Drug Resistance Clinical Trial
Official title:
An Evaluation of the Development of Nevirapine Induced Mutations in HIV Patients Initiating or Discontinuing Combination Antiretroviral Therapy
Hypothesis
Nevirapine resistance developed in women and infants in the HIVNET 006 and 012 cohorts as a
consequence of use of an agent with a long t½ as monotherapy in individuals with high viral
loads.
Objective 1 To demonstrate that Nevirapine resistance does not develop in HIV infected
patients when used as part of triple antiretroviral combination therapy between the
initiation of treatment and suppression of HIV RNA to <1000 copies/ml.
Objective 2 To demonstrate that resistance to nevirapine does not develop when patients with
suppressed HIV RNA discontinue combination antiretroviral therapy which contains nevirapine.
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.
Similarly, the K103N resistance mutation was detected 6 weeks after Nevirapine
administration in 3/15 (20%) women in the HIVNET006 phase I/II trial. This had the same
Nevirapine dosing schedule as HIVNET012 (12).
New information has become available based on recent post-marketing surveillance data
clarifying risk factors for severe life threatening and fatal hepatotoxicity with
nevirapine. Women with CD4 counts > 250 cellsmm3 at initiation of therapy including pregnant
women receiving chronic treatment for HIV infection are at considerably higher risk
(12-fold) of hepatotoxicity which in some cases has been fatal. The greatest risk of severe
and potentially fatal hepatic events occurs in the first 6 weeks of therapy. However, the
risk continues after this time and patients should be closely monitored for the first 18
weeks of therapy. For this reason, women with CD4 > 250/mm3 will not be included in
Objective 1 of this study.
Hypothesis
Nevirapine resistance developed in women and infants in the HIVNET 006 and 012 cohorts as a
consequence of use of an agent with a long t½ as monotherapy in individuals with high viral
loads.
Objective 1 To demonstrate that Nevirapine resistance does not develop in HIV infected
patients when used as part of triple antiretroviral combination therapy between the
initiation of treatment and suppression of HIV RNA to <1000 copies/ml.
Objective 2 To demonstrate that resistance to nevirapine does not develop when patients with
suppressed HIV RNA discontinue combination antiretroviral therapy which contains nevirapine.
;
Observational Model: Cohort, Time Perspective: Prospective
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