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A Randomized Trial of Treatment Interruption before Optimized Antiretroviral Therapy for Persons with Drug-Resistant HIV: 48-Week Virologic Results of ACTG A5086

  1. Constance A. Benson1,
  2. Florin Vaida1,
  3. Diane V. Havlir2,
  4. Gerald F. Downey3,
  5. Michael M. Lederman4,
  6. Roy M. Gulick5,
  7. Marshall J. Glesby5,
  8. Michael Wantman3,
  9. Christian J. Bixby6,
  10. Alex R. Rinehart7,
  11. Sally Snyder8,
  12. Rui Wang3,
  13. Sheran Patel6 and
  14. ACTG A5086 Study Team6,a
  1. 1University of California, San Diego School of Medicine, San Diego, and
  2. 2San Francisco General Hospital and University of California, San Francisco School of Medicine, San Francisco;
  3. 3Harvard School of Public Health, Boston, Massachusetts;
  4. 4Case Western Reserve University School of Medicine, Cleveland, Ohio;
  5. 5Weill Medical College of Cornell University, New York, New York;
  6. 6University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
  7. 7Virco Lab, Inc., Tibotec-Virco, Durham, North Carolina;
  8. 8Social and Scientific Systems, Inc., Silver Spring, Maryland
  1. Reprints or correspondence: Dr. Constance A. Benson, Antiviral Research Center, University of California, San Diego, 150 W. Washington St., Ste. 100, San Diego, CA 92103 (cbenson{at}ucsd.edu)
 
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Abstract

BackgroundThe role of structured treatment interruption (STI) before optimized antiretroviral therapy (ART) in patients with drug-resistant human immunodeficiency virus type 1 (HIV-1) is uncertain

MethodsAIDS Clinical Trial Group protocol A5086 was a prospective trial of 41 patients with multiple drug class–resistant HIV who were randomized to undergo a 16-week STI followed by optimized ART (STI) or immediate optimized ART (no STI). The primary end point was the proportion of subjects with HIV-1 RNA loads <400 copies/mL 48 weeks after randomization

ResultsOf 39 evaluable patients, 4 (19%) in the STI arm and 6 (33%) in the no STI arm had HIV-1 RNA loads <400 copies/mL at 48 weeks (P=.44). Median changes from baseline in CD4+ cell counts and HIV-1 RNA loads were similar for both arms. Standard genotypes at the end of STI showed nearly complete reversion to wild-type virus in a minority of patients (n=5; 28%). Virus with 3–drug class resistance reemerged even when ART included only 1 or 2 drug classes. Single-genome sequencing showed that each genome encoded resistance mutations for 3 drug classes

ConclusionsA 16-week STI before optimized ART did not improve virologic response. Genetic analyses strongly suggest that virologic failure resulted from the reemergence of virus present before STI that encoded 3–drug class resistance on the same genome

Because of limitations in present treatment options, a substantial proportion of patients with drug-resistant HIV-1 infection have uncontrolled viremia. The success of antiretroviral therapy (ART) in this setting diminishes with prior exposure to ART, and the success of any subsequent treatment response is due, in part, to the number of drugs in the new regimen to which the virus is susceptible [1–10]. There remains a pressing need for new drugs and strategies for treating persons with drug-resistant HIV-1

Data from previous uncontrolled studies suggested that a strategy of structured treatment interruption (STI) before the initiation of a new ART regimen improved the virologic response in individuals with multiple drug– and drug class–resistant HIV-1 [11–18]. One factor that predicted an improved virologic response was a nearly complete shift in genotype to wild-type HIV during STI [15–18]. Data from several randomized trials refuted the result of a clinical or virologic benefit of this strategy [19–24]

AIDS Clinical Trials Group (ACTG) A5086 proposed to test the hypothesis that starting an optimized ART regimen, with subjects selected by genotypic and phenotypic resistance testing coupled with a knowledge of their ART histories, would improve the virologic response in patients with multiple drug class–resistant virus if they interrupted ART for a period sufficient to allow the repopulation of plasma with more drug-susceptible virus before the resumption of a new ART regimen, compared with patients making an immediate switch to optimized ART

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Patients and Methods

Patient population and study designACTG A5086 was a prospective, randomized, multicenter trial that compared a 16-week period of STI followed by optimized ART with immediate optimized ART in HIV-1–infected persons (⩾18 years old) failing their current ART regimen. Eligibility criteria included a confirmed plasma HIV-1 RNA load >5000 copies/mL, virologic failure of at least 2 potent combination ART regimens, a history of extensive prior ART exposure (defined as treatment with ⩾2 nucleoside reverse-transcriptase inhibitors [NRTIs] for at least 12 months, ⩾2 protease inhibitors [PIs] each for at least 6 months, and ⩾1 nonnucleoside reverse transcriptase inhibitor [NNRTI] for at least 3 months), and receipt of a failing regimen for at least 8 weeks before entry and for at least 4 weeks before the performance of screening genotypic and phenotypic resistance testing. Additional conventional exclusion criteria were applied. Written informed consent was obtained from all participants, and the human-experimentation guidelines of the US Department of Health and Human Services and participating institutions were followed

Eligible subjects had preentry plasma samples tested for HIV-1 genotype, virtual phenotype, and phenotype (vircoTYPE HIV-1 and Antivirogram; Virco). Patients continued to receive their preentry ART regimen between screening and randomization unless this was clinically contraindicated. On the basis of the results of the preentry resistance tests and treatment history, an optimized ART regimen was selected at entry to include new or recycled drugs. Patients were randomized 1:1 to either interrupt ART for 16 weeks and then initiate their preselected optimized ART regimen (STI arm) or to immediately initiate their optimized ART regimen (no STI arm). The randomization was stratified by CD4+ cell count (<200 or ⩾200 cells/μL) and HIV-1 RNA load (<100,000 or ⩾100,000 copies/mL). Patients continued to receive their optimized ART regimen through at least week 24 unless toxicity developed or criteria for virologic failure were met. A single within-class NRTI or NNRTI substitution for intolerance was not considered to be a change in regimen. Virologic failure was defined as a <0.5 log10 decrease in HIV-1 RNA load from the time of starting to week 8 of optimized ART, a confirmed increase in HIV-1 RNA load of >1.0 log10 above the nadir achieved while receiving optimized ART, or a confirmed increase in HIV-1 RNA load of >1.0 log10 above baseline. Patients were monitored for 64 weeks after randomization

Enrollment and follow-upAccrual was closed before the planned 140 subjects were enrolled, in accordance with negative findings from a similar STI study [19] that affected accrual. Follow-up was continued for the patients enrolled, to characterize mechanisms of virologic failure, which was a planned secondary objective of the study

Samples for the determination of plasma HIV-1 RNA load, CD4+ cell count, and laboratory indicators of safety were obtained at baseline, 14 and 28 days after starting optimized ART, every 4 weeks through week 24, and then every 8 weeks thereafter. For patients who underwent STI, samples for plasma HIV-1 RNA load, CD4+ cell count, and genotypic analysis were obtained at day 7, every 2 weeks during the STI, and at the end of the STI. Plasma samples were batch tested at the end of the study for genotypic and phenotypic drug susceptibility at weeks 24 and 48; samples collected at the time of confirmed virologic failure were tested for genotypic susceptibility in real time, with results reported to sites

All subjects received chemoprophylaxis for opportunistic infections (OIs) as appropriate for their CD4+ cell count; screening for OIs was performed in accordance with standards of care. Subjects undergoing STI immediately received their new optimized ART regimen before the completion of the 16 week STI if they had a ⩾50% decrease in CD4+ cell count from baseline, at the discretion of the site investigator for a decrease in CD4+ cell count from a baseline of <40 cells/μL, or if they had a new or recurrent OI. Annual interim safety reviews were conducted to monitor the occurrence of AIDS-defining OIs, death, or the combination of these end points

Detailed HIV-1 drug-resistance analysesA planned secondary objective was to compare HIV-1 drug resistance in virus from plasma obtained at baseline, the end of the STI, and virologic failure after the start of optimized ART, to assess the reemergence of drug-resistant HIV-1. Standard genotype analyses of samples were performed using the ViroSeq HIV-1 genotyping system (version 2; Celera Diagnostics) and an ABI PRISM 3100 genetic analyzer (Applied Biosystems). For subjects in the STI arm, the extent of HIV-1 genotype reversion, compared with baseline mutations, was classified into 1 of 3 categories: complete reversion of all primary drug-resistance mutations (i.e., mutations at amino acid positions 41, 65, 67, 70, 74, 115, 184, 210, 215, 219, 69 insertion complex, and 151 complex for NRTIs; 100, 103, 106, 181, 188, 190, and 225 for NNRTIs; and 30, 33, 46, 48, 50, 53, 54, 82, 84, and 90 for PIs) [25], partial reversion of ⩾1 but not all primary drug-resistance mutations, or little/no reversion (reversion of 1 or 0 primary drug-resistance mutations)

End-point dilution reverse transcriptase–initiated polymerase chain reaction, also known as “single-genome sequencing” [26], was used to detect low-frequency (minor) HIV-1 variants not detected by standard genotyping at the time points stated above for those patients who had complete reversion of primary mutations. The genetic relatedness of single genomes at these time points were compared using the neighbor-joining method in PHYLIP (version 3.573c; Department of Genome Sciences, University of Washington) [27]

Statistical analysesThe proportion of patients in each arm with plasma HIV-1 RNA loads <400 and <50 copies/mL at week 48 after randomization (the primary end point) and at weeks 24, 48, and 64 after the initiation of ART and randomization, respectively, were compared using a stratified exact test based on the hypergeometric distribution. Patients with missing end points were excluded; however, a sensitivity analysis was also performed with missing end points treated as failure. The 95% confidence interval (CI) for the difference between the proportions used normal asymptotic approximation with the Wilson correction. The exact Gehan-Wilcoxon&amp;rank test was used to compare changes in log10 HIV-1 RNA load from baseline. Other secondary end points were compared using exact Wilcoxon&amp;rank or asymptotic log-rank tests as appropriate. The genotypic sensitivity score, based on screening virus samples, was calculated using the Stanford resistance score (available at: http://hivdb.stanford.edu) [28], and the phenotypic sensitivity score was calculated by assigning each drug a score of 1 for a fold IC50 for virus at or below the assay cutoff value for sensitivity and a score of 0 otherwise. Viruses with a lopinavir fold IC50 between 10 and 40 were given a score of 0.5

MonitoringThe National Institute of Allergy and Infectious Disease Data and Safety Monitoring Board conducted an interim safety review in November of 2002 that was based on data accrued through October 2002. Annual reviews by an independent interim safety monitoring committee of the ACTG were conducted thereafter

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Results

Accrual and baseline demographicsForty-one patients were enrolled from 13 sites over the course of 18 months; 21 were randomized to undergo STI and 20 to no STI. Thirty-nine patients completed 48 weeks of treatment; 1 patient randomized to not undergo STI withdrew consent, and a second died before week 48. There were no statistically significant differences in any baseline characteristics (table 1). The median genotypic (1.5 and 1.0 in the STI and no STI arms, respectively) and phenotypic (2.5 and 2.0, respectively) susceptibility score for the optimized regimen and the median number of drugs in the optimized regimen (4; range, 3–6) were similar in both arms. The most common optimized regimen in both arms included a boosted PI and 2 or 3 NRTIs—16 patients in the STI arm received a single boosted PI, 3 received double-boosted PIs, and 1 received T-20; in the no STI arm, 14 patients received a single boosted PI, 5 received double-boosted PIs, and 2 received T-20. The majority of patients in each arm received ⩾1 “recycled” drug. Thirty-seven (93%) of 40 patients continued to receive their initially prescribed regimen for at least 24 weeks, and 27 (68%) continued to receive their originally assigned ART regimen for 48 weeks. There were no significant differences between arms with respect to time receiving the initially selected ART regimen since randomization or since the initiation of optimized ART (P=.67 and P=.66, respectively)

Of the 21 patients randomized to undergo STI, 16 (76%) completed the full STI. Of the 5 who did not, 4 initiated optimized ART at weeks 7 and 15 (2 each) because of protocol-defined CD4+ cell count criteria, and 1 discontinued the STI at week 3 because of fatigue. The median duration of follow-up in the study was 63 weeks

Virologic responsesFour (19%) of 21 patients who underwent STI and 6 (33%) of 18 patients who did not undergo STI had plasma HIV-1 RNA loads <400 copies/mL at week 48 (95% CI, 40.1%–13.5%; P=.44). Three (14%) of 21 patients who underwent STI and 5 (28%) of 18 who did not undergo STI had plasma HIV-1 RNA loads <50 copies/mL at week 48 after randomization (P=.45). Similarly, there were no differences between arms in the proportions of patients with plasma HIV-1 RNA loads <400 and <50 copies/mL at week 24 after the start of their optimized ART regimen (P=.33 and P=.060, respectively). Figure 1A illustrates the overall change from baseline in plasma HIV-1 RNA load by treatment arm; although there was an expected difference at week 16 (P=.004 in favor of the no STI arm), there were no significant differences at week 24 or 48. Virologic failure after the initiation of optimized ART occurred in 13 (62%) of 21 patients in the STI arm and 10 (56%) of 18 patients in the no STI arm (P=.70)

Figure 1
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Figure 1

A Change in plasma HIV-1 RNA load (95% confidence interval [CI]) from baseline to week 64 (48 weeks after initiation of optimized antiretroviral therapy [ART]). B Change in CD4+ T cell count (95% CI) from baseline to week 64. STI, structured treatment interruption

HIV-1 drug-resistance analysesThree of 21 patients who underwent STI were excluded from the final resistance analyses; 2 samples were mislabeled at baseline, and 1 patient died before completing the study. Nine of the remaining 18 patients had virologic failure of their optimized ART regimen. Only 5 (28%) of 18 patients had complete reversion of baseline primary drug-resistance mutations by the end of STI. Of these 5 patients, 3 (60%) had virologic failure (table 2). The remaining 13 patients had partial or little/no reversion of primary resistance mutations, and 8 (62%) of these patients had virologic failure

Figure 2
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Figure 2

Phylogenetic analysis of single genome sequences from representative subject 42. Single-genome sequences were obtained from plasma at study baseline (BSL), the end of the structured treatment interruption (STI), and virologic failure (VF); these were used to construct the phylogenetic tree with the neighbor-joining PHYLIP method. Sequences from BSL and VF are clustered and are distinct from the majority of sequences at STI. The 2 sequences from STI encoding 3–drug class resistance (table 3) are highlighted to show their relatedness to sequences from BSL and VF but not other sequences from TI

Table 1
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Table 1

Baseline characteristics of study subjects

Table 2
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Table 2

Genotypic shift toward wild-type virus at the end of structured treatment interruption (STI)

Standard HIV genotypes at baseline and at virologic failure were very similar for each of the patients who had virologic failure. In the 3 subjects who had virologic failure despite complete reversion of primary drug-resistance mutations at the end of STI, the virus at virologic failure showed 3–drug class resistance, despite the use of only 1 or 2 drug classes in the optimized ART regimen (table 3). Single-genome sequencing performed at baseline and virologic failure on samples from these 3 subjects demonstrated that multiple drug and drug-class resistance was due to viral genomes encoding resistance mutations on the same genome. As shown in table 4, the genomes at baseline from the representative subject, 42, were monotonously similar—each of them encoded all primary resistance mutations. Results were similar for subjects 131 and 831 (not shown). Single-genome sequencing further demonstrated that resistance mutations at baseline persisted after STI and that sequences from baseline and virologic failure were closely related. For example, in subject 42 (table 4), 2 of 51 genomes tested at the end of STI had almost all of the mutations that were present at baseline; these were missed by standard genotyping. Phylogenetic analyses showed that the sequences with drug-resistance mutations at the end of STI were more closely related to the baseline and failure sequences than to the remainder of the sequences at the end of STI (figure 2). Similar findings were observed for subjects 131 and 831 (not shown). Removing the drug-resistance mutations by setting them to wild-type did not alter the results of phylogenetic analyses

Table 3
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Table 3

Reemergence of 3–drug class (nucleoside reverse-transcriptase inhibitor [NRTI], nonnucleoside reverse-transcriptase inhibitor, and protease inhibitor [PI]) resistance after structured treatment interruption (STI)

Table 4
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Table 4

Standard genotype vs. single-genome sequencing in representative subject 42

Immunologic responsesWith the exception of the expected change in CD4+ cell count from randomization to week 16, which favored the no STI arm (P<.001), a comparable increase in CD4+ cell count after the initiation of optimized ART occurred in both arms (P=.49) (figure 1B)

Safety and clinical eventsThere were no significant differences between arms in the development of or time to any grade ⩾3 adverse event or clinical end point. Six patients in the STI arm had HIV-related clinical events that included oropharyngeal candidiasis (4), herpes zoster (1), and non-Hodgkin lymphoma (1, at week 66); only 1 patient had a clinical event during the STI (herpes zoster). Six subjects in the no STI arm had clinical events, including mucocutaneous herpes simplex (3), oropharyngeal candidiasis (1), and herpes zoster (1). One patient in the no STI arm died of bacterial sepsis with end-stage liver disease at week 48

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Discussion

The present study was designed to test the hypothesis that a period of STI followed by the initiation of an optimized ART regimen, constructed on the basis of genotypic and phenotypic susceptibility testing and ART history, would improve the virologic outcome of HIV-1–infected individuals with limited treatment options because of multiple drug and drug-class resistance [11–16]. Although the limited sample size reduced the statistical power to address the primary virologic end point, no results favoring the STI arm were observed. Furthermore, we did not demonstrate a difference in clinical events or CD4+ cell counts

The more notable findings of our study result from the detailed drug-resistance analyses, which provide an explanation of the failure of STI to improve virologic response. In contrast to other published data [17–21, 24], only 28% of participants randomized to undergo STI in our study had extensive reversion of primary genotypic resistance mutations to wild type during the STI. There was no association between extensive reversion of primary resistance mutations during the STI and an improved virologic response to optimized ART. The reason for the observed lack of extensive reversion is unclear. Although the extent of genotypic mutations at baseline and the baseline genotypic and phenotypic susceptibility to the drugs in the optimized ART regimens of patients in our study were similar to those reported in other studies, it is possible that we selected participants with more-prolonged virologic failure in the presence of multiple drugs, resulting in a smaller population of residual wild-type virus

A central question that we explored was whether resistant minor viral variants persist in patients who have complete reversion of primary resistance mutations, as determined by standard genotyping, after STI. Although it remains possible that the reemergence of drug resistance may arise from archived drug-resistant virus, we provide several lines of evidence that resistant virus persists after STI and that this leads to virologic failure: this result expands on the results of an earlier report by Hance et al. [29]. First, standard genotyping and single-genome sequencing coupled with phylogenetic analyses revealed closely related virus populations at baseline and at virologic failure, despite complete or partial reversion to wild-type virus at the end of STI. Second, single-genome sequencing showed the persistence of drug-resistant variants at the end of STI that were missed with standard genotyping. These variants were related but were not identical to baseline variants and were genetically distant from the majority of the variants present at the end of the STI. Third, 3–drug class resistance reemerged at virologic failure, despite the use of regimens of only 1 or 2 drug classes, which suggests linkage of resistance mutations on the same genome and reselection of these genomes during optimized therapy. Our findings refute the primary hypothesis of our study and support the conclusion that STI is not an effective strategy for treatment of multiple drug class–resistant HIV-1, because drug-resistant variants persist and are rapidly reselected with the reinitiation of optimized ART that is based on the same drug classes as those used before STI

Our overall results are consistent with those of 4 of 5 randomized trials that evaluated STI preceding optimized ART in this setting [19–23] but contrast those of the Agence National de Recherche du SIDA 097 study, which reported that an 8-week STI followed by the initiation of a multiple-drug ART regimen was associated with an improved virologic response at weeks 24, 32, and 48 after randomization, compared with no STI [24]. Major differences from our study included a shorter period of STI, a larger proportion of individuals with a complete shift in genotype to wild-type virus, lower baseline CD4+ cell counts, and a larger number of drugs in the optimized ART regimen. Loss of at least 1 major genotypic resistance mutation during STI was identified as one of the factors associated with improved virologic response after the resumption of optimized ART, although this relationship was not seen in our and other randomized studies. Interestingly, a follow-up single-arm study by the same investigators to test this relationship reported no virologic benefit of STI and failed to demonstrate an improved response with reversion to wild-type virus [30]

We conclude, on the basis of the preponderance of published data and our own findings, that STI before the reinitiation of optimized ART is not associated with improved virologic or immunologic response, compared with the immediate administration of optimized ART in patients with multiple drug class–resistant HIV-1 and limited treatment options. More important, we provide convincing evidence for the persistence of drug-resistant viral variants, despite reversion to wild-type virus in plasma after STI, as the likely explanation for the failure of STI in this setting

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AIDS Clinical Trial Group (ACTG) A5086 Protocol Team Members

In addition to the authors, other members of the ACTG A5086 protocol team included the following: L. Meixner and J. Kunkel (University of California, San Diego); V. Hughes and T. Stroberg (Weill Medical College of Cornell University, New York, NY); M. Carlson and S. Chafey (School of Medicine, University of California, Los Angeles); M. Marcelo Gonzalez and S. Souza; (University of Hawaii, Honolulu); D. McMahon and B. Rutecki (University of Pittsburgh, Pittsburgh, PA); B. Putnam (University of Colorado Health Sciences Center, Denver); M. Kilby and K. Savage (University of Alabama, Birmingham); K. Cavanagh and C. Gonzalez (New York University/Bellevue Hospital, New York, NY); C. Colegate and S. Kohrs (University of Cincinnati, Cincinnati, OH); M. Dube and D. O’Connor (Indiana University, Bloomington); D. Mildvan and S. Middleton (Beth Israel Medical Center, New York, NY); J. Nicotera and V. Bailey (Vanderbilt University School of Medicine, Nashville, TN); and J. Santana and O. Mendez (University of Puerto Rico, San Juan)

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Acknowledgments

We thank Laureen Copfer, for careful review and preparation of the manuscript, and the patients who donated their time and effort to participate in the study

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Footnotes

  • ↵Presented in part: 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, 8–11 February 2004 (abstract 58)

    Financial support: National Institutes of Health (grants AI 38858, AI 27670, AI 38855, AI 51951, AI 27663, AI 46383, AI 46386, AI 51966, RR 0047, AI 25879, AI 32770, RR 00051, P30-AI 27767, AI 32775, RR 00032, AI 27665, RR 00096, AI 46370, AI 46339, AI 25859, AI 27660, AI 34853, AI 34832, and AI 25897)

    Potential conflicts of interest: A.R.R. is an employee of Tibotec Therapeutics, the parent company of Virco, which manufactured the drug-resistance assays used in the study. All other authors: no conflicts reported

    Clinical trials registry: NCT00011128 (http://www.ClinicalTrials.gov)

  • ↵Study group members are listed after the text

  • Received January 26, 2006.
  • Accepted July 4, 2006.
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  1. J Infect Dis. (2006) 194 (9): 1309-1318. doi: 10.1086/508289
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