Sorting Out the Credit for Better Outlook in AIDS

Sorting Out the Credit for Better Outlook in AIDS

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Jan-Feb 99	Rank Last Period Nov-Dec 98
1	S.M. Hammer, et al., "A controlled trial with two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," New Engl. J. Med., 337(11):725-33, 11 September 1997. [15 U.S. and U.K. institutions] *XV174	35	1
2	H.J. Alter, et al., "The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease," New Engl. J. Med., 336(11):747-54, 13 March 1997. [NIH, Bethesda, MD; Genelabs Technologies, Redwood City, CA] *WM640	24	†
3	P.M. Ridker, et al., "Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men," New Engl. J. Med., 336(14):973-9, 3 April 1997. [Harvard Medical Sch., Boston, MA; Harvard Sch. Public Health, Boston; Brigham and Women’s Hosp., Boston, MA; U. Vermont, Burlington] *WR385	22	2
4	B. Pitt, et al., "Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)," The Lancet, 349(9054):747-52, 15 March 1997. [7 institutions worldwide] *WN124	22	7
5	F.J. Palella, et al., "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New Engl. J. Med., 338(13):853-60, 26 March 1998. [5 U.S. institutions] *ZD284	21	†
6	M.J. Alter, et al., "Acute non-A-E hepatitis in the United States and the role of hepatitis G virus infection," New Engl. J. Med., 336(11):741-6, 13 March 1997. [Ctrs. Disease Control, Atlanta, GA; Genelabs Tech., Redwood City, CA] *WM640	19	†
7	I.M. Graham, "Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project, " JAMA-J. Amer. Med. Assoc., 277(22):1775-81, 11 June 1997. [22 institutions worldwide] *XC499	18	†
8	P.D. Delmas, et al., "Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women," New Engl. J. Med., 337(23):1641-7, 4 December 1997. [Hop. Edouard Herriot, Lyons, France; Ctr. Clin. & Basic Res., Ballerup, Denmark; Lilly Res. Labs, Indianapolis, IN] *YJ871	18	10
9	M. Sano, et al., "A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease," New Engl. J. Med., 336(17):1216-22, 24 April 1997. [6 U.S. institutions] *WV332	17	†
10	J.R. Downs, et al., "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS," JAMA-J. Amer. Med. Assoc., 279(20):1615-22, 27 May 1998. [7 U.S. institutions] *ZP489	17	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

n early signal for the existence of the disease we now call AIDS (acquired immunodeficiency syndrome) was the unusual demand in the early 1980s for a drug used to treat what up to that point had been a rare infection, Pneumocystis carinii pneumonia. This was one of a series of opportunistic infections (OI) that take advantage of the severely lowered immunity found with human immunodeficiency virus (HIV) disease. For a long time the only drug available for tackling HIV itself was zidovudine (azidothymidine, or AZT). Today there is a wide range of agents on the market or in development. Often used in combination, these have been shown in trials (of which paper #1 is an example) to be effective clinically and against laboratory endpoints such as CD4+ T-lymphocyte counts and plasma HIV load. At the same time the image of AIDS has shifted from that of a universally fatal illness to one that might even be curable. Should we make the leap and say that the pharmacological advances and the better prospects for patients are causally linked? That is the question the HIV Outpatient Study investigators asked themselves (paper #5).

This is the real world of AIDS, as seen at nine U.S. clinics where data on 3,500 outpatients are recorded–as opposed to the sometimes artificial, albeit scientifically more disciplined, setting of the randomized trial. The data here relate to 1,255 of those patients. Death rates per 100 patient-years in this outpatient series fell from 29.4 in 1995 to 16.7 the following year and to about 12 in the first half of 1997. Rates for opportunistic infections with P. carinii, cytomegalovirus, and Mycobacterium avium complex also fell. And the use of combination anti-HIV therapy, especially regimens including protease inhibitors (see paper #1) rose. Statistical techniques were used to try to iron out the uncertainties about cause and effect that stem from the non-randomized design of the study.

Access to highly active antiretroviral therapy (HAART) is one problem, especially for those responsible for AIDS globally. Even in these clinics in major U.S. cities, attendees with private insurance were more likely to get a protease inhibitor than were those dependent on Medicare or Medicaid. Another pressing issue is when to begin HAART–i.e., as soon as possible, or wait? For some countries HAART simply cannot be afforded so its timing is academic. Brazil finds it difficult but at least is trying to offer modern treatments, so Science Watch asked Mauro Schecter, an AIDS specialist with the Hospital Universitario Clementino Fraga Filho in Rio de Janeiro, how he saw this paper.

"It is really an important paper," he agrees, while adding that it would be a mistake to say that "it proves the ‘hit early, hit hard’ strategy is correct." This is because the benefit in the study was seen in patients at risk of death or an OI. Graphs on mortality in British Columbia, Canada, and in Europe show that "the rates had already fallen by a comparable magnitude before protease inhibitors came into general use," Schechter adds. As its title shows, this article is indeed about patients with advanced disease (those selected already had CD4+ cell counts below 100 per cubic millimeter. For them, the authors suggest that an intensive HAART-type drug regimen that includes a protease should be "the standard of care for patients with advanced HIV infection."

It was left to the accompanying editorialists, Bernard Hirschel and Patrick Francioli, from Switzerland, to raise the timing issue more generally (NEJM 338:806-8, 1998)–and, like Schechter, they warn against extrapolating to less-advanced disease from the data offered by Pallella et al.

The question of timing (and intensity) is a scientific one, reflecting more than just a concern about drug costs and side effects, and the case for holding back has been set out by San Francisco AIDS specialist Jay A. Levy in a recent article (see The Lancet, 352:982-3, 1998).

Mr. David W. Sharp, MA (Cambridge), is Deputy Editor of The Lancet, London, U.K.