Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country, prospective cohort study

Abstract

Background: Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure.

Methods and findings: We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load >or=400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%-13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7-12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval.

Conclusions: Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy.

Figure 1. Interval between exposure to single-dose nevirapine and starting NNRTI-based antiretroviral therapy in the NNRTI Response Study—Zambia, Kenya, Thailand (2005 – 2008).

Figure 2. Study Schema for the NNRTI Response Study—Zambia, Kenya, Thailand (2005–2008).

Among the 779 women who completed 24 wk follow-up on NNRTI-based ART (excluding the three women who were temporarily off therapy), self-reported adherence over the five visits by week 24 was greater than 95% for 440 (95%) of 461 NVP-unexposed women and 300 (94%) of 318 NVP-exposed women (p = 0.5). Among the 724 women who completed 48 weeks on NNRTI-based ART, self-reported adherence over the two visits at weeks 36 and 48 was greater than 95% for 419 (97%) of 433 NVP-unexposed women and 280 (96%) of 291 NVP-exposed women (p = 0.7). f/u, follow-up; LTFU, lost to follow-up.

Figure 3. Time between exposure to single-dose NVP and starting antiretroviral therapy and the probability of treatment failure in the NNRTI Response Study—Zambia, Kenya, Thailand (2005–2008).

Locally weighted regression (LOESS) models of the risk of treatment failure as a function of the time interval between NVP ingestion and starting ART. The left panel defines treatment failure according to the study's primary definition; the right panel defines treatment failure according to a planned secondary definition (see Methods). The horizontal dotted line indicates the failure rate among the women who were not exposed to single-dose NVP. The individual plusses (+) indicated on each panel represent individual patients who were either failing (top) or not failing (bottom).