Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial Daniel R. Kuritzkes*, Ian Marschner†, Victoria A. Johnson‡, Roland Bassett†, Joseph J. Eron§, Margaret A. FischlII, Robert L. Murphy¶, Kenneth Fife**, Janine Maenza††, Mary E. Rosandich*, Dawn Bell‡‡, Ken Wood§§, Jean-Pierre Sommadossi‡, Carla PettinelliII II and the National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators Objective: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddI), or stavudine (d4T). Design: Randomized, placebo-controlled, partially double-blinded multicenter study. Setting: Adult AIDS Clinical Trials Units. Patients: Treatment-naive HIV-infected adults with 200–600 × 106 CD4 T lymphocytes/l. Interventions: Patients were openly randomized to a d4T or a ddI limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddI (400 mg/day), ddI plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. Main outcome measure: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. From the *University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver, Colorado, the †Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, the ‡University of Alabama at Birmingham School of Medicine and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, the §University of North Carolina at Chapel Hill, North Carolina, the IIUniversity of Miami, Miami, Florida, the ¶Northwestern University, Chicago, Illinios, **Indiana University, Indianapolis, Indiana, the ††Johns Hopkins University School of Medicine, Baltimore, Maryland, the ‡‡Adult AIDS Clinical Trials Group Operations Center, Rockville, Maryland, the §§Frontier Science & Technology Research Foundation, Amherst, New York and the IIIIDivision of AIDS, NIAID, NIH, Bethesda, Maryland, USA. Sponsorship: Supported in part by the AIDS Clinical Trials Group (AI-38858), Statistical and Data Management Center (AI-38855) and AIDS Clinical Trials Unit awards from the NIAID (AI-32770, AI-32775) and by Virology Advanced Technical Laboratory Awards from the Adult AIDS Clinical Trials Group (subcontracts of AI-38858). Additional support was received from General Clinical Research Grants RR-00046 and RR-00051 and the Flow Cytometry Core Laboratory of the University of Colorado Cancer Center (CA-46934). Victoria Johnson was supported in part by a research grant from the NIH (AI-40876). Note. Presented in part at the 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, February 1–5, 1998. Abstract 1. Requests for reprints to: D.R. Kuritzkes, Division of Infectious Disease, University of Colorado Health Sciences Center, 4200 E. Ninth Ave B-168, Denver, CO 80262, USA. Date of receipt: 9 November 1998; revised: 25 January 1999; accepted: 1 February 1999. © Lippincott Williams & Wilkins 685 686 AIDS 1999, Vol 13 No 6 Results: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddI monotherapy) versus 0.82 log10 (ddI plus 3TC; P > 0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddI plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddI limb. Conclusions: 3TC added significantly to the virologic effects of d4T, but not ddI, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4T as a component of initial combination antiretroviral therapy. © 1999 Lippincott Williams & Wilkins AIDS 1999, 13:685–694 Keywords: HIV, lamivudine, zidovudine, stavudine, combination therapy, antiretroviral therapy Introduction Several uncontrolled pilot studies suggest that the com- bination of 3TC plus d4T produces sustained virologic Current treatment guidelines for the treatment of HIV- and immunologic improvement [17,18]. Studies to 1 infection recommend the use of a combination of examine the combination of 3TC with ddI, a nucleoside analogue inhibitors of reverse transcriptase nucleoside analogue that also confers significant clinical together with a protease inhibitor or non-nucleoside benefit, have not been performed. The AIDS Clinical reverse transcriptase inhibitor [1,2]. Most studies cited Trials Group (ACTG) protocol 306 tested the hypoth- in support of these guidelines have used the combina- esis that 3TC was uniquely effective in combination tion of zidovudine (ZDV) and lamivudine (3TC) as the with ZDV and superior to 3TC in combination with nucleoside component of such triple-therapy regimens. either d4T or ddI. The combination of 3TC plus ZDV results in greater virologic and immunologic improvement than either drug alone and confers significant clinical benefit despite the rapid emergence of 3TC resistance [3–8]. Methods Resistance to 3TC is conferred by a point mutation in the HIV-1 reverse transcriptase gene that results in a This multicenter, randomized, placebo-controlled, methionine to valine substitution at codon 184 double-blind trial was conducted by 21 collaborating (M184V) [9–12]; within weeks of initiating 3TC, wild- units of the Adult ACTG. The protocol was reviewed type HIV-1 in the plasma is replaced by variants carry- and approved by the institutional review boards of: the ing this mutation [13]. Introduction of the M184V Northwestern University, University of North mutation restores ZDV susceptibility in HIV-1 strains Carolina, Indiana University, University of Colorado that carry ZDV resistance mutations [11,14,15]. Health Sciences Center, John Hopkins University, Moreover, the frequency of ZDV resistance mutations University of Alabama at Birmingham School of in HIV-1 isolates from patients receiving ZDV plus Medicine, University of Rochester Medical Center, 3TC is significantly lower than that seen during ZDV Stanford University, Ohio State University, University monotherapy [4,16]. Therefore it has been proposed of Washington, University of California, San Diego, that the sustained activity of 3TC in combination with University of Puerto Rico, University of California, ZDV is due to the prevention or reversal of ZDV Los Angeles, Washington University, St. Louis, resistance [16]. University of Miami, University of Pennsylvania, University of Hawaii, Case Western Reserve Because a number of HIV-1-infected individuals University, Beth Israel Deaconess Medical Center, cannot tolerate ZDV it was important to determine Vanderbilt University Medical Center. Informed con- whether 3TC could be used in combination with other sent was obtained from all subjects participating in this available nucleoside analogues. However, if the benefits study. Conduct of this study conformed to human of 3TC are due solely to suppression of ZDV experimentation guidelines of the US Department of resistance, the rapid emergence of 3TC resistance could Health and Human Services. limit the activity of treatment regimens in which 3TC is combined with other nucleoside analogues such as Patients didanosine (ddI) or stavudine (d4T) for which similar Individuals with documented HIV-1 infection, at least favorable resistance interactions have not been described. 12 years of age with CD4 T-lymphocyte counts of Combination nucleoside therapy with 3TC Kuritzkes et al. 687 200–600 × 106/l and less than 7 days of antiretroviral 3TC placebos. In the ddI limb, patients received either nucleoside analogue treatment were eligible. Eligibility ZDV plus 3TC with ddI placebo, ddI plus 3TC with criteria also included a Karnofsky score ≥ 80%, a hemo- ZDV placebo, or ddI with ZDV and 3TC placebos. At globin of ≥ 90 g/l for men and ≥ 85 g/l for women, a study week 24, patients entered step 2 of the study: neutrophil count of ≥ 1000 × 106 cells/l, a serum patients on monotherapy had 3TC added to their regi- creatinine concentration ≤ 1.5 times the upper limit of men in a blinded fashion (beyond week 24 these arms normal, serum concentrations of alanine aminotrans- are referred to as the d4T/ or ddI/delayed 3TC arms, ferase and aspartate aminotransferase ≤ 5 times the respectively). Patients on combination therapy upper limit of normal, and a serum amylase concentra- remained on their originally assigned regimens. Step 2 tion ≤ 1.5 times the upper limit of normal (unless the continued for an additional 24 weeks for a total study serum lipase concentration was ≤ 1.5 times the upper duration of 48 weeks. A subset of patients at four sites limit of normal). Patients were excluded if they had were also enrolled in a pharmacology substudy to eval- unexplained temperature elevations to ≥ 38.5°C for uate pharmacokinetic interactions of 3TC with either 7 consecutive days within 30 days prior to randomiza- ZDV, d4T or ddI, which will be reported separately. tion, had a history of acute or chronic pancreatitis, had moderate peripheral neuropathy [≥ grade 2 according ZDV (Retrovir) and 3TC (Epivir) were provided by to the National Institute of Allergy and Infectious GlaxoWellcome, Research Triangle Park, North Disease (NIAID) Division