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New Treatment Interruptions Study & Editorial
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"Structured Treatment Interruptions: A Risky Business"
EDITORIAL
Clinical Infectious Diseases Feb 15, 2005
Julio Montaner, Marianne Harris, and Robert Hogg
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
Following are excerpts from the editorial regarding the study published in CID this month. Following the editorial comments are the study results.
...with the exception of single treatment interruptions dictated by emerging toxicities, by comorbidities, or in patients who started therapy prematurely on the basis of prior guidelines, treatment interruptions are not recommended. Structured treatment interruption should be regarded strictly as an experimental procedure to be undertaken in the context of carefully designed, prospective, comparative clinical trials under the supervision of experienced investigators...
As an alternative approach with the potential to reduce drug exposure, promote adherence to therapy, and decrease treatment-related fatigue, several treatment interruption strategies are currently under evaluation. Treatment interruptions have been explored in various distinct clinical situations with different aims. For patients who initiated therapy during acute seroconversion, treatment interruption has been explored as a means to enhance HIV-specific immune response and, consequently, allow better control of viral replication in the absence of continued therapy. This remains an attractive yet elusive hypothesis. Until results of ongoing, prospective, controlled clinical trials are available, this intervention should be regarded as experimental in nature and cannot be recommended.
At the other end of the spectrum, the role of treatment interruption has been explored in the context of treatment failure during chronic, advanced infection with drug-resistant HIV. Early observational data suggested that this strategy could lead to reestablishment of a therapeutic response as the circulating virus became predominantly wild-type in the absence of drug selection pressure. Findings from longer follow-up of patients who underwent treatment interruption in this context have been less encouraging. Antiviral responses to the regimen that follows the treatment interruption tended to be transient, and perhaps more importantly, early viral rebound during the treatment interruption was typically associated with a clinically significant decrease in the CD4 cell count. In some patients, this was associated with clinical disease progression, and even when that was not the case, the CD4 cell count did not always recover predictably with reinstitution of therapy. As such, treatment interruption as a strategy to improve response to subsequent salvage therapy after recurrent treatment failure is not currently recommended.
Treatment interruption in successfully treated, chronically infected individuals has also been explored from a variety of standpoints. Perhaps the earliest form of treatment interruption in this situation pertains to those patients who, in the course of long-term management of chronic disease, stopped treatment because of issues of toxicity or the development of intercurrent conditions that precluded continuation of therapy. Not surprisingly, short-term interruptions (in the order of up to 3 months) were found to be quite common in the Swiss HIV cohort, with 24% of participants having had 1 such interruption and 4% having had >2 interruptions. Of note, there was no detectable increased risk of HIV-associated morbidity or mortality attributable to treatment interruptions in this study. Obviously, further prospective evaluation of this issue is required before precise guidelines can be developed regarding how to safely incorporate single treatment interruptions into clinical practice. Until then, available results suggest that a single treatment interruption is probably an acceptable practice, if it is clinically justified because of emerging significant toxicities or intercurrent illness.
A related scenario is that of successfully treated, asymptomatic, chronically infected individuals who initiated therapy years ago at a relatively high CD4 cell count on the basis of contemporary, now-outdated treatment guidelines. Recent work suggests that a single treatment interruption under appropriate medical supervision may be an acceptable practice in this situation. As long as the nadir CD4 cell count was >250 cells/mm3, most patients tend to be able to defer reintroduction of therapy for many months and possibly for >1 year without negative consequences. Of note, when successfully treated patients undergo an interruption in therapy, a rebound of the virus load to detectable and often very high levels is an inevitable result. Aside from the relatively uncommon issue of acute seroconversion--like symptoms when this occurs, patients should be appropriately counseled regarding safer sex and other practices to avoid transmission of HIV as they return to a relatively more contagious state.
Various forms of structured treatment interruptions scheduled at specific time points with specific thresholds for reinitiation of therapy have been explored in chronically infected patients. The aim was initially to boost HIV-specific immune responses and, more recently, to try to decrease overall drug exposure and thus reduce drug-related morbidity and drug costs. Comparison between these studies has been complicated by the heterogeneity in the thresholds for stopping and reinitiating therapy. Results of several studies exploring reinstitution of treatment at fixed time intervals, from months to weekly periods receiving and not receiving treatment (so-called "pulse" therapy), have now been reported. The overall effectiveness of this approach remains controversial. Among the important concerns in this context is the potential role of structured treatment interruptions or pulse therapy in promoting the emergence of drug-resistant strains of HIV. Indeed, substantial rates of emergence of drug-resistant HIV were observed among therapy-adherent patients treated with fixed intermittent regimens in the PART study. Similarly, other groups have observed the emergence of new and archived resistance mutations during structured treatment interruptions. Furthermore, the use of structured treatment interruptions or pulse therapy in patients with chronic HIV infection who have controlled viremia assumes that less drug treatment will be associated with less toxicity, lower cost, and improved adherence while preserving overall outcomes. Sobering news has emerged in this regard from the HIV Netherlands Australia Thailand Research Collaborative (HIVNAT) Stacatto trial, as reported in this issue of Clinical Infectious Diseases. An unacceptably high rate of viral breakthrough was observed in patients with previously controlled viremia who were randomized to receive antiviral therapy in cycles of 1 week on, 1 week off, leading to the early discontinuation of this arm of the study. On the basis of these observations, structured treatment interruptions, intermittent therapy, and pulse therapy during chronic HIV infection cannot be recommended at this time.
Considerable effort has focused on trying to characterize the potential role of treatment interruptions in patients who have acute or chronic HIV infection or who have experienced treatment failure. Although this issue arises frequently in the clinical setting, it is not adequately addressed by current therapeutic guidelines. Treatment interruptions can be expected to reduce pill burden, cost, and toxicity related to antiretroviral therapy. However, treatment interruptions can also be associated with a decrease in CD4 cell counts, an increase HIV-related morbidity, and a potential increase in HIV transmission resulting from uncontrolled viremia. Also, there is a very real concern that treatment interruptions can promote the emergence of drug-resistant HIV strains and, thus, have a negative impact on future therapeutic outcomes. Therefore, with the exception of single treatment interruptions dictated by emerging toxicities, by comorbidities, or in patients who started therapy prematurely on the basis of prior guidelines, treatment interruptions are not recommended. Structured treatment interruption should be regarded strictly as an experimental procedure to be undertaken in the context of carefully designed, prospective, comparative clinical trials under the supervision of experienced investigators. In this context, the results of several large, prospective, randomized trials currently underway that are evaluating various CD4 cell count--driven, intermittent therapy approaches, including the Stacatto, PART, CTN 164 (S. Walmsley, personal communication), Trivacan, Window, and SMART studies, are eagerly awaited.
"A Prospective, Randomized Trial of Structured Treatment Interruption for Patients with Chronic HIV Type 1 Infection"
Clinical Infectious Diseases Feb 15, 2005
Peter G. Cardiello,1,3 Elly Hassink,1,3 Jintanat Ananworanich,1 Preeyaporn Srasuebkul,1 Tarika Samor,1 Apicha Mahanontharit,1 Kiat Ruxrungtham,1,2 Bernard Hirschel,4 Joep Lange,3 Praphan Phanuphak,1,2 and David A. Cooper5
1The HIV Netherlands Australia Thailand Research Collaborative, The Thai Red Cross AIDS Research Center, and 2Faculty of Medicine, Division of Infectious Diseases, Chulalongkorn University, Bangkok, Thailand; 3International Antiviral Therapy Evaluation Center, Academic Medical Center, University of Amsterdam, The Netherlands; 4University Hospital of Geneva, Switzerland; and 5National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
ABSTRACT
Background. Structured treatment interruption was evaluated in 74 patients who had been pretreated with antiretrovirals, consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) for 1 year followed by 3 years of highly active antiretroviral therapy containing a protease inhibitor. Methods. Patients with a CD4 cell count of >350 cells/μL and a plasma viral load of <50 copies/mL were randomized to 3 therapy arms: (1) continuous therapy, (2) CD4 cell count--guided theory, and (3) week-on/week-off (WOWO) therapy. The efficacy and safety of structured treatment interruption and antiretroviral use were evaluated in human immunodeficiency type 1 (HIV-1)--infected patients. The study end points were percentage of patients who developed AIDS or who died and a CD4 cell count of >350 cells/μL. Intergroup differences were analyzed using analysis of variance and Kruskal-Wallis tests.
Study End Points
The primary end points were progression to AIDS or death. The secondary end points were proportion of patients with a CD4 cell count of >350 cells/μL, antiretroviral use, occurrence of adverse events, and the plasma viral load at the end of the study period. This study was underpowered as a result of the limited number of study subjects.
Analysis of Plasma Samples
Plasma HIV-1 RNA levels were assessed with the Roche Amplicor HIV-1 Monitor assay, version 1.5, which has a lower limit of detection of 50 HIV-1 RNA copies/mL. CD4 lymphocyte counts were determined by flow cytometry. Resistance sequences were analyzed on proviral DNA at the time of treatment failure in WOWO arm. Results. Baseline characteristics at the start of the structured treatment interruption were similar. At week 48, no patient had died, and 1 patient in the WOWO group had an AIDS-defining condition. The proportions of patients with a CD4 cell count of >350 cells/μL were 100%, 87%, and 96% in treatment arms 1, 2, and 3, respectively. The percentages of weeks of antiretroviral use were 100%, 41.1%, and 69.8% in arms 1, 2, and 3, respectively. The adverse events were not significantly different among arms (P = .27). Thirty-one percent of patients in the WOWO group experienced virological failure.
No patient died during the study. At least 1 AIDS Clinical Trial Group grade 3 or 4 adverse event over the 48-week study was observed in 11 (44%) of 25 patients in the continuous treatment arm, 15 (65%) of 23 patients in the CD4 cell count--guided treatment arm, and 12 (46%) of 26 patients in the WOWO treatment arm (P = .27). Comparison of the CD4 cell count--guided treatment arm and the WOWO treatment arm with the continuous treatment arm resulted in P values of .14 and .87, respectively. Only 1 patient, who was randomized to the WOWO treatment arm, had progression from CDC class A to class C disease. CDC-classified clinical events included papular pruritic eruptions in 1 patient, oral hairy leukoplakia in 1 patient, and esophageal candidiasis occurred in 1 patient, all of whom were in the WOWO treatment arm. The CD4 cell counts before the structured treatment interruption for these 3 patients were >500 cells/μL, and at the time of the diagnoses, the CD4 cell counts were >350 cells/μL, whereas the plasma viral load was undetectable in 2 patients and was 49,500 copies/mL in 1 patient. Conclusion. WOWO therapy maintained a CD4 cell count of >350 cells/μL in almost all patients but was associated with high virological failures rates (possibly resulting from previous dual-NRTI therapy), indicating that this strategy is less useful. Receipt of CD4 cell count--guided therapy resulted in comparable clinical outcomes to continuous therapy and may save antiretroviral-associated costs, but this needs to be confirmed by a larger trial.
RESULTS
A total of 74 HIV-1--infected Thai patients (36 male and 38 female patients) were randomized to this structured treatment interruption study. Baseline characteristics, including the CD4 cell count at the start of antiretroviral therapy, are noted in table 1. The number of patients, age, sex, plasma viral load, and median CD4 cell count before randomization were well matched for all treatment arms.
Patients were randomized to a treatment arm as soon as they were eligible, after finishing the previous once-daily therapy trial. One can see in table 1 that, although most patients were randomized 226 weeks after the start of the HIVNAT 001 trial or at the start of this structured treatment interruption trial, 17 patients did not meet the eligibility criteria until some weeks later, thus delaying their dates of randomization to this study. The median duration of patient follow-up after randomization was 48 weeks for the continuous and CD4 cell count-guided treatment arms and 49 weeks for the WOWO treatment arm (table 1).
The proportion of weeks of antiretroviral use over 48 weeks was 100% (interquartile range [IQR], 100%--100%) in the continuous treatment arm, 41.1% (IQR, 10.2%--60.7%) in the CD4 cell count--guided treatment arm, and 69.8% (IQR, 50.0%--98.0%) in the WOWO treatment arm (P < 001 for comparison of all 3 groups and for the CD4 cell count--guided treatment arm vs. the WOWO treatment arm). The proportion of patients with a CD4 cell count of ⩾350 cells/μL at the end of follow-up was 100% in the continuous treatment arm, 87% in the CD4 cell count--guided arm, and 96% in the WOWO treatment arm. Only 3 patients in the CD4 cell count--guided treatment arm had a CD4 cell count of <350 cells/μL at the end of the study (P = .03 for comparison of all 3 treatment arms, by Fisher exact test).
In the CD4 cell count--guided treatment arm, 5 patients did not restart antiretroviral therapy during the study. Nine patients restarted antiretroviral treatment once and subsequently ceased receipt of antiretroviral therapy. Of these 9 patients, 4 had to restart antiretroviral therapy 1 more time before the end of the study. One patient was not receiving antiretroviral therapy for 3 separate periods during the study. Finally, 8 patients started receipt of antiretroviral therapy only once but were receiving treatment at the end of the study. Eighteen (78%) of 23 patients received ⩾12 weeks of antiretroviral re-treatment. Of these 18, all had a plasma viral load of <500 copies/mL, and 10 had a plasma viral load of <50 copies/mL after re-treatment. In the CD4 cell count--guided treatment arm, 47% of patients whose CD4 cell counts had decreased by >30% chose to not start antiretroviral therapy until their CD4 cell count was <350 cells/μL.
No patient died during the study. At least 1 AIDS Clinical Trial Group grade 3 or 4 adverse event over the 48-week study was observed in 11 (44%) of 25 patients in the continuous treatment arm, 15 (65%) of 23 patients in the CD4 cell count--guided treatment arm, and 12 (46%) of 26 patients in the WOWO treatment arm (P = .27). Comparison of the CD4 cell count--guided treatment arm and the WOWO treatment arm with the continuous treatment arm resulted in P values of .14 and .87, respectively. Only 1 patient, who was randomized to the WOWO treatment arm, had progression from CDC class A to class C disease. CDC-classified clinical events included papular pruritic eruptions in 1 patient, oral hairy leukoplakia in 1 patient, and esophageal candidiasis occurred in 1 patient, all of whom were in the WOWO treatment arm. The CD4 cell counts before the structured treatment interruption for these 3 patients were >500 cells/μL, and at the time of the diagnoses, the CD4 cell counts were >350 cells/μL, whereas the plasma viral load was undetectable in 2 patients and was 49,500 copies/mL in 1 patient.
Seventeen patients in the continuous treatment arm, 20 patients in the CD4 cell count--guided treatment arm, and 20 patients in the WOWO treatment arm had been randomized at the start of this trial and thus had 48 weeks of follow-up data. Of these patients with 48 weeks of follow-up data, the median log10 plasma viral loads after 48 weeks were 1.69 copies/mL (IQR, 1.69--1.69 copies/mL) in the continuous treatment arm, 1.96 copies/mL (IQR, 1.69--4.12 copies/mL) in the CD4 cell count--guided treatment arm, and 1.70 copies/mL (IQR, 1.69--1.77 copies/mL) in the WOWO treatment arm. The percentages of patients in each arm who were randomized immediately and who had undetectable plasma viral loads (i.e., <50 copies/mL) after 48 weeks in this structured treatment interruption study were 100% in the continuous treatment arm, 45% in the CD4 cell count--guided treatment arm, and 72% in the WOWO treatment arm. The median CD4 cell count for patients with 48 weeks of follow-up data was 637 cells/μL (IQR, 484--794 cells/μL) in the continuous treatment arm, but it was 547 cells/μL (IQR, 373--596 cells/μL) in the CD4 cell count--guided treatment arm and 582 cells/μL (IQR, 468--787 cells/μL) in the WOWO treatment arm. The CD4 cell count decreased from the baseline level in all treatment arms, although the largest decrease in the CD4 cell count occurred in the CD4 cell count--guided treatment arm.
Treatment failure, which is defined in Methods and in table 2 as virological or immunological failure during treatment in the continuous and WOWO treatment arms, occurred in 8 (31%) of 26 patients in the WOWO treatment arm (7 patients had a plasma viral load of >1000 copies/mL, and 1 had a CD4 cell count of <350 cells/μL). Of the 7 patients with viremia, no drug resistance was found in 2 patients; for 4 patients, samples were not able to be amplified; and virus from 1 patient was found to have zidovudine resistance (codons 41, 210, and 215). None of the patients in the continuous treatment arm experienced treatment failure. The median time to treatment failure was 16 weeks after randomization (IQR, 8--32 weeks). Two patients were lost to follow-up. All patients with treatment failure had plasma viral loads of <50 copies/mL after a median time of 12 weeks of continuous twice-daily administration of antiretrovirals.
AUTHOR DISCUSSION
This structured treatment interruption trial demonstrates that adequate immunological function (i.e., a CD4 cell count of >350 cells/μL) may be preserved by use of a CD4 cell count--guided or WOWO approach to therapy withdrawal and reintroduction, compared with continuous antiretroviral therapy. However, the high rate of virological failure in the WOWO treatment arm indicates that this strategy may not be useful for patients who are receiving long-term antiretroviral treatment that includes dual-agent therapy. The rates of adverse events do not differ among the study arms, although 3 patients in the WOWO treatment arm had 3 new CDC-defined clinical events during this period. Significantly fewer antiretrovirals were used in the CD4 cell count--guided and WOWO treatment arms, which makes use of this structured treatment interruption approach worthy of additional study as a cost-saving strategy. In addition, the small sample size increases the likelihood of β error, because interarm differences may not be apparent, even if they exist. The short follow-up period could exacerbate this error. Results of a longer trial that is sufficiently powered to answer questions about the risks and benefits of structured treatment interruption are required to confirm our findings before conclusions can be drawn.
In patients who had 48 weeks of follow-up data, the plasma viral load was obviously not suppressed in the CD4 cell count--guided treatment arm, but it was suppressed in 72% of patients in the WOWO treatment arm. Immunological function was not preserved as well in the CD4 cell count--guided treatment arm as in the continuous and WOWO treatment arms. However, immune system preservation, as indicated by a CD4 cell count of >350 cells/μL, was found in all patients in the continuous treatment arm, in 87% of patients in the CD4 cell count--guided treatment arm, and in 96% of patients in the WOWO treatment arm. The differences in the pre--structured treatment interruption CD4 cell counts among treatment arms and the small cohort size may have been responsible for some differences between arms in the immunological and virological comparisons.
The high rate of treatment failures in the WOWO treatment arm may have been due to the occurrence of undetected mutations during previous suboptimal dual-NRTI antiretroviral therapy (for first year of antiretroviral treatment) or long-term HAART exposure (for the 3 years immediately preceding this structured treatment interruption study), even though only 1 patient was found to have resistance mutations. The WOWO approach was also problematic for the Staccato international structured treatment interruption trial, which measured the plasma viral load after the week without therapy, whereas our study checked the plasma viral load after the week with therapy. The 31% rate of failure in the WOWO treatment arm in our study may have been higher if the plasma viral load had been measured after the week without therapy. A small sample size and the lower median CD4 cell count in this treatment arm may have also affected the percentage of patients who met the failure criteria in the WOWO treatment arm. Adhering to a complicated regimen may have been more difficult, leading to antiretroviral failure due to poor adherence. Another study that used the weekly structured treatment interruption strategy had more success, but the cohort possibly had a shorter duration of antiretroviral exposure. The use of a triple-drug antiretroviral regimen containing efavirenz in a WOWO approach was successful in a proof-of-concept trial, perhaps indicating that the longer half-life of non-NRTI may be important for prevention of intermittent viremia and subsequent development of a drug-resistant virus. Finally, the greater number of visits to the clinic in the WOWO and the CD4 cell count--guided treatment arms may have had an impact on adherence and on some outcomes, but this is difficult to conclude with a small cohort and short study period.
This structured treatment interruption study demonstrates that all 3 study arms resulted in similar clinical function over this short follow-up period of up to 48 weeks, with the CD4 cell count--guided and WOWO treatment arms being the most cost-effective with regard to antiretroviral costs. The immune function was adequate in all arms if considering the percentage of patients with a CD4 cell count of >350 cells/μL, whereas the continuous and WOWO treatment arms were more successful than the CD4 cell count--guided treatment arm in maintaining the CD4 cell count at the baseline level. Calculations regarding the savings in antiretroviral costs must take into consideration the time that an antiretroviral-naive patient must take continuous therapy to achieve a plasma viral load of <50 copies/mL. Most patients (78%) in the CD4 cell count--guided treatment arm had received >12 weeks of re-treatment with antiretrovirals, thereby reducing some of the expected savings in antiretroviral-associated costs. Because this study was conducted before current antiretroviral initiation criteria were in place, these patients started receiving antiretroviral therapy while they had relatively high CD4 cell counts (100--500 cells/μL). Because current criteria for initiation of antiretroviral therapy indicate that a patient should begin therapy at relatively lower CD4 cell counts, this treatment cohort may not be reflective of the HIV-infected population in the developing world who are eligible for treatment. Because most patients in the CD4 cell count--guided treatment arm required re-treatment, use of this strategy may be less useful in areas in the developing world with resource limitations. Additionally, the high CD4 cell counts before the structured treatment interruption may have positively influenced the results in the CD4 cell count--guided treatment arm, which may not occur if a patient began to receive treatment with a lower CD4 cell count. The high treatment failure rate in the WOWO arm makes this strategy less useful in terms of virological control. The use of structured treatment interruption—in particular, the CD4 cell count--guided strategy—for virologically well-controlled patients with shorter (and more optimal) antiretroviral exposure and lower pre--antiretroviral therapy/pre--structured treatment interruption CD4 cell counts may prove to be an appropriate HAART administration strategy that can save costs associated with antiretroviral use, preserve adequate immune function, and provide comparable safety profiles to continuous HAART therapy.
Patients and Study Design
Patients were recruited from the Thai Red Cross Society's Anonymous STD/HIV screening clinic and the HIV outpatient immune clinic of King Chulalongkorn Memorial Hospital (Bangkok, Thailand). After 226 weeks, a group of 74 patients who were enrolled in the HIV Netherlands Australia Thailand Research Collaborative (HIVNAT) 001 trial series (which involved 1 year of dual--nucleoside reverse-transcriptase inhibitor [NRTI] therapy, followed by 3 years of protease inhibitor--based HAART) were randomized for this study if their most recent CD4 cell count was >350 cells/μL and their plasma viral load had been <50 copies/mL >6 months. This open-label, prospective study examined 3 antiretroviral regimen arms to evaluate 2 structured treatment interruption strategies: continuous treatment, CD4 cell count--guided treatment, and WOWO treatment. This small sample size limited our ability to obtain sufficient power to detect a difference between study arms. The study was approved by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University (Bangkok). Written informed consent was obtained from all patients.
Antiretroviral Therapy Regimens for All Treatment Arms
Antiretroviral therapy consisted of saquinavir soft-gel caps (1600 mg q.d.) boosted with ritonavir (100 mg q.d.) plus 2 NRTIs (standard doses of either zidovudine and lamivudine or didanosine and stavudine). The NRTI regimen was determined in the randomization process at the start of the HIVNAT 001 series several years before this structured treatment interruption trial.
Management of Antiretroviral Therapy
Continuous and WOWO treatment arms. Patients in the continuous treatment arm took their antiretrovirals every day. In the WOWO therapy arm, patients alternated between 1 week with therapy and 1 week without therapy, and the viral load was determined at the end of the week that included therapy to assess whether the patient's plasma viral load was suppressed.
Commencement of antiretroviral therapy in the CD4 cell count--guided arm and immunological failure criteria for the continuous and WOWO arms. The patients in the CD4 cell count--guided treatment arm began the study while not receiving therapy and only started antiretroviral therapy if the CD4 cell count had decreased in accordance with the criteria noted in table 2. The criteria for commencement or recommencement of antiretroviral therapy in the CD4 cell count--guided arm are the same as the criteria as for immunological failure in the continuous and WOWO treatment arms. In the continuous therapy arm and the WOWO treatment arm, treatment failure was defined as virological failure (i.e., the plasma viral load was >1000 copies/mL). The criterion of immunological failure was a decrease in the CD4 cell count to <350 cells/μL or by 30%. Patients in the continuous therapy arm and the WOWO treatment arm who met these treatment failure criteria discontinued therapy with once-daily saquinavir soft-gel caps and switched to continuous therapy with saquinavir soft-gel caps (1000 mg b.i.d.) and ritonavir (100 mg b.i.d.), in addition to the same 2 NRTIs. There were no treatment failure criteria for the CD4 cell count--guided treatment arm.
Cessation of antiretroviral therapy in the CD4 cell count--guided treatment arm. After receipt of >12 weeks of daily doses of HAART, patients in the CD4 cell count--guided treatment arm would stop therapy >1 time if the following conditions were met: the CD4 cell count increased to a level that is greater than the threshold of 50 cells/μL less than the baseline level (defined as the CD4 cell count at the start of structured treatment interruption) when the baseline CD4 cell count was 350--399 cells/μL, if the CD4 cell count recovered to >350 cells/μL when the baseline CD4 cell count was 400--500 cells/μL, or if the CD4 cell count increased to >70% of the baseline level when the baseline CD4 cell count was >500 cells/μL.
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