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HIV/AIDS in the Western Balkans : Priorities for Early Prevention in a High-Risk Environment
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.
In addition to the benefits antiretroviral therapy has for the individual being treated Komanduri and others ; Ledergerber and others , 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 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.
Obstacles to HIV Control
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. 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.
Effect of Antiretroviral Therapy on Transmission Dynamics. 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. A 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 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.
A positive HIV test can be confirmed within one month of infection. Infection is diagnosed in two ways: 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.
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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. 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. These results suggest that LMICs should not use a second confirmatory test unless the prevalence among patients is extremely low. 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 b. 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.
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 , 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.
Although a Zimbabwe study found that home visits were associated with extensive travel time and costs Hansen and others , 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. 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 Higginson and others' 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. Pain management is extremely important in HIV and is addressed in chapter 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. 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.
No estimates are available on the benefits of providing such care in terms of DALYs, especially to terminally ill patients. Psychosocial support is an integral component of the multidisciplinary management strategies that care providers regard as essential for people with HIV Murphy and others 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.
Cook's study of U. 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. Strong evidence indicates that malnutrition and AIDS work in tandem at both the individual and the societal levels.
This reciprocity must be considered when planning specific program responses. Protein deficiency is a well-known cause of cell-mediated immunodeficiency Vanek HIV-infected individuals need to consume more energy than uninfected 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 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.
The guidelines cite three types of nutrition supplements: 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. 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 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 Such programs targeted at communities at especially high risk are likely to be even more cost-effective World Food Programme 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 and occur progressively as uncontrolled HIV replication destroys the immune system Colebunders and Latif 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. 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. 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 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 ; Hoover and others ; Lanjewar and others ; Selik, Starcher, and Curran 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 ; Hira, Dore, and Sirisanthana a ; Sengupta, Lal, and Srinivas 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 ; Lui and others The time can be as short as 24 months Anzala and others in some individuals, whereas some long-term survivors remain disease free for longer than 15 years Easterbrook In developing countries, disease progression, though not as well studied, appears to be more rapid Morgan and others 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 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 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 The only way to halt or delay the progression of HIV disease is to interrupt viral replication.
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 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 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 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. 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 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.
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.
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 Hence, after five years, about 40 percent of HIV-infected people with latent tuberculosis will have developed active disease. 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 With the development of antiretroviral therapy in the s, the prevalence of many opportunistic infections has been greatly reduced, and the use of prophylaxis has decreased correspondingly Palella and others 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 Note that extensive clinical research is still being carried out in relation to the withdrawal of secondary prophylaxis following immune restoration 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 Long-term toxicities related to treatment may include atherosclerosis, lipodystrophy, hepatic failure, and cardiac failure. 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 The preferred first-line medications in developing countries are dictated by these considerations, in addition to pricing and patent concerns. 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. Current antiretroviral drugs can be divided into three classes: 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.
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 cells per cubic millimeter Palella and others 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 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 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 ; Wegner and others 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 , following a rise between and 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 ; Ledergerber and others Individuals with drug-resistant HIV typically have plasma viral RNA levels that remain 3- to 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 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 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 Those factors, in addition to the toxicity of the therapy, influence adherence and future disease progression rates Duran and others 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 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 , Laniece and others , Bautista and others , Liechty and Bangsberg 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 ; Mitty and others 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 Similarly, the mean duration of viral suppression for those who achieve suppression is also lower for subsequent regimens Deeks and others 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 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:. 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 , 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. 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.
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 Research has also shown that falling body mass index is highly predictive of disease progression Pistone and others 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 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.
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: 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.
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 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. 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.
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? 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.
Interventions in the Pipeline or in Trial. The following interventions are currently being developed or evaluated: 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. 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. 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. Finally, we would like to thank Martin Gross and Phillip Machingura for their invaluable contributions throughout this chapter. Turn recording back on. National Center for Biotechnology Information , U. Oxford University Press ; Lack of Coverage and Access to Prevention Services Notwithstanding these treatment strides, global efforts have not proved sufficient to control the spread of the pandemic or to extend the lives of the majority of those infected.
Lack of Rigorous Evaluations In addition to poor coverage of key interventions, perhaps the greatest challenge to effective global control is the lack of reliable evidence to guide the selection of interventions for specific areas or populations. 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.
Determinants of Infection HIV transmission predominantly occurs through three mechanisms: Sexual Transmission Worldwide, sexual intercourse is the predominant mode of transmission, accounting for approximately 80 percent of infections Askew and Berer Infectivity The per contact infectivity of HIV from sexual transmission varies depending on sexual activity Royce and others 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.
Perinatal Transmission Perinatal HIV transmission includes both vertical transmission and transmission during breastfeeding. Vertical Transmission Perhaps the most compelling evidence of the significance of viral load and transmission risk has been documented with respect to MTCT.
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. 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. 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.
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. General Interventions Relevant for All Modes of Transmission The following are general interventions not specifically targeting the mode of transmission: Information, education, and communication. 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. 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.
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 Limited data have shown differences in students who have been exposed to school-based sex education summarized in table 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 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.
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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 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 to fold lower. 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 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 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.
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 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 Methadone maintenance is both safe and effective as a treatment for drug addiction National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction 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 ; Needle and others 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 Blood screening for HIV is costly but has been shown to be cost-effective in numerous studies in developing countries see table 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.
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 However, after much investigation, WHO and the U. 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 Additional cost-effectiveness studies are needed to guide decisions regarding the optimal choice of technology in this area.
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.
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. VCT that is available to key populations with the highest levels of risk behavior and infection rates.
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. These prevention priorities should include the following:
Related HIV and AIDS:: Basic Elements and Priorities
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