Criteria for Changing Therapy

The goal of antiretroviral therapy, to improve the length and quality of the patient's life, is likely best accomplished by maximal suppression of viral replication to below detectable levels (currently defined as <50 copies/mL) sufficiently early to preserve immune function. However, this is not always achievable with a given therapeutic regimen and frequently regimens must be modified. In general, the plasma HIV RNA level is the most important parameter to evaluate response to therapy, and increases in levels of viremia that are significant, confirmed and not attributable to intercurrent infection or vaccination indicate failure of the drug regimen regardless of changes in the CD4⁺ T cell counts. Clinical complications and sequential changes in CD4⁺ T cell count may complement the viral load test in evaluating a response to treatment. Specific criteria that should prompt consideration for changing therapy include:

• Less than a 0.5-0.75 log₁₀ reduction in plasma HIV RNA by 4 weeks following initiation of therapy, or less than a 1 log₁₀ reduction by 8 weeks (CIII);
• Failure to suppress plasma HIV RNA to undetectable levels within 4-6 months of initiating therapy (BIII). In this regard, the degree of initial decrease in plasma HIV RNA and the overall trend in decreasing viremia should be considered. For instance, a patient with 10⁶ viral copies/mL prior to therapy who stabilizes after 6 months of therapy at an HIV RNA level that is detectable but <10,000 copies/mL may not warrant an immediate change in therapy.
• Repeated detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance (BIII). However, the degree of plasma HIV RNA increase should be considered; the physician may consider short-term further observation in a patient whose plasma HIV RNA increases from undetectable to low-level detectability (e.g., 50-5000 copies/mL) at 4 months. In this situation the patient should be followed very closely. It should be noted, however, that most patients who fall into this category will subsequently show progressive increases in plasma viremia that will likely require a change in the antiretroviral regimen.
• Any reproducible significant increase, defined as 3-fold or greater, from the nadir of plasma HIV RNA not attributable to intercurrent infection, vaccination, or test methodology except as noted above (BIII);
• Undetectable viremia in the patient receiving double nucleoside therapy (BIII). Patients currently receiving 2 NRTIs who have achieved the goal of no detectable virus have the option of continuing this regimen or may have modification to conform to regimens in the strongly recommended category (Table 12). Prior experience indicates that most of these patients on double nucleoside therapy will eventually have virologic failure with a frequency that is substantially greater compared to patients treated with the strongly recommended regimens.
• Persistently declining CD4⁺ T cell numbers, as measured on at least two separate occasions (CIII); and
• Clinical deterioration (DIII). In this regard, a new AIDS-defining diagnosis that was acquired after the time treatment was initiated suggests clinical deterioration but may or may not suggest failure of antiretroviral therapy. If the antiretroviral effect of therapy was poor (e.g., <10-fold reduction in viral RNA), then a judgment of therapeutic failure could be made. However, if the antiretroviral effect was good but the patient was already severely immunocompromised, the appearance of a new opportunistic disease may not necessarily reflect a failure of antiretroviral therapy, but rather a persistence of severe immunocompromise that did not improve despite adequate suppression of virus replication. Similarly, an accelerated decline in CD4⁺ T cell counts suggests progressive immune deficiency providing there are sufficient measurements to assure quality control of CD4⁺ T cell measurements.

A final consideration in the decision to change therapy is the recognition of the still limited choice of available agents and the knowledge that a decision to change may reduce future treatment options for the patient. This may influence the physician to be somewhat more conservative when deciding to change therapy. Consideration of alternative options should include potency of the substituted regimen and probability of tolerance of or adherence to the alternative regimen. Clinical trials have shown that partial suppression of virus is superior to no suppression of virus. On the other hand, some physicians and patients may prefer to suspend treatment in order to preserve future options or because a sustained antiviral effect cannot be achieved. Referral to or consultation with an experienced HIV clinician is appropriate when one is considering a change in therapy. When possible, patients requiring a change in an antiretroviral regimen but without treatment options using currently approved drugs should be referred for consideration for inclusion in an appropriate clinical trial.

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