|Year : 2020 | Volume
| Issue : 5 | Page : 32-38
Cost-Effectiveness of antiretroviral therapy: A systematic review
Indrani Gupta1, Damini Singh2
1 Professor, Health Policy Research Unit, Institute of Economic Growth, University of Delhi, Delhi, India
2 Ph.D Fellow, Centre for Economic Studies and Planning, Jawaharlal Nehru University, Delhi, India
|Date of Submission||16-Nov-2019|
|Date of Decision||27-Feb-2020|
|Date of Acceptance||04-Mar-2020|
|Date of Web Publication||14-Apr-2020|
Prof. Indrani Gupta
Institute of Economic Growth, University Enclave, University of Delhi (North Campus), Delhi - 110 007
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: The mobilization of resources to prevent and treat human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) is unparalleled in the history of public health. The uptake of antiretroviral therapy (ART) has been rapid and unprecedented and made possible by the availability of funding – external and domestic. To justify continuous funding of ART in resource-scarce settings, a spate of cost-effectiveness studies has been undertaken in a number of countries. This paper is based on a systematic review of global studies on cost-effectiveness analysis of ART. Objectives: The major objective was to review the existing literature on cost-effectiveness of ART to determine whether ART has been cost-effective (CE) in different settings. Methods: We searched PubMed and Google Scholar for articles published between 2008 and 2017. We included studies that measured costs as well as effectiveness of HIV treatment – specifically ART – using incremental cost-effectiveness ratio as one of the outcomes. Results: We identified 15 studies that met the search criteria for inclusion in the systematic review. The review confirms that ART programs have been CE across different settings, contexts, and strategies. Conclusion: The review would be useful for countries that are straining to raise funds for the health sector, generally, and for AIDS prevention and control program, specifically. This would also be beneficial for carrying out similar studies, if necessary, and as an advocacy tool for garnering additional funding.
Keywords: Antiretroviral treatment, cost-effectiveness, human immunodeficiency virus
|How to cite this article:|
Gupta I, Singh D. Cost-Effectiveness of antiretroviral therapy: A systematic review. Indian J Public Health 2020;64, Suppl S1:32-8
|How to cite this URL:|
Gupta I, Singh D. Cost-Effectiveness of antiretroviral therapy: A systematic review. Indian J Public Health [serial online] 2020 [cited 2021 Sep 18];64, Suppl S1:32-8. Available from: https://www.ijph.in/text.asp?2020/64/5/32/282422
| Introduction|| |
Funding for human immunodeficiency virus (HIV) prevention and treatment continues to be critical in many developing countries. The United Nations Program on HIV/acquired immunodeficiency syndrome (AIDS) analysis on resource availability indicates that the international resources for HIV peaked in 2013 but subsequently stabilized. Countries have now been depending mostly on domestic resources; 57% of total resources available in low- and middle-income countries in 2016 came from domestic resources. However, the resources to combat HIV are grappling against competing and equally important priorities in the health sector, and countries have to increasingly depend on sound evaluation techniques to justify and allocate resources among competing uses.
It is estimated that to reduce HIV incidence by 90% relative to the 2010 level, a more than three-fold increase of the current annual funds will be necessary globally until 2030, with scaling up treatment, prevention, and targeting key populations being the major priorities.
The reduced cost of antiretroviral drugs has paved the way for an increased accessibility of antiretroviral therapy (ART) in the developing countries, with the focus of funding shifting from prevention to treatment of HIV/AIDS. The current global target, agreed to by the United Nations General Assembly in June 2016, is for 30 million people living with HIV to have access to the treatment by 2020. The investment of financial as well as human capital, along with advances in clinical research and treatment regimens, has resulted in increased effectiveness of ART and moved the world toward the goal of “90-90-90” treatment by 2020: 90% of people living with HIV should know their HIV status, 90% of such people have access to treatment, and 90% of people being treated have suppressed viral loads.
The uptake of ART globally has been rapid and unprecedented and made possible by availability of funding, especially from the Global Fund to Fight AIDS, tuberculosis (TB), and Malaria. The progress in terms of global provision of ART was the largest in the world's most affected regions, i.e., Eastern and Southern Africa. The improvement in the provision of HIV treatment has led to a 26% decline in AIDS-related deaths globally, from an estimated 1.5 million in 2010 to 1.1 million in 2015.
Some argue that the rapid increase in spending on HIV treatment has led to a decline in funding for other prevention services, indicating (a) an urgency to increase total funding for health globally and at national level; (b) an urgency to base resource allocation decisions on sound evidence.
To justify continuous funding of ART in resource-scarce settings, a spate of cost-effectiveness studies has been undertaken in a number of countries based on varied methodologies and across different contexts. Such studies can help in setting priorities and garnering continuous funding for programs, such as ART.
In this article, we attempted to do a systematic review of global studies on cost-effectiveness analysis (CEA) of ART. The main objective is to see whether ART has been cost-effective (CE) in different settings. This review would be useful as an advocacy tool for developing countries that have launched free ART programs and would like to see funding expanded to scale up and sustain such programs. Similar studies can also be undertaken in countries that need evidence of effectiveness of ART programs and can compare methodologies and results with the studies reviewed in this paper.
| Materials and Methods|| |
The review was done by searching PubMed databases and Google Scholar, using the following keywords: ART, antiretroviral treatment, HIV treatment, HIV care, and support, each in combination with the term cost-effectiveness. The search was restricted to the period 2008–2017.
We followed two stages of inclusion in our review. First, we included any study that met all these three criteria: (i) it measured costs as well as effectiveness, (ii) it was related to HIV treatment, specifically ART, and (iii) it used standard methods for the estimation of cost and effectiveness.
Second, studies that met these inclusion criteria were excluded if (a) they were related to gene or drug-specific cost-effectiveness of ART, (b) they had estimated the cost of an intervention based on data earlier than 2008, (c) they were systematic reviews, (d) CEA was linked with any opportunistic infection, except TB, and (e) they were not published in the English language.
For the target population, we did not define specific exclusion criteria. Even if a study was restricted to a particular type of population but dealt with the cost-effectiveness of ART, we included it in our review.
For interventions/prognostic factor/exposure, we included those studies that specifically tested the intervention in the form of treatment, i.e., ART. If the studies were found to be related to cost-effectiveness of HIV screening or monitoring or HIV testing, they were excluded from the review. Studies covering only aspects related to HIV prevention were not included. For example, studies on the cost-effectiveness of HIV preprophylaxis or prevention of mother-to-child transmission were excluded.
In defining the criteria for the alternative to which the intervention was being compared, studies that compared ART intervention to no ART, or expansion of ART or early versus delayed ART, were included. Studies that compared specific drugs as alternatives were excluded.
For the types of outcomes, we included only those studies that used incremental cost-effectiveness ratio (ICER) as one of the outcomes.
The number of records that were identified with the use of the search criteria yielded 2819 studies. The EndNote software, produced by Clarivate Analytics(Headquarters-Philadelphia, United States), was used to remove the duplicates. After the removal of duplicates (n = 1245), 1434 studies were excluded using the inclusion/exclusion criteria. In total, 15 studies were found to be relevant which met the search criteria for inclusion in the systematic review. The PRISMA diagram [Figure 1] shows the stages of the systematic review.
A majority of the studies have used the ability-to-pay for goods and services to define the threshold below which an intervention is considered to be CE. If the ICER of an intervention is lower than the national annual gross domestic product (GDP) per capita, then it is considered to be very CE. If it costs less than three times the annual per capita GDP, then it is still considered to be CE. This is in accordance with the criteria given by the WHO-CHOICE project.
| Results|| |
[Table 1] presents the ICERs from the selected studies.
|Table 1: Incremental cost-effectiveness ratios of antiretroviral treatment programs based on a systematic review|
Click here to view
The results on ICER seem to indicate that ART has been very CE in all the countries. However, the target populations have differed widely, making comparisons a bit difficult. Below, we mention briefly each of these studies.
Using Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric Model with published and P1060 data, the authors analyzed the cost-effectiveness of ART by comparing two different medicines, namely lopinavir/ritonavir and nevirapine, for HIV-infected children aged <3 years in South Africa. Both ART regimens turned out to be very CE when compared to non-ART. The ICER of the first-line lopinavir/ritonavir compared to non-ART was calculated at $800/years of life saved (YLS). The ICER of the first-line nevirapine compared to non-ART was $930/YLS in the absence of first-line lopinavir/ritonavir.
Using the CEPAC-International Model, the cost-effectiveness of the third-line ART was examined in Côte d'Ivoire by comparing four types of intervention after a person fails the second-line treatment. The interventions included the following- to continue second-line ART (C-ART2); C-ART2 with an adherence reinforcement intervention (AR-ART2); immediate switch to third-line ART (IS-ART3); and C-ART2 with AR, switching patients with persistent failure to ART3 (AR-ART3). It was found that when compared to C-ART2, AR-ART2 has an ICER of $1100/YLS and AR-ART3 had an ICER of $3600/YLS when compared to AR-ART2.
With the help of CEPAC-US model, cost-effectiveness of three long-acting ART (LA-ART) strategies was compared to daily oral ART. The authors also reported the maximum annual cost at which each LA-ART strategy reaches an ICER of ≤$100,000/quality-adjusted life year (QALY), which is taken to be a measure of the willingness-to-pay threshold. LA-ART, after multiple failures, becomes CE at an annual drug cost of $48,000. At the cost of ≤$48,000/patient-year, the mean lifetime cost amounted to $400,000 for LA-ART after multiple failures, $469,000 for second-line LA-ART, and $624,000 for first-line LA-ART. Taking into account these three mean lifetime costs, the ICER ($/QALY) was calculated at $100,000, $3,399,000, and $4,184,000, respectively.
The CE of the Rapid Initiation of ART in Pregnancy (RAP) Program in South Africa was evaluated, which comprised a package of interventions intended to accelerate the process of HIV diagnosis to initiate ART in pregnant women. The RAP services were seen to be highly CE with an ICER of US $1160 per QALY averted compared to the standard prevention of mother-to-child transmission services.
The CE of providing antiretroviral treatment was evaluated by comparing the cohorts taking treatment at standard public healthcare centers (Ministry of Health Program) to the cohorts taking treatment at public healthcare centers operated under the Disease Relief through Excellent and Advanced Means (DREAM) program. DREAM program comprised ART treatment with rigorous laboratory monitoring of patients through CD4 and viral load testing, counseling and education, and extensive use of information technology aimed to improve adherence. The study was based in Malawi and the authors used 2010 cost data to calculate the ICER. Following the Africa Region-E-WHO Regional GDP per capita threshold ($2154), the ICER was very CE at $1640 per disability-adjusted life year (DALY) saved. Thus, even when the DREAM program costs were 67% higher than the Malawi National Program, it was still CE in comparison to the Malawi National Program.
A study in China evaluated the cost-effectiveness of an intervention called “One4All,” by simulating HIV transmission and progression in Guangxi, China. The One4All intervention comprised counseling, rapid point-of-care HIV screening, CD4 and viral load testing, and same-day quick delivery of results. The One4All testing intervention was more expensive than the standard model of care, but by expediting the treatment, it created large gains in the effectiveness of the program. The ICER of “One4All” intervention was CNY 11,678 per QALY gained, highly CE by the WHO standards.
By comparing the early initiation of ART with delayed ART and using computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, the cost-effectiveness of early antiretroviral therapy (ART) in persons infected with HIV in serodiscordant couples was assessed in South Africa and India. The cost-effectiveness threshold was taken to be the annual per capita GDP of $8100 in South Africa and $1500 in India. Early ART – as compared to delayed ART – was cost-saving over a 5-year period in South Africa. However, in both countries, early ART turned out to be very CE over lifetime of individuals. Considering a period of lifetime, early ART was very CE with $590 per life-year saved in South Africa. In India, early ART was CE over a 5-year period with $1800 per life-year saved and very CE over a lifetime with $530 per life-year saved.
In a study done on four countries (South Africa, Zambia, India, and Vietnam), representing four different cases (generalized epidemic, moderate antiretroviral therapy coverage; generalized epidemic, high antiretroviral therapy coverage; concentrated epidemic, moderate antiretroviral therapy coverage; and concentrated epidemic, low antiretroviral therapy coverage), the cost-effectiveness of different eligibility criteria for adult antiretroviral therapy under standard and expanded treatment coverage was assessed for 20 years. Three eligibility criteria for ART initiation were examined: CD4 count of 350 cells/μL or less; CD4 count of 500 cells/μL or less; and all HIV-positive adults. The results indicated that earlier eligibility (higher CD4 count threshold) for ART was very CE in low- and middle-income settings. The ICERs for changing CD4 count threshold from 350 cells/μL to 500 cells/μL were $273–$1691 per DALY averted over 20 years (South Africa), $749 per DALY averted (Zambia), and $290 per DALY averted (Vietnam). ICERs for changing eligibility to all HIV-positive adults compared with eligibility for those with CD4 counts of 350 cells/μL or less were $438–$3790 per DALY averted (South Africa), $790 per DALY averted (Zambia), $289 per DALY averted (Vietnam), and $131–$241 per DALY averted (India).
To assess the CE of initiating combination ART at a CD4 count between 250 and 350 cell/μL (early) versus <250 cell/μL (delayed), a study was conducted in Uganda. Using the per capita GDP ($490) of Uganda as the threshold for defining cost-effectiveness, the results showed that the ICER, in terms of cost/DALY averted of the early versus delayed initiation of ART, ranged from $260 to $270.
A CE analysis of early versus standard ART was done in Haiti. The ICER over 3 years for early versus standard ART was US$3975/YLS, and US$2050/YLS if research-related tests are not included in the cost estimation. Thus, an early initiation of ART (with a CD4 cell count between 200 and 350 cells/mm3) was seen as CE.
To look at treatment expansion for HIV patients in Vietnam, three CD4 initiation thresholds (350 cells/mm3, 500 cells/mm3, and treat all people living with HIV, irrespective of CD4 cell counts, respectively) were assessed. Using a Markov Model, the results show that increasing the eligibility criteria for initiation of ART (with CD4 ≤ 500 cells/mm3 or no CD4-based criteria) was CE. Both strategies would result in ICERs of $500–$660 per QALY gained.
Using dynamic mathematical model of HIV transmission and disease progression, the cost-effectiveness of expanding ART to 75% for high-risk (injection drug users, men who have sex with men) and low-risk individuals in the age group 15–64 was measured in the U.S. This study found that expanding ART costs $20,300/QALY gained.
With the Progression and Transmission of HIV/AIDS Model, CE of increasing early linkage from 65% to 85% was estimated in the USA. Assuming that an intervention costing $100,000 or less per QALY gained was CE, the study calculated the ICER of increasing early linkage to care to be $62,200 per QALY gained considering only benefits to the first generation of HIV-infected persons (index persons). Approximately $5100 could be spent on early linkage for each HIV-diagnosed person in a CE way. The paper also concluded that the main source of variation in the cost-effectiveness values occurred due to variation in CD4 count at diagnosis.
An examination of the CE of immediate antiretroviral therapy (ART) of HIV-infected children under 24 months of age in nonbreastfed children was attempted in Thailand. Using a decision-analytic model of HIV diagnosis and disease progression, the authors compared early infant diagnosis (EID) using DNA polymerase chain reaction with immediate ART (Early-Early) and early infant HIV diagnosis (EID) with deferred ART based on immune/clinical criteria (Early-Late), with clinical/serology-based diagnosis and deferred ART (reference category). They found that the ICER of Early-Late and Early-Early strategies was $5149 and $2615, respectively, per life-year gained, as compared to the reference strategy. The Early-Early strategy was most CE.
Analyzing ART for TB patients in South Africa, it was found that if patients with CD4 counts <50 cells/mm3 were provided with an early initiation of ART, it led to significant benefits in terms of survival of the patients. The authors used the SAPiT trial and randomized 642 HIV-TB co-infected patients to three arms, either receiving ART within 4 weeks of starting TB treatment (early treatment arm; Arm-1), after the intensive phase of TB treatment (late treatment arm; Arm-2), or after completing TB treatment (sequential arm; Arm-3). The ICER in terms of cost per death averted in moving from sequential (Arm-3) to late-integrated treatment (Arm-2) amounted to $4199, which was below the per capita GDP of South Africa ($5758 at 2009 prices). Thus, late initiation of ART during TB treatment (Arm-2) was a CE strategy for TB patients.
| Discussion|| |
The systematic review of cost-effectiveness studies on ART was done with the main objective of assessing if ART programs have been CE globally. The studies were mainly country-focused, pertained to different periods, and compared the nominal ICERs to GDP per capita prevailing at the time of the study in these countries. To that extent, the results were not strictly comparable to each other, unless converted to values in a particular comparison year, using a common deflator. This can be viewed as a limitation, but since the aim was not to compare the values of ICERs but to assess whether a majority of the studies found ART to be CE, this was not a major drawback. Furthermore, there may be a possibility of selection bias if some eligible studies which were unpublished could not be included in the review.
The review indicated that irrespective of the country, target group, qualifying criteria for ART, and other parameters, ART strategies have been CE. While fewer studies evaluated entire ART programs, those that did–for example, China and Malawi–did find that the overall ART programs were very CE.
Other findings consistently indicated that strategies comprising early detection of HIV status and early initiation of treatment were always CE, irrespective of the particular strategy and group targeted. Thus, strategies targeting serodiscordant couples or pregnant mothers – if initiated early – are CE.
Moreover, lower the cost of the provision, better is the ICER, indicating the need for lowering the components of ART programs, especially spending on drugs and kits. Testing and counseling are integral part of the ART programs. It is important to note that with countries like India having moved to “test-and-treat” criterion for initiating ART, it is vital not only to maintain the current levels of funding but also to increase the total funding for AIDS control programs. In the same vein, finding ways to cut down on the programmatic costs of ART is also critical.
Developing countries, with low government finances for health, need similar estimates, to garner additional funding for ART. The ART program – once initiated – cannot be stopped or curtailed but needs continuous expansion to cover uncovered pockets. In the face of an unchanging health resource envelope, there is an urgent need to give evidence that the funds are being put to good use, to be able to garner more resources from national budgets or finance ministries of countries. While the effectiveness of ART is now widely accepted, hard evidence always helps in arguing a case, and this can be a good bargaining point for national AIDS control programs. It might also help allocate more resources to the health sector generally, which would help other disease priorities as well as health systems strengthening in developing countries.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Moher D, Liberati A, Tetzlaff J, Altman D. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.
Hutubessy R, Chisholm D, Edejer TT. Generalized cost-effectiveness analysis for national-level priority-setting in the health sector. Cost Eff Resour Alloc 2003;1:8.
Ciaranello AL, Doherty K, Penazzato M, Lindsey JC, Harrison L, Kelly K, et al
. Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age. AIDS 2015;29:1247-59.
Ouattara EN, Ross EL, Yazdanpanah Y, Wong AY, Robine M, Losina E, et al
. Clinical impact and cost-effectiveness of making third-line antiretroviral therapy available in Sub-Saharan Africa: A model-based analysis in Côte d'Ivoire. J Acquir Immune Defic Syndr 2014;66:294-302.
Ross EL, Weinstein MC, Schackman BR, Sax PE, Paltiel AD, Walensky RP, et al
. The clinical role and cost-effectiveness of long-acting antiretroviral therapy. Clin Infect Dis 2015;60:1102-10.
Zulliger R, Black S, Holtgrave DR, Ciaranello AL, Bekker LG, Myer L. Cost-effectiveness of a package of interventions for expedited antiretroviral therapy initiation during pregnancy in Cape Town, South Africa. AIDS Behav 2014;18:697-705.
Orlando S, Diamond S, Palombi L, Sundaram M, Shear Zimmer L, Marazzi MC, et al
. Cost-effectiveness and quality of care of a comprehensive ART program in Malawi. Medicine (Baltimore) 2016;95:e3610.
Zang X, Tang H, Min JE, Gu D, Montaner JS, Wu Z, et al
. Cost-effectiveness of the 'One4All' HIV linkage intervention in Guangxi Zhuang Autonomous Region, China. PLoS One 2016;11:e0167308.
Walensky RP, Ross EL, Kumarasamy N, Wood R, Noubary F, Paltiel AD, et al
. Cost-effectiveness of HIV treatment as prevention in serodiscordant couples. N Engl J Med 2013;369:1715-25.
Eaton JW, Menzies NA, Stover J, Cambiano V, Chindelevitch L, Cori A, et al
. Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: A combined analysis of 12 mathematical models. Lancet Glob Health 2014;2:e23-34.
Sempa J, Ssennono M, Kuznik A, Lamorde M, Sowinski S, Semeere A, et al
. Cost-effectiveness of early initiation of first-line combination antiretroviral therapy in Uganda. BMC Public Health 2012;12:736.
Koenig SP, Bang H, Severe P, Jean Juste MA, Ambroise A, Edwards A, et al
. Cost-effectiveness of early versus standard antiretroviral therapy in HIV-infected adults in Haiti. PLoS Med 2011;8:e1001095.
Tran DA, Wilson DP, Shakeshaft A, Ngo AD, Reyes J, Doran C, et al
. Cost-effectiveness of antiretroviral therapy expansion strategies in Vietnam. AIDS Patient Care STDS 2014;28:365-71.
Long EF, Brandeau ML, Owens DK. The cost-effectiveness and population outcomes of expanded HIV screening and antiretroviral treatment in the United States. Ann Intern Med 2010;153:778-89.
Gopalappa C, Farnham PG, Hutchinson AB, Sansom SL. Cost effectiveness of the National HIV/AIDS Strategy goal of increasing linkage to care for HIV-infected persons. J Acquir Immune Defic Syndr 2012;61:99-105.
Collins IJ, Cairns J, Ngo-Giang-Huong N, Sirirungsi W, Leechanachai P, Le Coeur S, et al
. Cost-effectiveness of early infant HIV diagnosis of HIV-exposed infants and immediate antiretroviral therapy in HIV-infected children under 24 months in Thailand. PLoS One 2014;9:e91004.
Naidoo K, Grobler AC, Deghaye N, Reddy T, Gengiah S, Gray A, et al
. Cost-effectiveness of initiating antiretroviral therapy at different points in TB treatment in HIV-TB co-infected ambulatory patients in South Africa. J AIDS (1999) 2015;69:576.