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HCV co-infected patients treated with direct-acting antivirals
Accepted Manuscript Letter to the Editor Occurrence of hepatocellular carcinoma in HIV/HCV co-infected patients treated with direct-acting antivirals Hamid Hasson, Marco Merli, Emanuela Messina, Sherrie Bhoori, Stefania Salpietro, Giulia Morsica, Enrico Regalia, Sabrina Bagaglio, Adriano Lazzarin, Caterina Uberti-Foppa, Vincenzo Mazzaferro PII: DOI: Reference:
S0168-8278(17)30203-9 http://dx.doi.org/10.1016/j.jhep.2017.03.032 JHEPAT 6484
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
15 February 2017 19 March 2017 30 March 2017
Please cite this article as: Hasson, H., Merli, M., Messina, E., Bhoori, S., Salpietro, S., Morsica, G., Regalia, E., Bagaglio, S., Lazzarin, A., Uberti-Foppa, C., Mazzaferro, V., Occurrence of hepatocellular carcinoma in HIV/HCV co-infected patients treated with direct-acting antivirals, Journal of Hepatology (2017), doi: http://dx.doi.org/ 10.1016/j.jhep.2017.03.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Occurrence of hepatocellular carcinoma in HIV/HCV co-infected patients treated with direct-acting antivirals
To the Editor: We read with great interest the manuscripts by Conti et al. and Cheung et al. on the incidence of de novo hepatocellular carcinoma (HCC) in patients with liver cirrhosis treated with interferon-free anti-HCV direct-acting antivirals (DAAs)-based regimens [1, 2]. Their papers followed a “note of caution” related to an unexpected high incidence of recurring HCC after resection or ablation while on DAAs-based therapy [3], and this triggered a controversial debate with potential clinical implications [4]. A rapid decrease in cancer immuno-surveillance due to an abrupt reduction of liver natural killer (NK) cells and of their cytotoxic activity [5] has been claimed as a possible factor enhancing a faster progression of HCC foci [1], together with restriction of HCV replication within HCC tissue in comparison with surrounding non-tumorous tissue [6]. In this perspective, the decrease in cancer immuno-surveillance appears to be even more relevant in HIV-infected patients, who often show multifocal HCC at diagnosis with a subsequent aggressive course [7] and whose already impaired immune system, with possibly reduced NK cells even before anti-HCV therapy [8], represents a risk factor for development of cancer [9]. Moreover, in the last decade, HCC incidence in HIV-infected subjects showed to be incremental, especially in patients with liver cirrhosis and low current CD4 cells count [10]. From January 2015 to January 2017, 118 HIV/HCV-co-infected patients with advanced liver disease (defined as METAVIR F3-F4 at transient elastography), without history of HCC and no evidence of focal liver lesions by ultrasound or magnetic resonance imaging, started treatment with interferon-sparing DAAs-based regimens (for 12 or 24 weeks) at our centre and completed follow-up to post-treatment week 24. Informed consent was
obtained from all patients for data collection. All patients were on antiretroviral therapy for at least six months before anti-HCV treatment. The major demographic, clinical, virological and biochemical characteristics are described in Table 1. Sustained virological response (SVR) was achieved in 114 (97%) subjects at posttreatment week 12. During standard surveillance (liver ultrasound and alfa-fetoprotein every six months) for a median follow-up of 87 (74-95) weeks since anti-HCV treatment baseline (54 [41-68] weeks after achieving SVR), de novo HCC was diagnosed in 3/118 (2.5%) patients with advanced liver disease at 20, 36, and 61 weeks after beginning of anti-HCV treatment. While the former patient showed evidence of HCC while still on antiviral treatment (week 20), the other two were diagnosed at post-treatment weeks 12 and 37. According to BCLC classification, two patients were in stage A and one patient was in stage B. All three of these patients had liver cirrhosis, were infected by genotype 3 and were treated with daclatasvir, sofosbuvir and ribavirin for 24 weeks, achieving SVR. As previously stated, none showed liver nodules at imaging assessment performed by an expert radiologist within 3 months before antiviral treatment baseline. Two of them had an increase in alfa-fetoprotein (AFP) level (347 ng/ml from 72 ng/ml at baseline and 135 ng/ml from 54 ng/ml at baseline, respectively), while a decreasing trend of AFP levels was observed in patients without de novo HCC during DAAs-based therapy (pre-treatment 6.7 [4.9-14.7] ng/ml, end-of-treatment 4.9 [3.4-6.5] ng/ml, post-treatment week 24 4.0 [3.0-5.7] ng/ml). Moreover, patients with de novo HCC showed a higher APRI score at DAAs inception (3.83 [2.54-5.77]) than those HCC-free (1.56 [0.92-3.29]). Kaplan-Meier curves for cumulative incidence of HCC according to overall vs. genotype 3 patients are shown in Fig. 1. In this real-life series of HIV/HCV co-infected patients with advanced liver disease (METAVIR F3 or above) successfully treated with DAAs, the incidence of HCC during and immediately after DAAs-based therapy did not appear to be increased in comparison with
HCV-positive/HIV-negative historic controls [1, 2]. Nonetheless, the occurrence of de novo HCC exclusively observed in patients with HCV genotype 3 infection, known to be burdened by a higher risk of developing liver cancer, may suggest special attention in the surveillance of this subset patients. Considering the trend of AFP levels during DAAs-based therapy in patients with de novo HCC compared to those without HCC, monitoring AFP levels may be helpful enhancing early cancer detection. In conclusion, our experience with DAA-based therapy in HIV/HCV co-infected patients did not show an incremental cancer trend during early follow-up, while an expected high rate of SVR was confirmed. Nonetheless, since a rapid decrease of the inflammatory activity in the liver micro-environment during DAAs-based therapy is suspected to favor the growth of HCC foci in patients with liver cirrhosis, strict surveillance is mandatory, especially in patients with additional known risk factor for HCC (eg. genotype 3, diabetes, metabolic syndrome, HIV co-infection).
Financial support No financial support was received in relation to this manuscript.
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contribution HH, MM, EM, GM, SB, ER, and VM managed the patients, designed the study, analyzed data and wrote the manuscript. SS collected data and organized the database. CUF and AL coordinated the analysis and reviewed the manuscript.
References [1] Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65:727--733. [2] Cheung M C, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 2016; 65:741-747. [3] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65:719-726. [4] Llovet J M, Villanueva A. Liver cancer: Effect of HCV clearance with direct-acting antiviral agents on HCC. Nat Rev Gastroenterol Hepatol 2016; 13:561-562. [5] Serti E, Chepa-Lotrea X, Kim YJ, Keane M, Fryzek N, Liang TJ et al. Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function. Gastroenterology 2015; 149:190-200. [6] Harouaka D, Engle RE, Wollenberg K, Diaz G, Tice AB, Zamboni F et al. Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue. Proc Natl Acad Sci USA 2016; 113:1365-1380. [7] Bräu N, Fox RK, Xiao P, Marks K, Naqvi Z, Taylor L et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol 2007; 47:527-537. [8] Nowicki M J, Vigen C, Mack WJ, Seaberg E, Landay A, Anastos K et al. Association of cells with natural killer (NK) and NKT immunophenotype with incident cancers in HIVinfected women. AIDS Res Hum Retroviruses 2008; 24:163-168.
[9] Kesselring A, Gras L, Smit C, van Twillert G, Verbon A, de Wolf F et al. Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis 2011; 52:1458-1465. [10] Gjærde L I, Shepherd L, Jablonowska E, Lazzarin A, Rougemont M, Darling K et al. Trends in Incidences and Risk Factors for Hepatocellular Carcinoma and Other Liver Events in HIV and Hepatitis C Virus-coinfected Individuals From 2001 to 2014: A Multicohort Study. Clin Infect Dis 2016; 63:821-829.
Hamid Hasson1,* Marco Merli1 Emanuela Messina1 Sherrie Bhoori2 Stefania Salpietro1 Giulia Morsica1 Enrico Regalia2 Sabrina Bagaglio1 Adriano Lazzarin1 Caterina Uberti-Foppa1 Vincenzo Mazzaferro2
1
Infectious Diseases Clinic, IRCCS Ospedale San Raffaele, Milano, Italy; 2Liver Surgery,
Transplantation and Gastroenterology, University of Milan and Istituto Nazionale Tumori Fondazione IRCCS, Milano, Italy
*Corresponding author: Address: Infectious Diseases Clinic, IRCCS Ospedale San Raffaele, Via Stamira d’Ancona 20, 20127 Milano, Italy. Tel.: +39 02 2643 7945; fax +39 02 2643 7030. E-mail address: [email protected] (H. Hasson)
Table 1. Baseline characteristics of 118 HIV/HCV co-infected patients undergoing DAAs-based therapy. Medians (interquartile ranges) are reported for continuous variables and absolute frequencies (percentages) for categorical ones.
Fig. 1. Survival curves for cumulative incidence of HCC in all patients and in those infected by genotype 3
Patient characteristics Demography Gender male Age years 2 Body mass index, kg/m Comorbidities Diabetes Metabolic syndrome HBsAg positive Chronic kidney disease, n HIV-related immunovirological status 3 White blood cells, x 10 /µl 3 Absolute lymphocyte count, x 10 /µl 3 Absolute neutrophil count, x 10 /µl CD4 cells count, cells/µl Nadir CD4 cells count, cells/µl CD8 cells count, cells/µl CD4/CD8 ratio HIV-RNA <50 copies/ml, n HCV-related status and treatment Naïve to anti-HCV therapy, n Baseline HCV-RNA, log IU/ml HCV genotype, n 1a 1 non-a 2 3 4 Antiviral regimens Sofosbuvir + ribavirin Simeprevir + sofosbuvir ± ribavirin Daclatasvir + sofosbuvir ± ribavirin Ledipasvir/sofosbuvir ± ribavirin Ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin Ombitasvir paritaprevir/ritonavir + ribavirin Ribavirin use, n Liver status Liver stiffness, kPa Liver cirrhosis, n MELD score Child-Turcotte-Pugh stage, n A B ALT, U/L AST, U/L Albumin, g/dl Total bilirubin, mg/dl 3 Platelets, x 10 /µl Pseudocholinesterases, kU/L INR APRI score FIB-4 score Alfa-fetoprotein, ng/ml
n = 118
89 (75%) 54 (53–57) 24 (22–26) 14 (12%) 12 (10%) 6 (5%) 2 (2%)
5.4 (4.1–6.7) 1.9 (2.4–1.4) 2.7 (2.0–3.6) 560 (390–783) 159 (81–248) 646 (503–861) 0.8 (0.6–1.2) 111 (94%) 56 (47%) 5.9 (5.2–6.2) 48 (41%) 18 (15%) 5 (4%) 24 (20%) 23 (20%) 11 (9%) 41 (35%) 25 (21%) 30 (26%) 7 (6%) 4 (3%) 105 (89%) 17 (12–26) 86 (73%) 7 (7–9)
81 (94%) 5 (6%) 90 (73–117) 73 (48–127) 4.1 (3.9–4.3) 0.71 (0.55–1.12) 122 (84–166) 5.9 (4.1–7.5) 1.05 (1.0–1.1) 1.56 (0.94–3.47) 3.59 (2.21–5.50) 6.8 (5.0–15.0)
S0168-8278(17)30203-9 http://dx.doi.org/10.1016/j.jhep.2017.03.032 JHEPAT 6484
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
15 February 2017 19 March 2017 30 March 2017
Please cite this article as: Hasson, H., Merli, M., Messina, E., Bhoori, S., Salpietro, S., Morsica, G., Regalia, E., Bagaglio, S., Lazzarin, A., Uberti-Foppa, C., Mazzaferro, V., Occurrence of hepatocellular carcinoma in HIV/HCV co-infected patients treated with direct-acting antivirals, Journal of Hepatology (2017), doi: http://dx.doi.org/ 10.1016/j.jhep.2017.03.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Occurrence of hepatocellular carcinoma in HIV/HCV co-infected patients treated with direct-acting antivirals
To the Editor: We read with great interest the manuscripts by Conti et al. and Cheung et al. on the incidence of de novo hepatocellular carcinoma (HCC) in patients with liver cirrhosis treated with interferon-free anti-HCV direct-acting antivirals (DAAs)-based regimens [1, 2]. Their papers followed a “note of caution” related to an unexpected high incidence of recurring HCC after resection or ablation while on DAAs-based therapy [3], and this triggered a controversial debate with potential clinical implications [4]. A rapid decrease in cancer immuno-surveillance due to an abrupt reduction of liver natural killer (NK) cells and of their cytotoxic activity [5] has been claimed as a possible factor enhancing a faster progression of HCC foci [1], together with restriction of HCV replication within HCC tissue in comparison with surrounding non-tumorous tissue [6]. In this perspective, the decrease in cancer immuno-surveillance appears to be even more relevant in HIV-infected patients, who often show multifocal HCC at diagnosis with a subsequent aggressive course [7] and whose already impaired immune system, with possibly reduced NK cells even before anti-HCV therapy [8], represents a risk factor for development of cancer [9]. Moreover, in the last decade, HCC incidence in HIV-infected subjects showed to be incremental, especially in patients with liver cirrhosis and low current CD4 cells count [10]. From January 2015 to January 2017, 118 HIV/HCV-co-infected patients with advanced liver disease (defined as METAVIR F3-F4 at transient elastography), without history of HCC and no evidence of focal liver lesions by ultrasound or magnetic resonance imaging, started treatment with interferon-sparing DAAs-based regimens (for 12 or 24 weeks) at our centre and completed follow-up to post-treatment week 24. Informed consent was
obtained from all patients for data collection. All patients were on antiretroviral therapy for at least six months before anti-HCV treatment. The major demographic, clinical, virological and biochemical characteristics are described in Table 1. Sustained virological response (SVR) was achieved in 114 (97%) subjects at posttreatment week 12. During standard surveillance (liver ultrasound and alfa-fetoprotein every six months) for a median follow-up of 87 (74-95) weeks since anti-HCV treatment baseline (54 [41-68] weeks after achieving SVR), de novo HCC was diagnosed in 3/118 (2.5%) patients with advanced liver disease at 20, 36, and 61 weeks after beginning of anti-HCV treatment. While the former patient showed evidence of HCC while still on antiviral treatment (week 20), the other two were diagnosed at post-treatment weeks 12 and 37. According to BCLC classification, two patients were in stage A and one patient was in stage B. All three of these patients had liver cirrhosis, were infected by genotype 3 and were treated with daclatasvir, sofosbuvir and ribavirin for 24 weeks, achieving SVR. As previously stated, none showed liver nodules at imaging assessment performed by an expert radiologist within 3 months before antiviral treatment baseline. Two of them had an increase in alfa-fetoprotein (AFP) level (347 ng/ml from 72 ng/ml at baseline and 135 ng/ml from 54 ng/ml at baseline, respectively), while a decreasing trend of AFP levels was observed in patients without de novo HCC during DAAs-based therapy (pre-treatment 6.7 [4.9-14.7] ng/ml, end-of-treatment 4.9 [3.4-6.5] ng/ml, post-treatment week 24 4.0 [3.0-5.7] ng/ml). Moreover, patients with de novo HCC showed a higher APRI score at DAAs inception (3.83 [2.54-5.77]) than those HCC-free (1.56 [0.92-3.29]). Kaplan-Meier curves for cumulative incidence of HCC according to overall vs. genotype 3 patients are shown in Fig. 1. In this real-life series of HIV/HCV co-infected patients with advanced liver disease (METAVIR F3 or above) successfully treated with DAAs, the incidence of HCC during and immediately after DAAs-based therapy did not appear to be increased in comparison with
HCV-positive/HIV-negative historic controls [1, 2]. Nonetheless, the occurrence of de novo HCC exclusively observed in patients with HCV genotype 3 infection, known to be burdened by a higher risk of developing liver cancer, may suggest special attention in the surveillance of this subset patients. Considering the trend of AFP levels during DAAs-based therapy in patients with de novo HCC compared to those without HCC, monitoring AFP levels may be helpful enhancing early cancer detection. In conclusion, our experience with DAA-based therapy in HIV/HCV co-infected patients did not show an incremental cancer trend during early follow-up, while an expected high rate of SVR was confirmed. Nonetheless, since a rapid decrease of the inflammatory activity in the liver micro-environment during DAAs-based therapy is suspected to favor the growth of HCC foci in patients with liver cirrhosis, strict surveillance is mandatory, especially in patients with additional known risk factor for HCC (eg. genotype 3, diabetes, metabolic syndrome, HIV co-infection).
Financial support No financial support was received in relation to this manuscript.
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contribution HH, MM, EM, GM, SB, ER, and VM managed the patients, designed the study, analyzed data and wrote the manuscript. SS collected data and organized the database. CUF and AL coordinated the analysis and reviewed the manuscript.
References [1] Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65:727--733. [2] Cheung M C, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 2016; 65:741-747. [3] Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65:719-726. [4] Llovet J M, Villanueva A. Liver cancer: Effect of HCV clearance with direct-acting antiviral agents on HCC. Nat Rev Gastroenterol Hepatol 2016; 13:561-562. [5] Serti E, Chepa-Lotrea X, Kim YJ, Keane M, Fryzek N, Liang TJ et al. Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function. Gastroenterology 2015; 149:190-200. [6] Harouaka D, Engle RE, Wollenberg K, Diaz G, Tice AB, Zamboni F et al. Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue. Proc Natl Acad Sci USA 2016; 113:1365-1380. [7] Bräu N, Fox RK, Xiao P, Marks K, Naqvi Z, Taylor L et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol 2007; 47:527-537. [8] Nowicki M J, Vigen C, Mack WJ, Seaberg E, Landay A, Anastos K et al. Association of cells with natural killer (NK) and NKT immunophenotype with incident cancers in HIVinfected women. AIDS Res Hum Retroviruses 2008; 24:163-168.
[9] Kesselring A, Gras L, Smit C, van Twillert G, Verbon A, de Wolf F et al. Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis 2011; 52:1458-1465. [10] Gjærde L I, Shepherd L, Jablonowska E, Lazzarin A, Rougemont M, Darling K et al. Trends in Incidences and Risk Factors for Hepatocellular Carcinoma and Other Liver Events in HIV and Hepatitis C Virus-coinfected Individuals From 2001 to 2014: A Multicohort Study. Clin Infect Dis 2016; 63:821-829.
Hamid Hasson1,* Marco Merli1 Emanuela Messina1 Sherrie Bhoori2 Stefania Salpietro1 Giulia Morsica1 Enrico Regalia2 Sabrina Bagaglio1 Adriano Lazzarin1 Caterina Uberti-Foppa1 Vincenzo Mazzaferro2
1
Infectious Diseases Clinic, IRCCS Ospedale San Raffaele, Milano, Italy; 2Liver Surgery,
Transplantation and Gastroenterology, University of Milan and Istituto Nazionale Tumori Fondazione IRCCS, Milano, Italy
*Corresponding author: Address: Infectious Diseases Clinic, IRCCS Ospedale San Raffaele, Via Stamira d’Ancona 20, 20127 Milano, Italy. Tel.: +39 02 2643 7945; fax +39 02 2643 7030. E-mail address: [email protected] (H. Hasson)
Table 1. Baseline characteristics of 118 HIV/HCV co-infected patients undergoing DAAs-based therapy. Medians (interquartile ranges) are reported for continuous variables and absolute frequencies (percentages) for categorical ones.
Fig. 1. Survival curves for cumulative incidence of HCC in all patients and in those infected by genotype 3
Patient characteristics Demography Gender male Age years 2 Body mass index, kg/m Comorbidities Diabetes Metabolic syndrome HBsAg positive Chronic kidney disease, n HIV-related immunovirological status 3 White blood cells, x 10 /µl 3 Absolute lymphocyte count, x 10 /µl 3 Absolute neutrophil count, x 10 /µl CD4 cells count, cells/µl Nadir CD4 cells count, cells/µl CD8 cells count, cells/µl CD4/CD8 ratio HIV-RNA <50 copies/ml, n HCV-related status and treatment Naïve to anti-HCV therapy, n Baseline HCV-RNA, log IU/ml HCV genotype, n 1a 1 non-a 2 3 4 Antiviral regimens Sofosbuvir + ribavirin Simeprevir + sofosbuvir ± ribavirin Daclatasvir + sofosbuvir ± ribavirin Ledipasvir/sofosbuvir ± ribavirin Ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin Ombitasvir paritaprevir/ritonavir + ribavirin Ribavirin use, n Liver status Liver stiffness, kPa Liver cirrhosis, n MELD score Child-Turcotte-Pugh stage, n A B ALT, U/L AST, U/L Albumin, g/dl Total bilirubin, mg/dl 3 Platelets, x 10 /µl Pseudocholinesterases, kU/L INR APRI score FIB-4 score Alfa-fetoprotein, ng/ml
n = 118
89 (75%) 54 (53–57) 24 (22–26) 14 (12%) 12 (10%) 6 (5%) 2 (2%)
5.4 (4.1–6.7) 1.9 (2.4–1.4) 2.7 (2.0–3.6) 560 (390–783) 159 (81–248) 646 (503–861) 0.8 (0.6–1.2) 111 (94%) 56 (47%) 5.9 (5.2–6.2) 48 (41%) 18 (15%) 5 (4%) 24 (20%) 23 (20%) 11 (9%) 41 (35%) 25 (21%) 30 (26%) 7 (6%) 4 (3%) 105 (89%) 17 (12–26) 86 (73%) 7 (7–9)
81 (94%) 5 (6%) 90 (73–117) 73 (48–127) 4.1 (3.9–4.3) 0.71 (0.55–1.12) 122 (84–166) 5.9 (4.1–7.5) 1.05 (1.0–1.1) 1.56 (0.94–3.47) 3.59 (2.21–5.50) 6.8 (5.0–15.0)