PI Perspective 21: Themes ... The IVth Conference on Human Retroviruses and Opportunistic Infections

Important note: Information in this article was accurate in March, 1997. The state of the art may have changed since the publication date.

PI Perspective 21: Themes ... The IVth Conference on Human Retroviruses and Opportunistic Infections

Project Inform - March, 1997

The fourth meeting of the Human Retrovirus Conference in Washington, D.C., in late January brought new evidence that the recent advances in AIDS treatment are producing sustained results. The short-term dramatic benefits reported from the use of triple-drug combinations and new classes of drugs have been extended over much longer periods. Similarly, some of the key questions about the depth of response – whether the new drugs effectively suppress virus in lymph tissues and other body sites – were answered positively. Perhaps most importantly, the conference helped to clarify strategies for guiding individual treatment decisions. While many questions remain unanswered, the general direction of treatment strategy has never been clearer. Even where treatment failure exists, as it surely does for many people, its causes are for the most part now understandable. This gives reason to hope that we may yet be able to solve them. The challenge of widening the success of treatment is to get people at all levels – physicians, insurers, government officials, patients and caregivers – to understand the new data and act upon it. Vested financial interests, demands for unattainable forms of evidence, lack of information and the inertia of past practices continue to loom as major obstacles to effective treatment for those with HIV.

The presence of such obstacles is especially frustrating in light of new data that treatment has begun to reduce the rates of hospitalization, new infections and death. Preliminary analysis shows that it has also reduced the overall cost of HIV treatment, despite the high cost of the drugs. This news comes at a time when only a modest percentage of infected people are able to use the new drugs in the most effective manner. The current reductions in death and disease perhaps offer only a hint of what may be possible once effective treatment is available for everyone.

Despite the positive scientific tone of the conference, the meeting was held in an atmosphere of surprisingly intense political division. More than 5000 people attempted to register to attend but only 2400 were permitted entry. Not only were some members of the HIV-infected community denied entry, but also thousands of researchers and practicing clinicians, along with a large number of people from the pharmaceutical industry. In this regard, the meeting was a return to the days when activists and physicians had to fight their way into scientific meetings. The stakes in this debate over the future nature and size of the conference are addressed in "A Conference on the Verge of Disfunction" on page 5.

A New Consistency

One of the most encouraging aspects of the meeting was the degree to which new research questions are producing consistent and complimentary answers:

Reduction in viral load was consistently shown to correlate with clinical benefits – as measured by a reduction in the rate of disease progression and death (see "Virology" on page 6).

Reduction of viral load below the lowest limit of detection resulted in the longest duration of treatment effect and the greatest suppression of resistance (see "Virology" on page 6).
Even people with advanced disease appear to have a profound antiviral response to the better therapies.
Two or more highly active antivirals, used for the first time, have routinely produced viral load reductions to undetectable levels in most volunteers.
Reduction of viral load in the blood stream results in similar reductions in lymph tissue, vaginal secretions, and semen. These data raise difficult new questions about whether effective HIV suppression may also diminish a person’s ability to transmit the virus.
Finally, the advances make a true difference in the things that matter most – freedom from disease, suffering and death. Reports from both Europe and the United States show that rates of death, new infections and hospitalizations started a downslide beginning in early 1996, just as the new therapies became available.

This wave of consistency gives new confidence that the advances of the last year are not a fluke. It is becoming clearer as to what works and what doesn’t, and this confidence should make it easier now to develop therapies that are easier to use, less toxic and less costly.

All this good news, of course, comes against the backdrop of a painful gap between study results and practical outcomes in the real world. An ever-increasing number of people do not have the option of using therapies in the idealized fashion seen in clinical trials. For them, much of the current news tells only of lost opportunities. One ray of hope is the growing understanding of why therapy fails the imminent availability of other new drugs. Armed with this knowledge, people can at least be in a better position to plan future steps along the treatment trail.

Endurance

One of the great fears researchers, physicians and patients have shared since the advent of the new therapies is that the benefits would soon diminish, as happened with the previous drugs. Some have argued that AZT promised similar dramatic benefits and a potential cure, but drug failure and toxicity quickly dashed such hopes. The comparison is deeply flawed since no one ever suggested that the benefits of AZT monotherapy were anything but limited and short-lived. No one spoke of "eradication" or undetectable viral load in 1987, or reported the kind of dramatic benefits seen today. The combination therapies today offer viral suppression ten to a thousand times better than those of previous therapies. The new perspective added at the Conference is that the benefits are lasting longer than most expected. While older drugs used as single agents routinely failed to suppress virus for more than a few months, the new combinations seem to be maintaining near zero levels of viral reproduction for a year or more in many people. How long "or more" means remains speculative as few people have been on the drugs for more than 1½ years.

The newest data show little or no drop in effectiveness over time – at least in those who maintain proper use of the drugs. Drugs can still fail for any of three common reasons: (1) unacceptable side effects or discomfort; (2) the daily routine proves untenable; or (3) other factors, such as poor absorption which hampers effective uptake of the drug. Frustrating as they are, such limitations help tell us what needs to be improved in the next generation of drugs. It also tells us that the health care delivery system needs to include support services to increase adherence to the difficult regimens.

Long-term data suggest that it is easier to keep viral load below the level of detection than it is to get to that low level in the first place. But once there, the low level of viral activity makes it easier to suppress viral resistance for long periods. One implication of this is that if drugs can be made sufficiently tolerable and easy to use, effective lifetime therapy might be achievable.

Unanswered Questions

Despite these surprisingly positive advances, few well-informed people believe that the AIDS epidemic will be over any time soon. Difficult questions remain in many areas.

One of the most striking areas of uncertainty is the degree of immune restoration people can expect in response to effective antiviral therapy. Ideally, complete suppression of HIV would permit the immune system to heal itself. This may indeed happen for some people. But it is not clear that this is possible for everyone, especially those who have already progressed to serious levels of immune deficiency. Conference reports on this were all over the map:

Some researchers reported striking evidence of the reappearance of lost cells in the immune system, signaling at least some level of genuine immune restoration.
Some provided case reports of people suffering from untreatable opportunistic infections which suddenly responded after starting three-drug therapies.
Others reported the opposite: people with serious immune depression who saw large increases in CD4+ cell counts after treatment, yet experienced major opportunistic infections, suggesting that immune restoration was at best incomplete.

This lack of uniformity in immune response might seem a sign of inconsistency, but analysis suggests it is to be expected. Cell numbers are not the sole measure of the status of the immune system. Scientists talk in terms of cell numbers because they are the only simple measures we have to describe the immune system. Aside from cell numbers, there are critical tissue sites that affect immune function, such as the lymph tissue in lymph nodes, the gastrointestinal tract, the tonsils and the rectal mucosa. We know that the status of the thymus gland and bone marrow, however unmeasurable, almost certainly have a profound effect on the ability to restore normal immune responses. People differ widely in the health of these tissue and organ sites, independent of CD4+ cell counts. It should not be a surprise, then, that immunologic response to antiviral therapy will differ. The question is what to do about it. What forms of immune restoration therapy will have the greatest effect, and when will they be available? Other than continued interest in IL-2, few answers are being offered.

A few other unanswered questions:

Will the long-term benefits now being seen hold up for another year? Two years? Four?
Is it possible to create drugs that are easier to use, less expensive and have less long-term toxicity? The fact that we need them doesn’t guarantee we can produce them.
What will be the cost, in body and in spirit, of a lifetime regimen of multi-drug treatments?
Why does regrowth of CD4+ cells seem to stop short of reaching truly "normal" levels in most people? Why is there so little CD4+ response in some people, despite good antiviral response? The currently popular model of HIV dynamics does not adequately explain either phenomena.
Even if HIV is effectively controlled for a lifetime, can the immune system be rebuilt?
When will we be able to build an effective vaccine for HIV disease?

Some of these questions can only be answered by time, while others will require much additional research. Proposed answers today are largely speculative. What is certain though, is that until we answer these and related questions, today’s hope of effective therapy will serve more as a model than a reality for many of the people infected with HIV.

Societal Consequences

It is for now an accepted fact that the new advances in HIV therapy have little relevance for impacting the epidemic world-wide. Problems of cost, distribution, compliance and medical infrastructure pose enormous obstacles. Even within the US and other developed nations, optimum therapy is still being employed by a modest subset of those who need it. Additional obstacles include:

Physician and institutional education: achieving results promised by clinical trials doesn’t come easily. Physicians must be retrained to think in terms of long-term strategies and to understand how the use of each new drug affects the use of others. Many of the practices considered "state of the art" just a year ago, such as starting people on two-drug nucleoside combinations like AZT plus 3TC, are now believed to be unwise. Most treatment practices still amount to little more than "serial monotherapy" in which patients and physicians leap to add each new drug as soon as it becomes available. Hospitals and medical institutions often lag a year or more behind the current state of knowledge. Institutional formularies for AIDS in managed care often seem to be written by people who don’t understand current treatment science.

Patient and community reorientation: years of bad news about past therapies and drug toxicity have left many individuals and many whole communities understandably but unduly skeptical about the hope offered by the new treatments. While such skepticism may have had only modest consequences in an era of weaker drugs, today its cost can be measured in years of life lost. Anti-treatment messages are still common in many communities and cities. Overstatement of the challenges of treatment compliance and lack of support for compliant behaviors can frighten many people away from getting the treatment they need. Newsletter writers, case workers and other service providers can either act as gateways to the new knowledge and its benefits, or gatekeepers who in effect block access to treatment for others because of their own biases and outdated knowledge base. Without changed attitudes and information, vast numbers of people will fail to take advantage of important medications, even when they are technically available to all. This issue is already reaching critical proportions in the increasing volume of treatment information being provided to the patient community. A growing amount is coming from groups who, however well intended, are inexperienced in the subject.

Lack of simpler treatment regimens: while this is partially a matter of better drug formulation, it is also a matter of drug testing. The difficult regimens required today merely reflect the ways the drugs were initially tested. Additional studies, using the same drugs, may find simpler and easier ways to use them.

Inequitable distribution of Federal and State dollars: funds set aside to help pay for treatment are subject to intense political debate within AIDS-affected communities. As long as the demand for funds to support personal treatment must compete against demand for funds to support organizational needs, support services and bureaucratic structures, some people will be treated with great unfairness.

Our AIDS service organizations and support systems of the last 10 years have largely been built to support people in the process of dying. Today, there is a growing need for services to help those newly able to go on living. The issues for many people today center around re-engaging with life: employment, paying off accumulated debt, childcare, relationships and getting square with the IRS. These can be profound challenges for people whose lives have been turned around by effective treatment. Before we heed calls to simply "downsize" our AIDS service agencies, it may be wiser to first rethink and at least partially reorient their functions.

A related point is the effect of treatment on the transmission of HIV. Will some HIV-infected people, invigorated by the success of their own treatment, misread scientific discussions about how this success might affect transmission? What does the phrase "undetectable viral load in semen or vaginal secretions" say to people who have been controlling their sexual practices for the last decade? Most confusing of all will be data, possible in the near future, showing that transmission rates dip in treated populations. If a "statistical reduction in transmission" is interpreted to invite "risk-free unprotected sex," surely the net rate of transmission may rise over the long term, with the added danger of transmission of drug-resistant strains. "Reduced risk" of transmission is not the same as "zero risk". Who will lead – and carry on – the community debates triggered by this imminent phenomenon?

Another risk is that the media will continue to overstate the success of AIDS treatment, leaving the public and the Congress with the view that AIDS is over or fading away. This is hardly a theoretical concern, since any reading of the last six months of the popular media suggests that this is already the case. Some of our leading news periodicals have all but pronounced the end of the epidemic in their headlines, while hiding the details in the small print. This could have disastrous consequences in terms of support for care, prevention and research programs.

In Summary

The IVth Human Retrovirus Conference signaled a consolidation of views and a growing consensus on the status of AIDS research and treatment. In that regard, it was a positive and helpful event. Yet, people are still dying, and will continue to do so. However effective and durable the new treatments are for some, their benefits elude the grasp of others. With each advance and step forward, we are left ever more acutely aware of those being left behind, those who can’t pay the price of admission, those who can’t tolerate the drugs, and those who are blocked by every wall society puts in their way. This is an odd time for people fighting AIDS, a time of great relief and reassurance in some ways, and a time of new fears, risks and outright danger in other ways. It is not a time to drop our guard or risk the loss of ground already gained. Renewed commitment, courage and determination must moderate whatever euphoria each of us chooses to allow ourselves. There is much work yet to be done.

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Always watch for outdated information. This article first appeared in 1997. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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©1997. AEGiS.