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Therapeutics

Indinavir plus zidovudine and lamivudine reduced the progression to AIDS in patients with previous zidovudine therapy

ACP J Club. 1998 Mar-April; 128:43. doi:10.7326/ACPJC-1998-128-2-043

Related Content in this Issue
• Companion Abstract and Commentary: Indinavir plus zidovudine and lamivudine reduced HIV RNA levels in most HIV-infected persons with previous antiretroviral treatment


Source Citation

Hammer SM, Squires KE, Hughes MD, et al., for the AIDS Clinical Trials Group 320 Study Team. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med. 1997 Sep 11;337:725-33.


Abstract

Objective

To compare the efficacy and safety of indinavir plus zidovudine and lamivudine with zidovudine and lamivudine in patients with HIV infection who have had previous zidovudine therapy.

Design

Randomized, double-blind, placebo-controlled trial with a median follow-up of 38 weeks.

Setting

33 AIDS Clinical Trials Units and 7 National Hemophilia Foundation Sites in the United States and Puerto Rico.

Patients

1156 patients (mean age 39 y, 83% men) who had HIV infection. Inclusion criteria were ≥ 3 months of previous zidovudine treatment (median 21 mo), no previous treatment with protease inhibitors, ≤ 1 week of previous lamivudine treatment, and acceptable laboratory values. Follow-up was 95%.

Intervention

577 patients were allocated to indinavir, 800 mg every 8 hours; zidovudine, 200 mg 3 times daily; and lamivudine, 150 mg twice daily. 579 patients were allocated to the same dose of zidovudine and lamivudine and to a matching placebo. Stavudine could be substituted for zidovudine for toxicity or disease progression (n = 109).

Main outcome measures

The primary outcome measure for efficacy was the development of a new AIDS-defining event or death. The primary outcome measure for safety was the occurrence of grade 3 or 4 adverse events.

Main results

Analysis was by intention to treat. Fewer patients who received indinavir plus zidovudine and lamivudine had AIDS-defining events or died than did patients who received zidovudine and lamivudine (P = 0.001) (Table). 21% of patients receiving indinavir plus zidovudine and lamivudine had grade 3 or 4 adverse events compared with 18% of patients receiving zidovudine and lamivudine (P = 0.17).

Conclusion

The combination of indinavir, zidovudine, and lamivudine resulted in fewer deaths and AIDS-defining events than zidovudine and lamivudine alone in patients with HIV infection who had had previous zidovudine therapy.

Sources of funding: National Institute of Allergy and Infectious Diseases; National Center for Research Resources; Merck and Co.

For article reprint: Dr. S.M. Hammer, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Boston, MA 02215, USA. FAX 617-632-0760.


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

Outcome 3 drugs EER Zidovudine plus lamivudine CER RRR (95% CI) ABI |EER-CER| NNT (CI)
AIDS or death 6% 11% 47% (21 to 65) 5% 20 (12 to 50)

*Abbreviations defined in Glossary; RRR, ARR, NNT, and CI 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.