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Therapeutics

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

ACP J Club. 1996 Nov-Dec;125:58. doi:10.7326/ACPJC-1996-125-3-058


Source Citation

Katlama C, Ingrand D, Loveday C, et al., for the Lamivudine European HIV Working Group. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. A randomized controlled comparison with zidovudine monotherapy. JAMA. 1996 Jul 10; 276:118-25.


Abstract

Objective

To determine the effectiveness of lamivudine and zidovudine combination therapy compared with zidovudine monotherapy in patients with HIV-1.

Design

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

Setting

14 hospitals in Europe.

Patients

129 patients who were ≥ 18 years of age (mean age 35 y, 74% men) and were infected with HIV-1, had received minimal previous zidovudine therapy (≥ 70. Exclusion criteria were abnormal liver function, neutrophil count, hemoglobin level, platelet count, creatinine level, or serum amylase level; previous anti-HIV therapy other than zidovudine; history of peripheral neuropathy; or intolerance to zidovudine. Follow-up was 88%.

Intervention

Patients were allocated to zidovudine, 600 mg/d, and lamivudine, 300 mg twice daily (n = 65), or zidovudine plus lamivudine placebo (n = 64). After 24 weeks, all patients could receive lamivudine.

Main outcome measures

Change in CD4+ cell count, HIV-1 RNA viral load, and adverse and toxic events.

Main results

Analysis was by intention to treat. At 24 weeks, patients who received combination therapy had an increase in CD4+ cells of 80 cells/µL compared with a decrease of 10 cells/µL in patients on zidovudine monotherapy (P < 0.001). 13% of patients who received combination therapy had a CD4+ cell count below baseline compared with 57% of patients who received zidovudine monotherapy { P < 0.001}*. {This absolute risk reduction of 44% means that 2 patients would need to be treated with combination therapy (rather than zidovudine monotherapy) for 24 weeks to prevent 1 additional patient from having a CD4+ cell count below baseline, 95% CI 2 to 4; the relative risk reduction was 77%, CI 55% to 89%.}* Patients who received combination therapy had a greater mean reduction in viral load at 24 weeks than did patients who received zidovudine monotherapy (P = 0.008 by the immune capture method and P < 0.001 by the Roche method). The groups did not differ for clinical events or toxic effects, which were mild.

Conclusion

Lamivudine plus zidovudine combination therapy was well tolerated and more effective than zidovudine monotherapy in increasing CD4+ cell count and reducing viral load in patients with HIV-1.

Sources of funding: Glaxo Wellcome Research and Development and Agence Nationale de Recherches sur le SIDA, France.

For article reprint: Dr. C. Katlama, Service des Maladies Infectieuses, Parasitaires et Tropicales, Hospitalier Pitié Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France. FAX 33-142-160-126.

*Numbers calculated from data in article.


Commentary

Lamivudine plus zidovudine was more effective than continued zidovudine monotherapy 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.