First it was kidney stones. Blood in the urine. Hyperbilirubinemia. Yellowed whites of the eyes. An unquantifiable array of quality-of-life issues. The occasional gastric reflux. Annoying but only infrequently life-threatening. A Letter to Physicians warned of the appearance of diabetes. Reports of hypogonadism emerged. Cholesterol and triglyceride levels sky-rocketed. Then came "Crix gut." "Protease paunch." Facial wasting: hollowed out cheek and eye cavities. Something called "buffalo hump": strange disfiguring accumulations of fat around the back of the neck and shoulders. In fact, the up-dated list of possible side-effects from Crixivan now includes: nephrolithiasis (kidney stones), hyperbilirubinemia, hyperglycemia (high blood sugar), acute hemolytic anemia (rapid breakdown of red blood cells), interstitial nephritis (inflammation of the kidney tissues), anaphylaxis (allergic reaction), increased bleeding in persons with hemophilia, alopecia (hair loss), liver failure, ketoacidosis, abdominal pain, nausea, diarrhea, vomiting, acid regurgitation, dry mouth, loss of appetite, dry skin, insomnia, taste perversion, rash, sore throat, skin discoloration, fatigue, weakness, flank pain and headache. And that's just from one drug. Forget the kidneys. What about the liver? And what are ritonavir, saquinavir and nelfinavir doing to the gastrointestinal tract? Most recently we've received reports of life-threatening anaphylactic shock (and several deaths) related to 1592 (abacavir). Then came word of DMP-266 (efavirenz) treated monkeys giving birth to one-eyed, cleft-palated young -- some without a brain! Add to this the peripheral nerve damage from ddI, d4T and ddC. The pancreatic toxicity from ddI and 3TC. The anemia/leukopenia from AZT and 3TC. And god knows what chromosomal damage from all of these impostors of the body's natural DNA building blocks, and one has to ask, At what point will the damage from these drugs outweigh the benefit?
Several clinical studies in the U.S. and Europe have been investigating the concept of a subtractive approach to anti-HIV therapy, in which people receive aggressive treatment ("induction" therapy) with three or four drugs for a period of time in order to try to suppress their viral load to below the limit of detection (anywhere from 50 copies/mL to 500 copies/mL). Then the study participants are switched to a less intensive one- or two-drug regimen ("maintenance" therapy) to try to maintain that suppression.
While the idea of so-called maintenance therapy has been controversial since it was first proposed over a year ago, there are a number of reasons worth investigating the possibility. In other fields of medicine -- and, indeed, in other areas of HIV medicine -- this induction/ maintenance method is well established. Many cancers and opportunistic infections are successfully treated with an initial period of intensive therapy, followed by less intensive maintenance therapy thereafter. If it is possible to successfully step down anti-HIV therapy in this way, the potential benefits might include:
- Reduced risk of long-term toxicities
- Reduced risk of the development
of resistance to multiple agents
- Less onerous daily regimens
- Lower cost
At the 5th Conference on Retroviruses and Opportunistic Infections in Chicago last month, data were presented from the first two induction/maintenance-type trials to produce results, one from France and the other from the U.S. Both were quick to fail.
Both trials started with the three drugs AZT, 3TC and indinavir (Crixivan). The French trial (ANRS 072 a/k/a "Trilege") enrolled 397 treatment naïve individuals and switched study participants after 12 weeks of induction to the maintenance regimens of AZT+3TC or AZT+indinavir. The American trial (ACTG 343) included 309 participants, both treatment naïve and AZT-experienced (more or less a 50-50 mix) and switched them to maintenance regimens (AZT+3TC or indinavir monotherapy) after 24 weeks' induction. Both trials were stopped early because the maintenance regimens were less effective than continuing the triple therapy, as measured by the proportion of participants with HIV RNA >500 copies/mL in the French study and >200 copies/mL in the U.S. trial (see table at top of first page).
Obviously, more sensitive assays could have been employed and study participants not switched until the lowest possible viral load threshold was crossed. But in a Trilege sub-analysis, even among those study participants whose viral loads were suppressed below 50 copies/mL, 19% on the AZT+3TC arm and 13.8% on the AZT+indinavir arm broke through after a mean of 8.5 months on the maintenance therapy regimen.
While not the hoped-for results, the Trilege and 343 results are far from the last word on the induction/maintenance model. Investigators for a similar U.K. induction/maintenance study, called ProCom, note that the duration of the induction phase may be of critical importance in determining the success or failure of such an approach. The U.K. study will also be using different drugs: nelfinavir, soft-gel saquinavir (Fortovase), ddI and d4T. A fourth study, "ADAM," of Amsterdam's Joep Lange will throw DMP266 into the maintenance therapy mix. Finally, a Glaxo-Wellcome study (curiously underwritten by the tax-payer funded ACTG) will explore a 36-week induction regimen of all four of G-W's antiretrovirals (AZT, 3TC, 1592 and 141W) in acute seroconverters. Maintenance regimens in the study (ACTG 371) will consist of double or triple combinations of these agents.
In reality, the study design of both Trilege and 343 were flawed from the outset. And more than a few enlightened lookers-on (certain AIDS activists and M.I.T.'s mathematical modeler Lawrence Wein among them) had vociferously predicted failure from the outset. Not only was 343's decision to randomly assign AZT pre-treated individuals to a maintenance regimen consisting solely of AZT+3TC a tad suspect, but Trilege's choice of a mere 3 months of induction therapy blatantly defied the current understanding of viral clearance in lymphoid tissue. As François Raffi, lead investigator for the Trilege study, confessed in a heavy French accent, "We now know from the data of Ashley Haase's group that even as late as 6 months into therapy there is still actively replicating HIV-RNA in the lymphoid tissue."
In a presentation last October in Hamburg, former NIAID researcher Giuseppe Pantaleo suggested it would be necessary to wait until participants have "undetectable" viral load in a series of lymph node biopsies before successfully reducing the number of drugs. His elegant algorithm calls for 12-18 months of induction therapy at which time serial lymph node biopsies would be performed utilizing the most sensitive techniques. If no RNA and no DNA are detected, Pantaleo says that stopping therapy altogether may be a legitimate option. If only DNA is detected, a less aggressive regimen should keep the virus suppressed, Pantaleo explained. On the other hand, if any evidence of on-going replication (i.e., detectable HIV-RNA) is found, Pantaleo believes that the original aggressive regimen would need to be continued.
Others argue that switching to entirely new drugs for one's maintenance regimen makes more sense than simply subtracting one or two of the drugs used as part of the induction regimen. ACTG 343's Diane Havlir went so far as to predict, "We may need to employ immune modulators in combination with antiretroviral agents."
In a March 13 letter to U.K. AIDS advocates, the ProCom organizers announced that after reviewing the results from Trilege and ACTG 343 they had decided to extend the induction phase of ProCom to 28-40 weeks, and that study participants will switch to the maintenance phase only after achieving two viral load results <50 copies/mL. The committee also decided to restrict recruitment to treatment naïve individuals. With perhaps a lingering hint of crow on her tongue, Havlir conceded that working out a successful induction/maintenance treatment model for HIV infection "will be much harder than we initially thought." A New England investigator, one of many in the Chicago Sheraton audience who had quietly looked on -- months ago -- while the 343 deck had been stacked to virtually assure its failure, observed, "Pity it took 300 patients to prove that." Pity, indeed.
Lower or Longer, Little Difference
(Percentage of Patients Breaking Through)
|Maintenance Therapy Group
||Duration of Induction
*Includes the 191 (of 277) Trilege study participants whose HIV-RNA was suppressed to <50 cps/mL
**Includes all 309 ACTG 343 participants (whose HIV-RNA was suppressed to <200 copies/mL)
The Agenda Ahead
TAG Policy Director and Recent McArthur Fellow Warns Against Premature Declarations of Victory
The plight of AIDS prevention
Mark Harrington, propelled further into the limelight by his recent selection as a recipient of a McArthur genius award, has been out on the lecture circuit of late. And as he tours the country he bears the burden of negotiating that ever so delicate balance between celebration and caution. Celebration over the treatment advances of the past two years; caution about the pitfalls that lie ahead and of the danger in claiming victory prematurely. Following are excerpts from his remarks.
As we enter 1998, it is timely to consider the unfinished business of AIDS activism. We have much to celebrate. Just 18 months ago, quite suddenly, HIV became a treatable disease. This treatment revolution has bought us a precious window of opportunity. But it would be a grave mistake to believe -- as some in the media would have us believe -- that the AIDS epidemic is anywhere near over.
Around the country -- and elsewhere in the world -- where people have access to the latest combination therapies, laboratory monitoring and treatment information, we have seen dramatic and continuing declines in AIDS-related opportunistic infections and deaths. But it would be a mistake to conclude -- as some have -- that the AIDS epidemic is over.
The Challenges of Antiretroviral Therapy: Resistance, Adherence, Access
We cannot afford to succumb to the premature belief that AIDS is under control. It it not. Our most difficult work lies ahead. We must begin planning immediately for the likelihood that the new treatment advances will be only temporary. Already, a full one quarter of the patients in David Ho's triple combo therapy study have had their virus rebound -- at least temporarily -- from "undetectable" levels. Protease combination therapy is not a panacea -- and becoming "undetectable" is no guarantee of staying that way.
It is becoming clear that once resistance develops to any single protease inhibitor, the chances of having an optimal response to any subsequent protease inhibitor are seriously diminished. The same problem appears likely to apply to the non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine and efavirenz (formerly known as DMP-266). The problem of cross-resistance is also turning out to greatly limit the efficacy of the new nucleoside analogue agent abacavir (formerly known as 1592U89). Thus, for the large and growing population of individuals failing on triple combination antiretroviral therapy, therapeutic options appear limited despite the likely approval -- or, at least, much broader availability -- of such new drugs in 1998 as abacavir, adefovir, efavirenz and amprenavir.
There is a very real danger that many people who don't need it yet or aren't ready for it will be put on treatment prematurely. While the dogma of "Hit hard" has clearly been proved, the "Hit early" part still begs the question: How early? The recent HHS treatment guidelines only evade the question by recommending that "treatment be offered" and that "the strength of the recommendation depends on the likelihood of progression as assessed by viral load and CD4 count." Furthermore, no clinical trials are yet planned to address this critical public health question. So we may never know the right time to start antiretroviral therapy in healthy asymptomatics.
Linked to this uncertainty is the increasing importance of strategies to enhance adherence to complex medical regimens by individuals on combination antiretroviral therapy. Since it still appears that HIV infection is likely to be lifelong, so will be treatment -- once it is irrevocably begun. Yet past experience with adherence even over short periods of time -- such as in combination treatment for TB or for organ transplant rejection -- is mixed at best.
If people aren't given the information and support they need to use the drugs properly, and if the drugs fail, the patients might be blamed. The only solution to this dilemma is more research, more treatment education programs for patients and physicians, and more money for health care. Yet treatment education programs remain tiny and inadequate within most AIDS service organizations, which were founded and grew in a very difference environment -- when AIDS programs focused either on primary prevention or on end-stage services and care.
We are also beginning to experience a crisis of solidarity within the AIDS community. For those with access to health care, treatment and information, AIDS can sometimes be managed. For many others, these interventions are not accessible. Our country is going through one of its periodic reactionary fits where life-saving services are denied to poor people (and recent immigrants), who are blamed for their plight. If we really care about ending AIDS, we must tackle the national health care crisis.
The Plight of AIDS Prevention
A safe and effective AIDS vaccine is still years -- or decades -- away. In the meantime, we must continue to relay on two cheap, low-tech approaches which have already saved more lives than antiviral therapy: the latex condom and the clean needle. Our government still refuses to fund these programs, and as a result, thousands of citizens become infected unnecessarily each year.
A dangerous idea which began circulating last year is the fantasy that triple drug therapy is a valid "morning after pill" for potential HIV exposure. This is a dangerous high-tech pipe dream for which no supporting data exist. It's a lot easier to use a 50 cent condom every time you have sex than to get infected and start taking a $20,000 a year "morning after" regimen for the rest of your life. The drug companies would love it, and we should fight it! Condoms may not be fun, but they are a lot more fun than triple combo therapy! And cheaper too.
Streamlining AIDS Research
Research advocates will have their hands full this year keeping the 1.5 billion dollar AIDS research effort sponsored by the National Institutes of Health (NIH) on track. After four valiant years at the helm, former Office of AIDS Research (OAR) director William E. Paul has returned to the laboratory to dedicate himself to the quest for an AIDS vaccine. While Dr. Paul built a strong foundation and helped restructure and streamline the previously fragmented NIH AIDS research effort, much work remains to be done. NIH still runs twelve inefficient, overlapping clinical trials networks to study new drugs for AIDS. The vaccine discovery effort needs the continuing supervision of Nobel Prize laureate David Baltimore and the AIDS Vaccine Research Committee -- and the promised opening of the new AIDS Vaccine Laboratory in 2000. The search for a new OAR director will take up the first half of the year, and it is critical that NIH not lose momentum in implementing the sweeping reforms recommended by the Levine Committee in 1996.
The NIH is also due for Congressional reauthorization in 1998, and the provisions empowering the OAR to oversee the AIDS research effort must be renewed if OAR is to continue as a strong central coordinating point for the 24 byzantine NIH institutes which conduct AIDS research. Moreover, the AIDS research budget remains under attack by some disease constituencies who feel it is more productive to attack the successes of AIDS research advocates rather than struggle alongside them -- and other disease groups -- to increase the entire NIH budget. Luckily, it appears that in 1998 there is bipartisan support in Congress for increasing the NIH budget by as much as 15% per year, which would double the overall bio-medical research budget by the year 2003!
AIDS As a Global Problem
Finally, we must remember that AIDS is a global problem. Last year, 1.5 million people died of AIDS. By the 2000 it will surpass malaria and tuberculosis as the leading infectious cause of death worldwide. The U.S. funds 85% of the world's AIDS research. It is up to us to ensure that the fruits of that research are not limited to only those who dwell within the fifty states.
TAG Takes on an Executive Director
On March 1, 1998 the Treatment Action Group (TAG) announced the appointment of Odell Mays as its first Executive Director. A Stanford and NYU alumnus and former director of the New York Peer AIDS Education Coalition, Inc., an organization dedicated to HIV prevention among street youth, Mays brings to TAG a background in both business and fiscal administration as well as AIDS advocacy. He began his career as a senior buyer for IBM and was later a tax consultant for Deloitte & Touche. He held several other corporate positions before leaving for the non-profit world in 1994 to become Director of Finance and Administration for the Center on AIDS, Drugs and Community Health at Hunter College Brookdale Campus. Mays previously served as a board member of Gay Men of African Descent and currently holds the position of treasurer of the Board of Directors of the New York City Lesbian and Gay Community Services Center. He has also been active for nearly a decade with God's Love We Deliver.
Mays said, "The level of commitment and passion in TAG is impressive, as is the focus, intensity and intelligence of TAG's staff, Board and volunteer work on issues related to AIDS research and advocacy. I am excited to be joining TAG's efforts to speed up AIDS research focusing on efforts to develop effective treatments for AIDS and a preventive vaccine."
TAG's policy staff welcome the addition of Odell as Executive Director to our efforts and believe he will help us to maintain our leadership role in formulating new policy responses to the AIDS crisis.