In response to the widespread use of KEMRON or other forms of low-dose oral interferon alpha (IFN-alpha) by many HIV-infected patients and the controversy surrounding this use, the AIDS Research Advisory Committee (ARAC) requested that all information currently available on this form of therapy be reviewed and a report prepared for the Committee by staff of the National Institute of Allergy and Infectious Diseases (NIAID). The NIAID report contained summaries of 13 studies of low-dose oral IFN-alpha.
On March 31, 1992, ARAC, an advisory committee to the NIAID established by federal legislation, examined the NIAID report and prepared the following assessment. Much of the information in the report is preliminary, unpublished and not yet peer-reviewed, and there were some differences in the designs of the studies analyzed in the NIAID report. Nonetheless, the striking beneficial results reported by Dr. Davy Koech and colleagues have not been reproduced by other researchers to date. Specifically, the report by Dr. Koech described an increase in CD4+ (also called T4) cells and a conversion from HIV antibody-positive to HIV antibody-negative status in some patients receiving KEMRON.
Pending the outcome and final analysis of well-designed ongoing studies, the ARAC recommends that NIAID: 1) communicates widely its report and the ARAC assessment; 2) continues to encourage the completion of ongoing studies; and most importantly, 3) continues to encourage HIV-infected patients to seek treatment with therapies whose efficacious have been established in well- designed, controlled clinical research studies. ARAC also recommends that patients and their physicians together reconsider the value of continued use of KEMRON or other forms of low-dose oral IFN-alpha given the information in this assessment and in the NIAID report. At this point, ARAC cannot recommend the use of KEMRON or other forms of low-dose oral IFN-alpha. ARAC shares the disappointment of all HIV-infected populations that the original, exciting, positive results observed with this therapy have not been confirmed in preliminary results of subsequent well-designed controlled studies.
ARAC, in accord with its legislative mandate, is charged with developing recommendations for NIAID pertaining to the assessment of alternative and complementary therapies for HIV infection. ARAC's membership includes non-federal medical professionals, researchers and persons with HIV infection. Given the ARAC's legislative mandate and the perception that a significant segment of the HIV-infected community is using KEMRON, or other forms of low-dose oral IFN-alpha, ARAC recommended that NIAID review all available information about clinical trials of low-dose orally administered IFN-alpha.
II. SOURCES OF INFORMATION
On March 31, ARAC reviewed a report prepared by staff of the Division of AIDS, NIAID, entitled An Interim Report: Low-dose Oral Interferon Alpha as a Therapy for Human Immunodeficiency Infection (HIV-1): Completed and Ongoing Clinical Trials. This report is limited in scope to evaluating whether the reported findings of improvement of the immune system and change from HIV positive to HIV negative in earlier studies were observed by researchers in later studies. The NIAID report contains summaries of 13 studies of KEMRON or other formulations of low-dose oral IFN-alpha that have been completed or are ongoing to date. The sources of information in the NIAID report include published reports and abstracts, and personal communication with researchers about completed or ongoing but as yet unpublished studies.
III. SUMMARY OF FINDINGS
Dr. Koech and colleagues form the Kenyan Medical Research Institute conducted and published the initial study of low- dose oral IFN-alpha in the treatment of HIV infection in the Journal of Molecular Biotherapy in 1990. For six weeks, the investigators treated 40 HIV-infected patients (with symptoms and without symptoms) with 2-2.5 IU/kg of natural human IFN-a (KEMRON) given orally. The researchers reported that eight out of 40 (or 20 percent) patients had blood tests showing a disappearance of HIV antibodies by screening (ELISA) and confirmation (Western Blot) tests. In addition, the authors reported substantial improvement in CD4+ (also called T4) lymphocyte count and in clinical symptoms. These results led to use of this compound in some HIV-affected communities and prompted further clinical research. Similarly, striking results were reported by Dr. Koech and colleagues in two subsequent reports.
Unfortunately, subsequent investigations from around the world have not reproduced these striking improvements. In a study involving 108 patients in Cameroon, Congo, Zimbabwe, Kenya and Ivory Coast in which Dr. Koech participated, HIV antibodies did not disappear in any patients. In another study conducted in Zimbabwe, with 32 patients enrolled, there was only a non- significant and temporary increase in CD4+ count after four weeks of KEMRON. Information about these studies was reported in a World Health Organization (WHO) press release in September 1990 and led WHO to design a clinical study that would evaluate more rigorously the benefits of low-dose oral IFN-alpha. This study, with a projected enrollment of 400 patients, is under way.
In a personal communication with NIAID staff, Dr. Joseph Hassett at Mount Sinai Medical Center in New York City reported neither a disappearance of HIV antibodies nor a pronounced increase in CD4+ cells to date. At the time of the NIAID report, this study had enrolled 38 patients. It is still in progress. Also, no increase in CD4+ cells has been reported thus far in a study involving 67 patients conducted in Thailand (based upon the NIAID staff report of their personal communications with the sponsors of this study which is currently undergoing final analysis).
Similarly, in an abstract presented at the VII International conference on AIDS describing a German study (31 patients enrolled) and based upon the NIAID staff report of their personal communications with the authors of a Canadian study (149 patients enrolled), there were no reports of sustained increases in CD4+ count or losses of HIV antibody in patients receiving low-dose IFN-alpha administered orally. Two other studies, one in Zambia, Africa and another in Amarillo, Texas, are still enrolling patients and/or analyzing the data collected.
It is interesting to note that two of the later studies provide preliminary information suggesting some improvement of symptoms; three others from which information is available do not. A thorough evaluation of this issue cannot be conducted at this time, but must await the completion of these studies as well as the five other studies from which no information on clinical symptoms is currently available.
There may be a number of important reasons for the differences in the results between earlier studies and those conducted later. Most importantly, differences in study design may influence differences in study results. Whenever clinical studies are conducted using an open-label design without adequate controls, as in the case of the Koech study, it is difficult to interpret results since a number of factors other than the drug may be responsible for the results observed. Differences in dosage and formulation of the low-dose oral IFN-alpha may also affect study results, although several of the subsequent trials have used the same drug formulation and similar or identical dosages. Finally, concerns exist about the standardization of laboratory testing for CD4+ cell counts in the earlier studies.
In summary, based upon the NIAID report, ARAC concludes that the results of markedly improved immune status and loss of HIV antibodies reported by Dr. Koech and colleagues in their original studies are not supported by more recent and more easily interpreted clinical trials. ARAC acknowledges that much of the data currently available is preliminary. The present status of our knowledge strongly supports the need for completion of ongoing research of low-dose oral IFN-alpha. However, the current information does not suggest that low- dose oral IFN-alpha is an effective therapy for HIV infection.
ARAC appreciates the deeply held beliefs of those HIV-infected persons who have perceived that they benefitted from KEMRON or other formulations of low-dose oral IFN-alpha. We understand fully the need to find effective therapies that improve the quality and quantity of life, especially given the devastation and human toll of HIV infection. To this end, ARAC pledges, in accordance with its legislative mandate, to continue to assist NIAID in the pursuit of promising HIV therapies.
Bases upon the preceding review and conclusion, ARAC strongly recommends the following:
1. NIAID should continue to encourage the completion and analysis of ongoing studies of low-dose oral IFN-alpha.
2. NIAID should provide an updated report within one year on the results of ongoing studies for review by ARAC.
3. Upon receiving and reviewing this updated information, ARAC will provide an updated assessment for NIAID to circulate widely.
4. NIAID should widely circulate its current report, together with this assessment by ARAC, making every effort to ensure that it reaches health care professionals and HIV-infected patients in those communities where the use of low-dose oral IFN-alpha is prevalent.
5. Pending the outcome of ongoing studies, ARAC strongly encourages HIV-infected patients to seek treatment with therapies whose efficacious have been established in well-designed, controlled clinical trials.
6. ARAC cannot recommend the use of low-dose oral IFN-alpha in AIDS patients at this time. Patients and their physicians should carefully review the value of KEMRON or other forms of low-dose oral IFN-alpha given the information in this assessment.
A copy of this executive summary and the full report are available from the AIDS Clinical Trials Information Service, 1-800-TRIALS-A.