Combination antiretroviral therapy (ART), consisting of three or more drugs from at least two classes, provides durable virologic and immunologic responses, leading to dramatic reductions in rates of AIDS and death, in HIV-positive individuals [1,2]. However, treatment is lifelong and can lead to toxicities that vary according to the drugs used. The risk of drug resistance mutations, which are most likely to occur when adherence to treatment is incomplete, also varies between different drugs.
The most recent US guidelines recommend that an ART regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI), ritonavir-boosted protease inhibitor or recently raltegravir, an integrase inhibitor, should be started when the CD4 cell count falls below 500 cells/μl [3,4]. Recently available regimens include more potent and less toxic drugs with simpler dosing schedules and longer half-lives, which has improved treatment response and adherence to therapy [5–8]. However, ART regimens often need to be replaced because of virological failure or toxicity, or for simplification [3,9,10].
On the basis of a large dataset assembled through a collaboration between cohort studies of HIV-positive individuals (ART Cohort Collaboration), we estimated the cumulative incidence of first-regimen modification (switching to a different drug class, substitution/addition within class, or switch to a nonstandard regimen), treatment interruption or death, in patients who were antiretroviral-naive when they started ART. We also examined associations of patient and regimen characteristics with these events.
Cohorts and patients
The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of cohort studies from Europe and North America that was established with the aim of describing the prognosis of antiretroviral-naive patients starting ART (http://http://www.art-cohort-collaboration.org). Briefly, it includes HIV-1-positive patients aged at least 16 years who start ART with a combination of at least three drugs, including NRTIs, protease inhibitors, or NNRTIs, while antiretroviral-naive. The database was updated in September 2010.
We combined data from 18 cohorts [11–27]. Patients were included in the analyses presented here if they started ART with a regimen containing at least three antiretroviral drugs, with at least two NRTIs and a NNRTI or a ritonavir-boosted protease inhibitor, between 1 January 2002 and 30 June 2009, and remained on their initial regimen for at least 1 month (to ensure that they were genuinely taking their drugs and to exclude the subgroup who were on a regimen for a very short period of time). Because of later availability of data on treatment interruptions, start dates were 1 January 2005 for the French Hospital Database on HIV (FHDH) and Frankfurt cohorts, and 1 January 2004 for the Spanish cohort of naive HV-infected patients (CoRIS). A small number of patients were excluded because their first regimen included one of the following drugs (N = 222): etravirine, enfuvirtide, tipranavir, raltegravir; or because they received one of the following drugs at any time (N = 105): zalcitabine, alovudine, capravirine, DPC 083, delavirdine, emivirine, lodenosine, loviride, mozenavir, rilpivirine, saquinavir soft gel and vicriviroc. These exclusions were either because very few patients started ART with these drugs, or because the drugs are no longer recommended for use due to their lack of potency or toxicities.
First change in ART regimen was defined as a change of at least one antiretroviral drug (‘modification’) or cessation of all antiretroviral drugs (‘interruption’), for more than 1 month. Thus, patients who changed formulations of their treatment but not the drugs included in it, changing for example from one pill combination of tenofovir/emtricitabine and efavirenz to one pill combination of tenofovir/emtricitabine/efavirenz, were not considered to have changed their treatment. Patients who reverted to their first regimen within 1 month were analysed as having continued without modification or interruption. Treatment modifications were further categorized as change to a different drug class (from protease inhibitor to NNRTI or from NNRTI to protease inhibitor), substitution/addition within drug class, or as a switch to a nonstandard regimen when the new treatment did not include at least a NNRTI or a protease inhibitor as part of a triple or more drug regimen or a protease inhibitor with either a boosted protease inhibitor or a NNRTI in a dual regimen. Patients who changed to a different drug class at the same time they changed their NRTIs within the NRTI drug class were classified as having changed to a different drug class. The most common switches to nonstandard regimens were to abacavir or tenofovir-containing regimens of at least three NRTIs, which were assumed to be genuine treatment modifications. All other switches to nonstandard regimens were verified by the contributing cohort.
For each patient, we calculated the time from starting an eligible ART regimen to the first of the five competing events: change of drug class; substitution/addition within drug class; switch to a nonstandard regimen; regimen interruption or death before regimen change (treatment modification or interruption). In the absence of one of these events, follow-up ended at the last follow-up visit or on 30 June 2010, whichever occurred first. The cumulative incidence of these five events over time was estimated using a competing risk approach . Overall cumulative mortality (including deaths after modification/interruption) was estimated using the Kaplan–Meier method. Patients were defined as lost to follow-up if they were not seen in the 12 months prior to the cohort-specific database close date.
We estimated associations of patient characteristics at the time of starting ART (baseline), and of characteristics of the first ART regimen, with regimen modification, interruption and death using univariable and multivariable competing risk regression models . All analyses were stratified by cohort in order to take into account differences in clinical practice within the cohorts. The patient characteristics examined were: age, AIDS status, CD4 cell count, plasma viral load at baseline, HIV transmission group split by sex [MSM, male IDUs, female IDUs, male heterosexuals, female heterosexuals, male other and female other (where ‘other’ includes transmission through blood or other unknown routes)], and calendar period of initiation of ART [divided into 2002–2005 and 2006–2009, because publication of the Strategies for Management of Antiretroviral Therapy (SMART) study in 2006 could have led to change in clinical practice, particularly for patients considering interruption ]. At around the same time, boosted lopinavir was changed from capsule formulation to a tablet formulation which was better tolerated. Regimen characteristics examined were first protease inhibitor or NNRTI drug, and the NRTI backbone combination (3TC and tenofovir was combined with FTC and tenofovir). Stata version 11.0 was used for all analyses.
A total of 21 801 patients, followed up for a median of 28 months [interquartile range (IQR) 14–45], were eligible for analysis (total 55 941 patient-years). Of these, 10 242 patients (crude percentage, 47.0%) did not change their first ART regimen, 2673 (12.3%) had a class change, 4983 (22.9%) changed drugs within the same class, 1130 (5.2%) switched to a nonstandard regimen, 2346 (10.8%) interrupted treatment and 427 (2.0%) died before modification or interruption. Prior to any of these changes, patients were followed up on their first regimen for a median of 13 months (IQR 6–26), with a total 32 823 person-years follow-up on first ART regimen. Four thousand, two hundred and forty-one (19.5%) patients were lost to follow-up, with the proportion lost ranging from 2.3 to 38.0% across cohorts.
Table 1 shows patient characteristics according to initial regimen. Both men (8602/16028) and women (3751/5773) were more likely to start a protease inhibitor-based regimen than an NNRTI regimen, but the excess was greater in women. Initiation of a boosted protease inhibitor-based regimen became more frequent in later calendar years in all risk groups, except in North American cohorts, where NNRTI-based regimens were the most frequently prescribed both in 2002–2005 (2046/3230, 63.3%) and in 2006/2009 (998/1538, 64.9%). The most frequent first regimens contained either lopinavir (37% of patients) or efavirenz (35%), with efavirenz being the most commonly prescribed regimen in the earlier calendar years (4793/11740, 40.8% in 2002–2005; 2832/10061, 28.2% in 2006–2009). First NRTI backbone most commonly included emtricitabine-tenofovir (46%) or zidovudine-lamivudine (36%), but zidovudine-lamivudine was the most commonly prescribed NRTI backbone in the earlier calendar period.
Table 2 displays the frequency of types of change to first regimen, according to whether the regimen contained an NNRTI or boosted protease inhibitor. Treatment modification was common for both boosted protease inhibitor (42.4%) and NNRTI (37.6%) regimens. Although the proportions of patients who died before regimen change or interrupted treatment appeared similar for each type of initial regimen, subdistribution hazard ratios (SHRs) adjusted for cohort showed that rates of interruption and of all types of modification except class change were lower for patients initiated on an NNRTI-based regimen than on a boosted protease inhibitor regimen. Patients frequently substituted or added drugs within the same class: 2985 patients (57.0% of those who modified their treatment) in the boosted protease inhibitor group and 1998 patients (56.3% of those who modified their treatment) in the NNRTI group. One thousand, one hundred and thirty patients (5.2%) switched to a regimen not considered to be standard in current guidelines (although triple NRTI regimens were recommended during the period of follow-up) . Changes to nonstandard regimens included switches to: triple NRTI (N = 643), single drugs (N = 215), dual therapy (N = 221) and regimens containing fusion or integrase inhibitors (N = 7). Single drugs were mono NRTI, mono NNRTI, mono protease inhibitor, rarely mono boosted protease inhibitor (and very rarely mono boosted darunavir). Dual regimens were NRTI + either NRTI, NNRTI, or protease inhibitor.
Figure 1 shows that the cumulative incidence of class change (accounting for substitutions/additions within drug class, switches to nonstandard regimens, interruptions and death as competing events) rose from 7.9% [95% confidence interval (CI) 7.6–8.3] at 1 year to 14.7% [14.2–15.3] at 3 years, of substitutions/additions from 13.6% [13.2–14.1] to 26.6% [25.9–27.3], of change to nonstandard regimen from 3.8% [3.6–4.1] to 6.0% [5.7–6.4], of interruption from 7.7% [7.4–8.1] to 12.4% [11.9–12.9] and of death before regimen change from 1.3% [1.2–1.5] to 2.3% [2.0–2.5]. Estimated overall 3-year cumulative mortality, including deaths after switching or interruption, was 4.6% [4.2–4.9].
Older patients were less likely to have a class change compared to younger patients, but were more likely to substitute/add within the same drug class (Table 3). Older patients are more likely to be adherent to treatment, and show more durable virologic responses than younger patients . Examination of the reported reasons for substituting/adding within class showed that older patients were more likely to substitute because of side effects. Older patients were also less likely to interrupt treatment and more likely to die before regimen change, as were patients with AIDS before start of ART and patients with low CD4 cell counts. Patients with AIDS were less likely to switch to a nonstandard regimen. Lower CD4 cell counts were associated with higher rates of changing class and higher rates of substitutions. In analyses stratified by sex, the association of baseline CD4 cell count with interruption appeared greater in women (SHR 3.53; 95% CI 2.70–4.61 for 351–500; and 5.24; 3.99–6.88 for >500 versus ≤100 cells/μl) than men (1.26; 1.04–1.53; and 2.04; 1.67–2.51, respectively). After adjustment for other factors, IDUs and men infected through other (blood or unknown) transmission routes had lower rates of class change compared to MSM. Men in the IDU, heterosexual and ‘other’ transmission groups, and female IDUs, had lower rates of change within class than MSM. Heterosexual men had lower rates of switch to nonstandard regimen. All transmission groups, except men infected through other routes, had higher rates of interruption, and all transmission groups except heterosexuals and women infected through other routes had higher rates of death than MSM.
Compared with efavirenz, use of lopinavir was associated with higher rates of class change (SHR 1.1, 95% CI 1.0–1.3), whereas use of atazanavir was associated with lower rates of class change (0.6, 0.5–0.7), and both were associated with higher rates of substitutions (1.2, 1.1–1.3 for both). Lopinavir and other protease inhibitors had higher rates of switch to nonstandard regimen, compared to efavirenz. Nevirapine and lopinavir were associated with higher rates of interruption (1.5, 1.3–1.7; and 1.4, 1.2–1.5, respectively); and there was some evidence that lopinavir and atazanavir were associated with higher rates of death before regimen change (1.4, 1.1–1.8; and 1.4, 1.0–2.0, respectively). Similar patterns were seen in analyses of mortality up to 3 years after start of ART, including mortality after modification or interruption. Considering NRTI background, zidovudine-lamivudine, abacavir-lamivudine and other combinations were associated with higher rates of substitution/addition within class and for switches to nonstandard regimens compared to emtricitabine-tenofovir. Zidovudine-lamivudine and other NRTI backgrounds were associated with higher rates of interruption. Starting ART in 2006–2009 was associated with decreased rates of any treatment substitution (0.9, 0.8–1.0) and of switch to a nonstandard regimen (0.4, 0.3–0.4) compared to starting ART in 2002-05.
Reasons for changing ART were available for 4999 (22.9%) patients (Table 4). Side effects were the main reason for ART change (40.3%), whereas treatment failure was not commonly reported as a reason for change (7.9%). Changing class due to treatment failure was common among patients initiated on NNRTIs (39.4%), but not for patients initiated on boosted protease inhibitors (7.0%). For patients on boosted protease inhibitors, common reasons for class change, change within class, or switch to nonstandard regimen were side effects (40.0, 52.8 and 26.2%, respectively) and simplification (34.9, 18.2 and 36.2%, respectively). For patients on NNRTI, side effects were also a common reason for these changes (38.4, 57.2 and 54.1%, respectively), but simplification was not. Reasons for interruption were mainly patient's choice (i.e. decision or noncompliance, 39.6%) and side effects (18.2%). The observed higher rates of class change and changes within class in patients with lower CD4 cell counts appeared to be due to treatment failure (perhaps, lower achieved CD4 cell counts rather than virological failure) rather than to toxicity or side effects.
Among 21 801 patients followed for a median of 28 months, 11 132 (51%) modified or interrupted their first ART regimen, whereas 427 (2%) died whilst on their first regimen. The 1 and 3-year cumulative incidences of treatment modification were 25 and 47%, respectively. When modifying their treatment, 57% of patients changed their regimen within the same drug class, whereas 13% switched to a nonstandard regimen. By 3 years, 12.4% of patients had interrupted treatment: rates of interruption were markedly higher for patients infected via IDU and patients who started ART when their CD4 cell count was above the 350 cells/μl threshold recommended in treatment guidelines published during the study period . We found no evidence that rates of interruption were lower in patients who started ART more recently. Greater immunodeficiency at start of ART was associated with higher rates of class change or change within class. Compared to efavirenz, lopinavir and other protease inhibitors (excluding atazanavir) had higher rates of all types of modification and interruption, atazanavir had lower rates of class change and a higher rate of change within class, and nevirapine had a higher rate of interruption. Tenofovir/emtricitabine backbone had the lowest rate of change within class and switch to nonstandard regimens, and the lowest rate of interruption together with abacavir/lamivudine. The main reasons for ART change were side effect and simplification for patients on boosted protease inhibitor and side effect for patients on NNRTI and failure for patients on NNRTI switching to protease inhibitor. The main reason for interruption was patient's choice.
We analysed a large dataset assembled from 18 cohort studies of HIV-positive people treated with ART in Europe and North America. Patients were recruited from a wide range of clinical settings with long follow-up: this allowed us to assess different types of regimen modification and premodification mortality, as well as examining changes over calendar time. Although we adjusted for a range of patient and regimen characteristics, together with calendar period and cohort, unmeasured confounding factors could have introduced residual biases. We could not assess patterns of change for patients on single tablet regimens as the data were not available. Neither could we assess ART regimens containing recently introduced and potent drugs such as etravirine, raltegravir and darunavir, because too few patients started treatment with these drugs. Reasons for changes of therapy were assessed for less than 1/4 of the patients within the different cohorts, and so it is difficult to be certain that the reasons for changes which were recorded could be extrapolated to the whole study population.
Although 84% of patients started ART when their CD4 cell count was lower than the 350/μl threshold recommended in treatment guidelines published during the study period , mortality was low, as in other cohort studies conducted in industrialized countries . Mortality before regimen change was associated with well established risk factors such as IDU transmission group, older age and more advanced disease at the beginning of ART. Lopinavir and atazanavir were associated with higher mortality than efavirenz. Causes of death were not assessed in this study, but protease inhibitors are associated with higher rates of cardiovascular disease than NNRTIs .
The rate of treatment interruption was high, with one-third of all interruptions occurring within the first 6 months of starting first ART. Interruption could relate to poor health and to patients stopping their treatment soon before dying. However, cumulative 3-year mortality was much lower than the cumulative incidence of interruption and interruption was more common in patients with high CD4 cell count. Therefore, interruptions were probably motivated by short-term side effects or toxicities of ART, or arose because of non adherence in patients who did not feel a pressing need to stay on treatment as suggested by the analysis of patients with available data on reasons for ART change [35–39].
Markedly higher rates of interruption among patients starting ART at higher CD4 cell counts are of concern given the benefits of earlier treatment . This pattern was most marked among women, perhaps because of cessation of short-term treatment that was commenced during pregnancy, or to side effects of treatment that are more frequent in women [41,42]. The risk of potentially severe cutaneous or hepatitic side effects due to NNRTI is greater at higher CD4 cell counts . The SMART study, which established that treatment interruption leads to higher rates of AIDS, death and serious non-AIDS events, was published midway through the study period, in 2006 . We found no evidence that, after adjusting for other factors, rates of interruption declined after 2006. With an increasing proportion of patients starting ART at high CD4 cell counts, before they have experienced severe HIV-related morbidity, interventions to promote adherence may improve long-term outcomes.
High rates of change in first ART have previously been reported in cohort studies in industrialized countries [10,33,44]. A total of 53.1% of patients starting first ART after 2001 in Switzerland changed at least once within the first 2 years, mainly with drug substitutions (50.8%). Very few patients (5.1%) changed their regimen because of virological failure. Within the first year, 29.7% of patients starting ART modified it, with half of these changes being due to drug intolerance and/or toxicity . To our knowledge, this is the first study to examine different types of regimen modification. The high rates of change within the same drug class observed in our study are likely to have been due to toxicity or for reasons of convenience, in contrast to resource-limited settings where rates of switching are lower and mainly driven by virological failure [10,33,44,45].
Among many other factors, such as comorbidity, long-term toxicity, convenience and pill burden, the choice of initial ART regimen should be based on both the potential for rapid virological suppression and on the likely tolerability and durability of the regimen. Whereas effects on virological suppression are well established from randomized trials, durability in practice may be better assessed in cohort studies. When considering first protease inhibitor/NNRTI we found efavirenz and atazanavir to be associated with the lowest and lopinavir the highest rates of class change. Efavirenz and atazanavir were also associated with the lowest, and lopinavir and nevirapine the highest, rates of interruption of ART. The NRTI backbone emtricitabine/tenofovir was associated with the lowest rates change within class, switch to nonstandard regimen and interruption. The high rate of lopinavir change could have been driven by the availability of better-tolerated new protease inhibitors. Of note, HLA-B5701 screening for abacavir hypersensitivity was only available at the end of the study and rates of abacavir change were thus probably higher than they would be in the current period. These findings strengthen arguments for using these well tolerated, once-daily drugs. Although atazanavir appeared to be associated with low rates of class change and interruption, few patients starting regimens containing this drug were included in our analyses, and no patient starting darunavir was included in the study. In the rapidly changing field of antiretroviral therapy, further studies including this and other newer once-daily well tolerated drugs, such as rilpivirine, etravirine, darunavir and integrase inhibitors, and new co-formulations will be of interest. More, long-term toxicity such as dyslipidaemia, diabetes mellitus and metabolic side effects, altogether with kidney impairment are important factors in the choice of antiretroviral therapy.
Among patients starting ART in industrialized countries between 2002 and 2009, the rate of modifications to first regimen was high, particularly during the first months of treatment. The most common modifications were substitutions or additions within the same drug class but rates of interruption were also high, particularly among patients starting ART at high CD4 cell counts. The findings of this study of a large population of unselected patients emphasize the need for new better tolerated drugs, preferably in once-daily formulations, in order to improve adherence and to lower rates of side effects.
S. Abgrall, S.M. Ingle, M.T. May, R. Cornish, D. Costagliola, P. Mercie, M. Cavassini, J. Reekie, H. Samji, M.J. Gill, H.M. Crane, J. Tate, T.R. Sterling, A. Antinori, P. Reiss, M.S. Saag, M.J. Mugavero, A. Phillips, C. Manzardo, J.C. Wasmuth, C. Stephan, J.L. Guest, J.L.G. Sirvent, J.A.C. Sterne, Antiretroviral Therapy Cohort Collaboration.
The ART Cohort Collaboration is supported by the UK Medical Research Council grant G0700820. Sources of funding of individual cohorts include the Agence Nationale de Recherche contre le SIDA (ANRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the French, Italian, Spanish and Swiss Ministries of Health, The Swiss HIV Cohort Study, supported by the Swiss National Science Foundation, the Stichting HIV Monitoring, the European Commission, the British Columbia and Alberta Governments, the Michael Smith Foundation for Health Research, the Canadian Institutes of Health Research, the VHA Office of Research and Development and unrestricted grants from GlaxoSmithKline, Roche and Boehringer-Ingelheim. Supported in part by the ‘Spanish Network for AIDS Research’ (RIS; ISCIII-RETIC RD06/006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
Sophie Abgrall has received travel grants from Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, GlaxoSmithKline and Janssen, fees for speaking from Janssen and Bristol-Myers-Squibb, fees for board membership from Janssen-Cilag. Jonathan Sterne has received lecturing fees from Gilead Sciences. Peter Reiss has served as a scientific advisor to Bristol-Myers Squibb, Gilead Sciences, Grupo Ferrer, GlaxoSmithKline, Janssen Pharmaceutica, Merck & Co, and Viiv Healthcare. He has served on data and safety monitoring boards and endpoint adjudication committees for Janssen Pharmaceutica and his institution has received honoraria for speaking engagements at scientific conferences from Bristol-Myers Squibb, Gilead Sciences, Inc, GlaxoSmithKline. He has received research support from Gilead Sciences, ViiV Healthcare, Merck & Co, Janssen Pharmaceutica, Bristol-Myers Squibb, Abbott, and Boehringer Ingelheim Pharmaceuticals. Tim Sterling has received research grants for HIV observational studies from Pfizer and BMS and is on the Data Safety Monitoring Board for TB clinical trial by Otsuka. Mike Saag serves as a consultant and /or am an investigator for the following companies: Avexa, BI, BMS, Gilead, Merck, Monogram, Pfizer, ViiV, Tibotec, and Vertex. John Gill serves as a consultant and /or as an investigator for the following companies: BMS, Gilead, Merck, ViiV and Tibotec. Michael Mugavero has been a consultant (advisory board) for Bristol-Myers Squibb, Gilead Sciences and Merck Foundation, and has received grant support (to UAB) from Bristol-Myers Squibb, Pfizer and Definicare. Andrew Phillips has received fees for board membership from GSK, consultancy fees from Viiv, BMS, Gilead, Janssen, GSK. Jan-Christian Wasmuth has fees for board membership and grants from Abbott, payment for lectures from BMS, Boehringer, Pfizer and Tibotec. Christian Manzardo has received fees for speaking, development of educational presentations and travel grants and from various pharmaceutical companies including Abbott, ViiV Healthcare and Janssen Pharmaceutica. Patrick Mercie has received travel grants, consultancy fees, fees for speaking from various pharmaceutical companies including Abbott, Bristol-Myers-Squibb, Gilead Sciences and GlaxoSmithKline. Andrea Antinori has received consultancy fees from Bristol-Myers-Squibb, Gilead Sciences, Janssen-Cilag and Abbott, grants from Bristol-Myers-Squibb and Pfizer, travel grants from Abbott. Matthias Cavassini has received consultancy fees from Bristol-Myers-Squibb, Gilead Sciences and Janssen-Cilag, grants from Gilead and MSD, travel grants from Boehringer-Ingelheim and Gilead Sciences, payment for educational presentations from BMS. Rosie Cornish, Jodie Guest, Joanne Reekie, Janet Tate, Hasina Samji, Christophe Stephan, Juan Luis Gomez Sirvent, Heidi Crane and Margaret May have no conflicts of interest.
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