In the past several years, highly active antiretroviral therapy (HAART) has led to dramatic declines in morbidity and mortality in HIV-infected patients in the developed world.1,2–4 Initial promising results and the belief that HIV could be eradicated in 2–4 years led to recommendations to treat HIV-infected patients with antiretroviral agents aggressively at early stages of disease.5–7 Recent experience, however, has somewhat tempered the enthusiasm for HAART in asymptomatic, chronically infected individuals with relatively preserved immune function.8
Widespread use of antiretroviral therapy (ART) has been associated with a number of problems. Success of ART is closely associated with high adherence rates but adherence is often difficult due to burdensome pill counts and adverse effects.9 Medication side effects are associated with decreased quality of life and may be a factor leading to poor adherence. Suboptimal adherence is associated with the development of viral resistance, which may ultimately result in virologic and immunologic failure. Options for patients in whom ART fails are limited.
Several recent observational cohort studies support a delay in initiating ART.10–16 In these studies, the main benefit of ART on disease progression and death has been in patients with CD4+ cell counts <200, and initiating ART at higher CD4+ cell counts was not associated with clinical benefit.11,12,17 In addition, recent virologic models suggest that eradication of HIV with currently available ART is not feasible.12,17
Reflecting the realities of difficulties with adherence, increased toxicities, and apparent lack of negative consequences of delaying ART in asymptomatic HIV-infected individuals, recent guidelines suggest withholding ART until the CD4 cell count is <350 cells/μL. However, many patients initiated HAART under previous more aggressive treatment guidelines when therapy was recommended for asymptomatic patients with CD4+ cell counts <500 cells/μL or HIV RNA (by polymerase chain reaction) >5000–20,000 copies/mL.6,7,18,19 Thus, many patients currently receiving ART would not be treated today. Many of these patients are aware of the toxicities and potential consequences of ART and have either stopped ART or are interested in stopping ART. The consequences of stopping ART in this patient population have not been extensively studied.
We reviewed our experience with patients who stopped ART for any reason for at least 5 weeks to determine the clinical, virologic, and immunologic consequences of this strategy.
The patient population was from 2 sites: the Amelia Court HIV clinic at Parkland Hospital, a 900-bed county hospital in Dallas, Texas, which serves as the primary teaching hospital for the University of Texas Southwestern Medical Center, and AMH Group, a private practice in Dallas. The Amelia Court clinic provides comprehensive care for approximately 3500 HIV-infected patients and the AMH Group provides care for approximately 1200 HIV-infected patients. All patients who interrupted ART for at least 5 weeks were identified by surveying HIV care providers at the Amelia Court clinic. During the study period, Amelia Court clinic providers were queried regularly about whether any patients had interrupted ART. In most cases patients were identified prospectively. Patients at the AMH group were identified by providers reviewing records of all patients who had interrupted ART. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas.
Inclusion criteria for the study included patients who stopped ART for at least 5 consecutive weeks and who had a documented CD4 cell count of >250 cells/μL at the time of stopping therapy. Using a standardized data collection form, the medical records of all patients who met the inclusion criteria were reviewed for the following data: age, HIV risk, race, sex, antiretroviral history, date of ART initiation, date of ART cessation, date of restarting ART (if applicable), CD4 cell count prior to ART initiation, CD4 cell counts while receiving ART and after stopping ART and after restarting ART (if applicable), HIV viral load prior to ART initiation, while receiving ART, and after stopping ART and after restarting ART (if applicable), reason for stopping ART and restarting ART (if applicable), and development of any Centers for Disease Control (CDC) category B or C events after stopping ART and the development of the acute retroviral rebound syndrome after ART cessation.
HIV viral load measurements were all done by the Roche HIV-1 Amplicor test, version 1.0 or version 1.5 (Roche Diagnostics, Nutley, NJ). The lower limits of detection of these assays are 400 copies/mL and 50 copies/mL, respectively.
SAS version 8.2 for Windows and STATView version 5.01, SAS Institute, Inc. (Cary, NC), were used to conduct the statistical analyses. Fisher exact test or χ2 was used to compare categorical variables. We analyzed predictors of reaching the combined endpoint of CD4 <250 cells/μL or restarting ART using a multivariate logistic regression model. After confirming that multicolinearity was not a problem, a multivariate logistic regression was performed using as potential predictors the variables pre-ART CD4 (dichotomized at ≤250 vs. >250 cells/μL), CD4 at time of stopping ART, age at time of stopping ART, and total number of antiretroviral agents. Except for pre-ART CD4 cell count, these variables were all examined as continuous variables. A backward stepwise procedure was used to select the best set of predictors. The 2-variable model was superior to the univariate models. Because of the small number of subjects reaching the endpoint, multivariate analyses were performed separately for the CD4 variables and the viral load variables. Alpha was not adjusted across these 2 analyses because a type II error was judged to be of greater concern than a type I error in this context. If one of these variables is judged to be significant when in actuality it is not, then future studies will reveal it. If, however, one is declared to be insignificant, then that variable may not be employed in future studies for the error to be corrected.
All values given are medians and HIV viral load results are log10 unless otherwise specified. Unless otherwise specified, a P value of 0.05 was considered significant.
A total of 110 patients were initially identified. Of these 107 met the inclusion criteria of stopping ART for at least 5 consecutive weeks with a CD4 count of >250 cells/μL. Patient characteristics are shown in Table 1. The median time on ART was 45 months (range 3.8–164 months). Patients had previously received a median of 4 antiretroviral medications at the time of stopping ART. The mean follow-up was 293 days (median 252 days, range 24–950 days).
The pre-ART CD4 cell count was >250 cells/μL in 89% and >350 cells/μL in over three-fourths of subjects. The median of the lowest CD4 cell count recorded at any time prior to stopping ART was 377 cells/μL (range 120–712 cells/μL). The median peak CD4 cell count recorded at any time prior to stopping ART was 853 cells/μL (range 384–3509 cells/μL). The mean increase in CD4 cells while on ART was 290 cells/μL (median 276 cells/μL).
At time of stopping ART, only 2 patients had a CD4 cell count <350 cells/μL and 61% of patients had an HIV viral load that was less than the level of detection. Among patients with an undetectable viral load, the first-generation Amplicor test (version 1.0) was used in 40% of patients (level of detection <400 copies/mL) and the second-generation assay (version 1.5) was used in 60% of patients. Figure 1 shows the CD4 increase while on ART and the decline after stopping ART. The slope of the CD4 decrease was significantly greater from time of stop to the first time point (0–60 days): 65 cells/mo compared with subsequent time points, P < 0.01. After the first time point, the slope of the CD4 cell decline was relatively constant (8 cells/mo) through the follow-up period of 13 months. Similarly, the increase in HIV viral load was rapid from time of stopping ART to the first time point (0–60 days) (2.54 log) but then remained constant after that without a significant increase. The majority of patients reached a postcessation viral setpoint by the first timepoint. It is likely that the actual viral load setpoint occurred sooner but we did not have sufficient earlier time points. At the end of the 13-month follow-up period, the median CD4 cell count remained above that of the pre-ART CD4 cell count and the median viral load remained slightly less than the pre-ART viral load (median pre-ART viral load 4.35 log-copies vs. postcessation viral load of 3.92 log-copies).
Six patients maintained an undetectable HIV viral load while off therapy for >2 months. Two patients were off therapy for almost 6 months and did not have a detectable viral load (167 and 180 days, respectively). All of these patients had a measured detectable viral load prior to initiation of ART.
Patients generally tolerated being off ART well. There was 1 patient with the retroviral rebound syndrome and a 2nd patient who had subjective fevers and malaise but did not have the complete retroviral rebound syndrome. In both cases symptoms at least partially improved after restarting ART. No AIDS-defining events were recorded during the period of follow-up.
Forty-one patients restarted ART at a median CD4 count of 388 cells/μL after a median time off ART of 6.4 months (range 1.3–35 months). The median viral load at the time of restarting ART was 4.85 log copies/mL (range undetectable to 5.87 log). Reasons for restarting ART are listed in Table 2. For several patients there was more than one reason for restarting ART. The most common reason for restarting medications was that the health care provider recommended restarting treatment. In the majority of cases, providers followed Department of Health and Human Services (DHHS) ART guidelines for restarting HAART. A drop in CD4 cell count was more likely to result in restarting ART compared with a rise in HIV viral load.
Potential predictors of reaching the combined endpoint of CD4 <250 cells/μL or restarting ART were analyzed (Table 3). In univariate analysis, lower pre-ART CD4 cell count, total number of prior ART drugs, and older age were significantly associated with reaching the endpoint, and there was a trend toward higher pre-ART HIV viral load being associated with reaching the endpoint. In contrast, neither viral load at ART stop nor CD4 at stop were significant.
Table 4 shows results of multivariate analysis. Only 7 patients reached a CD4 <250 cells/μL (median time 7 months). The median time to reaching the combined endpoint of CD4 <250 cells/μL or restarting ART was 8.9 months (mean 10.2 months). All 10 patients with pre-ART CD4 <250 cells/μL restarted ART or reached a CD4 of <250 cells/μL compared with 23 of 82 patients with pre-ART CD4 ≥250 cells/μL. Pre-ART CD4 <250 cells/μL was the best predictor of reaching the endpoint: odds ratio for CD4 >250 cells/μL vs. ≤250 cells/μL was 0.156 (P = 0.03). Older age at time of ART cessation and cumulative number of antiretrovirals taken prior to ART cessation remained predictive of reaching the combined endpoint in the multivariate model. In contrast, none of the following parameters predicted reaching the combined endpoint: pre-ART viral load, highest CD4 on ART, CD4 at time of stopping ART, and viral load at ART stop.
Follow-up time was somewhat limited in patients who restarted therapy (median 93 days, range 26–520 days). The median CD4 count increased by 77 cells from time of restart to the first time point (median 35 days) and by 137 cells by the 2nd time point (median 110 days). The median viral load decreased by 1.88 log from time of restart to the first time point. At the 2nd time point after restarting ART, the median viral load was undetectable.
Patients with AIDS clearly benefit from receipt of HAART with improved survival and lower morbidity.1,11,14,20–24 The benefits of HAART in asymptomatic patients with relatively preserved immunologic function are less clear. To date the majority of studies have not demonstrated a clinical benefit of HAART in patients with CD4 cell counts >350 cells/mm3, while some but not all studies have shown a benefit of starting HAART in patients with CD4 cell counts in the 201–350 range.11,14,22,24–26 One recent observational study demonstrated a modest benefit on clinical progression among patients who initiated HAART at CD4 cell counts >350 cells/mm3; however, almost half of patients who initiated HAART in this study experienced toxicity requiring discontinuing of therapy.27
HAART is associated with significant treatment-limiting toxicity. A recent study demonstrated that the median duration of HAART for ART-naive patients was only 1.6 years and that medication toxicity was the reason for stopping medication in half the patients.28 In another study, only 23% of patients had long-term virologic suppression for >2 years and the most common reason for changing treatment regimen was drug toxicity or intolerance.29 Coupled with the fact that adherence is difficult over the long term and poor adherence often leads to viral resistance, the enthusiasm for administering HAART to asymptomatic patients with high CD4 cell counts has been tempered in recent years. This is reflected in the recently updated antiretroviral treatment guidelines by the DHHS and the British HIV Society, which only firmly recommend initiation of HAART in patients with CD4 cell counts <200 cells/μL.8,30
Given the change in the recommendations for HAART initiation reflecting a less aggressive approach, many patients currently receiving HAART would not be offered HAART today. The dilemma that follows from this is what to do with the patient who was started on HAART previously but would not meet current guidelines. Patients and providers are requesting to stop HAART due to side effects, costs, or simply not wanting to receive HAART until it is needed. Limited data are available on the consequences of treatment discontinuation in patients without AIDS.31,32
Our study attempts to answer important questions regarding the consequences of stopping ART in patients who would not meet current ART treatment guidelines. From our study cohort it appears that stopping therapy in patients with a pre-ART CD4 cell count >250 cells/μL is safe and is not associated with any adverse outcomes. The best predictors of CD4 decline or restarting ART were the pre-ART CD4 cell count, age, and increased antiretroviral experience (cumulative number of antiretrovirals). These parameters are consistent with other studies. No CDC category B or C events occurred in patients who stopped ART. Two patients had fever following interruption. One of these patients experienced a definite retroviral rebound syndrome and the other patient had a possible retroviral rebound syndrome. Others have noted the retroviral rebound syndrome at a rate similar to ours in patients undergoing treatment interruptions.31,33,34 Other potentially adverse outcomes were not noted, but our retrospective cohort does not rule out long-term adverse consequences.
From our data it appears the pre-ART viral load set point is not reset following an ART interruption. We found no significant increase in viral load after the first time point (0–60 days). It is likely that the post-ART cessation viral set point occurs significantly earlier than 60 days but we did not have early data points to determine this. The CD4 cell count fell rapidly after ART cessation and then stabilized after the first time point. The median CD4 cell count remained above the pre-ART CD4 cell count at 13 months of follow-up.
A few other studies of ART cessation in a population similar to ours have been reported.31,32 Tebas et al32 reported on 72 subjects who stopped ART for a median of 36 weeks. The median nadir CD4+ cell count prior to ART was 285 cells/mm3 and the median pre-ART HIV-1 viral load was 26,053 copies/mL. At ART interruption, the median CD4+ cell count was 554 cell/mm3. Subjects experienced a median CD4+ decline off ART of 16 cells/mo. In multivariate analysis, only older age and the increase in CD4+ cell count while on ART were associated with the rate of CD4+ cell count decline after ART cessation, while CD4+ nadir, baseline viral load, and duration of undetectable viral load were not. Half of the subjects had a postcessation HIV-1 viral load that was lower than the pre-ART viral load. Eleven subjects restarted ART. Four subjects had a CD4+ decline to <200 cells/mm3 and had an AIDS-defining event or serious infection. No subjects experienced the acute retroviral syndrome after stopping ART.
Tarwater et al31 reported on 105 patients without AIDS who elected to stop therapy and planned to resume therapy based on laboratory or clinical parameters.31 The median pre-ART CD4 count was 412 cells/μL and the median HIV viral load was 36,000 copies/mL. Fifty-seven remained off therapy for a median of 114 weeks. In multivariate analysis, low pre-ART CD4 count predicted restarting therapy and viral load rebound during treatment interruption correlated with CD4 cell decline. No patients experienced adverse drug effects but 3 patients experienced the retroviral rebound syndrome. Most patients were able to achieve an undectable viral load after resuming ART.
Ruiz et al34 enrolled 122 patients with undetectable viral loads on HAART and CD4 >500 for at least 6 months to continue or interrupt therapy. Forty-three percent of patients in the interrupt-therapy group remained off therapy for 48 weeks. The CD4 count fell a median of 335 cells/mm3 or 33 cells/mo and the HIV viral load increased to 4.1 log. The majority of those who restarted therapy (median time of 8 weeks) did so due to a viral load that rose to >100,000 copies/mL.
Another group conducted an observational retrospective study of 140 patients with preinterruption CD4 counts of >500 cells/μL (median 804 cells/μL) and nadir of >250. The median time to restarting ART was 104 weeks. Predictors of therapy resumption were CD4 nadir, time with undetectable viral load, viral load prior to interruption, and slope of pre-ART CD4 count.35
Finally, Maggiolo et al36 randomly assigned 114 patients with on-therapy CD4 cells >800 cells/μL and undectable HIV viral loads to either continue or stop ART. ART was restarted for CD4 decrease to <400 cells/μL. Twenty-one percent of patients restarted ART and all had a rapid rebound in CD4 count upon restarting. The pre-ART CD4 nadir count was the only predictor of CD4 decline and time to restarting ART. Of note, total cholesterol decreased by 40 mg/dL in the treatment interruption arm.
While in general ART interruption in carefully selected patients with preserved CD4 cell counts appears safe, there are potential negative consequences. Although studies have not documented opportunistic complications, most studies have been relatively short term. Another possible negative outcome of stopping therapy, which we could not document since our study is retrospective, is the potential for increased HIV transmission due to the increase in HIV viral load, which occurs after therapy cessation. Patients who undergo treatment interruption should be counseled about this possibility and be educated about safe sex practices.
In addition, there is a concern for the development of resistance mutations emerging during treatment interruption. It appears that this problem, which appears to be rare, has mostly occurred in the setting of drugs with long half-lives such as the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and efavirenz.37 In such cases it may be prudent to stop the NNRTI several days prior to stopping the other antiretroviral drugs, to prevent exposure of the virus to the NNRTI alone, which may increase the likelihood of resistance developing.
While it is known that ART is associated with numerous adverse effects, studies have not looked at the impact of ART on patient quality of life before and after therapy cessation in patients with relative preservation of the immune system. If the strategy of stopping ART in patients with relatively preserved immunologic function does not result in any adverse clinical, immunologic, or virologic consequences, it could result in less drug-related toxicity and resistance, as well as significant cost savings.
Our study has certain limitations. It is likely that some patients at our sites who discontinued ART were not included in our study because their clinicians could not recall them at the time of the queries. This may limit the ability to extrapolate to other settings. However, by querying all HIV care providers it is unlikely that we missed a significant number of patients who stopped therapy for >5 weeks. Since some of our subjects were identified retrospectively, we do not have monthly data points on some patients. However, all patients had at least one CD4 and viral load measurement after stopping ART. Finally, we only included patients who stopped therapy for at least 5 weeks to exclude patients who did not undergo a clinically significant treatment interruption. Thus it is possible that outcomes would be worse if we included all patients who stopped therapy. However, in our cohort we estimated that we excluded <5% of patients by requiring patients to be off therapy for >5 weeks.
In summary, we have demonstrated that in patients with high CD4 cell counts prior to ART initiation (>250 cells/μL) it is safe to stop ART in the short term. Pre-ART CD4 ≤250 cells/μL was the best predictor of CD4 decline or restarting therapy. Our results should help patients and physicians make an informed decision on the likely consequences of stopping ART. Prospective studies are needed to more accurately predict the immunologic, virologic, and clinical course following discontinuation of ART.
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