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In the Eye of the Storm

tagline 1997

Having Temporarily Suspended Disbelief, Would-Be Eradicatee Looks Forward to Still Uncertain Future


‘A perilous seduction’

Irrational exuberance might not be the sole domain of streets Broad and Wall. Speculation in AIDS futures has also seen quite a run over the past 18 months. While both seem to be rooted in unseemly corporate profitability, the latter wave of euphoria appears to have begun to cede to a harsh and tenacious reality (if not yet to the full enormity of the therapeutic and funding crises ahead.) And as the pendulum begins its inexorable swing back to a more sober state of affairs (see Nightline, July 25, 1997 as well as the front page of The New York Times, August 22, 1997), Gregg Gonsalves offers his view of "The State of AIDS," which he first delivered at a D.C. forum sponsored by the AIDS Action Council this past July.

I found out I was HIV+ positive a little over two years ago in March of 1995. At that time, I was helping take care of my cousin Carl, who died of AIDS that year in July. It was a gruesome death from lymphoma that dragged on for months and months. At that time, there was nothing that could have saved Carl and nothing that looked like it could spare me from his fate. How dramatically the popular outlook has changed in the past two years. As one of ten volunteers in a clinical trial run by David Ho and Marty Markowitz at the Aaron Diamond AIDS Research Center, I am now taking a triple combination of AZT, 3TC and nelfinavir. Since beginning treatment, my viral load has plummeted from some 200,000 copies per cubic milliliter of blood to under 100, and there is no detectable HIV RNA in my gut-associated lymphoid tissue (GALT), semen or cerebrospinal fluid (CSF). My T-cells have risen from 270 per cubic milliliter to 470. And while I do not think I will escape a death from this horrible disease, I do think I have been given a substantial respite from disease progression -- at least for now.

We've all heard virologic success stories like this in the press over the past year. Today, however, I would like to focus on the caveats about these triple and quadruple combination regimens -- and their failure to offer significant hope for hundreds of thousands of people with HIV infection. For the past 18 months, our expectations and our public policy have been driven by a giddy optimism. It's now time though, I'm afraid, to remove the rose-colored glasses and face the real challenges that lie ahead.

The new intensive treatment strategies, now known as highly active antiretroviral therapy (or HAART), are indeed remarkably successful in suppressing viral replication in patients with little history of taking anti-HIV medications. Thousands and thousands of HIV+ individuals, however, (including many of my friends who have been infected for more than a couple of years) have listened to the prevailing medical wisdom of years past and taken AZT, ddI and ddC, combined these drugs or added 3TC or d4T. Many later took saquinavir, the grossly impotent but deftly marketed protease inhibitor when it was the first of its class of drugs commercially available in the fall and winter of 1995. The result: thousands of HIV+ individuals are resistant to many of the component drugs in the triple combinations that have shown so much promise in patients nave to antiretroviral therapy. If they have developed protease inhibitor cross-resistance from earlier saquinavir use, the newer and more potent protease inhibitors, ritonavir, indinavir and nelfinavir are of limited use to them. If they haven't developed protease cross-resistance, but are resistant to AZT and its cousins, they will likely get some benefit from the use of protease inhibitors, but are essentially using a single agent to control HIV. Monotherapy, even with the most potent protease inhibitor, cannot hold the virus at bay for long.

What do we know about my own chances -- and of people like me -- for beating this virus? I have no detectable virus in my body right now, but even this claim is partly artifactual (for reasons I'll soon explain). No one now believes that even the most successful of these combination regimens is capable of completely shutting down viral replication. The embers may be gray and smoldering, but they continue to burn. What my bloodwork and clinical picture will look like in a year or two from now is anybody's guess. My future depends on several factors. First, if I am to get the most out of the drugs I am taking and want to forestall the development of drug resistance, I will have to maintain a daunting daily medication regimen. I take over two dozen pills a day. In addition, to my antiretroviral therapy, I take a drug to control the debilitating diarrhea caused by the protease inhibitor and a drug to control the esophagitis that sent me to the emergency room this winter. If I miss even a single dose of my pills, I greatly increase the risk of HIV's developing resistance to these agents.

Even if I can take my drugs regularly for the next few years, my future is far from certain. Recently, 3 of the 10 people in my clinical trial found out their virus had broken through, with once "undetectable" plasma HIV levels becoming detectable again and beginning to climb upward. What happened is uncertain, but it’s clear that being "undetectable" doesn't mean there is no viral replication taking place. In fact, recent studies show that most individuals who are "undetectable" by commercially available assays have detectable levels of virus using the more sensitive assays available in research laboratories. What's more, being "undetectable" by even the most sensitive test still means there are thousands of infected cells in the body. Even in the presence of highly active antiretroviral therapy that's working, we now know that HIV can continue to evolve and develop drug resistance.

Will I too break through on my therapy one day? The pertinent question, it seems, is not ‘if’ but ‘when.’ I had a scare a few months ago when the amount of the virus in my blood blipped up to detectable levels and then went back down again. After sequencing the virus from that unsettling episode, my doctors told me there was no evidence I had developed genetic resistance to the drugs I am taking. Because we now know that triple combination therapy can fail without the development of specific drug-resistance mutations, their consoling words left me cold. It is clear that I am playing a game of beat-the-clock with a wily adversary. To throw yet another roadblock in the way of the virus, I am thinking of adding a fourth drug to my already onerous ‘cocktail.’ If I still can’t hold back the virus and break through, I will have few (if any) therapeutic options left. There is almost nothing in the new drug pipeline that isn’t cross-resistant to the drugs currently on pharmacy shelves.

Will we ever be able to claim victory over the virus using the drugs we have now? All evidence to date suggests not. Even if I am successful in keeping the virus from replicating inside me, the virus has integrated its DNA into the DNA of many of my T-cells and macrophages and quietly sits waiting for its day in the sun. It will take a long time on therapy -- estimates range from 3 to 6 years -- for the cells harboring viral DNA to be rooted out of my body. Meanwhile, there are places in my body where the drugs can’t reach -- particularly the brain -- that act as sanctuary sites for my viral invader. And the clock is ticking. And ticking.

We haven’t beaten HIV, not by a long shot. We are in the eye of the storm, and that second wall of wind is likely to strike us with all the brutal impact of the first. Yes, we’ve seen our friends rise from their deathbeds. Miraculously, the disabled returned to work. We’ve bought ourselves some time, but we mustn’t fool ourselves into thinking the storm has passed. That’s the perilous seduction of the eye. If we craft national policy on AIDS based on this false sense of security -- an idea that the worst of this epidemic is over -- we’re going to get one hell of a surprise and another hell of a mess to clean up a few years hence.

The twentieth century has been one of incredible hubris when it comes to pestilence. We thought we had beaten common bacterial infections and diseases like tuberculosis through antibiotics, or like malaria through antiparasitic drugs and the destruction of mosquitoes with pesticides. In each of these cases, it is the bug that had the last laugh as it roared back evading our most sophisticated attacks. We can acknowledge the progress we have made in the treatment of HIV infection without succumbing to a premature triumphalism that will eventually undo us. We can take advantage of the virus’ momentary retreat to fortify ourselves and plan for the next battle. Here are a few that we can do right now:

  1. Expedite Drug Discovery. The cross-resistance profile of the drugs we have now means that people with HIV infection who are antiretroviral naïve have one or two rounds of triple combination therapy to use against HIV before they are defenseless against the virus. Those who have long histories of previous antiretroviral use may already have no therapeutic options left. We need to develop drugs that are effective against drug-resistant strains of HIV and that are directed against other targets besides the viral reverse transcriptase and protease. Drugs like these are years away. AIDS treatment advocates need to turn their energies toward drug discovery efforts and toward speeding the development of novel antiretroviral agents. We can begin by scrutinizing federally sponsored programs such as the National Institute of Allergy and Infectious Disease’s National Cooperative Drug Discovery Groups and its Strategic Program for Innovative Research on AIDS Therapies (SPIRAT); the National Cancer Institute’s Developmental Therapeutics Program and its Frederick Cancer Research and Development Center; the National Institute for General Medical Sciences’ structural biology program and the National Institute of Diabetes and Digestive and Kidney Diseases’ small integrase discovery program.
     
  2. Refine the Standard of Care. Many doctors are now recommending early treatment with triple combination regimens and the new federal guidelines for the use of antiretroviral therapy recommend their use in selected settings in early disease. While we know that the new therapies for HIV infection can extend survival and disease-free time in patients with intermediate and advanced HIV infection, we do not know if early use of these drugs will accomplish the same goals. It quite possible that the long-term effects of these therapies will cannabilize the short-term benefits of viral suppression. We need to know the relative merits of early versus deferred highly active antiretroviral therapy by conducting a clinical study to answer this question. Prescribing early intervention with these powerful agents when they may not be warranted may deprive patients of effective therapeutic options in the future. Adherence to these complicated regimens may become difficult to maintain over the long term leading to the development of multi-drug resistance in a large population of HIV+ individuals.
     
  3. Assess the Efficacy of New Diagnostic Tools. Genotypic and phenotypic assays of viral resistance are now in development and are already being used by a few physicians to guide the care of their patients. The usefulness of these tests in clinical practice is yet to be determined and needs to be assessed through clinical studies.
     
  4. Assess the Epidemiology of Drug Resistance. Thousands of people with HIV are already resistant to the full armamentarium of antiretroviral therapies. Many others who are now on triple combination regimens will also develop drug resistant strains of the virus. With the widespread use of these agents, transmission of multi-drug resistant strains of HIV is likely to occur. The National Institutes of Health should set up a program to track the prevalence of drug resistance and the incidence of transmission of drug resistant strains of HIV.
     
  5. Return to the Immune System. While we can suppress HIV replication to very low levels, we cannot restore immune systems ravaged by years of infection with the virus. We need to invest in basic and clinical immunological research which can help us understand the extent of immunological damage caused by HIV and ways to reverse the process. In addition, we need to understand more about the biology of cells of the immune system such as dendritic cells, macrophages, and brain macrophages or microglia which may provide sanctuary for HIV under HAART.
     
  6. Educate People with HIV and Their Primary Care Providers. While the treatment of HIV infection has always been complicated, the new therapies make the optimal treatment of the disease an even more sophisticated task. New resources need to be made available to train medical providers in the complexities of HIV polytherapy and to educate patients about the benefits and risks of these new regimens. A portion of these resources can be marshalled through the use of existing funds appropriated by Congress for the Ryan White Care Act and the AIDS Education and Training Centers. While a new funding line for treatment education is unlikely to be forthcoming from such a penny-pinching Congress, AIDS advocates have to be creative in identifying dollars for this important work. In addition, the pharmaceutical industry should establish a fund run by an independent and unbiased third party to support community based treatment education programs.