Calendar time trends in the incidence and prevalence of triple-class virologic failure in antiretroviral drug-experienced people with HIV in Europe

Article · November 2011with15 Reads
DOI: 10.1097/QAI.0b013e31823fe66b · Source: PubMed
Abstract
Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years. Calendar time trends in the incidence and prevalence of TCVF from 2000 to 2009 were assessed in patients who started ART from January 1, 1998, and were followed within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Of 91,764 patients followed for a median (interquartile range) of 4.1 (2.0-7.1) years, 2722 (3.0%) developed TCVF. The incidence of TCVF increased from 3.9 per 1000 person-years of follow-up [95% confidence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per 1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to 6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at December 31, 2000, and then increased to 2.4% (95% CI: 2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF prevalence seems to have stabilized and has remained below 3%. The prevalence of TCVF in people who started ART after 1998 has stabilized since around 2005, which most likely results from the decline in incidence of TCVF from this date. The introduction of improved regimens and better overall HIV care is likely to have contributed to these trends. Despite this progress, calendar trends should continue to be monitored in the long term.
1 Figures
EPIDEMIOLOGY AND PREVENTION
Calendar Time Trends in the Incidence and Prevalence of
Triple-Class Virologic Failure in Antiretroviral
Drug-Experienced People With HIV in Europe
The Pursuing Later Treatment Options II (PLATO II) project team* for the Collaboration of
Observational HIV Epidemiological Research Europe (COHERE) Group*
Background: Despite the increasing success of antiretroviral
therapy (ART), virologic failure of the 3 original classes [triple-
class virologic failure, (TCVF)] still develops in a small minority of
patients who started therapy in the triple combination ART era.
Trends in the incidence and prevalence of TCVF over calendar time
have not been fully characterised in recent years.
Methods: Calendar time trends in the incidence and prevalence of
TCVF from 2000 to 2009 were assessed in patients who started ART
from January 1, 1998, and were followed within the Collaboration of
Observational HIV Epidemiological Research Europe (COHERE).
Results: Of 91,764 patients followed for a median (interquartile
range) of 4.1 (2.07.1) years, 2722 (3.0%) developed TCVF. The
incidence of TCVF increased from 3.9 per 1000 person-years of fol-
low-up [95% condence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per
1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then
declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to
6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to
0.42%) at December 31, 2000, and then increased to 2.4% (95% CI:
2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF
prevalence seems to have stabilized and has remained below 3%.
Conclusions: The prevalence of TCVF in people who started ART
after 1998 has stabilized since around 2005, which most likely
results from the decline in incidence of TCVF from this date. The
introduction of improved regimens and better overall HIV care is
likely to have contributed to these trends. Despite this progress,
calendar trends should continue to be monitored in the long term.
Key Words: antiretroviral therapy, HIV, treatment experienced
patients, triple class failure, virologic failure
(J Acquir Immune Dec Syndr 2012;59:294299)
INTRODUCTION
The primary objective of antiretroviral therapy (ART) is
to achieve and sustain viral load levels below the limit of
detection of current assays (generally 50 copies/mL)
1,2
so that
accumulation of resistance mutations can be prevented and
immune reconstitution can occur. The success of ART means
that suppression is established and maintained in most treated
people.
36
However, virologic failure, which includes both
failure to achieve viral suppression and conrmed viral
rebounds, still develops in a small minority.
710
Virologic
failure may be the consequence of the presence of resistance
mutations or of insufcient drug levels due to reasons such as
poor adherence, drug intolerance, insufcient drug dosages,
or drugdrug interactions.
1,2
Thus, although virologic failure
of a drug does not necessarily correspond to presence of
resistance to that drug or mean that the drug is no longer an
option for future use, it is clearly a negative outcome reect-
ing some problem with the course of treatment. Further, it is
an outcome that can be reasonably completely ascertained due
to regular viral load monitoring in all patients.
Recommended rst-line regimens in resource-rich countries
consist of 2 nucleos(t)ide reverse transcriptase inhibitors and
either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or
a ritonavir-boosted protease inhibitor (PI/r).
1,2,11
Despite the low
Received for publication June 21, 2011; accepted October 28, 2011.
The Pursuing Later Treatment Options II project is funded by Medical
Research Council award G0700832. The Collaboration of Observational
HIV Epidemiological Research Europe study group has received generic
funding from the Agence Nationale de Recherches sur le SIDA et les
Hépatites Virales (ANRS), France; HIV Monitoring Foundation, the
Netherlands; and the Augustinus Foundation, Denmark. Collaboration
of Observational HIV Epidemiological Research Europe receives funding
from the European Union Seventh Framework Programme (FP7/2007
2013) under EuroCoord grant agreement no: 260694. A list of the funders
of the participating cohorts can be found on the Regional Coordinating
Centre websites athttp://www.cphiv.dk/COHERE/tabid/295/Default.aspx
and http://etudes.isped.u-bordeaux2.fr/cohere.
The funding sources had no role in study design; in the collection, analysis,
and interpretation of data; in the writing of the article, or in the decision to
submit it for publication.
No member of the PLATO II analysis and writing committee has any
nancial or personal relationships with people or organizations that could
inappropriately inuence this work, although some members of the group
have, at some stage in the past, received funding from a variety
of pharmaceutical companies for research, travel grants, speaking
engagements or consulting fees.
The members of the PLATO II Project Team for the COHERE group are
listed in the Appendix I.
Correspondence to: Fumiyo Nakagawa, MSc, Research Department of
Infection and Population Health, UCL, Royal Free Campus, Rowland
Hill Street, London NW3 2PF, United Kingdom (e-mail: f.nakaga-
wa@ucl.ac.uk).
Copyright © 2012 by Lippincott Williams & Wilkins
294 |www.jaids.com J Acquir Immune Defic Syndr Volume 59, Number 3, March 1, 2012
rate with which people cumulatively experience virologic failure
to each of these 3 original drug classes [triple-class virologic
failure, (TCVF)] these rates are non-negligible and, furthermore,
have not decreased over time.
12
Although patients in resource-rich
countries with TCVF have access to newer classes of antiretro-
virals (fusion and integrase inhibitors and CCR5 antagonists
1316
)
and partially or fully active drugs from within the original classes,
eventual exhaustion of treatment options is a concern.
Previously, most patients with virologic failure were
those who initiated ART with monotherapy or dualther-
apy.
17,18
Trends in incidence and prevalence of TCVF over
time have not been fully characterized in recent years, specif-
ically in patients who started therapy in the triple combination
ART era. The aim of this study was to describe calendar time
trends in the incidence and prevalence of TCVF between
2000 and 2009 in routine clinical populations in Europe in
patients who started ART from 1998 onwards.
METHODS
COHERE is a collaboration of most HIV observational
cohorts in Europe.
19
Twenty-eight of these cohorts participate
in the Pursuing Later Treatment Options II (PLATO II) pro-
ject,
12,20
which is a follow-up study of the original PLATO
collaboration reported in 2004.
17
This analysis (on data
merged in 2010) was restricted to antiretroviral-naive patients
16 years or older who started ART from 1998 onwards.
Patients were included only if they had at least 4 months
(122 days) of follow-up.
Virologic failure of a drug was dened as 1 viral load
measurement above 500 copies/mL despite 4 months of
continuous drug use. TCVF was dened as virologic failure
of at least 2 nucleos(t)ide reverse transcriptase inhibitors, 1
NNRTI and 1 PI/r. Triple-class exposure was dened as
having experienced such drugs for at least 4 months with
a viral load measurement available.
Patient follow-up was calculated from the date of
starting ART until the date of TCVF or the last viral load
measurement if they did not experience TCVF. The incidence
of TCVF in a given year was the number of ART-experienced
patients who developed TCVF within the year, divided by the
total person-years of follow-up in that year. The prevalence
was calculated at the end of each year, as the proportion of
ART-experienced patients under follow-up in that year in
whom TCVF had been attained at some point previously. To
be included in any given calendar year, patients had to start
ART before the end of that year and have at least 1 viral load
measurement during that year. Patients were followed to the
date of their last viral load measurement.
All Pvalues are two-sided. Analyses were performed
using SAS software, version 9.1 (SAS Inc, Cary, NC).
RESULTS
Data on 91,764 patients from 26 cohorts were included.
Most (71%) were male and at ART initiation, median
(interquartile range) age, CD4 cell count and viral load were
37 (31-44) years, 271 (134-430) cells/mL and 4.7 (3.7-5.2)
log
10
copies/mL respectively. Patients were followed for
a median of 4.1 (2.0-7.1) years from ART initiation, during
which time 2722 (3.0%) developed TCVF. The total observed
follow-up time was 428,391 person-years. The characteristics
of patients under follow-up in each year (Table 1) remained
fairly constant throughout the study period, except for initial
regimen type where the proportion of patients starting with
NNRTI or PI/r gradually increased over time, whereas the use
of unboosted PI decreased. The prevalence of triple-class
exposure increased steadily over time from 1.7% in 2000 to
17.0% in 2009. In addition to the number of people under
follow-up in each year, we show the number for whom their
last recorded viral load was in the year.
The incidence and prevalence of TCVF for each
calendar year are shown in (Fig. 1). The incidence of TCVF
initially increased from 3.9 per 1000 person-years of follow-
up (95% CI: 3.7 to 4.1) in 2000 to 8.8 per 1000 person-years
of follow-up (95% CI: 8.5 to 9.0) in 2005, which was when
the incidence was at its peak. By 2009, it had decreased to 5.8
per 1000 person-years of follow-up (95% CI: 5.6 to 6.1). The
prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at
the end of 2000, which then increased to 2.4% (95% CI:
2.24% to 2.50%) by the end of 2005. Since 2005, the prev-
alence of TCVF appears to have stabilized and has remained
below 3%, with prevalence (95% CI) of 2.6% (2.51% to
2.77%), 2.8% (2.65% to 2.92%), 2.9% (2.73% to 2.99%),
and 2.5% (2.33% to 2.66%), respectively, at the end of
2006, 2007, 2008, and 2009.
DISCUSSION
In this large study based on 91,764 patients seen in
clinics around Europe who started therapy after January 1,
1998, we found that 2722 (3.0%) developed TCVF by the end
of 2009. Although the cumulative proportion of people
exposed to all 3 classes has gradually increased since 2000,
the prevalence of TCVF has reached a somewhat stable level
at below 3%. This seems to be due in part to the decrease in
incidence of TCVF since 2005, which dropped to 5.8 per
1000 person-years of follow-up by the end of 2009. These
trends are most likely attributable to the use of potent
antiretrovirals, in particular, improved rst-line regimens
and use of xed-dose combinations providing greater regimen
stability in recent years.
21
Other reasons for the improvements
made in the last 5 years could be a mixture of earlier diag-
nosis, better quality care, enhanced knowledge of adherence,
and a better understanding of ART (eg, timing of initiation,
toxicities, drugdrug interactions). There has also been
increased use and improved interpretation of drug resistance
testing, allowing physicians to choose appropriate regimens
for antiretroviral-naive patients infected with drug-resistant
strains and patients with detectable viral load.
22
We have previously described factors associated with
the rate of development of TCVF after ART initiation in this
patient group.
12
The main factors identied to predict a higher
rate of TCVF were younger age, risk category other than
MSM, and a lower CD4 cell count and higher viral load at
start of ART. Interestingly, in that analysis, we did not iden-
tify a lower risk of TCVF for patients starting ART in more
recent calendar years. However, this discrepancy is thought to
J Acquir Immune Defic Syndr Volume 59, Number 3, March 1, 2012 Trends of Triple-Class Virologic Failure
Ó2012 Lippincott Williams & Wilkins www.jaids.com |295
TABLE 1. Patient Characteristics in the PLATO II Study at the End of Each Calendar Year
2000 2001 2002 2003 2004
Number under follow-up 24966 31087 37047 42950 48289
Number with last ever viral load measurement (%)* 1245 (5) 1572 (5) 1919 (5) 2964 (7) 2743 (6)
Male (%) 18225 (73) 22456 (72) 26612 (72) 30584 (71) 34245 (71)
Risk group (%)
MSM 9193 (37) 11394 (37) 13610 (37) 15874 (37) 18145 (38)
Heterosexual male 4247 (17) 5404 (17) 6619 (18) 7796 (18) 8780 (18)
Heterosexual female 4859 (19) 6340 (20) 7845 (21) 9461 (22) 10839 (22)
IDU 4369 (18) 4988 (16) 5457 (15) 5767 (14) 5859 (12)
Other 2298 (9) 2961 (10) 3516 (9) 4052 (9) 4666 (10)
Initial regimen (%)
2 NRTI + 1 NNRTI 7074 (28) 9653 (31) 11928 (32) 14717 (34) 17346 (36)
2 NRTI + 1 PI/r 1716 (7) 2998 (10) 4666 (13) 6555 (15) 9025 (19)
2 NRTI + 1 unboosted PI 10773 (43) 11424 (37) 11696 (31) 11665 (27) 11365 (23)
3 NRTI 1137 (5) 2057 (6) 2955 (8) 3622 (9) 3758 (8)
Other from original 3 classes4266 (17) 4952 (16) 5797 (16) 6376 (15) 6757 (14)
Other including newclasses0 (0) 3 (0) 5 (0) 15 (0) 38 (0)
At start of ART, median (IQR)
Age, yrs 36 (3142) 36 (3142) 36 (3143) 36 (3143) 37 (3143)
CD4 cell count, cells/m 279 (124454) 269 (120443) 262 (117434) 260 (119427) 260 (120420)
Viral load, log
10
copies/mL 4.7 (3.95.3) 4.7 (3.95.3) 4.7 (3.95.3) 4.7 (3.95.3) 4.7 (3.95.3)
Years on ART, median (IQR) 0.6 (01.4) 1.1 (0.12.2) 1.6 (0.32.9) 2.1 (0.53.7) 2.5 (0.64.4)
Prevalence of TCE, % 1.7 3.7 5.5 7.3 9.6
2005 2006 2007 2008 2009
Number under follow-up 54104 58663 60578 59731 33640
Number with last ever viral load measurement (%)* 4191 (8) 6378 (11) 8160 (13) ——
Male (%) 38361 (71) 41611 (71) 43178 (71) 43012 (72) 25221 (75)
Risk group (%)
MSM 20699 (38) 22954 (39) 24328 (40) 24624 (41) 14750 (44)
Heterosexual male 9804 (18) 10500 (18) 10673 (18) 10320 (17) 5455 (16)
Heterosexual female 12265 (23) 13297 (23) 13589 (22) 12920 (22) 6107 (18)
IDU 6126 (11) 6280 (11) 6240 (10) 5900 (10) 3756 (11)
Other 5210 (10) 5632 (10) 5748 (10) 5967 (10) 3572 (11)
Initial regimen (%)
2 NRTI + 1 NNRTI 20040 (37) 22432 (38) 24175 (40) 24828 (42) 14598 (43)
2 NRTI + 1 PI/r 11750 (22) 14497 (25) 16207 (27) 16455 (27) 9336 (28)
2 NRTI + 1 unboosted PI 11255 (21) 10663 (18) 9736 (16) 8792 (15) 5031 (15)
3 NRTI 3836 (7) 3771 (7) 3388 (6) 3005 (5) 1151 (3)
Other from original 3 classes7112 (13) 7153 (12) 6861 (11) 6328 (11) 3261 (10)
Other including newclasses111 (0) 147 (0) 211 (0) 323 (0) 263 (1)
At start of ART, median (IQR)
Age, yrs 37 (3143) 37 (3144) 37 (3244) 37 (3244) 38 (3244)
CD4 cell count, cells/m 261 (122420) 264 (128420) 270 (132424) 274 (137430) 284 (138453)
Viral load, log
10
copies/mL 4.7 (3.95.3) 4.7 (3.85.3) 4.7 (3.85.3) 4.7 (3.85.2) 4.7 (3.95.3)
Years on ART, median (IQR) 2.9 (0.85.1) 3.2 (0.95.7) 3.5 (1.16.4) 3.9 (1.47.1) 4.8 (2.08.0)
Prevalence of TCE, % 11.7 13.2 14.7 15.9 17.0
*The number of people who had their last viral load measurement taken in that calendar year, whether the reason for this was loss to follow-up or death.
Any combination of NRTIs, NNRTIs, and PIs not listed above.
Any combination of drugs including those from the newclasses (which are CCR5 antagonists, integrase inhibitors, and fusion inhibitors).
§461 of 91,764 (0.5%) patients from the whole study period did not have an initial CD4 cell count recorded.
MSM, men who have sex with men; IDU, injecting drug user; NRTI, nucleos(t)ide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI,
protease inhibitor; PI/r, ritonavir-boosted PI; ART, antiretroviral therapy; IQR, interquartile range; TCE, triple-class exposure.
PLATO II Project Team for COHERE J Acquir Immune Defic Syndr Volume 59, Number 3, March 1, 2012
296 |www.jaids.com Ó2012 Lippincott Williams & Wilkins
be due to the different initial regimens used by the 2 studies
and because our analysis includes 2 extra years of follow-up.
Estimates for both prevalence and incidence vary across
previous studies due to differences in denition of TCVF,
ART regimen, and study setting. Here, we adopted the same
denition as in previous PLATO II analyses.
12
Alternative
denitions include the following: viral load measurement
above 1000 copies/mL required for virologic failure,
17,2325
at least 6 months continuous use of a drug required for viro-
logic failure,
3,26
and inclusion of patients who had been on
monotherapy or dualtherapy before combination ART.
17,26
The results of our current analysis are largely applicable to
current practice as our inclusion criteria require that patients
started therapy after the time that triple combination ART was
in widespread use. In the EuroSIDA study, the prevalence of
TCVF rose from 0% in 2000 to 5.6% in 2005 in patients who
started ART after 1999, and there was some evidence that the
incidence of TCVF decreased with increasing calendar year
of follow-up.
24
In the UK CHIC study, the proportion of
patients who had experienced TCVF grew from 0.9% in
2000 to 3.9% in 2007, and using a mathematical model, it
was predicted that this increase would continue until 2012,
although the number with TCVF and without viral suppres-
sion was projected to remain stable.
26
In the Danish HIV
Cohort,
25
the risk of TCVF decreased from 1997 to 2003,
and the prevalence of TCVF stabilized after 2000 and did
not rise above 7%.
Development of TCVF is associated with a greater
likelihood of experiencing a CD4 cell count less than 200
cells/mL
3
and increased clinical progression.
17,23
Other impli-
cations of TCVF include potential for transmission of multi-
drug-resistant HIV strains,
27
higher costs to health systems
owing to increased prices of newer drugs, and the need for
more frequent contact with healthcare providers. As the du-
ration on therapy increases for patients with TCVF, further
virologic failure of the remaining available drugs in the orig-
inal 3 classes, as well as the newer drug classes, may well
continue. Although we have shown here that the prevalence
of TCVF has not been increasing over the last 5 years, it is
important to continue monitoring these trends over extended
periods of time.
It should be noted that there are some limitations to this
study. Patients were only included if they started ART post-
1998, which makes our cohort somewhat articial in that
clinic populations will also include some people who started
ART before 1998, often with mononucleoside or dual-
nucleoside regimens. Since there is inevitably a time lag
between initiation of ART and the rst time that TCVF can
occur (because TCVF nearly always requires at least two
separate regimen failures and at least one switch in regimen),
the restriction to patients starting ART after 1998 is the likely
explanation for the observed increase in incidence from 2000
to 2005. Another limitation as mentioned by the PLATO II
project team
12
is that patients included in COHERE may not
be representative of the population of European patients on
ART because they are likely to have increased access to care
and treatment due to cohort participation in various research
studies. Further, it should be noted that TCVF does not in all
cases mean that resistance to the 3 classes is present; TCVF
will also occur as a result of poor adherence without resis-
tance and without complete and regular genotypic data and
data on adherence, it is difcult to establish the cause of
TCVF. On the other hand, some people who do not experi-
ence virologic failure of a drug by our denition may never-
theless have developed resistance. This may occur, for
example, if drugs were switched before the viral load had
reached 500 copies/mL. We are separately investigating to
what extent we can document the presence of triple class
resistance in people with TCVF.
In summary, the prevalence of TCVF among people
starting ART since 1998 has stabilized since around 2005 to
a relatively low level of below 3%, which most likely results
from the decline in incidence of TCVF from 2005. The
introduction of improved regimens and better HIV care is
likely to have contributed to these trends. Despite the
improvements seen in the last decade, the serious implications
of TCVF call for further long-term research. New antiretro-
viral drugs may be necessary to sustain current low levels of
incidence and prevalence.
FIGURE 1. Incidence per 1000 person-years of follow-up of
triple-class virologic failure (TCVF) over calendar time among
patients who started ART since 1998 (Top). Prevalence of
TCVF (%) over calendar time among patients who started ART
since 1998 (Bottom). For both graphs, vertical lines represent
95% CIs, the two horizontal dashes on either side represent
95% confidence limits and the circles represent the point
estimates.
J Acquir Immune Defic Syndr Volume 59, Number 3, March 1, 2012 Trends of Triple-Class Virologic Failure
Ó2012 Lippincott Williams & Wilkins www.jaids.com |297
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APPENDIX 1: The Members of the PLATO II
Project Team For the COHERE Group
Analysis and Writing Committee
Fumiyo Nakagawa, Rebecca Lodwick, Dominique Costagliola, Ard
van Sighem, Carlo Torti, Daniel Podzamczer, Amanda Mocroft, Bruno
Ledergerber, Maria Dorrucci, Alessandro Cozzi-Lepri, Klaus Jansen, Bernard
Masquelier, Federico García, Stephane De Wit, Christoph Stephan, Niels
Obel, Gerd Fätkenheuer, Antonella Castagna, Helen Sambatakou, Cristina
Mussini, Jade Ghosn, Robert Zangerle, Xavier Duval, Laurence Meyer,
Santiago Perez-Hoyos, Céline Fabre Colin, Jesper Kjaer, Genevieve Chene,
Jesper Grarup, Andrew Phillips.
PLATO II Project Team
Antonella Castagna (San Raffaele), Dominique Costagliola (ANRS
CO4 FHDH), Alessandro Cozzi-Lepri (ICONA), Andrea De Luca (ICONA),
Stephane De Wit (St Pierre Cohort), Frank de Wolf (ATHENA), Maria
Dorrucci (CASCADE), Xavier Duval (ANRS CO8 COPILOTE), Gerd
Fätkenheuer (Cologne Bonn), Federico García (CoRIS), Jade Ghosn (ANRS
CO6 PRIMO), Huldrych Günthard (SHCS), Klaus Jansen (KOMPNET),
Louise Jørgensen (Danish HIV Cohort), Ali Judd (CHIPS), Bruno Leder-
gerber (SHCS), Sergio Lo Caputo (Italian Master Cohort), Rebecca Lodwick
(statistician), Bernard Masquelier (ANRS CO3 AQUITAINE), Laurence
Meyer (ANRS CO2 SEROCO), Amanda Mocroft (EuroSIDA), Cristina
Mussini (Modena Cohort), Antoni Noguera-Julian (CORISPE-cat), Niels
Obel (Danish HIV Cohort), Dimitrios Paraskevis (AMACS), Roger Paredes
(EuroSIDA), Santiago Pérez-Hoyos (GEMES-Haemo), Andrew Phillips
(PLATO II project leader; UK HIV Drug Resistance Database / UK CHIC),
Deenan Pillay (UK HIV Drug Resistance Database / UK CHIC), Daniel
Podzamczer (PISCIS), José T. Ramos (Madrid Cohort), Christoph Stephan
(Frankfurt HIV Cohort), Pat A. Tookey (NSHPC), Carlo Torti (Italian Master
Cohort), Giota Touloumi (AMACS), Ard van Sighem (ATHENA), Josiane
Warsawski (ANRS CO1 EPF), Robert Zangerle (AHIVCOS).
COHERE Steering Committee
Contributing cohorts: Robert Zangerle (AHIVCOS), Giota Touloumi
(AMACS), Josiane Warszawski (ANRS CO1 EPF/ANRS CO11
PLATO II Project Team for COHERE J Acquir Immune Defic Syndr Volume 59, Number 3, March 1, 2012
298 |www.jaids.com Ó2012 Lippincott Williams & Wilkins
OBSERVATOIRE EPF), Laurence Meyer (ANRS CO2 SEROCO), François
Dabis (ANRS CO3 AQUITAINE), Murielle Mary Krause (ANRS CO4
FHDH), Jade Ghosn (ANRS CO6 PRIMO), Catherine Leport (ANRS CO8
COPILOTE), Frank de Wolf (ATHENA), Peter Reiss (ATHENA), Maria
Prins (CASCADE), Heiner Bücher (CASCADE), Caroline Sabin (CHIC),
Diana Gibb (CHIPS), Gerd Fätkenheuer (Cologne Bonn), Julia Del Amo
(CoRIS), Niels Obel (Danish HIV Cohort), Claire Thorne (ECS), Amanda
Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Christoph Stephan (Frankfurt),
Santiago Pérez-Hoyos (GEMES-Haemo), Antoni Noguera-Julian (NENEXP
and CORISPE-cat), Andrea Antinori (ICC), Antonella dArminio Monforte
(ICONA), Norbert Brockmeyer (KOMPNET), José Ramos (Madrid Cohort),
Manuel Battegay (MoCHIV), Andri Rauch (SHCS), Cristina Mussini
(Modena Cohort), Pat Tookey (NSHPC), Jordi Casabona (PISCIS), Jose
M. Miró (PISCIS), Antonella Castagna (San Raffaele), Stephane de Wit
(St. Pierre Cohort), Tessa Goetghebuer (St Pierre Paediatric Cohort), Carlo
Torti (Italian Master Cohort), Ramon Teira (VACH), Myriam Garrido
(VACH). European AIDS Treatment Group: David Haerry.
Executive committee: Ian Weller (Chair, University College London),
Jordi Casabona (PISCIS), Dominique Costagliola (FHDH), Antonella
dArminio-Monforte (ICONA), Manuel Battegay (MoCHIV), Maria Prins
(CASCADE), Frank de Wolf (ATHENA), Jesper Grarup (Head of Copenha-
gen Regional Coordinating Centre), Genevieve Chene (Head, Bordeaux
Regional Co-ordinating Centre).
Regional co-ordinating centres: Bordeaux RCC cohorts: Céline Colin,
Christine Schwimmer, Guillaume Touzeau; Copenhagen RCC cohorts: Jesper
Kjaer, Maria Paulsen.
Project leaders and statistical analysis: Julia Bohlius, Vincent Bouteloup,
Heiner Bucher, Alessandro Cozzi-Lepri, François Dabis, Antonella dArminio
Monforte, Frank de Wolf, Maria Dorrucci, Matthias Egger, Frederik Engsig,
Hansjakob Furrer, Ole Kirk, Olivier Lambotte, Charlotte Lewden, Rebecca
Lodwick, Sophie Matheron, Laurence Meyer, Jose Miro, Amanda Mocroft, Niels
Obel, Roger Paredes, Andrew Phillips, Massimo Puoti, Joanne Reekie, Caroline
Sabin, Alexandra Scherrer, Colette Smit, Jonathan Sterne, Rodolphe Thiebaut,
Claire Thorne, Carlo Torti, Viktor von Wyl, Linda Wittkop, Jim Young.
J Acquir Immune Defic Syndr Volume 59, Number 3, March 1, 2012 Trends of Triple-Class Virologic Failure
Ó2012 Lippincott Williams & Wilkins www.jaids.com |299
    • The Plato II study (Nakagawa et al. 2012) showed that, in Europe, the prevalence of patients who had failed on all three major drug classes (NRTI, NNRTI and PI) increased steadily after 1996, but remained stable from 2005. This is probably because the incidence of multi-class resistance went down, which, in turn, can be attributed to improvements in monitoring, simpler and less toxic regimens, which led to better adherence, and better pharmacodynamics, which made regimes more robust to sub-optimal adherence (Lundgren, 2012).
    [Show abstract] [Hide abstract] ABSTRACT: Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis.
    Full-text · Article · Jun 2013
  • Full-text · Article · Aug 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Background. Low CD4 counts are the main factor leading to clinical progression in HIV-1 infection. We aimed to investigate factors affecting CD4 counts after triple-class virological failure (VF).Methods. We included individuals with triple-class VF who started ART since 1998 from the COHERE database. CD4 counts from triple-class VF onwards were analyzed using generalized estimating equations.Results. The analyses included 2424 individuals with a total of 23,922 CD4 values. In adjusted models (excluding current viral load and year), CD4 counts were higher with regimens which included boosted protease inhibitors (+22 cells/µL, 95% CI 3.9-41, p=0.017) or drugs from the new classes (+39; 15-62, p=0.001) when compared to NNRTI based regimens. These associations disappeared when current viral load and/or calendar year were included. Compared to viral load levels <2.5 log(10) copies/mL, levels from 2.5-3.5, 3.5-4.5, 4.5-5.5 and >5.5 log(10) copies/mL were associated with lower CD4 counts of 51, 84, 137 and 186 cells/µL, respectively(p<0.001).Conclusions. The approximately linear relationship between log viral load and CD4 indicates that there are likely immunologic benefits from lowering viral load even by modest amounts that do not lead to undetectable viral loads. This is important for patients with low CD4 counts and few drug options.
    Full-text · Article · Dec 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Resistance of Human Immunodeficiency Virus (HIV) to antiretrovirals is a clinically important issue despite the availability of five antiretroviral drug classes. Although the incidence of HIV resistance might have stabilized or even decreased in patients starting their first Highly Active Antiretroviral Therapy (HAART) regimen in recent years, the prevalence of failure to the three original antiretroviral classes is estimated to range from 2.1% to 16% after HAART initiation. International guidelines recommend the use of at least two active drugs in constructing a new antiretroviral regimen to obtain virologic success, and adding a compound with a different mechanism of action often increases the chances of virologic response. With the introduction of new drug classes and new-generation compounds of older classes in the antiretroviral armamentarium, the chances of achieving virologic success in patients with resistance to all three original antiretroviral classes are certainly higher than in the past. Patients who experience virologic failure and show resistance to new antiretrovirals are, however, described both in randomized trials and clinical settings. Although HAART regimens using various associations of the newest antiretrovirals led to very high rates of virologic success in patients with previous failure to all three original drug classes, there are circumstances in which patients cannot benefit from two fully active drugs, especially after prior exposure to several suboptimal therapies or functional monotherapies. These patients often need a holding regimen while awaiting new and effective antiretrovirals. This article reviews strategies that might be effective options to obtain virologic success in patients with triple class failure, and treatment strategies for patients who do not have two active drugs to construct a new effective antiretroviral regimen after virologic failure.
    Article · Feb 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Background. Low CD4⁺ T-cell counts are the main factor leading to clinical progression in human immunodeficiency virus type 1 (HIV-1) infection. We aimed to investigate factors affecting CD4⁺ T-cell counts after triple-class virological failure. Methods. We included individuals from the COHERE database who started antiretroviral therapy from 1998 onward and who experienced triple-class virological failure. CD4⁺ T-cell counts obtained after triple-class virologic failure were analyzed using generalized estimating equations. Results. The analyses included 2424 individuals with a total of 23 922 CD4⁺ T-cell count measurements. In adjusted models (excluding current viral load and year), CD4⁺ T-cell counts were higher with regimens that included boosted protease inhibitors (increase, 22 cells/µL [95% confidence interval {CI}, 3.9–41]; P = .017) or drugs from the new classes (increase, 39 cells/µL [95% CI, 15–62]; P = .001), compared with nonnucleoside reverse-transcriptase inhibitor–based regimens. These associations disappeared when current viral load and/or calendar year were included. Compared with viral levels of <2.5 log10 copies/mL, levels of 2.5–3.5, 3.5–4.5, 4.5–5.5, and >5.5 log10 copies/mL were associated with CD4⁺ T-cell count decreases of 51, 84, 137, and 186 cells/µL, respectively (P < .001). Conclusions. The approximately linear inverse relationship between log10 viral load and CD4⁺ T-cell count indicates that there are likely immunologic benefits from lowering viral load even by modest amounts that do not lead to undetectable viral loads. This is important for patients with low CD4⁺ T-cell counts and few drug options.
    Full-text · Article · Mar 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Background Highly active antiretroviral therapy (HAART) has reduced morbidity and mortality in patients infected with human immunodeficiency virus (HIV). Studies have documented high interindividual variability in the pharmacokinetics of antiretroviral drugs, which may impair the success of HAART if not managed properly. Therapeutic drug monitoring (TDM) is a useful diagnostic tool that helps clinicians to optimize drug doses so that drug concentrations associated with the highest therapeutic efficacy are obtained with a reduced risk of concentration-dependent adverse effects. The aim of this study was to assess whether use of TDM improves clinical outcomes and cost of illness. Methods A retrospective cohort study was conducted at L Sacco University Hospital in Milan, Italy, in HIV-infected patients aged ≥18 years with at least one prescription of antiretroviral drugs for which TDM was applied. The inclusion period was from January 2010 to December 2011, with a follow-up period of up to 12 months. Laboratory and administrative databases were analyzed and matched with each other. Results The cohort consisted of 5,347 patients (3,861 males and 1,486 females) of mean age 43.9±12.5 years. We found that TDM had been used in 143 of these patients, among whom adherence with therapy was significantly higher than among those in whom TDM had not been used (94% versus 78%). In TDM-controlled patients, the mean length of HIV-related hospitalization stay and mean cost of hospitalization were significantly reduced with respect to those observed in the group in which TDM had not been used (7.21 days versus 29.47 days and €293 versus €688, respectively). Conclusion Inclusion of TDM as part of routine clinical optimization of drug dosing in HIV-infected patients is associated with higher adherence to therapy, reduced length of hospitalization stay, and reduced cost of illness.
    Full-text · Article · Jul 2014
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