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Background Tuberculosis case-finding interventions are critical to meeting World Health Organization End TB strategy goals. We investigated the impact of community-wide tuberculosis active case finding (ACF) alongside scale-up of human immunodeficiency virus (HIV) testing and care on trends in adult tuberculosis case notification rates (CNRs) in Blantyre, Malawi. Methods Five rounds of ACF for tuberculosis (1–2 weeks of leafleting, door-to-door enquiry for cough and sputum microscopy) were delivered to neighborhoods ("ACF areas") in North-West Blantyre between April 2011 and August 2014. Many of these neighborhoods also had concurrent HIV testing interventions. The remaining neighborhoods in Blantyre City ("non-ACF areas") provided a non-randomized comparator. We analyzed TB CNRs from January 2009 until December 2018. We used interrupted time series analysis to compare tuberculosis CNRs before ACF and after ACF, and between ACF and non-ACF areas. Results Tuberculosis CNRs increased in Blantyre concurrently with start of ACF for tuberculosis in both ACF and non-ACF areas, with a larger magnitude in ACF areas. Compared to a counterfactual where pre-ACF CNR trends continued during ACF period, we estimated there were an additional 101 (95% confidence interval [CI] 42 to 160) microbiologically confirmed (Bac+) tuberculosis diagnoses per 100 000 person-years in the ACF areas in 3 and a half years of ACF. Compared to a counterfactual where trends in ACF area were the same as trends in non-ACF areas, we estimated an additional 63 (95% CI 38 to 90) Bac + diagnoses per 100 000 person-years in the same period. Conclusions Tuberculosis ACF was associated with a rapid increase in people diagnosed with tuberculosis in Blantyre. [ABSTRACT FROM AUTHOR]

Background TB is a leading cause of morbidity among HIV positive individuals. Accurate algorithms are needed to achieve early TB diagnosis and treatment. We investigated the use of Xpert MTB/RIF Ultra in combination with chest radiography for TB diagnosis in ambulatory HIV positive individuals. Methods This was a randomised controlled trial with a 2-by-2 factorial design. Outpatient HIV clinic attendees with cough were randomised to four arms: Arm 1—Standard Xpert/no chest radiography (CXR); Arm 2—Standard Xpert/CXR; Arm 3—Xpert Ultra/no CXR; and Arm 4—Xpert Ultra/CXR. Participants were followed up at days 28 and 56 to assess for TB treatment initiation. Results We randomised 640 participants. Bacteriologically confirmed TB treatment initiation at day 28 were: Arm 1 (8.4% [14/162]), Arm 2 (6.9% [11/159]), Arm 3 (8.2% [13/159]) and Arm 4 (5.6% [9/160]) and between Xpert Ultra group (Arms 3 and 4) (6.9% [22/319]) vs Standard Xpert group (Arms 1 and 2) (7.8% [25/321]), risk ratio 0.89 (95% CI 0.51 to 1.54). By day 56, there were also similar all-TB treatment initiations in the x-ray group (Arms 2 and 4) (16.0% [51/319]) compared with the no x-ray group (Arms 1 and 3) (13.1% [42/321]), risk ratio 1.22 (95% CI 0.84 to 1.78); however, the contribution of clinically diagnosed treatment initiations were higher in x-ray groups (50.9% vs 19.0%). Conclusions Xpert Ultra performed similarly to Xpert MTB/RIF. X-rays are useful for TB screening but further research should investigate how to mitigate false-positive treatment initiations. [ABSTRACT FROM AUTHOR]

Background Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. Methods Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0–8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and C max) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. Results Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (C max) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. Conclusions Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes. [ABSTRACT FROM AUTHOR]

Background Empirical tuberculosis (TB) treatment in human immunodeficiency virus (HIV)–positive inpatients is common and may undermine the impact of new diagnostics. We sought to describe empirical TB treatment and compare characteristics and outcomes with patients treated for TB after screening. Methods This was a retrospective observational cohort study of HIV-positive inpatients treated empirically for TB prior to TB screening. Data on clinical characteristics, investigations, and outcomes were collected from medical records. Comparison cohorts with microbiologically confirmed or empirical TB treatment after TB screening with Xpert MTB/RIF and urine lipoarabinomannan assays were taken from South African Screening for Tuberculosis to Reduce AIDS-Related Mortality in Hospitalized Patients in Africa (STAMP) trial site. In-hospital mortality was compared using a competing-risks analysis adjusted for age, sex, and CD4 cell count. Results Between January 2016 and September 2017, 100 patients excluded from STAMP were treated for TB empirically prior to TB screening. After enrollment in STAMP and TB screening, 240 of 1177 (20.4%) patients received TB treatment, of whom 123 had positive TB tests and 117 were treated empirically. Characteristics were similar among early empirically treated patients and those treated after TB screening. 50% of early empirical TB treatment was based on radiological investigations, 22% on cerebrospinal or pleural fluid testing, and 28% on clinical features alone. Only 11 of 100 empirically treated patients had subsequent microbiological confirmation. In-hospital mortality was lower in patients with microbiologically confirmed TB compared to those treated empirically (adjusted subdistribution hazard ratio, 0.5 [95% confidence interval,.3–.9). Conclusions Empirical TB treatment remains common in severely ill HIV-positive inpatients. These patients may benefit from TB screening using existing rapid diagnostics, both to improve confirmation of TB disease and reduce overtreatment for TB. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) is the major killer of people living with human immunodeficiency virus (HIV) globally, with suboptimal diagnostics and management contributing to high case-fatality rates. Methods A prospective cohort of patients with confirmed TB (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (Rapid urine-based Screening for Tuberculosis to reduce AIDS Related Mortality in hospitalized Patients in Africa [STAMP] trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days). Results Of 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower hemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (hazard ratio, 0.9; P =.729). Conclusions Mortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use. [ABSTRACT FROM AUTHOR]

Background This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. Methods Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. Results Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < . 01). Serial sputum colony counting negativity at month 2 (P < . 05), isoniazid C MAX (P < .05), isoniazid C MAX/minimum inhibitory concentration ([MIC] P < . 01), and isoniazid AUC0-24/MIC (P < . 01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < . 05) and earlier progression to biphasic bacillary decline (P < . 01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < . 05). Conclusions Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as C MAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV)–infected individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality. Methods We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi. Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF assay (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED-FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis. Results Prevalent TB was diagnosed in 24 of 1001 (2.4%) individuals enrolled in clinics randomized to Xpert, compared with 10 of 841 (1.2%) in clinics randomized to LED-FM. All-cause mortality was 22% lower in the Xpert arm than in the LED-FM arm (6.7 vs 8.6 per 100 person-years; RR, 0.78 [95% confidence interval {CI},.58–1.06]). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage 3 or 4) disease had lower mortality in clinics randomized to Xpert than to LED-FM (RR, 0.43 [95% CI,.22–.87]). Conclusions In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV. Clinical Trials Registration NCT01450085. [ABSTRACT FROM AUTHOR]

Globally, men have a higher epidemiologic burden of tuberculosis (incidence, prevalence, mortality) than women do, possibly due to differences in disease incidence, treatment initiation, self-cure, and/or untreated-tuberculosis mortality rates. Using a simple, sex-stratified compartmental model, we employed a Bayesian approach to explore which factors most likely explain men's higher burden. We applied the model to smear-positive pulmonary tuberculosis in Vietnam (2006–2007) and Malawi (2013–2014). Posterior estimates were consistent with sex-specific prevalence and notifications in both countries. Results supported higher incidence in men and showed that both sexes faced longer durations of untreated disease than estimated by self-reports. Prior untreated disease durations were revised upward 8- to 24-fold, to 2.2 (95% credible interval: 1.7, 2.9) years for men in Vietnam and 2.8 (1.8, 4.1) years for men in Malawi, approximately a year longer than for women in each country. Results imply that substantial sex differences in tuberculosis burden are almost solely attributable to men's disadvantages in disease incidence and untreated disease duration. The latter, for which self-reports provide a poor proxy, implies inadequate coverage of case-finding strategies. These results highlight an urgent need for better understanding of gender-related barriers faced by men and support the systematic targeting of men for screening. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus self-testing (HIVST) is effective, with scale-up underway in sub-Saharan Africa. We assessed cost-effectiveness of adding HIVST to existing facility-based HIV testing and counseling (HTC) services. Both 2010 (initiate at CD4 <350 cells/μL) and 2015 (initiate all) World Health Organization (WHO) guidelines for antiretroviral treatment (ART) were considered. Methods. A microsimulation model was developed to evaluate cost-effectiveness, from both health provider and societal perspectives, of an HIVST service implemented in a cluster-randomized trial (CRT; ISRCTN02004005) in Malawi. Costs and health outcomes were evaluated over a 20-year time horizon, using a discount rate of 3%. Probabilistic sensitivity analysis was conducted to account for parameter uncertainty. Results. From the health provider perspective and 20-year time horizon, facility HTC using 2010 WHO ART guidelines was the least costly ($294.71 per person; 95% credible interval [CrI], 270.79--318.45) and least effective (11.64 quality-adjusted life-years [QALYs] per person; 95% CrI, 11.43--11.86) strategy. Compared with this strategy, the incremental cost-effectiveness ratio (ICER) for facility HTC using 2015 WHO ART guidelines was $226.85 (95% CrI, 198.79--284.35) per QALY gained. The strategy of facility HTC plus HIVST, using 2010 WHO ART guidelines, was extendedly dominated. The ICER for facility HTC plus HIVST, using 2015 WHO ART guidelines, was $253.90 (95% CrI, 201.71--342.02) per QALY gained compared with facility HTC and using 2015 WHO ART guidelines. Conclusions. HIVST may be cost-effective in a Malawian population with high HIV prevalence. HIVST is suited to an early HIV diagnosis and treatment strategy. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV) infection is a recognized risk factor for stroke among young populations, but the exact mechanisms are poorly understood. We studied the clinical, radiologic, and histologic features of HIV-related ischemic stroke to gain insight into the disease mechanisms.Methods: We conducted a prospective, in-depth analysis of adult ischemic stroke patients presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, in 2011.Results: We recruited 64 HIV-infected and 107 HIV-uninfected patients. Those with HIV were significantly younger (P < .001) and less likely to have established vascular risk factors. Patients with HIV were more likely to have large artery disease (21% vs 10%; P < .001). The commonest etiology was HIV-associated vasculopathy (24 [38%]), followed by opportunistic infections (16 [25%]). Sixteen of 64 (25%) had a stroke soon after starting antiretroviral therapy (ART), suggesting an immune reconstitution-like syndrome. In this group, CD4+ T-lymphocyte count was low, despite a significantly lower HIV viral load in those recently started on treatment (P < .001).Conclusions: HIV-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution-like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments. [ABSTRACT FROM AUTHOR]

Background. Antiretroviral therapy (ART) has led to increased survival of children with vertically acquired human immunodeficiency virus infection. Significant morbidity arises from respiratory symptoms, but aetiology and pulmonary function abnormalities have not been systematically studied. Methods. Human immunodeficiency virus-positive children aged 8-16 years were systematically recruited within clinics in Blantyre, Malawi. Clinical review, quality of life assessment, spirometry, and chest radiography were performed. Results. One hundred sixty participants had a mean of age 11.1 (range, 8-16) years and 50.0% were female. Cough was present in 60 (37.5%) participants, and 55 (34.4%) had moderate or severe dyspnoea. Thirty-four (22.1%) participants had digital clubbing. Thirty-three (20.6%) participants were hypoxic at rest. One hundred eighteen (73.8%) of the children were receiving ART; median CD4 count was 698 cells/μL in these compared with 406 cells/μL in ART-naive individuals (P < .001). From 145 spirometry traces (90.6%), mean forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were 1.06 and 0.89 standard deviations below predicted mean, respectively. Twenty-one (14.5%) traces demonstrated obstructive defects and 26 (17.9%) reduced FVC. Lung function abnormality was not associated with any clinical findings. Of the 51 individuals with abnormal lung function, the mean increase in FEV1 after salbutamol was 3.8% (95% confidence interval, 0.02-7.53). "Tramlines" and ring shadows were seen on chest radiographs in over half of cases. Conclusions. Symptoms of chronic lung disease were highly prevalent with 2 main clinical phenotypes: "cough" and "hypoxia". Lung function abnormalities are common, poorly responsive to bronchodilators, and apparent throughout the age range of our cohort. Pathological causes remain to be elucidated. Cough and hypoxic phenotypes could be a useful part of diagnostic algorithms if further validated. [ABSTRACT FROM AUTHOR]

We aimed to model the incidence of infection with Mycobacterium tuberculosis among adults using data on infection incidence in children, disease prevalence in adults, and social contact patterns. We conducted a cross-sectional face-to-face survey of adults in 2011, enumerating "close" (shared conversation) and "casual" (shared indoor space) social contacts in 16 Zambian communities and 8 South African communities. We modeled the incidence of M. tuberculosis infection in all age groups using these contact patterns, as well as the observed incidence of M. tuberculosis infection in children and the prevalence of tuberculosis disease in adults. A total of 3,528 adults participated in the study. The reported rates of close and casual contact were 4.9 per adult per day (95% confidence interval: 4.6, 5.2) and 10.4 per adult per day (95% confidence interval: 9.3, 11.6), respectively. Rates of close contact were higher for adults in larger households and rural areas. There was preferential mixing of close contacts within age groups and within sexes. The estimated incidence of M. tuberculosis infection in adults was 1.5-6 times higher (2.5%-10% per year) than that in children. More than 50% of infections in men, women, and children were estimated to be due to contact with adult men. We conclude that estimates of infection incidence based on surveys in children might underestimate incidence in adults. Most infections may be due to contact with adult men. Treatment and control of tuberculosis in men is critical to protecting men, women, and children from tuberculosis. [ABSTRACT FROM AUTHOR]

Background. Antibiotic-tolerant bacterial persistence prevents treatment shortening in drug-susceptible tuberculosis, and accumulation of intracellular lipid bodies has been proposed to identify a persister phenotype of Mycobacterium tuberculosis cells. In Malawi, we modeled bacillary elimination rates (BERs) from sputum cultures and calculated the percentage of lipid body-positive acid-fast bacilli (%LB + AFB) on sputum smears. We assessed whether these putative measurements of persistence predict unfavorable outcomes (treatment failure/relapse). Methods. Adults with pulmonary tuberculosis received standard 6-month therapy. Sputum samples were collected during the first 8 weeks for serial sputum colony counting (SSCC) on agar and time-to positivity (TTP) measurement in mycobacterial growth indicator tubes. BERs were extracted from nonlinear and linear mixed-effects models, respectively, fitted to these datasets. The %LB + AFB counts were assessed by fluorescence microscopy. Patients were followed until 1 year posttreatment. Individual BERs and %LB + AFB counts were related to final outcomes. Results. One hundred and thirty-three patients (56% HIV coinfected) participated, and 15 unfavorable outcomes were reported. These were inversely associated with faster sterilization phase bacillary elimination fromthe SSCCmodel (odds ratio [OR], 0.39; 95% confidence interval [CI], .22-.70) and a faster BER from the TTP model (OR, 0.71; 95% CI, .55-.94). Higher %LB + AFB counts on day 21-28 were recorded in patients who suffered unfavorable final outcomes compared with those who achieved stable cure (P = .008). Conclusions. Modeling BERs predicts final outcome, and high %LB + AFB counts 3-4 weeks into therapy may identify a persister bacterial phenotype. These methods deserve further evaluation as surrogate endpoints for clinical trials. [ABSTRACT FROM AUTHOR]

Global progress toward universal human immunodeficiency virus (HIV) testing remains slow. Interest in HIV self-testing is high and may increase knowledge of HIV status; however, empirical research on selftesting is limited, resulting in lack of evidence on which to base policy recommendations.Inadequate uptake of testing for human immunodeficiency virus (HIV) remains a primary bottleneck toward universal access to treatment and care, and is an obstacle to realizing the potential of new interventions for preventing HIV infection, including treatment for prevention and preexposure prophylaxis. HIV self-testing offers an approach to scaling up testing that could be high impact, low cost, confidential, and empowering for users. Although HIV self-testing was first considered >20 years ago, it has not been widely implemented. We conducted a review of policy and research on HIV self-testing, which indicates that policy is shifting toward a more flexible approach with less emphasis on pretest counseling and that HIV self-testing has been adopted in a number of settings. Empirical research on self-testing is limited, resulting in a lack of an evidence base upon which to base policy recommendations. Relevant research and investment in programs are urgently needed to enable consideration of developing formalized self-testing programs. [ABSTRACT FROM AUTHOR]

A high burden of cardiac disease was found among 110 consecutive adolescents with vertically-acquired human immunodeficiency virus infection in Zimbabwe: 37% had an NYHA score =2:echocardiography showed two thirds had LVH, 24% had LV diastolic dysfunction and 31% had RV dilatation.Background. At least one-third of human immunodeficiency virus (HIV)–infected infants survive to adolescence even without antiretroviral therapy (ART), but are at high risk of complications including cardiac disease. We investigated the characteristics of cardiac disease among adolescents with HIV infection diagnosed in late childhood who were receiving ambulatory HIV care in Harare, Zimbabwe.Methods. Consecutive adolescents with vertically acquired HIV attending 2 HIV outpatient treatment clinics were studied. Assessment included clinical history and examination, and 2-dimensional, M-mode, pulsed- and continuous-wave Doppler echocardiography.Results. Of 110 participants (47% male; median age, 15 years; interquartile range, 12–17 years), 78 (71%) were taking ART. Exertional dyspnea, chest pain, palpitations, and ankle swelling were reported by 47 (43%), 43 (39%), 10 (9%), and 7 (6%), respectively. The New York Heart Association score was ≥2 in 41 participants (37%). Echocardiography showed that 74 participants (67%) had left ventricular (LV; septal and/or free wall) hypertrophy and 27 (24%) had evidence of impaired LV relaxation or restrictive LV physiology. The estimated pulmonary artery systolic pressure (ePASP) was >30 mm Hg in 4 participants (3.6%); of these 2 also had right ventricular (RV) dilatation. Another 32 participants (29%), without elevated ePASP, had isolated RV dilatation.Conclusions. A significant burden of cardiac disease was seen among adolescents with vertically acquired HIV infection. More than half were asymptomatic yet had significant echocardiographic abnormalities. These findings highlight the need to screen this population in order to better define the geography, natural history, etiopathogenic mechanisms, and management (including the timing and choice of optimal therapeutic ART and cardiac drug interventions) to prevent development and/or progression of HIV-associated cardiac disease. [ABSTRACT FROM AUTHOR]

Unlike therapeutics, novel diagnostic tests for infectious diseases are licensed on the basis of accuracy rather than health impact. Scaling up these tests with the intent to improve population health raises distinctive ethical concerns of equipoise, equity, and informed consent.In the last decade, many new rapid diagnostic tests for infectious diseases have been developed. In general, these new tests are developed with the intent to optimize feasibility and population health, not accuracy alone. However, unlike drugs or vaccines, diagnostic tests are evaluated and licensed on the basis of accuracy, not health impact (eg, reduced morbidity or mortality). Thus, these tests are sometimes recommended or scaled up for purposes of improving population health without randomized evidence that they do so. We highlight the importance of randomized trials to evaluate the health impact of novel diagnostics and note that such trials raise distinctive ethical challenges of equipoise, equity, and informed consent. We discuss the distinction between equipoise for patient-important outcomes versus diagnostic accuracy, the equity implications of evaluating health impact of diagnostics under routine conditions, and the importance of offering reasonable choices for informed consent in diagnostic trials. [ABSTRACT FROM AUTHOR]

A high burden of chronic lung disease (CLD) was found among 116 consecutive adolescents with vertically acquired human immunodeficiency virus in Zimbabwe. The main cause of HIV-associated CLD appears to be obliterative bronchiolitis, which has not previously been recognized among this patient group.Background. Long-term survivors of vertically acquired human immunodeficiency virus (HIV) infection are reaching adolescence in large numbers in Africa and are at high risk of delayed diagnosis and chronic complications of untreated HIV infection. Chronic respiratory symptoms are more common than would be anticipated based on the HIV literature.Methods. Consecutive adolescents with presumed vertically acquired HIV attending 2 HIV care clinics in Harare, Zimbabwe, were recruited and assessed with clinical history and examination, CD4 count, pulmonary function tests, Doppler echocardiography, and chest radiography (CXR). Those with suspected nontuberculous chronic lung disease (CLD) were scanned using high-resolution computed tomography (HRCT).Results. Of 116 participants (43% male; mean age, 14 ± 2.6 years, mean age at HIV diagnosis, 12 years), 69% were receiving antiretroviral therapy. Chronic cough and reduced exercise tolerance were reported by 66% and 21% of participants, respectively; 41% reported multiple respiratory tract infections in the previous year, and 10% were clubbed. More than 40% had hypoxemia at rest (13%) or on exercise (29%), with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg) in 7%. Forced expiratory volume in 1 second (FEV1) was <80% predicted in 45%, and 47% had subtle CXR abnormalities. The predominant HRCT pattern was decreased attenuation as part of a mosaic attenuation pattern (31 of 56 [55%]), consistent with small airway disease and associated with bronchiectasis (Spearman correlation coefficient (r2 = 0.8) and reduced FEV1 (r2 = −0.26).Conclusions. Long-term survivors of vertically acquired HIV in Africa are at high risk of a previously undescribed small airway disease, with >40% of unselected adolescent clinic attendees meeting criteria for severe hypoxic CLD. This condition is not obvious at rest. Etiology, prognosis, and response to treatment are currently unknown. [ABSTRACT FROM AUTHOR]

Background. Mother-to-child transmission of human immunodeficiency virus (HIV) infection was extremely common in southern Africa during the 1990s, and a substantial minority of infected infants have survived to reach adolescence undiagnosed. Studies have shown a high prevalence of HIV infection in hospitalized adolescents who have features associated with long-standing HIV infection, including stunting and frequent minor illnesses. We therefore investigated the epidemiology of HIV infection at the primary care level. Methods. Adolescents (aged 10-18 years) attending two primary care clinics underwent HIV and Herpes simplex virus-2 (HSV-2) serological testing, clinical examination, and anthropometry. All were offered routine HIV counseling and testing. Patients attending for acute primary care (APC) who were HIV infected were asked about their risk factors. Results. Five hundred ninety-four participants were systematically recruited (97% participation), of whom 88 (15%) were attending for antenatal care. HIV infection prevalence was higher among APC attendees than among antenatal care attendees (17% vs 6%; P< .007), but for the prevalence of HSV-2 infection, a marker of sexually acquired HIV, the converse was true (4% vs 14%; P< .002). Seventy (81%) of 86 HIV-positive APC attendees were previously undiagnosed. They had a broad range of presenting complaints, with a median CD4 cell count of 329 cells/mL (interquartile range, 176-485 cells/μL) and a high prevalence of stunting, compared with the corresponding prevalence among HIV-negative attendees (40% vs 12%; P< .001). Maternal transmission was considered to be likely by 69 (80%) of the 86 HIV-positive APC attendees, only one of whom was HSV-2 positive. Conclusions. Unrecognized HIV infection was a common cause of primary care attendance. Routine HIV counseling and testing implemented at the primary care level may provide a simple and effective way of identifying older long-term survivors of mother-to-child transmission before the onset of severe immunosuppression and irreversible complications. [ABSTRACT FROM AUTHOR]

Background: Recent data from antenatal clinic (ANC) surveillance and general population surveys suggest substantial declines in human immunodeficiency virus (HIV) prevalence in Zimbabwe. We assessed the contributions of rising mortality, falling HIV incidence and sexual behaviour change to the decline in HIV prevalence.Methods: Comprehensive review and secondary analysis of national and local sources on trends in HIV prevalence, HIV incidence, mortality and sexual behaviour covering the period 1985-2007.Results: HIV prevalence fell in Zimbabwe over the past decade (national estimates: from 29.3% in 1997 to 15.6% in 2007). National census and survey estimates, vital registration data from Harare and Bulawayo, and prospective local population survey data from eastern Zimbabwe showed substantial rises in mortality during the 1990s levelling off after 2000. Direct estimates of HIV incidence in male factory workers and women attending pre- and post-natal clinics, trends in HIV prevalence in 15-24-year-olds, and back-calculation estimates based on the vital registration data from Harare indicated that HIV incidence may have peaked in the early 1990s and fallen during the 1990s. Household survey data showed reductions in numbers reporting casual partners from the late 1990s and high condom use in non-regular partnerships between 1998 and 2007.Conclusions: These findings provide the first convincing evidence of an HIV decline accelerated by changes in sexual behaviour in a southern African country. However, in 2007, one in every seven adults in Zimbabwe was still infected with a life-threatening virus and mortality rates remained at crisis level. [ABSTRACT FROM AUTHOR]

Understanding the epidemiology and clinical course of tuberculosis is hampered by the absence of a perfect test for latent tuberculosis infection. The tuberculin skin test (TST) is widely used but suffers poor specificity in those receiving the bacille Calmette-Guérin vaccine and poor sensitivity in individuals with human immunodeficiency virus (HIV) infections. TST responses for a target population in Harare, Zimbabwe (HIV prevalence, 21%), recruited in 2005–2006, were interpreted by using a separate calibration population in Harare, for which interferon-gamma release assays (enzyme-linked immunosorbent spot (ELISpot)) results were also known. Statistical fitting of the responses in the calibration population allowed computation of the probability that an individual in the target population with a given TST and HIV result would have tested ELISpot positive. From this, estimates of the prevalence of tuberculosis infection, and optimal TST cutpoints to minimize misdiagnosis, were computed for different assumptions about ELISpot performance. Different assumptions about the sensitivity and specificity of ELISpot gave a 40%–57% prevalence of tuberculosis infection in the target population (including HIV-infected individuals) and optimal TST cutpoints typically in the 10 mm–20 mm range. However, the optimal cutpoint for HIV-infected individuals was consistently 0 mm. This calibration method may provide a valuable tool for interpreting TST results in other populations. [ABSTRACT FROM PUBLISHER]

An introduction is presented in which editor discusses various articles within the issue on topics including global tuberculosis (TB) Program at World Health Organization (WHO), implications of urbanization on current and future TB control efforts and impact of diabetes mellitus on TB.

Background. Symptomatic human immunodeficiency virus (HIV) infection during late childhood and adolescence may be an emerging problem in southern Africa, but it is one that is poorly described. We investigated social and clinical features in patients of this age group presenting to a HIV treatment clinic with special adolescent services in Harare, Zimbabwe. Methods. All patients aged 8-19 years and their guardians who attended an adolescent HIV treatment clinic were asked to consent to an interview and a review of medical notes. Results. Of 32 patients, 17 (53%) were male. The median CD4 cell count at presentation was 101 cells/μL (interquartile range, 35-197 cells/μL). Sixty-two percent experienced stunting (mean Z score for height-for-age, -2.55; 95% CI, -2.00 to -3.10), and all presented with World Health Organization stage 3 or 4 HIV infection. The median age at the first HIV test was 11 years, with a median of 3.5 years delay since the first HIV-related illness. Recurrent respiratory tract infections, skin complaints, diarrhea, and past tuberculosis were the most common HIV-related complaints. Seventeen patients (55%) were double orphans, and 10 (62%) surviving parents were known to be HIV positive. Conclusions. In this small study, HIV-infected adolescents were profoundly immunosuppressed, with characteristics suggesting long-standing HIV infection. The equal sex distribution and high incidence of parental and sibling mortality were consistent; the majority of children had HIV-infected parents and, therefore, were potentially long-term survivors of HIV infection due to mother-to-child transmission. Greater recognition of the substantial burden of undiagnosed HIV infection and acquired immunodeficiency syndrome in this age group is needed, together with services aimed at reducing barriers to earlier diagnosis and initiation of treatment. [ABSTRACT FROM AUTHOR]

Background. African hospitals have experienced major increases in admissions for tuberculosis, but they are ill-equipped to prevent institutional transmission. We compared institutional rates and community rates of tuberculin skin test (TST) conversion in Harare, Zimbabwe Methods. We conducted a cohort study of TST conversion 6, 12, and 18 months into training among 159 nursing and 195 polytechnic school students in Harare. Students had negative TST results (induration diameter, ⩽9 mm) with 2-step testing at the start of training. Results. Nursing students experienced 19.3 TST conversions (increase in induration diameter, ⩾10 mm) per 100 person-years (95% confidence interval [CI], 14.2–26.2 conversions per 100 person-years), and polytechnic school students experienced 6.0 (95% CI, 3.5–10.4) conversions per 100 person-years. The rate of difference was 13.2 conversions (95% CI, 6.5–20.0) per 100 person-years. With a more stringent definition of conversion (increase in the induration diameter of ⩾10 mm to at least 15 mm), which is likely to increase specificity but decrease sensitivity, conversion rates were 12.5 and 2.8 conversions per 100 person-years in nursing and polytechnic school students, respectively (rate difference, 9.7 conversions per 100 person-years; 95% CI, 4.5–14.8 conversions per 100 person-years). Nursing students reportedly nursed 20,868 inpatients with tuberculosis during 315 person-years of training. Conclusions. Both groups had high TST conversion rates, but the extremely high rates among nursing students imply high occupational exposure to Mycobacterium tuberculosis. Intense exposure to inpatients with tuberculosis was reported during training. Better prevention, surveillance, and management of institutional M. tuberculosis transmission need to be supported as part of the international response to the severe human immunodeficiency virus infection epidemic and health care worker crisis in Africa. [ABSTRACT FROM AUTHOR]

Background. Cough lasting for ≧3 weeks (i.e., chronic cough) indicates that a patient has suspected tuberculosis (TB). At the primary health care level, the spectrum of disease that causes chronic cough has not been previously investigated in a setting with a high prevalence of human immunodeficiency virus (HIV) infection. Methods. A total of 544 adults with chronic cough were recruited systematically from 2 primary health care clinics, and they were evaluated using preset first- and second-line investigations and diagnostic case definitions. Results. The overall prevalence of HIV infection among the study cohort was 83%. TB was the most common diagnosis, with 207 HI V-positive patients (46%) and 27 HIV-negative patients (3 0%) having confirmed or probable TB. Of these, 145 HIV-positive patients with TB (70%) and 20 HIV-negative patients with TB (74%) had smear- positive cases of TB. Only 17 HIV-positive and 2 HIV-negative patients had smear-negative but culture-positive cases of TB. Lower respiratory tract infections (n = 178; HIV prevalence, 79%) and pneumonia (n = 87; HIV prevalence, 89%) were the next most common diagnoses. Asthma (n = 26; HIV prevalence, 46%), posttuberculous disease and other fibrotic lung disease (n = 34; HIV prevalence, 88%), and cardiac disease (n = 15; HIV prevalence, 93%) were more common than were Pneumocystis jiroveci pneumonia and cryptococcosis (n = 8 and n = 5, respectively; HIV prevalence, 100%), and we found no cases of nocardiosis or histoplasmosis. Conclusions. TB was diagnosed for 43% of patients who presented with chronic cough to primary health care clinics in Harare, with 71% having smear-positive disease. The findings of TB culture added relatively little to the findings of fluorescent microscopy of concentrated sputum specimens. The prevalence of HIV infection was high across a range of diagnoses, suggesting that an HIV test should be recommended in the initial investigation of chronic cough. [ABSTRACT FROM AUTHOR]

During the last decade, annual tuberculosis (TB) case-notification rates increased 4-fold, to >4000 cases/100,000 person-years, in the study workforce, among whom prevalence of human immunodeficiency virus (HIV) was 30% in 2000. Three separate cohort studies, totalling 6454 HIV-negative participants, were combined and analyzed for time trends. Observed incidence of TB varied between 962 (1991-1994) and 1589 (1999-2000) cases/l00,000 person-years (P = .17, test for trend). There was, however, a progressive increase in age, and, for each period, older age was associated with increased incidence rates of TB (P<.001). Having adjusted for age differences, there was no significant association between incidence of TB and calendar period (P = .81, test for trend). Relative to 1991-1994, multivariate-adjusted incidence-rate ratios were 0.94, for 1995-1997, 0.96, for 1998-1999, and 1.05, for 1999-2000. Preventing a secondary epidemic of TB among HIV-negative individuals may be achievable with conventional means, even in settings with a high burden of HIV-associated TB. [ABSTRACT FROM AUTHOR]

Deals with a study which determined the mortality and morbidity among South African miners infected with HIV. Methods; Results; Discussion.

Pneumocystis carinii is a common cause of pneumonia in individuals who are immunosuppressed by HIV infection. Use of molecular biological techniques show that P. carinii is a fungus and that infection in man is not a zoonosis. Invasive tests such as sputum induction or bronchoscopy are used to make the diagnosis of P. carinii pneumonia. Life long primary prophylaxis is given to HIV positive individuals with CD4+ lymphocyte counts <0.20 x 109/L or a CD4: total lymphocyte ratio of <1.5, constitutional symptoms, or with other AIDS defining diseases. Secondary prophylaxis is given after a first episode to prevent a recurrence. First choice for primary and secondary prophylaxis is oral co-trimoxazole 960 mg od or three times a week. In patients who are intolerant to co-trimoxazole, nebulised pentamidine or dapsone (with or without pyrimethamine) are second and third choices. In a patient with acute PCP disease, severity should be assessed using clinical, radiographic and blood gas criteria as those with moderate or severe disease will benefit from adjuvant glucocorticoids. Co-trimoxazole (120 mg/kg/day in divided doses for 21 days) is first choice therapy for PCP of all degrees of severity. In patients who fail to respond to co-trimoxazole or who are intolerant to it, second line treatment is iv pentamidine in those with severe disease and oral dapsone with trimethoprim, oral clindamycin with primaquine or iv pentamidine in those with mild or moderately severe disease. [ABSTRACT FROM PUBLISHER]

Three hundred eighty-eight human immuno deficiency virus (HIV)-negative clients in Zimbabwe were retested at 3 months using 2 parallel rapid tests. One operator error (risk, 0.26%; 95% confidence interval, 0.0065%-1.4%) and no "true" seroconversions (upper 95% confidence limit, 0.96%) were detected. High-risk behavior was not significantly reduced. Policies recommending routine retesting need to be reconsidered. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the treatment of tuberculosis.

A response from the authors of the article "A review of self-testing for HIV: research and policy priorities in a new era of HIV prevention" in the 2013 issue is presented.