Objectives Abnormal hearing tests have been noted in HIV-infected patients in several studies, but the nature of the hearing deficit has not been clearly defined. We performed a cross-sectional study of both HIV+ and HIV− individuals in Tanzania using an audiological test battery. We hypothesized that HIV+ adults would have a higher prevalence of abnormal central and peripheral hearing test results compared to HIV− controls. Additionally, we anticipated that the prevalence of abnormal hearing assessments would increase with anti-retroviral therapy (ART) use, and treatment for tuberculosis (TB). Design Pure-tone thresholds, distortion product otoacoustic emissions (DPOAEs), tympanometry, and a gap detection test were performed using a laptop-based hearing testing system on 751 subjects (100 HIV− in the U.S., plus 651 in Dar es Salaam Tanzania including 449 HIV+ [130 ART− and 319 ART+], and 202 HIV−, subjects. No U.S. subjects had a history of TB treatment. In Tanzania, 204 of the HIV+, and 23 of the HIV−, subjects had a history of TB treatment. Subjects completed a video and audio questionnaire about their hearing as well as a health history questionnaire. Results HIV+ subjects had reduced DPOAE levels compared to HIV− subjects, but their hearing thresholds, tympanometry results, and gap detection thresholds were similar. Within the HIV+ group, those on ART reported significantly greater difficulties understanding speech-in-noise, and were significantly more likely to report that they had difficulty understanding speech than the ART− group. The ART+ group had a significantly higher mean gap detection threshold compared to the ART− group. No effects of TB treatment were seen. Conclusions The fact that the ART+/ART− groups did not differ in measures of peripheral hearing ability (DPOAEs, thresholds), or middle ear measures (tympanometry), but that the ART+ group had significantly more trouble understanding speech and higher gap detection thresholds, indicates a central processing deficit. These data suggest that: (a) hearing deficits in HIV+ individuals could be a central nervous system (CNS) side effect of HIV infection, (b) certain ART regimens might produce CNS side effects that manifest themselves as hearing difficulties, and/or (c) some ART regimens may treat CNS HIV inadequately, perhaps due to insufficient CNS drug levels, which is reflected as a central hearing deficit. Monitoring of central hearing parameters could be used to track central effects of either HIV or ART.

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.

Objectives In our cross-sectional study of human immunodeficiency virus (HIV)-infected adults, we showed lower distortion product otoacoustic emissions (DPOAEs) in HIV+ individuals compared to controls as well as findings consistent with a central auditory processing deficit in HIV+ adults on anti-retroviral therapy. We hypothesized that HIV+ children would also have a higher prevalence of abnormal central and peripheral hearing test results compared to HIV− controls. Design Pure-tone thresholds, DPOAEs, and tympanometry were performed on 244 subjects (131 HIV+, and 113 HIV−, subjects). Thirty-five of the HIV+, and 3 of the HIV−, subjects had a history of tuberculosis treatment. Gap detection results were available for 18 HIV− and 44 HIV+ children. Auditory brainstem response (ABR) results were available for 72 HIV− and 72 HIV+ children. Data from ears with abnormal tympanograms were excluded. Results HIV+ subjects were significantly more likely to have abnormal tympanograms, histories of ear drainage, tuberculosis, or dizziness. All audiometric results were compared between groups using a two-way ANOVA with HIV status and ear drainage history as grouping variables. Mean audiometric thresholds, gap detection thresholds, and ABR latencies did not differ between groups, although the HIV+ group had a higher proportion of individuals with a hearing loss >25 dB HL in the better ear. The HIV+ group had reduced DPOAE levels (p<0.05) at multiple frequencies compared to HIV− subjects. No relationships were found between treatment regimens or delay in starting treatment and audiological parameters. Conclusions As expected, children with HIV+ were more likely to have a history of ear drainage, and to have abnormal tympanograms. Similar to the adult findings, the HIV+ group did not show significantly reduced audiometric thresholds, but did have significantly lower DPOAE magnitudes. These data suggest that: (a) HIV+ children often have middle ear damage which complicates understanding the direct effects of HIV on the hearing system, and (b) even when corrected for confounders DPOAEs were lower in the HIV+ group. Previous studies suggest ototoxicity from anti-retroviral drugs is an unlikely cause of the reduced DPOAE magnitudes. Other possibilities include effects on efferent pathways connecting to outer hair cells or a direct effect of HIV on the cochlea.

Disseminated TB in HIV occurs with cellular immune responses indicating prior mycobacterial infection, and IS6110 analysis suggests an often lethal combination of reactivation and newly acquired infection. Control will require effective prevention of both remotely and recently acquired infection, and wider use of empiric therapy in patients with advanced AIDS and prolonged fever.