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25% of Women in WIHS Stop HAART for at least 6 Months
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--factors for women stopping HAART in WIHS
"Factors and Temporal Trends Associated With Highly Active Antiretroviral Therapy Discontinuation in the Women's Interagency HIV Study"
JAIDS Journal of Acquired Immune Deficiency Syndromes
1 April 2005
25% of women discontinued HAART for at least 6 months during study follow-up of 5 years...discontinuation rates were higher in recent years of follow-up compared to previously
women who discontinued were more likely to be Latina (35% vs. 24%) and less likely to be white
women who discontinued HAART were more likely to be depressed, to have had AIDS, lower initial CD4 counts increases on HAART, higher viral load...suggesting that women may be more likely to discontinue HAART if the viral load or CD4 response are not very successful
the authors suggest that access to treatment for depression may be helpful; that adherence is associated with depressive symptoms, and it is therefore possible that individuals became depressed because their lack of adherence led to therapeutic failure and elevated HIV RNA levels.
authors: Ahdieh-Grant, Linda PhD, MPH*; Tarwater, Patrick M PhD ; Schneider, Michael F MS*; Anastos, Kathryn MDà; Cohen, Mardge MD¤; Khalsa, Ann MDa; Minkoff, Howard MD¦; Young, Mary MD#; Greenblatt, Ruth M MD**
From the *Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; University of Texas School of Public Health, Houston, TX; àMontefiore Medical Center, Bronx, NY; ¤Cook County Hospital, Chicago, IL; aUniversity of Southern California School of Medicine, Los Angeles, CA; ¦Maimonides Medical Center, Brooklyn, NY; #Georgetown University Medical Center, Washington, DC; and **Departments of Medicine and Epidemiology, University of California, San Francisco, CA.
The study was based in the WIHS, a multisite cohort study of the natural history of HIV infection in women. WIHS is an inner city longitudinal study of women. Participants were recruited from October 1994 through November 1995, during which time 2059 HIV-seropositive and 569 HIV-seronegative women were enrolled at 6 sites. WIHS participants were interviewed every 6 months after an initial baseline visit. Blood specimens were collected for ascertainment of CD4 cell counts and plasma HIV RNA levels.
Since its introduction in late 1995, the success of highly active antiretroviral therapy (HAART) for extending AIDS-free survival and lowering AIDS-related mortality rates has been well-documented and widely acknowledged. In recent years, the challenges of adherence to complex regimens and failures of sustaining immunologic and virologic responses have come to the forefront of discussions regarding antiretro-viral treatment, and it is now generally recognized that long-term adherence to antiretroviral therapies (ARTs) is closely related to the occurrence of adverse effects. The risks of potentially severe adverse effects influence decisions regarding initiation of HAART in asymptomatic patients and regimen switching among patients on therapy. Adverse effects may also influence decisions to discontinue HAART.
The primary purpose of the current analysis was to identify temporal trends in discontinuation by comparing the hazard of HAART discontinuation in 3 consecutive periods in the era during which the benefits of HAART have been clearly established. Period 1 was defined as October 1, 1995 to March 31, 1998; period 2 was defined as April 1, 1998 to June 30, 1999; and period 3 was defined as July 1, 1999 to September 30, 2000. Periods were chosen to create an approximately equal number of at-risk person-years in each period.
WIHS investigators have previously shown that the prevalence of HAART discontinuation increased from 3% in late 1996 to 9% in mid-1999 in the Women's Interagency HIV Study (WIHS). Using longitudinal data that were prospectively collected through September 2000 from the WIHS, we found that nearly 25% of women discontinued HAART for at least 6 months during study follow-up of 5 years. After controlling for time since initiation of HAART and associated factors, we found that the risk of discontinuation was over 1.5 times greater after 1998 as compared with the prior 2.5 years, suggestive that discontinuation has become more acceptable as the burden of frequently associated side effects has become more recognized. Furthermore, Latina and African-American women were more likely than white women to discontinue HAART, an association that was significant in the initial 2 calendar periods. Compared with those who remained on HAART, women who discontinued were more likely to be Latina (35% vs. 24%) and less likely to be white (10% vs. 21%) (P < 0.001). Given that the distribution of ethnicity did not change between the calendar periods, this observation is of concern and warrants additional investigation.
In calendar-stratified analyses, investigators found that relative to white ethnicity, African-American (RH = 4.11) or Latina ethnicity (RH = 4.32) and injection drug use (RH = 4.15) were significantly associated with HAART discontinuation in the first calendar period and that ethnicity (RH = 2.86 for African-American ethnicity and RH = 5.00 for Latina ethnicity) and higher pre-HAART HIV RNA levels (RH = 1.35) were significantly associated with HAART discontinuation in the second calendar period. In the last calendar period, no factors were significantly associated with HAART discontinuation in the multivariate analysis.
Factors that were examined for association with HAART discontinuation included ethnicity, pre-HAART age, pre-HAART CD4 cell count, pre-HAART HIV RNA, pre-HAART antiretroviral experience, pre-HAART depressive symptom status, pre-HAART self-reported health status, pre-HAART report of injection drug use, pre-HAART AIDS, pre-HAART pregnancy status, complexity of the initial HAART regimen (eg, drug classes and number of drugs), and initial immunologic and virologic changes.
Discontinuers were more likely to have had AIDS (P = 0.032). Discontinuers also had a significantly (P = 0.010) lower median increase in CD4 cell count from pre-HAART initiation to the first on-HAART visit of 24 cells/ƒÊL, nearly 50% lower than the median increase for those who continued on HAART. Likewise, 28% of the discontinuers' HIV RNA levels remained or became undetectable compared with 38% of those who stayed on HAART (P = 0.011).
A multivariate analysis of post-HAART initiation exposures found that high HIV RNA levels (relative hazard [RH] = 1.36, P < 0.001) and high depressive symptom scores (RH = 1.53, P = 0.012) were associated with HAART discontinuation. The adjusted hazard of discontinuation was higher in the 2 most recent calendar periods compared with the first (RH = 1.61, P = 0.026; RH = 1.56, P = 0.074, respectively). The increasing risk of HAART discontinuation in recent calendar periods and changes in the clinical factors associated with discontinuation reflect ongoing and dynamic shifts in the approach to HAART utilization.
The importance of psychosocial factors in modulating the risk of discontinuation is not unexpected, and our results suggest that factors other than response to treatment play an important role in predicting HAART discontinuation. Prior studies have shown that adherence is associated with depressive symptoms, and it is therefore possible that individuals became depressed because their lack of adherence led to therapeutic failure and elevated HIV RNA levels. Furthermore, given that depressive symptoms can be evaluated and depression can be treated, our findings emphasize that access to treatment of depression may have important implications for the management of HIV-infected individuals on ART.
Consistent with the current findings, recent studies by Mocroft et al and Monforte et al found that individuals with higher recent HIV RNA levels were significantly more likely to discontinue HAART as compared with those with lower HIV RNA levels. This association between high HIV RNA levels and the discontinuation of HAART suggests that individuals discontinue regimens that are not successfully suppressing HIV RNA. Mocroft et al also found that women and older individuals were less likely to discontinue HAART, as were individuals who used nelfinavir-containing regimens. We did not find any significant association between HAART discontinuation and the number of drugs or the drug classes in the initial HAART regimen. A recent analysis by Dorrucci et al similarly found no difference in the time to discontinuation by specific type of regimen.
AUTHOR CONCLUSIONS: There are several notable strengths of the current study. First, it involved a large number of individuals who initiated HAART and were followed for up to 5 years. Information on ART use was updated every 6 months based on self-report; the validity of such self-reported data has been previously demonstrated. Second, although several previous studies examined the risk of discontinuation, only 1 distinguished between discontinuation of all ART as compared with the modification of certain components of the HAART regimen. Consistent with our findings, this study found that 26% of 556 participants discontinued HAART. Third, the cohort study on which this analysis was based collects data on a prospective longitudinal basis as compared with previous studies that have relied on retrospective chart review.
Beyond these strengths, our analysis contributes to the literature on HAART discontinuation by applying methods that allow for the incorporation of the duration of HAART use. Although the use of calendar period as a time-dependent external variable has been established for the purpose of estimating population effectiveness, we have applied the methodology to evaluate temporal trends in HAART discontinuation among women with equal durations of HAART use.
In summary, our understanding of the long-term clinical implications of ART is greatly facilitated by the existence of large cohort studies in which the date of HAART initiation is well defined. Studies with ongoing follow-up of HIV-infected individuals allow for the investigation of landmark events in the treated history of HIV infection, including HAART initiation, switching between antiretroviral regimens, treatment response and failure, and HAART discontinuation. Furthermore, such studies are essential to track changes in the anticipated increase in rates of those toxicities associated with the prolonged use of HAART.
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