Helminthiasis: A Systematic Review of the Immune Interactions Present in Individuals Coinfected with HIV and/or Tuberculosis

Helminth infections are highly endemic in parts of the world where the two killer epidemics caused by Mycobacterium tuberculosis (M.tb) and the human immunodeficiency virus (HIV) intersect. Sub-Saharan Africa is hardest hit by this epidemiological overlap. Consequently, several studies have investigated the immunological outcomes of helminth coinfection with either HIV or M.tb, to elucidate the central hypothesis that chronic infection with helminths exacerbates the course of HIV and tuberculosis disease. However, there is no conclusive evidence to confirm whether helminth-induced immunity modulates HIV- and TB-specific immune responses and their pathogenesis or vice versa. The present chapter summarizes the epidemiology, clinical course, and immune interactions during helminths and HIV/TB coinfections and undertakes a systematic review of the existing literature published from Africa on this subject. The aim was to determine if chronic helminthiasis has a negative impact on HIV and TB infections. A PubMed search was undertaken with no language and time restrictions. Search terms used included a varied combination of “Helminth coinfection and immunity and TB coinfection or TB immunity and HIV coinfection or HIV immunity and Africa.” Names of individual species were also permutated in the search terms. Reviews and bibliographies of selected articles were screened to identify additional relevant articles or studies. Of the total 1021 articles retrieved, 47 were relevant with 31 helminth and HIV coinfection and 16 helminths and TB coinfection articles. While many studies failed to find a negative impact of helminth infection on immune responses to HIV and/or TB, a significant number found evidence of deleterious effects of coinfection with helminths such as immune activation, impaired Th1 responses to TB antigens, higher viral loads, lower CD4+ counts, and increased risks of antiretroviral immunologic failure, mother to child HIV transmission or TB disease. Some of the helminth-induced immune dysregulation was reversed by deworming, while some studies found no benefit of antihelminthic treatment. More studies particularly in Southern Africa are needed to increase the much sought evidence of the impact of deworming among HIV-infected individuals as this seems the most feasible, cost-effective intervention with little or no serious adverse effects. Lastly, with the expansion of ART and increased access to HIV treatment, the effects of helminths on vaccines, TB, and antiretroviral treatments efficacy also need serious consideration, in light of the suggestive evidence of possible immunologic failure due to helminth coinfection

TB transmission is associated with prolonged stay in a low socio-economic, high burdened TB and HIV community in Cape Town, South Africa

Abstract Background While several studies have assessed the associations between biological factors and tuberculosis (TB) transmission, our understanding of the associations between TB transmission and social and economic factors remains incomplete. We aimed to explore associations between community TB transmission and socio-economic factors within a high TB-HIV burdened setting. Methods We conducted a cross-sectional molecular epidemiology study among adult patients attending a routine TB clinic. Demographic and clinical data were extracted from TB registers and clinical folders; social and economic data were collected using interviewer-administered questionnaires; Mycobacterium tuberculosis isolates were genotyped and classified as clustered/non-clustered using IS6110-based Restriction Fragment Length Polymorphism. Composite “social” and “economic” scores were generated from social and economic data. Data were analyzed using StataCorp version 15.0 software. Stratified, bivariable analyses were performed using chi-squared. Wilcoxon signed rank tests; univariable and multivariable logistic regression models were developed to explore associations in the social, economic, traditional and composite TB risk factors with TB transmission. Results Of the 505 patient Mtb  strains, 348(69%) cases were classified as clustered and 157(31%) were non-clustered. Clustered cases were more likely to have lived longer in the study community, (odds ratio [OR] = 1.05, 95% Confidence interval [C.I]:1.02–1.09, p = 0.006); in the same house (OR = 1.04, C.I: 0.99–1.08, p = 0.06); and had increased household crowding conditions (i.e fewer rooms used for sleeping, OR = 0.45, C.I:0.21–0.95, p = 0.04). Although a higher proportion of clustered cases had a low economic score, no statistically significant association was found between clustering and either the economic score (p = 0.13) or social score (p = 0.26). Conclusions We report a novel association between Mtb transmission and prolonged stay within a high burdened community. Transmission was also associated with fewer rooms for sleeping in a household. Increased social interaction and prolonged residence in a high burdened community are important factors linked to Mtb transmission, possibly due to increased probability of higher effective contact rates. The possible importance of degrees of poverty within low socio-economic setting warrants further study

TB transmission is associated with prolonged stay in a low socio-economic, high burdened TB and HIV community in Cape Town, South Africa

Background While several studies have assessed the associations between biological factors and tuberculosis (TB) transmission, our understanding of the associations between TB transmission and social and economic factors remains incomplete. We aimed to explore associations between community TB transmission and socio-economic factors within a high TB-HIV burdened setting. Methods We conducted a cross-sectional molecular epidemiology study among adult patients attending a routine TB clinic. Demographic and clinical data were extracted from TB registers and clinical folders; social and economic data were collected using interviewer-administered questionnaires; Mycobacterium tuberculosis isolates were genotyped and classified as clustered/non-clustered using IS6110-based Restriction Fragment Length Polymorphism. Composite “social” and “economic” scores were generated from social and economic data. Data were analyzed using StataCorp version 15.0 software. Stratified, bivariable analyses were performed using chi-squared. Wilcoxon signed rank tests; univariable and multivariable logistic regression models were developed to explore associations in the social, economic, traditional and composite TB risk factors with TB transmission. Results Of the 505 patient Mtb  strains, 348(69%) cases were classified as clustered and 157(31%) were non-clustered. Clustered cases were more likely to have lived longer in the study community, (odds ratio [OR] = 1.05, 95% Confidence interval [C.I]:1.02–1.09, p = 0.006); in the same house (OR = 1.04, C.I: 0.99–1.08, p = 0.06); and had increased household crowding conditions (i.e fewer rooms used for sleeping, OR = 0.45, C.I:0.21–0.95, p = 0.04). Although a higher proportion of clustered cases had a low economic score, no statistically significant association was found between clustering and either the economic score (p = 0.13) or social score (p = 0.26). Conclusions We report a novel association between Mtb transmission and prolonged stay within a high burdened community. Transmission was also associated with fewer rooms for sleeping in a household. Increased social interaction and prolonged residence in a high burdened community are important factors linked to Mtb transmission, possibly due to increased probability of higher effective contact rates. The possible importance of degrees of poverty within low socio-economic setting warrants further study

Trends and determinants of ever having tested for HIV among youth and adults in South Africa from 2005–2017: Results from four repeated cross-sectional nationally representative household-based HIV prevalence, incidence, and behaviour surveys

Background HIV testing contributes to the prevention and control of the HIV epidemic in the general population. South Africa has made strides to improve HIV testing towards reaching the first of the UNAIDS 90–90–90 targets by 2020. However, to date no nationally representative analysis has examined temporal trends and factors associated with HIV testing among youth and adults in the country. Aim This study aimed to examine the trends and associations with ever having tested for HIV among youth and adults aged 15 years and older in South Africa using the 2005, 2008, 2012 and 2017 nationally representative population-based household surveys. Methods The analysis of the data collected used multi-stage stratified cluster randomised cross-sectional design. P-trend chi-squared test was used to identify any significant changes over the four study periods. Bivariate and multivariate logistic regression analysis was conducted to determine factors associated with HIV testing in each of the survey periods. Results Ever having tested for HIV increased substantially from 2005 (30.6%, n = 16 112), 2008 (50.4%, n = 13 084), 2012 (65.5%, n = 26 381), to 2017 (75.2%, n = 23 190). Those aged 50 years and older were significantly less likely to ever have tested for HIV than those aged 25–49 years. Those residing in rural areas were significantly less likely to have tested for HIV as compared to people from urban areas. There was a change in HIV testing among race groups with Whites, Coloureds and Indian/Asians testing more in 2005 and 2008 and Black Africans in 2017. Marriage, education and employment were significantly associated with increased likelihood of ever testing for HIV. Those who provided a blood specimen for laboratory HIV testing in the survey rounds and were found to have tested positive were more likely to have ever tested for HIV previously. Conclusion The results show that overall there has been an increase in ever having an HIV test in the South African population over time. The findings also suggest that for South Africa to close the testing gap and reach the first of the UNAIDS 90–90–90 targets by 2020, targeted programmes aimed at increasing access and utilization of HIV testing in young people, males, those not married, the less educated, unemployed and those residing in rural areas of South Africa should be prioritised

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: A prospective cohort study

BACKGROUND: Delays in seeking and accessing treatment for rifampicin-resistant tuberculosis (RR-TB) and multi-drug resistant (MDR-TB) are major impediments to TB control in high-burden, resource-limited settings. METHOD: We prospectively determined health-seeking behavioural patterns and associations with treatment outcomes and costs among 68 RR-TB patients attending conveniently selected facilities in a decentralised system in Harare, Zimbabwe. RESULTS: From initial symptoms to initiation of effective treatment, patients made a median number of three health care visits (IQR 2-4 visits) at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410). Cumulatively, RR-TB patients most frequently first visited private facilities, i.e., private pharmacies (30%) and other private health care providers (24%) combined. Median patient delay was 26 days (IQR 14-42 days); median health system delay was 97 days (IQR 30-215 days) and median total delay from symptom onset to initiation of effective treatment was 132 days (IQR 51-287 days). The majority of patients (88%) attributed initial delay in seeking care to "not feeling sick enough." Total delay, total cost and number of health care visits were not associated with treatment or clinical outcomes, though our study was not adequately powered for these determinations. CONCLUSIONS: Despite the public availability of rapid molecular TB tests, patients experienced significant delays and high costs in accessing RR-TB treatment. Active case finding, integration of private health care providers and enhanced service delivery may reduce treatment delay and TB associated costs

Role of the Interleukin 10 Family of Cytokines in Patients With Immune Reconstitution Inflammatory Syndrome Associated With HIV Infection and Tuberculosis

Background.  The interleukin 10 (IL-10) family comprises cytokines structurally related to IL-10 that share signaling receptors that have conserved signaling cascades. The immunopathogenesis of immune reconstitution inflammatory syndrome (IRIS) in patients with human immunodeficiency virus (HIV) infection and tuberculosis remains incompletely understood. We hypothesized that a deficiency of IL-10 and its homologs may contribute to the immunopathology of IRIS in these patients. Methods. We performed a case-control analysis involving patients with HIV infection and tuberculosis who had IRIS at clinical presentation (tuberculosis-IRIS) and similar patients with HIV infection and tuberculosis who did not develop tuberculosis-IRIS (non-IRIS). Peripheral blood mononuclear cells (PBMCs) were cultured in the presence or absence of heat-killed Mycobacterium tuberculosis for 6 and 24 hours. Messenger RNA was analyzed by quantitative reverse transcription polymerase chain reaction analysis. Cytokine concentrations in serum were also determined. Results. Cultures of PBMCs stimulated with M. tuberculosis for 24 hours yielded higher IL-10 and interleukin 22 (IL-22) transcript levels for tuberculosis-IRIS patients, compared with non-IRIS patients. Analysis of corresponding serum samples showed significantly higher concentrations of IL-10 and IL-22 in tuberculosis-IRIS patients, compared with non-IRIS patients. Conclusions. IL-10 and IL-22 were differentially induced in PBMCs from tuberculosis-IRIS patients after in vitro stimulation, and higher concentrations of their corresponding proteins were detected in serum (in vivo). The higher levels of IL-10 observed in this study may represent a compensatory antiinflammatory response during tuberculosis-IRIS. The elevated levels of IL-22 suggest an association between this cytokine and immunopathology during tuberculosis-IRIS

Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study

BackgroundBedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.MethodsWe did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL). Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done.FindingsIn total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.InterpretationBedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.FundingDoris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust

Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa : a retrospective cohort

Abstract: Background Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis- resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment. Methods We did a retrospective longitudinal cohort study of adults (aged >= 18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 mu g/mL). Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done. Findings In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred. Interpretation Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed. Funding Doris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license