The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring and potential delays in detecting virologic failure on genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease progression. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment. We have observed declining incidence among Rakai cohort participants since the introduction of ARVs and safe male circumcision with an even greater decline among men (benefiting from both MMC and exposure to female partners on treatment) supporting the current scale up of combination HIV prevention. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We analyzed antiretroviral drug susceptibility in HIV from 38 participants failing first and second line antiretroviral treatment (ART) regimens in Rakai, Uganda. At baseline, four (13%) of 31 participants had mutations associated with resistance to either nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTIs or NNRTIs). Most participants failing first-line ART had mutations to NNRTIs (86%) and lamivudine (81%), but only 22% had other NRTI mutations. None of the six participants failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Concern has also been raised regarding the potential impact of hormonal contraception and the risk of virologic failure in women. Consistent with current World Health Organization guidelines, we found no deleterious effect of injectable contraceptive use on response to ART in our cohort. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings; most programs use clinical or immunological monitoring (IM) only. We compared the genotypic resistance patterns between patients with VLM to those with IM in Kampala, Uganda. 559 antiretroviral naive clients were enrolled in a prospective cohort, initiated ART, and monitored with viral load and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36-40 months and immunologically monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Virologic failure rates at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and 10% in the IM group at 36-40 months. 59% patients in the VLM group compared to 90% in the IM group, (P<0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. Routine viral load monitoring during the first 3 years of ART reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. Early viral load monitoring may also offer an additional tool to improve adherence and reduce the risk of virologic failure. Of 1,841 patients with at least 48 weeks of follow-up, 1,699 (92%) had an undetectable VL at 24 weeks (early suppressors). Of the remaining 142 (8%) patients who had a detectable VL at 24 weeks, 60% of whom went on to be undetectable at 48 weeks (late suppressors). The majority of late suppressors (84%) remained suppressed well beyond 48 weeks. Variables significantly predicting non-suppression by 48 weeks included: 24 week VL>2,000 copies/ml (OR=7.9; 95% CI 3.6-17.4) and age <30 (OR=2.8; 95% CI 1.3-6.2). The majority of patients with detectable VL at 24 weeks went on to full suppression which remained durable well beyond 48 weeks. We have continued to examine the etiology of severe sepsis in Ugandan hospitals and evaluate interventions to improve mortality outcomes. A follow-up intervention study evaluated the impact of early fluid resuscitation and intensive monitoring among 426 Ugandan patients presenting with severe sepsis. This simple, early intervention lowered the risk of mortality by 26% compared to standard of care management. Nearly 1 in 4 adult HIV-infected patients hospitalized with severe sepsis in 2 Ugandan hospitals had MTB bacteremia. In our sepsis study we showed that an MTB bacteremia risk score can improve early diagnosis of MTB bacteremia particularly in settings with increased HIV and MTB co-infection such as Uganda. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda. We enrolled 440 HIV-1, HSV-2 dually infected adults with CD4+ T-cell counts 300-400 cells/L and not on antiretroviral therapy in a randomized controlled trial with each arm receiving either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (p=0.029), with Acyclovir reducing overall disease progression by 25% compared to placebo (p=0.04). In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals not yet on ARVs, particularly among those with high viral loads. In a secondary analysis, we found that the rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. We also found no difference in HPV prevalence suggesting that at least early immune reconstitution is insufficient to promote HPV clearance. Liver disease is a leading cause of mortality among HIV-infected persons. The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (P=0.008). HIV infection was associated with a 50% increase in liver fibrosis. Fibrosis was also associated with male gender, herbal medicine use, heavy alcohol consumption, occupational fishing and chronic HBV infection. Among HIV-infected participants, ART reduced fibrosis risk (P=0.030). Elevated sCD14 levels were strongly associated with liver disease in the HIV-positive population in the absence of microbial translocation. These findings suggest that monocytes may have alternative properties associated with liver disease in HIV-infected versus HIV-uninfected Africans. Operational research on how best to improve the quality of HIV care delivered in this setting has also been an important component of our activities. We conducted a study that demonstrated that task shifting to PHWs positively affected structural and programmatic functions of care delivery by improving clinical organization, medical care access, treatment fatigue, and patient-provider communication. Qualitative analyses found improvements in patient care and logistics and broad support for the mHealth (mobile phone) intervention among patients, clinic staff, and PHWs. Excluding supervisory staffing costs, yearly costs for the PHW intervention was $8475, resulting in a yearly cost per patient of $8.74, per virologic failure averted cost of $189, and per patient lost to follow-up averted cost of $1025.