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Addition of 7 days of zidovudine plus nevirapine to peripartum single-dose nevirapine effectively reduces nevirapine resistance postpartum in HIV-infected mothers in Malawi
Global Health Sciences Literature Digest
Published November 1, 2010
Journal Article

Farr Sl, Nelson JAE, Ng'ombe TJ, Kourtis AP, Chasela C, Johnson JA, Ksahuba ADM, Tegha GL, Wiener J, Eron JJ, Banda HN, Mpaso M, Lipscomb J, Matiki C, Fiscus SA, Jamieson DJ, van der Horst C, BAN Study Team. Addition of 7 days of zidovudine plus nevirapine to peripartum single-dose nevirapine effectively reduces nevirapine resistance postpartum in HIV-infected mothers in Malawi. J Acquire Immune Defic Syn. 2010; 54:515-23.

In Context

Nevirapine (NVP) is an effective antiretroviral drug for decreasing the risk of mother-to-child transmission (MTCT) of HIV. However, its long half-life and low threshold for resistance increase the risk of genotypic resistance in mothers who receive only a single dose for prevention of MTCT. A recent meta-analysis found that 36% (95% CI: 23, 51%) of mothers who received single-dose (sd) NVP in labor had NVP resistance 6-8 weeks postpartum and that 53% (95% CI: 38, 67%) of infants exposed to sdNVP and who subsequently became infected with HIV had genotypic resistance.(1) New regimens are needed that reduce the incidence of NVP resistance.

Objective

To evaluate if prophylaxing mothers and newborns with 7 days of zidovudine (AZT) + lamivudine (3TC) will decrease the postpartum emergence of NVP-resistance in HIV-infected mothers and infants.

Setting/Population

Pregnant HIV-infected women ≤30 weeks of gestation who were attending antenatal clinics in Lilongwe, Malawi. This is a sub-study of the Breastfeeding, Antiretrovirals and Nutrition (BAN) study.(2)

Methods

All women with CD4+ counts <250 cells/µL received antiretroviral therapy (ART); those with CD4+ counts ≥250 cells/µL were offered single-dose NVP at labor and an additional 7 days of twice daily AZT and 3TC. In the larger BAN study, mother-infant pairs were then randomized to receive 28 weeks of maternal and infant ART prophylaxis or placebo during the breastfeeding period. All participants for this sub-study came from the placebo arm. The comparison group for the sub-study was HIV-infected pregnant women who received NVP at the same clinic but who were not part of the BAN study (i.e., they did not receive 7 days of post-partum AZT+3TC). Serum and breast milk were tested for NPV, AZT and 3TC concentrations and genotypic resistance 2 and 6 weeks postpartum. Mutations were classified based on the Stanford University Drug Resistance Database.(3)

Results

One hundred thirty-two women received sdNVP+AZT+3TC, and 110 women received sdNVP alone; 66 (60%) of these 110 women had evaluable specimens. At 2 weeks postpartum, 4 women in the sdNVP+AZT+3TC group had significantly lower viral loads and a lower proportion with detectable NVP levels, although these differences disappeared by 6 weeks. At 2 weeks, 4 (10%) of 40 women in sdNVP+AZT+3TC group and 31 (74%) of 42 women in the sdNVP group had NVP resistance mutations; at 6 weeks the proportion with NVP mutations in the sdNVP group had fallen to 41 (64%) of 64 women. In multivariate analysis, addition of AZT+NVP to sdNVP was associated with an 82% reduction in the risk of NVP resistance at 6 weeks (RR=0.18, 95% CI: 0.10, 0.34). The most prevalent NVP resistance mutations in plasma were K103N/S, V106A/M, Y181C/I and Y188C/L/H. At 6 weeks, 2 additional women in the sdNVP+AZT+3TC group and 1 woman in the sdNVP group had developed a 3TC-resistance mutation (M184V). Seven women had sufficient viral loads to test for resistance in breast milk. None of 4 women in the sdNVP+AZT+3TC group had NVP resistance mutations compared to 3 of 3 in the sdNVP group. Fourteen infants were infected; 6 (7.1%, 95% CI: 5.1, 9.1%) of 515 infants in the overall BAN study who had received sdNVP+AZT+3TC group were infected compared to 8 (13.9%, 95% CI: 6.5, 24.7%) of 66 in the sdNVP alone group. In the 14 infected infants, 1 of 6 whose received sdNVP+AZT+3TC had NVP resistance compared to 3 (38%) of 8 who had received sdNVP alone.

Conclusions

A seven-day supplemental regimen of AZT+3TC given to postpartum women who had received sdNVP was independently associated with an 82% reduction in the risk of NVP resistance and a 49% reduction in the risk of MTCT.

Study Quality

This is an unconventional design for an experiment, essentially using contemporaneous controls not selected to participate in the trial. It is unclear why the controls were not selected for the program, which introduces the possibility of selection bias, although with biological endpoints, such as this study had, likely obviates it. A more conventional design would have been to randomize eligible women to the two arms. The larger issue is the that only 40 (30%) of the 132 women who participated in the sdNVP+AZT+3TC arm had specimens available for the main 2-week and 6-week NVP resistance outcomes, and only 42 (38%) of the 110 women in the sdNVP arm had specimens available for the 2-week outcome and 64 (58%) for the 6-week outcome. It is unclear what the effect of this under participation is or whether it leads to systematic error. Somewhat reassuring, however, is that the results of this study have also been found in five other studies that supplemented sdNVP with short courses of ART.(4, 5, 6, 7, 8)

Programmatic Implications

These findings suggest that NVP resistance in mothers and infected babies can be decreased with a 7-day regimen of AZT+3TC given to both mothers and babies. While the unconventional design of this study precludes complete agreement with these results, the fact that a South African study found a similar reduction in NVP resistance with a 7-day course of AZT+3TC strongly suggests that this regimen is effective. The new WHO PMTCT prevention guidelines have included 7 days of post-partum AZT+3TC as part of option A for preventing transmission from women with ≥350 CD4+ cells/µL.(4, 9)

References

  1. Arrive E, Chaix ML, Nerrienet E, et al. The TEmAA ANRS 12109 Phase II Trial, Step 1: tolerance and viral resistance after single-dose nevirapine and short-course of tenofovir disoproxil fumarate and emtricitabine to prevent mother-to-child transmission of HIV-1 [Abstract]. 15th Conference on Retrovirals and Opportunistic Infections; Boston, MA; February 4, 2008.
  2. Van der Horst C, Chasela C, Ahmed Y, et al. Modifications of a large HIV prevention clinical trial to fit changing realities: A case study of the Breastfeeding, Antiretroviral, and Nutrition (BAN) protocol in Lilongwe, Malawi. Contemp Clin Trials. 2009; 30:24-33.
  3. Stanford University Drug Resistance Database.
  4. McIntyre JA, Hopley M, Moodley D, et al. Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial. PLoS Med. 2009; 6:e1000172.
  5. Chaix ML, Ekouevi DK, Rouet F, et al. Low risk of nevirapine resistance mutations in the prevention of mother-to-child transmission of HIV-1: Agence Nationale de Recherches sur le SIDA Ditrame Plus Abidjan, Cote d'Ivoire. J Infect Dis. 2006; 193:482-487.
  6. Chi BH, Sinkala M, Mbewe F, 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. Lancet. 2007; 370:1698-1705.
  7. Lallemant M, Jourdain G, Ngo-Giang-Huong N, et al. Efficacy and safety of 1-moth post-partum zidovudine and didanosine to prevent HIV-1 nevirapine resistance mutations following intrapartum single-dose nevirapine [Abstract]. 16th Conference on Retroviruses and Opportunistic Infections; San Francisco, CA; February 10, 2009.
  8. Van Dyke R, Jourdain G, Shapiro D, et al. A Phase II Study of the incidence of nevirapine resistance mutations in HIV-infected Thai women receiving a single intrapartum dose of NVP followed by a postpartum tail of ZDV/ddl or ZDV/ddl/LPV/r: IMPAACT P1032 [Abstract]. 16th Conference on Retroviruses and Opportunistic Infections; San Francisco, CA; February 10, 2009.
  9. WHO. Rapid advice: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Geneva: World Health Organization, 2009.