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.3–6 However, virologic failure, which includes both failure to achieve viral suppression and confirmed viral rebounds, still develops in a small minority.7–10 Virologic failure may be the consequence of the presence of resistance mutations or of insufficient drug levels due to reasons such as poor adherence, drug intolerance, insufficient drug dosages, or drug–drug 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 reflecting 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 first-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 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 antiretrovirals (fusion and integrase inhibitors and CCR5 antagonists13–16) 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 dualtherapy.17,18 Trends in incidence and prevalence of TCVF over time have not been fully characterized in recent years, specifically 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.
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) project,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 defined as 1 viral load measurement above 500 copies/mL despite 4 months of continuous drug use. TCVF was defined as virologic failure of at least 2 nucleos(t)ide reverse transcriptase inhibitors, 1 NNRTI and 1 PI/r. Triple-class exposure was defined 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 P values are two-sided. Analyses were performed using SAS software, version 9.1 (SAS Inc, Cary, NC).
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/μL and 4.7 (3.7-5.2) log10copies/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 prevalence 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.
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 first-line regimens and use of fixed-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 diagnosis, better quality care, enhanced knowledge of adherence, and a better understanding of ART (eg, timing of initiation, toxicities, drug–drug 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 identified 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 identify a lower risk of TCVF for patients starting ART in more recent calendar years. However, this discrepancy is thought to 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 definition of TCVF, ART regimen, and study setting. Here, we adopted the same definition as in previous PLATO II analyses.12 Alternative definitions include the following: viral load measurement above 1000 copies/μL required for virologic failure,17,23–25 at least 6 months continuous use of a drug required for virologic 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 suppression 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/μL3 and increased clinical progression.17,23 Other implications of TCVF include potential for transmission of multidrug-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 duration on therapy increases for patients with TCVF, further virologic failure of the remaining available drugs in the original 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 artificial in that clinic populations will also include some people who started ART before 1998, often with mononucleoside or dual-nucleosideregimens. Since there is inevitably a time lag between initiation of ART and the first 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 team12 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 resistance and without complete and regular genotypic data and data on adherence, it is difficult to establish the cause of TCVF. On the other hand, some people who do not experience virologic failure of a drug by our definition may nevertheless have developed resistance. This may occur, for example, if drugs were switched before the viral load had reached 500 copies/μL. 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 antiretroviral drugs may be necessary to sustain current low levels of incidence and prevalence.
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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 Ledergerber (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 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 d'Arminio 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 d'Arminio-Monforte (ICONA), Manuel Battegay (MoCHIV), Maria Prins (CASCADE), Frank de Wolf (ATHENA), Jesper Grarup (Head of Copenhagen 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 d'Arminio 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.