The Cost-Effectiveness of Dolutegravir in Combination with Tenofovir and Lamivudine for HIV Therapy: A Systematic Review

Introduction

Antiretroviral therapy (ART) has played a significant role in HIV control, and integrase strand transfer inhibitors (INSTIs), such as dolutegravir (DTG), are becoming more widely used.¹ In 2016, the World Health Organization issued guidelines for the use of antiretroviral drugs for the treatment and prevention of HIV infection. Since 2018, WHO has recommended a combination of tenofovir disoproxil fumarate and lamivudine or emtricitabine plus DTG as the preferred first-line regimen for HIV therapy and updated this guidance in 2021.^2,3 This guideline provides a more comprehensive view of DTG as an ARV in the first-line due to the significant risk of neural tube defects risk and observed efficacy.⁴

DTG shows excellent efficacy and tolerability with a low risk of toxicities.^5,6 DTG with two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) has shown significant efficacy in HIV suppression in individuals.^7,8 DTG-based regimens may be more effective for CD4 recovery and virologic suppression than EFV-based regimens, making them a preferred treatment option for initial HIV treatment.⁹ DTG also has fewer drug interactions than EFV, a better genetic barrier to developing drug resistance, and is particularly effective against HIV-2 infection, which is inherently resistant to EFV. The efficacy or effectiveness of health-care interventions has been assessed in clinical trials by measuring outcomes.

The availability of DTG as a once-daily generic fixed-dose formulation at lower prices in most low- and middle-income countries (LMICs) further supports the recommended use of DTG.⁴ However, it must be determined whether the intervention is cost-effective and feasible to implement.¹⁰ Cost-effectiveness analysis (CEA) is used to improve resource allocation efficiency and assess the relative costs and health benefits of various competing health therapies.¹¹ Comparing studies and interventions using cost-effectiveness analyses can assist stakeholders in making evidence-based health policies.¹²

Furthermore, initial regimens recommended for most people living with HIV are expenses over $36,000 per patient per year, with an average 6% increase since 2012, ART costs outpaced overall inflation rates.¹³ The cost of antiretroviral therapy should be one of many factors considered in regimen selection because it can affect adherence and overall costs to the healthcare system, insurers, and society.⁷ According to previous studies, DTG may result in lower costs for HIV treatment and be the most efficacious core agents belonging to integrase strand transfer inhibitors (INSTIs).^14,15 This study aims to review evidence of the cost-effectiveness of DTG in combination with tenofovir and lamivudine compared with the standard of care for HIV therapy.

Methods

Study Design and Search Strategies

This study was focused on a systematic review of CEA assessing DTG in combination with tenofovir and lamivudine for HIV treatment. A literature search was conducted in several electronic databases, such as PubMed, ScienceDirect, and EBSCO, by two principal investigators (SA and AMU). The time frame for the research database was set to run from January 2018 to May 2023. The research question was developed using the population, intervention, comparator, and outcome (PICO) format to conduct a systematic review most suitable to answer the research question (see Table 1). The search term strategies were used in combination with the problem or disease keyword “HIV” or “human immunodeficiency virus” the keyword intervention was “dolutegravir” or “combination of dolutegravir” the keyword comparison was “efavirenz regimen” and the keyword outcome was “cost-effectiveness.” The authors used Mendeley Reference Manager version 1.19.8 to extract articles and check for duplicates, and the related articles were manually screened by two researchers based on the title and abstract. In particular, full-text screening was used to determine the studies potentially eligible according to the established inclusion criteria. As a result, the final articles collected were referred to the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) checklist.¹⁶ The quality rating of eligible studies was scored as excellent (100%), good (76–99%), moderate (51–75%) or low (<50%).^17,18

Table 1 PICO for Search Term of Systematic Review

Inclusion and Exclusion Criteria

The inclusion criteria were articles that studied cost-effectiveness of combination of tenofovir-lamivudine-DTG compared to tenofovir-lamivudine-efavirenz (TLE). The articles were published from January 2018 to May 2023, and the full-text articles are available in English. Articles that only examined clinical efficacy and cost-effectiveness studies were not compared with the EFV regimen; design studies were undertaken as review articles or systematic reviews; and not full-text articles were excluded.

Results

Selected Studies

The search strategy identified 145 potential publications in PubMed, ScienceDirect, and EBSCO databases. After removing duplicates, 142 articles were manually screened for inclusion in the review based on title and abstract by two reviewers. A total of 123 articles were excluded after pre-assessing the title and abstract. From 19 articles included in the full-text assessment, 14 articles were excluded because the studies only discussed clinical efficacy, not compared with efavirenz regimen, not full-text articles, and one article was published before 2018. Only five articles met the inclusion criteria following the evaluation of full-text articles (see Table 2). The article selection process is presented in Figure 1.

Table 2 Study Characteristics

Figure 1 Article selection flow process. Abbreviations: HIV, human immunodeficiency virus; WHO, World Health Organization; DTG, dolutegravir; ART, antiretroviral; QALY, quality-adjusted life years; ICER, incremental cost-effectiveness ratio.

Modelling Design

Table 2 provides a description of the study’s characteristics. The selected studies were conducted in sub-Saharan Africa, India, and China. Cost-effectiveness analyses of tenofovir-lamivudine-DTG combinations conducted between 2018 and 2020 were also discussed. Three of the five studies used an individual-based simulation model of sexual HIV transmission, progression, and ART’s effect on adults.^20,21,23 The cost-effectiveness of preventing AIDS complications international model¹⁹ and the dynamic Markov model²² have been implemented in other studies (see Table 3).

Table 3 Modelling Method

The studies discussed the following outcomes: disability-adjusted life-years (DALYs), quality-adjustable life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Most studies have compared the cost-effectiveness of DTG in combination with tenofovir and lamivudine to that of existing standard treatments, such as tenofovir, lamivudine, and EFV.^19–23 Punekar et al used EFV and ritonavir-boosted lopinavir, both of which combined with two of the NRTI classes of ART in China.

A CEA should use time horizons extending beyond the present time to accurately assess the value of medical interventions.²⁴ The model’s time horizon should be long enough to capture relevant differences in outcomes across strategies.²⁵ McCreesh investigated the effect of different time horizons on the cost-effectiveness of the model and concluded that cost-efficiency would increase over time. In the first year, implementation of the intervention was highly unlikely, but it was cost-effective for more than 10 years.²⁶ Philips et al applied a 20-year time horizon in all studies to consider the future implications of current decisions. Punekar et al employed a short-term horizon at 5-year intervals according to the mean period of first-line ART in China, and Zheng et al employed multiple time horizons.

Discount rate selection significantly impacts the outcomes of economic evaluations of health interventions and policies.²⁷ Almost all studies applied the same discount rate for costs and health outcomes, which was 3%, following the general discount rate in global health.²⁷ There is a distinction in the discount Punekar et al use to comply with China’s inflation index, which was 2.3%.

Outcome Summary

Implementing DTG, tenofovir, and lamivudine was cost-effective and cost-saving (see Table 4). The substitution of DTG with EFV in sub-Saharan Africa would likely impact public health owing to its efficacy, lower risk of side effects, and cost-effectiveness.^20,21,23 Phillips et al conducted a study in 2018 to describe the pretreatment HIV drug resistance of NNRTIs and provided a treatment option.

Table 4 Research Outcome

Over the 20 years, the results showed that 50,669 net DALYs were averaged for first-line DTG for all ART initiators, which was higher than that of the comparator.²⁰ Phillips et al continued those studies in 2019. They found that DTG-based regimens were the most cost-effective in 83% of setting scenarios, with net DALYs averted per year ranging from 30,000 to 85,000 compared with tenofovir, lamivudine, and EFV from a healthcare perspective. The last study was conducted by Phillips et al in 2020 to update the assessment of the risks and benefits of DTG-based regimens. In women planning pregnancy, initiation of tenofovir, lamivudine, and DTG averted more DALYs (83%), was cost-effective (87%), and showed net DALYs averted per year of 16,735.

According to Zheng et al DTG in combination with tenofovir and lamivudine is more cost-effective than the standard of care for HIV in India, with an ICER of $130/year of life-saved (YLS), which is less than 50% of India’s annual Gross Domestic Product (GDP). A study in China by Punekar et al showed that incremental cost-effectiveness analyses of DTG plus tenofovir and lamivudine resulted in 0.006 incremental QALYs with cost savings of RMB 467 compared with EFV plus tenofovir and lamivudine. The report provided ART costs in Renminbi (RMB), the People’s Republic of China’s official currency.²² Another result of the study was that compared to ritonavir-boosted lopinavir (LPV/r) in first-line failure, LPV/r had higher QALYs (4.224 vs 4.221) and a lower cost (RMB 238,746 vs RMB 244,364); thus, DTG in combination with tenofovir plus lamivudine dominated in both settings.

Sensitivity Analyses

Each study conducted a sensitivity analysis, and the types of sensitivity analyses applied were one-way, multiway, and probabilistic sensitivity analyses. Sensitivity analysis helps measure and evaluates the uncertainty of economic evaluation outcomes.^28,29 All models considered several critical parameters, such as clinical efficacy, prevalence of adverse events, cost, and utility varying within plausible ranges in the sensitivity analysis.^19–23 Zheng et al found two most essential parameters in one-way sensitivity analysis: the annual cost of the DTG regimen and the monthly probability of late virologic failure. Afterward, they conducted a multiway sensitivity analysis, simultaneously varying the annual cost of DTG and the monthly probability of virologic failure after 48 weeks on DTG, which remained cost-effective compared to standard of care (SoC). Regimen costing less than $102 per person per year was cost-effective, with an ICER less than 50% of per capita GDP. Despite costing more than twice that of SoC ($200), DTG is cost-effective with an ICER of less than 50% of GDP, as long as the late virologic failure probability is less than 0.21% per month. Punekar et al assessed the model’s robustness with multiple one-way deterministic sensitivity analyses by varying CD4+, adverse event prevalence, cost, and utilities combined with probabilistic sensitivity analyses to estimate the impact of these parameters. A one-way sensitivity analysis showed that improving CD4 and cost are critical drivers for cost-effectiveness and indicated that the cost-effectiveness of the DTG regimen was 98.2% in treatment-naive HIV.

Table 5 presents the quality evaluation results of the included CEAs using the CHEERS checklist. According to quality appraisal, the reporting quality varied from 84.6% to 94.2%. About 17 of 28 items were the most compliant with the CHEERS checklist (100%). Some studies needed to meet a few items in the CHEERS checklist, such as the characterizing heterogeneity and distributional effects as an approach to engage with patients and others affected by the study. Details on the CHEERS checklist criteria are provided in Supplementary Table S1.

Table 5 Quality Appraisal of Included Studies

Discussion

In 2021, the global HIV program was making decisions regarding new antiretroviral therapy (ART) regimens with fewer side effects and higher resistance barriers, which may improve adherence and viral suppression.¹⁴ A fixed-dose combination of DTG, lamivudine, and tenofovir was available for over 18 million adults and 100,000 children in 60 countries, as reported in 2022.³⁰ Affordable antiretrovirals have played a significant role in increasing global antiretroviral therapy coverage.³¹

Research articles have been conducted in several countries to compare people living with HIV using a DTG-based regimen to a tenofovir-based regimen as therapy to assess its cost-effectiveness from a public health perspective. Based on the results of this review, the use of DTG in combination with tenofovir and lamivudine may be more effective for viral suppression in the treatment of HIV, and the transition to the DTG regimen was more cost-effective than first-line HIV therapy with tenofovir. Three studies were performed in sub-Saharan Africa, one of which was in India and China, where HIV prevalence was the highest in sub-Saharan Africa and India.³² The WHO reported the situation and trends in 2022: the global number of people living with HIV was 39.0 million; the number of people living with HIV in the African Region and India was 25.6 and 2.5 million, respectively.³³

The modelling method was used to assess the cost-effectiveness of the antiretroviral HIV policy. The outcomes of each study were distinct, but they all point to the same conclusion. Net costs, health benefits expressed as life-years or QALYs gained, and ICERS are the most common outcomes.³⁴ The CEA method used ICER/YLS, which defines the net cost per unit of benefit gained from intervention per year saved by using the DTG regimen.¹⁹ DALY is a measure of the overall disease burden, expressed as the number of healthy years of life lost due to illness, disability, or early death. The net DALY is calculated as the sum of DALYs plus the ratio of costs to the cost-effectiveness threshold.²⁰ The viral suppression rate is higher than the EFV-based regimen (>75%).^19–23

Even though this study is the first systematic review on the cost-effectiveness of DTG in combination with tenofovir and lamivudine for HIV therapy, it has several limitations. This study focused on specific interventions within specific patient characteristics that might lead to clinical variation in heterogeneity. Although an exhaustive search was performed, not all relevant studies were included. A search strategy that uses these terms results in irrelevant references. No additional relevant data in the search results discussed the cost-effectiveness of fixed-dose DTG with tenofovir and lamivudine in other countries. Nonetheless, policymakers in LMICs and high-income countries should consider using alternative therapies because of their cost-effectiveness. A DTG-based regimen is recommended as the preferred drug in antiretroviral initiators because of its population health benefits and cost-effectiveness, which aligns with the WHO recommendation. Overall, the reporting quality of the included studies varied from 84.6% to 94.2%, showing all the excellent quality.

Conclusion

This systematic review showed that the transition to HIV treatment using a combination of DTG, tenofovir, and lamivudine in several countries was potentially cost-effective or cost-saving because it can reduce the population burden of diseases. Since the HIV therapy guideline is a living document, further study is required when the guideline has been updated.