Didier Laureillard

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.).

Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients.

Objectives:To determine the prevalence, determinants of positivity, and clinical utility of serum cryptococcal polysaccharide (CPS) antigen testing among HIV-infected patients in 2004 in Cambodia, an area highly endemic for cryptococcosis. Methods:All HIV-infected patients with a CD4+ count <200 cells/mm3 attending 1 of 2 Phnom Penh hospitals for the first time were systematically screened for serum CPS. Patients with positive test results were further investigated to identify those with cryptococcal meningitis (CM), pulmonary cryptococcosis, or isolated positive cryptococcal antigenemia (IPCA). Results:The median (interquartile range [IQR]) CD4+ count of 327 enrolled patients was 24 (IQR: 8 to 65) cells/mm3. The prevalence of cryptococcal infection was 59 (18.0%) of 327 cases, of which 41 were CM and 10 were IPCA. In the absence of serum CPS detection, 17 (28.8%) of 59 cryptococcal infections would have been missed on the day of consultation. In patients with no specific symptoms of meningoencephalitis, the prevalence of positive serum CPS detection was 32 (10.8%) of 295 cases. Countryside residence (adjusted odds ratio [AOR] = 3.6), headache (AOR = 3.2), body mass index <15.4 kg/m2 (AOR = 3.4), CD4+ count <50 cells/mm3 (AOR = 4.0), and male gender (marginally, AOR = 2.1) were all independently associated with a positive test result. Conclusion:Serum CPS screening among AIDS patients with a CD4+ count <100 cells/mm3 is useful in areas highly endemic for cryptococcosis, allowing early diagnosis and treatment of this opportunistic infection.

Positive outcomes of HAART at 24 months in HIV-infected patients in Cambodia

Objectives:African and Asian cohort studies have demonstrated the feasibility and efficacy of HAART in resource-poor settings. The long-term virological outcome and clinico-immunological criteria of success remain important questions. We report the outcomes at 24 months of antiretroviral therapy (ART) in patients treated in a Médecins Sans Frontières/Ministry of Health programme in Cambodia. Methods:Adults who started HAART 24 ± 2 months ago were included. Plasma HIV-RNA levels were assessed by real-time polymerase chain reaction. Factors associated with virological failure were analysed using logistic regression. Results:Of 416 patients, 59.2% were men; the median age was 33.6 years. At baseline, 95.2% were ART naive, 48.9% were at WHO stage IV, and 41.6% had a body mass index less than 18 kg/m2. The median CD4 cell count was 11 cells/μl. A stavudine–lamivudine–efavirenz-containing regimen was initiated predominantly (81.0%). At follow-up (median 23.8 months), 350 (84.1%) were still on HAART, 53 (12.7%) had died, six (1.4%) were transferred, and seven (1.7%) were lost to follow-up. Estimates of survival were 85.5% at 24 months. Of 346 tested patients, 259 (74.1%) had CD4 cell counts greater than 200 cells/μl and 306 (88.4%) had viral loads of less than 400 copies/ml. Factors associated with virological failure at 24 months were non-antiretroviral naive, an insufficient CD4 cell gain of less than 350 cells/μl or a low trough plasma ART concentration. In an intention-to-treat analysis, 73.6% of patients were successfully treated. Conclusion:Positive results after 2 years of advanced HIV further demonstrate the efficacy of HAART in the medium term in resource-limited settings.

Response to highly active antiretroviral therapy among severely immuno-compromised HIV-infected patients in Cambodia.

Background:HAART efficacy was evaluated in a real-life setting in Phnom Penh (Médecins Sans Frontières programme) among severely immuno-compromised patients. Methods:Factors associated with mortality and immune reconstitution were identified using Cox proportional hazards and logistic regression models, respectively. Results:From July 2001 to April 2005, 1735 patients initiated HAART, with median CD4 cell count of 20 (inter-quartile range, 6–78) cells/μl. Mortality at 2 years increased as the CD4 cell count at HAART initiation decreased, (4.4, 4.5, 7.5 and 24.7% in patients with CD4 cell count > 100, 51–100, 21–50 and ≤ 20 cells/μl, respectively; P < 10−4). Cotrimoxazole and fluconazole prophylaxis were protective against mortality as long as CD4 cell counts remained ≤ 200 and ≤ 100 cells/μl, respectively. The proportion of patients with successful immune reconstitution (CD4 cell gain > 100 cells/μl at 6 months) was 46.3%; it was lower in patients with previous ART exposure [odds ratio (OR), 0.16; 95% confidence interval (CI), 0.05–0.45] and patients developing a new opportunistic infection/immune reconstitution infection syndromes (OR, 0.71; 95% CI, 0.52–0.98). Similar efficacy was found between the stavudine–lamivudine–nevirapine fixed dose combination and the combination stavudine–lamivudine–efavirenz in terms of mortality and successful immune reconstitution. No surrogate markers for CD4 cell change could be identified among total lymphocyte count, haemoglobin, weight and body mass index. Conclusion:Although CD4 cell count-stratified mortality rates were similar to those observed in industrialized countries for patients with CD4 cell count > 50 cells/μl, patients with CD4 cell count ≤ 20 cells/μl posed a real challenge to clinicians. Widespread voluntary HIV testing and counselling should be encouraged to allow HAART initiation before the development of severe immuno-suppression.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial.

Objective:To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434). Methods:ART-naive adults with CD4+ cell count of 200 cells/&mgr;l or less, newly diagnosed tuberculosis, and at least one follow-up visit after ART initiation were included in this analysis. Each case of suspected TB-IRIS was systematically validated by two physicians not involved in patients’ management. Factors associated with occurrence of TB-IRIS were identified using the Cox proportional hazard model. Results:Among 597 patients, 26% experienced TB-IRIS with an incidence rate of 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4–44.4]. Main clinical manifestations included new or worsening lymphadenopathy (77.4%) and fever (68.4%). Chest radiograph revealed new or worsening abnormalities in 53.4%. Symptoms resolved in 95.5% of patients. Six deaths were directly related to TB-IRIS. Initiating ART early increased the risk of TB-IRIS by 2.61 (95% CI 1.84–3.70). Extrapulmonary or disseminated tuberculosis, CD4+ cell count of 100 cells/&mgr;l or less, and HIV RNA concentration more than 6 log10 copies/ml were also significantly associated with higher risk of TB-IRIS. Conclusion:Shortening the delay between tuberculosis treatment onset and ART initiation to 2 weeks was associated with an increased risk of developing TB-IRIS. However, TB-IRIS was generally easily manageable. Given the marked reported survival advantage of early ART initiation after tuberculosis treatment onset, these data indicate that fear of TB-IRIS should not be an impediment to early ART in adults with advanced immunodeficiency in resource-limited, high burden settings.

Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis

Immune reconstitution inflammatory syndrome (IRIS) is a common and potentially serious complication occurring in HIV-infected patients being treated for tuberculosis (TB) using combined antiretroviral treatment. A role of adaptive immunity has been suggested in the onset of IRIS, whereas the role of natural killer (NK) cells has not yet been explored. The present study sought to examine the involvement of NK cells in the onset of IRIS in HIV-infected patients with TB and to identify predictive markers of IRIS. A total of 128 HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) trial were enrolled in Cambodia. Thirty-seven of the 128 patients developed IRIS. At inclusion, patients had low CD4 cell counts (27 cells/mm(3)) and high plasma viral load (5.76 and 5.50 log/mL in IRIS and non-IRIS patients, respectively). At baseline, NK-cell degranulation capacity was significantly higher in IRIS patients than in non-IRIS patients (9.6% vs 6.38%, P < .005). At IRIS onset, degranulation capacity did not differ between patients, whereas activating receptor expression was lower in IRIS patients. Patients with degranulation levels > 10.84% had a higher risk of IRIS (P = .002 by log-rank test). Degranulation level at baseline was the most important IRIS predictor (hazard ratio = 4.41; 95% confidence interval, 1.60-12.16). We conclude that NK-degranulation levels identify higher IRIS risk in HIV-infected patients with TB.

High frequency of integrase Q148R minority variants in HIV-infected patients naive of integrase inhibitors.

Background:Integrase positions 148 and 155 represent main determinants of resistance to integrase inhibitors. We assessed the prevalence of minority variants harboring such mutations in integrase-naive HIV-infected patients. Methods:Two groups of patients were studied: 40 heavily antiretroviral-experienced patients, initiating a raltegravir-based therapy and 51 antiretroviral-naive patients. Allele-specific real-time PCR (AS-PCR) systems, developed for Q148H, Q148R and N155H mutations, were performed at baseline for antiretroviral-experienced patients. Samples from antiretroviral-naive patients were tested with the Q148R AS-PCR assay. Results:The limits of detection of AS-PCR systems were 0.10, 0.10 and 0.05% for Q148H, Q148R and N155H mutations, respectively. AS-PCR systems were successful in 79 of 91 samples. In antiretroviral-experienced patients, Q148R minority variants were frequently detected (26/32 patients, 81%) at low-level frequency (median = 0.40%), whereas no minority variants exhibiting Q148H or N155H mutation were found. Twenty-four of 26 patients exhibiting Q148R variants were virological responders but four of them displayed a delayed virological response occurring between W18 and W36. Two patients exhibited virological failure under raltegravir, both harboring Q148R minority variants at baseline. However, we did not find any association between the presence of Q148R minority variants and an increased risk of virological failure. Q148R minority variants were also found in 86% of antiretroviral-naive patients, a prevalence significantly higher than that of K103N minority variants (26%). Conclusion:Q148R variants were frequently detected, always at low-level, in antiretroviral-experienced and naive patients. Although their presence was not consistently associated with virological failure, their impact on long-term viral suppression needs to be further investigated.

Dependence of Efavirenz- and Rifampicin-Isoniazid–Based Antituberculosis Treatment Drug-Drug Interaction on CYP2B6 and NAT2 Genetic Polymorphisms: ANRS 12154 Study in Cambodia

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.

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.

Randomised Pharmacokinetic Trial of Rifabutin with Lopinavir/Ritonavir-Antiretroviral Therapy in Patients with HIV-Associated Tuberculosis in Vietnam

Background Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured. Methods This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir. Results Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 – 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations. Conclusions Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis. Trial Registration ClinicalTrials.gov NCT00651066