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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e318220f016
Supplement Article

Optimizing Antiretroviral Product Selection: A Sample Approach to Improving Patient Outcomes, Saving Money, and Scaling-up Health Services in Developing Countries

Amole, Carolyn D BA; Brisebois, Catherine BS; Essajee, Shaffiq MD; Koehler, Erin BA; Levin, Andrew D MD, PhD; Moore, Meredith C MSc; Brown Ripin, David H PhD; Sickler, Joanna J MBA, MPH; Singh, Inder R MBA, MPP, MS

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Author Information

From the Access Programs, Clinton Health Access Initiative (CHAI).

The authors have no funding or conflicts of interest to disclose.

Correspondence to: Inder R. Singh, MBA, MPP, MS, 383 Dorchester Avenue, Suíte 400, Boston, MA 02127 (e-mail: isingh@clintonhealthaccess.org).

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Abstract

Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.

Access to HIV medicines in low-income and middle-income countries has grown from fewer than 200,000 patients on treatment in 2000 to more than 5 million in 2010, driven by a significant increase in donor and government funding, reaching $18 billion in 2010.1 Despite this impressive progress, work remains. Antiretroviral (ARV) coverage rates remain below 40%, and the recent global financial crisis will likely slow the pace of ongoing treatment scale-up. The two largest donors, responsible for approximately 60% of global funding for HIV treatment programs, are facing significant constraints. Funding from the United States President's Emergency Plan for AIDS Relief (PEPFAR) has essentially flatlined, and pledges to the Global Fund to Fight AIDS, Tuberculosis and Malaria fell short of the lowest funding scenario provided to donors in the last cycle.2

In this context, many countries face hard choices and critical tradeoffs. Should national programs prioritize earlier initiation of antiretroviral treatment to reduce morbidity and mortality, better-tolerated medicines to improve patient outcomes, expanded coverage of interventions for prevention of mother-to-child transmission to curb vertical transmission or other initiatives? As these debates take place, we argue that more attention should be paid to opportunities that save cost and enable expanded coverage without compromising quality of care. ARV product selection, the choice of which formulations and regimens to procure for patients, offers opportunities to reduce the cost of HIV treatment while achieving better or equivalent patient outcomes. Here we describe 3 specific examples, which could save more than $300 million over the coming 5 years. The lessons and principles of ARV product selection can and should be applied to procurement practices more broadly in resource-constrained settings.

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PRINCIPLES OF PRODUCT SELECTION

Since 2002, the World Health Organization (WHO) has issued evidence-based guidelines on the use of ARV drugs for treatment of HIV-infected patients. While WHO recommendations are developed primarily based on evidence from clinical trials of clinical safety and efficacy, they also consider feasibility, acceptability, and cost.3 However, the WHO guidelines leave specific product selection decisions to national AIDS control programs. In addition to the public health considerations recommended by WHO—epidemiological context, health care system strengths and weaknesses, and availability of financial and human resources—national HIV/AIDS programs can consider other factors when selecting specific products and drug formulations for procurement, such as:

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Availability

In most countries, products must be registered with the National Drug Regulatory Authority. Timelines and requirements for registration review vary significantly by product and country, so new drug formulations sometimes face long delays before becoming available in specific countries.

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Convenience

Recent studies have highlighted the connection between the convenience of a regimen and patient adherence. Suboptimal adherence can be associated with low drug levels, leading to the development of drug resistance and resulting in poor patient outcomes. Regimens with a low pill burden or those that can be dosed once daily have been shown to have adherence advantages over less convenient regimens and should therefore be prioritized, when clinically appropriate, over less convenient regimens.4

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Price

Current and future price trends are important to consider, as pricing for key ARV formulations can change dramatically due to advances in manufacturing or greater competition from the entry of new suppliers. For example, over the last 4 years, the prices of tenofovir (TDF) and efavirenz have declined by about 60% and 70%, respectively, putting the price of once-daily TDF-based regimens within 30% of the cost of twice-daily regimes based on zidovudine (AZT). This difference is expected to decrease to 15% within the coming year, and further reductions are likely.5,6 This type of data, if accessible and appropriately used, can be enormously helpful to AIDS control programs as they consider treatment options.

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Logistics

Product selection decisions must be made with regard for the broader program context. For example, in-country supply chain systems often struggle to cope with the extensive number of drugs needed to effectively care for HIV-infected patients. Regimens that require cold chain management or those that require a patient to take multiple medications per day are much more resource intensive than regimens that can be administered as a once-daily heat-stable fixed-dose combination (FDC), in which multiple drugs are combined into 1 pill. In addition, certain drugs have specific clinical and laboratory monitoring requirements, such as screening for anemia with AZT, which requires laboratory resources and may not be practical in some settings.

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SPECIFIC OPPORTUNITIES

Taking these key issues into considerations, we have identified a trio of opportunities that countries could immediately exploit to lower ARV expenditures while maintaining or improving quality of care:

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Boosted Atazanavir-Containing Regimens in Contrast to Boosted Lopinovir-Containing Regimens for Second-Line Therapy

The WHO recommends atazanavir boosted with ritonavir (ATV/r) and lopinavir boosted with ritonavir (LPV/r) as the preferred protease inhibitors for second-line therapy.3 Unlike LPV/r, ATV has not been widely used in developing markets due to the lack of a heat-stable formulation of ritonavir (RTV). Heat-stable RTV is now available, making ATV a viable option for resource-limited settings. FDC and copack formulations of ATV/r are in development and should become available shortly.

ATV/r has demonstrated comparable efficacy to LPV/r in clinical trials, with lower risk of elevated cholesterol and improved gastrointestinal tolerability.7 In the context of a second-line treatment regimen, ATV/r can be administered more conveniently as 2 pills taken once daily versus 4 pills once or twice daily for LPV/r. Once available, the ATV/r FDC will offer an even greater convenience benefit as 1 pill to be taken once a day. ATV/r is currently priced at a 30% discount to LPV/r, with the differential expected to increase over the coming 5 years. Based on an analysis conducted in 18 countries, we estimate that the cost savings associated with adopting ATV/r in place of LPV/r exceeds $160 million over the next 5 years. Some countries have already taken advantage of this opportunity; India recently adopted ATV/r as the preferred protease inhibitor in its national treatment guidelines and will begin prescribing the drug in early 2011 for all new second-line patients. As a result, India expects to save roughly $18 million on antiretroviral treatment expenditures over the next 5 years. (See Figure 1 for countries included. Analysis assumes 100% uptake among all new second-line patients, according to the CHAI ARV forecasting model over the next 5 years and uses average prices currently accessed in-country for LPV/r compared with CHAI ceiling prices for ATV + RTV. The savings estimates are not discounted).

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Lamivudine Instead of Emtricitabine (in Both First-Line and Second-Line Therapy)

Based on 3 key studies, both the United States' Food and Drug Administration and the WHO have deemed lamivudine (3TC) and emtricitabine (FTC) clinically interchangeable,3,8-10 though direct head-to-head comparisons are limited. One small study11 found higher rates of treatment failure with a once-daily TDF/3TC/NVP regimen compared with twice daily AZT/3TC/NVP. However, the study's small size, the presence of other variables, and a lack of confirmatory evidence from other trials suggest other factors may have had a role in the observed difference. Indeed, another small study12 looking at twice daily dosing of NVP with daily FTC rather than 3TC also found unacceptable rates of failure, implicating NVP as the more problematic component. FDC containing TDF + 3TC are available in generically accessible countries and are priced roughly 20% less than TDF + FTC, allowing for between $50 and $80 million in savings over the next 5 years if adopted preferentially over TDF + FTC combinations. Patient numbers are based on the CHAI ARV forecasting model over the next 5 years and average prices currently accessed in-country are used to calculate savings. The range accounts for difference between new patients only versus new and existing. The savings estimates are not discounted. Recognizing this cost-saving opportunity, Uganda has dramatically reduced its use of FTC during the past year, and FTC is now prescribed for only a fraction of patients on TDF-containing regimens. Based on the prices Uganda was accessing at the time of its decision, the country estimated that it would save approximately $10 million over 5 years.

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In Second-Line Therapy, TDF + 3TC Instead of Abacavir + Didanosine

The 2010 WHO guidelines demoted abacavir (ABC) + didanosine (ddI) as preferred nucleosides in second-line treatment regimen options, yet many patients remain on this combination.3 The vast majority of patients in low-income countries are currently on stavudine based first-line regimens and would therefore be eligible for the alternative option of TDF + 3TC, which offers clinical, convenience, and cost advantages. TDF + 3TC is available as a once-daily, 1-pill FDC, whereas ABC + ddI requires a patient to take 5 pills daily. ABC + ddI have also been reported to be associated with increased risk of cardiovascular events, unlike TDF + 3TC.13,14 Finally, TDF + 3TC is approximately 75% less costly than ABC + ddI—a differential that could result in more than $40 million in savings over the next 5 years if all newly failing patients are instead put on TDF-based or AZT-based second-line regimens. (See Figure 1 for countries included. Analysis assumes 100% uptake among all new second line patients failing d4T based first line regimens and uses average prices currently accessed in country for TDF + 3TC versus ABD + ddI).6

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DISCUSSION

With the ongoing need to scale up ARV treatment in a resource-constrained environment, the 3 opportunities described above provide patients with superior or equivalent treatment options while achieving considerable savings for national programs and donors. If these opportunities were implemented, approximately 750,000 additional patients could be treated for 3 years in developing countries assuming average first-line treatment price of $137 per patient per year2.

All of these efficiencies, however, are contingent on national programs proactively reviewing their formularies and assessing them for potential optimization opportunities. Analysis of countries' patient regimen data can highlight the use of suboptimal treatments, from a clinical and a cost perspective. By standardizing and consolidating regimens, countries can simplify their supply chains and procure key ARV at better prices. Technology and treatment standards will continue to evolve, requiring programs to systematically reevaluate. For example, the development of new products, potentially including dose-reduced forms of existing ARV, over the next 3-5 years will provide additional opportunities to decrease expenditures without compromising treatment outcomes. In the near term, optimizing product selection offers a direct way to enhance treatment, generate significant savings, and continue to move toward the goal of universal access to HIV treatment in the developing world.

A number of barriers exist to executing against this approach in most resource-constrained settings. We characterize these barriers as ones relating to incentives, to capacity for analysis of product tradeoffs, and to communication channels.

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Incentives Problem

Despite the financial crisis and funding gap, HIV treatment programs are still well funded relative to many other programs. Although striving to provide high-quality care, programs are not always incentivized to find the most efficient allocation of resources possible. For example, a country with a large existing Global Fund grant may have more urgent priorities than one with more limited funding that is under pressure to find new ways to ensure further scale-up.

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Capacity for Analysis of Product Trade-Offs

Consolidated access to product availability, best prices, and convenience metrics, in conjunction with clinical safety and efficacy, may not be readily available to program staff.

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Gap in Communication Channels

Lack of formal communication structures between guidelines committees, key opinion leaders, and budget and procurement teams create additional barriers to programs achieving these opportunities. These types of communication structures ensure that synthesized analyses of product trade-offs are placed into the hands of key decision makers when they make product selection and procurement decisions.

With the right incentives, information, and communication structures in place, significant opportunities exist to increase health system efficiencies in HIV and beyond. As more countries look to integrate treatment vertically and leverage best practices across disease states, these efficiencies are particularly important to identify and pursue. Exploring opportunities to save costs while maintaining or improving quality of care through product selection—in HIV and other diseases with multiple treatment options or other fungible commodities—can provide countries with much-needed funds to expand and improve their health care systems. Beyond the savings incurred, taking an integrated holistic approach to product selection also creates the communications channels and networks required to truly integrate heath care services in developing countries.

Identifying opportunities and approaches to overcoming health system inefficiencies, like with optimizing ARV product selection, will be vital to sustaining and strengthening quality care in resource-limited settings.

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ACKNOWLEDGMENTS

CHAI would like to thank the UK Government's Department for International Development and the Bill and Melinda Gates Foundation for their funding of CHAI's work to enhance access to medicines and commodity procurement efficiency in the developing world.

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REFERENCES

1. Aids 2031 Costs and Financing Working Group. Costs and Choices: Financing the Long-Term Fight Against AIDS. Washington, DC: Results for Development Institute; 2010.

2. World Health Organization (WHO). Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector: Progress Report 2010. Geneva, Switzerland: WHO; 2010.

3. WHO. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach—2010 Rev. Geneva, Switzerland; WHO; 2010.

4. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. NIH Web site. 2008. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 9, 2011.

5. Médecins Sans Frontières. Untangling the Web of Price Reductions: A Pricing Guide for the Purchase of ARVs for Developing Countries. 8th ed. Geneva, Switzerland: Médecins Sans Frontières; 2006. Available at: http://utw.msfaccess.org/downloads. Accessed February 9, 2011.

6. Clinton Health Access Initiative. Antiretroviral (ARV) Price List. November 2010. William J. Clinton Foundation; 2010. Available at: http://www.clintonfoundation.org/what-we-do/clinton-health-access-initiative/information-center-resources. Accessed February 9, 2011.

7. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53:323-332.

8. DeJesus E, McCarty D, Farthing CF, et al. Once daily versus twice daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial. Clin Infect Dis. 2004;39:411-418.

9. Madruga JR, Cassetti I, Suleiman JM, et al. The safety and efficacy of switching stavudine to tenofovir DF in combination with lamivudine and efavirenz in HIV-1—infected patients: three-year follow-up after switching therapy. HIV Clin Trials. 2007;8:381-390.

10. Benson CA, van der Horst C, LaMarca A, et al. Open label equivalence trial comparing 3TC 150 mg BID with FTC 200 mg QD. AIDS. 2004;18:2269-2276.

11. Rey D, Hoen P, Chavanet P, et al. High rate of early virological failure with once-daily tenofovir/lamivudine/nevirapine combination in naïve HIV-1-infected patients. J Antimicrob Chemother. 2009;63:380-388.

12. 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-naïve HIV-infected patients. Clin Infect Dis. 2008;46:1127-1129.

13. Sabin CA, Worm SW, Weber R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction (MI)? Recent use of abacavir and didanosine, but not of thymidine analogues, is associated with risk of myocardial infarction. Copenhagen HIV Program Web site. 2008. Available at: http://www.cphiv.dk/Portals/0/Files/Jens_CROI08_957c_300108.pdf. Accessed February 9, 2011.

14. Viread [package insert]. Foster City, CA: Gilead Science, Inc; 2010.

Keywords:

ARV

© 2011 Lippincott Williams & Wilkins, Inc.

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