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In a nutshell
- Problem: HIV/AIDS is one of the leading causes of adult deaths in the developing world.
- Program: Antioretroviral therapy (ART) is a treatment for HIV/AIDS that can prolong and improve patients' lives, and potentially reduce the risk that they will infect others.
- Track record: ART does effectively prolong life. However, it is not entirely clear (a) for how long it can prolong life, (b) what the long-term side effects of treatment may be, and (c) how different types of individuals respond (e.g., effectiveness for drug users versus others).
- Cost-effectiveness: ART is estimated to cost over $100 per year of treatment provided. We previously concluded that this made ART substantially less cost-effective than many other global health interventions, but we plan to revisit this conclusion in light of falling confidence in other cost-effectiveness estimates.
- Basics of the program
- Program track record
Basics of the program
What is the program? What problem does it target?
Anti-retroviral therapy (ART) is a treatment for HIV/AIDS. It does not cure the disease;1 rather, it aims to increase life expectancy,2 reduce opportunistic infections,3 and may potentially reduce the likelihood that an infected individual transmits the virus to another.4 (More on HIV/AIDS)
What are the components required to implement this program - how does it work?
A successful ART program requires all of the following:
- Diagnosis. A means for testing individuals to identify those in need of treatment. In the case of ART, diagnosis consists of more than merely testing an individual for HIV/AIDS. This is because when the disease is far enough along, the toxicity of the drugs may outweigh the benefits of starting treatment.5
- Distribution. A method for distributing the drugs to those who need them.
- Drugs. Antiretroviral drugs can be costly. (For more, see our cost-effectiveness section below.)
- Patient adherence to drug regimen. ART consists of a relatively complex drug regimen to which patients must strictly adhere.6 And because ART does not cure HIV/AIDS,7 patients must adhere to the regimen as long as they remain alive.
- Monitoring of the patient's response to treatment. ART may cause negative side effects in a patient.8 In addition, laboratory monitoring may be needed for purposes of noticing decreased efficacy or the development of resistance.9
Program track record
Micro evidence: Has this program been rigorously evaluated and shown to work?
A review by the Cochrane Collaboration states, "Combination antiretroviral therapy administered to HIV-infected individuals has been shown to decrease viral replication, improve immunologic function and delay the progression of HIV infection."10
People on ART do not appear to have fully normal lifespans. A recent review of 14 studies following patients who had received ART in high-income countries as far back as 1996 found that those on treatment lost 247 "potential person-years of life" (years of life between the ages of 20 and 64) per 1,000 person-years.11 These figures vary significantly based on a patient's background characteristics. For example, injecting drug users receiving ART lost 506 "potential person-years of life" per 1,000 person-years.12
Evidence also suggests (though not highly rigorously) that ART can also reduce the chances that a patient transmits the virus to others.13
Macro evidence: Has this program played a role in large-scale success stories?
The Disease Control Priorities Report states that "because antiretroviral therapy has historically been unavailable in most developing countries, national programs have lacked the means to undertake a comprehensive approach to HIV/AIDS (notable exceptions are Argentina, Brazil, and Mexico, which provide universal coverage for antiretroviral therapy)."14 We also have seen references to Botswana as an example of successfully implementation of mass coverage of ART.15
What are the potential downsides of the intervention?
ART can harm patients by causing complications from latent or undiagnosed opportunistic infections,16 causing direct side effects,17 or by causing other illnesses over the long term due to the drugs' toxicity.18
The cost-effectiveness of providing a patient with ART depends on:
- A patient's adherence to the regimen. A patient must adhere closely to the drug regimen or it can quickly become ineffective. (For more, see our discussion of drug adherence, above.) In practice, it appears that patient adherence can vary significantly.19
- The cost of drugs. The cost of drugs has changed significantly since the introduction of ART.20
The most recent estimate we've found of drug costs comes from The Global Fund to Fight Aids, Tuberculosis and Malaria, which reports median expenditures on drugs of $188 per person per year of first-line ART drugs21, and $588 per person per year for all ART program costs22 across its large, broad global project portfolio.23 We have also examined data from the William J. Clinton Foundation's HIV/AIDS Initiative (CHAI), which provides drug procurement services for some of the ART drugs purchased by more than 70 countries.24 In 2007, according to this data, the cost of a year's worth of ART was $299 for first-line drugs and $709 for second-line drugs.25
- The effectiveness of the drugs. Based on a review of 14 studies of long-term patients on ART (discussed above), we believe that a year's worth of ART saves .50-.75 years of life.
The Disease Control Priorities Report estimates that ART costs $350-$1,494 per disability-adjusted life-year (DALY) averted in Sub-Saharan Africa.26 This is equivalent (from a simple conversion calculation)27 to $129.50-$552.78 per year spent on ART, which seems roughly consistent with the drug price estimates given directly above. (More on the DALY metric.)
We previously concluded that this made ART substantially less cost-effective than many other global health interventions, but we plan to revisit this conclusion in light of falling confidence in other cost-effectiveness estimates.
- Antiretroviral Therapy Cohort Collaboration. 2008. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: A collaborative analysis of 14 cohort studies. Lancet 372: 293-9.
- AVERT. HIV & AIDS in Botswana. http://www.webcitation.org/archive?url=http://www.avert.org/aids-botswan... (accessed April 16, 2010). Archived by WebCite® at http://www.webcitation.org/5p2oaKxqE.
- Centers for Disease Control and Prevention. Effect of Antiretroviral Therapy on Risk of Sexual Transmission of HIV Infection and Superinfection. http://www.cdc.gov/hiv/topics/treatment/resources/factsheets/art.htm (accessed October 28, 2010). Archived by WebCite® at http://www.webcitation.org/5toWmi1Op.
- Copenhagen Consensus. Copenhagen Consensus 2008. http://www.copenhagenconsensus.com/Default.aspx?ID=953 (accessed April 16, 2010). Archived by WebCite® at http://www.webcitation.org/5p2vqZV71.
- Gates Foundation. Working with Botswana to confront the AIDS crisis. http://www.gatesfoundation.org/learning/Pages/Botswana-ACHAP-AIDS-progre... (accessed April 16, 2010). Archived by WebCite® at http://www.webcitation.org/5p2vuDHuy.
- Global Fund. Innovation and impact (2010) (PDF).
- Jamison, Dean T. et al., eds. 2006. Disease control priorities in developing countries (2nd edition) (PDF). Washington DC: Oxford University Press and The World Bank.
- Jamison, Dean, Prabhat Jha, and David Bloom. 2008. Copenhagen Consensus 2008 challenge paper: Diseases (PDF).
- Lopez, Alan et al., eds. 2006. Global burden of disease and risk factors (PDF). New York: Oxford University Press.
- Rutherford, G., P. Sangani, and G.E. Kennedy. 2000. Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection. Cochrane Database of Systematic Reviews 2003, Issue 4. Summary available at http://www.cochrane.org/reviews/en/ab002037.html (accessed April 16, 2010). Archived by WebCite® at http://www.webcitation.org/5p2vrBI7s.
- WebMD. HIV: Taking antiretroviral drugs. http://www.webmd.com/hiv-aids/taking-antiretroviral-drugs-for-hiv-infection (accessed July 8, 2010). Archived by WebCite® at http://www.webcitation.org/5r4mPqn0x.
- William J. Clinton Foundation. Access programs. http://www.clintonfoundation.org/what-we-do/clinton-hiv-aids-initiative/... (accessed April 16, 2010). Archived by WebCite® at http://www.webcitation.org/5p2vqyfYp.
- William J. Clinton Foundation. Antiretroviral price list (2009) (PDF).
- William J. Clinton Foundation. Annual report (2007) (PDF).
- World Health Organization. 2008. Global burden of disease: 2004 update (PDF).
"Taking antiretroviral drugs for HIV will not cure your infection. But it may allow you to stay healthy for a long time." WebMD, "HIV: Taking Antiretroviral Drugs."
"Combination therapy with multiple antiretroviral drugs is associated with prolonged survival. Whereas monotherapies are associated with one year or less of additional survival, the survival benefit conferred by combination therapy appears to be sustainable for extended periods (Palella and others 2003). Long-term toxicities related to treatment may include athero- sclerosis, lipodystrophy, hepatic failure, and cardiac failure. Researchers are still evaluating the effects of these toxicities on HIV/AIDS mortality." Jamison et al. 2006, Pg 355.
"Antiretroviral therapy is effective in reducing viral load and partially enabling immune restoration, thereby preventing the onset and recurrence of opportunistic infections. If taken strictly according to directions, antiretroviral therapy can induce a sustained recovery of CD4 cell reactivity against opportunistic pathogens in severely immunosuppressed patients (Li and others 1998). The effectiveness of antiretroviral therapy is determined by its ability to rapidly reduce viral load and to sustain low levels of viral activity. This viral activity is what has an independent effect on increasing or decreasing sus- ceptibility to opportunistic infections (Kaplan and others 2001)." Jamison et al. 2006, Pg 354.
"In addition to the benefits antiretroviral therapy has for the individual being treated (Komanduri and others 1998; Ledergerber and others 2001), it almost certainly has other effects on populations where therapy is widely available. Effective antiretroviral therapy appears to decrease the infectiousness of treated individuals. Chemoprophylaxis in exposed, uninfected people may reduce transmission. In addition, availability of treatment may destigmatize the disease and make prevention programs more effective (Castro and Farmer 2005)." Jamison et al. 2006, Pg 349.
"Initiating antiretroviral therapy has a proven benefit for patients with a CD4 count of fewer than 350 cells per cubic millimeter (Palella and others 2003). In patients with a higher CD4 count, the benefits of antiretroviral therapy are believed to be outweighed by the toxicities that may accrue from continued drug exposure (Mallal and others 2000)." Jamison et al. 2006, Pg 357.
"With certain drugs, resistance can develop in as little as two weeks if therapy is suboptimal (which can be less than 90 percent adherence). Conversely, patients who adhere to therapy can obtain continued viral suppression for many years without the need for second- or third-line options. Patients in resource-limited countries are likely to be subjected to a number of influences that challenge their ability to adhere to the prescribed therapy, including limited education and the consequent poorer understanding of their disease state, unstable housing and financial circumstances, a limited number of treatment options, and clinicians with limited antiretroviral therapy treatment experience (Kitahata and others 1996)." Jamison et al. 2006, Pg 358.
"Taking antiretroviral drugs for HIV will not cure your infection. But it may allow you to stay healthy for a long time." WebMD, "HIV: Taking Antiretroviral Drugs."
"The effectiveness of antiretrovirals depends on not only the benefits conferred, but also the associated side effects, the toxicity level of the drugs, and the patients' adherence to the drug regimen. The ability of care providers to detect incipient toxicity at an early stage also influences the magnitude of side effects and toxicities. In low-income settings with limited laboratory capacity, a greater proportion of side effects will not be detected until they become severe." Jamison et al. 2006, Pg 357.
"Laboratory monitoring determines when antiretroviral therapy should be initiated and when it should be changed because of toxicity, lack of efficacy, or resistance. The optimal frequency and precision of monitoring depends on numerous factors." Jamison et al. 2006, Pg 358-9.
Rutherford, Sangani and Kennedy, 2000, Abstract.
- Antiretroviral Therapy Cohort Collaboration 2008, Pg 294, Table 2.
- "Potential years of life lost (PYLL) were calculated as the sum of years that HIV-positive participants in our analyses lost because of premature death. PYLL is calculated with death before the age of 65 years being considered premature, since this is deemed to be the age at which most people retire. PYLL were expressed as per 1000 person-years from age 20 to 64 years." Antiretroviral Therapy Cohort Collaboration 2008, Pg 295.
Antiretroviral Therapy Cohort Collaboration 2008, Pg 296, Table 4.
See Centers for Disease Control and Prevention, "Effect of Antiretroviral Therapy on Risk of Sexual Transmission of HIV Infection and Superinfection."
Jamison et al. 2006, Pg 332.
- Gates Foundation, "Working with Botswana to confront the AIDS crisis."
- AVERT, "HIV & AIDS in Botswana."
"Initiating antiretroviral therapy can also have detrimental effects by causing complications from latent or undiagnosed opportunistic infections, especially in resource-poor settings." Jamison et al. 2006, Pg 354.
"It is well documented that initiating antiretroviral therapy in severely immunosuppressed patients can result in illnesses associated with reconstitution of the immune system (Shelburne and others 2005)." Jamison et al. 2006, Pgs 354-5.
"Long-term toxicities related to treatment may include atherosclerosis, lipodystrophy, hepatic failure, and cardiac failure. Researchers are still evaluating the effects of these toxicities on HIV/AIDS mortality." Jamison et al. 2006, Pg 355.
"Studies in India, Mexico, Senegal, and Uganda point to poor adherence (which for some classes of drugs can be adherence of less than 95 percent), inadequate doses and regimes, and poor monitoring as factors that contribute to more rapid development of antiretroviral therapy resistance (Oyugi and Bangsberg 2004, Laniece and others 2004, Bautista and others 2003, Liechty and Bangsberg 2003). By contrast, experiences in Haiti and Uganda suggest that it is possible to achieve adherence rates in developing countries equal to or better than those observed in high-income countries (Farmer and others 2001; Mitty and others 2002)." Jamison et al. 2006, Pg 358.
"In recent years, the most volatile parameter in cost-effectiveness analyses for HIV/AIDS has been the prices of antiretroviral drugs, which have dropped by about two orders of magnitude for some LMICs. Price reductions have not been consistent across countries, nor have they necessarily been larger for the poorest countries. This variability in pricing greatly complicates the establishment of national guidelines regarding which regimens to prescribe under which circumstances, because the ranking of regimens varies among and within countries as relative prices change." Jamison et al. 2006, Pg 357.
"In 2008, the overall median price of commonly used drug regimens for all countries with Global Fund programs was US$ 188 (IQR: US$ 171 – $US 209). The median price increased with national income level." Global Fund, "Innovation and Impact (2010)," Pg 70.
"Based on these estimates, in 2008, the overall median cost of providing first-line ART for Global Fund programs was around US$ 588 per patient-year (IQR: US$ 571 – US$ 609): US$ 526 in low-income countries, US$ 645 in lower-middle income countries and US$ 740 in upper-middle income countries." Global Fund, "Innovation and Impact (2010)," Pg 70.
See the summary of Global Fund-supported programs starting on Global Fund, "Innovation and Impact (2010)," Pg 106 for a sense of the scope of the Global Fund's project portfolio.
"CHAI's Access Programs have worked with generic pharmaceutical companies to negotiate affordable prices for HIV/AIDS medicine. Since 2003, CHAI has completed pricing agreements for 40 formulations of antiretrovirals (ARVs) with eight companies. Currently, more than 70 countries have access to reduced pricing for these medicines." William J. Clinton Foundation, "Access Programs."
William J. Clinton Foundation, "Annual Report (2007)," Pg 14. See William J. Clinton Foundation, "Antiretroviral Price List (2009)" for a complete list of drug prices as of August 2009. A more recent list may be available at http://www.clintonfoundation.org/what-we-do/clinton-hiv-aids-initiative/....
Context on first- vs. second-line drugs:
"Studies from high-income countries have unequivocally demonstrated that the probability that an antiretroviral therapy regimen will achieve viral suppression diminishes with each subsequent regimen (Deeks and others 1999) ... Thus, the expected survival benefit per month of antiretroviral therapy declines with each change of regimen. In contrast, the monthly cost of therapy rises as a patient moves from first-line to more expensive protease inhibitor–based second-line and subsequent therapies. Given this steadily declining cost-effectiveness, wealthier countries are likely to offer a greater number of regimen changes than poorer countries." Jamison et al. 2006, Pg 358.
Jamison et al. 2006, Pg 62, Table 2.B.1.
A year spent with AIDS is equated with 0.505 DALYs, while a year spent with an HIV infection that has not progressed to AIDS is equated with 0.135 DALYs (see official disability weights at Lopez et al. 2006, Pg 119). World Health Organization 2008 implies that a year of someone with AIDS receiving ART can be equated to a year with HIV that has not progressed to AIDS: "The disability weight for AIDS cases receiving antiretroviral therapy was set to be the same as that for HIV cases, apart from the terminal stage assumed to be have the same duration and disability weight as AIDS cases not receiving antiretroviral therapy." For simplicity, we assume that ART is always used to treat people with AIDS and affects their quality of life such that it is equivalent to having non-advanced HIV (this assumption is generous to the ART intervention in cost-effectiveness terms, since in fact ART may often be used to treat earlier-stage HIV and may not translate cleanly from one year of treatment to one year of full-blown AIDS averted).
We thus equated each year on ART with 0.37 DALYs (0.505 - 0.135).