Giving zidovudine and lamivudine for four days after birth of their babies to mothers who have received single dose nevirapine during labour significantly reduces the risk that they will develop resistance to nevirapine, and may preserve their future treatment options, a South African study has found.
There has been growing concern that resistance to nevirapine caused by single dose treatment designed to prevent mother to child transmission may lead to long-lasting resistance to the entire class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In developing countries treatment regimens for adults depend on NNRTIs which are cheaper and easier to take than protease inhibitors.
Recent Thai data have caused particular concern; a study published this week in the New England Journal of Medicine showed that mothers exposed to nevirapine during labour who started treatment for their own health had a significantly poorer virological response to treatment.
James Macintyre presented results of the TOPS study – Treatments Options Preservation Study – as a late breaker on Thursday at the Fifteenth International AIDS Conference in Bangkok.
Investigators conducted a prospective study involving 300 mother-infant pairs. The study had three treatment arms. Individuals were randomised to receive either single dose nevirapine, or single dose nevirapine plus four days of Combivir (zidovudine/lamivudine combination tablet), or single dose nevirapine plus seven days of Combivir.
Nevirapine was provided to mothers during labour and to infants within 24-72 hours of birth. Twice-daily Combivir was started in the mothers during labour and in their babies as soon as possible after birth.
Maternal resistance to non-nucleoside analogues (NNRTIs), and, where appropriate nucleoside analogues (NRTIs), was assessed two and six weeks after labour using genotypic resistance testing. HIV transmission from mother-to-baby was determined by using HIV DNA or RNA testing two and six weeks after birth.
Investigators presented data for the first 61 mothers with six weeks of follow-up and HIV sequencing. On entry to the study the median CD4 cell count was 318 cells/mm3 and median viral load was 32,600 copies/ml. All the women were infected with HIV subtype C.
HIV sequencing at weeks two and six showed that nine of the 18 women (50%) randomised to receive single dose nevirapine alone had NNRTI resistance compared to only one of the 20 (5%) women randomised to receive single dose nevirapine plus four days Combivir, and three of the 23 women (13%) treated with single dose nevirapine and seven days of Combivir.
The four day Combivir regimen reduced the risk of resistance fivefold in comparison to nevirapine alone. However Prof. Hoosen Coovadia warned, in a question from the audience, “we must be careful about expressing early data in percentage figures when looking at 20 patients, especially given the risk that it will be misused by newspapers [to draw inappropriate conclusions]”.
The most common NNRTI resistance-conferring mutations were K103N (eight instances), Y181C (seven cases), A190G (five women), Y188C (four individuals), V106A (detected in three women), and V106M (also observed in three women). No mutations conferring resistance to NRTIs were detected.
There were a total of 68 live births, and four of these infants were infected with HIV in the womb. In addition one baby was infected with HIV during or after birth.
No treatment-related severe adverse reactions were seen in either the mothers or their infants.
Dr Macintyre cautioned against over-interpretation of these results – they should not signal the end of programmes using nevirapine alone, he said.
“We must be very careful and responsible in what we say about nevirapine until we have more information from studies, since we have very limited options available.”
He was referring in particular to the South African Medicines Control Council decision to change the labeling of nevirapine in South Africa to warn that nevirapine is no longer recommended for sole use in prevention of mother to child transmission due to the risk of resistance, a decision which caused huge controversy at the International AIDS Conference.
Tim Farley of the World Health Organisation told the conference that it would issue technical guidance on the implications of new data from the conference as soon as possible, but that it was wrong to consider the situation an emergency, as some delegates had urged.
However, a second South African study carried out by Dr Lynn Morris and colleagues from the National Institute for Communicable Diseases in Johannesburg and presented in an earlier form at the Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco in February 2004 showed that 14% of mothers still had resistance mutations associated with nevirapine treatment six months after delivery (compared with 38% at six weeks). This prospective study, which recruited 623 women at two major centres in South Africa, reported data on 157 resistance tests carried out at month 6, and will continue to accumulate data for 24 months of follow-up. It will examine the impact of nevirapine treatment on response to treatment, response to nevirapine in a second pregnancy, and transmission of drug resistant virus to sexual partners.
McIntyre J et al. Addition of short course Combivir to single dose Viramune for prevention of mother-to-child transmission of HIV-1 can significantly decrease the subsequent development of maternal NNRTI-resistant virus. Fifteenth International AIDS Conference, Bangkok, late breaker abstract LbOrB09, 2004.