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Generic Antiretrovirals and the Uncertain Future of HIV Care in the United States - Editorial & study
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Download the PDF here
Download the PDF here
Ann Intern Med. 15 January 2013
Renslow Sherer, MD
Generic antiretroviral drugs have contributed to remarkable achievements in the global HIV epidemic. Mortality has decreased by 24% since 2005, new HIV infections have decreased by 20% since 2001, and 8 million persons are receiving treatment (1). In the United States, 10 available generic antiretrovirals have been used infrequently because of greater toxicity and inferior efficacy. However, when generic efavirenz becomes available in 2013, a regimen of generic efavirenz and lamivudine with branded tenofovir will become a credible alternative to branded regimens.
In this issue, Walensky and colleagues (2) mathematically model the effect of the substitution of generic efavirenz and lamivudine in all people living with HIV (PLWHIV) in the United States who were assumed to receive the branded coformulation of these drugs with tenofovir. They found a 50% reduction in drug costs and a savings of $960 million in care costs in 1 year. They also found reduced treatment efficacy, resulting in 4.4 months of life lost per patient lifetime. Even with substantial variations in the model's assumptions, large-scale cost savings were achieved, and the comparative cost-effectiveness of branded antiretrovirals exceeded the standard threshold of $100 000 per quality-adjusted life-year. Recent studies in Europe and the United Kingdom also report substantial savings with generic antiretrovirals (3 - 5).
Can a regimen of combined generic and branded antiretrovirals perform as well as a preferred branded 1-pill, once-daily coformulation? Current HIV treatment guidelines uniformly recommend the use of coformulated antiretrovirals because of convenience, superior patient adherence, patient and clinician preference, and lower insurance copayments. Most available evidence support these recommendations (6). In 1 exception, once-daily regimens of 2 or 3 equipotent antiretrovirals were not inferior to a branded once-daily coformulation (7). Similarly, although guidelines recommend once-daily dosing when possible, 1 of 4 "preferred" initial regimens is dosed twice daily, and 7 of 11 studies in a meta-analysis found no difference between once- and twice-daily regimens (8).
Would even a small reduction in efficacy be acceptable? In the study by Walensky and colleagues, poorer survival with generics resulted from minor differences of uncertain clinical significance between lamivudine and emtricitabine in resistance outcomes and virologic efficacy from limited trial data (9 - 10). The best regimen choice in their model was generic efavirenz and coformulated emtricitabine plus tenofovir, a 2-pill, once-daily option with similar efficacy and lower cost. Large-scale effectiveness trials that compare generics, including abacavir, with branded coformulations will be critical in assessing the comparability of regimens that contain generic antiretrovirals and defining differences in adherence, virologic success, and health care use. How these studies will be supported is unclear.
Angst and uncertainty about HIV care abound at this time. According to the national version of the "Gardner Cascade," fewer than one third of PLWHIV in the United States have sufficient disease control with treatment, and fewer than half (36%) are reliably receiving care (11). This unacceptably poor performance is worthy of soul-searching. Fortunately, the National AIDS Strategy offers measured and specific guidance to our response to expand HIV testing and improve recruitment and retention in care (12 - 13). Nonetheless, our HIV care "system" is a fragile edifice with disparate parts. Public sources, such as Medicaid, Medicare, and the Ryan White Care Act, support 80% of care for PLWHIV, and the Ryan White Care Act covers only care, drugs, and services that are not supported by Medicare and Medicaid. Under the Affordable Care Act (ACA), 32 million uninsured Americans will enter Medicaid starting in 2014, but of 37 states under single-party control, 24 are hostile to ACA and 20 currently plan not to participate in Medicaid expansion (14). Making matters worse, rules for ACA that were recently issued left the definition of "essential health benefits" and drug formulary composition up to states (15). As a result, existing state-to-state disparities in HIV care and access to antiretrovirals will probably persist or worsen.
In addition to these strains, the Ryan White Care Act, which serves more than 500 000 PLWHIV and provides treatment for 200 000 persons, is up for reauthorization in 2013. High-quality HIV care evolved within the HIV multidisciplinary team with guidance, training, and funding from the act. Many care innovations-such as the HIV medical home and HIV prevention and treatment integrated with maternal-child health, mental health, and substance abuse treatment-may be at risk if the act is subsumed into Medicaid under ACA (16). Community health centers are prioritized under ACA, but many lack skills and capacity for HIV care and will require training. The act's budgets will probably be further strained in states opting out of Medicaid expansion (17). Because half of its expenditures are for medications, generic antiretrovirals will be a critical issue in the reauthorization debate and in state Medicaid formulary budgets. Vigilance by HIV advocates will be critical at the federal and state levels to ensure that the act has sufficient flexibility to improve outcomes in states that expand Medicaid eligibility to include most PLWHIV and in states that decline Medicaid expansion. Activism to persuade reluctant states to expand Medicaid eligibility and to safeguard multidisciplinary HIV care models in the transition into Medicaid will also be crucial.
HIV advocates and caregivers might more readily embrace generic antiretrovirals if, as Walensky and colleagues suggest, the savings were diverted to address other funding needs within the field of HIV medicine, but no such mechanism exists. Perhaps a large, simple trial should be conducted in which generic and branded antiretrovirals are compared and patients in the generic group are allowed to use the cost savings of their regimen to support their annual health insurance premiums, in which case I predict rapid accrual. In any case, Walensky and colleagues' study is a wake-up call to PLWHIV and their clinicians: The era of generic antiretrovirals in the United States has come. The noted infectious diseases physician John G. Bartlett has predicted that the annual cost of antiretrovirals in 10 years will be less than $200, and he has not often been wrong when forecasting HIV care trends in the United States (18).
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Economic Savings Versus Health Losses: The Cost-Effectiveness of Generic Antiretroviral Therapy in the United States
Ann Intern Med. 15 January 2013
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; and Bruce R. Schackman, PhD
from Jules: i didnt see any discussion about the PK of generics, if they are equivalent? have they been researched adequately? what about quality control in manufacturing?
"Generic drugs will save money but may reduce health benefits, a tradeoff that may be controversial.......Some may reject such interventions as substandard and therefore eliminate their consideration on ethical grounds........We project that a population-wide switch from first-line branded ART to generic-based ART in the United States will result in lifetime average savings of $42 500 per eligible patient, with a modest loss of survival of only 0.37 QALY. On a population-wide basis, the aggregate savings in the first year alone would amount to nearly $1 billion. When potential decrements in the short- and long-term efficacy of generic-based regimens are accounted for, we find that the incremental cost-effectiveness of a first-line branded regimen becomes unattractive by a standard recently used in the United States (>$100 000/QALY)
However, economic evaluation of "decremental cost-effectiveness" can identify opportunities to improve efficiency in health care delivery by reallocating resources to higher-value, life-saving alternatives. This is particularly true as an increasing number of proven effective but costly interventions further stretch the resources of the U.S. health care system. The U.S. 2010 National HIV/AIDS Strategy (36) is explicitly financed by "repurposed" rather than new funds (37). In an era in which dedication to the national HIV mission requires "redirected" financing, the potential $1 billion savings from generic-based regimens might be an efficient source available for national reinvestment (38). For example, fewer than half of the state AIDS Drug Assistance Programs in the United States include protease inhibitor-based hepatitis C virus (HCV) regimens ($90 100 per treatment course) in their formularies, despite these drugs having ICERs less than $100 000/QALY (as reported in monoinfected patients) (39 - 40). For every 15 persons who switch to a generic-based HIV regimen (potential annual savings of approximately $6100/person), 1 person co-infected with HIV and HCV could be treated for and potentially cured of chronic hepatitis C (39). With approximately 300 000 U.S. persons co-infected with HIV and HCV and eligible for these new HCV therapies, this would represent a major treatment opportunity, although it remains unclear whether such saved resources would be reallocated in this direction (40 - 41).
Our assumptions about generic drug efficacy and pricing are conservative. We assumed, on the basis of in vitro clinical trials and observational data, that daily lamivudine would be less effective and would promote more resistance than emtricitabine when used as either a first- or second-line regimen. We also assumed an adherence advantage for a daily single-pill regimen because, with 1 exception, literature on observational studies indicates that there is a relationship between taking fewer pills and better HIV regimen adherence (4,42 - 44). Taken as a whole, these assumptions suggest that the potential loss of life expectancy for generic-based ART could be as high as 0.37 QALY. To put this value in perspective, this is also the approximate survival benefit associated with intensive hypertension control in patients with type 2 diabetes (45). Our 75% price reduction is justified by evidence that generic prices decrease by as much as 80% to 85% of published branded prices when 5 or more manufacturers enter a market (46 - 47). More than 7 suppliers currently provide FDA-approved generic efavirenz outside the United States under the auspices of the U.S. President's Emergency Plan for AIDS Relief (48)."
ABSTRACT
Background: 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.
Objective: 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.
Design: Mathematical simulation of HIV disease.
Setting: United States.
Patients: HIV-infected persons.
Intervention: No ART (for comparison); 3-pill, generic-based ART; and branded ART.
Measurements: Quality-adjusted life expectancy, costs, and incremental cost-effectiveness ratios (ICERs) in dollars per quality-adjusted life-year (QALY).
Results: 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.
Limitation: The efficacy and price reduction associated with generic drugs are unknown, and estimates are intended to be conservative.
Conclusion: 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.
Primary Funding Source: National Institute of Allergy and Infectious Diseases.
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Editors' Notes
Context
· 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.
Contribution
· 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.
Caution
· Simulation models may not reflect real-world results.
Implication
· The use of first-line, generic-based HIV treatment in the United States could save nearly $1 billion a year.
-The Editors
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A convenient, frequently prescribed, and currently recommended first-line antiretroviral therapy (ART) regimen is branded tenofovir-emtricitabine-efavirenz, which is coformulated as a single once-daily pill (1). For the first time since the initial U.S. Food and Drug Administration (FDA) approval of combination ART in 1996, there is the potential for a potent and largely generic first-line ART regimen. In January 2012, generic versions of lamivudine became available in the United States (2), and generic versions of efavirenz are expected soon (3). A once-daily, 3-pill regimen of generic efavirenz, generic lamivudine, and branded tenofovir could substantially reduce the costs of first-line ART.
However, even if the suppressive efficacy, tolerability, and safety of generic lamivudine and efavirenz meet the required FDA standards of their proprietary equivalents, at least 2 potential disadvantages remain (Appendix Table 1). First, the increased pill burden-3 pills versus 1 pill daily-could hinder adherence and reduce viral suppression, thus leading to worse outcomes (4 - 5). Second, although lamivudine is generally considered to be a safe alternative to emtricitabine, lamivudine has been associated with slightly inferior antiretroviral efficacy and an increased frequency of drug resistance on treatment failure in laboratory and clinical studies (6 - 9). Given these tradeoffs, we sought to assess the clinical effect, cost, and cost-effectiveness of generic-based ART compared with branded coformulated alternatives.
Discussion
We project that a population-wide switch from first-line branded ART to generic-based ART in the United States will result in lifetime average savings of $42 500 per eligible patient, with a modest loss of survival of only 0.37 QALY. On a population-wide basis, the aggregate savings in the first year alone would amount to nearly $1 billion. When potential decrements in the short- and long-term efficacy of generic-based regimens are accounted for, we find that the incremental cost-effectiveness of a first-line branded regimen becomes unattractive by a standard recently used in the United States (>$100 000/QALY) (32 - 34).
The market for antiretroviral drugs in the United States, largely financed with governmental support, was estimated at nearly $9 billion in 2011 (35). Much is at stake as major components of effective HIV therapy become generically available this year. The importance of this analysis lies not only in its relevance to the current discussion of generic efavirenz but also in the development of a framework by which future generations of generic antiretroviral drugs-and the tradeoff between drug efficacy and cost savings-may be evaluated. Our assessment may be updated on report of head-to-head comparisons of the 2- and 3-pill generic regimens or of other generic regimens, including those using abacavir. These studies would be most helpful if they described the relative efficacy (that is, immediate virologic suppression and durability over time) and resource utilization (for example, hospitalizations and drug costs) associated with these 2 alternatives.
Generic drugs will save money but may reduce health benefits, a tradeoff that may be controversial. Fewer than 0.4% of published cost-effectiveness analyses report on interventions that confer a combination of lower health benefits and lower costs. Some may reject such interventions as substandard and therefore eliminate their consideration on ethical grounds. However, economic evaluation of "decremental cost-effectiveness" can identify opportunities to improve efficiency in health care delivery by reallocating resources to higher-value, life-saving alternatives. This is particularly true as an increasing number of proven effective but costly interventions further stretch the resources of the U.S. health care system. The U.S. 2010 National HIV/AIDS Strategy (36) is explicitly financed by "repurposed" rather than new funds (37). In an era in which dedication to the national HIV mission requires "redirected" financing, the potential $1 billion savings from generic-based regimens might be an efficient source available for national reinvestment (38). For example, fewer than half of the state AIDS Drug Assistance Programs in the United States include protease inhibitor-based hepatitis C virus (HCV) regimens ($90 100 per treatment course) in their formularies, despite these drugs having ICERs less than $100 000/QALY (as reported in monoinfected patients) (39 - 40). For every 15 persons who switch to a generic-based HIV regimen (potential annual savings of approximately $6100/person), 1 person co-infected with HIV and HCV could be treated for and potentially cured of chronic hepatitis C (39). With approximately 300 000 U.S. persons co-infected with HIV and HCV and eligible for these new HCV therapies, this would represent a major treatment opportunity, although it remains unclear whether such saved resources would be reallocated in this direction (40 - 41).
Our assumptions about generic drug efficacy and pricing are conservative. We assumed, on the basis of in vitro clinical trials and observational data, that daily lamivudine would be less effective and would promote more resistance than emtricitabine when used as either a first- or second-line regimen. We also assumed an adherence advantage for a daily single-pill regimen because, with 1 exception, literature on observational studies indicates that there is a relationship between taking fewer pills and better HIV regimen adherence (4,42 - 44). Taken as a whole, these assumptions suggest that the potential loss of life expectancy for generic-based ART could be as high as 0.37 QALY. To put this value in perspective, this is also the approximate survival benefit associated with intensive hypertension control in patients with type 2 diabetes (45). Our 75% price reduction is justified by evidence that generic prices decrease by as much as 80% to 85% of published branded prices when 5 or more manufacturers enter a market (46 - 47). More than 7 suppliers currently provide FDA-approved generic efavirenz outside the United States under the auspices of the U.S. President's Emergency Plan for AIDS Relief (48).
We note several limitations in this analysis. The $100 000/QALY threshold for cost-effectiveness, although frequently cited, may be debated (33,49 - 50). Higher willingness-to-pay thresholds could result in branded regimens falling within a range considered acceptable. Although we conducted this analysis from the U.S. health system perspective, we acknowledge that the savings realized from a policy switch to generic-based regimens may be applied differently from one payer to the next (for example, state AIDS Drug Assistance Programs vs. state Medicaid programs or the U.S. Veterans Administration); these savings may not be reinvested in HIV care or even in health care. They may also be greater than we project. If efforts to improve HIV case identification and linkage to and retention in care are successful, this would increase the outlay for HIV medications and the anticipated savings from generic drugs could exceed our $920 million estimate (51).
Compared with a slightly less effective regimen containing generic drugs, we found that the incremental cost-effectiveness for the branded 1-pill, first-line ART regimen exceeds $100 000/QALY. Starting or switching to generic-based regimens would initially yield annual savings approaching $1 billion for programs that fund HIV treatment in the United States.
Results
Base-Case Results
In the base case, the discounted per-person quality-adjusted life expectancies from age 43 years were 4.05 QALYs (undiscounted, 4.58 QALYs) for no ART; 12.08 QALYs (undiscounted, 18.36 QALYs) for 3-pill, generic-based ART; and 12.45 QALYs (undiscounted, 19.32 QALYs) for branded ART (Table 2). Mean duration of receipt of the first-line regimen decreased from 12.1 years for branded ART to 10.0 years for 3-pill, generic-based ART (both undiscounted). Per-person discounted lifetime costs increased from $131 200 (no ART) to $300 300 for generic-based ART and $342 800 for branded ART. Compared with no ART, 3-pill, generic-based ART resulted in an ICER of $21 100/QALY. The ICER for branded ART, compared with generic-based ART, was $114 800/QALY (Table 2 and Figure 1).
Two-Pill, Generic-Based ART
Two-pill, generic-based ART resulted in greater survival than 3-pill, generic-based ART in the base case (12.25 vs. 12.08 QALYs). When 3- and 2-pill, generic-based ART and branded ART were compared incrementally, ICERs were $21 100/QALY for 3-pill, generic-based ART versus no ART; $95 400/QALY for 2-pill, generic-based ART versus 3-pill, generic-based ART; and $130 600/QALY for branded versus 2-pill, generic-based ART (Table 2 and Appendix Figure 2).
Sensitivity Analyses
Three-Pill, Generic-Based ART
The ICER for branded ART compared with 3-pill, generic-based ART was sensitive to the comparative cost and efficacy of generic-based ART (Figure 2). At the base-case efficacy of generic-based ART (24-week suppression, 78%; probability of late failure, 0.45%/month), branded ART had an ICER greater than $100 000/QALY, provided that the discount from AWP for generic-based ART was greater than 69% (Figure 2). If the probability of 24-week suppression remained lower for 3-pill, generic-based ART than for branded ART but the monthly probability of late failure was the same (0.21%), the ICERs of branded compared with 3-pill, generic-based ART were substantially higher at every combination of 24-week efficacy and price reduction for generic-based ART (Appendix Figure 3). Under such conditions, even modest price reductions (>40% AWP) for the generic regimen components resulted in ICERs greater than $100 000/QALY for branded ART compared with generic-based ART (Appendix Figure 3).
Two-Pill, Generic-Based ART
Results for 2-pill, generic-based ART were similarly sensitive to regimen efficacy-most important, to the probability of late failure-and costs. When 2-pill, generic-based; 3-pill, generic-based; and branded ART all had the same probability of late failure (0.21% at 24 weeks), 2-pill, generic-based ART had an ICER less than $100 000/QALY compared with 3-pill, generic-based ART at price reductions of 50% AWP ($62 600/QALY) (Table 3). If branded and 2-pill, generic-based ART had similar probabilities of late failure (0.21%) (lower than that of 3-pill, generic-based ART [0.45%]), 2-pill, generic-based ART became much more attractive. At all price reductions examined, 2-pill, generic-based ART was the best choice because it dominated (was more effective and less costly than) 3-pill, generic-based ART and because of the very high ICERs for branded ART ($101 300 to $2 540 100/QALY) (Table 3).
Other Sensitivity Analyses
In other sensitivity analyses, we saw variability in outcomes but no material effect on the qualitative cost-effectiveness findings when we changed the efficacy of second-line ART to capture changes related to potential lamivudine-related resistance (branded ART ICERs, $109 300 to $120 600/QALY), when we considered a healthier presenting cohort (mean CD4 count, 0.650 x109 cells/L; branded ART ICER, $143 200/QALY), or when we adjusted background mortality rates by risk group (branded ART ICER, $117 400/QALY) (Appendix Tables 3, 4, 5, and 6).
Potential Savings in the First Year
The per-person undiscounted savings for 3-pill and 2-pill, generic-based ART compared with branded ART were $6100/year and $3700/year. We estimate that there are 2500 persons newly diagnosed and initiating ART ("incident cases") and 147 300 HIV-infected persons ("prevalent cases") currently receiving an efavirenz-based regimen who could switch to generic-based ART in the United States (30). Combining the benefits from incident and prevalent cases, the potential estimated savings in the first year associated with the use of 3-pill, generic-based ART in the base case were $920 million; the anticipated savings were substantially less for 2-pill, generic-based ART ($560 million). Anticipated savings in the first year from 3-pill, generic-based ART ranged from $200 million to $1.29 billion at price reductions of 35% to 95% from AWP (Appendix Figure 4).
Methods
Analytic Overview
We evaluated 3 strategies for HIV-infected persons eligible to initiate an efavirenz-based regimen: no ART (for comparison); 3-pill, generic-based ART consisting of efavirenz (generic), lamivudine (generic), and tenofovir (Viread; Gilead Sciences, Foster City, California); or branded ART, consisting of the 1-pill efavirenz-emtricitabine-tenofovir formulation (Atripla; Gilead Sciences and Bristol-Myers Squibb, Newark, New Jersey). For ease of identification, we refer to the "generic-based ART strategy" even though it contains 1 branded component. In the base case, generic-based ART differs from branded ART in 3 ways. First, viral suppression efficacy in first-line therapy is presumed to be lower because of increased pill burden (poorer adherence) and decreased potency (substitution of lamivudine for emtricitabine). Second, viral suppression efficacy in second-line therapy is presumed to be lower because of reported increased frequency of M184V mutations associated with failure of first-line viral suppression from lamivudine versus emtricitabine. Finally, first-line drug costs are lower. We varied all of these parameters in sensitivity analyses.
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-US Model, a previously published mathematical simulation of HIV (10 - 14), to project clinical outcomes (quality-adjusted life-years [QALYs]) and economic outcomes (per-person lifetime costs) for the 3 strategies. These projections were then used to evaluate incremental cost-effectiveness ratios (ICERs), which we report from a U.S. health system perspective, discounted at 3% per year (15). We also projected the undiscounted savings in the first year among all patients who are receiving or starting an efavirenz-based treatment and are eligible to switch from branded to generic-based ART.
The CEPAC-US Model
The CEPAC-US Model characterizes HIV disease progression as a sequence of monthly transitions between "health states." These states comprise current status, relevant history, quality of life, and resource use and determine the risk for future clinical events. Health states are stratified by CD4 cell count (5 strata), HIV RNA level (6 strata), ART regimen, and disease acuity (for example, treatment-related toxicity or opportunistic infection). In the model, the level of HIV RNA determines the rate of the decrease in CD4 cell count, and the CD4 cell count determines the frequency of opportunistic infections and AIDS-related deaths. Patients face a risk for HIV-related mortality (opportunistic infections and otherwise) or age- and sex-adjusted background mortality (16).
We capitalized on the model's capacity to consider early-regimen mutations and virologic failure in determining the efficacy of subsequent regimens. Per current U.S. guidelines (1), we assumed that all newly presenting patients initiate therapy immediately. Effective ART functions to suppress HIV RNA and increase CD4 cell count at rates reported (Table 1 and Appendix Table 2) (20 - 27). Quarterly clinic visits and monitoring of CD4 cell count and HIV RNA confirm the possibility of "early suppression" followed by "late failure," 2 model-based parameters that define ART efficacy (Appendix Figure 1). Early suppression of a regimen is the fraction of patients virologically suppressed after 24 weeks. Patients with suppression subsequently have a probability of late failure, defined as a monthly probability of virologic rebound after initial suppression. Once detected, virologic failure results in a switch to a subsequent regimen and another-albeit diminishing-opportunity for suppression. The model translates input variation in adherence and regimen selection into changes in ART efficacy and thereby into changes in clinical and cost outcomes.
Input Parameters
Further details on the protocols we used for model validation and to assemble appropriate literature-derived estimates are available in the Appendix and elsewhere (14).
Cohort
The entering cohort was modeled similarly to newly diagnosed HIV-infected patients in the United States in 2009 (28), among whom 84% were male. Recent U.S. data suggest a mean CD4 count at presentation of 0.317 x 109 cells/L (Table 1) (17,28).
ART Efficacy
In the no-ART strategy, patients follow the natural progression of HIV disease without access to ART. A clinical trial using coformulated 1-pill tenofovir-emtricitabine-efavirenz found that branded ART results in 24-week virologic suppression of 85%, with a 0.21% monthly probability of late failure after 24 weeks (20). For this strategy, we used a second-line, protease inhibitor-based regimen with a 24-week suppression efficacy of 73% (21 - 22). A clinical trial of efavirenz, lamivudine, and tenofovir found that 3-pill, generic-based ART leads to 24-week virologic suppression of 78% (24). Using trial data, we derived the monthly probability of failure after 24 weeks as 0.45%, which is substantially higher than that of branded ART. To capture the laboratory-described increased risk for M184V mutations resulting from first-line lamivudine, we also decreased the suppression rate of second-line ART by 5%, from 73% with branded ART to 68% with generic-based ART (6 - 7). Because there are currently no data suggesting that efavirenz-based toxicity will differ between the brand-name and generic drugs, we attribute this difference to first-line lamivudine use only. Efficacies and costs for subsequent ART regimens (provided in Appendix Table 2) are otherwise identical between treatment strategies.
An intermediate alternative to 3-pill, generic-based ART is a 2-pill formulation that uses coformulated tenofovir-emtricitabine (Truvada; Gilead Sciences) and generic efavirenz. Recognizing the uncertainty surrounding the comparative efficacy of once-daily regimens consisting of 1, 2, or 3 pills, we examined all options together in generalized sensitivity analyses designed to illuminate the tradeoffs among early efficacy, late failure, and costs. We began with a 24-week suppressive efficacy of 84% and a monthly probability of failure thereafter of 0.43% with 2-pill, generic-based ART (23); we maintained the full potency of the second-line regimen because of the inclusion of emtricitabine in the first-line regimen (Table 1). Other efficacy and cost combinations were also examined.
Costs
The annual cost for branded ART is $15 300 (19), 77% of the published average wholesale price (AWP) for standard dosing (Table 1) (29). We assumed a 75% price reduction from AWP (including discounts) for the generic components of the 3-pill, generic-based ART regimen ($9200/year) and the 2-pill, generic-based ART regimen ($11 600/year) and explored reductions from 35% to 95%. Subsequent ART regimen, laboratory monitoring, and costs of routine care are shown in Appendix Table 2. All costs are in 2009 U.S. dollars.
Sensitivity Analyses
We used 1-way and multiway sensitivity analyses to understand the effect of uncertainty in efficacies of early virologic suppression, probabilities of late failure, and the comparative cost savings from generic-based ART. We also examined alternative second-line ART efficacies associated with an increased presence of M184V mutations and considered cohorts with higher or lower CD4 cell counts leading to varying durations of ART. Finally, we examined the effect on our results from risk-group adjustments to our estimates of non-HIV-related mortality.
Potential Savings in the First Year
To determine the potential savings in the United States during the first year, we multiplied the number of persons eligible to start or switch to generic-based ART by the per-person savings. "Incident cases" likely to be prescribed efavirenz were calculated as the product of the anticipated new diagnoses in the United States per year (8294 in 2009) (28), the estimated fraction of HIV-infected persons receiving ART (36%) (30), and the likelihood that an efavirenz-based regimen is selected as first-line therapy (85%) (31). "Prevalent cases" who switched from an efavirenz-based branded regimen to the generic-based alternative were calculated as the product of Centers for Disease Control and Prevention-based projections of the number of persons living with HIV in the United States (1 200 000) (28), the estimated proportion receiving ART (36%) (30), and the estimated proportion receiving an efavirenz-based ART regimen (34%) (Gebo K. Personal communication.) (30). We multiplied the number of persons eligible for a generic start or switch by the potential per-person savings associated with generic-based ART in the first year. These savings are the difference between the undiscounted annual costs of branded ($15 300) and generic ($9200) ART ($6100 per person).
Role of the Funding Source
The National Institute of Allergy and Infectious Diseases supported the study. The funding source did not have any role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication.
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