Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events: A randomized trial

Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, and Hospital Universitario de Valme, Seville, Spain.
Annals of internal medicine (Impact Factor: 17.81). 09/2009; 151(3):149-56. DOI: 10.7326/0003-4819-151-3-200908040-00127
Source: PubMed

ABSTRACT More than 50% of patients who start efavirenz treatment develop limiting neuropsychiatric adverse events (NPAEs).
To assess whether stepwise dosing of efavirenz decreases the incidence and severity of NPAEs while maintaining virologic efficacy.
Randomized, double-blind, controlled trial.
7 HIV clinics in Spain.
114 HIV-infected patients eligible for efavirenz treatment plus 2 nucleoside or nucleotide reverse transcriptase inhibitors.
Random assignment (by computer-generated sequence) to receive efavirenz, 200 mg/d on days 1 through 6, 400 mg/d on days 7 through 13, and 600 mg/d on day 14 and after, or efavirenz, 600 mg/d, from day 1. Both groups received 2 nucleoside or nucleotide reverse transcriptase inhibitors chosen by the patient's physician.
Neuropsychiatric symptoms and sleep quality were assessed by questionnaires at 0, 7, 14, and 30 days. The primary outcome was efavirenz-related NPAEs during the first 2 weeks, and the secondary outcome was plasma HIV RNA level at 24 weeks.
Compared with the stepped-dose group, the full-dose group had higher incidence and severity of dizziness (66.0% vs. 32.8%; P = 0.001), hangover (45.8% vs. 20.7%; P = 0.008), impaired concentration (22.9% vs. 8.9%; P = 0.038), and hallucinations (6.1% vs. 0%; P = 0.056) during the first week. From week 2, the incidence of efavirenz-related NPAEs was similar in both groups, although the severity was greater in the full-dose group. Virologic and immunologic efficacy seemed similar in both groups.
The sample size was calculated on the basis of a high absolute difference in rates of efavirenz-related NPAEs between the groups. A lower absolute difference and a larger sample size could have made the differences between groups reach statistical significance beyond the first week. In addition, the sample size does not allow confirmation of similar efficacy between treatment groups.
Stepwise dose escalation of efavirenz over 2 weeks reduces the incidence and intensity of efavirenz-related NPAEs while maintaining efficacy.
Consejería de Salud, Junta de Andalucía, Spain.

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Available from: Antonio Rivero, Dec 12, 2014
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    • "High efavirenz plasma concentrations were associated with an increased occurrence of CNS side effects of all severity grades. It has been previously reported that up to 50% of patients receiving efavirenz - especially if they had a slow CYP2B6 metabolizer genotype - were likely to experience CNS toxicity [41], [42], [43], [44], [45]. In our study, we observed a lower occurrence of CNS side effects than in those studies. "
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    ABSTRACT: To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients. HIV-infected adults with CD4+ T cell count ≤200/mm3 received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis. Efavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001). Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity. NCT01300481.
    PLoS ONE 03/2014; 9(3):e90350. DOI:10.1371/journal.pone.0090350 · 3.23 Impact Factor
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    ABSTRACT: People with HIV infection have several risk factors for developing neuropsychiatric adverse events: preexisting conditions, HIV disease stage, and antiretroviral treatment. The most widely used system for assessing neuropsychiatric adverse events in clinical trials is the US Division of AIDS severity grading scale, from Grade 1 (mild) to Grade 4 (life-threatening). First-line treatment with efavirenz has been associated with higher rates of neuropsychiatric adverse events than several other antiretrovirals. A MEDLINE search identified 17 randomized clinical trials of first-line HAART with two nucleoside analogs plus efavirenz, of which 13 reported neuropsychiatric adverse events using the Grade 1-4 system. The percentage of patients with graded neuropsychiatric adverse events, and the system used for analysis, was compared across the trials. Of the 13 trials identified, there were five different methods used to report neuropsychiatric adverse events: Grade 1-4 all, Grade 1-4 drug related, Grade 2-4 all, Grade 2-4 drug related, Grade 3-4 all, Grade 3-4 drug related, and adverse events leading to discontinuation. In addition, three trials used questionnaire-based methods instead of the Division of AIDS grading system. There were a significantly higher percentage of patients with Grade 1-4 neurological or psychiatric adverse events in the efavirenz versus comparator arms in the DMP-006, TMC278-C204, and STARTMRK trials. There were generally too few patients with each individual neuropsychiatric adverse event to allow meaningful comparisons of treatment arms. There were no significant differences in Grade 3 or 4 neuropsychiatric adverse events between the treatment arms in the ACTG 5142 or 2NN trials. In summary, there is a wide range of different systems used to report neuropsychiatric adverse events in HIV clinical trials. Use of a standardized endpoint would improve the interpretability of results across clinical trials.
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    ABSTRACT: While combination antiretroviral therapy (CART) has decreased the incidence of HIV-associated dementia, the severest form of HIV-associated neurocognitive disorders (HAND), mild neurocognitive disorder and asymptomatic neurocognitive impairment continue to persist, and there is evidence that neurocognitive deficits present even in acute HIV infection. Recent studies demonstrate that CART regimens with higher central nervous system (CNS) penetration effectiveness ranks may improve neurocognitive functioning. Considering these factors, earlier treatment initiation may be considered to protect the CNS. The functional impact of HAND on daily activities should be monitored. Areas that need further research are potential neurotoxicity of antiretrovirals, the eradication of potential latent reservoirs in the brain, when to start treatment to protect the CNS, and the neurological impact of HIV on the CNS in acute infection.
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