A single dose of tenofovir (Viread) and FTC (emtricitabine, Emtriva) taken in addition to single-dose nevirapine (Viramune) during labour can significantly reduce the risk of subsequent nevirapine resistance, a study published in The Lancet on November 7th shows.
The study was conducted in Zambia and included 397 HIV-positive pregnant women who were in good enough health not to require treatment with potent antiretroviral therapy. At week 32 of pregnancy, the women commenced a short-course of treatment with AZT (zidovudine, Retrovir), and during labour took a single dose of nevirapine. However, 198 of the women were randomised also to take a single dose of tenofovir and FTC during labour. The study showed that women who received tenofovir and FTC were significantly less likely to have resistance to nevirapine two and six weeks later.
An editorial accompanying the study says the addition of tenofovir and FTC is “a new, effective and feasible approach to reducing nevirapine resistance and one that should be seriously considered for implementation.”
The provision of a single dose of nevirapine to women in women in labour and their infants just after birth forms the basis of strategies to reduce mother-to-child transmission of HIV in many resource-limited settings.
But between 20% - 60% of women who receive single-dose nevirapine develop resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), the class of antiretrovirals to which nevirapine belongs. Nevirapine resistance has also been shown to develop when the drug is used alongside single-dose nucleoside reverse transcriptase inhibitor therapy consisting of AZT and 3TC (lamivudine, Epivir).
However, nevirapine resistance usually fades to levels undetectable by standard resistance tests within a year of exposure to single-dose nevirapine.
Although nevirapine resistance in women exposed at delivery has not been shown to compromise the subsequent effectiveness of triple drug NNRTI-based antiretroviral therapy for mothers when judged by the risk of developing clinical illness, several studies have shown that in the short-term at least, nevirapine resistance that subsequently disappears is nevertheless associated with a lower likelihood of viral load suppression below 400 copies/ml in those who start treatment within six months of labour. A similar response has not been seen in women who had a longer interval between labour and triple drug antiretroviral therapy, suggesting that eventually the mutations cease to matter.
Studies looking at nevirapine resistance after single-dose nevirapine are reviewed here.
Supporting single dose nevirapine with additional drugs
Tenofovir and FTC are antiretroviral drugs that are used worldwide. They both have a long half-life and drug regulatory authorities in the US have categorised them as “probably safe” during pregnancy.
Investigators wished to see if taking a single dose of these two drugs with nevirapine during labour reduced the risks of subsequent maternal NNRTI resistance. In theory, three drugs with similarly long half-lives should suppress viral load for longer, reducing the risk of resistance to nevirapine.
They therefore designed a study involving HIV-positive pregnant women using public sector health facilities in Lusaka, Zambia. The study ran between 2005 and early 2007.
All the women were given a single 200mg dose of nevirapine to take home. They were instructed to take this dose at the onset of labour. None of the women recruited to the study qualified for antiretroviral therapy under WHO antiretroviral treatment guidelines. However, as per the WHO HIV pregnancy guidelines, the women were given AZT which they were instructed to start taking during the 32nd week of pregnancy.
Half the women were then randomised to receive a single dose of oral tenofovir (300mg) and FTC (200mg) during labour.
Blood samples were obtained from the women two and six weeks after labour to test for the presence of drug resistance.
Testing of umbilical cord blood samples showed that 315 (82%) of women took their single-dose nevirapine. The proportion of women taking the drug did not differ between the treatment and control arm. The women who were randomised to take tenofovir/FTC took this treatment a mean of 3.5 hours before delivery.
Women who received tenofovir and FTC had a lower viral load two weeks after delivery. The investigators found that 63% of women who received these drugs had a viral load below 400 copies/ml compared to 53% of women in the control arm, a statistically significant difference (p = 0.043). Furthermore, amongst the women with detectable viral load at week two, it was lower in those who received tenofovir and FTC (mean 2500 copies/ml vs. 6300 copies/ml, p = 0.004).
Women who received tenofovir and FTC were much less likely to have NNRTI-resistant virus present at week two (RR, 0.27; 95% CI, 0 – 0.66) and week six (RR, 0.47; 95% CI, 0.29 – 0.76).
When the investigators analysed their results according to maternal viral load at the time of delivery, they found that the addition of tenofovir and FTC had the greatest benefit in terms of preventing NNRTI resistance for women whose viral load was 10,000 copies/ml or above (week two, p = 0.001; week six, p = 0.003).
NNRTI resistance mutations were found in 14% of women in the control arm, but just 3% of women in the tenofovir/FTC arm. No tenofovir, FTC or AZT resistance was detected.
The rate of mother-to-child transmission of HIV was 6% in the tenofovir/FTC arm and 8% in the control arm, a non-significant difference. Most of these transmissions occurred in the womb before AZT therapy was started.
No side-effects attributable to tenofovir or FTC were observed in either the mothers or their infants at weeks two and six. Creatinine, liver function and haemoglobin were comparable between the treatment and control arms.
“Addition of a single dose of combined tenofovir and emtricitabine to the antiretroviral prophylaxis regimen of short-course zidovudine and nevirapine effectively reduced the frequency of postpartum resistance to non-nucleoside reverse transcriptase inhibitors”, write the investigators.
The accompanying editorial is generally enthusiastic about the findings of the study. But it does point out that a number of questions about the safety and efficacy of this strategy remain unanswered. These include the risk of resistance for women with low viral loads (under 2000 copies/ml) and the risk of not only nevirapine but also tenofovir and FTC resistance for infants.
The authors of the editorial also question the circumstances in which tenofovir and FTC in addition to nevirapine might be used. They note, “combination three-drug prophylaxis might in the future be increasingly available to all pregnant HIV-1-infected women regardless of CD4 cell count, which would make single-dose nevirapine obsolete.”
Nevertheless they conclude that the study shows “that addition of single-dose tenofovir/emtricitabine to short-course [AZT] and single-dose nevirapine…is effective and feasible”.
Chi BH et al. Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. The Lancet (published online November 7th, 2007).
Lockman S et al. Reduction of HIV-1 drug resistance after intrapartum single-dose nevirapine The Lancet (published online November 7th, 2007).