Rochelle P. Walensky, MD, MPH; Paul E. Sax, MD; Yoriko M. Nakamura, BA; Milton C. Weinstein, PhD; Pamela P. Pei, PhD; Kenneth A. Freedberg, MD, MSc; A. David Paltiel, PhD; Bruce R. Schackman, PhD
Note: This study was exempt from the Institutional Review Board by the Partners Human Research Committee Protocol 200P001927.
Acknowledgment: The authors thank Kelly Gebo, MD, MPH, and the HIV Research Network for supplying helpful data.
Grant Support: By grants R37-AI42006 and R01-AI093269 from the National Institute of Allergy and Infectious Diseases.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1790.
Reproducible Research Statement: Study protocol, statistical code, and data set: Details are available in the Appendix, on the CEPAC Web site (http://web2.research.partners.org/cepac/mainpage.html), and from Dr. Walensky (address below).
Requests for Single Reprints: Rochelle P. Walensky, MD, MPH, Division of Infectious Disease, Medical Practice Evaluation Center, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.
Current Author Addresses: Drs. Walensky, Pei, and Freedberg and Ms. Nakamura: Medical Practice Evaluation Center, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.
Dr. Sax: Brigham and Women's Hospital, Infectious Disease, 75 Francis Street, Boston, MA 02115.
Dr. Weinstein: Harvard School of Public Health, 718 Huntington Avenue, Boston, MA 02115.
Dr. Paltiel: Yale School of Public Health, PO Box 208034, 60 College Street, New Haven, CT 06520.
Dr. Schackman: Department of Public Health, Weill Cornell Medical College, 411 East 69th Street, New York, NY 10021.
Author Contributions: Conception and design: R.P. Walensky, P.E. Sax, M.C. Weinstein, K.A. Freedberg, A.D. Paltiel.
Analysis and interpretation of the data: R.P. Walensky, P.E. Sax, Y.M. Nakamura, M.C. Weinstein, P.P. Pei, K.A. Freedberg, A.D. Paltiel, B.R. Schackman.
Drafting of the article: R.P. Walensky, P.E. Sax, Y.M. Nakamura, M.C. Weinstein, P.P. Pei, A.D. Paltiel.
Critical revision of the article for important intellectual content: R.P. Walensky, P.E. Sax, M.C. Weinstein, P.P. Pei, K.A. Freedberg, A.D. Paltiel, B.R. Schackman.
Final approval of the article: R.P. Walensky, P.E. Sax, M.C. Weinstein, P.P. Pei, K.A. Freedberg, A.D. Paltiel, B.R. Schackman.
Provision of study materials or patients: R.P. Walensky.
Statistical expertise: R.P. Walensky, M.C. Weinstein, P.P. Pei.
Obtaining of funding: R.P. Walensky, K.A. Freedberg.
Administrative, technical, or logistic support: R.P. Walensky, Y.M. Nakamura, P.P. Pei, K.A. Freedberg.
Collection and assembly of data: R.P. Walensky, P.E. Sax, Y.M. Nakamura, B.R. Schackman.
U.S. HIV treatment guidelines recommend branded once-daily, 1-pill efavirenz–emtricitabine–tenofovir as first-line antiretroviral therapy (ART). With the anticipated approval of generic efavirenz in the United States, a once-daily, 3-pill alternative (generic efavirenz, generic lamivudine, and tenofovir) will decrease cost but may reduce adherence and virologic suppression.
To assess the clinical effect, costs, and cost-effectiveness of a 3-pill, generic-based regimen compared with a branded, coformulated regimen and to project the potential national savings in the first year of a switch to generic-based ART.
Mathematical simulation of HIV disease.
No ART (for comparison); 3-pill, generic-based ART; and branded ART.
Quality-adjusted life expectancy, costs, and incremental cost-effectiveness ratios (ICERs) in dollars per quality-adjusted life-year (QALY).
Compared with no ART, generic-based ART has an ICER of $21 100/QALY. Compared with generic-based ART, branded ART increases lifetime costs by $42 500 and per-person survival gains by 0.37 QALYs for an ICER of $114 800/QALY. Estimated first-year savings, if all eligible U.S. patients start or switch to generic-based ART, are $920 million. Most plausible assumptions about generic-based ART efficacy and costs lead to branded ART ICERs greater than $100 000/QALY.
The efficacy and price reduction associated with generic drugs are unknown, and estimates are intended to be conservative.
Compared with a slightly less effective generic-based regimen, the cost-effectiveness of first-line branded ART exceeds $100 000/QALY. Generic-based ART in the United States could yield substantial budgetary savings to HIV programs.
National Institute of Allergy and Infectious Diseases.
In the United States, provision of HIV treatment relies heavily on government funding. A recommended option for first-line treatment of HIV infection is the daily administration of a single pill containing 3 branded drugs.
In a mathematical simulation, daily administration of 3 pills (2 of which are generic drugs and 1 of which is a branded drug) taken simultaneously dramatically reduced cost and only slightly reduced survival gain compared with the use of a fully branded regimen.
Simulation models may not reflect real-world results.
The use of first-line, generic-based HIV treatment in the United States could save nearly $1 billion a year.
Appendix Table 1.
Tradeoffs Between Generic-Based and Branded ART
Base-Case Inputs for Model of Generic-Based Versus Branded ART in the United States
Appendix Table 2.
Base-Case ART Efficacy Inputs and Costs for Later ART Regimens in Analysis of First-Line Generic-Based Versus Branded ART in the United States
Simplified schema of modeled patients as they progress through first-line ART (branded or generic-based) in the CEPAC Model.
Squares indicate decision nodes, and circles indicate chance nodes. ART = antiretroviral therapy; CEPAC = Cost-Effectiveness of Preventing AIDS Complications.
Clinical Outcomes, Cost, and Cost-Effectiveness of Generic-Based Versus Branded ART in the United States
Clinical and economic outcomes of branded and 3-pill, generic-based ART.
Per-person lifetime costs are on the x-axis, and life expectancy in QALYs is on the y-axis. The dotted-and-dashed line indicates the anticipated incremental cost-effectiveness ratio of branded ART compared with no ART in the absence of a generic alternative. ART = antiretroviral therapy; QALY = quality-adjusted life-year.
Clinical and economic outcomes of branded compared with 2-pill and 3-pill, generic-based ART.
Per-person lifetime costs are on the x-axis, and life expectancy QALYs in on the y-axis. The dotted-and-dashed line indicates the anticipated incremental cost-effectiveness ratio of branded ART compared with no ART in the absence of a generic alternative. ART = antiretroviral therapy; QALY = quality-adjusted life-year.
Two-way sensitivity analyses with base-case rates of late failure.
The graph shows the changes in the ICER of branded ART compared with 3-pill, generic-based ART (y-axis) as a function of the generic drug price reduction (x-axis) and the early efficacy of 3-pill, generic-based ART in HIV RNA suppression. In the base case, branded ART has an ICER greater than $100 000/QALY as long as the generic drug discount from the AWP is greater than 69% (circle). This figure represents results when the monthly probability of late failure (after 24 wk) is 0.45% for both 3-pill, generic-based ART and 0.21% for branded ART. ART = antiretroviral therapy; AWP = average wholesale price; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.
Two-way sensitivity analyses with equal rates of late failure for generic-based and branded ART.
The graph shows the changes in the ICER of branded ART compared with 3-pill, generic-based ART (y-axis) as a function of the generic drug price reduction (x-axis) and the early efficacy of 3-pill, generic-based ART in HIV RNA suppression. This figure represents results when the monthly probability of late failure (after 24 wk) is 0.21% for both 3-pill, generic-based ART and branded ART. Even modest price reductions (>40%) for the generic regimen components result in ICERs for branded ART greater than $100 000/QALY (circle). ART = antiretroviral therapy; AWP = average wholesale price; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.
Three-Way Sensitivity Analysis of 2-Pill Versus 3-Pill, Generic-Based ART; Probability of Late Failure After 24 Weeks; and Price Reduction
Appendix Table 3.
Sensitivity Analysis of Second-Line ART Efficacy for 3-Pill, Generic-Based ART
Appendix Table 4.
Sensitivity Analysis Showing the Effect on Clinical Outcomes, Cost, and Cost-Effectiveness for Alternative Mean CD4 Cell Counts of Presenting Cohort
Appendix Table 5.
Sensitivity Analysis Showing the Effect on Clinical Outcomes, Cost, and Cost-Effectiveness When Background Mortality Is Adjusted by Risk Group
Appendix Table 6.
Three-Way Sensitivity Analysis of 2-Pill Versus 3-Pill, Generic-Based ART; Probability of Virologic Failure After 24 Weeks; and Price Reduction When Background Mortality Is Adjusted by Risk Group
Potential annual cost savings in the United States with 3-pill or 2-pill, generic-based ART compared with branded ART.
The potential annual savings for 2-pill or 3-pill, generic-based ART are compared with branded ART over a range of generic drug price reductions. The x-axis shows the price reductions, which range from 35% to 95%; the base case of 75% savings is indicated by the arrow. The y-axis shows the amount of money projected to be saved (million 2009 U.S. dollars) over a 1-y horizon. Calculations in this analysis assume that all persons maintain their designated generic or branded ART regimen for the first year and do not switch to a subsequent line of therapy before the end of 12 mo. ART = antiretroviral therapy; AWP = average wholesale price.
Comparison of CEPAC Model outcomes and data reported from WIHS.
Kaplan–Meier survival curves based on data from WIHS were compared with preliminary, model-estimated survival over 36 mo in women with CD4 counts <0.050 × 109 cells/L and >0.350 × 109 cells/L. Lines with symbols represent model-based projections, whereas those without symbols represent WIHS data. CEPAC = Cost-Effectiveness of Preventing AIDS Complications; WIHS = Women's Interagency HIV Study.
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Gottfried Hirnschall (1), Cornelis de Joncheere (2)
(1) Director, HIV/AIDS Department, World Health Organization, Geneva, Switzerland (2) Director, Department of Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland
January 18, 2013
Generic antiretroviral therapy is safe and effective
Rochelle Walensky and colleagues provide important estimates of the potential cost savings associated with the introduction of generic-based antiretroviral therapy (ART) in the United States . Using conservative assumptions, they estimate first-year savings of up to US$ 920 million and lifetime average savings of US$ 42,500 per eligible patient. However, the authors of the study caution that this may require a tradeoff between drug efficacy and cost savings, as the regimens proposed in the model are not available fixed-dose combinations and may have inferior efficacy and could lead to poor adherence.
We would like to highlight three points related to this analysis.First, the assumption of inferior efficacy is based on the suggesting that lamivudine (3TC) has poorer efficacy than emtricitabine (FTC). This assumption is in contrast to a recent systematic review that found no evidence of any difference between the two drugs in terms of efficacy and safety . Second, the assumption of poorer adherence is based on the fact that generic formulations are not available as fixed-dose combinations. This may be the case in the United States, but quality-assured generic fixed-dose combinations of tenofovir, emtricitabine and efavirenz (TDF+FTC+EFV) do exist and are used in other parts of the world. .Third, each of the scenarios includes the originator TDF product because TDF is patented in the US, and the estimated cost of this regimen is US$ 9,200 per patient/year. However, a fixed-dose combination of TDF+FTC+EFV including generic TDF is currently available internationally and costs less than US$ 200 per patient/year .Taken together, these points suggest that potential cost savings in the United States of using generic regimens could be even greater than concluded by this analysis, with no negative consequences in terms of efficacy or adherence. It is important to also highlight that in this analysis, presumed differences between generic and originator regimens are associated with the use of different drugs (3TC versus FTC), and formulations (separate tablets rather than fixed-dose combinations), and not the use of generic drugs per se:
Walensky et al rightly consider quality-assured generic and originator drugs to be equivalent in terms of safety and efficacy. Despite ongoing doubts and controversies about the use of generic antiretrovirals over the last decade , comparative studies have found no differences in safety or efficacy between originator and quality-assured generic antiretrovirals . Ensuring access to affordable antiretroviral therapy has been an essential precondition of the global scale up of antiretroviral therapy, and both generic and originator companies have an important role to play in ensuring that current and future antiretroviral regimens are accessible and affordable for all who need them.
The study by Walensky et al opens an important discussion about the extent to which patients in the United States are able to access more affordable, fixed-dose antiretroviral regimens that are already available in many other countries. Unfortunately, the findings of the modeling study are being portrayed as indicative of the need to make an ethical trade-off between cost savings and efficacy . Such an interpretation is misleading and is not supported by the extensive global evidence of the efficacy of quality-assured generic ART.
1.Walensky RP, Sax PE, Nakamura YM, Weinstein MC, Pei PP, Freedberg KA, Paltiel AD, Schackman BR. Economic savings versus health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med. 2013 Jan 15;158(2):84-92. doi: 10.7326/0003-4819-158-2-201301150-00002.
2. Pharmacological equivalence and clinical interchangeability of lamivudine and emtricitabine: a review of current literature: Technical update on treatment optimization. World Health Organization, Geneva, July 2012.
3. Untangling the web of antiretroviral price reductions. Medecins Sans Frontieres, Geneva, July 2012. Accessed http://utw.msfaccess.org/
4. Ford N, 't Hoen E. Generic medicines are not substandard medicines. Lancet. 2002 Apr 13;359(9314):1351;
5. Stringer J, Mwango A, Giganti M et al. Effectiveness of generic and proprietary first-line antiretroviral regimens in a primary health care setting in Lusaka, Zambia: a cohort study. Int J Epidemiol 2012;41:448–59.
6. Study questions generic HIV drug use. BBC, 16 January 2013. Available : http://www.bbc.co.uk/news/health-21012160
Rochelle P. Walensky, MD, MPH, A.David Paltiel, PhD, and Bruce R. Schackman, PhD
Massachusetts General Hospital
February 26, 2013
We thank Drs. Hirnschall and de Joncheere for their letter. They provide important new information and useful global context, both of which strengthen the case in support of the once-daily, 3-pill formulation of generic efavirenz, generic lamivudine, and tenofovir that will soon be available in the United States (1).
The World Health Organization (WHO) review – a report that was motivated by in vitro studies suggesting pharmacologic differences between emtricitabine and lamivudine that we noted (2) – finds clinical equivalence between the two drugs. Because this result was not available at the time that we conducted our analysis, we adopted a conservative approach, assigning the branded formulation a small efficacy advantage. Despite our deliberate bias against it, the generic regimen containing lamivudine emerged as the strongly preferred approach. Adopting the equivalence findings demonstrated in the WHO review, which we considered in sensitivity analyses, would make an already-strong argument in favor of generics even stronger.
Drs. Hirnschall and de Joncheere also remark that using the fixed-dose combinations of generic ART available globally may eliminate the adherence disadvantage that we ascribed to multi-pill formulations. We agree. However, our objective in this paper was to limit the scope to options that will soon be available in the American market under US patent law: namely, a once-daily, three-pill, formulation with generic efavirenz, generic lamivudine, and tenofovir or a once-daily, two-pill formulation with generic efavirenz and the fixed-dose combination emtricitabine/tenofovir. Policy makers in the US will imminently face the question of how to evaluate these options. We demonstrate that these generic regimens are strongly preferred, from a cost-effectiveness perspective, even in the absence of single-pill fixed-dose generic drugs available elsewhere in the world.
The introduction of quality-assured generic antiretrovirals has saved the lives of millions of people around the world. Our analysis does not challenge the critical impact and tremendous value of that endeavor. Indeed, we find that the case in support of generics is overwhelming, from both a clinical and an economic point of view.
Jennifer Y. Lee, MD, Timothy P. Flanigan, MD
February 27, 2013
The Impact of Generic Antiretroviral Medications on ADAP
In “Economic Savings Versus Health Losses: The Cost-Effectiveness of Generic Antiretroviral Therapy in the United States,” Walensky and colleagues predict that switching from branded once-daily 1-pill efavirenz-emtricitabine-tenofovir to a once-daily 3-pill generic based alternative of generic efavirenz, generic lamivudine, and branded tenofovir in the United States will decrease costs by $920 million in the first year alone. Given the current financial strain placed upon the US health care system, particularly with respect to the financing of costly branded antiretroviral medications by struggling programs such as the AIDS Drug Assistance Program (ADAP), these significant cost-savings make generic HIV antiretroviral therapy an attractive prospect.
As the highest-expenditure portion of Part B of the greater Ryan White program, ADAP required a total budget of $1,885,764,620 in FY 2011, representing a 5% budget increase from the previous year. ADAP supplies life-sustaining antiretroviral medications to patients who face otherwise insurmountable barriers to treatment. In 2010, ADAP provided medications to 226,419 people, a number that has steadily increased over the years. Many ADAP clients are the most in-need patients from traditionally marginalized groups, with many considered minorities and 44% falling under the federal poverty line . Even with ADAP, however, access to necessary medications may be denied to patients, as ADAP funds are strained, limiting the number of patients receiving medication. Waiting lists, limiting available drugs, and raising the eligibility criteria have all been methods used unfortunately to restrict access to medications .
The prospective $920 million first-year cost savings resulting from a switch to a generic-based 3-pill antiretroviral therapy, framed in the context of ADAP, then becomes even more attractive and significant. In FY2011, ADAP total drug expenditures came to $135,138,130. Taking the month of June 2011 as representative, 91.7% of total drug expenditures can be attributed to antiretrovirals . If, keeping with Walensky et al.’s assumption that generic pricing would result in a 75% price reduction from the average wholesale price, meaning that a 3-pill generic-based ART regiment would cost $9200/year, instead of the current $15300/year for branded ART (which is 77% of the published AWP for standard dosing), a cost savings of $49,406,676 on antiretroviral medication expenditures could have been achieved by ADAP in 2011.
Cost savings from the switch to generic antiretroviral therapy would be crucial for cash-strapped HIV care programs like ADAP, hopefully allowing them to ultimately provide necessary medications to many more patients in need.
1. Kaiser Family Foundation [Internet]. Menlo Park, CA: Kaiser Family Foundation [cited 2013 February 23]. HIV/AIDS; [about 4 screens]. Available from: http://www.statehealthfacts.org/comparecat.jsp?cat=11&rgn=6&rgn=1
2. HIV/AIDS Bureau, Health Resources and Services Administration [Internet]. Rockville, MD: U.S. Department of Health and Human Resources [cited 2013 February 23]. A Living History: The Ryan White HIV/AIDS Program: Part B. Available from: http://hab.hrsa.gov/livinghistory/programs/Program_Part_B_Essay.pdf
Walensky RP, Sax PE, Nakamura YM, Weinstein MC, Pei PP, Freedberg KA, et al. Economic Savings Versus Health Losses: The Cost-Effectiveness of Generic Antiretroviral Therapy in the United States. Ann Intern Med. 2013;158:84–92. doi: 10.7326/0003-4819-158-2-201301150-00002
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