The Case for More Cautious, Patient-Focused Antiretroviral Therapy

Many experts in the field of HIV are increasingly uncertain of the proper way to use antiretroviral therapy. The current standard goal of such therapy, immediate suppression of viremia, often does not mesh with clinical reality. For physicians, the major goal of treatment is maintaining the long-term health of the patient while avoiding drug-related toxicity and preserving future treatment options. A study by Palella and colleagues (1) is often used as proof of the value of protease inhibitor-based therapy. However, it could also be argued that this study supports the view that delaying therapy until a patient's CD4+ count is less than 100 cells/mm3 results in impressive clinical benefit. In wealthy countries, current recommendations for care of patients with HIV infection are typified by early use of potent combinations of antiretroviral drugs (2-4). Such therapy has spectacularly reduced AIDS-related morbidity and mortality in the United States (5). Guidelines for treatment of HIV infection have served an important purpose in quickly validating the effective use of costly potent therapy so that government agencies and insurance companies would support it. However, now that effective therapy has been firmly established as the standard of care in wealthy countries and rapid onset of disease and death is no longer the routine, it is important to reexamine treatment goals. When HIV RNA tests for viral load were introduced and three classes of drugs became available, it became possible to more effectively suppress and monitor the rate of HIV replication (6-9). Many remember the thrill experienced in 1996 when the preliminary results of the pivotal ritonavir trial were first presented (10). At the HIV clinic where I work in St. Paul, Minnesota, physicians quickly began prescribing protease inhibitor-based therapy for patients who were ill, had high viral levels, or had low CD4+ T-cell counts. Deaths in our HIV population decreased 85% in a 1-year period, and the care of HIV-infected persons became a predominantly outpatient-focused activity. Widespread use of early, aggressive therapy (11) was adopted on the basis of several assumptions about the effect of such treatment on HIV pathogenesis (Table). One key assumption that supported early use of therapy was that ongoing HIV replication caused irreversible damage to the immune system (12). However, many recent studies have clearly shown that potent treatment often reverses much of the damage over a period of years and that naive CD4+ T-lymphocyte counts usually increase slowly (13), even in patients with advanced HIV infection (14). More surprising was the observation that the lymphoid tissue architecture and follicular dendritic cell network could be restored even when therapy was started late in the disease process (15). However, HIV-specific immunity is one key aspect of immune function that is irreversibly lost in the early stages of HIV infection (16). Because not every patient who receives potent therapy experiences substantial immune reconstitution, future research must examine factors (such as residual thymic function or baseline naive CD4+ T-cell count [17, 18]) that may predict treatment success or failure in an individual patient. Table. Assumptions Underlying Use of Early Aggressive Antiretroviral Therapy Another key assumption is that a given regimen will completely suppress HIV replication. Many studies have shown that the nadir of plasma viral level is correlated with the duration of virologic effect (19). Pivotal studies have demonstrated that protease inhibitors provide greater clinical benefit than dual reverse transcriptase inhibitors (8). However, in a study by Demeter and coworkers (20), only 56% of patients receiving protease inhibitor-based therapy had plasma viral levels below the standard level of detection and only 27% had RNA levels below the level of detection for an ultrasensitive assay after 40 weeks of treatment. Henry and colleagues (21) performed a study in which an ultrasensitive assay (with a detection limit of 40 copies/mL) was able to detect virus in 71% of patients whose RNA levels were below the detection limit for standard assays (<500 copies/mL). Seventy-one percent of patients in this study had detectable levels of RNA. Even when plasma RNA levels are lower than the detection limits of ultrasensitive assays in carefully selected patients, evidence suggests that HIV replication is ongoing (22, 23). Success as measured by a virologic standard is therefore extremely dependent on assays. In clinical practice, the rates of virologic success for potent regimens are lower than those seen in published studies; after 1 year, viral suppression often remains below standard detection limits in 37% to 60% of patients (24, 25). Therefore, current potent regimens do not completely inhibit HIV replication in most patients. Another assumption that underlies early use of treatment is that potent therapy will prevent the emergence of drug-resistant strains of HIV. However, resistance develops during ongoing HIV replication in the presence of anti-HIV drugs, a scenario that occurs in most patients. Furthermore, widespread use of potent therapy will lead to the steady evolution of resistant HIV strains that can be transmitted to newly infected persons. Erice and coworkers (26) reported the first case of zidovudine-resistant HIV-1, and new infections with multidrug-resistant strains of HIV-1 have been described (27-30). How to minimize the evolution of HIV-1 resistance both in individual patients and in populations is a key issue for the long-term control of HIV-1. Three general strategies that address this concern are available. Clinicians can attempt to completely suppress viral replication, delay therapy, or use therapies with nonoverlapping resistance patterns. Only the option of delaying (no) therapy would be certain to minimize resistance. If this situation does not change, the use of complex and expensive resistance tests will become routine (31). Clinical studies have shown that HIV-1 often changes from a non-syncytium-inducing phenotype to a syncytium-inducing phenotype in late-stage HIV infection (32). That change is believed to be related to viral pathogenicity but often is not observed even in late-stage patients with advanced AIDS. Possible factors that could be related to viral pathogenicity or fitness are a subject of much interest and debate. In a primate model, virus prototypes with characteristics of late-stage disease have been shown to result in a more rapid clinical course when transferred to uninfected animals (33, 34). Although it may seem reasonable to believe that use of potent therapy could delay or prevent the evolution of more virulent strains of the virus, few data support that argument. From an evolutionary perspective, without a reasonable chance for a cure, it may be best to use HIV therapy to shepherd the virus down a pathway that allows replication but avoids increased pathogenicity, thereby establishing a long-term balance between HIV and the immune system. Data on the relations among levels of HIV-1 RNA, CD4+ T-cell counts, and clinical outcomeswhich have been obtained from several cohort studies that include follow-up data for up to 10 years (6, 35)are fundamental to the early use of therapy for HIV infection. However, those data were generated at a time when potent therapy was not available and prophylaxis against key AIDS-related pathogens was not the standard of care. It is just as important to identify patients who are not at risk for AIDS-related clinical events over a reasonable period (for example, 3 years) as it is to identify those who are at high risk. Data from the AIDS Clinical Trials Group (ACTG) 175 cohort indicated that patients with CD4+ counts less than 300 cells/mm3 and HIV RNA levels less than 10 000 copies/mL had only a 4% chance of progressing to clinical AIDS over a 3-year period while receiving nucleoside therapy (36). Continued monitoring of a patient's surrogate markers provides a better assessment of his or her risk for clinical disease than use of baseline values (37). This approach can individualize treatment in a more specific manner than the general recommendations, which are based on population-oriented threshold values. Perhaps more than any other assumption, the hope that potent antiretroviral therapy could cure HIV infection within a reasonable time frame powered enthusiasm for immediately beginning treatment. Routine clearance of virus from the blood suggested that a cure could be possible. However, Haase and colleagues (38) found that 99.9% of the virus was located in the lymphoid tissue; Cavert and coworkers (39) determined that the virus persisted there after it was cleared from the blood. Recent studies in patients who had the best virologic responses in the research setting have suggested that cure with current potent treatment may be possible after 10 years of therapy (22), 60 to 115 years of therapy (40), or never (41, 42). Even when cytokines, such as interleukin-2, are used to purge the virus from its hiding places (43) in selected patients, the disease will not be cured (44). Therefore, it is safe to conclude that a cure is extremely unlikely with the current approach to treatment. According to standard guidelines, therapy should promptly be changed when a given regimen is found to be failing virologically. This is done because of concern that immunologic and clinical failure would soon follow (2-4). However, recent data suggest that during a 12- to 18-month period, a virologic-immunologic disconnect is often seen (45-47) in which virologic failure may occur without immunologic or clinical failure. In practice, changes in therapy are made before patients' risk for such events increases. With this approach, clinicians can quickly run out of reasonable options and it can be difficult to determine which previously used drugs failed because of resistance. Recent studi