Interruptions In Antiretroviral Therapy

10-10-2006 | Categories:

Noncompliance

Touloumi, G et al. Highly Active Antiretroviral Therapy Interruption: Predictors and Virological and Immunologic Consequences. Journal of Acquired Immune Deficiency Syndromes 42(5): 554-561, 2006.

Findings

The headlines of the stories about this study, including this one, tend toward variations of “One Patient In Six On ART Interrupt Treatment.”

The final paragraph of the original article itself puts it this way:

In conclusion, in this large observational study, a substantial and increasing number of subjects interrupt HAART. Discontinuing treatment seems to be safe for subjects with a well-retained immune system. However, subjects above 40 years old, with a pre-HAART CD4 below 200 cells/KL or with limited immune reconstitution during HAART (CD4 at TI below 350 cells/KL), had the greatest proportionate decrease in CD4 cell counts during TI. For such subjects, if TI is considered, caution and close monitoring are essential to ensure that risks are minimal.

Commentary

I originally selected this article for my reading list on the assumption that, because its subject was interruptions in treatment, it would include information re the causes of this noncompliance. As it turns out, however, “… reasons for TI [Treatment Interruption] or adherence rates were not available in our study.” This is not only disappointing to those of us interested in patient compliance, but it also results in uncertainty about the ’s findings because it potentially skews the characteristics of the group selected for the study.

The patient data for the study was extracted from the information gathered from the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included cohorts totaling 8300 seroconverters. Selection criteria follow:

Subjects were included in the current analyses if their date of seroconversion was estimated using the midpoint method or on the basis of laboratory evidence of seroconversion, their HIV test interval was less than 3 years, they had initiated a stable (for at least 90 days) first HAART regimen at least 1 year after seroconversion, and if they had HIV RNA and CD4 cell count measurements at HAART initiation and at least one additional measurement of each marker during HAART. … Individuals who had previously been on suboptimal therapy also had to have added or changed at least 2 drugs simultaneously. Treatment interruption was defined as a discontinuation of all drugs for at least 14 days. … Patients who interrupted HAART but resumed therapy within 14 days were not defined as having TI. Subjects initiating HAART during the first year after seroconversion were not included in this study because they consist of a selective group treated close to primary infection and will be subject to a separate analysis. …

The authors elaborate on the advantages of using the CASCADE data:

The wellestimated seroconversion dates in CASCADE enabled us to investigate the effect of the pre-ART history on TI consequences, whereas the wide range of ages, mode of infections, and the representation of both sexes allowed us to study the effect of these demographic characteristics on the probability of TI and its consequences.

These study’s criteria eliminated 6749 of the original 8300 CASCADE subjects. While the remaining 1551 subjects constitutes a respectable N, the results of treatment interruption in those 6749 patients not studied is hardly trivial.

Further, as Bernard points out¹

The investigators only measured clinical progression via the development of a clinical AIDS event, or death. Seven people who did not have AIDS when they began ART developed a clinical AIDS event during their treatment interruption. Eight people who did not have AIDS when they began ART developed a clinical AIDS event whilst on ART. In addition, two people with AIDS when they began ART experienced another AIDS illness during their treatment interruption, compared with one person with prior AIDS who remained on ART. However, the investigators found that there was no statistically significant difference between the rate of developing a new AIDS illness whilst interrupting treatment compared with remaining on ART. ( 0.037 vs. 0.019 cases per person per year; p=0.158). Although the investigators note that nine individuals in the study died without an AIDS diagnosis, they do not provide any further data. Since the SMART study found an increased risk of non-AIDS deaths during treatment interruptions, information on whether these deaths occurred on or off treatment would have been illuminating.

By choosing a subset of treatment-interrupters that accounts for less than 14% of the total patients available and for which information about the reasons for the treatment interruption is lacking while, in effect, eliminating the most noncompliant group of patients from consideration, by not investigating non-AIDS deaths, and by limiting the definition of clinical progression to a clinical AIDS event or death, the study restricts the generalization of its findings.

Consequently, its conclusion that “discontinuing treatment seems to be safe for subjects with a well-retained immune system” appears venturesome, especially given previous studies that indicate an increase mortality rate when treatment is interrupted.

Footnotes