HIV/AIDS: 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. 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, toxoplasma 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 highincome 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 highincome 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 antiretroviral 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, andHolmes 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 antiretroviral 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 costeffectiveness of care and treatment options for opportunistic infections and antiretroviral therapy. In most resource-limited settings, few specialized diagnostic facilities are available for opportunistic infections. Clinicians have little training in the diagnosis and management of complex opportunistic infections, and laboratory backup is either nonexistent or so expensive that end users cannot afford it. The spectrum of opportunistic infections in LMICs is such that most require highly technical facilities for confirmation of diagnosis. Consider M. tuberculosis, the most prevalent such infection in Thailand. The rate of latent tuberculosis becoming clinically active in the presence of HIV increases from a lifetime risk of 10 percent in the general population to an annual risk of 10 percent for those coinfected with HIV (Pape and others 1993).Hence, after five years, about 40 percent of HIV-infected people with latent tuberculosis will have developed active disease. Primary Prophylaxis for Opportunistic Infections Before the advent of antiretroviral therapy, the use of prophylaxis to decrease the risk of acquiring opportunistic infections was the only intervention available to delay the onset of lifethreatening infections (Kitahata and others 1996). With the development of antiretroviral therapy in the 1990s, the prevalence of many opportunistic infections has been greatly reduced, and the use of prophylaxis has decreased correspondingly (Palella and others 2003). Nevertheless, prophylaxis for opportunistic infections remains necessary in patients who lack access to antiretroviral therapy, in extremely immunosuppressed patients until the therapy takes effect, in patients who do not wish to or who cannot take antiretroviral therapy, in patients for whom such therapy fails, and in the small group of patients who are unable to recover sufficient CD4 cells despite good inhibition of viral replication (Berenguer and others 2004). Note that extensive clinical research is still being carried out in relation to the withdrawal of secondary prophylaxis following immune restoration with antiretroviral therapy. Treatment of HIV Infection with Antiretroviral Therapy Combination therapy with multiple antiretroviral drugs is associated with prolonged survival. Whereas monotherapies are associated with one year or less of additional survival, the survival benefit conferred by combination therapy appears to be sustainable for extended periods (Palella and others 2003). Long-term toxicities related to treatment may include atherosclerosis, lipodystrophy, hepatic failure, and cardiac failure. Researchers are still evaluating the effects of these toxicities on HIV/AIDS mortality. Cost-EffectivenessConsiderations in theChoiceandInitiation 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.
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