An Evaluation of the Development of Nevirapine Induced Mutations in HIV Patients Initiating or Discontinuing Combination Antiretroviral Therapy

The HIVNET 012 clinical trial demonstrates a cost effective strategy to prevent maternal fetal transmission of HIV. In this study, a single 200 mg dose of Nevirapine was given to pregnant Ugandan women at the onset of labour and a single 2 mg/kg dose to their infants within 72 hours of birth (1). Given the efficacy, simplicity and low cost of this regime, the World Health Organization recently recommended implementation of this regimen as one of several options for prevention of maternal fetal transmission of HIV in resource limited settings.

Pharmacokinetic studies have demonstrated that 200 mg of Nevirapine given to the mother during labour results in concentrations >100 mg/mL (10 times the in vitro IC50) in the newborn. Nevirapine elimination is prolonged in both mothers and infants with median t½ of 36.8 to 65.7 hours. Administration of 200 mg orally to the mother and a single 2 mg/kg oral dose to the infant at 48-72 hours, maintains serum concentration in the infants >100 mg/ml through 7 days of life (2, 3)

Early studies demonstrated that the use of Nevirapine monotherapy resulted in a rapid selection of Nevirapine resistant mutations (4). This was associated with loss of antiviral activity and return of the viral load to baseline within 12 weeks. It appeared very soon that the non-nucleoside reverse transcriptase inhibitors were drugs with a low genetic barrier and that a single mutation in the reverse transcriptase gene induced a high level of phenotypic resistance (5). Similarly, when Nevirapine was used in combination with a single nucleoside, and there was incomplete suppression of viral replication, resistance emerged to the non-nucleoside reverse transcriptase inhibitor (6).

In contrast, when used as part of triple antiretroviral combination and there was successful inhibition of viral replication to <50 copies/ml, the viral response was maintained in 50% of patients out to 48 weeks (7, 8, 9, 10). However, again when virologic control is lost, resistance to Nevirapine emerges rapidly in 50-100% of patients (11). It is unclear whether or not these mutations developed during the initial suppression of viral load replication or during rebound of viremia with failure.

Given the pharmacokinetics of Nevirapine in pregnant women and infants, concern was raised that mother and child would be exposed to Nevirapine monotherapy for one to several days and that the selection of resistant mutants could arise limiting this strategy over the long term. In fact, a recent sub-analysis of the HIVNET 012 cohort found Nevirapine resistant mutations in 21/111 (19%) of women tested at 6-8 weeks after delivery. The K103N was the most common mutation. Women with the highest baseline viral load developed the mutations more frequently. Nevirapine resistant mutations were also detected in 11/24 or (46%) of infected infants at 6-8 weeks. In contrast to the mothers, the Y181C was the most commonly detected.