1. Would-Be Eradicatee Looks Forward to Still Uncertain Future
2. Data from the 23rd ACTG Meeting Document Reduction in Number of Opportunistic Infections in the Era of HAART
3. The Opportunistic Infections of ACTG 320

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.

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.

   
   

Since the approval and wide-spread use of protease inhibitors in mid-1996, AIDS clinicians and primary care physicians across the country all insist they are seeing a marked decrease in AIDS-related opportunistic infections (OIs) in their HIV-positive patients. Until now, this was all wonderful yet anecdotal news. At the 23rd AIDS Clinical Trials Group (ACTG) Meeting in Washington, D.C. (July 19-23, 1997), a number of investigators presented epidemiologic data which clearly demonstrate that the rate of most OIs has indeed fallen.

The most striking presentation, which one would have missed unless one happened to stumble into the Protozoa Pathogen Study Group symposium, came from Tulane University’s Rebecca Clark. Clark presented epidemiologic data from the CDC sponsored Adult Spectrum of Disease Cohort (ASDC) from December 1994 to July 1997. Baseline characteristics were used to group 1,181 patients before 1996 and 1,248 patients after 1996. A quick scan of the baseline characteristics revealed three important statistically significant differences between the groups: 1) The percentage of women in the latter group increased from 15.6% to 19.5% (p=0.01); 2) The percentage of gay/bisexual individuals in the latter group decreased from 49.7% to 43.1% (p<0.01); and 3) The latter group improved immunologically (53.5% of the individuals before 1996 had CD4 counts <50 cells compared to 43.5% after 1996 (p<0.01)). Although these data extend only through the first six months of 1997, it is presumed that the the trend will continue throughout the end of the year. When comparing the rate of the most common OIs, including Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) Mycobacterium avium complex (MAC), esophageal candidiasis, and wasting from 1994, 1995 and 1996 with those from the first six months of 1997, the decrease is staggering.

In comparing the 18 months before and after January 1996, however, the data reveal that only 5 of the 11 OIs have decreased significantly: MAC, CMV, KS, wasting, PCP. Decreases in the incidence of cryptococcal meningitis, toxoplasmosis, cryptosporidiosis, and esophageal candidiasis, by contrast, were not significant (although the reductions in meningitis and toxoplasmosis approached significance). Furthermore, the marked and visible decrease in opportunistic infections in Clark’s study did not occur until the calendar year 1997 -- even though 3 of the 4 protease inhibitors were approved and available by mid-1996. Is it enough to say that these decreases are solely due to the antiviral effect of triple combination therapy? Might there not be other factors involved, such as increased use MAC prophylaxis, steroid usage or dietary changes for the prevention of wasting, or a change in sexual behavior in order to avoid KSHV and thus Kaposi’s?

A preliminary data analysis of the OI events in ACTG 320 was presented by USC’s Judith Currier, an excellent young investigator who’s taking the ACTG by storm. ACTG 320 was Merck’s indinavir clinical endpoint study which randomized 1,156 patients with CD4 counts <200 and at a minimum of six months’ prior AZT therapy to add either 3TC (n=579) or to add both 3TC and indinavir (n=577). To no one’s surprise, ACTG 320 was stopped early because of statistically significant differences in deaths and AIDS events favoring the protease inhibitor-containing group. There were 60 OIs in the group that added one drug and 31 OIs in the group that added both 3TC and indinavir. A detailed analysis of the clinical events in ACTG 320 is currently underway (as well as a possible comparative analysis with ACTG 175). Nonetheless, it is probably safe to say that the incidence of OIs in the triple therapy arm of ACTG 320 is the lowest ever documented in a study of this size with this patient population. It will be interesting to see whether or not some of these OIs (i.e., PCP and MAC) developed in individuals on prophylaxis and also at what CD4 count. That is, Did increases in CD4 cell counts protect these individuals from new opportunistic infections?

CD4 cell increases and an "undetectable" viral load are one thing, but this decrease in life-threatening OIs is the proof of the pudding and arguably the reason we are finally seeing a substantial decline in AIDS deaths. Numerous studies have documented the deleterious effect OIs have on HIV-infected persons: the inflammatory cascade where one OI seems to lead directly to another; the independent predictability of at least six OIs to shorter survival; and the well-documented viral load surges which accompany many OIs. So, in the ineradicable mantra of Martha Stewart, this reduction in OIs is "a good thing."

Nevertheless, investigators at the ACTG meeting expressed caution that we are in a "honeymoon phase." Clinical follow-up of ACTG 320 was, after all, less than one year. And widespread use of protease inhibitors has just recently crossed the one year mark. There are many who fear that in 6 to 18 months we might see a substantial number of patients fail their protease inhibitor regimens (because of resistance and noncompliance) and experience anew a marked increase in the incidence of opportunistic infections.

If this is indeed to be the case, only effective OI prophylactic regimens, (TMP-SMX for PCP and clarithromycin or azithromycin for MAC) can insure patients with viral break-through and faltering CD4 cell counts protection from the opportunistic infection menace. Even then, prevention of CMV will remain problematic. Roche’s outrageously expensive oral ganciclovir (the closest thing we have to a prophylactic against CMV -- whatever happened to lobucavir?) is only truly effective in CMV DNA-PCR-negative patients (that is, those at the lowest risk of developing CMV disease). What are we to do with those high-risk patients with high levels of CMV DNA in their blood? Don’t look for any help from Basel. Roche execs are said to be reconsidering the potential market for its oral ganciclovir prodrug (RS-79070) now that the incidence of CMV disease appears to have fallen so. But such a short-sighted business decision would be, well, myopic. Even if this business is all about the bottom line, slowing or discontinuing the development of RS-79070 is (in as little as a year or two from now) very likely to be exposed as strategic miscalculation. Woe to s/he who wields that red pen.