BACKGROUNDCryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. METHODSIn this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. RESULTSThe trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P = 0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P = 0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P = 0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P = 0.003), renal events (22 vs. 7, P = 0.004), and cardiac events (8 vs. 0, P = 0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. CONCLUSIONSDexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.

Several factors that undermine uptake of ART have been highlighted; targeted measures urgently need to be addressed by TB-HIV programmes to overcome these barriers.

Background Daily co-trimoxazole is recommended for African adults living with HIV irrespective of antiretroviral treatment, immune status, or disease stage. Benefits of continued prophylaxis and whether co-trimoxazole can be stopped following immune reconstitution are unknown. Methods We conducted a randomized, controlled trial at two sites in Malawi that enrolled HIV-infected adults with undetectable viral load and CD4 count of &gt;250/mm 3 and randomized them to continue daily co-trimoxazole, discontinue daily co-trimoxazole and begin weekly chloroquine, or discontinue daily co-trimoxazole. The primary endpoint was the preventive effect of co-trimoxazole prophylaxis against death or World Health Organization (WHO) HIV/AIDS Stage 3-4 events, using Cox proportional hazards modelling, intention to treat population. Results 1499 adults were enrolled. The preventive effect of co-trimoxazole on the primary endpoint was 22% (95%CI -14-47%, p=0.20) versus no prophylaxis and 25% (95%CI -10-48%, p=0.14) versus chloroquine. When WHO HIV/AIDS Stage 2 events were added to the primary endpoint, preventive effect increased to 31% (95%CI 3-51%, p=0.032) and 32% (95%CI 4-51%, p=0.026), respectively. Co-trimoxazole and chloroquine prophylaxis effectively prevented clinical malaria episodes (3.8 and 3.0, respectively, versus 28/100 person-years, p&lt;0.001). Conclusions Malawian adults living with HIV who immune reconstituted on ART and continued co-trimoxazole prophylaxis experienced fewer deaths and WHO HIV/AIDS Stage 3-4 events compared to prophylaxis discontinuation, though statistical significance was not achieved. Cotrimoxazole prevented a composite of death plus WHO HIV/AIDS Stage 2-4 events. Given poor healthcare access and lack of routine viral load monitoring, co-trimoxazole prophylaxis should continue in adults on ART after immune reconstitution in sub-Saharan Africa.

BackgroundCompensating participants of biomedical research is a common practice. However, its proximity with ethical concerns of coercion, undue influence, and exploitation, demand that participant compensation be regulated. The objective of this paper is to discuss the current regulations for compensation of research participants in Malawi and how they can be improved in relation to ethical concerns of coercion, undue influence, and exploitation.Main textIn Malawi, national regulations recommend that research subjects be compensated with a stipend of US$10 per study visit. However, no guidance is provided on how this figure was determined and how it should be implemented. While necessary to prevent exploitation, the stipend may expose the very poor to undue influence. The stipend may also raise the cost of doing research disadvantaging local researchers and may have implications on studies where income stipend is the intervention under investigation. We recommend that development and implementation of guidelines of this importance involve interested parties such as the research community and patient groups.ConclusionCompensating human research subjects is important but can also act as a barrier to voluntary participation and good research efforts. Deliberate measures need to be put in place to ensure fair compensation of research participants, avoid their exploitation and level the field for locally funded research.

1. A 35-year-old man was referred to Zomba Central Hospital in June 2014 from a health center with a presenting complaint of enlarged breasts. This had started gradually, approximately six months prior. He did not experience any pain or discharge from his nipples. He had no other complaints and felt generally healthy. In early 2013 he had been concomitantly diagnosed with pulmonary tuberculosis and HIV infection and was started on cotrimoxazole prophylaxis and antiretroviral therapy (ART) with tenofovir, lamivudine, and efavirenz, which is the standard first-line adult ART regimen, known in Malawi as regimen 5A. At that point, he had WHO clinical stage III HIV disease; a CD4 count was not done. There was no further relevant past medical history. He looked healthy and had normal vital signs. The rest of the physical examination was normal except for bilateral, symmetrical, elastic, and concentric swelling of the breasts, without discrete nodules, skin changes, or lymphadenopathy in the axillae and neck. There were no features of lipodystrophy and no stigmata of chronic liver disease. The genital examination was normal, without palpable abnormalities of the normal-sized testes. Upon laboratory investigation, his CD4 count was 130 cells/µL and a full blood count was normal apart from the presence of macrocytosis. Liver enzymes were unremarkable.2. In October 2014, we saw a 56-year-old male who presented with development of painless bilateral breast enlargement. This had started in May 2014, followed by spontaneous regression and then subsequent worsening from August 2014. The left breast was more conspicuously affected. He also mentioned experiencing weight loss but had no other symptoms. He was diagnosed with HIV infection in 2005 and started on ART in 2008 due to a low CD4 count of 83 cells/µL. While on his first ART regimen-stavudine, lamivudine, and nevirapine-he experienced progressive peripheral neuropathy and was eventually switched to a regimen of zidovudine, lamivudine, and nevirapine, after which his CD4 count was 409 cells/µL and plasma HIV-1 RNA was undetectable. Six months later, in January 2010, he developed severe anaemia, secondary to zidovudine, and his ART regimen was changed again, this time to tenofovir, lamivudine, and efavirenz (regimen 5A). He had no other significant past medical history and the only medications he used were cotrimoxazole prophylaxis and tenofovir, lamivudine, and efavirenz. Bilateral breast enlargement (left more than right, see Figure 1) was the only abnormality found on physical examination, with the same pertinent negative findings as in the first case presented in this report.