Published in the Bulletin of Experimental Treatments for AIDS September 1997 issue, by the San Francisco AIDS Foundation.

September 1997 Table of Contents

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When HIV Breaks Through

by Diane Cenko

Nearly 2 years after FDA approval of the first protease inhibitor and the advent of combination highly active antiretroviral therapy (HAART) to treat HIV, it has become apparent that the benefits of the drugs are not realized equally by all who use them. While the majority of those who are treated with HAART initially experience significant reductions in viral load, others find that the virus is not completely suppressed and that viral load subsequently returns to higher levels in a short time. Steven Deeks, MD, Associate Professor of Clinical Medicine at the University of California at San Francisco and a physician at San Francisco General Hospital (SFGH) suggests that as many as one-third of the patients on HAART seen at the city HIV/AIDS ward have experienced drug failure. Deeks further cites reports from the St. Petersburg, FL, International Workshop on Drug Resistance, Treatment Strategies and Eradication that some individuals—especially those who have used many of the existing antiretroviral drugs as monotherapy or sequentially—may experience almost no reduction in viral load from HAART.

Resistance is usually identified as the most likely, but not the only, cause of this less-than-desirable response to therapy. Resistance can occur when a therapeutic regimen is not potent enough to suppress HIV completely. Because HIV replication is not precise, mutations in the virus occur which cause the new HIV particles to dif-fer from the original. These new versions of the virus may be able to replicate in the presence of a drug, resulting in stable or increasing levels of detectable virus.

The recently released draft of the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (BETA, June 1997, page 11) strongly emphasizes the importance of preventing resistance. However, prevention of resistance may no longer be an option for many. The problem for these people is to identify individual strategies to forestall a breakthrough in viral load, regardless of resistance.

While the federal guidelines define and identify the parameters of a “failing regimen” and offer recommendations about when to make a change in therapy, the members of the advisory group that developed the guidelines emphasize that “there are very few clinical data to support specific strategies for changing therapy.” Specific strategies may be needed by the estimated one-third of HIV positive individuals who are not able to achieve and maintain undetectable viral load. While no specific strategies have yet been spelled out, there are extrapolations from clinical research data and occasional anecdotal reports that point to areas for further investigation.

Working to Resolve the Problem

Responsibility for resolving the problem of treatment failure is shared by people with HIV/AIDS, physicians, researchers, drug manufacturers and AIDS activists. Successful strategies are unlikely to be found without significant research efforts requiring unprecedented cooperation and collaboration.

One area requiring attention and collaboration is the lack of widely available stocks of drug-resistant, mutant HIV. According to Dean Winslow, MD, Senior Medical Research Scientist at Agouron Pharmaceuticals, the Intercompany Collaboration (ICC)—a group of pharmaceutical companies working together to promote cooperative research—in June 1997 passed a resolution requesting researchers at all member companies to share drug-resistant HIV isolates with the National Institutes of Health’s AIDS Research Reagent Repository. Dupont Merck Pharmaceuticals has begun to recognize the need to test products on drug-resistant, mutant strains of HIV (particularly the 184V mutant) as well as on wild-type virus, which is the viral strain that is normally found prior to the initiation of any antiretroviral therapy. Many drugs perform well only in the presence of wild-type virus, while others do well with both wild-type and mutant virus.

Protease Inhibitor Response Project

To address some of the problems of treatment failure and to identify others as yet unknown, new collaborations have begun to form. In San Francisco, Rick Loftus, a research associate at the Gladstone Institute of Virology and Immunology (GIVI) and a member of ACTUP/Golden Gate, has organized the Protease Inhibitor Response Project (PIRP) to collect much-needed data on individuals whose combination therapy has produced unusual results.

For the purposes of this study, unusual results include:

• rapid rebound in viral load (within 6 months of starting therapy)
• little change in viral load (decrease to no less than one-third of the starting value)
• delayed viral load response (3-fold change after more than 2 months)
• CD4 cell increases despite little change in viral load
• viral load increase in response to treatment.

PIRP began in late 1996 as a website for the collection of vital information in response to increasing reports from physicians of viral breakthrough or lack of response to antiretroviral therapy among their patients. According to Loftus, “In the clinic, we collected information on individuals with rebound viral loads of 500,000 copies/mL and above who were ready to try anything. We also heard about some people who had no initial response [to HAART] at all. Unfortunately, there was not much anyone could recommend for these individuals that was based on scientific data. With the accumulation of the information from the website, we will be able to analyze each situation and begin to look for patterns. We won’t know what patterns will emerge until we see more data. Only then will we be able to begin to develop strategies to combat the problem.” The PIRP website may also become a forum for discussion among people with HIV/AIDS and physicians, who will be able to post information about effective treatment options and share experiences instantly.

Although only a few months old, PIRP has begun to collect information on how individual physicians are applying what is known from clinical trials and clinical experience to assist individual patients. Through contact with AIDS specialists around the country, an anecdotal database on the current state of clinical practice is being developed. For example, Daniel Kuritzkes, MD, reports alternating different drug combinations frequently in an effort to “outrun” the ability of the virus to mutate. Paul Bellman, MD, suggests boosting blood levels of drugs by using one drug to help another drug achieve higher plasma concentrations.

Brad Saget, MD, and Steve Scheibel, MD, in San Francisco have reported bombarding the virus with 6 or 7 drugs simultaneously, even though this type of regimen may be difficult to tolerate. The idea of a “washout,” or removing all antiretroviral drugs for a period of time to allow mutant strains of the virus to return to wild-type, is also being explored to determine if it is possible to re-establish drug sensitivity once it has been lost. These and other approaches will be discussed and evaluated on the website.

Loftus believes that PIRP may have an immediate impact on HIV drug research and development practices. “Not many companies realize that they are developing components of combinations rather than therapies to use alone,” said Loftus. “Until they make that leap in understanding, they will continue to run into problems with drug development. They are not yet fully sensitive to the risks of drug resistance and the importance of trying to minimize that risk in clinical studies. In the old days, we probably would have agitated for people with HIV to participate in Phase I studies, where they ‘wash out’ all drugs and basically end up on monotherapy for a few weeks or months. People participated in Phase I studies in order to gain access to something new that might benefit them. Now I think that we might consider studying absorption and other Phase I issues in HIV negative volunteers, so that we don’t put HIV positive individuals at risk of losing the potential to respond to a new, promising agent.”

The PIRP website may be found at www.pirp.org [not currently active as of Nov. 17 1998--ed]. Physicians or HIV positive individuals who wish to participate in the project will be asked a series of questions designed to help identify the underlying reasons for viral breakthrough—in essence, to provide a limited treatment history. These responses, which are kept confidential, are analyzed by a team of researchers and physicians who hope to identify patterns which can ultimately point to new directions for successful therapy. Individuals without computer access who wish to participate may write to: Rick Loftus, c/o Gladstone Institute of Virology and Immunology, PO Box 419100, San Francisco, CA 94141-9100.

Breakthrough Clinic Established

A promising development in the effort to deal with the growing problem of drug failure is a clinic scheduled to open in early October at SFGH. Still without an official name, planners have dubbed it the “Breakthrough Clinic.” The clinic is an outgrowth of a collaborative effort between community activists, researchers from GIVI, physicians from SFGH and other healthcare providers. The clinic will provide a unique opportunity to closely examine the problem of viral breakthrough by incorporating expertise from many diverse medical specialties.

Robert Grant, PhD, Director of the Virology Core Lab at GIVI and a strong supporter of the clinic, defined the problem to be studied. Grant said, “The question of why some people have viremia [the presence of virus in blood plasma] while on therapy is complex. Drug resistance is just one part of the problem. As many as half may fail without any evidence of genotypic resistance at all. There are additional issues of adherence or compliance to the prescribed regimen, absorption problems due to intestinal illness, drug interactions which can reduce plasma levels of antiretroviral drugs, and drug levels that are not adequate in all tissues, especially the central nervous system (CNS). The clinic will respond to why the problem is occurring and recommend possible interventions based on what is found. Patients will still be treated by their own physicians.”

Grant stresses that the clinic will not be developing new drugs, but rather will be a focal point for information. The existing model of oncology “tumor boards” in many hospitals is one way to structure this project. HIV genotypic testing [determining the virus’ gene pattern], phenotypic testing [determining how a virus reacts to drugs in a test tube] and determination of plasma drug levels, as well as examination of viral load in the CNS and other sequestered sites, will be routine matters for clinic participants. Consultations among specialists will focus on innovative and aggressive approaches that might include immune-modulating therapies, radiation, use of corticosteroids and cellular modulators, and novel ways to use existing antiretroviral drugs.

Grant believes that the clinic may also benefit drug researchers. Aside from the obvious economic issues, drug companies have been slow to react to the need for therapies for mutant viruses because they have not always had easy access to adequate samples. It is hoped that the “Breakthrough Clinic” may help resolve that problem and foster cooperation between drug manufacturers and those in clinical practice.

Warner Greene, MD, PhD, Director of GIVI and another strong supporter of this new concept, emphasizes that the clinic will provide a unique, multidisciplinary assessment not currently available elsewhere. Greene envisions that consultations and individual patient assessments will be a collaborative effort by such diverse medical specialists as immunologists, neurologists, infectious disease/AIDS specialists, experts in compliance issues, pharmacologists and bench scientists. “We’re not yet sure what we will find,” said Greene, “but we are confident that a great deal will be learned. We will have as a goal the refinement of therapy and the hope of offering alternatives.”

Deeks is anxious to begin seeing patients in the clinic. “We are now in a ‘catch-22’ situation in which when a breakthrough occurs on a potent regimen, we think the regimen should be changed immediately. But clinically there are not sufficient treatment options available because of the broad cross-resistance between current drugs. We may want to recommend that therapy be changed quickly, but for some individuals there is nothing to change to,” says Deeks, who has been studying the problem of protease inhibitor failure at SFGH for several months. Deeks encourages his patients to understand fully the biology and basic science behind HIV resistance. “Once you understand why compliance with a therapeutic regimen is so important, you are more likely to have success in maintaining it.”

Learning About Resistance

Understanding the complex nature of HIV drug resistance may pose one of the most difficult challenges for anyone attempting to come to grips with the nature and treatment of HIV disease. Dealing with personal treatment decisions in a climate of potential drug resistance is like being on a fast-moving train with no conductor. The goal is to get control of the train and put it back on the track. Information must be gathered quickly from as many relevant and reliable sources as possible, including basic science resources, practicing physicians and clinical trials. In a time when questions far exceed answers, an ability to obtain and evaluate information from many sources will be extremely useful.

Diane Cenko is a volunteer at Project Inform.

For more information

The following are some of the most current sources of information on drug resistance and treatment decisions.

Paul Bellman, MD, has put together a compendium of information about viral resistance and his clinical experience in dealing with it. Long-Term Survivors of HIV Infection discusses strategies for evaluating resistance, the potency of antiretroviral drugs and the constant search for maximally potent regimens. Included are reports of clinical trials relevant to resistance issues, as well as experiences from his clinical practice. A copy of this 60-page document can be obtained from Paul C. Bellman, MD, 99 University Place, 3rd Floor, New York, NY 10003; 212-673-1000.

Project Inform offers several fact sheets on treatment strategies, resistance, viral load tests and other topics related to maximizing treatment options. PI Perspective newsletter volumes 20, 21 and 22 are particularly relevant. Call the Project Inform Hotline at 800-822-7422 or access the organization’s website at www.projinf.org.

The Department of Health and Human Service’s Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, reprinted in the June 1997 issue of BETA, are available by calling 800-458-5231. This document is also available on the BETA website at www.sfaf.org/beta.html or from the government’s HIV/AIDS Treatment Information Service at www.hivatis.org/guidelin.html.

The Report of the NIH Panel to Define Principles of Therapy of HIV Infection, a document which accompanies the guidelines, is a useful tool for individuals who want to grasp the basic science behind treatment strategies. This document can be obtained by calling 800-458-5231 or from www.hivatis.org/guidelin.html.

Steven Deeks, MD, has provided a comprehensive update from the most recent International Workshop on Drug Resistance, Treatment Strategies and Eradication, held in June 1997. The complete text of his summary is available through the HIV Insite website at hivinsite.ucsf.edu.

Preventing HIV-1 Drug Resistance, by Jon Condra and Emilio Emini (Science and Medicine 4:1, January 1997), is a technical but thorough description of viral dynamics and the genetic basis of drug resistance.

Approaches to the Prevention and Management of HAART Failure, by Michael Saag, MD, published by the International AIDS Society-USA, February 22, 1997, targets physicians.

Page last updated 3 October 1997