at the same timeline. They did not detect a difference in the latter two arms, confirming that although combination therapy with NVP is effective the exact duration of treatment is yet to be defined.

One of the more interesting findings to emerge recently has been the understanding of viral shedding and resistance evolution in breast milk. Even with the prevention of transmission during labour, significant infection of around 15% can still occur during breastfeeding, with most infection taking place within the first six weeks post-partum. Therefore, understanding the pattern of drug resistant virus strains in breast milk remains crucially important. Dara Lehman from the Fred Hutchinson Cancer Research Center in Seattle reported from a study of 30 women in Nairobi who planned to breastfeed and had been treated with single dose NVP. Breast milk was sampled two to four times each week between the time of delivery and the week 6 post-partum and compared against breast milk viral loads from 30 women treated in the Thai-CDC cohort on short-course AZT. Using allele-specific PCR assay to detect K103N they found that 40% of women treated with NVP had the 103N mutation present in breast milk.

So two conclusions and one caution emerge from PMTCT studies to date. Firstly, if prevention of HIV is the goal, administering NVP plus supplementary therapy (AZT or AZT/3TC) in only the infant may suffice and safeguard mother from unnecessary exposure to drug resistance. Bob Grant from University California, San Francisco (UCSF) suggested that treatment given only to the infant was working because it functioned as a post-exposure prophylactic (PEP). This was further supported by Dan Kuritzkes from Harvard Medical School who noted that continued treatment given to the infant may serve as both PEP and pre-exposure prophylaxis (PREP) to a child who is consistently exposed to HIV through breastfeeding. Secondly therefore, having prevented HIV transmission during delivery the next goal should be to devise optimal strategies for reducing viral load in breast milk to reduce infection during weaning. Finally, we need to question whether, given the immense limitations of obtaining antiretroviral treatment in resource-limited countries, it is ethical to further limit these options by conferring resistance through monotherapy with a single dose of a drug with a known long intracellular half-life and a low genetic barrier? Can we ethically attempt suboptimal therapies even for prevention when the intervention may compromise further treatment, especially for those most vulnerable and least empowered? Importantly, as Ray Schinazi from Emory University noted, where is the logic in securing the baby’s survival when in the absence of treatment the mother will not be around to take care of the child?