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.
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Keywords:© 2015 Lippincott Williams & Wilkins, Inc.
AIDS event; death; HIV; low-level viremia; virological failure