Introduction
After several years of impressive gains in survival following the introduction of potent antiretroviral therapies (ART), recent discussions have turned to the rather urgent question of the long-term clinical implications of these medications. Such discourse has resulted from increasing recognition of the toxicities and side-effects often associated with such therapies, leading some patients and their clinicians to consider therapy discontinuation. Even in the absence of side-effects, discontinuation of therapy in a structured and controlled fashion has been recently proposed as an approach to bolster control of HIV [1]. In this report, we examined the factors associated with and consequent to discontinuing potent ART in a large cohort of HIV-infected women in the USA.
A major challenge, as well as one of the most critical aspects of successful treatment for individuals infected with HIV, is that the need for ART might be life-long. It is not expected, however, that individuals will remain on the same regimen indefinitely, as development of drug resistance will require changes in therapy over time. Current guidelines suggest that in patients with few remaining options of ART, continued treatment for as long as possible is advised if there is an observed clinical and immunological benefit, notwithstanding persistent viraemia. Additionally, however, there is increasing acknowledgement that toxicities may necessitate drug interruption, dose reduction, or substitution of one or more of the drug components in a regimen [2].
The effectiveness of potent ART at the population level has been demonstrated in several cohorts, including the Women's Interagency HIV Study (WIHS), a prospective multi-centre study in the USA [3]. The ongoing utilization of these therapies is therefore a central concern for the individual patient, as well as for the prevention of emergent resistance. It has been shown previously that the majority of WIHS participants reporting potent ART at a given visit continue to report its ongoing use at subsequent visits [4]. There have been, however, an increasing number of potent ART users who either downshift to non-potent ART or who discontinue ART completely. The factors predictive of such discontinuation have not been extensively described, although two recent studies [5,6] found that high HIV RNA levels predicted discontinuation. Furthermore, the documentation of immunological and virological consequences of potent ART discontinuation continues to be of interest.
We have previously quantified the central role of CD4 cell count and HIV RNA level in predicting potent ART initiation at different calendar times [4] and the salutary impact of potent ART on these key markers of HIV disease has been demonstrated in both clinical trials [7-9] and cohort studies [3,10]. Our goal here was to examine whether these markers were also associated with the discontinuation of therapy, specifically, to describe the extent to which CD4 cell count and HIV RNA levels predict discontinuation as well as the short-term consequences of discontinuation on these key markers.
As compared to potent ART initiation, characterization of potent ART discontinuation is more complex and the factors of interest (e.g., inadequate response to therapy) are more difficult to quantify. It is unlikely that sustained high HIV RNA levels and low CD4 cell counts due to drug resistance or less than optimal adherence (i.e., therapy failure) are the sole or even primary reasons for ART discontinuation. However, given the pivotal role of these markers in predicting ART initiation and in tracking disease progression, it was of interest to investigate the extent to which they predict potent ART discontinuation. More importantly, especially for clinicians treating HIV-infected patients, it was of interest to investigate the extent to which CD4 cell count and HIV RNA are impacted by discontinuation of potent ART. We emphasize the distinction between switching ART medications while remaining on potent ART versus downshifting or full discontinuation of all ART. The frequency and correlates of the former - antiretroviral switching - in the WIHS is currently under extensive investigation [11].
In summary, we investigated trends related to the discontinuation of potent ART over a 3 year period among participants in the WIHS and characterized these trends according to immunological and virological parameters. Understanding the features of potent ART discontinuation and its consequences at the population level is critical, given increasing concerns of significant toxicities due to prolonged therapy use.
Methods
Data collection and study population
This study was based in the WIHS, an ongoing multi-site study of the natural history of HIV infection in women [12]. During a 13 month recruitment period from October 1994 through November 1995, 2059 HIV-seropositive and 569 HIV-seronegative women were enrolled in five cities (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay Area, California; Washington DC Metropolitan Area). After a baseline visit, participants have had follow-up visits every 6 months, consisting of an extensive interviewer-administered questionnaire, a physical examination, and phlebotomy for the determination of CD4 cell count and plasma HIV RNA level. T-cell subsets were determined by immunofluorescence using flow cytometry in laboratories participating in the NIAID NIH Quality Assurance Program. Plasma HIV RNA level was measured using NucliSens (Organon Teknika, Durham, North Carolina, USA), in laboratories participating in the NIAID NIH VQA Program, with a lower threshold for detection of 400 copies/ml at study visits completed after October 1997.
At each visit, participants were shown photo-medication cards and were asked brand and generic drug names of the antiretroviral medications they used since their previous visit and drugs they were currently using. Interventions were not provided by the study itself and patients may have seen their treating physician in between study visits. Therapy regimens were categorized as non-potent ART or potent ART. Potent ART was defined by: (i) two or more nucleoside analogue reverse transcriptase inhibitors (NRTI) in combination with at least one protease inhibitor (PI) or one non-NRTI (NNRTI) (93% of observations classified as potent ART); (ii) one NRTI in combination with at least one PI and at least one NNRTI (5%); (iii) a regimen containing ritonavir and saquinavir in combination with one NRTI and no NNRTI (2%); and (iv) an abacavir-containing regimen of three or more NRTI in the absence of both PI and NNRTI (< 0.5%). Combinations of zidovudine and stavudine with either a PI or NNRTI were not considered potent ART. All other combinations of drugs not listed above were considered to be non-potent ART and changes from potent ART to any of these combinations are referred to hereafter as 'downshifting'. Discontinuation was reserved to describe transitions from potent ART to no use of antiretroviral therapy whatsoever.
The study population for this analysis included WIHS participants who reported use of potent ART prior to 30 September 1999. At each 6 month calendar period after 1 October 1996 (the approximate date of the introduction of potent ART), the pertinent sample for the analysis was composed of those individuals who reported any use of potent ART since their last visit. Current therapy use at the time of each visit was assessed for all individuals who reported potent ART since their last visit. Therefore, participants could transition at their current visit to one of three therapy groups, each representing a distinct outcome of interest: continuing potent ART (includes individuals who switched from one potent regimen to another); changing from potent ART to non-potent combination ART (downshifting); and discontinuing all ART.
Statistical methods
The initial step in the analysis was to compare selected variables at the visit preceding potent ART initiation between the three groups. Variables examined included CD4 cell count, HIV RNA level, clinical site at which the subject was seen, report of injecting drug use, age, and prior exposure to antiretroviral therapy. We also examined the number of visits contributed after potent ART initiation for each group. Subsequent analyses focused on the immunological and virological predictors and consequences of both downshifting and discontinuing.
Next, for each calendar period after October 1996, we determined the number of women who had reported potent ART in the previous 6 months according to their current therapy group. The proportion of individuals in each group was determined and the Mantel-Haenszel chi square test was used to evaluate a possible trend of increasing non-continuation of potent ART (i.e., downshifting or discontinuing) over time.
After documenting the number of women who transitioned from potent ART to other therapy groups, the next step was to characterize these transitions by CD4 cell count and HIV RNA. Fig. 1 describes the algorithm used to ascertain marker levels and changes in marker levels at two time periods: prior to and following ART discontinuation, respectively. For these analyses, we considered the four most recent calendar periods only, October 1997 to March 1998 (period 1), April 1998 to September 1998 (period 2), October 1998 to March 1999 (period 3), and April 1999 to September 1999 (period 4). Therapy use was assessed at the current visit (v0) and since the last visit (between v-1 and v0).
Predictors of discontinuation
Exposure
To examine factors related to the prediction of ART discontinuation, we determined CD4 cell counts and HIV RNA levels 6 months prior to the respective transitions (v-1).
Outcome
As described, there were three possible outcomes at each transition. For this analysis, we focused on the predictors of discontinuing all ART versus continuing potent ART and excluded individuals who downshifted to non-potent ART.
Consequences of discontinuation
Exposure
To examine the consequences of discontinuation, we investigated the short-term effect of both downshifting to non-potent ART and of discontinuing all ART in terms of subsequent CD4 cell counts and HIV RNA markers. The exposure of interest was classified as either continual use of potent ART, downshifting to non-potent ART, and discontinuing all ART. It was assessed at v0 among individuals reporting the use of potent ART between v-1 and v0.
Individuals who reported that they discontinued one or more drugs at v0 due to unpleasant side-effects or because the drug was toxic were classified as having discontinued due to side-effects.
Outcome
The outcomes of interest for this analysis were 6 month changes in CD4 cell count and HIV RNA levels subsequent to the report of potent ART. Mean CD4 cell count change was computed as the difference between respective values measured at v-1 and v0. For HIV RNA, we computed the proportion of individuals who demonstrated an increase in viral load. A viral load increase was defined as a measurement of undetectable HIV RNA (< 400 copies/ml) at visit v-1 and detectable HIV RNA at visit v0. A 1 log10 increase in HIV RNA between visits was also defined as a viral load increase. Linear regression was used to estimate mean differences of CD4 cell count changes between those who continued on potent ART (defined as the reference group) and both those individuals who downshifted to non-potent ART and those who discontinued all ART. Similarly, logistic regression was used to compare the odds of HIV RNA increase between these same groups.
To evaluate the association between reported side-effects and the consequences of discontinuation, we compared median CD4 cell count changes between those reporting and those not reporting side-effects as the reason for therapy discontinuation.
Results
A total of 1072 HIV-infected women initiated potent ART between October 1994 and September 1999, of whom 1058 reported the use of potent ART after October 1996. Among the later, 223 (21.1%) discontinued all ART at some time by September 1999; 289 (27.3%) were always on therapy, but downshifted to mono- or combination therapy; and 546 (51.6%) persistently took potent ART after initiation. These three groups of participants were similar in respect to site, age (overall median, 38.3 years), injecting drug use (4.9% overall), CD4 cell count (overall median, 261 × 106/l), and prior ART experience (84.5% overall). However, HIV RNA levels were highest in individuals who downshifted to non-potent ART or who ever discontinued ART. This observation underscored the need to investigate these relationships longitudinally, i.e., HIV RNA levels at the time of ART discontinuation. The median number of visits after potent ART initiation among individuals who continued potent ART, individuals who downshifted to non-potent ART, and individuals who discontinued all ART was 3, 5, and 4, respectively.
The overall rates of 6 month downshifting and discontinuation were 10.0% and 6.7%, respectively (Table 1). The proportion of individuals discontinuing all ART increased from 2.9% (October 1996 to March 1997) to 9.1% (April 1999 to September 1999), a trend that was statistically significant (P < 0.001). In contrast, there was a significant (P < 0.001) and steeper decrease in the percentage of individuals downshifting to non-potent ART, from 17.7% (October 1996 to March 1997) to 4.4% (April 1999 to September 1999). Because there was little discontinuation during the first two periods, subsequent analyses focused on the four most recent periods only. During the four most recent periods, median CD4 cell counts of potent ART users 6 months prior to continuing potent ART, downshifting to non-potent ART, or discontinuing all ART were 352, 292, and 320 × 106/l, respectively. Similarly, during the three most recent calendar periods where HIV RNA testing with a threshold of 400 copies/ml was available, the proportion of potent ART users with HIV RNA below this level 6 months prior to continuing potent ART, downshifting to non-potent ART, or discontinuing all ART was 45.3, 27.6, and 19.6%, respectively.
Due to intense efforts and attention at the local study sites, the retention rate in the WIHS has remained extremely high [13]. Those individuals who initiated potent ART and who were lost to follow-up prior to potent ART discontinuation or the end of study follow-up were similar to those not lost to follow-up with regard to median age and injecting drug use at potent ART initiation. However, as expected, their median CD4 cell count was lower and their median HIV RNA level was higher, indicating more advanced disease progression. We hypothesize that given that those lost to follow-up were sicker (i.e., higher HIV RNA levels and lower CD4 cell counts) than those not lost to follow-up, their full retention would have resulted in higher overall discontinuation rates.
Predictors of discontinuation
There was no consistent association between CD4 cell count and ART discontinuation, although in the two most recent periods there was a suggestion that lower CD4 cell counts were associated with increased discontinuation: in period 4 12.3% of individuals with CD4 cell counts < 200 × 106/l discontinued potent ART, compared to 5.7% among individuals with CD4 cell counts > 500 × 106/l (Fig. 2a). With regard to HIV RNA levels, higher HIV RNA levels were associated with a higher proportion of discontinuation (Fig. 2b) with significant trends detected in all calendar periods: period 2 (P = 0.005), period 3 (P = 0.015), and period 4 (P < 0.001). Women with HIV RNA levels < 400 copies/ml were least likely to discontinue all ART.
Consequences of discontinuation
The group that continued on potent ART experienced CD4 cell count increases in each 6 month calendar period (Table 2). Compared to this group, those who discontinued all ART experienced decreases in CD4 cell counts at all four calendar periods with mean differences in CD4 cell count changes of -70.5 × 106/l (P = 0.005), -83.1 × 106/l (P = 0.001), -57.3 × 106/l (P = 0.031), and -61.6 × 106/l (P = 0.003), for periods 1, 2, 3, and 4 respectively. The group that downshifted to non-potent ART generally experienced small increases in CD4 cell count that were not significantly different from the reference group.
We found that individuals who discontinued all ART were more likely to experience increases in HIV RNA at the time of discontinuation compared both to individuals who continued on potent ART and to individuals who downshifted to non-potent ART (Table 3). Compared to those continuing potent ART, the group that discontinued all ART experienced increases in HIV RNA in all calendar periods, with odds ratios of 2.13 (P = 0.119), 4.09 (P < 0.001), and 4.23 (P < 0.001) for periods 2, 3 and 4, respectively. However, the group that downshifted to non-potent ART was not more likely to experience an increase in HIV RNA, compared to those continuing potent ART.
We found that more than one-third of individuals who discontinued all ART reported side-effects (Table 4, 45.3% in period 3 and 35.9% in period 4). Furthermore, the median CD4 cell count decline associated with discontinuation among individuals reporting side-effects was smaller than that of individuals not reporting side-effects (P = 0.147).
Discussion
Although potent ART has altered the prognosis of HIV infection by extending AIDS-free survival and decreasing rates of mortality, serious concerns have been raised regarding regimen complexity, treatment failure due to the emergence of resistant strains, and drug toxicities. It is increasingly acknowledged that certain of these adverse events are severe [14] and for some individuals they may reach a level of intolerability that leads to therapy discontinuation.
Among women being followed in the WIHS, we documented an upward trend in the rates of potent ART discontinuation. Individuals with lower RNA levels were less likely to discontinue ART. However, CD4 cell count was not consistently associated, although there was a suggestion that higher counts were associated with lower rates of discontinuation. Further, individuals who discontinued potent ART experienced both CD4 cell count declines and HIV RNA level increases. Side-effects were the most frequently cited reason for ART discontinuation and CD4 cell count declines were smaller among those who discontinued due to side-effects compared to those who discontinued for other reasons.
A recent cross-sectional analysis found that among 126 individuals who discontinued potent ART, the most frequent reasons were side-effects and patient's fear of side-effects [15], observations that we confirmed. The role of immunological and virological markers was not evaluated [15]. In keeping with our observations, a study from the Netherlands of 99 individuals followed for 450 days found that the most common reason for discontinuation was increasing viral load [5]. Being non-naive to ART and having a lower CD4 cell count at potent ART initiation were also associated. Most recently, Monforte et al. followed 862 potent ART users for 45 weeks and noted that more than 35% of individuals discontinued their regimens. The two primary reasons for discontinuation were toxicity and treatment failure. Higher HIV RNA levels were associated only with discontinuation due to failure [16]. Our study extends these findings by its focus on the role of markers of disease progression and its examination of the consequences of discontinuation in a large cohort of individuals followed for a 3 year period. Future studies to examine the association of compliance and potent ART discontinuation will be of interest. We have recently reported that higher levels of adherence are associated with elevated CD4 cell counts and undetectable HIV RNA levels [17].
In this paper, we document the acute deleterious virological and immunological effects of discontinuing all ART. In contrast, we did not observe a parallel negative effect due to downshifting to non-potent ART. This observation should not be interpreted as an indication that this practice is appropriate and may indicate that it simply takes longer than 3 months for the putative deleterious effects of downshifting to manifest. In fact, it has been suggested that downshifting may be more harmful than complete discontinuation with regard to the emergence of resistance virus [14]. It is likely that this concern is the impetus for the decreased frequency of downshifting over time, with the proportion of individuals downshifting to non-potent ART decreasing from 11.3% to 4.4% in our cohort (Table 1).
Several small, highly controlled studies have indicated that short-term monitored interruption of potent ART may lead to improved immune control of HIV, but the evidence is as yet inconclusive and the follow-up in these studies has been relatively short [18-20]. Prior work has indicated that discontinuation of ART is associated with a significant increase in HIV viraemia, even in persons with non-detectable viral loads for an extended period [21,22]. Although we could not formally examine structured therapy interruption, our results indicate that discontinuation of potent ART is associated with short-term virologic and immunologic deterioration. Of interest, this deterioration was less pronounced in participants who stopped because of toxicity or side-effects. Our data suggest that structured intermittent therapy will require close supervision and ultimately may be of benefit to a selected and well-characterized subgroup of individuals with sustained viral suppression. Additional controlled studies of such regimens of structured interruption will be of great interest and importance.
The discontinuation of potent ART may result from diametrically opposite reasons: when therapy failure (i.e., high HIV RNA levels and declining CD4 cell counts) renders the side-effects of an ineffective treatment unacceptable and when therapy success causes individuals who are feeling well to discontinue in order to preclude potential toxicities. Were both scenarios to be at play in our study population, we would have observed a U-shaped pattern between HIV RNA level and discontinuation, rather than the linear one illustrated in Fig 2. As mentioned above, our data suggest that the presence or absence of side-effects is associated with the consequences of discontinuation, i.e., CD4 cell count decline is more pronounced among those discontinuing potent ART without side-effects (Table 3).
It is plausible that among individuals for whom HAART has been very successful (i.e., sustained viral suppression and substantial increases in CD4 cell counts), discontinuation may be an option with beneficial consequences. However, of the 26 individuals in our study who discontinued potent ART with HIV RNA levels < 400 copies/ml and with a median CD4 cell count of 402 × 106/l, the absolute decline in CD4 cell counts was 155 × 106/l and the proportional decline was 27% (data not shown). This suggests that potent ART discontinuation should be considered only at substantially higher CD4 cell counts. Of importance in this respect, we noted that individuals with higher CD4 cell counts (i.e., > 700 × 106/l) at the time of discontinuation experienced declines that were less than those experienced by individuals who discontinued at lower CD4 cell counts.
A fuller description of these patterns will require the ongoing and longer follow-up of our cohort and the analysis of larger numbers of individuals who discontinue potent ART. Such additional investigations will allow for a more complete understanding of the association between adverse events and their impact on potent ART discontinuation. Such understanding is critical given that, in spite of increasing concerns regarding their use, potent ART is the most effective means to treat HIV disease.
Acknowledgements
Data in this manuscript were collected by the WIHS Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (K. Anastos); Brooklyn, NY (H. Minkoff); Washington DC Metropolitan Consortium (M. Young); The Connie Wofsy Study Consortium of Northern California (R. Greenblatt, H. Palacio); Los Angeles County/Southern California Consortium (A. Levine); Chicago Consortium (M. Cohen); Data Coordinating Center (A. Muñoz, S. J. Gange).
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