18. HIV/AIDS Prevention and Treatment

Care and Treatment

This section reviews evidence of the cost-effectiveness of HIV/AIDS care and treatment interventions in resource-limited settings. Until relatively recently, the majority of HIV clinical care in resource-limited countries was confined to managing the terminal stage of infection, including extremely late diagnosis of opportunistic infections and cancers, use of basic palliative symptom management, and short-term hospitalization just before death. Few people were aware of their HIV status until the onset of severe HIV-associated illness, and most did not seek help from the health care system until they were already terminally ill.

The advent of primary prophylaxis and treatment for opportunistic infections, including tuberculosis, prolonged survival to a limited extent but did nothing to restore immune function. Such restoration was not possible until the advent of antiretroviral therapy. Because clinical intervention in HIV is so recent in resource-limited settings, few cost-effectiveness studies are available. Those that are available on the treatment of and prophylaxis for opportunistic infections were largely conducted before the availability of antiretroviral therapy and therefore need to be reestimated to be relevant for decision making today. Fortunately, because the determinants of biological responses are better conserved across countries and cultural settings than the determinants of behavior, effectiveness data from high-income countries can help inform decisions about treatment in resource-limited settings.

Unlike drugs for many other high-burden health conditions in developing countries, antiretroviral therapy for HIV and drugs for some of its associated opportunistic infections depend on medications that are still under patent protection. Nevertheless, generic drug makers in India and Thailand have produced a range of effective antiretroviral therapies that combine multiple drugs into single tablets and reduce the pill burden to one tablet twice daily. These companies have made it possible for prices to drop dramatically for some antiretroviral therapy combinations—to less than US$250 per year, compared with more than US$4,000 for the same combinations (from the original manufacturers) in high-income countries. In response to this threat, some multinational pharmaceutical companies have introduced a system of price differentiation among countries depending on their per capita income and HIV/AIDS burden.

In addition, the World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) includes a provision that permits compulsory licensing of pharmaceutical products in cases of national emergency and other circumstances of extreme emergency, which is clearly the case for HIV/AIDS in much of the developing world. A 2003 World Trade Organization decision also made it easier for low- and middle-income countries (LMICs) to import cheaper generics made under compulsory licensing if the countries are unable to manufacture the medicines themselves (WTO 2003). As a result, some countries, including Brazil, India, and Thailand, have begun to produce generic versions of antiretroviral drugs to be sold at greatly reduced prices. The TRIPS provision has also improved developing countries' bargaining power with large pharmaceutical companies, to the point that some countries have been able to secure drugs from the original manufacturers at substantially reduced prices. As a result, the relative cost-effectiveness of different drug combinations has been in rapid flux, increasing the importance of updating recommendations frequently.

Diagnostic HIV Testing

A positive HIV test can be confirmed within one month of infection. Infection is diagnosed in two ways: by a biological test that detects the presence of HIV antibodies or by diagnosis of an opportunistic infection that is a clear sign of HIV disease. The most widely used biological test in high-income countries, conducted in a laboratory on a blood sample, is called an ELISA (enzyme-linked immunosorbent assay). Obtaining a result may take several days. Rapid tests that can provide results in 20 minutes are being used more widely as their costs fall. When the prior probability of infection is low and resources are abundant, following up an initially positive ELISA with a second ELISA—and even a Western blot test if the second ELISA is positive—may be appropriate (this is typically done in high-income countries).

However, in a high-prevalence environment where the prior probability is high and resources are scarce, such an approach is almost certainly not cost-effective. Each additional confirmatory test decreases the number of false positive results, thereby averting the costs associated with such a result. The costs of averting a false positive result range from US$425 with a single confirmatory rapid test or ELISA to more than US$500,000 for a confirmatory Western blot test following two positive ELISAs as the prevalence of HIV in patients who are clinically suspected of being infected is varied from 5 to 50 percent (these calculations are based on assumptions in John Snow, Inc. 2003 and WHO 2004). These results suggest that LMICs should not use a second confirmatory test unless the prevalence among patients is extremely low.

Palliative Care

Palliative care has traditionally focused on patients in the terminal stages of disease. More recent definitions of palliative care, including WHO's definition, have been broadened to encompass quality-of-life issues of patients and their families throughout the course of a life-threatening illness (WHO 2002b). The control of pain and other symptoms is the crux of any palliative care model, but the WHO model also addresses patients' and their families' psychological, social, and spiritual problems. Under this definition, in many developing countries, most people living with HIV/AIDS are not receiving the minimum standard of palliative care. Of the 5 million people living with HIV/AIDS in South Africa, one of the wealthiest countries in Sub-Saharan Africa, Carlisle (2003) estimates that only 250,000 have access to palliative care services. In the face of a growing epidemic of historic dimensions, the provision of comprehensive palliative care represents a critical, but neglected, global priority.

Health care professionals have promoted community home-based care as an affordable way to expand the coverage of palliative care (Hansen and others 1998), but the great heterogeneity among home-based care programs complicates comparisons. Most programs for which data are available are community-based outreach programs administered by local clinics or hospitals. These programs can consist of simple home visits to provide basic care for AIDS patients or may be comprehensive schemes that provide care, palliative medications, meals, psychosocial support and counseling, and links to primary and secondary health care.

Studies indicate that home-based care has considerable potential to deal cost-effectively with the palliative care needs of HIV/AIDS patients (Ramsay 2003; UNAIDS 2001; Uys and Hensher 2002; Wenk, Bertolino, and Pussetto 2000). Although a Zimbabwe study found that home visits were associated with extensive travel time and costs (Hansen and others 1998), little research has examined the extent to which home-based care can be used to substitute for hospitalization, nor is evidence available to determine the most cost-effective combination of palliative care strategies. Most people living with HIV/AIDS do incur some end-of-life costs in the formal health care sector. In one South African study, primary care clinic and hospital costs accounted for 39 and 18 percent, respectively, of the costs of care in the last year of life, whereas community home-based care accounted for 42 percent (Uys and Hensher 2002).

Higginson and others' (2003) meta-analysis concludes that overall evidence demonstrates a positive effect of home-based palliative care, especially its effect on pain management and symptom control. Available data do not permit estimating a cost per DALY of community-based palliative care programs, but a review of available studies suggests that palliative care provided by health professionals in the home is unlikely to be cost-effective in low-income countries. However, low-cost, community-based models have been developed that require minimal external resources and function almost like care cooperatives among affected households. These models are likely to be highly cost-effective.

Symptom-based Care

Pain management is extremely important in HIV and is addressed in chapter 52. Diarrhea, nausea, vomiting, and skin problems are all symptoms that are targeted for treatment in palliative care. Oral rehydration for diarrheal treatment costs pennies per episode. Nausea and vomiting are prevalent in people with AIDS and can lead to anorexia and weight loss (UNAIDS 2000). Treating nausea costs an estimated US$1.75 per episode (Willbond and others 2001), and continuous treatment of nausea and vomiting in end-stage patients costs about US$2 per day (World Bank 1997).

Approximately 90 percent of people with HIV suffer from some form of skin condition. These conditions include infections, drug reactions, scabies, pressure sores, and cancers. Skin often becomes dry in the middle and late stages of AIDS because of dehydration caused by persistent diarrhea, vomiting, and malabsorption. The cost of treating an episode of skin rash is estimated to be US$2 (UNAIDS 2000). No estimates are available on the benefits of providing such care in terms of DALYs, especially to terminally ill patients.

Psychosocial Support

Psychosocial support is an integral component of the multidisciplinary management strategies that care providers regard as essential for people with HIV (Murphy and others 2004). Support for patients and families can have a positive effect on adherence to therapies and can contribute to the critical aim of integrating prevention with treatment and care.

Psychosocial support and counseling has a positive effect on the quality of life of people living with HIV/AIDS. Cook's (2004) study of U.S. women demonstrated that the use of mental health services was associated with reduced mortality and that AIDS-related deaths were more likely among women who had symptoms of chronic depression. While results have not been replicated in resource-constrained countries, an assessment of clinic-based psychosocial support and counseling services in northern Thailand showed that 50% of PLWHA became more positive about their lives and 40% stated that they learned how to live with the disease (Tsunekawa and others 2004). Although few data are available on the costs of various strategies, interventions for psychosocial support appear to be cost-effective—especially where innovative solutions, such as group counseling sessions, are implemented. Although studies indicate an improved quality of life for these patients, little information is available on the cost of the interventions. Additional evaluation research is needed to guide decisions about how much to invest in psychosocial support.

Nutrition Programs and Food Security

Strong evidence indicates that malnutrition and AIDS work in tandem at both the individual and the societal levels. Infection with HIV increases the risk of malnutrition in the individual, while malnutrition worsens the impact of HIV and AIDS. Similarly, HIV/AIDS can both cause and be worsened by food insecurity. This reciprocity must be considered when planning specific program responses.

Protein deficiency is a well-known cause of cell-mediated immunodeficiency (Vanek 1953). HIV-infected individuals need to consume more energy than uninfected individuals: as much as 10 percent greater consumption for asymptomatic individuals and 20 to 30 percent more for symptomatic individuals. Malnutrition alters the susceptibility of individuals to HIV infection and their vulnerability to its various sequelae, increases the risk of HIV transmission from mothers to babies, and accelerates the progression of HIV infection (Gillespie, Haddad, and Jackson 2001).

Small studies of adults with AIDS, including those on anti-retroviral therapy, have shown that daily micronutrient supplementation increases bodyweight, reduces HIV RNA levels, improves CD4 counts, and reduces the incidence of opportunistic infections. Fawzi and others' (2004) large trial among pregnant women infected with HIV in Tanzania demonstrates that multivitamin supplements (a) decrease the risk of progression to WHO stage 4 (progression from HIV to AIDS, the most advanced level of HIV infection) or death from AIDS-related causes and (b) reduce many HIV-related symptoms. The multivitamins used in the trial cost US$15 per person per year (Fawzi and others 2004).

The World Food Program guidelines prioritize three nutrition interventions for people living with HIV/AIDS: counseling on specific behaviors, prescribed or targeted nutrition supplements, and links with food-based interventions and programs. The guidelines cite three types of nutrition supplements: food rations to manage mild weight loss and nutrition-related side effects of antiretroviral therapy and to address nutritional needs in food-secure areas; micronutrient supplements for specific HIV-positive risk groups; and therapeutic foods for addressing moderate and severe malnutrition in HIV-positive adults and children. Cost-effectiveness data in support of these recommendations are not available, but the low costs of supplementation, coupled with the likely benefits to other malnourished household members, suggest that such interventions will be highly cost-effective.

Infection with HIV/AIDS can severely undermine an individual's food security, affecting the availability, stability, access to, and use of essential foods. The epidemic is stunting progress in rural development and causing significant increases in rural poverty and destitution in the countries most affected by the epidemic (Bonnard 2002). Thus, interventions must consider the epidemic's impact on the broader community and not solely on people living with the disease. Care-related household and community-level interventions include school feeding with special take-home rations for families caring for orphans, food for training programs that promote income-generating activities, and food for work to support homestead production activities (Van Liere 2002). Chapter 56 estimates that sustained community nutrition programs would save US$200 to US$250 per DALY. Such programs targeted at communities at especially high risk are likely to be even more cost-effective (World Food Programme 2001).

Treatment of Opportunistic Infections and Secondary Prophylaxis

Even as the availability of antiretroviral therapy increases in many developing countries, appropriate diagnosis and management of life-threatening opportunistic infections, including HIV-associated cancers, remain the most important aspects of the care of patients with HIV disease. Opportunistic infections usually begin five to seven years after infection (Munoz, Sabin, and Phillips 1997) and occur progressively as uncontrolled HIV replication destroys the immune system (Colebunders and Latif 1991). Figure 18.1 describes the cascade of infections that occur as the immune system is depleted. Opportunistic infections are typically caused by organisms that exist in the environment of the body (on the skin, in the lungs and gastrointestinal system) and remain latent until HIV has impaired the immune system.
[Figure 18.1]

The epidemiology of opportunistic infections is complex; it is related to the severity of individual immune depletion and shows considerable intercountry variation. Each infection has its unique clinical expression, requiring specific diagnostic techniques and treatment. Many opportunistic infections can be prevented by judicious use of chemoprophylaxis, ranging from the low-cost (cotrimoxazole to prevent Pneumocystis jiroveci pneumonia [PCP] at less than US$20 per year) to the extremely expensive (ganciclovir to prevent cytomegalovirus at more than US$10,000 per year) (Schneider and others 1995; Spector and others 1996). In high-income countries, antiretroviral therapy has so effectively controlled viral replication that the process of HIV-related immune destruction has been slowed or halted, leading to marked declines in the incidence of opportunistic infections and a dramatic reduction in their resultant high death toll (McNaghten and others 1999). Unfortunately, the emerging problem of poor adherence to drug regimes is now making HIV resistance to antiretroviral therapy more prevalent in high-income countries, triggering a resurgence of opportunistic infections.

More than 20 infections and cancers have been associated with severe immune depletion. The most common pathogens and cancers include bacteria such as Mycobacteria tuberculosis and avium; protozoa such as Cryptosporidium, Strongyloides, and Toxoplasma; fungi such as Candida, PCP, Cryptococcus, Aspergillis, and Penicillium (the latter largely restricted to South and Southeast Asia); viruses such as cytomegalovirus, herpes simplex, and herpes zoster; and cancers such as Kaposi sarcoma and non-Hodgkin lymphoma.

The range of complications arising from continued HIV infection varies from country to country, reflecting the differences in infectious agents that populations have encountered earlier in life or are exposed to when immunosuppressed. In high-income countries, the most common opportunistic infections are PCP, esophageal candidiasis, cytomegalovirus retinitis, cryptococcal meningitis, toxoplasma encephalopathy, cryptosporidium diarrhea, and human herpes virus-8 and Kaposi sarcoma (Bacellar and others 1994; Hoover and others 1993; Lanjewar and others 1996; Selik, Starcher, and Curran 1987). In resource-limited countries, because of the higher background prevalence of infectious agents, it is more common to encounter tuberculosis, cryptococcal meningitis, toxo-plasma encephalopathy, infectious diarrhea, and nonspecific wasting (slim disease) (Hira and others 1998; Hira, Dore, and Sirisanthana 1998a; Sengupta, Lal, and Srinivas 1994).

The time from HIV infection to manifestation of the first AIDS-defining illness varies within populations. In high-income countries, reports on the natural history of untreated HIV infection suggest that AIDS occurs between 7 and 10 years after infection (Alcabes and others 1993; Lui and others 1988). The time can be as short as 24 months (Anzala and others 1995) in some individuals, whereas some long-term survivors remain disease free for longer than 15 years (Easterbrook 1994). In developing countries, disease progression, though not as well studied, appears to be more rapid (Morgan and others 1997). Once an AIDS-defining illness occurs, the average time to death seems to be similar across countries, reported at approximately 12 to 18 months in Uganda and the United States (Carre and others 1994).

The time from presentation with an AIDS-defining opportunistic infection to death depends on the type of infection, the availability of care, and the patient's adherence to prescribed prophylaxis and treatment. Even as access to antiretroviral therapy increases, prophylaxis for opportunistic infections remains one of the most important ongoing and successful care strategies for patients with advanced HIV disease. In high-income countries, the widespread use of such simple interventions as cotrimoxazole for PCP prophylaxis has had a significant effect in delaying the onset of PCP, the most common initial AIDS-defining event, thus positively influencing survival (Hoover and others 1993). However, prophylaxis for opportunistic infections appears to be underused in LMICs.

Prevention of PCP or any other opportunistic infection does not halt the relentless erosion of the immune system and provides only a short-term prolongation of life (Morgan and others 1997). The only way to halt or delay the progression of HIV disease is to interrupt viral replication.

Role of Antiretroviral Therapy in Relation to Opportunistic Infections

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 susceptibility to opportunistic infections (Kaplan and others 2001).

Initiating antiretroviral therapy can also have detrimental effects by causing complications from latent or undiagnosed opportunistic infections, especially in resource-poor settings. One of the challenges in initiating antiretroviral therapy in resource-limited settings is that patients tend to present late in their illness, usually when they have an opportunistic infection that prompts them to seek medical care, or in the case of countries with lax pharmaceutical policy, when they buy anti-retroviral therapy from a private pharmacy. 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). These illnesses can occur with all presenting opportunistic infections and may be more serious than the infection itself. The major problem with care of patients in this situation is that they may believe the illness is a side effect of their antiretroviral therapy and refrain from medicating. Training clinicians to recognize and treat immune reconstitution disease is therefore essential.

Management of Opportunistic Infections

The three components of effective management of oppportunistic infections are diagnosis, treatment, and secondary prophylaxis. As immune function continues to deteriorate, secondary prophylaxis is required to prevent recurrence of the treated infection. Some of the most common infections, such as PCP, can be diagnosed with a reasonable degree of confidence by clinical history and treated empirically (Kaplan, Masur, and Holmes 2002). Less frequently occurring infections often require sophisticated diagnostic equipment and skilled clinicians to confirm a diagnosis from a wide range of pathogenic possibilities before starting complex and expensive treatment. For example, toxoplasmosis can be accurately diagnosed only by a lumbar puncture and CT brain scan (and in some cases an MRI), and cryptosporidium diagnosis requires specialized laboratory techniques.

The full spectrum of options for treating opportunistic infections in developing countries has not been systematically evaluated for cost-effectiveness. Because of the effect of anti-retroviral therapy on both the efficacy of treatment of individual infections and on life expectancy (and therefore on potential DALYs gained from treating a life-threatening infection), the limited economic evaluations conducted are already out of date. In particular, chronic infections such as Mycobacterium avium complex and cytomegalovirus may be more effectively treated over the medium term by reversing immunosuppression with antiretroviral therapy than by directly treating the infectious agent. Other treatment regimens for opportunistic infections that were marginally cost-effective before antiretroviral therapy may now become substantially more cost-effective if the patient can begin the therapy following treatment of the infection, thereby extending life expectancy. Table 18.7 shows the cost-effectiveness of care and treatment options for opportunistic infections and antiretroviral therapy.

In most resource-limited settings, few specialized diagnostic facilities are available for opportunistic infections. Clinicians have little training in the diagnosis and management of complex opportunistic infections, and laboratory backup is either nonexistent or so expensive that end users cannot afford it. The spectrum of opportunistic infections in LMICs is such that most require highly technical facilities for confirmation of diagnosis. Consider M. tuberculosis, the most prevalent such infection in Thailand. The rate of latent tuberculosis becoming clinically active in the presence of HIV increases from a lifetime risk of 10 percent in the general population to an annual risk of 10 percent for those coinfected with HIV (Pape and others 1993). Hence, after five years, about 40 percent of HIV-infected people with latent tuberculosis will have developed active disease.

Primary Prophylaxis for Opportunistic Infections

Before the advent of antiretroviral therapy, the use of prophylaxis to decrease the risk of acquiring opportunistic infections was the only intervention available to delay the onset of life-threatening infections (Kitahata and others 1996). With the development of antiretroviral therapy in the 1990s, the prevalence of many opportunistic infections has been greatly reduced, and the use of prophylaxis has decreased correspondingly (Palella and others 2003). Nevertheless, prophylaxis for opportunistic infections remains necessary in patients who lack access to antiretroviral therapy, in extremely immunosuppressed patients until the therapy takes effect, in patients who do not wish to or who cannot take antiretroviral therapy, in patients for whom such therapy fails, and in the small group of patients who are unable to recover sufficient CD4 cells despite good inhibition of viral replication (Berenguer and others 2004). Note that extensive clinical research is still being carried out in relation to the withdrawal of secondary prophylaxis following immune restoration with antiretroviral therapy.

Treatment of HIV Infection with Antiretroviral Therapy

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 atherosclerosis, lipodystrophy, hepatic failure, and cardiac failure. Researchers are still evaluating the effects of these toxicities on HIV/AIDS mortality.

Cost-Effectiveness Considerations in the Choice and Initiation of Antiretroviral Therapy

WHO has issued global guidelines for scaling up antiretroviral therapy access; the guidelines promote a combination of stavudine, lamivudine, and nevirapine (as a fixed-dose formulation) as initial therapy. A number of clinical trials have produced results outlining differential efficacy for a number of antiretroviral therapy combinations, which provide guidance in the selection of appropriate drugs for treating HIV (Yeni and others 2004). The preferred first-line medications in developing countries are dictated by these considerations, in addition to pricing and patent concerns.

In recent years, the most volatile parameter in cost-effectiveness analyses for HIV/AIDS has been the prices of anti-retroviral 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. Box 18.6 discusses the three classes of drugs used in antiretroviral therapy.

Because of their higher manufacturing costs and their more recent introduction into the market, protease inhibitors are more expensive than either nucleoside reverse transcriptase inhibitors or nonnucleoside reverse transcriptase inhibitors. They are also more difficult to manufacture, making them less attractive to generic manufacturers. Although the difference is less marked, nucleoside reverse transcriptase inhibitors tend to cost less than nonnucleoside reverse transcriptase inhibitors.

Ranking different antiretroviral therapy regimens by their cost-effectiveness is more complex than doing so for most therapeutic situations, because a high proportion of patients will develop resistance to or intolerance of initial therapy and will need to stop their initial regimen and then initiate a second (and perhaps a subsequent) regimen, if available. One U.S. cohort study suggests that for 50 percent of patients the prescribed protease inhibitor-based regimen fails within a year (Deeks and others 1999). As a result, the cost-effectiveness of a regimen is a function not only of its effectiveness in isolation, but also of its impact on the effectiveness of future regimens. Thus, the comparative cost-effectiveness of different sequences of regimens needs to be considered.

The effectiveness of antiretrovirals depends on not only the benefits conferred but also the associated side effects, the toxicity level of the drugs, and 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. As a result, the relative cost-effectiveness profiles will change depending on the availability of toxicity monitoring.

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). Concerted research efforts are needed to gauge both the average costs of care and the survival benefits of identifying patients and initiating antiretroviral therapy while their immune function is still competent, compared with the costs and survival benefits associated with starting care late, on presentation of an opportunistic infection—as is currently the norm in LMICs.

Drug Resistance

Drug resistance occurs as the virus evolves to escape the inhibitory effects of antiretroviral drugs. The capacity of HIV to mutate is extraordinary, as the wide diversity of HIV variants that occurs worldwide demonstrates. Viral diversification is driven by low-fidelity enzymes (which have a high rate of mutation) that carry out replication of the viral genome.

Drug resistance resulting from being infected by a drug-resistant HIV strain is known as primary drug resistance. Secondary drug resistance develops as a consequence of treatment. Primary HIV drug resistance to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors has been reported (Salomon and others 2000; Wegner and others 2000). The first reports of transmission of drug resistance have typically occurred within a few years of a drug's introduction into clinical practice. The proportion of newly infected people who acquire drug-resistant HIV has implications for the choice of first-line regimen. Primary resistance in recently infected individuals in high-income countries is stable or has been in decline since 2000, following a rise between 1996 and 1999. Almost nothing is known regarding primary drug resistance among those recently infected in low-income countries, although this question will become more important with the increased availability of antiretroviral therapy in resource-limited settings.

Drug resistance is associated with increases in plasma viral RNA levels and attenuation of the responses of CD4 counts to therapy. Nonetheless, clinical and epidemiological observations suggest that drug resistance does not completely offset the benefits of therapy (Deeks and others 1999; Ledergerber and others 1999). Individuals with drug-resistant HIV typically have plasma viral RNA levels that remain 3- to 10-fold lower than pretreatment levels. Furthermore, patients with drug resistance experience more rapid immunological decline and disease progression if they discontinue their drugs (Nijhuis, Deeks, and Boucher 2001).

Importance of Adherence to Prescribed Therapy

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. Research has shown that drug adherence is one of the most important predictors of continued treatment response (Mannheimer and others 2002). 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). Those factors, in addition to the toxicity of the therapy, influence adherence and future disease progression rates (Duran and others 2001) and lead to an increase in drug resistance. Thus, poorly coordinated scale-up of antiretroviral therapy in some developing countries has the potential to jeopardize both the duration of clinical benefit for the first wave of patients who receive substandard care and future response rates as the prevalence of drug resistance increases (Harries and others 2001).

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).

Second-Line and Subsequent Therapies

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). Similarly, the mean duration of viral suppression for those who achieve suppression is also lower for subsequent regimens (Deeks and others 1999). This finding is entirely expected because failing a previous regimen is associated with lower adherence, higher toxicity, or side effects and increased resistance, all of which increase the probability of similar problems occurring with subsequent regimens. 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.

Laboratory Monitoring of Immune Function to Guide Therapy

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, principally the following:

• the expected rate of change of variables of interest

• the expected frequency of events, such as development of resistance, adherence failure, and side effects

• the relative cost of monitoring versus the cost of providing ineffective treatment

• the magnitude of the secondary effects of monitoring (motivating prevention, motivating adherence).

WHO has suggested a pragmatic approach to monitoring, with inexpensive, easy-to-measure parameters (bodyweight or body mass index, body temperature, hemoglobin, liver enzymes, and clinical symptoms) for monitoring in low-income countries. More specialized markers—namely, CD4 count, viral load, and resistance genotyping—would be restricted to sentinel sites and tertiary care services (Gutierrez and others 2004), at least initially.

The large price reductions for antiretroviral drugs are only now starting to be mirrored in the costs of monitoring tests as new technologies are introduced, collective bargaining is undertaken, and international pressure mounts on diagnostic manufacturers to provide more favorable pricing for LMICs. Commercial cytometric CD4 measurements are now available to some developing countries at less than US$5 per test (R. Gohde, personal communication, 2004). Viral load testing is still significantly more expensive, but even those prices have dropped to US$20 following negotiations on behalf of low-income countries by the William Jefferson Clinton Foundation. Even when the potential savings become an operational reality in developing countries, the costs of laboratory monitoring will still represent an important proportion of the costs of providing antiretroviral therapy.

Monitoring to Guide Initiation of Antiretroviral Therapy

If laboratory monitoring is performed, its optimal frequency must be determined. The closer patients get to an antiretroviral therapy threshold, the more often they must be tested to detect a CD4 decline that falls within a specific CD4 range. As use of antiretroviral therapy expands in LMICs and as the costs of drugs fall relative to the costs of laboratory monitoring, collecting empirical data and constructing models to compare different monitoring strategies is becoming increasingly urgent.

In the absence of capacity to perform CD4 counts, several studies suggest that total lymphocyte count can be used as a proxy because of the correlation between the two counts (Badri and Wood 2003). Research has also shown that falling body mass index is highly predictive of disease progression (Pistone and others 2002). In light of those findings, the cost-effectiveness of CD4 monitoring in developing countries must be considered in terms of its incremental improvement over total lymphocyte monitoring or body mass index monitoring rather than being compared with no monitoring at all.

Testing for Primary Resistance

Testing for resistance in individual patients is still costly, because of both the cost of the diagnostic kit and the sophisticated laboratory capacity required to perform the tests. Because primary resistance is far less prevalent in LMICs than in high-income countries, no serious consideration is being given at this time to initiating individual resistance testing in the developing world. However, the choice of optimal first-line and subsequent treatment strategies should be guided by information about the prevalence of primary resistance to different antiretroviral drugs in a particular country, which indicates that population-level monitoring of the prevalence of resistance among antiretroviral-naive people living with HIV/AIDS is important.

Monitoring Response to Therapy

Ideally, therapeutic failure should be detected as soon as possible to permit the implementation of clinical strategies to address toxicity, drug resistance, or poor adherence. Therapeutic failure leads to rising viral load and falling immune competence and to the subsequent development of opportunistic infections. Unfortunately, earlier detection comes at a price: testing for increases in viral load, which can be detected soonest, is more expensive than CD4 testing, which in turn is more expensive than the less sensitive monitoring of total lymphocyte count, which is more expensive than monitoring body mass index or waiting until clinical signs of failure appear. Where facilities for detecting early failure are absent, first-line therapy should be replaced by a completely new combination at failure, usually a protease inhibitor-based combination.

Monitoring Toxicity

Available antiretroviral drugs have significant toxicity. Such toxicity is often insidious, progressing unnoticed until the patient's health has been seriously impaired. Examples include zidovudine-associated anemia, nevirapine-associated impaired liver function, and didanosine-associated pancreatitis. Fortunately, the most commonly encountered serious toxicities can be detected either on clinical examination or with inexpensive laboratory tests. Data on the relative cost-effectiveness of different toxicity monitoring regimens are unavailable. Current guidelines identify what monitoring should be conducted in conjunction with specific antiretroviral drugs, depending on whether laboratory capacity is available (WHO 2004).

Unfortunately, in the absence of a quantitative analysis of the costs of monitoring and the benefits associated with early detection of toxicity, it is difficult to provide guidance on the minimum laboratory capacity that should accompany the delivery of specific treatment combinations. Clearly, extremely low-cost monitoring tests are warranted for toxicities that occur frequently. The preeminent example is anemia monitoring for patients receiving zidovudine. Hemoglobin levels can be monitored for less than US$0.02 per test, which is almost certainly cost-effective given that the incidence of anemia with zidovudine therapy is approximately 10 percent in advanced-stage patients and that anemia frequently progresses to life-threatening levels if not detected.