Report from the World Health Organization's immunization and vaccines-related implementation research advisory committee (IVIR-AC) meeting, virtual gathering, 26 February-1 March 2024.

The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings.

Cost-Utility Analysis of Dabigatran and Warfarin for Stroke Prevention Among Patients With Nonvalvular Atrial Fibrillation in India.

OBJECTIVES: Dabigatran has a better safety profile and requires less monitoring, but is costlier than warfarin. This study evaluated the cost-utility of dabigatran relative to warfarin for preventing stroke in nonvalvular atrial fibrillation (NVAF) in India. METHODS: A Markov decision analysis model was developed to compare dabigatran (110 or 150 mg twice a day) to warfarin titrated to target prothrombin time in patients with NVAF at high risk of stroke. Model utilities and transition probabilities were based on literature and costs on market prices. Data on out-of-pocket expenses and income lost were taken from a nationally representative survey. We adopted a societal perspective and discounted both costs and outcomes at 3%. Ischemic stroke, intracranial bleed, other major bleeds, and death were outcomes of NVAF. The model projected the costs, life-years, and quality-adjusted life-years (QALYs) for each intervention over a lifetime. We used gross domestic product per capita of India (US dollars [US$]1889) as the cost-effectiveness threshold. Sensitivity analyses were conducted. RESULTS: Treatment with either dose of dabigatran was associated with gain in life-years and QALYs compared with warfarin. The discounted incremental cost-effectiveness ratios/QALYs for both doses of dabigatran (110 mg US$7519; 150 mg US$6634) were above the cost-effectiveness threshold, and the probability of being cost-effective at this threshold was low. Cost of dabigatran was an important factor in determining incremental cost-effectiveness ratio. Price reduction of 150 mg dose by 49% will make it cost-effective. CONCLUSIONS: Dabigatran is not cost-effective in the Indian societal context. Reducing the price of dabigatran 150 mg by half will make it cost-effective.

Assessing cost-effectiveness of hepatitis C testing pathways in Georgia using the Hep C Testing Calculator.

The cost of testing can be a substantial contributor to hepatitis C virus (HCV) elimination program costs in many low- and middle-income countries such as Georgia, resulting in the need for innovative and cost-effective strategies for testing. Our objective was to investigate the most cost-effective testing pathways for scaling-up HCV testing in Georgia. We developed a Markov-based model with a lifetime horizon that simulates the natural history of HCV, and the cost of detection and treatment of HCV. We then created an interactive online tool that uses results from the Markov-based model to evaluate the cost-effectiveness of different HCV testing pathways. We compared the current standard-of-care (SoC) testing pathway and four innovative testing pathways for Georgia. The SoC testing was cost-saving compared to no testing, but all four new HCV testing pathways further increased QALYs and decreased costs. The pathway with the highest patient follow-up, due to on-site testing, resulted in the highest discounted QALYs (123 QALY more than the SoC) and lowest costs ($127,052 less than the SoC) per 10,000 persons screened. The current testing algorithm in Georgia can be replaced with a new pathway that is more effective while being cost-saving.

Construction & assessment of a unified curated reference database for improving the taxonomic classification of bacteria using 16S rRNA sequence data.

Background & objectives: For bacterial community analysis, 16S rRNA sequences are subjected to taxonomic classification through comparison with one of the three commonly used databases [Greengenes, SILVA and Ribosomal Database Project (RDP)]. It was hypothesized that a unified database containing fully annotated, non-redundant sequences from all the three databases, might provide better taxonomic classification during analysis of 16S rRNA sequence data. Hence, a unified 16S rRNA database was constructed and its performance was assessed by using it with four different taxonomic assignment methods, and for data from various hypervariable regions (HVRs) of 16S rRNA gene. Methods: We constructed a unified 16S rRNA database (16S-UDb) by merging non-ambiguous, fully annotated, full-length 16S rRNA sequences from the three databases and compared its performance in taxonomy assignment with that of three original databases. This was done using four different taxonomy assignment methods [mothur Naïve Bayesian Classifier (mothur-nbc), RDP Naïve Bayesian Classifier (rdp-nbc), UCLUST, SortMeRNA] and data from 13 regions of 16S rRNA [seven hypervariable regions (HVR) (V2-V8) and six pairs of adjacent HVRs]. Results: Our unified 16S rRNA database contained 13,078 full-length, fully annotated 16S rRNA sequences. It could assign genus and species to larger proportions (90.05 and 46.82%, respectively, when used with mothur-nbc classifier and the V2+V3 region) of sequences in the test database than the three original 16S rRNA databases (70.88-87.20% and 10.23-24.28%, respectively, with the same classifier and region). Interpretation & conclusions: Our results indicate that for analysis of bacterial mixtures, sequencing of V2-V3 region of 16S rRNA followed by analysis of the data using the mothur-nbc classifier and our 16S-UDb database may be preferred.

Estimating the price at which hepatitis C treatment with direct-acting antivirals would be cost-saving in Japan.

In Japan, 1.5-2 million people are chronically infected with hepatitis C virus (HCV) infection. New direct-acting antiviral agents (DAA) offer an unprecedented opportunity to cure HCV. While the price of HCV treatment decreased recently in most countries, it remains one of the highest in Japan. Our objective was to evaluate the cost-effectiveness of HCV treatment in patients of different age groups and to estimate the price at which DAAs become cost-saving in Japan. A previously developed microsimulation model was adapted to the Japanese population and updated with Japan-specific health utilities and costs. Our model showed that compared with no treatment, the incremental cost-effectiveness ratio (ICER) of DAAs at a price USD 41,046 per treatment was USD 9,080 per quality-adjusted life year (QALY) gained in 60-year-old patients. HCV treatment became cost-effective after 9 years of starting treatment. However, if the price of DAAs is reduced by 55-85% (USD 6,730 to 17,720), HCV treatment would be cost-saving within a 5 to 20-year time horizon, which should serve to increase the uptake of DAA-based HCV treatment. The payers of health care in Japan could examine ways to procure DAAs at a price where they would be cost-saving.

Cost-effectiveness of generic pan-genotypic sofosbuvir/velpatasvir versus genotype-dependent direct-acting antivirals for hepatitis C treatment.

BACKGROUND AND AIM: Treatment of hepatitis C virus (HCV) infection with low-cost generic direct-acting antivirals (DAAs) available in India and other developing countries needs determination of HCV genotype ("genotype-dependent" regimens). Generic velpatasvir, a DAA that obviates the need for genotype determination ("pan-genotypic" regimen), recently became available but is costlier. The aim of this study was to evaluate the cost-effectiveness of genotype-dependent versus pan-genotypic DAA treatments in India. METHODS: A previously validated microsimulation model, adapted to Indian population, was used to compare the costs and long-term outcomes of three scenarios: no treatment, treatment with genotype-dependent regimens, and treatment with pan-genotypic regimen. Input parameters were derived from literature. Using a payer's perspective and lifetime time horizon, quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratio were calculated. Both deterministic and probabilistic sensitivity analyses were also conducted. RESULTS: At the current price ($US223 for 4 weeks), pan-genotypic regimen was cost-saving compared with no treatment. Compared with genotype-dependent regimens, it increased QALYs by 0.92 and increased costs by $US107 but was deemed cost-effective with an incremental cost-effectiveness ratio of $US242 per QALY gained. Probabilistic sensitivity analysis also supported the cost-effectiveness of pan-genotypic regimen. At the reduced price of $US188 for 4 weeks, the pan-genotypic regimen will become cost-neutral to genotype-dependent regimens (current price: $US100 for 4 weeks). CONCLUSIONS: At current prices, velpatasvir-based pan-genotypic regimen is cost-effective for HCV treatment in India where generic drugs are available. A reduction in the prices of pan-genotypic regimen has the potential to make its use cost-saving while simplifying treatment in community-level programs aimed at HCV elimination.

Estimation of Hepatitis C Disease Burden and Budget Impact of Treatment Using Health Economic Modeling.

Oral direct-acting antiviral agents have revolutionized treatment of hepatitis C virus (HCV) infection. Nonetheless, barriers exist to elimination of HCV as a public health threat including low uptake of treatment, limited budget allocations for HCV treatment, and low awareness rates of HCV status among infected people. Mathematical modeling provides a systematic framework to analyze and compare potential solutions and elimination strategies by simulating the HCV epidemic under different conditions. Such models evaluate impact of interventions in advance of implementation. This article describes key components of developing an HCV burden model and illustrates its use by simulating the HCV epidemic in the United States.

Cost-effectiveness of hepatitis C treatment using generic direct-acting antivirals available in India.

BACKGROUND & AIMS: Availability of directly-acting antivirals (DAAs) has changed the treatment landscape of hepatitis C virus (HCV) infection. The high price of DAAs has restricted their use in several countries. However, in some countries such as India, generic DAAs are available at much cheaper price. This study examined whether generic DAAs could be cost-saving and how long it would take for the treatment to become cost-saving/effective. METHODS: A previously-validated, mathematical model was adapted to the HCV-infected population in India to compare the outcomes of no treatment versus treatment with DAAs. Model parameters were estimated from published studies. Cost-effectiveness of HCV treatment using available DAAs was calculated, using a payer's perspective. We estimated quality-adjusted life years (QALYs), disability-adjusted life years (DALYs), total costs, and incremental cost-effectiveness ratio of DAAs versus no treatment. One-way and probabilistic sensitivity analyses were conducted. RESULTS: Compared with no treatment, the use of generic DAAs in Indian HCV patients would increase the life expectancy by 8.02 years, increase QALYs by 3.89, avert 19.07 DALYs, and reduce the lifetime healthcare costs by $1,309 per-person treated. Treatment became cost-effective within 2 years, and cost-saving within 10 years of its initiation overall and within 5 years in persons with cirrhosis. Treating 10,000 HCV-infected persons could prevent 3400-3850 decompensated cirrhosis, 1800-2500 HCC, and 4000-4550 liver-related deaths. The results were sensitive to the costs of DAAs, pre- and post-treatment diagnostic tests and management of cirrhosis, and quality of life after sustained virologic response. CONCLUSIONS: Treatment with generic DAAs available in India will improve patient outcomes, provide a good value for money within 2 years, and be ultimately cost-saving. Therefore, in this and similar settings, HCV treatment should be a priority from a public health as well an economic perspective.

Hepatitis A: epidemiology in resource-poor countries.

PURPOSE OF REVIEW: Transmission of hepatitis A virus (HAV) infection is primarily fecal-oral. Symptomatic hepatitis, severe disease, and death are more likely to occur when infection occurs at an older age. Improvements in socioeconomic and hygienic conditions have led to a change in its epidemiology worldwide. RECENT FINDINGS: In the last two decades, improved hygiene in several resource-poor countries has led to reduced transmission of HAV, an increase in average age at infection, and, consequently, a paradoxical increase in morbidity and mortality because of hepatitis A. In Argentina, introduction of one dose (instead of the conventional two doses, to reduce costs) of inactivated HAV vaccine at 12-month age in a universal childhood immunization program during such 'epidemiologic transition' has markedly reduced the incidence of symptomatic hepatitis A, and of fulminant hepatitis and liver transplantation caused by HAV infection. The monetary value of medical and nonmedical benefits of this strategy outweighed the expenditure on vaccination. These excellent results were possibly contingent upon a high vaccination coverage. SUMMARY: Resource-poor countries should closely monitor the epidemiology of HAV infection and periodically undertake cost-effectiveness analyses of HAV immunization strategies. This should allow timely identification of epidemiologic transition and introduction of preventive strategies before HAV infection becomes a public health problem.

Effect of maternal education on choice of location for delivery among Indian women.

BACKGROUND: Delivery in a healthcare facility is associated with better outcomes for both mother and child. However, in India, a large proportion of deliveries take place outside health facilities. We studied the effect of maternal education on the choice of location for delivery in the Indian population. METHODS: Data from the National Family Health Survey 3 (NFHS-3) were used. The survey included women who were selected using a multi-stage (2-stage for urban areas and 3- stage for rural areas), stratified (based on demographic or social factors) sampling technique; the primary sampling units selected were proportional to population size, and the subsequent steps used simple random sampling. Effect of maternal education on the choice of place for delivery (home, public or private facility) was investigated through a multinomial logistic regression model. The model adjusted for several factors at individual, household and community level, the survey design effect and included sampling weights. RESULTS: Of the 124 385 women aged 15-49 years included in the NFHS-3 dataset, 36 850 (29.6%) had had one or more childbirth during the past 5 years. A little more than half of all the deliveries were at home, and approximately a quarter each of the remaining deliveries were at public and private facilities, respectively. Maternal education was strongly and independently associated with the choice of location of delivery. For the choice sets of public facility versus home delivery and private facility versus home delivery, a clear dose-response relationship was apparent-higher maternal education was associated with a higher probability of delivery at a public or private health facility compared to home. CONCLUSION: Level of maternal education was a significant independent predictor of choice of location for childbirth among Indian women. Compared to cash incentives to increase facility-based delivery, improving maternal education may be a better way to achieve long term and sustained increase in facility deliveries in India.

Recurrent duodenal ulcer haemorrhage: a pharmacoeconomic comparison of various management strategies.

BACKGROUND: Duodenal ulcer (DU) bleeding has a 7 - 13% mortality rate and bleeding often recurs. Prevention of recurrence is, therefore, an important goal. Eradication of Helicobacter pylori or maintenance treatment with a proton pump inhibitor (PPI) may reduce recurrent DU bleeding. Economic comparison of these options is sparse. METHODS: After the control of index bleeding with endotherapy and drugs, three strategies were evaluated: empirical treatment for possible H. pylori infection followed by a PPI for 2 months; test for H. pylori, eradication if positive, maintenance PPI if negative; maintenance PPI alone. Probability and direct cost data were obtained from a Medline search and Indian hospitals, respectively. Cost-minimisation, cost-utility, one- and two-way sensitivity analyses and threshold values were evaluated. RESULTS: Treatment of H. pylori, particularly empirical, was the preferred strategy and dominated maintenance treatment with PPI. The test-and-treat strategy was better than the empirical treatment strategy only when the probabilities of H. pylori eradication, ulcer healing following eradication and of frequency of H. pylori infection in bleeding DU were less than 58, 73 and 58%, respectively. CONCLUSIONS: Eradication of H. pylori is preferred in preventing recurrent bleeding from DU.

Assessment of cost-effectiveness of universal hepatitis B immunization in a low-income country with intermediate endemicity using a Markov model.

BACKGROUND/AIMS: Most countries with high hepatitis B (HB) virus endemicity and most high-income countries have introduced immunization programmes against this infection. However, several low-income countries with intermediate HB endemicity have not done so. We performed a cost-effectiveness analysis of universal childhood HB immunization in such countries using India as an example, since available data on this aspect are limited. METHODS: Marginal cost of every life-year and quality-adjusted life-year (QALY) gained with universal HB vaccination was calculated using a Markov model. Two types of analyses (including and excluding expenditure on treatment of long-term complications of HB infection) were done. Several sensitivity analyses and Monte-Carlo simulation were performed. RESULTS: Universal immunization reduced the HB carrier rate by 71%, and increased the number of years and QALY lived by a birth-cohort by 0.173 years (61.072 vs. 60.899 years) and 0.213 years (61.056 vs. 60.843 years), respectively. Marginal costs were US$16.27 per life-year gained and US$13.22 per QALY gained, much lower than annual per capita income. One-way sensitivity analysis and Monte-Carlo simulation confirmed the robustness of the conclusions. CONCLUSIONS: Universal HB immunization is highly cost-effective in low-income countries with intermediate endemicity rates.

Treatment of chronic hepatitis B with interferon-alpha: cost-effectiveness in developing countries.

BACKGROUND: Treatment with interferon-alpha (IFN) has been shown to be cost-effective in developed countries. However, cost-effectiveness In developing countries such as India has not been studied. METHODS: Using the Markov transitional probability model, we studied two cohorts of young patients (30 years of age) with chronic hepatitis B, one untreated and the other treated with interferon (IFN), 5 million units daily for 16 weeks, with evidence of viral replication and chronic hepatitis, but not cirrhosis, and were followed up over a 30-year period. Rates of disease progression, efficacy of IFN and quality of life associated with various disease states were estimated from the available literature. Direct costs were estimated using Indian prices of IFN and from the usual costs of medical treatment in India based on expert opinion. Unrelated mortality rates were modelled on age-specific death rates of the general population. The efficacy of IFN was judged In terms of extra life-years and quality-adjusted life-years (QALY) gained, and marginal cost-effectiveness and cost-utility. Several sensitivity analyses, both undiscounted and with discounted analyses, were done. RESULTS: At the end of the 30-year period, fewer patients in the IFN-treated group developed cirrhosis or decompensated cirrhosis, or were dead. The average life span of the treated cohort was 25.14 years, a gain of 0.6 years over the untreated cohort (24.54years). The QALY lived bythetwocohortswere 23.69 and 22.75 years, respectively, representing a gain of 0.94 years for the IFN-treated group. The cost Incurred by the IFN-treated group was Rs 300,000, and that for the untreated cohort was Rs 40 700, a substantial difference. Using the baseline estimates, undiscounted costs per year of life gained and per QALY gained were Rs 432,500 and Rs 276,900, respectively; these estimates are 20.5 and 13.1 times the per capita gross national income of the Indian population. Sensitivity analyses showed that changes in various parameters led to only minor changes in these estimates. Use of discounting led to an increase in marginal cost per life-year or QALY gained. CONCLUSION: In developing countries with a low per capita Income, IFN therapy for chronic hepatitis B may not be cost-effective. A careful consideration of cost-effectiveness is therefore essential before Instituting IFN therapy in patients with chronic hepatitis B In such populations.