Considerations for Initiating Therapy in the Patient with Asymptomatic HIV Infection

Initial placebo-controlled trials of zidovudine clearly established that antiretroviral treatment was associated with clinical benefit in HIV-infected individuals with advanced HIV disease and immunosuppression (24). Later studies of immediate versus delayed zidovudine therapy in HIV-infected patients without AIDS demonstrated only a modest and transient advantage in favor of immediate therapy when probabilities of AIDS-free survival were compared (25). As more nucleoside analogue reverse transcriptase inhibitors became available, it was shown that combinations of these drugs provided additional, more durable clinical benefit compared with monotherapy (25). When protease inhibitors became available, studies in patients with advanced HIV disease demonstrated substantial additional clinical benefit when protease inhibitor plus dual nucleoside regimens were compared with dual nucleoside therapy alone (26-28). These clinical trials data as well as observational data indicating that the risk of opportunistic diseases increases markedly when the CD4⁺ T cell count declines to <200 cells/mm³ strongly support the recommendation that all patients with a CD4⁺ T cell count <200 cells/mm³ or clinically-defined AIDS should be offered antiretroviral therapy.

Although there is theoretical benefit to antiretroviral therapy for patients with CD4⁺ T cell counts greater than 200 cells/mm³ , no studies have been conducted comparing immediate versus delayed potent combination antiretroviral therapy in these patients. A major dilemma confronting patients and practitioners is that the antiretroviral regimens currently available that have the greatest potency in terms of viral suppression and CD4⁺ T cell preservation are medically complex, are associated with a number of specific side effects and drug interactions, and pose a substantial challenge for adherence. Furthermore, the development of mutations associated with drug resistance can render therapy less effective or ineffective. Thus, decisions regarding treatment of asymptomatic, chronically infected individuals with CD4⁺ T cell counts >200 cells/mm³ must balance a number of competing factors that influence risk and benefit.

The optimal time to initiate antiretroviral therapy is not known. Table 4 summarizes the potential benefits and risks of early and of delayed initiation of therapy in the asymptomatic patient that the clinician and the patient must consider in deciding when to initiate therapy. Potential benefits of early therapy include earlier suppression of viral replication; preservation of immune function; prolongation of disease-free survival; and decrease in the risk of viral transmission. Risks include i) the adverse effects of the drugs on quality of life; ii) the inconvenience of most of the suppressive regimens currently available leading to reduced adherence; iii) development of drug resistance over time because of early initiation of therapy; iv) limitation of future treatment options due to premature cycling of the patient through the available drugs; v) the risk of transmission of virus resistant to antiretroviral drugs; vi) serious and unknown toxicities associated with some antiretroviral drugs (e.g., elevations in serum levels of cholesterol and triglycerides, alterations in the distribution of body fat, insulin resistance and even frank diabetes mellitus); and vii) the unknown durability of effect of the currently available therapies. The benefits of delayed therapy include minimization of treatment-related negative effects on quality of life and drug-related toxicities; preservation of treatment options; and delay in the development of drug resistance. Risks of delayed therapy include the theoretical possibility that some damage to the immune system that might otherwise be salvaged by earlier therapy is irreversible; the possibility that suppression of viral replication may be more difficult at a later stage of disease; and the increased risk of HIV transmission to others during a longer untreated period.

The strength of the recommendation for therapy must balance the readiness of the patient for treatment; consideration of the prognosis for disease-free survival in the absence of treatment as determined by baseline CD4⁺ T cell count, viral load, (Table 5 and Figure 1), and the slope of the CD4⁺ T cell count decline; and assessment of the risks and potential benefits associated with initiating antiretroviral therapy. [Note that the HIV RNA values shown in Table 5 and Figure 1 (first line or column) were obtained with the bDNA assay from the Multicenter AIDS Cohort Study (MACS). Expected values of HIV RNA obtained with the RT-PCR assay are also shown in Table 5 and Figure 1; comparison of the results obtained from the RT-PCR and bDNA assays using the manufacturer’s controls consistently indicate that the HIV-1 RNA values obtained by RT-PCR are approximately two times higher than those obtained by the bDNA assay (4). Thus, the MACS HIV RNA values have been multiplied by approximately 2 to be consistent with current RT-PCR values. A third test for HIV RNA, the Nucleic-Acid Sequence Based Amplification (NASBA), is currently used in some clinical settings. However, formulas for converting values obtained from either bDNA or RT-PCR assays to NASBA-equivalent values cannot be derived from the limited data available at this time. [This information will be added to the guidelines when it becomes available.]

Increasing recognition of the risks associated with initiation of antiretroviral therapy has shifted expert opinion to a more conservative position concerning the initiation of therapy compared with earlier editions of these guidelines. In general, it is now felt that patients with fewer than 350 CD4⁺ T cells/mm³ should be offered therapy (Table 6) (AII). This recommendation is based in part on the substantial short-term risk of disease progression for untreated patients with fewer than 350 CD4⁺ T cells/mm³ at all levels of plasma HIV RNA (Table 5 and Figure 1). In addition, data from observational cohorts suggest that i) initiation of therapy at a CD4⁺ T cell count <200 cells/mm³ is associated with shorter survival compared with initiation of therapy at higher CD4⁺ T cell counts (29), and ii) initiation of therapy at CD4⁺ T cell counts >350 cells/mm³ was associated with a higher rate of AIDS-free survival at 2 years compared with deferral of therapy (30). For asymptomatic patients with CD4⁺ T cell counts >350 cells/mm³ , rationale exists for both conservative and aggressive approaches to therapy. The conservative approach is based on the recognition that robust immune reconstitution still occurs in most patients who initiate therapy with CD4⁺ T cell counts in the 200-350 cells/mm³ range, and that toxicities and adherence challenges may outweigh benefits at CD4⁺ T cell counts >350 cells/mm³ . In the conservative approach, high levels of plasma HIV RNA (i.e., >30,000 by bDNA or 55,000 RT-PCR) are an indication for more frequent monitoring of CD4⁺ T cell counts and plasma HIV RNA levels, but not necessarily for initiation of therapy. In the aggressive approach, asymptomatic patients with CD4⁺ T cell counts >350 cells/mm³ and levels of plasma HIV RNA >30,000 (bDNA) or 55,000 (RT-PCR) would be treated because of the risk of immunologic deterioration and disease progression. The aggressive approach is supported by the observation in many studies that suppression of plasma HIV RNA by antiretroviral therapy is easier to achieve and maintain at higher CD4⁺ T cell counts and lower levels of plasma viral load (6, 31- 34). Long-term clinical outcomes data, however, are not available to fully endorse this approach.

Data are conflicting regarding sex-specific differences in viral load and CD4⁺ T cell counts (see “Considerations for Antiretroviral Therapy in Women”). Several studies (35-41), though not others (42-45), have concluded that after adjustment for CD4⁺ T cell count, levels of HIV RNA are lower in women compared with men. In those studies that have indicated a possible gender difference in HIV RNA levels, women have had RNA levels that ranged between 0.13 to 0.28 log10 lower than observed in men. In two studies of HIV seroconverters, HIV RNA copy numbers were significantly lower in women than men at seroconversion, but these differences decreased over time, and median viral load in women and men became similar within 5-6 years after seroconversion (36, 37, 41). Some data suggest that CD4⁺ T cell counts may be higher in women than men (46). However, importantly, rates of disease progression do not differ in a sex-dependent manner (39, 41, 47, 48). Taken together, these data suggest that sex-based differences in viral load occur predominantly during a window of time when the CD4⁺ T cell count is relatively preserved, when treatment is recommended only in the setting of high levels of plasma HIV RNA. Clinicians may wish to consider lower plasma HIV RNA thresholds for initiating therapy in women with CD4⁺ T cell counts >350 cells/mm³ , although there are insufficient data to determine an appropriate threshold. In patients with CD4⁺ T cell counts <350 cells/mm³ , very small sex-based differences in viral load are apparent; therefore, no changes in treatment guidelines for women are recommended for this group.

Thus, the decision to begin therapy in the asymptomatic patient with >200 CD4⁺ T cells/mm³ is complex and must be made in the setting of careful patient counseling and education. The factors that must be considered in this decision are: 1) the willingness and readiness of the individual to begin therapy; 2) the degree of existing immunodeficiency as determined by the CD4⁺ T cell count; 3) the risk of disease progression as determined by the CD4⁺ T cell count and level of plasma HIV RNA (Table 5 and Figure 1; see also reference(1); 4) the potential benefits and risks of initiating therapy in asymptomatic individuals, as discussed above; and 5) the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. In this regard, no individual patient should automatically be excluded from consideration for antiretroviral therapy simply because he or she exhibits a behavior or other characteristics judged by some to lend itself to nonadherence. Rather, the likelihood of patient adherence to a complex drug regimen should be discussed and determined by the individual patient and clinician before therapy is initiated. To achieve the level of adherence necessary for effective therapy, providers are encouraged to utilize strategies for assessing and assisting adherence; in this regard, intensive patient education regarding the critical need for adherence should be provided, specific goals of therapy should be established and mutually agreed upon and a long-term treatment plan should be developed with the patient. Intensive follow up should take place to assess adherence to treatment and to continue patient counseling for the prevention of sexual and drug injection-related transmission (see "Adherence to Potent Antiretroviral Therapy").

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