Anthony E. Butterworth

Comparison of two active case-finding strategies for community-based diagnosis of symptomatic smear-positive tuberculosis and control of infectious tuberculosis in Harare, Zimbabwe (DETECTB): a cluster-randomised trial

Summary Background 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. Methods 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. Findings 46 study clusters were identified and randomly allocated equally between intervention groups, with 55u2008741 adults in the mobile van group and 54u2008691 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). Interpretation Wide implementation of active case finding, particularly with a mobile van approach, could have rapid effects on tuberculosis transmission and disease. Funding Wellcome Trust.

Uptake of workplace HIV counselling and testing: a cluster-randomised trial in Zimbabwe.

Background 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). Methods and Findings 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). Conclusions 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.

Epidemiology of Tuberculosis in a High HIV Prevalence Population Provided with Enhanced Diagnosis of Symptomatic Disease

Background Directly observed treatment short course (DOTS), the global control strategy aimed at controlling tuberculosis (TB) transmission through prompt diagnosis of symptomatic smear-positive disease, has failed to prevent rising tuberculosis incidence rates in Africa brought about by the HIV epidemic. However, rising incidence does not necessarily imply failure to control tuberculosis transmission, which is primarily driven by prevalent infectious disease. We investigated the epidemiology of prevalent and incident TB in a high HIV prevalence population provided with enhanced primary health care. Methods and Findings Twenty-two businesses in Harare, Zimbabwe, were provided with free smear- and culture-based investigation of TB symptoms through occupational clinics. Anonymised HIV tests were requested from all employees. After 2 y of follow-up for incident TB, a culture-based survey for undiagnosed prevalent TB was conducted. A total of 6,440 of 7,478 eligible employees participated. HIV prevalence was 19%. For HIV-positive and -negative participants, the incidence of culture-positive tuberculosis was 25.3 and 1.3 per 1,000 person-years, respectively (adjusted incidence rate ratio = 18.8; 95% confidence interval [CI] = 10.3 to 34.5: population attributable fraction = 78%), and point prevalence after 2 y was 5.7 and 2.6 per 1,000 population (adjusted odds ratio = 1.7; 95% CI = 0.5 to 6.8: population attributable fraction = 14%). Most patients with prevalent culture-positive TB had subclinical disease when first detected. Conclusions Strategies based on prompt investigation of TB symptoms, such as DOTS, may be an effective way of controlling prevalent TB in high HIV prevalence populations. This may translate into effective control of TB transmission despite high TB incidence rates and a period of subclinical infectiousness in some patients.

Schistosomiasis and HIV-1 Infection in Rural Zimbabwe: Effect of Treatment of Schistosomiasis on CD4 Cell Count and Plasma HIV-1 RNA Load

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 incidence during a cluster-randomized trial of two strategies providing voluntary counselling and testing at the workplace, Zimbabwe.

Objective:To investigate HIV incidence during a trial of two voluntary counselling and testing (VCT) strategies. Counselling may promote beneficial behavioural change, although knowledge of negative status does not appear to contribute further benefit. Design:The parent cluster-randomized trial demonstrated much greater uptake of VCT when counselling and rapid testing were available on-site (intensive VCT) than through pre-paid vouchers to an external provider (standard VCT). Anonymous HIV tests had been requested from all employees at enrolment and after 2 years intervention. Methods:The study setting was 22 businesses in Harare, Zimbabwe. Participants were 3146 HIV-negative individuals remaining in employment at the end of intervention, of whom 2966 (94.3%) consented to repeat testing. VCT linked to basic HIV care was provided and the main outcome measures were HIV incidence under each study arm, as a retrospective secondary analysis. Results:Mean VCT uptake in this cohort was 70.7 and 5.2%, respectively, in the intensive and standard arms. Crude HIV incidence was 1.21 per 100 person-years, with non-significantly higher rates in the intensive VCT arm [mean site incidence 1.37 and 0.95 per 100 person-years, respectively; adjusted rate ratio 1.49 (95% confidence interval 0.79–2.80). Conclusions:Highly acceptable VCT did not reduce HIV incidence in this predominantly male cohort. HIV incidence was highest in the high uptake VCT arm, lending support to a US trial in which rapid testing appeared to have adverse behavioural consequences in some HIV-negative clients. Careful comparison of outcomes under different counselling and testing strategies is needed to maximize HIV prevention from global scale-up of VCT.

Effect of Optional Home Initiation of HIV Care Following HIV Self-testing on Antiretroviral Therapy Initiation Among Adults in Malawi: A Randomized Clinical Trial

IMPORTANCEnSelf-testing for HIV infection may contribute to early diagnosis of HIV, but without necessarily increasing antiretroviral therapy (ART) initiation.nnnOBJECTIVEnTo investigate whether offering optional home initiation of HIV care after HIV self-testing might increase demand for ART initiation, compared with HIV self-testing accompanied by facility-based services only.nnnDESIGN, SETTING, AND PARTICIPANTSnCluster randomized trial conducted in Blantyre, Malawi, between January 30 and November 5, 2012, using restricted 1:1 randomization of 14 community health worker catchment areas. Participants were all adult (≥16 years) residents (nu2009=u200916,660) who received access to home HIV self-testing through resident volunteers. This was a second-stage randomization of clusters allocated to the HIV self-testing group of a parent trial.nnnINTERVENTIONSnClusters were randomly allocated to facility-based care or optional home initiation of HIV care (including 2 weeks of ART if eligible) for participants reporting positive HIV self-test results.nnnMAIN OUTCOMES AND MEASURESnThe preplanned primary outcome compared between groups the proportion of all adult residents who initiated ART within the first 6 months of HIV self-testing availability. Secondary outcomes were uptake of HIV self-testing, reporting of positive HIV self-test results, and rates of loss from ART at 6 months.nnnRESULTSnA significantly greater proportion of adults in the home group initiated ART (181/8194, 2.2%) compared with the facility group (63/8466, 0.7%; risk ratio [RR], 2.94, 95% CI, 2.10-4.12; Pu2009<u2009.001). Uptake of HIV self-testing was high in both the home (5287/8194, 64.9%) and facility groups (4433/8466, 52.7%; RR, 1.23; 95% CI, 0.96-1.58; Pu2009=u2009.10). Significantly more adults reported positive HIV self-test results in the home group (490/8194 [6.0%] vs the facility group, 278/8466 [3.3%]; RR, 1.86; 95% CI, 1.16-2.97; Pu2009=u2009.006). After 6 months, 52 of 181 ART initiators (28.7%) and 15 of 63 ART initiators (23.8%) in the home and facility groups, respectively, were lost from ART (adjusted incidence rate ratio, 1.18; 95% CI, 0.62-2.25, Pu2009=u2009.57).nnnCONCLUSIONS AND RELEVANCEnAmong Malawian adults offered HIV self-testing, optional home initiation of care compared with standard HIV care resulted in a significant increase in the proportion of adults initiating ART.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT01414413.

Provider-initiated symptom screening for tuberculosis in Zimbabwe: diagnostic value and the effect of HIV status

OBJECTIVEnTo assess the diagnostic value of provider-initiated symptom screening for tuberculosis (TB) and how HIV status affects it.nnnMETHODSnWe 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.nnnFINDINGSnWe 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.nnnCONCLUSIONnEven 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.

Schistosomiasis and HIV-1 Infection in Rural Zimbabwe: Implications of Coinfection for Excretion of Eggs

BACKGROUNDnStunted 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.nnnMETHODSnIn 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.nnnRESULTSnIn 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.nnnCONCLUSIONnThe 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.

Reduced mortality and CD4 cell loss among carriers of the interleukin-10 -1082G allele in a Zimbabwean cohort of HIV-1-infected adults.

Objectives:To evaluate the effect on HIV progression of single nucleotide polymorphisms in promoters of the genes for tumour necrosis factor (TNF)-α and interleukin (IL)-10 and known to influence cytokine production. Methods:Survival was documented for 4.3 years after baseline for 198 HIV-1-infected and 180 HIV-uninfected individuals from the Mupfure Schistosomiasis and HIV Cohort in rural Zimbabwe. Polymorphisms determined were −592C>A and −1082A>G for IL-10 and −238G>A and −308G>A for TNF-α. CD4 cell counts, plasma HIV RNA, soluble TNF receptor II (sTNF-rII), IL-8 and IL-10 were also measured. Results:Mortality was lower in carriers of the IL-10 −1082G high-producer allele (hazard ratio, 0.47; P < 0.01). CD4 cell count decrease in participants reporting for the follow-up at 3 years was attenuated in carriers of this allele (P < 0.01). In univariate analysis, plasma IL-10, IL-8, and sTNF-rII correlated negatively with CD4 cell count, positively with HIV RNA, and higher levels predicted mortality. In multivariate analysis only sTNF-rII was an independent predictor of HIV progression markers and mortality. Indeed, sTNF-rII predicted mortality (P < 0.01) at a level of significance comparable to HIV RNA (P < 0.01) and CD4 cell count (P < 0.05). Conclusions:In carriers of IL-10 −1082G, an allele linked to increased IL-10 production, survival was doubled and CD4 cell decrease was attenuated compared with noncarriers. Only sTNF-rII and not plasma IL-10 was an independent predictor of HIV progression markers and mortality. This study supports immune activation as a driving force in HIV pathogenesis and indicates a protective role of IL-10 −1082G that should be evaluated in other cohorts.

Risk factors for mortality in smear-negative tuberculosis suspects: a cohort study in Harare, Zimbabwe

OBJECTIVEnTo investigate mortality rates and risk factors for death among smear-negative tuberculosis (TB) suspects.nnnDESIGNnCohort study nested within a cluster-randomised trial of community-based active case finding. Smear-negative TB suspects were followed for 12 months, with home tracing where necessary. We calculated mortality rates and used regression analysis to investigate the relationship between clinical characteristics and death.nnnRESULTSnBetween February 2006 and June 2007, 1195 smear-negative TB suspects were followed for 1136.8 person-years. Human immunodeficiency virus (HIV) prevalence was 63.3%. During follow-up, 139 participants died (11.6%) and mortality rates remained high throughout; 119 (16.5%) HIV-positive individuals and 13 (3.1%) HIV-negative individuals died (HR = 5.8, 95%CI 3.3-10.4, P < 0.001). Advanced immunosuppression was the main risk factor for death among HIV-positive participants, with CD4 count < 50 cells/μ l associated with a 13-fold increased risk of death. Antiretroviral treatment (ART) was initiated by only 106 (14.7%), with long delays in accessing care.nnnCONCLUSIONnHIV-positive smear-negative TB suspects are at high and sustained risk of death. Current guidelines for the management of HIV-infected TB suspects are limited, and this study adds to evidence that specific policies are required to promote earlier HIV and TB diagnosis and reduce delays in ART initiation.