Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus-1.

BACKGROUND: The risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1-infected individuals are likely to progress to active disease is unknown. METHODS: Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma samples in 421 HIV-1-infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. Individuals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations. RESULTS: Unstimulated samples showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC > 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly. CONCLUSIONS: Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.

Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial.

BACKGROUND: Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy. METHODS: For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086. FINDINGS: 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6-3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8-4·7; hazard ratio [HR] 0·63, 95% CI 0·41-0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90-4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21-0·86] and 0·43 [0·20-0·96]; for positive tests 0·86 [0·37-2·00] and 0·55 [0·26-1·24], respectively). INTERPRETATION: Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status. FUNDING: Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).

Tuberculosis Diagnosis and Preventive Monotherapy Among Children and Adolescents Exposed to Rifampicin-Resistant Tuberculosis in the Household.

Background: Children and adolescents with household exposure to multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) are at high risk of developing TB disease. Tuberculosis preventive therapy (TPT) is recommended, but programmatic experience is limited, particularly for adolescents. Methods: We conducted a prospective cohort study to describe MDR/RR-TB diagnosis and TPT provision for individuals aged <18 years with MDR/RR-TB exposure. Participants were assessed for TB either in homes or health facilities, with referral for chest x-ray or specimen collection at clinician discretion. The TPT regimens included levofloxacin, isoniazid, or delamanid monotherapy for 6 months, based on source patient drug-resistance profile. Results: Between March 1, 2020 and July 31, 2021, 112 participants were enrolled; median age was 8.5 years, 57 (51%) were female, and 6 (5%) had human immunodeficiency virus. On screening, 11 (10%) were diagnosed with TB: 10 presumptive MDR/RR-TB and 1 drug-susceptible TB. Overall, 95 (94% of 101) participants started TPT: 79 with levofloxacin, 9 with isoniazid, and 7 with delamanid. Seventy-six (80%) completed TPT, 12 (13%) were lost to follow up, and 7 (7%) stopped TPT early due to adverse events. Potential adverse events were reported for 12 (13%) participants; none were serious. There were no further TB diagnoses (200 days median follow up). Conclusions: Post-MDR/RR-TB exposure management for children and adolescents resulted in significant MDR/RR-TB detection and both high TPT initiation and completion. Tuberculosis preventive monotherapy was well tolerated and there were no further TB diagnoses after initial assessment. Key factors supporting these outcomes included use of pediatric formulations for young children, monotherapy, and community-based options for assessment and follow up.

Effect of antiretroviral therapy on the diagnostic accuracy of symptom screening for intensified tuberculosis case finding in a South African HIV clinic.

BACKGROUND: Current symptom screening algorithms for intensified tuberculosis case finding or prior to isoniazid preventive therapy (IPT) in patients infected with human immunodeficiency virus (HIV) were derived from antiretroviral-naive cohorts. There is a need to validate screening algorithms in patients on antiretroviral therapy (ART). METHODS: We performed cross-sectional evaluation of the diagnostic accuracy of symptom screening, including the World Health Organization (WHO) algorithm, to rule out tuberculosis in HIV-infected individuals pre-ART and on ART undergoing screening prior to IPT. RESULTS: A total of 1429 participants, 54% on ART, had symptom screening and a sputum culture result available. Culture-positive tuberculosis was diagnosed in 126 patients (8.8%, 95% confidence interval [CI], 7.4%-10.4%). The WHO symptom screen in the on-ART compared with the pre-ART group had a lower sensitivity (23.8% vs 47.6%), but higher specificity (94.4% vs 79.8%). The effect of ART was independent of CD4(+) count in multivariable analyses. The posttest probability of tuberculosis following a negative WHO screen was 8.9% (95% CI, 7.4%-10.8%) and 4.4% (95% CI, 3.7%-5.2%) for the pre-ART and on-ART groups, respectively. Addition of body mass index to the WHO screen significantly improved discriminatory ability in both ART groups, which was further improved by adding CD4 count and ART duration. CONCLUSIONS: The WHO symptom screen has poor sensitivity, especially among patients on ART, in a clinic where regular tuberculosis screening is practiced. Consequently, a significant proportion of individuals with tuberculosis would inadvertently be placed on isoniazid monotherapy despite high negative predictive values. Until more sensitive methods of ruling out tuberculosis are established, it would be prudent to do a sputum culture prior to IPT where this is feasible.

Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy.

CONTEXT: Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described. OBJECTIVE: To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006. INTERVENTIONS: Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine. MAIN OUTCOME MEASURES: Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed. RESULTS: The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7). CONCLUSION: In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.

Effectiveness of patient adherence groups as a model of care for stable patients on antiretroviral therapy in Khayelitsha, Cape Town, South Africa.

BACKGROUND: Innovative models of care are required to cope with the ever-increasing number of patients on antiretroviral therapy in the most affected countries. This study, in Khayelitsha, South Africa, evaluates the effectiveness of a group-based model of care run predominantly by non-clinical staff in retaining patients in care and maintaining adherence. METHODS AND FINDINGS: Participation in "adherence clubs" was offered to adults who had been on ART for at least 18 months, had a current CD4 count >200 cells/ml and were virologically suppressed. Embedded in an ongoing cohort study, we compared loss to care and virologic rebound in patients receiving the intervention with patients attending routine nurse-led care from November 2007 to February 2011. We used inverse probability weighting to estimate the intention-to-treat effect of adherence club participation, adjusted for measured baseline and time-varying confounders. The principal outcome was the combination of death or loss to follow-up. The secondary outcome was virologic rebound in patients who were virologically suppressed at study entry. Of 2829 patients on ART for >18 months with a CD4 count above 200 cells/µl, 502 accepted club participation. At the end of the study, 97% of club patients remained in care compared with 85% of other patients. In adjusted analyses club participation reduced loss-to-care by 57% (hazard ratio [HR] 0.43, 95% CI = 0.21-0.91) and virologic rebound in patients who were initially suppressed by 67% (HR 0.33, 95% CI = 0.16-0.67). DISCUSSION: Patient adherence groups were found to be an effective model for improving retention and documented virologic suppression for stable patients in long term ART care. Out-of-clinic group-based models facilitated by non-clinical staff are a promising approach to assist in the long-term management of people on ART in high burden low or middle-income settings.

A morbidity survey of South African primary care.

BACKGROUND: Recent studies have described the burden of disease in South Africa. However these studies do not tell us which of these conditions commonly present to primary care providers, how these conditions may present and how providers make sense of them in terms of their diagnoses. Clinical nurse practitioners are the main primary care providers and need to be better prepared for this role. This study aimed to determine the range and prevalence of reasons for encounter and diagnoses found among ambulatory patients attending public sector primary care facilities in South Africa. METHODOLOGY/PRINCIPAL FINDINGS: The study was a multi-centre prospective cross-sectional survey of consultations in primary care in four provinces of South Africa: Western Cape, Limpopo, Northern Cape and North West. Consultations were coded prior to analysis by using the International Classification of Primary Care-Version 2 in terms of reasons for encounter (REF) and diagnoses. Altogether 18856 consultations were included in the survey and generated 31451 reasons for encounter (RFE) and 24561 diagnoses. Women accounted for 12526 (66.6%) and men 6288 (33.4%). Nurses saw 16238 (86.1%) and doctors 2612 (13.9%) of patients. The top 80 RFE and top 25 diagnoses are reported and ongoing care for hypertension was the commonest RFE and diagnosis. The 20 commonest RFE and diagnoses by age group are also reported. CONCLUSIONS/SIGNIFICANCE: Ambulatory primary care is dominated by non-communicable chronic diseases. HIV/AIDS and TB are common, but not to the extent predicted by the burden of disease. Pneumonia and gastroenteritis are commonly seen especially in children. Women's health issues such as family planning and pregnancy related visits are also common. Injuries are not as common as expected from the burden of disease. Primary care providers did not recognise mental health problems. The results should guide the future training and assessment of primary care providers.

Correcting for mortality among patients lost to follow up on antiretroviral therapy in South Africa: a cohort analysis.

BACKGROUND: Loss to follow-up (LTF) challenges the reporting of antiretroviral treatment (ART) programmes, since it encompasses patients alive but lost to programme and deaths misclassified as LTF. We describe LTF before and after correction for mortality in a primary care ART programme with linkages to the national vital registration system. METHODS AND FINDINGS: We included 6411 patients enrolled on ART between March 2001 and June 2007. Patients LTF with available civil identification numbers were matched with the national vital registration system to ascertain vital status. Corrected mortality and true LTF were determined by weighting these patients to represent all patients LTF. We used Kaplan-Meier estimates and Cox regression to describe LTF, mortality among those LTF, and true LTF. Of 627 patients LTF, 85 (28.8%) had died within 3 months after their last clinic visits. Respective estimates of LTF before and after correction for mortality were 6.9% (95% confidence interval [CI] 6.2-7.6) and 4.3% (95% CI 3.5-5.3) at one year on ART, and 23.9% (95% CI 21.0-27.2) and 19.7% (95% CI 16.1-23.7) at 5 years. After correction for mortality, the hazard of LTF was reversed from decreasing to increasing with time on ART. Younger age, higher baseline CD4 count, pregnancy and increasing calendar year were associated with higher true LTF. Mortality of patients LTF at 1, 12 and 24 months after their last visits was respectively 23.1%, 30.9% and 43.8%; 78.0% of deaths occurred during the first 3 months after last visit and 45.0% in patients on ART for 0 to 3 months. CONCLUSIONS: Mortality of patients LTF was high and occurred early after last clinic visit, especially in patients recently started on ART. Correction for these misclassified deaths revealed that the risk of true LTF increased over time. Research targeting groups at higher risk of LTF (youth, pregnant women and patients with higher CD4 counts) is needed.

Seven-year experience of a primary care antiretroviral treatment programme in Khayelitsha, South Africa.

OBJECTIVES: We report on outcomes after 7 years of a community-based antiretroviral therapy (ART) programme in Khayelitsha, South Africa, with death registry linkages to correct for mortality under-ascertainment. DESIGN: This is an observational cohort study. METHODS: Since inception, patient-level clinical data have been prospectively captured on-site into an electronic patient information system. Patients with available civil identification numbers who were lost to follow-up were matched with the national death registry to ascertain their vital status. Corrected mortality estimates weighted these patients to represent all patients lost to follow-up. CD4 cell count outcomes were reported conditioned on continuous virological suppression. RESULTS: Seven thousand, three hundred and twenty-three treatment-naive adults (68% women) started ART between 2001 and 2007, with annual enrolment increasing from 80 in 2001 to 2087 in 2006. Of 9.8% of patients lost to follow-up for at least 6 months, 32.8% had died. Corrected mortality was 20.9% at 5 years (95% confidence interval 17.9-24.3). Mortality fell over time as patients accessed care earlier (median CD4 cell count at enrolment increased from 43 cells/microl in 2001 to 131 cells/microl in 2006). Patients who remained virologically suppressed continued to gain CD4 cells at 5 years (median 22 cells/microl per 6 months). By 5 years, 14.0% of patients had failed virologically and 12.2% had been switched to second-line therapy. CONCLUSION: At a time of considerable debate about future global funding of ART programmes in resource-poor settings, this study has demonstrated substantial and durable clinical benefits for those able to access ART throughout this period, in spite of increasing loss to follow-up.