Of 420 women screened, 177 were eligible for treatment and met inclusion criteria, and 166 (94%) were enrolled; 99 were sdNVP exposed, and 67 were sdNVP unexposed (). After we excluded women who did not initiate treatment or who had no follow-up data, 154 women were retained; 94 were sdNVP exposed, and 60 were sdNVP unexposed. Characteristics of the cohort are shown in . sdNVP-exposed and sdNVP-unexposed women had similar pretreatment CD4 cell counts and viral loads but differed in some characteristics (e.g., more sdNVP-exposed women were employed or had a refrigerator and television, and more sdNVP-unexposed women had household members living with HIV infection) ().
Flow chart of study population. NVP, nevirapine.
Pretreatment characteristics of 154 HIV-infected women who initiated therapy in Johannesburg, South Africa, by single-dose nevirapine (sdNVP) exposure status.
Initial and sustained virologic response
Almost all women achieved a viral load <50 copies/mL by week 24. The cumulative probability of viral suppression by week 24 was 0.975 among sdNVP-exposed women and 0.913 among sdNVP-unexposed women (P = .21); among women who experienced viral suppression, the time to suppression was similar (). Among sdNVP-exposed women, there was a borderline trend toward greater suppression if exposure had occurred 24–36 months previously (all of these women experienced viral suppression by month 6), compared with exposure 18–23 months previously (probability of suppression, 0.941) (P = .048).
Virologic and immunologic response to nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based therapy among 94 single-dose nevirapine (sdNVP)–exposed women and 60 sdNVP-unexposed women in Johannesburg, South Africa.
Among women who experienced viral suppression, there was no difference between sdNVP-exposed and sdNVP-unexposed women with regard to the risk of viral rebound by week 78 (P = .57). Of 88 sdNVP-exposed women who experienced viral suppression by week 24, 16 did not maintain suppression through week 78 (cumulative probability of rebound, 0.194); we censored data for 7 women who were lost to follow-up. Of 54 sdNVP-unexposed women who achieved viral suppression by week 36, 8 did not maintain suppression (cumulative probability of rebound, 0.151); we censored data for 1 woman who died during week 6 of severe toxicity complications (). Among sdNVP-exposed women, there was no trend between viral rebound and time after exposure. Interestingly, 5 of 16 women in the sdNVP-exposed group who experienced viral rebound subsequently had resuppression of the viral load without having changed their drug regimens after enhanced adherence support was provided. There were no differences between the groups with regard to immunologic response (). The risk of switching to a second-line treatment regimen was similar among NVP-exposed women (0.098; n = 8) and unexposed women (0.138; n = 8).
Pretreatment resistance mutations
K103N mutations were detected by AS-PCR in 10 (10.6%) of 94 sdNVP-exposed women before they commenced treatment; the mutations were detected in viral RNA for 10 women (10.6%) and in viral DNA for 3 women (3.2%). K103N mutations were also detected by AS-PCR in 9 (15.0%) of 60 sdNVP-unexposed women before treatment; they were detected in viral RNA for 8 women (13.3%) and in viral DNA for 3 women (5.0%). Samples with the highest percentages of K103N mutations detected by AS-PCR also had K103N mutations detected by population sequencing ().
Baseline resistance mutations in RNA and DNA, as detected by K103N allele–specific real-time PCR (AS-PCR) and population sequencing, among single-dose nevirapine (sdNVP)–exposed women and sdNVP-unexposed women.
Detection of K103N mutations by AS-PCR before treatment was a strong predictor of inadequate virologic response (). Eleven (57.9%) of 19 women who were either exposed or unexposed to sdNVP and who had K103N mutations detected by AS-PCR in either viral DNA or RNA had inadequate virologic response; 3 did not experience viral suppression (viral load, <50 copies/mL), and 8 experienced initial suppression followed by rebound (viral load, >400 copies/mL). Despite having K103N mutations detected before treatment, 7 women (36.8%) attained and sustained viral suppression; 1 was lost to follow-up. The cumulative probability of inadequate virologic response by week 78 was 0.609 among women with pretreatment K103N mutations and 0.151 among those without (P < .001).
Table 4 Risk of inadequate viral response to nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based therapy, by pretreatment detection of K103N mutations by allele-specific PCR in DNA and RNA specimens obtained from single-dose nevirapine (sdNVP)–exposed (more ...)
Of all 30 women who experienced an inadequate virologic response, 11 (36.7%) had K103N mutations detected before the commencement of treatment, and only 1 woman (3.3%), who had been exposed to sdNVP, had another major NNRTI-related mutation (Y181C) detected before treatment ().
Detection of resistance mutations in pretreatment and posttreatment plasma viral RNA specimens obtained from women with inadequate virologic responses.
Posttreatment resistance mutations
The earliest rebound samples (i.e., samples obtained at the time of or soonest after viral rebound) from all women with inadequate virologic response were sequenced (). Phylogenetic analysis revealed that all sequences were HIV-1 subtype C, and all samples from the same individual clustered together. The M184V mutation was more common among sdNVP-unexposed women than sdNVP-exposed women (9 of 12 vs. 6 of 18; P = .03), but the majority of all women had at least 1 NNRTI-associated mutation (13 of 18 sdNVP-exposed women vs. 10 of 12 sdNVP-unexposed women; P = .48).
Other predictors of virologic response
Viral suppression occurred more rapidly if the pretreatment viral load was <100,000 copies/mL (P < .001), but the proportion of women who achieved and sustained viral suppression by week 24 was the same. There was a nonsignificant association between the presence of the K103N mutation and lower CD4 cell counts and higher viral loads before treatment. The association between pretreatment presence of the K103N mutation and inadequate virologic response remained after adjustment for viral load and CD4 cell count. There continued to be no association between sdNVP exposure and inadequate virologic response after adjustment for pretreatment viral load, CD4 cell count, and K103N mutation presence. Adjustment for any of the variables that were found to differ between the sdNVP-exposed and sdNVP-unexposed groups () also did not affect this association. Failure to complete high school, presence of a child at home with HIV infection, and a lack of alcohol use were associated with inadequate viral response in univariate analyses. Inclusion of these factors in multivariable analysis did not change the association between sdNVP exposure status and treatment response.
Poor adherence to treatment, which was defined as returning >20% of pills for any of the 3 drugs or not returning pills, was assessed during the first 4 weeks after commencement of therapy, and treatment adherence rates did not differ between those with or without a later inadequate viral response (6.7% and 4.3% of these women, respectively, had poor adherence to treatment; P = .58). Poor adherence determined at the time of viral rebound or at the last visit if viral suppression occurred was significantly associated with inadequate viral response (42.1% of such women had poor adherence), compared with sustained viral suppression (20.9% of such women had poor adherence), among women who did not have K103N mutations detected before the commencement of treatment (P = .046). Adjustment for treatment adherence did not affect associations between exposure and virologic response.