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Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero
Global Health Sciences Literature Digest
Published July 26, 2010
Journal Article

Lidstrom J, Li Q, Hoover DR, et al. Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero. AIDS. 2010 Jan 28;24(3):381-6.

In Context

Daily nevirapine (NVP) prophylaxis for infants 6-14 weeks of age decreases the risk of post-natal human immunodeficiency virus (HIV) transmission compared with single-dose NVP with or without one week of zidovudine (ZDV).(1, 2) Although extended prophylaxis should not be provided to infants infected in utero with HIV, prophylaxis may be initiated before HIV infection has been diagnosed. Infants infected in utero are more likely to develop NVP resistance than infants with intrapartum or postnatal HIV infection.(3)

Objective

To examine NVP resistance among infants infected in utero who received extended NVP or extended NVP plus ZDV

Setting

Blantyre, Malawi

Study Design

Secondary analysis of data obtained from a randomized clinical trial

Participants

Infants who acquired post-natal HIV infection, were born to women enrolled in the Post-Exposure Prophylaxis of Infants (PEPI)2 trial, and received extended NVP or extended NVP plus ZDV.

Outcome

NVP resistance

Methods

Plasma obtained at 14 weeks was genotyped using the ViroSwq HIV-1 genotyping system. Sequences were analyzed for mutations associated with NVP and ZDV resistance. Virus subtypes were determined by phenotypic analysis.

Results

There were 161 infants enrolled in the extended prophylaxis arm who became infected in utero: 79 in the NVP-only arm and 82 in the NVP plus ZDV arm. Plasma was available for 105 of these infants and genotyping was obtained for 88 (83.8%): 43 infants in the NVP arm and 45 infants in the NVP plus ZDV arm. Infant prophylaxis was stopped at a median of six weeks. All 88 infants had HIV subtype C.

The proportion of these 88 infants with one or more NVP resistance mutations detected in the 14-week sample was lower in the extended NVP plus ZDV arm than in the extended NVP arm (62.2% vs. 86.0%; P=0.015). This association remained after controlling for infant age when prophylaxis was discontinued, median maternal pre-NVP viral load, and administration of maternal single-dose NVP (odds ratio [OR] 4.76, 95% confidence interval (CI): 1.48-15.3, P=0.01). None of these variables were significantly associated with resistance.

Reduced risk of NVP resistance was observed in the subgroup of infants with extended NVP plus ZDV whose prophylaxis was stopped by six weeks (54.5% for extended NVP plus ZDV vs. 85.7% for extended NVP, P=0.007). Reduced risk was not seen in the subgroup of infants whose prophylaxis was continued after six weeks (83.3% for extended NVP plus ZDV vs. 87.5 for extended NVP, P=1.00).

None of the infants had ZDV resistance detected in the 14-week sample, consistent with the high genetic threshold for ZDV resistance.(3) However, two infants in the extended NVP arm and one infant in the extended NVP plus ZDV arm had one or more mutations associated with resistance to other nucleoside reverse transcriptase inhibitors. The mothers of these infants had initiated highly active antiretroviral therapy (HAART) for their own health prior to the 14-week visit.

Conclusions

Adding ZDV to extended NVP prophylaxis significantly reduces the risk of developing NVP resistance at 14 weeks if NVP was stopped at six weeks.

Quality Rating

This was a very good study. The data come from a well-designed and -conducted randomized clinical trial.

Programmatic Implications

This study highlights the importance of diagnosing HIV infection among exposed infants as close to the time of delivery as possible. It recommends continuing to closely monitor infants so prophylaxis can be discontinued as soon as infection is detected. These steps may help reduce the rate of NVP resistance among infants. It appears that the addition of ZDV to extended NVP prophylaxis may also contribute to reduced risk of developing NVP resistance. These factors should be considered in programs for preventing mother-to-child transmission.

References

  1. Six week Extended-Dose Nevirapine (SWEN) Study Team. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet 2008;372:300-13.
  2. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008;359:119-29.
  3. Church JD, Mwatha A, Bagenda D, et al. In utero HIV infection is associated with an increased risk of nevirapine resistance in Ugandan infants who were exposed to perinatal single dose nevirapine. AIDS Res Hum Retroviruses 2009;25:673-7.