Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial.

BACKGROUND: Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival. METHODS: We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count ≤200 cells/µL and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial. RESULTS: Six hundred sixty-one patients enrolled contributed to 1366.1 person-years of follow-up; 149 (22.5%) died. There were 8.3 deaths per 100 person-years (95% confidence interval [CI], 6.4-10.7) in the early-ART group and 13.8 deaths per 100 person-years (95% CI, 11.2-16.9) in the late-ART group (P = .002). Tuberculosis was the primary cause of death (28%), followed by other HIV-associated conditions (19%). Factors independently associated with mortality in the first 26 weeks were the age, body mass index, hemoglobin, interrupted or ineffective tuberculosis treatment before identification of drug resistance, disseminated tuberculosis, and nontuberculous mycobacterial disease. After 50 weeks in the trial, the most frequent causes of death were non-HIV related or tuberculosis related, including drug toxicity; factors associated with mortality were late ART, loss to follow-up, and absence of cotrimoxazole prophylaxis. CONCLUSIONS: Despite ART introduction, mortality remained high, with tuberculosis as the leading cause of death. Reducing tuberculosis-related mortality remains a challenge in resource-limited settings and requires innovative strategies. Clinical Trials Registration. NCT00226434.

Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

BACKGROUND: Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy. METHODS: We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower. After beginning the standard, 6-month treatment for tuberculosis, patients were randomly assigned to either earlier treatment (2 weeks after beginning tuberculosis treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival. RESULTS: A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log(10) copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P=0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P<0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients. CONCLUSIONS: Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4+ T-cell counts of 200 per cubic millimeter or lower. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.).

Risk factors for hepatitis C transmission in HIV patients, Hepacam study, ANRS 12267 Cambodia.

In 2009, we conducted a case-control study to explore the routes of HCV transmission in people living with HIV/AIDS (PLHIV) in Cambodia. Cases were HCV/HIV co-infected patients (who tested RT-PCR positive for HCV-RNA or had confirmed presence of HCV antibodies) (n = 44). Controls were HIV mono-infected patients, with no HCV antibodies (n = 160). They were recruited among the PLHIV presenting at one national reference centre of HIV/AIDS. Multivariate analysis showed that factors associated with the co-infection were the age older than 50 years (OR 5.4, 95 % confidence interval (CI) 1.5-19.6), the exposure to multiple parenteral infusions before the year 2000 (OR 3.4, 95 % CI 1.5-7.6), to surgery (OR 2.6, 95 % CI 1.2-5.7) and to fibroscopy (OR 2.4, 95 % CI 1.0-5.7). These results show the need to implement HCV screening in PLHIV, to support the implementation of national infection control guidelines, and to reinforce public awareness on the risks linked to parenteral medications.

Virological failure and HIV-1 drug resistance mutations among naive and antiretroviral pre-treated patients entering the ESTHER program of Calmette Hospital in Cambodia.

INTRODUCTION: In resource limited settings, patients entering an antiretroviral therapy (ART) program comprise ART naive and ART pre-treated patients who may show differential virological outcomes. METHODS: This 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. RESULTS: On 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. CONCLUSION: In 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.

Short communication: three years follow-up of first-line antiretroviral therapy in cambodia: negative impact of prior antiretroviral treatment.

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.

High efficacy of lopinavir/r-based second-line antiretroviral treatment after 24 months of follow up at ESTHER/Calmette Hospital in Phnom Penh, Cambodia.

BACKGROUND: The 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. METHODS: Seventy 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. RESULTS: Of 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. CONCLUSIONS: These 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.