Combination antiretroviral therapy (ART) has dramatically reduced HIV-related morbidity and mortality  through its ability to suppress HIV replication. HIV viremia strongly predicts progression to AIDS and death . According to current international treatment guidelines, the goal of ART is therefore to reach and to maintain undetectable plasma HIV viral load [3,4]. In recent years, the improvement of assays quantifying plasma viral load has progressively led to decreasing the thresholds for detecting viremia, currently between 20 and 50 copies/ml in clinical practice. Around 20% of HIV-infected patients receiving combination ART show transient rebounds of viremia, and 4–10% experience persistent episodes of detectable viremia at low levels, between 50 and 500 copies/ml [5–8].
There is no evidence that transient rebounds of viremia (‘blips’, usually defined as detectable viremia up to a maximum of 500 copies/ml preceded and followed by visits showing undetectable viremia) are associated with subsequent virological or immunological failure [8–10]. By contrast, persistent low-level viremia (LLV) might be associated with negative consequences such as virological failure [6,10–13], emergence of drug resistance [7,14–18], and immunological deterioration . The optimal management of patients experiencing LLV is still unclear due to the lack of controlled comparison data, especially in the range of 50–200 copies/ml, and the impact of LLV on clinical outcomes remains unknown. Although achieving an undetectable viral load remains the goal of ART, we cannot assert that LLV must be considered as virological failure requiring treatment modification or more frequent virological monitoring. The Department of Health and Human Services (DHHS, USA) guidelines currently define virological failure as a confirmed viral load above 200 copies/ml , but there are currently no international guidelines on how to manage patients experiencing LLV and further studies are assuredly needed to establish the effect of LLV on HIV prognosis.
We aimed to assess the prognostic impact of different levels of LLV (50–199 and 200–499 copies/ml) on clinical (AIDS events and death) and virological outcomes (virological failure) among HIV-infected patients receiving potent combination ART.
We analyzed data from 18 cohorts in Europe and North America, contributing to the ART Cohort Collaboration (ART-CC)  (http://http://www.bris.ac.uk/art-cc). Briefly, ART-CC includes patients with confirmed HIV infection, aged at least 16 years, who started combination ART after 1996 without previous treatment with antiretroviral drugs. Contributing cohorts (listed in the ‘Acknowledgements’ section) have received approval from the ethics committees or institutional review boards, used standardized methods of data collection, and scheduled follow-up visits at least every 6 months. The NHS Health Research Authority South West – Cornwall and Plymouth Research Ethics Committee, UK, has approved the ART-CC study (REC reference 12/SW/0253).
Patients were eligible for inclusion in the current analysis if they: started (‘baseline’) an ART regimen composed of two nucleoside reverse transcriptase inhibitors (NRTIs, among zidovudine, didanosine, stavudine, abacavir, tenofovir, emtricitabine, and lamivudine) with either a non-nucleoside reverse transcriptase inhibitor (NNRTI, among efavirenz, nevirapine, etravirine, and rilpivirine) or a protease inhibitor-boosted with ritonavir (PI/r, among atazanavir, darunavir, and lopinavir), which was continued for at least 6 months; achieved viral load below 50 copies/ml within 3–9 months after ART initiation (virological suppression); and all viral loads were measured by virological assays with lower limit of quantification 50 copies/ml or less. Demographic, clinical, and biological characteristics, and ART regimen of eligible participants were extracted from the cohort database, which was compiled in 2012.
Low-level viremia 50–199 was defined as at least two consecutive viral loads between 50 and 199 copies/ml for at least 1 month, and LLV200–499 as at least two consecutive viral loads between 50 and 499 copies/ml for at least 1 month, with at least one viral load between 200 and 499 copies/ml, after virological suppression. The primary outcome was occurrence of clinical events (first AIDS event after ART initiation, defined as a clinical event listed in category C, according to the classification of the Centers for Disease Control and Prevention (CDC) for HIV infection as revised in 1993 , and death). The secondary outcome was occurrence of a first virological failure, defined as at least two consecutive viral loads at least 500 copies/ml or one viral load at least 500 copies/ml, followed by a modification of at least one therapeutic class in ART regimen. The date of virological failure was the date of the first of these viral loads at least 500 copies/ml. Baseline characteristics of patients experiencing LLV (LLV50–199 and LLV200–499) were compared with those of patients who did not experience LLV (group ‘no LLV’) using Kruskal–Wallis tests for continuous variables and chi-square tests for categorical variables.
Follow-up started at the date of the first viral load below 50 copies/ml, within 3–9 months after ART initiation. Patients without virological failure or clinical events were right-censored at the date of the last follow-up visit. LLV was analyzed as a time-varying covariate in which patients were included in the LLV50–199-exposed group from the first date they experienced an episode of LLV50–199, and in the LLV200–499-exposed group from the first date they experienced an episode of LLV200–499. Once patients were exposed to a higher category of LLV, they remained in this category for the remaining follow-up time. Thus, there were three groups: no LLV: time from start of follow-up to first LLV50–199/LLV200–499; LLV50–199: time from first LLV50–199 (before first LLV200–499) to date of first LLV200–499; and LLV200–499: time from first LLV200–499.
Extended Kaplan–Meier curves (as described here: http://www.tandfonline.com/doi/pdf/10.1198/000313005X70371) were used to examine the distributions of time to virological failure and clinical events by LLV group, and comparisons between them were made using log-rank test. We used Cox proportional-hazards regression models stratified by cohort to estimate crude and adjusted hazard ratios for associations of LLV (50–199 and 200–499 copies/ml, compared to <50 copies/ml), with first virological failure and first AIDS event/death. Models were adjusted for sex; baseline age (<30, 30–49 and ≥50 years); ART regimen (NNRTI or PI/r-based regimen); transmission group [MSM, injection drug user (IDU), heterosexual, other/unknown]; CD4+ cell count (0–49,50–199, 200–349, ≥350 cells/μl); viral load (<4.5 log, 4.5–4.9 log, ≥5 log copies/ml); AIDS stage; and period of ART initiation (1997–2002, 2003–2006, ≥2007). The proportional hazards assumption was checked graphically and by tests based on Schoenfeld residuals. Cox models restricted to patients experiencing LLV were used to estimate the association of cumulative duration of LLV (1–3, 3–6, 6–12, and >12 months) and type of ART regimen at LLV (NNRTI or PI/r-based regimen) with first virological failure and first AIDS event/death, adjusted for same variables. Cox models restricted to patients who did not modify their ART regimen during LLV were performed to assess the impact of switching antiretroviral drugs during LLV on the outcomes. All statistical analyses were performed using Stata software (version 12.0; College Station, Texas, USA).
Among the 17 902 included patients (median age 39.6 years, 76% men, median baseline CD4+ 229 cells/μl, 59% starting NNRTI-based regimens), 624 (3.5%) experienced at least one episode of LLV50–199 with no LLV200–499 [median duration 5.8, interquartile range (IQR) 3.2–8.6 months] and 482 (2.7%) at least one episode of LLV200–499 (median duration 6.4, IQR, 3.6–11.2 months). The mean number of viral load measures per year of follow-up was similar in the three groups [4.22, 95% confidence interval (CI) 4.18–4.27 in the no LLV group; 4.42, 95% CI 4.29–4.56 in the LLV50–199 group; and 4.23, 95% CI 4.10–4.37 in the LLV200–499 group]. Among the 624 patients who experienced at least one episode of LLV50–199, 59 (9.5%) modified their ART regimen (at least one class of antiretroviral drugs) during LLV (8.9 and 8.3% among patients receiving NNRTI and PI/r-based regimen, respectively). Among the 482 patients who experienced at least one episode of LLV200–499, 64 (13.3%) modified their ART regimen during LLV (13.7 and 6.4% among patients receiving NNRTI and PI/r-based regimen, respectively). Baseline characteristics of the included patients according to the occurrence of LLV50–199 or LLV200–499 are described in Table 1. Patients who experienced LLV were more likely to have had an AIDS event (CDC stage C) before starting ART, had lower CD4+ cell counts and higher viral load at start of ART, were more likely to start with a PI/r-containing ART regimen, and tended to start ART less recently than those who did not experience LLV.
During 54 641 person-years of follow-up (PYFU) (median 2.3 years, IQR 1.0–4.3), 1903 patients (10.6%) experienced virological failure [1745 (10.4%) among 16 796 patients without LLV, 49 (7.9%) among 624 patients experiencing LLV50–199, and 109 (22.6%) among 482 patients experiencing LLV200–499], corresponding to 3.48 virological failure per 100 PYFU (95% CI 3.33–3.64).
Among the 1903 patients experiencing virological failure, 961 (50.5%) modified their ART regimen (at least one therapeutic class) within 6 months after virological failure. Among the patients who modified their ART regimen, 77.2% had viral load below 50 copies/ml within 6 months after ART modification and 81.9% within 12 months after ART modification, whereas among the patients who stayed under the same ART regimen, 14.1% had viral load below 50 copies/ml within 6 months after virological failure and 26.4% within 12 months after virological failure.
On the basis of the Kaplan–Meier estimates, the time by which 90% of patients remained free of virological failure (virological failure 90% survival time) was 2.7 (95% CI 2.5–2.8) years (Fig. 1a). The virological failure 90% survival time was 2.8 (95% CI 2.6–3.0) years for patients without LLV, 2.2 (1.1–3.5) years for patients with LLV50–199 (P = 0.160 compared with patients without LLV), and 1.1 (0.3–1.9) years for patients with LLV200–499 (P < 0.001 compared with patients without LLV).
Both before and after adjusting for patient characteristics at start of ART, LLV200–499 was strongly associated with virological failure [adjusted hazard ratio (aHR) 3.97, 95% CI 3.05–5.17]. By contrast, LLV50–199 was weakly associated with virological failure (aHR 1.38, 95% CI 0.96–2.00). We found weak evidence of association between ART regimen at inclusion and risk of virological failure (aHR for PI/r-based versus NNRTI-based regimen 1.14, 95% CI 0.99–1.31). Baseline AIDS stage, CD4+ cell count, age, transmission group, and period of ART initiation were strongly associated with virological failure (Table 2). In sensitivity analyses restricted to patients experiencing LLV, neither type of ART regimen at LLV (PI/r-based versus NNRTI-based regimen), modification of ART regimen during LLV (at least one class of antiretroviral drug), nor cumulative duration of LLV was associated with virological failure (Table 3). In sensitivity analyses restricted to patients who did not modify their ART regimen during LLV among both patients receiving PI/r and NNRTI, LLV200–499 was still strongly associated with virological failure (aHR 4.39, 95% CI 2.90–6.63 for PI/r; and aHR 3.51, 95% CI 2.31–5.34 for NNRTI), whereas LLV50–199 was not (aHR 0.91, 95% CI 0.46–1.78; and aHR 1.59, 95% CI 0.93–2.74 for PI/r and NNRTI, respectively).
During 68 230 PYFU (median 3.1 years, IQR 1.6–5.3), 480 (2.7%) patients died [432 (2.6%) among 16 796 patients without LLV, 24 (3.8%) among 624 patients experiencing LLV50–199, and 24 (5.0%) among 482 patients experiencing LLV200–499], corresponding to 0.70 (95% CI 0.64–0.77) deaths per 100 PYFU with a 95% survival time of 7.1 (6.4–7.9) years. Furthermore, 532 (3.0%) patients experienced at least one post-ART AIDS event, corresponding to 0.80 (0.73–0.87) AIDS events per 100 PYFU, with a 95% survival time to AIDS event of 8.1 (7.3–9.1) years.
On the basis of Kaplan–Meier estimates, the time by which 90% of patients remained free of clinical events (AIDS event/death) (Fig. 1b) was not different between the three groups, as this time was 8.6 (95% CI 7.7–8.9) years for patients without LLV, 5.7 (3.8–10) years for patients with LLV50–199, and 8.3 (4.1–10) years for patients with LLV200–499 (P = 0.229). No difference was found when these analyses were restricted to either AIDS event or death, respectively (data not shown).
Table 4 shows that in multivariate analyses, neither LLV50–199 nor LLV200–499 was associated with AIDS event/death (aHR 1.13, 95% CI 0.81–1.68; and aHR 0.95, 95% CI 0.62–1.48, respectively). No difference was found when these analyses were restricted to either AIDS event (aHR 1.11, 95% CI 0.79–1.61; and aHR 0.81, 95% CI 0.51–1.28 for LLV50–199 and LLV200–499, respectively) or death (aHR 1.19, 95% CI 0.78–1.82; and aHR 1.11, 95% CI 0.72–1.71 for LLV50–199 and LLV200–499, respectively). Baseline CD4+ cell count, AIDS stage, age, transmission group, and period of ART initiation were strongly associated with AIDS event/death. In sensitivity analyses restricted to patients experiencing LLV, neither type of ART regimen at LLV (PI/r-based versus NNRTI-based regimen), modification of ART regimen during LLV (at least one class of antiretroviral drug), nor cumulative duration of LLV was associated with AIDS event/death (Table 3).
In this cohort study which included HIV-infected patients with viral load below 50 copies/ml 3–9 months after starting potent combination ART, 6.2% of patients experienced LLV (LLV50–199 in 3.5% of patients and LLV200–499 in 2.7%). LLV200–499 was strongly associated with virological failure, but not with AIDS event/death. By contrast, there was little evidence that LLV50–199 was associated with either virological or clinical outcomes. Modification of ART regimen during LLV did not influence either the clinical or the virological outcome.
The prevalence of LLV in our study is consistent with previous studies, which found a prevalence of LLV between 50 and 500 copies/ml among patients on stable ART around 4–10% [6–8]. The phenomenon of LLV could result from the release of virus from stable reservoirs such as latently infected resting memory CD4+ T cells that are activated by antigenic stimulation [23–25]. It could also result from ongoing viral replication [25,26] because of suboptimal therapy (especially within anatomical compartments less accessible to antiretroviral drugs), facilitated by variations in drug concentrations (attributable to pharmacokinetic issues or incomplete adherence to drug regimens) and/or the emergence of drug resistance-associated mutations.
The prognostic implications and optimal management strategy for LLV are still uncertain, because of a lack of controlled comparison data, especially for patients experiencing LLV between 50 and 199 copies/ml. The optimal target level of viral load suppression amongst patients receiving ART, and conversely the definition of virological failure, is also unclear . Whilst currently used third-generation viral load assays have a lower limit of quantification of 20–50 copies/ml and can report qualitative RNA detection below these thresholds, the DHHS (USA) guidelines currently define virological failure as a confirmed viral load above 200 copies/ml . This study provides evidence to support these guidelines, and against lowering that threshold.
Rates of virological failure were higher in patients who experienced LLV200–499 than in patients with sustained viral suppression, whereas LLV50–199 was only weakly associated with virological failure in our study. There are few data regarding the impact of persistent LLV between 50 and 500 copies/ml on virological outcome, especially LLV between 50 and 199 copies/ml. Our results support those of previous large studies which have reported a higher risk of virological failure in patients experiencing persistent LLV between 50 and 500 copies/ml than in those who maintained viral suppression [6,11,12], but these studies did not focus on LLV between 50 and 199 copies/ml. Greub et al. found that among 2055 patients achieving viral suppression, two consecutive viral loads between 50 and 500 copies/ml increased the risk of virological failure (viral load >500 copies/ml) by more than five times (hazard ratio 5.8, 95% CI 4.26–7.90). Geretti et al. found that among 1386 patients, the risk of virological failure (viral load >400 copies/ml) for patients with persistent LLV (defined as two consecutive viral loads between 50 and 400 copies/ml) was more than double that for patients whose viral load remained undetectable (hazard ratio 2.29, 95% CI 1.22–4.29). Unlike our study, Laprise et al. found in their study including 1357 patients that both LLV50–199 copies/ml and LLV200–499 copies/ml (persistent for at least 6 months) doubled the risk of virological failure (defined as viral load >1000 copies/ml) compared with patients who maintained an undetectable viral load. Nevertheless, inclusion criteria differed from our study: whereas we only included patients under potent combination of antiretroviral drugs who achieved viral suppression, their patients were included if they had at least one viral load measurement and had received any antiretroviral drug for at least 12 months, regardless of the type of antiretroviral drug regimen .
We cannot exclude the fact that the association of LLV200–499 with the occurrence of viral load was partly explained by the fact the levels of viremia in this group are closest to the threshold of virological failure. Nevertheless, this hypothesis should be minimized by the fact that the mean number of viral load measures per year of follow-up was similar in the three groups (no LLV, LLV50–199, and LLV200–49). Therefore, we believe that this association has a real clinical significance.
Resistance data were not available in the ART-CC database. Several recent studies have found that ongoing low-level viral replication (below 500 copies/ml) in patients receiving combination ART may promote the emergence and selection of drug-resistance mutations [14–16], even for LLV50–199 , which could negatively impact future ART options. For example, Delaugerre et al. showed that 11 of 37 patients with persistent LLV episodes below 500 copies/ml while receiving ART developed at least one drug-resistance mutation. Moreover, Gonzalez-Serna et al. and Swenson et al. found that emergent HIV drug resistance at LLV was strongly associated with subsequent virological failure. Resistance genotyping should be performed in patients with persistent LLV and ART should be modified if resistance is detected.
The type of quantification assays might modify the prevalence of LLV. Highly sensitive quantification assays have shown discrepancies between them, especially evident at low levels of viremia, resulting in a significant difference in number of patients with detectable viral load [28–32]. All viral load measurements in our study were quantified with virological assays with lower limit of quantification below 50 copies/ml. However, the lack of accurate data regarding the precise type of quantification assays used in all patients did not allow us to include this variable in the multivariate analyses to account for interassay variability.
Although there is a lower ‘genetic barrier’ for NNRTI versus PI/r, which might be expected to increase the risk of emergent drug resistance and hence the risk of subsequent virological failure during LLV under NNRTI-based regimens, no association was found between the type of ART regimen at LLV (PI/r-based versus NNRTI-based regimen) and virological failure in the sensitivity analysis restricted to patients experiencing LLV. The modification of the ART regimen during LLV (especially with NNRTI-based regimens) could be a potential confounder, although only a small proportion of our patients modified their ART during LLV.
Although viral load has long been recognized as a prognostic factor for clinical progression, there is little literature on the association between LLV below 500 copies/ml and clinical outcomes. Zhang et al. found no association between LLV (50–400 copies/ml) and non-AIDS disease. In our study, neither LLV50–199 nor LLV200–499 was associated with AIDS event/death, compared with prolonged suppression. However, the lack of evidence of association between LLV and clinical outcomes may be due to the small number of endpoints and/or the fact that most of the patients who modified treatment after virological failure were re-suppressed. Moreover, the median clinical follow-up was 3.1 years, which might be insufficient to demonstrate an impact of LLV on mortality, mediated by virological failure or other mechanisms. LLV is one of the potential underlying causes of persistent immune activation and inflammation in HIV patients under ART, which could contribute to mortality and non-AIDS morbidity, including cardiovascular and end-organ disease [34–37]. Furthermore, LLV could contribute to the replenishment of latent viral reservoir , which is one of the obstacles to achieving eradication of HIV.
In conclusion, among patients virologically suppressed 3–9 months after starting potent combination ART and with a median follow-up of 2.3–3.1 years, persistent LLV between 200 and 499 copies/ml was strongly associated with virological failure, but not with AIDS event/death. The lack of association of persistent LLV between 50 and 199 copies/ml with virological failure or clinical outcomes, supports current guidelines, which define virological failure as a confirmed viral load above 200 copies/ml.
We thank all patients, doctors, and study nurses associated with the participating cohort studies.
Contribution of authors: Philippe Morlat and Geneviève Chene conceived the idea. Jonathan Sterne is the Principal Investigator for the ART Cohort Collaboration, which funded the research. Marie-Anne Vandenhende, Suzanne Ingle, Margaret May, and Jonathan Sterne did statistical analyses. Marie-Anne Vandenhende, did the literature search and wrote the first draft of the paper. All authors contributed to study design, collection of data, data interpretation, writing the paper, and approved the final version. Marie-Anne Vandenhende, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding: This work was supported by the UK Medical Research Council and the Department for International Development (DFID) (grants G0700820 and MR/J002380/1). Jonathan Sterne was supported by NIHR Senior Investigator Award NF-SI-0611–10168. Sources of funding of individual cohorts include the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the French, Italian and Spanish Ministries of Health, the Swiss National Science Foundation (grant 33CS30_134277), the Ministry of Science and Innovation and the “Spanish Network for AIDS Research (RIS; ISCIII-RETIC RD06/006), the Stichting HIV Monitoring, the European Commission (EuroCoord grant 260694), the British Columbia and Alberta Governments, the National Institutes of Health (NIH) [UW Center for AIDS Research (CFAR) (NIH grant P30 AI027757), UAB CFAR (NIH grant P30-AI027767), The Vanderbilt-Meharry CFAR (NIH grant P30 AI54999), National Institute on Alcohol Abuse and Alcoholism (U10-AA13566, U24-AA020794), the US Department of Veterans Affairs, the Michael Smith Foundation for Health Research, the Canadian Institutes of Health Research, the VHA Office of Research and Development and unrestricted grants from Abbott, Gilead, Tibotec-Upjohn, ViiV Healthcare, Merck Sharp & Dohme-Chibret, GlaxoSmithKline, Pfizer, Bristol Myers Squibb, Roche and Boehringer-Ingelheim.
Writing committee: Marie-Anne Vandenhendea,b, Suzanne Inglec, Margaret Mayc, Geneviève Chenea, Robert Zangerled, Ard Van Sigheme, M. John Gillf, Carolynne Schwarze-Zanderg, Beatriz Hernandez-Novoah, Niels Obeli, Ole Kirki,j, Sophie Abgrallk,l,m, Jodie Guestn, Hasina Samjio, Antonella D’Arminio Monfortep, Josep M. Llibreq, Colette Smithr, Matthias Cavassinis, Greer A. Burkholdert, Bryan Shepherdu, Heidi M. Cranev, Jonathan Sternec, and Philippe Morlata,b.
Institutional affiliations: aINSERM U897 and CIC-EC7, University of Bordeaux Segalen, ISPED (Bordeaux School of Public Health), CHU de Bordeaux, F-33000 Bordeaux, France; bService de médecine interne et maladies infectieuses, CHU de Bordeaux, F-33000 Bordeaux, France; cSchool of Social and Community Medicine, University of Bristol, Bristol, UK; dDepartment of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, Austria; eStichting HIV Monitoring, Amsterdam, the Netherlands; fDivision of Infectious Diseases, University of Calgary, Calgary, Canada; gDepartment of Internal Medicine I, University Hospital Bonn, Germany; hHospital Ramón y Cajal, Madrid, Spain; iDepartment of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; jCopenhagen HIV Programme, Panum Institute, University of Copenhagen, Denmark; kUPMC Université Paris 06, UMR-S 943, F-75013, Paris, France; lINSERM, UMR-S 943, F-75013, Paris, France; mAP-HP; Hôpital Avicenne, Service des maladies infectieuses et tropicales, Bobigny F-93000, France; nHIV Atlanta VA Cohort Study (HAVACS), Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA; oDivision of Epidemiology and Population Health, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada; pClinic of Infectious Diseases & Tropical Medicine, San Paolo Hospital, University of Milan, Italy; qUniversity Hospital Germans Trias i Pujol and ‘Lluita contra la SIDA’ Foundation, Badalona, Spain; rResearch Department of Infection and Population Health, UCL, London, UK; sService of Infectious Diseases, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; tDivision of Infectious Disease, Department of Medicine, University of Alabama, Birmingham, USA; uDepartment of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; vCenter for AIDS Research, University of Washington, Seattle, USA
ART-CC contributing cohorts: Austrian HIV Cohort Study, AIDS Therapy Evaluation Project, Netherlands (ATHENA); Danish HIV Cohort Study, Agence Nationale de la Recherche sur le SIDA et les hépatites virales (ANRS) CO3 Aquitaine Cohort, France; ANRS CO4 French Hospital Database on HIV (FHDH); EuroSIDA Study Group; Italian Cohort of Antiretroviral-Naive Patients (ICONA); Köln/Bonn Cohort, Germany; Proyecto para la Informatización del Seguimiento Clínico-epidemiológico de la Infección por HIV y SIDA (PISCIS) Cohort, Spain; Cohorte de la Red de Investigación en Sida (CoRIS), Spain ; Royal Free Hospital Cohort, London, UK; HAART Observational Medical Evaluation and Research (HOMER), British Columbia, Canada; South Alberta Clinic Cohort, Canada; Swiss HIV Cohort Study (SHCS); 1917 Clinic Cohort from the University of Alabama (UAB), USA; HIV Atlanta Veterans Affairs Cohort Study (HAVACS), USA; Vanderbilt-Meharry Center for AIDS Research, Nashville, Tennessee, USA; University of Washington HIV Cohort, Seattle, USA.
The funders had no role in the design and conduct of this study or in the decision to submit the manuscript for publication.
Conflicts of interest
Suzanne Ingle, Margaret May, Jodie Guest, Robert Zangerle, Beatriz Hernández-Novoa, Carolynne Schwarze-Zander have no conflicts of interest. Marie-Anne Vandenhende has travel/meeting expenses from Janssen-Cilag, Gilead and Merck Sharp & Dohme-Chibret and is a board member for Gilead. In the past 4 years, Geneviève Chêne has received consulting fees from Roche and has received travel grant from Lundbeck. G. Chêne has had scientific responsibilities in projects receiving specific grant supports that are managed through her Institution or a nonprofit society: from the French Agency for Research on AIDS and Viral Hepatitis (ANRS), the European Commission (Framework Program 7), UK Medical Research Council, US National Institute of Health (NIH), Fondation Plan Alzheimer, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron, Fit Biotech LTD, Gilead Sciences, GlaxoSmithKline, Jansen Cilag, Merck Sharp & Dohme-Chibret, Pfizer, Roche, Tibotec, ViiV Healthcare. G. Chêne serves as Academic Editor of Plos ONE and is on the editorial board of BMC Infectious Diseases Journal. Philippe Morlat has received honoraria or travel/meeting expenses from Abbott, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme-Chibret, Pfizer, Janssen-Cilag and ViiV Healthcare. Josep M Llibre has received research funding, consultancy fees, and lecture sponsorships from or has served on advisory boards for Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Glaxo Smith-Kline, Janssen-Cilag, Merck Sharp & Dohme, and ViiV Healthcare.Antonella d’Arminio Monforte is a board member for Bristol-Myers Squibb, Abbvie, Gilead, Janssen, and Merck Sharp & Dohme-Chibret, and has grants pending from Merck Sharp & Dohme-Chibret, Janssen and Gilead. Matthias Cavassini has consulted for Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead, Merck Sharp & Dohme-Chibret and Janssen Cilag, has grants pending from Bristol-Myers Squibb, Gilead and Merck Sharp & Dohme-Chibret, has received payment for service on speakers bureaus from Gilead and travel/meeting expenses from Boehringer-Ingelheim, Bristol-Myers Squibb and Gilead. M. John Gill is a board member for Abbvie, Gilead, Merck Sharp & Dohme-Chibret, Janssen and ViiV Healthcare. Jonathan Sterne has received payment for development of educational presentations from Gilead. Heidi M. Crane has grants pending from NIH, AHRQ, CDC, HRSA and has received payment for development of educational presentations from WebMD. Niels Obel has received research funding from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, Janssen-Cilag and Swedish Orphan. Colette Smith has funding from BMS, prepared educational material for ViiV, Janssen, BMS, Gilead and attended an Ad board for Gilead. Ole Kirk had prior board membership at ViiV Healthcare, received payment for lectures and/or for development of educational presentations from Abbott, Gilead and Tibotec/Janssen Cilag, and had expenses to travel/accommodations/meetings covered by Abbott, Bristol-Myers Squibb, Gilead, Merck and ViiV Healthcare. Sophie Abgrall is a board member for Janssen-Cilag, and has received payment for service on speakers bureaus from Gilead, and travel/meeting expenses from Janssen-Cilag, Gilead and Abbott.
1. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators
. N Engl J Med
2. Thiebaut R, Morlat P, Jacqmin-Gadda H, Neau D, Mercie P, Dabis F, et al. Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment. Groupe d’Epidemiologie du SIDA en Aquitaine (GECSA)
3. EACS. European AIDS Clinical Society. European Guidelines for treatment of HIV infected adults in Europe. Version 6.1 (2012). http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf
4. Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel
5. Cohen C. Low-level viremia in HIV-1 infection: consequences and implications for switching to a new regimen
. HIV Clin Trials
6. Greub G, Cozzi-Lepri A, Ledergerber B, Staszewski S, Perrin L, Miller V, et al. Intermittent and sustained low-level HIV viral rebound in patients receiving potent antiretroviral therapy
7. Taiwo B, Gallien S, Aga E, Ribaudo H, Haubrich R, Kuritzkes DR, et al. Antiretroviral drug resistance in HIV-1-infected patients experiencing persistent low-level viremia during first-line therapy
. J Infect Dis
8. Garcia-Gasco P, Maida I, Blanco F, Barreiro P, Martin-Carbonero L, Vispo E, et al. Episodes of low-level viral rebound in HIV-infected patients on antiretroviral therapy: frequency, predictors and outcome
. J Antimicrob Chemother
9. Havlir DV, Bassett R, Levitan D, Gilbert P, Tebas P, Collier AC, et al. Prevalence and predictive value of intermittent viremia with combination HIV therapy
10. Karlsson AC, Younger SR, Martin JN, Grossman Z, Sinclair E, Hunt PW, et al. Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia
11. Geretti AM, Smith C, Haberl A, Garcia-Diaz A, Nebbia G, Johnson M, et al. Determinants of virological failure after successful viral load suppression in first-line highly active antiretroviral therapy
. Antivir Ther
12. Sungkanuparph S, Groger RK, Overton ET, Fraser VJ, Powderly WG. Persistent low-level viraemia and virological failure in HIV-1-infected patients treated with highly active antiretroviral therapy
. HIV Med
13. Laprise C, de Pokomandy A, Baril JG, Dufresne S, Trottier H. Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation
. Clin Infect Dis
14. Delaugerre C, Gallien S, Flandre P, Mathez D, Amarsy R, Ferret S, et al. Impact of low-level-viremia on HIV-1 drug-resistance evolution among antiretroviral treated-patients
. PLoS One
15. Li JZ, Gallien S, Do TD, Martin JN, Deeks S, Kuritzkes DR, et al. Prevalence and significance of HIV-1 drug resistance mutations among patients on antiretroviral therapy with detectable low-level viremia
. Antimicrob Agents Chemother
16. Gallien S, Delaugerre C, Charreau I, Braun J, Boulet T, Barrail-Tran A, et al. Emerging integrase inhibitor resistance mutations in raltegravir-treated HIV-1-infected patients with low-level viremia
17. Swenson LC, Min JE, Woods CK, Cai E, Li JZ, Montaner JS, et al. HIV drug resistance detected during low-level viraemia is associated with subsequent virologic failure
18. Gonzalez-Serna A, Min JE, Woods C, Chan D, Lima VD, Montaner JS, et al. Performance of HIV-1 drug resistance testing at low-level viremia and its ability to predict future virologic outcomes and viral evolution in treatment-naive individuals
. Clin Infect Dis
19. Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection
20. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2014. http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
21. May MT, Ingle SM, Costagliola D, Justice AC, de Wolf F, Cavassini M, et al. Cohort profile: Antiretroviral Therapy Cohort Collaboration (ART-CC)
. Int J Epidemiol
22. CDC CfDCaP. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults
. MMWR Recomm Rep
23. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection
24. Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection
. J Allergy Clin Immunol
25. Tobin NH, Learn GH, Holte SE, Wang Y, Melvin AJ, McKernan JL, et al. Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus
. J Virol
26. Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged antiretroviral therapy
. Nat Med
27. Doyle T, Geretti AM. Low-level viraemia on HAART: significance and management
. Curr Opin Infect Dis
28. Ruelle J, Debaisieux L, Vancutsem E, De Bel A, Delforge ML, Pierard D, et al. HIV-1 low-level viraemia assessed with 3 commercial real-time PCR assays show high variability
. BMC Infect Dis
29. Sire JM, Vray M, Merzouk M, Plantier JC, Pavie J, Maylin S, et al. Comparative RNA quantification of HIV-1 group M and non-M with the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 v2.0 and Abbott Real-Time HIV-1 PCR assays
. J Acquir Immune Defic Syndr
30. Karasi JC, Dziezuk F, Quennery L, Forster S, Reischl U, Colucci G, et al. High correlation between the Roche COBAS(R) AmpliPrep/COBAS(R) TaqMan(R) HIV-1, v2.0 and the Abbott m2000 RealTime HIV-1 assays for quantification of viral load in HIV-1 B and non-B subtypes
. J Clin Virol
31. Lima V, Harrigan R, Montaner JS. Increased reporting of detectable plasma HIV-1 RNA levels at the critical threshold of 50 copies per milliliter with the Taqman assay in comparison to the Amplicor assay
. J Acquir Immune Defic Syndr
32. Verhofstede C, Van Wanzeele F, Reynaerts J, Mangelschots M, Plum J, Fransen K. Viral load assay sensitivity and low level viremia in HAART treated HIV patients
. J Clin Virol
33. Zhang S, van Sighem A, Kesselring A, Gras L, Smit C, Prins JM, et al. Episodes of HIV viremia and the risk of non-AIDS diseases in patients on suppressive antiretroviral therapy
. J Acquir Immune Defic Syndr
34. Hunt PW. HIV and inflammation: mechanisms and consequences
. Curr HIV/AIDS Rep
35. Tien PC, Choi AI, Zolopa AR, Benson C, Tracy R, Scherzer R, et al. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort
. J Acquir Immune Defic Syndr
36. Hsue PY, Deeks SG, Hunt PW. Immunologic basis of cardiovascular disease in HIV-infected adults
. J Infect Dis
2012; 205 (Suppl 3):S375–S382.
37. Justice AC, Freiberg MS, Tracy R, Kuller L, Tate JP, Goetz MB, et al. Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV?
. Clin Infect Dis