The Delta trial

THE LANCET

Letters to the Editor

The Delta trial

Trial 1

SIR—Sherer’s commentary (Aug 3, p 278) fails to distinguish between point and interval estimates of relative risk of disease progression or death, which are shown in the figure accompanying his commentary. Sherer therefore concludes from the point estimates alone that there is a benefit in terms of relative risk of disease progression or death for individuals with previous zidovudine therapy who received combination therapy with zidovudine and didanosine or zidovudine and zalcitabine compared with zidovudine alone for both the Delta and ACTG 175 trial, but not for the NuCombo trial. This view does not follow because the interval estimates of relative risk (RR) as indicated by the confidence intervals, rather than the point estimates, shown in the figure, indicate that the risk of disease progression or death for individuals with previous zidovudine experience treated with combination therapy compared with those treated with zidovudine alone are not significantly different; the confidence intervals include RR=1, for all three trials. The requisite statistical significance, p<0·05, is not met by these results. There is, therefore, no statistically significant benefit for zidovudineexperienced individuals in any of these three trials of combination therapy. Further, the toxic effects of drug therapy, which affect a patient’s quality of life and ability to function, is an important factor when considering whether to initiate a new drug treatment.2 Physicians should not only start at the bedside, as Sherer recommends, but also be provided with interpretations of the results of clinical trials that allow them and their patients to make the best decisions about anti-HIV drug therapy. Malcolm D Z aretsky Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA

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Sherer R. Delta in the real world. Lancet 1996; 348: 278–79. Lenderking W, Gelber R, Cotton D, et al. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. N Engl J Med 1994; 330: 738–43.

Combination: zidovudine plus

Delta 1/2

Z alcitabine Didanosine ACTG 175 Z alcitabine Didanosine CPCRA 007 Z alcitabine Didanosine

Progression to AIDS or death No needed to treat per year

Absolute risk per 1000 patient-years

RR

69 (31;
330) 32 (20; 69) 96 (40;
256) 57 (32; 275) 129 (31;
59) 72 (26;
91)

14·5 (
3·0;32·1) 31·7 (14·6; 48·9) 10·5 (
3·9; 24·8) 17·6 (3·6; 31·5) 7·7 (
16·9; 32·4) 13·8 (
11·0; 38·7)

0·90 (0·79; 1·02) 0·79 (0·69; 0·89) 0·82 (0·62; 1·08) 0·69 (0·52; 0·93) 0·96 (0·87; 1·08) 0·94 (0·84; 1·05)

Table: Absolute and relative risk for progression to AIDS or death in Delta, ACTG 175, and CPCRA 007 trials of zidovudine combined with zalcitabine or with didanosine versus zidovudine alone

Clinical information in this form underscores the fact that individual benefit from combination therapy is higher with early therapy and that the expected benefit of antiretroviral combination therapy with higher and sustained viral load suppression may be very important. Heiner C Bucher Medizinische Universitäts-Poliklinik, Kantonsspital Basel, CH-4031 Basel, Switzerland

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Sherer R. Delta in the real world. Lancet 1996; 348: 278–79. Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91. Hammer S, Jatzenstein D, Hughes M, et al for the ACTG 175 Team. Nucleoside monotherapy vs combination therapy in HIV infected adults: a randomised double-blind trial in persons with CD4 200500/mm3. Presentation at 5th European Conference of Clinical Aspects and Treatment of HIV Infection (Copenhagen, September, 1995). Saravolarz L, Collins G, Hodges J, et al for the CPCRA 007 Team. A randomised comparative trial of ZDV plus ddI vs ZDV plus ddC in persons with CD4 cell counts <200/mm3. Presentation at Third Conference on Retroviruses and Opportunistic Infections (Washington Jan 28–Feb 1, 1996); abstr LB4: p 161. Sackett DL, Haynes BR, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine. Boston: Little Brown: 1991.

Author’s reply 1

SIR—In his commentary on the Delta trial Sherer asks for better teaching of physicians who care for HIV-infected patients, to improve doctors’ understanding and handling of new antiretroviral drug combinations and viral load tests. Sherer’s interpretation of the results for the Delta, ACTG 175, and CPCRA 007 trials2–4 would have been clearer if he had presented the absolute risk reduction given and “numbers needed to treat” for the antiretroviral combination therapies investigated.5 The absolute risk reduction from combination therapy is higher in trials with higher mean CD4 cell counts at baseline (table). For the zidovudine/didanosine groups the absolute risk reduction when compared with zidovudine is substantial. In all three trials, the associated reduction in viral load at 6 months (information that is available in many trials in progress that provide only surrogate marker data) is 25–50% lower than found after newer, more potent antiretroviral regimens.

Vol 348 • November 2, 1996

SIR—Zaretsky’s analysis is oversimplified; the resulting broad brush with which he paints combination therapy in zidovudine-experienced patients does a disservice to clinicians making clinical decisions. He is correct that the benefits of combination therapy were diminished in zidovudine-experienced patients by comparison with zidovudine-naive patients in NuCombo, ACTG 175, and Delta 1 and 2, and, as I stated in my commentary, there was no statistical benefit detected for zidovudine-experienced patients in NuCombo.1–3 At best, the benefits that were observed in Delta and ACTG 175 in zidovudine-treated patients are modest. However, Zaretsky errs by basing his observations only on the figure in the commentary rather than the data from these three completed trials. In Delta 2,1 as shown in figure 1 (p 287) participants (all of whom were zidovudine experienced) in the zidovudine/didanosine group had a small but significant benefit in mortality compared with zidovudine alone (RR 0·77, CI 0·59–0·05), a

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THE LANCET

difference of 23 deaths (103/362 vs 126/355), and a reduction in mortality of 23%, as indicated by the investigators. No benefit was seen with zidovudine/ zalcitabine in zidovudine-experienced patients, and the aggregate for combination therapy was not significant. In zidovudine-experienced patients in ACTG 175, the combined endpoint event rate was 38% with zidovudinemonotherapy versus 24% for the combination therapy arms, a 42% reduction (p<0·001). Combination therapy with two nucleosides is a viable treatment option in experienced patients with sufficient potency to reduce viral replication by a half to one log. Of combinations studied in these three trials, zidovudine plus didanosine seemed to perform best, but the trials were not designed to address this question. In view of potent new agents against HIV, combinations with two nucleosides alone in zidovudine-experienced patients may be expected to be only modestly better than single nucleoside therapy. Clinicians are well advised to monitor patients with viral load and consider additional agents in treatment-experienced patients.4 Renslow Sherer HIV Center, Division of Infectious Disease, Cook County Hospital, Rush Medical College, Chicago, IL 60612, USA

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Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91. Hammer S, Katzenstein D, Hughes M, et al, for the ACTG Study Team. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996; 335: 1081–90. Saravolatz L, Collins G, Hodges J, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med 1996; 335: 1099–106. Cameron B, Health-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. Third conference on retroviruses and opportunistic infections, Jan 28, 1996, Washington DC, Abstract LB6a.

In total, 74% of patients stopped treatment over the average follow-up time of 2·5 years. This proportion is so high that doubts must be expressed about the value of the drugs, and possibly also in the interpretation of some of the results, since they refer only to those remaining in the trial, and these lives may be to some extent a select group. (Table 3 shows that many of those who stopped treatment did so because of adverse events.) When the investigators state that “the discontinuation rate is likely to underestimate any therapeutic effect of combination treatment”, they should have said that this refers to the benefits relative to treatment by a single drug: the effect of the withdrawals may be to overstate the benefits of all the drug treatments. From the CD4 counts, the benefits of the treatments are clearly temporary—ie, there was an initial rise in the median CD4 count that differed according to the drug combination (greatest for those who received zidovudine and didanosine combination and who had not previously taken zidovudine) lasting for a few weeks; but that progress thereafter followed the same declining trend in all groups (as was also seen in the Concorde trial). Is there therefore any purpose in continuing any of these regimens for more than about 2 months? There are short-term benefits in the drug combinations (corresponding to the early changes in the median CD4 counts, as shown in figure 1), but there is a possibility that later experience will be worse than for those not treated, as is the case with zidovudine alone; there are grounds for suspecting this because of the similar chemical structures and modes of operation of zidovudine, didanosine, and zalcitabine. Consequently, for those who have not progressed to latest stages of the disease, it is unclear whether treatment by the drug combinations is likely to increase life expectancy. Even if it does so, the quality of the extra lifetime gained is likely to be poor because of toxic side-effects. Further evidence that the benefits of drug combinations are small comes from Fischl and colleagues,4 who report an initial rise in the median CD4 count followed by a continuous decline, and Graham et al,5 who report that “the absolute increase in survival was modest, however, and longer-term survival remained poor”. William F Scott

SIR—It is unfortunate that in the Delta trial (Aug 3, p 283)1 there was no placebo control, since, in the words of the investigators, “the benefits of zidovudine in HIV-infected individuals are small and do not last long”, and there is doubt as to whether zidovudine extends survival of those who have not yet progressed to symptomatic AIDS. The Concorde trial2 showed no difference in the survival rates for symptom-free HIV-positive individuals between those given immediate and those given deferred zidovudine, and Chaisson et al3 found previous use of zidovudine to be a negative indicator, with an increase in the risk ratio for death or disease progression of 1·7 (95% CI 1·2–2·4). A broad picture of the outcomes may be gained from figure 2, which shows the changes in the median CD4 cell counts. When viewed as a pointer to therapeutic practice, the trial raises great concern about the very large number of drop-outs. For example, as shown in figure 2, of the 669 patients in Delta 1 who began on zidovudine, only 169 (and of the 335 patients who began on zidovudine in Delta 2, only 68) remained in the trial after 144 weeks. The number of serious adverse events was very large, as shown by the following data (from table 6):

Z idovudine only Z idovudine plus didanosine Z idovudine plus zalcitabine

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Total no of patients

Number with at least one serious adverse event

1055 1080 1072

312 289 368

Department of Actuarial Mathematics and Statistics, Heriot-Watt University, Edinburgh EH14 4AS, UK

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Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91. Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994; 343: 871–81. Chaisson RE, Keruly JC, Moore RD. Sex, race, drug use and progression of human immunodeficiency virus disease. N Engl J Med 1995; 333: 751–56. Fischl MA, Stanley K, Collier AC, et al, for the NIAID AIDS Clinical Trials Group. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. Ann Intern Med 1995; 122: 24–32. Graham NMH, Hoover DR, Park LP, et al, for the Multicenter AIDS Cohort Study Group. Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Ann Intern Med 1996; 124: 1031–38.

SIR—It is gratifying that the Delta trial1 shows a significant survival advantage for zidovudine-naive patients receiving didanosine or zalcitabine in addition to zidovudine. Included in the Delta trial protocol, but not reported, were quality of life data in the form of Karnofsky performance scores, as assessed by the clinician and visual analogue scores of wellbeing, as recorded by the patient. Patient’s weight was also recorded at each visit. What were the effects of antiretroviral

Vol 348 • November 2, 1996