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Interruption of Antiretroviral Treatment in HIVInfected Patients with Preserved Immune Function Is Associated with a Low Rate of Clinical Progression: A Prospective Study by AIDS Clinical Trials Group 5170

  1. Daniel J Skiest1,
  2. Zhaohui Su2,
  3. Diane V Havlir3,
  4. Kevin R Robertson5,
  5. Robert W Coombs6,
  6. Pat Cain4,
  7. Tianna Peterson7,
  8. Amy Krambrink2,
  9. Nasreen Jahed8,
  10. Deborah McMahon9,
  11. David M Margolis1 and
  12. AIDS Clinical Trials Group 5170 Study Teama
  1. 1 Baystate Medical Center, Springfield
  2. 2 Harvard School of Public Health, Boston, Massachusetts
  3. 3 University of California, San Francisco
  4. 4 Stanford University Medical Center, Stanford, California
  5. 5 University of North Carolina, Chapel Hill
  6. 6 University of Washington, Seattle
  7. 7 University of Texas Southwestern Medical Center, Dallas
  8. 8 Social & Scientific Systems, Inc., Silver Spring, Maryland
  9. 9 University of Pittsburgh, Pittsburgh, Pennsylvania
  1. Reprints or correspondence: Dr. Daniel J. Skiest, Baystate Medical Ctr., 759 Chestnut St., Springfield, MA 01106 (daniel.skiest{at}bhs.org).
 
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Abstract

Background. We sought to determine the safety of treatment interruption (TI) and to identify parameters that would define patients with human immunodeficiency virus (HIV) for whom TI is safer.

Methods. AIDS Clinical Trials Group 5170 was a multicenter, 96-week-long, prospective study of HIV-infected patients receiving antiretroviral therapy (ART) who had CD4+ cell counts >350 cells/mm3 and who underwent TI.

Results. A total of 167 patients were enrolled. The median nadir in CD4+ cell count was 436 cells/mm3. The initial decrease (i.e., during the first 8 weeks) in CD4+ cell count after ART interruption was 20 cells/mm3/week; the subsequent decrease was 2.0 cells/mm3/week until week 96. Both the CD4+ cell count before enrollment and the increase in CD4+ cell count during ART predicted early decrease; later decrease was predicted by the level of interleukin- 7 at enrollment. A Centers for Disease Control and Prevention (CDC) diagnosis of a category B or C event was made for 2 and 2 patients, respectively (all had CD4+ cell counts >350 cells/mm3). At week 96, 17 patients had CD4+ cell counts ≤250 cells/mm3, and 46 patients had resumed ART; 5 patients died (unrelated to HIV or acquired immunodeficiency syndrome). In a multivariate analysis, a higher nadir in CD4+ cell count (>400 cells/mm3), a lower HIV load (<50 copies/mL) at the time of TI, and an HIV load ≤22,000 copies/mL before ART predicted a longer time to the primary end point (CDC category B or C event, death, CD4+ cell count ≤250 cells/mm3, or resumption of ART).

Conclusion. Disease progression after TI was low in this cohort. A higher nadir in CD4+ cell count, a lower HIV load before ART, and an HIV load ≤50 copies/mL at the time of TI predicted a longer time to the primary end point.

Combination antiretroviral therapy (ART) has prolonged survival and has decreased morbidity due to AIDS [1–3]. Initial guidelines recommended ART for patients with preserved immune function [4, 5]. The inability of ART to eradicate HIV infection and the growing recognition of ART toxicity subsequently led to changes in treatment guidelines; a more conservative approach was embraced, with ART being delayed until HIV had progressed to thresholds associated with reductions in HIV-associated morbidity and mortality [6, 7]. However, the optimal time at which ART should begin remains a debated topic.

Because of the initial enthusiasm for early initiation of ART, some patients receiving treatment would not have been offered treatment under current consensus treatment guidelines [8, 9]. The optimal management of these patients is not known. If therapy can be safely discontinued for a period of time, without a substantial risk of disease progression, patients may benefit from decreased adverse effects and toxicity, decreased potential for viral resistance, and economic savings.

We sought to evaluate both the safety of ART treatment interruption (TI) in such a population and the changes in toxicity after TI. Furthermore, we sought to identify clinical and biological factors predictive of prolonged clinical stability and of a decrease in CD4+ cell count after ART. Finally, we sought to evaluate the subsequent success of ART in those patients who resumed it after TI.

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Patients and Methods

AIDS Clinical Trials Group (ACTG) 5170 was a multicenter, observational, prospective, 2-step study of asymptomatic HIVinfected patients who wished to discontinue ART. The study was approved by the institutional review board at each site. All patients gave written consent before being enrolled.

Patients. Eligibility criteria for step 1 included (1) confirmed HIV-1 infection, (2) age >12 years, (3) CD4+ cell count >350 cells/mm3 immediately before the first ART, (4) current CD4+ cell count >350 cells/mm3, (5) plasma HIV-1 RNA load <55,000 copies/mL at screening, (6) current ART with≥2 drugs for ≥6 months, and (7) Karnofsky score ≥70. Exclusion criteria were (1) pregnancy, (2) breast-feeding, (3) use of chemotherapy, investigational agents, or immunomodulators during the 30 days preceding enrollment in the study, (4) active use of drugs or alcohol, (5) serious illness requiring systemic treatment and/or hospitalization during the 30 days preceding enrollment in the study, (6) serious medical condition that would have a negative impact on participation in the protocol, (7) history of Centers for Disease Control and Prevention (CDC) category B or C HIV-related illness [10], (8) hepatitis B therapy with lamivudine, tenofovir, or high-dose adefovir, in the absence of ART, or (9) nonadherence to ART.

Study Design. Patients underwent TI when they were enrolled in the study (i.e., at step 1) and were monitored for up to 96 weeks. Patients receiving a nonnucleoside reverse-transcriptase inhibitor were advised to discontinue it 48 h before other ART was discontinued. Assessments were conducted every 4 weeks through week 16, every 8 weeks through week 48, and then every 12 weeks. Baseline assessments included physical examination, routine laboratory tests including lipid and metabolic panels, CD4+ and CD8+ cell counts, HIV load, and HIVresistance testing (by standard genotyping assays). Assays of plasma interleukin 7 (IL-7) (Human IL-7 Quantikine High Sensitivity; R&D Systems) and insulin-like growth factor—1 (IGF-1) (Human IGF-1 Quantikine; R&D Systems) were performed according to the manufacturer's instructions. Flow-cytometric measurements of CD4+ and CD8+ T cell activation were performed according to the ACTG consensus method [11]. CD4+ and CD8+ cells were designated as activated when they were positive for both CD38+ and HLA-DR, as described in detail elsewhere [12]. T cell—receptor excision circles (TRECs) were assayed as described elsewhere [13]. At subsequent visits, routine laboratory testing was performed, CD4+ and CD8+ cell counts and HIV load were measured, and protocol-adherence and symptoms were assessed.

Patients were eligible for step 2 if they and/or their providers desired to resume ART; such patients were monitored for either ≥24 weeks or 96 weeks after enrollment in step 1, whichever was longer. The protocol did not specify the ART regimen for step 2. Patients were excluded from step 2 if they had received >4 doses of antiretroviral medications while enrolled in step 1. The protocol strongly recommended that patients resume ART if their CD4+ cell count fell to ≤250 cells/mm3. Evaluations after resumption of ART were made at months 1, 2, 4, and 6 and then every 3 months.

The primary end point in the study was the time to first CDC category B or C event, death, CD4+ cell count ≤250 cells/ mm3, or resumption of ART. The secondary end points in the study were (1) time to CDC category B or C event, death, or CD4+ ≤250 cells/mm3; (2) decrease in CD4+ cell count during step 1; (3) change in HIV load during step 1 and step 2; and (4) signs, symptoms, and laboratory abnormalities. Virologic failure in step 2 was defined as an HIV load >400 copies/mL at the last visit before patients switched regimens or discontinued study and an HIV load at week 4 that did not decrease by ≥1.0 log10 from the step 2 baseline level. Adverse events were graded by the Division of AIDS grading system [14].

Predictors of the rate of immunological and clinical progression were analyzed by Cox proportional hazard models. Analyses of the secondary end point censored follow-up at resumption of ART. The variables with P ≤ .10 in unadjusted (univariate) analyses were included in a subsequent, multivariate analysis. For each patient who discontinued ART during step 1, 2 phases of the slopes of the decrease in CD4+ cell count were estimated—that during the first 8 weeks and that from week 8 to the end of step 1. The changing time point for the 2 phases of the slopes was chosen on the basis of the plots of the decrease in CD4+ cell count and the maximum likelihood resulting from the fitting of the data into a mixed linear model with repeated measurements [15]. The correlation between each phase of the slope of the decrease in CD4+ cell count and various biomarkers measured at enrollment in the study was analyzed by Pearson's correlation. All tests were 2-sided, and P < .05 was considered to be significant. Statistical analyses were performed by SAS (version 9.1).

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Results

Study population. A total of 167 patients from 31 sites were enrolled; their demographic and baseline characteristics are presented in table 1. The median duration of follow-up was 96 weeks after TI and 45 weeks after resumption of ART. Of the 167 patients enrolled, 144 completed the study; the remaining 23 discontinued it before all assessments had been completed. Although enrollment in the study required the CD4+ cell count to be >350 cells/mm3 within 6 months of initial ART, the nadir in the CD4+ cell count within 6 months of initial ART was <350 cells/mm3 in 23 (14%) of the patients. A total of 137 (82%) of the patients had an HIV load ≤400 copies/mL.

Dynamics of CD4+ cell count and HIV load after discontinuation of ART. The slope of the decrease in CD4+ cell count after TI occurred in 2 distinct phases (figure 1A): a rapid decrease (20 cells/week) during the first 8 weeks after discontinuation of ART was followed by a much slower decrease (2.0 cells/week) afterward. A steeper early decrease was predicted by a higher CD4+ cell count before enrollment (P=.0007) and by a greater increase in CD4+ cell count during ART (difference between CD4+ cell count before enrollment and nadir in CD4+ cell count) (P=.0028). TREC, IGF-1, IL-7, CD4+ cell activation, CD8+ cell activation, HIV load before enrollment, and nadir in CD4+ cell count did not predict an early decrease in CD4+ cell count. The second-phase (i.e., after 8 weeks) in the slope of the decrease in CD4+ cell count was somewhat predicted by the level of IL-7 before enrollment (P=.061). Also, a greater decrease in CD4+ cell count after week 12 was predicted by a higher level of IL-7 before enrollment (P=.010).

Table 1.
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Table 1.

Baseline characteristics of patients (n=167).

Figure 1.
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Figure 1.

Plots of (A) CD4= cell count and (B) HIV load, after interruption of treatment. The thicker black line denotes the slope in the median value, and the horizontal tic marks at the top and bottom of each vertical line indicate the interquartile range.

The rate of virological rebound was rapid during the first 8 weeks (mean, 2.1 log10 increase; see figure 1B). An HIV-load set point after TI (defined as a <0.5-log10 change between HIVload measurements) was attained in 159 of the 167 patients enrolled; of the remaining 8 patients, 3 resumed ART and 5 left the study before a set point was observed. Median time to HIV-load set point was 4.3 weeks (interquartile range [IQR], 3.1–8.4 weeks). In 122 (77%) of the 159 patients, the HIV-load set point was attained by week 8, and by weeks 12 and 16 it was attained in 143 (90%) and 154 (97%) of them, respectively. A total of 98 patients completed 96 weeks of follow-up after TI. In patients who did not resume ART, the median HIV-load increase between weeks 8 and 96 was 366 copies/mL.

Primary end point: clinical disease progression, death, or resumption of ART. During 96 weeks of study, there were 2 CDC category B events (i.e., multidermatomal herpes zoster and peripheral sensory neuropathy) in 2 patients and 3 CDC category C events (i.e., recurrent bacterial pneumonia) in 2 patients, all occurring after week 48. All CDC category C events occurred after resumption of ART. Also, 4 patients developed thrombocytopenia (platelet count, <55,000/mm3) after TI, and 1 patient met the case definition for acute retroviral-rebound syndrome. The most common diagnoses were localized herpes zoster (11 episodes in 10 patients), hypertension (in 9 patients), and bacterial infection (12 episodes in 9 patients). Other clinical events are listed in table 2.

Of the 5 deaths (age range, 41–53 years) that occurred during the study, 3 occurred during the first 48 weeks, and 2 occurred afterward; 4 of these 5 patients died during TI (TI range, 2 days–91 weeks), and 1 had resumed ART 10 weeks before death. Three patients had a history of significant coronary artery disease; the cause of death was definitely cardiac disease in 2 patients and possibly cardiac disease in another 2 patients. The remaining 1 of the 5 deaths was due to sepsis. The CD4+ cell count immediately before death was 137–845 cells/mm3, and it was >350 cells/mm3 in 4 of the 5 patients. The proximate HIV load was <3500 copies/mL (range, 120–69,095 copies/mL) in 4 of the 5 patients.

By week 48, 12 patients reached a confirmed CD4+ cell count ≤250 cells/mm3, and 26 patients had reinitiated ART; through week 96, 5 additional patients reached a confirmed CD4+ cell count ≤250 cells/mm3, and 20 additional patients resumedART (figure 2). Univariate predictors of time to the primary end point were examined (table 3); a higher nadir in CD4+ cell count, a higher CD4+ cell count before enrollment, a lower HIV load before enrollment, and a smaller decrease in CD4+ cell count at week 4 predicted a longer time to the week 48 primary end point. In the multivariate analysis, only a higher nadir in CD4+ cell count predicted the week 48 primary end point (table 4).

Table 2.
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Table 2.

Clinical events occurring while antiretroviral therapy (ART) was discontinued (step 1) and after it was resumed (step 2).

Figure 2.
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Figure 2.

Time to primary end point (i.e., CD4+ cell count ≤250, first Centers for Disease Control and Prevention category B or C event, death, or resumption of antiretroviral therapy (ART). The black, middle line denotes the median time, and the upper and lower lines comprise the 95% confidence interval.

Table 3.
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Table 3.

Univariate analysis of time to primary and secondary end points, analyzed by use of the Cox proportional hazards model.

Table 4.
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Table 4.

Multivariate analysis of time to primary and secondary end points, analyzed by use of the Cox proportional hazards model.

At week 96, a higher nadir in CD4+ cell count, a higher CD4+ cell count before enrollment, a lower HIV load (≤50 copies/ mL before enrollment), and a lower HIV load before ART were significant univariate predictors of a longer time to the primary end point (table 3). In the multivariate analysis, a higher nadir in CD4+ cell count and a lower HIV load both before enrollment and before ART were significant predictors of a longer time to the primary end point (table 4). A primary end point was attained in 12 (52%) of the 23 patients in whom the nadir in CD4+ cell count was ≤350 cells/mm3, compared with 14 (40%) of 35 patients in whom it was 351–400 cells/mm3 and 28 (26%) of 109 in whom it was >400 cells/mm3.

Secondary end point: clinical disease progression or death. At both week 48 and week 96, a higher nadir in CD4+ cell count, a higher CD4+ cell count before enrollment, and a lower HIV load before enrollment were significant univariate predictors of a longer time to the secondary end point (i.e., CD4+ cell count ≤250 cells/mm3, first CDC B or C event, or death); at week 48 only, a lower proportion of activated CD4+ cells was a significant univariate predictor of a longer time to the secondary end point (table 3). In the multivariate analysis, the nadir in CD4+ cell count and the HIV load before enrollment were, at week 96 only, significant predictors of a longer time to the secondary end point (table 4).

Symptoms and laboratory abnormalities. Grade 3 or 4 signs and symptoms (i.e., severe and life threatening, respectively) were recorded in 26 (16%) of the 167 patients after TI and in 5 (12%) of 42 evaluable patients after resumption of ART. The most commonly reported grade 3 or 4 signs and symptoms after TI were musculoskeletal pain, diarrhea, fatigue, fever and/or night sweats, dyspnea, nausea, and vomiting. The cumulative rate of grade 3 or 4 signs and symptoms was 0.25/ patient-year after TI, compared with 0.56/patient-year after resumption of ART. One or more grade 3 or 4 abnormal laboratory values were recorded in 27 patients after TI and in 11 patients after resumption of ART. The overall rate of grade 3 or 4 laboratory abnormalities after TI was 0.17 events/patientyear, compared with 0.66 events/patient-year after resumption of ART.

Resumption of ART. Of 46 patients who elected to resume ART, 42 (91%) enrolled in step 2. Reasons for resumption were as follows: decision by patient (26%), decrease in CD4+ cell count (21%), attainment of CD4-cell-count threshold (17%), suggestion by provider (12%), increase in HIV load (5%), nonspecific HIV-related symptoms (2%), new hypertension (2%), and treatment for hepatitis C (2%). Of the 46 patients who resumed ART, 32 (70%) resumed a regimen containing other antiretroviral agents, and 27 of these 32 patients had virologic suppression at week 96; of the 14 remaining patients, who resumed the same ART, 6 had virologic suppression. In the 40 patients who remained in step 2 for ≥16 weeks, the median CD4+ cell count at step 2 enrollment was 359 cells/mm3, which rose to 510 cells/mm3 by week 16. From the beginning of step 2 to the last visit in step 2 (median length of follow-up, 46 weeks), the median increase in CD4+ cell count was 167 cells/ mm3 (IQR, 64–281 cells/mm3).

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Discussion

Although ART benefits patients with advanced immune suppression [1–3, 18–22], its benefit for patients with preserved immunological function has been debated [1, 18, 21–25]. Both the toxicity associated with ART and the challenges of treatment adherence make long-term therapy difficult. Reflecting these realities, current treatment guidelines strongly recommend that ART be initiated only in patients with CD4+ cell counts <200 cells/mm3 [8, 9].

In light of the changes that have been made in the recommendations for initiation of ART, it would not be prescribed today in many patients who are currently receiving it. In addition, some patients who are likely to benefit from ART either cannot tolerate it or cannot adhere to the treatment regimen. In a recent study, nearly 20% of patients underwent TI for some reason during the first 2 years of ART [26]. The optimal management of such patients is not known. In some patients who experience toxicity, treatment fatigue, or poor adherence to treatment, continuing therapy may lead to irreversible toxicity or virological resistance.

The present prospective study of TI in individuals with preserved immune function illustrates that the majority of patients with both high CD4+ cell counts and either low or undetectable HIV load can discontinue ART for up to 96 weeks and have a low risk of HIV disease progression. It should be noted that, although the enrollment criteria required that the CD4+ cell count be >350 cells/mm3 at the time of TI, the majority of subjects had a CD4+ cell count >500 cells/mm3 at that time. Two patients developed an AIDS-defining event, and 2 others developed a non—AIDS-defining event (CDC category B); all of these events developed >1 year after TI. The rate of other clinical events—which included localized herpes zoster, mucosal candidiasis, retroviral rebound syndrome, and thrombocytopenia— was low and was likely related to preserved immune function in the study cohort. Individuals in whom either AIDS or more-minor HIV-related conditions (i.e., CDC category B events) had been diagnosed were specifically excluded from the study. These findings are similar to those of other studies of TI in similar populations [27–32]. However, recent studies with differing study designs have found a higher rate of clinical events [33, 34]. These studies did not exclude patients with AIDS or HIV-related conditions, and they enrolled subjects who had a broad range of immune impairment and lower nadirs in CD4+ cell counts. One study with a high event rate (mainly bacterial infections) enrolled patients in Africa, where the background rate of concomitant infections may be higher [34]. Rapid progression and more-frequent clinical events in these study populations might be expected. The present study's results, showing a low rate of AIDS-related events after TI in a homogenous population with preserved immune function, should not be extended to other, dissimilar populations.

Both abnormalities in laboratory results and severe or lifethreatening signs and symptoms occurred at a higher rate in patients who had resumed ART. This finding may reflect the adverse effects and toxicity of ART, an important parameter to consider in the weighing of the risks versus the benefits of ART. Adverse effects may result in lower adherence and, in turn, to virologic resistance. Because newer antiretroviral medications may result in lower toxicity and fewer adverse effects, the benefits of TI may diminish in the future.

Although there were 5 deaths in the present study, none were due to AIDS-related conditions, and it is noteworthy that, in 4 of the 5 deaths, the CD4+ cell count was >350 cells/mm3 and the HIV load was >3500 copies/mL; furthermore, 3 of the deceased patients had a documented history of atherosclerotic heart disease, and, in 2 (or possibly all) of these 3, the cause of death was likely related to a cardiac event. It is not clear whether the death rate in the present study was greater that what would be expected in this population. However, in light of renewed HIV replication's ability to induce immune activation, viremia may have led to inflammation and endothelial dysfunction, which would have contributed to myocardial infarction; previous studies have suggested that high levels of HIV replication correlate with impairment of endothelial function [35–37]. Without a control group matched for cardiovascular risk factors, we are unable to make a definitive conclusion on the basis of our observations of cardiovascular-related deaths; future studies should assess this issue.

Three important predictors of time to the primary end point were (1) the nadir in CD4+ cell count, (2) an undetectable HIV load before TI, and (3) the HIV load before ART (>22,000 vs. ≤22,000 copies/mL). In only 26% of the patients in whom the nadir in CD4+ cell count was >400 cells/mm3 was the primary end point attained by week 96. The majority of these 54 end points were not clinical events, with 32 (59%) of them being resumption of ART. When we excluded resumption of ART as an end point, the HIV load before TI and the nadir in CD4+ cell count were predictive. Despite attempts to identify other predictors of clinical stability after TI, we found that age, sex, race, CD4+ cell count at TI, TREC, IL-7, IGF-1, CD4+ cell activation, and CD8+ cell activation were not strongly predictive of outcome. Thus, knowledge of the nadir in CD4+ cell count, the HIV-load set point before ART, and the current HIV load are important when TI is being considered.

Several previous studies have demonstrated that a high nadir in CD4+ cell count [15, 27–30, 38–44] is the best predictor both of subsequent clinical events and of either a decrease in CD4+ cell count or a resumption of ART after TI, whereas the other significant predictors in the present study—namely, HIV load both before ART and at the time of TI—were not consistently found to be predictors in these previous studies. Two retrospective studies found that HIV load before ART was predictive [39, 41], whereas other retrospective studies did not [30, 44, 45]. In agreement with the findings of the present study, a recent study found that a higher HIV load at the time of TI was predictive of a shorter TI and/or attainment of a CD4+ cell count of <350 cells/mm3 [27]. However, other prospective studies have not shown that the HIV load at the time of TI is a predictor of subsequent outcomes [15, 43, 44]. The reason why a detectable HIV load at the time of TI might predict a decrease in CD4+ cell count in patients who discontinue therapy is not obvious; it may be a marker of adherence to the treatment regimen and may be indicative of a group that is more hesitant to resume ART.

The present study provides important clinical information regarding changes, in CD4+ cell count and in HIV load, that occur after TI. There was a 2-phase change in CD4+ cell count after TI—a rapid decrease in CD4+ cell count during the first 8 weeks after TI, followed by a much slower decrease after week 8. The best predictor of the initial decrease in CD4+ cell count was the increase in CD4+ cell count during ART, a result that also has been seen in other studies of TI [29, 31, 38, 40, 42, 46, 47]. It appears that the increase in CD4+ cell count during ART is rapidly lost after TI and that, in most patients, the count returns to a set point. This set point is likely determined by the nadir in CD4+ cell count before ART. The results of the present study suggest that patients with high levels of IL-7 are at greater risk of a decrease in CD4+ cell count during the second phase of decay—that is, >8 weeks after TI. In a study of sooty mangabeys infected with simian immunodeficiency virus, high levels of IL-7 were found to be correlated with an early decrease in CD4+ cell count after acute infection [48]. IL- 7 is an important cytokine in T-cell homeostasis and thymopoesis, and high levels of IL-7 in stable patients receiving ART may be a marker for low “thymic reserve.”

The HIV load also showed a 2-phase change after TI: a rapid increase during the first 8 weeks was followed by stable viremia afterward. By week 8, the viral set point after discontinuation of ART had been established in 122 (73%) of the 167 patients. These results replicate the experience of previous, smaller studies, which have suggested a rapid initial slope in the decrease in CD4+ cell count and an increase in HIV load occur during the first 8–12 weeks and are followed by a much slower decrease in CD4+ cell count and an increase in HIV load afterward [15, 29–31, 42, 44, 46, 47].

TI in carefully selected patients with preserved CD4+ cell counts appears to result in a low risk of disease progression, but potential negative consequences include the potential for increased transmission of HIV [49]. Patients who undergo TI should be counseled about this possibility and be reeducated about risk reduction. An additional concern is the potential for the development of resistance mutations during TI. The potential for resistance may be heightened when the interrupted regimen combines drugs with prolonged half-lives (e.g., nonnucleoside reverse-transcriptase inhibitors [50) and drugs with short half-lives (e.g., nucleoside analogues). The optimal timing of TI in such cases remains to be determined.

In summary, in a carefully selected group of patients with high nadirs in CD4+ cell counts and high current CD4+ cell counts, TI was not associated with rapid disease progression. However, adverse events were observed even in this selected group. A high nadir in CD4+ cell count, an undetectable HIV load before discontinuation of therapy, and a lower HIV load before initial ART were associated with a lower risk of a decrease in CD4+ cell count, AIDS-related conditions, resumption of ART, or death. TI in selected patients could avoid drug toxicity and other costs of therapy, but this possibility must be weighed against concerns about infrequent adverse events after TI.

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AIDS Clinical Trials Group 5170

The members of the AIDS Clinical Trials Group are Daniel J. Skiest and Tianna Petersen (University of Texas Southwestern Medical Center at Dallas [group A3751]) (supported by AIDS Clinical Trials Unit [ACTU] grant 3 U01 AI046376-05); Deborah McMahon and Nancy Mantz (University of Pittsburgh [group A1001]); Diane Havlir and Michele Downing (San Francisco General Hospital [group A0801]); Beverly Sha (Rush University Medical Center) and Jessica Shore (Rush University Medical Center and Northwestern University; Northwestern AIDS Clinical Trials Unit [groups A2701, A2702, and A2705]) (supported by ACTU grant AI 25915); Sylvia Stoudt and Debbie Slamowitz (Stanford University [group A0501]) (supported by ACTU grant 5UO1 AI027666); Linda Meixner and Susan Cahill (University of California, San Diego [group A0701]) (supported by ACTU grant AI27670); Peter Frame and Michelle Saemann (University of Cincinnati [group A2401]) (supported by ACTG grant AI-25897); Alexandra Nesbitt and Joseph J. Eron Jr. (University of North Carolina [UNC] at Chapel Hill [group A3201]) (supported by ACTU grant AI25868, General Clinical Research Center [GCRC] grant RR00046, and UNC Center for AIDS Research [CFAR] grant AI50410); Timothy Wilkin and Todd Stroberg (Cornell Clinical Trials Unit [groups A7803 and A7804]) (supported by Columbia-Cornell ACTU grant AI46386 and Weill Medical College GCRC grant M01 RR00047); Charles Gonzalez and Margarita Vasquez (New York University/New York City HHC at Bellevue Hospital Center [group A0401]) (supported by ACTU grant AI27665 and GCRC grant M01 RR00096); Ann C. Collier and Shelia Dunaway (University of Washington, Seattle [group A1401]) (supported by ACTU grant AI 27664); Karen T. Tashima and Pamela Poethke (The Miriam Hospital [group A2951]) (supported by Miriam Hospital ACTU grant AI46381); Ian Frank and Joyce Okawa (University of Pennsylvania, Philadelphia [group A6201]) (supported by ACTU grant U01-AI 032783-13 and CFAR grant 5-P30-AI-045008-07); Eric S. Daar and Sadia Shaik (Harbor—University of California, Los Angeles, Medical Center [grant A0603]) (supported by ACTU grant AI27660); Donna Mildvan and Ronald D'Amico (Beth Israel Medical Center [group A2851]) (supported by Beth Israel ACTU grant AI46370); William A. O'Brien and Gerianne Casey (University of Texas Medical Branch at Galveston [group A6301]) (supported by ACTU grant PHS 5U01AI032782); Connie A. Funk and Luis M. Mendez (University of Southern California [USC] [group A1201]) (supported by ACTU grant AI27673); Kimberly Gray and Ge-Youl Kim (Washington University, St. Louis [grant A2101]) (supported by ACTU grant A125903); Jane Reid and Carol Greisberger (University of Rochester [A1101]) (supported by ACTU grant AI27658 and GCRC grant 5-M01 RR00044); Winston Cavert and Christine Fietzer (University of Minnesota [group A1501]) (supported by ACTU grant AI27661); Nathan Thielman and Lee McClurkin (Duke University Medical Center [group A1601]) (supported by ACTU grant 5U01-AI-39156-09); and Deborah K. O'Connor and Mitchell Goldman (Indiana University [group A2601]) (supported by ACTU grant AI25859).

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Acknowledgments

AIDS Clinical Trials Group 5170 thanks Dr. Ronald Bosch (Harvard School of Public Health) for his assistance with statistical methods; David Rusin (Frontier Science & Technology Research Foundation Inc.) for his assistance with data retrieval; and Dr. Elizabeth Adams (Division of AIDS) for oversight of safety issues.

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Footnotes

  • ↵a Members of AIDS Clinical Trials Group 5170 are listed after the text.

  • Potential conflicts of interest: D.J.S. has received honoraria from or has been a consultant to Bristol Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Abbott Pharmaceuticals and has received research grants from GlaxoSmithKline and Bristol Myers Squibb. D.M. has received honoraria from or been a consultant to Merck and Tibotec, Inc.; D.M.M. has received grants, research materials, honoraria, or has been a consultant to Gilead Sciences, Monogram Biosciences, Merck, Abbott, Bristol Myers Squibb, GlaxoSmithKline, Boehringer-Ingelheim, Biotron Ltd., Roche, and Trimeris.

  • Presented in part: 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado, 5–8 February 2006 (oral abstract 101).

  • Financial support: AIDS Clinical Trials Group (National Institute of Allergy and Infectious Diseases grant AI38858 and Statistical Data Analysis Center grant AI38855; General Clinical Research Center units (National Center for Research Resources grant).

  • Received September 1, 2006.
  • Accepted November 20, 2006.
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  1. J Infect Dis. (2007) 195 (10): 1426-1436. doi: 10.1086/512681
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