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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
Global Health Sciences Literature Digest
Published August 30, 2010
Journal Article

Stringer JSA, McConnell MS, Kiarie J, et al. 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. PLoS Med. 2010 Feb 16;7(2):e1000233.

In Context

Single-dose nevirapine (SD NVP) is routinely provided to HIV-infected pregnant women to prevent perinatal transmission. Thirty percent of women who receive NVP, either alone or as part of a non-suppressive regimen, will develop high-level drug resistance to antiretroviral therapy (ART) with non-nucleoside reverse transcriptase inhibitors (NNRTIs).(1) Although most resistance wanes over time,(2, 3) there is evidence that low-level resistance persists(4) and draws into question the effectiveness of NNRTI-based regimens in women previously exposed to SD NVP.


To evaluate the effectiveness of NNRTI-based regimens in women exposed to SD NVP and to determine an optimal time to initiate NNRTI-based treatment


Five public clinics in Lusaka, Zambia; Nairobi, Kenya; and Bangkok, Thailand

Study Design

Prospective observational non-inferiority cohort


Non-pregnant women aged 18 years and older, who met the clinical criteria of each country for ART initiation, who were initiating ART with an NNRTI regimen, and who had not received ART other than as prophylaxis against perinatal HIV transmission


Virologic failure


Women initiating ART at study sites were enrolled. Exposure dates for NVP were determined using a number of factors, including review of labor and delivery records and verbal confirmation of SD NVP exposure if the woman correctly identified a NVP tablet in a picture. For NVP-exposed women, the date of exposure was the delivery date, and for women with multiple exposures, the most recent delivery date was used. Women whose exposure status could not be verified were not enrolled. The NVP-exposed women were primarily referred through postnatal care services, while NVP-unexposed women self-referred for care. Consequently, self-referred women presented with greater immunocompromise than did those referred through postnatal care services. Therefore, NVP-exposed and -unexposed women were frequency matched by CD4 count and clinical stage at enrollment.

All participants received a physical examination and viral load and CD4 tests. First-line treatment consisted of two NRTIs and one NNRTI (either NVP or efavirenz [EFV]). Patients with active tuberculosis (TB) infection received treatment for acute TB before initiating ART. Women were seen once before treatment and then at 2, 4, 6, 8, 16, 24, 36, and 48 weeks after treatment began. Viral loads and CD4 cell counts were measured at 24 and 48 weeks. Women with viral loads of 400 copies/mL or more at either of these visits were evaluated for adherence and retested. Women with persistently high viral loads could be switched to a ritonavir-based protease inhibitor at the clinician's discretion. If a patient missed a visit, staff called or visited the patient at home. Adherence was dichotomized as <95% or ≥95% and was based on self-report from patients regarding the seven days prior to the visit. The virologic failure outcome was assessed at 48 weeks and included women who died, were no longer receiving NNRTI-based treatment, or had a viral load ≥400 copies/mL. The failure rate for the NVP-exposed group was considered equivalent to the NVP-unexposed group if the upper bound of the 95% confidence interval for the difference between the two groups was not greater than 10%.


A total of 878 women were enrolled, 355 (40%) were NVP-exposed. NVP-exposed women were younger, had higher CD4 counts, and lower viral loads at baseline then unexposed women.

At 48 weeks of follow-up, 58 (6.6%) women died including 38 who died before beginning therapy. There were 53 (60%) women who were lost to follow-up or withdrew and 43 (4.9%) had their treatment regimen switched by their clinician.

There were 114 (32.1%) NVP-exposed women who had treatment failure at 48 weeks compared to 132 (25.2%) of the NVP non-exposed women, resulting in a difference in failure rate of 6.9% (95% CI: 0.8%-13.0%), exceeding the predefined 10% non-inferiority margin. Factors associated with treatment failure were an interval of less than six months between NVP exposure and the start of an NNRTI regimen and the following clinical findings at baseline: lower CD4 count; World Health Organization (WHO) clinical stage III or IV, hemoglobin <8.0 g/dL, and body mass index <18 kg/m2. Women enrolled at the African sites had higher failure rates. Although there was an overall difference in the rate of treatment failure between the two groups, there was no statistically significant difference in the rate of treatment failure between the NVP-exposed and -unexposed groups for women who initiated ART more than six months after exposure. Limiting the definition of treatment failure as virologic failure resulted in essentially the same findings-the rate of failure decreases with an increase in the interval between NVP exposure and initiation of an NNRTI regimen.


Prior exposure to SD NVP is associated with increased risk of treatment failure for women receiving an NNRTI-based regimen, but the risk is substantially reduced if the NNRTI-based treatment is initiated at least 12 months after NVP exposure.

Quality Rating

This was a high-quality study. Although the exposed and unexposed groups were not clinically comparable, the authors adjusted for this through frequency matching based upon clinical criteria. The methods adequately established that the outcome was not present at the start of the study and the measurement of the outcome was appropriate. The primary outcome was defined conservatively, providing additional strength to the study.

Programmatic Implications

The findings from this study support evidence from other studies(5, 6) that NNRTI-based ART can be given to women previously exposed to SD NVP if there is a sufficient time lag between NVP exposure and beginning ART. Given the important role that NNRTIs play in the treatment of HIV, clinicians and policy makers should feel reassured that SD NVP could continue to be provided to prevent perinatal transmission without compromising the mother's future opportunity for NNRTI-based treatment.


  1. McConnell MS, Stringer JS, Kourtis AP, Weidle PJ, Eshleman SH. Use of single-dose nevirapine for the prevention of mother-to-child transmission of HIV-1: does development of resistance matter? Am J Obstet Gynecol 2007;197(3Suppl):S56-63.
  2. Eshleman SH, Guay LA, Wang J, et al. Distinct patterns of emergence and fading of K103N and Y181C in women with subtype A vs. D after single-dose nevirapine: HIVNET 012. J Acquir Immune Defic Syndr 2005;40:24-9.
  3. Loubser S, Balfe P, Sherman G, et al. Decay of K103N mutants in cellular DNA and plasma RNA after single-dose nevirapine to reduce mother-to-child HIV transmission. AIDS 2006;20:995-1002.
  4. Flys T, Nissley DV, Claasen CW, et al. Sensitive drug resistance assays reveal long-term persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some women and infants after the administration of single-dose NVP: HIVNET 012. J Infect Dis 2005;192:24-9.
  5. 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.
  6. Kuhn L, Semrau K, Ramachandran S, et al. Mortality and virologic outcomes after access to antiretroviral therapy among a cohort of HIV-infected women who received single-dose nevirapine in Lusaka, Zambia. J Acquir Immune Defic Syndr 2009;52:132-6.