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Therapeutics

Indinavir plus zidovudine and lamivudine reduced HIV RNA levels in most HIV-infected persons with previous antiretroviral treatment

ACP J Club. 1998 Mar-April; 128:42. doi:10.7326/ACPJC-1998-128-2-042

Related Content in this Issue
• Companion Abstract and Commentary: Indinavir plus zidovudine and lamivudine reduced the progression to AIDS in patients with previous zidovudine therapy


Source Citation

Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997 Sep 11;337:734-9.


Abstract

Objective

To compare the efficacy and safety of 3 treatments (indinavir alone, zidovudine plus lamivudine, and a combination of all 3) in patients with HIV infection and previous antiretroviral therapy.

Design

Randomized, double-blind, placebo-controlled trial with 24 weeks of follow-up.

Setting

4 clinical sites in the United States.

Patients

97 patients (mean age 40 y, 85% men) who had HIV infection and ≥ 6 months of previous zidovudine therapy (median 29.7 mo). Inclusion criteria included serum HIV RNA ≥ 20 000 copies/mL (median 43 190 copies/mL) and CD4+ cell counts of 50 to 400/mm3 (median 144/mm3). Exclusion criteria included previous lamivudine or HIV-protease inhibitor therapy. Follow-up was 91%.

Intervention

31 patients were allocated to indinavir, 800 mg every 8 hours; 33 to zidovudine, 200 mg every 8 hours, plus lamivudine, 150 mg every 12 hours; and 33 to all 3 drugs. Matching placebos were used.

Main outcome measures

The main outcome measures were changes in the serum HIV RNA levels and CD4+ cell counts. A secondary outcome was the number of adverse events.

Main results

Serum HIV RNA levels decreased in all 3 groups. The decrease was greater for the 3-drug group than for the other 2 groups (P < 0.001) and for the indinavir group compared with the zidovudine plus lamivudine group (P = 0.005). RNA levels decreased to < 500 copies/mL at week 24 in 90% of patients in the 3-drug group compared with 43% of patients in the indinavir group and 0% in the zidovudine plus lamivudine groups (P ≤ 0.01) (Table). CD4+ cell counts increased in all 3 groups and were greater for the indinavir-containing treatments than for zidovudine plus lamivudine (P ≤ 0.01), but there was no difference between indinavir alone and the 3-drug group (P = 0.36). No differences existed among the groups for the number of severe adverse events.

Conclusion

The combination of indinavir, zidovudine, and lamivudine reduced levels of HIV RNA to below detection in most patients with HIV infection who had previously received antiretroviral therapy compared with indinavir alone or zidovudine and lamivudine.

Sources of funding: National Institutes of Health and Merck Research Laboratories.

For article reprint: Dr. R.M. Gulick, NYU Medical Center, Department of Medicine, 550 First Avenue, New York, NY 10016, USA. FAX 212-263-8264.


Table. Indinavir, zidovudine, and lamivudine (3 drugs) vs zidovudine and lamivudine*

Outcome at 24 wk 3 drugs EER Zidovudine and lamivudine CER ABI |EER-CER| NNT
Decrease in HIV RNA levels to < 500 copies/mL 90% 0% 90% 2

*Abbreviations defined in Glossary; ABI and NNT calculated from data in article.


Commentary

These studies by Gulick and Hammer and their colleagues show how protease inhibitors have revolutionized the treatment of HIV infection. Although reverse transcriptase inhibitors can slow the progression of HIV-induced immunodeficiency, the protease inhibitors are a profoundly more potent weapon in our arsenal.

Part of the reason for this difference is explained by the mechanisms of action of these 2 drug classes. The reverse transcriptase inhibitors inhibit the viral enzyme that allows transcription of viral RNA into a complementary strand of DNA that is then integrated into the human genome. Once there, the complementary strand of DNA is translated into messenger RNA that codes for HIV proteins, which assemble into mature virions. The efficacy of reverse transcriptase inhibitors is limited by 2 major factors. First, if integration of the complementary strand of DNA has already occurred, reverse transcriptase inhibitors have no effect on viral protein production. Second, the reverse transcriptase of HIV is sloppily translated from messenger RNA and has a high mutation rate. This, coupled with the fact that over 1010 HIV virions are produced per day (1), accounts for the rapid emergence of resistance to reverse transcriptase inhibitors.

Protease inhibitors act at a different stage of viral replication by inhibiting a virally coded aspartate protease that cleaves large precursor polyproteins into smaller proteins necessary for viral assembly. The protease inhibitors work to prevent viral replication after integration of the complementary strand of DNA into the cell genome and, unlike reverse transcriptase inhibitors, can prevent infected cells from producing viral progeny. Unfortunately, resistance is also a problem when protease inhibitors are used as monotherapy.

These 2 studies show the clinical consequences of these different mechanisms of action. Gulick and colleagues show the dramatic difference in ability to suppress viral load when a protease inhibitor is added to 2 reverse transcriptase inhibitors. None of the patients who received 2 reverse transcriptase inhibitors had viral loads suppressed below the limit of detection compared with 90% of the patients who received a protease inhibitor and 2 reverse transcriptase inhibitors.

Hammer and colleagues showed decreases in viral load as well as a substantial reduction in AIDS or death, or death alone. Of note, this benefit was seen in patients with severe immunodeficiency (CD4+ < 50/mm3), a finding that has been difficult to show with reverse transcriptase inhibitor monotherapy or combination therapy. Thus, the protease inhibitors show renewed promise in treating even the most advanced cases of AIDS.

Both studies were done using viral load assays with limits of detection of 500 copies/mL. Gulick and colleagues also used an assay with a lower limit of 50 copies/mL. Newer assays permit detection levels as low as 25 copies/mL. It is not clear how many patients would have had demonstrable viral loads if these more sensitive assays were available.

Although the most recently published guidelines for antiretroviral therapy from the International AIDS Society-USA panel give clinicians the option of initiating therapy with a protease inhibitor (2), the 2 studies reviewed here provide strong evidence of the beneficial effect of the routine use of protease inhibitors. These agents may well be partially responsible for the first-ever decrease in deaths from AIDS seen in the United States in 1996 (3).

Fred A. Zar, MD
St. Francis HospitalEvanston, Illinois, USA

Fred A. Zar, MD
St. Francis Hospital
Evanston, Illinois, USA


References

1. Perelson AS, Neumann AU, Markovitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996:271:1582-6.

2. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. JAMA. 1997;277:1962-9.

3. Update: Trends in AIDS incidence—United States, 1996. MMWR Morb Mortal Wkly Rep. 1997;46:861-7.