Whereas the use of effective combination antiretroviral therapies (cARTs) has considerably reduced the prevalence of HIV-associated wasting, the prevalence of overweight and obesity has increased among HIV-infected individuals partly due to improved health [1–6]. Obesity can alter the pharmacokinetics of drugs . Consequently, standard drug doses may be insufficient in heavy individuals. Suboptimal treatment response has indeed been reported in a morbidly obese HIV-infected patient treated with the standard 600 mg efavirenz (EFV) dose . Furthermore, EFV levels were shown to be inversely correlated to body weight [9,10].
Obesity is also characterized by a chronic state of inflammation with the release of pro-inflammatory or immune-modulating factors . The impact of overweight and obesity on the immune response in HIV infection remains unclear. Studies from the pre-cART era found that overweight and obesity were associated with a slower disease progression [12–14]. Conversely, in a more recent study, overweight and obesity have been associated with lower CD4+ recovery after cART initiation , although this had not been consistently reported [16,17].
There are currently no comparisons of the virological and immunological responses to initial EFV-containing regimens in HIV-infected individuals across a wide range of body weights. We hypothesized that heavy individuals may be underdosed and, consequently, may have a less vigorous virological response or be at risk for virological failure or may have an inferior immune response to treatment compared to normal-weight patients.
The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) includes 33 HIV cohorts within the EuroCoord network (http://www.EuroCoord.net) .
All HIV-infected adults enrolled in COHERE and starting an EFV-containing regimen were considered for inclusion. Patients were excluded if their weight was missing or if they did not have at least one viral load measurement before and after EFV initiation. To limit confounding, the analysis was limited to cART-naive individuals.
Weight, rather than BMI, was considered, as height was not provided routinely by all cohorts. Analyses were performed by stratifying weight into six groups defined as: I (underweight) – below 55 kg; II (normal weight) – at least 55, below 80 kg; III – at least 80, below 85 kg; IV – at least 85, below 90 kg; V – at least 90, below 95 kg; and VI – at least 95 kg. Baseline weight, CD4+ cell count, and viral load were selected as the most recent values prior to EFV initiation.
Kaplan–Meier plots were used to describe the time to initial viral suppression after treatment initiation and the time to subsequent virological rebound. Initial viral suppression was defined as the first viral load 50 copies/ml or less, and virological rebound was defined as the first two consecutive viral load above 50 copies/ml. For our primary analyses of virological rebound, treatment switches were ignored. However, several sensitivity analyses considered variations to this definition (see below). Cox proportional-hazard regression analyses were used to compare weight groups before and after adjustment for sex, age, mode of HIV acquisition, ethnicity, hepatitis/abnormal liver function test, pretreatment CD4+ cell count and viral load, prior AIDS, nucleoside reverse transcriptase inhibitor (NRTI) backbone, protease inhibitor co-administration, cohort and calendar year.
Sensitivity analyses were performed to investigate the robustness of the results to the way in which the virological rebound endpoint was defined. In particular, analyses were repeated after censoring each individual's follow-up on the date of EFV discontinuation, if this occurred prior to virological rebound; the primary analysis was repeated after including into the definition of virological rebound individuals with one viral load above 50 copies/ml, who then changed their cART regimen and discontinued EFV; the virological rebound definition was modified to require two viral loads above 400 copies/ml or 1000 copies/ml; and virological rebound was defined as one viral load above 50 copies/ml.
Furthermore, analyses were performed after stratifying by sex and ethnicity, with tests of interaction performed to assess whether there were significant differences in the associations between sex, white/non-white ethnicity, and the weight groups.
The change in absolute CD4+ cell count during follow-up was calculated as the difference between the CD4+ values measured 6 and 12 months after EFV start and the baseline value. The impact of weight on the CD4+ cell count change 6 and 12 months after EFV start was analyzed using multiple linear regression analyses adjusted as described above. Statistical analyses were performed using SAS version 9.13 (Cary, North Carolina, USA).
In total, 19 968 individuals from 12 different cohorts were included. The demographic and clinical characteristics of the study population differed by weight categories as described in Table 1. When looking at the weight distribution in different calendar periods, the proportion of heavier individuals was greater in more recent years (Table 1, Supplementary Fig. 1, https://links.lww.com/QAD/A625).
Overall, 16 188 (81.1%) individuals achieved an undetectable viral load after starting EFV. Adjusted Cox regression analyses for the time to initial undetectable viral load showed that underweight individuals were less likely to attain an undetectable viral load relative to normal-weight individuals [relative hazard 0.91; 95% confidence interval (CI) 0.86, 0.97; P = 0.004], whereas no statistical difference was observed between heavier and normal-weight groups (Table 2a, Supplementary Fig. 2a, https://links.lww.com/QAD/A625).
Of the 16 188 patients attaining an undetectable viral load, 5525 (34.1%) subsequently experienced viral load rebound. Cumulative probability of virological rebound was significantly higher for underweight compared to normal-weight individuals (P = 0.0001, log-rank test) (Supplementary Fig. 2b, https://links.lww.com/QAD/A625). However, no significant differences were observed among weight categories for the time to viral rebound in adjusted Cox analyses (Table 2b). The results remained consistent when repeating the analyses after censoring at the time of EFV discontinuation or when using different thresholds for viral rebound. Furthermore, no substantial differences were seen in the associations between weight group and either the time to initial viral suppression or subsequent viral rebound when stratifying by sex or ethnicity (all interaction P values >0.05).
The absolute CD4+ values 6 and 12 months after therapy initiation were significantly higher with increasing weight categories (Table 2c). In adjusted multivariable linear regression analyses, the difference in absolute CD4+ cell counts remained significant for the heaviest individuals both at 6 [beta estimate 14.4, standard error (SE) 7.1, P = 0.04] and 12 (beta estimate 17.2, SE 8.6, P = 0.05) months (Table 2d). However, the CD4+ cell recovery was comparable between heavier and normal-weight individuals.
Overall, 22.7% of our study population fell in the heavy-weight categories. The proportion of heavier individuals tended to be greater in more recent years. Also, heavier individuals were older, less likely to have acquired HIV infection via intravenous drug user (IDU) or to have AIDS prior to EFV start, more likely to have higher baseline CD4+ values or to be treated with tenofovir + emtricitabine. Collectively, these observations may reflect calendar trends towards an earlier diagnosis and treatment with effective drugs [19,20]. Changes in demographics may also be responsible for the observed changes in weight distribution over the years. Consistent with our observations, a recent analysis of the Swiss HIV Cohort Study showed that increasing overweight and obesity rates were explained by the aging of the HIV population, fewer IDU, earlier treatment initiation, and better cART coverage over the years .
We showed no difference in the virological response to EFV-based therapy between heavy and normal-weight individuals. Of note, the ability to detect differences may have been limited by the small number of patients weighting above 120 kg. EFV 900 mg once daily (q.d.) has been shown to produce a similar exposure in individuals weighting 100–120 kg than the exposure obtained with the standard EFV 600 mg q.d. dosage in normal-weight individuals . Interestingly, EFV given at 400 mg q.d. has been shown to be noninferior to the standard dose when combined with tenofovir and emtricitabine in treatment-naïve patients . Thus, one could speculate that the standard EFV dose has an efficacy margin which is sufficient for a certain degree of obesity. This efficacy margin may also result from the use of more potent NRTI backbone in recent years . In our study, underweight individuals had a significantly longer time to initial viral suppression compared to normal-weight individuals. Of note, the proportion of individuals infected through IDU and with AIDS prior to EFV initiation was higher in the underweight category; thus the longer time to initial suppression might be a consequence of poorer adherence, later presentation, or more advanced disease possibly resulting in drug malabsorption. However, there was no difference in the time to viral rebound between these weight categories after adjustment.
Obesity has been associated with the release of factors which may impact the immune function . Leptin has notably been shown to promote T-cell proliferation and activation in vitro[23,24]. Thus, heavy individuals might have a different pattern of immune reconstitution. We showed that heavier individuals had higher CD4+ cell counts at baseline and after initiating EFV, whereas the pattern of CD4+ recovery was comparable to normal-weight individuals and within expected ranges . The observed higher baseline CD4+ values may reflect calendar trends towards earlier diagnosis and treatment, but could also be related to leptin-associated T-cell proliferation. An increase in CD4+ cell counts has indeed been described both in obese HIV-uninfected [26,27] and HIV-infected populations [17,28]. Underweight individuals had lower baseline CD4+ values, but a higher recovery compared to normal-weight individuals. Lower CD4+ values at baseline could result from the underlying malnutrition or a more advanced disease, whereas younger age and higher nadir CD4+ cell count might explain the higher recovery .
Despite previous reports of sex differences in EFV exposure [30,31] and in leptin level [32,33], which was shown to be inversely correlated to HIV replication , our study did not find any sex difference in the association with weight. Of note, the ability to detect a difference may have been limited by the small number of women. In addition, despite known ethnicity-related genetic differences in EFV metabolism , we did not find any evidence that the association with weight differed by ethnicity. Again, this could possibly result from the small proportion of individuals of known black ethnicity.
Strengths of this study include the large size and the broad geographical representation. However, this observational study has limitations. Most cohorts do not measure levels of EFV; therefore we could not correlate our observations to drug concentrations. Data on EFV dosage were not available; thus potential adjustments cannot be excluded. The effect of adherence on treatment response could not be assessed, although adherence patterns are not expected to differ between heavy and normal-weight categories. The number of individuals with extreme weights was low, limiting any conclusions that could be drawn for severely obese patients.
In conclusion, in this large European collaborative study, virological and immunological responses to initial EFV-containing regimens given at the standard 600 mg dose were not impaired in heavy treatment-naive individuals, suggesting that the standard dosage is appropriate across a wide weight range. However, due to the limited number of individuals weighting above 120 kg, response to EFV should be monitored carefully in severely obese individuals.
The Efavirenz and Obesity Project Working Team included Catia Marzolini, Caroline Sabin, François Raffi, Marco Siccardi, Cristina Mussini, Odile Launay, David Burger, Bernardino Roca, Jan Fehr, Stefano Bonora, Amanda Mocroft, Niels Obel, Frederic-Antoine Dauchy, Robert Zangerle, Charalambos Gogos, Nicola Gianotti, Adriana Ammassari, Carlo Torti, Jade Ghosn, Genevieve Chêne, Jesper Grarup, and Manuel Battegay.
Members of the collaboration of Observational HIV Epidemiological Research Europe (COHERE) group: 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, and ANRS CO13 HEPAVIH), Murielle Mary Krause (ANRS CO4 FHDH), Jade Ghosn (ANRS CO6 PRIMO), Catherine Leport (ANRS CO8 COPILOTE), Peter Reiss (ATHENA), Ferdinand Wit (ATHENA), Maria Prins (CASCADE), Heiner Bucher (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 Perez-Hoyos (GEMES-Haemo), Osamah Hamouda (German ClinSurv), Barbara Bartmeyer (German ClinSurv), Nikoloz Chkhartishvili (Georgian National HIV/AIDS), Antoni Noguera-Julian (CORISPE-cat), Andrea Antinori (ICC), Antonella d’Arminio Monforte (ICONA), Norbert Brockmeyer (KOMPNET), Luis Prieto (Madrid PMTCT Cohort), Pablo Rojo Conejo (CORISPES-Madrid), Antoni Soriano-Arandes (NENEXP), Manuel Battegay (SHCS), Andri Rauch (SHCS), Cristina Mussini (Modena Cohort), Pat Tookey (NSHPC), Jordi Casabona (PISCIS), Jose M. Miro (PISCIS), Antonella Castagna (San Raffaele), Deborah Konopnick (St. Pierre Cohort), Tessa Goetghebuer (St Pierre Pediatric Cohort), Carlo Torti (Italian Master Cohort), Ramon Teira (VACH), Myriam Garrido (VACH), David Haerry (European AIDS Treatment Group).
COHERE Executive Committee: Stéphane de Wit (Chair, St Pierre University Hospital), Jordi Casabona (PISCIS), Dominique Costagliola (FHDH), Antonella d’Arminio-Monforte (ICONA), Manuel Battegay (SHCS), Julia del Amo (CoRIS), Amanda Mocroft (EuroSida), Dorthe Raben (Head, Copenhagen Regional Coordinating Centre), Genevieve Chêne (Head, Bordeaux Regional Coordinating Centre). Paediatric Cohort Representatives: Ali Judd, Pablo Rojo Conejo.
COHERE Regional Coordinating Centres: Bordeaux RCC: Diana Barger, Céline Colin, Christine Schwimmer, Monique Termote, Linda Wittkop; Copenhagen RCC: Maria Campbell, Nina Friis-Moller, Jesper Kjaer, Dorthe Raben, Rikke Salbol Brandt.
Project Leaders and Statisticians: Manuel Battegay, Julia Bohlius, Vincent Bouteloup, Heiner Bucher, Alessandro Cozzi-Lepri, François Dabis, Antonella d’Arminio Monforte, Julia del Amo, Maria Dorrucci, Matthias Egger, Hansjakob Furrer, Ali Judd, Ole Kirk, Olivier Lambotte, Sara Lodi, Sophie Matheron, Laurence Meyer, Jose Miro, Amanda Mocroft, Susana Monge, Fumiyo Nakagawa, Roger Paredes, Andrew Phillips, Massimo Puoti, Caroline Sabin, Colette Smit, Jonathan Sterne, Rodolphe Thiebaut, Claire Thorne, Carlo Torti, Giota Touloumi, Marc van der Valk, Linda Wittkop, Natasha Wyss.
The COHERE acknowledgement appendix may be found at: http://www.chip.dk/COHERE/Acknowledgements/tabid/320/Default.aspx
The COHERE study group has received unrestricted funding from: Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS), France; HIV Monitoring Foundation, The Netherlands; and the Augustinus Foundation, Denmark. COHERE receives funding from the European Union Seventh Framework Programme (FP7/2007–2013) under EuroCoord grant agreement n°260694. A list of the founders of the participating cohorts can be found at http://www.cohere.org.
The study sponsors had no role in the design of the study, the collection, analysis and interpretation of data, the writing of the report or the decision to submit the paper for publication.
Conflicts of interest
C.M. is a recipient of a grant for the clinical research from the University of Basel (grant DMS2265).
No member of the working team for this report has any financial relationship with organizations that could influence this work, although most members of the group have received in the past funding for research, travel grants, consultancy fees or speaking engagements as detailed below.
Support for travel to meetings for the study or other purposes: G.C. (Eu FP7 EuroCoord).
Grants/grants pending: C.Ma. (University of Basel), M.B. (Abbvie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Pfizer, ViiV), G.C. (Eu FP7 EuroCoord), J.F. (Abbvie, BMS, Gilead, Janssen, MSD, ViiV), J.Gh. (Merck), N.G. (Janssen, Gilead, ViiV), J.Gr. (EuroCoord), A.M. (see funding acknowledgements), C.Mu. (COHERE), N.O. (BMS, Glaxo, Boehringer-Ingelheim, Gilead), C.S. (Eu FP7), C.T. (Gilead), Robert Zangerle (Gilead).
Board membership: A.A. (MSD), M.B. (Gilead, MSD, Pfizer, ViiV), S.B. (ViiV, Merck, Gilead, Janssen, Abbvie), J.F. (Federal Commission for Sexual Health), J.Gh. (Merck, BMS, Gilead), N.G. (Janssen, Gilead, Abbvie), C.Mu. (BMS, MSD, ViiV, Gilead, Abbvie, Janssen), F.R. (Gilead, Janssen, Merck, MSD, ViiV), C.S. (Gilead, ViiV, Janssen, BMS), M.S. (Janssen, ViiV, Simcyp), C.T. (Gilead, ViiV).
Consultancy: J.F. (BMS, Gilead, Janssen, MSD, ViiV), C.G. (Pfizer, Gilead), F.R. (Gilead, Janssen, Merck, ViiV).
Payment for lectures including service on speakers bureaus: S.B. (ViiV, Gilead, Merck, BMS, Janssen, Abbvie), G.C. (Gilead, Tibotec-Janssen, Roche, MSD, Boehringer-Ingelheim, BMS, Glaxo, ViiV, Mylan, Abbvie, Pfizer for ANRS trials and for IWHOD), C.G. (BMS, Pfizer, Gilead), C.Mu. (BMS, MSD, ViiV, Gilead, Abbvie, Janssen), F.R. (Gilead, Janssen, Merck, ViiV), C.S. (Gilead, BMS, Abbvie, Janssen, ViiV), C.T. (Gilead, ViiV, Roche).
Travel, accomodations, teaching expenses unrelated to activities listed: G.C., J.F. (Abbvie, BMS, Gilead, Janssen, MSD, ViiV), J.Gh. (Merck, BMS, Gilead, ViiV), F.R. (ViiV), C.S. (BMS), N.G. (Janssen, Gilead), R.Z. (GSK, Janssen).
Payment for development of educational presentations: F.R. (Abbvie, Merck), C.S. (Gilead, BMS, ViiV, Janssen).
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