Cost-Effectiveness Analysis of Combination Therapies for Visceral Leishmaniasis in the Indian Subcontinent

Visceral leishmaniasis (VL) is a serious health problem in the Indian subcontinent affecting the rural poor. It has a significant economic impact on concerned households. The development of drug resistance is a major problem and threatens control efforts under the VL elimination initiative. With an unprecedented choice of antileishmanial drugs (but no newer compound in clinical development), policies that protect these drugs against the emergence of resistance are required. A possible strategy that has been successfully used for malaria and tuberculosis is the use of combination therapies. This study is the first comprehensive assessment of the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent. The analysis was done from the societal perspective, including both health provider and household costs. The present work shows that combination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on emergence of drug resistance, the use of combination therapy should be considered in the context of the VL elimination programme in the Indian subcontinent

Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of clinically suspected or confirmed uncomplicated typhoid fever in South Asia: a randomised controlled trial protocol.

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia.  A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia. Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)

The drug and vaccine landscape for neglected diseases (2000–11): a systematic assessment

Background: In 1975–99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011. Methods: We searched databases of drug regulatory authorities, WHO, and clinical trial registries for entries made between Jan 1, 2000, and Dec 31, 2011. We defined neglected diseases as malaria, tuberculosis, diarrhoeal diseases, neglected tropical diseases (NTDs; WHO definition), and other diseases of poverty according to common definitions. Findings: Of the 850 new therapeutic products registered in 2000–11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products. Only four new chemical entities were approved for neglected diseases (three for malaria, one for diarrhoeal disease), accounting for 1% of the 336 new chemical entities approved during the study period. Of 148 445 clinical trials registered in Dec 31, 2011, only 2016 (1%) were for neglected diseases. Interpretation: Our findings show a persistent insufficiency in drug and vaccine development for neglected diseases. Nevertheless, these and other data show a slight improvement during the past 12 years in new therapeutics development and registration. However, for many neglected diseases, new therapeutic products urgently need to be developed and delivered to improve control and potentially achieve elimination. Funding: None

Results in the baseline analysis.

<p>*Numbers in the table are rounded.</p><p>**Extended dominance.</p

Cost estimates of each treatment strategy per patient treated (US$ 2008).

1<p>Includes costs of contraceptives, administration (intravenous kits, solutions, syringes), laboratory investigations. It also includes the cost per inpatient bed-day and outpatient visit obtained.</p>2<p>Total costs of strategies with MF in this table do not include cost of AmB given to women in childbearing age that refuse to take contraceptives and are therefore different from total costs mentioned in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000818#pntd-0000818-t004" target="_blank">table 4</a>.</p

Root decision tree with different pathways depending on whether miltefosine is included in the strategy.

<p>Root decision tree with different pathways depending on whether miltefosine is included in the strategy.</p

Two-way sensitivity analysis on price of AmBisome and miltefosine.

<p>Two-way sensitivity analysis on price of AmBisome and miltefosine.</p

Model parameters.

a<p>Estimates obtained from expert opinion (Delphi method).</p>b<p>Baseline values were varied ±50% in sensitivity analysis.</p>c<p>Average of figures reported for Bangladesh 58.1% (2004); India 56.3% (2006); Nepal 48.0% (2006).</p

Optimum population-level use of artemisinin combination therapies: a modelling study

Background: Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria. Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains. Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness. We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs. Methods: With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance. We compared simultaneous distribution of artemether–lumefantrine, artesunate–amodiaquine, and dihydroartemisinin–piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure. The main assessment criterion was total number of treatment failures per 100 people per year. Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution. Findings: Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended. This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission. Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread. Interpretation: Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Funding: Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation

Baseline results without dominated options (simple or extended).

<p>Baseline results without dominated options (simple or extended).</p