Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults.
BACKGROUND
Although antiretroviral treatment (ART) has led to a decline in morbidity and mortality of HIV-infected patients in developed countries, it has also presented challenges. These challenges include increases in pill burden; adherence to treatment; development of resistance and treatment failure; development of drug toxicities; and increase in cost of HIV treatment and care. These issues stimulated interest in investigating the short-term and long-term consequences of discontinuing ART, thus providing support for research in structured treatment interruptions (STI). Structured treatment interruptions of antiretroviral treatment involve taking supervised breaks from ART. STI are defined as one or more planned, timing pre-specified, cyclical interruptions in ART. STI are attempted in monitored clinical settings in eligible participants. STI have generated hopes of reducing drug toxicities, decreasing costs and total time on treatment in HIV-positive patients. The first STI was attempted in the case of a patient in Germany, who later permanently discontinued treatment. This successful anecdotal case report led to several trials on STI worldwide.


OBJECTIVE
The objective of this systematic review was to assess the effects of structured treatment interruptions (STI) of antiretroviral therapy (ART) in the management of chronic suppressed HIV infection, using all available high-quality studies.


METHODS
Nine databases covering the time period from January 1996 to March 2005 were searched. Bibliographies were scanned and experts contacted in the field to identify unpublished research and ongoing trials. Two reviewers independently extracted data, and evaluated study eligibility and quality. Disagreements were resolved in consultation with a third reviewer. Data from 33 studies were included in the review.


METHODS
STI is a planned, timing pre-specified experimental intervention. In our review, we decided to include all available intervention trials in HIV-infected patients, with or without control groups. We reviewed evidence from 18 randomized and non-randomized controlled trials, and 15 single arm trials. Single arm trials were included because these pilot studies made significant contribution to the early development and refutation of hypotheses in STI.


METHODS
Trials included in this review varied in study participants, methodology and reported inconsistent measures of effect. Due to this heterogeneity, we did not attempt to meta-analyse them. Results were tabulated and a qualitative systematic review was done


RESULTS
For the purpose of this review, STI strategies were classified either as a timed-cycle STI strategy or a CD4-guided STI strategy. In timed-cycle STI strategy, a predetermined period of fixed duration (e.g. one week, one month) off ART was attempted followed by resumption of ART, while closely monitoring changes in CD4 levels and viral load levels. Predetermined criteria for interruption and resumption were laid out in this strategy. Timed-cycle STI fell out of favor due to reports of development of resistance in many studies. Moreover, there were no significant immunological and virological benefits, and no reduction in toxicities, reported in these studies. In CD4-guided STI strategy, ART was interrupted for variable durations guided by CD4 levels. Participants with high nadir CD4 levels qualified for this approach. A reduction in costs of ART, a reduction in mutation, and a better tolerability of this CD4-guided STI strategy was reported. However, concerns about long-term safety of this strategy on immunological, virological, and clinical outcomes were also raised.


CONCLUSIONS
Timed-cycle STI have not been proven to be safe in the short term. Although CD4-guided STI strategy has reported favorable outcomes in the short term, the long-term safety, efficacy and tolerability of this strategy has not been fully investigated. Based on the studies we reviewed, the evidence to support the use of timed-cycle STI and CD4-guided STI cycles as a standard of care in the management of chronic suppressed HIV infection is inconclusive.
Pai
N P
NP
University of California at Berkeley, Division Of Epidemiology, School of Public Health, 140 Warren Hall, Division of Epidemiology, University of California at Berkeley, Berkeley, California 94720, USA. nitika@berkeley.edu
Tulsky
J P
JP
Lawrence
J
J
Colford
J M
JM
Reingold
A L
AL
D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D002908:Chronic Disease; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic
D044966:Anti-Retroviral Agents