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(Editor’s note: AIDS Alert provides this special report on the First International AIDS Society [IAS] Conference on HIV Pathogenesis and Treatment, held July 8-11, 2001, in Buenos Aires, Argentina. Our coverage includes a look at structured treatment interruption, an article about HIV patients on antiretroviral treatments who have experienced hepatotoxicity, and a special question-and-answer article about a new type of protease inhibitor.)
Although there still is no clear consensus on the usefulness of structured treatment interruption (STI) as a therapeutic method for HIV patients, the strategy is gaining more respect as researchers from around the world continue to study the use of STI.
Intermittent therapy, in which patients stop their antiretroviral therapy and then resume it in a cyclic way, may prove feasible, says Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD, and chief of the NIAID Laboratory of Immunoregulation. He spoke about interrupted treatment at the First International AIDS Society Conference on HIV Pathogenesis and Treatment, held July 8-11, 2001, in Buenos Aires, Argentina.
Fauci told conference attendees about a NIAID study in which 10 HIV patients who had reached undetectable levels of plasma viremia during therapy were switched to a 14-day cycle that entailed seven days with therapy and seven days without antiretroviral treatment. Investigators found that after 14 months of the intermittent therapy cycle, the virus ceased to rebound in these patients. In addition, patients had better adherence and less toxicity, Fauci says.
While those results look promising, they leave many questions about whether drug resistance will eventually develop in these patients, and what their ultimate treatment course should be. For these reasons, treatment interruption should be studied in a large clinical trial over several years, Fauci adds.
Other research on treatment interruption presented at the IAS conference included a study led by Franco Lori, MD, co-director of the Research Institute for Genetic and Human Therapy in Washington, DC. Lori, who is one of the most vocal proponents of STI, points to the successful use of STI in studies of chimps with SIV. "The animals could control the virus on treatment equally well whether they were randomized to receive continuous or intermittent therapy," Lori says. "It didn’t make a difference."
Lori, who continues to study the use of STI with human patients, presented an abstract at the conference stating that viral loads rebounded in the STI group at each therapy interruption and that the rate of rebound did not change significantly.1 The study involved 60 drug-naive patients with chronic HIV infection who received either ddI-d4T-IDV or ddI-d4T-HU. After 12 weeks of therapy, they received either 24 weeks of fixed-schedule STI with three weeks on and three weeks off antiretroviral treatment for four cycles, or they had continuous antiretroviral therapy.
When therapy was restarted, the viral loads decreased to values similar to those in the continuous antiretroviral therapy group, so the study’s results were mixed, and no conclusions about STI’s therapeutic value may be drawn. "The truth is that very many people are running STI trials, and I think we’ll have great answers within some years," Lori says. "We don’t have a recipe now, and as excited as we are, we can’t tell them exactly how to do it now."
Treatment interruption has also been studied recently in Italy, Spain, Canada, and the United States. For instance, Spanish investigators in June published studies that show the use of STI with chronic HIV-1 infection has positive effects on immune responses and holds potential for future therapeutic strategies.2,3
Researchers in Vancouver, Canada, presented at the July IAS conference an abstract that studied long-term treatment interruption that was not initiated as a therapeutic strategy. The Canadian investigation, which involved the British Columbia Centre for Excellence in HIV/AIDS in Vancouver, was a retrospective study of patients who had interrupted treatment because their therapy wasn’t working or due to side effects, explains Marianne Harris, MD, clinical research advisor at the British Columbia Centre for Excellence in HIV/AIDS.
"So we looked at those people once they restarted therapy to see what happened during the time they were off treatment," Harris says. Patients were all heavily treatment-experienced and included some who had failed regimens and some rescue therapy patients. Their duration of being off treatment was anywhere from five to 111 weeks, she adds.
Investigators studied patients’ viral loads and CD4 cell counts from the last time they were on therapy with treatment interruption and then compared these to viral loads and CD4 cell counts when therapy was restarted, Harris says. "But the major thing we were interested in looking at was what happened with their resistance," Harris says. "There has been this suggestion that treatment interruptions are beneficial because your predominant viral population goes back to wild-type in many cases, and therefore, when you start therapy, you will respond better — but that’s not what we found."
Although the patients had lost some of their resistance mutations, they responded just as poorly to treatment as those who had retained their resistance mutations, Harris says. Investigators concluded that long-term antiretroviral treatment interruption caused significant increases in viral loads and a decrease in CD4 counts. Also, most of the patients had lost their resistance to certain drugs, including 3TC, abacavir, and protease inhibitors, while sustaining resistance to non-nucleoside reverse transcriptase inhibitors and AZT.4
"The bottom line is we’re not doing treatment interruption as a therapeutic strategy, but sometimes it happens," Harris says. "People have to stop because of toxicity or running out of options, and the important thing is to monitor them during that period, especially their CD4 cell count."
Washington University investigators in St. Louis also studied the effects of prolonged discontinuation of antiretroviral therapy and presented their findings at the IAS conference. That study concluded that CD4 cell counts declined progressively after discontinuing successful therapy, although most patients remained asymptomatic, and 11 patients had restarted their therapy and again reached undetectability.5 Researchers had studied 72 patients and the use of pulses of highly active antiretroviral therapy, which is an initiation and discontinuation of treatment at specific CD4 thresholds. The study concluded that strategies of intermittent therapy with prolonged periods of treatment interruption should be further evaluated.5
1. Lori F, Foli A, Tomasoni L, et al. STI vs. continuous HAART during chronic HIV infection. Abstract presented at the First International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina; July 8-11, 2001.
2. Ruiz L, Carcelain G, Martinez-Picado J, et al. HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection. AIDS 2001; 15:F19-27.
3. Garcia F, Plana M, Ortiz GM, et al. The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS 2001; 15:F29-40.
4. Tesiorowski A, Harris M, Harrigan R, et al. Impact of treatment interruption on plasma viral load, CD4 count and virtual phenotypes (VIRCO) in HIV patients who failed multiple courses of antiretroviral therapy. Abstract presented at the First International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina; July 8-11, 2001.
5. Tebas P, Henry K, Mondy K, et al. Effects of prolonged discontinuation of successful antiretroviral therapy. Abstract presented at the First International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina; July 8-11, 2001.