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Increasing Trend to Stop HAART in MACS
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"Interruption and Discontinuation of Highly Active Antiretroviral Therapy in the Multicenter AIDS Cohort Study"
JAIDS Journal of Acquired Immune Deficiency Syndromes
1 March 2005
Li, Xiuhong MS*; Margolick, Joseph B MD, PhD; Conover, Craig S MD, MPH; Badri, Sheila MD; Riddler, Sharon A MD; Witt, Mallory D MDAa; Jacobson, Lisa P PhD*
From the *Department of Epidemiology and Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Cook County Bureau Health Service, Infectious Diseases, John Stroger Hospital, Chicago, Illinois; Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania; and AaDivision of HIV Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California.
The percentage interrupting HAART decreased from 10.5% in 1997 to 5.2% in 1999 and then increased to 7.7% in 2001. This inflection in the proportion interrupting HAART over time was significant. The percentage discontinuing HAART increased from 2.9% in 1997 to 6.5% in 2001, with a significant linear trend (P = 0.016). The median time off HAART in those discontinuing HAART was 61 days.
AUTHOR CONCLUSIONS
"....our findings indicate that interruption and discontinuation of HAART are gradually increasing in the population...
...frequently reported short interruptions have been shown to lead to virologic failure..
...Among those with more advanced HIV disease education, particularly among younger individuals, is needed to emphasize the importance of minimizing unnecessary treatment interruptions. Given the relation to depression, offering mental health services may enhance continuous use of HAART.."
"There has been great interest in the interruption and discontinuation of HAART in clinical practice because of drug resistance, severe toxicity, and the high cost of HAART. In this study, the proportion of HAART users interrupting therapy decreased since 1997 but increased after 1999. The low proportion discontinuing therapy has increased over time. The increasing trend may reflect changes in standard treatment guidelines, suggesting a more conservative approach, difficulty in maintaining continuous use of HAART, and/or the impact of alternative interruption strategies recently introduced in clinical trials as well as in the news. The increasing trend of discontinuation of HAART in this cohort was consistent with a report from the Women's Interagency HIV Study (WIHS).
Recommended interruptions (ie, those made in concordance with physicians) also may have resulted from practical needs. Physicians may prefer that all medications are halted rather than using partial suboptimal regimens. Little is known about the consequences of interrupting HAART by the clinicians or patients outside of the STI clinical trials.6-10 Therefore, we studied not only the consequences but the determinants of HAART interruption to understand better why interruptions occur in the general HIV-1-infected population. Whereas our analysis of independently ascertained markers of HIV disease stage (low CD4 cell count and high HIV RNA level) predicted interrupting HAART for >7 days, host characteristics (eg, age, race, lower adherence) were associated with short interruption of HAART (≤7 days). These factors, which indicate personal decision making, were consistent with the finding that those with short interruptions were less likely to have their interruptions prescribed by their physicians, indicating that the short interruptions may be a compliance issue. The finding that taking a 3TC-containing regimen was protective against short-term interruption might be explained by the fact that 3TC has lower toxicity than other antiretroviral drugs. Future analyses need to differentiate those who discontinue HAART for personal reasons, side effects, and as a result of physician recommendation, because these causes relate to different lengths of time off HAART and may have different consequences.
The observation that higher HIV RNA level and lower CD4 cell count predicted discontinuation of HAART is consistent with the findings of other studies. We also found that depression and lower adherence to HAART were associated with subsequent discontinuation of HAART. Depressive symptoms have been associated with reduced adherence to HAART.26,27 In addition, we found that younger age and taking a regimen containing abacavir or lopinavir predicted discontinuing HAART. Although these regimens may represent salvage therapy, use of antiretroviral therapy before HAART initiation, length of time on HAART, and number of prior HAART regimens were not independently associated with discontinuation.
Short-term HAART interruption (≤7 days) among chronically infected HIV patients with an HIV RNA level <10,000 copies/mL did not seem to affect the treatment benefit. Thus, it is possible that short interruptions may be associated with reductions in cost and drug-related toxicity, although these reductions are probably minimal. This potentially viable treatment strategy would need to be tested in large controlled trials. We also could not assess the effect of repeated interruptions; thus, the results need to be viewed with caution. Longer interruptions, as shown here and in a recently reported study, seem to have negative effects on HIV disease. In a recent presentation, longer interruptions were associated with the development of drug-resistant virus, thus limiting the choice of antiretrovirals on resumption of HAART. Long-term effects of short- and long-term interruptions need to be studied, not only on immune reconstitution but on viral drug resistance and viral replicative capacity.
ARTICLE TEXT & RESULTS
The Multicenter AIDS Cohort Study (MACS) is an ongoing prospective study of HIV infection among homosexual men in the United States.11-14 A total of 5622 men were recruited: 4954 in 1984 through 1985 and 668 in 1987 through 1991 at 4 centers located in Baltimore, Chicago, Los Angeles, and Pittsburgh.
Given the substantial interest in this area, our goal was to determine the extent, determinants, and consequences of short-term interruption and prolonged discontinuation of HAART that occur in the population. We hypothesized that the proportion of the population discontinuing HAART has changed over time and is associated with markers of disease stage. We further hypothesized that short and limited discontinuation with resumption of HAART would not affect CD4 cell count. Current guidelines suggest a conservative approach to treatment; thus, clinicians are starting to recommend discontinuing HAART among those with relatively high CD4 cell counts and low HIV RNA levels. The consequences of such discontinuation are not known, however. Structured treatment interruption (STI) strategies are being tested in clinical trials but have not yet yielded sufficient data for translation into clinical practice. Using historical information in a cohort of HAART users may provide insight.
Abstract
Objective: Identify the determinants and consequences of interrupting and discontinuing highly active antiretroviral therapy (HAART) among a population-based cohort of HIV-infected men.
Methods: Longitudinal analyses were applied to 2916 person-visit pairs (589 men) of continuous HAART use, 243 person-visit pairs (154 men) during which HAART was interrupted, and 151 person-visit pairs (130 men) in which HAART was discontinued by the second visit. HIV RNA increase was defined as ≥1 log10 copies/mL across the visit pairs.
Results: Younger age, black race, geographic location, higher HIV RNA level, depression, shorter time on HAART, lower medication adherence, and not taking a lamivudine-containing regimen predicted interrupting HAART use. Younger age, higher HIV RNA level, depression, and taking an abacavir- or lopinavir-containing regimen predicted discontinuing HAART. Among men with ≤1000 HIV RNA copies/mL, approximately 5% of those who interrupted HAART for ≤7 days and those who continued HAART had an HIV RNA increase. Men with longer interruptions and HAART discontinuers had significantly higher rates of HIV RNA increases (35.7% and 70.5%, respectively). Discontinuation and long interruptions resulted in lower CD4 cell counts.
Among those interrupting HAART from April 1999 onward, 44.7% stopped all antiretrovirals for <4 days the last time, 25.0% stopped for 4 to 7 days, and 30.3% stopped for >7 days. Compared with continuing HAART, the independent predictors for interrupting HAART for ≤7 days were younger age (OR = 1.30, 95% CI: 1.02, 1.65), black race (OR = 2.42, 95% CI: 1.23, 4.74), CES-D score ≥16 (OR = 2.17, 95% CI: 1.26, 3.73), and lower adherence to HAART (OR = 4.53, 95% CI: 2.66, 7.72). Those whose HAART regimen contained 3TC were less likely to interrupt therapy for ≤7 days (OR = 0.44, 95% CI: 0.25, 0.77). Predictors of missing all antiretrovirals for >7 days (40 person-visit pairs) were lower CD4 cell count (OR = 1.72, 95% CI: 1.08, 2.72), higher HIV RNA level (OR = 1.64, 95% CI: 1.22, 2.21), and CES-D score ≥16 (OR = 2.27, 95% CI: 1.03, 4.98).
HAART discontinuers were significantly more likely to report stopping because of side effects than HAART interrupters: 58% versus 34%, respectively (P < 0.001). Also, 50.5% of the discontinuers reported that stopping was a result of their physician's recommendation compared with 32.6% of interrupters (P < 0.001). The proportion of discontinuers reporting discontinuation of HAART as a personal decision was similar to that of interrupters (33% and 30%, respectively, P = 0.505), however.
Information on physician concordance for interruptions was collected since April 2000. Overall, 32.6% of the group who interrupted HAART reported that the interruption was prescribed by their physician. The extent of physician concordance differed by the length of the interruption: 20.3% of interruptions for ≤7 days were prescribed by physicians compared with 58.6% of interruptions for >7 days (P < 0.001).
Consequences of Interruption and Discontinuation of HAART:
Among individuals with ≤1000 HIV RNA copies/mL at Vi, 5.2% of the men who continued HAART use had a ≥1 log10 HIV RNA increase in the next 6 months. Such increases were more likely in those interrupting or discontinuing HAART than in those continuing HAART (Table 3). The increase in HIV RNA among those interrupting HAART was mostly driven by those who stopped antiretroviral therapy for >7 days (35.7% had a ≥1 log10 HIV RNA increase; OR = 10.07, P < 0.001 compared with continuing HAART). Only 5.4% of those interrupting HAART for <7 days had such HIV RNA increases.
Among those with 1001 to 10,000 HIV RNA copies/mL at Vi, less than 3% of those interrupting or continuing HAART had a ≥1 log10 HIV RNA increase. Only those who discontinued HAART were significantly (P < 0.001) more likely to have such an HIV RNA increase.
Those who discontinued HAART also had changes in CD4 cell count of -13.2% (P < 0.001), -5.3% (P = 0.10), and -11.7% (P = 0.028) in the 3 HIV RNA strata, respectively, representing significant differences from those who continued HAART. The consequences of interrupting and discontinuing HAART did not change when adjusted for age and race (data not shown).
Conclusions: Host characteristics play a role in short interruptions, whereas longer interruptions may be clinically indicated. These longer stoppages had further virologic and immunologic consequences, however.
MORE RESULTS
A total of 687 MACS participants initiated HAART from April 1997 to September 2001 and contributed 3950 person-visit pairs.
The percentage continuing HAART remained stable and ranged from 85.8% to 90.3% over time. The percentage interrupting HAART decreased from 10.5% in 1997 to 5.2% in 1999 and then increased to 7.7% in 2001. This inflection in the proportion interrupting HAART over time was significant (P = 0.013 for the quadratic term). The percentage discontinuing HAART increased from 2.9% in 1997 to 6.5% in 2001, with a significant linear trend (P = 0.016). The median time off HAART in those discontinuing HAART was 61 days.
Univariately, younger age (P = 0.001), black race (P < 0.001), lower CD4 cell count (P = 0.011), higher HIV RNA level (P < 0.001), CES-D score ≥16 (P < 0.001), shorter time on HAART (P = 0.004), and not taking 3TC (P = 0.004) predicted interrupting HAART. Interruption differed by geographic location as well; those in Baltimore and Chicago were slightly more at risk for interrupting HAART than those in Pittsburgh and Los Angeles.
With the exception of CD4 cell count, these factors remained independent predictors of interrupting HAART. After 1998, when adherence data were ascertained, men with lower adherence (<100%) were more likely to interrupt HAART in the following 6 months (odds ratio [OR] = 3.52, 95% confidence interval (CI): 2.18, 5.68; from the multivariate model). When adherence was included in the model, younger age and shorter time on HAART were no longer statistically significant, because younger age was associated with nonadherence (P = 0.004) and the restriction to after 1998 removed those with shorter times on HAART.
Multivariately, CD4 cell count and using a regimen containing amprenavir did not independently predict discontinuing HAART. Restricting the analysis to data collected after 1998, <100% adherence predicted discontinuing HAART univariately (OR = 2.02, 95% CI: 1.20, 3.39). After controlling for other determinants, the effect of lower adherence was slightly diminished and was not statistically significant (OR = 1.62, 95% CI: 0.97, 2.71).
The average percent increases in CD4 cell count over 6 months for the continuing HAART group were 7.9%, 5.3%, and 5.5% for those with HIV RNA levels ≤1000, 1001 to 10,000, and >10,000 copies/mL at visit 1, respectively. Average percent increases in CD4 cell count for those interrupting HAART overall did not significantly differ from those for the HAART continuers. The mean percent changes in CD4 cell count for those interrupting HAART for ≤7 days were 13.7% (P = 0.152 compared with continuing HAART), 4.3% (P = 0.893), and -7.4% (P = 0.106) in the 3 HIV RNA strata, respectively. Those who interrupted HAART for >7 days also had a similar mean percentage of CD4 changes compared with the continuing HAART group when starting with ≤1000 HIV RNA copies/mL (13.3%; P = 0.552) and 1001 to 10,000 HIV RNA copies/ml (4.2%; P = 0.897). The mean percent change in CD4 for those who interrupted HAART for >7 days was -11.5% (P = 0.01) for those who had an HIV RNA level >10,000 copies/mL at Vi, however.
To assess whether discontinuation had longer consequences, we compared the 78% of the interrupters and the 42% of the discontinuers who resumed HAART from Vi+1 to Vi+2 and for whom we had biomarker data at Vi+2 with those who continuously used HAART. Although few of those who discontinued and resumed HAART had any subsequent increase in HIV RNA levels from Vi+1 to Vi+2 (data not shown), the discontinuers still were more likely to have a ≥1 log10 HIV RNA increase at Vi+2 as compared with that measured at Vi (compared with continuous HAART users; OR = 2.03, 95% CI: 0.72, 5.72). Similarly, although their percent change in CD4 cell count from Vi+1 to Vi+2 (ie, after resuming use of HAART) was similar to that of those who continuously used HAART, it did not compensate for the decrement observed from Vi to Vi+1. Whereas the continuous HAART users had an annual increase of 10.6% (95% CI: 9.2, 12.0) on average by Vi+2, the discontinuers overall had an annualized loss of 1.3% of their Vi CD4 cell count at Vi+2, representing a significant (P = 0.02) difference in the change of CD4 cell count. Compared with those who continuously used HAART, there were no significant differences in the change of HIV RNA level and CD4 cell count at Vi+2 for those who interrupted therapy between Vi and Vi+1.
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