Initiating Therapy in the Patient with Asymptomatic HIV Infection

Once the patient and physician have decided to initiate antiretroviral therapy, treatment should be aggressive, with the goal of maximal suppression of plasma viral load to undetectable levels. Tables VIII and IX summarize the recommendations regarding when to initiate therapy and what regimens to use. In general, any patient with less than 500 CD4+ T cells/mm³ or greater than 10,000 (bDNA) or 20,000 (RT-PCR) copies of HIV RNA/mL of plasma should be offered therapy (AII). This recommendation is based on the relationship between viral load, CD4+ T cell counts, and rates of HIV disease progression in men. Recent data suggest that viral load in women is approximately 50% lower compared with viral load in men for the same rate of CD4+ T cell decline and time to AIDS (61). These findings are limited to non-pregnant women who acquired HIV primarily by injection drug use, and have not been consistently observed (62). No changes in current guidelines for viral load threshold to offer treatment are recommended because these differences are within the error of the viral load assay and the applicability of these conclusions to other populations of women with HIV infection is unknown. The strength of the recommendation for therapy should be based on the readiness of the patient for treatment as well as a consideration of the prognosis for disease-free survival as determined by viral load, CD4+ T cell count (Table V and Figure 1), and the slope of the CD4+ T cell count decline. Note that the values for bDNA shown in Figure 1 and Table V (first line or column) are the uncorrected HIV RNA values obtained from the Multicenter AIDS Cohort Study (MACS). RT-PCR values are also shown in Table V 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 values must be 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.

In current practice there are two general approaches to initiating therapy in the asymptomatic patient: a therapeutically more aggressive approach that would treat most patients early in the course of HIV infection due to the recognition that HIV disease is virtually always progressive; and a more therapeutically cautious approach in which therapy may be delayed because the balance of the risk of clinically significant progression and other factors discussed above are felt to weigh in favor of observation and delayed therapy. The aggressive approach is heavily based on the Principles of Therapy (1), particularly the Principle that one should begin treatment before the development of significant immunosuppression and one should treat to achieve undetectable viremia; thus, all patients with less than 500 CD4+ T cells/mm³ would be started on therapy as would patients with higher CD4+ T cell numbers who have plasma viral load >10,000 (bDNA) or 20,000 (RT-PCR) (Table VIII). The more conservative approach to the initiation of therapy in the asymptomatic individual would delay treatment of the patient with <500 CD4+ T cells/mm³ and low levels of viremia who have a low risk of rapid disease progression, according to the data in Table V; careful observation and monitoring would continue. Patients with CD4+ T cell counts >500/mm³ would also be observed, except those at substantial risk of rapid disease progression because of a high viral load. For example, the patient with 60,000 (RT-PCR) or 30,000 (bDNA) copies of HIV RNA/mL, regardless of CD4+ T cell count, has a high probability of progressing to an AIDS-defining complication of HIV disease within 3 years (32.6% if CD4+ T cells are greater than 500/mm³) and should clearly be encouraged to initiate antiretroviral therapy. On the other hand, a patient with 18,000 copies of HIV RNA/mL of plasma, measured by RT-PCR, and a CD4+ T cell count of 410/mm³ has a 5.9% chance of progressing to an AIDS-defining complication of HIV infection in 3 years (Table V). The therapeutically aggressive physician would recommend treatment for this patient to suppress the ongoing viral replication that is readily detectable; the therapeutically more conservative physician would discuss the possibility of initiation of therapy, but recognize that a delay in therapy due to the balance of considerations discussed above is also reasonable. In either case, the patient should make the final decision regarding acceptance of therapy following discussion with the health care provider of specific issues relevant to his/her own clinical situation.

When initiating therapy in the patient naÔve to antiretroviral therapy, one should begin with a regimen that is expected to achieve sustained suppression of plasma HIV RNA, a sustained increase in CD4+ T cell count, and a favorable clinical outcome (i.e. delayed progression to AIDS and death). Additional consideration should be given to the regimen's pill burden, dosing frequency, food requirements, convenience, toxicity, and drug interaction profile compared with other regimens. Strongly recommended regimens include either indinavir, nelfinavir, ritonavir + saquinavir, or efavirenz in combination with one of several 2 NRTI combinations (Table IX). Clinical outcome data support the use of a PI in combination with 2 NRTIs (25-27) (BI). It should be noted that ritonavir as the sole PI is considered as an alternative agent because of the difficulty many patients have tolerating standard doses of ritonavir (50), and because of the drug's many interactions. A similar rationale applies to saquinavir-SGC, because of the difficulty many patients have tolerating standard doses and because of the large pill burden associated with its use. There is no reason to switch a patient off of a ritonavir or saquinavir-based regimen if they are tolerating it and if the regimen is effective. Ritonavir potentiates the levels of other PIs through its inhibition of the cytochrome P450 pathway that metabolizes PIs. The combination of ritonavir with saquinavir produces a 20-fold increase in saquinavir steady-state levels and significantly reduces the overall pill burden (63, 64). Although clinical data are too preliminary to warrant endorsement, combinations of ritonavir + indinavir (65) or ritonavir + amprenavir (66) have excellent pharmacokinetic profiles and may allow for more convenient dosing.

Disappointing results with antiretroviral regimens prescribed in the setting of virologic failure with a previous regimen suggest that the first regimen affords the best opportunity for long-term control of viral replication. Because the genetic barrier to resistance is greatest with PIs, many would consider a PI + 2 NRTIs to be the preferred initial regimen. However, efavirenz + 2NRTIs appears to be at least as effective as PI + 2 NRTIs in suppressing plasma viremia and increasing CD4+ T cell counts (55), and many would argue that such a regimen is the preferred initial regimen because it may spare the toxicities of PIs for a considerable time (BII). Although no direct comparative trials exist that would allow a ranking of the relative efficacy of the NNRTIs, the demonstrated ability of efavirenz in combination with 2 NRTIs to suppress viral replication and increase CD4+ T cell counts to a similar degree as a PI with 2 NRTIs support a preference for efavirenz over the other available NNRTIs at this time. Abacavir + 2 NRTIs, a triple NRTI regimen, has been used with some success as well (56) (CII). Such a regimen, however, may have short-lived efficacy when the baseline viral load is >100,000 copies/mL. Using 2 NRTIs alone does not achieve the goal of suppressing viremia to below detectable levels as consistently as does a regimen in the "strongly recommended" or "alternative" categories and should be used only if more potent treatment is not possible (DI). Use of antiretroviral agents as monotherapy is contraindicated (DI), except when there are no other options, or in pregnancy to reduce perinatal transmission as noted below. When initiating antiretroviral therapy, all drugs should be started simultaneously at full dose with the following three exceptions: dose escalation regimens are recommended for ritonavir, nevirapine, and in some cases, ritonavir plus saquinavir.

Hydroxyurea has been used investigationally in combination with antiretroviral agents for treatment of HIV infection, however its utility in this setting has not been established. Clinicians considering use of hydroxyurea in a treatment regimen for HIV should be aware of the limited and conflicting nature of data in support of its efficacy, and the importance of monitoring patients closely for potentially serious toxicity (see Hydroxyurea).

Detailed information comparing the different nucleoside RT inhibitors, non-nucleoside RT inhibitors, the protease inhibitors, and drug interactions between the protease inhibitors and other agents can be found in Tables X-XVI. In addition, because certain investigational new drugs are available to physicians for use in selected patients, Table XVII has been provided for the physician treating patients under investigational protocols. Particular attention should be paid to Tables XII-XV regarding drug interactions between the protease inhibitors and other agents, as these are extensive and often require dose modification or substitution of various drugs. Toxicity assessment is an ongoing process; assessment at least twice during the first month of therapy and every 3 months thereafter is a reasonable management approach.

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