Single-dose nevirapine is a highly cost-effective strategy to reduce perinatal HIV-1 transmission. Its major disadvantage is the selection of nevirapine resistance in 20% to 30% of women, probably attributable to the long elimination half-life of nevirapine. To develop intervention strategies, it is important to know the interpatient variability in nevirapine half-life in women receiving a single dose of nevirapine.
HIV-negative, healthy, nonpregnant Dutch women were eligible for this study. After administration of a single 200-mg dose of nevirapine to the subjects, blood was sampled for measurement of nevirapine twice a week for a total of 21 days. Nevirapine plasma levels were determined by a validated high-performance liquid chromatography method with a lower limit of quantification of 0.15 mg/L. The primary end point was the first sample with an undetectable nevirapine concentration.
Forty-four subjects participated. The median age, height, and body weight (interquartile range) were 26 (21-33) years, 1.72 (1.68-1.75) m, and 64 (59-75) kg, respectively. The median elimination half-life of nevirapine was 56.7 hours, with a range of 25.6 to 164 hours. The time to the first undetectable nevirapine plasma concentration was 10 days in 4 subjects, 14 days in 12 subjects, 17 days in 12 subjects, and 21 days in 9 subjects. In the remaining 7 subjects, nevirapine was still detectable on day 21, the last day of sampling. Time to an undetectable nevirapine plasma concentration was influenced by oral contraceptive use but not by age, height, body weight, body surface area, alcohol use, or smoking.
Most women who received a single 200-mg nevirapine dose still had detectable plasma concentrations of nevirapine after more than 2 weeks. This information is valuable for designing intervention studies to prevent the development of nevirapine resistance.
"Given the high frequency of mutation, some minority resistant mutants are always preexisting, albeit in trace quantities, at the moment therapy is initiated. Because of the long half-life of single dose NVP, with blood levels detectable up to 2–3 weeks after exposure [3,4], the duration of sub-therapeutic NVP concentrations may present a significant hazard of developing resistance for the mother. There is a risk of treatment failure after single dose NVP exposure, if the treatment includes a NNRTI . "
[Show abstract][Hide abstract] ABSTRACT: Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood.
We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically).
Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated.
Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens.
Theoretical Biology and Medical Modelling 12/2008; 5:25. DOI:10.1186/1742-4682-5-25 · 0.95 Impact Factor
"Only the new NNRTI TMC 125, which is still in the approval process, seems to be unaffected by those mutations. One possible explanation for the rapid development of resistance mutations is the long half-life of NNRTIs (Muro et al 2005). "
[Show abstract][Hide abstract] ABSTRACT: Boris Julg, Johannes R BognerMedizinische Poliklinik, Department of Infectious Diseases, University of Munich Medical School, Downtown Campus, GermanyAbstract: In July 2006 Atripla™ was approved by the US Food and Drug Administration (FDA), combining the active ingredients of one NNRTI and two NRTIs. Atripla™ is the first “one-pill-daily” regimen licensed for the treatment of HIV-1 infection in patients older than 18 years. Atripla™ contains efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg. It therefore combines 3 compounds which have been widely used before and which were recommended for initial therapy due to their potency, tolerability, and safety profile. Efficacy and safety data of efavirenz, tenofovir DF, and emtricitabine are reviewed compared with other antiretroviral drugs, which are used as initial therapy for treatment-naive patient.Keywords: Atripla™antiretroviral therapy, new “one-pill-daily” regimen, review efficacy and safety data
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