Pharmacodynamic Modeling of Bacillary Elimination Rates and Detection of Bacterial Lipid Bodies in Sputum to Predict and Understand Outcomes in Treatment of Pulmonary Tuberculosis.

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.

Effect of optional home initiation of HIV care following HIV self-testing on antiretroviral therapy initiation among adults in Malawi: a randomized clinical trial.

IMPORTANCE: Self-testing for HIV infection may contribute to early diagnosis of HIV, but without necessarily increasing antiretroviral therapy (ART) initiation. OBJECTIVE: To 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. DESIGN, SETTING, AND PARTICIPANTS: Cluster 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 (n = 16,660) 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. INTERVENTIONS: Clusters 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. MAIN OUTCOMES AND MEASURES: The 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. RESULTS: A 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; P < .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; P = .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; P = .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, P = .57). CONCLUSIONS AND RELEVANCE: Among 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01414413.

Optimizing outpatient serial sputum colony counting for studies of tuberculosis treatment in resource-poor settings.

Serial Sputum Colony Counting (SSCC) is an important technique in clinical trials of new treatments for tuberculosis (TB). Quantitative cultures on selective Middlebrook agar are used to calculate the rate of bacillary elimination from sputum collected from patients at different time points during the first 2 months of therapy. However, the procedure can be complicated by high sample contamination rates. This study, conducted in a resource-poor setting in Malawi, assessed the ability of different antifungal drugs in selective agar to reduce contamination. Overall, 229 samples were studied and 15% to 27% were contaminated. Fungal organisms were particularly implicated, and samples collected later in treatment were at particular risk (P < 0.001). Amphotericin B (AmB) is the standard antifungal drug used on SSCC plates at a concentration of 10 mg/ml. On selective Middlebrook 7H10 plates, AmB at 30 mg/ml reduced sample contamination by 17% compared with AmB at 10 mg/ml. The relative risk of contamination using AmB at 10 mg/ml was 1.79 (95% confidence interval [CI], 1.25 to 3.55). On Middlebrook 7H11 plates, a combination of AmB at 10 mg/ml and carbendazim at 50 mg/ml was associated with 10% less contamination than AmB at 30 mg/ml. The relative risk of contamination with AmB at 30 mg/ml was 1.79 (95% CI, 1.01 to 3.17). Improved antifungal activity was accompanied by a small reduction in bacillary counts, but this did not affect modeling of bacillary elimination. In conclusion, a combination of AmB and carbendazim optimized the antifungal activity of selective media for growth of TB. We recommend this method to reduce contamination rates and improve SSCC studies in African countries where the burden of TB is highest.

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.

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 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). 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.

Interpreting tuberculin skin tests in a population with a high prevalence of HIV, tuberculosis, and nonspecific tuberculin sensitivity.

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.

Identifying recent Mycobacterium tuberculosis transmission in the setting of high HIV and TB burden.

BACKGROUND: Accurate 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. METHODS: The 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 gamma 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. RESULTS: In 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). CONCLUSIONS: Contact 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.

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

OBJECTIVE: To assess the diagnostic value of provider-initiated symptom screening for tuberculosis (TB) and how HIV status affects it. METHODS: 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. FINDINGS: 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. CONCLUSION: 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.

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)-alpha 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-alpha. 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.

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.

Nursing and community rates of Mycobacterium tuberculosis infection among students in Harare, Zimbabwe.

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, < or =9 mm) with 2-step testing at the start of training. RESULTS: Nursing students experienced 19.3 TST conversions (increase in induration diameter, > or =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 > or =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.

Schistosomiasis and HIV in rural Zimbabwe: efficacy of treatment of schistosomiasis in individuals with HIV coinfection.

BACKGROUND: There is evidence from experimental models that the praziquantel-induced clearance of schistosomiasis is dependent on the host's immune response. Consequently, human immunodeficiency virus (HIV)-related immunodeficiency may impair the effect of praziquantel treatment. METHODS: In a prospective cohort study, schistosome-infected subjects who were or were not coinfected with HIV were treated with praziquantel and followed up 3, 6, and 12 months after treatment. Quantitative measures of intensity of schistosomiasis (egg counts and levels of circulating anodic antigen in serum) and immunodeficiency (CD4+ cell counts and viral loads) were collected. RESULTS: Cure rates based on egg counts 3 months after treatment were satisfactory and were similar for HIV-positive individuals (cure rate, 86%) and HIV-negative individuals (cure rate, 85%); the magnitude of decrease in egg count was equal. Cure rates based on circulating anodic antigen levels were much lower than cure rates based on egg counts, with HIV-positive individuals experiencing significantly less clearance of schistosomiasis (cure rate, 31%) than HIV-negative individuals (cure rate, 52%), whereas the magnitude of decrease in circulating anodic antigen was also lower among HIV-positive individuals (P < .01). CONCLUSION: The effect of praziquantel may be limited to affecting the fecundity of adult schistosomes in the immunocompromised host, thus reducing egg excretion while leaving schistosomes metabolically active, as shown by the fact that levels of antigen production are maintained. Special guidelines for treatment of schistosomiasis in HIV-coinfected individuals may need to be developed.

Voluntary counseling and testing by nurse counselors: what is the role of routine repeated testing after a negative result?

Three hundred eighty-eight human immunodeficiency 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.

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.

Chronic cough in primary health care attendees, Harare, Zimbabwe: diagnosis and impact of HIV infection.

BACKGROUND: Cough lasting for > or = 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 HIV-positive patients (46%) and 27 HIV-negative patients (30%) 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.

Regression of hepatosplenomegaly in Kenyan school-aged children after praziquantel treatment and three years of greatly reduced exposure to Schistosoma mansoni.

Evaluating regression of morbidity associated with parasitic infections is an important component of community-based control programmes. We performed an intervention against Schistosoma mansoni infection, focusing on hepatosplenomegaly in the absence of periportal fibrosis, in a cohort of 67 Kenyan children aged 7-18 years from Makueni District, selected on the basis of hepatosplenomegaly detected by ultrasonography. Clinical and ultrasound examinations were conducted annually for three years after treatment, and the source of infection (a river) was regularly treated with molluscicide, thereby severely reducing exposure to schistosomiasis. Malaria transmission was uninterrupted. The prevalence of hard spleens, and the magnitude of clinically assessed splenomegaly along the mid-axillary and mid-clavicular lines decreased monotonically over time, independently of age, whereas clinically measured hepatomegaly along the mid-sternal line and the prevalence of firm livers decreased in an age-specific manner, being more pronounced amongst children aged 14 years or older at enrolment. Ultrasound data were less informative, and did not concur with clinical observations. These results demonstrate that praziquantel treatment reduces hepatosplenomegaly in the absence of exposure to S. mansoni, even with continuing exposure to malaria. The lack of complete resolution of hepatosplenomegaly in most children suggests, among other things, a residual organomegaly attributable to malaria.

Exposure to malaria affects the regression of hepatosplenomegaly after treatment for Schistosoma mansoni infection in Kenyan children.

BACKGROUND: Schistosoma mansoni and malaria infections are often endemic in the same communities in sub-Saharan Africa, and both have pathological effects on the liver and the spleen. Hepatosplenomegaly associated with S. mansoni is exacerbated in children with relatively high exposure to malaria. Treatment with praziquantel reduces the degree of hepatosplenomegaly, but the condition does not completely resolve in some cases. The present analysis focused on the possibility that exposure to malaria infection may have limited the resolution of hepatosplenomegaly in a cohort of Kenyan schoolchildren. METHODS: Ninety-six children aged 6-16, from one community in Makueni district, Kenya, were treated with praziquantel. At baseline, all children had hepatomegaly and most had splenomegaly. The source of S. mansoni infection, a river, was molluscicided regularly over the following three years to limit S. mansoni re-infection, whereas malaria exposure was uninterrupted. Hepatic and splenic enlargement was assessed annually outside the malaria transmission season. RESULTS: Children living in an area of relatively high exposure to both infections presented with the largest spleens before treatment and at each follow-up. Spleens of firm consistency were associated with proximity to the river. The regression of hepatomegaly was also affected by location, being minimal in an area with relatively low S. mansoni exposure but high exposure to malaria, and maximal in an area with relatively low exposure to both infections. CONCLUSIONS: The outcome of treating cases of hepatosplenomegaly with praziquantel in this cohort of Kenyan children depended strongly on their level of exposure to malaria infection. Furthermore, a residual burden of hepatosplenic morbidity was observed, which was possibly attributable to the level of exposure to malaria. The results suggest that exposure to malaria infection may be a significant factor affecting the outcome of praziquantel treatment to reduce the level of hepatosplenic morbidity.

Micro-geographical variation in exposure to Schistosoma mansoni and malaria, and exacerbation of splenomegaly in Kenyan school-aged children.

BACKGROUND: Schistosoma mansoni and Plasmodium falciparum are common infections of school aged children in Kenya. They both cause enlargement of the spleen, but their relative contribution to the condition of splenomegaly remains unknown in areas where both infections are endemic. Here, we have investigated whether relatively high exposure to both infections has a clinically measurable effect on this condition. METHODS: 96 children aged 6-16 years living along a ten kilometre stretch and within 4 km south of a river that is a source of both S. mansoni and malaria infections were examined clinically for splenomegaly along the mid clavicular line (MCL) and mid axillary line (MAL). The survey was conducted outside the malaria transmission season. The consistency of the organ was recorded as soft, firm or hard. Mapping of the locations of houses and the course of the river was undertaken. Egg counts were mapped at the household level, as were IgG3 responses to Plasmodium falciparum schizont antigen (anti-Pfs IgG3), in order to identify areas with relatively high exposure to both infections, either infection or neither infection. ANOVA was used to test for differences in egg counts, IgG3 levels and the magnitude of spleen enlargement between these areas. RESULTS: 4 contiguous sectors were identified, one where anti-Pfs IgG3 responses and S. mansoni egg counts were both high, one where only anti-Pfs IgG3 responses were high, one where only egg counts were high, and one where both anti-Pfs IgG3 responses and egg counts were low. Spleen MAL and MCL values were significantly higher amongst children from the sector with highest IgG3 levels and highest egg counts but similar amongst children from elsewhere. Both egg counts and anti-Pfs IgG3 responses were significantly higher in children with MAL values > or =4 cm. Hardening of spleens was associated with proximity of domicile to the river. CONCLUSIONS: Micro-geographical variation in exposure to S. mansoni and malaria infections can be exploited to investigate the chronic impact of these two infections. These results provide firm evidence that relatively high exposure to both infections exacerbates splenomegaly even outside the malaria transmission season. Major implications include assessing the burden of infection in school age-children.

Long term study on the effect of mollusciciding with niclosamide in stream habitats on the transmission of schistosomiasis mansoni after community-based chemotherapy in Makueni District, Kenya.

BACKGROUND: Schistosoma mansoni infection is a persistent public health problem in many Kenyan communities. Although praziquantel is available, re-infection after chemotherapy treatment is inevitable, especially among children. Chemotherapy followed by intermittent mollusciciding of habitats of Biomphalaria pfeifferi, the intermediate host snail, may have longer term benefits, especially if timed to coincide with natural fluctuations in snail populations. METHODS: In this cohort study, the Kambu River (Intervention area) was molluscicided intermittently for 4 years, after mass chemotherapy with praziquantel in the adjacent community of Darajani in January 1997. The nearby Thange River was selected as a control (Non-intervention area), and its adjacent community of Ulilinzi was treated with praziquantel in December 1996. Snail numbers were recorded monthly at 9-10 sites along each river, while rainfall data were collected monthly, and annual parasitological surveys were undertaken in each village. The mollusciciding protocol was adapted to local conditions, and simplified to improve prospects for widespread application. RESULTS: After the initial reduction in prevalence attributable to chemotherapy, there was a gradual increase in the prevalence and intensity of infection in the non-intervention area, and significantly lower levels of re-infection amongst inhabitants of the intervention area. Incidence ratio between areas adjusted for age and gender at the first follow-up survey, 5 weeks after treatment in the non-intervention area and 4 months after treatment in the intervention area was not significant (few people turned positive), while during the following 4 annual surveys these ratios were 0.58 (0.39-0.85), 0.33 (0.18-0.60), 0.14 (0.09-0.21) and 0.45 (0.26-0.75), respectively. Snail numbers were consistently low in the intervention area as a result of the mollusciciding. Following termination of the mollusciciding at the end of 2000, snail populations and infections in snails increased again in the intervention area. CONCLUSION: The results of this study demonstrate that in the Kenyan setting a combination of chemotherapy followed by intermittent mollusciciding can have longer term benefits than chemotherapy alone.

The risk and timing of tuberculosis diagnosed in smear-negative TB suspects: a 12 month cohort study in Harare, Zimbabwe.

BACKGROUND: Cases of smear-negative TB have increased dramatically in high prevalence HIV settings and pose considerable diagnostic and management challenges. METHODS AND FINDINGS: 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. CONCLUSION: 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.

Schistosomiasis and infection with human immunodeficiency virus 1 in rural Zimbabwe: systemic inflammation during co-infection and after treatment for schistosomiasis.

We previously reported that treatment for schistosomiasis in persons infected with human immunodeficiency virus 1 (HIV-1) attenuated HIV replication as measured by plasma HIV RNA. We investigated systemic inflammation as measured by plasma levels of soluble tumor necrosis factor-alpha receptor II (sTNF-rII), interleukin-8, (IL-8), and IL-10 during schistosomiasis and HIV co-infection and after schistosomiasis treatment. The cohort was composed of 378 persons who were or were not infected with HIV-1, Schistosoma haematobium, or S. mansoni. Schistosomiasis-infected persons were randomized to receive praziquantel (40 mg/kg) at baseline or at the three-month follow-up. sTNF-rII and IL-8 were positively associated with schistosomiasis intensity as measured by circulating anodic antigen (CAA), regardless of HIV status. Interleukin-10 was positively associated with CAA in HIV-negative participants. IL-8 levels were higher in S. mansoni-infected individuals. Treatment for schistosomiasis caused a decrease in levels of sTNF-rII (P < 0.05) and IL-10 (P < 0.001). Our results indicate that schistosomiasis treatment may attenuate HIV replication by decreasing systemic inflammation.