On and On into the Multiple AIDS Drug Era

On and On into the Multiple AIDS Drug Era

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Mar- Apr 98	Rank Last Period Jan- Feb 98
1	F.M. Sacks, et al., "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," New Engl. J. Med., 335(14):1001-9, 3 October 1996. [8 U.S. andCanadian institutions]	50	3
2	J.W. Mellors, et al., "Prognosis in HIV-1 infection predicted by the quantity of virus in plasma," Science, 272(5265):1167-70, 24 May 1996. [U. Pittsburgh, PA; Chiron Corp., Emeryville, CA	44	2
3	M. Packer, et al., "The effect of carvedilol on morbidity and mortality in patients with chronic heart failure," New Engl. J. Med., 334(21): 1349-55, 23 May 1996. [7 U.S. institutions]	35	8
4	G.S. Omenn, et al., "Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease," New Engl. J. Med., 334(18):1150-5, 2 May 1996. [8 U.S. institutions]	28	9
5	N.G. Stephens, et al., "Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)," The Lancet, 347(9004):781-6, 23 March 1996. [Cambridge U., U.K.; Papworth Hosp., Cambridge, U.K.; St. Thomas Hosp., London, U.K.; Brunel U., Uxbridge, U.K]	24	6
6	M. Packer, et al., "Effect of amlodipine on morbidity and mortality in severe chronic heart failure," New Engl. J. Med., 335(15):1107-14, 10 October 1996. [10 U.S. institutions	22	†
7	C.H. Hennekens, et al., "Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease," New Engl. J. Med., 334(18):1145-9, 2 May 1996. [Brigham and Women's Hosp., Boston, MA; Harvard Sch. Publ. Hlth., Boston, MA; Harvard U. Sch. Med., Boston, MA; U. Oxford, U.K.] *UG831	21	10
8	A. Schomig, et al., "A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents," New Engl. J. Med., 334(17):1084-9, 25 April 1996. [Technical U. Munich, Germany]	20	4
9	R.G. Will, et al., "A new variant of Creutzfeldt-Jakob disease in the UK," The Lancet, 347(9006):921-5, 6 April 1996. [Western Gen Hosp., Edinburgh, U.K.; London Sch. Hygiene Trop. Med., U.K.; INSERM, Paris, France; U. Gottingen, Germany; Ist. Super. Sanita, Rome, Italy; Erasmus U., Rotterdam, The Netherlands]	19	†
10	K. Masuko, et al., "Infection with hepatitis GB virus C in patients on maintenance hemodialysis," New Engl. J. Med., 334(23):1485-90, 6 June 1996. [6 Japanese institutions	19	†

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

By the time you read this the 12th World AIDS Conference will have finished in Geneva. The 11th conference, held two years ago in Vancouver, Canada, had ended on a hopeful note, at least for countries with well-funded health-care systems. Evidence was emerging that combinations of drugs active against the human immunodeficiency virus (HIV) could lower circulating HIV levels, even to the point of disappearance on currently available assays of viral load. Two groups, whose papers now edge towards the Top Ten, document some of the grounds for optimism. They are the AIDS Clinical Trials Group 320 Study Team (see S.M. Hammer, et al., New Engl. J. Med., 337[11]:725-33, 11 September 1997; currently at #12 with 19 citations during March-April 1998) and Roy M. Gulick and colleagues in the same issue (pp. 734-9; as of the March-April count this report had not yet attained "Hot Paper" status but seems certain to do so next period).

The first widely used, and for a long time the only, anti-HIV drug was zidovudine(azidothymidine or AZT), an abandoned agent dusted down and given new life by the Wellcome (now Glaxo-Wellcome) pharmaceutical company. Today there are many drugs that are active against various sites in the viral reproduction cycle of HIV; for example, recently launched is the non-nucleoside reverse transcriptase inhibitor nevirapine (Viramune).

The two trials in the September 11, 1997 issue of the New England Journal of Medicine compared a protease inhibitor (indinavir) combined with zidovudine plus lamivudine (also known as 3TC) with zidovudine plus lamivudine only; the second trial looked at indinavir alone as well. Not everyone who is HIV-infected has AIDS, so clinical trialists, as here, measure the speed of progress to AIDS and death. Now that measurement of HIV RNA in a blood sample has become so sensitive, another indicator of success is the HIV viral load in plasma, measured in "copies"/mL.

Combination therapy roughly halved the rate of progression and the mortality rate in one trial (#12) and it had a significantly greater impact on viral load in both studies.

The modern approach to HIV, using three or four or even five drugs in combination and trying to achieve a more potent antiviral effect while at the same time lessening the risk of resistance, is called "highly active antiretroviral therapy," or HAART. A reverse transcriptase inhibitor and a protease inhibitor seem to be key elements of HAART, and 1998 formularies list eight to ten agents.

Where AIDS is most prevalent (i.e., Africa) these drug combinations are least affordable. This point is well brought home by one of NEJM's deputy editors, Dr. Robert Steinbrook, in an editorial accompanying these two studies (pp. 779-80). A special federal program to help with drug costs for poor and uninsured AIDS patients in the United States was budgeted at $385 million last year, yet a worst-case scenario estimates that as few as one in eight eligible patients may be receiving this help. It is easy to run up an annual drug bill of $10,000 per AIDS patient.

The elements of HAART are not free from side-effects--for example, with various anti-HIV drugs, abnormal fat distribution ("buffalo hump"), pancreatitis, severe rash, and cardiac problems--but the clinical evidence of efficacy, hinted at in 1996, is sure to be cemented in Geneva. However, the affordability of combination regimens will once again be the specter at the feast. On June 29 in Geneva, the U.K.'s Department of International Development launched its book Care and Support for People with HIV/AIDS in Resource-Poor Settings. This work will never make the Science Watch Top Ten, but the issue it addresses deserves just as much attention as the clinical science in #12 and so many other journal articles, in my view.

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