Goals of Therapy

Eradication of HIV infection cannot be achieved with currently available antiretroviral regimens; in large measure, this is due to the establishment of a pool of latently infected CD4⁺ T cells during the very earliest stages of acute HIV infection (85) that persists with an extremely long half-life, even with prolonged suppression of plasma viremia to <50 copies/mL (86-89). The primary goals of antiretroviral therapy are maximal and durable suppression of viral load, restoration and/or preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality (Table 10). In fact, adoption of treatment strategies articulated in these guidelines has resulted in substantial reductions in HIV-related morbidity and mortality (90-92).

Plasma viremia is a strong prognostic indicator in HIV infection (3). Furthermore, reductions in plasma viremia achieved with antiretroviral therapy account for much of the clinical benefit associated with therapy (93). Therefore, suppression of plasma viremia as much as possible for as long as possible is an important goal of antiretroviral therapy. However, this goal must be balanced against the need to preserve effective treatment options. Switching antiretroviral regimens for any detectable level of plasma viremia may rapidly exhaust treatment options; reasonable parameters that may prompt a change in therapy are discussed (see "Criteria for Changing Therapy").

HAART often leads to increases in the CD4⁺ T cell count of 100-200 cells/ml or more, although individual responses are quite variable. CD4⁺ T cell responses are generally related to the degree of viral load suppression (94). In turn, continued viral load suppression is more likely among those who achieve higher CD4⁺ T cell counts during therapy (95). A favorable CD4⁺ T cell response can occur with incomplete viral load suppression and may not necessarily indicate a poor prognosis (96). The durability of these immunologic responses that occur with suboptimal suppression of viremia is unknown. Therefore, while viral load is the strongest single predictor of long-term clinical outcomes, strong consideration should also be given to sustained rises in CD4⁺ T cell counts and partial immune restoration. The urgency of the need to change therapy in the presence of low level viremia is clearly tempered by this observation. The expectation that continuing the existing therapy in this situation will inevitably lead to rapid accumulation of drug resistant virus may not always be realized. One reasonable strategy is maintenance of the regimen, but with redoubled efforts at optimizing adherence, and more frequent monitoring.

Partial reconstitution of immune function induced by HAART may allow for elimination of unnecessary therapies, such as some of those used for prevention and maintenance therapy against opportunistic infections. The appearance of näive T cells (97, 98), partial normalization of perturbed T cell receptor Vß repertoires (99), and evidence of residual thymic function in patients receiving HAART (100, 101) suggest that partial immune reconstitution frequently occurs in these patients. Further evidence of functional immune restoration can be found in the return during HAART of in vitro responses to microbial antigens associated with opportunistic infections (102), and the lack of cases of Pneumocystis carinii pneumonia (PCP) among patients who discontinued primary PCP prophylaxis when their CD4⁺ T cell counts rose to >200 cells/mm³ during HAART (103-105). Current guidelines include some recommendations regarding the discontinuation of prophylaxis and maintenance therapy for certain opportunistic infections in the setting of HAART-induced increases in CD4⁺ T cell counts (2).

Tools to Achieve the Goals of Therapy
Although as many as 70-90% of antiretroviral drug-näive patients achieve maximal viral load suppression 6-12 months after initiation of therapy, only about 50% of patients in a city clinic setting achieve similar results (31, 32). Predictors of virologic success include low baseline viremia and high baseline CD4⁺ T cell count (31-33), rapid decline of viremia (6), decline of viremia to <50 HIV RNA copies/mL (6), adequate serum levels of antiretroviral drugs (6, 106), and adherence to the drug regimen (32, 49, 53). While optimal strategies for achieving the goals of antiretroviral therapy have not yet been fully delineated, efforts to improve patient adherence to therapy are likely important (see Adherence to Potent Antiretroviral Therapy).

Another tool to maximize the benefits of antiretroviral therapy is the rational sequencing of drugs and the preservation of future treatment options for as long as possible. Table 11 shows the possible advantages and disadvantages of three alternative regimens, including a PI with 2 NRTIs, an NNRTI with 2 NRTIs, or a 3 NRTI regimen. The goal of a class-sparing regimen is to preserve or "spare" one or more than one class of drugs for later use. By sequencing drugs in this fashion, it may be possible to extend the overall long-term effectiveness of the available therapy options. Moreover, this strategy makes it possible to selectively delay the risk of certain side effects uniquely associated with a single class of drugs. The efficacy of PI-containing HAART regimens has been demonstrated to include durable viral load suppression, partial immunologic restoration, and decreased incidence of AIDS and death (26-28). Viral load suppression and CD4⁺ T cell responses that are similar to those observed with PI-containing regimens have been achieved with selected PI-sparing regimens, such as efavirenz + 2 NRTIs (107) or abacavir + 2 NRTIs (108); however, it is not yet known whether such PI-sparing regimens will provide comparable efficacy with regard to clinical endpoints.

The presence of drug resistant HIV in treatment-experienced patients is a strong predictor of virologic failure and disease progression (109-111). The results of several prospective studies indicate that the virologic response to a new antiretroviral regimen after virologic failure on a previous regimen can be significantly improved when results of resistance testing were available to guide the choice of drugs in the new regimen (10, 11). Thus, resistance testing appears to be a useful tool in selecting active drugs when changing antiretroviral regimens in the setting of virologic failure (see "Testing for Drug Resistance").

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