Considerations for Changing a Failing Regimen

As with the initiation of antiretroviral therapy, the decision to change regimens should be approached with careful consideration of several complex factors. These factors include: recent clinical history and physical examination; plasma HIV RNA levels measured on two separate occasions; absolute CD4⁺ T lymphocyte count and changes in these counts; remaining treatment options in terms of potency, potential resistance patterns from prior antiretroviral therapies and potential for compliance/tolerance; assessment of adherence to medications; and preparation of the patient for the implications of the new regimen which include side effects, drug interactions, dietary requirements and possible need to alter concomitant medications. Failure of a regimen may occur for many reasons, including initial viral resistance to one or more agents, altered absorption or metabolism of the drug, multi-drug pharmacokinetics that adversely affects therapeutic drug levels, and poor patient adherence to a regimen. In this regard, it is important to carefully assess patient adherence prior to changing antiretroviral therapy; health care workers involved in the care of the patient, such as the case manager or social worker, may be of assistance in this evaluation. Clinicians should be aware of the prevalence of mental health disorders and psychoactive substance use disorders in certain HIV-infected persons; inadequate mental health treatment services may jeopardize the ability of such individuals to adhere to their medical treatment. Proper identification of and intervention in these mental health disorders can greatly enhance adherence to medical HIV treatment.

It is important to distinguish between the need to change therapy due to drug failure versus drug toxicity. In the latter case, it is appropriate to substitute one or more alternative drugs of the same potency and from the same class of agents as the agent suspected to be causing the toxicity. In the case of drug failure where more than one drug had been used, a detailed history of current and past antiretroviral medications, as well as other HIV-related medications, should be obtained. Testing for antiretroviral drug resistance may also be very helpful in maximizing the number of active drugs in a regimen (“Testing for Drug Resistance”). Viral resistance to antiretroviral drugs is an important, but not the only, reason for treatment failure. Genetically distinct viral variants emerge in each HIV-infected individual over time after initial infection. Viruses with single drug resistant mutations exist even prior to therapy, but are selected for replication by antiviral regimens that are only partially suppressive. The more potent a regimen is in durably suppressing HIV replication, the less likely the emergence of resistant variants. Thus the goal of therapy should be to reduce plasma HIV RNA to below detectable limits using the most sensitive assay available (<50 copies/mL), thereby providing the strongest genetic barrier possible to the emergence of resistance.

Three different populations of patients should be considered with regard to a change in therapy: 1) individuals who are receiving incompletely suppressive antiretroviral therapy, such as single or double nucleoside therapy, with detectable or undetectable plasma viral load (discussed further below); 2) individuals who have been on potent combination therapy and whose viremia was initially suppressed to undetectable levels but has again become detectable; and 3) individuals who have been on potent combination therapy and whose viremia was never suppressed to below detectable limits.

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