Browsing by Author "Bennett, John"

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    Impact of CD8R T-cell activation on CD4R T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy
    (AIDS (London, England), 2011) Hunt, Peter W.; Caoa, Huyen L.; Muzoora, Conrad; Ssewanyana, Isaac; Bennett, John; Emenyonu, Nneka; Kembabazi, Annet; Neilands, Torsten B.; Bangsberg, David R.; Deeks, Steven G.; Martin, Jeffrey N.
    To assess whether T-cell activation independently predicts the extent of CD4þ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART). Prospective cohort study. HIV-infected adults starting ART and achieving a plasma HIV RNA level (VL) less than 400 copies/ml by month 6 were sampled from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara, Uganda. CD4 count, VL, and the percentage-activated (CD38þHLA-DRþ) T cells were measured every 3 months. Of 451 HIV-infected Ugandans starting ART, most were women (70%) with median pre-ART values: age, 34 years; CD4 count, 135 cells/ml; and VL, 5.1 log10 copies/ml. Of these, 93% achieved a VL less than 400 copies/ml by month 6 and were followed for a median of 24 months, with 8% lost to follow-up at 3 years. Higher pre- ART CD8þ T-cell activation was associated with diminished CD4 recovery after year 1, after adjustment for pre-ART CD4 count, VL, and sex (P¼0.017). Thirty-four participants died, 15 after month 6. Each 10% point increase in activated CD8þ T cells at month 6 of suppressive ART was associated with a 1.6-fold increased hazard of subsequent death after adjusting for pretherapy CD4 count (P¼0.048). Higher pre-ART CD8þ T-cell activation independently predicts slower CD4þ T-cell recovery and higher persistent CD8þ T-cell activation during ART mediated viral suppression independently predicts increased mortality among HIV infected Ugandans. Novel therapeutic strategies aimed at preventing or reversing immune activation during ART are needed in this setting.
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    The Kynurenine Pathway of Tryptophan Catabolism, CD4+ T-Cell Recovery, and Mortality Among HIV-Infected Ugandans Initiating Antiretroviral Therapy
    (The Journal of infectious diseases, 2014) Byakwaga, Helen; Boum, Yap; Huang, Yong; Muzoora, Conrad; Kembabazi, Annet; Weiser, Sheri D.; Bennett, John; Cao, Huyen; Haberer, Jessica E.; Deeks, Steven G.; Bangsberg, David R.; McCune, Joseph M.; Martin, Jeffrey N.; Hunt, Peter W.
    Human immunodeficiency virus (HIV) infection–induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown. We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the “KT ratio”) in HIV-infected Ugandans before and during antiretroviral therapy (ART)–mediated viral suppression and its association with the rate of subsequent CD4+ T-cell count recovery and mortality. Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4+ T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4+ T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4+ T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4+ T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016). The kynurenine pathway of tryptophan catabolism independently predicts poor CD4+ T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.
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    Treatment as long-term prevention: sustained reduction in HIV sexual transmission risk with use of antiretroviral therapy in rural Uganda
    (AIDS (London, England), 2014) Siedner, Mark J.; Musinguzi, Nicholas; Tsai, Alexander C.; Muzoora, Conrad; Kembabazi, Annet; Weiser, Sheri D.; Bennett, John; Hunt, Peter W.; Martin, Jeffrey N.; Haberer, Jessica E.; Bangsberg, David R.
    Suppressive antiretroviral therapy (ART) substantially decreases HIV transmission in clinical research settings. We sought to measure the frequency and correlates of periods of transmission risk among individuals taking ART during multiple years of observation in rural, southwestern Uganda. Observational cohort study. We collected sexual behavior and viral load data in a Ugandan cohort of people living with HIV/AIDS from the time of ART initiation. We defined each 90-day visit as a potential transmission period if HIV-1 RNA was more than 400 copies/ml and the participant reported sexual transmission risk behavior, defined as unprotected sexual contact with at least 1 HIV-uninfected partners or partners of unknown serostatus in the prior 90 days. Results: We evaluated data from 463 individuals on ART over a median 3.5 years of observation and 5293 total study visits. During that time, over half (259, 56%) had detectable viremia or reported sexual transmission risk behavior at least once. However, only 23 (5%) had both simultaneously, at 28 (<1%) of all visits. Transmission sexual behavior was reported at 6% of visits with detectable viremia. In multivariable regression modeling, correlates of transmission risk periods included younger age, lower CD4þ cell count, low household asset ownership and increased internalized stigma. Although detectable viremia and/or sexual transmission risk behavior occurred in over half of individuals, ART reduced periods of HIV transmission risk by over 90% during up to 6 years of observation time. These findings provide further support for provision of ART, along with interventions to promote long-term adherence, to reduce HIV transmission in HIV-endemic settings.