Evaluation of New Antiretrovirals

abstract & commentary

Synopsis: An open label, randomized, multicenter trial comparing efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults demonstrated excellent efficacy of the protease inhibitor-sparing regimen.

Source: Staszewski S, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999;341:1865-1873.

Few studies of highly active antiretroviral therapy (HAART) have included a regimen containing newer nonnucleoside reverse transcriptase inhibitors (NNRTIs) as initial therapy in HIV patients. The current study compared the efficacy of two regimens containing efavirenz (efavirenz plus zidovudine and lamivudine, and efavirenz plus indinavir) to a standard three-drug regimen containing a protease inhibitor plus two nucleoside reverse transcriptase inhibitors (NRTIs). The design was an open label, randomized, multicenter trial involving 34 different sites in the United States, Europe, and Canada. Patients were naive to the study drugs and were followed up for a total period of 48 weeks. The maker of efavirenz, Dupont Pharmaceuticals, sponsored the study. A total of 450 patients were enrolled.

After 48 weeks of treatment the regimen of efavirenz, zidovudine, and lamivudine proved more effective than indinavir, zidovudine, and lamivudine in suppressing viral load to less than 50 copies/mL. The superiority of the efavirenz regimen held up with both an analysis based on treatment received as well as analysis based on an intention to treat (90% vs 79% and 64%, P < 0.05 vs 43%, respectively, P < 0.05). In the intention-to-treat analysis, the regimen of indinavir and two NRTIs was less effective compared with efavirenz regimens (43% vs 47% and 64%, respectively, P < 0.05) while in the analysis according to treatment received, the indinavir and two NRTI combination was as effective as efavirenz and indinavir (79% vs 75%). Also, the efavirenz, lamivudine, and zidovudine regimen was significantly more effective than the other two regimens in suppressing HIV RNA to less than 50 copies/mL in patients who had a baseline viral load of more than 100,000 copies/mL (90% vs 72% vs 75%, P < 0.05) as well as in patients with viral loads of less than 100,000 copies/mL.

Significant increases above baseline CD4 cell counts were found in all three groups at all points (mean increases of 201, 185, and 180 cells/mm3 in the group given efavirenz and NRTIs, the group given indinavir and NRTIs, and the group given efavirenz and indinavir, respectively). More patients discontinued treatment in the indinavir group due to side effects compared with efavirenz-containing regimens. Among the latter group, rash and CNS side effects were more commonly observed but no patients stopped treatment because of them.

Comment by nili Gujadhur, md

Currently, a limited number of drugs are available for the treatment of patients with HIV infection and there is no consensus on the ideal initial HAART regimen. Many patients are inadequately treated with protease inhibitors because of these agents’ side effects (nausea, vomiting, diarrhea, and renal stones), requirements for drug, dietary restrictions, and heavy pill burden. Furthermore, they cause metabolic disturbances such as insulin resistance and hyperlipidemia, leading to increased atherogenicity and cardiovascular risk, lipodystrophy, and peripheral muscle wasting, which, in turn, constitutes a true psychological dilemma for the patient. On the other hand, NNRTIs have a low threshold for emergence of resistance, but have good oral bioavailability and long serum half-lives, thus enabling a once-daily dosing schedule. Side effects to efavirenz itself include rash, CNS symptoms (e.g., insomnia, dizziness, and somnolence) that disappear with time.

In the present study, in the analysis according to treatment received—which provides a more realistic assessment—the percentage of patients with HIV RNA less than 50 copies/mL was not significantly different in the two groups except at weeks 16 and 48. In the intention-to-treat analysis, more patients in the indinavir, AZT, and lamivudine group stopped treatment because of side effects compared to the efavirenz-containing regimens. Also, patients using the efavirenz regimen had to take fewer pills, which may have generated superior compliance, possibly improving outcomes in that group. Thus, in asymptomatic patients, the NNRTI efavirenz seems as effective—at least in the short run—as protease inhibitors, even in patients with high initial viral loads. The potential for rapid development of resistance with the use of this class of drugs must be weighed against their user friendliness. HIV prescribers need to balance the opportunity for successful long-term suppression of viral replication with compliance. Protease-sparing regimens like the one used in the study have minimal drug interaction, do not require dietary restriction, and involve taking fewer pills. Longer term studies using genotyping and phenotyping of recrudescent HIV will be required to assess the ultimate use of protease-sparing regimens. (Dr. Gujadhur is Subspecialty Fellow, Division of Allergy, Immunology, and Infectious Diseases, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ.)

Protease-sparing regimens, like the one used in the study by Staszewski et al:

a. have minimal drug interaction.

b. do not require dietary restriction.

c. involve taking fewer pills.

d. need longer term studies using genotyping and phenotyping of recrudescent HIV to assess the ultimate use of them.

e. All of the above