Kuhn L, Semrau K, Ramachandran S. Mortality and virologic outcomes after access to antiretroviral therapy among a cohort of HIV-infected women who received single-dose nevirapine in Lusaka, Zambia. Acquir Immune Defic Syndr. 2009 Sep;52(1):132-6.
Single-dose nevirapine has been used to prevent maternal transmission of HIV to infants. It also has been associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs),(1) the class of drugs used as first-line therapy in Zambia. Initiation of antiretroviral therapy (ART) with NNRTIs within six months of nevirapine plus zidovudine for prevention of mother-to-child transmission (PMTCT) has been associated with reduced efficacy.(2, 3) Use of NNRTIs more than six months following single-dose nevirapine was not associated with decreased efficacy as measured by clinical response and CD4 cell counts.(4) Given the limited sensitivity of these markers, use of viral load may identify decreased efficacy that was missed by previous measurements.
OBJECTIVE: To determine mortality among HIV-infected women who received single-dose nevirapine for PMTCT followed by ongoing maternal ART and to measure the association between virologic failure and the time between single-dose nevirapine and ART initiation in these women
Two antenatal clinics in Lusaka, Zambia
Women who had enrolled in a cohort study of infant feeding practices between May 2001 and September 2004
Mortality and HIV viral load
A total of 1378 women were enrolled in the infant feeding trial (randomized trial of long vs. short duration of breastfeeding) and followed for 24 months after delivery. All enrolled women had received single-dose nevirapine for PMTCT. Programs for HIV care were initiated in Lusaka in May 2004, and these programs were made available to the women in the infant feeding trial. Antiretroviral therapy became available in November 2004 at one site and in April 2005 at the other. At the time ART became available there were 418 women in follow-up and who were invited to enroll in this study. Women who had completed the infant feeding trial were contacted and offered entry into this study.
There were 335 women who were screened for ART eligibility. There were 269 who were eligible and 217 women initiated NNRTI-based ART.(4) Blood samples were obtained every three months for monitoring CD4 cells and every six months for later viral-load testing.
Mortality was measured only among women who survived more than six weeks beyond delivery and who were not known to have discontinued ART. Women who had not died by 24 months were censored. Survival among these women was compared to the women in the cohort before the availability of ART using the Kaplan Meier product limit test. Predictors of mortality were determined using Cox proportional hazards modeling.
Women who had higher parity, survival of the index child, Clinic A attendance, fewer missed appointments, HIV clinical stage ≥2, and disclosure of HIV status were more likely to participate than were other women in the infant feeding trial. An additional 199 women who had completed follow-up were located and screened: 107 were eligible for ART, and 86 initiated therapy.
Mortality among women on ART was reduced by 50% compared with women in the cohort prior to ART availability (relative hazard (RH) = 0.46, 95% confidence interval (CI): 0.23-0.91; P = 0.03) in the period once ART became available. Of 872 HIV-infected women in the cohort surviving and still in follow-up six weeks after delivery, 53 died before 24 months after delivery in the period before the availability of ART and 11 died in the period after. The probability of death by 12 months was 4.3% and by 24 months 10.3% in the pre-ART era. Reduction in mortality associated with access to ART remained significant (RH = 0.47, 95% CI: 0.23 to 0.93) after adjustment for CD4 count (RH = 0.57 per each 100 cells/mL increase, 95% CI: 0.45 to 0.71) and viral load (RH = 2.14 per each log10 copies/mL increase, 95% CI: 1.36 to 3.37) as measured during pregnancy.
There were 161 women exposed to single-dose nevirapine who remained on ART at six months. Of these, 70.8% achieved a viral load of <400 copies/mL and 40.4% a viral load of 50 copies/mL. Greater viral suppression was associated with longer duration between single-dose nevirapine and ART initiation. Of eight women exposed to single-dose nevirapine within six months of starting therapy, only three (37.5%) achieved a viral load of 400 copies/mL by six months after therapy compared with 59.1% of 22 women who started within six to 12 months after exposure, 72.1% of 61 who started within 12-24 months, and 77.1% of 70 who started more than 24 months after exposure (P = 0.01). Other factors associated with viral suppression were not having transmitted HIV to the infant and unemployment. The greater suppression achieved with longer time since single-dose nevirapine remained significant after controlling for these other factors.
NNRTI-based ART was found to be effective among women exposed to single-dose nevirapine for PMTCT, but efficacy was attenuated up to 12 months.
This was a good cohort study; one of its strengths was that the exposed and unexposed subjects came from the same original trial, thereby providing good comparability. Also, the outcome assessment was good and the degree of subjects lost to follow-up was acceptable, as was the duration of follow-up. It was not possible to assess the extent to which the study population was representative of pregnant women in Zambia or the degree of adherence to ART, factors that could have biased the findings.
This study provides data in support of ART for HIV-infected women who received single-dose nevirapine. It does appear that NNRTI-based ART is more efficacious the greater the time between single-dose nevirapine and ART initiation. The continued attenuation of viral load among women initiating ART 12 months after single-dose nevirapine demonstrates the duration of the resistance effect. Diagnosis of HIV during pregnancy and earlier initiation of maternal ART should be prioritized.
- Arrive E, Newell ML, Ekouevi DK, et al. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007;36:1009-21.
- Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004;351:229-40.
- Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007;356:135-47.
- Chi BH, Sinkala M, Stringer EM, et al. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS. 2007;21:957-64.