In-kind nutritional supplementation for household contacts of persons with tuberculosis would be cost-effective for reducing tuberculosis incidence and mortality in India: a modeling study.

Background: Undernutrition is the leading cause of tuberculosis (TB) globally, but nutritional interventions are often considered cost prohibitive. The RATIONS study demonstrated that nutritional support provided to household contacts of persons with TB can reduce TB incidence. However, the long-term cost-effectiveness of this intervention is unclear. Methods: We assessed the cost-effectiveness of a RATIONS-style intervention (daily 750 kcal dietary supplementation and multi-micronutrient tablet). Using a Markov state transition model we simulated TB incidence, treatment, and TB-attributable mortality among household contacts receiving the RATIONS intervention, as compared to no nutritional support. We calculated health outcomes (TB cases, TB deaths, and disability-adjusted life years [DALYs]) over the lifetime of intervention recipients and assessed costs from government and societal perspectives. We tested the robustness of results to parameter changes via deterministic and probabilistic sensitivity analysis. Findings: Over two years, household contacts receiving the RATIONS intervention would experience 39% (95% uncertainty interval (UI): 23-52) fewer TB cases and 59% (95% UI: 44-69) fewer TB deaths. The intervention was estimated to avert 13,775 (95% UI: 9036-20,199) TB DALYs over the lifetime of the study cohort comprising 100,000 household contacts and was cost-effective from both government (incremental cost-effectiveness ratio: $229 per DALY averted [95% UI: 133-387]) and societal perspectives ($184 per DALY averted [95% UI: 83-344]). The results were most sensitive to the cost of the nutritional supplement. Interpretation: Prompt nutritional support for household contacts of persons with TB disease would be cost-effective in reducing TB incidence and mortality in India. Summary: Undernutrition is the leading cause of tuberculosis in India. Using a Markov state-transition model, we found that food baskets for household contacts of persons with tuberculosis would be cost-effective in reducing tuberculosis incidence and mortality in India. Research in context: Evidence before this study: Undernutrition is the leading risk factor for TB worldwide. Recently, the RATIONS study demonstrated a roughly 40% reduction in incident TB among household contacts who received in-kind macronutrient and micronutrient supplementation. Added value of this study: Although the RATIONS study demonstrated a dramatic reduction in incident TB, it is unclear if nutritional interventions to prevent TB are cost-effective. Previously, only one cost-effectiveness analysis of nutritional interventions for household contacts has been published. Due to lack of published data, that study had to make assumptions regarding the impact of nutritional interventions on TB incidence and mortality. In this study, we conducted an economic evaluation of a RATIONS-style intervention to reduce incident TB and mortality in India using observed data. Implications of all the available evidence: In-kind nutritional supplementation for household contacts of individuals with TB disease would be cost-effective in reducing incident TB and TB mortality, particularly if TB programs leverage economies of scale to bring down the cost of the nutritional intervention.

Nutritional Supplementation Would Be Cost-Effective for Reducing Tuberculosis Incidence and Mortality in India: The Ration Optimization to Impede Tuberculosis (ROTI-TB) Model.

BACKGROUND: Undernutrition is the leading cause of tuberculosis (TB) in India and is associated with increased TB mortality. Undernutrition also decreases quality of life and economic productivity. METHODS: We assessed the cost-effectiveness of providing augmented rations to undernourished Indians through the government's Targeted Public Distribution System (TPDS). We used Markov state transition models to simulate disease progression and mortality among undernourished individuals in 3 groups: general population, household contacts (HHCs) of people living with TB, and persons living with human immunodeficiency virus (HIV). The models calculate costs and outcomes (TB cases, TB deaths, and disability-adjusted life years [DALYs]) associated with a 2600 kcal/day diet for adults with body mass index (BMI) of 16-18.4 kg/m2 until they attain a BMI of 20 kg/m2 compared to a status quo scenario wherein TPDS rations are unchanged. We employed deterministic and probabilistic sensitivity analyses to test result robustness. RESULTS: Over 5 years, augmented rations could avert 81% of TB cases and 88% of TB deaths among currently undernourished Indians. Correspondingly, this intervention could forestall 78% and 48% of TB cases and prevent 88% and 70% of deaths among undernourished HHCs and persons with HIV, respectively. Augmented rations resulted in 10-fold higher resolution of undernutrition and were highly cost-effective with (incremental cost-effectiveness ratio [ICER] of $470/DALY averted). ICER was lower for HHCs ($360/DALY averted) and the HIV population ($250/DALY averted). CONCLUSIONS: A robust nutritional intervention would be highly cost-effective in reducing TB incidence and mortality while reducing chronic undernutrition in India.

Management of drug-resistant tuberculosis.

Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts.

Undernutrition and Tuberculosis: Public Health Implications.

Almost 800 million people are chronically undernourished worldwide, of whom 98% are in low- and middle-income countries where tuberculosis is endemic. In many tuberculosis-endemic countries, undernutrition is a driver of tuberculosis incidence and associated with a high population attributable fraction of tuberculosis and poor treatment outcomes. Data suggest that undernutrition impairs innate and adaptive immune responses needed to control Mycobacterium tuberculosis infection and may affect responses to live vaccines, such as BCG. Given its impact on tuberculosis, addressing undernutrition will be a vital component of the World Health Organization End TB strategy. This narrative review describes the effect of undernutrition on the immune response, vaccine response, and tuberculosis incidence, severity, and treatment outcomes.

An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. METHODS/DESIGN: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. DISCUSSION: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

The cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy: a model-based analysis.

BACKGROUND: In settings with high tuberculosis (TB) prevalence, 15-30% of HIV-infected individuals initiating antiretroviral therapy (ART) have undiagnosed TB. Such patients are usually screened by symptoms and sputum smear, which have poor sensitivity. OBJECTIVE: To project the clinical and economic outcomes of using Xpert MTB/RIF(Xpert), a rapid TB/rifampicin-resistance diagnostic, to screen individuals initiating ART. DESIGN: We used a microsimulation model to evaluate the clinical impact and cost-effectiveness of alternative TB screening modalities - in all patients or only symptomatic patients - for hypothetical cohorts of individuals initiating ART in South Africa (mean CD4 cell count = 171 cells/µl; TB prevalence 22%). We simulated no active screening and four diagnostic strategies, smear microscopy (sensitivity 23%); smear and culture (sensitivity, 100%); one Xpert sample (sensitivity in smear-negative TB: 43%); two Xpert samples (sensitivity in smear-negative TB: 62%). Outcomes included projected life expectancy, lifetime costs (2010 US$), and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs less than $7100 (South African gross domestic product per capita) were considered very cost-effective. RESULTS: Compared with no screening, life expectancy in TB-infected patients increased by 1.6 months using smear in symptomatic patients and by 6.6 months with two Xpert samples in all patients. At 22% TB prevalence, the ICER of smear for all patients was $2800 per year of life saved (YLS), and of Xpert (two samples) for all patients was $5100/YLS. Strategies involving one Xpert sample or symptom screening were less efficient. CONCLUSION: Model-based analysis suggests that screening all individuals initiating ART in South Africa with two Xpert samples is very cost-effective.