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Controversies and Unresolved Issues in Antiretroviral Therapy: An Expert Interview With Dr. Martin S. Hirsch

Authors: Mark A. Wainberg, PhDFaculty and Disclosures


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Editor's Note:

A decade ago, highly active antiretroviral therapy (HAART) was widely introduced in the developed world. This medical breakthrough revolutionized the treatment of HIV and quickly became the standard of care for HIV disease. However, a number of controversies remain in regard to current treatment guidelines, such as when to start therapy and whether structured treatment interruptions can minimize toxicities and costs without compromising virologic and immunologic benefits. Mark Wainberg, PhD, Director, McGill University AIDS Centre, Jewish General Hospital and Professor of Medicine and Microbiology, McGill University, Montreal, Quebec, Canada, interviewed Martin S. Hirsch, MD, Professor of Medicine, Harvard Medical School and Physician, Massachusetts General Hospital in Boston, Massachusetts, for Medscape HIV/AIDS at "HIV Management 2006: The New York Course," held May 5-6, 2006 in New York City. Dr. Hirsch has been at the forefront of HIV research since the disease was first recognized -- and is a researcher who asked and answered many seminal questions that moved this field forward. At the meeting, Dr. Hirsch summarized current therapeutic controversies and remaining challenges, and afterward he shared some insights from his presentation.

Dr. Wainberg: Hi. My name is Mark Wainberg of the McGill University AIDS Center in Montreal, and today my guest for Medscape HIV/AIDS is Professor Martin Hirsch of the Harvard University School of Medicine. Dr. Hirsch has been a treatment leader really from the inception of our field. He has helped train a huge number of individuals who have gone on to make their own contributions and that must give you a tremendous amount of satisfaction, Dr. Hirsch.

Dr. Hirsch: Well, that's what I enjoy most, and it's a pleasure to be here with you, Mark.

Dr. Wainberg: We've made huge progress since the onset of the epidemic through the development of antiretroviral drugs. We're here at this meeting marking the 10th anniversary of HAART, and let me just get a perspective from you on what you see as some of the events that will guide us through the next 10 years.

Dr. Hirsch: I share the enthusiasm that we've made enormous progress over the past 25 years, and in the 10 years since the development of HAART. I think, as we're hearing at this meeting, HAART will continue to improve. It is improving already, and I think that anyone who gets infected in 2006 has a very good chance of living a perfectly normal, healthy life, which certainly wasn't the case when you and I got into this many years ago.

Dr. Wainberg: It's been gratifying for both of us to have seen these transitions. Now we can look forward to a long future with good health and maintaining an active role in the workplace. Of course, we have to temper our happiness by noting that many millions of people in developing countries are not so fortunate, and we want to make life as good for them as it is for people in the United States and elsewhere.

You just mentioned people who get infected in the year 2006. That by definition means somebody in the very early stages of infection, perhaps somebody who is still in primary HIV infection. In your talk, you mentioned that you thought that there was rationale to treat these people earlier. How early should we be treating? Should we be going out of our way to identify these people whenever possible and to treat them aggressively as early as possible?

Dr. Hirsch: We certainly should go out of our way to identify these people, and a lot of groups are actively searching such people out. There is certainly a good rationale to consider early therapy in these individuals to (1) maintain their HIV-specific immune responses, (2) reduce transmission, (3) perhaps even shorten the acute syndrome that they have, and (4) lower the viral set point that they may eventually end up with. You have to balance that with the known toxicities of these drugs both in the short term and the long term, the difficulty to adhere to these medications for long periods of time, and the cost involved.

The book is still open as to whether we should aggressively treat these people early or wait until a later stage when their CD4+ cell count has dropped to whatever the current recommended level is for treating. There are no good data yet that this approach has really prolonged life and is a cost-effective way of approaching treatment, so it is a debatable point. Some people do treat these individuals very aggressively and some people wait. I don't think that we have enough data to say which is the right approach.

Dr. Wainberg: What about some of these people who get infected with multidrug-resistant viruses? They're going to archive all of their resistance mutations. Should they represent a category of person in whom there's a lot more to gain by treating than by waiting because they might have a lot to lose?

Dr. Hirsch: They do have a lot to lose, but one can also make the argument that we are developing better drugs. We've heard at this meeting today that there are CCR5 inhibitors, integrase inhibitors, and many other new drugs coming along. The best approach in those individuals may actually be to wait until you are forced to treat, and treat with the best available drugs at that time.

Dr. Wainberg: You said in your presentation that if people are most infectious shortly after HIV acquisition, then there is clearly a public health rationale to begin treatment earlier. We have to convince people who are newly infected that they have a tremendous amount to gain through earlier intervention, should our drugs make that possible. However, I think that we cannot neglect the public health aspects that are probably even more important in the developing countries, in this context, than in the United States.

Dr. Hirsch: I think that's certainly true, and the best studies on this have come from Africa, from Wawer's group,[1] which was published in the Journal of Infectious Diseases last year. They suggest that the likelihood of transmission during acute HIV syndrome is probably 12 times that seen during chronic infection. Some argue that that is a good public health rationale [for earlier treatment]. Whether it's good for the individual is another question. If you start somebody on treatment during acute HIV infection, the question always comes up; then how long do you treat them? I think that that's the problem. If you could start somebody early, and treat him/her basically forever, that would be a good strategy to follow. However, if you are going to stop treatment after 12 months, 24 months, or 36 months, the data that I've seen suggest that after a short time off therapy, you're probably no better off than you were when you started, although that remains a controversial area.

Dr. Wainberg: Let's talk about structured treatment interruptions. We heard about the disappointing data in regard to the SMART [Strategies for Management of Anti-Retroviral Therapy] study[2] presented at the 13th Conference on Retroviruses and Opportunistic Infections in Denver earlier this year [CROI; February 5-8, 2006; Denver, Colorado]. I'm a member of one of the committees in regard to the OPTIMA [Options in Management With Anti-Retrovirals] trial,[3,4] which is also one of these huge trials that is having problems in regard to enrollment. Are we still going to be able to do these kinds of studies? Is there room still to do them, in your opinion, or should we lose hope in regard to the concept of treating people in a pulsed way over shorter periods of time?

Dr. Hirsch: I share your pessimism about treatment interruption, based on the SMART study. However, there are ongoing studies that look at what happens if you set the thresholds of CD4+ cell counts higher. The SMART study only restarted individuals on therapy when their CD4+ cell counts dropped down to 250/mcL, and that is apparently too low to let the CD4+ cell count drop. There are other studies, some of which were presented also at CROI in Denver that suggested if you set the threshold at 350 CD4+ cells/mcL, you may be able to get away with this.[5] Some studies suggest that this could still be an appropriate thing to do in the right populations with the right CD4+ cell count thresholds. However, right now the guidelines from the United States[6] and other countries would suggest that treatment interruption should only be done in the setting of a controlled clinical trial.

Dr. Wainberg: I think that there is still room to do these kinds of studies, and I think that the OPTIMA study, which is an effort in this direction, will hopefully continue to enroll patients so that we will all have additional useful information on this topic. However, as you said earlier, one of the goals of therapy is to protect the immune system. As you know, we've been using in our experimental settings substances, such as IL-2 [interleukin-2] and more recently IL-7, as immunomodulators. Do you have hope that these will represent a new paradigm someday in treatment?

Dr. Hirsch: Well, we should always have hope, Mark. I know more about interleukin-2 than interleukin-7, and I think that the former does boost CD4+ cell counts at the price of substantial early toxicity and reduced early quality of life. Whether they have a long-term clinical benefit is now being evaluated by large studies, such as the SILCAAT Whether they have a long-term clinical benefit is now being evaluated by large studies, such as the SILCAAT [study of IL-2 in people with low CD4+ T-cell counts on active anti-HIV therapy] and ESPRIT [study of IL-2 in people with CD4+ T-cell counts > 300 /mcL on active anti-HIV therapy].

Hopefully within the next year or two we will get data to lead us one way or another. Right now, I don't think that we can say that interleukin-2 or any of the other nonspecific modulators of immune response really provide a long-term clinical benefit, but they might.

Dr. Wainberg: Let's get back to the drugs that we ought to be using now in first-line therapy, and perhaps for people who have failed in initial treatment. Is there still any justification to begin with a thymidine-based regimen?

Dr. Hirsch: We have to distinguish the developed world from the developing world. Most people in the developed world are shifting on the basis of some recent studies to a tenofovir-FTC [emtricitabine]-based regimen rather than an AZT [zidovudine]-3TC [lamivudine]-based regimen. I think the guidelines would still suggest that both of these are reasonable alternatives. We know that you get a slightly better adherence rate to the tenofovir-based regimen, largely because of early AZT toxicity, and that thymidine analogs can cause a lot of problems down the road with mitochondrial toxicity, which may lead to lipid abnormalities that you can prevent or ameliorate with a tenofovir-based regimen. We don't have as much experience with tenofovir over the long run. We know that it can cause renal toxicity, so I would still keep my mind a bit open there, but if I were starting someone without renal problems on therapy today in the United States, I probably would start them on tenofovir-FTC and efavirenz. The story is very different, as you well know, in Africa and southeast Asia, where cost has to be considered very heavily and the most recommended regimens in these countries are with thymidine analogs, particularly with d4T [stavudine]-based regimens, which we don't use much in the developed world anymore.

Dr. Wainberg: I agree with you; d4T is perhaps the most toxic of all the drugs in the armamentarium, but coming back to the general concept of thymidine analogs, I think there are some data to suggest that maybe we'll get our biggest bang for the buck out of the thymidine analogs, principally zidovudine, if we use it in patients who already have a K65R or M184V or even an L74V mutation. Maybe that's really going to be the ideal time to use a drug such as zidovudine.

Dr. Hirsch: I think that certainly makes good sense.

Dr. Wainberg: I think that we've covered a lot of ground. Is there something else that you'd like to talk about that we should have covered during this interview but have not?

Dr. Hirsch: I just wish you well in your International Congress in Toronto this summer.[7]

Dr. Wainberg: Well, thank you, and continue to be a beacon of inspiration for all of us in the field as you have been for all of these years.