HIV-associated drug-resistant TB: expanded treatment options and emerging threats.

The impact of HIV viral suppression on multidrug resistant tuberculosis (MDR-TB) treatment outcomes among people with HIV (PWH) has not been clearly established. Using secondary data from a cluster-randomized clinical trial among people with MDR-TB in South Africa, we examined the effects of HIV viral suppression at MDR-TB treatment initiation and throughout treatment on MDR-TB outcomes among PWH using multinomial regression. This analysis included 1479 PWH. Viral suppression (457, 30.9%), detectable viral load (524, 35.4%), or unknown viral load (498, 33.7%) at MDR-TB treatment initiation were almost evenly distributed. Having a detectable HIV viral load at MDR-TB treatment initiation significantly increased risk of death compared to those virally suppressed (relative risk ratio [RRR] 2.12, 95% CI 1.11-4.07). Among 673 (45.5%) PWH with a known viral load at MDR-TB outcome, 194 (28.8%) maintained suppression, 267 (39.7%) became suppressed, 94 (14.0%) became detectable, and 118 (17.5%) were never suppressed. Those who became detectable (RRR 11.50, 95% CI 1.98-66.65) or were never suppressed (RRR 9.28, 95% CI 1.53-56.61) were at significantly increased risk of death (RRR 6.37, 95% CI 1.58-25.70), treatment failure (RRR 4.54, 95% CI 1.35-15.24), and loss to follow-up (RRR 7.00, 95% CI 2.83-17.31; RRR 2.97, 95% CI 1.02-8.61) compared to those who maintained viral suppression. Lack of viral suppression at MDR-TB treatment initiation and failure to achieve or maintain viral suppression during MDR-TB treatment drives differences in MDR-TB outcomes. Early intervention to support access and adherence to antiretroviral therapy among PWH should be prioritized to improve MDR-TB treatment outcomes.

The impact of HIV viral suppression on multidrug resistant tuberculosis (MDR-TB) treatment outcomes among people with HIV (PWH) has not been clearly established. Using secondary data from a cluster-randomized clinical trial among people with MDR-TB in South Africa, we examined the effects of HIV viral suppression at MDR-TB treatment initiation and throughout treatment on MDR-TB outcomes among PWH using multinomial regression. This analysis included 1479 PWH. Viral suppression (457, 30.9%), detectable viral load (524, 35.4%), or unknown viral load (498, 33.7%) at MDR-TB treatment initiation were almost evenly distributed. Having a detectable HIV viral load at MDR-TB treatment initiation significantly increased risk of death compared to those virally suppressed (relative risk ratio [RRR] 2.12, 95% CI 1.11–4.07). Among 673 (45.5%) PWH with a known viral load at MDR-TB outcome, 194 (28.8%) maintained suppression, 267 (39.7%) became suppressed, 94 (14.0%) became detectable, and 118 (17.5%) were never suppressed. Those who became detectable (RRR 11.50, 95% CI 1.98–66.65) or were never suppressed (RRR 9.28, 95% CI 1.53–56.61) were at significantly increased risk of death (RRR 6.37, 95% CI 1.58–25.70), treatment failure (RRR 4.54, 95% CI 1.35–15.24), and loss to follow-up (RRR 7.00, 95% CI 2.83–17.31; RRR 2.97, 95% CI 1.02–8.61) compared to those who maintained viral suppression. Lack of viral suppression at MDR-TB treatment initiation and failure to achieve or maintain viral suppression during MDR-TB treatment drives differences in MDR-TB outcomes. Early intervention to support access and adherence to antiretroviral therapy among PWH should be prioritized to improve MDR-TB treatment outcomes.

OBJECTIVES/GOALS: Guidelines suggest people with HIV (PWH) receive routine HIV viral load (VL) testing at least yearly and upon diagnosis with multidrug-resistant tuberculosis (MDR-TB). Many PWH and MDR-TB in South Africa seem to be missing VL results. This study’s goal was to find results which may be available from the National Health Laboratory Service (NHLS). METHODS/STUDY POPULATION: We abstracted HIV laboratory results, specifically baseline VL and CD4 count and VL at MDR-TB cure, from PWH enrolled in a cluster-randomized clinical trial of nurse case management for PWH and MDR-TB in South Africa who were cured of MDR-TB. For any participant missing one or more of these results, we thoroughly searched the electronic NHLS database using multiple separate searches varying terms including patient name, surname, date of birth, medical record number where available, and South African identification number. Returned results were compared to results abstracted from the parent study and any additional results were entered into the parent study data. RESULTS/ANTICIPATED RESULTS: Of 929 PWH cured of MDR-TB, 879 (94.6%) were missing at least one expected VL or CD4 result in the parent study database. Though our search strategy was successful in identifying participants and returning CD4 and VL results, we rarely found additional results that were not already in the parent study database. Following the search and entry of the few additional results retrieved, 116 (12.4%) participants were missing a baseline CD4, 309 (33.3%) missing baseline VL, and 385 (41.4%) missing VL at MDR-TB cure, representing 572 individuals or 61.6% of participants with at least one unavailable result. This high level of unavailability of key laboratory results used to guide MDR-TB and HIV treatment suggests that these tests were either not ordered, not collected, or not completed due to electronic gatekeeping at NHLS. DISCUSSION/SIGNIFICANCE: Unknown CD4 count or VL leaves PWH open to including MDR-TB treatment failure and death. Our search strategy found additional results but was time-consuming and cumbersome. Limitations included lack of information on why laboratory results were missing, which limits our ability to make recommendations for better collection and reporting.

Substance use disorder (SUD), a common comorbidity among people with HIV (PWH), adversely affects HIV clinical outcomes and HIV-related comorbidities. However, less is known about the incidence of different chronic conditions, changes in overall comorbidity burden, and health care utilization by SUD status and patterns among PWH in Florida, an area disproportionately affected by the HIV epidemic. We used electronic health records (EHR) from a large southeastern US consortium, the OneFlorida + clinical research data network. We identified a cohort of PWH with 3 + years of EHRs after the first visit with HIV diagnosis. International Classification of Diseases (ICD) codes were used to identify SUD and comorbidity conditions listed in the Charlson comorbidity index (CCI). A total of 42,271 PWH were included (mean age 44.5, 52% Black, 45% female). The prevalence SUD among PWH was 45.1%. Having a SUD diagnosis among PWH was associated with a higher incidence for most of the conditions listed on the CCI and faster increase in CCI score overtime (rate ratio = 1.45, 95%CI 1.42, 1.49). SUD in PWH was associated with a higher mean number of any care visits (21.7 vs. 14.8) and more frequent emergency department (ED, 3.5 vs. 2.0) and inpatient (8.5 vs. 24.5) visits compared to those without SUD. SUD among PWH was associated with a higher comorbidity burden and more frequent ED and inpatient visits than PWH without a diagnosis of SUD. The high SUD prevalence and comorbidity burden call for improved SUD screening, treatment, and integrated care among PWH.

Background: The emergence of resistance to drugs used to treat tuberculosis (TB) and particularly multidrug resistance TB (MDR-TB) has become a significant health problem and obstacle to effective TB control in India. Present study was conducted to study clinical and sociodemograohic profile of MDR and rifampicin resistant TB patients registered for treatment under RNTCP in Yavatmal district of Maharashtra state.Methods: All drug resistant (MDR and rifampicin resistant) TB patients residents of Yavatmal district, treated at DOTS plus site with Standardized Treatment Regimen (STR) from 1st quarter 2009 to 3rd quarter 2013 were included. Data was obtained from electronic treatment register maintained at DOTS Plus site.Results: There were total 60 confirmed MDR and rifampicin resistant TB patients from Yavatmal district. Male patients (65.00%) were comparatively more than females (35.00%). Almost half (46.67%) of the patients belonged to the productive age group i.e. 30-45 years followed by another one third (35.00%) in the age group of 15-30 years. 93.33% patients were previously treated under RNTCP (under CAT II), out of them 48.51% were failure, 37.50% relapse and 14.29% defaulter.Conclusions: Among MDR and rifampicin resistant TB patients, maximum patients were males, belonged to the social and productive age group, HIV negative and previously treated due to treatment failure.

Challenging the management of drug-resistant tuberculosis

Control of Mycobacterium tuberculosis infection continues to be an issue, particularly in countries with a high tuberculosis (TB) burden in the tropical and sub-tropical regions. The effort to reduce the catastrophic cost of TB with the WHO’s End TB Strategy in 2035 is still obstructed by the emergence of drug-resistant TB (DR-TB) cases as result of various mutations of the MTB strain. In the approach to combat DR-TB, several potential antitubercular agents were discovered as inhibitors for various existing and novel targets. Host-directed therapy and immunotherapy also gained attention as the drug-susceptibility level of the pathogen can be reduced due to the pathogen’s evolutionary dynamics. This review is focused on the current progress and challenges in DR-TB treatment. We briefly summarized antitubercular compounds that are under development and trials for both DR-TB drug candidates and host-directed therapy. We also highlighted several problems in DR-TB diagnosis, the treatment regimen, and drug discovery that have an impact on treatment adherence and treatment failure.

BackgroundDespite advances in drug-resistant tuberculosis (DR-TB) diagnosis, treatment, and service delivery, individuals with DR-TB often face significant socioeconomic and psychosocial challenges due to limited resources. These challenges can hinder retention in care, undermining the progress made in DR-TB management. As a consequence, advances in DR-TB diagnostics and treatment have not resulted in DR-TB programs meeting the 75% treatment success targets set by the World Health Organization (WHO).MethodsWe interviewed people with DR-TB who had disengaged from care and their family members to identify barriers and facilitators to retention in care as well as possible strategies to address these barriers. We recruited 16 people with DR-TB and 8 family members from five health facilities in Johannesburg, Gauteng Province, South Africa. All DR-TB patients disengaged from DR-TB care for ≥ 45 days. Semi-structured interviews and focus group discussions were used to collect data, which were analysed through thematic content analysis using a multidimensional adherence model.ResultsThe facilitators of retention in care were positive interactions with health care workers (HCWs), nutritional support, transport from local clinics to DR-TB sites, self-motivation, and emotional support from family members. Barriers to optimal retention in care included a limited understanding of DR-TB disease and treatment, transport challenges, side effects of the medication, pill burden, stigma and discrimination experienced at health care facilities other than DR-TB facilities, food insecurity, and financial difficulties, which included loss of income and a lack of transport money and mental health challenges such as fear, anxiety and feeling lonely and unsupported.ConclusionThe findings from this study highlight the need for TB treatment programs to collaborate with people being treated for DR-TB and their families to understand facilitators and barriers to retention in care and how these could be addressed to facilitate optimal retention in care.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

ABSTRACTIntroduction: Drug-resistant tuberculosis (DR-TB) is a growing global health threat and children are especially vulnerable to becoming infected and sick with DR-TB. There is a growing body of evidence on the optimal diagnosis, treatment and prevention of DR-TB in this vulnerable population.Areas covered: A comprehensive review of the literature on DR-TB in children was done using PubMed and Ovid databases up to 31 December 2016. Topic areas covered included diagnosis of DR-TB, treatment of DR-TB – including novel medications and regimens, prevention of DR-TB, community-based care, and stigma/discrimination. After presenting a case that highlights some of these challenges in each of these areas, for which we will propose mechanisms for overcoming them.Expert commentary: Overcoming the challenges facing children with DR-TB, requires a paradigm shift at multiple levels. The ‘trickle down’ approach to pediatric DR-TB has been woefully inadequate and it is essential that pediatric DR-TB – preventing it, diagnosing it, and treating it – be made a priority.

In 2018, shorter treatment regimens (STR) for people with drug-resistant tuberculosis (DR-TB) were introduced in Tanzania and included kanamycin, high-dose moxifloxacin, prothionamide, high-dose isoniazid, clofazimine, ethambutol and pyrazinamide. We describe treatment outcomes of people diagnosed with DR-TB in a cohort initiating treatment in 2018 in Tanzania. This was a retrospective cohort study conducted at the National Centre of Excellence and decentralised DR-TB treatment sites for the 2018 cohort followed from January 2018 to August 2020. We reviewed data from the National Tuberculosis and Leprosy Program DR-TB database to assess clinical and demographic information. The association between different DR-TB regimens and treatment outcome was assessed using logistic regression analysis. Treatment outcomes were described as treatment complete, cure, death, failure or lost to follow-up. A successful treatment outcome was assigned when the patient achieved treatment completion or cure. A total of 449 people were diagnosed with DR-TB of whom 382 had final treatment outcomes: 268 (70%) cured; 36 (9%) treatment completed; 16 (4%) lost to follow-up; 62 (16%) died. There was no treatment failure. The treatment success rate was 79% (304 patients). The 2018 DR-TB treatment cohort was initiated on the following regimens: 140 (46%) received STR, 90 (30%) received the standard longer regimen (SLR), 74 (24%) received a new drug regimen. Normal nutritional status at baseline [adjusted odds ratio (aOR)=6.57, 95% CI (3.33-12.94), p < 0.001] and the STR [aOR=2.67, 95% CI (1.38-5.18), p=0.004] were independently associated with successful DR-TB treatment outcome. The majority of DR-TB patients on STR in Tanzania achieved a better treatment outcome than on SLR. The acceptance and implementation of STR at decentralised sites promises greater treatment success. Assessing and improving nutritional status at baseline and introducing new shorter DR-TB treatment regimens may strengthen favourable treatment outcomes.

Emergence of bedaquiline-resistant tuberculosis and of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains with rpoB Ile491Phe mutation not detected by Xpert MTB/RIF in Mozambique: a retrospective observational study

SummaryBackgroundThere is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa.MethodsIn this qualitative study using Bury’s framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2–6 weeks after treatment initiation), middle (2–6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed.FindingsFrom March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery.InterpretationPeople with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens.FundingUS National Institutes of Health.

Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen. Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods. Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients. Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.

People with HIV (PWH) have an increased risk of cardiovascular disease, and many receive lipid-lowering therapy (LLT). However, it is unknown if PWH treated with LLT remain at a higher residual cardiovascular risk than persons from the general population. We investigated the risk of elevated biomarkers of inflammation and dyslipidemia associated with cardiovascular disease, among PWH and controls receiving LLT. In this cross-sectional study, we included PWH from the Copenhagen Comorbidity in HIV infection (COCOMO) study and population controls from the Copenhagen General Population Study (CGPS), frequency matched 1:4 on age and sex. Among these, 142 PWH and 428 controls reported current treatment with LLT and were included in the analysis. We used multivariable logistic regression models to assess the association between HIV and biomarkers including high-sensitivity C-reactive protein (hs-CRP) ≥3.0 mg/L, low-density lipoprotein cholesterol (LDL-C) ≥2.6mmol/L, and triglycerides (TG) ≥2.26 mmol/L combined with high-density lipoprotein cholesterol (HDL-C) ≤1.03 mmol/L. PWH had a higher risk of elevated hs-CRP (adjusted odds ratio (aOR) 1.97 [1.17-3.32], p = 0.01) and of elevated TG (aOR 3.36 [1.94-5.81], p < 0.01). No difference according to LDL-C risk was found. Our findings remained robust in sensitivity analyses adjusting for SCORE2 category, physical activity and exposure to thymidine analogues, and in subgroup analyses by antiretroviral therapy regimen, except for hs-CRP among PWH on protease inhibitor-based regimens. PWH receiving LLT had higher risk of elevated hs-CRP and TG compared to controls. This warrants increased attention and monitoring of treatment goals in PWH receiving LLT.