TAGline/Volume 6 Issue 1
Letter from Glasgow
Scottish Scribe Tells of Resistance Testing Success, Superinfection, Flaws in Dual Protease Regimens
In contrast to U.K. Drug Therapy Congresses past, where physician attendance from the U.S. was rife but that of U.S. activists lackluster, this year's late autumn retreat was graced not only with the presence but the participation of David Barr and Mark Harrington. Where Barr, for the past 3 years head of D.C.-based Forum for Collaborative HIV Research delivered a carefully reasoned and provocative address on the by now fully appreciated difficulties of adherence to HIV medications (see accompanying article), Harrington invoked the lessons of ten years of AIDS activism for the opening night plenary crowd (see December 1998 TAGline). Mark's quick and dirty summary of the meeting, one most notable for the imposing integration of drug company marketing events and the paucity of new data, appears below.
David Barr and I took the night flight across the Atlantic, landed in Paris at dawn, and flew over dazzling Scottish greenswards into Glasgow on November 7. Our lodgings adjoined the Glasgow Conference Centre, which resembles a miniature version of the Sydney opera house, and a canal. The light was silvery and slant, like the skin of a mackerel, and it was cold but brisk. The next morning, I wrote my speech, which was intended to be a retrospective view of the last ten years of AIDS treatment activism.
After the speech, several European treatment activists, despite being disgruntled at not having one of their own selected for the opening plenary, approached me -- Ana Sousa Passos from Lisbon, Rob Camp from Barcelona and, a new one, Nikos Dedes from Athens who told me,
"Your speech was very politically correct."
AdvertisementI hung out at the post-opening reception for half an hour, talking with activists and sipping wine, then took a bus to the conference VIP dinner at a 19th century shipping magnate's mansion on Devonshire gardens. I talked with Mark Wainberg, current president of the International AIDS Society, about the global epidemic and the Durban conference; with virologist Doug Richman about resistance; with the CDC's Kevin de Cock about barebacking and reinfection; and with U.K. statistician Janet Darbyshire about the importance of the when-to-start-therapy trial, which she was eager to jump-start.
"Because you mentioned the EATG [European AIDS Treatment Group] four times."
"Well, we are in Europe after all."
Most of the Fourth International Congress on Drug Therapy in HIV Infection appeared to be designed for European clinicians who were unable to make it to the Retrovirus conference or to Geneva, as it was a series of plenary lectures which extensively reprised scientific presentations from early in the year, sometimes with minor updates. Its chief feature seemed to be the pharmaceutical fair and the many drug company-sponsored satellite symposia, which I boycotted. David Barr gave an excellent speech on adherence [see below]. However, there was little new science to report.
A Frustrating Community Forum
Monday, November 9th, I was to participate in a community forum alongside the U.K.'s Edward King, Peter Busse of NAPWA South Africa, and EATG chair Arjen Broekhuisen, who refused to participate on the grounds that the EATG had not been given a slot at the opening plenary. He gave a fifteen-minute explanation of this decision. "Why," he queried with brimming indignation at the Forum's opening, "Why, at a European AIDS meeting, were the opening night keynote lectures delivered by people from San Diego, Atlanta and New York? Does Europe offer so little?" According to Mike Barr's scathing HCG review of the meeting, "the lion's share of the allotted time was squandered with self-indulgent grandstanding, disingenuous protestations and futile efforts to lead the discussion in a constructive direction."
Update on the South African Epidemic
However, Peter Busse, director of South Africa's National Association of People with AIDS (NAPWA), eloquently described the birth and growing pains of an activist group in a developing country with an exploding epidemic. NAPWA South Africa was founded as a volunteer organization in 1994 and has slowly evolved into a community-based, non-governmental organization with a budget of approximately $180,000. There are currently seven provincial coordinators. The main issues for NAPWA South Africa currently are disclosure and visibility, community building and mobilization. Most of NAPWA's members are women. According to current estimates, up to three million South Africans are HIV-infected and up to 1,500 new infecctions occur daily. Condom use, at 3% of the sexually active population, is dangerously low.
Since the first all-race elections in 1994, most non-governmental organization (NGO) funding to South Africa has gone through the government. Few funders support NGOs directly. NAPWA South Africa receives some funding from InterFund, a Scandinavian charity. According to Busse, despite speeches at international fora such as Davos*, President Nelson Mandela has not made speaking of AIDS a domestic priority, and treatment is not a political priority.
On the treatment front, just about 200 people can afford the cost of highly active antiretroviral therapy [HAART], and a few hundred others are currently receiving HAART in clinical trials, although there is no guarantee that they will continue to have access when the studies conclude. The South African health minister, who is engaged in a struggle with the pharmaceutical industry over pricing, has declined to provide AZT to HIV-infected pregnant women, in spite of the fact that Glaxo-Wellcome was offering the drug free. Busse stated that NAPWA South Africa could benefit from formal skills building training on advocacy, lobbying and coalition-building with other groups such as gay and lesbian civil rights groups.
Planning a New International Treatment Activist Network
On Tuesday, November 10, an international group of activists met to start planning a new international treatment information network utilizing existing websites and adding new material for activists in three languages -- English, French and Spanish -- to improve information exchange around the world. We will continue planning this at the Sixth Retrovirus Conference in Chicago during February 1999.
Some scientific tidbits:
Two Groups Find No Third Compartment Decay
Neither Brigitte Autran's chronically infected cohort in France (N=317) nor Luc Perrin's acutely infected cohort in Switzerland (N=3) demonstrated any reduction in cell-associated HIV DNA provirus in resting CD4 cells over two years of follow-up (Autran, abstract PL2.2; Perrin, abstract PL1.1). Robert Siliciano's updated estimate of the half life of the reservoir of latently infected resting memory CD4+ T cells stands at 16 months. Even at an estimated pool of fewer than 1,000,000, this means it would take 22.9 years to turn over and die given normal rates of turnover of these cells.
Once-Daily Salvage Regimen
A German team switched 24 people with viral load beneath the limit of detection (<500 copies/mL) from a protease-containing triple therapy regimen to a once-daily regimen of ddI, 3TC and nevirapine. (They previously showed the efficacy of this regimen in 70 injecting drug users.) At 16 weeks, 18/24 (75%) continued to have a viral load below 500 copies/mL. Of the six treatment failures, five were NNRTI-experienced (Rottmann, abstract OP2.1).
Four Drugs Rescue Amprenavir Failures
Rob Murphy showed by-now familiar data on the 70% efficacy (viral load beneath limit of quantitation, henceforth BLQ) of d4T, 3TC, indinavir and nevirapine in patients who failed amprenavir monotherapy or amprenavir plus AZT and 3TC. Monotherapy failures fared better than those who failed triple therapy (Murphy, abstract OP2.4).
Dual Protease Regimens May Not Reach the CSF or Genital Fluids
Gisolf and colleagues from the Dutch Prometheus group reported that a majority (4/7, 57%) of patients on ritonavir/saquinavir dual therapy maintained measurable HIV RNA in their cerebrospinal fluid (CSF) at week 12, versus a small minority (1/11, 9%) of those on ritonavir/saquinavir/d4T (p<0.05). Drug sampling was performed on serum and CSF from thirteen patients. While all three drugs were detectable in serum, ritonavir and saquinavir levels were beneath the limit of quantification in the majority of patients' CSF (Gisolf, abstract OP1.2). A second paper found that ritonavir and saquinavir levels in seminal fluid were just 2-4% of those in plasma (Taylor, abstract P40).
Baby-Dose Ritonavir Enables BID Indinavir Dosing, without Food Restrictions
Co-administration of 100 mg BID of ritonavir plus 800 mg BID of indinavir increases indinavir trough levels and allows indinavir to be taken twice daily -- with food. More pharmacokinetics on this combination, also reported in Geneva, were presented in Glasgow (Burger, abstract P38; Van Heeswilk, abstract P55). Roche also demonstrated similar 32-week activity between soft-gel saquinavir (a.k.a. Fortovase) twice (1,600 mg BID) or thrice (1,200 mg TID) daily in a randomized study with 829 subjects (Carey, abstract P68).
Randomized French Salvage Study Suggests Genotypic Resistance Testing Improves Likelihood of Successful Switching
In an exciting late-breaker, Durant and colleagues presented results from the French VIRADAPT study. They randomized 108 patients who failed virologically (viral load over 10,000 copies/mL and at least six months' prior nucleosides and at least three months' prior protease inhibitors) to switch regimens based on a) physician judgement, taking into consideration U.S. treatment guidelines; or b) treatment modified by results of genotypic resistance testing (test unspecified).
Those randomized to arm B were statistically more likely to have a viral load beneath the limit of quantitation (BLQ) at both month 3 (p=0.038) and month 6 (p=0.047) (Durant, abstract OP7.1). This is the first randomized evidence I am aware of which prospectively demonstrates the clinical benefit associated with use of genotypic resistance testing.
Possible Superinfection in Sweden
Anders Sonnenborg of Stockholm's Karolinska Institute analyzed 50 HAART failures. One intriguing case suggested the possibility of superinfection by a partner who had previously experienced viral rebound. In this case, viruses from both partners (the one who rebounded first and the one who rebounded later) showed similar mutations in the protease enzyme and the V3 loop, suggesting re-infection (Sonnenborg, abstract PL3.3). A team from Italy found that, in 5/13 subjects (38%), viral mutations differed in plasma and semen (Liuzzi, abstract P232).
Lipodystrophy Found in French Dual Nucleoside Patients
Saint-Marc and colleagues used computerized tomography and bioimpedance analysis to investigate whether lipodystrophy (ratio of body, intra-abdominal and subcutaneous fat versus controls) occurred in patients on dual nucleoside therapy. Surprisingly, they found lipodystrophy in 18/44 (40.9%) dual nucleoside patients -- all of whose regimens included d4T (Saint-Marc, abstract P152).
Rifabutin Associated with Increased Mortality
ENTA 10, a European study investigating whether rifabutin might work as prophylaxis for M. tuberculosis (TB) as well as Mycobacterium avium complex (MAC), or whether rifabutin MAC prophylaxis predisposed TB to resistance to the rifamycin drugs, was conducted over the cusp of the HAART era and was not able to answer its primary question due to the advent of HAART and the subsequent lack of clinical endpoints. However, 504 subjects with CD4 counts below 200 cells/mL were enrolled and randomized to rifabutin (300 mg/d) or placebo. Curiously, although mycobacterial endpoints were identical in the two arms (13 on rifabutin, 12 on placebo after about 670 days), mortality was greater in the rifabutin arm (34 on rifabutin, 17 on placebo). No reason was given for this difference (de Wit, abstract P292).
Additional summaries and reports of the Glasgow meeting can be found in the London based newsletter AIDS Treatment Update and up-coming issues of Jules Levin's NATAP Report, IAPAC's JIAPAC as well as on the internet at www.healthcg.com/hiv.
* Klaus Schwab's World Economic Forum, first organized in 1971, an annual international summit of business leaders and other high net worth individuals in the Swiss Alps; see Lewis Lapham's engaging outsider's look at the January 1997 meeting: The Agony of Mammon: The Imperial Global Economy Explains Itself to the Membership in Davos, Switzerland; Verso 1998: "...heads of state, finance ministers, policy intellectuals, Nobel Prize-winning physicists, corporate executives as thick upon the ground as pine needles," and, "...the lesser nations of the earth become colonies not of governments but of corporations, the law of nations construed as the rule of money, and the world's parliaments intimidated by the force of capital in much the same way that in the eighteenth and nineteenth centuries they had been intimidated by the force of arms."
|At a Glance: South Africa
|Number of people living with HIV: 3,000,000
New infections per day: 1,500
(Est'd.) frequency of condom use: 3%
Access to antiretroviral medications:
Private means: 200 triple therapy
1,000 dual nucleoside or monotherapy
Clinical trials: 1,000-2,000 *
Total: 2,200-3,200 (0.07-0.11%)
AZT for HIV-infected pregnant women:
Provision recently denied by health ministry
* No continued access once trial ends
|VIRADAPT: Physician Judgment vs. Genotypic Resistance Results for Treatment Switching Decisions Upon Virologic Rebound *
||Mean Decrease in Plasma HIV RNA
|Genotypic Test Results
|* One hundred and eight randomized patients were required to have failed virologically (plasma RNA >10,000 copies/mL) and have 6 months or greater nucleoside analogue exposure and 3 months or greater protease inhibitor exposure.
| (Below) limit of quantification = 500 copies/mL.
|(Durant, abstract OP7.1)|
Tidy Clinical Science Stares Down Quotidien Chaos Theory; Might Not 'Late, Hard' Be Better After All?
As part of an afternoon Glasgow plenary session entitled "Key Issues in Treatment Failure" (Wednesday 11 November 1998, 4th International Congress on Drug Therapy in HIV Infection, Glasgow, Scotland, U.K.), David Barr turned the accepted paradigm on its head and noted that, more often than not, it is the therapy that fails the patient -- and not the other way around. "HAART is a remarkable treatment strategy," he writes, "but it is also an extremely fragile and unforgiving strategy. If we all don't give this issue the respect it deserves, then it will eat us." Read on, read on.
Last night I was out at dinner and then some friends and I went on for a few drinks. We got to the bar at about 11:00 and as one drink led to another and more people came and went, the time rolled by. I was having a good time. I wasn't on drugs. I wasn't drunk. I was just happy to be out socializing and getting a feel for a new city. At one point, I looked at my watch and realized it was 2:30. I was over two hours late for my pills.
I'm not really much of a party kind of guy. At home, I am quite happy to stay in. My routine is pretty set. I am also a very adherent guy. Sometimes I am late or early for my pills, but very rarely is it more than an hour either way. In nearly three years of HAART, I've missed maybe five doses. Here a slight change of routine and I forgot about my medication and was later than I should be. Probably not a catastrophe and not the most compelling adherence story. But, it is telling as to how something as simple as hanging out with your friends can interfere with HAART.
I was thirty-three when I found out I was HIV-infected. I am forty-three now. I had under 350 T-cells ten years ago. Had I started HAART then, there would have been lots of opportunities for staying out too late, or crossing one too many time zones, or having an argument with my boyfriend or forgetting to get to the pharmacy before it closed or simply just falling asleep in front of the television. And these are pretty simple and luxurious examples. I don't also have to take care of children. I don't worry that someone at work is going to discover my HIV secret because I am taking pills in the middle of the day. I have a home and a refrigerator. I have a doctor who takes the time to explain my medications and answer my questions. And I have uninterrupted access to health care.
Adherence to treatment is the issue where the wonders of science come face-to-face with every day life, where randomized controlled studies come face-to-face with chaos theory. The extraordinary work done by scientists and physicians (and the massive investments of time and money from industry) can all be undone if the patients can't take the pills. Clearly, HAART is a remarkable treatment strategy. But, it is also an extremely fragile and unforgiving strategy. If we all don't give this issue the respect it deserves, then it will eat us. Each time therapy fails a patient -- either because of side effects, or the difficulties of adherence, or because of sub-optimal pre-treatment, or because the physician and patient were never taught how to use the drugs properly -- every time therapy fails a patient, we lose a little ground to the chaos. We move closer towards HAART becoming irrelevant. We can only withstand so much treatment failure until we are spending so much time dealing once again with late stage AIDS that anti-viral therapy loses its impact and value.
So, what do we know about adherence to treatment? A year ago, the Forum for Collaborative HIV Research, along with the NIH Office of AIDS Research and the National Minority AIDS Council, held a conference about research into adherence to therapy. The conference brought together HIV clinicians, bio-medical and behavioral researchers, community educators, industry and government representatives and third-party payers. We presented an overview of the literature in treatment adherence and scoped out the issues in HIV care and treatment. The participants were then put to work and developed a research agenda for adherence to HIV treatment. We focused on the bio-medical and behavioral research issues that can lead to a better understanding of 1) the factors that affect a patient's ability to adhere to therapy; 2) the interventions that can assist a patient in treatment adherence; and 3) the methods to measure adherence. The research agenda, summaries of the conference presentations, and a background paper on adherence research with a bibliography is in the Conference Report, which I am happy to make available to you.
We know that patients have a hard time taking pills. We know that the more complex the regimen, the more difficult it is to comply. Adherence levels fall as the number of pills, the number of drugs and number of times per day you take pills increase. Required changes in diet and the length of time a patient is expected to be on therapy will effect adherence levels. Research shows that adherence gets more difficult the longer the patient in on treatment. Changes in routine, depression, beliefs about health care and medicine, and self-esteem will all affect adherence levels. Communication between the physician and the patient is cited as a key factor in adherence, as is good patient understanding of the logistics and purpose of therapy.
In HIV, the challenge is particularly rough. The regimens are complex, and patients are expected to start therapy early in the course of the disease and stay on therapy for the rest of their lives. The side effects of therapy will interfere with quality of life -- if not life itself. For late-stage patients, the large numbers of drugs and their interactions can be particularly difficult to manage. And, for the largest group of patients for whom therapy is now indicated, their first experience of feeling physically ill will often come from the pills they are taking -- not from HIV disease. For the asymptomatic patient, HAART won't make you feel better, but it can make you feel worse. The motivation for good adherence can be lacking. Numbers on a piece of paper from a test result are not always the best motivators. The challenge of adherence is confronted when the patient is far from the office visit getting viral load results.
Adherence rates are lousy in every disease. Even where the regimen has been made as simple as possible -- one pill a day for hypertension, for example -- the adherence rates are very poor. One ACTG study showed that 11% of patients in the controlled setting of a clinical trial missed a dose in the past 24 hours. Thirty-six percent missed a dose in the last two weeks. Forty-three percent of patients said they forgot to take their pills. Thirty-six percent said they fell asleep. Twenty-seven percent cited a change in routine. Are these surprising reasons? Not to me. If I am expected to take these pills forever and I am supposed to be leading a normal life, then the pills become a part of every day life. We will forget to take the pills -- just as we forget our keys or forget to turn off the coffee pot. We will fall asleep. We will have other crises or other joys in our lives that will make us forget for a moment that we have a life-threatening illness and must take our pills every day on time or else we will develop irreversible cross-resistant viral mutations and die.
Can we predict who will be adherent? Overall, no. The research is clear that demographic characteristics -- including education levels, income status, race, gender, age and a history of drug use -- are not predictors for adherence. There are good data from San Francisco showing that homelessness is not cause for non-adherence. Active alcohol or substance abuse is a predictor for poor adherence. The research suggests that the only demographic group that seems to be per se non-compliant to medication are physicians. The development of a good tool for doctors and patients to predict adherence is an essential and missing element of good care. The work that is done to determine if one is ready for therapy may be the most important work for successful long-term treatment.
Buzzers, beepers, timers, calendars, phone calls, multi-compartmental pill boxes -- these can all help create a structure for adherence. But, while I think there is an important role for these tools, we shouldn't think that these gadgets are the answer alone. Yes, simpler regimens will help. Yes, reminders will help. But we can't escape the psycho-social complexities of this issue, even though we'd like to.
I remember two counseling sessions I did back when I was running a treatment education program. Two guys came in on separate occasions, both had known they were positive for years. They were knowledgeable about HIV treatment and had never been on therapy before. Their T-cells were mid-range, but stable. The viral load test became available and, for both of them, the reading came in high. Both their doctors suggested that they now begin treatment. They were devastated. The recommendation of therapy meant to them that they were now sick and were facing death. They still felt fine. The pills, for both of them, were really their first physical manifestation of AIDS. Most of the day, they felt fine. But, every time they reached for the pill bottle, they had AIDS. So if you are in that situation and you don't want to be reminded of AIDS for a few days, then a drug holiday has a certain rationale.
When you adhere to therapy, you are taking good care of yourself. But, sometimes, we don't want to take good care of ourselves. Sometimes, it is our self-destructive behavior that feels most comfortable and familiar. What better way to self-destruct than to not take the medication.
I view the challenge of adherence to treatment as similar to that of primary HIV prevention. Both issues require that patients make significant behavioral changes in their lives. Personally, I think incorporating safer sex into one's life may be easier than living in a fasting state nine hours a day. Ice cream at around 11:30 at night is a drug that works too. And like prevention, the consequences of poor adherence can be devastating. As I said earlier, this is a very fragile and very unforgiving treatment strategy.
Having good information and a good support system is cited as one of the most important factors in achieving good adherence. From my experience in treatment education, I feel strongly that it is essential that patients understand the concepts of viral replication, how the drugs affect replication and how drug resistance develops in order to understand why adherence is so important. Not only is it essential to teach these concepts, it is possible. Already, models for teaching these ideas to patients in a simple and clear fashion are available. And all patients -- regardless of education level -- can learn them if they are presented properly and, most important, respectfully.
Certainly, the physician has a role to play in patient education, but that is not enough. Patient education and support is essential, and doctors are often under too much pressure to take the required time. Also, patients may not feel comfortable asking questions or raising their concerns with their doctor. Every person who has contact with people living with HIV has the opportunity to engage in an adherence intervention. The case manager, the drug treatment counselor, the peer educator, the nurse, the pharmacist, the receptionist -- they all have the opportunity to ask how it is going, answer a question, help the patient design a routine and strategy that is useful for him or her.
Developing individualized structures to assist patients in their daily lives is important. Find the things that motivate the person: you take your pills just before you pick your daughter up from school or right before you make her lunch for the next day. It will be different for each of us. And most important, preparing the patient for treatment before starting is essential. You really have to be ready to make the commitment to this regimen. I can't imagine ever giving a patient a prescription to start treatment on the same day as s/he got his or her first viral load.
The infrastructure of HIV social services can be put to work to address this issue, provided that training in treatment issues is offered for the staff and volunteers at the community-based organizations and for all staff at health care delivery centers. Yes, this is all a lot to ask for. But without it, this treatment strategy -- in which we have all invested so much of our lives and our hopes -- will fail. Talk to your patients. Listen to them. And know that so far, as we have done time and again in AIDS, we are doing something remarkable. The adherence rates in HIV treatment are unbelievably good -- even if they are not yet good enough. Thank you.