home materials & merchandise hotline calendar press links
	I am   A woman A gay man A bisexual A transgendered person A straight man A lesbian An immigrant Newly diagnosed Worried about HIV I need   HIV/AIDS basics Legal issues Treatment fact sheets HIV & STI testing HIV/AIDS glossary Treatment Issues Statistics Nutrition Register as a client          Press information Annual report SNiP Tips Careers & internships Make a donation
HIV/AIDS & Health > Treatment > Treatment Issues > Volume 14, number 3/4

Past Issues Volume 14, number 3/4 Spring 2000   Contents Antiretroviral Retreat 'Hit Early' takes a beating after the 7th Retrovirus Conference, January 30 to February 2, 2000 AIDS Denialism 'Gears' Up Long-term adverse events associated with HAART provide new fuel to those who believe HIV is not the cause of AIDS Improving the Quality Of Survival The community sends a consensus statement to the National Institutes of Health Better Stop Your Stoppin' Dr. Steven Miles worries that too many patients are quitting anti-HIV therapy because of its side effects Latest Lipo Info Update from the Retrovirus Conference How the Mitochondria Have Fallen Nucleoside analog toxicity to mitochondrial DNA theorized to play a greater role in lipodystrophy than earlier thought Still Trying to Interrupt (STIs) But the virus won't let us get in a word edgewise Dual Protease Inhibitors Are two better than one? How about three? Treatment Briefs Nelfinavir: twice daily use and new formulation; Agenerase oral solution warning Agonizing Reappraisal of Early Antiretroviral Therapy     By Theo Smart The Conference on Retroviruses and Opportunistic Infections is the most comprehensive yearly scientific meeting covering research on HIV and the treatment of HIV disease. Yet the thing that most impressed me at this year's meeting, in San Francisco, was not a data presentation or posters on an exciting new class of drugs or any other scientific breakthrough. It was the sight of my friend Luis, coming toward me in the conference hotel with black eyes and a bruised and bandaged face. I thought he had been mugged or savagely beaten. No, he cheerfully reassured me, he had just had cosmetic surgery in which fat was liposuctioned from his waist and injected into his cheeks. He paid to have it done because he had begun to notice his face grow a little gaunt — a change that has been observed in many patients on antiretroviral therapy. Later that week, while eating at restaurants along the Castro, I watched people streaming up and down the street. The body composition changes associated with anti-HIV therapy, collectively referred to as lipodystrophy were everywhere, often among the most robust gym bodies. Mind you, just five years ago, this neighborhood was strikingly different. The very ill were a common sight, in wheelchairs, with catheters, often blind or wasting. Little of that is in evidence today. Thanks to antiretroviral therapy, the Castro's health in 2000 appeared dramatically better than the Castro in 1995. But even so, it was not quite right. But what is more worrisome is that this is just the tip of the iceberg. There are potentially far more serious consequences of long-term antiretroviral therapy lurking unseen beneath the surface: metabolic changes leading to compromised organ systems, and now (fresh news at the conference) osteoporosis. Most grave are the increasing reports of heart disease, which has been observed in people with HIV before. While there is no definitive proof of an increase in incidence on HAART and there are always other risk factors, the cluster of metabolic changes associated with anti-HIV therapy is consistently associated with an increased risk of heart disease. One poster funded by Agouron noted that there was no increase in heart disease in patients taking different protease inhibitors over the course of 48 weeks, but the brevity of the study makes a mockery of long-term follow-up. Meanwhile, I keep noticing heart attacks in the HIV community's obituaries. At the conference, I discovered that Steve Whitson, editor of the treatment news magazine Positively Aware, and a beautiful soul, had died of a heart attack just a few days earlier. While it is not clear whether antiretroviral-related toxicity contributed to his death, as with many such cases, one can never be completely sure. No one can question that antiretroviral therapy has dramatically improved both the longevity and the quality of life of people with AIDS. A number of studies have shown that the benefits of antiretroviral therapy far outweigh its risks in people with advanced disease. However, in our initial euphoria over the great advance that HAART represented for people with AIDS, antiretroviral therapy has been routinely recommended and given to patients with HIV who were several years away from even being in danger of opportunistic infections. Now the tide seems to be turning against this practice. Many experts are questioning whether patients are being treated far too early and raising the alarm that antiretroviral therapy may be harming these patients more than helping them. At the Retrovirus Conference, Washington University's Dr. William Powderly surprised many in the audience by saying, "we now are looking at treating patients for a long period of time with drugs that have at least the potential for serious morbidity and possible mortality. Therefore, we should be asking the question of whether somebody who has no symptoms and is in no immediate risk of clinical progression should be exposed to these drugs at all or at least until they need them." A couple of weeks later, in an article in the Annals of Internal Medicine (February 15, pages 306-11), Dr. Keith Henry of the University of Minnesota presented a strong case against early treatment, concluding that "it is time for clinicians to rethink their approach to the treatment of HIV infection." Some speak even more plainly. In March, one very controversial article in Gear magazine by AIDS denialist journalist Celia Farber quoted UCLA's Dr. Steven Miles as saying, "large numbers of people are being inappropriately treated with drugs they don't need. And their lives are probably being shortened, yes" (see "Celia Farber and Denial in the Streets of San Francisco" below). Still, when later interviewed by Treatment Issues, Dr. Miles worried that already the pendulum has swung "too far in the other direction" and that people who probably should be on treatment have quit or are afraid to start (see "Has the Pendulum Swung Too Far in the Opposite Direction?" below). Hitting Hard or Striking Out against the Virus Early? It's a central tenet of medicine to treat infectious disease as soon as possible. However, HIV is a very slow disease that takes a very long time to progress to life-threatening illness in most patients. It would be a mistake to treat it like a bacterial infection. There were a number of reasons why early treatment of HIV disease initially seemed like, and may still be, a good idea. However, on close inspection most of these reasons were hypothetical and are yet to be clinically validated. The major hypothesis now seems more than a little outdated. "Perhaps more than any other assumption," writes Dr. Henry, "the hope that potent antiretroviral therapy could cure HIV infection within a reasonable time frame powered enthusiasm for immediately beginning treatment." This was the hope of the Vancouver AIDS Conference in 1996 — that viral replication could be completely stopped by HAART — leading in time to eradication as posited by Dr. David Ho. However, low levels of viral replication have since been found to persist in most patients on HAART, replenishing a small pool of infected cells. With the addition of immunotherapeutic agents, therapeutic vaccines, and other experimental approaches, eradication may yet occur, but again, these are experiments. "It is safe to conclude that a cure is extremely unlikely with the current approach to treatment," Dr. Henry wrote. Dr. Powderly concurred: "it is not for the foreseeable future an achievable goal." However, access to viral load testing at roughly the same time as Vancouver played an important role in clinicians' preference for early treatment. Large cohort studies such as the Multicenter AIDS Cohort Study (MACS) demonstrated that viral load levels (or set points) were predictive of the time a patient had until progression to illness (see table below). Higher levels of virus predicted more rapid progression rates, and some clinicians used these data to argue for reserving treatment until absolutely necessary (just before the evolution of clinical events). But another important take-home message was that all but those with the lowest viral loads eventually progressed, although it could take more than a decade. At the same time, these tests could be used to see the effect of treatment on the virus and when that treatment failed. At the very least, having an undetectable viral load gave the appearance that the disease was under control. But the difficulties in taking the medications (adherence and toxicity) and the rates of failure and development of resistance were much worse than initially hoped. Says Dr. Miles, "The problem is that the community did not weigh the pros and cons of treatment. We underestimated the risk of failure and toxicity and overestimated the benefit. At the same time, the commercial message from the pharmaceutical industry was that if you get the viral load down to zero, these drugs would last forever." But they don't. And he continued, "zero was not zero; it was merely undetectable." The truth is, treatment of patients whose immune systems are not seriously deteriorated and who have several years to clinical progression often leads to a year or so of undetectable virus and then the development of resistance. This runs counter to another one of the postulated reasons for beginning early — that treating earlier gives the virus less chance to diversify in the body and develop mutant strains resistant to drug therapy. However, numerous studies suggest that, while mutant strains occur with each replication cycle, the mutations so slow down viral replication that mutant strains rarely get a strong foothold in the body in the absence of treatment. Only under the selective pressure of therapy does much resistance become established. In fact, this may even happen in patients responding well to treatment. One piece of bad news at the Retrovirus Conference, presented by Dr. Richard D'Aquila, was the detection of resistance in latently infected cells, in patients whose virus was normally suppressed to below 50 copies/ml on therapy, but who had experienced temporary 'blips' of viral activity (abstract 238). Such 'blips' are common, and now the data suggest that they may eventually lead to failure, even in those patients who appear to be having some of the best responses to therapy. Dr. Henry writes, "in my clinicÉ some patients who were never at imminent risk for AIDS-related clinical events harbor virus strains that are resistant to all available drugs." Resistance is made all the more likely because adherence to treatment is difficult, and the consequence of anything less than perfect adherence can be significant. In one study last year, patients on protease inhibitor-based regimens who described themselves as being at least 95% adherent had a 81% chance of having an undetectable viral load at week twelve, while those who were just a little less adherent (80 to 90%) had only a 50% chance of being undetectable.1 Naturally, the chance of a patient not being fully adherent only increases over time. Furthermore, people with HIV often have complicated lives which makes the likelihood of poor adherence greater, with problems such as poverty and disenfranchisement, low self-esteem, depression, alcoholism and illicit drug use. While these are extremely difficult issues to deal with, it may make more sense to treat the "context" of HIV infection before treating the virus with drugs. "Working with the patient for a long time about adherence and waiting for less complicated therapies may be a better long-term strategy," says Dr. Henry. Since HIV is often slow to cause illness, many patients could have the time to try to tackle these issues. The consequences of not doing so and being poorly adherent are too great. One outcome could be exhausting the activity of treatment before patients really need it. Dr. Miles thinks we've been here before. For example, although AZT monotherapy had shown clinical benefit in people with AIDS, the Concorde study showed that the early use of AZT, a drug with limited effect and substantial toxicity, in patients with asymptomatic disease was no better, and in fact, was even slightly worse than delayed treatment. "But that study's message was lost on the medical community. That message was that if your drug's benefit is of a finite time, and you are not going to get sick during that time, then it is very hard to show clinical benefit," said Dr. Miles. That benefit is even more difficult to demonstrate when it is being undermined by toxicity, which in many patients on HAART sets in long before danger of progression. Since HAART has only been in use for four years, the adverse events reported so far might be just a foretaste of what is yet to come. "The patients that I see today — there's no way they are going to stay on these drugs for ten years," says Dr. Miles. Dr. Powderly thinks that we have confused the short-term goals of antiretroviral therapy with the long-term goal of treatment: "The goal of antiretroviral therapy is to maximally suppress the virus with the best tolerated regimen, but that is not the goal of treatment. The goal of treatment is that we prolong meaningful survival for our patients." This would be easier to do if we had better drugs. "If you had perfect drugs that lasted forever, we would say treat everybody," says Dr. Miles. "But if our drugs aren't perfect and don't last forever, then we should only treat those at immediate risk of progression. Our dilemma is that we are somewhere in the middle." Still, it would be a mistake to think that treatment at some point before progression offers no benefit. Therapy can delay AIDS if employed at the right moment. Studies have shown that HAART delays immunologic deterioration in patients and that should delay subsequent clinical progression. Even a dual nucleoside analog regimen delayed progression in ACTG 175 when used by patients with up to 350 CD4 cells at baseline. But studies have also shown that HAART can produce a miraculous immunologic recovery in more advanced patients. Ironically, such a positive response in people with AIDS provides theoretical support for delaying therapy until just before developing AIDS — the more effective therapy is at reconstituting and sustaining health, the more likely it is that a patient will develop serious long-term complications of therapy before experiencing clinical progression. If this is the case, it might make sense to postpone treatment until the last possible moment. However, other studies indicate that more sustained responses to therapy are seen in patients with higher CD4 cell counts and lower viral loads when treatment begins. These include two of the papers cited in Dr. Henry's article as evidence that the drugs don't work as well in the real world as in drug company sponsored studies. Henry writes, "In clinical practice, the rates of virologic success for potent regimens are lower than those seen in published studies; after one year, viral suppression often remains below standard detection limits in 37% to 60% of patients." However, the low rates of success in the studies cited by Henry were partly because therapy was delayed in some patients. In one of the studies, following patients in Southern Alberta, the study specifically reported that predictors of failure were having a higher viral load and lower CD4 cell count at the initiation of therapy.2 The same was true in the second study, conducted in an inner-city setting, which also found that factors such as missed clinic visits (which could reflect poor adherence) were predictive of drug failure.3 Both studies suggest that waiting to begin therapy increases the risk of early failure. So when is the better time to start? How far from clinical progression, at what viral load, at what CD4 cell count does the clinical payoff from starting therapy justify the risks of toxicity or becoming resistant to the drugs? Unfortunately, we just don't know. "Studies are needed to show how to use antiretroviral therapy to the best long-term advantage for the patient," said Dr. Powderly. Activists have been saying this for some time; in fact, one day just before the Retrovirus Conference the Treatment Action Group sponsored a symposium on "Long-Term Effectiveness Clinical Trials in HIV/AIDS" to address this issue (see "Long-Term Effectiveness Clinical Trials in HIV/AIDS," below). Unfortunately, the question of when to start treatment cannot be adequately addressed without first characterizing the long-term side effects of HAART regimens. The exact contribution of each drug and each class of drug to the emerging toxicities needs to be mapped out. We need studies that look at all different types of regimens, including protease inhibitor and nucleoside analog-sparing regimens. For example, if nucleoside analogs are found to contribute more to long-term toxicity than protease inhibitors, then a dual PI regimen with, say, one of the more benign nucleosides such as 3TC may wind up being the best first-line approach to treatment. Or a different strategy could be to use more toxic but more potent regimens for first-line treatment, but only for a limited time. "We might increasingly see doctors choosing less toxic regimens or using the more toxic regimens for a while and then switching," says Dr. Miles. We also need to recognize that the regimen that is most effective at 24 or 48 weeks, the current standard for regulatory approval, may not be the best regimen for a patient in the long run. That same regimen may cause greater toxicity or even a greater fatality rate after, say, four years. "Let's say you have a study between two drug regimens," said Dr. Miles. "Ninety percent of patients are undetectable on one regimen at week 48 but only 50% are at year two because of drop-out from long-term side effects. On the other regimen only 70% are undetectable at week 48, but they stay undetectable until year two because there are no drop-outs because of long-term toxicity." It is common in drug studies today for the first regimen to be declared the victor at week 48, and patients rolled over onto that "more effective" regimen. The possible difference at two years goes unevaluated and is rarely even suspected. What about Me? Choosing the Frying Pan Or the Fire Calling for more clinical trials is fine, but what if you are a person with HIV now considering or on early antiretroviral therapy? Dr. Miles in particular had much to share on this topic: "Now there is a clear recognition that these drugs cannot be taken for the duration. That is a given. But given this toxicity, where is it appropriate to intervene?" If you have just recently seroconverted, the rationale for beginning treatment is slightly different than for those who have been infected longer. At this stage of infection, early treatment might be capable of preserving a virtually undamaged immune system, complete with an anti-HIV immune response that seems impossible to recover when treatment is postponed. Having an immune system that is primed to fight the virus may lead to more sustained treatment responses. Also, this immune response may be part of the reason why some people are "long-term nonprogressors" — their immune system may better contain the virus. But it is not at all clear yet that early treatment will turn a recent seroconverter into a long-term nonprogressor, or that these immune responses are clinically relevant. In the vast majority of patients who opt to discontinue therapy despite being undetectable for a year or two, the virus quickly rebounds (see STIs, page 12). "Post-seroconversion treatment is a wholly unsettled question because you are committing them to lifelong therapy without any evidence of benefit," said Dr. Miles. "Despite the preservation of HIV-specific immune responses, in the majority of patients who discontinue treatment, viral loads rebound, so it is not clear what those immune responses are doing. They should not be treated outside of an experimental protocol such as those at Aaron Diamond." Most people do not find out that they are HIV-infected quite so early. And most have years to contemplate when to start treatment. This decision should, of course, be made with the advice of your doctor but clearly treatment should begin before you are in danger of getting a life-threatening opportunistic infection such as PCP. This would mean starting therapy while you still have more than 200 CD4 cells. In the US, however, most doctors prefer not letting CD4 cell counts fall so low that there might be a danger of dropping to below 200 between clinic visits. Recently, the International AIDS Society modified its treatment guidelines, recommending starting treatment when the CD4 cell count falls below 350. However, some patients' CD4 cells counts could take years to fall from 350 to 200 cells. Again, data from the MACS suggests that both CD4 cell count and viral load should be consulted (see table below). A very high viral load (e.g. over 100,000/ml.), may indicate which patients are in greater danger of a sudden drop in CD4 cell counts and at subsequent risk of clinical progression. Most patients with lower viral loads take years to progress. Frequently monitoring CD4 cell counts and viral load may be a better course of action than going on treatment. "One of my patients with a low viral load is progressing but very slowly," continued Dr. Miles. "He will probably not progress to symptoms until he is 85. Should he go on treatment now? No. And if you were my patient, and I showed you the tables that came from the MACS. If that table says you have a four percent chance of getting sick over the next nine years — would you go on treatment? Probably not." Some people who have early signs of disease such as shingles or other conditions which can occur at higher CD4 cells may wish to begin treatment sooner. Dr. Miles cited one example. "I have an older patient around 57 with a pretty low viral load, but his CD4 cell count had been slowly dropping. Recently, it dropped to about 350 CD4 cells, and I suggested to the patient that maybe this was the time to do something. The patient wasn't sure that he wanted to stay on therapy, but decided to give it a six-month trial. I put him on a once-a-day regimen with nevirapine, ddI, and 3TC. Over the next couple of months, his viral load went undetectable, and his CD4 cell count began to creep back up to 500. At one of his visits, the patient said, 'You know, I actually feel a lot better on the medicine.' Little things that he never knew were being caused by HIV had gone away, and he had a lot more energy. I asked him whether he thought he would still go off therapy at six months. Now he said that he thought he might want to stay on drug." As Dr. Mile's example illustrates, it is also possible to start early treatment on a trial basis and see how it goes. A decision to begin early therapy is not necessarily a commitment to stay on it indefinitely. Many patients do not seem to be suffering serious side effects. You might be one of them, and your response to therapy may be better than if you wait until your viral load is higher. You can always quit if you don't tolerate therapy well, or if your lifestyle can not presently accomodate the drug dosing schedules. But if you cannot adhere to therapy right now, it would be be better to stop the drugs entirely, as long as you are not in danger of clinical progression. Many patients who have been experiencing serious side effects from therapy have already quit. But this is not a decision to be made lightly either. Chances are that your viral load and CD4 cell count will return to the point where you initiated therapy. Some patients should not even consider it. "For example," said Dr. Miles, "take two patients. One has a CD4 cell count of 43, and a viral load over 400,000. You put him on triple drug therapy and his viral load goes undetectable, and his CD4 cell count goes up to 750. Another patient has a viral load of 50,000 and a CD4 cell count of 600. You put him on therapy and he also goes undetectable, and his CD4 cell count goes to 750. Which one should not go off therapy?" The patient who started out with advanced disease could be at great risk of risk of progression if he quits treatment. Unfortunately, many are doing this anyway (see "Has the Pendulum Swung Too Far in the Opposite Direction?" below). But there are other options to consider first, such as a different treatment regimen or side effect management, or participating in a toxicity management study. The latter could have the dual benefit of possibly treating your condition, and providing solutions for which many other people with HIV are now waiting. This may be the best reason to wait before beginning treatment. Tomorrow's antiretrovirals should be better. At the very least, there should be more answers about how to manage the toxicity. Footnotes: 1. Paterson D et al. 6th Conference on Retroviruses & Opportunistic Infections, Chicago, 1999 Abstract 92. 2. Mocroft A et al. AIDS. 1998;12:2161-7. 3. Lucas GM et. Ann Intern Med. 1999;131:81-7.   Table: The Relative Risk of Progression to AIDS Within Three Years in the Multicenter AIDS Cohort Study Viral Load Below 200 201-350 CD4 Count 351-500 501-750 Above 750 Below 1,500 ** ** ** 3.7 0 1,501-7,000 ** ** 2.0 2.0 2.0 7,000-20,000 ** 8.1 8.1 8.1 3.2 20,000-55,000 40.1 40.1 16.1 16.1 9.5 Above 55,000 85.5 64.4 42.9 32.6 32.6 Viral load levels relate to results using the Roche Amplicor RT-PCR test. **Indicates a lack of data   Celia Farber and Denial in the Streets of San Francisco      [Editor's commentary] While in San Francisco for the Retrovirus Conference, I kept seeing wheat-pasted flyers that defaced posters for the San Francisco AIDS Foundation. "SFAF is homophobic," they said, or "HIV is a myth." It was clear to me that the AIDS denialists, those who believe that HIV is not the cause of AIDS, were experiencing a resurgence, at least in the City by the Bay. Since then they have disrupted treatment education forums, and lobbied Congress to not reauthorize the Ryan White Care Act. Their movement has been with us since the late '80's when they began spreading the message that it was not the virus making people sick, but other factors, including anti-HIV drugs such as AZT. They were partly right about one thing. Though not the cause of AIDS, the early nucleoside analogs sometimes made people ill. The drugs could also delay disease and improve survival as long as they continued to work against the virus (until resistance had set in). But at the time, it was much harder to tell when the drugs were, or had stopped, working because viral load tests were not available to clinicians for patient management. Instead, people were kept on therapy until clinical progression or major drops in CD4 cell counts, long after the drug's effectiveness had worn off. At that point, the nucleoside analogs were merely toxins that probably did cause more harm than good. However, the AIDS denialist movement became rather quiescent around the time the protease inhibitors appeared on the scene, and when triple combination therapy was shown to dramatically decrease HIV levels, and the incidence of AIDS-related opportunistic infections and death. Surely, as clearly as any other evidence, this seemed to prove once and for all that HIV caused AIDS and that keeping the virus suppressed kept the disease at bay. Over the last two years however, the AIDS denialist movement has gradually been picking up steam, at roughly the same time that the very visible signs of lipodystrophy appeared. Then shortly after the Retrovirus Conference, GMHC's hotline phones began to light up. Callers were frightened by an article that had appeared in Gear magazine, by longtime AIDS denialist journalist Celia Farber, describing the "unimaginable horror" of antiretroviral therapy. The article quotes respected physicians who complain that HAART is being used far too early and is harming otherwise healthy HIV-positive people. However, all of these doctors stressed that the drugs have had a dramatic beneficial impact on the treatment of AIDS. "There is absolutely no question whatsoever that protease inhibitors have helped people," said Dr. Joseph Sonnabend. "I have personally seen what was being called the Lazurus effect [where chronically ill people rise off their deathbeds]," she quoted Dr. Micheal Lange of St. Luke's Roosevelt as saying. But the article is mostly a vicious personal attack on Dr. David Ho. Says Dr. Mile's, who was also quoted in her article, "She had a very deliberate agendaÉ that she built her article around. It seemed to be to bash David Ho. I don't know why." Farber essentially blames lipodystrophy on protease inhibitors and Dr. Ho. She asserts that the protease inhibitors were approved mostly because of Dr. Ho's theory that eradication might be possible if the virus is fully suppressed by potent therapy. She ignores the body of clinical evidence of reduced opportunistic infections and AIDS-related mortality that led to marketing approval of ritonavir and the other protease inhibitors. Instead, she only notes reports of drug toxicity. Eventually, she gets back to old AIDS denialist rhetoric, which denies HIV's causative role in AIDS. Along the way, she includes comments from AIDS denialist "experts" such as mathematician Mark Craddock from the University of Technology-Sydney. He demonstrates his grasp of the microscopic with the following quote, "Ho's equations predict that over the course of 10 years, an HIV-positive person will produce more particles of HIV than there are atoms in the universe." Such sensationalism sells magazines. It also makes our jobs communicating the complex issues surrounding the long-term side effects of HIV treatment more difficult. People should be warned about how debilitating these side effects can be when making their treatment decisions. The trick is how to do this without panicking patients, and without scaring people who need to be on therapy. But I wonder whether this treatment education dilemma, and the resurgence of the AIDS denialist movement, could have been avoided if the HIV community had not initially been in a kind of collective denial about the potential long-term side effects of HAART. Some of us, including myself, were also a bit naive or over-optimistic that eradication would be so easily achievable. Until we had gathered more long-term data, caution was probably warranted before the treatment of those with less advanced disease became public health policy. I worry that I bear some responsibility as a treatment journalist, along with mainstream media and the pharmaceutical industry, for hyping the experimental approach of hitting hard and early. I certainly underestimated the potential for long-term toxicity. A proper respect for the consequences of drug therapy would have been a better thing. Fewer people might have been hurt. It is clear that some have been, and this has provided fuel for the AIDS denialist movement, which in turn is causing even more harm with their message that people don't have to practice safer sex or go on treatment at all. This should cause us to be more circumspect. AIDS is not a simple problem, and throwing drugs at it is not the simple solution we might hope it to be. Unfortunately, the drugs come with their own set of problems, and it may take us more than a few years to sort them all out.   Long-Term Effectiveness Clinical Trials in HIV/AIDS      A community meeting, Long-Term Effectiveness Clinical Trials in HIV/AIDS, met in San Francisco on January 29, 2000, the day before the Retrovirus Conference began. Approximately 50 activists met in response to the NIH's workshop on long-term studies in HIV infection that was held in Bethesda on January 12 and 13. The NIH workshop addressed the following questions: What are the high priority clinical questions to be addressed through long-term clinical studies in the era of HAART? What is the role of cohort studies and randomized clinical trials in addressing long-term clinical questions? What are the statistical challenges and alternative approaches in addressing long-term clinical questions? There were also breakout sessions on when to start, when to switch, and long-term clinical efficacy and tolerability of HAART. Participants of the NIH workshop provided summaries and led discussions of how the HIV/AIDS community should respond. As might be expected, everyone agreed that data on long-term treatment of HIV/AIDS — including information about toxicities and side effects, quality of life, treatment strategies (especially when to start and when to switch), and coinfections — would be valuable. However, there was less consensus when it came to logistics. For instance, which questions would require large, randomized trials, and how large would they have to be? What role could observational studies play? Would changes in treatment make the results obsolete? How difficult would it be to enroll participants? What should the clinical endpoints be? Ethical concerns about equipoise, determining the standard of care, and informed consent were also raised, as was the importance of getting input from a more diverse and representative group. Some, however, felt that money would be better spent on smaller trials focusing on more specific questions. Since this meeting, a Long-Term Effectiveness Research (LTER) Focus Group has formed to address these and other issues. It has issued the following consensus statement, which GMHC and a large number of other organizations have signed. Consensus Statement on Long-term Effectiveness Research       1. Too Many Questions, Not Enough Answers: The Urgent Need for Long-Term Effectiveness Research Every day thousands of people living with HIV agonize over questions about whether or not to begin antiretroviral therapy: How high can my viral load rise or my CD4 count fall before it's too late? How safe are the medications? If I start now, will the drug complications and toxicities outweigh the benefits? Should I wait for newer and better medications? How long can I afford to wait? Which is the best drug regimen to start with? And, along with almost everyone already on antiretrovirals, they worry about drug complications and resistance. What are the long-term complications and toxicities? What are my chances of getting them? If the drug regimen doesn't work or stops working, what should I do next? How long before I develop resistance to the drugs? How high can I let my viral load climb before I need to change drugs? What should I do when multi-drug resistance develops? Are the answers to these questions different for women and men? For different ethnicities? For different age groups? How about those with additional diseases, such as hepatitis, diabetes, cardiovascular disease or addiction disorders? These are issues that will affect the lives and health of hundreds of thousands of people, involve billions of dollars in annual medication and other health care costs, and influence the standards of HIV care for decades. Yet there is precious little scientific data to help us make these decisions. We, the undersigned, call on the National Institutes of Health to address this situation immediately. NIH must immediately commit significant financial and organizational resources to research these questions and develop, as expeditiously as possible, a detailed plan for that research. We are years behind where we should be and the lives and health of many are increasingly at risk. As a first step in this process, NIH should immediately consult with a variety of advisors — including members of the HIV/AIDS community, researchers, clinicians, statisticians, and members of the pharmaceutical industry — to begin development of a long-term clinical research plan. We insist upon full and immediate community participation in all stages of planning this research, utilizing the experience, knowledge and commitment of HIV/AIDS community activists reporting back to the larger affected community. 2. Priority Areas for Long-Term Effectiveness Research We call on NIH to demonstrate leadership and expedite the design and funding of long-term effectiveness research to answer these priority questions: When and how should antiretroviral therapy be started? When should antiretroviral therapy be changed and to what? What are the long-term complications and toxicities of antiretroviral therapy? What are the consequences of moderately unsuppressed viral load and treatment interruption? It is important that the answers are relevant to as many people living with HIV as possible including women, the elderly, adolescents, African Americans, Hispanics, and other ethnic groups as well as those living with hepatitis, diabetes, or other life-complications. 3. Design of Long-Term Effectiveness Research NIH must confront its institutional biases and restrictions and provide creative, collaborative and flexible leadership in conducting trials that will certainly be larger and longer than those it has traditionally conducted for HIV/AIDS. NIH should consult a wide range of experts, including those who have done long-term research in other fields of medicine. The NIAID funding cycle is currently five years. NIH needs to ensure that there is adequate funding for the longer time periods required to complete these kinds of studies. NIH must demonstrate leadership to begin collaboration among national and international HIV research networks and to secure the cooperation and participation of the pharmaceutical industry. The well being of those living with HIV must supersede personal and institutional agendas and in fighting. NIH should give priority to trial designs that permit analysis according to the subpopulations we have highlighted — whether by stratification, nested substudies or other appropriate trial design. The landscape of antiretroviral therapy is constantly changing. Trial designs must be flexible to accommodate new developments and ensure the relevance of answers at the conclusion. The length and size of these studies, as well as the great importance of the answers for determining proper standards of care for HIV treatment, require extraordinary efforts for recruitment and retention. NIH needs to conduct educational campaigns, targeted at patients and providers, to aid in the recruitment and retention of people from all affected communities. Trials should be conducted in the settings in which patients receive their regular medical care. The complexity of these trials may require assessments of their feasibility, including pilot studies. Not every question may require a randomized clinical trial. Some, such as the elucidation of long-term complications and toxicities of antiretroviral therapy, may be better answered with observational databases. Yet, NIH is ultimately responsible for guaranteeing that these questions will be answered in an efficient, ethical and scientifically rigorous manner. Too much time has already been lost. The risk of continued delay is too great. We call on NIH to act now.   Has the Pendulum Swung Too Far in the Opposite Direction?    By Theo Smart Despite Dr. Miles concerns that early antiretroviral therapy may be harming some patients, as noted in the Celia Farber article, he thinks that the drug bashing has gone a little too far. He is concerned that some patients who should be on treatment are quitting, and others afraid to start. "Sometimes I'd like to give the community Lithium, because we go from 'Oh, therapy is terrible,' to 'therapy is wonderful,' to 'therapy is terrible' and back again. "I have an oncologist colleague who draws a bell-shape curve to describe the community's response to new treatments. The curve starts at zero and you begin going up with phase I data that is promising, then there is a huge shift with good phase II data and the start of phase III studies and open label access programs. The highest point is reached when people realize that the one percent, toxicity that seemed minor before is actually causing problems in a significant number of people. At that point, the curve starts to descend and you go below zero when the drugs are bashed as horrible. But then the curve starts going back up again, as people begin to get an honest appraisal of the drug's benefit. "The real problem I see now is patients who really ought to be on drug but who have quit treatment since February and early March [after the Retrovirus Conference and the Gear article respectively]. That's the really devastating thing. People who should be on therapy are telling their doctors that everything is okay and then go home, and never pick up their scrips. There are large groups of patients who have heard about the toxicity, heard about treatment interruptions and have taken home the message that it is okay to go off treatment. "In LA, there were 20,000 fewer prescriptions filled in March because patients stopped taking their medications, and in April, another 8,000 stopped. "The pendulum has swung back, partly because of drug company marketing where one company is bashing the other companies' drugs as toxic. You just don't do that. It's like negative campaigning in an election. All the voters stay home." At the same time, Dr. Miles thinks that drug companies should be able, on the basis of controlled clinical trials, to report whether their drugs are less toxic than those of their competitors. "Manufacturers ought to be able to amend their product labeling, when data show that their product is less toxic than their competitors', because it would encourage them to do more toxicity research and to develop less toxic drugs. We need to find ways to use better tolerance as a differentiation feature for accelerated approval, and put less emphasis on efficacy." His message to manufacturers: "The war is not over — we've got to come up with new medicines, new drugs that are less toxic."   New Developments in Fat Redistribution and Metabolic Disorders Associated with HAART    By Gabriel Torres, M.D. The 7th National Conference on Retroviruses and Opportunistic Infections devoted a significant part of its oral and poster presentations to lipodystrophy, which is more accurately called HIV-related adipose redistribution syndrome (HARS). This disorder, a possible long-term complication of anti-HIV therapy, has become one of the leading obstacles in the management of HIV disease. Fear of it dissuades newly infected persons from starting treatment, and leads others who have been on therapy to interrupt or stop treatment altogether. The syndrome of fat redistribution has multiple characteristics. These include body habitus changes such as deposition of fat in the dorsocervical area (buffalo humps) and around the torso and waist (truncal adiposity); enlargement of the breasts; and loss of fat in the buttocks, limbs (peripheral lipodystrophy) and in the cheeks (facial fat atrophy), causing the hollowing of the cheeks and grooving of the nasolabial fold. It may or may not be accompanied by elevations in blood lipids (cholesterol and triglycerides) and/or blood glucose levels, which in many cases can accelerate the progression of coronary artery and cerebral artery disease leading to heart attacks and strokes. However, some researchers, such as Kathleen Mulligan, PhD, from UCSF, think that these characteristics may not all part of one syndrome (abstracts S20, 202). Rather, she posits that there may be more than one syndrome with distinct etiologies, some of which may actually be caused by nucleoside analogs not protease inhibitors (see box on facing page). This could at least partly explain why the basic science and animal studies evaluating possible causes of the fat metabolism do not seem to consistently explain all the various facets of the disorder and sometimes are contradictory. Some conflicting results may depend on which company was conducting the study. For example, one showed that amprenavir and saquinavir reduce triglycerides in mice fed a low fat diet, whereas another showed that indinavir, nelfinavir and saquinavir all lead to rises in triglyceride levels (abstract 37). Studies by Lenhard and others from Glaxo Wellcome (abstract 38) continued to show the effect of indinavir on retinoid receptors, which are involved not only in fat metabolism but also in the generation of skin and its appendages. This may explain the disorders of dry skin (xerosis), dry mouth (xerostomia), ingrown toe nails (paronychia), and alopecia (hair loss) seen sometimes with indinavir use. Another in vitro study showed that nelfinavir and ritonavir increased the production of triglycerides in the liver (abstract 39). Despite these suggestive studies, none can establish cause and effect, and many postulate that the disorder may have nothing to do with the therapy but may be a long-term consequence of HIV infection, since it has been seen in patients who have never been on protease inhibitors, those who have been on nucleoside therapy alone, and even a few that have never received treatment. Epidemiology Several studies attempted to evaluate the overall prevalence of the fat redistribution disorder in the HIV-infected population in their community. A very large Australian study (1350 patients) found a prevalence of 53% of body habitus changes by physician assessment, more commonly with those who used protease inhibitors (81%) than those who had not (33%) (abstract 201). One provocative study by Wanke and others from Boston found a significantly lower rate of fat deposition and atrophy among African-Americans and women than others. However, this study based its definition of fat atrophy and deposition on strict anthropometric measurements such as waist/hip ratios and triceps skinfold thickness, which may not truly measure the severity of the fat redistribution (abstract 24). In addition it found no association between HAART and the development of the syndrome, or an association with drug use, use of anabolics or appetite stimulants. The largest study (HIV Outpatient Study), conducted by the CDC, found that the risk factors for the development of the syndrome included age, years of HIV infection or years since an AIDS diagnosis, use of indinavir and/or d4T, and months since the lowest CD4 cell count (abstract 23). Another large study from Barcelona, Spain, reported that 13% of their cohort of 506 patients developed lipodystrophy after an average of 18 months. It found an association with older age, sexual transmission of HIV and longer duration of d4T therapy (abstract 15). Another European study by Rozenbaum and others found significantly higher incidence of the syndrome among the 203 patients: 60% had at least one sign of the condition, such as atrophy in 16%, hypertrophy in 23%, and both in 20% (abstract 14). They evaluated the metabolic abnormalities and found that elevated cholesterol and triglyceride levels were found in 34% and 30% respectively, and diabetes mellitus in 3%. One study (abstract 22) suggested that single slice computed tomography (CT) scanning through the umbilicus was very effective in detecting fat deposition in the subcutaneous and the intra-abdominal cavity, using the VAT:TAT ratio (visceral to total adipose tissue), which was highest in patients with clinical HIV disease on HAART and not significantly elevated in non-HIV-infected controls or in naive patients. Other studies found a correlation between lipodystrophy and elevated cortisol/DHEA ratios and in serum alpha interferon levels, both of which are involved in fat metabolism (abstract 203). Two studies also found an association with accelerated bone mineral loss (osteopenia and osteoporosis) using dual energy absorptiometry (abstracts 207 and 208). In one the rate among patients receiving HAART was 21% compared to 6% among those not receiving HAART; in the other study of patients with lipodystrophy, 28% had osteopenia and 9.5% had osteoporosis.   Mitochondrial Mayhem     By Theo Smart With the passage of time and accumulation of more data, we are learning more about the nature of lipodystrophy and metabolic complications. Still, there were widely varying reports on their incidence at the Retrovirus Conference. Much depends on how the syndrome is defined, but now the question seems to be "Is it one syndrome, or many?" It appears to be much more complicated than initially thought. In one symposia at the Retrovirus Conference, Kathleen Mulligan of UCSF explained, "Because a number of these problems were initially appreciated around the time that protease inhibitors came into widespread use, it was initially assumed that these problems were the result of protease inhibitor use. That assumption might have been premature or at least incomplete." Much of the focus has now been shifted to the toxicity of nucleoside analogs to mitochondrial DNA. Mitochondria are organelles within cells, small factories responsible for the cellular respiration that powers the cell. Each mitochondrion contains its own DNA, which serves as instructions for the production of some proteins used in cellular respiration. Unfortunately, polymerase gamma, the enzyme responsible for copying mitochondrial DNA, sometimes does not recognize that nucleoside analogs are not real DNA building blocks. When the enzyme uses the nucleoside analogs, there is decreased production of mitochondrial DNA, or production of mutant DNA, which in turn leads to decreased production of mitochondrial proteins. Without these proteins, cellular respiration and energy production drops, and cells may start to malfunction. This can lead to a range of clinical symptoms, depending upon which cells (and organs) are affected. These include polyneuropathy (seen with ddC, ddI, and d4T); myopathy (AZT); cardiomyopathy (AZT, ddC, ddI); liver problems like steatosis and lactic acidosis (AZT, ddI, d4T); gastrointestinal problems including pancreatitis and vomiting (AZT, ddI, d4T); hematological with pancytopenias (AZT); kidney toxicity such as proximal tubular dysfunction (adefovir); and now apparently, fat cells, leading to lipodystrophy. In a presentation at a community meeting, Dr. Kees Brinkman noted that mitochondrial toxicity causes a related syndrome, multiple symmetrical lipomatosis, in people without HIV. Drs. Cooper and Carr, who earlier reported on lipodystrophy in patients on protease inhibitors, recently reported a similar syndrome in patients who were only on nucleoside analogs and had developed lactic acidemia (abstract S21). Lactic acid is a waste product when cellular respiration is inadequate, and its accumulation can be quite dangerous, even fatal. What Cooper and Carr found were severe changes in body composition, with fat loss in the periphery, but with perhaps less truncal fat accumulation. In other words, nucleoside analogs may be responsible for fat loss, but not fat accumulation. A number of other studies have suggested that duration of nucleoside analog use may be associated with lipodystophy. Some have similarly associated nucleoside analog use with fat loss in the periphery (arms, legs, buttock) and face. d4T in particular was singled out, often by Glaxo Wellcome funded studies. But the association with d4T may be an accident of history (most who have used d4T have previously used AZT) or due to the fact that people susceptible to nucleoside analog mitochondrial toxicity may take d4T longer because AZT's toxicity is more immediate. Said Dr. Miles "people who drop off of AZT because of myopathy and anemia may simply be staying on d4T long enough for this toxicity to become noticeable." At present, these are just theories. Even so, some clinicians are already using nucleoside-sparing regimens in patients with severe facial wasting. Dr. Cassie Workman from Australia is one, despite the fact that "many people seem to act like not including a nucleoside analog in a combination is blasphemy," she told TI at a recent meeting. But if indeed nucleoside analogs are to blame for some aspects of lipodystrophy, then why has not the pattern been observed before? Well, indeed many believe it has, as Dr. Donald Kotler has long maintained (see Treatment Issues, March 1999). Now, particularly as people have been surviving longer, the effectiveness of HAART may simply have allowed the effect of mitochondrial toxicity become more noticeable over time.   Structured Treatment Interruptions and HIV Immune Response   By Gil Shepard Along with their new legitimacy as a potential treatment strategy, "drug holidays" are now known as structured treatment interruptions (STIs), and they are being studied in two very different contexts. First, some researchers have been exploring the use of STIs in a salvage population as a way of shifting viral population from resistant to wild type, perhaps eliminating the former (see Treatment Issues, "Going Wild (Type) with Structured Treatment Interruptions," September/October 1999). But, second, STIs are also being studied in people who have had undetectable, or very low, viral loads for an extended period. In this population, the rationale for the STI is to promote an immune response to HIV: an STI might allow endogenous HIV antigens to stimulate cellular immune responses. This could lead to partial immune control of the virus, allowing people to take drugs intermittently, or, in some cases, it could even result in complete immune control and the discontinuation of HAART. Such results are especially appealing because there is almost no chance that HAART can eliminate HIV from the body, because drug regimens are complicated, toxic, and difficult to adhere to, and because long-term side effects, such as lipodystrophy, are becoming more common and worrisome. Nevertheless, STIs also carry significant risk to the patient — without proven benefit — so they are not currently recommended. Unfortunately, many patients are not aware of the theory behind STIs and are simply stopping therapy, which leads to an increase in viral load and possible loss of CD4 cells in an uncontrolled setting. Another potentially serious risk is the development of drug resistance. At this point, such negative outcomes are much more likely than the handful of documented success stories. From Berlin to Bethesda and Brussels The use of STIs to boost the immune system was initially suggested by the now famous "Berlin patient," who started therapy (ddI, hydroxyurea and indinavir) before seroconversion but stopped treatment three times since then. The first time, viral load increased. The second and third times, however, viral load remained undetectable (the second interruption was due to a bout of hepatitis A). Remarkably, since the third interruption started in December of 1996, therapy has not been reinitiated and viral load is still undetectable. Although HIV antibodies haven't been detected, he has CD4 cells that respond to HIV's p24 protein and cytotoxic T-lymphocytes (CTLs) that are primed for HIV-infected cells. Somewhat similar results were obtained in a study at New York's Aaron Diamond Research Center. Thirty-eight men with primary HIV infection were put on AZT/3TC plus either ritonavir, indinavir, or ritonavir/indinavir. Eleven later discontinued therapy, two of whom had especially interesting results. Both stopped and restarted therapy several times, eventually stopping for two years. During that time, one's viral load ranged between 50 and 500 copies and the other's ranged between 50 and 2,000 copies. In addition, they had a strong population of anti-HIV CTLs. In both cases, therapy was initiated during primary infection and treatment was discontinued several times. It is not known what, if any, role these factors played, but there is some reason to think they might be important. Several studies suggest that after the first interruption in treatment, the immune system can manage to get more control over HIV — for some patients, viral loads rise more slowly and stabilize at lower levels. And many think that treatment during primary infection protects the immune system, which could mean that those treated early would have a better chance of controlling the virus without HAART. Some researchers are also using therapeutic vaccines, hydroxyurea, or IL-2 to help activate an immune response. Recently, there have been more conference reports of patients who discontinue therapy but have had no or little rebound in viral load. First, there was NIAID's NoHRT study (ICAAC, abstract 689). Dr. Davey reported on 18 patients who started HAART during chronic infection. The median CD4 count was 921, median time that viral load had been below 500 copies was 108 weeks, and the median time of a protease inhibitor-based HAART regimen was 137 weeks. Twelve (67%) had been previously treated with IL-2. One of the 18 patients had no detectable HIV DNA in peripheral blood mononuclear cells (PBMCs) and seven had undetectable levels of latently-infected resting CD4 lymphocytes (five of these seven had taken IL-2); of ten that had lumbar punctures, all had a cerebral spinal fluid viral load below 50 copies; and three of five who had lymph node biopsies had fewer than 50 copies per ten million cells. Despite the promising characteristics of this group, all had rebounds when they discontinued HAART and IL-2. Viral loads increased approximately 0.2 log per day and surpassed 50 copies in a mean of 11 days and 500 copies in 18 days. In addition, HIV was detectable in resting CD4 cells of all patients. No difference was noted in the rates of virologic rebounds between those who had and had not received IL-2 therapy. However, there was one notable result. The so-called "Bethesda patient" only had a slight rebound in viral load that ranged between 50 and 500 copies for six months. Unlike earlier cases, the Bethesda patient did not start treatment during primary infection. Not to be outdone, a team from Brussels presented an STI study in which three patients discontinued therapy without a rebound in viral load for 4 to 24 months (ECCAT, abstract 413). An initial group of seven patients started a variety of treatments during primary infection and continued for 12 to 36 months. Researchers did not find any regimen-specific differences between the four who had rebounds in viral load and the three who did not. However, they did note that the rebounders, in contrast with those who did not have rebounds, had increased markers of activated CD8 cells prior to the STI. HAART Initiated during Primary Infection At the Infectious Disease Society of America's conference in Philadelphia last November, Rosenberg presented results of a study designed to test whether initiating HAART early in primary infection would preserve an HIV-specific immune response (abstract 725). A total of 25 patients started HAART before seroconversion when no HIV antibodies were detected but there were high viral loads (median 13.3 million copies). Mean CD4 count was 418 cells. At baseline, patients were given a test to measure CD4 lymphoproliferative responses (LPRs), which determine the degree to which a patient's CD4 cells respond to HIV antigens. Results are given in terms of a stimulation index (SI). If the SI is below ten, it indicates an inadequate immune response. Initially three of the 25 (12%) had an SI above ten. HAART was initiated and all patients' viral loads were suppressed below the limit of detection (limit not given). After two months of drug therapy, 16 of 22 patients (73%) had an SI greater than ten (mean of 42) and two had an SI greater than 100. At month six, the mean SI increased to 44, where it remained through month twelve. At month twelve, thirteen of fifteen patients (87%) had an SI greater than ten. (The other two patients had drug-resistant HIV and responded to therapy slowly.) After one year of successful HAART, two of the patients consented to at least two STIs. The first interrupted therapy for a few weeks. Viral load peaked at 17,000 copies after about three weeks and the SI was over 100. Therapy was successfully restarted for four months, at which point the patient developed hepatitis A and had a second (unplanned) treatment interruption of about four weeks. After two weeks, viral load rebounded to 37,000 copies, but 72 hours later it fell to 6,000 and, after another 48 hours, to 400. Upon recovery from the hepatitis A infection, the viral load rose to 7,000 copies, HAART was reinitiated, and viral load became undetectable again. During this second STI, the SI was over 800, one of the highest SIs recorded in an HIV-positive person. A third STI lasted about three months. Generally, viral load remained below 5,000 copies, although there were two occasions on which it rose to 12,000 (the second time, the patient had gonorrhea of the throat) before falling again. With a viral load of 3,600, the patient restarted therapy and viral load became undetectable. The second patient underwent two STIs. During the first, which lasted about three weeks, viral load rebounded to 120,000; however, the SI went from 20 at baseline to 130. Viral load became undetectable once HAART was restarted. The second time, the patient's viral load remained below 5,000 copies for four months. At that point, therapy was initiated again and viral load became undetectable. This year's Retrovirus Conference included several other STI studies in which therapy was started during primary infection. From a group of fifteen patients, Altfeld reported on seven who underwent an STI (abstract 357). Mean baseline viral load for the entire group was 13.8 million copies, but it became undetectable after initiating HAART. Viral loads remained undetectable for at least one year, when the present study began. Ten of the fifteen also showed low levels of CTL responses against one to four epitopes (HIV protein sequences). All seven who discontinued therapy had a rebound in viral load within one to eight weeks, as well as an increase in CTL responses. There was both an increase in the number of HIV epitopes recognized (median two; range zero to three) and a greater magnitude of response to epitopes that had been previously recognized. In addition, two patients who had no CTL response prior to the STI developed one afterward. Two of the patients had a second STI, which resulted in a greater increase in cytotoxic T-lymphocyte (CTL) response. Zala presented results of an STI involving patients who initiated d4T, ddI, and nevirapine therapy, with or without hydroxyurea (abstract 558). Of eighteen patients (half of whom were taking hydroxyurea) who had completed their 48-week follow-up, 83% had viral loads below 500 copies and 67% were below 50 copies. From this group, eight underwent an STI after a median of 57 weeks (range 53 to 75 weeks) of therapy. While five of the eight were receiving hydroxyurea, researchers did not indicate whether any of the eight had undetectable viral loads prior to the STI. Viral loads rebounded to over 5,000 copies in all eight within 21 days of the STI. After peaking (peak viral loads were not reported), viral loads dropped by a median of 0.69 log (range 0.48 to 1.05). No significant differences were found between those who did and did not take hydroxyurea. Of interest, one patient who was not taking hydroxyurea discontinued therapy due to peripheral neuropathy at week 20, and his viral load remained below 50 copies after 46 weeks without therapy. At a Retrovirus late-breaker, Jin presented the first STI study that involved the use of an experimental, therapeutic vaccine (LB 12). Four patients who began treatment with AZT/3TC/ indinavir between seven and 100 days (median 60 days) after infection were enrolled. All achieved an undetectable viral load (<50 copies) after therapy, and this was sustained for 2.5 years. At that point, they began a course of an experimental vaccine that combined recombinant ALVAC 1452 and gp160. One week after their final vaccination and a median of 1162 days (3.2 years) of HAART, the patients discontinued therapy. Two patients had a rapid rebound in viral load, which became detectable at days thirteen and 23 and had a doubling time of 1.4 days. However, the other two did not have a detectable viral load until days 68 and 85, and doubling times were 4.5 and 3.2 days. In addition, the two with a delayed viral rebound had significant increases in CTLs to more than one viral antigen, whereas one of the normal rebounders had no measurable CTL response to the vaccines and the other only showed a response to the gag protein. Finally, after four and eight months off therapy, the slower rebounders had viral loads of 5,600 and 330 copies, respectively; at four months off therapy, the normal rebounders' viral loads were 3,500 and over 50,000 copies. In these four studies, patients undergoing an STI consistently had increases in viral load, but several patients also had either a spontaneous drop (Zala, Rosenberg) or lower viral loads with subsequent STIs (Rosenberg). There were also indications of a cellular immune response during the STIs in three studies — increased stimulation index (Rosenberg), greater CTL response (Altfeld, Jin), or a broader and more pronounced response to epitopes (Altfeld). And although hydroxyurea did not seem to have an effect on outcome, Jin's research indicates that a therapeutic vaccine might enhance a cellular immune response. HAART Initiated during Chronic Infection Returning to the IDSA conference, Haslett presented retrospective, cross-sectional data that imply patients who do not start HAART until chronic infection can also gain immune control over HIV during treatment interruption (abstract 15). Like Rosenberg (discussed above), Haslett compared the LPR SI of eleven patients who had stopped therapy for at least one week to eleven patients who had never stopped therapy. The "interrupters" had a median SI of 45, which was significantly higher than that of non-interrupters (median SI=3; p<0.05). Again, several presentations at the Retrovirus Conference involved STIs in people who started HAART during chronic infection, several of which were updates of reports given at earlier conferences. In a study presented by Garcia (LB 11), 10 patients who were treated with d4T, 3TC, and ritonavir or indinavir underwent three STIs. They had been on HAART for 52 weeks and had a viral load below 20 copies for at least 32 weeks before the first STI. Prior to each STI, all patients also had a viral load below 20 copies and seven were below five copies (one was lost to follow-up after the first STI). The STIs were spaced six months apart, and after each STI patients restarted the same drug therapy. After each STI, viral load rebounded with a doubling time of 2.23, 3.38, and 3.25 days for the first, second, and third stops, respectively. During the second treatment interruption, four patients initially had viral rebounds to pre-HAART levels, but levels then spontaneously dropped by 0.8 to 2.09 log. The four also showed HIV-specific CTL responses and strong CD4 cell responses to HIV antigens. Similarly, four patients had viral loads that were 0.6 to 1.5 log lower than pretreatment and showed HIV-specific cellular immune responses during the third STI. A study by Ruiz also showed a slower doubling time, from a mean of 1.6 to 2.2 days, between 12 patients' first and second STIs (abstract 354). While there was no change in the percentage of CD4 and CD8 cells during the STIs, viral load rebound did lead to a significant rise in CD38 expression (an indication of CD8 cell activation). There was no noticeable difference in outcomes between the five who did and the seven who did not take IL-2 before the study. In another IL-2 study, Smith examined nine patients on HAART and daily low-dose IL-2 therapy (abstract 355). (Typically, IL-2 is given in higher, cyclical doses.) HAART was discontinued, but patients remained on IL-2. Viral loads became detectable in all nine after 19 days and rapidly increased for the next two weeks (2.0 day doubling time) to almost 350,000 (±230,000) copies. However, over the next four weeks, viral load steadily decreased, stabilizing at a low of approximately 26,000 (±8,000) copies, a level that was significantly lower than the pre-HAART mean viral load (about 70,000 ±20,500, p<0.01). Just after viral load peaked, CD4 counts dropped by 24% compared to baseline. With viral rebound, there was also an increase in CD8 cells to about 200% of baseline, which remained high while viral load dropped. Without a control group, however, it is difficult to know the impact of this approach to IL-2 therapy. Papasavvas compared CD4 and CD8 cellular immune responses in five patients on HAART who underwent an STI to five untreated controls (abstract 353). In contrast with the control group, the STI group had significant increases in CD4 cell responses against p24 and gp160, which were followed by significant increases in interferon-gamma-secreting CD8 T-cell responses against HIV envelope antigens. After a median STI of 46 days, three of the five patients resumed HAART and maintained or further increased their cell-mediated HIV responses. The other two remained off therapy with viral loads below 1,080 copies and continued high cell-mediated responses. Lori presented a case-controlled study (abstract 352) comparing eight patients on HAART with nine on ddI and hydroxyurea (the PANDA cohort). In contrast with the HAART patients, the PANDA cohort had low but detectable viral loads and a strong HIV-specific cellular immune response. Groups were similar in terms of time on treatment (more than two years for both), CD4 counts (HAART=549±175, PANDA=495±127), and CD8 counts (HAART=874±203, PANDA = 805±335). However, seven of eight on HAART had a viral load below 50 copies while only one of nine in the PANDA cohort was below 50 copies. Both groups stopped treatment for up to eight weeks. Failure after the STI was defined as a rebound in viral load to greater than 10,000 copies or CD4 count decrease to below 200 cells. Five of the HAART patients failed by week six (one at week two and four at week six) and restarted therapy, and the average viral load rebounded from 97 to 16,863 copies (2.25 log). In addition, HAART patients' CD4 counts dropped an average of 208 cells and CD8 counts increased by an average of 323 cells (CD4/CD8 ratios dropped significantly, to below 0.3). In contrast, none of the PANDA patients failed during the STI; viral load increased from 843 to 1,596 copies (0.27 log) but fell to pre-STI levels by week eight; and CD4 and CD8 counts, as well as the CD4/CD8 ratios, remained stable. Interpreting the results is difficult, however, since the PANDA group, unlike the HAART group, also had an eight-week STI before this study. The largest prospective STI trial so far is the Swiss Intermittent Treatment Trial (SITT), which plans to enroll 120 patients. The trial design involves four cycles of two weeks off therapy followed by eight weeks of therapy. At week 40, treatment is discontinued indefinitely unless viral load rises above 5,000 copies. At the Retrovirus Conference, preliminary data were available (abstract 458). Median pre-HAART CD4 count was 398 cells and median viral load was 36,000 copies. Before beginning the study, patients had been on HAART for a median of 24 months and the median time with a viral load below 50 copies was 21 months. Of the 96 patients to undergo the first STI, 30% showed no increase in viral load. Fifty-four and 23 people went through the second and third STIs, respectively, but there was no evidence that viral rebounds were less frequent or smaller. Since this trial is much larger than the others, future data could prove especially interesting. Don't Try This at Home So far, STI trials have been small, and the number of people who have maintained an undetectable viral load without therapy is even smaller. Some context was provided by Sherer's retrospective examination of thirteen people who had viral loads below 500 copies after stopping therapy for a median of 2.5 years (Retrovirus, abstract 351). All of their antiretroviral regimens consisted of only one or two nucleoside analogs (median three months, range 1 to 54); two had received intermittent therapy, and two were treated during primary infection. Three of ten were heterozygous for the CCR-5 deletion, and two of twelve had clade A HIV. Pre-therapy viral loads were available for seven of the thirteen, and they ranged from below 500 to 9000. They conclude that isolated cases of individuals with low or undetectable viral loads after stopping therapy do not necessarily show exceptional therapeutic effect, especially if they were treated during primary infection before a viral set point had been achieved. Another reason for caution comes from Price's comparison of the viral load rebound in cerebrospinal fluid (CSF) to that in peripheral blood in four patients who stopped treatment (Retrovirus, abstract 306). Two patients had virtually no change in CSF/plasma viral load ratios (0.020 and 0.007). The other two, however, had a plasma viral load increase of 0.5-1.0 log and a CSF viral load increase of more than two to three log. As a result, the CSF/plasma ratio went from 0.01 to 0.61 in one patient and from 0.001 to 0.448 in the other. There was also an increase in white blood cell counts, from three to 31/mm3 in one and from zero to 46/mm3 in the other. While there were no neurological symptoms, the results suggest potential risks of STIs. STIs also pose a risk of drug resistance. This is especially true with patients who are taking non-nucleosides (NNRTIs), such as nevirapine or efavirenz, since these drugs have long half-life. If a person discontinues all drugs simultaneously, nucleoside analogs and protease inhibitors will leave the body more quickly than the NNRTIs; and HIV only needs to develop one mutation in order to become resistant to all available NNRTIs. In the trials discussed above, the development of resistance has not been a problem. However, these have been small studies in very controlled environments, so the potential for resistance to develop is not really known. Moreover, it's possible that each STI allows latent viral reservoirs to be reseeded with new virus. This could increase the amount of viral DNA in the latently infected cells, making future eradication more difficult. For the time being, then, the role of STIs in controlling HIV remains unclear, and they should never be undertaken without medical supervision. Determining whether or not they are useful — and, if so, for whom — requires more clinical studies. And while STIs have a number of attractions, they are a gamble. Those who have managed to suppress their viral loads for an extended period of time, especially if they have tolerable side effects, might be best off continuing with their current regimen or trying other options, such as a therapeutic vaccine.   STIs with Virologic Failure   By Gil Shepard In a late-breaker, Dr. Steve Deeks presented results from a prospective study of STIs in patients who were on protease inhibitor-based therapy and who had a viral load over 2,500 copies for at least twelve months (LB-10). Eighteen patients were randomized to discontinue therapy. They had about three years of protease inhibitor therapy and a detectable viral load for about 31 months (range, 28 to 33 months). Upon discontinuing therapy, mean CD4 count was 245 cells (range, 104 to 307), mean viral load was just below 40,000 copies (range, 10,000 to 100,000), and the median decrease in protease inhibitor susceptibility was 56-fold (range, 23 to 79). Viral load, CD4 levels and phenotypic resistance were measured weekly for the first 12 weeks, at which point therapy was restarted and tests were done every four weeks. At 12 weeks, the median CD4 decrease was 94 cells (28 to 120) and the median viral load increase was 0.82 log (0.34-0.92). In 16 patients, the virus shifted to a protease susceptible (<2.5 fold decrease in susceptibility) phenotype — or wild-type virus — after two to 15 weeks (mean 8.5 weeks). Slower reversion to wild-type virus was associated with more protease inhibitor resistant mutations at baseline and with a smaller viral load reduction on therapy as compared to pretherapy viral load. Nucleoside analog resistance persisted in seven patients, but typically at a much lower level than at baseline. Replicative fitness (the ability of the virus to reproduce) increased from a median of 22.3% to 67.1% (p=0.004). Deeks noted that prior to the reversion to a wild-type virus, there was a slow decline in CD4 cell counts and a slow rise in viral load; however, after the shift CD4 counts dropped and viral load increased dramatically. He suggested that the former could be associated with residual antiviral activity and the latter with an increase in replicative fitness. In four of eight patients who reverted to wild type, PBMC cultures (taken 12 to 36 weeks after discontinuing therapy) showed resistant virus that was identical to that at baseline. That is, while the virus in their blood had switched to protease inhibitor susceptible, resistant virus could still be found in PBMCs, which suggests that wild-type outgrew resistant virus but did not eliminate it. Moreover, it is possible that the other patients also still had resistant virus, even though tests could not detect it. Researchers also looked at the fractional replacement rate of CD4 cells. Prior to interrupting therapy, the rate in those patients on "failing" therapy was 0.011/day, which was significantly lower than the rate of 0.032/day observed in patients who were not on therapy. This suggests that despite having a detectable viral load, those patients receiving drug treatment had a longer CD4 half-life than patients receiving no treatment. In addition, during STIs, there was a reduction in either CD4 half-life or CD4 production. While Deeks did not draw any conclusions about STIs as a treatment option in this population, he did find evidence of continued antiretroviral therapy benefit even in cases where patients have resistant virus, which might be because the resistant virus is less fit than wild-type. This implies that, at least for patients with few or no treatment options, continuing drug therapy when viral load is detectable is more beneficial than discontinuing therapy altogether.   It Takes Two, Maybe   By Gil Shepard Initially used in salvage regimens, dual protease inhibitor therapy is now increasingly used earlier in treatment. (For discussions of dual protease inhibitors in salvage therapy, see Treatment Issues, "Salvage Therapy: Still More Intuition Than Data" January, 1999, and "The Great Salvage Therapy Drug Juggle" April, 1998.) The primary reasoning behind this strategy is that combining protease inhibitors can help overcome some of their shortcomings, such as poor biavailability and short half-lives. This is possible because they all are metabolized by the cytochrome P450 3A4 isoenzyme system. Ritonavir, in particular, inhibits this system, which means that administering ritonavir with other protease inhibitors can increase their blood levels. This allows lower or less frequent dosing and can remove food restrictions, resulting in fewer toxicities and improved adherence. Some combinations, such as ritonavir/saquinavir, and possibly ritonavir/indinavir, also appear to be very potent and long lasting. Nevertheless, federal guidelines do not recommend dual protease inhibitor therapy as first-line treatment, presumably due to concerns about side effects and drug-drug interactions, particularly since ritonavir interacts with a wide variety of drugs. There are also concerns that the use of two or more protease inhibitors could increase the risk of lipodystrophy and other metabolic toxicities. At this point, there are very little data on the long-term consequences of using dual protease inhibitor therapy. Recent conferences have included several studies of dual protease inhibitor therapy in both treatment-naive and treatment-experienced populations, which are discussed below. Ritonavir/Saquinavir The combination of ritonavir and saquinavir has been in use for several years now, most commonly at a reduced dose of 400 mg each, twice a day. Last winter, Cameron presented three year follow-up data on the combination in 144 patients (Retrovirus Conference, January 30 to February 2, 2000, abstract 533). Patients started on various doses of the two protease inhibitors, but all eventually went to 400/400 mg. Intensification with nucleoside analogs after week twelve was allowed for those with a viral load over 200 copies, and at week 48 for anyone who wished to do so. Through week 144, 120 patients (85%) had a suppression of viral load to below 200 copies (thirteen results were obtained after treatment intensification). However, 41 patients (34%) in this group had a viral rebound. Fifteen of the 41 then intensified treatment with nucleoside analogs, twelve of whom subsequently stayed below 200 copies through 144 weeks. That is, 91 (63%) of the 144 eventually maintained a viral load below 200 copies, and 53 (58%) were only taking ritonavir and saquinavir. While 50 (35%) of the original 144 patients discontinued treatment, 20% because of adverse reactions, no new safety issues were uncovered during the study. In another study involving intensification, 208 protease inhibitor- and d4T-naive patients were randomly assigned to receive ritonavir and saquinavir (400/400 mg) with or without d4T, twice daily (Gisolf, Retrovirus Conference, January 30 to February 2, 2000, abstract 527). If patients had a viral load over 400 copies after twelve weeks, nucleoside analog intensification was allowed. At 48 weeks on an intent-to-treat analysis, 63% of the ritonavir/saquinavir group had an undetectable viral load (limit not stated), compared to 69% of those who also received d4T (p=0.38). Twenty-eight patients who initially received only the protease inhibitors intensified therapy, as did three in the d4T group. Of those who intensified treatment, 97% had an undetectable viral load at their last visit. There was a ten percent dropout rate due to adverse events. The authors concluded that starting with ritonavir/saquinavir and intensifying the treatment if necessary was comparable to starting with three drugs, but longer follow-up is needed to determine this strategy's long-term efficacy. These reports follow a study presented last October at the Lisbon Conference (Lundgren, ECCAT, October 23 to 27, 1999, abstract 487). In that trial, 318 protease inhibitor-naive patients took two nucleoside analogs plus either ritonavir, indinavir, or ritonavir/saquinavir. At 48 weeks, 42% of those taking indinavir, 40% of those taking ritonavir, and 58% of those taking ritonavir/saquinavir had viral loads below 20 copies. Researchers noted that ritonavir as the only protease inhibitor was not well-tolerated, with twice as many patients dropping out of that arm as the other two (about 66% compared to 33%). Ritonavir/Indinavir Combining ritonavir with indinavir significantly increases the blood levels of indinavir and allows indinavir to be dosed twice daily without food restrictions. A recent study also concluded that low doses of ritonavir can triple the amount of indinavir in cerebrospinal fluid and increase semen indinavir levels seven-fold, which may affect HIV in these sanctuaries (van Praag, Retrovirus Conference, January 30-February 2, 2000, abstract 312). While Merck favors combining 800 mg of indinavir with 200 mg of ritonavir, Abbott argues that a 400/400 combination is most effective. Currently enrolling, ACTG A5055 will compare the 400/400 and the 800/200 doses in patients who are failing amprenavir, nelfinavir, saquinavir, or nelfinavir/saquinavir combination therapy. Two studies at the Lisbon Conference examined the 400/400 combination. The first included 92 treatment-naive patients who took ritonavir, indinavir, and two nucleoside analogs (Rockstroh, ECCAT, October 23 to 27, 1999, abstract 452). At 48 weeks, data were available for 88 patients, 24 of whom dropped out of the study. Ninety percent of the on-study population (70% including dropouts) had viral loads below 80 copies. These results, however, are less impressive than a ritonavir/saquinavir combination at 48 weeks. In the second study, there were 48 week data for 14 of 22 patients taking d4T, 3TC, ritonavir, and indinavir (Workman, ECCAT, October 23 to 27, 1999, abstract 620). Twelve of the 14 had viral loads below 50 copies. In both studies, patients had high blood lipid levels — including seven serious cases in the second study — and difficulties tolerating ritonavir, which, at that time, was only available in its notoriously horrible tasting liquid formulation. In an intensification study, Shulman presented data on adding ritonavir to patients with a detectable viral load on indinavir and two nucleoside analogs (Retrovirus Conference, January 30 to February 2, 2000, abstract 534). Indinavir Cmin increased 272% and Cmax decreased 51% while AUC was maintained. Of 17 patients who had reached 16 weeks, the median viral load dropped to below 100 copies. ABT-378/Ritonavir (Lopinavir) At the Retrovirus conference, Gulick had results from an ABT-378/ritonavir trial involving 100 treatment-naive patients (abstract 515). For the first 48 weeks, patients took d4T, 3TC and ABT-378/ritonavir in a dose of either 200/100 mg or 400/100 mg (Group I) or 400/100 or 400/200 mg (Group II); after 48 weeks, all patients switched to the 400/100 mg dose of ABT-378/ritonavir. Median baseline viral loads were 100,000 and 80,000 copies and median CD4 cell counts were 421 and 301 cells for Groups I and II, respectively. At week 72, 82% had a viral load below 400 copies (intent-to-treat analysis) and 80% were below 50 copies. Median CD4 increase was 275 cells. While only one percent of patients discontinued the trial due to adverse events (12% discontinued for other reasons), grade two to four events (moderate to severe side effects) included diarrhea (21%), nausea (15%), abnormal stools (8%), weakness (7%), headache (7%), and vomiting (5%). Grade three or four laboratory abnormalities were increased cholesterol (14%), increased triglycerides (12%), and increased liver enzymes (8%, half of whom had chronic hepatitis B or C). Nelfinavir/Saquinavir-sgc The SPICE study randomized 157 protease inhibitor-naive patients to receive saquinavir/ two nucleosides, nelfinavir/two nucleosides, saquinavir/nelfinavir/two nucleosides, or saquinavir/nelfinavir (Johnson, 6th Retrovirus Conference, 1999, abstract 389). Nelfinavir was dosed at 750 mg twice daily, and saquinavir was at 1200 mg three times daily in all but the dual protease inhibitor arm (800 mg, twice daily). At 48 weeks, the proportions of patients with a viral load below 50 copies were 42%, 42%, 51%, and 35% in the four arms, respectively. Of 22 patients with virologic failure who switched to quadruple therapy, 24% achieved a viral load below 50 copies. In the TIDBID study, three saquinavir-containing regimens were compared: saquinavir 1200 mg three times daily and two nucleoside analogs, saquinavir 1600 mg twice daily and two nucleoside analogs, or saquinavir 1200 mg twice daily, nelfinavir 1250 mg twice daily and one nucleoside analog (Cohen, 39th ICAAC, September 26 to 29, 1999, abstract 508). Of the 838 patients enrolled, 75% were treatment-naive (treatment-experienced patients received at least one new nucleoside analog). Data at 24 weeks showed that all three groups had similar viral suppression, with 40% and 60% below 50 copies on an intent-to-treat and as-treated analysis, respectively. CD4 cell changes were also similar in all groups, with about a 150 cell increase. Gastrointestinal side effects were most common, and diarrhea was more frequent in the dual protease arm (13% to 15% in the saquinavir arms and 23% in the saquinavir/nelfinavir arm). Dual, or Triple, PIs in Salvage Therapy Forty-eight week data from a salvage therapy trial involving ABT-378/ritonavir were presented at the last Retrovirus conference (Deeks, abstract 532). On an intent-to-treat analysis, 70% of patients had a viral load below 400 copies and 60% were below 50 copies. However, as Treatment Issues has noted previously (see September/October 1999), patients also took efavirenz (in addition to two nucleoside analogs) and were NNRTI naive, so it is impossible to tell how much ABT-378/ritonavir contributed to the results. Results from ACTG 398 — a study to determine whether a second protease inhibitor, combined with amprenavir, abacavir, efavirenz, and adefovir, would improve virologic response in protease inhibitor-experienced patients with a detectable viral load — were presented as a Retrovirus late-breaker (Hammer, LB 7). Based on prior protease inhibitor experience, 481 patients were randomized to also receive saquinavir (1600 mg, twice daily), indinavir (1200 mg, twice daily), nelfinavir (1250 mg, twice daily), or a placebo. Median baseline viral load was 51,600 copies and CD4 count was 202 cells. At week 24, 35% in the saquinavir arm, 38% in the indinavir arm, and 39% in the nelfinavir arm had viral loads below 200 copies, compared to 28% in the placebo arm (p=0.02). Prior NNRTI use was significantly associated with virologic failure, but previous protease inhibitor use (one vs. two or more) was not. Also at week 24, seven percent of the patients had stopped treatment, 33% due to toxicity and 19% due to virologic failure. Grade three to four adverse events were similar in all four arms, with gastrointestinal symptoms, hypertriglyceridemia, and hypophosphatemia being the most common. Two retrospective studies at the Third Salvage Therapy Workshop looked at indinavir (800 mg)/ritonavir (200 mg) in a salvage therapy setting. Grossman reported on 41 heavily pretreated patients (73% with NNRTI experience, 95% with prior indinavir or ritonavir experience) with a median viral load of 30,000 copies and CD4 count of 258 cells (abstract 27). At three, six, and nine months, 51%, 56%, and 62% of the patients, respectively, had viral loads below 400 copies. Median CD4 increase was about 75 cells at six months. Although there were no reports of kidney stones, nineteen of the 41 (46%) had adverse events, including nausea and vomiting (17% of the 41 patients), rash and dry skin (12%), diarrhea (5%), and paresthesia (3%). In the second study, Campo provided results for 27 heavily pretreated patients who took at least one nucleoside analog and/or NNRTI in addition to the protease inhibitors (abstract 7). Fifteen patients (56%) attained viral suppression (<400 copies). In addition, four of four with baseline phenotypic resistance and ten of thirteen with baseline genotypic resistance to indinavir and ritonavir attained a viral load below 400 copies. Responders had higher initial CD4 counts (283 vs. 150) and lower viral loads (156,500 vs. 228,000). Of interest, however, baseline resistance to indinavir and ritonavir was associated with a better response to therapy. To explain this counter-intuitive result, Campo suggested that resistance could have be an indication of adherence. That is, those who were adherent on failing regimens developed resistance, and they were more likely to be adherent on the salvage regimen. Given the small numbers and retrospective nature of the study, however, it is difficult to draw any strong conclusions about the relationship betw