Low doses of zidovudine plus didanosine are less effective than higher doses of didanosine monotherapy: a randomized trial in patients pretreated with zidovudine

Objective: To compare the clinical efficacy and tolerance of didanosine (ddI) monotherapy with low-dose zidovudine/didanosine (AZT/ddI) therapy among HIV-infected patients previously treated with AZT.Methods: A randomized controlled trial was carried
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  ORIGINAL RTICLE zyxwvutsrqp Low doses of zidovudine plus didanosine are less effective than higher doses of didanosine monotherapy: a randomized trial in patients pretreated with zidovudine zyxwv hilzjye Sudre’, Jean Philippe Chave’, Christian zyxw ug3 Anne Iten’, Heiner C. Bucher4, Pietro L. Ernazza5, Hansjakob Furrer‘, Enos Bernasconi 7, Norbert0 Ceserani’, Manuel Battegay4, Jan I/on Overbeck’> 6, Ignaxio Cassis 7, Adriano Ldzxarin’, Victor Gabriel I Bernard]. Hirschel‘ and the Swiss HIV Cohort Study zyxwvut   ’ zyxwvuts niversity Hospital, Geneva, 2University Hospital, Lausanne, ’University Hospital, Zurich, ‘University Hospital, Basel, 5University Hospital, St Gallen, and %Jniversity Hospital, Bern, Switzerland; and 70spedale Civico, Lugano, and XOspedale San Raffaele, Milano, Italy Objective: To compare the clinical efficacy and tolerance of didanosine (ddl) monotherapy with low-dose zidovudine/ didanosine (AZT/ddl) therapy among HIV-infected patients previously treated with AZT. Methods: A randomized controlled trial was carried out of ddl 400 mg daily versus AZT/ddl 300/200 mg daily among patients with CD4 cell counts s350 rnm3 and prior AZT treatment for at least 16 weeks. Fifty eight patients received ddl monotherapy and 66 combined treatment. Results: Patients were similar with respect to demographic, clinical and laboratory characteristics, and prior AZT treatment. Median duration of follow-up was 17.3 months. In the ddl group, 20 patients (34 ) discontinued treatment because of toxicity, compared to 19 (29 ) in the AZT/ddl group (p=0.38). There was no statistically significant difference in CD4 change between the two groups. In the ddl group, 16 patients (28 ) developed a clinical endpoint (death or AIDS- defining opportunistic infection), compared to 33 (50 ) in the combined therapy group (relative riskl.8; 95 confidence interval 1.1-2.9; p=O.OI). Conclusions: For fairly advanced AZT-pretreated patients, monotherapy with ddl was clinically and statistically superior to the low-dose AZT/ddl combination in preventing AIDS-defining illness and death. When access to drugs is limited, e.g. in under-resourced countries, combining available drugs and reducing dosage may be less effective than a single drug at the conventional dosage. Key words: Randomized trial, zidovudine, didanosine, HIV, AIDS, combination therapy, drug dosage, antiretroviral INTRODUCTION clinical progression [2], and combined therapy is currently (1997) recommended as the initial treatment Long-term zidovudine (AZT) monotherapy is associ- of HIV infection [3]. At the time this study was ated with the emergence ofresistant HIV strains [l] nd designed (1992), however, switching therapy from *Mernbcrs ofthe Swiss HIV Cohort Study- (SHCS) arc: M. httegay, Ph. Burgisser, L. Jeannrrod, M. Eggcr, P Erh (prehldent of the group ‘Laboratory’), W. Fmz, M. Flepp @resident of the gruup ‘Clinic‘il’), I Francioli (president of the SHCS, Univcrvty Hospital, Lausanire, Switzcrland). P. Gob. U. Gruninaer (Ohscrvers of the Federal Officc of Corresponding author and reprint requests: Philippe Sudre, DMI, HBpital Universitaire de Geneve, rue Micheli-du-Crest 24, CH-1211 Geneve 4 Switzerland Tel: f41 22 372 9808 E-Mail: Philippe.Sudre@HCUGE.CH Accepted 31 May 1997 Fax: +41 22 372 9820 ., Public Hcalth), H. Hirschel (president of the Scicntific Hoard), R. Ledcrgcrbcr, R. Luthy, R. Malinvcmi, L. Mattcr, M. Opravil, F I’accdud, L. Perrin, W. Pichler, M. Kickenbach (manager ofthc Data Coordination Center), zyxwvuts   Rutachmann, I Vcrnazza, J. von Overbeck 629  630 zyxwvutsrqponm linical Microbiology and Infection, Volume zyxwv   Number 6, December 1997 zyx AZT to didanoside (ddI) was logical, as AZT-resistant isolates remain susceptible to ddI [4]. It was not clear, however, whether continuing AZT with ddI in patients who had already received AZT for several months would be more beneficial than stopping AZT when ddI was started. In addition, available data suggested that higher doses of ddI were not providing a clinical advantage [5,6] and were associated with more side effects [6]. This randomized clinical trial was therefore designed to compare among HIV-infected patients previously treated with AZT the clinical efficacy and tolerance of two treatments options: ddI 400 mg alone, and low-dose combination therapy with AZT 300 mg plus ddI 200 mg. Regardless of the duration and the type of drugs previously received, drug dosage and compliance deter- mine treatment effectiveness. In the year 2000, 90% of the 30 million to 40 million HIV-infected persons will live in resource-poor countries [7] where drug access is often limited and cheaper treatment options with monotherapy or lower drug dosage are likely to be used even if not recommended. This study represents a careful controlled investigation of the potential impact of low drug dosage and poor compliance with mono- therapy. METHODS This was a multicenter, randomized, open label, con- trolled trial. Central block randomization (1 1) was organized to ensure an equal distribution of patients by treatment arm. Monotherapy patients received two ddI tablets of 100 mg twice daily (400 mg/day) and combined therapy patients one AZT tablet of 100 mg three times a day (300 mg/day) plus two ddI tablets of 50 mg twice-daily (200 mg/day). The mean + SE) dose of ddI was 6.3 LO. 1) mg/kg/day among patients in the ddI monotherapy arm and 3.1 (20.1) mg/kg/day in the combined therapy arm. Primary endpoints were new AIDS-defining events as in the 1993 European AIDS definition [8] and death. Other outcome measures were HIV p24 antigen (p24), CD4 cell counts and weight change. Measurement of viremia was not considered reliable or feasible at the time when this study was initiated. A toxicity end- point was reached when suspected toxicity led to dose reduction or drug withdrawal and was at least partly reversible after discontinuation of treatment. The following were considered severe adverse events: (1) hemoglobin <90 g/L or decrease of 30 g/L from baseline value; (2) neutrophils <750/mm3; (3) total serum or pancreatic amylase >2 times upper normal limit (UNL); (4) creatinine kmase (CK) >3 times UNL; (5) peripheral neuropathy (grade I1 or more); (6) other toxicity, grade 111 (severe) or grade IV (hfe- threatening). Adverse events were graded according to the recommendations of the American Clinical Trials Group. Intolerance was defined as the occurrence of side effects which did not quahfj as toxicity but resulted in definitive treatment interruption. zy U participants except those recruited in Italy (three) were previously enrolled in the Swiss HIV Cohort Study (SHCS) [9]. The inclusion criteria were HIV infection, CD4 cell count (350/mm3, prior use of AZT (>300mg/day) for at least 16 weeks and Karnofsky score zyxwv 80 Patients were not eligible if the likelihood of their complying with the study was considered too poor by their physician, if they had a history of clinical pancreatitis or if they were <16 years of age. Patients were excluded if one of the following applied: hemoglobin < 90 g/L; neutrophils < 750/mm3; platelets <25 OOO/mm3; alanine aminotransferase (ALT), and alkaline phosphatases >3 times UNL; creatinine >260 mmol/L; serum amylases >2 times UNL. Baseline laboratory values were measured <14 days prior to trial entry. The trial physician visited the centers twice a year to monitor the data-recording procedures and validate endpoints. The study was approved by the local ethics committee of each participating center. All participants gave written informed consent after reading a patient information sheet. To minimize the potential for introducing bias, all randomized patients were included in the com- parisons, irrespective of whether and how long they complied with their allocated regimen (intention-to- treat analysis). Statistical methods for univariate group comparisons included chi-square tests for proportion and t-tests for the continuous variables. The time to occurrence of first primary endpoints were compared in both arms using the log-rank test, Kaplan-Meier analysis and proportional hazards regression models. Baseline characteristics of patients Baseline characteristics of 124 eligible patients were similar in both groups and there were no statistically significant differences for any of the measured variables (age, gender, transmission category, CD4, weight, prior AZT, p24 antigen, AIDS diagnosis). However, patients randomized in the AZT/ddI arm had slightly lower CD4 cell count (144/mm3 versus 157/mm3), and a larger proportion were already diagnosed with AIDS (30% versus 22%). Eight patients were lost to follow- up or left the country without reaching a clinical or a toxicity endpoint (four in each group). The median follow-up was 17.3 months, similar in both groups (183 person years of observation).  Sudre et al: Randomized trial of low-dose AZT/ddl versus ddl alone zyxwvu 3 zy Toxicity and tolerance zyxwvutsrqpon here were 12 toxicity endpoints in the monotherapy arm and 10 in the combined therapy arm. This difference was not statistically significant (NS). The most common side effects with both treatments were pancreatic and hematologic disturbances. In both groups, 14% of patients discontinued treatment because of intolerance. Intolerance was more common at the beginning of treatment (35% in the first month) whereas toxicity tended to appear after several months (39% after 1 year). Overall, 39 patients discontinued treat- ment, due to intolerance or toxicity. The average duration of treatment was 11 months, in both study arms. The median time to toxicity or intolerance was 11.5 months with monotherapy and 9.9 months with AZT/ddI (NS, log-rank test). Efficacy endpoints The mean rate of CD4 cell count change (Table 1) was -2.0/mm3 per month of follow-up in the monotherapy arm and -1.5/mm3 in the combined therapy arm (NS). The evaluation of other hematologic variables, i.e. leukocytes, lymphocytes, hemoglobin and platelets, did not indicate a statistically significant advantage for either treatment. Weight loss was lower among rnono- therapy patients than combined therapy patients, and the weight difference between the groups was 2.1 zyxwvu g zyxwvuts =0.03 . There were less patients who developed an AIDS- defining event in the monotherapy group (15, 25.9%) than in the combined therapy group (27, 40.9%). This difference was not statistically significant (relative risk Table 1 Clinical endpoints by treatment group RR) 1.6; 95% CI 0.9-2.7). The most common clinical events were candidosis and herpes zoster in the mono- therapy arm and candidosis, lymphoma and weight loss in the combined therapy arm. There were nine deaths among patients receiving ddI monotherapy (15.5%) and 17 (25.8%) among those receiving combined therapy (RR 1.7; CI 0.8-3.4). In both groups, the main causes of deaths were respiratory (pneumonia), neurologic, lymphoma and Kaposi sarcoma. Considering death and clinical events together, the difference between the two treatment options was large and statistically significant: half the patients (33/66) receiving combined therapy died or experienced an AIDS-defining event compared to 27.6% (16/58) ofthose receiving monotherapy (RR 1.8; CI 1.1-2.9;p=0.01). When the duration offollow- up was taken into account in a Cox proportional hazard analysis of AIDS-defining events or death (Figure l), the advantage provided by monotherapy was statistically significant (relative hazard (RH) 1.9; CI 1.1-3.5; p=0.03). This difference remained when CD4 cell counts were adjusted to take account of the slight im- balance between the two groups at the beginning of the study. After 6 months, 1 year and 2 years of follow- up, 96%, 78% and 64% of the patients still followed were alive and free of AIDS-defining events in the monotherapy group and 89%, 76% and 36% in the combined therapy group. (p (log rank)=0.03). The advantage provided by ddI monotherapy was consistent across all predetermined CD4 cell-count groups (<50 CD4, 62% versus 69%; 50-150 CD4, 33% versus 70%; >150 CD4, 14% versus 27%). ddI AZT/ddI N=S8 N=66 9 5 zyxw ) Significance elative risk,' CIh (1 ) zyxw utrunie Ikaths 9 (15.5%) 17 (25.8 ) 1.7 1.8-3.41 (1.16' AIDS-defining cvent 15 (25.9 ) 27 (40.9%) 1.6 0.9-2.71 0.08 or death 16 (27.6%) 33 (50.0%) 1.8 [1.1-2.9] 0.01 ' >SO dccrcasc in CD4' 23 zyxwvutsr 40 ) 26 (39%) 0.99 [O.h4-1 341 0.08' clinical events (median) 28 months 19 monthc 1.8 I1.0-3.3] 0.03 CD4 (per rnni ) -27.3 -11.1 +13.8 [-16.8: +44.4] 0.37' of follow-up (per mm') -2.0 -1.5 -0.47 [-2.8; +1.7] 0.62' Weight kg) -1.4 -3.5 t2.1 10.3: 3 81 0.03 AIDS-defining event Time alive and frcc of Continuous variables Dflcrecricc <:I14 change pcr month7 Kisk among patients receiving AZT/ddI relative to those receiving ddI alone. <:1: Confidence interval. 'Chi-quared teyt for proportions. dLog-rank test. 'Results were identical in all (:D4 subgroups. ft-test (cornparison of differences between hadine value and last follow-up value)  632 zyxwvutsrqpo linical Microbiology and Infection Volume 3 Number 6 December 1997 ‘O0I zyxwvutsr   event free 40 zyxwvutsrq ddl zy   00/200 I 2o zyxwvutsrqp   0 0 200 4 6 800 Time (Days) Figure 1 Incidence of AIDS defining clinical events and death (Cox proportional hazard model). DISCUSSION Among patients with (350 CD4 cells/mm3 pretreated with AZT, the risk of death and AIDS-defining clinical events was 80% greater among those receiving com- bined therapy with low-dose AZT/ddI (300/200 mg daily) than among those receiving ddI monotherapy (400 mg daily). This difference was statistically signi- ficant and it was consistent in all CD4 groups. Data published after the initiation of this trial confirmed that, in AZT-pretreated patients, ddI alone is better than AZT [lo-131, especially among patients with >lo0 CD4 cells/mm3 [12]. Of four other trials comparing AZT with a ddI/AZT combination [3,5, 14,151, two did not show an advantage in adding ddI to AZT compared to AZT alone among AZT- experienced patients. Combination therapy, however, was advantageous for those not previously exposed to AZT [3,14]. In the AIDS Clinical Trial Group (ACTG) 175 trial [15], both ddI alone and AZT/ddI were better than AZT alone. In these trials [3,14,15] drug dosage was higher (AZT 600 mg daily, ddI 400 mg daily) than in the present trial. In the trial conducted by Collier et a1 [5], combination therapy provided a small advantage in terms of CD4 cell count and was less toxic. The superiority of ddI monotherapy over AZT/ ddI remains somewhat unexpected. It does not seem, however, to result &om a bias in favor of monotherapy patients. It is unlikely, for example, that the unblinded nature of the trial provided an artificial placebo- like advantage in favor of this group and there is no evidence of differential discontinuation, as the duration of treatment was identical in both groups. Patients in the two groups were comparable in almost ll respects, although those receiving monotherapy had slightly more CD4 cells and less advanced disease. The differ- ences were small and not statistically significant, and the crude and the CD4-adjusted relative risks of death or AIDS-defining events were almost identical. Lastly, these results are quite similar to those of the Delta 2 trial [3], where 46 of patients in the AZT/ddI arm experienced an AIDS-defining event or death com- pared with 50% in this trial. Because patients had received several months of monotherapy with AZT prior to randomization and were, in general, still receiving this drug, it is likely that many were harboring AZT-resistant viral strains. One can therefore postulate that the addition of low-dose ddI had little impact on viral replication and did not change the natural course of the disease. In comparison, switching to ddI 400 mg daily might have been more effective in decreasing viral load and slowing down disease progression. The dose of ddI prescribed in combination with AZT was almost as low as in the Alpha trial [6] (3.1 mg/kg/day versus 2.8 mg/kg/day). In that trial [6], ddI 200 mg daily was as effective as 750 mg daily but patients were all intolerant to AZT and they had more advanced HIV disease than patients in this trial. Similarly, the difference between ddI alone and AZT/ddI in this trial was smallest among patients with advanced immunodeficiency.  Sudre et al: Randomized trial of low-dose AZT/ddl versus ddl alone zyxwvut 33 zy The prescription of low-dose AZT/ddI to patients who had probably developed resistance to AZT was probably equivalent to low-dose ddI monotherapy. Switching from AZT to a higher dose of a single drug to which patients had not previously been exposed was more effective. This study dustrates the influence of adequate dose and prior drug antiretroviral treatment. Because poor compliance results in suboptimal dosage and is more likely with complex drug combinations [16], these results reinforce the importance of using simple drug protocols and helping the patients to adhere to prescribed regimens. Similarly, when both physicians and patients may be tempted to combine available drugs and reduce dosage (e.g. to decrease cost), such a strategy may be less effective than the provision of a single drug at the conventional dosage. Prior treatment, drug dosage and compliance critically influence outcome and may become the limiting factors in the use of the potent antiretroviral drugs which are now becoming available. zyxwvut Acknowledgments This study was funded in part by the Federal Office of Public Health (Project No. 92-7118), Bern, by Wellcome AG, Reinach, and by Bristol-Myers Squibb AG, Baar, Switzerland. This paper was presented in part at the 11th International Conference on AIDS, Vancouver, BC, 7-12 July, 1996. Annex 1 zyxwvutsrqpon ist of participating physicians in this trial M. Rattegay, K. Boggidn, E. Berchtold, H. C. Bucher, V Rurquier, I Cassis, N. Ceserdni, A. Christ, N. Denereaz, zyxwvutsrq . Dudle, J. Fabbri, G. Figueras, T. Fluckiger, A. Girard, C. Groeneweg, S. Henzi, M. Herman, B. Hirschel, A. Iten, C. Jauslin, L. Jelk, R. M. Jolidon, V Joos, J. Jost, L. Kaiser, G. Kaufmann, P Legendre, C. Mazzocato, A. Meynard, M. Monnat, R. Nuesch, M. Olmari, J. L. Pagani, M. Pechere, C. Petignat, C. Renold, C. Roedel, E Roos, C. Ruef, U. Schnyder, D. Steiner, M. Steuerwald, C. Suter, F Thome, R. Thurnheer, M. Tumshirn, F? Vernazza, R. Weber, S. Zehnder. References Japour AJ, Welles S, D’Aquila RT, et al. Prevalence and clinical significance of zidovudine resistance mutations in human immunodeficiency virus isolated from patients after long-term zidovudme treatment. J Infect Dis 1995; 171: D’Aquila RT, Johnson VA, Welles SL, et al. Zidovudine resistance and HIV-1 disease progression during antiretro- viral therapy. Ann Intern Med 1995; 122: 401-8. Aber V Aboulker JR Babiker AG, et al. Delta: a randomised double-blind controlled trial comparing combinations of zidovudme plus dldanosine or zalcitabine with zidovudme 1172-9. 4 zyxwvu   6 7 8 9 10 11 12. 13. 14. 15 16 alone in HIV-infected individuals. Lancet 1996; 348: 283- 91. Kozal MJ, Kroodsma K, Winters MA, et al. Didanosine resistance in HIV-infected patients switched Gom zidovudlne to didanosine monotherapy. Ann Intern Med 1994; 121: Colher AC, Coombs RW, Fischl MA et al Combination therapy with zidovudine and didanosine compared with zidovudme alone in HIV-1 infection. Ann Intern Med 1993; Alpha International Coordmating Committee. The Alpha trial: European/Australian randomized double-blind trial of two doses of mdanosine in zidovudine-intolerant patients with symptomatic HIV dlsease. AIDS 1996; 10: 867-80. Mertens TE, Burton A. Estimates and trends of the HIV/ AIDS epidemic. AIDS 1996; lO(supp1 A): S221-8. Ancelle-Park R. Expanded European AIDS case definition. Lancet 1993; 341: 441. Ledergerber B, von Overbeck J, Egger M, Luthy R, Swiss HIV Cohort Study (SHCS). The Swiss HIV Cohort Study: rationale, organization and selected baseline characteristics.  Soz Praventivmed 1994; 39: 387-94. Kahn JO, Lagakos SW, kchman DD, et al. A controlled trial comparing continued zidovudme with hdanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. N Engl J Med 1992; 327: 581-7. Montaner JSG, Schechter MT, Rachhs A, et al. Didanosine compared with continued zidovudme therapy for HIV- infected patients with 200 to 500 CD4 cells/mm’-a double-blind, randomized, controlled trial. Ann Intern Med Spruance SL, Pavia AT, Peterson D, et al. Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine: a randomized, double-blind clinical trial. Ann Intern Med 1994; 120: 360-8. Dolin R, Aniato DA, Fischl MA, et al. Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudme. AIDS Clinical Trials Group. Arch Intern Med Saravolatz LD, Winslow DL, Colhns G, et al. Zidovudme alone or in combination with &&nosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic &meter. N Engl J Med 1996; 335: 1099-106. Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic &meter. N Engl J Med 1996; 335: Eldred L, Wu A Chaisson RE, Moore RD. Adherence to antiretroviral therapy in HIV disease [abstract 2511. In: 4th Conference on Retroviruses and Opportunistic Infections, Washngton. Alexandria: IDSA Foundation for Retro- virology zyxwv   Human Health, 1997: 110. 263-8. 119: 786-93. 1995; 123: 561-71. 1995; 155: 961-74. 1081-90.
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