AZT, ACYCLOVIR, AND THE CASE FOR EARLY TREATMENT

Regulatory issues are not the only obstacles to access to care. Even when treatments are legally available, many patients will not benefit because of lack of standards of care, and lack of insurance reimbursement even in many cases when physicians agree. Such problems are especially apparent on the issue of whether antiviral or other treatments should be started before symptoms have appeared or T-helper cell counts have fallen below 200.

For several years the San Francisco-based organization Project Inform has developed a pioneering treatment strategy dealing with HIV infection. The key premise of this strategy asserts that HIV and AIDS are chronic, manageable conditions, not the death sentences bemoaned by the media/medicine/government complex. The prescription for action which grew from this premise is 1) early testing for the presence of HIV or immune dysfunction, and 2) flexible antiviral or immune-boosting treatment before the appearance of symptoms, possibly without waiting for the approval of a promising treatment by the Food and Drug Administration (FDA). Though much of the medical establishment still dismisses or ignores it, the message proposed by Project Inform is proving correct with the passage of time and with the accumulation of pointless deaths. Health officials from government and academia alike have been slow to advocate any plan of action, or standard of care, to account for everyone with HIV, symptomatic or not.

Even within the limits of FDA-approved drugs there are treatment opportunities now available to seropositive asymptomatic people to optimize their chances of staying healthy. Two of them are AZT (Zidovudine) and acyclovir (Zovirax). Since its initial approval by the FDA, AZT has remained the most prominently discussed and intensively studied treatment for HIV and related infections. At the recent International Conference on AIDS in Montreal, for example, there were over 370 sessions which discussed some aspect of AZT. Despite pervasive and often unfounded mistrust of its efficacy, and despite its very real toxicity and the limits of its antiretroviral activity, AZT has proven to be of immune- preserving and life-prolonging usefulness for many people with HIV. In addition, its capacity to reach the central nervous system makes AZT useful for treating HIV neuropathy, and the neurologic impairment sometimes called AIDS dementia complex (ADC).

Side effects on the other hand, especially from the "high" dose of 1200 mg daily, completely prevent many people from using AZT. And for people who can tolerate the drug, long-term studies indicate that prolonged use of AZT on the originally approved dosing schedule often leads to unacceptable bone marrow suppression. Prolonged use may create AZT-resistant virus as well, although laboratory tests have shown that isolates of HIV which have become resistant to AZT are still susceptible to other anti-retrovirals such as DDI and DDC. AZT-induced anemia can be reversible if the drug is temporarily discontinued, or may be managed with periodic blood transfusions, or may possibly be prevented by also taking erythropoietin (EPO), a red cell growth factor recently approved by the FDA.

There are HIV and AIDS-related treatments which appear to enhance AZT. This has meant that the same anti-retroviral potency might be achieved by combining such an agent with lower, less toxic amounts of AZT. One possibility, reported in AIDS TREATMENT NEWS #79, is the anti-clotting drug dipyridamole (Persantine). This is a prescription drug which extended the activity of AZT in the test tube. But there is no evidence yet that it will do the same, or do it safely, in people. The beneficial combination best studied is AZT and acyclovir (reported in AIDS TREATMENT NEWS #47, December 4, 1987, although much more work has been published since then). Acyclovir is relatively non-toxic and two European studies presented at the Montreal conference (Walger, P and others, abstract W. B. P. 318, and Weber, R and others, abstract W. B. P. 321) suggested that AZT with acyclovir was superior to AZT alone. Acyclovir is also used to suppress latent infections of the herpes viruses, including herpes simplex, CMV, and herpes zoster, all of which have been discussed as factors that may facilitate the growth of HIV.

One small but illustrative AZT/acyclovir study, conducted by Harry Hollander and others at the University of California in San Francisco, began with 20 HIV+ asymptomatic participants almost two years ago. Ten of the participants were placed on 100 mg of AZT (half the dose originally recommended by the manufacturer, Burroughs-Wellcome) with 400 mg of acyclovir (twice the dose recommended for treating initial herpes infections) five times daily. The other ten participants received the same amount of AZT, with 800 mg of acyclovir.

Three participants withdrew from the study (two after 10 weeks and the other after 38 weeks) because of subjective toxicities (side effects that the patients told the physicians about, but were not measured by laboratory tests). Unfortunately, three other participants developed AIDS (at weeks 6, 8, and 62). These six participants had entered the study with a lower median T4-helper cell count than the other fourteen participants (210 versus 544), and the three who developed symptoms had each tested positive with the first p24 antigen results. The remaining participants continue to tolerate this drug combination without serious side effects and remain asymptomatic. Three have had at least one positive p24 titer, all below 25 pg/ml, and one participant who began the study with low titer antigenemia now tests negative. Helper cells have remained stable -- from a baseline median of 503 to 588 at week 78.

The investigators concluded that the combination of AZT with acyclovir is generally well-tolerated, with no statistical consequences seen between the two acyclovir doses (although the three participants who withdrew for subjective toxicity were all on the higher dose). They added that larger trials are necessary to determine the efficacy of the combination.

Nevertheless, some implications may be useful for people now considering whether to treat an asymptomatic HIV infection, with or without AZT. The combination was apparently better tolerated by participants with a higher T4-helper cell count. Additionally, progression to illness was uniformly seen in those participants with the poorest laboratory predictors: depressed helper cells and elevated p24 antigen levels. A reasonable conclusion, one reflected by the Project Inform strategy, is that early intervention in HIV infection is easier to cope with, and more effective therapeutically, than applying an equivalent treatment after helper cells have been seriously depleted or AIDS-related symptoms have developed.

This was not a placebo-controlled study, fortunately, since there is ample epidemiological evidence that without any treatment intervention most people with HIV will eventually progress to illness. AIDS TREATMENT NEWS has spoken to many people who are currently asymptomatic but watching their T4-helper cells fall or p24 antigen level rise (if they're lucky enough to get these tests). Many physicians would defend not treating these asymptomatic patients, with a rationale mentioned below. Other physicians are tending to treat earlier than the appearance of symptoms by following such progression markers as thrombocytopenia and elevated beta 2 microglobulin, in addition to helper
cell counts and p24 antigen levels.

If most or all HIV infections eventually progress to illness, what is the basis for telling an asymptomatic seropositive person to "leave well enough alone" or "if it ain't broke, don't fix it"? And if the treatments now available for HIV are more effective the earlier they are initiated, what is the point of waiting until symptoms appear? There are objections which warn of "wasting" the AZT option by offering it early to asymptomatic people only to see them become anemic or reach resistance of the drug, leaving them without an antiviral if symptoms develop. This objection appears weak from two perspectives. For one, AZT or other early treatment options will not have been wasted if they forestall the progression to illness until another generation of anti-HIV drugs becomes available. Secondly, the option may be wasted precisely by waiting until symptoms appear, when drugs of all kinds are more difficult to tolerate and less potent against the immune deficiency.

If acyclovir or other agents can permit a decrease in the dosage of AZT, then many more people with HIV may have access to the only approved HIV treatment. And preliminary results of a large NIH study indicate that survival rates for patients on a full dose of AZT were no better than for those taking a low dose, without acyclovir as a factor. Whether AZT is absolutely more effective when combined with acyclovir or dipyridamole is not clear yet, but the originally recommended high dose of AZT appears to be unnecessary in any case. We have also spoken to many people who feel their physicians rely too heavily on AZT because they are unwilling to consider other potential antivirals such as dextran sulfate or hypericin which have not been approved for the treatment of HIV and AIDS. When AZT is routinely prescribed for someone who is not benefiting from it and who may benefit from another promising, but unapproved, treatment, then the letter of the law is obstructing the pursuit of the patient's health. Hopefully, accessibility to various treatments of promise will increase with growing public political pressure.

The indications which earned AZT an FDA approval were a T4- helper cell count below 200 or a diagnosis of AIDS. These could be exactly good predictors of a poor response to AZT, in light of the study described above and others. Many clinicians are prescribing AZT earlier than the FDA indications, but many insurance companies will only reimburse within the FDA parameters. Which means that without an FDA/NIH-backed "standard of care" which reflects the growing medical consensus, hundreds of thousands of U. S. citizens known to be HIV+ may not receive AZT or acyclovir or anything else, unless they can join an NIH drug trial or until they become ill (and are less able to manage AZT's toxicity). And for years, people who could not tolerate AZT were offered no other alternative by the NIH or FDA until the recent DDI announcement (see related article on DDI in this issue).

There were hundreds of drugs and drug combinations discussed at the Montreal conference, one or more of which may someday be a successful treatment for HIV. At present there is no NIH/FDA- approved treatment plan for everyone with HIV, which leaves thousands of doctors lacking authoritative leadership and a standard of care to apply to their HIV+ patients. Innovative physicians have been staying abreast of current treatment options without the guidance or permission of the national healthcare bureaucracy, and their patients are lucky for it: they tend to receive treatment, AZT or otherwise, before the appearance of opportunistic infections and they find out about other options if AZT ceases to be one. But people without innovative doctors will not fare as well, and for them the vacuum of leadership is unfair and perhaps deadly.

FOR MORE INFORMATION

Project Inform's HIV treatment strategy can be requested by calling 800/822-7422 from outside of California, 800/334-7422 inside California, and 415/558-9051 from San Francisco or other countries. Fact sheets are also available which discuss potential treatments for HIV, both approved and unapproved. The following periodicals, like AIDS TREATMENT NEWS, also report on new developments in the treatment of AIDS and HIV infection.

*TREATMENT ISSUES discusses new and now-standard therapies for HIV and related infections. Sent free of charge, but donation welcome. Write to GMHC, Dept. of Medical Information, 129 West 20th St., N. Y., NY 10011.

*BETA, (BULLETIN OF EXPERIMENTAL TREATMENTS FOR AIDS) offers thorough coverage of anti-HIV drugs. Published by the San Francisco AIDS Foundation, three issues have appeared in the last year. Call 415/863-2437.

* AIDS/HIV EXPERIMENTAL TREATMENT DIRECTORY, published by the American Foundation for AIDS Research (AmFAR) lists and describes a wide spectrum of treatments currently in development or in clinical trials. Call 212/719-0033.



STATEMENT OF PURPOSE

AIDS TREATMENT NEWS reports on experimental and complementary treatments, especially those available now. It collects information from medical journals, and from interviews with scientists physicians, and other health practitioners, and persons with AIDS or ARC.

Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS TREATMENT NEWS does not recommend particular therapies, but seeks to increase the options available.

We also examine the ethical and public-policy issues around AIDS treatment research.