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African hospitals report high death rate in HIV-associated meningitis

An evidence review has found that approximately half of hospital patients with cryptococcal, tuberculosis or pneumococcal meningitis died within two weeks or during hospitalisation. The analysis of 79 studies by researchers at the University of Washington School of Medicine – Seattle, Botswana Harvard AIDS Institute Partnership, the London School of Hygiene and Tropical Medicine, Welcome Centre for Infectious Diseases Research in Africa, and the University of Cape Town, compared deaths from HIV‐associated meningitis in two different settings: hospitals and clinical trials.

Despite improved access to effective antiretroviral treatment (ART) in sub-Saharan Africa, a high proportion of people living with HIV remain virally unsuppressed, leaving them at increased susceptibility to potentially fatal infections such as meningitis. A 2017 analysis found cryptococcal meningitis alone causes around 15% of HIV‐associated deaths worldwide – almost three‐quarters of which occur in sub-Saharan Africa.

Treatment for HIV‐associated meningitis is challenging, even in high-income countries, and outcomes are even worse in countries with limited resources. The recommended approach for treating cryptococcal meningitis is initial treatment with amphotericin, an effective but highly toxic drug that is given intravenously, followed by treatment with a drug called fluconazole. But in resource‐constrained settings, fluconazole alone is often used as it costs less, can be administered orally, and is less toxic.

The research found approximately half of people diagnosed with cryptococcal, tuberculosis or pneumococcal meningitis – the most common types of HIV-related meningitis – died within two weeks or during hospitalisation in routine care settings. Although outcomes for pneumococcal meningitis were similar in hospitals and clinical trials, a significant difference was found between the two settings for cryptococcal meningitis.

Overall, 44% of people with cryptococcal meningitis died in hospital settings, regardless of whether they were given amphotericin or fluconazole, compared to 21% in clinical trials when only amphotericin was given. This suggests the death rate found in routine care is likely to be linked to multiple factors that arise within hospitals and is not purely the result of the drugs on offer.

When examining the data regionally, more than 50% of patients with cryptococcal meningitis died within two weeks in West and Central Africa; a significantly higher rate than in Southern Africa where 37% of people died.

The proportion of people with pneumococcal meningitis who died within two weeks was similar in clinical trials and hospital settings, at around 54%. This may be reflective of the less intensive treatment currently recommended for pneumococcal disease.

The proportion of people dying within two weeks from TB-related meningitis was found to be 46% in hospital settings. Two studies looked at medium and longer-term outcomes for TB-related meningitis. These found more than two‐thirds of people receiving treatment for TB meningitis in hospital settings died. However, a lack of data meant the review was unable to compare these results with those from clinical trials of a similar nature. One trial from South Africa reported that 12% (3 out of 34) of participants died within nine‐months, but this study excluded people with severe TB and those who did not initiate ART or were judged to have poor drug adherence.

Few studies evaluated by the review looked at longer‐term outcomes among people with HIV-related meningitis who survived in the short or medium term. In addition, most studies reported outcomes for people treated at hospital referral clinics, where staffing, pharmaceutical and laboratory resources are likely to be better than in lower‐level health facilities.

The findings of this study indicate that better strategies and preventative measures, such as improved screening for cryptococcal meningitis and childhood pneumococcal vaccinations, are needed to reduce deaths from HIV‐associated meningitis in the region. It also suggests that increasing access to amphotericin alone will not be enough to significantly reduce the number of people with HIV who die as a result of meningitis.

Introduction: HIV‐associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub‐Saharan Africa (SSA). We performed a systematic review and meta‐analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings.
Methods: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized‐controlled trials (RCTs) or investigator‐managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short‐term (in‐hospital or two weeks), medium‐term (up to 10 weeks) and long‐term (up to six months).

Results and discussion: Seventy‐nine studies met inclusion criteria. In routine care settings, pooled short‐term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole‐based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short‐term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short‐term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized‐controlled trials. Few studies evaluated long‐term outcomes.
Conclusions: Mortality rates from HIV‐associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV‐associated meningitis in the region.

Mark W Tenforde, Alida M Gertz, David S Lawrence, Nicola K Wills, Brandon L Guthrie, Carey Farquhar, Joseph N Jarvis

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