The Agony of Bangkok line The Irony of Bangkok

From the Treatment Action Group (TAG): Marcia’s Manifesto: Saving Pharma from Itself A monthly paper of research and policy TAGline en español Volume 11 Issue 9 September 2004

Prescription for Profits Party Pooper The Agony of Bangkok Thai Activist Exhorts Veteran NEJM Editor I find it hard to imagine that a system this corrupt can be a good thing, or that it is worth Conference Crowd To Takes on Big Pharma As the vast amounts of money spent on it. In addition, we have to ask ourselves whether it Stand Firm Against U.S. No One Before; Calls for really is a net benefit to the public to be taking so many drugs. In my view, we have become Patent Regime and Sweeping Reforms an overmedicated society. ‘Masks of Fake Concern’ Marcia Angell, MD, August 2004 The Truth About the Drug Companies: How ‘Weaning us off the dope’ They Deceive Us And What To Do About It ‘Trading away health’

Just as the hand-wringing PR exer- The following is the text of an cise that has become the interna- TDM, ¡Stat! address delivered by Thai AIDS tional AIDS conference was wind- Treatment Action Group director ing down halfway across the Paisan Suwannawong at the open- globe, this little item hit the news- Más Mezclas ing ceremony of the 15th stand in the states: Rechazadas International AIDS Conference which Debido A took place in Bangkok this summer. July 15, 2004—Members of a gov- Special thanks to Paisan for his per- ernment panel, which earlier this Preocupaciones Por mission to reprint. week recommended more aggres- Concentración sive use of statin medications for * * * ood evening, ladies, gentlemen, people at the highest risk of dying from heart disease, failed to dis- ‘Combos locos y explosivos’ Gand friends. Welcome to close financial links to the compa- * * Bangkok. Sorry if I am a little ner- nies that make the drugs. vous, but I am not used to speaking on stage; I am more experienced The revised consensus guidelines Yasmin Halima y Rob Camp with speaking on the street. First, I were issued by none less than the asistieron al Taller de would like to say thank you to the American Heart Association and Farmacología de un día de people who supported my invitation were drawn up by a government duración que se llevó a cabo to speak, and thank you to the panel of experts in the field, con- inmediatamente después de la International AIDS Society because vened by the NIH’s own National Conferencia 2004 sobre Retrovirus. it means a lot to me to be able to Heart, Lung, and Blood Institute. Aquí reproducimos el informe que speak here from the perspective of a The new rules, if sustained, would prepararon acerca de algunas com- drug user living with HIV. lower serum cholesterol targets to binaciones locas, por no decir a point where 7 million more explosivas. Agradecen a todos los I would like to tell you a little bit Americans would be encouraged to presentadores por haber revisado about myself. I grew up in one of start taking the cholesterol lower- su información. Bangkok’s biggest slums, not far ing medications of Pfizer, Merck, from here. I saw many people using BMS and AstraZeneca. (At $3,000 Statins + HAART drugs, but never imagined that I a year and 20-30% margins, we’re Muchas personas VIH+ están sien- would become a drug user myself. talking an additional $4-6 billion a do tratadas actualmente con drogas The first time I smoked marijuana, year in profits—with little more de statin para manejar el aumento it felt like a challenge because all than the stroke of a pen.) de los lípidos. Es esencial compren- the public campaigns said drugs der las interacciones farmacológicas were “bad” and “dangerous.” I found New York Newsday first reported entre los statins y las drogas de it wasn’t true, so I continued to — continued on next page — — sigue en la página 13 — — continued on page 5 — — continued from first page, col. 1 — most egregious of these marketing- the story in its Thursday edition. masquerading-as-medicine maneu- It Wasn’t Always Like This Eight of the nine panel members vers. In fact, the two notable revi- The Truth About the Drug Companies had earned money specifically sions to HIV’s standard-of-care fol- [excerpts] from cholesterol drug makers, lowed on the heels of therapeutic including Pfizer, Merck, BMS and setbacks (results of the early vs. There used to be something faintly disreputable AstraZeneca. The NIH’s Dr. James about really big fortunes. You could choose to do deferred AZT “Concorde” study, well or you could choose to do good, but most peo- Cleeman and Dr. Rose Marie circa 1993; and the failure of the ple who had a choice in the matter thought it diffi- Robertson, of the AHA, both said eradication hypothesis, around cult to do both. That belief was particularly strong among scientists and other intellectuals. They could they felt financial disclosure had 1998) and resulted in retrench- choose to live a comfortable but not luxurious life in been covered because all but two ment rather than new aggressivi- academia, or they could “sell out” to industry and do less important but more remunerative work. One of the authors had also served on ty—albeit not without sustained of the results has been a growing pro-industry bias the 2001 consensus panel—and intervention to limit the damage. in medical research... and CME programs—exactly that they had made their industry where such bias doesn’t belong. (page 8) connections known then. But might that portion of the Big Many members of the FDA’s eighteen advisory Pharma enthralled research and committees have financial connections to interest- ed companies [see page 7 of this issue]. Although he summer imbroglio set famil- treatment establishment still be there are conflict-of-interest rules that prohibit par- iar alarm bells sounding: foxes clinging onto a model of overmed- ticipation in such cases, the agency regularly T waives them on the unlikely grounds that some- guarding the hen house, physicians icatization in order to please its one’s advice is indispensable. (page 210) and researchers as pharma shills. industry pimps? After all, the NIH’s Med ed writers and circuit speakers are often paid Of course, guidelines meddling is hallowed Principles of consultants for the drug companies. They are usu- among the oldest tricks in the Big Antiretroviral Therapy seem ally required to disclose financial ties [see page 8 Pharma playbook. The wisest, per- immune to re-evaluation—even (web version only, of this issue], and that disclo- sure is supposed to make it acceptable that they haps privileged, clinicians routinely though the science and hypotheses have them. But drug companies or their agents, the eschew such interference and hope on which they were based have MECCs, often suggest the topic and speaker—and even put together the slides. (page 140) nothing untoward will befall them largely been overtaken by events. for their brave and educated inso- “It’s the virus, stupid” sprang from It’s hard to believe that close and remunerative per- sonal ties with drug companies do not add to the lence. But the fact remains that its en-coffined slumber on the strong pro-industry bias in medical research and guidelines of all guises in all special- wings of hope—fueled by the rally- education. Big pharma not only controls the details ties whack quite a wallop in estab- ing cries of medical marketers— of the way clinical trials are performed, but as backup, it also works to win the hearts and lishing prescription patterns and the and has since taken on a life of its minds of researchers. (page 104) standard-of-care. And thus, not own. But where the silver dagger Drug companies are extremely generous to doctors unlike the Swiftboat veterans’ to return it to its repose? in their ‘education’ activities... Doctors are invited to media blitz in swing electoral states, dinners in expensive restaurants or on junkets to luxurious settings to act as ‘consultants’ or ‘advi- efforts to influence them suck in tens When otherwise patient friendly sors.’ The doctors listen to speakers and provide of millions of dollars a pop. researchers and community docs some minimal response about how they like the self-satisfyingly state, with all the company drugs or what they think of a new adver- tising campaign. That enables drug companies to Perhaps due to an historic vigi- authority their years of furtive phar- pay doctors just for showing up [$1,000 a pop for lance among AIDS activists and ma hustling has bought them, before the coveted high prescribers as of August 2004]. Participants may also receive training to serve on clinician advocates (or to its infec- a conference crowd that “lifelong speakers’ bureaus, so that they too can become tious nature), the field of HIV medi- antiretroviral therapy is not really a company shills. p141 cine has so far been spared the problem (anymore) because easier to Such gifts would trigger a red bribery take, less toxic combos are now alert in the mind of just about any pub- Pharmaceutical Industry Revenue available or just over the horizon”; lic official or government contractor. But † and Expense Breakdown, 2002 when Trizivir and Viread+Sustiva or not, it seems, in the minds of many doc- Kaletra are considered treatment tors. (page 128) sparing “maintenance” regimens in Research Why do doctors pretend they believe drug compa- virtually all the studies pretending to nies are interested in education? (Some of them & Development $31 billion re-explore this approach (see inset, actually believe it.) The answer is: It pays. Doctors would lose the travel and entertainment and other Marketing $67 billion bottom of page 6); when patient emoluments too many of them have come to believe advocates on federal panels sign off are entitlements to their profession. Many doctors Profits $36 billion on (or instigate) sweeping prohibi- become indignant when it is suggested that they might be swayed by all this industry largesse. But tions which diminish our treatment why else would drug companies put so much †Based on total worldwide sales of $217 billion. options and further bottleneck the money into them? (page 147) progress of clinical care; we, my fel- One of the more sobering indications of the extent to low HIVers, activists, clinicians, which big pharma has compromised the research Source: Public Citizen Congress Watch, “2002 Drug community is its extensive inroads into the NIH Industry Profits: Hefty Pharmaceutical Company Margins researchers, need to rediscover our Dward Other Industries,” June 2003 (cited in M Angell, itself. (page 103) 2004) activist rage and imagination.

-2- “How to Save the Pharmaceutical Industry—And Get Our Money’s Worth”

Seven broad problems:

1. Too many me-too drugs and too few innovative ones. 2. Key information about R&D, marketing and pricing is kept secret. 3. Drug companies have too much control over clinical research on their own products. 4. Drug companies control medical education about their own products. 5. The FDA is too much “in thrall” of the industry it is supposed to regulate. 6. Patents and other exclusive marketing rights are too long and too elastic. 7. Prices are too high and too variable. Seven key reforms:

1. Shift the emphasis from me-too to innovation.

• U.S. patent law should be enforced in its original form.

2. Strengthen the FDA.

• Repeal the Prescription Drug User Fee Act (or allow it to expire in 2006). • Increase public funding for the agency. • Exclude experts with financial ties to industry from the FDA’s advisory committees.

3. Create an institute to oversee clinical trials.

4. Curb monopoly marketing rights.

• The clock on patents should not begin ticking until the drugs come to market. • The loopholes in the Hatch-Waxman Act should be closed so that exclusivity cannot be stretched out for years.

5. Get Big Pharma out of medical education.

• Once and for all, we should clarify a simple fact: Drug companies are not providers of education—and they cannot be.

- No laws, regulations, or guidelines should be based on the idea that they are. - The medical profession needs to take full responsibility for educating its members just as other professions do.

There are a few simple steps to make this happen:

1) Medical schools should teach students about drugs, not leave such education to industry-sponsored programs and teaching materials. 2) Teaching hospitals should regard drug [.] reps just as they do other salespeople (who are not allowed to traipse around at will, promoting their wares and offering gifts and meals to medical students and doctors in training.] 3) The profession needs to take responsibility for continuing medical education (CME). Just as there should be no private clinical research industry, there should be no private medical education industry hired by the drug companies. 4) Professional associations need to be self-supporting. 5) Direct-to-consumer advertising should be prohibited in the United States—just as it is in other advanced countries.

6. Open the “black box” of R&D and marketing costs.

• The pharmaceutical industry should be regarded as a public utility: its books should be open.

7. Establish reasonable and uniform pricing.

• Drug prices should be not only transparent but reasonable and as uniform as possible for all purchasers. • President Bush’s Medicare reform bill (2003) should be repealed and replaced by a simple measure that guarantees all Medicare bene- ficiaries appropriate coverage of their drug costs, with government-negotiated payments to industry and a medically based formulary.

Source: Angell M, “The Truth About the Drug Companies: How They Deceive Us and What to Do About It,” (Random House, 2004)

The field of HIV/AIDS seems rampage had even the bloated in this context that an important poised, once again, at a cross- pharma front men crying foul, the voice may have serendipitously roads. Only this time activism and more insidious issues—an risen to stimulate our latent activist advocacy are deafening only in anachronistic treatment paradigm, memory cells: former NEJM editor their silence. While the black and a research and regulatory estab- Marcia Angell via her gutsy decon- white, demagogic issues such as lishment high-jacked by industry— struction of (nearly) all that ails us. Abbott’s notorious price gouging go entirely unaddressed. It is with- — continued on next page —

-3- — continued from page 3 — which need to return to their mis- eager to point out that they moon- arcia Angell wasn’t always a sion, she argues, of serving the lighted for “all the major drug com- crusader. Some may remem- public interest. panies” with HIV products express- Mber her rather uncritical endorse- ly “to avoid any question of bias.” ment of the design and conduct of Angell’s epiphanal moment is said Others note that Angell’s scorched the seminal AZT study (at 1,500 to have occurred in the spring of earth solution (barring anyone with mg a day; it’s now dosed at 600— 2000 when newly required conflict- pharma ties from key panel posts) and 500 mg or less, outside the of-interest disclosures for authors would only be self-defeating. Were U.S.) when it appeared in the exceeded the available page space. financial ties to drug companies an pages of her little journal, circa The study in question was of an automatic disqualifier, the argu- 1987. Others haven’t forgiven her antidepressant drug, nefazodone, ment goes, there’d be only empty her tough stance against alterna- developed by Bristol-Myers Squibb. chairs at empty tables. (Angell dis- tive medicine. But with the release All but one of the study investiga- agrees.) of her new book late last month, tors reported consultancy arrange- “The Truth About the Drug ments, speaking honoraria, and For the time being, the only remedy Companies: How They Deceive Us membership on pharma advisory deemed workable is that of disclo- and What We Can Do About It,” Dr. boards—in most cases, with phar- sure requirements—ironically, Angell appears to have Goliath pre- ma companies producing similar what appears to have sparked cariously centered within the cross types of drugs. Visibly frustrated, Angell’s fiery exposé in the first hairs of a populist sling shot; her Angell referred readers to the jour- place. But, as she is quick to point rousing philippic having trans- nal’s website for the complete list out, does the mere act of disclosing formed an otherwise mild man- of pharma financial entangle- financial ties to industry then ren- nered Harvard lecturer into a pre- ments. In disgust, she penned a der them acceptable? In the best of sent day Daniel J. Goldhagen of now legendary accompanying edi- all worlds, certainly not, but it the medical profession. torial for the issue, “Is Academic looks like that’s all we have for Medicine for Sale?” now (and what made pages 7-8 of She clearly doesn’t buy the this issue possible). While the Nussbaumian “good intentions” If we have become inured to apoc- major journals and a couple of the defense; instead, she lays out the ryphal tales such as that of the med-ed/CME web sites are doing evidence like an expert prosecu- section chief who supplemented a reasonable job of highlighting tor—and goads us all to cease the his income to the tune of $500,000 industry ties, professional associa- charade. For those among us who, a year through pharma consulting tions, the ACTG, the FDA Antiviral over the years, have come to rely gigs or the clinical trials sites paid Advisory Committee and some less on drug company beneficence for $12,000 per patient enrolled—with reputable treatment information little luxuries here and there (and a $30,000 bonus if the number providers make it difficult if not maybe even some extra pocket reaches six, Angell’s manifesto impossible to know who’s writing money), implementation of the threatens to shake us from our stu- what for whom. TAGline welcomes Angell agenda will not be painless. por. And in a hodge-podge effort to comments, corrections, updated Her clear and cogently articulated depict the HIV KOLs and consen- disclosure and other information at vision is of a reformed medical pro- sus makers in this regard, two [email protected]. † fession as much as it is a reformed extra pages of TAGline’s back-to- school issue are dedicated Dr. pharmaceutical industry—both of Pharmaceutical Industry Angell, in support of her campaign Marketing + Med Ed Budget, 2001 Why the Famed $800M Drug to bring medicine back to the peo- Is Really Closer to $200M ple and to save Big Pharma from Marketing $19.1 B its most egregious excesses. Free samples $10.5 B The famed Tufts† number = $802 M Drug reps 5.5 Back out imputed arly reviewers of the data note DTC advertising 5.5 opportunity costs” = $403 M that acceptance of financial Medical journal ads .4 Adjust for R&D Egoodies (not to mention the tax breaks = $266 M§ unquantifiable triumvirate of fame, Medical Education $35.0 B friendship and flattery) is not in and Communication §The $266 million estimate applies to NMEs (“new molecu- lar entities”), developed entirely in-house, only. Angell notes itself evidence of objectivity’s loss. Companies (“MECC”) that since most newly licensed drugs entering the market In fact, without exception, the half these days are neither really new nor developed entirely in- house (i.e., they are often acquired after early promising dozen or so New York City HIV Total $54.1 B testing at smaller R&D outfits), the real cost per drug is probably somewhere “well under $100 million.” docs informally queried about their advisory and lecture circuit rela- Source: Robert Pear, “Drug Companies Increase †Joseph DiMasi,Tufts Center for the Study of Drug Spending on Efforts to Lobby Congress and Development, 11/30/2001 tionships with Big Pharma were Governments,” NYT, March 14, 2004. A1

-4- — continued from first page, col. 3 — rassed to see my friends, whose Network developed a proposal for a smoke it. Then I started smoking lives seemed so successful. It was peer-driven HIV prevention, care heroin, and became addicted with- so lonely. I felt I had nothing at and support intervention for injec- out realizing it. I didn’t have any those times. The only thing I could tors, and submitted it to the Global money, I was feeling withdrawal think of was to go back to using Fund. We had to bypass the coun- symptoms, and my friend offered to drugs. try coordinating mechanism and share his heroin and inject me. Yes, lobby with the help of international it was scary the first time. Finally thirteen years ago I got off AIDS activists to get political sup- port for our proposal. In I got arrested at least twen- October, we were awarded ty times. Most of the time, I a 1.3 million dollar grant, did not have any drugs on but we still haven’t me. The police would plant Contaminated needles account received the money. Even drugs on me and force me for the largest share of new infections though the Thai govern- to confess, and beat me if I ment says its current poli- did not sign their docu- in Eastern Europe and Asia. cy is to treat drug users ment. I could not carry a as “patients,” not “crimi- needle around, because if nals,” it is still illegal to be the police arrested me the a drug user. We continue charge would be more seri- to be arrested and offered ous. drugs. I knew I really needed help. I the choice of prison or military-run decided to go to a “TC,” or “thera- rehabilitation centers. Is this harm heard about the risk of getting peutic community.” This is how I reduction or harm production? HIV from sharing needles, but found out how I had HIV. The test Iwhen you are craving heroin, you still is a requirement for entering Every minute a person is infected don’t think about anything else. You the TC. There was no pre- or post- with HIV by using a dirty needle. just want to inject. I was in prison test counseling. In fact, my results Globally, one in three of all new HIV twice. The conditions were terrible were given to my sister—not to me. infections outside of Africa is IDU- and we had to stay in our cells for related. In fact, contaminated nee- more than fifteen hours a day. For Today, not much has changed. dles account for the largest share of me, there is nothing worse than los- Drug users are still seen as morally new infections in Eastern Europe ing your rights and your freedom. I weak and bad people. We face stig- and Asia. The World Health am not surprised that people use ma and discrimination in society Organization says drug users have drugs and inject in prison, even if and in the health care setting. We an equal right to all levels of care, they never used or injected before. I experience constant police harass- but in practice we are denied access believe that I got HIV in prison ment and ineffective services. In to antiretroviral treatment, as well because I injected almost every day Thailand, injecting drug users or as basic prevention interventions there. “IDUs” are the only group whose like clean needles. Methadone is 50% HIV prevalence has not still illegal in many countries and Getting off drugs is not easy. Many changed in fifteen years. One third should be included on the WHO times, I went into drug treatment of all new HIV infections are IDU- Essential Drug List. There are many just to please my family, get away related, and this number is increas- harm reduction interventions which from the police, or take a break ing. Yet there has been no effective have been proven to help IDUs stay because the amount of drugs I response from the government. free of HIV, including clean needles needed was getting expensive, not and methadone. We need these because I wanted to quit; and the In a recent war on drugs in means of prevention in place now! attitudes of treatment staff only Thailand, over 2,500 people were And we need access to treatment made me feel worse. killed extra-judicially in the first now! three months of the campaign. More Other times, I really did want to than 50,000 people were arrested, Drug users, like other politically, quit. But can you imagine how it hundreds of thousands were forced socially, or economically marginal- feels to leave a treatment program into military-run rehabilitation cen- ized groups, are easily abused by and go back home with nothing to ters, and drug users were forced the government and others, who do? How difficult it is to find a job underground and away from ser- exploit them for money or ser- and explain where you’ve been? My vices that were already difficult to vices. We often do not enjoy even own family would watch my every access. the most basic human rights. In move; I could see in their eyes they Thailand, this is true for sex work- did not trust me. I was too embar- Last year, the Thai Drug Users’ ers, men who have sex with men,

-5- migrant workers and undocu- programs that promote them are the Thai Court ruled that, because mented citizens as well. not funded, or are de-funded. patents can lead to high prices and limit access to medicines, patients he world we live in today is not a Evidence shows that widespread have the right to sue the patent world of sharing but of advan- access to antiretrovirals leads to holder. This was a very important tage-taking,T profit-seeking, and huge improvements in health and battle that we won. competition to “get ahead.” It is a quality of life, with significant world motivated by greed reductions in health care and other But the war is not over. Recently, and controlled by corpora- the Thai government tions, which do not recog- entered Free Trade nize the value of a human Agreement negotiations being. While an elite few Market-driven prevention policies with the United States. amass enormous wealth, and the emphasis on “abstinence only” We know the U.S. unilat- basic needs are denied to erally pushes for intellec- many millions. have proved to be harmful at worst tual property protection and totally useless at best. that is stricter than what Today, many of our gov- is agreed internationally. ernments are run by these This means that Thailand, elite, who are more inter- now producing generic ested in protecting their antiretrovirals for most personal investments than promot- costs, because of improved health who need them, will no longer be ing public welfare. They invest pub- and productivity among people liv- able to sustain this important pro- lic resources in projects whose prof- ing with HIV/AIDS and their fami- gram. We are demanding the Thai its go into the pockets of their lies. The most painful experience I government refuse to trade away friends instead of providing for the can think of, after living with HIV the health of its people by negotiat- welfare of society. Governments pri- for thirteen years, is being poor and ing intellectual property protections vatize our public utilities, as well as HIV-positive. Again and again, I for medicines. our education and health care sys- watched many friends die in front of tems. Social welfare programs and me, from terrible opportunistic The U.S. government and its poli- other forms of assistance become infections, simply because they cies affect the ability of people all issues of charity, not rights or enti- were poor and could not afford over the world to enjoy their basic tlement. As a result, our public hos- treatment. What kills us is not rights and needs. Many poor coun- pitals are overloaded and under- AIDS, but greed. tries cannot provide basic services funded, severely compromising the like health care because they have availability and quality of treatment Multinational pharmaceutical com- to pay back enormous debt to the and care offered. panies inflate the prices of their U.S. and Western banks. While drugs without thought for poor peo- thousands die of AIDS everyday Of course, tackling AIDS isn’t just ple. They use they wealth to influ- from lack of funds, there is unlimit- about health care and antiretrovi- ence U.S. and European govern- ed funding for war. Billions of dol- rals. Prevention, harm reduction, ment policy to ensure that intellec- lars are freely available for the poverty reduction and decent living tual property rights are weighed in killing and destruction in Iraq, while standards are all part of the their favor. Other governments say the Global Fund is out of money. process; but governments, like the they are too worried about adher- This is because of the broken United States, or international orga- ence and drug resistance to offer promises of rich donor countries nizations, like the World Trade treatment, when the truth is they that refuse to pay their fair share. Organization (WTO), make the task don’t want to pay or suffer reper- much more difficult. Market-driven cussions from their trading partners I have no simple solutions for policies and the emphasis on “absti- by breaking patents. achieving world peace, but I do nence-only” have already proved to know that the U.S. government, led be harmful or, at best, totally use- our years ago, Thai people with by that criminal, George Bush, less. It is outrageous that today con- HIV/AIDS asked the govern- wages war and occupies countries servative groups, especially in the Fment to use a compulsory license like Iraq in the name of peace. The U.S., are advancing a moralistic ide- for ddI, but the government was too U.S. is too arrogant to listen to the ology that contradicts scientific evi- afraid of trade and other sanctions United Nations, and the Thai gov- dence about HIV prevention. from the U.S. Ultimately, we took ernment shows its loyalty to the Though condoms and clean needles Bristol Myers-Squibb to court and U.S. by sending Thai troops to Iraq. are the most effective tool we have won the right to produce tablet-form to prevent the transmission HIV, ddI, locally. In the final judgment, — continued on next page —

-6- Four years ago, at UN General Governments and corporations hate of us here. Yes, it’s not easy to Assembly Special Session (UNGASS) activists because we know what achieve in the world we live in on HIV/AIDS, after activists they are up to, and we are pulling today, but the world belongs to all of demanded an urgent response to the masks of fake concern from us to change. the global AIDS treatment crisis, their face to reveal their true nature. Kofi Annan called on all the world’s But to me, activists are to be hon- Five years ago, doctors, nurses, and governments to develop what he ored. Activists are my true friends. many other people told me and my described as a “war chest.” This They stand by my side when I face friends that access to antiretrovirals became the Global Fund. At the last discrimination and injustice. They was an impossible dream. Recently, international AIDS conference, the have the courage to stand up to Thailand announced that it would World Health Organization those in power who use their posi- provide antiretrovirals to all who launched its “3 by 5” initiative; yet, tions for their own benefit. They are need it, starting with 50,000 people today, six million people are still the ones who can help provide a by the end of this year. Today, I waiting for their drugs. AIDS doesn’t way forward to fight AIDS and urge all of us to dream of a day wait and neither do we. Faced with injustice in this world. when our world will be filled with the abuse of power and greed of cor- love, sharing and peace. And I porations, we cannot wait for our “Access for all” is the theme of this believe that when we dream togeth- governments to act. conference and the dream of many er, our dreams come true. †

The Irony of Bangkok How To Get 6M Poor People On Antiretroviral Therapy—And 1M Rich People Off

In a brief July editorial, “Freedom of Choice,” UK-based AIDS Treatment Update editor Edwin Bernard captures the essence of the present day therapeutic conundrum. “It’s ironic,” he writes, “that whilst the main focus of this summer’s XV International AIDS Conference in Bangkok was on finding ways to get everyone who needs therapy onto HAART, treatment interruption has become a hot topic in well-resourced coun- tries, as concerns over resistance and side effects are increasingly recognised as issues in managing HIV disease.”

Whereas at last summer’s IAS conference in Paris, two key week on, week off (WOWO) intermittent treatment studies (the Dutch Staccato study and the NIH’s own WOWO trial) led to disappointment, this year there has been renewed interest in the concept of pulsed therapy driven by CD4 cell count measures (cycling on and off ART according to pre-defined CD4 count thresholds), due in part to promising prelimi- nary results from the Italian BASTA trial and publicity surrounding the ongoing SMART trial, which is currently enrolling study volunteers in 22 countries worldwide. There was even an admittedly symbolic renaissance of exploration into induction/maintenance approaches.

The BASTA study has patients go off therapy at a CD4 cell count of 800 and then back on at a threshold of 400. The stop/re-start threshold for SMART (www.smart-trial.org) are lower: off treatment once the CD4 cell count rises above 350; re-start if it falls below 250. Edwin’s excel- lent overview of these two key studies can be found at http://www.aidsmap.com.

New or updated results from CD4-guided pulse therapy studies (and one intermittent rx protocol) presented at Bangkok include:

• Ananworanich J, Siangphoe U, Cardiello P, et al. A randomized trial of continuous, CD4-guided and one week on—one week off HAART in 74 patients with chronic HIV infection: week 108 results. Abstract WeOrB1283.

• Cohen CJ, Morris A, Bazner S, et al. The FOTO Study: A pilot study of short-cycle treatment interruption, taking antiretroviral medications for Five days On, Two days Off (FOTO), for those with viral load suppression. Abstract TuPeB4575.

• Mussini C, Cozzi-Lepri A, Borghi V, et al. A multicentre study on CD4 count-guided treatment interruptions. Abstract TuPeB4569.

• Ruiz L, Gomez G, Domingo P, et al. A multicenter randomized controlled clinical trial of continuous vs. intermittent HAART guided by CD4+ T cell counts and plasma HIV RNA levels: two-year follow-up. Abstract TuPeB4567

Intriguing results from studies exploring a second therapy-sparing treatment approach, “induction/maintenance”, include:

• Arribas JR, Pulido F, Lorenzo A, et al. Simplification to lopinavir/r single-drug HAART: 24 weeks results of a randomized, controlled, open label, pilot clinical trial (OK Study). Abstract TuPeB4486.

• Girard PM, Cabie A, Michelet C, et al. EFV/TDF vs EFV/3TC/TDF as maintenance regimen in virologically controlled patients under HAART: a 6-month analysis of the COOL Trial. Abstract TuPeB4493.

• Markowitz M, Hill-Zabala C, Lang J, et al. Maintenance with Trizivir (TZV) or TZV + efavirenz (EFV) for 48 weeks following a 48-week induc- tion with TZV + EFV in antiretroviral-naive HIV-1 infected subjects. Abstract LbOrB14.

• Ruane P, Luber A, Gaultier C, et al. Maintenance therapy using lopinavir/ritonavir (LPV/r) alone with well-controlled HIV Infection. Abstract TuPeB4577.

• van Raalte R, Heere B, Regez R, et al. Induction-maintenance strategy re-evaluated: initial boosted-PI in combination with triple NRTI, fol- lowed by triple NRTI maintenance. Abstract TuPeB4597.

-7- Camel’s Nose Under the Tent Who Evaluates and Licenses the Drugs You’re Taking? cf. M Angell, “The Hard Sell... Lures, Bribes, and Kickbacks”

1. Who approves your drugs? FDA’s Antiviral Advisory Committee (AVAC) membership and ties to industry:

Roy M. (“Trip”) Gulick, MD, MPH, Chair Consultancy fees from two pharma companies (not identified) of less than $20,000 a year; and research funding from two pharma companies (not identified) of less than $20,000 a year (per 2004 AVAC transcript). Consultancy fees from: Bristol-Myers Squibb, GlaxoSmithKline, Triangle, Trimeris; Speaking fees from: Abbott, Agouron, GlaxoSmithKline, Pharmacia-Upjohn (now part of Pfizer), Triangle.†

Tara P. Turner, Pharm. D., Executive Secretary “Nothing to report”

Victor G. DeGruttola, Sc.D. Pharmaceutical stock ownership totaling less than $5,000

Janet A. Englund, MD “Nothing to report”

Courtney V. Fletcher, Pharm. D. (Consumer Rep) Pharmaceutical stock ownership totaling less than $50,000

Princy N. Kumar, MD Pharmaceutical stock ownership (including but not limited to Schering-Plough) totaling less than $30,000; advisory fees from Schering§

Wm. Christopher Mathews, MD “Nothing to report”

Kenneth E. Sherman, MD, Ph.D. Pharmaceutical stock ownership totaling less than $25,000 Angell: “The FDA’s advisory commit- tees should not include experts with Lauren V. Wood, MD financial ties to industry. The notion “Nothing to report” that they are somehow indispensable is not credible. No one is indispens- able. The truth is that experts who Eugene Sun, MD (nonvoting industry representative) have deals with drug companies are Employed by Abbott Laboratories; not required to make disclosures being co-opted, just as the FDA is co- opted by user fees.” TTATDC, p 244 Joel Morganroth, MD (nonvoting consultant) Not required to make disclosures

Douglas G. Fish, MD (voting consultant) “Nothing to report”

Peter R. Kowey, MD Consultancy and speaking fees from pharma companies totaling less than $100,000 a year.

D. Roger Illingworth, MD, Ph.D. Consultancy and speaking fees from two pharma companies totaling less than $60,000 a year.

Rory P. Remmel, Ph.D. “Nothing to report”

Thomas R. Tephly, MD, Ph.D. “Nothing to report”

Ronald G. Washburn, MD Pharmaceutical stock ownership totaling less than $150,000

Matthew Sharp (voting patient representative) “Nothing to report”

Aggregate total disclosed: Less than $400,000 per year

Source: DHHS/FDA/CDER transcript, Antiviral Drugs Advisory Committee (AVAC) Meeting, Tuesday, May 13, 2003. “NDA 21-567 and 21- 568, Reyataz™ (atazanavir sulfate) capsules and powder for oral use, Bristol-Myers Squibb Company, proposed for the treatment of HIV infection in combination with other antiretroviral agents”; †per 2000 disclosure; § (per 11/02 documents)

-8- Dancing with the Devil Who Tests (and Reports on) the Drugs You’re Taking—and Formulates Your Treatment? cf. M Angell, “The Hard Sell... Lures, Bribes, and Kickbacks”

2. Who (at the NIH) tests your drugs? ACTG HIV Reseach Agenda Committee (RAC) membership and ties to industry:

Joseph J. Eron, Jr., M.D. Consulting arrangements with GlaxoSmithKline, Merck, Triangle, Trimeris. Research grants: GlaxoSmithKline, Merck, Abbott, Agouron, Triangle, and Trimeris.

Roy (Trip) Gulick, M.D., M.P.H. Consultancy fees from two pharma companies (not identified) of less than $20,000 a year; and research funding from two pharma companies (not identified) of less than $20,000 a year.# Consultancy fees from: Bristol-Myers Squibb, GlaxoSmithKline, Triangle, Trimeris; Speakers bureau services for: Abbott, Agouron, GSK, Pharmacia-Upjohn (now part of Pfizer), Triangle.

Ann C. Collier, M.D. Consulting arrangements with Merck. Research grants: Agouron, Merck, Hoffmann-LaRoche, Glaxo-Wellcome, and Anor Med.

Eric S Daar, M.D. Consulting arrangements with Abbott, Boerhinger Ingelheim, GlaxoSmithKline, Gilead, Serono, ViroLogics. Speaking honoraria from: Abbott, Boehringer Ingelheim, GlaxoSmithKline, Gilead, Roche, Merck, Serono, ViroLogics, Ortho. Research grants: Abbott, Bayer, GlaxoSmithKline, Gilead, Roche, Merck, ViroLogics, Serono.†

Margaret A. Fischl, M.D. Consultancy arrangements with and grant support (not broken out in disclosure) from: Abbott, Agouron, Bristol-Myers Squibb, DuPont, GlaxoSmithKline, Triangle.§ Angell: “You need to know that your doctor’s decisions are based solely on what is best for Richard Haubrich, M.D. Speakers bureau member for: Agouron, GlaxoSmithKline, Trimeris, ViroLogics; Grant support from same.† you. And doctors need to be weaned from their dependence on drug company largesse.” Victoria A. Johnson, M.D. TTATDC, p 262 (Nothing found)

John W. Mellors, M.D. Consultancy fees from: Agouron, Bristol-Myers Squibb, DuPont (now part of BMS), GlaxoSmithKline, Gilead, Merck, Novirio, Pharmasett, Triangle, Virco, Visible Genetics††; Grant support: BMS, Chiron, DuPont (now part of Bristol), GlaxoSmithKline, Merck. Angell: “It is impossible to know to what extent these financial Andrew R. Zolopa, M.D. deals influence judgments Consulting arrangements with Abbott, Bristol-Myers Squibb, and Merck. Research grants: Abbott, Bristol-Myers Squibb, and DuPont.† about... research priorities or the interpretation of results, but they certainly are cause for concern.” 3. Who sets your treatment guidelines? TTATDC, p 105 International AIDS Society (IAS) guidelines panel membership and ties§ to industry: (U.S. based members only. Pharma ties of the six extra-U.S. panel members (Yeni, Cooper, Gatell, Gazzard, Montaner, Vella) are extensive.)

Scott Hammer Consultancy fees and grants (not broken out in disclosure): Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Roche-Trimeris, Shionogi, Shire BioChem, Tibotec-Virco, Triangle.

Charles Carpenter Angell: “Increasingly, panel mem- “None to report” bers and med ‘educators’ are Margaret Fischl required to disclose their financial Advisory fees and grant support (not broken out in disclosure) from: Abbott, Agouron/Pfizer, Bristol-Myers Squibb, DuPont, GlaxoSmithKline, Triangle. ties. And that disclosure is sup- posed to make it acceptable that Martin Hirsch they have them.” TTATDC, p140 Consultancy and lecture fees and grant support from: Bristol-Myers Squibb, GlaxoSmithKline, Merck, Schering-Plough, Takeda, Trimeris.

David Katzenstein Stock holdings, advisory fees, speaking honoraria and grant support (not broken out in disclosure) from: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, ViroLogics, Visible Genetics, patent US 5,968,730 on PCR assay (October 15, 1999).

Doug Richman Consultancy arrangements with Abbott, Bristol-Myers Squibb, Chiron, Gilead, GlaxoSmithKline, Merck, Pfizer, Roche, Takeda, Triangle, ViroLogics.

Mike Saag Grant support from or served as a consultant (not broken out in disclosure) or on the speakers bureau for Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Hoffmann-La Roche, Ortho Biotech/JNJ, Pfizer/ Agouron, Pharmacia & Upjohn, Schering-Plough, Shire, TherapyEdge, Tibotec/Virco, Triangle, Trimeris, and ViroLogics.

Mauro Schecter Consultancy fees, speaking honoraria and grant support (not broken out in disclosure) from: Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Roche.

Melanie Thompson Consultancy and advisory fees, lecture sponsorship, speaking honoraria and grant support (not broken out in disclosure) from: Abbott, Agouron, Agouron/Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron, DuPont, Gilead, GlaxoSmithKline, Merck, Oxo-Chemie, Roche, Serono, Triangle, Trimeris, ViroLogics.

Chip Schooley Stock holdings (options), consultancy and lecture fees, honoraria and grant support (not broken out in disclosure) from: Agouron, AnorMed, Bristol-Myers Squibb, Merck, Mojave, Pan Pacific Pharmaceuticals, Hoffmann-La Roche, Tanox Biosystems, Triangle, Vertex, ViroLogics.

Paul Volberding Consultancy fees and honoraria from: Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithkline, Merck.

4. Who provides your with up-to-date treatment information? Patient (and clinician CME/”med-ed”) education outfits, magazines, websites—and ties to industry: (internet only)

Medscape.com, TheBody.com, clinicaloptions.com/imedoptions.com, hivandhepatitis.com, Poz, PRN (Physicians Research Network), AAHIVM (Am. Academy of HIV Medicine), aidsmap.com

† Medscape disclosures, 2001; § JAMA required disclosures from IAS guidelines panels, 2004 (IAS itself does not make this information available); # FDA AVAC transcript (see source reference on preceding page); †† per JAMA 1999

-9- Romper el Silencio, v2 tantes internacionales pos y sesiones estratégicas más de la comunidad VIH prolongadas. Como en el 2002, Estrategia de Apoyo a los desarrollen una relación los participantes del 2do. taller de trabajo con WHO, la asistieron a las conferencias Tratamientos en el Asociación Stop TB, el acerca de la coinfección Segundo Taller Anual Fondo Global y otros TB/VIH organizadas por la interesados, para repre- IUATLD, se reunieron con ofi- TB/VIH Internacional sentar de manera más ciales del programa de TB y Organizado por TAG efectiva a las comu- trabajaron extensivamente en nidades afectadas en red en la reunión de la Unión Activistas de 31 países temas referidos a pre- para establecer relaciones más vención, investigación, fuertes con salud pública tratamiento y programas nacional y regional, oficiales de En vistas del éxito obtenido en de atención enfocados en los programas de TB y el Primer Taller Internacional la coinfección TB/VIH. VIH/SIDA, la Organización TB/VIH de Educación Mundial de la Salud (WHO— Comunitaria y Movilización, lle- 5. Brindar la oportunidad World Health Organization), la vado a cabo junto con la 33ª. de que los represen- Asociación Stop TB, el Fondo Conferencia organizada por la tantes internacionales Global para la lucha contra el Unión Internacional contra la de la comunidad VIH SIDA, la tuberculosis y la Tuberculosis y Enfermedad desarrollen una relación malaria (GFATM) y otros para Pulmonar (IUALTD) acerca de la de trabajo con salud representar de manera más Salud Pulmonar, que se realizó pública nacional y efectiva a las comunidades en Montreal en el 2003, el regional y TB y los ofi- afectadas. Segundo Taller Internacional ciales de los programas TB/VIH de Educación de VIH/SIDA, a fin de Más de un millón de personas Comunitaria y Movilización se que puedan trabajar de en el mundo muere de tubercu- propuso los siguientes objetivos: manera conjunta en la losis cada año, según la implementación de Organización Mundial de la 1. Educar a los represen- futuras iniciativas con- Salud. La tuberculosis, una tantes de la comunidad cernientes a la temática enfermedad 100% curable, hoy VIH acerca de los difer- TB/VIH. en día causa silenciosamente entes aspectos de las más muertes que nunca en la investigaciones, preven- 6. Brindar la oportunidad historia de la humanidad. ción, tratamiento y de que los represen- política referidas a la tantes internacionales “TB es el mayor asesino de las coinfección TB/VIH. de la comunidad VIH Personas que Viven con desarrollen planes y VIH/SIDA (People Living with 2. Otorgar poder a los rep- estrategias para movi- HIV/AIDS—PLWHA). Lo sé resentantes de la comu- lizar a sus comunidades, porque ví morir a mis her- nidad VIH para movilizar a sus legisladores y a manos. Yo también estaría y diseminar información sus recursos para mejo- muerto. Hoy estoy vivo porque acerca de la coinfección rar la lucha contra tuve acceso a tiempo a un TB/VIH en sus comu- TB/VIH a nivel nacional tratamiento para la TB”, dijo nidades locales. y regional y para facili- Winstone Zulú de la Red de tar su participación en Personas que viven con VIH en 3. Dotar a los represen- el diálogo global acerca Zambia, durante la conferencia tantes de la comunidad de dichas políticas. en París de la IUATLD del VIH de las habilidades 2003. “Nunca pensé que la necesarias para ayudar El 2do. taller incorporó varios tuberculosis fuera un problema a que sus comunidades cambios a fin de atender las hasta que perdí a cuatro her- comprendan, participen necesidades identificadas por manos a causa de esta enfer- y provean información los participantes durante el medad en un lapso de tres en las investigaciones y 1er. taller. Asistieron 50 partic- años”, dijo. ensayos clínicos. ipantes. El taller tuvo una duración de dos días y medio. “Muchas personas desconocen 4. Brindar la oportunidad Hubo más oportunidades para que tienen tuberculosis hasta de que los represen- la interacción de pequeños gru- que es demasiado tarde”, sostu-

-10- vo Nomfundo Dubula, de la Treatment Action Group (TAG). países, incluyendo Nigeria, Campaña de Acción de El taller fue diseñado para Ucrania, Sudáfrica, Brasil, Tratamiento de Sudáfrica. estimular la discusión acerca Zambia, Tailandia, Kenia y “Padecí tuberculosis también y de los principales problemas Nigeria revelaron que, a pesar fue difícil continuar con la med- que alimentan la co-epidemia de sus más de tres décadas de icación”, dijo ella. “La detección TB/VIH y las estrategias para existencia, los programas temprana y el tratamiento rápi- abordarlos. nacionales de TB siguen siendo do salvaron mi vida. No lo groseramente sub-fondeados y hubiera logrado sin requieren de un com- ayuda. El temor a tener promiso político más que iniciar nuevamente fuerte para frenar la el tratamiento si no marea que constituye completaba mis dosis esta epidemia. fue lo que me hizo El activismo por el sida no puede seguir adelante”. sostenerse sin el activismo por la TB. Pareciera que los pro- gramas de TB tienen “La dificultad en el casi nada, en com- diagnóstico de los casos paración con los pro- de TB nos ha robado la gramas nacionales de vida de muchas VIH, que gozan de Personas que Viven con Para muchos de los más de 60 abultados presupuestos, el VIH/SIDA en Brasil”, dijo Ezio activistas en tratamiento de 31 soporte de donaciones exter- Santos-Filho, del Grupo Por la países que asistieron al taller, nas, alto grado de voluntad VIDDA, un grupo de VIH-posi- las discusiones en los diversos política y compromiso, la tivos en Río de Janeiro. grupos actuaron como un ele- involucración de la población mento para abrir los ojos ante civil y de la comunidad, el “El activismo por el SIDA no los estragos que, sin ser dicho, apoyo de grupos de pares puede sostenerse sin el activis- la TB está causando en muchas establecidos y recursos mo por la TB”, sostuvo Fabio comunidades, su relación humanos entrenado. Scano, del programa Stop TB, de intrínseca con el VIH y la la WHO. “La movilización social necesidad de adoptar estrate- El Dr. Gani Alabi, del staff de y la participación comunitaria gias proactivas para limitar WHO que trabaja en TB en el que impulsó la respuesta al esta “epidemia silenciosa”. Sudoeste de Nigeria, dijo, problema del VIH/SIDA es nece- “Nigeria posee un comité de saria para luchar contra la TB”. Se identificaron varios factores VIH/SIDA fuerte, encabezado que alimentan esta situación, por el Presidente, un comité Una mirada más profunda a la tales como la creciente inciden- multisectorial conformado por epidemia mundial de TB no cia de nuevos infectados con representantes de muchos sec- pudo haber sido más forzada, VIH, las empobrecidas instala- tores, incluyendo grupos prove- en tanto los científicos e intere- ciones para realizar diagnósti- nientes de la sociedad civil que sados se reunieron durante cos, la baja detección de trabaja en VIH/SIDA. Estas cuatro días en el otoño del nuevas infecciones de TB y la intervenciones reciben muchos 2003 para examinar las ten- falta de profesionales bien fondos y cuentan con el person- dencias actuales, los avances entrenados para el cuidado de al que necesitan. científicos y los progresos real- la salud. Otros factores Desgraciadamente, los progra- izados en el control de la epi- incluyen el “agotamiento cere- mas de control de TB en el país demia global. bral”, los fondos insuficientes no cuentan con este tipo de destinados a los programas apoyo”. Los científicos se reunieron nacionales de TB, la falta de bajo la égida de la IUATLD. liderazgo político, la insufi- Continuó diciendo: “Aunque Mientras que los investigadores ciente provisión de drogas para existe una política de intercambiaban información los centros de tratamiento de tratamiento de TB gratuito, durante la conferencia, los TB y la incidencia de la muchos de los centros de involucrados en tratamientos resistencia multi-droga. tratamiento de TB no cuenta participaron del Taller de con las drogas necesarias para Educación y Movilización Los informes de situación pre- sus clientes cuando ellos las Comunitaria para la coinfec- sentados sobre el estado de los necesitan. La WHO planea ción TB/VIH organizado por el programas de TB en muchos — sigue en la próxima página —

-11- — viene de la página anterior — nacionales de TB y movilizarse da, también son componentes comenzar a integrar los pro- para lograr un mayor compro- críticos del cuidado de gramas de TB/VIH en seis miso político y financiero por TB/VIH. estados del país, seleccionados parte de los gobiernos, agen- para tal fin, pero se necesita cias de donación y grupos En los últimos 100 años ha compromiso político y civiles para los programas de habido diferentes fases en el financiero para que ésto se control de la TB. apoyo a la TB, desde los haga realidad”. movimientos sanitarios hasta DOTS. Hoy se registra Karyn Kaplan, del un impulso para ligarlo Treatment Action a la fortaleza de los Group de Tailandia Los programas de TB tienen movimientos interna- (TTAG) también señaló cionales de acceso al que mientras que el casi nada en comparación con los tratamiento de SIDA, Fondo Global para la programas nacionales de VIH, que gozan pero la involucración lucha contra el de abultados presupuestos. de PWA (People With VIH/SIDA, Aids) en todos los nive- Tuberculosis y Malaria les como estrategia presenta una gran principal, es difícil de oportunidad para replicar con TB, dado financiar propuestas que ¿Cómo puede el activismo que, a diferencia del VIH, no es expandan las intervenciones en sida contribuir al control de una condición para toda la vida. TB, ha habido escaso o ningún la TB? compromiso significativo de En los EE.UU., el precio anual PLWHA (Personas Viviendo con Los movimientos activistas del AZT ($10.000) desde su HIV/SIDA) o de aquellos afecta- SIDA han desarrollado habili- aprobación en 1987 generó una dos por la TB en los dades y estrategias que pueden indignación de tal magnitud Mecanismos de Coordinación adaptarse para ser utilizados que contribuyó a la fundación de Países en aquellos países en campañas contra TB y de ACT UP. Las estrategias que deberían estar peleando TB/VIH. Una de las principales “Involucrados/No Involucrados” por recibir fondos. estrategias es incrementar el pueden ser útiles y complemen- gasto nacional en investigación, tarias: los activistas identifican Al finalizar las deliberaciones, prevención, tratamiento y los problemas y se reúnen con los participantes recomen- cuidado. Lograr mayores fon- los legisladores, al mismo tiem- daron la integración de los dos para los Institutos po que generan presión a programas ya existentes de Nacionales de Salud ha sido través de los medios y la movi- VIH y TB y la necesidad de uno de los principales objetivos lización social. movilizar el apoyo comunitario de TAG. para la Directly Observed El precio de las drogas sigue Treatment Strategy (DOTS) en El presupuesto para la investi- siendo un problema, aunque la la reducción de la expansión gación de TB es bastante presión continua ha hecho de TB. reducido en comparación con bajar los precios de las terapias la carga que implica esta antiretrovirales genéricas. No Los activistas también pro- enfermedad. Mientras que el obstante, en la mayoría de los pusieron varias otras activi- NIH gasta $ 2.700 millones escenarios de los países menos dades de seguimiento a nivel cada año en investigación desarrollados, las terapias anti- país para apoyar la actividad sobre VIH/SIDA, gasta apenas retrovirales necesitarán ser de DOTS. En el primer lugar de algo más de $200 millones en gratuitas. Los países más ricos la lista de recomendaciones se investigaciones sobre TB. Se necesitarán proveer los recur- encuentra la necesidad de necesitan más investigaciones sos para que esto suceda. Aún organizar talleres para pro- en regímenes más cortos de si los programas de terapias mover la capacidad de com- TB, mejores drogas, diagnósti- antiretrovirales costaran $500 prender el tratamiento y edu- cos en el punto de uso, inter- por persona por año, para tres cación comunitaria acerca de acción entre drogas antiretro- millones de personas ésto sig- los signos y síntomas de la TB, virales y drogas TB. Drogas nificaría sólo un gasto de la adherencia y cumplimento para prevenir y tratar las $1.500 millones, que es el de las drogas. También acor- infecciones oportunistas, tales costo semanal de la ocupación daron reforzar las coaliciones como cotrimoxasol e isoniazi- norteamericana a Iraq. †

-12- — viene de la primera página — algo llamado rabdomiolisis gas statin, demostró una acumu- VIH. Algunos statins han sido impli- (básicamente, la rotura de lación de los niveles de ácido sim- cadas en mayor medida que otras fibras musculares que da vastatin notablemente alta, con en su potencial para interactuar con por resultado la liberación incrementos que rondaron el terapéuticas antiretrovirales. en sangre de los contenidos 3,000% de la fibra muscular. Ello Es extremadamente importante puede someter los riñones a Pravastatin, por contraste, es implementar modificaciones en el un nivel de stress que metabolizado de manera diferente e estilo de vida, tales como involucra varias vías de dejar de fumar. Los oxidación a través del sis- ajustes dietarios también tema CYP450—pero, sig- constituyen un modo efi- nificativamente, no con ciente para bajar los nive- CYP3A. Entonces, los les de colesterol y pueden Todos los statins poseen la capacidad niveles de pravastatin en provocar reducciones de de ser severamente tóxicos. sangre se reducen hasta 10-20%. Para (alrededor de un 50%) reducir los niveles de cuando se lo coadminis- colesterol de un modo aún tra con ritonavir. más significativo, podría ser necesaria la utilización Los dos metabolitos de statin a fin de disminuir los cause daño renal) y disfun- activos de atorvastatin son genera- niveles de colesterol de LDL. ciones hepáticas, que dos por el CYP3A, por lo que la dependen de la dosis. inhibición del CYP3A4 llevará nue- Hydrochlorothiazide (una droga vamente a incrementar los niveles diurética y antihipertensiva, comer- • Comprender el metabolismo de atorvastatin en sangre (tal como cializada bajo el nombre de de las drogas statin facili- sucede con simvastatin) Aquí, la (Hydrodiuril) y atorvastatin tará la predicción de posi- diferencia clave radica en que los deberían controlar la presión arteri- bles interacciones de droga- niveles en sangre del metabolito al y el colesterol LDL, pero fre- a-droga. activo disminuyen cuando el sis- cuentemente aparecen mialgias y tema CYP3A es inhibido. En tal debilidad muscular luego de un caso, el incremento total en el nivel corto tiempo de administradas. Se Estructura de los Statins de atorvastatin activo no es tan recomienda monitorear los valores Simvastatin y lovastatin son pro- grande: el incremento es alrededor serológicos de LFT y CPK para drogas de lactona, que deben ser del doble con ritonavir. observar si se incrementan—ya que convertidas a la forma de ácido statin posee el potencial de causar hidróxido para lograr ser más Con nelfinavir se observa un efecto toxicidad muscular. En tal caso, se lipofílicas y activas. Rosuvastatin similar al visto con ritonavir: se recomendaría discontinuar el (Crestor) es el más nuevo en su incrementan los niveles de atorvas- statin. Cambiar a fenofibrate clase (y es objeto de mucha aten- tatin y los de simvastain lo hacen (TriCor) puede reducir los valores ción por parte de los medios con significativamente. Información con del VLDL (lipoproteínas de muy relación al riesgo de toxicidad lopinavir/r (Kaletra) también mues- baja densidad), pero no es tan efec- renal). Los statins son metaboliza- tra incrementos en los niveles de tivo para reducir los incrementos dos por CYP450. atorvastatin—de hasta 5 veces. en los niveles de LDL-C (lipoproteí- (Aunque en este estudio se exami- nas de colesterol de baja densidad) Impacto de los inhibidores e naron únicamente los niveles de inductores CYP450 sobre el atorvastatin no modificados, sin Algunos puntos importantes para metabolismo de los Statins que se examinara el nivel activo tener en mente: Simvastatin es significativamente total de atorvastatin. Kaletra no metabolizado en ácido simvastatin mostró ningún cambio significativo • No todos los statins son por la vía del CYP3A. La inhibición con pravastatin) iguales—tanto en términos de CYP3A4, como sucede con de eficacia o en su propen- muchos de los inhibidores de pro- Otros estudios han demostrado que sión a la interacción con teasa de VIH, puede conducir a la exposición a pravastatin se otras drogas aumentos poco significativos de los reduce en un 50% con el uso de niveles del ácido simvastatin—y a ritonavir y saquinavir, en un 40% • Todos los statins poseen la toxicidades indeseadas. Un estudio con efavirenz y en un 50% con nel- capacidad de ser severa- que investiga el impacto de riton- finavir. Efavirenz ha sido probado mente tóxicos, incluyendo avir en el metabolismo de las dro- — sigue en la próxima página —

-13- HAART Continuo y la Ley de Rendimientos Decrecientes Investigadores Franceses Cuestionan Los Beneficios del Tratamiento Antiretroviral de Por Vida

“El efecto de una terapia antiretroviral altamente activa durante 5 años” Jean-Pierre Viard y colaboradores (Service d’Immunologie Clinique, Centre Hospitalier Universitaire Necker-Enfants Malades, París)

[extractos]

Se hace cada vez más difícil imaginar prescripciones de tratamientos anti VIH para toda la vida, dados los efectos descriptos a largo plazo, tales como lipodistrofia (encontrado en cerca el 60% de los pacientes), desórdenes metabólicos, un posible incre- mento del riesgo cardiovascular, toxicidad mitocondrial y una calidad de vida alterada. En otras palabras, el inconveniente de un tratamiento a muy largo plazo puede tener un mayor peso que los beneficios de mantener alto el recuento de células CD4, considerando que los tratamientos que se mantienen por más de dos a cuatro años no resultarán en reducciones más signi- ficativas de la carga ADN del VIH-1. Para aquellos pacientes con altos valores de células CD4 (Ej: >400 células/mL) luego de este período [>2-4 años] en HAART, sería razonable considerar suspender la terapia cuando el nivel de ADN de VIH-1 alcan- za su piso más bajo y esperar a que el paciente vuelva a alcanzar el criterio de iniciación de tratamiento?

El presente estudio, aunque limitado en sus conclusiones debido al reducido número de pacientes, enfatiza la tendencia a nivelar, con el tiempo, de los efectos del HAART. Mantener la terapia por más de tres años es necesario para evitar que se vuelvan a colmar los compartimentos de células que producen el virus activamente, pero es poco probable que la prolon- gación del tratamiento provea ningún beneficio adicional en términos de reducción del reservorio viral.

[Entre los pacientes que participaron de este estudio] se registró un incremento muy leve de las células CD4 luego de 18 meses de tratamiento. Más interesante aún, el incremento absoluto del recuento de células CD4 no fue diferente entre los pacientes que comenzaron con un valores por debajo o por encima del valor medio de la población, y no se registró ningún beneficio importante a largo plazo en ninguno de los grupos. Hacia el mes 30, la mayoría de los pacientes habían alcanzado un recuento de células CD4 constante de >400 células/mL, y casi todos aquellos que iniciaron el estudio con un recuento de células CD4 por encima de la media (135 células/mL) alcanzaron ese nivel hacia fines del seguimiento. El beneficio inmunológico de mantener el HAART parece discutible en el caso de los pacientes que alcanzaron dichos niveles en los recuentos de células CD4, habiendo llegado a un grado razonable de seguridad tanto de protección ante infecciones opor- tunistas como para considerar la interrupción del tratamiento.

En síntesis, los datos que aquí se presentan muestran que el ADN VIH-1 parece no estar influenciado por el HAART luego del tercer año y confirman que la recuperación en el recuento de células CD4 es menos evidente luego de 18 meses de tratamiento. En base a estas observaciones, cuestionamos los beneficios de un tratamiento de por vida para la infección por VIH.

Fuente: Jean-Pierre Viard y colaboradores: “Efecto de terapias antiretrovirales altamente activas durante 5 años”. AIDS 2004;18:45-49.

— viene de la primera página — eficacia de pravastatin podría estar severamente afectados por los como un potente inductor del comprometida de alguna manera, inhibidores del sistema CYP3A4 metabolismo del simvastatin, pro- en tanto que su metabolismo es (Ej.: inhibidores de la proteasa), duciendo reducciones de un 60% inducido. De todos modos, atorvas- estos statins no deberían ser coad- en la exposición y de un 30% en la tatin debería ser utilizado con pre- ministrados con los PIs. de atorvastatin. Reducciones signi- caución, ya que la interacción ficativas en los niveles de simvas- droga-a-droga con antiretrovirales Virtualmente no existen datos acer- tatin, atorvastatin y pravastatin utilizados habitualmente podrían ca de rosuvastatin, por lo que el hacen más lento el descenso en los dar como resultado niveles peli- uso de esta droga (Crestor) con- niveles del colesterol LDL en pres- grosamente altos de atorvastatin en comitante con HAART debería ser encia de efavirenz. combinación con inhibidores de la evitada, al menos por ahora. proteasa—y niveles inútilmente Existen preocupaciones inqui- Un simple análisis de los datos bajos al combinarse con efavirenz (y etantes, sobre todo, acerca de daño disponibles sobre los statins sug- muy probablemente también con muscular (rabdomiolisis) y su efec- eriría que pravastatin y fluvastatin nevirapine, auque es difícil con- to sobre los riñones. son seguros para ser utilizados con seguir datos al respecto). los inhibidores CYP450 3A4, Statins y nevirapine aunque podría haber más datos En tanto que los niveles de droga Actualmente no hay datos acerca de disponibles acerca de fluvastatin. La en simvastatin y lovastatin se ven la interacción para los statins y nevi-

-14- rapine. Hasta que estos datos estén plica debido a factores tales como monitoreos de las cargas virales y disponibles, se sospecha que los los cambios hormonales y metabóli- realizar el monitoreo terapéutico de efectos de la interacción serán simi- cos, así como también por la droga tan pronto como fuera posi- lares a los producidos con efavirenz. necesidad de asegurar a la madre y ble. El monitoreo terapéutico de al feto. El uso del monitoreo ter- droga debería realizarse dos sem- Tenofovir y otros NRTIs apéutico de droga (TDM) puede anas después de iniciado el Tenofovir sufre un complejo proce- constituir una guía para los clínicos tratamiento y la interpretación de so metabólico que puede llegar a en el manejo de pacientes que sus resultados debería ser utilizada registrar significantes para ajustarlo (junto con variaciones en el nivel de la respuesta virológica) droga entre pacientes y, por lo tanto, trae consigo Resistencia y PK el riesgo de efectos adver- El cuidado de pacientes sos y respuestas antivi- Simvastatin y lovastatin no deberían que han tenido experien- rales. Se ha probado tam- ser coadministrados con los PIs. cias anteriores con múlti- bién que tenofovir incre- ples agentes antiretrovi- menta las concentraciones rales y una limitada canti- de ddI en plasma, aunque dad de opciones para el mecanismo de esta cambiar, representan un interacción no está aún desafío. Las opciones ter- esclarecido. tienen niveles de droga por debajo o apéuticas pueden ser guiadas com- por encima del nivel óptimo. prendiendo las mutaciones significa- La forma activa de drogas nucleóti- tivas que hacen a la resistencia a las das análogas como el AZT, ddI, 3TC Ejemplo: Una mujer embarazada drogas y el impacto de cambios acu- y análogos nucleótidos, tales como inicialmente muestra una buena mulativos en la mutación viral. tenofovir, es el derivado fosforilado respuesta al HAART, a pesar de los producido dentro de las células bajos niveles de nelfinavir en plas- Es poco probable que algún cambio anfitrionas. Estos “anabolitos” per- ma, pero un día su carga viral inde- de NRTI tenga mucho efecto en manecen dentro de la célula y allí tectable hace un salto. Los niveles presencia de un número elevado de son desfosforiladas. Lo que es más de nelfinavir sean probablemente NAMs (mutaciones de análogos importante, el nivel de desfosforil- relevantes en este punto—se deberá nucleótidos) más el M184V. ización dentro de la célula puede incrementar la frecuencia de los Basándose en la opinión de los diferir del nivel de desaparición monitoreos de la carga viral. expertos y en la reciente debacle del (media-vida o t1/2) del nucleótido Aumentar la dosis de nelfinavir GSK 30009 (abacavir + 3TC+ teno- que circula en el plasma. puede llegar a ayudar a elevar los fovir es una prohibición!), con cua- niveles de nelfinavir en sangre. Lo tro o más TAMs (mutaciones de La media-vida del tenofovir (circu- más apropiado sería hacer ambas análogos de timidina), el impacto de lante en plasma) es de aproximada- cosas (repetir las cargas virales e nuevos NRTIs es escaso. La coad- mente 17 horas, mientras que el incrementar la dosis) ministración de tenofovir y ddI pro- del anabolito desfosforilado puede duce un incremento en las concen- ser de 50 horas –un PK más que Los niveles en plasma de nelfinavir traciones de ddI en plasma, y teno- adecuado para soportar su dosis de pueden mantenerse bajos durante fovir + lopinavir/r incrementa los una vez al día. La fosforilización el embarazo. No se conoce si estos niveles de tenofovir. intracelular (de Tenofovir, pero niveles bajos están asociados a también de todos los análogos respuestas antivirales por debajo de La habilidad de los inhibidores de la nucleótidos) es difícil de medir. Si el lo óptimo. Con nelfinavir, un régi- proteasa para inhibir el virus con anabolito desfosforilizado consti- men de TID (Tres veces al día) mutaciones resistentes acumuladas tuye la medida importante, podría dar como resultado niveles es un fenómeno relativo. Los virus estaríamos dando sobredosis, por de droga más confiables (aunque pueden no ser completamente sus- ejemplo, de Tenofovir cuando lo un estudio anterior sobre ACTG ceptibles, pero pueden seguir man- prescribimos una vez al día? encontró que éste no es el caso) teniendo cierto grado de actividad. Alguien ha investigado esto? Serían de utilidad los futuros estu- Necesitamos comprender el impacto dios farmacocinéticos sobre el uso de la resistencia, así como combinar Nelfinavir y el monoitoreo ter- de nelfinavir en mujeres lo que pudieran ser drogas parcial- apéutico de droga durante el embarazadas? mente activas en un régimen que embarazo confiera la mayor actividad acumu- La utilización de drogas antiretrovi- Algunos clínicos recomendarían lativa. Integrando las intervenciones rales durante el embarazo se com- incrementar la frecuencia de los — sigue en la última página —

-15- farmacológicas y virológicas droga esperados, la dosis más alta fuera necesario utilizar esta com- podemos mejorar la actividad del fue mejor: la posibilidad de alcan- binación, probablemente sea una inhibidor de la proteasa y mejorar zar el objetivo de concentraciones buena idea realizar monitoreos los resultados terapéuticos. de 5,500 ng/mL (que permite pre- terapéuticos de droga para corre- decir una respuesta antiviral a gir cualquier desequilibrio en las Los principios farmacológicos se largo plazo) fue más alta en el dosis ya ajustadas. † basan en la relación riesgo/benefi- grupo al que se suministró la dosis cio. Otro estudio de ACTG se pre- de cuatro tabletas. Por favor, dirigirse a nuestra web- gunta si incrementar los niveles del site: www.aidsinfonyc.org/ tag para inhibidor de la proteasa tiene un Lexiva y Kaletra un No-No? obtener la versión completa de la impacto sobre la supresión viral. Es Hasta ahora, ha habido escasos información de Rob, con tablas y necesario observar el balance de la estudios definitivos que docu- cuadros (tanto para las cifras de potencia del régimen en relación menten la interacción antagonista statins como para las de media-vida con cualquier aumento en la toxici- entre lopinavir/r y amprenavir. de tenofovir), † dad: Se verá comprometida la Cuando estas drogas se usan en TAGline is published monthly by the Treatment Action Group (TAG), a 501(c)(3) non-profit treatment adherencia de los pacientes? Un combinación, los niveles en sangre advocacy organization in New York City. pequeño estudio piloto comparó la de las dos principales drogas que utilización de cuatro tabletas de las componen (lopinavir y ampre- Editor Mike Barr Kaletra (un total de 533 mg de navir) bajan a niveles peligrosa- Translation lopinavir y 133 mg de ritonavir) con mente ineficaces. Aunque evadir Alexander E. McCurry tres tabletas de Kaletra, dos veces este combo es la manera más acer- Board of Directors al día, pero con el agregado de 200 tada de seguir, el monitoreo ter- Barbara Hughes mg adicionales de ritonavir (un apéutico de droga podría ser útil President total de 400 mg de lopinavir y 300 para indicar la dosificación en Laura Morrison Secretary/Treasurer mg de ritonavir). Como era de casos donde las opciones terapéuti- Lynda Dee, Esq. esperarse, los resultados del estu- cas son escasas. Richard Lynn, Ph.D. Alby P. Maccarone, Jr. dio mostraron un incremento en la Mark O’Donnell Jason Osher incidencia de efectos adversos, Los datos acerca de la interacción Bruce R. Schackman, Ph.D. tanto eventos gastrointestinales de lopinavir/r para la nueva ver- Gregory Thompson como incremento en los lípidos— sión de amprenavir (fosampre- Founding Director entre aquellos en el grupo que reci- navir o Lexiva en los EE.UU.—y Peter R. Staley bieron la dosis más baja de por algún motivo, Telzir en Executive Director lopinavir, pero la más alta de riton- Europa) son aún difíciles de Mark Harrington avir (una dosis de más del doble) obtener. Aunque amprenavir y Basic Science Project Director Richard Jefferys fosamprenavir no son exacta- Antiviral Project Director En otro estudio similar del que par- mente bio equivalentes, son los Rob Camp ticiparon individuos con múltiples suficientemente parecidos en su Coinfection Project Director mutaciones resistentes PI, también aspecto químico como para consti- Tracy Swan Administrator se elevó el régimen de proteasa a tuir ambos una señal de alarma. Jacqueline Gipson cuatro píldoras de Kaletra, en lugar En lo que se refiere a las interac- Honorary Board of Advisors de tres (533 mg de lopinavir y 133 ciones, se han observado escasas Arthur J. Ammann, M.D. Constance Benson, M.D. mg de ritonavir) dos veces al día. Al diferencias entre los dos. Dadas Ross Bleckner David Caddick menos con relación a los niveles de sus complejas interacciones, si Barry Diller Matthew Epstein Judith Feinberg, M.D. Harvey V. Fineberg, M.D., Ph.D. Elizabeth Glaser (In memoriam) Margaret A. Hamburg, M.D. Would you like to continue David D. Ho, M.D. Michael Isbell, Esq. Donald Kotler, M.D. Mathilde Krim, Ph.D. receiving TAGline? Susan E. Krown, M.D. Jonathan M. Mann, M.D., M.P.H. (In memoriam) Michael Palm (In memoriam) A one-year subscription is $30 for individuals, $50 for institutions. James G. Pepper Send your check, payable to TAG, to us at: William Powderly, M.D. Joseph A. Sonnabend, M.D. Timothy J. Sweeney Tommy Tune Treatment Action Group (TAG) Urvashi Vaid 611 Broadway, Suite 612 Simon Watney Treatment Action Group New York, New York 10012-2608 611 Broadway, Suite 612 New York, NY 10012 Tel. (212) 253-7922 (If you have previously sent TAG a donation of $30 or more, we would like to Facs. (212) 253-7923 E-mail: [email protected] thank you with a complimentary one-year subscription.) www.treatmentactiongroup.org