Risk/benefit of HIV therapy 10 July 2003
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Peter J Flegg,
Physician
Blackpool, UK, FY3 8NR

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Re: Risk/benefit of HIV therapy

Once again the HIV dissidents and the HIV orthodoxy appear to be at an impasse regarding the risks and benefits of therapy. On the one hand, Carl Williams and Chris Tyler are apparently persuaded that the drugs are nothing but toxic poisons, with no merit or benefit whatsoever. This view is incorrect and unbalanced, but perhaps understandable in a world where the perception of risk can become so readily distorted that parents would rather their children face infections than be immunised, or will mutter into a mobile phone clamped to their ear about the unacceptable hazard from the mobile phone mast up the road, at the same time dragging on their umpteenth cigarette of the day.

The risk of harm from HIV therapy is real, but it is a risk well worth taking. We are not talking about some trivial complaint here, but a life-threatening and currently incurable illness. Since the late 1990s, the focus of therapy has shifted from using drugs that are as potent as possible to a strategy of using drugs that are as tolerable as possible while still remaining effective.

The dissidents' case is not advanced by confusing real with imaginary problems and describing them in lurid and emotive terms ("agonizing death of many thousands", "eating away the lining of the intestines", "fraudulent human trials"). Complete denial that therapy is associated with patients living longer, healthier lives does not help either. Carl Williams wishes to have references as to the efficacy of the drugs. I hope he takes the time to look at these studies and only then makes his mind up, rather than scouring the medical literature for the odd phrase that can be presented out of context as evidence to justify his predetermined convictions.

There are numerous clinical trials, and several meta-analyses of RCTs, which demonstrate the superiority of HIV therapy over no therapy (1-3). Carl Williams is living in cloud cuckoo land if he thinks it is ethical to conduct a RCT which is placebo-based on every newly available HIV drug. Drugs have to be tested against the most effective currently available therapy. But RCTs alone are not the only studies that show HIV therapy works, there is an abundance of data from large cohort studies, which provide a more realistic impression of how the drugs are used in clinical practice. These studies look at tens of thousands of patients and are remarkably consistent in demonstrating that the more drugs you take, the lower your risk of disease or death.(4-11). If you couple evidence like this with the evidence HIV physicians experience on a day to day basis in their clinics while treating patients and managing their side effects, the benefits of therapy are patently obvious.

Oh, and by the way, Carl Williams may indeed have cited recent papers about HIV drug toxicities (unlike Chris Tyler, who quotes only two references in 12 that were published in the last 5 years). In the first of these, the phrase "The indisputable benefits of therapy in patients with advanced disease are not so clear in asymptomatic patients with high CD4+ cell counts" appears and is actually cited by him. Well can I say now I agree with this entirely! His second reference quotes "In some patients, this [drug-related] morbidity could be worse than what one could expect from the progression of HIV-associated immune disease itself over the same period of time". Note the words "some" and "could" (not "most" and "will"). For his 3rd reference he quotes "more than two thirds of patients presented one or more clinical or laboratory adverse events which could have been due to antiretroviral treatment". Yes, adverse events can be frequent, but can also be minor, tolerable, self-limiting or even irrelevant (e.g. macrocytosis with zidovudine ). It is the lack of a suitable clinical context into which this statement is placed that makes me decry the "Google for -toxicity-" approach rather than a measured analysis of risk/benefit. This last quote came from the Swiss Cohort Study. Will Carl now accept the conclusions of the Swiss Study concerning efficacy of the drugs (11), or does he want to cherry-pick through articles until he encounters something that reinforces his confirmational bias?

References:

1. Staszewski S et al. Reductions in HIV-1 Disease progression for zidovudine/lamivudine relative to control treatments: a meta-analysis of controlled trials. AIDS 1997; 11:477-83.

2. HIV Trialists Collaborative Group. Zidovudine, didanosine and zalcitabine in the treatment of HIV infection: meta-analysis of the randomised evidence. Lancet 1999; 353: 2014-25

3. Jordan R et al. Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy. BMJ 2002; 324: 757-60.

4. McNaghten, A.D., et al. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS Diagnosis. AIDS 1999 13:13, 1687-95.

5. Kaplan, J., et al. Epidemiology of Human Immuno-deficiency Virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clinical Infectious Diseases, 2000; 30 (Supplement 1), S5-14.

6. Mocroft, A., et al. Changing patterns of mortality across Europe in patients infected with HIV-1. The Lancet, 352: 1725-30, Nov. 28, 1998.

7. Mocroft, A., et al. AIDS across Europe, 1994-98: the EuroSIDA study. The Lancet, 356: 291-96, July 22, 2000.

8. Palella, F., et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine, 338:13, 853-60, 1998, March 26.

9. DeMartino, M. et al. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. Journal of the American Medical Association, 284:190-7, July 12, 2000.

10. Dorrucci, Maria et al. Temporal changes in the rate of progression to death among Italians with known date of HIV seroconversion: Estimates of the population effect of treatment. Journal of Acquired Immune Deficiency Syndromes, 22:1, 65-70, Sept. 1, 1999.

11. Egger, M. et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: Prospective multicentre study. British Medical Journal, 315: 1194-9, Nov. 8, 1997.

Competing interests:   Attendance at meetings sposored by HIV drug companies