Cost-Effectiveness of Tenofovir as First-Line Antiretroviral Therapy in India

doi:10.1086/649884

Clin Infect Dis. Author manuscript; available in PMC 2011 November 28.

Published in final edited form as:

Clin Infect Dis. 2010 February 1; 50(3): 416–425.

doi: 10.1086/649884

PMCID: PMC3225050

NIHMSID: NIHMS330189

Cost-Effectiveness of Tenofovir as First-Line Antiretroviral Therapy in India

Melissa A. Bender, MD,¹ Nagalingeswaran Kumarasamy, MBBS, PhD, Kenneth H. Mayer, MD,² Bingxia Wang, PhD, Rochelle P. Walensky, MD, MPH,³ Timothy Flanigan, MD,² Bruce R. Schackman, PhD,⁴ Callie A. Scott, BA, Zhigang Lu, MD, and Kenneth A. Freedberg, MD, MSc⁵, For the CEPAC-International investigators

Divisions of General Medicine and Infectious Diseases and the Partners AIDS Research Center, Massachusetts General Hospital, Boston, MA (MAB, BW, RPW, CAS, KAF), the Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA (RPW), the Harvard University Center for AIDS Research (KAF), Boston, MA, Harvard Medical School (MAB, KAF, RPW, BW); the Harvard School of Public Health (KAF), Boston, MA; Y.R. Gaitonde Centre for AIDS Research and Education, Chennai, India (NK); Department of Public Health, Weill Cornell Medical College, New York, NY (BS) and Miriam Hospital, Brown Medical School, Providence, RI (KHM, TF)

Corresponding author: Melissa A. Bender, MD, Massachusetts General Hospital, 50 Staniford Street, 9^th Floor, Boston, MA 02114, 617-726-1993 (phone); 617-726-2691 (fax), Email: mbender/at/partners.org

¹National Institute of Allergy and Infectious Diseases (K01 AI074495 and T32 AI007433), Harvard University Center for AIDS Research (P30 AI060354), Doris Duke Charitable Foundation Operations Research on AIDS Care and Treatment in Africa (ORACTA) Award (2007015), Harvard Medical School Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine Award.

²Lifespan/Tufts/Brown University Center for AIDS Research (P30AI042853).

³Doris Duke Charitable Foundation Clinical Scientist Development Award (2005075).

⁴National Institute on Drug Abuse (K01 DA017179).

⁵National Institute of Allergy and Infectious Diseases (K24AI062476 and R01 AI058736).

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Abstract

Background

World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy. We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India, compared to current practice using stavudine or zidovudine.

Methods

We used a state-transition model of HIV disease to examine strategies using different nucleoside reverse transcriptase inhibitors, combined with lamivudine and nevirapine, compared to no ART: 1) stavudine; 2) stavudine, with substitution by zidovudine after six months; 3) zidovudine; 4) tenofovir. Data were from the Y.R. Gaitonde Centre for AIDS Research and Education in Chennai, India and published studies.

Results

Discounted mean per person survival was 36.9 months (40.1 months undiscounted) with no ART, 115.5 months (145.3) with stavudine-containing ART, 115.6 months (145.5) with stavudine and six-month zidovudine substitution, 115.7 months (145.6) with zidovudine-containing ART, and 125.9 months (162.2) with initial tenofovir. Discounted lifetime medical costs were $610 with no ART and ranged from $5,560 with stavudine-containing ART to $5,720 with zidovudine-containing ART. Initial tenofovir had an incremental cost-effectiveness ratio of $670/year of life saved compared to no ART and was more economically efficient than the other regimens. Results were most sensitive to variations in the costs of first-line tenofovir, access to additional ART after failure, mean initial CD4 count, and quality of life adjustment.

Conclusions

Using tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for initial therapy for HIV-infected patients in India.

Keywords: HIV, cost-effective, India, antiretroviral treatment, resource-limited settings

INTRODUCTION

There are approximately 2.5 million people in India living with HIV infection [1]. In the US and Europe, first-line therapy usually includes tenofovir – a nucleotide analogue that is more effective and considerably less toxic than stavudine, which is not recommended [2]. Current (World Health Organization) WHO guidelines for ART in resource-limited settings recommend either stavudine or tenofovir as part of initial combination therapy [3]. In much of Asia and other resource-limited settings, the most common first-line regimens for HIV-infected patients still contain either stavudine or zidovudine, which are less costly than tenofovir [3,4]. While effective, stavudine is associated with several toxicities including lipodystrophy, neuropathy, pancreatitis, and the rarer but potentially fatal lactic acidosis; anemia is a common toxicity from zidovudine [5]. In comparison, tenofovir is relatively well tolerated, though it may be associated with nephrotoxicity [6]. Tenofovir has been found to be more effective than other nucleoside reverse transcriptase inhibitor (NRTI) agents [7]. Recent price negotiations have reduced the cost of tenofovir in many developing countries, but access remains limited [8].

The National AIDS Control Organization of India has published a detailed plan for scaling up HIV prevention and treatment, stating a goal that all HIV-infected individuals have access to comprehensive HIV care by 2011 [9]. As both the government and private agencies are increasing ART access throughout India, there is an opportunity to provide evidence-based guidance on the optimal selection of treatment regimens. Our objective was to project the clinical outcomes, cost, and cost-effectiveness of various first-line ART regimens in India.

METHODS

Overview and Treatment Strategies

We adapted a published model of HIV disease and treatment in international settings, including southern India [10]. To evaluate the benefits and costs associated with different first-line ART regimens, we simulated four strategies for the NRTI component, along with lamivudine and nevirapine, each compared to no ART. The four ART strategies included cotrimoxazole prophylaxis and: 1) a stavudine-containing regimen with zidovudine substituted for stavudine for specified grade 3 or 4 toxicities (severe lactic acidosis, neuropathy, and lipodystrophy) (“initial stavudine”) [11]; 2) a stavudine strategy with zidovudine uniformly substituted after six months to minimize the risk of lipodystrophy and lactic acidosis (“initial stavudine-to-zidovudine”) [12]; 3) a zidovudine strategy with a switch to stavudine, if and when anemia developed (“initial zidovudine”); and 4) a tenofovir-containing regimen in which zidovudine was substituted if nephrotoxicity developed (“initial tenofovir”). We assessed the clinical and cost outcomes associated with each strategy. All patients had access to two sequential “lines” of ART, reflecting national guidelines in India [13]. Second-line ART, which included tenofovir or zidovudine and a protease inhibitor (PI), was initiated following first-line ART failure. We summarized results using the incremental cost-effectiveness ratio: the increase in cost divided by the increase in years of life saved (YLS), or quality-adjusted life years (QALYs) saved, compared to the next lower cost alternative [14]. Results are reported in 2005 US dollars per life year saved. The analysis was from a modified societal perspective, excluding costs of patients’ time and travel, and all costs and life years were discounted at 3% per year [14].

Model

Using first-order Monte Carlo simulation, the model tracks patients selected randomly from an initial distribution of age, sex, CD4 count, HIV RNA level, and history of opportunistic infection (OI). Initiation of ART decreases HIV RNA levels and, for those who are virologically suppressed, increases CD4 counts, which then decreases the probability of OIs and mortality. (See Appendix for references and additional model details.)

The Commission on Macroeconomics and Health of the WHO has suggested that cost-effectiveness ratios below three times the per capita gross domestic product (GDP) in a country (US$1,860 in India) might be considered “cost-effective,” and ratios below the GDP itself ($620 in India) might be considered “very cost-effective [15].” We used the three times GDP threshold as a comparative benchmark. The study was approved by the Ethics Board at the Y.R. Gaitonde Centre for AIDS Research and Education (YRG CARE) in Chennai, India and the Partners HealthCare Human Subjects Committee, in Boston, MA, USA.

Model Input Data

Cohort Characteristics

Patients in the simulated cohort had demographic and disease characteristics based on an HIV-infected cohort of approximately 7,000 patients from YRG CARE, the largest non-governmental HIV care center in India, between 1996 and 2004 (Table 1) [10,16]. Mean age was 33 years; baseline mean CD4 count was 318/μL (SD 291/μL); and 66% of the subjects were male.

Table 1

Selected model input parameters

ART Effectiveness and Toxicity

In the absence of clinical trial data from India, the effectiveness of alternative ART regimens was from a published observational cohort in India and from clinical trials in the US (Table 1). For first-line regimens including either stavudine or zidovudine, we used 24-week virologic suppression of 73% (<400 copies/mL) and, for those suppressed, a CD4 count increase of 132 cells/μL at 24 weeks; once suppressed, probability of virologic failure after 48 weeks (“long-term”) was estimated at 5%/month [10,17]. For first-line tenofovir, we used 85% suppression at 24 weeks and assumed the same immunologic benefit as for the other regimens (132 cells/μL) [7,17]. Tenofovir had an estimated long-term virologic failure probability of 1%/month [7,18]. We incorporated local strategies for managing reported toxicities, including single-drug substitutions of another NRTI for patients who developed grade 3 or 4 toxicity (or after six months for stavudine) (Table 1) [11,12]. Those who experienced virologic failure switched to an appropriate second-line regimen (Appendix).

Costs

Costs of ART were derived from the Clinton Foundation HIV/AIDS Initiative price list (Appendix) [4]. CD4-specific inpatient and outpatient utilization associated with routine HIV care, acute events, and death were based on data from YRG CARE in Chennai [16,19].

Sensitivity Analyses

We conducted sensitivity analyses on all major parameters in the model, including the costs of first- and second-line ART; access to only one or three lines of ART; effectiveness of tenofovir compared to other agents; second-line ART stopping criteria; probability of and time to severe lactic acidosis and other ART toxicities; and initial mean CD4 count. Because of limited data on nephrotoxicity from tenofovir in resource-limited settings, we conducted two-way sensitivity analyses varying the incidence of nephrotoxicity in both first- and second-line ART from 1.6% (base case) to 16% and mortality from 1.0% to 90%. We also assigned utilities reflecting quality of life (QOL) to all health states and ART toxicities, and we projected quality-adjusted life expectancy. Utility weights ranging from 0.0 (death) to 1.0 (perfect health) were derived from studies conducted in the US or clinical judgment [20].

RESULTS

Primary Analysis

In a cohort with mean CD4 count of 318 cells/μL, co-trimoxazole treatment alone (no ART) led to a projected mean discounted life expectancy of 36.9 months (40.1 months undiscounted) with discounted lifetime cost of $610 (Table 2). Initial stavudine led to a discounted life expectancy of 115.5 months (145.3 months) at a cost of $5,560. Initial stavudine-to-zidovudine resulted in a mean discounted life expectancy of 115.6 months (145.5 months) at a cost of $5,570. Initial zidovudine led to a discounted life expectancy of 115.7 life months (145.6 months) at a cost of $5,720. Finally, initial tenofovir increased life expectancy to 125.9 months (162.2 months) with a total cost of $5,590 (Table 2).

Table 2

Summary Base Case Results of a Cost-effectiveness Analysis of First-Line ART Regimens in India^a

Initial stavudine was associated with 280 deaths from ART toxicity per 100,000 people, compared to 130 deaths/100,000 when used with a six-month zidovudine substitution, 60/100,000 deaths from initial zidovudine, and 10/100,000 deaths from initial tenofovir (Table 2, right column).

Initial stavudine and initial stavudine-to-zidovudine had higher cost-effectiveness ratios than the next more costly strategies, representing an economically inefficient use of resources (“weakly dominated”) [21]. Initial zidovudine resulted in lower life expectancy and higher cost than initial tenofovir, also representing an inefficient use of resources. Initial tenofovir had an incremental cost-effectiveness ratio of $670/YLS compared to no ART (co-trimoxazole alone).

Sensitivity Analyses

Access to and cost of additional lines of ART

With access to three lines of ART, discounted life expectancy for initial tenofovir increased to 132.0 months, and the incremental cost-effectiveness of initial tenofovir increased to $830/YLS compared to no ART. When we decreased the cost of the lopinavir/ritonavir component of second-line ART by 25–75%, the lifetime cost for all first-line alternatives was reduced. When these costs were decreased by 75%, initial tenofovir became even more cost-effective, at $390/YLS compared to no ART.

Effectiveness of tenofovir

We assumed that all first-line regimens had equal 48-week effectiveness but varied the probability of long-term virologic failure for tenofovir compared to initial stavudine or zidovudine (Table 3) [17]. When we reduced this advantage by 25–100% (ultimately rendering equal the efficacy of all first-line alternatives), tenofovir remained the only economically efficient strategy, with incremental cost-effectiveness ratios of $700-$740/YLS compared to no ART.

Table 3

Sensitivity Analysis: Cost-effectiveness of Tenofovir for Initial Antiretroviral Treatment in India^a

Incidence of and mortality from nephrotoxicity

We then varied nephrotoxicity from tenofovir in both first- and second-line ART. When the frequency of nephrotoxicity was 1.6% in either first- or second-line regimens containing tenofovir, even a mortality rate from nephrotoxicity as high as90% had little impact on mean total life expectancy (Figure 1) or the cost-effectiveness results (Table 3).

Figure 1

Life expectancy impact of a two-way sensitivity analysis on the incidence of and mortality from nephrotoxicity among tenofovir recipients. The upper three lines represent nephrotoxicity from initial tenofovir; the lower lines represent initial stavudine (more ...)

Mean initial CD4 count

We also varied the mean initial CD4 count between 50 and 500 cells/μL. A mean initial CD4 count of 500 cells/μL decreased the incremental cost-effectiveness ratio of initial tenofovir to $590/YLS, while a much lower initial CD4 count of 50 cells/μL increased the ratio to $920 cells/YLS.

Quality of life

In results adjusted to reflect quality of life, initial tenofovir resulted in a discounted life expectancy of 86.4 quality-adjusted life months (QALMs; 110.4 undiscounted) and a cost-effectiveness ratio of $1,000/QALY compared to no ART. All other strategies were economically inefficient. We performed the same adjustments for a scenario in which patients had access to only one line of ART, yielding similar results (Table 3).

Cost of tenofovir

We varied the cost of tenofovir-containing first-line ART from its base case of $14/month down to $7/month and up to $100/month, with commensurate changes in the tenofovir component of second-line ART for those who fail initial stavudine or initial zidovudine (Figure 2). When two lines of ART were available, initial tenofovir was associated with an incremental cost-effectiveness ratio less than three times per capita GDP in India. If only one line of ART was available, then the cost-effectiveness results were more sensitive to changes in tenofovir cost, but initial tenofovir remained a cost-effective option throughout a plausible range of costs.

Figure 2

Results of a two-way sensitivity analysis on the cost of initial tenofovir as its cost is varied from the current cost of initial stavudine (US$7/month, left side of the figure), through the base case current cost of initial tenofovir (US$14/month), and (more ...)

Additional sensitivity analyses

Alternative ART stopping criteria for patients who failed second-line ART (stop immediately upon virologic failure or upon severe OI) did not substantially affect the cost-effectiveness results (Table 3). Other parameters with limited impact included the probability of lactic acidosis resulting from stavudine and its associated mortality, quality of life decrements from ART toxicity, time to ART toxicity, duration of neuropathy and lipodystrophy, and mean initial CD4 count.

DISCUSSION

Newer ART agents, including tenofovir, are both highly effective and safer than older NRTIs, but stavudine remains the backbone of first-line ART regimens in India and many other resource-limited countries due to its lower cost [7,22]. We conducted a cost-effectiveness analysis of first-line ART regimens in India, focusing on the role of tenofovir. We found that initial tenofovir increased life expectancy by about 10.4 months compared to stavudine or zidovudine. At the current price of tenofovir-containing ART ($14/person/month), the incremental cost-effectiveness ratio for initial tenofovir in India was $670/YLS compared to no ART. The alternative strategies represented a less efficient use of resources. The main determinants of these results were the cost of tenofovir, access to and cost of additional lines of ART, and mean initial CD4 count. Sensitivity analyses adjusted for quality of life increased the incremental cost-effectiveness ratio of the tenofovir-based strategy to $1,000/YLS.

Some studies suggest that tenofovir may be associated with nephrotoxicity and potentially renal failure [6]. Moreover, renal disease is more prevalent in HIV-infected patients than the general population, regardless of ART exposure [23]. Several US-based trials show no increase in nephrotoxicity from tenofovir with careful monitoring and minimal long-term consequences from any decline in renal function [24,25]. However, renal toxicity may pose higher risks in resource-limited settings, where experience with tenofovir and access to laboratory monitoring are limited, and where death from acute renal failure may approach 90% [26,27]. Sensitivity analyses on nephrotoxicity within a clinically plausible range did not offset the virologic advantages conferred by tenofovir, suggesting that the benefits would outweigh any potential harm.

In a cost-effectiveness analysis on the use of tenofovir for first-line ART in South Africa, Rosen et al. found that tenofovir reduced toxicity and had a high incremental cost-effectiveness ratio of about $9,000/QALY compared to stavudine using monthly costs of $17 for tenofovir and $3.39 for stavudine in US$2007 [28]. There are several important differences between the Rosen and the current study including treatment efficacy, treatment cost, and analysis time frame. The current analysis used data reflecting improved effectiveness and smaller differences in cost between initial tenofovir and other first-line alternatives, and it evaluated clinical and cost outcomes over a lifetime rather than just 2 years.

We also examined a scenario in which patients had access to only one line of ART, reflecting current limitations in ART rollout capacity, as well as a scenario anticipating access to three lines of ART. We found that the increased efficacy of first-line tenofovir over the alternatives improved its cost-effectiveness when only one line of ART was available. We observed the opposite, though modest, effect when patients had access to a costly third-line regimen. The cost-effectiveness results were stable despite changes in the cost of initial tenofovir when two lines of ART were available, likely because the higher cost of initial tenofovir was offset by the alternative with other strategies, a higher-cost, tenofovir-containing second-line regimen. When only one line of ART was available, the cost of initial tenofovir was more important. These findings together emphasize the importance of policies enhancing access to second-line, and eventually third-line, treatment in optimizing the use of limited resources for HIV treatment. Patients with better adherence may be at greater risk for developing ART toxicities, since drug exposure is a risk factor for adverse events [29]. Toxicities such as lipodystrophy and neuropathy may decrease both adherence and the durability of first-line ART, though this is not clear [30,31]. To address these uncertainties, we varied the effectiveness advantage of tenofovir [7,17]. Although some have shown that tenofovir and stavudine have similar virologic outcomes, we used data that likely reflect lower adherence over time for patients on stavudine due to more chronic toxicities, and we tested this assumption in sensitivity analyses [32].

A very small study suggested that tenofovir combined with nevirapine rather than efavirenz may reduce virologic suppression [33]. If these early findings are substantiated, the selection of a non-nucleoside reverse transcriptase inhibitor (NNRTI) for use with tenofovir should take this into account [2].

The discounted total lifetime costs of three of the ART strategies (initial tenofovir, initial stavudine, and initial stavudine-to-zidovudine), were similar and all around $5,600. Patients who experienced virologic failure on initial tenofovir switched to a less expensive second-line regimen containing zidovudine. Because patients spend the remainder of their lives on the second-line regimen, total costs were about the same as for those who started on a less costly initial regimen. This suggests that second-line ART costs are more important contributors to total lifetime costs than first-line ART costs.

This analysis has several limitations. First, there are limited published data comparing the effectiveness of alternative ART regimens in resource-limited settings. For stavudine- and zidovudine-based first-line ART, we used data from an observational cohort in India, but for initial tenofovir we used US clinical trials, which may reflect better outcomes. We assumed that decreased long-term adherence is implicitly included in the higher long-term virologic failure rates for initial stavudine and zidovudine, and we examined this assumption in extensive sensitivity analyses. In a sensitivity analysis examining equal effectiveness (short-term and long-term) for all first-line ART regimens, we found that tenofovir resulted in equal discounted life expectancy as initial zidovudine, but tenofovir remained the only efficient first-line ART alternative, with an incremental cost-effectiveness ratio of $740/YLS compared to initial stavudine. We did not explicitly model loss to follow-up, but we did examine the consequence of reduced adherence on treatment outcomes using the long-term failure parameter and found that it would render tenofovir more attractive.

Second, there are limited data about ART toxicities in resource-limited settings. We used published data from India on adverse events related to stavudine and zidovudine but US-based estimates for nephrotoxicity and other toxicities. Sensitivity analyses (Figure 1) suggest that nephrotoxicity is unlikely to alter the finding that tenofovir represents an attractive component of first-line ART in resource-limited settings.

Third, this study did not examine outcomes for individuals co infected with HIV and hepatitis B. Given the burden of hepatitis B in India, this analysis likely underestimates the benefits of tenofovir-based therapy [34,35].

Finally, there are scant data on the quality of life impact of ART in India [36]. We found that including plausible quality of life effects increased the cost-effectiveness ratio of tenofovir-based first-line ART to $1,000 compared to no ART from the base case ratio of $670/YLS, but this higher ratio still represents the most efficient use of resources and meets criteria for cost-effectiveness. We examined the quality of life impact for only selected health states in the model.

Determining the best use of limited resources for HIV care is challenging, because the additional expense of initial tenofovir could potentially mean that some HIV-infected patients may not receive needed treatment. Thus, while initial tenofovir may be deemed cost-effective by WHO criteria, it could challenge short-term budget constraints in some countries.

This study has several implications for guidelines on first-line ART in India. While stavudine and zidovudine are effective components of first-line ART, recent substantial price reductions in tenofovir make it a very viable treatment option. As the cost of tenofovir continues to decline, its use will become even more attractive. Incorporating tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for HIV-infected patients in India.

Acknowledgments

We thank the Y.R. Gaitonde Centre for AIDS Research & Education, Chennai, India, and especially A.K. Ganesh and the Natural History Study team at YRG CARE. (Ms. Rasmi and Ms. Glory, research nurses; Mr. S. Anand, data manager; Mr. Guru and Mr. Siva, data entry personnel). We are also indebted to the Scientific Advisory Board for CEPAC-International.

We are grateful to all of the CEPAC-International investigators for their contributions to this project, including:

Y.R. Gaitonde Centre for AIDS Research & Education, Chennai, India: A.K. Ganesh. We thank the Natural History Study team at YRGCARE. (Ms. Rasmi and Ms. Glory, research nurses; Mr. S. Anand, data manager; Mr. Guru and Mr. Siva, data entry personnel).

Harvard School of Public Health, Boston, MA: Kara Cotich, Sue J. Goldie, April D. Kimmel, Marc Lipsitch, Chara Rydzak, George R. Seage III, Milton C. Weinstein, Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Faculté de Médecine de Lille, France, Laboratoire de Recherches Economiques et Sociales, CNRS URA 362, Lille, France: Yazdan Yazdanpanah, Sylvie Burban INSERM U593, Bordeaux, France: Xavier Anglaret, Roger Salamon, Delphine Gabillard, Hapsatou Touré

Programme PAC-CI, Abidjan, Côte d’Ivoire: Xavier Anglaret, Thérèse N’Dri-Yoman, Siaka Touré, Catherine Seyler, Eugène Messou, Christine Danel, Eric Ouattara University of Cape Town, Cape Town, South Africa: Robin Wood, Catherine Orrell Perinatal HIV Research Unit, WITS Health Consortium, Johannesburg, South Africa: Glenda Gray, James McIntyre, Neil A. Martinson, Lerato Mohapi

Yale University, New Haven, Connecticut: A. David Paltiel

Massachusetts General Hospital, Harvard Medical School, Boston, MA: Wendy Aaronson, Ingrid Bassett, John Chiosi, Jennifer Chu, Andrea Ciaranello, Nomita Divi, Mariam O. Fofana, Heather E. Hsu, Benjamin Linas, Elena Losina, Bethany Morris, Brandon Morris, Anjali Saxena, Caroline Sloan, Lauren Uhler, Stacie Waldman, Lindsey L. Wolf.

We are also indebted to the Scientific Advisory Board for CEPAC-International, including: Richard Chaisson (Johns Hopkins Medical School, Baltimore, Maryland, USA); Victor De Gruttola (Harvard School of Public Health, Boston, Massachusetts, USA); Joseph Eron (University of North Carolina, Chapel Hill, North Carolina, USA); Raman R. Gangakhedkar (National AIDS Research Institute (NARI), Pune, India; Jonathan Kaplan (Centers for Disease Control and Prevention, Atlanta, Georgia, USA); Salim Karim (University of KwaZulu Natal, Durban, South Africa); Therese N’Dri Yoman (University of Cocody-Abidjan, Abidkan, Côte d’Ivoire); Douglas Owens (Stanford University, Palo Alto, California, USA); John Wong (Tufts-New England Medical Center, Boston, Massachusetts, USA).

Funding Source: Supported by the National Institute of Allergy and Infectious Diseases (K01 AI074495 and T32 AI007433 to M.A.B, K24AI062476 and R01 AI058736 to K.A.F.), Harvard University Center for AIDS Research (P30 AI060354 to M.A.B.), National Institute on Drug Abuse (K01 DA017179 to B.R.S.), Doris Duke Charitable Foundation Operations Research on AIDS Care and Treatment in Africa (ORACTA) Award (2007015 to K.A.F. and M.A.B.), Doris Duke Charitable Foundation Clinical Scientist Development Award (2005075 to R.P.W.), Harvard Medical School Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine Award (to M.A.B.), and the Lifespan/Tufts/Brown University Center for AIDS Research (P30AI042853 to T.F. and K.H.M.).

APPENDIX: Cost-Effectiveness of Tenofovir as First-Line Antiretroviral Therapy in India

Methods Appendix

Model

Details of the structure of the CEPAC-International model have been described elsewhere [1]. Briefly, patients transition one by one through the state transition model, which stratifies patients by both CD4 count and HIV RNA [1,2]. These characteristics, as well as the transition probabilities between disease states in the absence of treatment, are based on published cohorts [3,4]. Patients may develop opportunistic infections (OI), and they transition between acute health states (OI, drug toxicity) and chronic health states until death. CD4-specific data on incidence of major and minor OIs in untreated HIV infection were derived from the YRG CARE cohort [5]. ART initiation reduces HIV RNA levels and increases CD4 counts for those patients with a virologic response. This rise in CD4 count then decreases the probability of OIs and mortality [6,7]. We derived age- and sex-specific background mortality estimates from WHO life tables for India [8].

Virologic failure

Those individuals meeting clinical criteria for virologic failure on stavudine- or zidovudine-based regimens switched to a second-line regimen containing tenofovir, emtricitabine, and boosted lopinavir, with a 48-week virologic suppression rate of 68%, a CD4 cell count increase of 121 cells/μL, and an estimated long-term probability of virologic failure of 2%/month [9,10]. Patients who failed initial tenofovir switched to zidovudine/lamivudine with boosted lopinavir; in the absence of long-term data on this combination, we used the same virologic and immunologic outcomes as for the other second-line regimen. ART failure was defined as a 50% fall in CD4 count from peak for first-line ART, a 90% fall from peak for second-line ART, or any severe OI after six months on ART(OI) [11,12]. CD4 counts we re measured every six months.

Access to ART after meeting clinical criteria for virologic failure

We used two lines of ART in the base case analysis, but we examined through sensitivity analyses the potential impact of three lines of ART. In these sensitivity analyses, we assumed that 24-week virologic suppression, CD4 count increase, and probability of long-term suppression were the same as for the second-line regimen, and we used a cost of $80/month.

Toxicity from second-line ART

For tenofovir-containing second-line ART, we used a monthly probability of nephrotoxicity of 0.04, a mean time to toxicity of six months, and for those who developed nephrotoxicity, we assumed a 1% probability of mortality [10,13]. For zidovudine-containing second-line ART, we used a monthly probability of anemia of 0.133 and a mean time to toxicity of four months [14]. For both second-line regimens, we used a probability of grade 3/4 gastrointestinal toxicity of 0.032, and a mean time to toxicity of 11 months [15].

Costs

ART costs were converted from US$2008 to US$2005 using exchange rates of 42.38 (US$2008 to 2008 Indian rupee) and 0.02288 (2005 Indian rupee to US$2005) as well as the appropriate GDP deflators [16,17]. Health care utilization for each patient was multiplied by the daily costs for inpatient and outpatient care, and all costs were converted to US$2005 [12,18].

Additional model parameters

For severe lactic acidosis resulting from stavudine, we used a probability of acute mortality of 0.4 [19]. For sensitivity analyses on quality of life, we used the best available data from the US, or clinical judgment (Table A1) [20].

Table A1

Additional selected model input parameters

Analysis

Model runs simulate one million patients with each strategy to ensure stable model outcomes including OIs, toxicity, mean life expectancy, as well as total lifetime costs and cost-effectiveness. The model is programmed in the C++ programming language.

Results Appendix

Sensitivity analysis on the effectiveness of tenofovir

Short-term

We varied the relative 24-week virologic effectiveness advantage of initial tenofovir over initial stavudine between 16% (the base case) and 0% (no advantage). Eliminating the effectiveness advantage – while maintaining the long-term (after 48-week) effectiveness compared to other first-line regimens – reduced discounted life expectancy from 125.9 life months to 121.3 life months and discounted lifetime costs from $5,590 to $5,510. This had minimal impact on the cost-effectiveness results: initial tenofovir remained the only efficient strategy, with an incremental cost-effectiveness ratio of $700/YLS compared to no ART.

APPENDIX REFERENCES

1. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep 11;337(11):725–33. [PubMed]

2. Palella FJ, Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26;338(13):853–60. [PubMed]

3. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997 Jun 15;126(12):946–54. [PubMed]

4. Multicenter AIDS Cohort Study (MACS) Public Dataset: Release PO4. National Technical Information Service; 1995.

5. Wang B, Kumarasamy N, Divi N, et al. Incidence of opportunistic infections (OIs) within specific CD4 strata in HIV-infected patients in Southern India [abstract WePe0279]. XVI International AIDS Conference; August 16, 2006; Toronto, Canada.

6. Losina E, Yazdanpanah Y, Deuffic-Burban S, et al. The independent effect of highly active antiretroviral therapy on severe opportunistic disease incidence and mortality in HIV-infected adults in Cote d’Ivoire. Antivir Ther. 2007;12(4):543–51. [PMC free article] [PubMed]

7. Cole SR, Hernan MA, Robins JM, et al. Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models. Am J Epidemiol. 2003 Oct 1;158(7):687–94. [PubMed]

8. Lopez A, Ahmad O, Guillot M, et al. World Mortality in 2000: life tables for 191 countries. Geneva: World Health Organization; 2002.

9. Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005 Apr 29;19(7):685–94. [PubMed]

10. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS. 2006 Mar 21;20(5):711–8. [PubMed]

11. World Health Organization (WHO) [Accessed 13 March 2009];Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: Towards universal access. 2006 Available at: http://www.who.int/hiv/pub/guidelines/adult/en/index.html.

12. Freedberg KA, Kumarasamy N, Losina E, et al. Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy. AIDS. 2007 Jul;21(Suppl 4):S117–28. [PMC free article] [PubMed]

13. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis. 2005 Apr 15;40(8):1194–8. [PubMed]

14. Kumarasamy N, Venkatesh KK, Cecelia AJ, et al. Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. AIDS Patient Care STDS. 2008 Apr;22(4):337–44. [PubMed]

15. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008 May 15;358(20):2095–106. [PubMed]

16. [Accessed 12 January 2009];Historic lookup. 2009 Available at: http://www.x-rates.com/cgi-bin/hlookup.cgi.

17. The World Bank Group. [Accessed 20 November 2008];World Development Indicators, India GDP Deflator. 2007 Available at: www.worldbank.org.

18. Homan R, Ganesh A, Duraisamy P, et al. Economic analyses of YRG CARE services: Implications for program sustainability. Research Triangle Park, NC, USA: Family Health International; 2000.

19. Claessens YE, Chiche JD, Mira JP, Cariou A. Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors. Crit Care. 2003 Jun;7(3):226–32. [PMC free article] [PubMed]

20. Schackman BR, Goldie SJ, Freedberg KA, Losina E, Brazier J, Weinstein MC. Comparison of health state utilities using community and patient preference weights derived from a survey of patients with HIV/AIDS. Med Decis Making. 2002 Jan-Feb;22(1):27–38. [PubMed]

21. Losina E, Anglaret X, Yazdanpanah Y, et al. Impact of opportunistic diseases on chronic mortality in HIV-infected adults in Côte d’Ivoire. S Afr Med J. 2006 Jun;96(6):526–9. [PubMed]

22. Yazdanpanah Y, Losina E, Anglaret X, Goldie SJ, Walensky RP, Weinstein MC, et al. Clinical impact and cost-effectiveness of co-trimoxazole prophylaxis in patients with HIV/AIDS in Côte d’Ivoire: a trial-based analysis. AIDS. 2005 Aug 12;19(12):1299–308. [PubMed]

23. Anglaret X, Chêne G, Attia A, et al. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d’Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet. 1999 May 1;353(9163):1463–8. [PubMed]

24. Schackman BR, Scott CA, Walensky RP, Losina E, Freedberg KA, Sax PE. The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV. AIDS. 2008 Oct 1;22(15):2025–33. [PMC free article] [PubMed]

25. Lenert LA, Feddersen M, Sturley A, Lee D. Adverse effects of medications and tradeoffs between length of life and quality of life in human immunodeficiency virus infection. The American Journal of Medicine. 2002. 2002 Aug 15;113(3):229–32. [PubMed]

26. Bagust A, Beale S. Modelling EuroQol health-related utility values for diabetic complications from CODE-2 data. Health Econ. 2005 Mar;14(3):217–30. [PubMed]

27. Goldie SJ, Kaplan JE, Losina E, et al. Prophylaxis for human immunodeficiency virus-related Pneumocystis carinii pneumonia: using simulation modeling to inform clinical guidelines. Arch Intern Med. 2002 Apr 22;162(8):921–8. [PubMed]

28. Cecelia AJ, Christybai P, Anand S, et al. Usefulness of an observational database to assess antiretroviral treatment trends in India. Natl Med J India. 2006 Jan-Feb;19(1):14–7. [PubMed]

29. Homan RK, Ganesh AK, Duraisamy P, Castle C, Sripriya, Franklin B, et al. Economic analyses of YRG CARE services. 2000.

Footnotes

Potential conflicts of interest. All authors: no conflicts.

References

1. UNAIDS. [Accessed 13 March 2009];2.5 million people in India living with HIV, according to new estimates. 2007 Available at: http://data.unaids.org/pub/PressRelease/2007/070706_indiapressrelease_en.pdf.

2. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. [Accessed 13 March 2009];Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2008 Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

3. World Health Organization (WHO) [Accessed 13 March 2009];Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: Towards universal access. 2006 Available at: http://www.who.int/hiv/pub/guidelines/adult/en/index.html.

4. The Clinton Foundation. [Accessed 13 March 2009];Antiretroviral (ARV) price list. 2008 Available at: http://www.clintonfoundation.org/download/?guid=62e82ddc-98de-102b-be34-001143e0d9b6.

5. Kumarasamy N, Venkatesh KK, Cecelia AJ, et al. Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. AIDS Patient Care STDS. 2008 Apr;22(4):337–44. [PubMed]

6. Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis. 2003 Apr 15;36(8):1070–3. [PubMed]

7. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251–60. [PubMed]

8. MSF. [Accessed 13 March 2009];Gilead’s Tenofovir’ Access Program’ for Developing Countries: A Case of False Promises? 2006 Available at: http://www.doctorswithoutborders.org/pr/2006/02-07-2006.cfm.

9. National AIDS Control Organization. National AIDS Control Programme -- Phase III [2006 – 2011] [Accessed 13 March 2009];Strategy and Implementation Plan. 2006 Available at: http://www.nacoonline.org/upload/Publication/Strategy%20and%20Implementation%20Plan%20-%20NACO%20Programme%20Phase%20III%20(2006-2011)%202006.pdf.

10. Freedberg KA, Kumarasamy N, Losina E, et al. Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy. AIDS. 2007 Jul;21(Suppl 4):S117–28. [PMC free article] [PubMed]

11. AIDS Clinical Trial Group. Division of AIDS: National Institute of Allergy and Infectious Diseases. 1996. Table of Grading Severity of Adult Adverse Experiences.

12. Kumarasamy N, Venkatesh K, Devaleenol B, et al. Safe substitution to AZT among HIV-infected patients initiated on d4T containing HAART from a resource-limited setting. International Journal of Infectious Disease. [in press]

13. National AIDS Control Organization. [Accessed 13 March 2009];Antiretroviral therapy guidelines for HIV-infected adults and adolescents including post-exposure prophylaxis. 2007 May; Available at: http://www.nacoonline.org/upload/Publication/Treatment%20Care%20and%20support/Antiretroviral%20Therapy%20Guidelines%20for%20HIV-Infected%20Adults%20and%20Adolescents%20Including%20Post-exposure.pdf.

14. Gold MR, Siegel JE, Russell LB, Weinstein MC, editors. Cost Effectiveness in Health and Medicine. New York, N Y: Oxford University Press; 1996.

15. International Monetary Fund. [Accessed 13 March 2009];World Economic Outlook Database: report for selected countries and subjects. 2008 Available at: http://www.imf.org/external/pubs/ft/weo/2004/01/data/dbcoutm.cfm?SD=2001&ED=2005&R1=1&R2=1&CS=3&SS=2&OS=C&DD=0&OUT=1&C=534&S=NGDPDPC&CMP=0&x=53&y=4.

16. Cecelia AJ, Christybai P, Anand S, et al. Usefulness of an observational database to assess antiretroviral treatment trends in India. Natl Med J India. 2006 Jan-Feb;19(1):14–7. [PubMed]

17. Zhou J, Kumarasamy N, Ditangco R, et al. The TREAT Asia HIV Observational Database: baseline and retrospective data. J Acquir Immune Defic Syndr. 2005 Feb 1;38(2):174–9. [PMC free article] [PubMed]

18. Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):535–40. [PubMed]

19. YRG CARE Pharmacy. Unit Costs for Components of HIV-Related Health Care 2005. Chennai, India:

21. Cantor SB. Cost-effectiveness analysis, extended dominance, and ethics: a quantitative assessment. Med Decis Making. 1994 Jul-Sep;14(3):259–65. [PubMed]

22. Laurent C, Kouanfack C, Koulla-Shiro S, et al. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet. 2004 Jul 3;364(9428):29–34. [PubMed]

23. Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. Clin Infect Dis. 2004 Oct 15;39(8):1199–206. [PubMed]

24. Moore R, Keruly J, Gallant J. Tenofovir and Renal Dysfunction in Clinical Practice. Boston, MA. Boston, MA. 2008; 15th Conference on Retroviruses and Opportunistic Infections; Feb 3–6, 2008.

25. Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007 Jun 19;21(10):1273–81. [PubMed]

26. Reid A, Stohr W, Walker AS, et al. Severe renal dysfunction and risk factors associated with renal impairment in HIV-infected adults in Africa initiating antiretroviral therapy. Clin Infect Dis. 2008 Apr 15;46(8):1271–81. [PubMed]

27. Sural S, Sharma RK, Singhal MK, et al. Acute renal failure in an intensive care unit in India--prognostic factors and outcome. J Nephrol. 1999 Nov-Dec;12(6):390–4. [PubMed]

28. Rosen S, Long L, Fox M, Sanne I. Cost and cost-effectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa. J Acquir Immune Defic Syndr. 2008 Jul 1;48(3):334–44. [PubMed]

29. Ammassari A, Antinori A, Cozzi-Lepri A, et al. Relationship between HAART adherence and adipose tissue alterations. J Acquir Immune Defic Syndr. 2002 Dec 15;31(Suppl 3):S140–4. [PubMed]

30. Duran S, Saves M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS. 2001 Dec 7;15(18):2441–4. [PubMed]

31. Corless IB, Kirksey KM, Kemppainen J, et al. Lipodystrophy-associated symptoms and medication adherence in HIV/AIDS. AIDS Patient Care STDS. 2005 Sep;19(9):577–86. [PubMed]

32. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191–201. [PubMed]

33. Lapadula G, Costarelli S, Quiros-Roldan E, et al. Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy-naive HIV-infected patients. Clin Infect Dis. 2008 Apr 1;46(7):1127–9. [PubMed]

34. Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut. 1996;38(Suppl 2):S56–9. [PMC free article] [PubMed]

35. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442–55. [PubMed]

36. Kohli RM, Sane S, Kumar K, Paranjape RS, Mehendale SM. Assessment of quality of life among HIV-infected persons in Pune, India. Qual Life Res. 2005 Aug;14(6):1641–7. [PubMed]

37. Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005 Apr 29;19(7):685–94. [PubMed]

38. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS. 2006 Mar 21;20(5):711–8. [PubMed]

39. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis. 2005 Apr 15;40(8):1194–8. [PubMed]