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Twelve-month follow-up of six week extended dose nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count.
Global Health Sciences Literature Digest
Published May 12, 2011
Journal Article

Omer SB. Six Week Extended Dose Nevirapine (SWEN) Study Team. Twelve-month follow-up of six week extended dose nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count. AIDS. 2011 Mar 27;25(6):767-76.

In Context

An estimated 430,000 children were infected with HIV in 2008, nearly all of which were acquired through mother-to-child HIV transmission, with breastfeeding accounting for an estimated one-third of these new infections.(1,2) In resource limited settings, infants of HIV-infected mothers who are not breastfed are at high risk for morbidity and mortality which can outweigh the risk associated with HIV infection itself. Most HIV-infected women in these settings lack access to safe water and affordable replacement feeding, therefore, strategies to reduce HIV transmission during breastfeeding, now recommended to continue up to 12 months of age, are critical.(3)

Three randomized, controlled trials have shown the efficacy of extended infant nevirapine (NVP) prophylaxis for prevention of HIV transmission during breastfeeding.(4,5,6) ) The PEPI study in Malawi reported an over 60% reduction in HIV transmission at 14 weeks among infants receiving 14 weeks of prophylaxis with NVP or NVP and zidovudine (ZDV) (2.8%) compared with infants who received single-dose NVP plus one week of ZDV (8.4%); there were no significant differences in mortality. (4) In the Six-week Extended-Dose Nevirapine (SWEN) study, previously reported by the authors, receipt of six weeks of postnatal NVP significantly reduced HIV transmission at six weeks compared with infants receiving single dose NVP (2.5% vs. 5.3%) (RR 0.54, 95%CI 0.34-0.85), but did not significantly reduce the risk of HIV transmission at six months (9.0% vs. 6.9%; RR 0.80; 95%CI 0.58-1.10), The extended-dose regimen also significantly reduced the risk of death (RR 0.47; 95% CI 0.26-0.87) and death or HIV transmission at 6 months of age (RR 0.73; 95% CI 0.55-0.97) compared with the single-dose NVP.(5) The BAN trial compared six months of daily infant NVP prophylaxis and six months of maternal triple drug combination prophylaxis to a control intervention of single-dose NVP with one week of ZDV/3TC among women with CD4>250/µl and no antepartum antiretroviral treatment.(6) Transmission rates at 28 weeks postpartum among infants uninfected at age two weeks was 5.7% in the control group compared to 2.9% in the maternal prophylaxis (p=0.009) and 1.7% in the infant NVP arm (p<0.001).

Objective

To evaluate the risk of HIV transmission, mortality, and HIV transmission or death through 12 months of age among infants in the SWEN trials.

Setting

Antenatal and delivery facilities in Addis Ababa, Ethiopia, Pune, India, and Kampala, Uganda

Population

Infants born to HIV-infected women who chose to breastfeed

Study Design

Three separate, but coordinated, randomized controlled trials

Outcomes

Primary study outcome was HIV transmission at 12 months of age among infants who were HIV PCR negative at birth. Secondary outcomes were mortality and HIV transmission or death.

Methods

From 2001 to 2007, pregnant women who presented to antenatal and delivery facilities were screened for HIV infection. Those who were identified as HIV infected were offered standard of care for PMTCT and provided with infant feeding counseling as recommended by World Health Organization (WHO) guidelines. Infants of women who intended to breastfeed were eligible for enrollment.

The three randomized controlled trials in the three countries were initially designed as separate studies; however, the protocols and procedures were coordinated and the data on primary endpoints and key variables were collected in a similar manner using a single data management center to allow future comparisons of the trial results. Due to lower than expected enrollment, the independent data safety monitoring board (DSMB) recommended that data from all three sites be combined for the primary analysis. In Ethiopia and Uganda, the local standard of care for PMTCT included single-dose NVP. In India, the standard of care included maternal ZDV or other antiretroviral therapy in addition to single-dose NVP. In Ethiopia and Uganda, women receiving antiretroviral treatment were not eligible, but women who became eligible after enrollment were included in all countries. In India, women receiving treatment were eligible; however, only two were enrolled.

The control arm consisted of a single 200 mg dose of NVP for mothers self-administered at onset of labor and a 2 mg per kg oral dose of NVP to their newborns. The six week extended-dose NVP arm consisted of the single-dose regimen and 5 mg oral NVP daily to infants from 8 to 42 days of age. Infants in both groups received multivitamins from day 8 to day 42, with split doses used in the control arm to mimic the extended NVP dosing. This was not a blinded study. Study drugs in both arms were discontinued if an infant was found to be HIV PCR positive within six weeks of age. An infant was considered HIV-infected if two independent HIV PCR results were positive at separate study visits or an HIV PCR result was positive and there were no further samples.

Only infants who were HIV-negative at birth were included in the primary combined analysis of the three trials. The primary analysis was a modified intention-to-treat. Cox regression analysis was used to evaluate the effects of the intervention on the study outcomes by baseline maternal CD4 cell count, and was also used to evaluate the effects between the study intervention and HIV transmission by six weeks for the mortality outcome.

Results

A total of 1890 infants, 987 infants in the single-dose group and 903 infants in the extended-dose group were included in the modified intention-to-treat analysis. Of these infants, information about study outcomes at 12 months was available for 91% of infants in the single-dose group and 89% of infants in the extended dose group.

Receipt of extended-dose NVP did not significantly reduce HIV transmission at 12 months (8.9%) compared to infants who received the single-dose (10.4%; RR 0.87; 95%CI 0.65-1.15). Cumulative mortality at 12 months was half in the extended-dose group (1.9%) compared to the single-dose group (4.96%; RR 0.53; 95%CI: 0.32-0.85). There was no significant difference in HIV transmission or death at 12 months in the extended dose group compared to the single dose group (RR 0.79; 95%CI 0.61-1.01). When stratified by maternal CD4 count the reduction in risk of death (RR 0.38; 95%CI 0.17-0.84) and HIV transmission or death (RR 0.54; 95% CI 0.35-0.85) for the extended-dose group was statistically significant only for those infants of mothers with CD4 counts >350 cells/µl. There was no difference for infants who mothers had CD4 cell counts <200 or 201-350 cells/µl. In a stratified analysis by infant HIV infection status at six weeks, the extended-dose NVP group had significantly fewer deaths compared to the single-dose group among the uninfected infants (HR 0.38, 95%CI 0.17-0.86), but no difference in mortality was found among the infants who were infected by six weeks of age. The proportion of infants with serious adverse events (grade 3 and 4 events) was not significantly different between the two study groups, however, there were more infants with grade 4 adverse events in the single-dose arm compared to the extended-dose arm (17.5% vs. k13.6%, p=0.02).

Conclusions

There was significantly lower mortality in the extended-dose NVP group compared to the single-dose NVP group at 12 months. When stratified by maternal CD4 cell count, infants of mothers with CD4 cell count >350 cells/µl had a 62% reduction in mortality and 46% reduction in HIV transmission or death in the extended-dose vs. the single dose.

Study Quality

Limitations included lack of blinding for caregivers, study staff, and investigators. In addition, the HIV infection rates at birth were similar in both arms in India and Ethiopia, however, in Uganda, a larger number of infants were infected at birth in the extended-dose arm compared to the single-dose arm. In the modified intent to treat analysis, this would not affect the results as those who were HIV-infected at birth were excluded from the analysis. Otherwise, the study was of good quality.

Programmatic Implications

The most effective way to reduce mother-to-child transmission of HIV and to protect maternal health is to identify those women in need of antiretroviral treatment and initiate treatment during pregnancy. For women who do not require antiretroviral therapy for their own health, evidence from the SWEN, PEPI and BAN trials support either infant-only or maternal prophylaxis as effective approaches to reducing HIV transmission and improving HIV-free survival in breastfeeding populations. Duration of postnatal infant prophylaxis regimens in the studies varied from six weeks to six months. New WHO guidelines now recommend these two approaches of ARV prophylaxis to either the mother or infant during breastfeeding in areas where breastfeeding is determined to be the most appropriate choice of infant feeding for HIV-infected women.(7)

References

  1. UNAIDS. Report on the global AIDS epidemic 2010.
  2. WHO, UNICEF, UNAIDS, UNFPA. HIV transmission through breastfeeding. WHO 2007
  3. WHO, UNICEF, United National Population Fund, UNAIDS. Rapid advice: revised WHO principles and recommendations on infant feeding in the context of HIV-November 2009. Geneva: WHO 2009.
  4. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. NEJM 2008; 359:119-129.
  5. Bedri A, Gudetta B, Isehak A, et al. 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; 372:300-313.
  6. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. NEJM. 2010; 362:2271-81
  7. WHO. Rapid advice: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Geneva: WHO 2009