December 18, 2001
In the past few years, "success" in controlling viral replication and HIV-disease progression has been hampered by an increase in morbidity and mortality from metabolic complications. It is also very difficult for many patients to maintain adherence to their antiretroviral agents. For these and other reasons, many patients with or without their doctors' guidance or supervision have opted to go into the so-called "holiday" or treatment interruption.
Whether physicians like it or not, with the treatment options currently available, treatment interruptions are here to stay. So we might as well try to figure out how to make them more successful, or at least less risky.
Some of the variables that can affect the outcome of treatment interruptions have been described in some studies in the past. (See The Body's coverage from the 8th Conference on Retroviruses and Opportunistic Infections.) But other prospective and more organized studies currently in progress will answer most of the questions we have today. The problem is that those studies are going to take years to complete and probably years more before valuable information is obtained from them. For now, our best solution is to rely on retrospective data from large cohort groups.
The CHORUS project is an ongoing community-based data collaboration from four large outpatient practices. More than 5,000 patients have been followed through their clinical, epidemiological, humanistic and economic aspects during their regular clinic care.
From the CHORUS data, 1,155 patients where identified after August 28, 1996 to have experienced at least one treatment interruption (TI) for longer than 14 days. Baseline lab values prior to, during and after treatment interruption were available for only 448 of those patients, so this was the population studied.
The investigators assessed the patients' virologic and immunologic success after reinitiation of therapy. Then the factors associated with virologic and immunologic success were evaluated. Virologic success was defined in this study as having a VL <500 copies/mL after reinitiation of therapy. Immunologic success was defined as reaching 90 percent of the baseline CD4 cells after reinitiation of therapy.
The factors associated with virologic and immunologic success were identified through guided stepwise logistic regression analysis. There was a complex but very well carried out statistical analysis to weigh the role of each success factor.
The results of this study showed that the majority of the patients (73.5 percent) were able to achieve 90 percent of their baseline CD4 counts after reinitiating antiretroviral therapy, but fewer (62.1 percent) were able to get their HIV RNA below 500 copies/mL. Only about half of the patients (52.7 percent) were able to recover both immunologic and virologic control.
Most importantly, patients suffered a total of 42 new opportunistic illnesses after reinitiating antiretroviral therapy (ART), including: HIV wasting (17), candida esophagitis (13), pneumocystis carinii pneumonia (PCP) (5), non-hodgkins lymphoma (NHL) (3), cytomegalovirus (CMV) retinitis (2), skin Kaposi's Sarcoma (KS) (2), and one case each of cryptococcal meningitis, HIV encephalopathy, lung KS, mycobacterium avium complex (MAC), central nervous system (CNS) lymphoma, tuberculosis (TB), and toxoplasma.
After statistical analysis was completed, the most significant predictive factors for success after treatment interruption were baseline CD4, baseline HIV, AIDS at baseline and duration of treatment interruption. There was a difference in response between patients who were suppressed at the time of treatment interruption (130) versus patients who were failing at the time of their treatment interruption (326).
From the suppressed group, 90 percent were able to achieve an HIV RNA <500 copies/mL again, while only 76 percent of the non-suppressed group were able to return to 90 percent of their baseline CD4 after reinitiation of ART. In this group of patients, duration of treatment interruption was the only factor associated with post-treatment interruption success.
This was a very large, complex study in which interpretations relied too much on statistical manipulation. It seems logical to believe that for patients undergoing treatment interruption, those with an undetectable viral load at the time of the interruption would do better than those who were failing at that time. On the other hand, there are too many other variables that may contribute to small differences.
I am not sure how much this study is going to help us sort these things out. I personally do not encourage my patients to go on treatment interruptions, but again, sometimes these are decisions beyond a physician's control. If patients are planning to go into a treatment interruption and are not responding to their current regimen, we may consider trying to control their viral load first. On the other hand, if controlling their viral load does not appear to be feasible, it may be a good idea to try to keep the duration of the treatment interruption as short as possible. This seems like a safe approach until data from prospective studies become available.
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