Stepped-dose Efavirenz Reduces the Incidence of Neuropsychiatric AEs
Stepped-dose Efavirenz Reduces the Incidence of Neuropsychiatric AEs
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Synopsis: In this study, 114 HIV-infected patients initiating therapy with efavirenz (EFV)-based antiretroviral therapy regimens were randomized to either stepped-dose EFV (200 mg/d on days 1-6, 400 mg/d on days 7-13, and 600 mg/d beginning on day 14) vs. EFV 600 mg/d. The full-dose group experienced a significantly higher incidence of neuropsychiatric adverse events (NPAE). Virologic and immunologic efficacy was similar in both groups.
Source: Gutierrez-Valencia A, et al. Stepped-dose vs. full-dose efavirenz for HIV infection and neuropsychiatric adverse events. Ann Int Med. 2009;151:1-9.
Patients eligible for EFV-based haart (EFV plus two nucleoside RT inhibitors) were randomized to EFV in an escalating dose over two weeks vs. standard 600 mg/d dosing. NPAEs and sleep quality were assessed by questionnaires over the first 30 days of therapy. The full-dose EFV group presented with higher incidence and severity of dizziness (66% vs. 33%), hangover (46% vs. 21%), impaired concentration (23% vs. 9%), and hallucinations (6% vs. 0%) during the first week. From week two onward, the incidence of EFV-related NPAEs was similar between the groups; virologic and immunologic efficacy was similar between the groups.
Commentary
Efavirenz is one of the most potent antiretroviral agents in our therapeutic armamentarium, with an in vitro IC50 against most wild-type HIV of < 0.01 uM. Its excellent oral bioavailability and long plasma half-life make once-daily dosing feasible. Beginning with clinical trials in HIV patients (which were first initiated in late 1995 when I was the medical director of oncology and viral diseases at DuPont Merck Pharmaceutical Co.), EFV has rightfully become established as the "standard of care" nnRTI and has a wonderful track record of efficacy, safety, and durability. It is generally well-tolerated, although it was predicted, from animal toxicology studies conducted at DuPont in the early 1990s, that CNS side effects would be likely in humans dosed at 600 mg daily (or higher doses). Clinical experience has borne this out. EFV is both a substrate and an inducer of the cytochrome P450 enzyme system, and has been shown to auto-induce its metabolism. This explains the commonly observed clinical phenomenon of NPAEs being quite severe during the first week or two of EFV therapy and then becoming much less severe as dosing continues.
This study from Spain explores a strategy of gradually escalating the dose of EFV over the first two weeks of therapy. The results of this trial support this as a useful strategy to reduce the frequency and severity of NPAEs. EFV has a low genetic barrier to the development of HIV resistance. A single substitution in reverse transcriptase (K103N) induces a 1,000-fold increase in the IC50 of HIV to EFV. It is clear that the authors of this study were concerned about the potential for development of resistance occurring during the brief dose-escalation lead-in period. Fortunately, the results obtained in this study showed no difference in virologic response or differences in development of resistance between the two groups. Indeed, some of the very early DuPont Merck clinical trials conducted in the mid-1990s used EFV doses lower than 600 mg without any discernible increased risk of virologic failure or development of resistance.
Patients eligible for EFV-based haart (EFV plus two nucleoside RT inhibitors) were randomized to EFV in an escalating dose over two weeks vs. standard 600 mg/d dosing. NPAEs and sleep quality were assessed by questionnaires over the first 30 days of therapy.Subscribe Now for Access
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