We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were administered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant inhibitory effect of isoniazid on efavirenz clearance.

ObjectiveTo assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.MethodsHIV-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.ResultsEfavirenz 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).ConclusionBody 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.Trial RegistrationClinicalTrials.gov NCT01300481

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Background: The optimal dose of efavirenz for HIVinfected patients receiving a tuberculosis regimen including rifampicin remains debated, especially for subjects weighing over 50 kg. To address this issue, we measured plasma efavirenz concentrations from Cambodian adults with tuberculosis enrolled in the CAMELIA randomized trial (ClinicalTrials.gov number, NCT01300481) 6 weeks after the onset of antiretroviral therapy. Methods: Efavirenz concentrations and proportions of patients with concentrations below 1,000 ng/ml were compared across patient body weight below or above 50 kg using a Student's t-test and a c 2 test, respectively. Factors associated with efavirenz concentrations below 1,000 ng/ml were identified by logistic regression analysis. Logistic regression analysis was also performed to check if efavirenz concentrations below 1,000 ng/ml were associated with virological failure. Results: Plasma efavirenz concentrations were higher in the 332 patients who weighed <50 kg compared with the 150 who weighed ≥50 kg (median [IQR] 2,859 [1,787-4,749] and 2,060 [1,425-3,575] ng/ml, respectively; P=0.02). However, the proportion of patients with efavirenz concentrations below 1,000 ng/ml was not different between those weighing less than or more than 50 kg (6% and 10%, respectively; P=0.13) and a body weight above 50 kg was not associated with a higher risk of plasma efavirenz concentrations below 1,000 ng/ml. When plasma efavirenz concentrations below 1,000 ng/ml were present, they were not associated with virological failure. Conclusions: The current WHO guidelines recommending 600 mg efavirenz daily irrespective of patient's body weight remains a safe and effective approach to treating coinfected adults needing simultaneous tuberculosis and HIV therapy. Efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor for HIV-infected patients starting antiretroviral therapy (ART) while on tuberculosis treatment. However, the optimal dosage of EFV during coadministration of tuberculosis treatment has remained a point of debate [1]. Current recommendations vary according to guidelines from using 600 mg EFV daily in HIV-infected adults receiving rifampicin, irrespective of body weight (BW) [2], to an increased daily dose of 800 mg EFV

Background Understanding the extent of viral hepatitis burden in specific subgroups, such as pregnant women and people living with HIV/AIDS (PLWHA), and their geographic distribution is essential for evidence-informed policy and mobilizing resources for targeted treatment and prevention efforts. However, in Cambodia, the epidemiology of hepatitis C remains uncertain. We estimated the hepatitis C virus (HCV) burden and transmission risk factors among PLWHA and pregnant women attending antenatal care (ANC) in Cambodia. Methods Between March and April 2016, we conducted a cross-sectional survey in four diverse geographical areas: the capital city of Phnom Penh and three provinces. We collected information on demographic characteristics and risk behaviors and performed HCV antibody (Anti-HCV) testing among pregnant women attending public ANC clinics and among those receiving HIV care at the hospitals. We computed the prevalence of HCV among the two population subsets and performed logistic regression analyses to identify risk factors associated with HCV antibody positivity. Results Of 935 participants enrolled, 510 (54.6%) were pregnant women and 425 (45.4%) were PLWHA. Anti-HCV prevalence was significantly higher in PLWHA than in pregnant women (29/425, 6.8% vs 5/510, 0.9%, P < 0.001). Of the geographic regions, Preah Sihanouk province (Southwest) had the highest anti-HCV prevalence among PLWHA (12.0%, P = 0.031). There was no significant geographic difference in anti-HCV prevalence among pregnant women. In multivariable analyses (data subset to PLWHA), HCV infection was significantly associated with having a family member positive for HCV (OR = 7.6 [95% CI: 1.01–57.84], P = 0.048) and a history of intravenous medication injection in the last 5 years (OR = 7.1 [95% CI: 2.79–18.10], P < 0.001). Conclusions HCV infection is relatively common among Cambodian PLWHA, likely related to intravenous medication injection and intra-familial viral transmission. Systematic HCV testing and care among PLWHA (and possibly their family members) might be necessary. Setting up a surveillance system for HCV might also be beneficial for some geographical regions and populations.