Objectives

Artesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ).

Methods

This was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Results

Exposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC₀₋₂₄ 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC₀₋₉₆ 14,571 versus 21,648 ng·h/mL, P < 0.01). The AUCDEAQ/AUC(amodiaquine) ratio was not different between groups (ART group 116 versus control group 102, P = 0.67).

Conclusions

Subjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.

Hearing loss is the most common sensory deficit in humans with causative variants in over 140 genes. With few exceptions, however, the population-specific distribution for many of the identified variants/genes is unclear. Until recently, the extensive genetic and clinical heterogeneity of deafness precluded comprehensive genetic analysis. Here, using a custom capture panel (MiamiOtoGenes), we undertook a targeted sequencing of 180 genes in a multi-ethnic cohort of 342 GJB2 mutation-negative deaf probands from South Africa, Nigeria, Tunisia, Turkey, Iran, India, Guatemala, and the United States (South Florida). We detected causative DNA variants in 25 % of multiplex and 7 % of simplex families. The detection rate varied between 0 and 57 % based on ethnicity, with Guatemala and Iran at the lower and higher end of the spectrum, respectively. We detected causative variants within 27 genes without predominant recurring pathogenic variants. The most commonly implicated genes include MYO15A, SLC26A4, USH2A, MYO7A, MYO6, and TRIOBP. Overall, our study highlights the importance of family history and generation of databases for multiple ethnically discrete populations to improve our ability to detect and accurately interpret genetic variants for pathogenicity.