Treatment Action Campaign News: September 29 2000 ------------------------------------------------- TAC news is divided into 2 sections, an "In Brief" section, which contains headlines and "BRIEF" descriptions of events, and an "In Depth" section which contains full versions of some of the events mentioned in the "In Brief" section. To subscribe or to unsubscribe, send an email to mailto:subscribe@tac.org.za with subscribe or unsubscribe in the subject field. Regards, Nathan Geffen on behalf of the Treatment Action Campaign www.tac.org.za ################################## IN BRIEF SECTION ---------------- * South Africa's highest Court has ended the debate on pre-employment testing for HIV/AIDS. Mr. Justice Sandile Ngcobo writing on behalf of a unanimous court stated that the right to equality and dignity of people with HIV is of greater public interest than "legitimate commercial concerns". The Court ordered that Mr. Jacques Hoffman be instated in the position of a cabin-crew member with South African Airways and ordered the company to pay the costs of the appellant. TAC welcomes this judgement. The full judgement is available on request (see In Depth). * Nelson Mandela has come down firmly on the side of science, by saying that HIV causes AIDS. This follows the confusing statements made by President Mbeki and some cabinet ministers during the last few weeks, which have indicated that they do not believe that HIV causes AIDS. (see In Depth) * IN BRIEF: TAC continues to prepare its court case against the Minister of Health for failing to implement a country-wide mother-to-child transmission programme. Preparation of the case has required an enormous amount of research. Therefore, it has taken longer than expected. However, TAC is committed to taking this legal action and progress is being made. The application will be made within the next few weeks. * IN BRIEF: TAC's planned defiance campaign to bring generic medication, particularly fluconazole, into South Africa is on track. * We reprint for fair use an article on the success of anti-retroviral therapy in the United States, written by Bruce Mirken for AIDS Treatment News (see In Depth). * We reprint for fair use a New England Journal of Medicine article on the benefits and risks of AZT for mother-to-child transmission prevention (see In Depth). * IN BRIEF: In a setback for access to treatment, the WTO has ruled that Canada's patents on new inventions expire too quickly (17 years instead of the WTO requirement of 20). It is an indictment of the pharmaceutical companies' profiteering motives that even though their products represented a fraction of the patented goods affected by the Canadian legislation, almost all the representations against the Canadian government were made by the pharmaceutical industry. ************************************************************ CONSTITUTIONAL COURT DEFENDS RIGHTS OF WORKERS WITH HIV/AIDS By Zackie Achmat 28 September 2000 South Africa's highest Court has ended the debate on pre-employment testing for HIV/AIDS. Mr. Justice Sandile Ngcobo writing on behalf of a unanimous court stated that the right to equality and dignity of people with HIV is of greater public interest than "legitimate commercial concerns". The Court ordered that Mr. Jacques Hoffman be instated in the position of a cabin-crew member with South African Airways and ordered the company to pay the costs of the appellant. The Court found that there were no rational medical grounds for excluding all people with HIV from employment. Judge Ncgobo stated that workers with HIV must not be "condemned to economic death by the denial of equal opportunity in employment". The Court ruled that the SAA pre-employment testing policy and the exclusion of Mr. Hoffman violated the Constitution. Thousands of workers with HIV/AIDS and their families will welcome this protection of the Constitutional Court. Justice Ngcobo said that "people who are living with HIV/AIDS are one of the most vulnerable groups in our society". He stated that: "Fear and ignorance can never justify the denial to people who are HIV positive of the fundamental right to be judged on their merits. Our treatment of people who are HIV positive must be based on on reasoned and medically sound judgments. They must be protected against prejudice and stereotyping." The Constitutional Court affirmed its belief in medical science by accepting all the evidence of the medical experts. HIV causes AIDS. It is transmitted through unprotected sex, infected blood entering the bloodstream of another person, and from mother to child. The Court states clearly that "HIV has never been shown to be transmitted through intact skin or casual contact". In addition, the Court accepted that anti-retroviral therapy has "dramatically altered" the natural progression of HIV. TAC welcomes this decision of the Constitutional Court and urges employers particularly on the mines, in domestic service, the insurance industry and across the country to respect the rights of workers with HIV/AIDS. TAC will make every effort to support Cosatu, Fedusa and Nactu educating its members, employers and government that prejudice kills and jobs will save lives. TAC salutes Mr. Jacques Hoffman for his sacrifice and tenacity, the AIDS Law Project and the Legal Resources on this victory for equality and justice. EXTRACTS FROM THE JUDGMENT: HOFFMAN v SAA Case CCT 17/00 The Constitutional Court argued that unfair discrimination impacted negatively on the rights of people with HIV/AIDS including the right to dignity. "At the heart of the prohibition of unfair discrimination is the recognition that under our Constitution all human beings, regardless of their position in society, must be accorded equal dignity. That dignity is impaired when a person is unfairly discriminated against. The determining factor regarding the unfairness of the discrimination is its impact on the person discriminated against. …(Para 27)" "Legitimate commercial requirements are, of course, an important consideration in determining whether to employ an individual. However, we must guard against allowing stereotyping and prejudice to creep in under the guise of commercial interests. The greater interests of society require the recognition of the inherent dignity of every human being, and the elimination of all forms of discrimination. Our Constitution protects the weak, the marginalised, the socially outcast, and the victims of prejudice and stereotyping. It is only when these groups are protected that we can be secure that our own rights are protected." (Para 33) "The appellant is living with HIV. People who are living with HIV constitute a minority. Society has responded to their plight with intense prejudice. They have been subjected to systemic disadvantage and discrimination. They have been stigmatised and marginalised. As the present case demonstrates, they have been denied employment because of their HIV positive status without regard to their ability to perform the duties of the position from which they have been excluded. Society's response to them has forced many of them not to reveal their HIV status for fear of prejudice. This in turn has deprived them of the help they would otherwise have received. People who are living with HIV/AIDS are one of the most vulnerable groups in our society. Notwithstanding the availability of compelling medical evidence as to how this disease is transmitted, the prejudices and stereotypes against HIV positive people still persist. In view of the prevailing prejudice against HIV positive people, any discrimination against them can, to my mind, be interpreted as a fresh instance of stigmatisation and I consider this to be an assault on their dignity. The impact of discrimination on HIV positive people is devastating. It is even more so when it occurs in the context of employment. It denies them the right to earn a living. For this reason, they enjoy special protection in our law. (para 28) ******************************************************************* Mr President: Madiba says HIV causes Aids (Reprinted for fair use.) September 28 2000 at 10:25AM – Daily News By Kaizer Nyatsumba South Africa's first democratically-elected president, Nelson Mandela, has showered praise on his successor, President Thabo Mbeki, but expressed serious reservations about the latter's views on the HIV and Aids issue as well as on his perceived reluctance to meet Tony Leon, the Democratic Party leader. In an exclusive interview with the Daily News, Mandela said he himself shared the "dominant (scientific) opinion which prevails throughout the world" that HIV caused Aids, and he would depart from it only if new research showed "conclusively that that view is wrong". "I would like to be careful," he said, "because (for) people in our positions, when you take a stand, you might find that established principles are undermined, sometimes without scientific backing, and so I would like to be very careful". However, Mandela said his experience with Mbeki, who had done "very well both locally as well as in Africa" since succeeding him, was that he always thought and planned carefully before taking a public position. Mandela said he nevertheless understood that Mbeki, who was busy with international problems in addition to national ones, "now and again must come under severe criticism". Contrary to public speculation that relations between him and Mbeki were frosty, Mandela said they were "very, very close indeed", they often phoned each other and he had good relations with the president, Deputy President Jacob Zuma and the entire cabinet. [snip] ***************************** AIDS Treatment Improves Survival: Answering the "AIDS Denialists" by Bruce Mirken September 8, 2000 Article available at: http://www.dnai.com/~jjames/atn350.html A sharp decline in AIDS deaths in the United States, Canada, Europe, and Australia began in 1996, coinciding with the widespread adoption of what has become known as "highly active antiretroviral therapy" (sometimes abbreviated "HAART"). These combination treatments have received much of the credit for the plunging death rate. But AIDS denialists have disputed this claim, branding it a "myth." The denialists-who prefer to call themselves "AIDS dissidents"-not only reject the evidence that HIV causes AIDS, most even reject the idea that the term "AIDS" describes a unique medical condition. The denialists include a handful of scientists who had substantial credentials but have done little or no research with actual AIDS patients. Although members of this movement don't agree completely, most reject virtually all accepted HIV/AIDS medical treatment, as well as the use of condoms and safer sex to prevent AIDS. Debate about the impact of anti-HIV drugs long precedes the advent of HAART. In 1992 this writer asked the late Michael Callen, an early AIDS activist and persistent skeptic about HIV, what would convince him that HIV caused AIDS. His immediate answer: "If antiretroviral drugs actually made people better." Callen, who unequivocally accepted the fact that AIDS was something new and deadly even as he doubted HIV's role in it, saw the minimal impact of the drugs available at the time-AZT, ddI and ddC, generally used as monotherapy (single drug treatment)-as corroborating his belief that HIV was not the cause. While factions in the denialist camp disagree about what actually makes people with AIDS sick, there is nearly universal agreement in the movement that anti- HIV drugs are useless or worse. HIV is irrelevant, they argue, so the drugs provide nothing but toxicity. "Die Offs" and "Shocking Statistics" When a steady stream of reports of improved health and decreasing death rates started to flood the media in 1996 and 1997, denialists like AZT: Poison by Prescription author John Lauritsen dismissed them as so much smoke and mirrors. In a March 1997 talk he attributed the apparent good news to the "psychological effect" of people with AIDS being "expected to have a Lazarus recovery" and to "the selective reporting of anecdotes."(1) He predicted that this house of cards would soon collapse, declaring, "I expect within the next half year or year we'll see a perfectly hideous crash, a die-off." But the die-off failed to materialize. The Centers for Disease Control and Prevention continued to log declines in AIDS deaths in 1997, 1998 and- tentatively, as reporting may still be incomplete-1999.(2,3) As it has become indisputable that the drop in AIDS deaths is real, other explanations have been put forth. In her book, What If Everything You Thought You Knew About AIDS Was Wrong?, Christine Maggiore suggests that "a more likely explanation for decreased deaths would be the change in the official AIDS definition adopted in 1993, which allows HIV positives with no symptoms or illness to be diagnosed with AIDS. Since 1993, more than half of all newly diagnosed AIDS cases are counted among people who are not sick." The logic behind this statement is unclear. If, as Maggiore argues, CD4 cell counts do not correlate with health or illness, then the 1993 addition of a CD4 count below 200 as an AIDS-defining condition has qualified some perfectly healthy people for an AIDS diagnosis. But giving otherwise healthy people an AIDS diagnosis would not necessarily affect either the number of people who had AIDS based on the old criteria or their survival prospects. If, as some charge, the drugs actually cause AIDS, it might even increase the number of AIDS deaths by encouraging healthy people to go on toxic regimens. In her book and on the Web site of Alive and Well AIDS Alternatives, Maggiore makes a second argument: "AIDS deaths began to decline in 1994, two years before the new 'AIDS cocktails' were made available for general use," and so shouldn't be credited with a trend that had already started.(4,5) In fact, according to the U.S. Centers for Disease Control and Prevention (CDC), U.S. AIDS deaths rose from 45,271 in 1993 to 49,677 in 1994 and 49,992 in 1995. AIDS deaths dropped to 36,930 in 1996, 20,945 in 1997 and 16,432 in 1998, the lowest number since 1986.(3) A variation on this argument-that the decline in AIDS deaths began well before the advent of HAART-was put forth by Celia Farber in the March, 2000 issue of Gear. She quotes David Pasquarelli, of the group that calls itself ACT UP San Francisco, writing that his organization "recently unearthed a 1997 study by San Francisco Health Department director Dr. Mitch Katz which exposes a shocking statistic which would appear to dispel the claim that the cocktails have caused AIDS deaths to plummet. Using stored blood samples and computer analyses, the study, published in the Journal of AIDS and Human Retrovirology, concluded that new HIV-antibody positive diagnoses peaked in 1982 in San Francisco-two years before AIDS even had a name." She notes that the study estimated new HIV infections in San Francisco at 500 per year from 1987 on, adding that "Katz has since confirmed the group interpreted his data correctly."(6) The study projected that reduced rates of HIV transmission would lead to fewer AIDS cases a decade later. But in announcing this "shocking" fact Farber never explains why she and Pasquarelli seem to fully accept estimates based on an assumption both have emphatically rejected: that HIV causes AIDS.(7) This also may be the only time ACT UP San Francisco has agreed with Katz, whom it accused of "genocide" in 1997 for studying post-exposure prophylaxis,(8) and more recently branded "a lying AIDS industry clown who pulls bogus HIV increases out of a hat in order to secure funding."(9) Farber's claim that Katz accepts ACT UP San Francisco's interpretation of his data is mistaken. The key conclusion, that reduced HIV transmission in the 1980s foreshadowed fewer AIDS cases in the 1990s, is stated explicitly in the article and requires no interpretation. Katz firmly disputes the claim that HAART has had no effect. The numbers of actual and projected AIDS cases-not mentioned in Farber's article-appear to back him up. Katz and colleagues, assuming that treatment would only be as effective as AZT monotherapy and adjusting for distortions caused by the 1993 change in the CDC AIDS definition, projected that the drop would level out beginning in 1995 with 1,283 new AIDS cases that year, 1,200 in 1996, 1,122 in 1997 and 1,115 in 1998.(7) But 1995 saw 1,743 AIDS cases, 40 percent above the projection. In 1996, the year protease-based combinations became the standard of care, new cases plunged to 1,178. They kept dropping to 899 in 1997 and 713 in 1998-more than a third below projected levels. "That," says Katz, "is the treatment effect."(10) What the Cohort Studies Say Still, the basic issue put forth by Farber, Pasquarelli and Maggiore needs to be answered: If some unknown factor or factors unrelated to treatment reduced the number of AIDS patients, HAART could be receiving undeserved credit for the drop in deaths. On the other hand, if it can be shown that HAART has substantially improved patients' survival it is at least partly responsible for the good news. The critical question, then, is: Is there evidence that HAART has improved the survival of HIV/AIDS patients? According to a leading denialist, University of California chemist David Rasnick, "It may come as a surprise that there is not even one study in the vast scientific, medical literature that shows that... a group of HIV-positive adults or children who take the anti-HIV drugs live longer or better quality lives than a similar group of adults or children who are HIV- positive and do not take the drugs."(11) In fact there is an abundance of such evidence. Some, from clinical trials, has been discussed in detail in medical articles and at conferences. But clinical trials, conducted on limited numbers of patients for a relatively short time, with care often provided by physicians with more HIV expertise than average doctors, might not reflect what happens to most patients. Real-world information on the impact of HAART in daily practice comes from what are known as cohort studies, which follow the experiences of specific groups of patients over extended periods of time. A number of large, prospective cohorts, specifically set up to track both the natural course of HIV infection and the effects of treatment and behavioral factors, have now reported results covering the pre- and post-HAART eras. Additionally, a number of individual hospitals and clinics have reported on the impact of HAART on their patients. The results from these cohorts, covering tens of thousands of patients from a wide range of locations and backgrounds, have been astonishingly consistent despite differing methodologies: When HAART is introduced, opportunistic infections and deaths drop. Patients on anti-HIV therapy do better than those on no therapy, and those on regimens involving more drugs do better than those on fewer. Most of these analyses, by focusing on deaths among patients already diagnosed with AIDS, are not affected by any overall reduction in the number of AIDS cases, whether due to reduced HIV transmission or some unknown factor. One of the world's largest AIDS cohorts is the CDC's Adult/Adolescent Spectrum of Disease Project. The ASD project began in 1990 and has enrolled over 49,000 participants at 93 hospitals and clinics in nine cities. As of January 1998, 19,565 had an AIDS diagnosis by the 1993 definition. During that period 9,280 deaths were recorded, and researcher Amy McNaghten and colleagues included in their analysis all except 188 deaths caused by murder, suicide or drug overdose. Average survival time after diagnosis increased in the later years of the study, coinciding with a shift from monotherapy (a single antiretroviral, such as AZT alone, or ddI alone) to two-drug regimens, and later to three-drug HAART combinations. All anti-HIV regimens improved survival compared to no treatment, with more intensive regimens producing greater improvement. Patients on three-drug combinations had a 1.6 times lower risk of death than those on dual therapy and a 2.5 times lower risk of death than those on monotherapy.(12) The ASD researchers later reported that incidence of AIDS-defining opportunistic infections in the whole study population of over 49,000 patients plummeted when HAART came into common use in 1996. Strikingly, 46 percent of PCP cases after 1996 occurred in people who had never been in HIV/AIDS care.(13) One of the most-cited reports came from the HIV Outpatient Study, which has followed over 3,500 patients in eight U.S. cities since 1992. Researchers analyzed data for all who had ever had a CD4 count below 100 (considered most vulnerable for opportunistic infections or death) from 1994 through June, 1997. Use of protease-inhibitor-containing regimens among these 1255 patients went from two percent in mid-1995 to 82 percent by June, 1997. Mortality (deaths per 100 person-years) remained roughly constant in 1994 and 1995, then dropped abruptly in the second quarter of 1996 and continued dropping. To determine the effect of treatment, investigators classified patients by type of therapy: no antiretrovirals, nucleoside analogue monotherapy, nucleoside combination therapy, and combination therapy including a protease inhibitor. Patients on no anti-HIV treatment were 1.5 times as likely to die as those on monotherapy, 2.9 times as likely to die as those taking combination nucleosides and 4.5 times as likely to die as those on protease inhibitor combinations. The risk of serious opportunistic infections was reduced in a nearly identical pattern.(14) Strikingly similar results were reported by the EuroSIDA cohort, a prospective observational cohort that began recruiting patients from across Europe in May 1994. In November 1998 researchers reported on all 4,270 patients enrolled who were over age 16 and had a CD4 count below 500. Through March 1998, 1,215 had died. As in the HIV Outpatient Study, the death rate was analyzed by treatment category. The results, published in The Lancet, are broken down into six-month periods, and the correlation between more intensive regimens and fewer deaths is consistent and dramatic. The lowest death rate recorded in any period for patients on no treatment was 50.3 per 100 person-years, while for those on one antiretroviral the death rate never rose above 22.3 per 100 person-years. On two drugs deaths never rose above 7.9 per 100 person years and on three or more drugs the highest rate recorded was 3.9 per 100 person-years. In other words, the lowest death rate for patients on no anti-HIV drugs was 13 times the highest death rate recorded for those on three or more. The researchers further noted that "in any given 6-month period, the death rate among patients taking protease inhibitors was much lower than among those not taking protease inhibitors."(15) The EuroSIDA researchers also examined opportunistic infection incidence for HAART and non-HAART patients. Patients with CD4 counts below 200 were over three times as likely to have an opportunistic infection if they weren't on HAART.(16) Several other large European cohorts have reported similar results, including the Swiss HIV Cohort,(17) the Italian HIV Seroconverter Study(18) and the Italian Register for HIV Infection in Children.(19) Local Studies with All HIV/AIDS Patients Certain localities have been able to assemble cohorts that reach essentially the entire population seeking care for HIV or AIDS-related illness. For example, since 1986 the Canadian province of British Columbia has distributed anti-HIV drugs at no cost through a centralized system under specific guidelines, making tracking and analysis relatively simple. In order to compare the real-world results of dual-nucleoside combinations vs. three-drug regimens including either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, researchers at the British Columbia Centre for Excellence in HIV/AIDS studied all HIV-positive patients in the system who began anti-HIV treatment from Oct. 1, 1994 through Dec. 31, 1996. In a multivariate analysis (using statistical methods to adjust for a variety of differences between patients), those on two drugs were over three times as likely to die as those on three.(20) San Francisco has an AIDS surveillance system which captures basic data for approximately 95 percent of the city's AIDS patients, and this data is particularly interesting in light of Farber's allegations. Unlike the study Farber cites, which used a complex collection of computer models and projections to estimate HIV infection rates and AIDS cases, this "active surveillance" system assembles data on actual patients from health care facilities, death certificates and other sources. An analysis of this information was published earlier this year in the American Journal of Epidemiology, with a year's worth of additional follow-up presented at the International AIDS Conference in Durban, South Africa (July 9-14, 2000). The first report found that survival after an AIDS diagnosis improved dramatically for those diagnosed in 1995 and 1996 compared to earlier periods. Researchers then analyzed all deaths among San Franciscans diagnosed with AIDS from 1993 through 1996 for whom treatment and CD4 data was available, finding that any antiretroviral treatment, before or after an AIDS diagnosis, significantly reduced the risk of death. When protease inhibitors were included the risk of death was cut by 75 percent compared to no treatment. The analysis included deaths from all causes, so any deaths from drug toxicities were included.(21) The research team's Durban presentation extended the findings through 1997 and again found that "antiretroviral therapy, especially combined with a protease inhibitor, strongly predicts improved survival."(22) A number of other presentations at Durban reported a similar association between HAART and reduced rates of death and illness. Dr. Gary Reiter of the River Valley HIV Clinic in Holyoke, Massachusetts presented an analysis of HIV patients seen at his clinic and another Holyoke facility from March. 31, 1997 to Dec. 31, 1999. 177 of 300 patients were on HAART, defined as any regimen that maintained HIV suppression below 25 copies. According to Reiter, baseline characteristics of HAART and non-HAART patients were similar, except that those not on therapy generally went untreated because of psychosocial instability, mental illness and/or substance abuse. 20 of 23 deaths were in the 123 non-HAART patients. None of the three HAART deaths were due to AIDS-related infections, but one was from a drug side effect: ddI-related pancreatitis.(22,23) Reiter, who began his career in San Francisco at the start of the AIDS epidemic, commented, "Those of us who've been involved with the epidemic since '81 know that antiretroviral therapy works. I had hundreds and hundreds of patients die in San Francisco (1981 to 1985) and then western Massachusetts (1987 to 1995) until we got effective therapy. We are coming up on four years now of no AIDS deaths in treated individuals."(24) Even early skeptics about some of the mainstream ideas have seen the value of anti-HIV treatment. Joseph Sonnabend, M.D., who treated some of the first AIDS patients about 20 years ago and whose early articles are still quoted on some denialist Web sites, now says, "the antiviral therapies available since about 1996 can be life saving in people with more advanced disease, and HIV clearly plays a central role in this disease." The "Drug-AIDS" Hypothesis It is worth noting that some in the denialist camp not only claim that anti-HIV treatment is worthless, but that it actually causes AIDS. The most well known of such theorists is University of California Berkeley molecular biologist Peter Duesberg, who has proposed that AIDS in the U.S. and Europe is caused entirely by recreational drugs and antiretroviral medications, especially AZT.(25,26) Many in the denialist movement who do not fully embrace Duesberg's hypothesis agree that anti-HIV drugs play a role in causing AIDS. Maggiore, for example, accuses AZT of killing HIV patients and suggests that all of the nucleoside analogues may constitute "AIDS by prescription."(27) Pasquarelli recently asserted that "the ONLY people dying are those who take poisonous AIDS drugs."(28) (emphasis in original) Such theories are difficult to sustain in light of the data cited above, and the broader picture backs up the studies. During the period in which AIDS deaths dropped by two thirds, sales of the drugs condemned as "toxic DNA chain terminators" skyrocketed. Sales of Glaxo's antiretrovirals, led by AZT and 3TC, quadrupled between 1995 and 1999.(29) Bristol-Myers Squibb, the other leading maker of nucleoside drugs, also reported large sales increases.(30) Since Duesberg's "drug-AIDS hypothesis" pins much of the blame on recreational drugs, it is plausible that a massive decline in recreational drug use might have overcome the exponential growth in use of allegedly murderous antiretrovirals, but the opposite appears to have happened. The government's major instrument for measuring rates of drug use, the National Household Survey on Drug Abuse, charted an almost unbroken rise in the use of illegal drugs during the 1990s. The survey noted substantial increases in use of many of the specific drugs Duesberg implicates in AIDS, including heroin, cocaine and inhalants.(31) While information on drug use by gay men, still disproportionately affected by AIDS, is less complete, there has been much discussion in the gay press and in popular books about increasingly heavy drug use in certain segments of the gay community, particularly the co-called "party circuit." At least one study has reported significant increases in both numbers of drug users and severity of drug use among young gay men from 1994 to 1997.(32) Might it be that this increase in use of anti-HIV and recreational drugs hasn't had enough time to do damage? While theoretically possible, such a proposition would directly contradict the arguments Duesberg made throughout the 1990s. In making an epidemiological case for drugs as the cause of AIDS, he cited evidence that drug use-as indicated by increases in drug-related arrests and hospital emergency room admissions-had risen in tandem with AIDS cases during the 1980s.(25,26) He has also argued that Kimberly Bergalis, famous for allegedly being infected with HIV by her dentist, was killed by AZT in just two years.(33) The arguments that once seemed to bolster the drug-AIDS hypothesis now severely undercut it. And the evidence overwhelming demonstrates that HAART has played a large role in reducing AIDS deaths in the last several years. This does not mean that antiretroviral drugs are benign or that their toxicities are not serious. Indeed, this and other HIV/AIDS publications have noted a growing movement away from the so-called "hit early and hard" approach precisely because the drugs now in use may well be too toxic for most patients to use indefinitely. There is much work to be done, both to develop new, safer treatments and to make better use of the ones we have. Indeed, one of the tragedies of the denialist movement is that it has distracted attention from these issues. By forcing researchers and activists to take time and energy defending what has already been proven, it has diverted effort from critical questions regarding what sort of research is needed and how to speed the development of better, less toxic therapies. References 1) Lauritsen, John, lecture at San Francisco HEAL meeting, Park Branch Public Library, March 14, 1997. 2) Crumbley, Dorcus, CDC spokeswoman, personal communication, 8/10/00. 3) Centers for Disease Control and Prevention, U.S. HIV and AIDS Cases Reported Through December, 1999 Year-End Edition, Vol. 11, No. 2., table 22. 4) Alive and Well AIDS Alternatives, "AIDS Myth Busters," http://www.aliveandwell.org, undated (viewed 8/14/00). 5) Maggiore, Christine, What if Everything You Thought You Knew About AIDS Was Wrong? 4th edition, American Foundation for AIDS Alternatives, 2000, p.21. 6) Farber, Celia, "Science Fiction," Gear, March, 2000. 7) Lemp, G., et al. "Projected incidence of AIDS in San Francisco: The Peak and Decline of an Epidemic." Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 1997, 16:3, 182-89. 8) ACT UP San Francisco flyer, "Genocide From the AIDS Office,"1997. 9) "Antigay AIDS scare sparks silly string scandal," ACT UP San Francisco press release, 8/9/00. 10) Katz, Mitchell, personal communication, 8/11/00. 11) Rasnick, David, "The AIDS blunder, how could it happen?" Rethinking AIDS, 8:8, 1-2, July 2000. 12) McNaghten, A.D., et al, "Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS Diagnosis," AIDS 1999 13:13, 1687-95. 13) Kaplan, J., et al, "Epidemiology of Human Immunodeficiency Virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy," Clinical Infectious Diseases, 2000; 30 (Supplement 1), S5-14. 14) Palella, F., et al, "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New England Journal of Medicine, 338:13, 853-60, 1998, March 26. 15) Mocroft, A., et al, "Changing patterns of mortality across Europe in patients infected with HIV-1," The Lancet, 352: 1725-30, Nov. 28, 1998. 16) Mocroft, A., and others, "AIDS across Europe, 1994-98: the EuroSIDA study," The Lancet, 356: 291-96, July 22, 2000. 17) Egger, M. and others, "Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: Prospective multicentre study," British Medical Journal, 315: 1194-9, Nov. 8, 1997. 18) Dorrucci, Maria and others, "Temporal changes in the rate of progression to death among Italians with known date of HIV seroconversion: Estimates of the population effect of treatment," Journal of Acquired Immune Deficiency Syndromes, 22:1, 65-70, Sept. 1, 1999. 19) DeMartino, M. and others, "Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection," Journal of the American Medical Association, 284:190-7, July 12, 2000. 20) Hogg, R.S., et al, "Improved survival among HIV-infected patients after initiation of triple-drug antiretroviral regimens," CMAJ, 1999: 160:659-65. 21) Schwarcz, S. and others, "Impact of protease inhibitors and other antiretroviral treatments on acquired immunodeficiency syndrome survival in San Francisco, CA 1987-1996," American Journal of Epidemiology. 152:2. 178-85, 2000. 22) Schwarcz, S. and others, "Trends in AIDS survival in San Francisco: Does treatment continue to be effective?" 13th International AIDS Conference, abstract # ThOrC722. 23) Reiter, G., and Wojnarowski, C., "Steep declines in mortality and no AIDS deaths in HAART treated patients," 13th International AIDS Conference, abstract # MoPe2491. 24) Reiter, G., personal communication, Aug. 13., 2000. 25) Duesberg, P., "The role of drugs in the origin of AIDS," Biomedicine and Pharmacotherapy, 46:3-15, 1992. 26) Duesberg, P. and Rasnick, D., "The AIDS dilemma: Drug diseases blamed on a passenger virus," Genetica, 104:85-132, 1998. 27) Maggiore, p. 30. 28) Pasquarelli, D., "Dynamic duo ready for trial!" Aug. 13, 2000. 29) Glaxo Wellcome, annual reports: 1996, 1997, 1998, 1999. 30) Bristol-Myers Squibb, annual reports: 1996, 1997, 1998, 1999. 31) Substance Abuse and Mental Health Services Administration, National Household Survey on Drug Abuse, 1999. 32) McNall, M. and Remafedi, G., "Relationship of amphetamine and other substance use to unprotected intercourse among young men who have sex with men," Archives of Pediatric and Adolescent Medicine, 153:1130-6, Nov., 1999. 33) Duesberg, P. Inventing the AIDS Virus, Chapter 9, Regnery, 1995. ***************************** The New England Journal of Medicine 14 September 2000 (Reprinted for fair use.) Editorial: Perinatal Exposure to Zidovudine -- Benefits and Risks Mother-to-child transmission of the human immunodeficiency virus (HIV) causes a chronic and ultimately fatal pediatric infection that is now essentially preventable with antiretroviral prophylaxis. In more developed countries, prophylaxis has dramatically reduced perinatal transmission, and the potential now exists to extend this success to less developed countries by the use of effective but shorter and less expensive antiretroviral regimens. However, all regimens of antiretroviral prophylaxis require administration to the mother during pregnancy, to the neonate after birth, or both. For the large number of infants now protected from HIV infection by antiretroviral prophylaxis, the prevention of the transmission of a fatal infection entails prenatal and neonatal exposure to one or more drugs with unknown toxicity. What has been achieved with antiretroviral prophylaxis? In developed countries such as the United States, substantial progress has been made toward eliminating new perinatal HIV infections since 1994, when the administration of zidovudine to HIV-infected women after the first trimester of pregnancy and during labor and to the newborn infants for six weeks was found to reduce perinatal transmission of HIV by two thirds. (1) By 1995, rapid incorporation of this regimen into clinical practice, combined with enhanced prenatal counseling and testing for HIV, had resulted in a decline in the rate of perinatal HIV transmission to 3 to 6 percent among infants born to infected mothers. Current reports suggest that the rate of transmission is 2 percent or less when the maternal viral load is reduced to undetectable levels by highly active combination antiretroviral therapy or when zidovudine prophylaxis is combined with elective cesarean section. (2) Since 1994, reflecting a decrease in perinatal transmission, the number of cases of pediatric AIDS reported in the United States has declined by 86 percent among infants under the age of one year and by 78 percent among children one to five years old. (3) Several shorter regimens of antiretroviral prophylaxis that are more suitable to use in less developed countries have also been found to reduce the rate of perinatal transmission by 38 to 50 percent, even among infants who are breast- fed. (2) Regimens of zidovudine alone or in combination with lamivudine that are administered to the mother during the last month of pregnancy and orally during labor and delivery or of zidovudine and lamivudine or a two-dose regimen of nevirapine given to the mother during labor and delivery and to the neonate after birth have been shown to be effective in clinical trials. Use of these simple, inexpensive prophylactic regimens in developing countries could prevent more than 220,000 of the 600,000 perinatal HIV infections that occur each year. Are there reasons to be concerned about adverse effects? Some nucleoside- analogue drugs, including zidovudine, are mutagenic in vitro and carcinogenic in rodents. (4) In rhesus macaques exposed to zidovudine in utero, incorporation of the drug into DNA has been observed in some fetal organs. Incorporation of zidovudine into DNA in cord-blood leukocytes has been reported in some children with prenatal exposure (5); however, whether this finding persists after the discontinuation of prophylaxis is unclear, as are the biologic implications of the finding. Some HIV-infected persons who receive long-term antiretroviral therapy have toxic effects thought to be related to mitochondrial dysfunction; these effects include myopathy, cardiomyopathy, hepatic steatosis, and lactic acidosis. Zidovudine and other nucleoside analogues have varying affinity for mitochondrial DNA polymerase gamma and can inhibit the synthesis of mitochondrial DNA, with resulting depletion of DNA and mitochondrial dysfunction. Although in most cases the toxic effects are reversible, in some cases evidence of toxicity persists after the drug has been discontinued, and in rare instances the effects have been fatal. Data on the short-term safety of prenatal and neonatal exposure to zidovudine are reassuring. In four placebo-controlled trials of perinatal zidovudine prophylaxis, the only toxic effect that was more frequent in infants exposed to zidovudine than in those not exposed was a transient, mild anemia that resolved by 12 weeks of age. (1,6,7,8) In addition, among infants without HIV infection who were enrolled in Pediatric AIDS Clinical Trials Group Study 076 and were followed for as long as six years, no significant differences have been observed between the zidovudine and placebo groups in terms of growth or immunologic, neurologic, and neurodevelopmental characteristics, and no cancers have been detected. (9,10) However, one asymptomatic zidovudine-exposed child had borderline abnormalities of the left ventricle on echocardiography at four years of age. This child had a normal cardiac examination when last assessed. Two children exposed to zidovudine who had normal vision had minor retinal abnormalities; in one child, the abnormality was genetic. Investigators in France recently reported that 8 uninfected children born to HIV-infected mothers in a cohort of 1754 children with prenatal and neonatal exposure to zidovudine or zidovudine plus lamivudine had evidence of mitochondrial dysfunction. (11) Progressive neurologic disease developed at four to five months of age in two infants exposed to zidovudine plus lamivudine, both of whom died at about one year of age. Among the other six uninfected children, three had neurologic symptoms -- accompanied, in one case, by a transient cardiomyopathy -- and three had no symptoms but had transient biochemical abnormalities. Four of these six children had been exposed to zidovudine alone, and two to zidovudine plus lamivudine. Although abnormalities in mitochondrial enzyme activity were reported in all eight children, no depletion of mitochondrial DNA was identified. The association of these findings with exposure to antiretroviral drugs has not been definitively proved, but it is clearly a source of concern. In six Erythrocebus patas monkeys exposed to zidovudine in utero at levels similar to or lower than those expected with zidovudine prophylaxis in human fetuses and sacrificed at birth, dose-related abnormalities in mitochondrial structure and function were found in heart and skeletal muscle at autopsy. (12) The U.S. Perinatal Safety Review Working Group, formed in February 1999 after the initial report of 2 infant deaths in France, carried out a retrospective review of 353 deaths in five large, prospective perinatal cohorts in U.S. studies that included more than 20,000 children, born to HIV-infected women, with or without exposure to antiretroviral drugs. No deaths similar to those reported in France were identified. (13) The working group is currently investigating whether there is any evidence of mitochondrial dysfunction among the living children in these cohorts. In the one cohort with a completed review, evaluation of 1954 living children without HIV infection did not identify any child with exposure to antiretroviral drugs who had symptoms that could be attributed to mitochondrial dysfunction. A separate examination of reported adverse events in 1798 children in three African countries who were enrolled in a placebo-controlled trial of zidovudine plus lamivudine for the prevention of perinatal transmission of HIV found no higher rate of neurologic abnormalities among children receiving the combination therapy than among those receiving placebo. (14) The report of Lipshultz and colleagues in this issue of the Journal provides further reassuring data on the safety of in utero exposure to zidovudine. (15) Serial echocardiograms were obtained prospectively from birth to five years of age in 382 non-HIV-infected infants born to HIV-infected women. Exposure to zidovudine was not associated with either acute or chronic abnormalities in cardiac structure or function. The number of children exposed to zidovudine was small (only 9 percent of the cohort). However, in the primate study discussed above, (12) abnormalities in mitochondrial enzyme activity and mitochondrial DNA depletion were present at birth in all six monkeys with in utero exposure to zidovudine that were examined, suggesting a high incidence of cardiac toxicity. In contrast, Lipshultz and colleagues found no evidence of early subclinical or clinical cardiac toxicity in infants exposed to zidovudine. Their results suggest that if cardiac toxicity does occur, it is uncommon. Over the next 10 years, as many as 60,000 children in the United States may be exposed to zidovudine and other antiretroviral drugs in utero, since combination therapy is now recommended for persons with HIV infection, including pregnant women. (4) Strategies to detect possible short-term or long-term adverse effects of prenatal and neonatal exposure to antiretroviral drugs are critical. Since 1994, the Public Health Service has recommended that children exposed to zidovudine and other antiretroviral drugs in utero have long-term follow-up. (4) Intensive prospective evaluation of children born to HIV-infected women in a long-term follow-up study by the Pediatric AIDS Clinical Trials Group, as well as in perinatal natural-history studies such as that conducted by Lipschultz and colleagues, will assist us in evaluating the potential toxic effects of perinatal exposure to antiretroviral drugs. In addition to these observational studies, enhanced population-based surveillance that includes monitoring of infants born to HIV-infected women could provide complementary information, as well as the possibility of matching data in surveillance registries to data in birth-defect and cancer registries in order to evaluate the risk of birth defects or cancer. Given the fatal nature of HIV infection, any long-term risk entailed by the in utero or neonatal exposure of children to antiretroviral drugs would have to be profound, occur early in life, and occur in a substantial proportion of those exposed in order to outweigh the proven benefit of antiretroviral prophylaxis in reducing perinatal transmission of HIV. Without antiretroviral prophylaxis, 25 of every 100 children born to HIV-infected women will become infected; with antiretroviral prophylaxis, 23 of these infants will be spared infection. The available data indicate that serious early toxic effects of in utero exposure to zidovudine, if they occur, are likely to be rare. Although continued vigilance with regard to toxicity is important, the risk of potential toxic effects is clearly outweighed by the benefit of reducing perinatal transmission by nearly 70 percent with the Protocol 076 regimen of zidovudine and by 40 to 50 percent with short-course antiretroviral interventions. Lynne M. Mofenson, M.D. National Institute of Child Health and Human Development Rockville, MD 20852 *************************************