Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults

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Abstract
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. 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. 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 Bibliographies were scanned and experts contacted in the field to identify unpublished research and ongoing trials.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. 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. 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 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. 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. 對成人慢性抑制性HIV的結構性暫停療法 儘管抗反轉錄病毒治療(antiretroviral treatment, ART)減少了已開發國家HIV感染者的罹病率及死亡率,但仍存有許多挑戰。 這些挑戰包括藥錠負擔的增加,對治療的配合度,治療失敗及抗藥性的產生,藥物毒性的產生,以及照顧治療HIV患者成本的增加。 這些議題刺激了研究者的興趣以了解短期和長期中斷ART的結果,也為策略性中斷抗反轉錄病毒治療(structured treatment interruptions, STI)的研究提供了支持。 STI是指在監督的情況下中斷ART，其定義為一或多次有計畫性地、事前有明確規定時間地、循環地中斷ART，且STI必須在選擇合適受試者且受臨床監測的情況下施行。STI對減少HIV陽性病人的藥物毒性、治療所需的費用及時間等方面點燃了希望。第ㄧ例嘗試STI的是一位德國的病患，之後可以從此不再治療， 這件成功的病例報告也因而促使了目前全世界對STI的許多臨床試驗。 這篇系統性回顧的目的是去評估處裡慢性控制中的HIV感染者對結構性中斷抗反轉錄病毒療法的效果,並採用可用的所有高品質的研究。 我們搜尋了橫跨1996年1月到2005年3月的九個資料庫。已掃描參考書目，也拜訪了在這未公開的研究或正在進行的試驗的專家。兩位檢閱者各自擷取資料並評估研究合格與否及品質相左的意見也在與第三方的檢閱者討論後弭平。本篇回顧包括了33篇研究。...