The Infectious Diseases Institute (IDI), established in 2001, was the first autonomous institution of Makerere University set up as an example of what self-governing institutes can do in transforming the academic environment to become a rapidly progressive University addressing the needs of society This paper describes the success factors and lessons learned in development of sustainable centers of excellence to prepare academic institutions to respond appropriately to current and future challenges to global health. Key success factors included a) strong collaboration by local and international experts to combat the HIV pandemic, along with b) seed funding from Pfizer Inc., c) longstanding collaboration with Accordia Global Health Foundation to create and sustain institutional strengthening programs, d) development of a critical mass of multi-disciplinary research leaders and managers of the center, and e) a series of strong directors who built strong governance structures to execute the vision of the institute, with subsequent transition to local leadership.Conclusion:Twenty years of sustained investment in infrastructure, human capital, leadership, and collaborations present Makerere University and the sub-Saharan Africa region with an agile center of excellence with preparedness to meet the current and future challenges to global health.

To better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1 env gp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples' sequences demonstrated, with one exception, that the women's founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women's founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men's viruses were found to link to the women's founders, nor did the women's env sequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others' findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters' blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen. IMPORTANCE Mucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males' genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.

Objective—Male circumcision reduces female-to-male HIV-1 transmission risk by approximately 60%. Data assessing the effect of circumcision on male-to-female HIV-1 transmission are conflicting, with one observational study among HIV-1 serodiscordant couples showing reduced transmission but a randomized trial suggesting no short-term benefit of circumcision. Correspondence to: Jared Baeten, University of Washington, 901 Boren Avenue, Suite 1300, Seattle, WA 98104, Tel – 206-520-3808, Fax – 206-520-3801, jbaeten@u.washington.edu. *The Partners in Prevention HSV/HIV Transmission Study team members are listed after the Acknowledgements Conference presentation: Presented in part at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, 19-22 July 2009 (abstract LBPEC06). Conflict of Interest: No authors report conflicts of interest regarding content for this manuscript. Authorship: Data were collected as part of the Partners in Prevention HSV/HIV Transmission Study, designed by CC. All authors contributed to the design of the present analysis and to the final draft of the manuscript. JB completed the first draft of the manuscript; DD performed the statistical analyses. Partners in Prevention HSV/HIV Transmission Study Team: University of Washington Coordinating Center and Central Laboratories, Seattle, USA: Connie Celum (principal investigator), Anna Wald (protocol co-chair), Jairam Lingappa (medical director), Jared Baeten, Mary S. Campbell, Robert W. Coombs, Lawrence Corey, James P. Hughes, Amalia Magaret, M. Juliana McElrath, Rhoda Morrow, James I. Mullins, William L. H. Whittington Study sites and site principal investigators: Cape Town, South Africa (University of Cape Town): David Coetzee; Eldoret, Kenya (Moi University, Indiana University): Kenneth Fife, Edwin Were; Gaborone, Botswana (Botswana Harvard Partnership): Max Essex, Joseph Makhema; Kampala, Uganda (Infectious Disease Institute, Makerere University): Elly Katabira, Allan Ronald; Kigali, Rwanda (Rwanda Zambia HIV Research Group, and Emory University): Susan Allen, Kayitesi Kayitenkore, Etienne Karita; Kisumu, Kenya (Kenya Medical Research Institute, University of California San Francisco): Elizabeth Bukusi, Craig Cohen; Kitwe, Zambia (Rwanda Zambia HIV Research Group, and Emory University): Susan Allen, William Kanweka; Lusaka, Zambia (Rwanda Zambia HIV Research Group, and Emory University): Susan Allen, Bellington Vwalika; Moshi, Tanzania (Kilimanjaro Christian Medical College, Harvard University): Saidi Kapiga, Rachel Manongi; Nairobi, Kenya (University of Nairobi, University of Washington): Carey Farquhar, Grace John-Stewart, James Kiarie; Ndola, Zambia (Rwanda Zambia HIV Research Group, and Emory University): Susan Allen, Mubiana Inambao; Orange Farm, South Africa (Reproductive Health Research Unit, University of the Witwatersrand): Sinead Delany-Moretlwe, Helen Rees; Soweto, South Africa (Perinatal HIV Research Unit, University of the Witwatersrand): Guy de Bruyn, Glenda Gray, James McIntyre; Thika, Kenya (University of Nairobi, University of Washington): Nelly Rwamba Mugo Data management was provided by DF/Net Research, Inc. (Seattle, USA) and site laboratory oversight was provided by Contract Lab Services (University of the Witwatersrand, Johannesburg, South Africa). NIH Public Access Author Manuscript AIDS. Author manuscript; available in PMC 2011 March 13. Published in final edited form as: AIDS. 2010 March 13; 24(5): 737–744. doi:10.1097/QAD.0b013e32833616e0. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Design/Methods—Data collected as part of a prospective study among African HIV-1 serodiscordant couples were analyzed for the relationship between circumcision status of HIV-1 seropositive men and risk of HIV-1 acquisition among their female partners. Circumcision status was determined by physical examination. Cox proportional hazards analysis was used. Results—1096 HIV-1 serodiscordant couples in which the male partner was HIV-1 infected were followed for a median of 18 months; 374 (34%) male partners were circumcised. Sixty-four female partners seroconverted to HIV-1 (incidence 3.8 per 100 person-years). Circumcision of the male partner was associated with a non-statistically significant ∼40% lower risk of HIV-1 acquisition by the female partner (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.35-1.10, p=0.10). The magnitude of this effect was similar when restricted to the subset of HIV-1 transmission events confirmed by viral sequencing to have occurred within the partnership (n=50, HR 0.57, p=0.11), after adjustment for male partner plasma HIV-1 concentrations (HR 0.60, p=0.13), and when excluding follow-up time for male partners who initiated antiretroviral therapy (HR 0.53, p=0.07). Conclusions—Among HIV-1 serodiscordant couples in which the HIV-1 seropositive partner was male, we observed no increased risk and potentially decreased risk from circumcision on male-to-female transmission of HIV-1.

Abstract: Sharing of pre-exposure prophylaxis (PrEP) medications is a concern for PrEP implementation. For HIV-1 serodiscordant couples, sharing may undermine the HIV-1 prevention benefit and also cause antiretroviral resistance if taken by HIV-1 infected partners. Within a PrEP efficacy trial among HIV-1 serodiscordant couples, we assessed the occurrence of PrEP sharing by self-report and plasma tenofovir concentrations in HIV-1 infected partners. PrEP sharing was self-reported at <0.01% of visits, and 0%–1.6% of randomly selected and 0% of purposively selected specimens from HIV-1 infected participants had detectable tenofovir concentrations (median: 66.5 ng/mL, range: 1.3–292 ng/mL). PrEP sharing within HIV-1 serodiscordant couples was extremely rare.

BACKGROUND Antiretroviral therapy (ART) markedly reduces the risk of HIV-1 transmission in serodiscordant partnerships. We previously found that younger age and higher CD4 counts were associated with delayed initiation of ART by HIV-1-infected partners in serodiscordant partnerships. Among those initiating ART, we sought to explore whether those same factors were associated with failure to achieve viral suppression. METHODS In a prospective study of HIV-1-infected persons who had a known heterosexual HIV-1-uninfected partner in Kenya and Uganda [Partners Pre-Exposure Prophylaxis (PrEP) Study], we used Cox proportional hazards regression to evaluate correlates of viral nonsuppression (HIV-1 RNA >80 copies/ml). RESULTS Of 1,035 HIV-1-infected participants initiating ART, 867 (84%) achieved viral suppression: 77% by 6 months and 86% by 12 months. Younger age [adjusted hazard ratio (aHR) 1.05 for every 5 years younger; p = .006], lower pretreatment CD4 count (aHR 1.26; p = .009 for ≤250 compared with >250 cells/μl), and higher pretreatment HIV-1 RNA quantity (aHR 1.21 per log10; p < .001) independently predicted failure to achieve viral suppression. Following initial viral suppression, 8.8% (76/867) experienced virologic rebound (HIV-1 RNA >200 copies/ml): 6.3% and 11.5% by 6 and 12 months after initial suppression, respectively. Age was the only factor associated with increased risk of virologic rebound (aHR 1.33 for every 5 years younger; p = .005). CONCLUSIONS For HIV-1-infected persons in serodiscordant couples, younger age was associated with delayed ART initiation, failure to achieve viral suppression, and increased risk of virologic rebound. Motivating ART initiation and early adherence is a key to achieving and sustaining viral suppression.

BACKGROUND:Intermittent shedding of human immunodeficiency virus type 1 (HIV) in semen occurs despite effective antiretroviral therapy (ART) and suppressed blood HIV-1 RNA levels.METHODS:We assessed the frequency, magnitude, and correlates of seminal HIV-1 RNA shedding in HIV-1-infected African men initiating ART.RESULTS:Seminal HIV-1 RNA was detected in 24% (37 of 155), 10% (5 of 49), and 11% (8 of 70) of samples collected 0-3, 4-6, and >6 months after ART initiation. When blood HIV-1 levels were suppressed, seminal HIV-1 RNA was detected in 8% (16 of 195), and 82% (13 of 16) had an HIV-1 RNA load of < 1000 copies/mL.CONCLUSIONS:Seminal HIV-1 RNA shedding was infrequent and present at low levels in HIV-1-infected African men with suppressed blood HIV-1 RNA.

OBJECTIVES:To evaluate the effect of on-site support in improving human immunodeficiency virus (HIV) rapid testing, tuberculosis (TB) sputum microscopy, and malaria microscopy among laboratory staff in a low-resource setting.METHODS:This cluster randomized trial was conducted at 36 health facilities in Uganda. From April to December 2010, laboratory staff at 18 facilities participated in monthly on-site visits, and 18 served as control facilities. After intervention, 128 laboratory staff were observed performing 587 laboratory tests across three diseases: HIV rapid testing, TB sputum microscopy, and malaria microscopy. Outcomes were the proportion of laboratory procedures correctly completed for the three laboratory tests.RESULTS:Laboratory staff in the intervention arm performed significantly better than the control arm in correctly completing laboratory procedures for all three laboratory tests, with an adjusted relative risk (95% confidence interval) of 1.18 (1.10-1.26) for HIV rapid testing, 1.29 (1.21-1.40) for TB sputum microscopy, and 1.19 (1.11-1.27) for malaria microscopy.CONCLUSIONS:On-site support significantly improved laboratory practices in conducting HIV rapid testing, TB sputum microscopy, and malaria microscopy. It could be an effective method for improving laboratory practice, without taking limited laboratory staff away from health facilities for training.

AIDS Research and Human RetrovirusesVol. 30, No. S1 Treatment as Prevention: Initiation, Adherence, and Monitoring on ARVFree AccessFrequency of Achieving Viral Suppression among HIV-infected Persons in Serodiscordant Partnerships Initiating Antiretroviral TherapyAndrew Mujugira, Connie Celum, Allan Ronald, Nelly Mugo, and Jared BaetenAndrew MujugiraUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Connie CelumUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Allan RonaldUniversity of Manitoba, Winnipeg, MB, CanadaSearch for more papers by this author, Nelly MugoUniversity of Washington, Seattle, WA, United StatesKenya Medical Research Institute, Nairobi, KenyaSearch for more papers by this author, and Jared BaetenUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5651.abstractAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookXLinked InRedditEmail P52.06Background: Antiretroviral therapy (ART) markedly reduces the risk of HIV transmission in serodiscordant partnerships. The concentration of HIV RNA in plasma is the principal measure of ART adherence and is also the prime determinant of HIV transmission risk.Methods: We used data from a prospective study of 928 HIV-infected persons from Kenya and Uganda who had a known heterosexual HIV-uninfected partner, to assess viral suppression after ART initiation. Plasma was archived 6-monthly and later tested for HIV RNA quantity. Kaplan-Meier methods, and Cox regression models, were used to identify independent predictors of viral suppression.Results: The median age was 35 years (interquartile range [IQR] 29, 41), and 502 (54%) were women. The median CD4 count and HIV RNA plasma concentration prior to ART start were 270 cells/μL (IQR 213, 370) and 4.34 log10 copies/ml (IQR 3.65, 4.85), respectively. The cumulative probabilities of achieving viral suppression at 6 and 12 months were 82.8% and 90.8% for HIV RNA concentration<400 copies/ml. Female gender (adjusted hazard ratio [AHR] 1.19; 95% CI: 1.02, 1.39; p=0.03) predicted viral suppression. Older age (AHR 1.04 per-5 year increase; 95% CI: 0.99, 1.08; p=0.03), higher education (AHR 1.14; 95% CI: 0.99, 1.31; p=0.07 for>7 years), and higher CD4 count (AHR 1.16; 95% CI: 0.97, 1.38 for>200 compared with<200 cells/μL) were of borderline significance.Conclusions: Three-quarters of HIV-infected persons with known HIV-uninfected partners achieved viral suppression within 6 months of ART initiation. These results support World Health Organization guidance recommending ART initiation for persons with known HIV-uninfected partners, which could be optimized by viral load monitoring to identify those needing adherence support.FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Andrew Mujugira, Connie Celum, Allan Ronald, Nelly Mugo, and Jared Baeten.Frequency of Achieving Viral Suppression among HIV-infected Persons in Serodiscordant Partnerships Initiating Antiretroviral Therapy.AIDS Research and Human Retroviruses.Oct 2014.A287-A288.http://doi.org/10.1089/aid.2014.5651.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

AIDS Research and Human RetrovirusesVol. 30, No. S1 Correlates of Protection and ExposureHIV-specific T and NK-cell Responses Do Not Correlate with Protection from Sexual Acquisition of HIVLaura Pattacini, Jared M. Baeten, Katherine K. Thomas, Tayler R. Fluharty, Pamela M. Murnane, Deborah Donnell, Elizabeth Bukusi, Allan Ronald, Nelly Mugo, Jairam R. Lingappa, Connie Celum, Juliana M. McElrath, Jennifer M. Lund, and Partners PrEP Study TeamLaura PattaciniFred Hutchinson Cancer Research Center, Seattle, WA, United StatesSearch for more papers by this author, Jared M. BaetenUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Katherine K. ThomasUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Tayler R. FluhartyFred Hutchinson Cancer Research Center, Seattle, WA, United StatesSearch for more papers by this author, Pamela M. MurnaneUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Deborah DonnellFred Hutchinson Cancer Research Center, Seattle, WA, United StatesUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Elizabeth BukusiUniversity of Washington, Seattle, WA, United StatesKenya Medical Research Institute, Nairobi, KenyaSearch for more papers by this author, Allan RonaldUniversity of Manitoba, Winnipeg, MB, CanadaSearch for more papers by this author, Nelly MugoUniversity of Washington, Seattle, WA, United StatesKenya Medical Research Institute, Nairobi, KenyaSearch for more papers by this author, Jairam R. LingappaUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Connie CelumUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Juliana M. McElrathFred Hutchinson Cancer Research Center, Seattle, WA, United StatesUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, Jennifer M. LundFred Hutchinson Cancer Research Center, Seattle, WA, United StatesUniversity of Washington, Seattle, WA, United StatesSearch for more papers by this author, and Partners PrEP Study TeamSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5181.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"HIV-specific T and NK-cell Responses Do Not Correlate with Protection from Sexual Acquisition of HIV." AIDS Research and Human Retroviruses, 30(S1), pp. A97–A98FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Laura Pattacini, Jared M. Baeten, Katherine K. Thomas, Tayler R. Fluharty, Pamela M. Murnane, Deborah Donnell, Elizabeth Bukusi, Allan Ronald, Nelly Mugo, Jairam R. Lingappa, Connie Celum, Juliana M. McElrath, Jennifer M. Lund, and Partners PrEP Study Team.HIV-specific T and NK-cell Responses Do Not Correlate with Protection from Sexual Acquisition of HIV.AIDS Research and Human Retroviruses.Oct 2014.A97-A98.http://doi.org/10.1089/aid.2014.5181.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Background Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of aciclovir on HIV-1 progression.Methods In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to aciclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mu L or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per mu L, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per mu L. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.Findings At enrolment, the median CD4 cell count was 462 cells per mu L and median HIV-1 plasma RNA was 4.1 log(10) copies per mu L. Aciclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned aciclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >= 350 cells per mu L, aciclovir delayed risk of CD4 cell counts falling to <350 cells per mu L by 19% (0.81, 0.71-0.93, p=0.002).Interpretation The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.

As a result of the pandemic of human immunodeficiency virus infection, more academic physicians involved in research are working in resource-limited settings, especially in the field of infectious diseases. These researchers are often located in close proximity to health care facilities with serious workforce shortages. Because institutions and funders support global health research, they have the opportunity to make a lasting impact on the health system by training local health workers where the research is being conducted. Academic researchers who spend clinical time in local health care centers and who teach and mentor students as part of academic social responsibility will build capacity, an investment that will yield dividends for future generations.

Introduction: Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.Methods: Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).Results: 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7-6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7-9.0, p = 0.001) and persons with HIV infection (IRR= 1.7, 95% CI = 1.0-2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8-5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs).Conclusions: HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.

Background. In the United States, clade B is the predominant human immunodeficiency virus (HIV) subtype, whereas in sub-Saharan Africa, clades A, C, and D are the predominant subtypes. HIV subtype may have an impact on HIV disease progression. The effect of HIV subtype on the risk of dementia has, to our knowledge, not been examined. The objective of this study was to examine the relationship between HIV subtype and the severity of HIV-associated cognitive impairment among individuals initiating antiretroviral therapy in Uganda.Methods. Sixty antiretroviral-naive HIV-infected individuals with advanced immunosuppression who were at risk of HIV-associated cognitive impairment underwent neurological, neuropsychological, and functional assessments, and gag and gp41 regions were subtyped. Subtype assignments were generated by sequence analysis using a portion of the gag and gp41 regions.Results. Thirty-three HIV-infected individuals were infected with subtype A, 2 with subtype C, 9 with subtype D, and 16 with A/D recombinants. Eight (89%) of 9 HIV-infected individuals with subtype D had dementia, compared with 7 (24%) of 33 HIV-infected individuals with subtype A (P = .004).Conclusions. These results suggest that, in untreated HIV-infected individuals with advanced immunosuppression who are at risk of developing HIV-associated cognitive impairment, HIV dementia may be more common among patients infected with subtype D virus than among those infected with subtype A virus. These findings provide the first evidence, to our knowledge, to demonstrate that HIV subtypes may have a pathogenetic factor with respect to their capacity to cause cognitive impairment. Additional studies are needed to confirm this observation and to define the mechanism by which subtype D leads to an increased risk of neuropathogenesis.

Fourteen university-based Ugandan and North American physicians in 2001 founded a unique organization at Makerere University Faculty of Medicine in Uganda, the Academic Alliance for AIDS Care and Prevention in Africa (AA), with programs in training, research, prevention, and care. Funding was obtained from Pfizer, Inc.; in 2004, the Infectious Disease Institute (IDI) was built to house the flagship training and care programs of the AA. Although HIV/AIDS was the initial priority, other infectious diseases have been added to the AA's mission, and training has been provided to date to individuals from 26 countries in Africa. These programs are now supported by the Academic Alliance Foundation (AAF), which is based in the United States. The authors describe the AA's programs to train health care workers and to offer ongoing support for health care professionals throughout Africa, as well as efforts to strengthen the health care system within Uganda. They also outline research and clinical services carried out by the IDI and research scholarship programs supported by the AAF. They state that it is too early to judge the success of the AA, and they acknowledge that the lack of trained health care providers and of an adequate care infrastructure are major challenges in Africa. They conclude that the critical challenge facing the AAF and the IDI is to diversify the funding base to sustain current program levels. They then enumerate issues that must be addressed to ensure long-term organizational strength and stability.

BACKGROUND:Cryptococcal meningitis (CM) is the proximate cause of death in 20%-30% of persons with acquired immunodeficiency syndrome in Africa. METHODS:Two prospective, observational cohorts enrolled human immunodeficiency virus (HIV)-infected, antiretroviral-naive persons with CM in Kampala, Uganda. The first cohort was enrolled in 2001-2002 (n = 92), prior to the availability of highly active antiretroviral therapy (HAART), and the second was enrolled in 2006-2007 (n = 44), when HAART was available. RESULTS:Ugandans presented with prolonged CM symptoms (median duration, 14 days; interquartile range, 7-21 days). The 14-day survival rates were 49% in 2001-2002 and 80% in 2006 (P < .001). HAART was started 35 +/- 13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006-2007, the survival rate continued to decrease after hospitalization, with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients, with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H(2)O; 81% of patients had elevated pressure (>200 mm H(2)O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures >250 mm H(2)O (odds ratio [OR], 2.1; 95% confidence interval [CI], 0.9-5.2; P = .09). Initial CSF WBC counts of <5 cells/mL were associated with failure of CSF sterilization (OR, 17.3; 95% CI, 3.1-94.3; P < .001), and protein levels <35 mg/dL were associated with higher mortality (OR, 2.0; 95% CI, 1.2-3.3; P = .007). CONCLUSIONS:Significant CM-associated mortality persists, despite the administration of amphotericin B and HIV therapy, because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome-related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.

Background:HIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART). Methods:From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enrolled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months. Results:Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations. Conclusions:These data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. Our data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.