The aims of this ANRS12154 open-label, single-center, multiple-dose pharmacokinetic study were to characterize nevirapine pharmacokinetics in a Cambodian population of HIV-infected patients and to identify environmental and genetic factors of variability, focusing on the CYP2B6, CYP3A5, and ABCB1 (MDR1) genes. A total of 170 Cambodian HIV-infected patients were included. Nevirapine trough concentrations were measured after 18 and 36 months of starting antiretroviral treatment and in samples drawn during a dosing interval in a subset of 10 patients. All data were analyzed by nonlinear mixed-effects modeling. The effect of covariates was investigated using the population pharmacokinetic model. Patients carrying homozygous lossof-function alleles CYP3A5 6986A>G, CYP2B6 516G>T, CYP2B6 1459C>T, and ABCB1 3435C>T represent 42.4%, 9.2%, 0%, and 18% of the population, respectively. The median nevirapine trough concentrations did not differ after 18 and 36 months of treatment (5,705 ng/ml [range, <50 to 13,871] and 5,709 ng/ml [range, <50 to 15,422], respectively). Interpatient and intrapatient variabilities of nevirapine apparent clearance were 28% and 17%, respectively. CYP2B6 516G>T and creatinine clearance were found to significantly affect nevirapine apparent clearance. The estimated nevirapine apparent clearances were 2.95 liters/h, 2.62 liters/h, and 1.86 liters/h for CYP2B6 516GG, CYP2B6 516GT, and CYP2B6 516TT genotypes, respectively. The impact of creatinine clearance was small. This study demonstrates that 95% of the patients had sustained nevirapine exposure well above the 3,000-ng/ml threshold. Nevirapine clearance was shown to be affected by CYP2B6 516G>T genetic polymorphism and creatinine clearance, although this explained only part of the interpatient variability, which remains low compared to that for other antiretroviral drugs.In resource-limited settings, nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTI) are the WHO-recommended backbone of first-line antiretroviral therapy. At the time of the study, nevirapine in combination with two nucleoside analog inhibitors of reverse transcriptase such as stavudine and zidovudine, in addition to lamivudine, was the recommended antiretroviral regimen in treatment-naïve patients, mainly because of the availability of WHO-prequalified low-cost generic fixed-dose combinations (7, 27). In Cambodia, the prevalence of HIV infection among the general population aged between 15 and 49 years peaked at 2% in 1998 and declined to 0.9% in 2006. This decrease has been attributed to many deaths among people infected during the early years of the epidemic before implementation of the continuum of care and the scaling-up of HIV prevention, care, and treatment programs. At the end of 2009, it is estimated that about 37,000 patients were on antiretroviral drug regimens and 69.5% were on a nevirapine backbone regimen (National Center for HIV/AIDS, Dermatology and STD [NCHADS]; http://www.nchads.org/). Therefore, worldwide, most patients living with AIDS who need antiretr...

BackgroundThe number of patients on second-line highly active antiretroviral therapy (HAART) regimens is increasing in resource-limited settings. We describe the outcomes after 24 months for patients on LPV/r-based second-line regimens followed up by the ESTHER programme in Phnom Penh, Cambodia.MethodsSeventy patients who initiated second-line HAART regimens more than 24 months earlier were included, and immuno-virological data analyzed. HIV RNA viral load was determined by real-time RT-PCR. HIV-1 drug resistance was interpreted according to the ANRS algorithm.ResultsOf the 70 patients, two were lost to follow up, three died and 65 (92.8%) remained on second-line treatment after 24 months of follow up (median duration of treatment: 27.4 months). At switch to second-line, the median CD4 T cell count was 106 cells/mm3 and the median viral load was 4.7 Log10. Second-line regimens prescribed were ddI/3TC/LPV/r (65.7%), ddI/TDF/LPV/r (10.0%), ddI/AZT/LPV/r (8.6%) and TDF/3TC/LPV/r (7.1%). The median CD4 T cell gain was +258 cells/mm3 at 24 months (n = 63). After 24 months of follow up, 92.3% (60/65) of the patients presented undetectable viral loads, giving an overall treatment success rate of 85.7% (CI: 75.6- 92.0) in intent-to-treat analysis.ConclusionsThese data suggest that a LPV/r-based second-line regimen is associated with a high rate of virological suppression and immune reconstitution after 24 months of follow up in Cambodia.

Background. Adherence to antiviral therapy is important for HIV-infected people living in low- and middle-income countries, because of poor access to alternative regimens. Methods. We conducted a cross-sectional survey of adherence in Cambodian patients enrolled in the ESTHER program and treated with WHO first-line regimen for at least 6 months. The survey was based on a self-report questionnaire, drug assay, MCV measurement, visual analog scale, and viral load HIV RNA. Results. Two hundred fifty-nine patients treated for a median of 16 months participated in the survey. At inclusion in the program, 158 patients (61%) were ARV-naïve. The virological success rate was 71% overall and 81% in previously ARV-naive patients. Considered individually, the measures suggested perfect adherence in 71% to 93% of patients. In multivariate analysis adjusted for sex and therapeutic status before HAART initiation, only the biological markers were associated with virological efficacy. Self-funded treatment before entry to the program was highly predictive of virological failure. Conclusion. Adherence was excellent in these Cambodian patients. Biological markers were predictive of virological efficacy. MCV might thus serve as a simple alternative for assessing adherence and predicting virological efficacy among patients receiving AZT- or d4T-based regimens.

BackgroundLopinavir/ritonavir (LPV/r) is widely used in Cambodia with high efficacy but scarce data exist on long-term metabolic toxicity.MethodsWe carried out a cross-sectional and retrospective study evaluating metabolic disorders and cardiovascular risk in Cambodian patients on LPV/r-based antiretroviral therapy (ART) for > 1 year followed in Calmette Hospital, Phnom Penh. Data collected included cardiovascular risk factors, fasting blood lipids and glucose, and retrospective collection of bioclinical data. We estimated the 10-year risks of coronary heart disease with the Framingham, Ramathibodi-Electricity Generating Authority of Thailand (Rama-EGAT), and the Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) risk equations. We identified patients with LDL above targets defined by the French expert group on HIV and by the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group (IDSA-AACTG).ResultsOf 115 patients enrolled—mean age 40.9 years, 69.2% male, mean time on LPV/r 3.8 years—40 (34.8%) had hypercholesterolemia (> 2.40 g/L), and 69 (60.0%) had low HDL cholesterol (< 0.40 g/L). Twelve (10.5%), 28 (24%) and 9 (7.7%) patients had a 10-year risk of coronary heart disease ≥ 10% according to the Framingham, D:A:D, and Rama-EGAT score, respectively. Fifty one (44.4%) and 36 (31.3%) patients had not reached their LDL target according to IDSA-AACTG and French recommendations, respectively.ConclusionPrevalence of dyslipidemia was high in this cohort of HIV-infected Cambodian patients on LPV/r. Roughly one third had high LDL levels requiring specific intervention.

There are few long-term data on ART-experienced patients in resource-limited settings. We performed a cross-sectional study of HIV-infected patients included in the ESTHER program in Calmette hospital, Phnom Penh, Cambodia, after 36 ± 3 months of cART. Therapeutic, clinical, and immunovirological outcomes were compared between patients who stated they were ART-naive (naive group), dual nucleoside reverse-transcriptase inhibitor (two-NRTI group), or fixed-dose combination of stavudine/lamivudine/nevirapine experienced (three-drug group) at entry to the program. A logistic regression model was used to evaluate the factors associated with virological failure (PCR HIV > 250 copies/ml). Among the 256 patients included in the analysis, 148 (58%) were ART naive while 50 (20%) had previously received two NRTIs and 58 (22%) three drugs. At entry to the program, all the patients received two NRTIs and one nonnucleoside reverse-transcriptase inhibitor (NNRTI). At evaluation, 46 patients (18%) were switched to a protease inhibitor-based regimen (9%, 32%, and 29% of the naive, two-NRTI, and three-drug groups; p < 0.0001). The median CD4 cell count increase was 180/μl overall (IQR: 96-276) and was higher in ART-naive than ART-experienced patients. In the intent-to-treat analysis, virological success was achieved in 83.5%, 67%, and 69% of the naive, two-NRTI, and three-drug groups, respectively (p = 0.002). Factors associated with virological failure were suboptimal previous ART exposure and WHO immunological failure criteria. The long-term efficacy of first-line cART is maintained in Cambodia. In ART-experienced patients, viral load monitoring needs to be available to establish early virological failure and preserve the potency of second line regimens.

IntroductionIn resource limited settings, patients entering an antiretroviral therapy (ART) program comprise ART naive and ART pre-treated patients who may show differential virological outcomes.MethodsThis retrospective study, conducted in 2010–2012 in the HIV clinic of Calmette Hospital located in Phnom Penh (Cambodia) assessed virological failure (VF) rates and patterns of drug resistance of naive and pre-treated patients. Naive and ART pre-treated patients were included when a Viral Load (VL) was performed during the first year of ART for naive subjects or at the first consultation for pre-treated individuals. Patients showing Virological failure (VF) (>1,000 copies/ml) underwent HIV DR genotyping testing. Interpretation of drug resistance mutations was done according to 2013 version 23 ANRS algorithms.ResultsOn a total of 209 patients, 164 (78.4%) were naive and 45 (21.5%) were ART pre-treated. Their median initial CD4 counts were 74 cells/mm3 (IQR: 30–194) and 279 cells/mm3 (IQR: 103–455) (p<0.001), respectively. Twenty seven patients (12.9%) exhibited VF (95% CI: 8.6–18.2%), including 10 naive (10/164, 6.0%) and 17 pre-treated (17/45, 37.8%) patients (p<0.001). Among these viremic patients, twenty-two (81.4%) were sequenced in reverse transcriptase and protease coding regions. Overall, 19 (86.3%) harbored ≥1 drug resistance mutations (DRMs) whereas 3 (all belonging to pre-treated patients) harbored wild-types viruses. The most frequent DRMs were M184V (86.3%), K103N (45.5%) and thymidine analog mutations (TAMs) (40.9%)Two (13.3%) pre-treated patients harbored viruses that showed a multi-nucleos(t)ide resistance including Q151M, K65R, E33A/D, E44A/D mutations.ConclusionIn Cambodia, VF rates were low for naive patients but the emergence of DRMs to NNRTI and 3TC occurred relatively quickly in this subgroup. In pre-treated patients, VF rates were much higher and TAMs were relatively common. HIV genotypic assays before ART initiation and for ART pre-treated patients infection should be considered as well.

In this survey, 213 patients in an antiretroviral treatment programme in Phnom Penh, Cambodia, were tested for GB virus C (GBV-C) RNA before treatment initiation. Most had advanced HIV infection, only 34 having CD4 cell counts > 200 cells/microl. GBV-C-RNA was detected in 35 patients. The proportion with positive GBV-C-RNA decreased dramatically with CD4 cell counts < 100 cells/microl. In multivariate analysis, low CD4 cell counts, tuberculosis, anaemia, and traditional medicine were independently and negatively associated with GBV-C-RNA detection.

In Cambodia, national programs to prevent mother-tochild transmission (MTCT) of HIV, scaled up since 2001, were hampered by lack of access to HIV early diagnosis in infancy. A low cost strategy to assess HIV-RNA viral load, was implemented in 2005 and applied to the early diagnosis in infants. Our objectives were i) to generate information on the early diagnosis of HIV infection in Cambodia, and ii) to estimate the in utero and perinatal MTCT rates of HIV-1 among mothers delivering at