Increased HIV Incidence in Wuchereria bancrofti Microfilaria Positive Individuals in Tanzania.

BACKGROUND: Infections with Wuchereria bancrofti are associated with reduced immunity against concomitant infections. Indeed, our previous study described a 2.3-fold increased HIV incidence among individuals with W. bancrofti infection, as measured by the circulating filarial antigen of the adult worm. This new study aimed to retrospectively determine microfilariae status of the participants to assess if the previously described increased HIV susceptibility was associated with the presence of MF in the same cohort. METHODS: CFA positive but HIV negative biobanked human blood samples (n = 350) were analyzed for W. bancrofti MF chitinase using real time PCR. RESULTS: The PCR provided a positive signal in 12/350 (3.4%) samples. During four years of follow-up (1109 person years (PY)), 22 study participants acquired an HIV infection. In 39 PY of W. bancrofti MF chitinase positive individuals, three new HIV infections occurred (7.8 cases per 100 PY), in contrast to 19 seroconversions in 1070 PY of W. bancrofti MF chitinase negative individuals (1.8 cases per 100 PY, p = 0.014). CONCLUSIONS: In the subgroup of MF-producing Wb-infected individuals, the HIV incidence exceeded the previously described moderate increased risk for HIV seen in all Wb-infected individuals (regardless of MF status) compared with uninfected persons from the same area.

Step towards elimination of Wuchereria bancrofti in Southwest Tanzania 10 years after mass drug administration with Albendazole and Ivermectin.

BACKGROUND: Lymphatic filariasis is a mosquito transmitted parasitic infection in tropical regions. Annual mass treatment with ivermectin and albendazole is used for transmission control of Wuchereria bancrofti, the infective agent of lymphatic filariasis in many African countries, including Tanzania. METHODOLOGY: In a general population study in Southwest Tanzania, individuals were tested for circulating filarial antigen, an indicator of W. bancrofti adult worm burden in 2009 before mass drug administration commenced in that area. Seven annual rounds with ivermectin and albendazole were given between 2009 and 2015 with a population coverage of over 70%. Participants of the previous study took part in a follow-up activity in 2019 to measure the effect of this governmental activity. FINDINGS: One thousand two hundred and ninety nine inhabitants of Kyela district in Southwest Tanzania aged 14 to 65 years who had participated in the study activities in 2009 were revisited in 2010/11 and 2019. Among this group, the prevalence of lymphatic filariasis of the 14-65 years olds in 2009 was 35.1%. A follow-up evaluation in 2010/11 had shown a reduction to 27.7%. In 2019, after 7 years of annual treatment and an additional three years of surveillance, the prevalence had dropped to 1.7%, demonstrating successful treatment by the national control programme. Risk factors for W. bancrofti-infection were the occupation as farmer, male sex, and older age. Most infected individuals in the 2019 follow-up study already had a positive test for filarial antigen in 2009 and/or 2010/11. CONCLUSIONS: This data supports the findings of the Tanzanian Neglected Tropical Disease Control Programme (NTDCP), who conducted Transmission Assessment Surveys and found an impressive reduction in the prevalence of LF in children. Our results complement this data by showing a similar decrease in prevalence of LF in the adult population in the same area. The elimination of LF seems achievable in the near future.

Hepatitis B, C and D virus prevalence in children and adults in Mbeya Region, Tanzania: results from a cohort study 2002 - 2009.

INTRODUCTION: sub-Saharan Africa bears a high prevalence for hepatitis B virus (HBV) infection. This analysis aims at elucidating the exposure to HBV across different age groups in Mbeya Region in Tanzania and determines prevalences of hepatitis C (HCV) and hepatitis delta antigen (HDV) infections. METHODS: plasma samples from children and adults with defined HIV status were analysed for HBV, HCV and HDV markers.\. RESULTS: hepatitis B (HBs)-antigen positivity was 8.3% (3/36) in the 0 to 5 years age group, 13.3% (8/60) in the 6 to 7 years, 17.2% (10/58) in the 8 to 14 years and 13.3% (8/60) in the 15 to 18 years age groups. In adults 5.0% of samples were HBs-antigen positive. Overall, 17.1% were HIV-1 positive. Adults infected with HIV-1 were significantly more often HBs-antigen positive (7.5%) than HIV-1 negative adults (4.5%; p<0.05). A serological sub-study including 174 adults showed that both total anti-HBs and total anti-HBc positivity increased with age in HBs-antigen negative participants. Across all age groups, HCV antibodies were found in 9 individuals, HDV antibodies in 3 individuals. CONCLUSION: children presented a high prevalence of HBs-antigen carriers, with lower levels in the younger children. Among adults, the overall prevalence of HBs-antigen was lower than in children, either corresponding to clearance of HBV over time or due to a die-off effect. HBs-antigen positive adults had higher frequencies of anti-HBc- and anti-HBe-antibodies, indicating better immunological control of HBV infection than children. This supports claims that HBV infections in Africa are mostly acquired in childhood and to a large extent cleared again by adulthood. One in 20 adults remains chronically infected, emphasising the importance of HBV vaccination strategies.

Schistosoma haematobium infection and environmental factors in Southwestern Tanzania: A cross-sectional, population-based study.

Schistosomiasis is a leading cause of morbidity in Africa. Understanding the disease ecology and environmental factors that influence its distribution is important to guide control efforts. Geographic information systems have increasingly been used in the field of schistosomiasis environmental epidemiology. This study reports prevalences of Schistosoma haematobium infection and uses remotely sensed and questionnaire data from over 17000 participants to identify environmental and socio-demographic factors that are associated with this parasitic infection. Data regarding socio-demographic status and S. haematobium infection were obtained between May 2006 and May 2007 from 17280 participants (53% females, median age = 17 years) in the Mbeya Region, Tanzania. Combined with remotely sensed environmental data (vegetation cover, altitude, rainfall etc.) this data was analyzed to identify environmental and socio-demographic factors associated with S. haematobium infection, using mixed effects logistic regression and geostatistical modelling. The overall prevalence of S. haematobium infection was 5.3% (95% confidence interval (CI): 5.0-5.6%). Multivariable analysis revealed increased odds of infection for school-aged children (5-15 years, odds ratio (OR) = 7.8, CI: 5.9-10.4) and the age groups 15-25 and 25-35 years (15-25 years: OR = 5.8, CI: 4.3-8.0, 25-35 years: OR = 1.6, CI: 1.1-2.4) compared to persons above 35 years of age, for increasing distance to water courses (OR = 1.4, CI: 1.2-1.6 per km) and for proximity to Lake Nyasa (<1 km, OR = 4.5, CI: 1.8-11.4; 1-2 km, OR = 3.5, CI: 1.7-7.5; 2-4 km; OR = 3.3, CI: 1.7-6.6), when compared to distances >4 km. Odds of infection decreased with higher altitude (OR = 0.7, CI: 0.6-0.8 per 100 m increase) and with increasing enhanced vegetation index EVI (OR = 0.2, CI: 0.1-0.4 per 0.1 units). When additionally adjusting for spatial correlation population density became a significant predictor of schistosomiasis infection (OR = 1.3, CI: 1.1-1.5 per 1000 persons/km2) and altitude turned non-significant. We found highly focal geographical patterns of S. haematobium infection in Mbeya Region in Southwestern Tanzania. Despite low overall prevalence our spatially heterogeneous results show that some of the study sites suffer from a considerable burden of S. haematobium infection, which is related to various socio-demographic and environmental factors. Our results could help to design more effective control strategies in the future, especially targeting school-aged children living in low altitude sites and/or crowded areas as the persons at highest need for preventive chemotherapy.

Wuchereria bancrofti infection is linked to systemic activation of CD4 and CD8 T cells.

BACKGROUND: Susceptibility to HIV has been linked to systemic CD4+ T cell activation in cohorts of seronegative individuals with high HIV-exposure risk. We recently described an increased risk of HIV transmission in individuals infected with Wuchereria bancrofti, the causative agent for lymphatic filariasis, in a prospective cohort study. However, the reason for this phenomenon needs further investigation. METHODOLOGY/PRINCIPAL FINDINGS: Two-hundred and thirty-five HIV negative adults were tested using Trop Bio ELISA for detection of W. bancrofti infection and Kato Katz urine filtration and stool based RT-PCR for detection of soil transmitted helminths and schistosomiasis. FACS analysis of the fresh peripheral whole blood was used to measure T cell activation markers (HLA-DR, CD38), differentiation markers (CD45, CD27), markers for regulatory T cells (FoxP3, CD25) and the HIV entry receptor CCR5. Frequencies of activated HLA-DRpos CD4 T cells were significantly increased in subjects with W. bancrofti infection (n = 33 median: 10.71%) compared to subjects without any helminth infection (n = 42, median 6.97%, p = 0.011) or those with other helminths (Schistosoma haematobium, S. mansoni, Trichuris trichiura, Ascaris lumbricoides, hookworm) (n = 151, median 7.38%, p = 0.009). Similarly, a significant increase in HLA-DRposCD38pos CD4 T cells and effector memory cells CD4 T cells (CD45ROposCD27neg) was observed in filarial infected participants. Multivariable analyses further confirmed a link between W. bancrofti infection and systemic activation of CD4 T cells independent of age, fever, gender or other helminth infections. CONCLUSIONS/SIGNIFICANCE: W. bancrofti infection is linked to systemic CD4 T cell activation, which may contribute to the increased susceptibility of W. bancrofti infected individuals to HIV infection.

Point of care Xpert MTB/RIF versus smear microscopy for tuberculosis diagnosis in southern African primary care clinics: a multicentre economic evaluation.

BACKGROUND: Rapid on-site diagnosis facilitates tuberculosis control. Performing Xpert MTB/RIF (Xpert) at point of care is feasible, even when performed by minimally trained health-care workers, and when compared with point-of-care smear microscopy, reduces time to diagnosis and pretreatment loss to follow-up. However, whether Xpert is cost-effective at point of care remains unclear. METHODS: We empirically collected cost (US$, 2014) and clinical outcome data from participants presenting to primary health-care facilities in four African countries (South Africa, Zambia, Zimbabwe, and Tanzania) during the TB-NEAT trial. Costs were determined using an bottom-up ingredients approach. Effectiveness measures from the trial included number of cases diagnosed, initiated on treatment, and completing treatment. The primary outcome was the incremental cost-effectiveness of point-of-care Xpert relative to smear microscopy. The study was performed from the perspective of the health-care provider. FINDINGS: Using data from 1502 patients, we calculated that the mean Xpert unit cost was lower when performed at a centralised laboratory (Lab Xpert) rather than at point of care ($23·00 [95% CI 22·12-23·88] vs $28·03 [26·19-29·87]). Per 1000 patients screened, and relative to smear microscopy, point-of-care Xpert cost an additional $35 529 (27 054-40 025) and was associated with an additional 24·3 treatment initiations ([-20·0 to 68·5]; $1464 per treatment), 63·4 same-day treatment initiations ([27·3-99·4]; $511 per same-day treatment), and 29·4 treatment completions ([-6·9 to 65·6]; $1211 per completion). Xpert costs were most sensitive to test volume, whereas incremental outcomes were most sensitive to the number of patients initiating and completing treatment. The probability of point-of-care Xpert being cost-effective was 90% at a willingness to pay of $3820 per treatment completion. INTERPRETATION: In southern Africa, although point-of-care Xpert unit cost is higher than Lab Xpert, it is likely to offer good value for money relative to smear microscopy. With the current availability of point-of-care nucleic acid amplification platforms (eg, Xpert Edge), these data inform much needed investment and resource allocation strategies in tuberculosis endemic settings. FUNDING: European Union European and Developing Countries Clinical Trials Partnership.

Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.

BACKGROUND: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. METHODS: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. FINDINGS: Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2<20% for the primary outcome). INTERPRETATION: Despite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact. FUNDING: US National Institutes of Health.

Xpert MTB/RIF Ultra assay for the diagnosis of pulmonary tuberculosis in children: a multicentre comparative accuracy study.

OBJECTIVES: We evaluated the diagnostic performance of the novel next-generation Xpert MTB/RIF Ultra (Xpert Ultra) in comparison to Xpert MTB/RIF (Xpert) assay for the detection of paediatric pulmonary tuberculosis in high burden settings. METHODS: From May 2011 to September 2012, children with suspected pulmonary tuberculosis were enrolled at two Tanzanian sites and sputum samples were examined using sputum smear, Xpert and culture. Xpert Ultra was tested between January and June 2017 using sputum pellets, which had been stored at -80°C. The diagnostic accuracy of Ultra versus Xpert was determined using well-defined case definitions as reference standard. RESULTS: In total, 215 children were included. The median age was 5.4 years, the HIV prevalence was 52% and 13% had culture-confirmed pulmonary tuberculosis. When only the first available sample of each patient was analysed, the sensitivity of Xpert Ultra was 64.3 % (95% CI: 44.1 to 81.4) while that of Xpert was 53.6% (95%CI: 33.9 to 72.5). The specificity of Xpert Ultra based on analysis of all available samples was 98.1% (95%CI: 93.4 to 99.7), that of Xpert was 100%. CONCLUSIONS: Xpert Ultra was found to have a higher sensitivity, but slightly reduced specificity compared to Xpert in detecting pulmonary tuberculosis in children.

Reduction of malaria prevalence after introduction of artemisinin-combination-therapy in Mbeya Region, Tanzania: results from a cohort study with 6773 participants.

BACKGROUND: A marked decline in malaria morbidity and mortality has been reported after the introduction of artemisinin-based combination therapy (ACT) in high malaria prevalence countries in Africa. Data on the impact of ACT and on the prevalence of malaria has so far been scarce for Southwest Tanzania. METHODS: Between 2005 and 2011, a large general population cohort in the Mbeya Region in the south-west of Tanzania has been surveyed within the EMINI-study (Evaluation and Monitoring of the Impact of New Interventions). Participants were examined once per year, including rapid diagnostic testing for malaria. ACT was introduced in the region according to national guidelines in the time period 2006/2007, replacing sulfadoxine/pyrimethamine as first-line therapy. In four study sites, 6773 individuals who participated in the first two of three consecutive survey visits in the period from 2006 to 2009 were included in this analysis. The prevalence of Plasmodium infection prior to and after the introduction of ACT was compared by logistic regression, with consideration of climatic variability, age, sex, socio-economic status and bed net use as potential confounders. RESULTS: A significant reduction over time in the prevalence of Plasmodium falciparum infection from 2.5 to 0.3% was shown across the four study sites. The decline was not explained by other factors included in the analysis, therefore, the decline over time most likely reflects the impact of introduction of ACT in the study area. CONCLUSIONS: The longitudinal study showed a significant and relevant decline in the prevalence of P. falciparum infection after introduction of ACT, which could not be explained by potential confounders. The data suggests that artemisinin-based combinations are not only an effective instrument for reduction of immediate morbidity and mortality, but also for reduction of transmission rates.

Trichuris trichiura infection and its relation to environmental factors in Mbeya region, Tanzania: A cross-sectional, population-based study.

BACKGROUND: The intestinal nematode Trichuris trichiura is among the most common causes of human infectious disease worldwide. As for other soil-transmitted nematodes, its reproductive success and thus prevalence and intensity of infection in a given area strongly depend on environmental conditions. Characterization of the influence of environmental factors can therefore aid to identify infection hot spots for targeted mass treatment. METHODOLOGY: We analyzed data from a cross-sectional survey including 6234 participants from nine distinct study sites in Mbeya region, Tanzania. A geographic information system was used to combine remotely sensed and individual data, which were analyzed using uni- and multivariable Poisson regression. Household clustering was accounted for and when necessary, fractional polynomials were used to capture non-linear relationships between T. trichiura infection prevalence and environmental variables. PRINCIPAL FINDINGS: T. trichiura infection was restricted to the Kyela site, close to Lake Nyasa with only very few cases in the other eight sites. The prevalence of T. trichiura infection in Kyela was 26.6% (95% confidence interval (CI) 23.9 to 29.6%). Multivariable models revealed a positive association of infection with denser vegetation (prevalence ratio (PR) per 0.1 EVI units = 2.12, CI 1.28 to 3.50) and inverse associations with rainfall (PR per 100 mm = 0.54, CI 0.44 to 0.67) and elevation (PR per meter = 0.89, CI 0.86 to 0.93) while adjusting for age and previous worm treatment. Slope of the terrain was modelled non-linearly and also showed a positive association with T. trichiura infection (p-value p<0.001). CONCLUSION/SIGNIFICANCE: Higher prevalences of T. trichiura infection were only found in Kyela, a study site characterized by denser vegetation, high rainfall, low elevation and flat terrain. But even within this site, we found significant influences of vegetation density, rainfall, elevation and slope on T. trichiura infection. The inverse association of rainfall with infection in Kyela is likely due to the fact, that rainfall in this site is beyond the optimum conditions for egg development. Our findings demonstrate that use of remotely sensed environmental data can aid to predict high-risk areas for targeted helminth control.

Linkage into care among newly diagnosed HIV-positive individuals tested through outreach and facility-based HIV testing models in Mbeya, Tanzania: a prospective mixed-method cohort study.

OBJECTIVE: Linkage to care is the bridge between HIV testing and HIV treatment, care and support. In Tanzania, mobile testing aims to address historically low testing rates. Linkage to care was reported at 14% in 2009 and 28% in 2014. The study compares linkage to care of HIV-positive individuals tested at mobile/outreach versus public health facility-based services within the first 6 months of HIV diagnosis. SETTING: Rural communities in four districts of Mbeya Region, Tanzania. PARTICIPANTS: A total of 1012 newly diagnosed HIV-positive adults from 16 testing facilities were enrolled into a two-armed cohort and followed for 6 months between August 2014 and July 2015. 840 (83%) participants completed the study. MAIN OUTCOME MEASURES: We compared the ratios and time variance in linkage to care using the Kaplan-Meier estimator and Log rank tests. Cox proportional hazards regression models to evaluate factors associated with time variance in linkage. RESULTS: At the end of 6 months, 78% of all respondents had linked into care, with differences across testing models. 84% (CI 81% to 87%, n=512) of individuals tested at facility-based site were linked to care compared to 69% (CI 65% to 74%, n=281) of individuals tested at mobile/outreach. The median time to linkage was 1 day (IQR: 1-7.5) for facility-based site and 6 days (IQR: 3-11) for mobile/outreach sites. Participants tested at facility-based site were 78% more likely to link than those tested at mobile/outreach when other variables were controlled (AHR=1.78; 95% CI 1.52 to 2.07). HIV status disclosure to family/relatives was significantly associated with linkage to care (AHR=2.64; 95% CI 2.05 to 3.39). CONCLUSIONS: Linkage to care after testing HIV positive in rural Tanzania has increased markedly since 2014, across testing models. Individuals tested at facility-based sites linked in significantly higher proportion and modestly sooner than mobile/outreach tested individuals. Mobile/outreach testing models bring HIV testing services closer to people. Strategies to improve linkage from mobile/outreach models are needed.

Why being an expert - despite xpert -remains crucial for children in high TB burden settings.

BACKGROUND: As access to Xpert expands in high TB-burden settings, its performance against clinically diagnosed TB as a reference standard provides important insight as the majority of childhood TB is bacteriologically unconfirmed. We aim to describe the characteristics and outcomes of children with presumptive TB and TB disease, and assess performance of Xpert under programmatic conditions against a clinical diagnosis of TB as a reference standard. METHODS: Retrospective review of children evaluated for presumptive TB in Mbeya, Tanzania. Baseline characteristics were compared by TB disease status and, for patients diagnosed with TB, by TB confirmation status using Wilcoxon rank sum test for continuous variables and the Chi-square test for categorical variables. Sensitivity and specificity were calculated to assess the performance of Xpert, smear, and culture against clinical TB. Kappa statistics were calculated to assess agreement between Xpert and smear to culture. RESULTS: Among children (N = 455) evaluated for presumptive TB, 70.3% (320/455) had Xpert and 62.8% (286/455) had culture performed on sputa. 34.5% (157/455) were diagnosed with TB: 80.3% (126/157) pulmonary TB, 13.4% (21/157) bacteriologically confirmed, 53.5% (84/157) HIV positive, and 48.4% (76/157) inpatients. Compared to the reference standard of clinical diagnosis, sensitivity of Xpert was 8% (95% CI 4-15), smear 6% (95% CI 3-12) and culture 16% (95% CI 9-24), and did not differ based on patient disposition, nutrition or HIV status. CONCLUSION: Despite access to Xpert, the majority of children with presumptive TB were treated based on clinical diagnosis. Reflecting the reality of clinical practice in resource limited settings, new diagnostics such as Xpert serve as important adjunctive tests but will not obviate the need for astute clinicians and comprehensive diagnostic algorithms.

Effect of Wuchereria bancrofti infection on HIV incidence in southwest Tanzania: a prospective cohort study.

BACKGROUND: The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti, on HIV incidence in southwest Tanzania. METHODS: In this population-based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis. FINDINGS: Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly 18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1·91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0·80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2·17 (95% CI 1·08-4·37, p=0·0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors. INTERPRETATION: To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented. FUNDING: European Union as part of EuropAid; German Federal Ministry of Education and Research; German Center for Infection Research.

Correction: Prevalence of Lymphatic Filariasis and Treatment Effectiveness of Albendazole/ Ivermectin in Individuals with HIV Co-infection in Southwest-Tanzania.

[This corrects the article DOI: 10.1371/journal.pntd.0004618.].

Association between different anti-Tat antibody isotypes and HIV disease progression: data from an African cohort.

BACKGROUND: The presence of IgG and IgM against Tat, an HIV protein important for viral replication and immune dysfunction, is associated with slow disease progression in clade B HIV-infected individuals. However, although Tat activities strictly depend on the viral clade, our knowledge about the importance of anti-Tat antibodies in non-clade B HIV infection is poor. The objective of this study was to investigate the association of different anti-Tat antibody isotypes with disease progression in non-clade B HIV-infected subjects and to study the relationship between anti-Tat humoral responses and immunological abnormalities. METHODS: Anti-clade B and -clade C Tat IgG, IgM and IgA titers were assessed in serum samples from 96 cART-naïve subjects with chronic HIV infection from Mbeya, Tanzania, and associated with CD4(+) T cell count, plasma viremia and CD4(+) and CD8(+) T cell phenotypes. RESULTS: Anti-Tat IgM were preferentially detected in chronic HIV-infected subjects with low T cell activation (p-value = 0.03) and correlated with higher CD4(+) T cell counts and lower viral loads irrespective of the duration of infection (p-value = 0.019 and p-value = 0.037 respectively). Conversely, anti-Tat IgA were preferentially detected in individuals with low CD4(+) T cell counts and high viral load (p-value = 0.02 and p-value < 0.001 respectively). The simultaneous presence of anti-Tat IgG and IgM protected from fast CD4(+) T cell decline (p-value < 0.01) and accumulation of CD38(+)HLADR(+)CD8(+) T cells (p- value = 0.029). CONCLUSIONS: Anti-Tat IgG alone are not protective in non-clade B infected subjects, unless concomitant with IgM, suggesting a protective role of persistent anti-Tat IgM irrespective of the infecting clade.

CD25+ FoxP3+ Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo.

UNLABELLED: Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro and facilitates homeostatic proliferation of CD25(+) FoxP3(+) CD4(+) T cells. CD25(+) FoxP3(+) CD4(+) T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25(+) FoxP3(+) CD4(+) T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV(+) and HIV(-) study volunteers. Different memory CD4(+) T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV(+) subjects, 51% (median) of CD25(+) FoxP3(+) CD4(+) T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67(+) cells were detected in CD25(+) FoxP3(+) memory CD4(+) T cells (median, 27.6%) in comparison to CD25(-) FoxP3(-) memory CD4(+) T cells (median, 4.1%; P < 0.0001). HIV DNA content was 15-fold higher in CD25(+) FoxP3(+) memory CD4(+) T cells than in CD25(-) FoxP3(-) T cells (P = 0.003). EnvV1V3 sequences derived from CD25(+) FoxP3(+) memory CD4(+) T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells might facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear. IMPORTANCE: Despite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replication in vivo is incompletely understood. In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25(+) FoxP3(+) memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferation in vivo Our results show that CD25(+) FoxP3(+) memory CD4(+) T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25(-) FoxP3(-) memory CD4 T cell subsets. The specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells probably facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.

Prevalence of Lymphatic Filariasis and Treatment Effectiveness of Albendazole/ Ivermectin in Individuals with HIV Co-infection in Southwest-Tanzania.

BACKGROUND: Annual mass treatment with ivermectin and albendazole is used to treat lymphatic filariasis in many African countries, including Tanzania. In areas where both diseases occur, it is unclear whether HIV co-infection reduces treatment success. METHODOLOGY: In a general population study in Southwest Tanzania, individuals were tested for HIV and circulating filarial antigen, an indicator of Wuchereria bancrofti adult worm burden, before the first and after 2 consecutive rounds of anti-filarial mass drug administration. PRINCIPLE FINDINGS: Testing of 2104 individuals aged 0-94 years before anti-filarial treatment revealed a prevalence of 24.8% for lymphatic filariasis and an HIV-prevalence of 8.9%. Lymphatic filariasis was rare in children, but prevalence increased in individuals above 10 years, whereas a strong increase in HIV was only seen above 18 years of age. The prevalence of lymphatic filariasis in adults above 18 years was 42.6% and 41.7% (p = 0.834) in HIV-negatives and-positives, respectively. Similarly, the HIV prevalence in the lymphatic filariasis infected (16.6%) and uninfected adult population (17.1%) was nearly the same. Of the above 2104 individuals 798 were re-tested after 2 rounds of antifilarial treatment. A significant reduction in the prevalence of circulating filarial antigen from 21.6% to 19.7% was found after treatment (relative drop of 8.8%, McNemar's exact p = 0.036). Furthermore, the post-treatment reduction of CFA positivity was (non-significantly) larger in HIV-positives than in HIV-negatives (univariable linear regression p = 0.154). CONCLUSION/SIGNIFICANCE: In an area with a high prevalence for both diseases, no difference was found between HIV-infected and uninfected individuals regarding the initial prevalence of lymphatic filariasis. A moderate but significant reduction in lymphatic filariasis prevalence and worm burden was demonstrated after two rounds of treatment with albendazole and ivermectin. Treatment effects were more pronounced in the HIV co-infected subgroup, indicating that the effectiveness of antifilarial treatment was not reduced by concomitant HIV-infection. Studies with longer follow-up time could validate the observed differences in treatment effectiveness.

Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality. METHODS: We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730. FINDINGS: Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0·83 (95% CI 0·73-0·96), p=0·012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0·82 [95% CI 0·70-0·96], p=0·015). No adverse events were associated with LAM testing. INTERPRETATION: Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. FUNDING: European Developing Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation.

Psychological distress and its relationship with non-adherence to TB treatment: a multicentre study.

BACKGROUND: The successful cure of tuberculosis (TB) is dependent on adherence to treatment. Various factors influence adherence, however, few are easily modifiable. There are limited data regarding correlates of psychological distress and their association with non-adherence to anti-TB treatment. METHODS: In a trial of a new TB test, we measured psychological distress (K-10 score), TB-related health literacy, and morbidity (TBscore), prior to diagnosis in 1502 patients with symptoms of pulmonary TB recruited from clinics in Cape Town (n = 419), Harare (n = 400), Lusaka (n = 400), Durban (n = 200), and Mbeya (n = 83). Socioeconomic, demographic, and alcohol usage-related data were captured. Patients initiated on treatment had their DOTS cards reviewed at two-and six-months. RESULTS: 22 %(95 % CI: 20 %, 25 %) of patients had severe psychological distress (K-10 ≥ 30). In a multivariable linear regression model, increased K-10 score was independently associated with previous TB [estimate (95 % CI) 0.98(0.09-1.87); p = 0.0304], increased TBscore [1(0.80, 1.20); p <0.0001], and heavy alcohol use [3.08(1.26, 4.91); p = 0.0010], whereas male gender was protective [-1.47(-2.28, -0.62); p = 0.0007]. 26 % (95 % CI: 21 %, 32 %) of 261 patients with culture-confirmed TB were non-adherent. In a multivariable logistic regression model for non-adherence, reduced TBscore [OR (95 % CI) 0.639 (0.497, 0.797); p = 0.0001], health literacy score [0.798(0.696, 0.906); p = 0.0008], and increased K-10 [1.082(1.033, 1.137); p = 0.0012], and heavy alcohol usage [14.83(2.083, 122.9); p = 0.0002], were independently associated. Culture-positive patients with a K-10 score ≥ 30 were more-likely to be non-adherent (OR = 2.290(1.033-5.126); p = 0.0416]. CONCLUSION: Severe psychological distress is frequent amongst TB patients in Southern Africa. Targeted interventions to alleviate psychological distress, alcohol use, and improve health literacy in newly-diagnosed TB patients could reduce non-adherence to treatment.

Test characteristics and potential impact of the urine LAM lateral flow assay in HIV-infected outpatients under investigation for TB and able to self-expectorate sputum for diagnostic testing.

BACKGROUND: The commercially available urine LAM strip test, a point-of-care tuberculosis (TB) assay, requires evaluation in a primary care setting where it is most needed. There is currently inadequate data to guide implementation in TB and HIV-endemic settings. METHODS: Adult HIV-infected outpatients with suspected pulmonary TB able to self-expectorate sputum from four primary clinics in South Africa, Zambia and Tanzania underwent diagnostic evaluation [sputum smear microscopy, Xpert-MTB/RIF, and culture (reference standard)] as part of a prospective parent study. Urine LAM testing (grade-2 cut-point) was performed on archived samples. Performance characteristics of LAM alone or in combination with sputum-based diagnostics were evaluated. Potential impact on 2 and 6-month morbidity (TBscore), patient dropout rates, and prognosis (death/ loss to follow-up) were evaluated. RESULTS: Among 583 participants with suspected TB that were HIV-infected or refused testing, the overall LAM sensitivity (95 % CI; n/N) and in the CD4 ≤ 100 cells/mm(3) sub-group was 22.7 % (16.6-28.7; 41/181) and 30.4 % (17.1-43.7; 14/46), respectively. Overall specificity was 93.0 % (90.5-95.6; 361/388). Amongst culture-positive TB cases, adjunctive LAM testing did not improve the sensitivity of either sputum Xpert-MTB/RIF [78.2 % (69.8-86.7; 72/92) versus 76.1 % (67.4-84.8; 70/92), p = 0.7] or smear-microscopy [56.2 % (45.9-66.5; 50/89) versus 43.8 % (33.5-54.1; 39/89), p = 0.1). Clinic-based LAM, as an adjunct to either smear microscopy or Xpert MTB/RIF same-day testing, would neither have decreased patient dropout, nor increased same-day treatment initiation in this clinical setting where same-day chest radiography was available. LAM positivity was associated with 6-month lost-to-follow-up/death (AOR 4.4; p = 0.002) but not TBscore (at baseline or change in TBscore 2-months post-treatment) (p = 0.17). CONCLUSIONS: In African HIV-TB co-infected outpatients able to self-expectorate sputum LAM had limited sensitivity even at low CD4 counts, and offered no significant incremental diagnostic yield over Xpert-MTB/RIF or smear microscopy. In primary care clinics with chest radiography and where empiric TB treatment is common, LAM seems unlikely to improve rates of same-day treatment initiation and patient dropout, however, the ability of LAM to identify patients at high risk of death or lost-to-follow-up may offer important prognostic value.