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Issue #162: February 2, 1998
FASTFAX is available by fax in the 215 and 610 area codes at no cost, or by mail anywhere for $20.00 per year, by calling 215-545-6868, and by E-mail by contacting and type the message SUBSCRIBE in the message section. Sources for some information in this issue include Journal of the American Medical Association, Journal of General Internal Medicine, Morbidity and Mortality Weekly Report, Reuters, New York Times, The Lancet.New Penn vaccine trial aims at "clearance" of HIV
Racial health gap worsens, studies say
Bad news on trials takes longer to publish
PCP drugs more common in "one-stop" clinics
Over-50 group surpasses young in AIDS reports
MAC prevention unavailable to many blacks, poor
HAART may worsen MAC infection
New Penn vaccine trial aims at "clearance" of HIV
A pilot clinical trial has begun in Philadelphia which uses a new approach to eliminating HIV in infected people.According to researchers at the University of Pennsylvania, the strategy involves a two-step process in which HIV-positive subjects are first treated with combination antiretroviral drug therapies to suppress viral replication, and then injected with a new plasmid DNA HIV vaccine.
The vaccine contains the HIV genes env, rev, gag and pol, which researchers hope will boost the immune system to achieve complete clearance of HIV from the body. The researchers plan to treat 21 HIV-positive subjects with this HIV DNA vaccine, manufactured by Apollon Inc., based in Malvern, according to a University press release
"The DNA vaccine approach...gives the immune system a stimulus similar to natural infection but without the risks of natural infection," Dr. Rob Roy MacGregor, principal investigator, told Reuters Health.
Dr. MacGregor's group performed a study several years ago with subjects in the initial stages of HIV infection who were given an earlier version of the DNA vaccine. "In that study, we did get improvement in some of the immune markers. The antibody levels went up statistically and the measures of lymphocyte response, the cell-mediated immune test, suggested that we might be getting a responses there as well." However, they detected no changes in CD4 cell counts or viral load.
Since then, he continued, it has been shown that the viral load and lymphocyte turnover is much more rapid than previously thought. "The economy of what is happening is much more brisk," as Dr. MacGregor put it.
Therefore, the strategy is now "...to try to dial down the CD4 turnover as much as we can, and then give the immune boost."
Overall, there are three "new wrinkles" in the current trial, he explained. Number one, it attempts "...to maximally suppress the viral turnover and therefore the CD4 turnover." This is expected to create a CD4 cell population with greater longevity which will be better able to battle residual virus.
Number two, the doses of vaccine will be higher than given in the previous trial. In this study, the starting dose is 100 micrograms of vaccine, which will ultimately increase to an even higher dose.
Number three, "...we're including more of the genes that are thought to be stimulatory of immune defense against HIV. Instead of using two HIV genes, this [vaccine] has four, the ones most thought to be associated with protection. We have been studying the envelope rev construct and the AVEG (AIDS Vaccine Evaluation Group) has been studying the gag/pol construct, he said, "...but no one has put the two together...in humans."
"I personally feel much more hopeful about this second trial than I did about the first one," Dr. MacGregor added. "We're hoping that this 'goosing' of the immune system...will be the second counterpunch in this one-two punch effort."
Racial health gap worsens, studies say
New York TimesA robust economy and years of government pressure have helped move minority groups closer to the mainstream. But when it comes to health, studies show a stubborn, daunting and in some respects growing disparity between black and white Americans.
For decades, blacks have suffered higher death rates from nearly all major causes. Although life expectancy has increased for all groups, differences persist. And government and academic research shows a widening gap between blacks and others in the incidences of asthma, diabetes, major infectious diseases and several forms of cancer.
The federal Centers for Disease Control and Prevention reports that from 1980 to 1994 the number of diabetes cases rose 33 percent among blacks, three times the increase among whites. The gap in cases of infectious diseases has grown by the same magnitude.
With breast cancer, the CDC reports that from 1990 to 1995 the death rate for all women fell 10 percent, from 23.1 per 100,000 to 21. But black women's higher rate did not budge from 27.5 per 100,000.
Similar numbers paint a bleak picture of the impact of AIDS on minority populations.
In Philadelphia, deaths among white people with AIDS dropped by 41% between 1995 and 1996, but only by 13% among African Americans, according to data released by the city's AIDS Activities Coordinating Office.
Over the 2-year period, three times as many blacks died from AIDS as whites.
The data is consistent with national trends, which showed that AIDS-related deaths among whites dropped by 21%, but only 2% among blacks.
The erosion of black Americans' health in relation to the health of Americans at large stands in stark contrast to blacks' advances in areas like jobs, education and housing that three decades of civil rights laws have helped promote.
In the economy of the 1990s, poverty among blacks has shrunk, and gaps in income have narrowed. Sociological barriers to economic progress like a high teen-age pregnancy rate have receded, too.
But blacks often receive less, and worse, health care than whites, analysts say, meaning that they are sicker than whites and typically die at about age 70, six or seven years earlier than whites.
"We have a two-tiered health care system," said Dr. Randall Morgan, an orthopedic surgeon and a former president of the predominantly black National Medical Association.
Limited education, violence and addiction remain partly to blame. But Clinton administration officials and analysts of health systems say they are finding growing evidence that race, discrimination and social and cultural factors influence the care people receive and, consequently, their health.
The chief White House adviser on health issues, Chris Jennings, said economic status was a big source of the gap. "But even if you control for that, race is huge," Jennings said. "If you pull out education, race is still huge."
The White House is grappling with new ways to address the problem, most likely in the president's budget proposal early next month. In response to a White House request, officials of the Department of Health and Human Services and the Health Care Financing Administration said they were compiling proposals to try to eliminate the gap after 2000.
Dr. Donald M. Berwick, a pediatrician in Boston and a member of President Clinton's commission on health care quality, said: "Tell me someone's race. Tell me their income. And tell me whether they smoke. The answers to those three questions will tell me more about their longevity and health status than any other questions I could possibly ask. There's no genetic blood test that would have anything like that for predictive value."
The growth of managed care, experts said, has had little effect. "The more we hear about the problems in the health care delivery system and managed care, the more the issues of minorities stand out," said Bailus Walker, health policy director for the Joint Center for Political and Economic Studies, which focuses on blacks.
Administrations since the '60s have been aware of the gap and have started dozens of programs, committees and conferences to tackle it.
The Department of Human Services has an Office of Minority Health, which among other activities publishes a newsletter, Closing the Gap. The department compiles ambitious annual reports on progress toward goals for 2000 to prolong healthy lives and reduce the disparities.
But the results are mixed. For many conditions that disproportionately touch blacks, including asthma, obesity, homicide, maternal mortality, diabetes and fetal alcohol syndrome, the report published in October shows the incidences not only falling short of the goals but also slipping in relation to the conditions in the late '80s and early '90s, on which the goals were based.
Morgan said government attempts to reduce the gap were modest and subject to sporadic financing. "We get a program, and then it's over," he said. "We can't get a sustained effort. The tragic thing is it's costing America more and more every day to have the premature babies -- not the ones who die -- who go on to drain the health system's resources."
Public health programs begun in Clinton's tenure have made little more headway against the gap than those of prior administrations, including Medicaid, the insurance program for the poor, and Medicare, the program for the elderly.
Programs that pay for prenatal care for mothers and nutrition and immunization for children have helped many additional children survive infancy. But deaths of black mothers in childbirth, although rare, jumped 48 percent from 1987 to 1995 (the rate soared in the late 1980s), compared with 7.6 percent for all mothers. And blacks still have two times the infant mortality rate of whites, a gap that has not changed in at least a decade.
Since the early '60s, the American Cancer Society said, black men's death rate from cancer rose 62 percent, compared with 19 percent for all American men. A gap in the incidence of prostate cancer has narrowed. But the incidence is 30 percent higher for black men, and 66 percent survive for five years, compared with 81 percent of white men.
In general, the nation has realized declining death rates from leading killers like heart attack, stroke and cancer. But blacks still suffer those and other disabling conditions sooner than whites.
As a result, new research sponsored by the National Institute for Aging shows that blacks enjoy 56 years of reasonably good health, eight years fewer than whites and Hispanic-Americans. In an institute survey, one-third of all blacks from 51-61 described their health as fair to poor, compared with one-fifth of all whites of the same ages.
Kenneth G. Manton, director of the Center for Demographic Studies at Duke University, who wrote an analysis of the survey, said: "If you look at the total population, you find a significant decline in chronic disability and institutionalization for people 65 and older. But if you break it down among blacks and whites, you find almost all the improvement is among whites."
Concern about the gap has entered White House planning for Clinton's last two years in office. It has risen with experts' doubts that the enactment last year of a five-year $24 million plan to provide care to half the 10 million uninsured children would help reduce the disparities.
Administration officials expect Clinton, in his budget message, to ask for additional money to improve minority groups' health. In addition, the officials say, he could ask for revisions of government health programs so that additional people like nurses and physicians in minority communities join in working on the stubborn roots of the gap.
The issue is also entering other arenas. The president's advisory board on race, which has been dwelling mostly on discriminatory barriers to economic opportunity, has begun soliciting testimony on health.
Berwick said he and other members of the health commission were urging the commission to include a proposal to close the gap in the panel's final report in March.
To curry support to close the gap, the president is likely to define the issue in terms of minority health, not simply black health.
Other minority groups suffer from some diseases more than blacks. American Indians have higher levels of diabetes. Hispanic-Americans tend to suffer more fatal and disabling strokes. Puerto Rican children have the highest incidence of asthma.
The CDC reports that in 1996, tuberculosis among Asian-Americans was nearly 15 times higher than among whites and nearly twice the level for blacks.
But as the largest minority group and the one with the highest death rates from most diseases, blacks arouse the most concern among experts.
"There is a minority group that is very disadvantaged with respect to health, and that's African-Americans," said Samuel H. Preston, a demographer and dean of the School of Arts and Sciences at the University of Pennsylvania. "It's not a minority problem. It's a black problem."
The intractability of the gap is stirring searches for explanations beyond the conventional one of disproportionately low income. Hispanic-Americans, too, are relatively poor and are much less likely to have health insurance than any other group. Yet the CDC finds that they stay healthy longer than non-Hispanic whites, as well as blacks.
Research has shown slight, apparently genetic, predispositions among blacks for prostate cancer, sickle cell anemia and underweight births. But analysts say the major disparities arise less from inherent differences among races than from attitudes toward the races and unequal care.
A study in October in The New England Journal of Medicine suggested something peculiarly American to being black and unhealthy beyond genes. For the study, two neonatologists in Chicago, Drs. James Collins and Richard David, surveyed the birth weights of all children born in Illinois from 1980 to 1995. They isolated the lowest-risk group of mothers, from 20 to 39, who were college educated, married to college-educated men, had prenatal care in their first trimesters and had no prior miscarriages or stillbirths.
The researchers found that 2.4 percent of the 12,361 American-born white mothers delivered underweight babies, compared with 3.6 percent of 608 mothers living in Illinois and born in sub-Saharan Africa, and 7.4 percent for American-born black mothers.
"These findings discredit the genetic theory of race as it applies to birth weight," the doctors said in a paper presented in November to the annual meeting of the American Public Health Association. "To understand this thing called race, we must turn our attention to the institutions and attitudes which perpetuate and justify unequal treatment of people on the basis of their physical appearance, language or culture."
In hospitals and clinics, said Sara Rosenbaum, director of the Center for Health Policy Research at George Washington University here, blacks often receive worse care than whites. "When you take black and white Americans," Ms. Rosenbaum said, "and exactly the same situation like being hospitalized for a heart attack and having the same insurance, the chance that the black patient will get the advanced care is much less than it is for the white patient. The medical system appears to treat them differently."
Analysts say solutions require attention to the health conditions of the very young, before the effects of poverty, toxic environments, bad diets, violence and untreated disease.
"Policy that only deals with people in their 50s is going to have a minor impact on eliminating differences because a series of health shocks has happened already," said James P. Smith, a senior economist at Rand Corp. who testified this month before the race commission.
Policy goals should also change, said Berwick in Boston.
"It isn't enough to say we're going to close the gap by equalizing services," he said. "I don't think that's the heart of the problem. It's not equality of access. It's equality of result that we should seek."
Bad news on trials takes longer to publish
While prompt publication of both positive and negative clinical trial results is important, new evidence shows that positive findings are published much sooner.Dr. John P.A. Ioannidis of the National Institutes of Health reviewed the times from enrollment to completion and from completion to publication of 109 efficacy trials performed by two trials teams for HIV interventions and sponsored by the NIH.
He reports in the January 28th issue of the Journal of the American Medical Association that "...even within multicenter trial groups of high efficiency, randomized efficacy trials are published more rapidly when results reach traditional levels of statistical significance." The median time from start of enrollment to publication was 6.5 years for negative trials vs. 4.3 years for positive trials.
"With some exceptions, most of this lag is generated after a trial has been completed," Dr. Ioannidis explains. For example, it takes, on average, only 1.7 years to publish positive results of a trial, but 3 years to publish negative results.
Dr. Ioannidis points out that this "publication lag" can "...affect evidence-based medicine and systematic reviews and may lead to spuriously larger treatment effects in early meta-analyses of the available evidence."
According to the NIH investigator, "Enthusiasm about the results of clinical research should not be based on its publication value....[as] nondefinitive trials may provide as important information as trials with high levels of statistical significance when seen in the context of other pieces of evidence."
PCP drugs more common in "one-stop" clinics
HIV-positive patients who attend clinics that offer a range of HIV-focused services in addition to primary medical care are more likely to receive prophylaxis for Pneumocystis carinii pneumonia (PCP), according to a report in the January issue of the Journal of General Internal Medicine."Provider experience in AIDS care has been linked to improved HIV patient survival," Dr. Barbara J. Turner of Jefferson Medical College in Philadelphia, said. "Little is known about the association of provider characteristics with delivery of PCP prophylaxis." In the current study, Dr. Turner's group evaluated 1,876 HIV-positive Medicaid patients treated at 125 clinics in New York.
Overall, 38% of the patients developed primary PCP and 44% received PCP prophylaxis. Dr. Turner's group found "...a striking association between the total number of clinic HIV-focused features and patient receipt of PCP prophylaxis." They estimated that a patient's likelihood of receiving PCP prophylaxis rose "...with the number of HIV-focused features offered by the clinic."
The "features" include case management, access to clinical trials, patient education programs, and access to programs that provide help in getting housing, substance abuse and mental health counseling, nutrition counseling, alternative therapies, etc.
Patients with complete Medicaid coverage prior to AIDS diagnosis and older patients were more likely to receive PCP prophylaxis, whereas women, drug users and patients with other chronic diseases were less likely to receive PCP prophylaxis.
Patients who attended clinics that had three or more HIV-related features had a 36% lower risk of developing PCP compared with patients who attended clinics with one or no HIV-related features. Based on these findings, the researchers support the efforts currently underway in New York to transfer HIV-positive Medicaid patients to managed care settings that offer HIV-focused features.
Over-50 group surpasses young in AIDS reports
An article on AIDS among persons aged 50 years or older in the January 23rd issue of the Morbidity and Mortality Weekly Report shows that persons in this age group accounted for 11% of all cases of AIDS-related opportunistic infections (AIDS-OI) reported to the Centers for Disease Control and Prevention in the 7 years from 1991 through 1996.The increase in AIDS-OIs was higher among older persons than among those aged 13-49 years (22% versus 9%) during the study period. The incidence of AIDS-OIs remained stable among homosexual men during this time, while among heterosexual men incident cases increased 94%. In men reporting injecting-drug use, the incidence rose 53%. The incidence of AIDS-OIs among men who received blood or blood products decreased 48% during the 7 years.
In the same period, the incidence of AIDS-OIs among women aged 50 years or older increased 106% for heterosexual contact and increased 75% for those who reported injecting-drug use. The incidence of AIDS-OIs among women who received blood or blood products during this time dropped 33%.
The CDC editors suggest that physicians may not test for HIV as soon in older persons as they do in those who are younger. This may explain the higher proportion of older persons with AIDS who die within 1 month of diagnosis. The editors also note that at least one survey of primary-care physicians shows that respondents "...were less likely to discuss symptoms suggestive of HIV infection or were less likely to counsel older patients for HIV testing than their younger patients."
Older persons also report a lower use of barrier protection during high-risk sexual encounters than younger persons, according to the MMWR study. CDC officials strongly urge increased HIV and AIDS surveillance among older persons as well as for those who are younger.
MAC prevention unavailable to many blacks, poor
UCLA researchers have reported that fewer than half of HIV-positive patients who meet the criteria for primary prophylaxis for Mycobacterium avium complex (MAC) actually receive it.Usually, those who don't receive protection against MAC are poor and people of color, the researchers said.
Primary prophylaxis for MAC has been recommended by the US Centers for Disease Control and Prevention since 1995 for patients with CD4 counts under 50 and no history of MAC. During a recent 14-month period, Dr. Steven Asch and colleagues at UCLA Medical Center, questioned 2,889 HIV-infected patients who receive regular medical care about MAC prophylaxis.
Preliminary results showed that of the patients who satisfied criteria for primary prophylaxis, only 41% received any MAC drug in the preceding 6 months. Use of MAC prophylaxis was significantly less common in patients with a low income, poor education, or lack of insurance and in ethnic minority groups.
The data also suggested that provider experience in treating HIV-infected patients did not appear to influence the use of prophylaxis, Dr. Asch said. He believes that removal of barriers through education of patients, physicians, and insurers may help increase the use of indicated prophylaxis for MAC, as well as for other opportunistic infections.
HAART may exacerbate MAC infection in advanced AIDS
Meanwhile, two reports, which appear in the January 24th issue of The Lancet, describe the effects of highly active antiretroviral therapy (HAART) upon the natural history of some common AIDS-related opportunistic infections. The first study reports the development of focal mycobacterial lymphadenitis following protease inhibitor therapy in patients with advanced HIV disease. The findings of the second report suggest that HAART can restore immunity to two GI pathogens in HIV-positive patients.In the first paper, Dr. Elizabeth M. Race and colleagues at Harvard Medical School in Boston, Massachusetts, describe "...a distinct clinical syndrome associated with the initiation of a protease inhibitor, sulphate, in patients with advanced HIV-1 disease."
Specifically, they described five patients with CD4 counts of less than 50 cells/microliter and subclinical Mycobacterium avium complex (MAC) infection who developed focal mycobacterial lymphadenitis and severe illness. All of the patients were afebrile and stable prior to initiation of indinavir, but within 1 to 3 weeks of starting indinavir "...all five patients required admission to hospital for severe, febrile syndromes of long duration, which were attributable to a previously subclinical MAC infection.
The authors think that the intense inflammatory reaction occurs as the number of competent immune cells rise and respond to the mycobacterial load. Based on these findings, Dr. Race's group suggests that screening and/or prophylaxis for subclinical MAC infection be performed "...before the beginning of protease inhibitor therapy in patients with advanced HIV infection."
In the second paper, an Australian team, led by Dr. Andrew Carr of St. Vincent's Hospital in Sydney, reports that, nine patients with HIV-related microsporidiosis or cryptosporidiosis experienced resolution of these conditions after beginning HAART.
Five patients had chronic microsporidiosis, three patients had chronic cryptosporidiosis and one patient was dually infected. Following HAART, all nine subjects "...had complete clinical response, gained a median 15 kg in weight, and ceased all antidiarrheal and antimicrobial therapies." At a median 13-month follow-up, five patients were still without symptoms, but "...four had recurrent diarrhea at 7-13 months (one with positive stool microscopy), associated with declining CD4 counts."
"The persistent CD8 cell and macrophage infiltrate, and the rapid time to relapse in patients with declining CD4 lymphocyte counts, suggest that neither infection was eradicated." Dr. Carr's group believes that although the most likely explanation for the improvements seen is immunologic restoration, immune function associated with HAART requires further investigation.
In addition to suppressing HIV infection, these two studies "...show that HAART also may exert an important effect on the natural history of opportunistic conditions," according to Dr. Kent A. Sepkowitz of the Memorial Sloan-Kettering Cancer Center in New York City.
Jan 26 In addition to suppressing HIV infection, these two studies "...show that HAART also may exert an important effect on the natural history of opportunistic conditions," according to Dr. Kent A. Sepkowitz of the Memorial Sloan-Kettering Cancer Center in New York City.
"The Carr paper has set the stage for a debate on the implications, for prophylactic treatment of opportunistic infection, of HAART-associated improvement to immune function." While it may be encouraging to discontinue OI prophylaxis, the psychological benefits of taking fewer pills will need to be balanced against the HIV-infected patient's safety, Dr. Sepkowitz points out.
"The Race paper shows that the single thing we know best in AIDS, the clinical presentation of opportunistic infection, may change fundamentally when immune function improves. Taken together, these reports show yet again that, even as therapeutic options improve, HIV infection continues to challenge and to surprise."
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