Combination and Monotherapy with Zidovudine and Zalcitabine in Patients with Advanced HIV Disease

Several nucleoside analogs, including zidovudine, zalcitabine, and didanosine, inhibit the replication of human immunodeficiency virus type 1 (HIV) in vitro and improve CD4 cell counts and suppress HIV p24 antigenemia in patients with HIV disease [1-8]. Zidovudine therapy delays HIV disease progression [1-3] and improves survival in patients with advanced HIV disease [1, 9]. Didanosine therapy delays HIV disease progression in patients with advanced HIV disease who had previously received zidovudine, suggesting that switching antiretroviral therapy may be an important strategy in treating HIV disease [10, 11]. The combination of the nucleoside analogs zidovudine and zalcitabine has additive to synergistic inhibitory activity against HIV in vitro, and viral isolates resistant to zidovudine remain susceptible to zalcitabine in vitro [12-14]. Combination therapy with zidovudine and zalcitabine causes a greater and more sustained increase in CD4 cell counts and suppression of HIV p24 antigenemia than does either drug used alone in patients with advanced HIV disease who have not previously received therapy with zidovudine or zalcitabine [15]. The clinical correlation of these findings is unknown. These observations prompted us to try to determine whether zalcitabine monotherapy or combination therapy with zidovudine and zalcitabine would improve clinical outcome in patients with advanced HIV disease who had previously received zidovudine. Methods Study Sample The study sample consisted of patients with symptomatic HIV disease who had a CD4 cell count of 300 cells/mm3 or less or patients with asymptomatic HIV disease who had a CD4 cell count of 200 cells/mm3 or less. Participants had previously received and tolerated at least 6 months of zidovudine treatment. The eligibility criteria also included a hemoglobin concentration of 92 g/L or more, a neutrophil count of 1.0 109/L or more, a platelet count of 75 109/L or more, serum alanine aminotransferase and aspartate aminotransferase levels no higher than five times the upper range of normal, Karnofsky performance status of 60 or more, and positive results of serum tests for HIV antibody. We excluded patients with a history of intolerance to zidovudine at a dose of 600 mg/d or less, previous zalcitabine therapy, mild or more severe peripheral neuropathy, or Kaposi sarcoma requiring systemic therapy; women of childbearing age who were pregnant or breast-feeding were also excluded. We accepted patients receiving chemoprophylaxis for Pneumocystis carinii pneumonia, candidiasis and herpes simplex virus infection, and those receiving erythropoietin and granulocyte colony-stimulating factor. We excluded persons taking other antiretroviral drugs, biological response modifiers, cytotoxic chemotherapy, drugs other than isoniazid that cause peripheral neuropathy, or investigational drugs. We recruited patients from 35 AIDS Clinical Trials Units and 16 National Hemophilia Foundation sites between December 1990 and August 1991. The study was approved by the institutional review board at each institution, and patients gave written informed consent. Study Design and Treatment Regimen The study was a multicenter, randomized, double-blind clinical trial that compared the safety and efficacy of zidovudine, zalcitabine, and the combination of zidovudine and zalcitabine. Randomization was weighted at 2:2:3, favoring the combination group. Patients were stratified by HIV disease status (symptomatic or asymptomatic), by duration of previous zidovudine therapy ( 1 year or >1 year), and by P. carinii pneumonia chemoprophylaxis regimen (systemic therapy, nonsystemic therapy, both, or neither). Zalcitabine (Hivid; Hoffmann-La Roche, Inc., Nutley, New Jersey) was given in two 0.375-mg tablets every 8 hours. Zidovudine (Retrovir; Burroughs Wellcome Co., Research Triangle Park, North Carolina) was given in two 100-mg capsules every 8 hours. The primary end point for the study was time to an acquired immunodeficiency syndrome (AIDS)-defining event or death, whichever occurred first. All end points were reviewed in a blinded manner by the study chairpersons. Patients continued to receive blinded study medication after the development of a primary study end point. The protocol was modified on 20 March 1992 to allow patients who had reached a primary study end point the option to cross over to open-label combination therapy. Secondary end points included survival, CD4 cell count changes, and decreased HIV p24 antigenemia. Management of Toxic Effects All study medications were interrupted, regardless of whether the toxicity was believed to be associated with either zidovudine or zalcitabine, in patients in whom a moderate or severe peripheral neuropathy or another severe or worse toxic effect developed. Once the toxicity grade returned to pretreatment values or a lower grade, study medications were restarted at one half the initial dose. Study medications were permanently discontinued in patients who had a recurrent moderate or severe peripheral neuropathy or another severe or worse toxic effect within a 30-day period. Patients who had recurrent toxic effects after more than 30 days, except for those with peripheral neuropathy, continued to receive study medications once the toxicity grade returned to a lower grade or to pretreatment values. Patient Evaluation Patients were evaluated at weeks 0, 4, 8, and 12, and every 8 weeks thereafter. The CD4 cell counts were measured within 60 days before study enrollment, at weeks 0, 2, and 4, every 4 weeks until week 52, and every 8 weeks thereafter. Blood for HIV p24 antigen determinations was collected at weeks 0, 2, 4, 8, 12, 24, 36, 48, and 60 and every 16 weeks thereafter. Determinations of HIV p24 antigen were done simultaneously on stored serum aliquots by an enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, Illinois). A positive assay result was one that detected an antigen level of 25 pg/mL or more. Laboratories measuring CD4 cell counts and serum p24 antigen levels had to meet the performance-monitored standards of the AIDS Clinical Trials Group. Statistical Analysis We assessed differences in proportions using the Fisher exact test. Time-to-event distributions were estimated using the Kaplan-Meier method and compared using the log-rank test and Cox proportional-hazards model [16], with stratification for HIV disease status, duration of previous zidovudine therapy, and P. carinii pneumonia prophylaxis [17]. Analyses were based on an intention-to-treat approach [18]. We censored data on toxic effects 30 days after crossover or discontinuation of study medications. We used the hazard ratios, expressed as relative risk, and 95% two-sided confidence intervals. All P values were two-sided and were not adjusted for multiple comparisons. A test of trend evaluating the interaction between pretreatment CD4 cell counts and treatment effect on the primary end point was based on Cox models and included the study stratification factors as covariates and pretreatment CD4 cell counts as a continuous variable. For completeness, two additional tests of trend used stratified Cox models in which pretreatment CD4 cell counts were modeled as a categorical variable. In one analysis, pretreatment CD4 cell count was modeled as a binary variable, above and below the median CD4 cell count (119 cells/mm3). In a second analysis, pretreatment CD4 cell count was modeled as a discrete variable with three levels ( 1,0, 1) corresponding to the three planned CD4 cell subgroups. Changes in CD4 cell counts and serum HIV p24 antigen levels were expressed as the percentage change from pretreatment values for each patient. Trends in CD4 cell counts over time were evaluated by estimating the slopes from pretreatment to the time of aggregate peak (week 2) and separately estimating the slopes for subsequent time points. We compared the slopes using nonparametric tests [19]. We also analyzed treatment differences for patients with pretreatment CD4 cell counts of less than 50 cells/mm3, 50 to 150 cells/mm3, and 150 cells/mm3 or greater. The three CD4 cell count subgroups were specified by the study chairpersons in June 1992, which was before any interim review of the primary end-point data and unblinding to the study results by the study chairpersons (March 1993). The three CD4 cell count subgroups were chosen based on documented associations between CD4 cell counts and survival and development of zidovudine resistance. Results Study Sample We enrolled 1001 patients in the study between December 1990 and August 1991. No patients were ineligible for the study, except for those granted an exemption by the study chairpersons. We excluded 10 patients from the analyses: 7 who never received study medications and were not followed and 3 who were lost to follow-up within the first 2 weeks of treatment. The patients included 888 (90%) men and 103 (10%) women; their median age was 37 years. Overall, 809 patients (82%) were white, 152 (15%) were black, and 3% were neither; 117 (12%) were Hispanic and 884 (88%) were non-Hispanic. Eight hundred nineteen (83%) patients had symptomatic HIV disease. The median duration of previous zidovudine therapy was 18 months. The median pretreatment CD4 cell count was 119 cells/mm3, and 254 of 925 patients had detectable levels of serum HIV p24 antigen ( 25 pg/mL) before treatment. The treatment groups were well balanced with regard to pretreatment characteristics (Table 1). Table 1. Patient Characteristics by Treatment Group* We randomly assigned 283 patients to the zidovudine group, 285 to the zalcitabine group, and 423 to the combination group. Three hundred eighty-six patients had 150 or more CD4 cells/mm3, 336 had 50 to 150 CD4 cells/mm3, and 269 had fewer than 50 CD4 cells/mm3. Overall, the treatment groups within each CD4 cell subgroup were well balanced with regard to pretreatment characteristics (data not shown). The median duration of foll