HIV/AIDS is a global pandemic with nearly 33 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with perinatal and heterosexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the results of a randomized clinical trial of circumcision to prevent HIV acquisition among 4,996 men in Uganda. At the end of the trial HIV incidence was 0.66% among circumcised men and 1.33% in the uncircumcised group with an estimated efficacy of 51%. The as-treated protective efficacy of circumcision was 55% and increased to 60% in those followed for 24 months. Now one year after stopping the trial, the protective efficacy of circumcision is 75%. No evidence of behavioral disinhibition has been noted. The rates of adverse events (AEs) related to male circumcision were also assessed among HIV-positive and HIV-negative men in Uganda. The risk of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV- negative participants, respectively. Infections were the most common AEs (2.6/100 in HIV-positive vs. 3.0/100 in HIV-negative men). Risk of other complications was similar in the two groups. AEs were more common in men who resumed sexual intercourse before wound healing compared to those who had waited. In addition to the protective efficacy against HIV acquisition, circumcision also reduced the frequency of genital ulcer by 50%. Since herpes is the predominant cause of genital ulcers, we examined the effect of circumcision on acquisition to herpes simplex virus type 2 (HSV-2) within the context of this trial. The cumulative probability of HSV-2 seroconversion over two years was 7.8% in the circumcision group compared to 10.3% in the control group with an adjusted estimate of efficacy of 28% (p = 0.008). HSV-2 incidence was lower in the circumcised group than the control group for all sociodemographic, behavioral, and STD symptom groups. Male circumcision did affect the incidence of syphilis although rates of syphilis were extremely low in this population. We examined the effect of male circumcision on the incidence of STDs in their wives compared to the wives of uncircumcised men. At one year follow-up, wives of circumcised men reported lower rates of genital ulceration (22% reduction), but no differences in vaginal discharge or dysuria. The risk of trichomonas infection was reduced in the wives of circumcised men (48% reduction) as were the risks of any bacterial vaginosis (BV) (40% reduction) and severe BV (61% reduction). Thus, it appears that male circumcision reduces HIV acquisition and the incidence of genital ulcers, particularly HSV-2 infection, and further reduces genital ulcer disease, trichomoniasis, and bacterial vaginosis in the wives of circumcised men. On the basis of these trials and their associated findings, the WHO and UNAIDS endorse male circumcision to reduce HIV acquisition in men internationally.? In studies in Lusaka, Zambia, we examined the efficacy of measles vaccination in children born to HIV-infected mothers. HIV-infected infants had lower levels of passively acquired antibodies to measles at birth than uninfected children. Of 696 children aged 2 to 8 months who received measles vaccine, 88% of the HIV-infected children developed antibody levels compared to 94% of the seronegative children. However, by 27 months after vaccination, only half of the HIV-infected children who survived and returned for follow-up maintained measles antibody levels compared to 92% of the uninfected children. In a follow-up of these children at three years, 39% of the 105 HIV-infected children had died compared to only a 1.6% mortality of HIV seronegative children. Anemia and % CD4 T-lymphocytes < 15% were significantly associated with mortality among the HIV-infected children. We further examined the risk factors for measles mortality in a population with a relatively high HIV prevalence in Zambia. Of 1,474 children 83% had confirmed measles and known HIV infection status. One-third of the HIV-infected children with measles were less than nine months of age, the age of routine measles vaccination, compared to one-fourth of the uninfected children. Death occurred during hospitalization in 23 (12.2%) of HIV-infected children with measles compared to 45 (4.3% of the HIV-uninfected children with measles (p < 0.001). After adjusting for age, sex, and measles vaccination status, HIV infection (OR = 2.5), < 8 years of maternal education (OR = 2.4) and the presence of a desquamating rash (OR = 2.2) were significant predictors of mortality due to measles. Thus, in a region of HIV prevalence co-infection with HIV more than doubled the odds of death in hospitalized children with measles. Increased mortality among HIV-infected children is further evidence that greater efforts are necessary to reduce transmission of HIV perinatally. ? We initiated a study to determine the frequency and transmission patterns of HIV-infected long-term non-progressors (LTNP) in Africa. A retrospective analysis of subjects in Uganda identified 4,813 HIV-infected individuals including 637 HIV seroconverters. Of all HIV-positive subjects, 4% were identified as LTNP defined as being infected for more than seven years with a CD4 cell count above 600 without ARVs. Of the HIV seroconverters, 9.1% were found to be LTNP and 1.4% were identified as HIV elite controllers, i.e., those who had no detectable viral load without ARV treatment. LTNP had significantly lower viral load setpoint than all other seroconverters (p < 0.001). The transmission frequency of HIV from a LTNP to their sex partner was 8.2% (5/61) and three of the five partners progressed to AIDS. In comparison the frequency of HIV transmission in discordant partnerships where the prevalent partner was not an LTNP was 21.9% (159/726) with ten recipients ultimately becoming LTNP. None of the four HIV elite controllers identified in this study transmitted to their partners at any time during follow-up, suggesting that naturally suppressed viral load below detectable levels results in a very low probability of transmission. Thus, LTNP can transmit HIV to their partners although at a significantly lower frequency than that observed among non-LTNP. The finding that transmissions may occur from an LTNP and result in progressive AIDS in the recipient indicates that the host immune response is responsible for predicting those individuals that can either control their virus to undetectable levels or suppress it significantly to slow their progression rate and reduce transmission. These data have implications for the future design of therapeutic vaccines. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.
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