Advertisement
The Body: The Complete HIV/AIDS Resource
Follow Us Follow Us on Facebook Follow Us on Twitter Download Our App
Professionals >> Visit The Body PROThe Body en Espanol
Read Now: TheBodyPRO.com Covers AIDS 2014
  
  • Email Email
  • Printable Single-Page Print-Friendly
  • Glossary Glossary

AIDS Treatment News
March 7, 1997

Contents:

  • Stanford NAC Study: Glutathione Level Predicts Survival
  • Glutathione-Depleting Drugs: Petition to the FDA
  • AIDS Survival: First Drop in Total Deaths in U.S.; Larger Drop in France
  • Protease Inhibitors: Major Study Stopped When 3-Drug Arm Proves Superior
  • Help Wanted: GMHC Treatment Education Director
  • San Francisco: Cattle Grazing, Reservoirs, and Cryptosporidiosis

    Stanford NAC Study: Glutathione Level Predicts Survival

    by John S. James
    A small randomized controlled trial of oral N-acetylcysteine (NAC) - organized primarily by Drs. Leonard and Leonore Herzenberg, both Ph.D., at Stanford University, and designed by them and Greg Dubs, Ph.D., who conducted the trial - was run in San Francisco in 1993 and 1994. A report from this study was published this week in the Proceedings Of The National Academy Of Sciences, USA1; it was also presented at a major immunology conference in San Francisco on February 22, receiving television and newspaper coverage. The basic findings were:

    1. For persons with a CD4 count under 200, an abnormally low level of glutathione - inside CD4 T-cells in the blood - was remarkably predictive of poor survival. (Glutathione is the major defense of those cells against oxidative stress.) Persons with a CD4 count under 200, who also had very low glutathione levels, had an estimated three-year survival as low as 20 percent - compared to 60 to 80 percent survival for those with CD4 below 200 but with adequate glutathione levels. (Survival results were presented for those with CD4 counts under 200, since in the three years after the blood measurement, there were not enough deaths to analyze in those with counts above 200. However, the survival difference was also statistically significant when everyone was included regardless of CD4 count.)

    2. Oral NAC helped to replenish low glutathione in blood cells. (This was at issue because of a widely circulated report, now shown by this study to be erroneous, that NAC was not bioavailable. Bioavailability was also shown in a recently published study from another group.2)

    Advertisement
    These findings alone do not prove that NAC is beneficial (since it would be possible that the low glutathione levels were only an incidental result of declining health, and not a cause of the decline). This study was not designed to test whether or not NAC was helpful, and it did not have enough volunteers to do so. However, followup studies two to three years later showed that persons who were given or chose to take NAC during the trial had considerably better survival than similar subjects who did not take NAC. But since the trial was not set up to make this comparison, the researchers emphasize that a larger controlled trial will be needed to determine for sure whether NAC has benefit.

    The results of the Stanford study could best be described under separate headings:

    1. glutathione levels as predictive of survival, without reference to NAC or other treatment; and
    2. a controlled trial showing the bioavailability of NAC; and
    3. uncontrolled observations suggesting that there may have been a survival benefit from taking NAC.

    Note: An earlier report of this study was presented in May 1996 at the Oxidative Stress and Redox Regulation conference at the Institut Pasteur in Paris. That presentation was described in AIDS Treatment News #250, July 5, 1996. See " For More Information: Paris Conference," below.

    The possible use of NAC to treat HIV disease was first suggested by Dr. Wulf Droge, in Heidelberg.

    Note: AIDS Treatment News may publish a followup article on NAC and its use. If you have information that should be considered, let us know.

    Glutathione Levels Predict Survival

    A total of 204 HIV-positive volunteers were screened for this study; 107 of them had a CD4 count greater than or equal to 200, and were excluded from most further analysis. Of the 97 who had a count less than 200, only 37 entered the NAC trial and had complete data to analyze. The 60 who did not enter the study are referred to as the no-trial cohort; the followup on these 60 provided the natural-history data on the survival consequences of low glutathione levels (in the absence of treatment attempting to correct the low levels).

    These 60 volunteers with a CD4 count under 200 did not enter the NAC trial for various reasons. Thirty nine of them were excluded because their glutathione levels were not low enough. (Since this trial was designed to study the effect of NAC on those with abnormally low glutathione levels, those with normal or near-normal levels were excluded. Since the volunteers had no way to know in advance whether or not their glutathione levels were low, many were screened who did not qualify for the NAC trial.) Others either declined to enter the study, were judged non-compliant, had a lab value outside the allowable range, or had some other protocol-defined exclusion. For each of these 60 people, a glutathione level was measured only once - and then survival was determined two to three years after that measurement.

    Glutathione levels were measured within individual cells, using flow cytometry - the same technology used to measure CD4 and CD8 cell counts. Blood cells from the patient were treated so that the glutathione within the cells was changed chemically, to a florescent substance which glowed when hit by certain laser light. The strength of the glow, indicating the concentration of glutathione in that cell, was measured as the cells were passed single file through a small tube, and the result for each cell was separately recorded by a computer. To help check that the technology was working correctly, the glutathione level in CD4 cells was correlated with that in the blood (measured by more standard chemical tests), and with that in CD8 cells, monocytes, natural killer cells, and B-cells; the glutathione levels turned out to be comparable no matter where they were measured. (The Herzenbergs developed the use of flow cytometry for medical purposes; their laboratory is among the best in the world in using this technology.) Unfortunately, the level of glutathione is difficult to measure, and therefore the test is only available for research at this time, not for practicing physicians.

    Two different statistical tests (logistic regression, and Kaplan-Meier analysis) were used to study survival differences related to glutathione levels in CD4 cells. In both cases, the results were highly statistically significant, showing that those with abnormally low levels had worse survival.

    The survival difference was large. The 60 patients in the no- trial cohort were divided into a high-glutathione group of 26 patients, and a low glutathione group of 34 patients. (The best cut-off value to divide the high vs. the low group was calculated by a statistical procedure called ROC analysis.) Three-year Kaplan-Meier estimates are about 60 to 80 percent survival in the high-glutathione group, vs. as low as 20 percent survival in the low-glutathione group. (Final figures are not available because some of the volunteers have not reached the three-year point yet; data are still being collected.) Everyone in both of these groups had a starting CD4 count under 200, and did NOT enter the randomized trial of NAC. The researchers told AIDS Treatment News that the glutathione level was particularly useful in predicting the survival of persons with low CD4 counts, even those with counts below 50. (Note that the three-year period usually started in 1994, before protease inhibitors and other recent HIV treatments were available; survival rates would be higher today.)

    Remember that these results do not prove that the low glutathione level necessarily CAUSED the worse survival. Glutathione levels can become abnormally low in many illnesses, not just HIV infection. At this time no one knows for sure whether the low glutathione levels help to cause the worse HIV survival, or are just incidental. Therefore, while the data suggest that measures to restore the missing glutathione may be helpful, this point is still unproven.

    NAC Bioavailability: A Controlled Trial

    NAC (N-acetylcysteine) has long been considered an "alternative" HIV treatment (which, in practice, means a treatment which is being used despite the lack of well-funded development). For several years it has been one of the most popular products sold in the AIDS buyers' clubs (it is also widely available in health-food stores). NAC is a chemical variant of the amino acid cysteine, which is found in most proteins in the diet; NAC is converted into cysteine in the liver, before reaching the general circulation. (Using cysteine itself as a dietary supplement can be harmful and is not recommended.)

    Glutathione is a peptide which consists of three amino acids: cysteine, glutamic acid, and glycine. Usually the cysteine is the one in shortest supply in the body; that is why taking NAC has been proposed by a number of researchers as an efficient way to raise glutathione levels. (See "For More Information: Paris Conference," below.)

    A major reason for the Stanford trial was to confirm that oral NAC does indeed raise the level of glutathione in CD4 and other immune-system cells. Due to a widespread misunderstanding of an earlier NAC study done several years ago at the U.S. National Institutes of Health, it has been widely believed by AIDS physicians that if NAC is taken orally, it is useless because almost none of it gets into the bloodstream. (For a short history of how this misunderstanding occurred, see "NAC: First Controlled Trial, Positive Results," AIDS Treatment News #250, July 5, 1996).

    A more detailed report of the Stanford trial is being prepared for a separate publication. Seventy eight volunteers were randomized to receive either NAC or placebo, but only 53 of them had full data available at the end of the trial. (This includes persons with CD4 count above 200, as well as those below 200; those in the latter group were included in the survival analysis.) By the end of the eight-week trial, average glutathione levels in whole blood were significantly raised in patients who were randomized to receive NAC, while the average level stayed the same for those randomized to placebo -- showing that the NAC was indeed bioavailable. (A different research group also found that NAC was bioavailable, in that it returned low levels of cysteine to normal, in blood plasma in persons with HIV and CD4 counts over 200.2)

    The Stanford study used a very high dose of NAC -- a total 3200 to 8000 mg per day, in divided doses. This dose was chosen because 8000 mg had been found to be less than the maximum tolerated dose in the National Institutes of Health study mentioned above -- and the protocol provided a standard way for volunteers to step down their dose if necessary. According to the researchers, lower doses may be sufficient for routine use. We talked to the Healing Alternatives Foundation, the buyers' club in San Francisco; they said that dose recommendations have varied, but they do not find anybody, or hardly anybody, using doses as high as those in the Stanford trial. Some people are taking 500 mg, two to four times a day (1000 mg to 2000 mg per day in divided doses); others take somewhat more. One of the researchers told us that some people take a low or moderate dose, but then add more NAC at times of stress, such as surgery or infection.There have been reports of high doses causing unpleasant side effects, including gastrointestinal distress or skin rashes; but the Stanford trial found that these reactions occurred equally in the NAC and placebo groups. (The side effects could be due to other substances in the NAC or placebo formulation, which ordinarily is used at a lower dose.) Neither the Stanford trial nor the earlier NIH trial found any serious adverse effects of NAC. Unfortunately there is no dose-response data (from the Stanford study or otherwise) to show whether or not higher doses are more effective in raising abnormally low intracellular glutathione levels, or whether lower doses are sufficient. Nutritionist Lark Lands, Ph.D., told AIDS Treatment News that gastrointestinal effects are reduced if NAC is taken with food -- and that, unlike some amino acids, NAC does not need to be taken on an empty stomach for good absorption.The bottom line is that there is no general agreement on the best dose and usage of NAC. Different doses and regimens are common -- but all the doses in common use are lower than those in the Stanford trial.

    NAC and Survival: Uncontrolled Data Only

    While the NAC study reported here included a controlled trial, that trial was not designed to test whether using NAC could provide clinical benefit. One reason is that the controlled trial was too small; only 37 volunteers with CD4 count under 200 completed the trial and have full data available for analysis. Also, the controlled trial (NAC vs. placebo) lasted only for two months, and then the participants were offered six months of open-label NAC, which nearly all chose to accept. Therefore, the best the researchers could have done was to compare six months vs. eight months of NAC; even with a much larger trial, it might be hard to detect a three-year survival difference between two arms which were so similar.Although this trial cannot provide controlled data on whether or not use of NAC can improve survival, it was noticed that those who took NAC had considerably better survival than would have been expected based on their CD4 counts and glutathione levels. To investigate this, the researchers retrospectively collected two matched groups, a NAC group (25 volunteers) and a no-NAC group (19 volunteers).The 25 in the NAC group were all enrolled in the NAC trial.

    Thirteen of them were randomized to NAC, and the other 12 were randomized to placebo for the 8-week controlled study, but then chose to take NAC during the 6-month open-label period.The 19 in the no-NAC group were those who met the basic criteria for entry into the trial, but for various reasons did not take any significant amount of NAC. "Three completed the placebo arm and declined open-label NAC; 9 left the trial, mainly within a week, citing symptoms such as nausea and rash, which were similar to symptoms reported by subjects who completed the trial; five declined to enter for personal reasons; and 2 were disqualified for trial entry only because they had recently changed their reverse transcriptase inhibitor regimen."1 There were no significant differences between these groups in "absolute counts and (glutathione) levels for CD4 and CD8 naive, memory, and overall T-cell subsets, and for B cells, monocytes and NK cells; hematocrit and other clinical laboratory tests; Karnofsky score; age, weight, and previous history of opportunistic infections. Of over 60 measurements tested, only plasma thioredoxin levels showed a significant difference between the NAC and no-NAC groups (the NAC group was lower, p=0.01)."1Kaplan-Meier estimates for survival showed a statistically significant advantage for the NAC group (p=0.002). For the group that took NAC for six to eight months, mortality was pushed back by about a year -- even in this group which started the trial with a low probability of survival, due to having both a low CD4 count and a low glutathione level. When the first death occurred in the NAC group, about half of those in the no-NAC group had died.The limitation of this data, of course, is that it is retrospective -- and membership in the NAC vs. no-NAC group was determined in large part by self-selection."The data from our study, taken as a whole, is consistent with low glutathione being associated with poor survival," said Leonore Herzenberg, one of the principle designers of the study. "The major question now is whether this low level is only incidental, or is it a cause of the poor survival? The fact that those who took NAC survived longer than a matched group which did not is consistent with the low glutathione level being a cause [of increased mortality]. But a controlled study designed to answer this question will be necessary for proof."

    Comment: Where Do We Go from Here?

    The published paper notes that, "If these findings are confirmed in prospective, long-term trials, they will provide a foundation for the use of NAC as an inexpensive, nontoxic adjunct therapy for HIV/AIDS, potentially valuable even in remote locations where only minimal medical supervision is available."The problem now is how to get definitive evidence on whether or not NAC improves survival of certain persons with HIV (those with low intracellular glutathione levels). To get this evidence, it would be necessary to run a larger and different survival trial -- which for many reasons would be difficult to do. Persons would have to be randomly assigned to take either NAC or a placebo, to see if those given NAC lived longer. There would be a number of practical obstacles:

    • Volunteers who had given informed consent would realize that they could easily obtain NAC on the side. Ways of preventing access -- such as running the trial in a developing country where healthcare was not available -- would present ethical problems.

    • Because protease inhibitors and other recent advances in HIV treatment are reducing AIDS death rates, it would be more difficult to show a survival difference in such a trial. (Volunteers in both arms of the NAC study would have to be allowed to use standard treatments, of course.)

    • No validated, accepted "surrogate markers" are available for such a trial. NAC is not an antiretroviral, and would not be expected to have any dramatic effect on viral load.

    • Because NAC is low cost and readily available, there is little incentive to study it. Therefore it would be difficult to finance the trial.

    Whether or not a controlled trial is workable, patients might consider using NAC without additional trial results, since there is little "down side" because this treatment is safe and inexpensive. The Stanford study(1) also showed that persons with HIV -- and especially those with a CD4 count under 200 -- are likely to have substantially lower intracellular glutathione levels than those who are HIV negative. The more advanced the HIV disease, the more likely it appears that intracellular glutathione levels may be in what seems to be a dangerous range. No test for glutathione is yet available for practicing physicians -- but since there is little reason not to use NAC, people may consider using it just in case their levels are low.

    This study and others also suggest that use of drugs which are known to lower glutathione -- such as acetaminophen, contained in Tylenol(R) and many other pain relievers -- be minimized or avoided by persons with advanced HIV infection. (See "Glutathione-Depleting Drugs: Petition to the FDA", below.)

    Drinking alcohol also lowers glutathione levels. In 1993, an FDA advisory committee recommended that the FDA issue a warning that acetaminophen could be dangerous with high alcohol use, because it could depress already-low glutathione levels. (An extreme deficiency of glutathione will damage the liver and kidneys, and can cause death.) The FDA did not require the warning, however -- probably because many experts wanted a broader investigation, including aspirin and other drugs, to be completed first.

    For More Information: Paris Conference

    A major conference about redox (oxidation and reduction) chemistry in AIDS and other diseases took place May 21-24, 1996 at the Institut Pasteur in Paris. The meeting, "Oxidative Stress and Redox Regulation: Cellular Signaling, AIDS, Cancer, and Other Diseases" divided the presentations into the following topics:

    • Oxygen free radicals: origin and targets.
    • Reactive oxygen species and cellular mechanisms: cell
    • differentiation, proliferation, apoptosis.
    • Transduction mechanisms.
    • Oxidants and intracellular signaling.
    • Antioxidant regulation in biological systems.
    • Oxidative stress and AIDS.
    • Oxidative stress, cancer, and other diseases.

    N-acetylcysteine (often spelled N-acetyl-cysteine) is mentioned in about 30 of the abstracts presented at the conference.

    The program and abstracts are available at http://www.immunet.org; on that page, select "Redox Conference Abstracts" in the directory. You can search for abstracts containing one or more key words; for example, try looking for "acetylcysteine" (and also for its other spelling, "acetyl-cysteine").

    References

    1. Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, and Herzenberg LA. Glutathione deficiency is associated with impaired survival in HIV disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA March 4, 1997; volume 94, number 5, pages 1967-1972.

    2. Akerlund, B., C. Jarstrand, B. Lindeke, A. Sonnerborg, A.-C. Akerblad, O. Rasool. Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo- controlled trial. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY 1996; volume 50, pages 457-461.

    Glutathione-Depleting Drugs: Petition to the FDA

    by John S. James

    Recently Leonore A. Herzenberg (one of the authors of the NAC/glutathione study described above), and this writer, submitted a petition to the FDA, asking that it investigate whether acetaminophen and other glutathione-depleting drugs should carry a warning label telling users that there may be more risk for HIV-infected persons (especially for those with advanced disease) than for the general public. The petition process is a formal mechanism for citizens to request an FDA investigation of a matter which may affect public health.

    Our petition is a three-page letter, which includes 9 references and several enclosures. The full text follows:

    A series of studies over the last 6 years have demonstrated a pronounced glutathione (GSH) deficiency is frequent in HIV- infected adults and children and tends to become more pronounced as HIV disease progresses (see enclosed reporting and references). Recent studies document this progressive loss of GSH in peripheral blood lymphocytes of HIV-infected subjects at different stages of the disease, and demonstrate that GSH-deficient subjects with CD4 T cell counts below 200/ul of blood (i.e., with CDC-defined AIDS) are substantially more likely to die within 2 to 3 years than comparable subjects with GSH levels in normal range (Herzenberg et. al., manuscript enclosed).

    We bring this GSH deficiency to your attention because certain commonly available drugs, notably acetaminophen, tend to deplete GSH and are potentially more toxic to GSH- deficient individuals Therefore, we are concerned that such drugs may be more dangerous for HIV infected individuals than previously thought. Specifically, the use of such drugs in the upper level of the safety range for uninfected individuals could be harmful to people with HIV infection, especially with AIDS.

    For the above reasons, we respectfully request an investigation into this matter to determine whether acetaminophen and other GSH-depleting drugs should be labeled with a utilization warning for HIV-infected people. We recognize the value of these drugs and believe it would be overly drastic to remove them from circulation or prevent access for HIV-infected individuals. A properly worded package insert warning should be adequate to prevent misuse by these individuals.

    We would appreciate action as promptly as possible on this petition. Acetaminophen is widely used within the HIV community often with physician's blessing and no caution with respect to overutilization. Many individuals consider it a totally safe drug that has only minimal consequences when overutilized. We hope that action by the agency will correct this impression and provide proper guidelines for utilization by HIV-infected people. Current evidence suggests that such action could be lifesaving.

    (signed):

    Leonore A. Herzenberg, Professor of Genetics, Stanford University School of Medicine

    John S. James, Editor and Publisher, AIDS Treatment News

    PS. We have included several articles demonstrating GSH depletion in HIV-infected people and/or exploring the consequences of GSH depletion and repletion in model systems and HIV infected individuals. You will note that in a number of these studies, investigators use N-acetylcysteine (NAC) to replenish GSH. We and others (Herzenberg, et. al., Akerlund et. al., see enclosures) have recently completed trials demonstrating that NAC replenishes GSH in these individuals. In addition, our study includes monitoring data (not placebo controlled) indicating that GSH replenishment may be beneficial for HIV-infected individuals and hence strengthening the link between GSH depletion and poor prognosis in HIV disease. This petition, however, does not concern NAC administration. It is being submitted solely to request that the agency consider requiring the inclusion of appropriate warnings for HIV-infected people with respect to utilization of drugs that may deplete glutathione. Enclosures:

    1. Herzenberg, Leonore A., Stephen De Rosa, J. Gregson Dubs, Mario Roederer, Michael T. Anderson, Stephen W. Ela, Stanley C. Deresinski, and Leonard A. Herzenberg. 1997. Glutathione deficiency is associated with impaired survival in HIV disease. PROC. NATL. ACAD. SCI. U.S.A., 94: 1967-1972;

    2. Akerlund, B., C. Jarstrand, B. Lindeke, A. Sonnerborg, A.- C. Akerblad, O. Rasool. 1996. Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo- controlled trial. EUR J CLIN PHARMACOL ., 50:457-461;

    3. Staal, Frank J.T., Stephen W. Ela, Mario Roederer, Michael T. Anderson, Leonore A. Herzenberg and Leonard A. Herzenberg. 1992. Glutathione deficiency and HIV infection. THE LANCET, 339:909-912;

    4. Staal, Frank J.T., Mario Roederer, Dennis M. Israelski, Jeff Bubp, Larry A. Mole, Dennis McShane, Stanley C. Deresinski, William Ross, Howard Sussman, Paul A. Raju, Michael T. Anderson, Wayne A. Moore, Stephen W. Ela, Leonore A. Herzenberg and Leonard A. Herzenberg. 1991. Intracellular glutathione levels in T cell subsets decrease in HIV infected individuals. J AIDS RES. AND HUMAN RETROVIRUSES, 8:305-311;

    5. Buhl, Roland, Kenneth J. Holroyd, Andrea Mastrangeli, Andre M. Cantin, H. Ari Jaffe, Faith B. Wells, Cesare Saltini, Ronald G. Crystal. 1989. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. THE LANCET (December 2, 1989) ii: 1294-1298.

    6. Eck, Has-Peter, Helmut Gmunder, Martin Hartmann, Detlet Petzoldt, Volker Daniel and Wulf Droge. 1988. Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1-infected patients. BIOL. CHEM. 370:101-108;

    7. Smith, C.V., T.N. Hansen, I.C. Hansen and W.T. Shearer. 1990. Abstract: Glutathione concentrations in plasma and blood are markedly decreased in HIV-infected children. Sixth International Conference on AIDS -- San Francisco, Friday 22 June 1990 II:368 (Abstract #2058);

    8. Selected references relevant to GSH deficiency and HIV/AIDS [a list of 27 references];

    9. Dubs, John Gregson, Malcolm Zaretsky, Stan Deresinski, Mario Roederer, Stephen De Rosa, Leonore A. Herzenberg, and Leonard A. Herzenberg. N-acetylcysteine restores glutathione in whole blood and in CD4 and CD8 T lymphocytes of HIV- infected persons in a placebo-controlled trial. In preparation (not enclosed).


    AIDS Survival: First Drop in Total Deaths in U.S.; Larger Drop in France

    by John S. James

    On February 28 the U.S. Centers for Disease Control and Prevention reported that, for the first time, the total deaths from AIDS had dropped in the U.S. The decline was 12% from the first six months of 1995 to the first six months of 1996.

    A CDC synopsis attributed the decline in deaths to "improvements in recent years in treatments which delay the progression of HIV and prevent opportunistic infections, coupled with the success of prevention efforts in slowing the growth of the epidemic overall. While it is too soon to determine the impact that protease inhibitors, as part of combination therapies, will have on these trends, these therapies promise to further lengthen the lifespan of persons living with HIV."

    However, the total number of new AIDS cases diagnosed may still be increasing. In 1995 (the latest year for which an estimate can be made) the number of new cases increased 2% over the previous year -- a smaller increase than in earlier years.

    Other major findings:

    • "In 1996, non-Hispanic blacks accounted for 41% of adults reported with AIDS, exceeding for the first time the proportion who were non-Hispanic white."
    • "Women accounted for an all-time high of 20% of adults reported with AIDS."
    • The decline in deaths from the first six months of 1995 to the first six months of 1996 varied by region of the country. The decline was 16% in the West, 15% in the Northeast, 11% in the Midwest, and 8% in the South.
    • By ethnic group, the decline in total deaths was 21% among non-Hispanic whites, 2% among non-Hispanic blacks, 10% among Hispanics, 6% among Asians/Pacific Islanders, and 32% among American Indians/Alaskan Natives.
    • Total deaths decreased 15% among men, but increased 3% among women.
    • Deaths decreased 18% among men who have sex with men, and 6% among injection drug users -- but increased 3% among persons infected through heterosexual contact.

    The full report is available through the CDC home page, http://www.cdc.gov.

    Comment: While the total number of deaths obviously reflects access to care, it also depends on the total number of cases. From 1995 to 1996 there was a large increase in the total number of persons diagnosed with AIDS who were infected heterosexually -- usually women infected by partners who used injection drugs. This would account for part of the disproportionate increase in the number of deaths among women.

    France Reports 25% Drop in Deaths

    On March 1, France reported a 25% reduction of AIDS deaths, from 1995 to 1996. (Unlike the U.S. figures, the French statistics included all of 1996, not only the first half.) France also reported a 21% reduction in diagnosed AIDS cases from the first half to the second half of 1996.

    The Health Ministry attributed the reduction in deaths to "the wide distribution of new treatments."

    Comment

    In comparing the French vs. the U.S. death statistics, it is important to remember that -- for better or for worse -- the U.S. is a much less centralized society than France, much less controlled by the central government. This could affect the comparison in many ways:

    • The U.S. could not report statistics for all of 1996 at this time, because the reporting would be too incomplete. France could report for the whole year. Therefore its survival statistics could reflect the impact of protease inhibitors much more than the U.S. statistics, which so far only looked at the first six months of 1996.

    • The U.S. has much greater variations in medical care than many other industrialized countries. In many parts of the U.S., the quality of AIDS care is likely to be very poor. New treatments could therefore take longer to impact the death rate.

    • The 21% decrease in France in the number of new cases diagnosed -- compared to increasing new cases in the U.S. -- might reflect inadequate U.S. AIDS prevention programs, due to political interference. These figures need attention, because they might help to document the cost of Federal mismanagement, and the extent of possible improvement if Congress would let health professionals do their job.


    Protease Inhibitors: Major Study Stopped When 3-Drug Arm Proves Superior

    ACTG 320, a controversial clinical trial conducted in 1,156 volunteers at 41 U.S. medical centers, was stopped early after the combination of indinavir (Crixivan(R))+AZT+3TC proved superior to AZT+3TC alone. There were 8 deaths in the triple-combination arm, vs. 18 in the double combination. Total cases of disease progression (AIDS-defining illness or death) were 63 in the AZT+3TC arm, vs. 33 with the triple combination.

    Participants in this study had CD4 counts below 200 (with a median of 86). All had taken AZT for at least three months, but had taken no more than one week of 3TC, and no protease inhibitors.

    Participants will now be offered various options, including rollover studies which may include experimental drugs DMP-266 and 1592 which otherwise are not widely available. Complete details are not available at this time. It will be important for participants to be well informed so that they can best choose among the options available to them.It is widely agreed that what is important about the treatments tested in this study was not the number of drugs, but the use of a combination powerful enough to reduce the viral load to undetectable levels. The viral load data are being analyzed now.

    The Controversy

    Strongly supporting this trial was the Treatment Action Group (TAG) in New York, which released a 3,000-word backgrounder, with a detailed table of the results, on February 24, the same day of the NIH announcement that the trial had been stopped. (The backgrounder is available through the TAG home page, http://www.aidsnyc.org/network/tag/tag.html) TAG Policy Director Mark Harrington stated, in a February 24 press release:

    "This study will probably mean that tens of thousands more people will live longer, healthier lives than would otherwise have been the case. Historically we've seen that well- designed controlled clinical trials are the most effective way to change treatment patterns for most people with AIDS. ACTG 320, along with other recent research findings, should convince skeptical insurers, physicians and patients that these potent combinations of anti-HIV therapies are safe, effective, and cost-efficient for the treatment of advanced HIV disease. That, in turn, should substantially increase patients' access to the drugs."

    Other activists, while strongly agreeing with the push for improving the standard of care, have long been unhappy with the study, for a number of reasons:

    • We already know that more viral suppression is better than less suppression. The main result of this trial was to prove that yet again.

    • One of the most important questions now is the long-term toxicity of the protease inhibitors and other antiretroviral drugs available. ACTG 320 does not help with that question, because it followed patients for up to a year (median 38 weeks).

    • ACTG 320 also does not help answer the question of when to start therapy. Only participants with CD4 count under 200 were enrolled in this trial, and the results were driven by those with CD4 counts under 50.

    • There are also concerns about the opportunity cost of using government resources for product-oriented trials which should be industry's responsibility, instead of using those resources for critical research questions which industry has little incentive to address.

    • Another issue is the enrollment of persons (often minorities) in suboptimal trials because they do not have better treatment options.

    We believe that it is long past time to stop reaching reflexively for "clinical endpoints" (death or serious disease progression) just because we are not quite ready to trust viral load. In theory, clinical-endpoint trials of a particular treatment combination could tell us whether the benefit of viral load reduction outweighs any long-term toxicity of the regimen (over the next five, 10, or 20 years). But in practice, long-term trials are not feasible when treatment is changing as rapidly and unpredictably as AIDS treatment is today. What, then, is the rationale for trials like ACTG 320?

    Or will we be forced to move now to a two-track rationale -- one for experts and patients with means, and another for insurance companies, government agencies, and non-expert physicians, who need body counts to persuade them to change to a modern standard of care?


    Help Wanted: GMHC
    Treatment Education Director

    Gay Men's Health Crisis, which publishes the newsletter TREATMENT ISSUES, is hiring a director of its Treatment Education and Advocacy department. Persons interested should send a resume, indicating that they are interested in this position, to: GMHC, Human Resources Dept., 129 W. 20th St., New York, NY 10011.

    The job description and qualifications are as follows:

    Manage the development and implementation of GMHC's treatment education services and drug development advocacy. Provide expertise on drug development, treatment education, secondary prevention, and health promotion. Represent GMHC as media spokesperson on state, local, and national levels, concerning treatment issues. Manage agency's technical assistance efforts for treatment education and collaborate with GMHC's Community Partnership Initiative. Develop and manage budget for Department of Treatment Education and Advocacy staff. Identify, develop and maintain grant-reporting requirements and collaborate with agency staff in the solicitation of government, foundation, and private donor grants. Extensive experience in HIV-related treatment and health education, including program development and management, staff supervision and budget/fiscal responsibility required. Excellent communication, organizational and coalition- building skills with in-depth knowledge of City, State, and Federal political structure necessary. Bilingual English/Spanish a plus.


    San Francisco: Cattle Grazing,
    Reservoirs, and Cryptosporidiosis

    by Rob Sabados
    The San Francisco Public Utilities Commission is considering a measure that would end its practice of allowing cattle to graze in San Francisco's watershed. The Commission is concerned that the cattle put San Francisco's water supply at risk of contamination with CRYPTOSPORIDIUM, a parasite that can kill people with AIDS and other immune disorders. According to the University of California, 40-60 percent of the state's rangeland cattle herds are infected with the parasite.

    The Commission's concern stems from the fact that many public health officials, including Milwaukee's epidemiologist, have linked cattle feces to the 1993 Milwaukee CRYPTOSPORIDIUM outbreak which made 403,000 people ill and killed more than 100. Health officials have also linked cattle feces to a more recent outbreak in British Columbia, Canada.

    San Francisco newspaper coverage so far suggests that there has been little representation from the AIDS community. The Commission has heard mainly from opponents of the grazing ban -- ranchers, the California Cattlemen's Association (which is concerned about setting a precedent for banning grazing on utility-district lands throughout the state), and the California Department of Forestry and the East Bay Regional Park District, which are concerned about increasing fire- control costs without the cattle to keep down the grass and brush. (See stories in the SAN FRANCISCO EXAMINER Feb. 26 page A5, the SAN FRANCISCO CHRONICLE Feb. 26 page A15, the SAN FRANCISCO EXAMINER Feb. 24 page A1, and a longer article in the SAN FRANCISCO EXAMINER Feb. 16, page C1.)

    The Commission has postponed its vote on this issue until May 12. There are efforts to develop a compromise which would protect public health and also consider agricultural interests. People wishing to contact the Commission should contact Commission secretary Romaine Boldridge at (415)554- 3155, or by fax at (415)554-3161 or by mail at 1155 Market St., San Francisco, CA 94103.

    [Note: Rob Sabados is the author of CRYPTOSPORIDIUM: CURRENT ISSUES IN BIOLOGY, LAW, MEDICINE, AND WATER QUALITY, published by Act Up/Golden Gate; see AIDS Treatment News issue #238, January 5, 1996.]


    Copyright 1997 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.




  
  • Email Email
  • Printable Single-Page Print-Friendly
  • Glossary Glossary

This article was provided by AIDS Treatment News.
 

Tools
 

Advertisement