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Objective To understand the HIV-hepatitis B virus (HBV) epidemic from a global perspective by clinically and virologically characterizing these viruses at the time of antiretroviral therapy (ART) initiation in a multi-national cohort. Methods and design HIV-infected subjects enrolled in two international studies were classified as HIV-HBV co-infected or HIV monoinfected prior to ART. HIV-HBV co-infected subjects were tested for HBV characteristics, hepatitis D virus (HDV), a novel non-invasive marker of liver disease, and drug-resistant HBV. Comparisons between discrete covariates used chi-square or Fisher’s exact tests (and Jonchkheere-Terpstra for trend tests) while continuous covariates were compared using Wilcoxon Rank-Sum Test. Results Of the 2105 HIV-infected subjects from 11 countries, the median age was 34 years and 63% were Black. The 115 HIV-HBV co-infected subjects had significantly higher ALT and AST values, lower body mass index, and lower CD4+ T-cell counts than HIV monoinfected subjects (median 159 cells/mL and 137 cells/mL, respectively, P=0.04). In the co-infected subjects, 49.6% had HBeAg-negative HBV, 60.2% had genotype A HBV, and 13% were HDV positive. Of the HBeAg-negative subjects, 66% had HBV DNA ≤2000 IU/ml compared to 5.2% of the HBeAg-positive subjects. Drug-resistant HBV was not detected. Conclusions Screening for HBV in HIV-infected patients in resource-limited settings is important since it is associated with lower CD4+ T-cell counts. In settings where HBV DNA is not available, HBeAg may be useful to assess the need for HBV treatment. Screening for drug-resistant HBV is not needed prior to starting ART in settings where this study was conducted.

Summary Background Mortality within the first 6 months after initiating antiretroviral therapy (ART) is common in resource-limited settings and is often due to tuberculosis (TB) among patients with advanced HIV disease. Isoniazid preventive therapy (IPT) is recommended in HIV-infected adults, but sub-clinical TB can be difficult to diagnose. We hypothesized that empiric TB treatment would reduce early mortality compared to IPT in high-burden settings. Methods We conducted a multi-country randomized clinical trial comparing empiric TB therapy (Empiric) vs. isoniazid preventive therapy (IPT) in HIV-infected outpatients initiating ART with CD4 counts <50 cells/mm3. Individuals were screened for TB using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available. The primary endpoint was survival (death or unknown status) at 24 weeks post randomization. Kaplan Meier estimates of the endpoint rates across arms were compared by the z-test. Registered at ClinicalTrials.gov (NCT01380080). Findings From October 31, 2011 until June 9, 2014, we randomized 850 participants (424 in Empiric arm and 426 in IPT arm); the median CD4 count at baseline was 18 cells/mm3 (IQR: 9, 32). At week 24, each arm had 22 primary endpoints, for rates of 5.2% in each arm (95% CI: 3.5% to 7.8% for Empiric and 3.4% to 7.8% for IPT; absolute risk difference of -0.06% (95% CI: −3.05% to 2.94%). Grade 3 or 4 signs or symptoms occurred in 50 (12%) in the Empiric arm and 46 (11%) in the IPT arm. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) in the Empiric arm and 97 (23%) in the IPT arm. Incident TB was more common in the Empiric arm (31 vs. 18 events, p=0.01). Interpretation Empiric TB therapy did not reduce mortality at 24 weeks in outpatient adults initiating ART with advanced HIV disease. The low mortality rate of the trial supports implementation of systematic TB screening and IPT in outpatients with advanced HIV disease.

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Rationale and Objectives Earlier initiation of antiretroviral therapy (ART) in HIV-tuberculosis(TB) is associated with increased immune reconstitution inflammatory syndrome (IRIS). The severity, frequency and complications of TB IRIS were evaluated in A5221, a randomized trial of earlier ART (within 2 weeks after TB treatment initiation) vs. later ART (8-12 weeks after TB treatment) in HIV-infected patients starting TB treatment. Methods and Measurements In 806 participants, TB IRIS was defined using published clinical criteria. Cases were classified as severe(hospitalization/death), moderate(corticosteroid use/invasive procedure), or mild(no hospitalization/procedures/steroids). Fisher's Exact, Wilcoxon, and log rank tests were used for comparisons. Main Results TB IRIS occurred in 61 (7.6%) patients: 10.4% in earlier vs. 4.7% later ART, 11.5% with CD4+ < 50 vs. 5.4% CD4+ ≥ 50 cells/mm3. The CD4+/ART arm interaction was significant, p=0.014, with 44.3% of TB IRIS occurring with CD4+ < 50 and earlier ART. TB IRIS occurred sooner with earlier vs. later ART initiation, at a median of 29 vs. 82 days after TB treatment initiation (p<0.001). IRIS manifestations included lymphadenopathy(59.0%), constitutional symptoms(54.1%), and radiographic changes(41.0%); CNS TB IRIS was uncommon (6.6%). TB IRIS was mild in 27.9%, moderate in 41.0%, and severe in 31.1%. No TB IRIS-associated deaths occurred. IRIS management required ≥ 1 invasive procedures in 34.4%, hospitalization in 31.1% and corticosteroids in 54.1%. Conclusions TB IRIS was more frequent with earlier ART initiation and CD4+ <50 cells/mm3. As ART is implemented earlier in HIV-TB co-infection, programs will require the diagnostic capabilities, clinical resources and training necessary to manage TB IRIS.

Rationale: In the context of rapid antiretroviral therapy rollout and an increasing burden of noncommunicable diseases, there are few contemporary data describing the etiology and outcome of community-acquired pneumonia (CAP) in sub-Saharan Africa. Objectives: To describe the current etiology of CAP in Malawi and identify risk factors for mortality. Methods: We conducted a prospective observational study of adults hospitalized with CAP to a teaching hospital in Blantyre, Malawi. Etiology was defined by blood culture, Streptococcus pneumoniae urinary antigen detection, sputum mycobacterial culture and Xpert MTB/RIF, and nasopharyngeal aspirate multiplex PCR. Measurements and Main Results: In 459 patients (285 [62.1%] males; median age, 34.7 [interquartile range, 29.4–41.9] yr), 30-day mortality was 14.6% (64/439) and associated with male sex (adjusted odds ratio, 2.60 [95% confidence interval, 1.17–5.78]), symptom duration greater than 7 days (2.78 [1.40–5.54]), tachycardia (2.99 [1.48–6.06]), hypoxemia (4.40 [2.03–9.51]), and inability to stand (3.59 [1.72–7.50]). HIV was common (355/453; 78.4%), frequently newly diagnosed (124/355; 34.9%), but not associated with mortality. S. pneumoniae (98/458; 21.4%) and Mycobacterium tuberculosis (75/326; 23.0%) were the most frequently identified pathogens. Viral infection occurred in 32.6% (148/454) with influenza (40/454; 8.8%) most common. Bacterial–viral coinfection occurred in 9.1% (28/307). Detection of M. tuberculosis was associated with mortality (adjusted odds ratio, 2.44 [1.19–5.01]). Conclusions: In the antiretroviral therapy era, CAP in Malawi remains predominantly HIV associated, with a large proportion attributable to potentially vaccine-preventable pathogens. Strategies to increase early detection and treatment of tuberculosis and improve supportive care, in particular the correction of hypoxemia, should be evaluated in clinical trials to address CAP-associated mortality.

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AimEarly warning scores (EWS) are widely used in well-resourced healthcare settings to identify patients at risk of mortality. The Modified Early Warning Score (MEWS) is a well-known EWS used comprehensively in the United Kingdom. The HOTEL score (Hypotension, Oxygen saturation, Temperature, ECG abnormality, Loss of independence) was developed and tested in a European cohort; however, its validity is unknown in resource limited settings. This study compared the performance of both scores and suggested modifications to enhance accuracy.MethodsA prospective cohort study of adults (≥18 yrs) admitted to medical wards at a Malawian hospital. Primary outcome was mortality within three days. Performance of MEWS and HOTEL were assessed using ROC analysis. Logistic regression analysis identified important predictors of mortality and from this a new score was defined.ResultsThree-hundred-and-two patients were included. Fifty-one (16.9%) died within three days of admission. With a cut-point ≥2, the HOTEL score had sensitivity 70.6% (95% CI: 56.2 to 82.5) and specificity 59.4% (95% CI: 53.0 to 65.5), and was superior to MEWS (cut-point ≥5); sensitivity: 58.8% (95% CI: 44.2 to 72.4), specificity: 56.2% (95% CI: 49.8 to 62.4). The new score, dubbed TOTAL (Tachypnoea, Oxygen saturation, Temperature, Alert, Loss of independence), showed slight improvement with a cut-point ≥2; sensitivity 76.5% (95% CI: 62.5 to 87.2) and specificity 67.3% (95% CI: 61.1 to 73.1).ConclusionUsing an EWS generated in developed healthcare systems in resource limited settings results in loss of sensitivity and specificity. A score based on predictors of mortality specific to the Malawian population showed enhanced accuracy but not enough to warrant clinical use. Despite an assumption of common physiological responses, disease and population differences seem to strongly determine the performance of EWS. Local validation and impact assessment of these scores should precede their adoption in resource limited settings.