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Therapeutics

Lamivudine plus zidovudine was more effective than continued zidovudine monotherapy for HIV-1 infection

ACP J Club. 1996 Nov-Dec;125:59. doi:10.7326/ACPJC-1996-125-3-059


Source Citation

Staszewski S, Loveday C, Picazo JJ, et al., for the Lamivudine European HIV Working Group. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. JAMA. 1996 Jul 10;276:111-7.


Abstract

Objective

To assess the safety and efficacy of zidovudine and lamivudine combination therapy compared with continued zidovudine monotherapy in patients with HIV-1 infection.

Design

24-week randomized, double-blind, placebo-controlled trial.

Setting

32 hospitals in Europe.

Patients

223 patients who were ≥ 18 years of age (mean age 38 y, 83% men), were seropositive for HIV-1, had a Karnofsky score of ≥ 70, had a CD4+ cell count between 100 and 400 cells/µL, and had received ≥ 24 weeks of zidovudine. Exclusion criteria were abnormal hemoglobin level, neutrophil count, platelet count, liver function, creatinine level, or serum amylase level; other anti-HIV therapy; history of peripheral neuropathy; or intolerance to zidovudine. Follow-up was 88%.

Intervention

Patients were allocated to zidovudine, 200 mg every 8 hours, and lamivudine, 150 mg every 12 hours (n = 75); zidovudine plus lamivudine, 300 mg every 12 hours (n = 75); or zidovudine plus lamivudine placebo (n = 73). After 24 weeks, all patients could receive lamivudine.

Main outcome measures

Change in CD4+ cell count, viral load, and clinical and toxic effects.

Main results

By week 24, patients who received low-dose and high-dose combination therapy had a mean CD4+ increase of 40 cells/µL compared with a mean decrease of 25 cells/µL in patients who received zidovudine monotherapy (P < 0.001 for both combination therapy groups compared with monotherapy). A 50% reduction in CD4+ cell count occurred in 3 patients (2%) who received combination therapy compared with 19% of patients who received zidovudine monotherapy (P < 0.001). {This absolute risk reduction of 17% means that 6 patients would need to be treated with combination therapy for 24 weeks (rather than zidovudine monotherapy) to prevent 1 additional patient from having a 50% reduction in CD4+ cell count, 95% CI 4 to 11; the relative risk reduction was 90%, CI 68% to 98%.}* Viral load decreased in patients who received either low-dose or high-dose combination therapy and increased in patients who received zidovudine monotherapy (P≤ 0.01). The groups did not differ for toxic effects.

Conclusion

Adding lamivudine to zidovudine increased CD4+ cell counts and reduced viral load compared with continued zidovudine monotherapy in patients with HIV-1 infection.

Source of funding: Glaxo Wellcome Research and Development.

For article reprint: Dr. S. Staszewski, Klinikum der Johann Wolfgang Goethe Universität, Zentrum der Inneren Medizin, Infektionsabulanz Haus 68, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. FAX 69-6301-7688.

*Numbers calculated from data in article.


Commentary

Lamivudine plus zidovudine was an effective initial therapy for HIV-1 infection

These 2 clinical trials confirm the results of an earlier report (1) and show that the combined activity of zidovudine and lamivudine is more effective than monotherapy in reducing plasma HIV RNA and increasing CD4+ cell counts in patients with HIV infection. The authors also extend their findings to patients with a mean of > 2 years of previous zidovudine therapy. In both the naive and experienced groups, the superior suppression of HIV with the combined regimen was well documented by 3 methods and further supported by increased CD4+ cell counts, decreased immune activation markers (β-2 microglobulin and neopterin), and a trend toward fewer Centers for Disease Control and Prevention category C events. A meta-analysis of 4 similar trials has confirmed these results (2). After 24 weeks, patients were allowed to receive open-label combination therapy; the results suggest that effects are maintained at 48 weeks, but the study design and number of patients do not allow for valid conclusions.

Limited effectiveness of zidovudine in the early treatment of HIV infection became evident about 4 years ago (3) and led to several trials of combination therapies. Not only zidovudine and lamivudine but also zidovudine and didanosine; zidovudine and zalcitabine; and more recently 3 drug combinations, including a protease-inhibitor (4), have been reported to be superior to zidovudine monotherapy in controlled clinical trials. Such treatments are also generally well-tolerated (5). The rationale for using combinations of 2 or more drugs includes maximizing the synergistic effects of drugs and avoiding the selective pressure that favors the appearance of drug-resistant HIV mutants. More than 80% of the patients treated with combination zidovudine and lamivudine developed the 184V mutation associated with resistance to lamivudine, but this may delay the appearance of zidovudine-resistant mutants and preserve zidovudine susceptibility. Although neither study was able to show clinical effectiveness or what is more important, a meaningful survival benefit, this is hardly surprising given the relentless but very slow course of HIV infection during clinical latency. Also, a much longer observation period is needed to determine whether the antiviral effect diminishes with time. The decrease in HIV RNA that was achieved, however, is an important primary end point that indicates lower viral replication and is likely to lead to slower disease progression. Several studies have shown the direct relation between baseline HIV RNA levels and the patient's progression to AIDS and death (6). Thus, monitoring viral burden becomes an indispensable aid in assessing prognosis and making treatment decisions, with a decrease in viral load being the goal of therapy and an early indicator (evident at 4 weeks) of its efficacy; in addition, an increase in viral load is more accurate than a change in CD4+ levels as an indication of the need to adjust therapy (6).

The authors provide compelling evidence that the combination of zidovudine and lamivudine is as virologically potent as the combinations of zidovudine and didanosine or zalcitabine. Other positive conclusions are that the rate of zidovudine-resistant mutations was reduced, the salutary effects of the addition of lamivudine are obtained without increasing toxicity, and patients who have been on prolonged zidovudine therapy still show substantial virologic response when lamivudine is added. These new findings are important. Nevertheless, the drug combination to be selected, the time to initiate therapy, and the alternative drugs to be used in the event of treatment failure or adverse reactions continue to create dilemmas (5). In conclusion, until an optimal therapy is established, patients with HIV-infection can, despite additional costs, at least be offered a more rational method of follow-up (monitoring viral load) and more effective therapy (early use of drug combinations).

Ami Schattner, MD
David Katzenstein, MDStanford University School of MedicineStanford, California, USA


References

1. Eron JJ, Benoit SL, Jemsek J, et al. N Engl J Med. 1995;333:1662-9.

2. Staszewski S, Bartlett I, Eron J, et al. XI International Conference on AIDS. Vancouver, 1996.

3. Concorde Coordinating Committee. Lancet. 1994;343:871-81.

4. Collier AC, Coombs RW, Schoenfeld DA, et al. N Engl J Med. 1996;334:1011-7.

5. Carpenter CC, Fischl MA, Hammer SM, et al. JAMA. 1996;276:146-54.

6. Havlir DV, Richman DD. Ann Intern Med. 1996;124:984-94.