A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.

BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS: Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

Survival after long-term ART exposure: findings from an Asian patient population retained in care beyond 5 years on ART.

BACKGROUND: This study investigated survival in people living with HIV being followed-up from 5 and 10 years after antiretroviral therapy (ART) initiation in a multi-country Asian cohort. METHODS: We included patients in follow-up >5 years after ART initiation. Factors associated with mortality beyond 5 and 10 years on ART were analysed using competing risk regression with time-updated variables. RESULTS: Of 13,495 patients retained after 5 years on ART, 279 subsequently died (0.56/100 person-years). Increased mortality was associated with age >50 years (sub-hazard ratio [sHR] 2.24, 95% CI 1.58, 3.15, compared with ≤40 years), HIV exposure through injecting drug use (sHR 2.17, 95% CI 1.32, 3.56), HIV viral load ≥1,000 copies/ml: sHR 1.52, 95% CI 1.05, 2.21, compared with <400), regimen (second-line regimen: sHR 2.11, 95% CI 1.52, 2.94, and third-line regimen: sHR 2.82, 95% CI 2.00, 3.98, compared with first-line regimen), HBV coinfection (sHR 2.23, 95% CI 1.49, 3.33), fasting plasma glucose ≥126 mg/dl (sHR 1.98, 95% CI 1.22, 3.21, compared with <100 mg/dl) and estimated glomerular filtration rate <60 ml/min/1.73 m2 (sHR 2.57, 95% CI 1.56, 4.22). Decreased mortality was associated with transmission through male-to-male sexual contact (sHR 0.44, 95% CI 0.22, 0.88, compared with heterosexual transmission) and higher CD4+ T-cell count (200-349 cells/µl: sHR 0.27, 95% CI 0.20, 0.38, 350-499 cells/µl: sHR 0.10, 95% CI 0.07, 0.16 and ≥500 cells/µl: sHR 0.09, 95% CI 0.06, 0.13, compared with <200 cells/µl). Results after 10 years were similar, but most associations were weaker due to limited power. CONCLUSIONS: Next to preventing ART failure, HIV programmes should carefully monitor and treat comorbidities, including hepatitis, kidney disease and diabetes, to optimize survival after long-term ART exposure.