Infectious Diseases Institute at Makerere University College of Health Sciences: a case study of a sustainable capacity building model for health care, research and training.

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.

The future of financing for HIV services in Uganda and the wider sub-Saharan Africa region: should we ask patients to contribute to the cost of their care?

Whilst multi-lateral funding for HIV/AIDS dramatically increased from 2004 to 2008, it has largely plateaued in the last 8 years. Across sub-Saharan Africa, up to 20 % of total spending on health is used for HIV services, and of this over 85 % is estimated to come from international funding rather than in-country sources. In Uganda, the fiscal liability to maintain services for all those who are currently receiving it is estimated to be as much as 3 % of Gross Domestic Product (GDP). In order to meet the growing need of increased patient numbers and further ART coverage the projected costs of comprehensive HIV care and treatment services will increase substantially. Current access to HIV care includes free at point of delivery (provided by Ministry of Health clinics), as well as out-of-pocket financing and health insurance provided care at private for- and not for- profit facilities. The HIV response is funded through Ugandan Ministry of Health national budget allocations, as well as multilateral donations such as the President's Emergency Plan for AIDS in Africa (PEPFAR) and Global Fund (GF) and other international funders. We are concerned that current funding mechanism for HIV programs in Uganda may be difficult to sustain and as service providers we are keen to explore ways in which provide lifelong HIV care to as many people living with HIV (PLHIV) as possible. Until such time as the Ugandan economy can support universal, state-supported, comprehensive healthcare, bridging alternatives must be considered. We suggest that offering patients with the sufficient means to assume some of the financial burden for their care in return for more convenient services could be one component of increasing coverage and sustaining services for those living with HIV.

Innovative Demand Creation for Voluntary Medical Male Circumcision Targeting a High Impact Male Population: A Pilot Study Engaging Pregnant Women at Antenatal Clinics in Kampala, Uganda.

BACKGROUND: Circumcision has been shown to be an effective method of HIV prevention; however, only 27% of Ugandan men aged 15-49 years are circumcised. There is a paucity of data on the role of intimate partners in generating demand for voluntary medical male circumcision (VMMC). We conducted a pilot study to assess the feasibility of a partner-focused intervention targeting males >25 years. METHODS: Among pregnant women in their third trimester attending antenatal care we evaluated the impact of a pilot behavior change intervention on VMMC through a quasi-experimental approach. We observed VMMC numbers among spouses of women as per standard practice (comparison phase), and after introducing a behavioral change communication package (intervention phase). Logistic regression was used to compare the odds of VMMC uptake between comparison and intervention phases. We used qualitative methods to evaluate the casual chain using a thematic approach. RESULTS: Of the 601 women studied, 90% articulated the health benefits of VMMC and 99% expressed interest in their spouse getting circumcised. Women's knowledge was not increased by the intervention. Four men were circumcised in the comparison and 7 in the intervention phase. The intervention was not associated with higher odds of circumcision (odds ratio 1.5, 95% CI: 0.3 to 6.0, P = 0.65). We interviewed 117 individuals overall with the main enablers for VMMC being: free VMMC, transport reimbursement, and health benefits. Deterrents included misconceptions, lost wages and fear of pain. Most of the uncircumcised men interviewed reported interest in VMMC. CONCLUSIONS: Our pilot intervention had no significant impact on increasing VMMC demand. The study demonstrated the feasibility of pregnant women engaging their spouses to discuss VMMC.

Rapid improvement in passive tuberculosis case detection and tuberculosis treatment outcomes after implementation of a bundled laboratory diagnostic and on-site training intervention targeting mid-level providers.

Background. Tuberculosis (TB) control is a public health priority with 3 million cases unrecognized by the public health system each year. We assessed the impact of improved TB diagnostics and on-site training on TB case detection and treatment outcomes in rural healthcare facilities. Methods. Fluorescence microscopy, Xpert MTB/RIF, and on-site training were introduced at 10 healthcare facilities. Using quasi-experimental methods, these 10 intervention healthcare facilities were compared with 2 controls and their own performance the previous year. Results. From January to October 2012, 186 357 and 32 886 outpatients were seen in the 10 intervention and 2 control facilities, respectively. The intervention facilities had a 52.04% higher proportion of presumptive TB cases with a sputum examination (odds ratio [OR] = 12.65; 95% confidence interval [CI], 5.60-28.55). After adjusting for age group and gender, the proportion of smear-positive patients initiated on treatment was 37.76% higher in the intervention than in the control facilities (adjusted OR [AOR], 7.59; 95% CI, 2.19-26.33). After adjusting for the factors above, as well as human immunodeficiency virus and TB retreatment status, the proportion of TB cases who completed treatment was 29.16% higher (AOR, 4.89; 95% CI, 2.24-10.67) and the proportion of TB cases who were lost to follow-up was 66.98% lower (AOR, 0.04; 95% CI, 0.01-0.09). When compared with baseline performance, the intervention facilities had a significantly higher proportion of presumptive TB cases with a sputum examination (64.70% vs 3.44%; OR, 23.95; 95% CI, 12.96-44.25), and these facilities started 56.25% more smear-positive TB cases on treatment during the project period (AOR, 15.36; 95% CI, 6.57-35.91). Conclusions. Optimizing the existing healthcare workforce through a bundled diagnostics and on-site training intervention for nonphysician healthcare workers will rapidly improve TB case detection and outcomes towards global targets.

Intra-facility linkage of HIV-positive mothers and HIV-exposed babies into HIV chronic care: rural and urban experience in a resource limited setting.

INTRODUCTION: Linkage of HIV-infected pregnant women to HIV care remains critical for improvement of maternal and child outcomes through prevention of maternal-to-child transmission of HIV (PMTCT) and subsequent chronic HIV care. This study determined proportions and factors associated with intra-facility linkage to HIV care and Early Infant Diagnosis care (EID) to inform strategic scale up of PMTCT programs. METHODS: A cross-sectional review of records was done at 2 urban and 3 rural public health care facilities supported by the Infectious Diseases Institute (IDI). HIV-infected pregnant mothers, identified through routine antenatal care (ANC) and HIV-exposed babies were evaluated for enrollment in HIV clinics by 6 weeks post-delivery. RESULTS: Overall, 1,025 HIV-infected pregnant mothers were identified during ANC between January and June, 2012; 267/1,025 (26%) in rural and 743/1,025 (74%) in urban facilities. Of these 375/1,025 (37%) were linked to HIV clinics [67/267(25%) rural and 308/758(41%) urban]. Of 636 HIV-exposed babies, 193 (30%) were linked to EID. Linkage of mother-baby pairs to HIV chronic care and EID was 16% (101/636); 8/179 (4.5%)] in rural and 93/457(20.3%) in urban health facilities. Within rural facilities, ANC registration <28 weeks-of-gestation was associated with mothers' linkage to HIV chronic care [AoR, 2.0 95% CI, 1.1-3.7, p = 0.019] and mothers' multi-parity was associated with baby's linkage to EID; AoR 4.4 (1.3-15.1), p = 0.023. Stigma, long distance to health facilities and vertical PMTCT services affected linkage in rural facilities, while peer mothers, infant feeding services, long patient queues and limited privacy hindered linkage to HIV care in urban settings. CONCLUSION: Post-natal linkage of HIV-infected mothers to chronic HIV care and HIV-exposed babies to EID programs was low. Barriers to linkage to HIV care vary in urban and rural settings. We recommend targeted interventions to rapidly improve linkage to antiretroviral therapy for elimination of MTCT.

Ebola outbreak response; experience and development of screening tools for viral haemorrhagic fever (VHF) in a HIV center of excellence near to VHF epicentres.

INTRODUCTION: There have been 3 outbreaks of viral hemorrhagic fever (VHF) in Uganda in the last 2 years. VHF often starts with non-specific symptoms prior to the onset of haemorrhagic signs. HIV clinics in VHF outbreak countries such as Uganda see large numbers of patients with HIV 1/2 infection presenting with non-specific symptoms every day. Whilst there are good screening tools for general health care facilities expecting VHF suspects, we were unable to find tools for use in HIV or other non-acute clinics. METHODS: We designed tools to help with communication to staff, infection control and screening of HIV patients with non-specific symptoms in a large HIV clinic during the outbreaks in Uganda. We describe our experiences in using these tools in 2 Ebola Virus Disease outbreaks in Uganda. RESULTS: During the Ebola Virus Disease (EVD) outbreaks, enhanced infection control and communication procedures were implemented within 24 hours of the WHO/Ministry of Health announcement of the outbreaks. During course of these outbreaks the clinic saw 12,544 patients with HIV 1/2 infection, of whom 3,713 attended without an appointment, suggesting new symptoms. Of these 4 were considered at risk of EVD and seen with full infection procedures; 3 were sent home after further investigation. One patient was referred to the National Referral Hospital VHF unit, but discharged on the same day. One additional VHF suspect was identified outside of a VHF outbreak; he was transferred to the National Referral Hospital and placed in isolation within 2 hours of arriving at the HIV clinic. DISCUSSION: Use of simple screening tools can be helpful in managing large numbers of symptomatic patients attending for routine and non-routine medical care (including HIV care) within a country experiencing a VHF outbreak, and can raise medical staff awareness of VHF outside of the epidemics.

Adverse events profile of PrePex a non-surgical device for adult male circumcision in a Ugandan urban setting.

BACKGROUND: Safe Male Circumcision is a proven approach for partial HIV prevention. Several sub Saharan African countries have plans to reach a prevalence of 80% of their adult males circumcised by 2015. These targets require out of ordinary organization, demand creation, timely execution and perhaps the use of SMC devices. OBJECTIVE: To profile Adverse Events rate and acceptance of PrePex, a non surgical device for adult male circumcision. METHODS: A prospective study, conducted at International Hospital Kampala, Uganda, between August and October 2012. Ethical approval was obtained from Uganda National Council of Science and Technology. RESULTS: Of 1,040 men received to undergo SMC, 678 opted for PrePex, 36 were excluded at an initial physical examination screening. 642 were enrolled and consented, and another 17 were excluded before device placement. 625 underwent the procedure. Average age was 24 years (± 7). Twelve moderate AEs occurred among 10 participants 12/625, (1.9%). These were all reversible. Five had device displacement, one had an everted foreskin; five had bleeding after the device was removed and one had voiding difficulties. The majority (279 out of 300) of men interviewed complained of some pain within the week of placement. Mean pain score at device placement (using visual analogue scale) was 0.5, at device removal 4.5 and within 2 min of removal the pain score was 1.4. Over 70% of the devices were placed and removed by non-physician clinicians. Presented with a choice, 60% of men chose PrePex over surgical SMC. Close to 90% would recommend the device to their friends. Odour from the necrotic skin was a concern. Removals done 1-2 days earlier than day 7 were beneficial and conferred no extra risk. CONCLUSION: AEs of a moderate or severe nature associated with PrePex were low and reversible. PrePex is feasible for mass safe male circumcision scaling up.

Home-based versus clinic-based care for patients starting antiretroviral therapy with low CD4⁺ cell counts: findings from a cluster-randomized trial.

OBJECTIVES: African health services have shortages of clinical staff. We showed previously, in a cluster-randomized trial, that a home-based strategy using trained lay-workers is as effective as a clinic-based strategy. It is not known whether home-based care is suitable for patients with advanced HIV disease. METHODS: The trial was conducted in Jinja, Uganda. One thousand, four hundred and fifty-three adults initiating ART between February 2005 and January 2009 were randomized to receive either home-based care or routine clinic-based care, and followed up for about 3 years. Trained lay workers, supervised by clinical staff based in a clinic, delivered the home-based care. In this sub-analysis, we compared survival between the two strategies for those who presented with CD4⁺ cell count less than 50 cells/µl and those who presented with higher CD4⁺ cell counts. We used Kaplan-Meier methods and Poisson regression. RESULTS: Four hundred and forty four of 1453 (31%) participants had baseline CD4⁺ cell count less than 50 cells/µl. Overall, 110 (25%) deaths occurred among participants with baseline CD4⁺ cell count less than 50  cells/µl and 87 (9%) in those with higher CD4⁺ cell count. Among participants with CD4 cell count less than 50  cells/µl, mortality rates were similar for the home and facility-based arms; adjusted mortality rate ratio 0.80 [95% confidence interval (CI) 0.53-1.18] compared with 1.22 (95% CI 0.78-1.89) for those who presented with higher CD4⁺ cell count. CONCLUSION: HIV home-based care, with lay workers playing a major role in the delivery of care including providing monthly adherence support, leads to similar survival rates as clinic-based care even among patients who present with very low CD4⁺ cell count. This emphasises the critical role of adherence to antiretroviral therapy.

Fournier's gangrene after adult male circumcision.

BACKGROUND: In the advent of mass voluntary medical male circumcision (VMMC) for the partial prevention of HIV, previously rare adverse events associated with adult male circumcision are likely to be encountered with higher frequency. Fournier's gangrene, defined as a polymicrobial necrotizing fasciitis of the perineal, perianal or genital areas, is one such rare and life-threatening adverse event. In this report, we present two cases that were identified in the context of a VMMC programme over a 3-year period during which approximately 100,000 adult circumcisions were performed. CASE PRESENTATIONS: Case 1: A 19-year-old male who had VMMC performed using the dorsal slit technique developed pain and blisters on the scrotal skin on the sixth postoperative day. He had no co-morbidities, and serology for HIV was negative. On examination, locally he had scrotal skin necrosis with an offensive odour and was dehydrated but afebrile. Repeated aggressive debridement was done while he stayed in a hospital for 3 weeks; at which point, he had healthy granulation tissue and was free of infection. The wound had closed spontaneously and completely by the fifth month. Case 2: A 52-year-old male who had VMMC performed with the sleeve resection method developed pain and swelling of the penis and scrotum on the fourth postoperative day. He had a low-grade fever of 37.6°C. He was not diabetic or immunosuppressed and had a negative HIV serology. He was admitted and was given IV antibiotics, and repeated aggressive debridement was performed. On the third week of hospitalization, he had healthy granulation tissue and received a split skin graft on the penile shaft. At 4 months, the scrotal defect had completely closed. CONCLUSION: Fournier's gangrene is a rare occurrence after adult male circumcision with associated high morbidity. These are the first descriptions in the VMMC era.

Reach and cost-effectiveness of the PrePex device for safe male circumcision in Uganda.

INTRODUCTION: Modelling, supported by the USAID Health Policy Initiative and UNAIDS, performed in 2011, indicated that Uganda would need to perform 4.2 million medical male circumcisions (MMCs) to reach 80% prevalence. Since 2010 Uganda has completed 380,000 circumcisions, and has set a national target of 1 million for 2013. OBJECTIVE: To evaluate the relative reach and cost-effectiveness of PrePex compared to the current surgical SMC method and to determine the effect that this might have in helping to achieve the Uganda national SMC targets. METHODS: A cross-sectional descriptive cost-analysis study conducted at International Hospital Kampala over ten weeks from August to October 2012. Data collected during the performance of 625 circumcisions using PrePex was compared to data previously collected from 10,000 circumcisions using a surgical circumcision method at the same site. Ethical approval was obtained. RESULTS: The moderate adverse events (AE) ratio when using the PrePex device was 2% and no severe adverse events were encountered, which is comparable to the surgical method, thus the AE rate has no effect on the reach or cost-effectiveness of PrePex. The unit cost to perform one circumcision using PrePex is $30.55, 35% ($7.90) higher than the current surgical method, but the PrePex method improves operator efficiency by 60%, meaning that a team can perform 24 completed circumcisions compared to 15 by the surgical method. The cost-effectiveness of PrePex, comparing the cost of performing circumcisions to the future cost savings of potentially averted HIV infections, is just 2% less than the current surgical method, at a device cost price of $20. CONCLUSION: PrePex is a viable SMC tool for scale-up with unrivalled potential for superior reach, however national targets can only be met with effective demand creation and availability of trained human resource.

The expanding role of civil society in the global HIV/AIDS response: what has the President's Emergency Program For AIDS Relief's role been?

Civil society has been part of the HIV/AIDS response from the very beginning of the epidemic, often becoming engaged before national governments. Traditional roles of civil society--advocacy, activism, serving as government watchdog, and acting as community caretaker--have been critical to the response. In addition, civil society organizations (CSOs) play an integral part in providing world-class HIV prevention and treatment services and helping to ensure continuity of care. The President's Emergency Program for AIDS Relief (PEPFAR) has significantly increased the global scale-up of combination antiretroviral therapy reaching for more than 5 million people in developing countries, as well as implementation of effective evidence-based combination prevention approaches. PEPFAR databases in 5 countries and annual reports from a centrally managed initiative were mined and analyzed to determine the numbers and types of CSOs funded by PEPFAR over a 5-year period (2006-2011). Data are also presented from Uganda showing the overall resource growth in CSO working for HIV. Case studies document the evolution of 3 indigenous CSOs that increased the capacity to implement activities with PEPFAR funding. A legacy of PEPFAR has been the growth of civil society to address social and health issues as well as recognition by governments that partnerships with beneficiaries and civil society result in better outcomes. Scale-up of the global response could not have happened without the involvement of civil society and people living with HIV. This game changing partnership to jointly tackle the problems that countries face may well be the greatest benefit emerging from the HIV epidemic.

Integration of HIV and TB services results in improved TB treatment outcomes and earlier prioritized ART initiation in a large urban HIV clinic in Uganda.

BACKGROUND: The World Health Organization recommends that treatment of tuberculosis (TB) in HIV-infected patients should be integrated with HIV care. In December 2008, a separate outdoor-integrated TB/HIV clinic was instituted for attendees of a large urban HIV clinic in Uganda. We sought to evaluate associated TB and HIV treatment outcomes. METHODS: Routinely collected clinical, pharmacy, and laboratory data were merged with TB clinic data for patients initiating TB treatment in 2009 and with TB register data for patients in 2007. TB treatment outcomes and (timing of) antiretroviral therapy (ART) initiation in ART-naive patients [overall and stratified by CD4+ T cell (CD4) count] in 2007 and 2009 were compared. Nosocomial transmission rates could not be assessed. RESULTS: Three hundred forty-six patients were initiated on TB treatment in 2007 and 366 in 2009. Median CD4 counts at TB diagnosis did not differ. TB treatment cure or completion increased from 62% to 68%, death or default decreased from 33% to 25% (P < 0.001). Fewer ART-naive TB patients were initiated on ART in 2009 versus 2007 (57% and 66%, P = 0.031), but this decrease was only in patients with CD4 counts >250 cells per cubic millimeter (19% vs. 48%, P = 0.003). More patients were started on ART during TB treatment (94% vs. 78%, P < 0.001). Moreover, the majority were now initiated during intensive phase (60% vs. 23%, P < 0.001). CONCLUSIONS: Integration of TB and HIV care has led to improved TB treatment outcomes and earlier, prioritized ART initiation. This supports rollout of a fully integrated TB/HIV service delivery model throughout high-prevalence TB and HIV settings.

Medical male circumcision for HIV/AIDS prevention in Uganda - the cost of disposable versus re-usable circumcision kits.

We evaluated the cost implications of medical male circumcisions for HIV prevention when performed using re-usable equipment that is sterilized after each use versus using single-use disposal kits. In Uganda, a re-usable circumcision kit results in a net saving of US$7.14-US$12.34 or 46-59%. In resource-limited settings seeking to expand access to medical male circumcision for HIV prevention, substantial cost reductions may be achieved by adopting re-usable circumcision kits.

Mass safe male circumcision: early lessons from a Ugandan urban site - a case study.

INTRODUCTION: It has been proven in several randomized clinical trials that HIV transmission from female to male is reduced by 60% and more among circumcised males. The national target for Uganda by 2015 is to circumcise 4.2 million adult males, an unprecedented number requiring a pragmatic approach and effective model(s) to deliver this target. The objective of the study was to describe early lessons learnt at a start up of a mass safe male circumcision (SMC) program in an urban Ugandan site, implemented through task shifting and a private public partnership approach. METHODS: A case study of an urban SMC site in Uganda's capital, Kampala with a catchment population of approximately 0.8 million adult males aged between 15 and 49 years. Client enrollment was voluntary; mobilization was by word of mouth and through the media. Non Physician clinicians (NPC) carried out the majority of the SMCs. The SMC and voluntary counseling and testing (VCT), adverse events (AE) management and follow up were done as per set national guidelines. The supervision was by a public and private service provider. All clients were consented. RESULTS: A total of 3000 males were circumcised in 27 days spread over four months. The AE rate was 2.1% all AEs were mild and reversible. No deaths occurred. The work rate was 111 SMCs per day. There was sufficient demand for SMC despite minimal mobilization effort. The bulk of the SMC work was successfully carried out by the NPCs. CONCLUSION: Private Public Partnership and task shifting approaches were successful at the start up phase and we anticipate will be feasible for the scale up.

HIV and identity: the experience of AIDS support group members who unexpectedly tested HIV negative in Uganda.

Living with HIV, for many of those infected, has meant adjusting to life with a stigmatised condition and, until recently, the threat of looming death. We explore the adjustment of a group of long-term former clients of The AIDS Support Organisation (TASO) in Uganda who, when tested for HIV during the rollout of antiretroviral therapy in 2004, were found to be HIV negative. In-depth semi-structured interviews with 34 former TASO clients were conducted between 2005 and 2007. Their narratives reveal a great deal about the biographical disruption they have faced, and the biographical work that they have undertaken in both the personal and the social dimensions of their lives in order to manage their new-found HIV-uninfected status. After the negative test result, as they were no longer HIV-infected, they had to leave TASO and that support was sorely missed, as was the friendship of TASO members to whom they often felt reluctant to disclose their new status. The identity 'reversal' or change was often handled privately. Compared with their transition to an HIV-positive identity, they now lacked a social dimension to their identity transformation as they managed their new identity in the face of self- and public doubt.

Developing independent investigators for clinical research relevant for Africa.

Sustainable research capacity building requires training individuals at multiple levels within a supportive institutional infrastructure to develop a critical mass of independent researchers. At many African medical institutions, a PhD is important for academic promotion and is, therefore, an important focal area for capacity building programs. We examine the training at the Infectious Diseases Institute (IDI) as a model for in-country training based on systems capacity building and attention to the academic environment. PhD training in Africa should provide a strong research foundation for individuals to perform independent, original research and to mentor others. Training the next generation of researchers within excellent indigenous academic centers of excellence with strong institutional infrastructure will empower trainees to ask regionally relevant research questions that will benefit Africans.

Utility of routine viral load, CD4 cell count, and clinical monitoring among adults with HIV receiving antiretroviral therapy in Uganda: randomised trial.

OBJECTIVE: To evaluate the use of routine laboratory monitoring in terms of clinical outcomes among patients receiving antiretroviral therapy (ART) in Uganda. DESIGN: Randomised clinical trial SETTING: A home based ART programme in rural Uganda. PARTICIPANTS: All participants were people with HIV who were members of the AIDS Support Organisation. Participants had CD4 cell counts <250 cells × 10(6)/L or World Health Organization stage 3 or 4 disease. INTERVENTIONS: Participants were randomised to one of three different monitoring arms: a viral load arm (clinical monitoring, quarterly CD4 counts, and viral load measurements), CD4 arm (clinical monitoring and CD4 counts), or clinical arm (clinical monitoring alone). MAIN OUTCOME MEASURES: Serious morbidity (newly diagnosed AIDS defining illness) and mortality. RESULTS: 1094 participants started ART; median CD4 count at baseline was 129 cells × 10(6)/L. Median follow-up was three years. In total, 126 participants died (12%), 148 (14%) experienced new AIDS defining illnesses, and 61(6%) experienced virological failure, defined as two consecutive viral loads >500 copies/mL occurring more than three months after the start of ART. After adjustment for age, sex, baseline CD4 count, viral load, and body mass index, the rate of new AIDS defining events or death was higher in the clinical arm than the viral load arm (adjusted hazard ratio 1.83, P = 0.002) or the CD4 arm (1.49, P = 0.032). There was no significant difference between the CD4 arm and the viral load arm (1.23, P = 0.31). CONCLUSION: In patients receiving ART for HIV infection in Uganda, routine laboratory monitoring is associated with improved health and survival compared with clinical monitoring alone. Trial registration Clinical Trials NCT00119093.

Mortality in an antiretroviral therapy programme in Jinja, south-east Uganda: a prospective cohort study.

BACKGROUND: There have been few reports of long-term survival of HIV-infected patients on antiretroviral therapy (ART) in Africa managed under near normal health service conditions. METHODS: Participants starting ART between February 2005 and December 2006 in The AIDS Support (TASO) clinic in Jinja, Uganda, were enrolled into a cluster-randomised trial of home versus facility-based care and followed up to January 2009. The trial was integrated into normal service delivery with patients managed by TASO staff according to national guidelines. Rates of survival, virological failure, hospital admissions and CD4 count over time were similar between the two arms. Data for the present analysis were analysed using Cox regression analyses. RESULTS: 1453 subjects were enrolled with baseline median count of 108 cells/µl. Over time, 119 (8%) withdrew and 34 (2%) were lost to follow-up. 197/1453 (14%) died. Mortality rates (95% CI) per 100 person-years were 11.8 (10.1, 13.8) deaths in the first year and 2.4 (1.8, 3.2) deaths thereafter. The one, two and three year survival probabilities (95% CI) were 0.89 (0.87 - 0.91), 0.86 (0.84 - 0.88) and 0.85 (0.83 - 0.87) respectively. Low baseline CD4 count, low body weight, advanced clinical condition (WHO stages III and IV), not being on cotrimoxazole prophylaxis and male gender were associated independently with increased mortality. Tuberculosis, cryptococcal meningitis and diarrhoeal disease were estimated to be major causes of death. CONCLUSION: Practical and affordable interventions are needed to enable earlier initiation of ART and to reduce mortality risk among those who present late for treatment with advanced disease.

Primary prophylaxis of cryptococcal disease with fluconazole in HIV-positive Ugandan adults: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Cryptococcal disease remains an important cause of morbidity and mortality in HIV-infected individuals in sub-Saharan Africa, despite the introduction of antiretroviral therapy. We studied fluconazole as primary prophylaxis against cryptococcal disease in patients awaiting or starting antiretroviral therapy in Uganda. METHODS: In this prospective, double-blind randomised controlled trial, we enrolled HIV-positive adults with CD4 counts less than 200 cells per µL, cryptococcal antigen (CrAg)-negative, naive for antiretroviral therapy, and coming from five local AIDS organisations in Masaka district, Uganda. Enrolment took place between Sept 14, 2004, and Feb 1, 2008. Participants were randomly allocated to placebo or 200 mg fluconazole three times per week (1:1) in blocks of 40. Randomisation was done with ralloc procedure in Stata. Participants were reviewed after 4 weeks and referred for antiretroviral therapy, then seen every 8 weeks. Participants discontinued trial treatment when CD4 counts reached 200 cells per µL (median 197 days). Primary endpoints were invasive cryptococcal disease and all-cause mortality. Secondary endpoints were time to first episode and incidence of oesophageal candidosis, time to first episode and incidence of oropharyngeal or vaginal candidosis, and time to first hospital admission or death. The primary safety endpoint was cessation of trial drug because of transaminase concentrations higher than five times the upper limit of normal (ULN), or other major adverse events. Analyses were done by intention to treat and included all participants enrolled in the trial. Participants and researchers were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN 76481529. RESULTS: Of 1519 individuals enrolled, 760 participants received fluconazole and 759 received placebo. 19 developed cryptococcal disease, one in the fluconazole group and 18 in the placebo group (p=0·0001); adjusted HR (aHR) 18·7 (95% CI 2·5-140·7). One case of cryptococcal disease could be prevented by treating 44·6 patients with baseline CD4 counts lower than 200 cells per µL. Fluconazole was effective against cryptococcal disease both before (aHR=11·0 [1·4-85·3]) and after start of antiretroviral therapy (no cases in fluconazole vs seven cases on placebo). Seven participants died from cryptococcal disease, none in the fluconazole group. All-cause mortality (n=189) did not differ between the two groups (p=0·46). Fluconazole reduced the time to first episode of oesophageal, and oropharyngeal and vaginal candidosis, as well as the incidence of all candidosis (p<0·0001), but had no effect on hospital admission or death. The frequency of elevated transaminases (>5×ULN) was similar between groups (aHR=0·94 [0·65-1·35]). CONCLUSIONS: Fluconazole was safe and effective as primary prophylaxis against cryptococcal disease, both before and during early antiretroviral treatment. Cryptococcal infection was less common than anticipated because of the rapid commencement of antiretroviral therapy and exclusion of those with positive CrAg. In patients with negative CrAg on screening, fluconazole prophylaxis can prevent cryptococcal disease while waiting for and in the early weeks of antiretroviral therapy, particularly in those with CD4 counts of less than 100 cells per µL. FUNDING: Medical Research Council, UK, and Rockefeller Foundation.