The U.S. Panel of the International AIDS Society has issued updated recommendations for antiretroviral therapy in adults with human immunodeficiency virus (HIV) infection. The recommendations constitute the panel's consensus as of December 1999. Included are recommendations about when to begin antiretroviral therapy, what therapy to use, how to monitor the therapy and when to change therapy.
Attaining higher CD4+ counts, even to within the normal range, can be achieved if antiretroviral therapy is started early when CD4+ counts are higher. However, resistance, long-term adverse effects, drug interactions and decreased compliance are issues that need to be considered. The panel generally recommends that antiretroviral therapy be initiated if the plasma HIV RNA level is more than 30,000 copies per mL, regardless of the CD4+ cell count. If the CD4+ count is below 350 cells per mm3 (350 × 106 per L), antiretroviral therapy should be started regardless of the HIV RNA load. Antiretroviral therapy is also recommended in patients with HIV RNA levels between 5,000 and 30,000 copies per mL and CD4+ counts between 350 and 500 cells per mm3 (350 and 500 × 106 per L).
It remains unclear whether antiretroviral therapy improves survival in patients with CD4+ cell counts in the range of 500 mm3. Patients with high CD4+ counts (greater than 500) and low HIV RNA loads (below 5,000) are at low risk of clinical progression of the disease in the ensuing three years.
All symptomatic patients with HIV infection should receive antiretroviral therapy. Opportunistic infections should usually be treated before antiretroviral therapy is started. For example, in the case of tuberculosis, rifampin–protease inhibitor interactions preclude the use of the antiretroviral agent during rifampin therapy. Thus, protease inhibitor therapy should be postponed until rifampin is discontinued.
Patients with primary HIV infection (the interval between infection to complete seroconversion, also known as acute HIV syndrome) should be referred to a clinical trial if possible. When participation in a clinical trial is not feasible, potent antiretroviral therapy should be started, and individualization of the initial antiretroviral regimen is necessary. Potency, tolerability and adverse effects should all be taken into account.
Antiretroviral therapy is usually initiated with two nucleoside reverse transcriptase inhibitors (nRTI; zidovudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir) plus one or two protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir), or two nRTIs and a nonnucleoside reverse transcriptase inhibitor (NNRTI; nevirapine, delavirdine and efavirenz).
Even a three-drug regimen, however, is often unsuccessful in patients at highest risk of clinical progression. High-risk patients have CD4+ counts of less than 50 cells per mm3 (50 × 106 per L) or HIV RNA levels of greater than 100,000 copies per mL. It is still reasonable in these patients to consider a potent three- or four-drug regimen, however.
Advantages and disadvantages of possible initial antiretroviral regimens are summarized in the accompanying table on page 182. Of the nRTIs, zidovudine and stavudine should not be prescribed together because of drug-drug antagonism. The combination of zalcitabine and didanosine or stavudine is not recommended because of overlapping toxicities. Abacavir is a potent drug in untreated patients.
CD4+ cell counts and HIV RNA levels should be monitored to determine the patient's response to antiretroviral therapy. Two measurements of the CD4+ count and HIV RNA level should be obtained at two separate visits before therapy is started or changed. After four weeks of treatment, the HIV RNA levels should show a 1.5- to 2.0-log decline. Early response predicts future HIV suppression, although the response may be slower in patients with higher initial HIV RNA levels. If the HIV RNA level has not dropped to less than 50 copies per mL after 16 to 24 weeks of antiretroviral therapy, drug resistance, poor compliance or poor drug absorption should be considered.
HIV RNA levels should be monitored approximately every month until the target HIV RNA level is reached and every two to three months thereafter. Viral rebound is likely during other illnesses and after vaccinations, so HIV RNA levels should not be checked at these times. At present, monitoring of antiretroviral drug levels does not appear to have a role unless there is a question of compliance or absorption. Although costly, drug-resistance testing is possible. However, little information exists about the optimal usefulness of such tests.
A change in the antiretroviral regimen should be considered if drug failure is suspected by the presence of inadequate viral suppression, lack of an increase in the CD4+ count or clinical progression. However, adherence to therapy must be verified before the regimen is changed. The recommendations state that a change in therapy should probably not be based solely on the CD4+ count.
When a change in the regimen is anticipated, the reason for the change guides the selection of new therapy. For example, if an NNRTI has caused a rash, substitution of another NNRTI should be done carefully, because these agents may share toxicity. If the drug that is causing an adverse effect cannot be identified, it is reasonable to discontinue all medications for a short period before resuming treatment. Rechallenge with abacavir should not occur. Toxicity and death have been reported with this agent.
If a change in therapy is considered because of virologic failure and the HIV RNA levels are low (but detectable), the addition of another agent is reasonable. Patients with persistently high HIV RNA levels probably have developed drug resistance. In this case, all medications should probably be changed. Success rates in patients who develop drug resistance are low. The new regimen should have the highest possible potency, tolerability and compliance. If the current regimen contains an NNRTI, another NNRTI should not be used because of the high rate of cross-reactivity. As long as is practicable, therapy should be continued, even in patients with advanced disease and continued viremia.
editor's note: This update report also contains information on interactions among the various antiretroviral agents and the potential for one drug to enhance another. The recommendations should be read by all physicians who provide care to HIV-positive patients. The article can be accessed online at www.jama.com.—g.b.h.