When the definition of treatment failure was narrowed to include only virologic outcomes (the “on treatment” analysis), we observed a similarly increased risk of virologic failure among women with shorter intervals between NVP exposure and starting NNRTI-based ART. In fact, by this secondary definition, the risk of failure was statistically evident even in those women starting NNRTI-based ART in our pre-defined category of 12 mo or more after exposure. It should be noted, however, that locally weighted regression analysis indicates a clear dose-response relationship between exposure interval and virologic failure, and that the increased risk of failure by either our primary or on-treatment failure definition is largely absent by 15 mo.

In 2004, Lallemant and colleagues reported on clinical outcomes of 269 Thai women who initiated NNRTI-based ART following participation in the Perinatal HIV Prevention Trial, where use of single-dose NVP was randomized [15]. At 6 mo after ART initiation, 96 (51%) of 188 NVP-exposed women had >50 virus copies/ml plasma compared to 13 (32%) of 41 women without prior exposure (p=0.03). In their study, the median time between delivery and ART initiation was short (6.1 mo), and the authors did not report comparisons of failure rates based upon interval between NVP exposure and starting ART. In a follow-up report presented in abstract form, the women were followed through 18 mo and no additional failures were observed in either group [23]. Thus, failure attributable to NVP exposure in their study appeared to manifest within the first 6 mo of therapy.

Working in Botswana, Lockman and colleagues in 2007 were the first to report that timing between NVP exposure and ART initiation might be an important predictor of subsequent virologic failure [17]. Like the Thai trial [15], participants in the Botswana study were randomized to single-dose NVP or placebo when they presented in labor. While NVP exposure was associated with increased risk of virologic failure at 6 mo (8.4% versus 5.0%; p=0.002), this risk was mainly attributable to recent exposure, defined as occurring within 6 mo of ART initiation. NVP-exposed women with greater exposure intervals appeared to have no additional risk of failure. This finding is consistent with observational studies in Zimbabwe [24], Côte d'Ivoire [25], Zambia [26],[27], and South Africa [28].

In this study, we also noted that the small group of women not virologically suppressed to <400 copies/ml at 24 wk, but who eventually achieved suppression at 48 wk with continued NNRTI-based therapy, contained a significantly greater proportion of women without prior single-dose NVP compared with those who did not achieve suppression by 48 wk. Although we cannot fully assess whether this finding might have resulted from differences in care between these two groups, it suggests that women with prior NVP exposure who do not achieve virologic suppression at 24 wk have a greater likelihood of remaining unsuppressed at 48 wk. This observation raises the possibility that clinicians should consider switching to second-line therapy for NVP-exposed women who do not achieve viral load suppression at 24 wk on NNRTI-based therapy.

Strengths of our study include its large cohort size, good follow-up rates, high reported adherence to treatment with correspondingly high virologic suppression, and inclusion of women with both short and long intervals between exposure to intrapartum NVP and starting ART. These characteristics of the study allowed a fairly nuanced analysis of the relationship between the exposure interval and risk of future virologic failure (Figure 3). In addition, the study's multi-country population and differing approaches to clinical HIV management support the external validity of our conclusions. The primary limitation of our study is that the exposure of interest—use of intrapartum NVP—was not randomized, leaving open the possibility that exposed and unexposed women may differ in some systematic way other than their single-dose NVP use. During the protocol planning process, we noted that NVP-unexposed women seeking care tended to have more advanced HIV disease than did exposed women. Even among women of similar CD4⁺ status, NVP-unexposed women had generally more advanced disease by WHO staging than did NVP-exposed women. Thus, we elected to group-match our enrollees on both CD4⁺ and WHO disease stage to mitigate this potential confounding. We decided not to use ultrasensitive viral load testing for patient management nor to categorize failure in our analysis for two reasons. First, the more sensitive viral load assay was not available at the African sites and would have required expatriation of study specimens, a practice that is increasingly discouraged by local authorities. Second, the less sensitive assay is the current standard for clinical practice in both African sites. We thus believed that use of a 400 copies/ml threshold would yield outcomes that reflected the realities of local clinical practice. Third, we followed women for 48 wk, and longer-term virologic response rates were not assessed. Finally, our results may not apply to women who receive a prophylactic “tail” of other drugs, such as ZDV/3TC [29] or single-dose tenofovir/emtricitabine [30] in order to reduce the emergence of single-dose NVP-related resistance.

Ever since the HIVNET 012 trial demonstrated its prophylactic efficacy [3], intrapartum NVP has been a nexus of controversy [31]–[33]. Perhaps the strongest opposition to single-dose NVP surrounds its potential to induce viral resistance and thereby adversely affect a mother's future treatment options. Fortunately, this report, along with others [5],[17],[24]–[27], provides some reassurance (Table 5). It is now evident that the risk of intrapartum NVP compromising a mother's future response to an NNRTI-containing regimen is confined mostly to women in whom ART will be needed within 12–15 mo of delivery. Where CD4⁺ testing is routinely available, programs could minimize the number of women who fall into this risk group by increasing the CD4⁺ threshold for starting ART in pregnancy to 350 cells/µl, as recommended in the 2006 WHO guidelines [29]. The benefit of this approach would be 2-fold. First, it would ensure that most women exposed to single-dose NVP would not need therapy for at least a year. Second, through the provision of suppressive therapy to precisely those women at highest transmission risk, it would prevent more perinatal HIV infections [29]. In the occasional circumstance where a woman did need therapy soon after single-dose NVP exposure, a protease inhibitor-containing regimen or a triple nucleoside regimen could be prescribed [34].