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Control of tuberculosis in settings with high HIV prevalence is a pressing public health priority. We tested two active case-finding strategies to target long periods of infectiousness before diagnosis, which is typical of HIV-negative tuberculosis and is a key driver of transmission. Clusters of neighbourhoods in the high-density residential suburbs of Harare, Zimbabwe, were randomised to receive six rounds of active case finding at 6-monthly intervals by either mobile van or door-to-door visits. Randomisation was done by selection of discs of two colours from an opaque bag, with one disc to represent every cluster, and one colour allocated to each intervention group before selection began. In both groups, adult (≥16 years) residents volunteering chronic cough (≥2 weeks) had two sputum specimens collected for fluorescence microscopy. Community health workers and cluster residents were not masked to intervention allocation, but investigators and laboratory staff were masked to allocation until final analysis. The primary outcome was the cumulative yield of smear-positive tuberculosis per 1000 adult residents, compared between intervention groups; analysis was by intention to treat. The secondary outcome was change in prevalence of culture-positive tuberculosis from before intervention to before round six of intervention in 12% of randomly selected households from the two intervention groups combined; analysis was based on participants who provided sputum in the two prevalence surveys. This trial is registered, number ISRCTN84352452. 46 study clusters were identified and randomly allocated equally between intervention groups, with 55 741 adults in the mobile van group and 54 691 in the door-to-door group at baseline. HIV prevalence was 21% (1916/9060) and in the 6 months before intervention the smear-positive case notification rate was 2·8 per 1000 adults per year. The trial was completed as planned with no adverse events. The mobile van detected 255 smear-positive patients from 5466 participants submitting sputum compared with 137 of 4711 participants identified through door-to-door visits (adjusted risk ratio 1·48, 95% CI 1·11–1·96, p=0·0087). The overall prevalence of culture-positive tuberculosis declined from 6·5 per 1000 adults (95% CI 5·1–8·3) to 3·7 per 1000 adults (2·6–5·0; adjusted risk ratio 0·59, 95% CI 0·40–0·89, p=0·0112). Wide implementation of active case finding, particularly with a mobile van approach, could have rapid effects on tuberculosis transmission and disease. Wellcome Trust.

To assess the diagnostic value of provider-initiated symptom screening for tuberculosis (TB) and how HIV status affects it. We performed a secondary analysis of randomly selected participants in a community-based TB-HIV prevalence survey in Harare, Zimbabwe. All completed a five-symptom questionnaire and underwent sputum TB culture and HIV testing. We calculated the sensitivity, specificity, and positive and negative predictive values of various symptoms and used regression analysis to investigate the relationship between symptoms and TB disease. We found one or more symptoms of TB in 21.2% of 1858 HIV-positive (HIV+) and 9.9% of 7121 HIV-negative (HIV-) participants (P < 0.001). TB was subsequently diagnosed in 48 HIV+ and 31 HIV- participants. TB was asymptomatic in 18 culture-positive individuals, 8 of whom (4 in each HIV status group) had positive sputum smears. Cough of any duration, weight loss and, for HIV+ participants only, drenching night sweats were independent predictors of TB. In HIV+ participants, cough of > or = 2 weeks' duration, any symptom and a positive sputum culture had sensitivities of 48%, 81% and 65%, respectively; in HIV- participants, the sensitivities were 45%, 71% and 74%, respectively. Symptoms had a similar sensitivity and specificity in HIV+ and HIV- participants, but in HIV+ participants they had a higher positive and a lower negative predictive value. Even smear-positive TB may be missed by provider-initiated symptom screening, especially in HIV+ individuals. Symptom screening is useful for ruling out TB, but better TB diagnostics are urgently needed for resource-poor settings.

To determine whether treatment of schistosomiasis has an effect on the course of human immunodeficiency virus type 1 (HIV-1) infection, individuals with schistosomiasis and with or without HIV-1 infection were randomized to receive praziquantel treatment at inclusion or after a delay of 3 months; 287 participants were included in the study, and 227 (79%) were followed up. Among the 130 participants who were coinfected, those who received early treatment (n=64) had a significantly lower increase in plasma HIV-1 RNA load than did those who received delayed treatment (n=66) (P<.05); this difference was associated with no change in plasma HIV-1 RNA load in the early intervention group (P=.99) and an increase in plasma HIV-1 RNA load in the delayed intervention group (P<.01). Among the 227 participants who were followed up, those who received early treatment (n=105) had an increase in CD4 cell count, whereas those who received delayed treatment (n=122) did not (P<.05); this effect did not differ between participants when stratified by HIV-1 infection status (P=.17). The present study suggests that treatment of schistosomiasis can reduce the rate of viral replication and increase CD4 cell count in the coinfected host

HIV counselling and testing is a key component of both HIV care and HIV prevention, but uptake is currently low. We investigated the impact of rapid HIV testing at the workplace on uptake of voluntary counselling and testing (VCT). The study was a cluster-randomised trial of two VCT strategies, with business occupational health clinics as the unit of randomisation. VCT was directly offered to all employees, followed by 2 y of open access to VCT and basic HIV care. Businesses were randomised to either on-site rapid HIV testing at their occupational clinic (11 businesses) or to vouchers for off-site VCT at a chain of free-standing centres also using rapid tests (11 businesses). Baseline anonymised HIV serology was requested from all employees. HIV prevalence was 19.8% and 18.4%, respectively, at businesses randomised to on-site and off-site VCT. In total, 1,957 of 3,950 employees at clinics randomised to on-site testing had VCT (mean uptake by site 51.1%) compared to 586 of 3,532 employees taking vouchers at clinics randomised to off-site testing (mean uptake by site 19.2%). The risk ratio for on-site VCT compared to voucher uptake was 2.8 (95% confidence interval 1.8 to 3.8) after adjustment for potential confounders. Only 125 employees (mean uptake by site 4.3%) reported using their voucher, so that the true adjusted risk ratio for on-site compared to off-site VCT may have been as high as 12.5 (95% confidence interval 8.2 to 16.8). High-impact VCT strategies are urgently needed to maximise HIV prevention and access to care in Africa. VCT at the workplace offers the potential for high uptake when offered on-site and linked to basic HIV care. Convenience and accessibility appear to have critical roles in the acceptability of community-based VCT.

Cases of smear-negative TB have increased dramatically in high prevalence HIV settings and pose considerable diagnostic and management challenges. Between February 2006 and July 2007, a cohort study nested within a cluster-randomised trial of community-based case finding strategies for TB in Harare, Zimbabwe was undertaken. Participants who had negative sputum smears and remained symptomatic of TB were follow-up for one year with standardised investigations including HIV testing, repeat sputum smears, TB culture and chest radiography. Defaulters were actively traced to the community. The objectives were to investigate the incidence and risk factors for TB. TB was diagnosed in 218 (18.2%) participants, of which 39.4% was bacteriologically confirmed. Most cases (84.2%) were diagnosed within 3 months, but TB incidence remained high thereafter (111.3 per 1000 person-years, 95% CI: 86.6 to 146.3). HIV prevalence was 63.3%, and HIV-infected individuals had a 3.5-fold higher risk of tuberculosis than HIV-negative individuals. We found that diagnosis of TB was insensitive and slow, even with early radiography and culture. Until more sensitive and rapid diagnostic tests become widely available, a much more proactive and integrated approach towards prompt initiation of ART, ideally from within TB clinics and without waiting for TB to be excluded, is needed to minimise the risk and consequences of diagnostic delay.

BackgroundStunted development and reduced fecundity of Schistosoma parasites in immunodeficient mice and the impaired ability of human immunodeficiency virus 1 (HIV-1)–infected humans to excrete schistosome eggs have been described. This study explores the effect that HIV-1–associated immunodeficiency has on the excretion of schistosome eggs in a large cohort of coinfected individuals MethodsIn a cross-sectional survey, urine and stool samples were obtained from and HIV-1 status was determined for 1545 individuals. More extensive data, including quantitative measures of intensity of infection in schistosomiasis and immunodeficiency, were collected in the Mupfure schistosomiasis and HIV longitudinal cohort, composed of 379 participants of whom 154 were coinfected with HIV-1 and Schistosoma parasites ResultsIn the cross-sectional survey, the overall prevalence of schistosomiasis was 43.4%, and 26.3% of the participants were infected with HIV-1. Schistosome infections were due to Schistosoma haematobium in 63.6% of cases, S. mansoni in 18.1% of cases, and dual infections in 18.4% of cases. Intensities of Schistosoma infections, measured by the number of eggs excreted and by the level of circulating anodic antigens, did not differ between HIV-1–negative and HIV-1–positive participants coinfected with S. haematobium, S. mansoni or both. CD4 cell counts were significantly lower in HIV-1–positive participants and in S. mansoni–infected HIV-1–negative participants than in other participants ConclusionThe present study suggests that adult HIV-1–related immunodeficiency does not impair the ability to excrete eggs in low-intensity infection with S. haematobium, S. mansoni or both and that infection with HIV-1 may not have major implications for diagnosis and surveillance of schistosomiasis

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 from the SSCC model (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.

Schoolchildren from 2 areas of Kenya, Kangundo and Kambu, have contrasting prevalences of hepatosplenomegaly, despite having similar prevalences and intensities of Schistosoma mansoni infection. However, in individual children, S. mansoni infection intensity is positively correlated with organomegaly. In a previous study, hepatosplenomegaly was associated with Th1-type anti-schistosome cytokine responses. Although the high-morbidity Kambu area had higher malaria transmission than did low-morbidity Kangundo, hepatosplenomegaly was not associated with clinical malaria or with patent malarial parasitemia. However, chronic exposure to malaria might be involved. Here, retrospectively, we assayed plasma from this original study, for anti-Plasmodium falciparum and anti-S. mansoni antibodies, to test whether greater exposure to Plasmodium was a cofactor for hepatosplenomegaly. We found that hepatosplenic children had significantly higher levels of anti-P. falciparum antibodies, compared with nonhepatosplenic children, a finding that strongly suggests that some experience of P. falciparum influenced the development of hepatosplenomegaly in these S. mansoni-infected children

Two populations with differing histories of Schistosoma mansoni and hepatitis C infection were compared directly for severity of disease and extent of comorbidity. Demographic, parasitologic, and ultrasound surveys were conducted on 2038 Egyptians and on 2120 Kenyans. Hepatitis B and C serologies and transaminase levels were obtained from a subset at each site. Despite significantly lower prevalence and intensity of infection, Egyptians had a higher prevalence of severe schistosomal fibrosis than Kenyans (36.8% vs. 4.6%). Hepatitis C infection was 3 times more prevalent among Egyptians, and evidence of hepatocellular damage was significantly greater among Egyptians. There was no interaction between S. mansoni infection or disease and the prevalence or severity of hepatitis C. For both infections, the intensity or prevalence of infection was a poor predictor of morbidity. The prevalence of disease in the Egyptian population from different pathogens suggests a generalized susceptibility to inflammatory liver disease.

BackgroundAccurate diagnosis of latent tuberculosis infection (LTBI) in recently exposed HIV-infected tuberculosis (TB) contacts is a public health priority because of the high risk of progression to active TB but is hampered by the high background prevalence of LTBI in high-burden populations and poor sensitivity of tuberculin skin testing (TST) in HIV co-infection.MethodsThe prevalence of LTBI in 222 recent household contacts of TB cases and 176 household contacts of community controls without TB in Harare, Zimbabwe were compared using TST and interferon γ enzyme-linked immunospot (ELISpot) responses to ESAT-6 (early secretory antigenic target-6) and CFP-10 (culture filtrate protein-10). TST and ELISpot results were correlated with markers of recent TB exposure and the impact of HIV co-infection was assessed.ResultsIn this high-incidence population, the proportion of ELISpot-positive contacts was not significantly different from community controls. However, ELISpot, unlike TST, revealed a higher prevalence of LTBI in recent contacts of sputum smear-positive cases than in contacts of controls. ELISpot results correlated significantly with positive sputum smear and culture status of the index case (adjusted OR 2.40, CI 1.12 to 5.14), even in the subgroup of HIV-infected contacts (adjusted OR 5.36, CI 1.11 to 25.93). and were independent of contacts' HIV status. TST results were also associated with positive smear and culture status of the index case (adjusted OR 4.41, CI 1.82 to 10.67) but were negatively associated with contacts' HIV status (adjusted OR 0.25, CI 0.10 to 0.60).ConclusionsContact investigations in high-burden populations should focus on contacts of sputum smear-positive cases in whom recent infection can be detected by ELISpot, even in the presence of HIV co-infection.