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To: Joe E. who wrote (3965)	3/26/1998 11:47:00 AM
From: Henry Niman	Respond to of 6136

Here's the NEJM editorial: Progress and Problems in the Fight against AIDS ------------------------------------------------------------------------ In this issue of the Journal, Palella et al. provide evidence of a massive decrease in morbidity and mortality related to human immunodeficiency virus (HIV) infection. (1) Among 1255 study participants who had at least one CD4+ cell count of fewer than 100 cells per cubic millimeter before enrollment, deaths decreased by 75 percent (from 35.1 to 8.8 per 100 person-years) between early 1994 and mid-1997, and the incidence of AIDS-defining diseases decreased by 73 percent (from approximately 50 to 13.3 per 100 person-years). During this period, progressively more intense antiretroviral therapy was introduced into clinical practice. These improvements occurred not in a selected population of volunteers who were following a strict protocol but in a mix of outpatients who were receiving individualized treatment. Although this type of study is not without potential methodologic bias, the data join a growing body of evidence that the number of inpatients with AIDS has decreased while the number of outpatients has increased. (2) AIDS surveillance data from New York City show a sharp downturn in deaths: the rates of death from AIDS fell 29 percent from 1995 to 1996, and they fell a further 44 percent from 1996 to mid-1997. (3) Data from Canada, (4) France, (5) Germany, (6) and Switzerland (7) all indicate that HIV-related morbidity and mortality in the most severely immunosuppressed patients decreased by 60 to 80 percent after the introduction of more active antiretroviral therapy. In 1995 and 1996, CD4+ cell counts stabilized in the average patient, rather than fell, as had occurred during each previous year. (7) It is likely that double-nucleoside therapy was responsible for the declines in mortality in 1995 and 1996 and that the addition of protease inhibitors resulted in further benefit in late 1996 and 1997. These results constitute a major achievement in the treatment of HIV infection, but they also raise new questions and problems. Should we hit HIV early and hard? Among more than 3500 patients who were seen at participating clinics, the 1255 analyzed by Pallela et al. (1) had the most severe immunosuppression. Strictly speaking, the clinical benefit of intense antiretroviral treatment has been demonstrated only in this category of patients. Highly active antiretroviral therapy has radically changed such patients' lives. As one HIV activist said, "Instead of classes on how to write wills, we now need classes on how to find employment." Does it follow that the same benefit will be observed in patients with less advanced disease? Our current understanding of the pathogenesis of AIDS and the ease with which viremia can be suppressed when highly active antiretroviral therapy is started early argue in favor of treating all HIV-infected patients, including those with nearly normal immune systems. However, for such persons, the risk-benefit ratio is uncertain, given the relatively slow progression of the untreated infection and problems such as side effects, lack of compliance, drug interactions, and effects on the quality of life. Short-term side effects require laboratory surveillance and often necessitate substituting one drug for another. We are only now beginning to identify the long-term side effects. Surprisingly, the use of protease inhibitors frequently leads to lipodystrophy, with peripheral loss of fatty tissue and hyperlipidemia. (8) Although these effects may be shrugged off in life-or-death situations, they are likely to matter to young asymptomatic patients who care about their body image, and who may worry about the risk of cardiovascular disease in the years ahead. Protease inhibitors interact with many drugs, and such interaction may preclude optimal treatment of intercurrent disorders. We need to know much more about the long-term complications and the safety of the drugs used to treat HIV. Highly active antiretroviral therapy also means a patient must take so many pills that the quality of life is affected. This burden may jeopardize adherence to therapy, with a resulting loss of clinical benefit and the selection and possibly the dissemination of resistant viruses. We need simpler treatments. A recent trial tested stopping one drug of a triple-drug combination a few months after viremia came under control. Unfortunately, the failure rate, as indicated by increasing viremia, was unacceptably high. (9,10) What should be done when treatment fails to control viremia, as happens in as many as 40 to 50 percent of cases? The future of these patients is uncertain, and there is an urgent need to define appropriate treatment strategies. How do we assess in vitro resistance? When should the treatment be stopped or changed? The recent massive decreases in morbidity and mortality despite incomplete control of viremia suggest that protease inhibitors may have beneficial effects even without suppressing the virus, perhaps because the viruses with mutated, drug-resistant proteases are less virulent than those killed by the drugs. With protease-inhibitor treatment, CD4+ cell counts rise even when viremia is not suppressed, (11) which implies that highly active antiretroviral therapy should be continued regardless of the effect on viremia, at least until better drugs are available. As the threats of AIDS and death lessen for patients receiving highly active antiretroviral therapy, the desire for unprotected sex and for procreation reemerge. If treatment drastically decreases the viral load in the blood, it has a similar effect in genital secretions. Patients seek our advice about their infectiousness, but we are unable, at present, to provide clear answers. Encouragement about the capacity for work is easier to give, at least in the short term. For long-term prognoses, data and follow-up remain insufficient. If HIV infection is perceived to be a treatable disease, will people become careless? Campaigns aimed at preventing HIV infection should contain clear messages regarding the present limits of highly active antiretroviral therapy. It is also important to convince the public and politicians that currently available therapy is not the end of the story and that funding for research and prevention must be pursued. The final question is who can afford highly active antiretroviral therapy? This treatment costs at least $12,000 per year. When the therapy is used in patients with advanced HIV infection in developed countries, these high costs are largely offset by the reduction in complications of AIDS, with attendant decreases in costs for hospital care. Highly active antiretroviral therapy represents a breakthrough, but one that is not accessible to most of the people in the world who are infected with HIV. For developing countries, the price of the drugs will preclude the use of highly active antiretroviral therapy. A typical country in sub-Saharan Africa, where 10 percent of the population may be infected with HIV, spends only $10 per year for each citizen's health care. At current prices, treatment of all HIV-infected persons in such a country would cost more than 100 times the total health care budget. For the average patient in Uganda or India, highly active antiretroviral therapy is an inaccessible dream. For the health ministry of a developing country, it is a diversion from more pressing needs and a threat to more cost-effective programs to combat HIV, such as the targeted distribution of condoms or the treatment of the sexually transmitted diseases that facilitate the spread of HIV. (12) Nothing is likely to bridge the gap between the rich and the poor countries, despite the efforts of the Joint United Nations Programme on HIV/AIDS and countries such as Brazil to bring antiretroviral treatment to selected patients. Only prevention and perhaps someday a vaccine are likely to make a real difference. Bernard Hirschel, M.D. 12th World AIDS Conference CH-1207 Geneva, Switzerland Patrick Francioli, M.D. University Hospital CH-1011 Lausanne, Switzerland

To: Joe E. who wrote (3965)	3/26/1998 11:54:00 AM
From: Henry Niman	Respond to of 6136

Here's the abstract for the NEJM paper: Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection Frank J. Palella, Jr., Kathleen M. Delaney, Anne C. Moorman, Mark O. Loveless, Jack Fuhrer, Glen A. Satten, Diane J. Aschman, Scott D. Holmberg, the HIV Outpatient Study Investigators ------------------------------------------------------------------------ Abstract Background and Methods. National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. Results. Mortality among the patients declined from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid. Conclusions. The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies. (N Engl J Med 1998;338:853-60.) Source Information From Northwestern University Medical School, Chicago (F.J.P.); the Health Research Network of Apache Medical Systems, Chicago (K.M.D., D.J.A.); the Centers for Disease Control and Prevention, Atlanta (A.C.M., G.A.S., S.D.H.); Oregon Health Sciences University, Portland (M.O.L.); and the State University of New York, Stony Brook (J.F.). Address reprint requests to Dr. Palella at Northwestern University Medical School, 303 E. Superior St., Passavant Pavilion, Rm. 828, Chicago, IL 60611-0949. The investigators participating in the HIV Outpatient Study are listed in the Appendix. Appendix The HIV Outpatient Study investigators were as follows: A.C. Moorman and S.D. Holmberg (project officers) and J.C. Von Bargen, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta; F.J. Palella and C. Gardner, Northwestern University Medical School, Chicago; M.O. Loveless and K. McKettrick, Oregon Health Sciences University, Portland; B.G. Yangco, K.D. Halkias, and C. Lapierre, Infectious Disease Research Institute, Tampa, Fla.; D.J. Ward and R. Deighton, Washington, D.C.; J. Fuhrer and L. Aronson-Ryan, State University of New York, Stony Brook; J.B. Marzouk, R.T. Phelps, P. Joseph, and M. Rachel, Adult Immunology Clinic, Oakland, Calif.; R.E. McCabe, Fairmont Hospital, Oakland, Calif.; W.A. Alexander and S. Lingam, Southside HealthCare, Atlanta; K.A. Lichtenstein, K.S. Greenberg, P. Zellner, B. Widick, and C. Stewart, Columbia Rose Medical Center, Denver; D.J. Aschman, K.M. Delaney, and K.M. Ragland, Health Research Network of Apache Medical Systems, Chicago.