Antiviral Therapy 2013; 18:345–354 (doi: 10.3851/IMP2436)
Original article
Decreasing rate of multiple treatment modifications
among individuals who initiated antiretroviral
therapy in 1997–2009 in the Danish HIV Cohort Study
Marie Helleberg1*, Gitte Kronborg2, Carsten S Larsen3, Gitte Pedersen4, Court Pedersen5, Lars Nielsen6,
Alex L Laursen3, Niels Obel1, Jan Gerstoft1
Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark
Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark
3
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
4
Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark
5
Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
6
Department of Infectious Diseases, Hillerød Hospital, Hillerød, Denmark
1
2
*Corresponding author e-mail: [email protected]
Background: We hypothesized that rates and reasons for
treatment modifications have changed since the implementation of combination antiretroviral therapy (cART)
due to improvements in therapy.
Methods: From a nationwide population-based cohort
study we identified all HIV-1-infected adults who initiated cART in Denmark 1997–2009 and were followed
≥1 year. Incidence rate ratios (IRRs) and reasons for
treatment modifications were estimated and compared
between patients, who initiated treatment in 1997–1999,
2000–2004 and 2005–2009. Rates of discontinuation of
individual antiretroviral drugs (ARVs) were evaluated.
Results: A total of 3,107 patients were followed for a
median of 7.3 years (IQR 3.8–10.8). Rates of first treatment modification ≤1 year after cART initiation did not
change (IRR 0.88 [95% CI 0.78, 1.01] and 1.03 [95% CI
0.90, 1.18] in 2000–2004 and 2005–2009, respectively,
compared with 1997–1999). Rates of multiple modifications decreased markedly (2000–2004 IRR 0.60 [95%
CI 0.53, 0.67] and 2005–2009 IRR 0.38 [95% CI 0.32,
0.46]). Rates of treatment modifications due to virological failure, toxicity and other/unknown reasons
decreased (IRR 0.25 [95% CI 0.14, 0.45], 0.69 [95% CI
0.56, 0.83] and 0.45 [95% CI 0.36, 0.57], respectively,
in 2005–2009 compared with 1997–1999), whereas
the rate of modifications with the aim of simplification
increased (IRR 1.85 [95% CI 1.52, 2.25]).
Conclusions: Rates of first treatment modification ≤1
year after cART initiation have not changed since the
early cART era, whereas the risk of multiple modifications has decreased markedly. Modifications due to virological failure and toxicity have decreased substantially,
whereas rates of switch to simpler and less toxic regimens have increased.
Introduction
HIV infection is often acquired at a young age and
the life expectancy of individuals initiating combination antiretroviral therapy (cART) has approached
that of the background population [1]. It is therefore
important to find a treatment regimen with long-term
durability in terms of efficacy, toxicity and acceptability. Antiretroviral therapy (ART) needs to be individualized according to comorbidities, resistance patterns,
genetics, potential drug–drug interactions and convenience to assure tolerability and adherence [2]. With the
introduction of combination therapy, suppression of
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AVT-12-OA-2611_Helleberg.indd 345
viral replication could be achieved, but many of the
antiretroviral drugs (ARVs) used in the early ART era,
caused debilitating short- and long-term side effects,
such as nausea, diarrhoea, lipodystrophy and neuropathy. Additionally the large pill burden and frequent dosing was a challenge for optimal adherence. A significant proportion of patients, who initiated combination
therapy in the early cART era had previously received
mono- or dual therapy and developed resistance.
In recent years several ARVs of different classes have
been introduced, which offer high efficacy, less toxicity
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and ease administration in terms of reduced pill burden
and dosing frequency [3]. Despite these improvements
previous studies have shown no decrease in rates of
treatment modification the first year after starting ART
[4,5]. We hypothesized that, although early treatment
modifications may be common, these changes usually
lead to a well-tolerated and efficient regimen and further alterations in the regimen have likely decreased as
treatment has become both better tolerated and more
effective. To test this hypothesis we assessed changes in
rates of and reasons for treatment modifications over a
13-year period in a nationwide cohort where HIV treatment has been successful, resulting in low incidence of
drug resistance [6] and long life expectancy of HIV
patients [1,7]. Trends in modifications of ARVs in initial regimen in the period 1997–2009 were evaluated.
Methods
In a nationwide, population-based cohort study we
estimated incidences of first, third and all treatment
modifications among HIV patients who initiated cART
in the period 1997–2009. Third treatment modification was used as a surrogate marker of multiple modifications. Risk factors and reasons for first treatment
modification were evaluated. Incidence rates (IRs) of
discontinuation of ARVs in first regimen were compared between individuals who initiated treatment in
1997–1999 versus 2000–2004 and 2005–2009. We
evaluated modifications of first-line ARV regimens
used in 1997–2009 by estimating the rates of discontinuation of individual ARVs in each calendar year.
Setting
Denmark has a population of 5.5 million, with an
­estimated HIV prevalence of 0.09% among adults. HIV
patients were during the study period seen as outpatients
at intended intervals of 12 weeks. There are eight specialized HIV care centres in Denmark. Antiretroviral treatment is provided at the centres free of charge and ARVs
approved by the European Medicines Agency are available in all regions of the country. Fixed-dose combinations
of zidovudine, lamivudine and abacavir were approved
in year 2000, of abacavir and lamivudine in 2004, of
tenofovir and emtricitabine in 2005 and of tenofovir,
emtricitabine and efavirenz in 2007. The national criteria for initiating ART have been described previously [8].
The national guidelines for recommended first-line regimens of ARVs and adherence to these have been evaluated by Petersen et al. [9]. Structured treatment interruptions have generally not been recommended in Denmark.
Data sources
The Danish HIV Cohort study, described in detail
elsewhere [8], is a population-based prospective
346 AVT-12-OA-2611_Helleberg.indd 346
nationwide cohort study of all HIV-infected individuals
who are treated at Danish HIV centres after 1 January
1995. Individuals are consecutively enrolled. Data are
updated yearly and includes demographics, date of HIV
infection, AIDS-defining events and date and cause of
death. CD4+ T-cell counts and HIV RNA measurements
are extracted electronically from laboratory data files.
Dates of initiation and modifications of ARVs as well as
reasons for treatment modifications are recorded. Only
information on generic drug name and not on formulation is recorded.
Study population
We included all HIV-1-infected individuals in the
Danish HIV Cohort Study who were ≥16 years at
treatment initiation, were resident in Denmark when
initiating cART in 1997–2009 and were followed for
at least 1 year after cART initiation.
Definitions
cART was defined as a treatment regimen of at least
three ARVs that included a non-nucleoside reverse
transcriptase inhibitor (NNRTI), a protease inhibitor
(PI), three nucleoside reverse transcriptase inhibitors
(NRTIs) or a two-drug regimen with a combination of
an NNRTI and a boosted PI.
Treatment modification was defined as discontinuation or switch of one or more ARVs. If several ARVs
were switched at the same time it was considered as
one modification.
Reasons for treatment modification were categorized
into four groups: virological failure, toxicity, simplification or other/unknown. Classification of virological
failure and toxicity were based on medical files. If failure or toxicity were not stated as the reason and modification led to reduction in pill burden or decrease in dosing frequency, the reason was classified as simplification.
Statistics
We calculated IRs of first and third treatment modification per 100 person-years (PY). IRs were compared
between individuals initiating treatment in 1997–1999
versus 2000–2004 and 2005–2009. IRs and IR ratios
(IRRs) were estimated using Poisson regression analyses. The following variables were included in multivariate analyses: gender, age (time-updated variable with
5-year intervals), origin, route of HIV transmission,
body weight, CD4+ T-cell count (<200 cells/ml, 200–350
cells/ml or >350 cells/ml), viral load, prior or current
AIDS-defining illness at time of cART initiation and
receipt of ART before cART. In analyses of first and
third treatment modification we calculated time from
date of cART initiation until date of first and third
modification, respectively. In analyses of incidence of
modifications by time after cART initiation time was
©2013 International Medical Press
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Decreasing rate of treatment modifications in an HIV cohort study
calculated from start of cART until date of last visit in
the HIV clinic. In analyses of reasons for first modification, follow-up time was censored when treatment was
modified for reasons other than the one under current
analysis. In analyses of time to modification of ARV
class, time was computed from cART initiation until
discontinuation or switch to a different class regardless of switches within class during that time interval. In
analyses of time to modification of individual ARVs in
first regimen, time was computed from cART initiation
until discontinuation of the drug under study regardless
of other modifications within that time interval. In all
analyses follow-up time was censored at the date of last
visit in the HIV clinic or 31 December 2010, whichever
came first.
IRs of discontinuation of individual ARVs were calculated for each calendar year. Only calendar years with
observation time >25 PY were analysed. SPSS statistical
software version 15.0 (Norusis; SPSS Inc., Chicago, IL,
USA) and Stata 8.0 (Stata Corporation, College Station,
TX, USA) were used for data analyses.
Results
We included 3,107 individuals, who were followed for
22,549 PY with a median follow-up time of 7.3 years
(IQR 3.8–10.8). The majority of study participants
were male (74.1%), of Danish origin (71.7%) and
infected through homosexual (44.9%) or heterosexual
contact (40.6%; Table 1). The proportion of individuals with CD4+ T-cell count <200 cells/ml at cART initiation decreased from 43.8% in 1997–1999 to 32.4%
in 2005–2009. The proportion of individuals who had
received ART before cART was 41.4% in 1997–1999
versus 1.6% in 2005–2009. Among individuals initiating cART in 1997–1999, 1,057 (86.7%) received a PI
and 22 (1.8%) received an NNRTI, whereas the corresponding numbers were 152 (18.7%) and 624 (77.0%)
in 2005–2009.
First and third treatment modifications
Overall 1,456 (46.7%) modified treatment within 1 year
of cART initiation. There were no significant differences
in time to first treatment modification within 1 year of
cART initiation between individuals initiating treatment
in the three periods (Figure 1A). In adjusted analyses
IRRs were 0.88 (95% CI 0.78, 1.01) and 1.03 (95% CI
0.90, 1.18) in 2000–2004 and 2005–2009, respectively,
compared with 1997–1999. More than 1 year after cART
initiation the rate of first modification was significantly
lower among individuals initiating cART in 2000–2004
and 2005–2009 compared with 1997–1999 (IRR 0.90
[95% CI 0.79, 1.00] and 0.42 [95% CI 0.33, 0.53]).
The risk of third treatment modification also decreased
markedly (Figure 1B). IRRs of third modification were
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0.64 (95% CI 0.56, 0.72) in 2000–2004 and 0.41 (95%
CI 0.34, 0.51) in 2005–2009.
Treatment modifications in the first and following
years after cART initiation
The rate of all modifications decreased both with calendar year of and time since cART initiation. The number
of treatment modifications per 100 PY within 1 year of
cART initiation decreased only modestly from IR 84.7
(95% CI 79.5, 90.1) to 76.5 (95% CI 71.2, 82.2) and
74.1 (95% CI 68.0, 80.7) among individuals initiating
treatment in 1997–1999, 2000–2004 and 2005–2009,
respectively. In the period 1–3 to years after cART initiation the IRs decreased substantially to 60.9 (95% CI
57.8, 64.1), 42.7 (95% CI 39.9, 45.7) and 27.1 (95% CI
24.2, 30.4) in 1997–1999, 2000–2004 and 2005–2009,
respectively. More than 3 years after cART initiation the
IRs were 47.5 (95% CI 46.1, 48.9), 37.1 (95% CI 35.3,
38.9) and 28.6 (95% CI 23.6, 34.6) in 1997–1999,
2000–2004 and 2005–2009, respectively.
Reasons for treatment modification
The overall IRs per 100 PY of first treatment modification due to virological failure, toxicity, simplification
and other/unknown reasons were 3.0 (95% CI 2.8, 3.2),
17.7 (95% CI 16.6, 18.9), 15.4 (95% CI 14.4, 16.5)
and 13.4 (95% CI 12.5, 14.4), respectively. IRs by year
of cART initiation are summarized in Additional file 1.
The risk of first treatment modification due to virological failure was substantially lower among individuals initiating treatment in 2000–2004 and 2005–2009
compared with 1997–1999 (Table 2). The risk of first
treatment modification due to toxicity only decreased
in the most recent period, whereas modifications with
the aim of simplification increased. Rates of first modification due to other/unknown reasons decreased both
among individuals initiating treatment in 2000–2004
and 2005–2009.
Factors associated with treatment modifications
Young age, baseline CD4+ T-cell count <200 cells/ml and
ART before HAART were associated with increased
risk of modification due to treatment failure (Table 2).
The risk of modification due to toxicity was increased
among females and those with low body weight. Baseline CD4+ T-cell count <200 cells/ml was associated
with increased likelihood of modification with the aim
of simplification, whereas young age and injection drug
use were associated with increased risk of modification
of other/unknown reasons.
Modifications of ARVs in initial regimen by year of
cART initiation
Compared with individuals receiving an initial regimen of
boosted PI+NRTI, rates of treatment modifications were
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M Helleberg et al.
lower among those receiving NNRTI+NRTI and higher
among those receiving unboosted PI+NRTI (Table 3).
NRTI backbones of stavudine + didanosine and stavudine
+ lamivudine were discontinued at significantly higher
rates than other NRTIs. The likelihood of discontinuation of zidovudine + lamivudine increased substantially
Table 1. Characteristics of the study population and ARVs in initial regimen by year of cART initiation
Characteristic
Year of cART initiation
1997–1999 2000–20042005–2009All
1,219 1,078810 3,107
Total, n
12,5987,5942,35722,549
Person-years
3,355
1,020
11,179
Treatment modifications, n6,804
11.4 (9.7–12.5)
7.3 (5.9–8.6)
2.8 (1.9–3.8)
7.3 (3.8–10.8)
Median observation time, years (IQR)
938 (77.0)
758 (70.3)
605 (74.7)
2,301 (74.1)
Male, n
38 (32–46)
38 (32–45)
39 (32–47)
38 (32–45)
Median age at baseline, years (IQR)
Origin
Denmark
925 (75.9)
732 (68.1)
567 (70.0)
2,224 (71.7)
142 (11.7)
186 (17.3)
109 (13.5)
437 (14.1)
Africa
Asia
42 (3.5)
78 (7.3)
56 (6.9)
176 (5.7)
Other
110 (9.0)
79 (7.4)
78 (9.6)
267 (8.6)
Route of transmission
Homosexual
594 (48.7)
403 (37.4)
397 (49.0)
1,394 (44.9)
Heterosexual
431 (35.4)
506 (46.9)
325 (40.1)
1,262 (40.6)
Injection drug use
140 (11.5)
101 (9.4)
52 (6.4)
293 (9.4)
Other
54 (4.4)
68 (6.3)
36 (4.4)
158 (5.1)
Median CD4+ T-cell count at baseline, 219 (111–318)
207 (100–309)
240 (142–318)
220 (110–310)
cells/ml (IQR)
CD4+ T-cell count <200 cells/ml
534 (43.8)
503 (46.7)
262 (32.4)
1,299 (41.8)
Median viral load at baseline,
4.6 (3.5–5.2)
4.9 (4.3–5.5)
4.7 (3.9–5.4)
4.8 (3.9–5.4)
log10 copies/ml (IQR)
AIDS at baseline
249 (20.4)
195 (18.1)
108 (13.3)
552 (17.8)
ART before cART
505 (41.4)
58 (5.4)
13 (1.6)
576 (18.5)
ARVs in initial regimen
ARV class
Boosted PI + NRTI
212 (17.4)
167 (15.5)
150 (18.5)
529 (17.0)
Unboosted PI + NRTI
845 (69.3)
64 (5.9)
2 (0.2)
697 (22.4)
NNRTI + NRTI
22 (1.8)
698 (64.7)
624 (77.0)
1,344 (43.3)
PI + NNRTI + NRTI
93 (7.6)
42 (3.9)
0 (0.0)
135 (4.3)
Triple NRTI
46 (3.8)
80 (7.4)
1 (0.1)
127 (4.1)
NRTI backbone
Zidovudine + 3TC
905 (74.2)
909 (84.3)
301 (37.2)
2,115 (68.1)
Stavudine + 3TC
183 (15.0)
22 (2.0)
2 (0.2)
207 (6.7)
Stavudine + didanosine
51 (4.2)
48 (4.5)
0 (0.0)
99 (3.2)
Abacavir + 3TC
15 (1.2)
109 (10.1)
142 (17.5)
266 (8.6)
Tenofovir + 3TC/FTC
0 (0.0)
11 (1.0)
347 (42.8)
358 (11.5)
Other
1 (0.1)
27 (2.5)
33 (4.1)
61 (2.0)
Third ARV
Ritonavir
214 (17.4)
1 (0.1)
0 (0.0)
215 (6.9)
Indinavir
367 (30.1)
10 (9.3)
1 (0.1)
378 (12.2)
Indinavir + ritonavir
8 (0.7)
42 (3.9)
0 (0.0)
50 (1.6)
Saquinavir
169 (13.9)
1 (0.1)
0 (0.0)
170 (5.5)
Saquinavir + ritonavir
206 (16.9)
85 (7.9)
1 (0.1)
292 (9.4)
Nelfinavir
189 (15.5)
88 (8.2)
0 (0.0)
277 (8.9)
Lopinavir + ritonavir
7 (0.6)
66 (6.1)
89 (11.0)
162 (5.2)
Atazanavir + ritonavir
0 (0.0)
7 (0.7)
71 (8.8)
78 (2.5)
Efavirenz
16 (1.3)
691 (64.1)
593 (73.2)
1,300 (41.8)
Nevirapine
99 (8.1)
76 (7.1)
46 (5.7)
221 (7.1)
Data are n (%) unless indicated otherwise. ART, antiretroviral therapy; ARV, antiretroviral drug; FTC, emtricitabine; cART, combination antiretroviral therapy; NNRTI,
non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; 3TC, lamivudine.
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Decreasing rate of treatment modifications in an HIV cohort study
Figure 1. Kaplan–Meier curves showing time to first and third treatment modification
B
1.0
0.8
0.6
0.4
0.2
0.0
0
1
4
2
3
Years after HAART initiation
5
Cumulative probability of third treatment modification
Cumulative probability of first treatment modification
A
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
Years after HAART initiation
10
12
Kaplan–Meier curves showing time to (A) first and (B) third treatment modification, stratified by year of combination antiretroviral therapy initiation (1997–1999, light
grey; 2000–2004, dark grey; 2005–2009, black).
Table 2. Incidence rate ratios of first treatment modification stratified by reasona
Failure
IRR (95% CI)
Toxicity
SimplificationOther/unknown
1.00 1.00
1.00
Male
Female
1.03 (0.61, 1.73)
1.25 (1.03, 1.51)
1.10 (0.90, 1.35)
Age, per 5 year increase
0.98 (0.97, 1.00)
1.00 (0.99, 1.01)
1.00 (0.99, 1.01)
Origin
Denmark 1.00 1.001.00
Africa
1.36 (0.75, 2.47)
0.89 (0.71, 1.12)
1.00 (0.79, 1.27)
1.56 (0.75, 3.28)
0.90 (0.67, 1.21)
0.79 (0.56, 1.12)
Asia
0.60 (0.31, 1.20)
0.92 (0.72, 1.17)
1.03 (0.80, 1.33)
Other
Route of transmission
Homosexual1.00
1.00 1.00
Heterosexual
0.64 (0.40, 1.02)
0.93 (0.78, 1.10)
0.92 (0.77, 1.11)
Injection drug use
0.79 (0.44, 1.43)
0.78 (0.60, 1.02)
0.77 (0.56, 1.05)
Other
0.48 (0.19, 1.24)
0.93 (0.69, 1.25)
0.85 (0.61, 1.18)
CD4+ T-cell count at baseline
<200 cells/ml
1.52 (1.05, 2.19)
1.03 (0.89, 1.20)
1.23 (1.04, 1.44)
200­–350 cells/ml1.00
1.00
1.00
>350 cells/ml
1.09 (0.67, 1.77)
1.16 (0.97, 1.39)
1.17 (0.96, 1.44)
Viral load, per log increase
1.04 (0.92, 1.18)
0.99 (0.94, 1.05)
1.00 (0.94, 1.05)
AIDS at baseline
0.92 (0.61, 1.38)
1.16 (0.98, 1.38)
0.83 (0.69, 1.01)
ART before cART
3.45 (2.30, 5.16)
0.92 (0.76, 1.11)
1.01 (0.80, 1.26)
Body weight, per kg increase
1.00 (0.99, 1.02)
0.99 (0.98, 0.99)
1.00 (0.99, 1.01)
Year of cART initiation
1997–19991.00 1.00 1.00
2000–2004
0.43 (0.27, 0.67)
1.06 (0.91, 1.24)
1.17 (0.99, 1.40)
2005–2009
0.42 (0.22, 0.78)
0.66 (0.54, 0.82)
1.85 (1.50, 2.28)
a
1.00
1.18 (0.95, 1.45)
0.98 (0.97, 0.99)
1.00
0.92 (0.71, 1.20)
0.71 (0.49, 1.05)
0.87 (0.66, 1.14)
1.00
0.96 (0.78, 1.18)
2.34 (1.86, 2.94)
0.96 (0.65, 1.41)
0.97 (0.81, 1.15)
1.00
1.20 (0.97, 1.48)
1.02 (0.96, 1.08)
1.08 (0.88, 1.32)
0.77 (0.63, 0.96)
0.99 (0.98, 1.00)
1.00
0.55 (0.46, 0.65)
0.41 (0.33, 0.53)
Multivariate Poisson regression analyses. ART, antiretroviral therapy; cART, combination antiretroviral therapy; IRR, incidence rate ratio.
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Table 3. Incidence rates and incidence rate ratios of discontinuation of ARVs in initial regimen stratified by year of cART initiationa
Year of cART initiation, IRR (95% CI)
IR (95% CI) per 100 PY1997–1999
2000–2004
ARV class
Boosted PI + NRTI
24.8 (22.5, 27.5)
1.00
1.4 (1.1, 1.8)
Unboosted PI + NRTI
37.2 (34.5, 40.1)
2.2 (1.8, 2.6)
4.4 (3.2, 6.0)
NNRTI + NRTI
11.0 (10.1, 12.0)
0.4 (0.2, 0.7)
0.4 (0.4, 0.5)
PI + NNRTI + NRTI
34.4 (29.0, 40.8)
1.8 (1.4, 2.3)
2.3 (1.7, 3.3)
Triple NRTI
26.6 (22.1, 32.1)
1.2 (0.9, 1.7)
1.3 (0.9, 1.7)
NRTI backbone
Zidovudine + 3TC
27.7 (26.5, 29.0)
1.00
2.3 (2.1, 2.6)
Stavudine + 3TC
29.8 (25.9, 34.2)
1.8 (1.5, 2.2)
16.2 (10.5, 24.8)
Stavudine + didanosine
43.7 (24.8, 76.9)
4.9 (3.7, 6.7)
5.8 (4.3, 7.8)
Abacavir + 3TC
15.9 (13.4, 18.9)
0.6 (0.4, 1.1)
1.0 (0.8, 1.3)
Tenofovir + 3TC/FTC
4.9 (3.6, 6.7)
NA
0.8 (0.3, 1.7)
Third ARV
Efavirenz
14.8 (13.6, 16.0)
1.00
1.3 (0.7, 2.5)
Nevirapine
24.8 (21.4, 28.9)
3.0 (1.6, 5.7)
2.0 (1.0, 3.9)
31.9 (29.0, 35.2)
3.1 (1.6, 5.6)
6.7 (3.4, 13.4)
Indinavir
Saquinavir + ritonavir
37.5 (34.1, 41.2)
3.8 (2.0, 7.1)
4.8 (2.6, 9.1)
Nelfinavir
43.0 (36.6, 50.6)
3.6 (1.9, 7.0)
8.0 (4.0, 16.0)
Lopinavir + ritonavir
37.1 (30.1, 45.8)
1.6 (0.5, 4.7)
3.2 (1.5, 6.6)
13.2 (8.9, 19.7)
NA
0.8 (0.2, 3.6)
Atazanavir + ritonavir
2005–2009
1.9 (1.4, 2.5)
NA
1.2 (1.0, 1.5)
NA
NA
23.2 (20.1, 26.8)
NA
NA
1.8 (1.3, 2.5)
0.6 (0.4, 0.9)
2.5 (1.3, 4.7)
1.9 (1.0, 4.11)
NA
NA
NA
5.8 (2.9, 11.5)
1.7 (0.8, 3.7)
Multivariate Poisson regression analyses. ARV, antiretroviral drug; cART, combination antiretroviral therapy; FTC, emtricitabine; IR, incidence ratio; IRR, incidence rate
ratio; NA, not applicable due to limited observation time; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI,
protease inhibitor; PY, person-years; 3TC, lamivudine.
a
among individuals initiating treatment in 2005–2009
compared with 1997–1999. The IRR of discontinuation
of abacavir + lamivudine also increased in 2005–2009,
whereas that of tenofovir + lamivudine/emtricitabine was
low throughout the study period. Switch from zidovudine
+ lamivudine or abacavir + lamivudine to coformulated
tenofovir + emtricitabine accounted for 72% of switches
of lamivudine. Rates of discontinuation of efavirenz were
lower than those of nevirapine and PIs other than atazanavir, but increased among individuals initiating treatment in 2005–2009 compared with 1997–1999.
Modifications of ARVs by calendar year
Rates of modification of regimens based on boosted
PI+NRTI and NNRTI+NRTI decreased significantly
over calendar time, whereas those of unboosted
PI+NRTI increased (Figure 2A). First-line regimens
with an NRTI backbone of stavudine + lamivudine
and zidovudine + lamivudine were largely abandoned
from 2001 and 2004, respectively (Figure 2B). The
IR of discontinuation of abacavir + lamivudine was
stable during the study period, whereas that of tenofovir + lamivudine/emtricitabine decreased to a very
low level.
The IRs of discontinuation of lopinavir + ritonavir,
efavirenz and nevirapine decreased during the study
period, whereas those of unboosted saquinavir, nelfinavir and indinavir increased significantly (Figure 2C).
350 AVT-12-OA-2611_Helleberg.indd 350
IRs of discontinuation of atazanavir were similar to
efavirenz and nevirapine (Additional file 1).
Discussion
We found that although the rate of treatment modifications within the first year of cART initiation has not
changed, the risks of later and multiple treatment modifications have decreased markedly. The rates of modifications due to virological failure, toxicity and other
reasons have dropped substantially, whereas the rate of
simplifications has increased. We believe this is the first
study demonstrating decreasing rates of treatment modifications since the early cART era. However, individuals who initiated treatment in the most recent period on
average still modified treatment once every fourth year
in the period more than 1 year after cART initiation.
Several studies have evaluated the proportions, rates
of and reasons for treatment modifications the first year
after cART initiation [4,5,10–15]. In these studies the
proportion of individuals, who switched or discontinued
ARVs within the first year of treatment were 30–50%,
which is in-line with our results. Only few have analysed
the long-term durability of ARVs in daily clinical practice or estimated the rate of multiple modifications.
Toxicity was the main reason for treatment modification and female gender and low body weight were associated with increased risk of treatment modification due
©2013 International Medical Press
25/04/2013 15:18:04
Decreasing rate of treatment modifications in an HIV cohort study
Figure 2. Incidence rates of discontinuation of ARV class, NRTI backbone and third ARV in initial regimen by calendar year
B
Boosted PI
Unboosted PI
NNRTI
Triple NRTI
80
70
60
50
40
30
20
10
0
Zidovudine + 3TC
Stavudine + 3TC
Stavudine + ddI
Abacavir + 3TC
Tenofovir + 3TC/FTC
90
80
70
60
50
40
30
20
10
19
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
0
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
IR/100 PY
90
IR/100 PY
A
C
120
Ritonavir
Saquinavir + rtv
Indinavir
Atazanavir + rtv
Nevirapine
IR/100 PY
100
80
60
Saquinavir
Nelfinavir
Lopinavir + rtv
Efavirenz
40
20
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
0
20 8
09
98
19
19
19
97
0
Incidence rates (IRs) of discontinuation of (A) antiretroviral drug (ARV) class, (B) nucleoside reverse transcriptase inhibitor (NRTI) backbone and (C) third ARV in
initial regimen by calendar year. ddI, didanosine; FTC, emtricitabine; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PY, person-years; rtv,
ritonavir; 3TC, lamivudine.
to toxicity, which has also been demonstrated previously
[5,16]. During the study period the risk of treatment
modifications due to toxicity decreased, presumably
reflecting the favourable safety profile of newer ARVs.
We found no association between CD4+ T-cell count at
cART initiation and risk of modification due to toxicity. In the Swiss HIV Cohort, higher CD4+ T-cell counts
were associated with increased risk of modifications due
to all reasons as well as toxicity [4,15,17], whereas others found no association [10,11,14]. In the present study,
low CD4+ T-cell counts at cART initiation was associated with increased risk of modification due to treatment failure, which is in agreement with findings from
other studies [5,12,18]. As we have previously shown,
receiving ART before cART was strongly associated
with increased risk of treatment modification due to failure [19]. Our finding of a markedly decreasing risk of
treatment failure has also been documented in previous
cohort studies [20,21].
Antiviral Therapy 18.3
AVT-12-OA-2611_Helleberg.indd 351
The question of when to start ART is controversial
and arguments for deferral of therapy in individuals with high CD4+ T-cell counts include concerns of
long-term toxicity of ART, non-adherence and development of resistance. Findings in this study point to the
increased risk of failure when treatment is initiated at
low CD4+ T-cell count and to the favourable durability of newer ARVs. One single adjustment of first-line
cART regimen is still needed up front for many individuals in order to find a regimen that is tolerated but
multiple modifications are increasingly infrequent as
well as modifications due to virological failure.
ARVs available early in the study period caused
considerable side effects, and rates of discontinuation of unboosted PIs, ritonavir and stavudine were
high. A substantial increase in discontinuation rates of
these drugs coincided with the introduction of ARVs
with fewer side effects. With the development of new
classes of ARVs and potent drugs, regimens that are
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M Helleberg et al.
acceptable and efficacious even in the presence of drug
resistance have become widely accessible. The convenience of coformulated tablets and drugs that can be
administered once daily reduces suboptimal adherence
[22,23]. Coformulated tablets of NRTIs were introduced in 2000 (zidovudine + lamivudine + abacavir),
2004 (abacavir + lamivudine) and 2005 (tenofovir +
emtricitabine). Concurrently with these improvements
in convenience and efficacy of antiretroviral therapy the
rate of modifications with the aim of simplification has
increased while the rate of modifications due to virological failure has decreased.
In many resource-replete countries drug resistance
testing has become routine before ART initiation to
reduce the risk of virological failure [24], but since the
prevalence of transmitted drug resistance among HIV
patients in the Danish HIV Cohort is only approximately 6% [25], this has not had major impact on the
overall rate of early treatment modifications.
Physicians may decide to make proactive switches to
prevent development of side effects. Emerging evidence
for long-term toxicity, for example, lipoatrophy associated with stavudine and zidovudine may partly explain
the increasing rates of discontinuation of these drugs
in the first years after the turn of the millennium [26].
Data from the ACTG 5202 study, disseminated in
2008, showed inferior virological response to abacavir
compared with tenofovir in individuals with pretreatment HIV RNA>100,000 copies/ml [27]. The
D:A:D study, also published in 2008, linked abacavir
to increased risk of cardiovascular disease [28,29].
Although the latter association has been debated
[30,31], these studies might have had some influence
on the use of abacavir in the recent period and partly
explain the slightly increasing rate of discontinuations
among individuals initiating cART in 2005–2009 and
that the IR of discontinuations of abacavir + lamivudine was higher than that of tenofovir + lamivudine/
emtricitabine in 2009, although both drugs cause few
side effects on the short term. However rates of discontinuation of abacavir were still low compared with
those of zidovudine, we therefore posit that the above
mentioned studies did not have a significant impact on
the use of abacavir in Denmark.
Most replacements of lamivudine were a consequence of switch to coformulated tenofovir + emtricitabine. There are few side effects of lamivudine and even
In the presence of the M184 resistance mutation it may
be beneficial to continue treatment because the mutation lowers HIV replication-fitness [32].
No drug has proved more efficacious than efavirenz
for suppression of viral load in treatment-naive individuals, but in recent years several alternative drugs have
been introduced, which are non-inferior to efavirenz
regarding virological response [33–36]. The immediate
352 AVT-12-OA-2611_Helleberg.indd 352
central nervous system adverse effects of efavirenz were
evident early after introduction of the drug [37, 38], but
persistence of subtle psychiatric and neurological disturbances related to efavirenz may only have been fully
recognized in recent years [39,40]. Even minor side
effects are not acceptable when alternatives are available and the introduction of PIs and integrase inhibitors
with few side effects may explain the increased rate of
discontinuations of efavirenz among individuals initiating cART in 2005–2009. Nevirapine was used in initial
regimen for a low proportion of patients throughout
the study period. Nevirapine has shown non-inferior
virological activity compared with efavirenz [41] and
atazanavir [42], but is not widely used due to the risk
of severe hypersensitivity reactions [43].
Major strengths of the study are the nationwide,
population-based design, which make the results
generalizable to resource-replete settings. The study
population was rather large, follow-up time was long
and included a wide span of calendar time, which
allowed us to analyse changing trends over time since
the early HAART era. The study was conducted in a
setting where HIV care is well-organized, ARVs are
widely available and treatment outcomes are favourable regarding retention in care [44], drug resistance
[6] and survival [1,7].
There are certain limitations of the study. Reasons
for treatment modifications were determined by chart
review and were not clearly stated in all cases. We classified the reason as ‘simplification’ if no other reason
was documented and the change led to a reduction in
pill burden or dosing frequency. We only had information on generic drug name and not the formulation and
thus we assumed that coformulated tablets were used
after the date, when they were introduced. We may
thereby have overestimated the proportion of modifications with the aim of simplification. Some treatment
modifications may have been proactive to prevent
future toxicity associated with long-term exposure to
ARVs. We were not able to discern proactive switches
from the category of ‘other’ reasons. Due to limited
observation time we could not evaluate the durability
of amprenavir, fosamprenavir, tipranavir and maraviroc, which have never been used in any considerable
amount in Denmark, and darunavir, etravirine and
raltegravir, which were usually used for salvage therapy during the study period and have only recently
been offered to treatment-naive patients. In analyses
of individual ARVs we only evaluated durability of
the initial regimen as the risk of modification of firstand second-line regimens are unlikely to be comparable. The study was observational and thus our results
reflect the mixed effects of changes in guidelines, physician’s opinions, characteristics of patients as well as
properties of available ARVs.
©2013 International Medical Press
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Decreasing rate of treatment modifications in an HIV cohort study
We conclude that although rates of first treatment
modification within 1 year of cART initiation have
not changed since the early cART era, the risks of later
and multiple treatment modifications have decreased
substantially. Rates of modifications due to virological
failure and toxicity have decreased markedly, whereas
rates of switch to simpler regimens have increased. In
the recent period where potent ARVs with few side
effects have become available, identifying a treatment
regimen with long-term durability is feasible but may
involve an early switch.
References
1.
2.
3.
4.
Acknowledgements
We thank the staff of our clinical departments for
their continuous support and enthusiasm. All of the
authors contributed to the conception and design
of the study and/or the analyses and interpretation
of the data. The manuscript was drafted by MH,
JG and NO and was critically reviewed and subsequently approved by all authors. The centres in the
Danish HIV Cohort Study are: the Departments of
Infectious Diseases at Copenhagen University Hospitals, Rigshospitalet (JG and NO) and Hvidovre (GK),
Odense University Hospital (CP), Aarhus University
Hospitals, Skejby (CSL) and Aalborg (GP), Herning
Hospital (ALL), Hillerød Hospital (LN) and Kolding
Hospital (Janne Jenson).
Disclosure statement
NO has received research funding from Roche,
Bristol–­Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, Janssen–
Cilag and Swedish Orphan. CP has received research
funding from Abbott, Merck Sharp & Dohme, GlaxoSmithKline and Janssen Pharma/Tibotec. JG has
received research funding from Abbott, Roche, Bristol–
Myers Squibb, Merck Sharp & Dohme, ViiV, Swedish
Orphan, Janssen Pharma/Tibotec and Gilead. ALL
is on the advisory board for Bristol–Myers Squibb,
GlaxoSmithKline and Janssen Pharma/Tibotec and
has received research funding from Abbott. MH, GK,
CSL, GP and LN declare no competing interests. No
funding sources were involved in study design, data
collection, analysis, report writing or the decision to
submit the paper for publication.
Additional file
Additional file 1: Rates of discontinuation (IR/100
years [95% CIs]) in initial regimen 1997–
person-­
2009 can be found at http://www.intmedpress.com/
uploads/documents/AVT-12-OA-2611_Helleberg_
Add_file1.pdf
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Accepted 29 September 2012; published online 16 October 2012
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