Dynamics of within-host Mycobacterium tuberculosis diversity and heteroresistance during treatment.

BACKGROUND: Studying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS). METHODS: We analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis. FINDINGS: Baseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required. INTERPRETATION: In this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations. FUNDING: Wellcome Trust, NIH/NIAID.

Tuberculosis infection prevention and control: why we need a whole systems approach.

Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an on-going project entitled Umoya omuhle ("good air"), conducted in two provinces of South Africa, that adopts an interdisciplinary, 'whole systems' approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A 'whole systems' approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission.

The patient costs of care for those with TB and HIV: a cross-sectional study from South Africa.

BACKGROUND: This study describes the post-diagnosis care-seeking costs incurred by people living with TB and/or HIV and their households, in order to identify the potential benefits of integrated care. METHODS: We conducted a cross-sectional study with 454 participants with TB or HIV or both in public primary health care clinics in Ekurhuleni North Sub-District, South Africa. We collected information on visits to health facilities, direct and indirect costs for participants and for their guardians and caregivers. We define 'integration' as receipt of both TB and HIV services at the same facility, on the same day. Costs were presented and compared across participants with TB/HIV, TB-only and HIV-only. Costs exceeding 10% of participant income were considered catastrophic. RESULTS: Participants with both TB and HIV faced a greater economic burden (US$74/month) than those with TB-only (US$68/month) or HIV-only (US$40/month). On average, people with TB/HIV made 18.4 visits to health facilities, more than TB-only participants or HIV-only participants who made 16 and 5.1 visits, respectively. However, people with TB/HIV had fewer standalone TB (10.9) and HIV (2.2) visits than those with TB-only (14.5) or HIV-only (4.4). Although people with TB/HIV had access to 'integrated' services, their time loss was substantially higher than for other participants. Overall, 55% of participants encountered catastrophic costs. Access to official social protection schemes was minimal. CONCLUSIONS: People with TB/HIV in South Africa are at high risk of catastrophic costs. To some extent, integration of services reduces the number of standalone TB and HIV of visits to the health facility. It is however unlikely that catastrophic costs can be averted by service integration alone. Our results point to the need for timely social protection, particularly for HIV-positive people starting TB treatment.

Integrating tuberculosis and HIV services in low- and middle-income countries: a systematic review.

OBJECTIVES: Given the imperative to scale up integrated tuberculosis (TB) and HIV services in settings where both are of major public health importance, we aimed to synthesise knowledge concerning implementation of TB/HIV service integration. METHODS: Systematic review of studies describing a strategy to facilitate TB and HIV service integration, searching 15 bibliographic databases including Medline, Embase and the Cochrane library; and relevant conference abstracts. RESULTS: Sixty-three of 1936 peer-reviewed articles and 70 of 170 abstracts met our inclusion criteria. We identified five models: entry via TB service, with referral for HIV testing and care; entry via TB service, on-site HIV testing, and referral for HIV care; entry via HIV service with referral for TB screening and treatment; entry via HIV service, on-site TB screening, and referral for TB diagnosis and treatment; and TB and HIV services provided at a single facility. Referral-based models are most easily implemented, but referral failure is a key risk. Closer integration requires more staff training and additional infrastructure (e.g. private space for HIV counselling; integrated records). Infection control is a major concern. More integrated models hold potential efficiencies from both provider and user perspective. Most papers report 'outcomes' (e.g. proportion of TB patients tested for HIV); few report downstream 'impacts' such as outcomes of TB treatment or antiretroviral therapy. Very few studies address the perspectives of service users or staff, or costs or cost-effectiveness. CONCLUSIONS: While scaling up integrated services, robust comparisons of the impacts of different models are needed using standardised outcome measures.

Contrasting predictors of poor antiretroviral therapy outcomes in two South African HIV programmes: a cohort study.

BACKGROUND: Many national antiretroviral therapy (ART) programmes encourage providers to identify and address baseline factors associated with poor treatment outcomes, including modifiable adherence-related behaviours, before initiating ART. However, evidence on such predictors is scarce, and providers judgement may often be inaccurate. To help address this evidence gap, this observational cohort study examined baseline factors potentially predictive of poor treatment outcomes in two ART programmes in South Africa, with a particular focus on determinants of adherence. METHODS: Treatment-naïve patients starting ART were enrolled from a community and a workplace ART programme. Potential baseline predictors associated with poor treatment outcomes (defined as viral load > 400 copies/ml or having discontinued treatment by six months) were assessed using logistic regression. Exposure variables were organised for regression analysis using a hierarchical framework. RESULTS: 38/227 (17%) of participants in the community had poor treatment outcomes compared to 47/117 (40%) in the workplace. In the community, predictors of worse outcomes included: drinking more than 20 units of alcohol per week, having no prior experience of chronic medications, and consulting a traditional healer in the past year (adjusted odds ratio [aOR] 15.36, 95% CI 3.22-73.27; aOR 2.30, 95%CI 1.00-5.30; aOR 2.27, 95% CI 1.00-5.19 respectively). Being male and knowing someone on ART were associated with better outcomes (aOR 0.25, 95%CI 0.09-0.74; aOR 0.44, 95%CI 0.19-1.01 respectively). In the workplace, predictors of poor treatment outcomes included being uncertain about the health effects of ART and a traditional healer's ability to treat HIV (aOR 7.53, 95%CI 2.02-27.98; aOR 4.40, 95%CI 1.41-13.75 respectively). Longer pre-ART waiting time (2-12 weeks compared to <2 weeks) predicted better treatment outcomes (aOR 0.13, 95% CI 0.03-0.56). CONCLUSION: Baseline predictors of poor treatment outcomes were largely unique to each programme, likely reflecting different populations and pathways to HIV care. In the workplace, active promotion of HIV testing may have extended ART to individuals who, without provider initiation, would not have spontaneously sought care. As provider-initiated testing makes ART available to individuals less motivated to seek care, patients may need additional adherence support, especially addressing uncertainty about the health benefits of ART.

Use of traditional medicine by HIV-infected individuals in South Africa in the era of antiretroviral therapy.

As antiretroviral therapy (ART) becomes more available in African countries, the potential for interaction with traditional medicines becomes more important. We carried out a cross-sectional survey among individuals with moderate or advanced HIV disease attending a workplace clinic providing ART in South Africa to determine prevalence of traditional medicine use, source, recommended products and costs. Among 44 clinic attendees (100% male, median age 42 years, 30 taking ART), 37 (84%) reported ever using traditional medicines, 25 obtained from a healer or herbalist, eight from their own fields and four from a pharmacy. Fourteen of the 44 (32%) were currently using traditional medicines, most frequently African potato (9/14) and Aloe vera (3/14). Seven out of 30 persons taking ART (23%) reported currently using traditional medicines. Participants spent 4 - 27 pounds per month on traditional medicines. Traditional medicine use is common among individuals with moderate and advanced HIV disease. Concomitant use with ART has the potential for drug interactions and should be discussed routinely in ART counselling. Further work is warranted to investigate whether commonly used traditional medicines interact with ART in vivo.