TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies; Volume 5 Number 3 -- March 28, 1991
Richard Dunne*, Carole Lemens

Alpha interferon was licensed by the Food and Drug Administration (FDA) to treat HIV-related Kaposi's sarcoma (KS) in 1988. It has been licensed for hepatitis C and warts caused by the human papilloma virus. The drug also seems promising in on-going clinical trials as a treatment for hepatitis B. Three versions of alpha interferon have been approved in the United States: Roferon (made by Hoffmann-La Roche); Intron-A (made by Schering-Plough); and Alferon-N (made by Purdue Frederick).

This article will focus on the potential role of alpha interferon as an anti-HIV early intervention strategy.

What is Early Intervention?

"Early intervention" in HIV disease does not have a standard definition, but most people use the phrase to mean treatment for asymptomatic individuals with T4 cell counts below 500. Clinical trials with many drugs have consistently shown that earlier treatment for HIV disease slows progression. Exactly when to begin treatment and what drugs are safe and effective for early use, however, are crucial topics which need further and more focused investigation.

Low-dose AZT is the only antiviral drug treatment licensed for early intervention. It is specifically recommended now for people with T4 counts under 500. Two large trials present evidence that AZT slows progression in people with T4 counts between 200-500 (l3), while another smaller study has somewhat different results (l4). Other early treatment options include drugs used as preventive measures against specific opportunistic infections (OIs).

It is important to note that for some people early intervention with AZT, or other early drugs, is not a realistic option. A variety of barriers may prevent people from choosing early intervention strategies, such as financial limitations, lack of knowledge about treatment options, or lack of access to quality medical care. Still other people may choose not to take medication, which might cause uncomfortable side effects when they are feeling relatively healthy. But there are many who advocate early use. And as we come closer to licensing ddI and ddC, two antiviral drugs similar to AZT, research is needed to determine whether these drugs might be effective in delaying the onset' of HIV illness and full-blown AIDS. To date there are no clinical trials to study ddl and ddC in people with T4 cell counts over 300.

Early Intervention with Alpha Interferon

Early administration of alpha interferon may work to prevent HIV reproduction when there are relatively small amounts of virus present in the body. At the same time, it may augment the effects of the body's defenses against infections. In theory, early alpha interferon may also prevent the development of tumors and malignancies related to AIDS. But when to begin treatment is still an unanswered question.

One early intervention study with alpha interferon alone reported favorable results in a small group of asymptomatic patients. The 12-week study divided 34 asymptomatic patients with T4 counts over 400 into two groups. The first group received 35 million units per day (MU/day) or less, and the second group received placebo. Due to toxicity, 35% of those on drug withdrew from the trial, and the treatment dose was reduced to an average of 17.5 MU/day. However, none of those who received drug progressed to AIDS, while five patients who received placebo progressed to AIDS over a follow-up period, ranging from 5-33 months (15).

In another study, 93 asymptomatic HIVinfected patients were given intramuscular injections of alpha interferon (3 MU/three times a week) for up to 34 months. The group on drug was compared to 57 patients who were not given any specific treatment. The study abstract reports that patients on drug developed symptoms significantly later than patients in the control group (16).

At high doses, alpha interferon is associated with great toxicity. Lower doses (below 5 MU/day), however, are much better tolerated. Some people feel that taking a potentially toxic drug in a state of relative health is not a sensible option. But others feel that the beneficial use of the drug may outweigh the adverse side effects. Presumably, these side effects would be diminished or would not occur when low doses of drug are used. For example, in the case of alpha interferon, early intervention dosage may require one MU/day, rather than 10-20 MU/day.

Initial side effects of low-dose alpha interferon may be flu- like symptoms such as fever, fatigue, and muscle ache. Some people develop a tolerance to these effects, while others may need to take special action to avoid them. One way to minimize these Symptoms is to take ordinary pain relievers like Motrin or Tylenol. Individuals are also advised to administer alpha interferon injections at night, so as to sleep through any unpleasant side effects.

Combination Alpha Interferon and AZT

It is commonly believed that the combination of AZT and alpha interferon may produce synergistic results. This means that the effects of the drugs together may be greater than the effect of each drug used singly. The synergism may be explained by the fact that AZT and alpha interferon interfere with HIV at separate steps in its viral reproduction, thus delivering a double-blow to the virus.

A safety study of combined AZT and alpha interferon was recently published (17). The intent of the study was to determine the maximum tolerated dose of both drugs together. Fifty-six patients with KS were enrolled. Since these patients had an AIDS diagnosis because of their KS and also had relatively low T4 counts on entry (between 175-275), this trial is not strictly an early intervention trial. But the results can probably be extrapolated and applied to less advanced patients. The authors of this study concluded that the maximum tolerated daily doses of alpha interferon and AZT are l 8MU and 600 mg, respectively. Larger doses resulted in serious toxicity, including low white blood cell counts and liver damage.

Another comparative study with asymptomatic HIV-infected persons with T cell counts over 500 suggests that the three methods of treatment (AZT alone, alpha interferon alone, and the two drugs combined) are equally well tolerated (18). Those participants on alpha interferon alone have shown a decline in viral activity as measured by a decline in p24 antigen levels, as well as an increase in T cell percentages.

Toxicity

Toxicity is an important issue when determining the usefulness of a treatment option. Neutropenia (abnormally low level of certain white blood cells) is the most common side effect of AZT and high-dose alpha interferon combined. The condition can be alleviated by granulocyte macrophage colony stimulating factor (GM-CSF), a drug which stimulates certain types of white blood cells (19). GM-CSF was recently licensed but not for people with AIDS [See "In Brief"].

AZT and low-dose alpha interferon also cause low white blood cell counts and liver abnormalities (20).

Access and Reimbursement

Alpha interferon is an extremely expensive drug. If alpha interferon alone or with AZT slows HIV progression, it is imperative that the drug be licensed specifically for HIV disease. Alpha interferon must become available to HIV-infected patients with or without KS by prescription, and patients must be reimbursed by insurance companies and Medicaid, in order for the drug to become truly accessible. Schering-Plough and Hoffmann-La Roche, manufacturers of the drug, offer programs that provide free drug to KS patients on alpha interferon who have already spent $9,800 during one year (a program known as "capping cost"). Both pharmaceutical companies also offer programs for indigent PWAs, who have no insurance to pay for prescription drugs. For further information, call Hoffmann-La Roche at 1-800-443-6676. A Schering-Plough representative declined to make the company's indigent program phone number available to Treatment Issues, but suggested that all interested patients contact the company through their physicians.

Current Trials

The following trials are actively recruiting patients. Two trials are investigating the use of combination alpha interferon and AZT in people who are asymptomatic. The three-armed studies compare AZT alone, alpha interferon alone, or a combination of the two drugs in individuals with T4 counts above 500. Interested parties should call 1 -800-77CLINIC. After enrollment in this study, the National Institutes of Health (NIH) will pay travel expenses to Bethesda, Maryland.

AIDS Clinical Trial Group (ACTG) #068 is a multicenter study being conducted at Beth Israel, Memorial Sloan-Kettering and Mount Sinai hospitals in New York City, and the University of Rochester, upstate New York. Patients entering must have an early ARC diagnosis, T cell counts above 200 and have p24 antigen levels over 70 pg/ml (a relatively high level of HIV activity, which excludes many patients). Participants will be randomly assigned to one of three groups: one group will receive AZT and alpha interferon for 24 weeks, and two groups will receive either AZT or alpha interferon alone for 12 weeks, followed by 12 weeks of the two combined. For more information contact Peter Berge of Beth Israel Medical Center in New York at (212) 420-4519; Bill Anselmo of Memorial Sloan-Kettering Cancer Center in New York at (212) 639-7163; Eileen Chusid of Mount Sinai School of Medicine in New York at (212) 241-8902; or Carol Plank of University of Rochester Medical Center in Rochester, New York at (716) 275- 0526.

Conclusion

Some issues still remain unresolved, concerning early use of alpha interferon alone and in combination with AZT. The safest and most effective dosage remains to be determined, although it is clear that many people cannot tolerate doses in the 20 MU/day range. Some people do better on less drug, while others experience few adverse side effects at high doses of drug (21). It is generally agreed that the best dosage should be determined on an individual basis under close medical Supervision. Current studies seek to determine a range that will be beneficial to many patients, as well as to determine at which point therapy might be most efficiently begun.

Some people with HIV infection feel they do not have time to wait until studies are complete. Treatment Issues conducted an informal survey of clinicians in New York City who are using alpha interferon combined with AZT as an antiviral treatment to find out what doses seem most promising. On average, doctors are trying 1-5 MU/day alpha interferon in combination with 300-500 mg/day AZT. People tolerate the drugs better when they start with lower doses. It should be emphasized that to date there is no clear-cut data about the safety and efficacy of this regimen.

* Richard Dunne died in December 1990. He worked on this article with Carole Lemens until the time of his death.

Footnotes:

13 Fischl N. The safety and efficacy of AZT in the treatment of subjects with mildly symptomatic HIV infection. Ann Intern Ned 112:727-737, 1990; and Volberding P. Zidovudine in asymptomatic HIV infection. NEJN 322:14;941-949, 1990.

14 Recent unpublished Veteran's Administration Study on AZT.

15 Lane CH. Interferon-alpha in patients with asymptomatic HIV infections. Ann Intern Ned 112:11; 805-811, 1990.

16 Rivero J. Long-term treatment with recombinant or natural alpha interferon in asymptornatic seropositive HIV-carriers prolong the incubation period. J Interferon Research 10:516, Nov 1990.

17 Fischl N. A phase I study of recombinant human interferon-alpha (2a) or human lymphoblastoid interferon-alpha (n1) and concomitant sidovudine in patients with AIDS-related kaposi's sarcoma. AIDS 4:1-10, 1991.

18 VI Internat Conf on AIDS, abstract ThB. 22., San Francisco, June 1990.

19 VI Internat Confer on AIDS, abstract, SB. 512, San Francisco, June 1990.

20 Personal communication, V. Davey.

21 ibid.

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