By Russell Schoch

April 1999

This letter is written to explain why I disagree with your medical advice to my son. Because of his recent viral load test, you said he should immediately begin treatment with the new combination of AZT and protease inhibitors.

Let me begin by saying that my first response to any proposed medical treatment is to ask critical questions. In 1989, when Andrew was invited to participate in a clinical trial of recombinant Factor VIII, I contacted several experts. I did not ask what was good about the new factor -- that had been pointed out. I asked instead what could go wrong, what possible harm there could be, how it could hurt my son. (My fears were assuaged, and Andrew took part in the trials.)

That same attitude guides me in thinking about anti-viral treatments for HIV-positive individuals. The simple explanation of why I am against the use of the new combination of drugs is that we've been here before: highly touted medical treatments which, after widespread use, show only ill effects.

AZT is the first instance. You'll recall the high hope placed, strangely, on this drug -- which was developed in the 1960s as chemotherapy for cancer but abandoned because it was too toxic for human use. Why, two decades later, an immune-suppression drug should have been put forward as treatment for an immune-suppression disease (AIDS) has mystified many people. But something was needed, and AZT was approved in 1987 after clinical trials, which had been unblinded, were ended prematurely. The most complete studies of this approval process have judged it harshly (John Lauritsen's Poison by Prescription: The AZT Story, and Bruce Nussbaum's Good Intentions; How Big Business and the Medical Establishment Are Corrupting the Fight Against AIDS.)

In the early 1990s, once the "magic" of AZT was beginning to wear off, with increasing concerns about its toxicity and its failure to help patients -- in fact, its ability to harm them -- other anti-viral drugs were sought for use in combination with AZT. Two "chemical cousins" of AZT, ddI and ddC, were rushed through incomplete trials on the basis of a surrogate marker, CD4 cells. (See Steven Epstein's account, "Activism, Drug Regulation, and the Politics of Therapeutic Evaluation in the AIDS Era: A Case Study of ddC and the 'Surrogate Markers' Debate,' Social Studies of Science, Vol. 27 [1997], 691-726).

Why use surrogate markers to approve drugs? Why substitute biological markers, oftentimes not very well understood, which can be measured (more or less accurately) only in a lab, for a more general examination of the actual effects on the health of the patient? Epstein is very clear about this: activists pressured the scientific establishment to use CD4 cells as a surrogate marker in order to assure the approval of a new drug (ddC). They were successful in achieving that end -- both ddC and ddI were approved in 1992. But it turned out to be a hollow victory: the drugs approved by this surrogate marker have not clinically benefited patients. And the CD4 count -- which had terrorized HIV-positive patients for more than a decade -- has now quietly lost significance.

The general notion of using surrogate markers in medicine--for cancer or cardiovascular disease, as well as for AIDS--has been criticized as inaccurate and therefore dangerous. (See, for example, Thomas R. Flemming and David L. DeMets, "Surrogate End Points in Clinical Trials: Are We Being Misled?," Annals of Internal Medicine, October 1996; Tim Peto, "Surrogate markers in HIV disease," Journal of Antimicrobial Chemotherapy, May 1996; and Jay Levy, "Surrogate Markers in AIDS research: Is there truth in numbers?" JAMA, July 10, 1996).

In 1993, a brief flurry of attention was given to research by Harvard medical student Yung-Kang Chow, who attacked what the press called "the Achilles heel of HIV" by combining AZT and ddI, plus either pyridinone or nevirapine. This "cocktail" worked wonders in test tubes -- but was soon found to be flawed, and was abandoned.

Next up was a new surrogate marker, "viral load." I put this in quotation marks because it is an inaccurate term if it is thought to be a direct measure of HIV in the blood, a common assumption. What it measures instead is RNA particles. The test "doesn't measure infectious virus, but is rather a surrogate for virus replication," says John Modlin of Dartmouth Medical School (quoted in Nature Medicine, October 1995).

One criticism of HIV as the cause of AIDS is that there is not enough HIV found in AIDS patients to do the damage HIV is said to cause. Only by using biology's most sophisticated amplifying technology, the polymerase chain reaction (PCR), was the "viral load" from AIDS patients seen to be dramatic enough to square with the theory. But Paul Philpott, in Reappraising AIDS (March 1996), points out that "100,000 HIVs measured by PCR correspond to only about 10 actual HIVs -- the same small amount that had previously been considered too low to be biologically significant. The other 999,900 HIVs are probably debris left over from HIV destroyed by immune mechanisms, defective (and thus inactive) virus produced by dysfunctional HIV, or artifacts of PCR technology."

The concept of viral load was given credence by papers on the viral dynamics of HIV in Nature (January 12, 1995) by David Ho et al. and by Xiping Wei et al. But the math and the science -- and the conclusions -- of these papers were severely criticized in 8 pages of letters from various scientists in the May 18, 1995 issue of Nature. And there have been fundamental criticisms ever since. In the February 1998 issue of Nature Medicine, Mario Roederer, of Stanford, wrote: "There has been considerable debate about this simple hypothesis [of Ho and Wei]. The Nature papers ignited a heated controversy that resulted in publication of several well-designed and informative studies, which raised serious doubts.... In this issue of Nature Medicine, reports by Pakker et al. and Gorochov et al. provide the final nails in the coffin for [Ho's and Wei's] models of T-cell dynamics...."

More recent research, by Warner Greene and others at UCSF and Berkeley, challenges "a core tenet in the scientific dogma of AIDS, a view that has dominated the field ever since a landmark 1995 study co-authored by famed New York AIDS expert David Ho." According to the report in the San Francisco Chronicle (January 5, 1999), their critique showed that the Ho thesis "was an illusion of faulty assumptions and poor measurement techniques."

Rarely in profiles of Time's "Man of the Year" do you see David Ho's thesis called "an illusion of faulty assumptions and poor measurement techniques," which years of criticisms have buried, with "the final nails in the coffin" now in place.

Ho used experimental protease inhibitors in the study that led to his notion of viral dynamics. Pharmaceutical companies had been working on protease inhibitors for HIV since the 1980s. But Searle abandoned its quest in November 1994 because (according to AIDS Treatment News, #210), "despite promising results in laboratory studies, two clinical trials have shown no indication of antiviral activity in people." Merck, according to the Wall Street Journal (February 25, 1994), also found out that its protease inhibitor failed as monotherapy. Roche's protease inhibitor, given to 400 patients for 18 months in trials, performed no better than a placebo (this was stated at a 1996 Gordon Conference on the chemotherapy of AIDS, although never publicly reported).

Hence, as was true of AZT, ddI, and ddC, the protease inhibitors did not work as monotherapy. But the allure of "combo's" remained. Buoyed by Ho's inaccurate viral dynamics theory, and using laboratory reports of their effects on "viral load," protease inhibitors were rushed through the FDA's approval process in record time -- again without ever having shown any clinical benefits for patients. The premise, and the promise, was that the new protease inhibitor cocktail "eradicated" the "viral load" from HIV-positive patients.

But what was new about "eradicating viral load"? A retrospective look at the European Delta study showed that the viral load of 40 percent of participants became 'undetectable' on the earlier combination therapy of AZT and ddI; even 5 percent did so on AZT monotherapy. "Apparently we have been reducing patients' viral load to undetectable levels for a decade -- but never knew it because the PCR technology has only recently been acquired and commercialized. If becoming 'undetectable' on nucleoside combos hasn't prevented progression to disease and death, why is 'undetectable' on the protease combinations impervious to failure -- except for the fact that we haven't followed patients long enough to see it?" ("The Morning After," by Mike Barr, Poz magazine, February 1997).

And is the protease inhibitor the key ingredient in the new cocktail, as most people assume? No. Nevirapine, the drug used by Chow in the early 1990s -- and also ineffective as monotherapy -- has been shown to be as effective as protease inhibitors in combination with AZT and nucleoside analogues. A February 1, 1999 UPI report from the 6th Conference on Retroviruses and Opportunistic Infections cited results from the Atlantic Study, which found "little difference in the ability of various three-drug combinations to control the virus, whether the regimens contain protease inhibitors or other drugs. A non-nucleoside drug, nevirapine, can produce equivalent results." Thus, all the credit given to protease inhibitors has not been warrented. It appears that any combination of drugs works (on surrogate markers) better than AZT alone.

This means that a flawed premise (Ho's viral dynamics), a misleading surrogate marker (viral load), and failed monotherapeutic drugs (protease inhibitors) -- mixed together with the failed and toxic AZT and its analogues -- are the basis of the latest anti-HIV treatment.

How have these drugs performed in the bodies of patients? Despite press reports of "miraculous" results in the first few months of treatments, researchers currently report that the cocktail doesn't work -- that is, it doesn't affect surrogate markers in laboratory tests -- in 50 percent of patients. Widespread use, however, has amply demonstrated the toxic effects of these drugs. (As one HIV-positive patient said to his doctor -- this was reported on the Internet -- "You take this for four days yourself and then tell me to take it the rest of my life!") There is a long and depressing list of "side effects" reported by users. A common complaint is gastrointestinal problems, including severe diarrhea. It seems that the "cocktail" not only inhibits the HIV protease, but essential intestinal enzymes as well, preventing the absorption of nutrients from food.

A dire "side effect" for hemophiliacs: On July 16, 1996, at the height of the hype for protease inhibitors, an advisory from the FDA warned health care providers that 15 HIV-positive hemophiliacs using the new protease inhibitors had episodes of spontaneous bleeding.

With that, I will conclude. One thing I have learned over the past decade is not to accept test-tube reports of drug-altered surrogate markers as a basis for medical treatment. It hasn't worked in the past with anti-HIV drugs, it is not working now with the new "cocktail," and I don't expect it to work in the future. I strongly oppose toxic drugs in general--and, in particular, when such drugs have not been shown to benefit anything but, however briefly, surrogate markers.

Given everything that has been discussed in this letter, I'm sure you will understand why I support my son's decision not to undergo treatment with the combination of AZT and protease inhibitors.

I would very much appreciate your response to my views.


Russell Schoch