Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 8 September, 1993
Derek Link

Combination AZT/ddC: ACTG 155

ACTG 155 was designed to assess the safety and efficacy of combination therapy with AZT and ddC compared with ddC monotherapy or continued AZT monotherapy in patients with at least six months of prior AZT use. The study was randomized and double- blinded. Patients enrolled were either symptomatic with under 300 CD4 cells or asymptomatic with under 200 CD4 cells. Primary endpoints in the study were time until occurrence of an AIDS- defining event or death. Secondary endpoints included survival, CD4 cell count changes, reduction in p24 antigen levels, weight gain, and change in Karnofsky score.

The study had three arms: AZT 200mg tid (three times daily), ddC 0.75mg tid, or AZT 200mg tid plus ddC 0.75 tid. Patients were randomized 2:2:3 respectively - which means that more patients were intentionally randomized into the combination arm. In March 1992, the study investigators amended the protocol to allow patients who reached an endpoint the option of receiving open-label AZT/ddC combination therapy.

The study accrued 1,001 patients, 991 of whom are included in the analysis: 283 received AZT, 285 received ddC, and 423 received combination therapy. The median follow-up time in the study was 17.1 months. There were no differences in baseline characteristics among randomization groups. The median age of study participants was 37. The study population was 90 percent male and 82 percent white. Sixteen percent had a history of IV drug use, and 83 percent entered the study with symptomatic disease. The median length of prior AZT use was eighteen months. The median baseline CD4 count was 119. Twenty-eight percent of patients entered with detectable p24 antigen.

Study investigators stratified patients by disease status, length of prior AZT, and type of PCP prophylaxis. In November 1992, the study investigators decided to examine three patient subgroups based on their baseline CD4 counts: those with under 50 CD4 cells, those with 50 to 150 CD4 cells, and those with 150 to 300 CD4 cells. Thirty- eight percent (388 patients) withdrew from the study after a median of 7.9 months. The two most common reasons cited for withdrawal were the desire to take another antiretroviral (33 percent) or patient request (27 percent).

Overall, the probability of suffering a severe side effect within twelve months was 44 percent for the AZT group, 40 percent for the ddC group, and 49 percent in the combination group. Severe toxicities were uncommon in the 150 to 300 CD4 group. Peripheral neuropathy was more common in the ddC and combination groups (22 and 23 percent respectively) than the AZT alone group (13 percent); peripheral neuropathy occurred most frequently in the under 50 CD4 group. In patients with 50 to 150 CD4 cells, stomatitis (ulcers in the mouth) was more common in the ddC group (8 percent) than the other two treatment groups (AZT 1 percent, combination 2 percent). In patients with under 50 CD4 cells, neutropenia was more common in the AZT and combination groups (41 and 35 percent respectively) than the ddC alone group (18 percent).

There were no differences among the three treatment arms in disease progression or death. The probability of remaining free of new AIDS-defining events or death by twelve months was 70 percent for the AZT arm, 67 percent for the ddC arm, and 73 percent for the combination group. These differences were not statistically significant. In addition, there were no significant differences by any stratification category.

When efficacy data are examined by CD4 cell subgroup, several points emerge. Most endpoints occurred in the under 50 CD4 cell group. There were no significant differences among any treatment arms in the under 50, or 50 to 150 CD4 cell groups. In the 150 to 300 CD4 cell group, the twelve-month probability of remaining event- free was 86 percent for the AZT group, 88 percent for the ddC group, and 95 percent for the combination group. In this patient subgroup, combination therapy was superior to AZT monotherapy but not to ddC monotherapy.

ACTG 155 has not yet been published in a peer-reviewed publication; therefore, conclusions drawn from the data may well change. However, researchers have discussed the study at several conferences, including the Ninth International AIDS Conference in Berlin and the NIH State of Art Panel on Antiretroviral Therapy last June. While Dr. Margaret Fischl, the study's principal investigator, stated at the NIH meeting that "155 is, in some ways, a negative study," she also emphasizes that the subgroup analysis of patients with 150 to 300 CD4 cells indicates benefit with the combination in patients with higher pretreatment CD4 counts who received prolonged AZT treatment.

Early AZT: Long Term Follow-up of ACTG 019

ACTG 019 was the seminal study of early AZT treatment in asymptomatics. The study began in July 1987 and randomized patients at all CD4 cell levels to receive AZT 500mg daily, AZT 1500mg daily, or placebo. In August 1989, study investigators terminated the under 500 CD4 cell group of ACTG 019 due to a dramatic reduction in the rate of progression to AIDS or death in the AZT arms after 19 months. At that time, the study investigators offered all patients AZT and followed them to assess the long-term safety and efficacy of the drug. ACTG 019 was the basis for the original government recommendation that all asymptomatic patients with under 500 CD4 cells start AZT. Dr. Paul Volberding presented the long-term follow-up data from this study at the Berlin AIDS Conference.

The data include 1565 patients (1338 in the original report plus 227 randomized after May 1989) followed for approximately 2.6 years: 493 patients were randomized to the placebo group, 542 to the AZT 500mg group, and 530 to the 1500mg AZT group. The study lost a significant number of patients to follow-up: 131 in the placebo group, 123 in the 500mg AZT group, and 129 in the 1500mg AZT group. Overall, 232 patients reached a primary endpoint. The study investigators analyzed the data in four ways. Patient outcome by original treatment group was analyzed. Overall, there were no differences in survival in any group up to 2.6 years. The investigators then analyzed time to progression after initiation of open-label AZT use in all patients. Overall, there was no difference in progression among the three arms. However, the study investigators note that they did not plan this analysis from randomization and thus it is statistically imbalanced. The investigators also analyzed those randomized to the placebo group. Starting AZT significantly reduced the risk of progression in the placebo group, but this effect waned over time. By one to two years, AZT's benefit disappeared.

The study investigators broke the data down into two CD4 cell subgroups: above 300 cells, and below 300. The investigators said they chose these groups arbitrarily because an equal number of events occurred in each. [However, the investigators also said that a 250 CD4 cell cutoff produced similar results, although these data were not described.] Overall, there was no survival advantage to AZT in either CD4 cell subgroup. Patients in the above 300 CD4 cell group had delayed progression to AIDS or death compared to the below 300 group.

Furthermore, the duration of AZT's benefit appeared longer in the above 300 group. The investigators assert that AZT appeared effective for no more than 1.5 years in the under 300 group. In the above 300 group, AZT's benefit appeared to extend beyond 1.5 years, although the investigators do not know how long the effect continues.

Although these data have not yet been published, study investigators distributed a summary of the most important findings. The authors conclude there is a "consistent pattern of a statistically significant but transient beneficial effect of AZT on the time to AIDS and death." Despite the noted transient benefit, the investigators caution, "There was no evidence that AZT prolonged survival overall or in any CD4 strata."

Earlier AZT: The BW 020 European-Australian Study BW 020, a Burroughs Wellcome-funded study of early AZT in asymptomatic patients with 750 to 400 CD4 cells, was recently published in the New England Journal of Medicine.[1] This randomized, placebo-controlled, double-blinded study began in 1988 and enrolled 993 patients in Australia and nine European nations. Patients received AZT 500mg bid (twice a day) or placebo for a median time of 94 weeks. Primary endpoints in the study were progression to AIDS or severe ARC (also called CDC Group IV C-1), progression to CDC group IV C-2 disease (symptoms, such as recurrent oral candidiasis, recurrent oral hairy leukoplakia, disseminated herpes zoster, and persistent diarrhea, that are indicative of a damaged immune system but not severe enough to be included in Group C-1), or two CD4 counts below 350. Additionally, the investigators developed a new category - early HIV clinical disease - which includes symptoms that, in the investigators' opinion, are indicative of early progressive HIV infection, yet do not meet the criteria for CDC group IV C-2. These symptoms include milder oral candidiasis, milder oral leukoplakia, and localized herpes zoster infection. Overall, the study confirmed the safety of early AZT therapy.

Reported toxicities were mild and their frequency low. Patient noncompliance was the most frequent reason for dose modifications - 14 percent in the placebo group, 18 percent in the AZT group. Hematological side effects caused a dose modification in 3 percent of placebo patients and 7 percent of AZT patients. Two percent of placebo patients and 6 percent of AZT patients reported nausea which resulted in dose modification. One percent of placebo patients and 3 percent of AZT patients reported headaches which resulted in dose modification. Other toxicities which occurred more frequently in the AZT group, but did not result in dose modifications, included: nausea, headache, asthenia (weakness), and anorexia.

The study investigators analyzed the data in several ways. Firstly, a combined analysis of disease progression was defined as progression to clinical endpoints (including progression to AIDS, ARC, or CDC Group IV C-2 diseases) plus CD4 cells dropping below 350. AZT significantly reduced disease progression compared to placebo. One hundred twenty-nine placebo patients reached this endpoint compared with 76 AZT patients.

Secondly, progression to AIDS was analyzed in the study. Ten placebo patients and six AZT patients progressed to AIDS during the study. This difference was not statistically significant. Thirdly, progression to CDC Group IV disease, which includes progression to AIDS and CDC Group IV C-2 symptoms, was analyzed. Twenty-two placebo patients and eleven AZT patients progressed to CDC group IV disease. This difference was statistically significant. The probability of progression to CDC Group IV disease at two years was 6 percent in the placebo group and 3 percent in the AZT group. Fourthly, AZT significantly reduced progression to CD4 cell levels below 350 in study participants. Seventy AZT patients dropped to below 350 CD4 cells compared with 113 placebo patients. Overall, progression to CD4 levels below 350 was reduced by 40 percent in AZT patients.

Finally, AZT significantly reduced the risk of developing clinical HIV disease as defined by the study investigators. Clinical HIV disease includes all patients who progressed to AIDS, CDC Group IV C-2 disease, and early HIV symptoms. At two years, AZT patients had a 9 percent risk of progression to clinical HIV disease compared with 15 percent in the placebo group.

On the crucial question of the duration of AZT's benefit, the study investigators assert that the "immunological effects of [AZT] therapy were clearly evident at 2.5 years and may extend for at least three years." The investigators conclude that data from several studies suggest that the duration of AZT's benefit is longer in patients with higher pretreatment CD4 counts. They state that "all these factors argue for early intervention with AZT in order to obtain the most prolonged benefit and allow patients to maintain a good quality of life."

Since BW 020 is the first study which shows a benefit to early AZT use in patients over 500 CD4 cells, its significance should not be underestimated. In fact, Burroughs Wellcome intends to use this study to support an expanded indication of AZT for patients over 500 CD4 cells in the United Kingdom, according to a recent report in Scrip, a respected, international pharmaceutical industry newsletter.

However, methodological questions with the study limit its immediate application to clinical care. Since this study used a new set of endpoints, the ability of these endpoints to predict ultimate clinical outcome must be established before firm conclusions can be made. Additionally, the published report leaves an important element of the study's statistical analysis unclear: was the study, and progression to AIDS in particular, analyzed as intention-to-treat? Intention-to-treat is a method of statistical analysis considered by the FDA and most leading statisticians to be the gold standard for efficacy studies. It will likely be some time before the statistical and methodological questions with this study are resolved.

Conclusions

These three, long-awaited clinical studies provide some important preliminary information on several crucial questions, such as the clinical efficacy of AZT/ddC combination therapy and the duration of early AZT's effect. However, the clinical application of these new findings is not immediately clear. ACTG 155 failed to define a clear role for AZT/ddC combination in the clinical management of patients who have received previous prolonged AZT monotherapy. Yet this treatment strategy was conditionally approved based on positive surrogate marker data from AZT-naive patients. Therefore, when and in whom should combination therapy be initiated? Answers to these questions must await the completion of ACTG 175 and other on- going studies of combination treatment in naive patients. Unfortunately, results from ACTG 175 are not expected until at least 1995.

Similarly, the long term follow-up of ACTG 019 and BW 020 both demonstrate that, while AZT's effect diminishes over time, it's benefits may be longer in patients with higher pretreatment CD4 cell levels. However, both studies failed to demonstrate a positive effect of long-term early AZT on progression to AIDS or death. Therefore, the crucial question faced by all perscribing physicians and patients - when to start AZT treatment - remains ambiguous from these data. Much larger studies, which enroll perhaps tens of thousands of patients, will likely be needed to resolve this question. FDA Committee to Review ddC

The FDA's Antiviral Advisory Committee will meet to review ddC monotherapy and combination therapy September 20, according to an announcement in the Federal Register August 26. Hoffmann LaRoche, the New Jersey-based affiliate of the Swiss drug company which manufactures ddC, will present new data from several studies, including CPCRA 002, a study comparing ddI with ddC in advanced AIDS patients, in a second attempt to obtain approval of ddC monotherapy. Hoffmann LaRoche first sought approval for ddC monotherapy at an Antiviral Advisory Committee meeting in April 1992 based on data from ACTG 114 and ACTG 119, two studies which compared AZT to ddC. At that time, the Committee recommended against approval of ddC monotherapy due to inadequate data supporting efficacy.

Presently, ddC is conditionally approved for use only in combination with AZT in patients with previous AZT experience. AZT/ddC combination therapy was the first treatment conditionally approved by the FDA. Conditional approval is a new regulatory mechanism which allows drugs to be marketed before their efficacy has been established. In exchange for early marketing rights, the sponsoring drug company must perform studies, determined by the FDA, which demonstrate the clinical efficacy of the drug. If subsequent studies show that the conditionally-approved drug does not produce a clinical benefit, the FDA may withdraw the drug from the market. In light of ddC's conditional approval, the Advisory Committee will also examine new data, particularly ACTG 155, on AZT/ddC combination therapy.

Documents obtained by Treatment Issues through a Freedom of Information Act request with the FDA describe the conditions of ddC's approval. Hoffmann LaRoche must present data which confirm that improvements in surrogate markers demonstrated with AZT/ddC combination therapy, such as increased CD4 cells, correlate with clinical efficacy. "Clinical endpoint data from ACTG 155 should provide primary information for the combination of surrogate markers," according to the documents. Other studies, including ACTG 175, a study of combination versus monotherapy nucleoside treatment as first line-therapy in asymptomatic patients, CPCRA 007, a study of combination therapy in advanced AIDS patients, and CPCRA 015, a large study of early versus late nucleoside treatment, "should also provide confirmatory data on clinical endpoints." While ACTG 175 and CPCRA 007 are ongoing, CPCRA 015 has not yet started and may never begin due to logistical problems.

Hoffmann LaRoche must also present data from other clinical studies to fulfill the conditional approval. According to the documents, the company must work towards the "finalization of the analysis and report of BW 27,433-28" (a Burroughs Wellcome study used for ddC's approval), pursue "alternative dosing regimens" of AZT/ddC combination therapy, and conduct a "large simple trial" of ddC. Hoffmann LaRoche must submit further toxicological and pharmacological data on the drug combination as well.

In addition, the Advisory Committee will review data on the toxic effects, such as liver toxicities and peripheral neuropathy, of various nucleoside analogs on September 21.

1 Cooper DA, et al. New England Journal of Medicine. 1993. 329: 297- 303.

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