Initiating Therapy in Advanced HIV Disease

All patients diagnosed with advanced HIV disease, which is defined as any condition meeting the 1993 CDC definition of AIDS (23) should be treated with antiretroviral agents regardless of plasma viral levels (AI). All patients with symptomatic HIV infection without AIDS, defined as the presence of thrush or unexplained fever, should also be treated. When the patient is acutely ill with an OI or other complication of HIV infection, the clinician should consider clinical issues such as drug toxicity, ability to adhere to treatment regimens, drug interactions, and laboratory abnormalities when determining the timing of initiation of antiretroviral therapy. Once therapy is initiated, a maximally suppressive regimen should be used, as indicated in Table 12. Advanced stage patients being maintained on an antiretroviral regimen should not have the therapy discontinued during an acute opportunistic infection or malignancy, unless there are concerns regarding drug toxicity, intolerance, or drug interactions.

Patients who have progressed to AIDS are often treated with complicated combinations of drugs and the potential for multiple drug interactions must be appreciated by clinician and patient. Thus, the choice of which antiretroviral agents to use must be made with consideration given to potential drug interactions and overlapping drug toxicities, as outlined in Tables 13, 14, 15, 16, 17, 18, and 19. For instance, the use of rifampin to treat active tuberculosis is problematic in a patient receiving a protease inhibitor, which adversely affects the metabolism of rifampin but is frequently needed to effectively suppress viral replication in these advanced patients. Conversely, rifampin lowers the blood level of protease inhibitors, which may result in suboptimal antiretroviral therapy. While rifampin is contraindicated or not recommended for use with all of the protease inhibitors, one might consider using rifabutin at a reduced dose, as indicated in Table 17; this topic is discussed in greater detail elsewhere (120). Other factors complicating advanced disease are wasting and anorexia, which may prevent patients from adhering to the dietary requirements for efficient absorption of certain protease inhibitors. Bone marrow suppression associated with ZDV and the neuropathic effects of ddC, d4T and ddl may combine with the direct effects of HIV to render the drugs intolerable. Hepatotoxicity associated with certain protease inhibitors may limit the use of these drugs, especially in patients with underlying liver dysfunction. The absorption and half-life of certain drugs may be altered by antiretroviral agents, particularly the protease inhibitors and NNRTIs whose metabolism involves the hepatic cytochrome p450 (CYP450) enzymatic pathway. PIs inhibit the CYP450 pathway, whereas NNRTIs have variable effects; nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz is a mixed inducer/inhibitor. CYP450 inhibitors have the potential to increase blood levels of drugs metabolized by this pathway. At times, adding a CYP450 inhibitor can improve the pharmacokinetic profile of selected agents (such as adding ritonavir therapy to saquinavir) as well as contribute an additive antiviral effect; however, these interactions can also result in life threatening drug toxicity, as indicated in Tables 16, 17, 18, and 19. Thus, health care providers should inform their patients of the need to discuss any new drugs, including over the counter agents and alternative medications, that they may consider taking, and careful attention should be given to the relative risks versus benefits of specific combinations of agents.

Initiation of potent antiretroviral therapy is often associated with some degree of recovery of immune function. In this setting, patients with advanced HIV disease and subclinical opportunistic infections such as MAI or CMV may develop a new immunologic response to the pathogen and thus new symptoms may develop in association with the heightened immunologic and/or inflammatory response. This should not be interpreted as a failure of antiretroviral therapy and these newly presenting opportunistic infections should be treated appropriately while maintaining the patient on the antiretroviral regimen. Viral load measurement is helpful in clarifying this situation.

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