The Body PRO Covers: The 8th Conference on Retroviruses and Opportunistic Infections

Structured Treatment Interruption: Novel Strategy or Oxymoron?

February 6, 2001

  • Prolonged HAART Initiated Within 120 Days of Primary HIV-1 Infection Does Not Result in Sustained Control of HIV-1 After Cessation of Therapy (Slide Session 288)
    Authored by M. Markowitz, X. Jin, B. Ramratnam, M. Louie, R. Kost, A. Hurley, S. Barsoum, G. Deschenes, C. Chung, A. Kim, T. He, L. Zhang, and D. D. Ho
    View the original abstract

  • Outcome After 1 Year of HAART, 3 Cycles of STI, and 12 Months Off Therapy Versus Natural Evolution Without ART in Early Chronic HIV-1 Infection (CHI): A Case-Control Study (Slide Session 289)
    Authored by F. Garcia, M. Plana, G. M. Ortiz, A. Soriano, C. Vidal, A. Cruceta, M. Arnedo, C. Gil, G. Pantaleo, T. Pumarola, T. Gallart, D. F. Nixon, J. M. Miro, and J. M. Gatell
    View the original abstract

Current guidelines for the management of acute infection call for aggressive antiretroviral therapy. The rationale behind this -- as is stated in the DHCP guidelines -- is to suppress the initial burst of viral replication, decrease the severity of acute disease, potentially alter the initial viral "set point," possibly reduce the rate of viral mutation due to the suppression of viral replication, reduce the risk of viral transmission, and preserve immune function. Many "possiblys" as you can see. That means that we do not really know what we should do.

The price of aggressive management of acute HIV infection is the long-term side effects of treatment for a disease that probably would not give the patient any problems for seven to ten years. Patients also risk developing resistance and not having therapeutic options when they "really" need them. So the issue is controversial.

During the fall, Rosemberg from Bruce Walker's group in Boston, published an important paper in Nature magazine that showed that a significant proportion of patients who had stopped therapy after being treated very early -- during acute primary infection -- and had gone through one or two cycles of treatment interruption, were able to control viral replication and maintain relatively low levels of virus in plasma, which suggests that in the future they will behave as "long-term non-progressors." The follow-up is too short to be sure that this is the case. However, this has been interpreted by many as "written in stone," and should be the way we treat all seroconverters.

There was a full symposia devoted to structured treatment interruptions, the big room was packed and the presentations were extremely interesting. I will comment on two of the presentations, maybe the most important during this session. The first presentation concerned treatment interruptions in patients who were treated during acute infection, and the second presentation was related to treatment interruptions in chronically infected patients.

Prolonged HAART Initiated Within 120 Days of Primary HIV-1 Infection Does Not Result in Sustained Control of HIV-1 After Cessation of Therapy (Slide Session 288)

In the first presentation (abstract 288) M. Markowitz presented the experience of the Aaron Diamond Center in New York. They gave antiretroviral therapy to 14 individuals relatively shortly after primary infection, but not as early as in the study reported in Nature by Rosenberg. Patients had a mean viral load of around 75,000 copies/mL, and a CD4 cell count of 522 on average before starting therapy. After being undetectable and on treatment for several years they decided to stop therapy and see what happened. Some of the patients also received a therapeutic HIV vaccine. Careful immune studies were done before and after discontinuation. In spite of the presence of CTL responses against HIV, all of the patients' viral loads became detectable. Most of the patients, however, maintained a relatively low viral load in the low 10K range. Half of the patients decided to restart therapy.

Marty Markowitz's conclusion was that this approach did not really work and that we need better treatments to reduce viral burden and "boost" the immune system before stopping therapy in this situation.

Why were the results different form Rosenberg study? The main difference between these two studies is that the patients in the Boston cohort had been more recently infected with HIV. Maybe this approach only works very early during infection. Alternatively, the Aaron Diamond cohort did not undergo structured treatment interruptions before discontinuing therapy, and that might be critical for the control of viral replication when therapy is discontinued.

There is still a lot to learn about how to treat acute HIV infection. The reader should be aware that current guidelines are based on a handful of patients and that many more studies are needed to define what to do in this clinical situation.

Outcome After 1 Year of HAART, 3 Cycles of STI, and 12 Months Off Therapy Versus Natural Evolution Without ART in Early Chronic HIV-1 Infection (CHI): A Case-Control Study (Slide Session 289)

The next presentation in this session was Garcia's, from Jose Maria Gatell's group in Barcelona (abstract 289). This cohort has already been presented in several meetings (as has the Markowitz study) during the last year.

This was originally an open-label, non-randomized study of ten individuals chronically infected with HIV who underwent three cycles of a structured treatment interruption. The group had been criticized in the past for not having a control group, so they decided to "match" controls from another study. They matched two patients to each one of the members of this cohort with similar viral loads and CD4 cell counts, but who did not receive HAART for a year.

Then they went ahead and compared the viral load and the CD4 responses of the patients who underwent the three consecutive treatment interruptions with the same parameters in patients who were off therapy for a year. The patients who had been involved in the structured treatment interruptions had a viral load that was 0.5 logs lower than the controls after one year of therapy, and their CD4 counts were higher.

The problem with this approach is that it is impossible to know if this effect is due to the structured treatment interruption or the year of HAART that the patients received in the first place. Patients who went through the structured treatment interruption had better CTL and immunologic markers. Viral rebounds were similar in each interruption, and only a few of the patients maintained a very low viral load.

The limitation of this study is its design. Case control studies are always retrospective, and the investigator cannot control for all the variables. The right way to answer the question would be to do a prospective randomized trial, but that could be very complicated.

There is much to learn about the role of structured treatment interruption in the management of chronically infected HIV patients. In general, the responses do not look as good as in early infected patients, but it seems possible to elicit an HIV specific immunity, which could control, at least partially viral replication.

We need larger, randomized trials to properly evaluate this intervention.

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