Clinical Alert: Important Therapeutic Information on Treatment of HIV Infection in HIV-Infected Patients Who Are Intolerant of or Have Failed Zidovudine Therapy.

National Institute of Allergy and Infectious Diseases (NIAID)
February 1, 1993

Summary:

Comparative DDI and DDC Treatment of HIV Infection in ZDV Intolerant Patients

Findings from a National Institute of Allergy and Infectious Diseases study may offer a new therapeutic option to clinicians treating patients with advanced HIV disease. The study was an open-label comparison of ddI and ddC with progression of disease, including death, and tolerance of the study drugs as the main endpoints.

This is preliminary information. A manuscript is being prepared for submission to a peer-reviewed medical journal.

For patients in this study, those who have failed or are intolerant of ZDV, ddC was found to be at least as efficacious as ddI in delaying disease progression and death. The results of this study suggest that ddC is an acceptable alternative monotherapy to ddI in patients intolerant of or failing on ZDV; ddC monotherapy delays clinical progression at least as long as ddI, and may provide a survival advantage. Since the majority of patients (66 percent overall) experienced disease progression with either treatment and the differences in outcome are not large, the toxicity profiles of these two drugs will be important to consider when choosing antiretroviral treatment for an individual patient.

The results of the ddI/ddC study are not intended to answer questions about the use of these therapies in previously untreated patients, the relative benefit of nucleoside therapy versus no nucleoside therapy in patients who have failed or are intolerant of ZDV, or the use of either ddI or ddC in patients who tolerate or derive benefit from ZDV. Other ongoing or recently completed studies address those questions. To guide clinicians in the integration of the results of these studies into their clinical practice, the Division of AIDS of NIAID will sponsor a conference on the state-of-the art of antiretroviral therapy in HIV infection. This conference is planned for summer 1993.

The study was conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), part of NIAID. The CPCRA ddI/ddC study opened in December 1990 and enrolled 467 patients by September 20, 1991, exceeding target accrual three months earlier than projected. All patients were followed for at least one year after the last patient was enrolled. The protocol ended follow-up on September 20, 1992. Study Population: 230 patients were randomized to receive ddI and 237 to receive ddC. Ten percent of the patients were women and two-thirds were white. Nearly a quarter of the patients enrolled had a history of injection drug use. The average age was 38 years. Approximately 63% of patients were ZDV intolerant, 48% of them because of hematologic intolerance. Intolerant patients had used ZDV an average of 14 months, whereas those failing ZDV had used it an average of 23 months. Approximately 66% of patients had a prior AIDS diagnosis. The median CD4+ cell count of the enrolled patients was very low, 37 cells per cubic millimeter. The use of concomitant medications at baseline was similar in the two groups.

For more information about the CPCRA ddI/ddC study, please call 1-800-TRIALS-A.

CLINICAL ALERT: IMPORTANT THERAPEUTIC INFORMATION ON TREATMENT OF HIV INFECTION IN HIV-INFECTED PATIENTS WHO ARE INTOLERANT OF OR HAVE FAILED ZIDOVUDINE THERAPY. Feb.1, 1993

Full Text:

The following is the text of a clinical announcement released by the National Institute of Allergy and Infectious Diseases (NIAID) on February 1, 1993.

Purpose of this Document

This document provides information on the results of a recently completed clinical trial that compared ddI and ddC in HIV-infected patients who were intolerant of or who had failed zidovudine therapy. Application of these results beyond this specific patient population can not be supported by this study. The study was conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), which is part of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. This information is provided to you, as a health care practitioner, to serve as preliminary information while a manuscript is being readied for submission to a peer-reviewed medical journal.

Introduction and Background

The CPCRA was established in 1989 to involve community physicians and their patients in studies of treatments for HIV. A unique feature of this program is its community-based focus for evaluating the effectiveness of a broad spectrum of therapies and treatment regimens. The CPCRA is comprised of 17 research units, consisting of consortiums of primary care physicians and nurses, located in 13 U.S. cities. These research units represent a significant geographic, racial and risk group diversity. Through this diversity, the CPCRA extends greater opportunity for participation in clinical research to those persons underrepresented in traditional, university-based HIV studies.

Study Design

The CPCRA ddI/ddC study was designed to answer the important clinical question of which one of the currently available nucleoside analogues should be given to a patient who can no longer tolerate or has failed ZDV therapy. The study was an open-label comparison of ddI and ddC with progression of disease, including death, and tolerance of the study drugs as the main endpoints.

The CPCRA ddI/ddC study opened in December 1990 and enrolled 467 patients by September 20, 1991, exceeding target accrual three months earlier than projected. All patients were followed for at least one year after the last patient was enrolled. The protocol ended follow-up on September 20, 1992.

Study Population

230 patients were randomized to receive ddI and 237 to receive ddC. Ten percent of the patients were women and two-thirds were white. Nearly a quarter of the patients enrolled had a history of injection drug use. The average age was 38 years. Approximately 63% of patients were ZDV intolerant, 48% of them because of hematologic intolerance. Intolerant patients had used ZDV an average of 14 months, whereas those failing ZDV had used it an average of 23 months. Approximately 66% of patients had a prior AIDS diagnosis. The median CD4+ cell count of the enrolled patients was very low, 37 cells per cubic millimeter. The use of concomitant medications at baseline was similar in the two groups.

Results

Main Endpoint

Disease progression, including death, occurred in 156 ddI patients and 150 ddC patients (rate per 100 person years: 92.3 for ddI vs 86.4 for ddC; relative risk = 0.93, p-value =0.56). Thus, there is no statistically significant difference between the two treatments based on this endpoint. The ddI group reported 100 deaths while the ddC group had 87 and the difference between the groups is approaching, but does not reach, a statistically significant level (relative risk 0.76, p-value = 0.072). There were small, not statistically significant differences in several characteristics with known prognostic value for progression of HIV disease and survival: number of CD4+ cells, AIDS diagnosis and Karnofsky score. These small baseline imbalances in important prognostic factors between the two groups, especially for Karnofsky score, indicate that the ddC group may have been, by chance, slightly more ill than the ddI group. It may bedifficult to distinguish the effect of the treatments under study from any inherent differences in those baseline characteristics. Adjusted analysis is done in order to make sure that any differences in outcome have not been influenced by those random baseline differences.

When analysis of these results was performed adjusting for these prognostic characteristics, the risk of progression of disease including death is in the direction of favoring ddC, although still not statistically significant (p = 0.11). The adjusted risk of death alone, however, does indicate an advantage for ddC (p = 0.002).

Disseminated Mycobacterium avium infection (MAI) infection was the most common non-fatal first event in both treatment groups (ddI=24 vs ddC=27), with Pneumocystis cariniipneumonia (PCP) and candidiasis following. Longitudinal analysis of data on CD4+ cells show that the average change after 2 months for those receiving ddI was significantly greater than for those receiving ddC. Between months 2 and 18, CD4+ cell counts declined in both groups.

Toxicity

While on initial study drug, at least one adverse experience was reported by 67% of patients on ddI and 66% on ddC. Many patients had multiple adverse experiences. Although the number and rates for patients with at least one adverse experience were similar in the two groups, the nature of these experiences were different. Peripheral neuropathy was seen significantly more frequently in patients receiving ddC (32 on ddI vs 69 on ddC, p<0.001), while stomatitis occurred only in ddC (8 patients). Pancreatitis was seen only in patients on ddI (4 patients). Diarrhea (48 vs 9, p<0.001) and abdominal pain (16 vs 7,p=0.030) occurred significantly more often in patients receiving ddI than in those receiving ddC.

Conclusions

The findings of the ddI/ddC study may offer a new therapeutic option to clinicians treating patients with advanced HIV disease. For patients in this study, those who have failed or are intolerant of ZDV, ddC was found to be at least as efficacious as ddI in delaying disease progression and death. The results of this study suggest that ddC is an acceptable alternative monotherapy to ddI in patients intolerant of or failing on ZDV; ddC monotherapy delays clinical progression at least as long as ddI, and may provide a survival advantage. Since the majority of patients (66 percent overall) experienced disease progression with either treatment and the differences in outcome are not large, the toxicity profiles of these two drugs will be important to consider when choosing antiretroviral treatment for an individual patient.

The results of this study, along with other recently released studies, provide additional information on the choice of antiretroviral agents for treatment of persons with HIV infection.

The results of the CPCRA ddI/ddC study are not intended to answer questions about the use of these therapies in previously untreated patients, the relative benefit of nucleoside therapy versus no nucleoside therapy in patients who have failed or are intolerant of ZDV, or the use of either ddI or ddC in patients who tolerate or derive benefit from ZDV. Other ongoing or recently completed studies address those questions. In order to guide clinicians in the integration of the results of these studies into their clinical practice, the Division of AIDS of NIAID will sponsor a conference on the state-of-the art of antiretroviral therapy in HIV infection. This conference is planned for summer 1993.

For more information about the CPCRA ddI/ddC study, please call 1-800-TRIALS-A.

The full text of this alert has been mailed to all libraries that are members of the National Network of Libraries of Medicine.