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Review
. 2006 Jul 19;2006(3):CD006148.
doi: 10.1002/14651858.CD006148.

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

N P Pai  1 , J Lawrence, A L Reingold, J P Tulsky
Affiliations
Review

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

N P Pai et al. Cochrane Database Syst Rev. .

Abstract

Background: Structured treatment interruptions (STI) of antiretroviral therapy (ART) have been investigated as part of novel treatment strategies, with different aims and objectives depending on the populations involved. These populations include: 1) patients who initiate ART during acute HIV infection; 2) patients with chronic HIV infection, on ART, with successfully suppressed viremia; and 3) patients with chronic HIV infection and treatment failure, with persistent viremia due to multi-drug resistant HIV (Hirschel 2001; Deeks 2002; Miller 2003). In an earlier Cochrane review (Pai 2005), we had summarized the evidence about the effects of STI in chronic suppressed HIV infection. In this review, we summarize the evidence on STI in patients with chronic unsuppressed HIV infection due to drug-resistant HIV. Unsuppressed HIV infection describes those patients who cannot suppress viremia, due to the presence of multi-drug-resistant virus. It is also referred to as treatment failure. Drug resistance is identified by the presence of resistant mutations at baseline.STI as a treatment strategy in HIV-infected patients with chronic unsuppressed viremia involves interrupting ART in controlled clinical settings, for a pre-specified duration of time. These interruptions have various aims, including the following: 1) to allow wild virus to re-emerge and replace the resistant mutant virus, with the hope of improving the efficacy of a subsequent ART regimen; 2) to halt development of drug resistance and to preserve subsequent treatment options; 3) to alleviate treatment fatigue and reduce drug-related adverse effects; and 4) to improve quality of life (Miller 2003; Montaner 2001; Vella 2000;).

Objectives: The objective of our systematic review was to synthesize the evidence on the effect of structured treatment interruptions in adult patients with chronic unsuppressed HIV infection.

Search strategy: We included all available intervention studies (randomized controlled trials and non-randomized trials) conducted in HIV-infected patients worldwide. We searched nine databases, covering the period from January 1996 to February 2006. We also scanned bibliographies of relevant studies and contacted experts in the field to identify unpublished research, abstracts and ongoing trials. In the first screen, a total of 3186 potentially eligible citations from nine databases and sources were identified, of which 2047 duplicate citations were excluded. The remaining 1139 citations were examined in detail, and we further excluded 951 citations that were modeling studies, animal studies, case reports, and opinion pieces. As shown in Figure 01, 188 citations were identified in the second screen as relevant for full-text screening. Of these, 60 basic science studies, editorials and abstracts were excluded and 128 full-text articles were retrieved. In the third screen, all full-text articles were examined for eligibility in our review. These were subclassified into three categories: 1) chronic suppressed HIV infection; 2) chronic unsuppressed HIV infection; and 3) acute HIV infection. Studies were further excluded if their abstracts did not contain enough information for inclusion in our reviews. A total of 62 studies were finally classified into chronic suppressed, acute, and chronic unsuppressed categories. Of these, 17 trials met the eligibility criteria for this review.

Selection criteria: Inclusion criteriaAll available randomized or non-randomized controlled trials investigating planned treatment interruptions among patients with chronic unsuppressed HIV infection. Early pilot non-randomized prospective studies on treatment interruptions of fixed and variable durations were also included. Relevant abstracts on randomized controlled trials were also included if they contained sufficient information. Exclusion criteriaEditorials, reviews, modeling studies, and basic science studies were excluded. Studies on STI among patients with chronic suppressed HIV infection were summarized in a separate review. Studies on STI in primary HIV infection were beyond the scope of this review.

Data collection and analysis: Two reviewers independently extracted data, evaluated study eligibility and quality. Disagreements were resolved in consultation with a third reviewer.A total of seventeen studies on STI were included in our review. However, due to significant heterogeneity across studies (i.e. in study design, populations, baseline characteristics, and reported outcomes; and in reporting of measures of effect, hazard ratios, and risk ratios), we considered it inappropriate to perform a meta-analysis.

Main results: In early pilot non-randomized trials, a pattern was evident across studies. During treatment interruption, a decline in CD4 cell counts, increase in viral load, and a shift in the level of genotypic drug resistance towards more of a wild-type HIV virus was reported. This suggests that STI may be used to increase drug susceptibility to an optimized salvage regimen upon treatment re-initiation. These studies generated useful data and hypotheses that were later tested in randomized controlled trials. Randomized controlled trials rated high on quality. Of the eight randomized controlled trials reviewed, seven had been completed while one was ongoing and remains blinded. Of the seven completed randomized controlled trials, six have reported consistent virologic and immunologic patterns, and found no significant benefit in virologic response to subsequent ART in the STI arm, compared to the control arm. In addition, the largest completed randomized trial reported greater numbers of clinical disease progression events and evidence of prolonged negative impact on CD4 cell counts in the STI arm (Beatty 2005; Benson 2004; Deeks 2001; Lawrence 2003; Walmsley 2005; Ruiz 2003). The single RCT with divergent findings from the others (GigHAART), reporting a significant virologic and immunologic benefit due to STI, was different in prescribing a shorter STI duration and a salvage ART regimen of 8-9 drugs. There were also differences in the patient population characteristics with this study, targeting those with very advanced HIV disease (Katlama 2004). Although we await the unblinded results of the eighth RCT (OPTIMA), the evidence so far does not support STI in the setting of chronic unsuppressed HIV infection with antiretroviral treatment failure (Brown 2004; Holodniy 2004; Kyriakides 2002; Singer 2006).

Authors' conclusions: The current available evidence primarily supports a lack of benefit of STI before switching therapy in patients with unsuppressed HIV viremia despite ART. There is evidence of harm in attempting STI in patients with relatively advanced HIV disease, due to the associated CD4 cell decline and the increased risk of clinical disease progression. At this time, there is no evidence to recommend the use of STI in this clinical category of patients with treatment failure.

PubMed Disclaimer

Conflict of interest statement

We certify that we have no affiliations or involvements in any organization or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, and expert testimony).

Figures

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Figure 1: Search Strategy of Included Studies.
See this image and copyright information in PMC

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References

References to studies included in this review

Beatty 2005 {published data only}
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Katlama 2004 {published data only}
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Miller 2000 {published data only}
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Walmsley 2005 {published data only}
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Youle 2000 {published data only}
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References to studies excluded from this review

Alexander 2003 {published data only}
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Altfeld 2002 {published data only}
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Ananworanich 2003 {published data only}
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Ananworanich 2005 {published data only}
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Bajaria 2004 {published data only}
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Blankson 2001 {published data only}
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Boschi 2004 {published data only}
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Cardiello 2005 {published data only}
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Fagard 2003 {published data only}
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Fagard 2005 {published data only}
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Fischer 2003 {published data only}
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Foli 2002 {published data only}
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Frost 2002 {published data only}
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Garcia 2003 {published data only}
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Garcia 2001 {published data only}
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Garcia 2002 {published data only}
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Grinberg 2000 {published data only}
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Gulick 2002 {published data only}
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Idemyor 2003 {published data only}
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Lori 2000 {published data only}
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Lori 2000b {published data only}
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Maroto 2005 {published data only}
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Martinez‐Picado 2002 {published data only}
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Metzner 2003 {published data only}
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Molto 2004 {published data only}
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Montes 2005 {published data only}
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Mussini 2005 {published data only}
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Neumann 1999 {published data only}
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Nuesch 2005 {published data only}
    1. Nuesch R, Ananworanich J, Sirivichayakul S, Ubolyam S, Siangphoe U, Hill A, et al. Development of HIV with drug resistance after CD4 cell count‐guided structured treatment interruptions in patients treated with highly active antiretroviral therapy after dual‐nucleoside analogue treatment. Clin Infect Dis 2005;40(5):728‐34. - PubMed
Ortiz 2001 {published data only}
    1. Ortiz GM, Wellons M, Brancato J, Vo HT, Zinn RL, Clarkson DE, et al. Structured antiretroviral treatment interruptions in chronically HIV‐1‐infected subjects. Proc Natl Acad Sci U S A 2001;98(23):13288‐93. - PMC - PubMed
Oxenius 2002 {published data only}
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Papasavvas 2004 {published data only}
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Parienti 2002 {published data only}
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Plana 2004 {published data only}
    1. Plana M, Garcia F, Oxenius A, Ortiz GM, Lopez A, Cruceta A, et al. Relevance of HIV‐1‐Specific CD4+ Helper T‐Cell Responses During Structured Treatment Interruptions in Patients With CD4+ T‐Cell Nadir Above 400/mm3. J Acquir Immune Defic Syndr 2004;36(3):791‐799. - PubMed
Ruiz 2001 {published data only}
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Schweighardt 2002 {published data only}
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Sommet 2003 {published data only}
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Taffe 2002 {published data only}
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Tuldra 2001 {published data only}
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Yerly 2003 {published data only}
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Yerly 2004 {published data only}
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References to ongoing studies

Holodniy 2004 {published data only}
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Kyriakides 2002 {published data only}
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