Combination antiretroviral therapy (ART) has led to prolonged survival and a decrease in AIDS-related complications.1-3 The optimal time to begin ART remains an unanswered question. Previous treatment guidelines recommended ART in patients with preserved immune function.4,5 However, the inability of ART to eradicate HIV infection and the growing recognition of ART toxicities led to reassessment of these treatment guidelines. Subsequent recommendations have suggested deferring ART until the CD4 cell count is less than 350 cells/mm3.6,7
The appropriate management of patients who began ART with high CD4 cell counts (eg, in accordance with previous treatment guidelines) has been the subject of study. We and others demonstrated that patients with high CD4 cells (and no prior AIDS-defining illnesses) could stop therapy for a period of time, with relatively low morbidity.8,9 However, due to the smaller sample size of these studies, the ability to recognize rare but significant events was limited. Other studies in patients with more advanced disease found somewhat higher morbidity and mortality in those who stopped ART.10,11 In Strategies for Management of Antiretroviral Therapy (SMART), the largest study, an increased risk for serious events was observed even among patients with CD4 preservation after treatment interruption (TI), albeit at a low frequency.11
Combination ART may be associated with poor tolerability, adverse metabolic consequences (eg, lactic acidosis, insulin resistance, hyperlipidemia), body habitus changes (lipoatrophy and lipohypertrophy), and in some cases may adversely affect quality of life (QOL) due to chronic side effects.7 We sought to determine the impact of stopping ART on QOL and to determine the metabolic consequences and effect on body habitus of stopping ART.
AIDS Clinical Trials Group (ACTG) 5170 was a multicenter, observational, prospective, 2-step study in asymptomatic HIV-infected patients who wished to discontinue ART. The primary objective of A5170 was to determine the rate of HIV progression in patients who underwent a prolonged TI. The objectives of this analysis were to determine secondary outcomes of TI including lipid changes, body habitus changes, and QOL. The criteria for enrollment in A5170 have been described previously.8 Briefly, the study included patients with documented HIV-1 infection, CD4 count >350 cells/mm3 immediately before first ART and at time of study entry, plasma HIV-1 RNA viral load (VL) <55,000 copies/mL at screening, currently receiving ART with ≥2 drugs for ≥6 months, Karnofsky score ≥70, and no history of Centers for Disease Control category B or C HIV-related illness. The study was approved by the institutional review boards at each site. All patients gave written consent before enrollment.
Patients underwent TI upon entry (step 1) and were followed up for up to 96 weeks. Baseline assessments included physical examination, routine laboratory tests including fasting lipid and metabolic panels, body circumference measurements, symptom self-reports, and instruments to assess QOL. Anthropometric measurements (body circumference-neck, arm, thigh, hip, waist) were made by trained study coordinators in a standardized fashion according to ACTG standard procedures at weeks 8, 24, 48, 72, and 96. Fasting lipid parameters [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides] were obtained at weeks 12 and 24.
QOL was assessed by 3 separate survey instruments [ACTG self-report, Symptoms Distress Module, and Multidimensional Health Status (MHS)], which have previously been used in ACTG studies.12 (1) The ACTG patient self-report form asked about level of functioning in the past 4 months and used a visual analog scale (0-100) to describe current state of health, with “death or worst possible health” at the low end and “perfect or best health” at the high end. (2) The Symptoms Distress Module comprised 20 patient symptoms, each on a scale from 0 to 4. The symptoms queried included both physical and psychological symptoms. Four responses were possible for each question: 0 indicated the subject does not have the symptom, 1 indicated the symptom was present but not considered bothersome, 2 indicated the symptom was present but minimally bothersome, 3 indicated the symptom was present and was bothersome, and 4 means the symptom was present and bothered the subject a lot. We devised 3 summary components to analyze these data: the number of symptoms reported, the number of bothersome symptoms reported (defined as answering a 3 or 4), and an overall symptom summary score (defined as the sum of all 20 symptom scores). (3) The MHS assessment consisted of 20 questions, which were drawn from a large pool of existing questions that make up the Medical Outcomes Study.13 This instrument assessed physical functioning, role functioning, pain, social functioning, mental health, cognitive functioning, and energy level.
Patient QOL assessments were done at baseline and at weeks 24, 48, 72, and 96 in step 1. We examined the change in QOL by looking at the difference in each week from step 1 baseline. A higher score indicates an increase in QOL. For the MHS, each question was categorized as representing either the “physical” or “mental” domain. The physical and mental domains were analyzed separately and a score was calculated for each domain. A total MHS score was also calculated.
Patients entered step 2 if patient and/or provider desired to reinitiate ART and were then followed up for at least 24 weeks. The same laboratory parameters and QOL measurement instruments described above were utilized in step 2.
Paired t tests compared changes in QOL score, number of symptoms, and lipids from baseline to each week of the scheduled evaluations. Because of extreme outliers and skewed data, Wilcoxon signed rank tests were used to compare changes in body measurements over time with baseline. In addition, generalized estimating equations (GEEs) were used to test the linear trend of changes in QOL scores and number of symptoms over time. To assess whether dropout has an impact on the above analyses, we performed 2 sensitivity analyses. In the first analysis, we repeated the above analyses but only included subjects who completed the 96 weeks of follow-up in step 1; in the second analysis, we used a linear mixed-effect model to evaluate the liner trend of changes in QOL scores and number of symptoms over time. In the linear model, subject-specific intercept and slope were modeled as random effects, and the time (in weeks) was modeled as a fixed effect. Results were similar to results obtained using the GEE approach.
The above analyses were repeated by the drug class that subjects were receiving at study entry [nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing, protease inhibitor (PI)-containing, and nucleoside reverse transcriptase inhibitor (NRTI)-only]. All tests were 2-sided, and P < 0.05 was considered significant. No adjustments for multiple comparisons were made. Statistical analyses were performed with SAS9.1 (SAS Institute, Cary, NC).
In all, 167 subjects enrolled; the mean age was 42 years and 83% were men. The median baseline and nadir CD4 counts were 833 cells/mm3 (interquartile range [IQR], 668-989 cells/mm3) and 436 cells/mm3 (IQR 375-510 cells/mm3), respectively. Eighty-two percent of participants had viral load <400 copies/mL at study entry. The median time on ART was 4.5 years, and the median number of antiretroviral drugs was 3 (range 3-9) (Table 1). At baseline, 60 patients (36%) were receiving NNRTI-based treatment, 62 (37%) patients were receiving PI-based treatment, and 39 patients (23%) were receiving combination nucleoside analogs without a PI or NNRTI. Six patients (4%) received a combination of an NNRTI and a PI without nucleoside analogs. Among patients receiving a nucleoside analog as part of their regimen, 149 received a thymidine analog (zidovudine or stavudine) as part of their regimen (irrespective of whether they were taking an NNRTI or PI). Of the 62 patients receiving a PI-based regimen, 8 received a ritonavir-boosted PI.
The main results of A5170 have been reported previously.8 Clinical progression was uncommon. By 96 weeks, 17 of 167 participants had confirmed CD4 ≤250 cells/mm3, 2 patients had a Centers for Disease Control category B and C event, and there were 5 deaths (none related to AIDS progression). Forty-six patients restarted ART.
QOL After TI
In general, study participants reported a high QOL on the visual analog scale at baseline, which did not significantly change during follow-up. Mean (median) QOL score was 83.4 (90) at baseline (n = 150) and was 83.0 (85) at week 96 (n = 105), on a scale of 0-100, P = 0.49. The overall test for trend using all time points did not indicate a significant change in self-reported QOL over time, GEE method P = 0.237 (Fig. 1). Post hoc analyses by drug class at time of interruption showed nonsignificant changes in QOL for PI and NNRTI groups and decrease in QOL (baseline to week 96) for the NRTI group (−5.5 at week 96, P = 0.03). Results from sensitivity analyses were similar to those from analyses using all subjects.
We further analyzed changes in QOL according to CD4 cell counts. We restricted this analysis to those 105 subjects who completed 96 weeks of follow-up without ART resumption. Among the 62 subjects with high (>85) week 96 QOL, 36 maintained a CD4 cell count ≥400 cells/mm3 while off of ART, compared with 26 who had a least one CD4 cell count 400 cells/mm3, P = 0.63. Thus, maintaining a high CD4 cell count was not predictive of higher QOL at 96 weeks.
We also compared QOL among subjects who stayed in step 1 (off ART) with those who entered step 2 (restarted ART). The median time to ART resumption was 48.7 weeks. Therefore, we compared QOL at week 48 in step 1 (among those remaining off ART) with QOL at step 2 entry (about to resume ART). Mean QOL was higher among those who remained off ART compared with those who resumed: 83 vs 72, P < 0.0001. This difference was not fully explained by differing QOL at baseline to step 1, for example, these groups had similar QOL before ART cessation (84 vs 81, respectively, P = 0.30).
The most frequently reported symptoms at baseline and which were reported by at least half of patients were fatigue (67%), feeling sad (58%), insomnia (56%), nervousness (55%), myalgias (55%), concerns about body fat deposits (55%), difficulty remembering things (54%), and bloating or abdominal discomfort (51%). After TI, the types of symptoms reported did not change appreciably (data not shown).
The mean number of patient-reported symptoms at baseline was 8.2 (n = 152); among the 105 subjects with data at week 96, the mean decreased from baseline by −1.2, P = 0.016 (Table 2). The overall test for trend using all time points indicated a significant decrease in number of symptoms from baseline (GEE method P = 0.043). The overall mean symptom summary score (sum of all 20 questions) also showed a significant decrease from baseline using data from all time points, GEE method P = 0.02. The mean number of bothersome symptoms did not significantly change over the course of the study, GEE method P = 0.29. Results from sensitivity analyses were similar to those from analyses using all subjects. In the subgroup analysis by drug class at baseline (NRTI, PI, and NNRTI), higher number of symptoms decreased from baseline to weeks 72 (−2.1, P = 0.02) and 96 (−1.8, P = 0.02), for those who had received a PI regimen at baseline, as compared with other drug classes (range −0.8 to −0.1, all P > 0.1). The symptom summary score also decreased from baseline to weeks 24, 48, and 72, only in those who were receiving a PI-based regimen at baseline (P = 0.01, P = 0.04, and P = 0.05, respectively).
Mean physical and mental health scores were high at baseline, 85.7 and 78.6, respectively and remained high throughout the period of TI. Among patients who remained off ART, the MHS scores did not change significantly at any subsequent week during TI compared with baseline. Results from sensitivity analyses were similar to those from analyses using all subjects.
No significant change in subjective QOL score, overall number of symptoms, type of symptoms, or MHS was observed in step 2 among the 46 subjects who reinitiated ART (data not shown).
Body circumference measures generally increased during TI for arm, waist, hip, and mid-thigh, for comparison of each subject's measurements vs baseline in patients who remained off ART (Table 3). Waist and hip circumference showed modest increases after TI at all time points, whereas arm circumference increased from week 24 onward and mid-thigh circumference increased after TI after week 48. In contrast, measurements of neck circumference did not change appreciably during TI. Results from sensitivity analyses were similar to those from analyses using all subjects.
We analyzed changes in lipid parameters through week 24, by excluding subjects (n = 5) who either stopped or started lipid-lowering agents during this part of the study. Decreases in fasting lipids occurred after TI (Table 4). At baseline, mean LDL cholesterol was 118 mg/dL. After TI, total, LDL, and HDL cholesterol and triglycerides decreased significantly at weeks 12 and 24 compared with baseline. No significant changes in fasting glucose levels were observed after TI. The frequency of grade 3 or 4 lipids or glucose was low at baseline (1%) and remained low throughout the study. The mean changes in LDL, total cholesterol, and triglyceride levels were similar in those patients on NNRTIs or PIs (significant decrease in all parameters). HDL decreased overall, an effect that was somewhat more pronounced in those patients on NNRTIs at baseline compared with those on PIs at baseline (change from baseline to week 24: −3.43 vs −7.47 mg/dL, PI vs NNRTI, P < 0.05). Those patients on NRTIs alone did not show significant changes in lipid parameters from baseline, although the number in this category was low.
Because both HDL cholesterol and total cholesterol (and LDL cholesterol) decreased with TI, we also compared the total cholesterol to HDL cholesterol ratio at baseline and each time point. At baseline the mean ratio was 4.8. There was no significant change in the ratio during step 1. Results from sensitivity analyses were similar to those from analyses using all subjects.
Upon resumption of ART, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides increased significantly within the first 8 weeks of resuming ART (data not shown).
Although most patients who start ART should continue treatment indefinitely, in practice there are some patients who will interrupt therapy for various reasons.14 Such reasons may include drug toxicity or intolerance, drug-related metabolic or body habitus changes, pill fatigue, lack of financial resources, and negative effects on QOL. TIs may be relatively brief (weeks to a few months) in cases of medication toxicity, short-term adherence difficulties, intolerance or may be longer (months to a few years), for example, in cases of ongoing substance abuse, lack of financial resources, or in cases in which therapy was recommended to be initiated at higher CD4 cell counts than is currently recommended. Because in practice TIs are common,14,15 it is important to know the effects of TI on QOL and on metabolic profile and body habitus. Such knowledge may help providers and patients who are faced with a scenario in which TI is being considered.
In our cohort of individuals with preserved immune function and no prior AIDS-related conditions, ART interruption was generally safe.8 Patient-reported QOL scores remained high after TI and did not significantly change after TI. The overall symptoms summary score decreased after TI. In addition, the mean number of symptoms per patient decreased during TI. Importantly, there was no evidence that QOL worsened by any of the measured parameters, for example, visual analog score, self-reported symptoms (including bothersome symptoms), or the physical or mental aspects of the MHS. Although QOL was generally high, the fact that QOL among those who resumed ART was lower than those who continued a drug holiday suggests there is a subset of individuals who feel worse off therapy. Although QOL scores were generally high, most patients did report some symptoms both at baseline and after TI. At baseline more than half of patients reported fatigue, feeling sad, insomnia, concerns about lipohypertrophy, feeling anxious, myalgias, and trouble remembering things. Although these symptoms generally decreased after TI, a majority of patients continued to have symptoms after TI. Prior studies have documented that symptoms associated with HIV disease progression and/or therapy adversely affect health-related QOL.16-21. Antiretroviral medications that result in increased symptoms and thus adversely affect QOL may result in decreased adherence,22 which may ultimately lead to virologic and clinical failure.
Although symptoms directly or indirectly related to HIV replication were generally low in our cohort, others have reported higher rates. Thus, whereas our study reported only 1 documented case of definite acute retroviral rebound syndrome (0.6%), some TI studies have reported higher rates of symptoms typical of acute retroviral syndrome.9 The possibility of transient ARS symptoms needs to be considered in patients undergoing TI. Furthermore, as we and others have reported, there is a small but finite risk of non-AIDS-defining conditions developing during TI, such as herpes zoster, mucosal candidiasis, and thrombocytopenia.8,9,11 The possibility of such conditions after a TI should be considered.
Few other studies have evaluated QOL after ART interruption. Small studies of intermittent short TI (30-day TIs) have reported differing results. Some have shown mild QOL improvements,23 whereas others have not.14,24 Another small nonrandomized, prospective study that compared a group that underwent TI with a group that did not undergo a TI found no improvement in physical or mental health scores after TI.25 A study by Ruiz et al26 did demonstrate improvement in psychosocial aspects of QOL among patients who underwent a TI compared with those who continued therapy. However, physical aspects of QOL did not differ among patients who continued therapy compared with those who interrupted therapy. A larger study, for example, SMART, recently reported that QOL decreased in patients receiving intermittent therapy compared with those who received continuous therapy.27 However, the SMART study population differed considerably from that of A5170. Patients who enrolled in SMART were more immunologically and clinically advanced and only three-fourths were receiving ART at the time of enrollment.
Lipoatrophy and lipohypertrophy, which are associated with ART, are considered negative consequences of ART by patients and adversely affect patient QOL. One study indicated that some patients were sufficiently concerned about the development of lipodystrophy that they were willing to trade years of life if they did not develop the syndrome.28 Approximately half of patients in our cohort were concerned about changes in body appearance including fat deposition and/or weight gain at the time of TI. However, we did not have a specific question to address patient concerns about lipoatrophy. Patients interrupting ART (a thymidine analog-containing regimen in the majority) had immediate increases in waist and hip circumference and delayed (small) statistically significant gains in arm and thigh circumference. Slow increases in limb fat in patients interrupting therapy have been shown in other studies and suggest a residual effect of these medications. These results are consistent with prior data showing that among nucleoside analogs, thymidine analogs are most commonly associated with lipoatrophy.29 Another recent study of prolonged TI reported some improvement in lipodystrophy in patients who underwent TI compared with those who continued ART; however, this study was limited by the fact that lipodystrophy was self-reported.9
Multiple ART regimens have been associated with adverse effects on lipid parameters, for example, increase in total and LDL cholesterol and triglycerides.30,31 Some studies have also documented a small but significant increased risk of cardiac events in patients receiving ART.32-34 Switching therapy to more “lipid-friendly” regimens or interrupting therapy may have beneficial effects on lipid parameters. We observed small but significant improvements in several lipid parameters in patients who interrupted ART. Total and LDL cholesterol improved (decreased), as did triglycerides. Similar changes in the above lipid parameters were observed in patients interrupting NNRTI- and PI-based regimens. HDL cholesterol decreased as well, an effect that was more pronounced in patients on an NNRTI at baseline. The decrease in HDL may negatively affect the overall cardiac risk profile; importantly, however, there was no significant change in the total to HDL cholesterol ratio. Our findings with regards to improvement of lipid mirror those of recent studies, which have also noted an improvement in lipid parameters after TI.9,35,36 However, 1 large study also noted that the total cholesterol to HDL cholesterol ratio increased, an effect which could negatively affect the cardiac risk profile.37
Our study has limitations. Although it was prospective, we did not include a control group in whom therapy was continued. Thus, we could not directly compare QOL in patients who continued therapy with those who interrupted therapy. However, we do have baseline QOL assessments and were thus able to compare each patient's QOL at various study time points with the baseline assessments. Similarly, we could not compare lipid parameters and body measurement in patients who continued therapy with those who interrupted therapy, but we did compare subsequent lipid and body measurements after TI with baseline values. As in other studies of lipodystrophy, changes in body fat occur very slowly after discontinuation of offending antiretroviral agents, and it is not clear if the body fat changes seen in our study are clinically significant. The majority of patients in our study interrupted a thymidine analog-containing regimen. Thus, it is not clear if similar results would be obtained with antiretroviral regimens not containing thymidine analogs. Our study also included few patients who interrupted a boosted PI, reflecting the prevailing clinical practice at the time. Thus, our results cannot necessarily be extrapolated to patients receiving this combination. Finally, because patients were free to restart ART at any time, there are decreasing numbers of patients contributing data over time. The sensitivity analysis which included only those subjects who were in step 1 for 96 weeks gave similar results to that which included all subjects, and the marginal model using the GEE method produced similar results to those given by the subject-specific model (liner mixed-effect model).
In conclusion, in patients with preserved immune function who started ART (most including a thymidine analog) at high CD4 cell counts and later discontinued therapy, QOL remained high. There was no evidence of worsening QOL in patients who underwent TI, and there was some improvement in overall symptoms. In addition, lipids (total cholesterol, LDL cholesterol, and triglycerides) generally improved after TI. After TI, arm and thigh circumference increased slowly, suggesting a mild improvement in limb fat. Despite the potential benefits of TI in our study, TI entails important risks, which must be carefully considered. Future TI studies should include evaluation of QOL, lipids, and lipodystrophy in addition to clinical, virologic, and immunological end points.
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