AZT PROVES USEFUL GIVEN EARLIER, AT LOWER DOSES

Three separate announcements in less than six weeks may change the course of the AIDS epidemic for thousands of people, and confirm the value of a treatment approach already in use by many with HIV. Reports from three clinical trials, when combined, have shown that AZT (Zidovudine), even at low doses, can slow the progression of HIV infection in people with moderately low helper cells but with few or no symptoms, and may be less toxic the earlier it is initiated. (The indications for AZT therapy approved so far by the Food and Drug Administration have been limited to people with a T4-helper cell count below 200 or a diagnosis of AIDS.) Following is a brief description of the details and sequence of recent developments, and the questions they raise about lack of access to health care for AIDS, and in the U. S. generally.

Lower Dose Shown Effective

On July 14 AIDS TREATMENT NEWS #83 reported preliminary results of an AZT/acyclovir study still in progress at the University of California in San Francisco. This is a small trial combining a low dose of AZT with two different amounts of acyclovir (Zovirax), testing the possibility that acyclovir enhances the activity of AZT, and simultaneously suppresses the threat of active herpes, shingles and perhaps CMV infections. Several simi- lar studies combining AZT and acyclovir were presented at the V International Conference on AIDS in Montreal last June, most of them suggesting that the combination was better than AZT alone. The anti-clotting drug dipyridamole (Persantine) may also extend the effectiveness of AZT (see AIDS TREATMENT NEWS #79), as well as the anti-gout medication probenecid, but neither has been tested with AZT enough to establish safety.

Although the UCSF study was designed to measure toxicity and not efficacy, we noted that AZT appeared to be more easily tolerated and more effective in reducing HIV activity when initiated before helper cells were seriously depleted or symptoms appeared. We added that such results had been predicted by some physicians, and would support the HIV early intervention strategy proposed by Project Inform, a San Francisco-based AIDS advocacy organization.

In the same article, we mentioned the July 12 announcement of results of a much larger trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID) demonstrating that survival rates for people taking a low dose of AZT (100 mg every four hours) were equal to those obtained by a high dose (250 mg at the same frequency). All of the 572 participants had experienced one episode of Pneumocystis carinii pneumonia (PCP) prior to entering the study; blood toxicities were less common in those receiving the lower dose. The researchers are continuing to evaluate the trial's data to identify the degree of neurologic improvement and the rate of development for new opportunistic infections. The principle investigator of that study was Margaret Fischl, M. D., of the University of Miami. On August 3 Dr. Fischl announced results of another important AZT trial, known as Protocol 016, which found that AZT delayed progression from the symptoms of ARC to infections of AIDS in a significant number of people.

Benefits of Treatment Determined For ARC

Protocol 016 began in August of 1987 and eventually recruited 713 individuals who met the study's parameters of a
T4-helper count between 200 and 800 and one or two symptoms of ARC. The participants were randomized to receive either 200 mg of AZT every four hours or a placebo on the same schedule. They were followed to observe any progression to "endpoints" -- which for this trial were defined as new or worsening ARC symptoms or development of AIDS-defining infections.

By July of this year it was clear that those participants getting a placebo had progressed to endpoints in markedly greater numbers than those getting AZT -- 36 versus 14. The bulk of progression was concentrated among those participants who entered the trial with helper cells below 500. And within this subgroup the contrast between placebo and active drug outcomes was sharper than in the group who entered with helper cells over 500. Additionally, side effects were experienced by only 5% of the participants, substantially less than the nearly 50% of people with AIDS who cannot tolerate AZT.

The researchers interpreted these results as showing that people who have ARC and who have less than 500 helper cells can benefit from AZT. They felt that the data are not sufficient to show benefit of AZT if helper cell counts are above 500, but nevertheless recommend testing for HIV antibodies to anyone who may be at risk. Those who test positive "should seek early treatment as appropriate."

These studies confirmed the approach used for over two years by many physicians and their patients: if AZT slows HIV activity in people with AIDS, but only for those who can tolerate the side effects, then why not begin the intervention at lower, less toxic doses, and before early symptoms advance to life-threatening infections? The next logical question to ask is whether people without any observable symptoms can intervene in the progression of HIV to prevent deterioration of their immune systems. The most recent AZT developments suggest that the answer is yes.

Value Seen in Treating Before Symptoms

On August 17 a study known as Protocol 019 of the AIDS Clinical Trials Group (ACTG), conducted by NIAID, was interrupted because it found growing evidence that AZT delayed progression to illness in many people who are HIV+ but asymptomatic. This trial began more than two years ago, in July of 1987, and was still recruiting until July of this year. A total of 3,200 partici- pants were recruited. All of these entered the trial without symptoms, but about 1,300 entered with a T4-helper cell count of less than 500.

The participants were randomized into three arms of the trial: one third received 1500 mg of AZT daily, another third received 500 mg a day, and the remainder got a placebo. Significantly, but to many observers not surprisingly, participants with helper cells under 500 were twice as likely to progress to ARC or AIDS if they got the placebo than if they received AZT. In the same group, disease progression was about the same in patients receiving 500 mg or 1500 mg of the active drug, and side effects of both doses were minimal. The principal investigator, Paul Volberding, M. D., of San Francisco General Hospital and the University of California, said that now all of the participants with fewer than 500 helper cells will be offered AZT. The study will continue for the group of participants with helper cells over 500, since among them the progression to symptoms was negligible. Protocol 019 is the largest AIDS clinical trial ever conducted.

The question of when to begin antiviral treatment if helper cells are declining but remain over 500 is being clarified by the growing refinement of prognostic indicators. In addition to an uneven decline in the number of T4-helper cells, HIV infection over time usually results in anemia (low red cells or hemoglobin), thrombocytopenia (low platelets), and increases in serum neopterin, beta 2 microglobulin, and p24 antigenemia. AZT has been connected with reversals of all of them, but singly they do not always indicate that AZT or any antiretroviral is warranted. When analyzed in combination they provide a more accurate picture from which to consider treatment intervention.

For example, some people may have consistently low helper cell counts (under 500) for several years without any external symptoms. In this situation, many physicians have not initiated AZT therapy unless the level of p24 antigen is high or rising, suggesting that the system may soon be destabilized by current HIV activity. A study at the University of California in Los Angeles found a strong correlation between elevated neopterin levels in HIV+ individuals and their subsequent progression to AIDS, and when neopterin levels were considered together with helper cell counts, the prognosis value was much greater than either gave alone (Melmed and others, 1989). Since helper cells can fluctuategreatly, two or even three counts must be charted over the course of several months to be meaningful. So testing for neopterin levels could hasten the process of identifying viral activity in an individual, or of determining the effectiveness of a new anti-viral treatment.

P-24 antigenemia and helper cell counts may be useful tools for monitoring asymptomatic seropositive people, but a study at the Northwestern University School of Medicine found that these tests did not predict the course of AIDS during treatment with AZT (Steinberg and others, 1989). Instead, decreased hemoglobin and platelets often predicted an increased chance of AZT-related toxicities in people who have had an opportunistic infection. This study suggests that the range of tests useful for predicting or monitoring the course of an HIV infection is narrowed as symptoms progress and immune functions become more impaired. In other words, the sooner HIV is confronted, the more tools may be available to assess questions of when and how much to treat.

One warning offered by Professor David Cooper, Director of

AIDS Epidemiology & Clinical Trials at the University of New South Wales, and also by Marcus Conant, M. D., of the University of California, San Francisco, is to avoid swallowing AZT capsules dry, without water or juice, since the drug is caustic enough to create ulcerations in the esophagus, which could then be misdiagnosed. On the other hand, an old caution to avoid combining AZT with acetaminophen (Tylenol) has been largely dismissed.

To improve AZT therapy further, trials continue which combine AZT with acyclovir, alpha interferon, DDC, interleukin II, granulocyte macrophage-colony stimulating factor (GM-CSF), and other drugs. NIAID is also sponsoring trials at the University of Miami and the University of California Los Angeles to determine if AZT given to seropositive women during the last trimester of pregnancy can prevent HIV transmission to their infants.

Vindication of the Early Treatment Strategy?

When all of these studies are considered together, they support the premise that the benefits of AZT can be obtained with lower, less toxic doses, and that these benefits decrease in proportion to immune deficiency.

Protocols 016 and 019 resulted in real advances for understanding how to interrupt the course of HIV. But they also verified the "underground" strategy of earlier, and therefore easier, treatment for HIV. The idea of intervening early in HIV infection is nearly as old as the epidemic, championed by many long-term survivors with HIV, both symptomatic and asymptomatic, by many progressive physicians, and by the persistent activism of Project Inform and ACT UP. The medical establishment has historically promoted early detection and treatment in other diseases, such as cancer, heart disease, diabetes, hypertension. But for the years preceding these recent announcements, people with HIV were dismissed with false pessimism in the media and inappropriate Federal regulations, and told to wait.

In light of the above studies, the original recommendations for using AZT may have been too much, too late, and too expensive. Now many researchers and activists agree that AZT, at least, is effective earlier, and in lower amounts, than the FDA approval indicated. The controversy regarding the optimal dosage and timing for AZT has long simmered in public discussions as well as medical literature, usually framed in a way which begged the question: "Why should asymptomatic patients be given a drug which may poison and impoverish them? " This view of the issue permitted thousands of asymptomatic people to drift aimlessly into illness.

Others have instead questioned the high cost of the only approved treatment for HIV, questioned the regulatory structure which discouraged the idea of informed choice for people with few choices, questioned a research process which sought recruits for AZT/placebo studies as late as July of 1989, and questioned the continuing dominance of AZT in the treatment landscape.

References

R Melmed, R N and others. Serum neopterin changes in HIV- infected subjects: Indicator of significant pathology, CD4 T- cell changes, and the development of AIDS. Journal of Acquired Immune Deficiency Syndromes, volume 2, number 1, pages 70-76, 1989.

Steinberg, J P and others. Predictors of outcome in AIDS patients receiving zidovudine. Journal of Acquired Immune Deficiency Syndromes, volume 2, number 3, pages 229-234, 1989.

Jacobson, M. How does zidovudine effect virologic immunologic markers of HIV activity? AIDS Medical Report, volume 2, number 2, pages 13-14, 1989.

Oskenhendler, E and others. Zidovudine for Thrombocytopenic Purpura Related to Human Immunodeficiency Virus (HIV) Infection. Annals of Internal Medicine, volume 110, number 1, pages 85-86, 1989.