Addition of lamivudine to zidovudine-based therapy reduced progression to AIDS and death in patients with HIV infection
ACP J Club. 1997 Nov-Dec;127:64. doi:10.7326/ACPJC-1997-127-3-064
CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet. 1997 May 17;349:1413-21.
To determine the effect of adding lamivudine or lamivudine plus loviride to zidovudine-based therapy in patients with more advanced HIV disease.
Randomized, double-blind, placebo-controlled trial with 52-week follow-up.
Study centers in Canada, Australia, Europe, and South Africa.
1895 patients (median age 36 y, 87% men) with HIV infection, CD4+ counts of 25 to 250/mm3 (median 126/mm3), and no previous use of lamivudine or nonnucleoside reverse-transcriptase inhibitors (NNRTIs). 1530 patients (83%) had had antiretroviral treatment (median duration of previous treatment 28 mo).
Patients were allocated to lamivudine (n = 937), lamivudine plus loviride (n = 475), or placebo (n = 483) in addition to their current treatment regimen of either zidovudine alone or zidovudine plus didanosine or zalcitabine. Follow-up was 97%.
Main outcome measures
The primary outcome was progression to a new AIDS-defining event or death. Use of health care resources was also assessed.
1840 patients were included in the intention-to-treat analysis. Lamivudine compared with placebo reduced the rate of progression to a new AIDS-defining event or death (P < 0.001) and overall death (P < 0.001) (Table). No benefit from the addition of loviride was seen. Fewer patients in the lamivudine group than in the placebo group required hospitalization (P = 0.002), unscheduled visits (P = 0.013), or treatment for HIV-related events (P < 0.001). Side effects did not differ among groups.
The addition of lamivudine, but not loviride, to zidovudine-based therapy reduced the rate of progression to AIDS and death in patients with more advanced HIV disease.
Sources of funding: Glaxo Wellcome Research and Development; Australian National Council on AIDS and Related Diseases; Dutch Ministry of Welfare, Health, and Sport.
For article reprint: Prof. D. Cooper, National Centre in HIV Epidemiology and Clinical Research, Faculty of Medicine, University of New South Wales, 376 Victoria Street, Sydney, New South Wales 2010, Australia. FAX 61-2-9360-1749.
Table. Addition of lamivudine or placebo to zidovudine-based therapy*
|Outcomes at 52 wk||Lamivudine EER||Placebo CER||RRR (95% CI)||ARR |EER-CER|||NNT (CI)|
|AIDS or death||9%||20%||53% (38 to 64)||11%||10 (7 to 15)|
|Overall death||2.5%||5.9%||57% (27 to 75)||3.4%||30 (16 to 80)|
*Abbreviations defined in Glossary; RRR, ARR, NNT, and CI calculated from data in article.
This large, finely designed, and carefully done study has shown the short-term superiority of lamivudine plus zidovudine-based therapy compared with zidovudine-based therapy alone. Unfortunately, despite being "fast-tracked" (published within 4 wk of receipt), the study no longer reflects state-of-the-art therapy. Indeed, except in rare situations, a regimen consisting solely of nucleoside reverse-transcriptase inhibitors (NRTIs) is now considered suboptimal. Although no differences were seen, the addition of an NNRTI, loviride, was also evaluated. The study, however, did not have sufficient power to detect a clinical benefit.
The lack of therapeutic effect of NRTIs was clearly shown in this study. The reduction in viral load with the combination of NRTIs was relatively small (less than 1 log) and not sustained, returning nearly to baseline within 28 weeks. Although combined NRTIs provide a short-term benefit, the goal of antiretroviral therapy should be a sustained, substantial reduction in virus.
Recently published guidelines now propose 2 NRTIs plus a protease inhibitor as the most efficacious regimen for persistent viral suppression—approximately 80% of compliant patients will respond with a plasma viral load below detectable levels (1). Judicious therapy will only be effective and remain as such if compliance is assured. Whether prolease inhibitor combinations or a combination of a prolease inhibitor with an NNRTI plus NRTIs is superior remains unknown. Studies in progress that assess these and other therapeutic agents will determine the most effective protocols. However, such studies as the Canada, Australia, Europe, and South Africa (CAESAR) trial have laid the foundation for our current treatment recommendations.
Aaron E. Glatt, MD
Catholic Medical Center of Brooklyn and QueensJamaica, New York, USA