JAIDS Journal of Acquired Immune Deficiency Syndromes:
Disadvantages of Structured Treatment Interruption Persist in Patients With Multidrug-Resistant HIV-1: Final Results of the CPCRA 064 Study
Lawrence, Jody MD*; Hullsiek, Katherine Huppler PhD†; Thackeray, Lisa M MS†; Abrams, Donald I MD*; Crane, Lawrence R MD‡; Mayers, Douglas L MD§; Jones, Michael C RN*; Saldanha, Jennifer M RN∥; Schmetter, Barry S BS¶; Baxter, John D MD, for the CPCRA 064 Study Team of the Terry Beirn Community Programs for Clinical Research on AIDS#
Received for publication January 21, 2006; accepted July 14, 2006.
From the *Department of Medicine, Positive Health Program, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA; †Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN; ‡Department of Medicine, Wayne State University School of Medicine, Detroit, MI; §Infectious Disease Research, Henry Ford Hospital, Detroit, MI; ∥Denver Public Health Department, Denver, CO; ¶Social & Scientific Systems, Inc., Silver Spring, MD; and #Department of Medicine, Cooper Hospital/University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Camden, NJ.
D. L. Mayers is currently affiliated with Boerhinger-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.
Supported by the National Institute of Allergy and Infectious Diseases under National Institutes of Health grants 5U01AI042170-10 and 5U01AI046362-03.
Other participating investigators in the CPCRA 064 Study Team of the Terry Beirn Community Programs for Clinical Research on AIDS are listed in the Appendix.
Reprints: Jody Lawrence, MD, Department of Medicine, University of California, San Francisco, Positive Health Program, San Francisco General Hospital, 995 Potrero Avenue, Building 80, Ward 84, San Francisco, CA 94110 (e-mail: firstname.lastname@example.org).
Background: We report the final results of Community Programs for Clinical Research on AIDS (CPCRA-064) study, a multicenter, prospective, randomized, controlled trial that determines the long-term clinical impact of structured treatment interruption (STI) in patients with multidrug-resistant (MDR) HIV-1.
Methods and Results: Two hundred seventy-four patients on stable antiretroviral therapy with MDR HIV-1 treatment failure were randomized to a 4-month STI, followed by an optimized antiretroviral regimen (STI arm, n = 140) or an immediate change to an optimized antiretroviral regimen (control arm, n = 134). Main outcome measures were progression of disease or death and changes from baseline in HIV RNA levels (log copies/mL) and CD4 cell counts (cells/mm3). The median baseline HIV RNA level was 5.0 log copies/mL, the median CD4 count was 147 cells/mm3, and the nadir CD4 count was 32 cells/mm3. The median follow-up was 37 months. After the STI period, there were no differences in HIV RNA level responses between treatment arms. Differences in CD4 count responses always favored the control arm, with an advantage of 84 cells from 0 to 4 months (P < 0.0001), 50 cells from 4 to 12 months (P < 0.0001), 45 cells from 12 to 24 months (P = 0.006), and 43 cells after 24 months (P = 0.07). Rates in the STI and control arms for first progression-of-disease event or death were 17.5 and 14.3, respectively (hazard ratio = 1.28; P = 0.22).
Conclusion: STI before changing regimens in patients with MDR HIV-1 treatment failure has a prolonged negative impact on CD4 cell count recovery and does not confer progression of disease or virologic benefits.
Many people with HIV-1 disease experience incomplete suppression of their HIV-1 despite highly active antiretroviral therapy (HAART).1-3 This can occur for various reasons, including difficulties with treatment adherence, exposure to suboptimal regimens, altered drug metabolism, and acquisition of drug-resistant virus during primary infection. Unfortunately, these conditions frequently lead to multidrug-resistant (MDR) HIV-1 and an absence of effective treatment options.4,5
The optimal therapeutic options for patients with MDR HIV-1 remain unclear. Continuing current therapy in the setting of persistent viremia carries the risk of accumulating additional HIV-1 drug-related mutations that may further compromise the efficacy of future treatments.6-9 Maintaining a failing regimen may also expose patients to unnecessary drug-related toxicities. Stopping all antiretroviral therapy can eliminate drug toxicities and permit the re-emergence of drug-sensitive virus but is frequently associated with an abrupt decline in CD4 cell counts.10-16 Determining which strategy is best for these patients is important to maximize their health and quality of life while awaiting new drugs that are effective against MDR HIV-1.
To address these issues, we developed a randomized clinical trial within the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA 064) for patients with MDR HIV-1. The primary goal was to determine whether a prescribed 4-month structured treatment interruption (STI) before switching therapy results in an improved response that delays clinical disease progression or death compared with a strategy of immediately initiating a new antiretroviral regimen.
The study was closed to enrollment early (in 2002) based on preliminary findings after a median follow-up of 12 months that showed STI was associated with greater progression of disease or death and did not lead to an improved HIV RNA level or CD4 cell count response.17 Study visits continued through June 30, 2004 for all randomized patients to assess the long-term impact of STI in this cohort. We report here the final study results, with a median of 37 (minimum of 24) months of patient follow-up.
The CPCRA 064 is a prospective randomized clinical end-point trial. Complete details of the study design, including the genotypic definition of MDR HIV-1, have been described in depth elsewhere.17 The institutional review board of each clinical site approved the protocol, and all patients or their parents or guardians gave written informed consent. The study was originally designed to enroll and follow 480 patients but was closed to enrollment early based on the recommendations of the Data and Safety Monitoring Board. When the study closed to enrollment, there were 274 patients randomized (from August 11, 2000 to June 27, 2002) from 16 clinical sites. Study visits continued until a common closing date (June 30, 2004) to obtain a minimum follow-up of 24 months. All patients were followed for death, progression of disease, and other events as well as for laboratory markers (CD4 cell counts and HIV RNA levels) through that common closing date.
HIV-1-infected patients on stable antiretroviral regimens with virologic failure (viral load >5000 copies/mL) and MDR HIV-1 virus were randomized to a 4-month STI, followed by the initiation of an optimized antiretroviral regimen (STI arm) or immediate initiation of an optimized antiretroviral regimen (control arm). Baseline genotypic (TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System; Bayer Diagnostics, Tarrytown, NY) and phenotypic (Antivirogram; Virco Lab, Raritan, NJ) drug resistance tests were provided to assist the patient's primary care provider in selecting an optimized regimen. Sixteen drugs were included in the genotypic and phenotypic panels.
The primary outcome for the study was new or recurrent clinical disease progression events or death. HIV-1 disease progression clinical events included those in the 1993 US Centers for Disease Control and Prevention revised AIDS case definition18 and a number of other serious opportunistic infections or cancers associated with HIV-1 immunodeficiency. A clinical events committee blinded to treatment assignment reviewed all primary events. Events classified as confirmed or probable using pre-established criteria by the Centers for Disease Control and Prevention were considered to be an end point. Secondary outcomes included changes from baseline in HIV-1 RNA levels, CD4 cell counts, and antiretroviral resistance; adverse events; targeted symptoms; self-reported adherence to antiretroviral treatment; and quality of life. Patients in the STI arm who experienced a progression-of-disease event or a greater than 50% decline in CD4 cell count during the 4-month STI period were encouraged to terminate the STI early.
Proportional hazards models, Kaplan-Meier curves, and log-rank tests were used to compare the treatment arms with respect to disease progression or death, time to CD4 cell count recovery, and adverse events. Hazard ratios are for the time to the first event and compare the STI arm with the control arm. Proportional hazards models for progression of disease adjust for prior progression of disease as well as baseline CD4 cell counts and HIV-1 RNA levels. Rates are given for 100 person-years of follow-up. Longitudinal regression models, with adjustment for baseline value, were used to compare the treatment arms for changes in CD4 cell counts and HIV-1 RNA levels. All HIV-1 RNA levels are reported as log10 copies/mL.
HIV-1 drug resistance mutations considered are from the October 2004 International AIDS Society definition19 and include 54 possible allelic mutations at 36 different codons. The mutations include 22 nucleoside reverse transcriptase inhibitor (NRTI) mutations, 15 nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, and 17 major protease inhibitor (PI) mutations. Quality of life was measured using the Medical Outcomes Study 12-item Short-Form General Health Survey (SF-12). Scores for each of 8 domains ranged from 0 (worst) to 100 (best). An overall quality-of-life score was calculated at each measurement time as the average score over all domains. Targeted symptoms were reported by grade (1 = mild to 4 = severe) at each visit using a toxicity manual developed by the National Institutes of Health, Division of AIDS. All participants underwent a second randomization to complete 1 of 2 instruments designed to capture self-reported adherence to antiretroviral medications during follow-up: a 7-day recall or a 3-day recall. For each instrument, an overall adherence score was calculated at each visit based on the percentage of antiretrovirals taken for that visit.
General linear models were used to compare changes in the number of drug resistance mutations, symptoms, and quality-of-life scores. Generalized estimating equations for correlated repeated binary measurements were used to compare the occurrence of viral load measurements less than 400 copies/mL and the use of prophylactic agents for opportunistic infections by treatment arm. Subgroups prespecified in the protocol were formed according to age, gender, race, baseline, and lowest CD4 cell count ever recorded, baseline HIV-1 RNA level, and antiretroviral treatment history. Analyses were conducted to determine whether differences between treatment arms varied by subgroups in clinical disease progression, survival, and changes in CD4 cell count and HIV-1 RNA level. All analyses were conducted according to the intention-to-treat principle, stratified according to randomization location, and based on a 2-sided type I error with an α-value of 0.05.
Baseline characteristics of the 2 treatment arms were similar (Table 1). The median baseline CD4 cell count (cells/mm3) was 155 in the STI arm and 133 in the control arm (P = 0.33). A total of 56% of the STI arm and 60% of the control arm had a progression-of-disease event recorded before randomization. The most common progression-of-disease events experienced before randomization were Pneumocystis jiroveci (previously carinii) pneumonia (PCP) in 33%, esophageal candidiasis in 16%, and Mycobacterium avium complex (MAC) in 7%.
The mean number of antiretroviral drugs ever prescribed was 10.8 in the STI arm and 10.5 in the control arm. The mean number of antiretroviral drugs in the failing regimen at the time of study entry was 3.6 for the STI arm and 3.7 for the control arm. For the STI and control arms, respectively, the mean numbers of active drugs in the failing regimen were 0.2 and 0.3 by genotype and 0.6 and 0.7 by phenotype. The mean number of drug resistance mutations present at randomization was 10.0 in the STI arm and 9.3 in the control arm. Among all 16 drugs considered in the genotypic panel, the mean numbers of drugs to which the virus was sensitive at randomization were 2.3 and 2.6 for the STI and control arms, respectively. In the phenotypic panel, the mean number was 4.7 for the 2 treatment arms.
Study Compliance With Randomization Assignment and Follow-Up
Two patients randomized to the STI arm (1.4%) did not start an STI, and 4 patients randomized to the control arm (3.0%) initiated an STI immediately after randomization. In the STI arm, the overall median duration of time off antiretroviral therapy during the STI period was 3.9 months. Twenty-eight percent (n = 39) of the STI arm terminated the STI early (median = 2.5 months, range: 0-3.5 months). The main reasons given for early STI termination included a decline in CD4 cell count (n = 29), a rise in HIV RNA level (n = 16), progression of disease (n = 3), and other causes (eg, weakness, hospitalization, worsened neuropathy, patient or clinician choice; n = 9). Twenty-six (66.7%) of those who terminated the STI early experienced at least a 50% decline in CD4 cell count during the STI. Median study follow-up was 37 months in the STI arm (with 1.4% lost to follow-up) and 38 months in the control arm (with 0% lost to follow-up).
Treatments Prescribed After Randomization
The first regimen prescribed after randomization included a mean of 3.8 drugs (2.3 NRTIs, 1.3 PIs, and 0.2 NNRTI) in the STI arm and 3.9 drugs (2.3 NRTIs, 1.4 PIs, and 0.2 NNRTI) in the control arm. The mean number of drugs in the first regimen to which the patient had not been previously exposed was 1.5 for the STI arm and 1.3 for the control arm. Using baseline resistance testing, the mean number of drugs in the first regimen to which the virus was sensitive by genotype was 0.9 for both treatment arms; by phenotype, the mean numbers were 1.3 for the STI arm and 1.6 for the control arm. Coformulated lopinavir/ritonavir (Kaletra) was included in the first regimen for a significantly higher percentage of patients in the STI arm than in the control arm (70% vs. 56%; P = 0.02). Other drugs whose inclusion in the first regimen was significantly different in the STI arm compared with the control arm were stavudine (d4T; 40% vs. 54%; P = 0.02), amprenavir (19% vs. 33%; P = 0.01), and ritonavir (14% vs. 29%; P < 0.001). Ritonavir was primarily used for boosting; only 3 patients were known to be on full-dose ritonavir.
The mean number of months on the first antiretroviral regimen prescribed after randomization was 12.1 for the STI arm and 11.6 for the control arm (P = 0.71). The mean number of antiretroviral regimen changes during follow-up was 3.9 for each treatment arm.
Genotypic Resistance Patterns After Randomization
The virus from patients in the STI arm shifted to a less drug-resistant genotype during treatment interruption. At the earlier of STI termination or the 4-month visit, the mean change in the number of mutations present was a decrease of 4.9 mutations in the STI arm (2.4 NRTI mutations, 0.8 NNRTI mutation, and 1.7 PI mutations) and no change in the control arm (P < 0.0001). Fifty-one percent of the STI arm lost at least half of the mutations present at randomization, and 26% lost all mutations. For the STI arm, the mean increases from baseline in the number of sensitive drugs according to genotype and phenotype at the earlier of STI termination or the 4-month visit were 6.3 and 6.4, respectively. At the 4-month visit, the control arm had no increase in the number of sensitive drugs according to genotype and a mean increase of 0.5 drug according to phenotype. For 19 patients in the control arm, resistance testing was not possible at the 4-month visit because of low viral load.
Disease Progression and Death
For progression of disease or death (the primary end point), 57 patients in the STI arm experienced a total of 102 events, whereas 48 patients in the control arm experienced a total of 81 events (Table 2; Fig. 1, top panel). The rates per 100 person-years for experiencing the first of progression-of-disease event or death in the STI and control arms were 17.5 and 14.3, respectively (hazard ratio = 1.28; P = 0.22). The most recent CD4 cell count before the first event was less than 100 cells/mm3 for 83% of events in the STI arm and for 67% of events in the control arm (P = 0.11). The mean proximal CD4 cell count before a progression-of-disease event or death was 70 cells/mm3 in the STI arm and 89 cells/mm3 in the control arm (P = 0.45).
In the STI arm, 50 events (88%) occurred after the study-defined STI period. Hazard ratios for progression of disease or death by time intervals are given in Figure 1 (bottom panel). In all intervals, the hazard ratio (STI arm compared with control arm) was ≥1; for the period of months 4 through 12, the hazard ratio was 2.20 (95% confidence interval: 0.99 to 4.88; P = 0.05).
The number of deaths was similar in each treatment arm (see Table 2). Considering progression-of-disease events, 44 patients in the STI arm experienced a total of 72 events, whereas 29 patients in the control arm experienced a total of 48 events. The most common progression-of-disease events were esophageal candidiasis, PCP, and cytomegalovirus (see Table 2). Of the 22 esophageal candidiasis events, 17 were classified as probable and 5 were classified as confirmed.
The odds of being on prophylaxis for PCP or MAC did not differ significantly by treatment arm for any time period (months 0-4, months 4-12, months 12-24, after month 24, or overall). The odds of being on an antifungal agent for any reason were significantly higher in the control arm than in the STI arm only for the period of months 4 through 12 (odds ratio = 1.71; P = 0.04). Among the patients who experienced an esophageal candidiasis event, this occurred in the period of months 4 through 12 in only 3 patients (18%) in the STI arm and 1 patient (20%) in the control arm. Most esophageal candidiasis events occurred after month 12: 11 (65%) in the STI arm and 3 (60%) in the control arm.
The hazard ratios for a progression-of-disease event or death did not vary by the study-defined subgroups listed earlier (data not shown).
CD4 Cell Counts and Plasma HIV-1 RNA Levels
The mean treatment arm differences in CD4 cell count change from baseline favored the control arm throughout follow-up (Fig. 2, top panel). For the period from randomization through 4 months (the study-defined STI period), the mean CD4 cell count was higher by 84 cells/mm3 in the control arm than in the STI arm (P < 0.0001; Table 3). The mean differences for months 4 through 12, months 12 through 24, and after month 24 were 50 cells/mm3 (P < 0.0001), 45 cells cells/mm3 (P = 0.006), and 43 cells/mm3 (P = 0.07), respectively.
The median time to the CD4 cell count being greater than the baseline CD4 cell count at a follow-up visit was 5.0 months for the STI arm and 1.2 months for the control arm (P < 0.001). The median time to the CD4 cell count being 50 cells greater than the baseline CD4 cell count was 13.0 months in the STI arm and 3.6 months in the control arm (P < 0.001). At the most recent follow-up visit before the end of the study, 50% of the STI arm and 40.3% of the control arm had a CD4 cell count less than 100 cells/mm3 (P = 0.11).
During the study-defined STI period, the mean treatment arm differences in HIV-1 RNA level change from baseline were significantly different and favored the control arm (see Fig. 2, bottom panel). For the follow-up period from randomization to month 4, the mean change from baseline HIV-1 RNA level was an increase of 0.4 log copies/mL in the STI arm and a decrease of 0.8 log copies/mL in the control arm (see Table 3; treatment arm difference of 1.2 log copies/mL; P < 0.0001). For the time after the study-defined STI period of months 4 through 12, months 12 through 24, and after month 24, the HIV-1 RNA level changes from baseline and the odds of having a viral load measurement less than 400 copies/mL were not significantly different between the treatment arms. At any follow-up visit, the percentage of patients with viral suppression <400 copies/mL did not exceed 25% for either treatment arm. Changes in CD4 cell count and HIV-1 RNA level did not vary by protocol-defined subgroups (data not shown).
Adverse Events, Antiretroviral Adherence, Quality of Life, and Symptoms
The rates for any grade 4 (serious) adverse event were not significantly different between the treatment arms for the first 4 months of follow-up, after 4 months of follow-up, or overall. Sixty-one patients in the STI arm and 55 patients in the control arm had at least 1 grade 4 adverse event (hazard ratio = 1.09; P = 0.66). The mean quality-of-life scores at baseline, month 4 (the end of the STI period), month 12, and month 24 were not significantly different for the treatment arms. The respective scores were 65.4, 63.5, 64.8, and 64.3 for the STI arm and 65.0, 66.5, 63.1, and 60.6 for the control arm. There were no significant differences between the treatment arms in the mean change from baseline for the proportions reporting symptoms by grade or self-reported adherence to antiretroviral treatment as measured with 7-day recall and 3-day recall (data not shown).
The participants in CPCRA 064 are representative of an expanding population of HIV-infected individuals in need of more effective treatment strategies. These patients were highly experienced with regard to antiretroviral treatment (97% had 3-class drug exposure), with elevated viral loads, MDR HIV-1, and advanced immunodeficiency. This randomized, prospective, clinical end-point study was designed based on findings from observational and small pilot studies of patients who interrupted HIV treatment for various lengths of time.10,11,20-22 We hypothesized that for patients with MDR HIV-1 and antiretroviral treatment failure, an STI would induce a shift toward a drug-sensitive viral population and result in an improved HIV-1 RNA response on treatment reinitiation with a new (optimized) regimen. We further hypothesized that this strategy would lead to a concomitant improvement in CD4 cell count on the new regimen and, ultimately, a reduction of at least 33% in progression-of-disease events or death in the STI arm compared with the control arm. A 16-week treatment interruption was chosen to allow adequate time to maximize reversion to wild-type virus while attempting to minimize the immediate risk of CD4 decline.
As reported previously, the CPCRA 064 study was closed to enrollment early when the STI arm showed an increase in progression-of-disease events or death and an unfavorable CD4 cell count response compared with the control arm.17 When the study closed to enrollment (June 2002), the median follow-up was 12 months, and it was not certain how long the negative impact of the 4-month STI would be sustained. These final results, based on a median follow-up of 37 months, confirm our preliminary findings on CD4 cell count response and provide additional information on the long-term impact of STI in this setting. With the current results, after an additional 24 months of study follow-up, there is not a persisting significant difference between treatment arms for progression of disease or death.
In our study, similar to others,10,11,16,20-25 the HIV-1 isolated from plasma shifted from a highly drug-resistant pattern toward a more drug-sensitive pattern during the STI in most patients based on standard HIV-1 population genotyping. This strategy failed to produce a superior overall HIV-1 RNA response in the STI arm compared with the control arm, however. After patients in the STI arm reinitiated therapy, the HIV-1 RNA response between the 2 randomized treatment arms was indistinguishable. Notably, both arms had a mean overall decrease in HIV-1 RNA level of approximately 0.7 log copies/mL less than baseline, which was maintained during follow-up. This response was achieved with a mean of only 3.9 drugs in the initially prescribed salvage regimen. Factors that likely contributed to this favorable virologic response in patients with MDR-resistant HIV-1 include the availability of genotypic and phenotypic drug resistance testing to help optimize the new salvage regimen and US Food and Drug Administration (FDA) approval of lopinavir/ritonavir (Kaletra) and tenofovir early on in this study. Although a significantly higher proportion of patients in the STI arm received coformulated lopinavir/ritonavir in their first regimen after randomization, more patients in the control arm were administered amprenavir and ritonavir. Of note, no patients in either treatment arm were prescribed atazanavir, tipranavir, or enfuvirtide in the first regimen. Because both randomization arms had similar HIV-1 RNA responses on treatment, it is unlikely that regimen differences contributed to the long-term CD4 count responses.
An important finding in the CPCRA 064 study is that even though the mean CD4 cell counts in the STI arm returned to baseline levels soon after treatment reinitiation, CD4 cell counts in the STI arm remained significantly lower than in the control arm for 24 months despite similar virologic responses. Impairment of immune recovery in the STI arm is also evident by the fact that the median time to reaching a CD4 cell count of 50 cells/mm3 greater than baseline was significantly longer (by 9 months) in the STI arm than in the control arm. At the beginning of the study, the proportion of patients with a CD4 cell count less than 100 cells/mm3 was similar in the 2 randomized treatment arms. Although this proportion remained fairly constant in the control arm during follow-up, in the STI arm, the proportion of patients with CD4 cell counts less than 100 cells/mm3 increased from 36% at the beginning of the study to 50% at the end. Because most clinical events occurred in patients who had CD4 cell counts less than 100 cells/mm3, these results further demonstrate that in this patient population, treatment interruption imposes an increased risk of immunosuppression that is clinically relevant and lasts well beyond the time the patient is off antiretroviral therapy.
Consistent with the observed CD4 count response and contrary to what we hypothesized, the STI did not result in a significant reduction in the primary end point of progression of disease or death for the STI arm. Because this study was closed to enrollment before complete accrual was obtained, power for progression of disease or death is lower than planned. The confidence interval for the overall hazard ratio excludes the hypothesized 33% reduction in events for the STI arm, however, and it seems that the STI arm was at increased risk for a progression-of-disease event or death during the period immediately after the STI (months 4-12). During that period, the difference between the treatment arms in concomitant use of antifungal medication may have contributed to the increased risk in the STI arm. The purpose for the antifungal agents (eg, systemic vs. topical, treatment vs. prophylaxis) was not recorded for this study, however. Importantly, only a few esophageal candidiasis events occurred during this period, and most occurred after month 12.
Despite differences in patient populations (eg, baseline CD4 counts) and treatment regimens used, 4 other smaller randomized trials have results that are consistent with our study, finding no immunologic or virologic benefit to prescribing an STI before switching salvage therapy in patients with MDR HIV-1 treatment failure.24,26-28 In contrast, a single smaller randomized study23 reported improved HIV-1 RNA level and CD4 cell count responses after STI in patients with extremely advanced HIV-1 disease treated with at least 7 antiretroviral agents. Final results from an ongoing randomized factorial trial of STI versus continuous therapy and standard HAART versus mega-HAART (5 or more drugs) for patients with MDR HIV-129 are not yet available.
The CPCRA 064 study is unique in that it is the first randomized trial of STI for patients with MDR HIV-1 and treatment failure that has a clinical end point in addition to virologic and immunologic outcomes, allowing us to determine the long-term impact of STI in this setting. These final results show no clinical, virologic, immunologic, or quality-of-life benefit to prescribing a 4-month treatment interruption before changing salvage regimens compared with immediately changing regimens in patients with MDR HIV-1 treatment failure. In these patients, we further demonstrate that STI is associated with a significant and prolonged impairment of CD4 cell count recovery that lasts well after treatment is reinitiated. Based on these results, antiretroviral treatment interruption in this patient population should be avoided.
The authors are indebted to the patients who participated in the study; to Lee Bacheler, Gary Collins, Thomas Dionne, Harry Dohnert, Marie Hoover, Sharon Mannheimer, Ana Martinez, Carla Pettinelli, John Omanoff, Ronald Reisler, Alex Rinehart, David Stein, Werner Verbiest, and Dean Winslow for their collaboration and contributions to the conduct of the study; and to Virco, Ltd. and Bayer Diagnostics for providing laboratory support.
1. Gulick RM, Mellors JW, Havlir D, et al. Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up. JAMA
2. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet
3. Phillips AN, Staszewski S, Lampe F, et al. Human immunodeficiency virus rebound after suppression to <400 copies/mL during initial highly active antiretroviral therapy regimens, according to prior nucleoside experience and duration of suppression. J Infect Dis
4. Sabin CA, Hill T, Lampe F, et al. Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study. BMJ
5. Mocroft A, Ledergerber B, Viard JP, et al. Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group. J Infect Dis
6. Kantor R, Shafer RW, Follansbee S, et al. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS
7. Karlsson AC, Younger SR, Martin JN, et al. Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia. AIDS
8. Coakley EP, Doweiko JP, Bellosillo NA, et al. HIV drug resistance profiles and clinical and virologic outcomes among HIV-infected subjects with stable detectable plasma viral loads <1000 copies/mL for at least 12 months [abstract 556]. Presented at: Ninth Conference on Retroviruses and Opportunistic Infections; 2002; Seattle.
9. Barbour JD, Wrin T, Grant RM, et al. Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. J Virol
10. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med
11. Miller V, Sabin C, Hertogs K, et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS
12. Youle M, Janossy G, Turnbull W, et al. Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. Royal Free Centre for HIV Medicine. AIDS
13. Tebas P, Henry K, Mondy K, et al. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4+ T cell decline in human immunodeficiency virus-infected patients: implications for intermittent therapeutic strategies. J Infect Dis
14. Izopet J, Souyris C, Sandres-Saune K, et al. Virological and immunological effects of salvage therapy following treatment interruption and a shift in HIV-1 resistance genotype. J Med Virol
15. Kaufmann D, Pantaleo G, Sudre P, et al. CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet
16. Jaafar A, Massip P, Sandres-Saune K, et al. HIV therapy after treatment interruption in patients with multiple failure and more than 200 CD4+ T lymphocyte count. J Med Virol
17. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med
18. Centers for Disease Control and Prevention. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep
19. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2004. Top HIV Med
20. Izopet J, Massip P, Souyris C, et al. Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen. AIDS
21. Verhofstede C, Wanzeele FV, Van Der Gucht B, et al. Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype. AIDS
22. Devereux HL, Youle M, Johnson MA, et al. Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS
23. Katlama C, Dominguez S, Gourlain K, et al. Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097). AIDS
24. Ruiz L, Ribera E, Bonjoch A, et al. Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. J Infect Dis
25. Halfon P, Durant J, Clevenbergh P, et al. Kinetics of disappearance of resistance mutations and reappearance of wild-type during structured treatment interruptions. AIDS
26. Benson C, Downey G, Havlir DV, et al. A 16-week treatment interruption does not improve the virologic responses to multidrug salvage therapy in treatment-experienced patients: 48-week results from ACTG A5086. Presented at: 11th Conference on Retroviruses and Opportunistic Infections; 2004; San Francisco.
27. Walmsley S, LaPierre N, Loutfy M, et al. CTN 164: a prospective randomized trial of structured treatment interruption vs immediate switching in HIV-infected patients experiencing virologic failure on HAART. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; 2005; Boston.
28. Beatty G, Lu J, Hunt P, et al. Randomized pilot study of immediate enfuvirtide-based therapy vs a treatment interruption followed by enfuvirtide-based therapy in highly treatment-experienced patients. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; 2005; Boston.
29. Kyriakides TC, Babiker A, Singer J, et al. An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial. Control Clin Trials
Participating Sites and Investigators
The following centers and investigators participated in the study: AIDS Research Alliance of Chicago: R. Luskin-Hawk, R. Verheggen, and M. Schultz; Bronx AIDS Research Consortium: E. Telzak, J. McGowan, and J. Shuter; Community Consortium of San Francisco: the Care Providers of the Castro Mission Health Center, P. A. Pell, and C. C. Child; Denver Community Program for Clinical Research on AIDS: D. Cohn, R. Fernandez, and F. Moran; Harlem Aids Treatment Group: E. Monde and L. Fuentes; Henry Ford Hospital: N. Markowitz, L. Faber, and L. Makohon; Houston AIDS Research Team: H. Cuervo, R. Manning, and R. Arduino; Louisiana Community AIDS Program: S. Pablovich and J. Walker; Philadelphia FIGHT: E. Tedaldi and FIGHT research staff; New England ProACT: M. Kozal, L. Andrews, and L. Daley; North Jersey Community Research Initiative: R. Sawyer and P. Andrew; Richmond AIDS Consortium: E. J. Fisher, P. W. Dodson, and M. L. Howe; Southern New Jersey AIDS Clinical Trials: K. Casey, D. Condoluci, and C. Graeber; The Research and Education Group (Portland): J. Sampson, S. Peterson, and D. Antoniskis; Washington Regional AIDS Program: B. Standridge, S. McHugh, and A. Labriola; and Wayne State University: M. Farrough and J. Kosmyna. Cited Here...
This article has been cited 11 time(s).
AIDS Care-Psychological and Socio-Medical Aspects of AIDS/HivA randomized comparison of two instruments for measuring self-reported antiretroviral adherenceAIDS Care-Psychological and Socio-Medical Aspects of AIDS/Hiv
AIDS Research and Human RetrovirusesDynamics of NRTI Resistance Mutations during Therapy InterruptionAIDS Research and Human Retroviruses
Journal of Theoretical BiologyModeling HIV persistence, the latent reservoir, and viral blipsJournal of Theoretical Biology
Predictive value of immune parameters before treatment interruption (TI) for CD4(+) T-cell count change during TI in HIV infection
Antiviral Therapy, 14(3):
AIDS Research and Human RetrovirusesShort-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load SuppressionAIDS Research and Human Retroviruses
Journal of Infectious DiseasesManaging antiretroviral therapy: Changing regimens, resistance testing, and the risks from structured treatment interruptionsJournal of Infectious Diseases
AIDS Patient Care and StdsProtease inhibitor resistance update: Where are we now?AIDS Patient Care and Stds
AIDS Research and Human RetrovirusesNK-Associated Regulatory Receptors in a Structured HAART Interruption of HIV-1-Positive IndividualsAIDS Research and Human Retroviruses
Infections in Medicine
Multidrug-resistant HIV: Is there a role for structured treatment interruption?
Infections in Medicine, 24(4):
Current Opinion in Infectious DiseasesTreatment interruption strategies: how great are the risks?Current Opinion in Infectious Diseases
HIV infection; salvage therapy; treatment failure; treatment interruption
© 2006 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.