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

 

Abstract

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.

Objectives

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.

Search 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 Bibliographies were scanned and experts contacted in the field to identify unpublished research and ongoing trials.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.

Selection criteria

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.

Data collection and analysis

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

Main 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.

Authors' 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.

 

Plain language summary

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

Structured treatment interruptions (STI) of antiretroviral therapy (ART) have been studied as an alternative strategy in the management of HIV-infected patients. STI involve planned, pre-specified cyclical interruptions in ART with an aim to alleviate treatment fatigue, provide possible immunological benefit, reduce drug toxicities and decrease costs of care. This systematic review aims to synthesize the evidence for use of STI as an alternative strategy in the management of chronic suppressed HIV infection. STI is a planned, experimental intervention, and the evidence from 33 available intervention trials has been summarized. Currently, several large STI trials are underway, investigating long-term effects of STI strategies. Their results will be available in a few years. Based on the studies we reviewed, we find that there is insufficient evidence to support the use of STI as a standard of care in the management of chronic suppressed HIV infection.

 

摘要

背景

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。

目標

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。

搜尋策略

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。

選擇標準

結構性中斷療法定義為ㄧ經計畫性的時間特異性的,循環的試驗的中斷抗反轉錄病毒療法。在我門的介入研究中,我們決定採納所有可用的對HIV感染者的介入性試驗,不論有無控制組。我們回顧了18個隨機或不隨機試驗的證據及15個無對照試驗。無對照試驗被採用是因為這些領航的報告明顯對早期中斷性療法假說有了明顯的貢獻。

資料收集與分析

本篇評論包括的試驗的受試者,研究方法,報告對治療效果評估均不一致。肇因於上述的異質性,我們不願意對這些資料進行整合分析。我們對這些試驗的結果整理製表且完成系統性有品質的分析。

主要結論

為了這篇評論文章的目標,我們將STI的策略分為兩種：時間循環式的(timedcycle)或以CD4導引(CD4guided)的方式。 時間循環式的STI是在ㄧ個事先決定的固定期間(例如ㄧ周或ㄧ個月)裡中斷ART並在之後恢復使用，期間予以密切監控CD4及病毒量的變化，中斷和恢復使用ART的條件在此策略中須事先言明。 結果顯示，此治療策略不再受到青睞，因許多研究指出會造成抗藥性，此外，在免疫學及病毒學上並沒有顯著的好處，也無助於藥物毒性的減低。 以CD4導引的STI，ART則是根據CD4的值而暫停，其中斷時間並不ㄧ定，在最低點的CD4值仍可維持較高的受試者適於此種策略。 回顧的這些研究中曾報告此策略可減少ART的費用、減少突變、也有較好的關於此種治療策略的耐受性。然而，這種策略在免疫學上、病毒學上及臨床結果的長期安全性也同時受到關注。

作者結論

時間循環的構結性暫停治療策略在短期已被證實不夠安全。儘管CD4導引的構結性暫停治療策略已被報導短期有較好結果但長期的安全性效果及耐受力都未被充分證實。基於我們回顧的研究,在處裡慢性控制中的HIV感染病人時,支持時間循環的暫停治療及CD4導引的暫停治療的證據 並不確定。

翻譯人

本摘要由臺北榮民總醫院易宏濤翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

結構性暫停抗反轉錄病毒療法已被研究為治療HIV感染病人的另ㄧ方法。這包括經計畫性的，時間特異性的,循環的中斷反轉錄病毒治療,目的是減輕治療的疲倦,提供可能的免疫好處,降低藥物毒性及減低照顧治療費用。 這篇系統回顧目標在統合使用結構性暫停抗反轉錄病毒療法作為治療慢性控制中的HIV感染的證據。結構性暫停療法為一計畫性,介入實驗,以及統整33篇可用的介入試驗的證據。 最近幾個大型的結構性暫停療法的試驗正在進行中，以研究此策略的長期療效。試驗的結果將在數年內發表。基於我們回顧的研究,我們發現並沒有足夠證據支持使用結構性暫停療法作為慢性控制中的HIV感染作為照護標準。