Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents
CHANGING A FAILING REGIMEN
Considerations for Changing a Failing Regimen 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 cell count and changes in these counts; remaining treatment options in terms of potency, potential resistance patterns from prior antiretroviral therapies, and potential for adherence/tolerance; assessment of adherence to medications; and psychological preparation of the patient for the implications of the new regimen (e.g., side effects, drug interactions, dietary requirements and possible need to alter concomitant medications) (see Principle 7). Failure of a regimen may occur for many reasons: initial viral resistance to one or more agents, altered absorption or metabolism of the drug, multidrug pharmacokinetics that adversely affect therapeutic drug levels, and poor patient adherence to a regimen due to either poor compliance or inadequate patient education about the therapeutic agents. In regard to the last issue, the healthcare provider should carefully assess patient adherence before changing antiretroviral therapy; healthcare workers involved in the care of the patient (e.g., the case manager or social worker) may be helpful 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 these persons 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 because of 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. Optimally and when possible, the regimen should be changed entirely to drugs that have not been taken previously. With triple combinations of drugs, at least two and preferably three new drugs must be used; this recommendation is based on the current understanding of strategies to prevent drug resistance (see Principles 4 and 5). Assays to determine genotypic resistance are commercially available; however, these have not undergone field testing to demonstrate clinical utility and are not approved by the FDA. The Panel does not recommend these assays for routine use at present.
The following three categories of patients should be considered with regard to a change in therapy: 1) persons who are receiving incompletely suppressive antiretroviral therapy with single or double nucleoside therapy and with detectable or undetectable plasma viral load; 2) persons who have been on potent combination therapy, including a PI, and whose viremia was initially suppressed to undetectable levels but has again become detectable; and 3) persons who have been on potent combination therapy, including a PI, and whose viremia was never suppressed to below detectable limits. Although persons in these groups should have treatment regimens changed to maximize the chances of durable, maximal viral RNA suppression, the first group may have more treatment options because they are PI naive.
Criteria for Changing Therapy
The goal of antiretroviral therapy, which is 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 <500 copies/mL) sufficiently early to preserve immune function.
However, this reduction cannot always be achieved with a given therapeutic
regimen, and frequently regimens must be modified. In general, the plasma
HIV RNA level is the most important parameter to consider in evaluating
response to therapy, and increases in levels of viremia that are substantial,
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 the following:
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 with patients treated with the preferred regimens.
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 (see Principle 7). This consideration 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 demonstrated that partial suppression of virus is superior to no suppression of virus. However, some physicians and patients may prefer to suspend treatment 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 the clinician is considering a change in therapy. When possible, patients who require a change in an antiretroviral regimen but without treatment options that include using currently approved drugs should be referred for consideration for inclusion in an appropriate clinical trial.
Therapeutic Options When Changing Antiretroviral Therapy
Recommendations for changes in treatment differ according to the indication
for the change. If the desired virologic objectives have been achieved
in patients who have intolerance or toxicity, a substitution should be
made for the offending drug, preferably with an agent in the same class
with a different toxicity or tolerance profile. If virologic objectives
have been achieved but the patient is receiving a regimen not in the preferred
category (e.g., two NRTIs or monotherapy), there is the option either to
continue treatment with careful monitoring of viral load or to add drugs
to the current regimen to comply with preferred treatment regimens. Most
experts consider that treatment with regimens not in the preferred category
is associated with eventual failure and recommend the latter tactic. At
present, few clinical data are available to support specific strategies
for changing therapy in patients who have failed the preferred regimens
that include PIs; however, several theoretical considerations should guide
decisions. Because of the relatively rapid mutability of HIV, viral strains
that are resistant to one or more agents often emerge during therapy, particularly
when viral replication has not been maximally suppressed. Of major concern
is recent evidence of broad cross resistance among the class of PIs. Evidence
indicates that viral strains that become resistant to one PI will have
reduced susceptibility to most or all other PIs.
Thus, the likelihood of success of a subsequently administered PI + two NRTI regimen, even if all drugs are different from the initial regimen, may be limited, and many experts would include two new PIs in the subsequent regimen.
Some of the most important guidelines to follow when changing a patient’s antiretroviral therapy are summarized (Table 13), and some of the treatment options available when a decision has been made to change the antiretroviral regimen are outlined (Table 14). Limited data exist to suggest that any of these alternative regimens will be effective (Table 14), and careful monitoring and consultation with an expert in the care of such HIV-infected patients is desirable. A change in regimen because of treatment failure should ideally involve complete replacement of the regimen with different drugs to which the patient is naive. This typically would include the use of two new NRTIs and one new PI or NNRTI, two PIs with one or two new NRTIs, or a PI combined with an NNRTI. Dose modifications may be required to account for drug interactions when using combinations of PIs or a PI and NNRTI (Table 12). In some persons, these options are not possible because of prior antiretroviral use, toxicity, or intolerance. In the clinically stable patient who has detectable viremia for whom an optimal change in therapy is not possible, it may be prudent to delay changing therapy in anticipation of the availability of newer and more potent agents. It is recommended that the decision to change therapy and design a new regimen should be made with assistance from a clinician experienced in the treatment of HIV infected patients through consultation or referral.
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