Obstacles to HIV Control

Obstacles to effective HIV control include lack of prevention and care coverage and lack of rigorous evaluations. Both are discussed below.

Action under Uncertainty

Even though the current deficit in evaluation research is glaring, the magnitude and seriousness of the global pandemic means that action is nevertheless required. Moreover, despite such gaps in knowledge, we can still improve control strategies by tailoring interventions to the nature and scope of the epidemic. Summarized below is what is known with regard to the burden of disease, the determinants of transmission, and the effectiveness and cost-effectiveness of existing prevention interventions.

Burden of Disease

As a result of large-scale implementation of data collection methods for surveillance worldwide and enhanced methods for validating and interpreting HIV-related data, the HIV/AIDS epidemic is probably one of the best documented epidemics in history. An increasing number of data sources contribute to reasonably accurate estimates and a more nuanced understanding of the epidemic's trends. Unfortunately, this relatively accurate picture of where the epidemic is and has been is not matched by similarly convincing maps of the factors that explain its spread.

Although no single country has been spared the virus, the epidemic has affected certain regions of the world disproportionately, and Sub-Saharan Africa remains by far the hardest hit region (table 18.1). With only 10 percent of the world's population, it accounts for more than 75 percent of all HIV infections worldwide and more than 75 percent of AIDS-related deaths estimated for 2003. Asia and the Pacific, with several large and populous countries, account for 7.4 million infections, or 19.5 percent of the current burden of disease. Prevention and treatment efforts in Sub-Saharan Africa and Asia—regions that together represent 85 percent of all current infections—have dictated, and will continue to dictate, global trends in the burden of HIV- and AIDS-related mortality.

Table 18.1

Deaths and Disability-Adjusted Life Years Attributed to AIDS by Region, Age, and Gender, 2001.

Between 1997 and 2001, the percentage of women living with HIV/AIDS increased from 41 to 50 percent. This trend is most apparent in Sub-Saharan Africa, where women represent 57 percent of adults living with HIV and 75 percent of HIV-infected young people. Even though women account for a smaller share of infections in Asia (28 percent), the disease burden among women and girls is likely to rise as the epidemic becomes generalized. More detailed information about the global burden of HIV/AIDS, regional differences, and trends over time is available in the UNAIDS (2005) report on the global AIDS epidemic.

Determinants of Infection

HIV transmission predominantly occurs through three mechanisms: sexual transmission, exposure to infected blood or blood products, or perinatal transmission (including breast-feeding). The likelihood of transmission is heavily affected by social, cultural, and environmental factors that often differ markedly between and within regions and countries. There is also some indication that molecular, viral, immunological, or other host factors might influence the likelihood of HIV transmission. For a more detailed discussion of sexual behaviors and the contextual determinants of infection, see chapter 17.

Sexual Transmission

Worldwide, sexual intercourse is the predominant mode of transmission, accounting for approximately 80 percent of infections (Askew and Berer 2003). Sexual intercourse accounts for more than 90 percent of infections in Sub-Saharan Africa. Although many people who know they are infected reduce their risk behaviors, studies in developed countries suggest that a substantial percentage nevertheless continue to engage in unprotected sex (Marks, Burris, and Peterman 1999). The risk of sexual transmission is determined by behaviors that influence the likelihood of exposure to an infected individual and by infectivity in the event of exposure. This also includes factors related to the infectiousness of the infected partner and the susceptibility of the uninfected partner.

Infectivity

The per contact infectivity of HIV from sexual transmission varies depending on sexual activity (Royce and others 1997). Anal intercourse carries a higher transmission probability than penile-vaginal intercourse, and male-to-female transmission is more likely than female-to-male transmission. Data on infectivity by transmission mode are shown in table 18.2.

Table 18.2

Estimated HIV Transmission Risk per Exposure.

Biological Mediators of Infectivity

Untreated STIs increase the risk of sexual HIV transmission several-fold (Institute of Medicine 1997). Numerous epidemiological studies have supported the association of genital ulcers in general and of genital herpes (herpes simplex virus 2, or HSV-2) in particular with HIV infection (Hook and others 1992). Not only does the biological interaction between HSV-2 and HIV enhance the transmission and acquisition of HIV, but HIV infection is also associated with more frequent reactivation of HSV-2. The presence of herpetic ulcers and lesions allows an entry point for HIV in the uninfected individual, and the presence of high copy numbers of HIV ribonucleic acid (RNA) in HSV-2 lesions in HIV-infected individuals underscores the importance for HIV prevention of controlling HSV-2 infections (Mbopi Keou and others 1999).

Vaginal infections are also emerging as important risk factors for HIV. For example, infection with trichomonas increases the risk for HIV seroconversion (Buve 2002). In addition, higher trichomonas rates have been detected in regions of Sub-Saharan Africa that have higher HIV rates, and investigators working throughout Sub-Saharan Africa report similar results, with odds ratios from 1.5 to 56.8 (Gregson and others 2001). In addition, studies have shown an increased risk of HIV acquisition in patients who have bacterial vaginosis (Martin and others 1999).

Circumcision also affects HIV transmission. In a meta-analysis of 27 studies (Weiss, Quigley, and Hayes 2000), uncircumcised men were almost twice as likely to be infected with HIV as those who were circumcised. Studies that controlled adequately for other risks and studies that separately assessed risk in high-risk populations, such as STI clinic attendees or truck drivers, found an even stronger protective effect of circumcision. Similarly, an ecological study comparing two high-prevalence Sub-Saharan African cities with two low-prevalence cities found that circumcised individuals were substantially less likely to be infected with HIV (Auvert and others 2001). Two recent studies conducted in Kenya and India (Donnelly 2004; Reynolds and others 2004) found that uncircumcised men had an HIV rate 7 to 11 times greater than circumcised men. More recently, results from a randomized controlled trial conducted in South Africa indicated that the risk of HIV acquisition was reduced by more than 60 percent of men randomized for circumcision (controlling for sexual behavior, including condom use and health seeking behavior) in a community where more than 30 percent of the women were infected (Auvert and others 2005).

Before circumcision among adult males becomes a widespread policy recommendation, results are still pending in two similar trials. Obviously one issue is the acceptability of such a procedure as well as the fact that some increase in high risk sexual activity was noted among the men who were circumcised, although this did not offset the results of the intervention.

The risk of sexual transmission is also strongly correlated with the plasma level of virus in the infected individual (Quinn and others 2000); thus, infectivity varies over the natural progression of the disease. Individuals are most infectious subsequent to infection and again during the late stage of the disease. Antiretroviral therapy significantly reduces the level of virus, often to the point that standard tests cannot detect HIV in the patient's blood (Palella and others 1998). Available data suggest that viral load reductions induced by antiretroviral therapy will lower infectiousness. Studies have shown a close relationship between the amount of viral suppression and the risk of vertical transmission (Garcia and others 1999). Quinn and others (2002) show that the risk of sexual transmission between couples in Africa was strongly related to the level of viral load in the infected partner.

Exposure to Infected Blood or Blood Products

Injection drug use and blood transfusion are two mechanisms of HIV exposure to infected blood. Determinants of each are discussed below.

Injection

Because of the efficiency of HIV transmission through needle sharing, the introduction of HIV into an urban network of injecting drugs users can quickly lead to extraordinarily high HIV prevalence in this population. Sharing of injection equipment and frequency of injection are both important correlates of HIV infection (Chaisson and others 1989). Attendance at shooting galleries, where sharing with anonymous injecting partners is likely to occur, is also an independent risk factor across many studies (Vlahov and others 1990). Injecting cocaine (associated with "booting" or "kicking," where blood is drawn into the syringe and then injected) and having a number of needle-sharing partners are also associated with HIV infection (Anthony and others 1991).

Blood Transfusion

The probability of becoming infected through an HIV-contaminated transfusion is estimated at more than 90 percent (UNAIDS 1997), and the amount of HIV in a single contaminated blood transfusion is so large that individuals infected in this manner may rapidly develop AIDS. Currently, between 5 and 10 percent of HIV infections worldwide are transmitted through the transfusion of contaminated blood products (WHO 2002a). Setting up and maintaining a safe blood supply will virtually eliminate HIV transmission through transfusions.

Perinatal Transmission

Perinatal HIV transmission includes both vertical transmission and transmission during breastfeeding. Determinants of each are discussed below.

Vertical Transmission

Perhaps the most compelling evidence of the significance of viral load and transmission risk has been documented with respect to MTCT. Maternal viral load, as quantified by RNA polymerase chain reaction, is associated with increased risk in each mode of vertical transmission. A recent randomized clinical trial in Kenya found that maternal plasma HIV RNA levels higher than 43,000 copies per milliliter were associated with a fourfold increase in vertical transmission (John and others 2001).

Independent of HIV RNA levels in maternal plasma, additional risk factors include cervical HIV deoxyribonucleic acid (DNA), vaginal HIV DNA, and cervical or vaginal ulcers. Chorioamnionitis has also been documented as a risk factor for MTCT among African mothers (Ladner and others 1998), as has exposure to maternal blood during labor and delivery. Newell (2003) estimates that for every hour an infant is exposed to ruptured membranes, the risk of transmission increases by 2 percent.

Breastfeeding

Transmission through breastfeeding is likely associated with an elevated viral load in the breast milk, which in turn is associated with maternal plasma viral load and CD4 T cell levels. Mastitis has also been associated with increased risk of vertical transmission. Meta-analyses suggest that the cumulative probability of HIV infection increases from 0.6 percent at age 6 months to 9.2 percent at age 3 (Read 2003). A study in Malawi, however, indicates that most transmission occurs in the early breastfeeding months, with an incidence per month of 0.7 percent at age 1 to 5 months, 0.6 percent at age 6 to 11 months, and 0.3 percent at age 12 to 17 months (Miotti and others 1999). In one study, infants who were breastfed in combination with receiving other supplementary foods were twice as likely to be infected at age 6 months than infants fed exclusively on breast milk or on formula (Coutsoudis and others 2001). The hypothesis is that antigens and bacterial contaminants present in supplemental fluids and foods consumed by infants who are not exclusively breastfed may cause inflammation and microtrauma to the infant's intestinal gut, thereby facilitating viral transmission. Another hypothesis is that mixed feeding increases the risk of subclinical or clinical mastitis in the mother, which could increase milk viral load (Semba and others 1999).

Decisions about breastfeeding are further complicated by recent data indicating possible increased mortality among breastfeeding mothers (Nduati and others 2001) and by the stigma associated with not breastfeeding in countries where abstaining from breastfeeding is tantamount to disclosing a woman's HIV status.

Effectiveness and Cost-Effectiveness of Prevention Interventions

Below we discuss the need for ongoing surveillance and contextual data to determine the effectiveness of HIV interventions and how best to implement those interventions. We then discuss the existing effectiveness and cost-effectiveness data.

Essential Background Data for Any Intervention

Because the prioritization of prevention strategies for any epidemic requires accurately identifying the epidemiological profile (discussed below), maintaining a sound and reliable public health surveillance system is a prerequisite for an effective prevention response. An understanding of HIV and STI prevalence and trends, as well as the prevalence and distribution of behaviors that contribute to the epidemic's spread, should be supplemented by national monitoring systems that track sources and uses of funding to promote greater accountability. In addition, data are needed to identify and characterize key contextual issues that affect the selection of interventions.

Although surveillance is essential for an optimally strategic public health response, its utility depends on the degree to which the information it yields is effectively deployed. As noted below, countries with concentrated epidemics should prioritize interventions that are targeted to the populations at highest risk. In Latin America, however, where information on national AIDS funding is strongest, the proportion of limited prevention resources that is not targeted to the populations at highest risk of infection varies from less than 5 percent to more than 50 percent (Saavedra 2000). This range strongly suggests that resource allocation is frequently not based on available epidemiological and effectiveness data.

Table 18.3 summarizes information about the effectiveness of the interventions discussed below.

Table 18.3

Effectiveness of HIV Interventions.

Cost-Effectiveness Estimates for Prevention Interventions

How countries spend funds and which interventions they prioritize should be guided by estimates of the relative cost-effectiveness of such interventions. Unfortunately, reliable estimates of cost-effectiveness are largely lacking, for a number of reasons. The main reason is that HIV prevention interventions are difficult to force into a typology that clearly distinguishes one intervention from another. For example, the counseling component of VCT has a strong information-sharing element that overlaps with (a) information, education, and communication (IEC) through the media; (b) peer interventions; and (c) the counseling component of STI treatment. Similarly, the psychological support offered through counseling is comparable to support provided through support groups or to interventions designed to increase social support. Such overlap and duplication among components of different interventions complicate efforts to estimate both the effectiveness and the cost-effectiveness of different interventions.

Several authors have recently reviewed estimates of cost-effectiveness for the prevention interventions described here (Creese and others 2002; Jha and others 2001; Marseille and others 2002; Walker 2003). These reviews address a number of methodological issues that will not be repeated here. The reviews agree that the availability of cost and cost-effectiveness analyses for HIV/AIDS prevention strategies is limited and that the need for such knowledge for planning and decision-making purposes is urgent.

Table 18.4 summarizes available cost-effectiveness estimates for the four UNAIDS epidemic profiles that are described later in table 18.5. The estimates of cost per disability-adjusted life year (DALY) saved assume a uniform 20 DALYs lost per infected adult (Murray and Lopez 1996) and 25 DALYs lost per infected child (Marseille and others 1999) and do not account for the increasing proportion of people living with HIV/AIDS in developing countries who will have access to antiretroviral therapy over the coming years.

Table 18.4

Cost-Effectiveness of Interventions by Epidemic Profile.

Table 18.5

Epidemic Profiles.

General Interventions Relevant for All Modes of Transmission

The following are general interventions not specifically targeting the mode of transmission:

• Information, education, and communication. This intervention includes education on HIV/AIDS and condom use through pamphlets, brochures, and other promotional materials in classroom or clinic settings or through the radio, television, or press. In general, discerning the effectiveness of IEC alone is difficult, because IEC is often included in condom promotion and distribution interventions. Here we consider the effectiveness of IEC in concert with condom promotion and distribution. Of all available prevention interventions, providing information and education about HIV/AIDS is perhaps the most difficult to assess for cost-effectiveness. Numerous studies have shown that information alone is typically insufficient to change risk behavior. Accurate information, however, is indisputably the basis for informed policy discourse—a vital ingredient in the fight against fear-based stigma and discrimination. In the absence of studies to guide the level of investment in IEC, the only reasonable alternative seems to be to implement IEC on the basis of data derived from relative levels of knowledge and understanding in the population. For example, if only 25 percent of the sexually active population were able to describe how HIV is transmitted and prevented, clearly more IEC would be needed, but if 75 percent of the population understood the basic facts about HIV/AIDS, the need for additional funding would be diminished.
• School-based sex education. School-based sex education programs, an aspect of IEC, provide information to young people and reinforce healthy norms in a school setting (Peersman and Levy 1998). Limited data have shown differences in students who have been exposed to school-based sex education (summarized in table 18.3). Box 18.2 reviews the effectiveness of abstinence-only education and comprehensive sex education, subsets of school-based sex education. In light of more recent controlled studies that have not shown an effect on condom use, STIs, or HIV infection, any cost-effectiveness estimate is extremely speculative.
• Voluntary counseling and testing. This intervention enables people to know their HIV status and provides counseling support to help them cope with the outcome. Knowledge of serostatus may lead individuals to avoid engaging in risky behaviors (Sweat and others 2000). Cost-effectiveness estimates of VCT vary widely, and as with many other prevention interventions, these estimates are extremely sensitive to the prevalence of HIV in the population that is seeking testing.
• Peer-based programs. Peer interventions use influential members of a targeted community to disseminate information or teach specific skills. Such interventions have generally been found to be effective in reducing unsafe behaviors. Work on the cost-effectiveness of peer-based interventions in developing countries has been minimal. In Chad, Hutton, Wyss, and N'Diekhor (2003) reviewed data on 12 prevention interventions and integrated them into a comparative analysis. Their findings suggest that peer education for sex workers is likely to be highly cost-effective and to entail one-fifth the cost of the next most favorable intervention, blood safety. However, the estimated cost-effectiveness for the same intervention directed toward young people and high-risk men is 33- to 36-fold lower.

Box 18.2

Comprehensive Sex Education Versus Abstinence-Only Education. The available data on sex education suggest the following: Sex education, including condom promotion, does not encourage or increase sexual activity (Kirby 2001). Sex education reduces risk (more...)

Interventions to Prevent Sexual Transmission

Below we discuss the effectiveness and cost-effectiveness of interventions that target sexual transmission of HIV:

• Condom promotion, distribution, and social marketing. Condom promotion, distribution, and social marketing vary by epidemic profile. The evidence on condom promotion and distribution programs indicates that such programs result in significantly higher condom use and significantly lower STI incidence (see table 18.3). Given the central role that condom promotion, distribution, and social marketing has played in HIV prevention programs, the lack of data on the relative cost-effectiveness of such programs 20 years into their implementation is striking. It is beyond dispute that the use of a condom by sexual partners who are HIV-discordant is extraordinarily cost-effective, given the low cost and high effectiveness of the condom in preventing HIV transmission. Information on the relative costs and effectiveness of different approaches to increasing condom use by serodiscordant sexual partners is not available, with the shortage of information being far more acute for effectiveness than for costs. In the absence of empirical evidence, decision makers are reduced to formulating policy on the basis of theory and common sense. Even inefficient use of condoms by seroconcordant couples is likely to be highly cost-effective because of the reduction in other STIs, cervical cancer, and unwanted pregnancies. However, more reliable information on strategies to optimize the effectiveness and cost-effectiveness of condom programs is urgently needed.
• STI screening and treatment. The latest analyses suggest that STI control may be most effective as an HIV prevention strategy when initiated earlier in the course of national epidemics and when sexual risk behaviors are high (Orroth and others 2003). In most developing countries, the greatest benefits from treating STIs almost certainly accrue from averting the morbidity and mortality caused directly by STIs rather than indirectly because of reduced HIV transmission. Estimates of the cost-effectiveness of STI treatment purely as a way to reduce HIV transmission vary widely.

Prevention of Mother-to-Child Transmission

The existing data on the effectiveness and cost-effectiveness of HIV interventions target MTCT in order of decreasing cost-effectiveness as follows:

• Avoidance of unwanted pregnancies among infected mothers. One of the most effective strategies to reduce HIV among infants is to provide better contraception services. See box 18.3 for details.
• Use of antiretroviral therapy. Evidence indicates that the provision of antiretroviral drugs to infected mothers significantly reduces vertical transmission (see table 18.4). The provision of antiretroviral therapy to prevent MTCT is highly cost-effective, to the point of being cost-saving for women who already know that they are infected. When screening of women is involved, cost-effectiveness declines as HIV prevalence falls, because of the larger number of women who must be screened to identify an HIV-positive woman (Rely and others 2003).
• Feeding substitution. Whereas in high-income countries the health community recommends complete avoidance of breastfeeding for HIV-infected mothers to prevent postnatal HIV transmission, in developing countries the feasibility of this approach is often limited by such factors as cost, sustainability, lack of safe water, health, and child spacing and by sociocultural factors (Coutsoudis 2002). Prolonged breastfeeding more than doubles the likelihood of MTCT (Nduati and others 2000). Because evidence indicates that mixed feeding (breast milk and formula or other substance) has a higher risk of transmission than exclusive breastfeeding (Coutsoudis and others 1999), mothers should be counseled on the superiority of early weaning over mixed feeding. Even fewer data are available on the cost-effectiveness of feeding substitution.

Box 18.3

Preventing Mother-to-Child Transmission: Antiretroviral Therapy or Contraception? The differential effect of contraceptive delivery versus antiretroviral therapy in preventing HIV can be shown by comparing the provision of effective contraception and (more...)

Prevention of Bloodborne Transmission

Below we discuss the effectiveness and cost-effectiveness of harm reduction for injecting drug users, implementation of blood safety practices, and provision of sterile injections:

• Harm reduction for injecting drug users. Harm reduction involves a combination of health promotion strategies for users, including needle and syringe exchange programs, ready access to effective drug treatment and substitution, and provision of counseling and condoms. Brazil, which has reduced the incidence of HIV and kept HIV prevalence from reaching projected levels, has relied on strong official support for harm reduction as a cornerstone of its national prevention program (Mesquita and others 2003). A limited number of studies have shown significant reductions in HIV incidence among those exposed to needle exchange programs, and several studies have shown significant reductions in needle sharing (see table 18.3). Methadone maintenance is both safe and effective as a treatment for drug addiction (National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction 1998) and may help reduce the risk of HIV transmission by enabling individuals to avoid the drug-using behaviors that can lead to HIV infection (Metzger, Navaline, and Woody 1998; Needle and others 1998). However, the effect of drug treatment modalities on the rate of HIV transmission is currently limited by laws in many countries that prohibit or restrict the use of methadone maintenance or other drug substitution strategies. The evidence supporting the cost-effectiveness of needle exchange programs in high-income countries is strong. However, little has been published in relation to developing countries, partly because these programs have not been as widely implemented as hoped. Given the low cost of syringes, the extremely high efficiency of HIV transmission by this route, and the demonstrated effectiveness of harm reduction programs in changing syringe-sharing behavior, needle exchange programs should be one of the most cost-effective interventions.
• Implementation of blood safety practices. Transmission of HIV can be virtually eliminated in health care settings through a blood safety program that ensures (a) a national blood transfusion service; (b) the recruitment of voluntary, low-risk donors; (c) the screening of all donated blood for HIV; and (d) the reduction of unnecessary and inappropriate transfusions (UNAIDS 1997). Available evidence indicates that HIV screening is effective in reducing HIV infections (see table 18.4). Blood screening for HIV is costly but has been shown to be cost-effective in numerous studies in developing countries (see table 18.3) (Foster and Buve 1995; Hutton, Wyss, and N'Diekhor 2003; Watts, Goodman, and Kumaranayake 2000). The evidence appears to support the WHO and UNAIDS recommendations that all countries, regardless of the nature of the epidemic in the country, should implement a comprehensive blood safety program.
• Universal precautions. A critical component of standard infection control in health care settings is a prohibition on reusing needles and syringes. A controversy has recently arisen among researchers who contend that HIV infections have been significantly misclassified because of the under-counting of cases that result from unsafe injection practices by misattributing such cases to heterosexual transmission (Gisselquist and others 2003). However, after much investigation, WHO and the U.S. Department of Health and Human Services concluded that even though transmission caused by unsafe injections may have been underreported, it nevertheless does not account for an appreciable amount of HIV transmission (WHO and UNAIDS 2003). Cost-effectiveness analyses indicate that a combined policy strategy of single-use syringes and interventions to minimize injection use could reduce injection-related infections by as much as 96.5 percent, or 8.86 million DALYs between 2000 and 2030, at an average cost of US$102 per DALY. Additional cost-effectiveness studies are needed to guide decisions regarding the optimal choice of technology in this area.

To prevent bloodborne transmission of HIV and other diseases, health care workers, emergency personnel, and others who might experience occupational exposure to blood or body fluids are advised to take universal precautions. This approach, which treats all bodily fluids as potentially infectious, includes the use of gloves, gowns, and goggles; the proper disposal of waste; and the use of sterile injection and other infection control practices (CDC 1989). Studies have demonstrated that the use of protective gear, such as gloves, reduces the likelihood of blood exposure in health care settings.

Although the cost-effectiveness of implementing universal precautions increases as HIV prevalence increases, universal precautions are unlikely to be cost-effective in resource-limited settings especially where HIV prevalence is low. Postexposure prophylaxis with antiretroviral agents is considered the standard of care after occupational needle-stick exposure to blood from an HIV-infected person. Cost-effectiveness analyses of postexposure prophylaxis have been conducted only in high-income countries and have concluded that this intervention is not cost-effective (Low-Beer and others 2000; Pinkerton, Holtgrave, and Bloom 1998).

Prevention in Theory and Practice: Using Epidemic Profiles and Contextual Factors to Inform Prevention Guidelines

Prevention studies and national experiences over the past 20 years strongly suggest that prevention strategies are likely to be most effective when they are carefully tailored to the nature and stage of the epidemic in a specific country or community. UNAIDS has developed epidemiological categories for characterizing individual epidemics on the basis of prevalence of infection in particular subpopulations and in the general population (table 18.5).

As a complement to the guidance provided by the epidemic profile, Grassly and others (2001) recommend assessing the prevalence of other STIs; estimating the extent of mixing between high- and low-risk groups (for example, men who have sex with men who have sexual contact with female partners); and estimating the prevalence of high-risk sexual behaviors in the population (such as lack of condom use with casual partners). They also cite two other critical contextual factors: the capacity of the health service and the social, economic, and legislative context, including social norms and attitudes about sexual and drug use behaviors and the acceptance of breastfeeding. Contextual factors that may play a role in the success of interventions include the status of women, the stigmatization of high-risk groups, and the presence of armed conflict and social upheaval. Together, the epidemic profile and the context in which the epidemic occurs suggest various prevention strategies.

General Prevention Guidelines by Type of Epidemic

Generally, it is more important to change the behavior of people who have high levels of risk behavior than it is to change that of people with lower levels of risk behavior. However, the difference in the effectiveness between the two falls as epidemics become more generalized, and as the average and maximum size of the connected components (number of people linked to each other directly or through others by their sexual or injecting risk behavior). Thus, in heavily affected countries, or those where the virus has the potential to spread rapidly, prevention interventions are likely to become extremely cost-effective even when targeted at individuals with relatively low levels of risk behavior. Consequently, countries with low-level and concentrated epidemics should emphasize interventions that target individuals at especially high risk of becoming infected or of transmitting the virus, whereas countries with generalized epidemics should also invest heavily in interventions that target entire populations or population subgroups. Thus, any determination of the likely effectiveness and cost-effectiveness of specific interventions in particular circumstances requires an accurate understanding of the stage and nature of the national epidemic.

The countrywide successes discussed in boxes 18.4 and 18.5 highlight population-level interventions that modify social norms as well as highlighting legislative and economic factors. Other examples include instituting government regulation of brothels and interventions to change social norms among sex workers in Thailand, implementing national sex education and blood safety programs in Senegal in concert with creating a national registry of sex workers, and mandating involvement by women in politics in Uganda.

Box 18.4

Thailand's 100 Percent Condom Program. Thailand's HIV prevalence, fueled primarily by high rates of commercial sex work and low levels of condom use, began to rise rapidly in the late 1980s. Beginning in 1989, the Thai government initiated a nationwide (more...)

Box 18.5

Uganda HIV/AIDS Prevention Program. Like many countries in Sub-Saharan Africa, Uganda experienced a rapid increase in HIV incidence and a generalization of the epidemic in the late 1980s and early 1990s. By 1991, overall HIV prevalence was 21 percent (more...)

Low-Level Epidemic

Providing widespread VCT, screening for STIs, universal precautions, and postexposure prophylaxis may not be cost-effective in a low-level epidemic. In this setting, such as in the Middle East and North Africa, HIV/AIDS control strategies should emphasize the following:

• surveillance and individual-level interventions that target key populations
• IEC, including limited education through the mass media and sex education in schools
• prevention programs for people living with HIV/AIDS and harm reduction for injecting drug users
• VCT that is available to key populations with the highest levels of risk behavior and infection rates
• MTCT prevention to mothers known to be infected with HIV
• screening all blood for transfusions and providing sterile injections
• addressing market inefficiencies in condom procurement and distribution—including strategies such as bulk purchases and incentives
• responding to community attitudes toward sexual activity, as they may dictate people's response to sex education materials.

Concentrated Epidemic

In a concentrated epidemic, as in countries in East Asia and the Pacific, Europe and Central Asia, Latin America and the Caribbean, and South Asia, prevention priorities should include the following:

• ongoing surveillance
• subsidized VCT and promotion of VCT among key populations
• HIV screening of pregnant women, guided by individuals' risk profiles
• peer-based programs for key populations to educate individuals at risk, promote safer behaviors, and distribute condoms
• harm reduction for injecting drug users, including needle exchange and drug substitution programs
• STI screening and treatment for key risk groups
• targeted distribution and promotion of condoms to key populations with condom distribution linked to VCT and STI care.

In addition, contextual factors, such as government acceptance of needle exchange programs, incarceration of drug users, and harassment of sex workers, will likely have a major impact on the effectiveness of prevention efforts. Because HIV/AIDS is typically concentrated in socially or economically marginalized populations in countries with concentrated epidemics, attention to socioeconomic factors and to the stigmatization of key populations will also be vital to an effective response.

Generalized Low-Level Epidemic

In a generalized low-level epidemic, such as in some countries in Sub-Saharan Africa (for example, Tanzania), the emphasis on targeted interventions must be maintained or even strengthened. Interventions for broader populations must also be aggressively implemented. These prevention priorities should include the following:

• maintaining surveillance of STIs, risk behaviors, and HIV infections in the entire population, with a particular focus on young people
• extending mass media IEC beyond basic education
• providing routine voluntary and confidential HIV testing and STI screening and promoting treatment beyond key populations
• providing subsidized and social marketing of condoms and strengthened distribution to ensure universal access
• offering HIV screening to all pregnant women
• broadening peer approaches and targeted IEC to include all populations with higher rates of STIs and risk behavior.

Contextual factors remain critical to the success of prevention efforts in generalized low-level epidemics, but population-level factors now have greater priority. The most important is likely to be the status of women, especially with regard to their ability to control their sexual interactions, to negotiate VCT, to be protected from abuse, and to have property rights following the death of a spouse.

Generalized High-Level Epidemic

In a generalized high-level epidemic, such as in some countries in Sub-Saharan Africa (for instance, Botswana and Zimbabwe), an attack on all fronts is required. Prevention efforts should focus on broadly based, population-level interventions that can mobilize an entire society so as to address prevention and care at all levels. Prevention should include the following:

• mapping and maintaining surveillance of risk behaviors, STIs, and HIV infection
• offering routine, universal HIV testing and STI screening and universal promotion of treatment
• promoting condom use and distributing condoms free in all possible venues
• providing VCT for couples seeking to have children
• counseling pregnant women and new mothers to make informed and appropriate choices for breastfeeding.
• implementing individual-level approaches to innovative mass strategies with accompanying evaluations of effectiveness
• using the mass media as a tool for mobilizing society and changing social norms
• using other venues to reach large numbers of people efficiently for a range of interventions—workplaces, transit venues, political rallies, schools and universities, and military camps
• establishing official institutional policies to provide for harm reduction among injecting drug users.

In a generalized high-level epidemic, contextual factors—such as poverty and the fragility of the health care infrastructure—will dramatically affect service provision at every level. The status of women, an important factor in all epidemics, becomes an overriding concern in this setting, requiring priority action to radically alter gender norms and reduce the economic, social, legal, and physical vulnerability of girls and women.

Prevention-Care Synergy

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).

However, these benefits in relation to reduced transmission may be offset by a "disinhibition" of risk behavior that is associated with greater availability of antiretroviral therapy, by the spread of drug-resistant HIV, or by increases in the incidence of exposure to partners with HIV infection because of increased survival. These sometimes opposing effects of offering therapy may differ to such a degree that the net effects of widespread therapy on transmission rates may vary among risk groups and across geographic regions.

Table 18.6 reviews the information available on the population effects of antiretroviral therapy and makes suppositions about potential effects for those areas for which data and research are lacking. The information in the table suggests that widespread therapy using currently available combination regimens will provide a net benefit in relation to the transmission of HIV. However, because confidence in this prediction is not high, the population consequences of therapy programs must be evaluated and monitored with active surveillance of prescribing patterns, sexual risk behavior, STI prevalence, HIV incidence and prevalence, and prevalence of primary drug resistance and sexual networks of risk behavior.

Table 18.6

Effect of Antiretroviral Therapy on Transmission Dynamics.

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.

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

Cascade of Infections and Cancers That Develop as Immune Function Is Depleted

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.

Table 18.7

Cost-Effectiveness of Care and Treatment for HIV/AIDS.

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.

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.

Box 18.6

Antiretroviral Drugs. Current antiretroviral drugs can be divided into three classes: Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were the first type of drug available to treat HIV infection in 1987. When HIV infects a cell, it copies (more...)

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.

Research Agenda

As in many other areas of public health in developing countries, a profound tension exists between (a) the need for research to discover new technologies and interventions for both prevention and care and (b) the need for research to learn how to effectively apply the technologies that are currently available. The most important barrier to control is lack of knowledge about how best to implement packages of existing interventions at the appropriate scale to maximize the effect of prevention and care interventions and to protect the human rights of those affected by the epidemic. Accurate surveillance data are needed on risk behaviors, and effectiveness research is needed to discern what interventions work where and how they do so. Unfortunately, few rigorous evaluations of new or existing interventions have been conducted using large prospective cohorts, with the result that, for many interventions, convincing data on effectiveness are not available. Finally, research on policy or structural interventions, which by definition must be conducted on a population level, is also insufficient. These interventions include the development and testing of such policy tools as changing the tax structure, regulating the sex industry, and guaranteeing property rights and access to credit for women.

Box 18.7 lists new prevention interventions in the pipeline. Although numerous promising interventions are listed, results for most of these strategies are at best years away. Centuries hence, when future generations study the history of our time and the epidemic that killed 50 million or perhaps many more, the most difficult question to answer may well be "why did they invest so little for so long in developing a vaccine?" Creating such knowledge is about as close as one can get to a pure international public good, and the lack of global cooperation in adequately funding such research is an indictment of global commitment to multilateral cooperation. However, given both the uncertainty about whether developing an effective vaccine is possible and the long delay until a new vaccine can be widely applied, vaccine development efforts must be accompanied by the development of other new biomedical and behavioral prevention technologies.

Box 18.7

Interventions in the Pipeline or in Trial. The following interventions are currently being developed or evaluated: Microbicides. Most microbicide products are currently in preclinical development; however, 18 products are being evaluated in clinical (more...)

In contrast, research on care and treatment has been far more successful than research on prevention, and innovation in new therapies continues apace. The ability of HIV to rapidly evolve resistance to antiretroviral drugs, combined with the existence of an important market in high- and middle-income countries, appears to ensure continued investment in new drug development. In addition, because treatment generally has important commercial returns, HIV therapies, unlike behavioral interventions, have benefited the most from private sector investment. The paradox is that research on the behavioral aspects of adherence to drug regimens would improve the effectiveness of antiretroviral therapy, and thereby benefit both commercial and public interests.

The greatest research challenges in relation to care and treatment in developing countries do not revolve around new drug development. They revolve around how to adapt care and treatment strategies to low-income, low-technology, low–human resource capacity settings in ways that maximize adherence; minimize toxicity, monitoring, and costs; and maximize the prolongation of high-quality life from antiretroviral therapy—all without damaging existing and often fragile health care infrastructure that must also address other health concerns. Although simplified regimens, such as delivering multiple drugs in a single tablet and fewer doses per day, are desirable everywhere, they are especially important in low-resource settings. Similarly, low-technology, low-cost monitoring tests for antiretroviral therapy toxicity and for immunological and virological responses to treatment are especially needed in low-income countries, which otherwise must centralize testing—an especially difficult prospect when transport and communications systems are poorly developed.

Conclusion

Despite the glaring deficits in AIDS research, the magnitude and seriousness of the global pandemic calls for action in the absence of definitive data. The appropriate mix and distribution of prevention and treatment interventions depends on the stage of the epidemic in a given country and the context in which it occurs. In the absence of firm data to guide program objectives, national strategies may not accurately reflect the priorities dictated by the particular epidemic profile, resulting in highly inefficient investments in HIV/AIDS prevention and care. This waste undoubtedly exacerbates funding shortfalls and results in unnecessary HIV infections and premature deaths. The lack of good data—and thus the ability to tailor responses to epidemics—may be somewhat understandable when the burden of disease is minimal and the resources dedicated to it are similarly small. Neither is the case for HIV/AIDS.

Acknowledgments

We are deeply indebted to Andrew Beggs, Susan Foster, James Kahn, Lilani Kumaranayake, Elliot Marseille, Fern Terris-Prestholt, Seema Vyas, and Charlotte Watts for their background papers that have informed this chapter. We also owe thanks to Sevgi Aral, Geoffrey Garnett, Robin Jackson, Marie Laga, Meg Newman, Mead Over, and David Vlahov for their work on several sections of this chapter. Finally, we would like to thank Martin Gross and Phillip Machingura for their invaluable contributions throughout this chapter.

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Footnotes

1

See http://www​.hivinsite​.org/global?page=cr-00-04 for a compilation of international guidelines.