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Cost-Effectiveness of Dolutegravir as a First-Line Treatment Option in the HIV-1–Infected Treatment-Naive Patients in Russia
VALUE IN HEALTH REGIONAL ISSUES 16 (2018) 1−7
Available online at www.sciencedirect.com
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Cost Effectiveness of Dolutegravir as a First-Line Treatment Option in the HIV-1−Infected Treatment-Naive Patients in Russia 1 2 3 D1XGabriel X Tremblay, PhD D2X X , Vasiliki D3X X Chounta, MSc D4X X , James D5X X Piercy, MSc D6X X , Tim D7X X Holbrook, BSc D8X X 3, 1 4 2 D9X X Shan Ashton Garib, MA D10X X , Evgeny D1X X K. Bukin, MD D12X X , Yogesh D13X X Suresh Punekar, PhD D14X X * 1 Purple Squirrel Economics, New York, NY, USA; 2ViiV Healthcare, Brentford, Middlesex, UK; 3Adelphi Real World, Bollington, Cheshire, UK; 4ViiV Healthcare, Moscow, Russia
ABSTRACT
Objectives: To evaluate the cost effectiveness of dolutegravir + abacavir/lamivudine (DTG + ABC/3TC) compared with raltegravir + abacavir/ lamivudine (RAL + ABC/3TC) and ritonavir-boosted darunavir + abacavir/lamivudine (DRV/r + ABC/3TC) in HIV-1−infected treatment-naive patients in Russia. Methods: A dynamic Markov model was developed with five response states and six CD4+-based health states. Efficacy estimated as probability of viral suppression (HIV RNA <50 copies/ml) at 48 weeks was obtained from a published network meta-analysis. Baseline cohort characteristics and health state utilities were informed using DTG phase 3 clinical trials. Health care resource use was obtained from literature and costed using published unit costs. Costs (presented in Russian rubles) included antiretroviral drug costs; HIV management costs such as routine care; costs of treating cardiovascular conditions, opportunistic infections, and drug-related adverse effects; and mortality costs. A patient lifetime analysis was conducted using the societal perspective. Outcomes were quality-adjusted life-years (QALYs), life-years, incremental cost per QALY ratio, and incremental cost
Introduction Among the countries of Eastern Europe and Central Asia, Russia has the largest number of HIV-1 infection diagnoses, with an estimated 103,438 new HIV diagnoses in 2016 [1,2]. This group of newly diagnosed patients with HIV is growing at a rate of 10% each year [1]. Despite such a large number of patients living with HIV, just over a third (37.3%) had access to antiretroviral therapy (ART) in 2015, with lack of adequate funding for diagnosis and treatment being a major barrier [1]. In Russia, HIV treatment and prevention initiatives are funded by central and regional governments, with limited contribution from local and international charitable institutions. Care is delivered through HIV-specific
per responder. Results: The viral suppression rate among patients receiving DTG + ABC/3TC was 71.7% compared with 65.2% for RAL + ABC/3TC and 59.6% for DRV/r + ABC/3TC. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/r + ABC/3TC. Total discounted costs for treatment over patient lifetime were RUB 2.89, 5.32, and 4.38 million for DTG + ABC/3TC, RAL + ABC/3TC, and DRV/r + ABC/3TC, respectively. Lifetime discounted QALYs were 12.73 for patients on DTG + ABC/3TC and 12.72 each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. DTG + ABC/3TC thus dominated the other two alternatives. Conclusions: With lower costs, higher response rates, and comparable QALYs, DTG + ABC/3TC can be considered as a cost-effective alternative. Key words: cost effectiveness, dolutegravir, economic analyses, HIV, Russia. Ó 2018 Published by Elsevier Inc. on behalf of ISPOR–The professional society for health economics and outcomes research..
centers, which are responsible for clinical research, monitoring and testing, HIV treatment, and counseling. In 2016, the Russian government announced a strategy to combat the spread of HIV by improving access to ART, which was one of its strategic initiatives [1]. Nevertheless, inadequate funding has remained a challenge. Despite increasing state funding for HIV treatment and prevention over the last few years, the 2016 funding of $325 million was estimated to cover only a fifth of the target population [3]. Therefore, access to effective and cost-saving ART remains an important priority to achieve Russia’s strategic objective of reducing AIDS-related deaths by 2020. ART usually comprises three antiretroviral agents, two nucleoside reverse transcriptase inhibitors, commonly referred to as
Conflicts of interest: Y. S. Punekar and V. Chounta are employees of ViiV Healthcare and hold stocks in the company. E. K. Bukin was an employee of ViiV Healthcare at the time of this study and holds stocks in the company. G. Tremblay and S. A. Garib are employees of Purple Squirrel Economics and received payment from ViiV Healthcare for consultancy during the conduct of this study. J. Piercy and T. Holbrook are employees of Adelphi Real World and received payment from ViiV Healthcare for consultancy during the conduct of this study. * Address correspondence to: Yogesh Suresh Punekar, ViiV Healthcare, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. E-mail: [email protected]. 2212-1099/$36.00 – see front matter Ó 2018 Published by Elsevier Inc. on behalf of ISPOR–The professional society for health economics and outcomes research. https://doi.org/10.1016/j.vhri.2018.08.001
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backbone, and a third agent, often referred to as a core agent, from a different antiretroviral class. In Russia, current core agents used in treatment-naive patients include non−nucleoside reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors (INIs) including ritonavir-boosted darunavir (DRV/r) and raltegravir (RAL) [4]. Dolutegravir (DTG) is a second-generation INI with a higher barrier to resistance, which received regulatory approval in Russia in 2014. In its phase 3 clinical program among HIV-1−infected treatment-naive patients, DTG has demonstrated superiority to DRV/r and noninferiority to RAL, two commonly used ARTs in Russia [5−7]. With the introduction of DTG, the objective of this analysis was to assess the cost effectiveness of DTG + backbone compared with RAL + backbone and DRV/ r + backbone for HIV-1−infected treatment-naive patients.
Methods Model Design A cost-effectiveness model was developed to estimate the clinical outcomes and costs of DTG + backbone compared with other core agents used in Russia with a societal perspective. DRV/r and RAL, the core agents most likely to be displaced by DTG, were selected as comparators. The model framework was a dynamic Markov model (also called a semi-Markov model) with a series of disease health states along with transition probabilities for each state that characterize
disease progression. The cycle length used in the model was 1 month and the overall time horizon was patient lifetime.
Model response states and health states Patients in the model transitioned between the five response states. Responder states modeled included responder maintaining ART; nonresponder maintaining ART; discontinuation due to failure; discontinuation due to other reasons such as intolerance, toxicity, poor adherence, or simplification; and death. Responders, defined as proportion of patients achieving viral suppression (HIV-1 RNA <50 copies/ml), maintained their ART. Nonresponders were allowed to remain on ART for a period of 6 months, consistent with the real-world treatment practice in Russia. Each patient was classified into one of these response states estimated using network meta-analysis (NMA) by Patel et al. [8]. Patients in each response state, except death, were further divided into CD4+-based health states (Fig. 1). Each patient’s CD4+ level was determined by the treatment used, the time on treatment, and the responder status. Responders were estimated to have higher CD4+ levels compared with nonresponders. Among responders, some treatments were estimated to have better CD4+ efficacy on the basis of NMA [8]. In addition, the time on treatment was also a key driver for the increase in CD4+ levels because the model assumed a linear increase until patients reached the trial efficacy at weeks 48 and 96, after which the CD4+ levels were expected to decrease [9]. Patients discontinuing their treatment were assumed to go back to their baseline CD4+ levels. This was a conservative assumption used to illustrate no incremental treatment effect after treatment withdrawal [10].
Fig. 1 – Model figure. AE, adverse event; ART, antiretroviral therapy.
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Model parameters The patient population used in the model was HIV-infected treatment-naive patients, similar to those who participated in the DTG phase 3 trials [5,7,11,12] and further presented in the NMA [8]. The analysis compared three treatment regimens. These were DTG added to abacavir/lamivudine (DTG + ABC/3TC), RAL added to abacavir/lamivudine (RAL + ABC/3TC), and DRV/r added to abacavir/lamivudine (DRV/r + ABC/3TC). These regimens were selected to represent commonly used alternatives and were perceived to be the most efficacious treatment alternatives in Russia [4]. ABC/3TC was used to represent common backbone across all three interventions because of its high usage in clinical practice in Russia. Because each of these regimens can be prescribed as two tablets (backbone + core agent) or three tablets (three medications separately), 64% of all patients were assumed to receive a backbone plus a core agent (i.e., two tablets). Patients discontinuing the DTG + ABC/3TC arm because of ART failure were assumed to switch to DRV/r + ABC/3TC, whereas those discontinuing for other reasons were assumed to switch to DRV/r + zidovudine (ZDV)/3TC. Corresponding treatment switches from the RAL + ABC/3TC arm were DRV/r + tenofovir (TDF)/3TC and efavirenz + ABC/3TC, and from the DRV/r + ABC/3TC arm were RAL + ABC/3TC and RAL + ZDV/3TC. The meta-analysis by Patel et al. [8] did not report specific efficacy estimates for ZDV/3TC or TDF/3TC backbones. Therefore, we used efficacy and CD4+ change reported for “other backbone” to represent these.
from a US observational study that showed that the increase after 4 years after ART initiation was relatively flat [12]. Ninetysix weeks after failing the last ART, patients will experience a decline in CD4+ cell count on the basis of links reported by Mauskopf et al. between viral load [9] and CD4+ cell count data from the multicenter AIDS cohort study [13]. The transition probabilities used in the model are presented in Table 1. Note that the discontinuation rates were derived from pooled data from phase 3 studies and were assumed to be identical for all comparator treatments.
Safety and tolerability Patients experiencing treatment-related adverse events (AEs) were assumed to experience a quality-of-life decrement and additional costs associated with that event. Those experiencing grade 2 to grade 4 AEs were assumed to switch to the next treatment and the associated transition probabilities were derived from the NMA [8]. Discontinuations due to AEs were assumed to occur in the first month of treatment (using discontinuation rate at week 48) and were derived from pooled data from DTG phase 3 studies. As a result, a common discontinuation rate was assumed across all comparator treatments. No a priori relationship was assumed between AEs such that a patient could potentially experience several AEs simultaneously. In such instances, the costs and utility decrements were assumed to be additive.
Comorbidities
Efficacy and transition probabilities Transition probabilities were estimated on the basis of a published NMA [8]. In this meta-analysis, authors included 31 phase 3 or 4 randomized controlled trials including 17,000 patients to estimate relative efficacy and safety of DTG compared with guideline-recommended core agents. They used Bayesian fixedeffect NMA models adjusting for the backbone to evaluate 48week viral suppression and changes in the CD4+ cell count in DTG and its comparators. The overall results showed DTG to be comparable with other INIs and superior to all other core agents. The study also reported no significant efficacy difference between all the available ART backbones. For transition probabilities beyond 48 weeks, changes in CD4+ cell count are based on pooled patient-level data of all the DTG trials [5,7,11,12]. The model assumes the same CD4+ cell count increase rate after 22 months for those suppressed on any regimen, although CD4+ cell count increase differs between treatment regimens. This assumption is consistent with the findings
Cardiovascular disease (CVD) is a common comorbidity among patients with HIV, which is also affected by the patients’ ART. The risk of developing CVD was estimated in each model cycle on the basis of published literature [14]. The risk of occurrence of acute opportunistic infections (AOIs) was dependent on the history of that specific opportunistic infection (OI), patient’s CD4+ cell count, and the time on and response status of the treatment. It was also estimated from literature [15]. Five types of OIs including bacterial, fungal, protozoal, viral, and other infections were considered.
Mortality Mortality included death due to HIV, AOI, CVD, or natural causes. HIV mortality was estimated on the basis of CD4+ cell count and a history of any OI. AOI mortality was estimated on the basis of frequency and severity of AOIs observed in relation to CD4+ cell counts [13]. Mortality rates used in the model are presented in
Table 1 – Model transition probabilities [8]. Parameters
Timeframe
DTG
DRV/r
RAL
Viral suppression
First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22
15.7% 0.2% 0.0% 0.46% 0.10% 0.05% 0.55% 0.12% 0.06% 1.03% 0.23% 0.10% 21.75 2.51 ¡2.32
11.5% 0.1% 0.0% 0.86% 0.06% 0.06% 0.62% 0.04% 0.04% 1.54% 0.10% 0.10% 16.85 0.56 ¡2.32
14.1% 0.0% 0.0% 0.86% 0.06% 0.06% 0.62% 0.04% 0.04% 1.54% 0.10% 0.10% 21.13 0.54 ¡2.32
Discontinuation due to failure (first-line)
Discontinuation with other cause (first-line)
Discontinuation (second-line plus)
CD4+ increase
DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; RAL, raltegravir.
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Table 2 – Health state−based utilities and costs used in the model. Health states Parameters
>500
350−500
200−350
100−200
50−100
0−50
Utilities Costs Routine care (in RUB) [22] Outpatient care Inpatient care AOI (in RUB) [15,23] Bacterial Fungal Protozoal Viral OI prophylaxis [24] PJP MAC Cardiovascular event [20−22] Indirect costs [25,26]
0.896
0.899
0.886
0.861
0.843
0.822
130 1,448 151 34 32 18 67
153 1,874 87 28 5 5 50
153 1,871 123 39 19 9 55
200 4,263 521 146 121 32 222
318 16,921 521 146 121 32 222
318 16,696 1,333 473 274 115 471
0 0 72 0
0 0 92 2,149
0 0 114 1,445
185 0 114 8,390
185 5,022 114 8,390
185 5,022 114 8,390
AOI, acute opportunistic infection; MAC, mycobacterium avium complex; OI, opportunistic infection; PJP, pneumocystis jiroveci pneumonia.
Appendix Table 1 in Supplemental Materials found at 10.1016/j. vhri.2018.08.001.
Utilities Health state−based utilities were derived from phase 3 studies of DTG trials and are presented in Table 2 [5,7,11,12]. Disutilities associated with AOIs were obtained from literature and were ¡0.328 for bacterial, protozoal, and other OIs and ¡0.237 for fungal and viral OIs [16]. Disutility associated with presence of CVD (¡0.098) was also obtained from published sources [17]. Disutilities were also applied for grade 2 to grade 4 AEs for the duration of the AE and are presented in Appendix Table 2 in Supplemental Materials found at 10.1016/j.vhri.2018.08.001 [18].
Costs ART costs ART costs were obtained in February 2017 from the Cursor tender database and the official Web site of the Unified Information Procurement System in Russia and are presented in Russian rubles (RUB) [19]. The monthly treatment costs of core agents were RUB 9,909 for DTG, RUB 30,940 for RAL, and RUB 15,502 for DRV/r. The monthly backbone costs were RUB 1,337 for ABC + 3TC and RUB 710 for both ZDV + 3TC and TDF + 3TC. The backbone costs were calculated as a weighted average price between single tablet and two tablets on the basis of market shares.
HIV management costs Costs associated with routine care, testing for ARTs, treatment of AOI, prophylaxis for opportunistic infections, and management of drug-related AEs were included (Table 2). Costs associated with management of frequent comorbidities such as CVD were also included. These were estimated using the prevalence of CVD among patients with HIV in Russia and associated health care resource use [20−22]. Costs of routine care included outpatient physician visits and inpatient HIV-related hospitalizations. All costs were estimated by health state on the basis of estimated resource use obtained from literature and are presented in Table 2 [22]. Diagnostic costs such as ultrasound (RUB 114), blood/transaminase test (RUB 79),
coagulation test (RUB 36), stool culture (RUB 762), fasting insulin (RUB 680), and glycemic curve (RUB 765) were included as baseline costs [23]. The costs of bacterial, fungal, protozoal, and viral AOIs were included in the HIV management costs. The monthly prevalence of each type of AOI for patients in each health state was obtained from literature [15] and costed using Russia-specific costs [23]. Two types of prophylaxis for opportunistic infections, pneumocystis jiroveci pneumonia and mycobacterium avium complex, were included in the HIV management costs [24]. A 1-month treatment with trimethoprim sulfamethoxazole 160/800 for pneumocystis jiroveci pneumonia and a 1-month treatment with azithromycin for mycobacterium avium complex were assumed and were costed using weighted prevalence by health states (Table 2). AE costs were derived using physician opinion and included costs associated with medication for AEs and use of health care resources such as physician visits or hospitalization (see Appendix Table 2 in Supplemental Materials).
Indirect costs The analysis was conducted using the societal perspective and thus indirect costs comprising productivity losses were included in the model. Productivity losses were estimated from literature [25]. In this study, authors used a socioeconomic survey based on the World Bank Living Standards Measurement Survey to capture information on lost working days and establish a link between CD4+ cell counts and loss of productivity. The productivity costs were then estimated using information on the national wages in Russia [26]. A scenario analysis excluding the productivity costs was also conducted. Considering the chronic nature of disease, a lifetime horizon was adopted. Both direct and indirect health care costs were included, and costs and benefits were discounted at 3.5% per year [27]. All costs are reported in Russian rubles and inflated using the consumer price index in Russia to 2017 values.
Model Validation The treatment pathway depicted in the model was compared with the World Health Organization HIV guideline to ensure consistency in the patient pathways. The model was internally
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validated by another expert not involved in the original model modeling to ensure accuracy and fit. This was further confirmed by co-authors who were modeling experts.
Economic Analyses The incremental efficacy in quality-adjusted life-years (QALYs) and incremental costs of DTG + ABC/3TC were compared separately with those of RAL + ABC/3TC and DRV/r + ABC/3TC. The incremental cost-effectiveness ratio (ICER) of DTG + ABC/3TC compared with those of RAL+ABC/3TC and DRV/r+ABC/3TC was calculated separately and reported as cost per responder and cost per QALY. Model robustness was assessed with multiple one-way deterministic sensitivity analyses by varying key parameters through plausible ranges of §20%, which was set arbitrarily. Parameters varied were CD4+ efficacy, AE prevalence, costs, and utilities. Probabilistic sensitivity analyses (PSAs) were conducted to assess uncertainty around several parameters simultaneously. Parameters included in the PSAs and their corresponding distribution and SDs are presented in Appendix Table 3 in Supplemental Materials found at 10.1016/j.vhri.2018.08.001.
Results The mean age of the patient cohort used in the model was 37 years, and 15% of patients were females. At baseline, approximately a third of patients were in CD4+ health states of 200 to 350 (35.6%) and 350 to 500 (31.6%). The CD4+ health state distribution for the remainder of the patients was 0 to 50 (2.3%), 50 to 100 (2.6%), 100 to 200 (7.7%), and more than 500 (20.1%). The base-case model predicted 71.7% patients on DTG + ABC/3TC, 65.2% on RAL + ABC/3TC, and 59.6% on DRV/ r + ABC/3TC to achieve and maintain viral suppression. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/ r + ABC/3TC. This resulted in 12.73 QALYs for patients on DTG + ABC/3TC and 12.72 QALYs each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. The total costs of HIV
treatment per patient over lifetime were RUB 2.89 million for DTG + ABC/3TC, RUB 5.32 million for RAL + ABC/3TC, and RUB 4.38 million for DRV/r + ABC/3TC. The incremental cost-effectiveness analyses showed DTG + ABC/3TC resulting in 0.01 incremental QALYs compared with RAL + ABC/3TC and DRV/ r + ABC/3TC, with cost savings of RUB 2.43 million compared with RAL + ABC/3TC and RUB 1.49 million compared with DRV/ r + ABC/3TC. DTG + ABC/3TC thus dominated the other two treatment alternatives. Detailed costs and outcomes with resultant ICERs are presented in Table 3. One-way sensitivity analyses suggested that changes in CD4+ cell counts and utility levels of health states were key drivers of cost-effectiveness results (see Appendix Figure 1 in Supplemental Materials found at 10.1016/j.vhri.2018.08.001). PSAs showed that the probability of DTG + ABC/3TC being cost-effective compared with both alternatives was 100% at a willingness-to-pay threshold as low as RUB 315,000/QALY (Figs. 2A and 2B) [28].
Discussion This analysis evaluated the cost effectiveness of DTG + ABC/ 3TC compared with RAL + ABC/3TC and DRV/r + ABC/3TC among HIV-1−infected treatment-naive patients in Russia. The model predicted more patients treated with DTG + ABC/ 3TC to achieve viral suppression and thereby more QALYs at lower costs compared with both RAL + ABC/3TC and DRV/ r + ABC/3TC. Thus, DTG + ABC/3TC dominated both comparators. Sensitivity analyses confirmed these results. This is consistent with the DTG clinical profile wherein DTG has demonstrated superiority over DRV/r and is numerically better than RAL [5−7]. This is also consistent with six previously published cost-effectiveness analyses that demonstrated DTG + backbone to be cost-effective or dominant compared with RAL + backbone or DRV/r + backbone [29−34]. In the reported analyses, we used efficacy data from an NMA by Patel et al. [8]. A more recent NMA by Kanters et al. [35] was available, but was not used because it did not report CD4+ comparisons essential for QALY calculations in our model [35]. Both NMAs reported consistent results for all ARTs in a treatment-naive
Table 3 – Costs, outcomes, and ICERs compared with DTG + ABC/3TC. Parameters Efficacy Responders (%) Months of response Life-years QALYs Costs (in RUB) Total (in millions) ART (in millions) Routine care AEs and other events Indirect costs End of life ICERs (including indirect costs) Costs/responder Costs/QALY ICERs (excluding indirect costs) Costs/responder Costs/QALY
DTG + ABC/3TC
RAL + ABC/3TC
DRV/r + ABC/3TC
71.7 116.6 14.3 12.73
65.2 108.6 14.3 12.72
59.6 98.9 14.3 12.72
2.89 2.13 390,275 68,338 260,690 35,493
5.32 4.54 397,786 67,551 275,225 35,493
4.38 3.59 405,554 69,603 287,170 35,493
DTG dominates DTG dominates
DTG dominates DTG dominates
DTG dominates DTG dominates
DTG dominates DTG dominates
ABC/3TC, abacavir/lamivudine; AE, adverse event; ART, antiretroviral therapy; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; RAL, raltegravir.
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Fig. 2 – Cost-effectiveness plane and cost-effectiveness acceptability curves for (A) DTG + ABC/3TC vs. RAL + ABC/3TC and (B) DTG + ABC/3TC vs. DRV/r + ABC/3TC. ABC/3TC, abacavir/lamivudine; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; RAL, raltegravir.
setting. We therefore believe that our results will be similar to those reported here using Kanters’ analyses. A previous costeffectiveness analysis using patient simulation model has demonstrated DTG + backbone to be a dominant treatment strategy compared with RAL + backbone or DRV/r + backbone [32]. Our results are consistent albeit the QALY benefit predicted in our analyses was small and unlikely to be clinically significant. Our analyses resulted in ICERs that can be considered conservative. Because of the limited information available in the NMA [8], we attributed no additional viral suppression or QALY benefit to DTG beyond 2 years despite one DTG clinical trial demonstrating continued efficacy up to 3 years [36]. Furthermore, several studies have demonstrated that if better viral suppression leads to improvements in CD4+ cell counts, then it may also lead to reduction in mortality [37]. Although all the interventions compared in these analyses have demonstrated improvements in CD4+ cell counts among HIV-1−infected treatment-naive patients, none has shown a conclusive benefit in mortality. We therefore excluded reduction in mortality attributable to CD4+ improvements from our analyses, resulting in a potential underestimation of DTG efficacy. It is also worth noting that we include only productivity loss in our assessment of indirect costs. Other costs are also potentially important here, such as travel time, caregiver requirement, and out-of-pocket expenditure. These were, however, not included because data were not available for these to be estimated. These results have significant health policy implications in Russia. Russian policymakers should focus on increasing
access to clinically superior and cost-effective HIV treatment. A 2015 analysis showed that Russia has significant work to do if it is to achieve the United Nations’ 90/90/90 goals. In that year, 49% of patients living with HIV were aware of their status, but only 11% were on treatment, of which only 9% were virally suppressed [38].
Conclusions Although the Russian government has recently announced a strategy to combat the spread of HIV by improving access to ART, funding continues to be a challenge. Even though the Russian Ministry of Finance allocated RUB 4 billion to tackle HIV in 2017, it is likely to be inadequate to achieve government targets outlined in its HIV strategy. As this analysis shows, treatments that achieve better viral suppression at lower costs, such as dolutegravir in first-line treatment, could assist Russia in tackling this HIV epidemic.
Acknowledgment We thank Anjali Radcliff for her contribution to the “Discussion” section regarding the impact of study results on government policies in Russia. Source of financial support: This analysis was sponsored by ViiV Healthcare, Brentford, UK.
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Supplemental Materials Supplemental material accompanying this article can be found in the online version as a hyperlink at http://dx.doi.org/10.1016/j. vhri.2018.08.001 or, if a hard copy of article, at www.valuein healthjournal.com/issues (select volume, issue, and article).
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[18] Kauf TL, Roskell N, Shearer A, et al. A predictive model of health state utilities for HIV patients in the modern era of highly active antiretroviral therapy. Value Health 2008;11:1144–53. [19] Cursor. Drug prices: Cursor tender database. Available from: http://cursor-is.ru. [Accessed February 15, 2017]. [20] Yakushin SS, Filippov EV. HIV infection and cardiovascular complications. Clinician 2011;2:6–12. [21] Imangianov SB, Abilmazhinova GD, Shukimbaeva AM. Cardiovascular diseases in HIV infected. Sci Public Health 2013;34:2011–3. [22] Krentz H, Gill M. Cost of medical care for HIV-infected patients within a regional population from 1997 to 2006. HIV Med 2008;9:721–30. [23] Agency for Evaluation of Healthcare Technologies. Scientific research report: Data collection for the adaptation of the pharmacoeconomic model for the cost-effectiveness analysis of the use of dolutegravir for HIV-infected patients treated in the Russian healthcare system [in Russian]. 2016. [24] Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2009. Available from: https://www.cdc.gov/mmwr/ preview/mmwrhtml/rr58e324a1.htm. [Accessed May 1, 2018]. [25] Thirumurthy H, Chamie G, Jain V, et al. Improved employment and education outcomes in households of HIV-infected adults with high CD4 cell counts: evidence from a community health campaign in Uganda. AIDS 2013;27:627–34. [26] Trading Economics. Russia average monthly wages. Available from: https://tradingeconomics.com/russia/wages. [Accessed May 3, 2018]. [27] National Institute for Health and Care Excellence. Guide to the methods of technology appraisal 2013. 2013. Available from: https:// www.nice.org.uk/process/pmg9/chapter/foreword. [Accessed June 25, 2018]. [28] Woods B, Revill P, Sculpher M, et al. Country-level cost-effectiveness thresholds: initial estimates and the need for further research. Value Health 2016;19:929–35. [29] Pialoux G, Marcelin AG, Cawston H, et al. Cost-effectiveness of dolutegravir/abacavir/lamivudine in HIV-1 treatment-naive (TN) patients in France. Expert Rev Pharmacoecon Outcomes Res 2018;18:83–91. [30] Restelli U, Rizzardini G, Antinori A, et al. Cost-effectiveness analysis of dolutegravir plus backbone compared with raltegravir plus backbone, darunavir + ritonavir plus backbone and efavirenz/tenofovir/emtricitabine in treatment na€ve and experienced HIV-positive patients. Ther Clin Risk Manag 2017;13:787–97. rez-Molina JA, Blasco AJ, et al. Costs and cost-efficacy anal[31] Rivero A, Pe ysis of the 2017 GESIDA/Spanish National AIDS Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults. Enferm Infecc Microbiol Clin 2018;36:268–76. gel N, Anger D, Martin M, et al. Cost-effectiveness of dolutegravir [32] Despie in HIV-1 treatment-naive and treatment-experienced patients in Canada. Infect Dis Ther 2015;4:337–53. [33] Stetka R, Psenkova M, Ondrusova M, et al. Cost-utility analysis of dolutegravir compared to raltegravir in treatment naive and treatment experienced patients in Slovak settings. Value Health 2014;17:A679. [34] Hren R, Refoios Camejo R. Cost-effectiveness analysis of dolutegravir for HIV patients in Slovenia. Value Health 2014;17:A673. [35] Kanters S, Vitoria M, Doherty M, et al. Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis. Lancet HIV 2016;3. e510−20 . [36] Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr 2015;70:515–9. [37] The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. CD4 cell count and the risk of AIDS or death in HIV-infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med 2012;9: e1001194. [38] Levi J, Raymond A, Pozniak A, et al. Can the UNAIDS 90-90-90 target be reached? A systematic analysis of national HIV treatment cascades. BMJ Glob Health 2017;2:e000227.
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Cost Effectiveness of Dolutegravir as a First-Line Treatment Option in the HIV-1−Infected Treatment-Naive Patients in Russia 1 2 3 D1XGabriel X Tremblay, PhD D2X X , Vasiliki D3X X Chounta, MSc D4X X , James D5X X Piercy, MSc D6X X , Tim D7X X Holbrook, BSc D8X X 3, 1 4 2 D9X X Shan Ashton Garib, MA D10X X , Evgeny D1X X K. Bukin, MD D12X X , Yogesh D13X X Suresh Punekar, PhD D14X X * 1 Purple Squirrel Economics, New York, NY, USA; 2ViiV Healthcare, Brentford, Middlesex, UK; 3Adelphi Real World, Bollington, Cheshire, UK; 4ViiV Healthcare, Moscow, Russia
ABSTRACT
Objectives: To evaluate the cost effectiveness of dolutegravir + abacavir/lamivudine (DTG + ABC/3TC) compared with raltegravir + abacavir/ lamivudine (RAL + ABC/3TC) and ritonavir-boosted darunavir + abacavir/lamivudine (DRV/r + ABC/3TC) in HIV-1−infected treatment-naive patients in Russia. Methods: A dynamic Markov model was developed with five response states and six CD4+-based health states. Efficacy estimated as probability of viral suppression (HIV RNA <50 copies/ml) at 48 weeks was obtained from a published network meta-analysis. Baseline cohort characteristics and health state utilities were informed using DTG phase 3 clinical trials. Health care resource use was obtained from literature and costed using published unit costs. Costs (presented in Russian rubles) included antiretroviral drug costs; HIV management costs such as routine care; costs of treating cardiovascular conditions, opportunistic infections, and drug-related adverse effects; and mortality costs. A patient lifetime analysis was conducted using the societal perspective. Outcomes were quality-adjusted life-years (QALYs), life-years, incremental cost per QALY ratio, and incremental cost
Introduction Among the countries of Eastern Europe and Central Asia, Russia has the largest number of HIV-1 infection diagnoses, with an estimated 103,438 new HIV diagnoses in 2016 [1,2]. This group of newly diagnosed patients with HIV is growing at a rate of 10% each year [1]. Despite such a large number of patients living with HIV, just over a third (37.3%) had access to antiretroviral therapy (ART) in 2015, with lack of adequate funding for diagnosis and treatment being a major barrier [1]. In Russia, HIV treatment and prevention initiatives are funded by central and regional governments, with limited contribution from local and international charitable institutions. Care is delivered through HIV-specific
per responder. Results: The viral suppression rate among patients receiving DTG + ABC/3TC was 71.7% compared with 65.2% for RAL + ABC/3TC and 59.6% for DRV/r + ABC/3TC. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/r + ABC/3TC. Total discounted costs for treatment over patient lifetime were RUB 2.89, 5.32, and 4.38 million for DTG + ABC/3TC, RAL + ABC/3TC, and DRV/r + ABC/3TC, respectively. Lifetime discounted QALYs were 12.73 for patients on DTG + ABC/3TC and 12.72 each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. DTG + ABC/3TC thus dominated the other two alternatives. Conclusions: With lower costs, higher response rates, and comparable QALYs, DTG + ABC/3TC can be considered as a cost-effective alternative. Key words: cost effectiveness, dolutegravir, economic analyses, HIV, Russia. Ó 2018 Published by Elsevier Inc. on behalf of ISPOR–The professional society for health economics and outcomes research..
centers, which are responsible for clinical research, monitoring and testing, HIV treatment, and counseling. In 2016, the Russian government announced a strategy to combat the spread of HIV by improving access to ART, which was one of its strategic initiatives [1]. Nevertheless, inadequate funding has remained a challenge. Despite increasing state funding for HIV treatment and prevention over the last few years, the 2016 funding of $325 million was estimated to cover only a fifth of the target population [3]. Therefore, access to effective and cost-saving ART remains an important priority to achieve Russia’s strategic objective of reducing AIDS-related deaths by 2020. ART usually comprises three antiretroviral agents, two nucleoside reverse transcriptase inhibitors, commonly referred to as
Conflicts of interest: Y. S. Punekar and V. Chounta are employees of ViiV Healthcare and hold stocks in the company. E. K. Bukin was an employee of ViiV Healthcare at the time of this study and holds stocks in the company. G. Tremblay and S. A. Garib are employees of Purple Squirrel Economics and received payment from ViiV Healthcare for consultancy during the conduct of this study. J. Piercy and T. Holbrook are employees of Adelphi Real World and received payment from ViiV Healthcare for consultancy during the conduct of this study. * Address correspondence to: Yogesh Suresh Punekar, ViiV Healthcare, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. E-mail: [email protected]. 2212-1099/$36.00 – see front matter Ó 2018 Published by Elsevier Inc. on behalf of ISPOR–The professional society for health economics and outcomes research. https://doi.org/10.1016/j.vhri.2018.08.001
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backbone, and a third agent, often referred to as a core agent, from a different antiretroviral class. In Russia, current core agents used in treatment-naive patients include non−nucleoside reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors (INIs) including ritonavir-boosted darunavir (DRV/r) and raltegravir (RAL) [4]. Dolutegravir (DTG) is a second-generation INI with a higher barrier to resistance, which received regulatory approval in Russia in 2014. In its phase 3 clinical program among HIV-1−infected treatment-naive patients, DTG has demonstrated superiority to DRV/r and noninferiority to RAL, two commonly used ARTs in Russia [5−7]. With the introduction of DTG, the objective of this analysis was to assess the cost effectiveness of DTG + backbone compared with RAL + backbone and DRV/ r + backbone for HIV-1−infected treatment-naive patients.
Methods Model Design A cost-effectiveness model was developed to estimate the clinical outcomes and costs of DTG + backbone compared with other core agents used in Russia with a societal perspective. DRV/r and RAL, the core agents most likely to be displaced by DTG, were selected as comparators. The model framework was a dynamic Markov model (also called a semi-Markov model) with a series of disease health states along with transition probabilities for each state that characterize
disease progression. The cycle length used in the model was 1 month and the overall time horizon was patient lifetime.
Model response states and health states Patients in the model transitioned between the five response states. Responder states modeled included responder maintaining ART; nonresponder maintaining ART; discontinuation due to failure; discontinuation due to other reasons such as intolerance, toxicity, poor adherence, or simplification; and death. Responders, defined as proportion of patients achieving viral suppression (HIV-1 RNA <50 copies/ml), maintained their ART. Nonresponders were allowed to remain on ART for a period of 6 months, consistent with the real-world treatment practice in Russia. Each patient was classified into one of these response states estimated using network meta-analysis (NMA) by Patel et al. [8]. Patients in each response state, except death, were further divided into CD4+-based health states (Fig. 1). Each patient’s CD4+ level was determined by the treatment used, the time on treatment, and the responder status. Responders were estimated to have higher CD4+ levels compared with nonresponders. Among responders, some treatments were estimated to have better CD4+ efficacy on the basis of NMA [8]. In addition, the time on treatment was also a key driver for the increase in CD4+ levels because the model assumed a linear increase until patients reached the trial efficacy at weeks 48 and 96, after which the CD4+ levels were expected to decrease [9]. Patients discontinuing their treatment were assumed to go back to their baseline CD4+ levels. This was a conservative assumption used to illustrate no incremental treatment effect after treatment withdrawal [10].
Fig. 1 – Model figure. AE, adverse event; ART, antiretroviral therapy.
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Model parameters The patient population used in the model was HIV-infected treatment-naive patients, similar to those who participated in the DTG phase 3 trials [5,7,11,12] and further presented in the NMA [8]. The analysis compared three treatment regimens. These were DTG added to abacavir/lamivudine (DTG + ABC/3TC), RAL added to abacavir/lamivudine (RAL + ABC/3TC), and DRV/r added to abacavir/lamivudine (DRV/r + ABC/3TC). These regimens were selected to represent commonly used alternatives and were perceived to be the most efficacious treatment alternatives in Russia [4]. ABC/3TC was used to represent common backbone across all three interventions because of its high usage in clinical practice in Russia. Because each of these regimens can be prescribed as two tablets (backbone + core agent) or three tablets (three medications separately), 64% of all patients were assumed to receive a backbone plus a core agent (i.e., two tablets). Patients discontinuing the DTG + ABC/3TC arm because of ART failure were assumed to switch to DRV/r + ABC/3TC, whereas those discontinuing for other reasons were assumed to switch to DRV/r + zidovudine (ZDV)/3TC. Corresponding treatment switches from the RAL + ABC/3TC arm were DRV/r + tenofovir (TDF)/3TC and efavirenz + ABC/3TC, and from the DRV/r + ABC/3TC arm were RAL + ABC/3TC and RAL + ZDV/3TC. The meta-analysis by Patel et al. [8] did not report specific efficacy estimates for ZDV/3TC or TDF/3TC backbones. Therefore, we used efficacy and CD4+ change reported for “other backbone” to represent these.
from a US observational study that showed that the increase after 4 years after ART initiation was relatively flat [12]. Ninetysix weeks after failing the last ART, patients will experience a decline in CD4+ cell count on the basis of links reported by Mauskopf et al. between viral load [9] and CD4+ cell count data from the multicenter AIDS cohort study [13]. The transition probabilities used in the model are presented in Table 1. Note that the discontinuation rates were derived from pooled data from phase 3 studies and were assumed to be identical for all comparator treatments.
Safety and tolerability Patients experiencing treatment-related adverse events (AEs) were assumed to experience a quality-of-life decrement and additional costs associated with that event. Those experiencing grade 2 to grade 4 AEs were assumed to switch to the next treatment and the associated transition probabilities were derived from the NMA [8]. Discontinuations due to AEs were assumed to occur in the first month of treatment (using discontinuation rate at week 48) and were derived from pooled data from DTG phase 3 studies. As a result, a common discontinuation rate was assumed across all comparator treatments. No a priori relationship was assumed between AEs such that a patient could potentially experience several AEs simultaneously. In such instances, the costs and utility decrements were assumed to be additive.
Comorbidities
Efficacy and transition probabilities Transition probabilities were estimated on the basis of a published NMA [8]. In this meta-analysis, authors included 31 phase 3 or 4 randomized controlled trials including 17,000 patients to estimate relative efficacy and safety of DTG compared with guideline-recommended core agents. They used Bayesian fixedeffect NMA models adjusting for the backbone to evaluate 48week viral suppression and changes in the CD4+ cell count in DTG and its comparators. The overall results showed DTG to be comparable with other INIs and superior to all other core agents. The study also reported no significant efficacy difference between all the available ART backbones. For transition probabilities beyond 48 weeks, changes in CD4+ cell count are based on pooled patient-level data of all the DTG trials [5,7,11,12]. The model assumes the same CD4+ cell count increase rate after 22 months for those suppressed on any regimen, although CD4+ cell count increase differs between treatment regimens. This assumption is consistent with the findings
Cardiovascular disease (CVD) is a common comorbidity among patients with HIV, which is also affected by the patients’ ART. The risk of developing CVD was estimated in each model cycle on the basis of published literature [14]. The risk of occurrence of acute opportunistic infections (AOIs) was dependent on the history of that specific opportunistic infection (OI), patient’s CD4+ cell count, and the time on and response status of the treatment. It was also estimated from literature [15]. Five types of OIs including bacterial, fungal, protozoal, viral, and other infections were considered.
Mortality Mortality included death due to HIV, AOI, CVD, or natural causes. HIV mortality was estimated on the basis of CD4+ cell count and a history of any OI. AOI mortality was estimated on the basis of frequency and severity of AOIs observed in relation to CD4+ cell counts [13]. Mortality rates used in the model are presented in
Table 1 – Model transition probabilities [8]. Parameters
Timeframe
DTG
DRV/r
RAL
Viral suppression
First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22 First 11 mo Months 12−22 After month 22
15.7% 0.2% 0.0% 0.46% 0.10% 0.05% 0.55% 0.12% 0.06% 1.03% 0.23% 0.10% 21.75 2.51 ¡2.32
11.5% 0.1% 0.0% 0.86% 0.06% 0.06% 0.62% 0.04% 0.04% 1.54% 0.10% 0.10% 16.85 0.56 ¡2.32
14.1% 0.0% 0.0% 0.86% 0.06% 0.06% 0.62% 0.04% 0.04% 1.54% 0.10% 0.10% 21.13 0.54 ¡2.32
Discontinuation due to failure (first-line)
Discontinuation with other cause (first-line)
Discontinuation (second-line plus)
CD4+ increase
DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; RAL, raltegravir.
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Table 2 – Health state−based utilities and costs used in the model. Health states Parameters
>500
350−500
200−350
100−200
50−100
0−50
Utilities Costs Routine care (in RUB) [22] Outpatient care Inpatient care AOI (in RUB) [15,23] Bacterial Fungal Protozoal Viral OI prophylaxis [24] PJP MAC Cardiovascular event [20−22] Indirect costs [25,26]
0.896
0.899
0.886
0.861
0.843
0.822
130 1,448 151 34 32 18 67
153 1,874 87 28 5 5 50
153 1,871 123 39 19 9 55
200 4,263 521 146 121 32 222
318 16,921 521 146 121 32 222
318 16,696 1,333 473 274 115 471
0 0 72 0
0 0 92 2,149
0 0 114 1,445
185 0 114 8,390
185 5,022 114 8,390
185 5,022 114 8,390
AOI, acute opportunistic infection; MAC, mycobacterium avium complex; OI, opportunistic infection; PJP, pneumocystis jiroveci pneumonia.
Appendix Table 1 in Supplemental Materials found at 10.1016/j. vhri.2018.08.001.
Utilities Health state−based utilities were derived from phase 3 studies of DTG trials and are presented in Table 2 [5,7,11,12]. Disutilities associated with AOIs were obtained from literature and were ¡0.328 for bacterial, protozoal, and other OIs and ¡0.237 for fungal and viral OIs [16]. Disutility associated with presence of CVD (¡0.098) was also obtained from published sources [17]. Disutilities were also applied for grade 2 to grade 4 AEs for the duration of the AE and are presented in Appendix Table 2 in Supplemental Materials found at 10.1016/j.vhri.2018.08.001 [18].
Costs ART costs ART costs were obtained in February 2017 from the Cursor tender database and the official Web site of the Unified Information Procurement System in Russia and are presented in Russian rubles (RUB) [19]. The monthly treatment costs of core agents were RUB 9,909 for DTG, RUB 30,940 for RAL, and RUB 15,502 for DRV/r. The monthly backbone costs were RUB 1,337 for ABC + 3TC and RUB 710 for both ZDV + 3TC and TDF + 3TC. The backbone costs were calculated as a weighted average price between single tablet and two tablets on the basis of market shares.
HIV management costs Costs associated with routine care, testing for ARTs, treatment of AOI, prophylaxis for opportunistic infections, and management of drug-related AEs were included (Table 2). Costs associated with management of frequent comorbidities such as CVD were also included. These were estimated using the prevalence of CVD among patients with HIV in Russia and associated health care resource use [20−22]. Costs of routine care included outpatient physician visits and inpatient HIV-related hospitalizations. All costs were estimated by health state on the basis of estimated resource use obtained from literature and are presented in Table 2 [22]. Diagnostic costs such as ultrasound (RUB 114), blood/transaminase test (RUB 79),
coagulation test (RUB 36), stool culture (RUB 762), fasting insulin (RUB 680), and glycemic curve (RUB 765) were included as baseline costs [23]. The costs of bacterial, fungal, protozoal, and viral AOIs were included in the HIV management costs. The monthly prevalence of each type of AOI for patients in each health state was obtained from literature [15] and costed using Russia-specific costs [23]. Two types of prophylaxis for opportunistic infections, pneumocystis jiroveci pneumonia and mycobacterium avium complex, were included in the HIV management costs [24]. A 1-month treatment with trimethoprim sulfamethoxazole 160/800 for pneumocystis jiroveci pneumonia and a 1-month treatment with azithromycin for mycobacterium avium complex were assumed and were costed using weighted prevalence by health states (Table 2). AE costs were derived using physician opinion and included costs associated with medication for AEs and use of health care resources such as physician visits or hospitalization (see Appendix Table 2 in Supplemental Materials).
Indirect costs The analysis was conducted using the societal perspective and thus indirect costs comprising productivity losses were included in the model. Productivity losses were estimated from literature [25]. In this study, authors used a socioeconomic survey based on the World Bank Living Standards Measurement Survey to capture information on lost working days and establish a link between CD4+ cell counts and loss of productivity. The productivity costs were then estimated using information on the national wages in Russia [26]. A scenario analysis excluding the productivity costs was also conducted. Considering the chronic nature of disease, a lifetime horizon was adopted. Both direct and indirect health care costs were included, and costs and benefits were discounted at 3.5% per year [27]. All costs are reported in Russian rubles and inflated using the consumer price index in Russia to 2017 values.
Model Validation The treatment pathway depicted in the model was compared with the World Health Organization HIV guideline to ensure consistency in the patient pathways. The model was internally
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validated by another expert not involved in the original model modeling to ensure accuracy and fit. This was further confirmed by co-authors who were modeling experts.
Economic Analyses The incremental efficacy in quality-adjusted life-years (QALYs) and incremental costs of DTG + ABC/3TC were compared separately with those of RAL + ABC/3TC and DRV/r + ABC/3TC. The incremental cost-effectiveness ratio (ICER) of DTG + ABC/3TC compared with those of RAL+ABC/3TC and DRV/r+ABC/3TC was calculated separately and reported as cost per responder and cost per QALY. Model robustness was assessed with multiple one-way deterministic sensitivity analyses by varying key parameters through plausible ranges of §20%, which was set arbitrarily. Parameters varied were CD4+ efficacy, AE prevalence, costs, and utilities. Probabilistic sensitivity analyses (PSAs) were conducted to assess uncertainty around several parameters simultaneously. Parameters included in the PSAs and their corresponding distribution and SDs are presented in Appendix Table 3 in Supplemental Materials found at 10.1016/j.vhri.2018.08.001.
Results The mean age of the patient cohort used in the model was 37 years, and 15% of patients were females. At baseline, approximately a third of patients were in CD4+ health states of 200 to 350 (35.6%) and 350 to 500 (31.6%). The CD4+ health state distribution for the remainder of the patients was 0 to 50 (2.3%), 50 to 100 (2.6%), 100 to 200 (7.7%), and more than 500 (20.1%). The base-case model predicted 71.7% patients on DTG + ABC/3TC, 65.2% on RAL + ABC/3TC, and 59.6% on DRV/ r + ABC/3TC to achieve and maintain viral suppression. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/ r + ABC/3TC. This resulted in 12.73 QALYs for patients on DTG + ABC/3TC and 12.72 QALYs each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. The total costs of HIV
treatment per patient over lifetime were RUB 2.89 million for DTG + ABC/3TC, RUB 5.32 million for RAL + ABC/3TC, and RUB 4.38 million for DRV/r + ABC/3TC. The incremental cost-effectiveness analyses showed DTG + ABC/3TC resulting in 0.01 incremental QALYs compared with RAL + ABC/3TC and DRV/ r + ABC/3TC, with cost savings of RUB 2.43 million compared with RAL + ABC/3TC and RUB 1.49 million compared with DRV/ r + ABC/3TC. DTG + ABC/3TC thus dominated the other two treatment alternatives. Detailed costs and outcomes with resultant ICERs are presented in Table 3. One-way sensitivity analyses suggested that changes in CD4+ cell counts and utility levels of health states were key drivers of cost-effectiveness results (see Appendix Figure 1 in Supplemental Materials found at 10.1016/j.vhri.2018.08.001). PSAs showed that the probability of DTG + ABC/3TC being cost-effective compared with both alternatives was 100% at a willingness-to-pay threshold as low as RUB 315,000/QALY (Figs. 2A and 2B) [28].
Discussion This analysis evaluated the cost effectiveness of DTG + ABC/ 3TC compared with RAL + ABC/3TC and DRV/r + ABC/3TC among HIV-1−infected treatment-naive patients in Russia. The model predicted more patients treated with DTG + ABC/ 3TC to achieve viral suppression and thereby more QALYs at lower costs compared with both RAL + ABC/3TC and DRV/ r + ABC/3TC. Thus, DTG + ABC/3TC dominated both comparators. Sensitivity analyses confirmed these results. This is consistent with the DTG clinical profile wherein DTG has demonstrated superiority over DRV/r and is numerically better than RAL [5−7]. This is also consistent with six previously published cost-effectiveness analyses that demonstrated DTG + backbone to be cost-effective or dominant compared with RAL + backbone or DRV/r + backbone [29−34]. In the reported analyses, we used efficacy data from an NMA by Patel et al. [8]. A more recent NMA by Kanters et al. [35] was available, but was not used because it did not report CD4+ comparisons essential for QALY calculations in our model [35]. Both NMAs reported consistent results for all ARTs in a treatment-naive
Table 3 – Costs, outcomes, and ICERs compared with DTG + ABC/3TC. Parameters Efficacy Responders (%) Months of response Life-years QALYs Costs (in RUB) Total (in millions) ART (in millions) Routine care AEs and other events Indirect costs End of life ICERs (including indirect costs) Costs/responder Costs/QALY ICERs (excluding indirect costs) Costs/responder Costs/QALY
DTG + ABC/3TC
RAL + ABC/3TC
DRV/r + ABC/3TC
71.7 116.6 14.3 12.73
65.2 108.6 14.3 12.72
59.6 98.9 14.3 12.72
2.89 2.13 390,275 68,338 260,690 35,493
5.32 4.54 397,786 67,551 275,225 35,493
4.38 3.59 405,554 69,603 287,170 35,493
DTG dominates DTG dominates
DTG dominates DTG dominates
DTG dominates DTG dominates
DTG dominates DTG dominates
ABC/3TC, abacavir/lamivudine; AE, adverse event; ART, antiretroviral therapy; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; RAL, raltegravir.
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Fig. 2 – Cost-effectiveness plane and cost-effectiveness acceptability curves for (A) DTG + ABC/3TC vs. RAL + ABC/3TC and (B) DTG + ABC/3TC vs. DRV/r + ABC/3TC. ABC/3TC, abacavir/lamivudine; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; RAL, raltegravir.
setting. We therefore believe that our results will be similar to those reported here using Kanters’ analyses. A previous costeffectiveness analysis using patient simulation model has demonstrated DTG + backbone to be a dominant treatment strategy compared with RAL + backbone or DRV/r + backbone [32]. Our results are consistent albeit the QALY benefit predicted in our analyses was small and unlikely to be clinically significant. Our analyses resulted in ICERs that can be considered conservative. Because of the limited information available in the NMA [8], we attributed no additional viral suppression or QALY benefit to DTG beyond 2 years despite one DTG clinical trial demonstrating continued efficacy up to 3 years [36]. Furthermore, several studies have demonstrated that if better viral suppression leads to improvements in CD4+ cell counts, then it may also lead to reduction in mortality [37]. Although all the interventions compared in these analyses have demonstrated improvements in CD4+ cell counts among HIV-1−infected treatment-naive patients, none has shown a conclusive benefit in mortality. We therefore excluded reduction in mortality attributable to CD4+ improvements from our analyses, resulting in a potential underestimation of DTG efficacy. It is also worth noting that we include only productivity loss in our assessment of indirect costs. Other costs are also potentially important here, such as travel time, caregiver requirement, and out-of-pocket expenditure. These were, however, not included because data were not available for these to be estimated. These results have significant health policy implications in Russia. Russian policymakers should focus on increasing
access to clinically superior and cost-effective HIV treatment. A 2015 analysis showed that Russia has significant work to do if it is to achieve the United Nations’ 90/90/90 goals. In that year, 49% of patients living with HIV were aware of their status, but only 11% were on treatment, of which only 9% were virally suppressed [38].
Conclusions Although the Russian government has recently announced a strategy to combat the spread of HIV by improving access to ART, funding continues to be a challenge. Even though the Russian Ministry of Finance allocated RUB 4 billion to tackle HIV in 2017, it is likely to be inadequate to achieve government targets outlined in its HIV strategy. As this analysis shows, treatments that achieve better viral suppression at lower costs, such as dolutegravir in first-line treatment, could assist Russia in tackling this HIV epidemic.
Acknowledgment We thank Anjali Radcliff for her contribution to the “Discussion” section regarding the impact of study results on government policies in Russia. Source of financial support: This analysis was sponsored by ViiV Healthcare, Brentford, UK.
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Supplemental Materials Supplemental material accompanying this article can be found in the online version as a hyperlink at http://dx.doi.org/10.1016/j. vhri.2018.08.001 or, if a hard copy of article, at www.valuein healthjournal.com/issues (select volume, issue, and article).
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