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Cross-sectional epidemiology of hepatitis C virus detection and treatment in HIV-infected patients
European Journal of Internal Medicine 22 (2011) 66–72
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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Original article
Cross-sectional epidemiology of hepatitis C virus detection and treatment in HIV-infected patients Javier Ena a,⁎, Rosa F. Ruiz-de-Apodaca b, Francisco Pasquau a, Concepción Amador a, Concepción Benito a a b
Department of Internal Medicine, Hospital Marina Baixa, Villajoyosa, Alicante, Spain Department of Pharmacy, Hospital Marina Baixa, Villajoyosa, Alicante, Spain
a r t i c l e
i n f o
Article history: Received 7 February 2010 Received in revised form 5 July 2010 Accepted 18 August 2010 Available online 15 September 2010 Keywords: Hepatitis C virus Human immunodeficiency virus Cross-sectional studies
a b s t r a c t Background: Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. Methods: Cross-sectional study. In a HIV referral clinic we assessed the proportion of patients eligible for hepatitis C virus evaluation and treatment according to consensus guidelines. Results: We identified 134 patients with hepatitis C virus and HIV co-infection. Twenty-one patients were excluded from the analysis due to never attending the HIV clinic (n = 12) or having hepatitis C virus RNA not detectable (n = 9). In the remaining 113 patients, only 61% had identification of hepatitis C virus genotype and quantification of hepatitis C viral load. Thirty-six patients started peginterferon plus ribavirin, and 16 (44%) achieved sustained virologic response. Seventy-seven patients did not receive treatment for hepatitis C virus due to the presence of medical contraindications (n = 22), provider barriers (n = 15), or patient barriers (n = 40). Multivariate analysis identified lower education degree (odds ratio: 4.53; 95% confidence intervals: 1.36–15.16, p = 0.014) and patient civil status single, separated or widower (odds ratio: 4.81; 95% confidence intervals: 1.54–14.99, p = 0.007) as the independent determinants associated to not initiating therapy for hepatitis C virus infection in patients with barriers. Conclusion: A minor proportion of HIV-infected patients received appropriate assessment and treatment for hepatitis C virus infection. Social disadvantages require multidisciplinary models of health care to improve hepatitis C virus treatment initiation and success. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction In Spain, approximately 42% of individuals with human immunodeficiency virus are co-infected with hepatitis C virus [1]. The introduction of highly active antiretroviral therapy has led to a prolongation of the life span in HIV-infected patients leaving hepatitis C virus co-infection as one of the most significant factors influencing the overall survival of this population [2]. Although the mechanism of interaction between hepatitis C virus and HIV is not completely understood, it is well known that patients with HIV/HCV co-infection show a faster rate of fibrosis progression resulting in more frequent occurrences of cirrhosis, end-stage liver disease, and hepatocellular carcinoma [3]. The treatment for hepatitis C virus in co-infected patients is similar to that of hepatitis C virus mono-infection; i.e., a combination of peginterferon plus ribavirin
⁎ Corresponding author. Servicio de Medicina Interna, Hospital Marina Baixa, Av Alcalde Jaume Botella Mayor 7, Villajoyosa 03570, Alicante, Spain. Tel.: +34 96 6859957; fax: +34 96 6859900. E-mail address: [email protected] (J. Ena).
[4]. Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus [5]. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. The aim of this study was to describe the characteristics of HIV-infected patients with hepatitis C virus infection attending a referral HIV clinic in Spain, assessing barriers to initiate therapy with peginterferon plus ribavirin. 2. Patients and methods 2.1. Setting The Hospital Marina Baixa is a 280-bed institution belonging to the Regional Health System (Agencia de Salut de la Comunitat Valenciana). It provides coverage to a population of 210,000 habitants in the East Coast of Spain. The HIV clinic at the Hospital offers clinical care by infectious diseases specialists, pharmacysts and nurses to patients with HIV infection who are evaluated at a 3-month interval. In the year 2008 a cohort of 380 patients with HIV infection attended the clinic. HIV-
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.08.006
J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72
infected patients with hepatitis C virus infection receive an integrated care within the HIV clinic and the treatment cost is fully covered by the Regional Health System. 2.2. Study design A cross-sectional study was conducted in patients attending the HIV clinic between January and March 2009. 2.3. Patient identification Patients with hepatitis C virus and HIV co-infection were identified by means of clinical records review. In addition, we reviewed the HIV and HCV serology records of the Clinical Microbiology Laboratory and the hepatitis C virus dispensation records of the Pharmacy Department from January 2002 to January 2009. 2.4. Patient assessments We reviewed the clinical records to collect information on demographics, attendance records and laboratory data including baseline HIV RNA, CD4 lymphocyte cell count, use of antiretroviral therapy, HBsAg status, hepatitis C virus genotype, hepatitis C virus RNA quantification, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, liver biopsy and liver transient elastography. Prediction of advanced liver fibrosis was carried out using the APRI index (also known as aspartate transferase platelet ratio index) [6], results of liver biopsy, and liver transient elastography. Advanced liver fibrosis was considered when APRI index was greater than 1.5, when liver biopsy showed F3–F4 in METAVIR index, or when values obtained by liver transient elastography were above 11.8 kPa [4]. In patients treated for hepatitis C virus infection, laboratory data were collected before starting therapy; in those not treated, laboratory data were collected recent to the cross-sectional study (past 4 months). Patients follow-up was considered until sustained virological response was confirmed at 24 weeks after finishing hepatitis C virus treatment, or until treatment discontinuation occurred due to drug toxicity, virological failure or death. 2.5. Definitions of contraindications for interferon therapy Medical contraindications to interferon therapy were defined based on the clinical practice guidelines and recent recommendations of the Executive Committee of the European AIDS Clinical Society [4]. Subjects with the following conditions were excluded: an active HIV-related opportunistic infection or cancer; an absolute neutrophil count below 1500/mm [3]; a platelet count below 70,000/mm [3]; a hemoglobin level below 11 g/dL for women, or below 12 g/dL for men; a serum creatinine level more than 1.5 times the upper limit of normal; evidence of decompensated liver disease; severe psychiatric disease, especially depression; clinically significant coexisting medical conditions; and, for women, pregnancy or unwillingness to practice contraception. In addition, we considered absolute contraindications for interferon plus ribavirin therapy: current (past 30 days) heavy alcohol use (more than 40 g per day in men and more than 20 g per day in women), recent (past 6 months) injection drug use, CD4 cell count of less than 100 cells/μL, advanced liver disease defined as a Child–Pugh score of equal or greater than 7, and suicidal ideation or attempt in the past 6 months. Relative contraindications were defined as current moderate alcohol use (less than heavy use but not abstinent), current injection drug use without needle sharing, CD4 count from 100 to 199 cells/μL, and significant depressive symptoms. Additionally we considered as contraindications for interferon therapy those patients denying consent for treatment and physician conviction of poor patient compliance.
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2.6. Statistical analysis Descriptive statistics were used to characterize the sample. To assess the determinants for those patients starting hepatitis C virus therapy compared to those who did not start the therapy for causes other than absolute or relative medical contraindications, we used Chi square test, Fisher exact test, odds ratios and 95% confidence intervals. Logistic regression analysis was used to assess independent determinats for not starting treatment for hepatitis C virus in patients with conditions other than medical contraindications compared with those patients who were treated with pegylated interferon plus ribavirin. Due to the small number of subjects we grouped education degree in two strata (low: no education or primary studies and high: secondary or university studies) and civil status in two strata (single–separated–widower and married– cohabitant). A P value of less than 0.05 was considered to indicate statistical significance. All analyses were carried out with the use of SPSS software for windows (release 15.0). 2.7. Ethical review The protocol was approved by the institutional review board of the Hospital Marina Baixa. Information obtained was recorded in such a manner that subjects cannot be recognized, directly or through identifiers linked to the subjects. The study was designed to identify opportunities to improve the health care of patients with hepatitis C virus and HIV co-infection. 3. Results We identified a total of 134 patients with HIV and hepatitis C virus co-infection after reviewing the Clinical Laboratory serology records, the Pharmacy Department dispensation records and the clinical records of patients attending the HIV clinic during the study period (Fig. 1). Twelve patients identified from the serology test register never attended the HIV clinic. Nine patients were hepatitis C virus antibody-positive but RNA negative, and as such, were excluded from the analysis. The remaining 113 co-infected patients were evaluated in detail (Table 1). This sample was predominantly male (68%). The median age was 43.88 years (Interquartile range: 41.55–47.63), 37% had never been married, 36% was currently married or cohabiting and 15% was separated or widower. Regarding education, 72% of patients had no education or primary studies. A total of 86 (76%) patients was receiving combination antiretroviral therapy and 64 had HIV viral load below the detection limit (50 copies/mL). Hepatitis C virus genotype assessment was carried out in 85 (75%) patients and hepatitis C virus viral load quantification was carried out in 73 (65%) patients and both in 69 (61%) patients. Approximately 56% of patients had unfavourable hepatitis C virus genotypes 1 or 4 for treatment. Regarding the determination of the degree of liver fibrosis, all patients had possibility for evaluation of APRI index but only 36 (32%) had liver biopsy (n = 13) or liver transient elastography (n = 24) carried out. A total of 22 patients had APRI index, liver biopsy or liver transient elastography results indicating advanced fibrosis. 3.1. Patients starting anti-hepatitis C virus therapy A total of 36 (32%) patients initiated anti-hepatitis C virus therapy. Patients received 180 μg of peginterferon alfa-2a subcutaneously weekly plus weighted-based ribavirin dosing (1000 mg per day for patients b75 kg, and 1200 mg per day for patients ≥75 kg). A safety assessment was performed in subjects at week 4 and every 12 weeks until the end of treatment. An efficacy assessment was performed at weeks 24, 48 and 60 with the use of a quantitative HCV RNA assay (Roche Cobas Amplicor 2.0). Treatment was maintained for 48 weeks in patients with virologic response (HCV RNA level of less than 60 IU/mL at a 24 week assessment). Sustained virologic response was confirmed at
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J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72
Fig. 1. Flow of patients included in the study.
week 60 in patients who completed anti-hepatitis C virus treatment. Treatment was discontinued if the patient developed drug intolerance or severe side effects to peginterferon or ribavirin or lack of virologic response. Twenty-six patients had HCV genotypes 1 or 4. The patients' main clinical characteristics are summarized in Table 2. Overall, most patients were married or cohabitant, with HIV viral load below the detection limit and had a mean CD4 cell count of 525/mm [3]. A total of 32 (89%) patients was on antiretroviral treatment when they started therapy for hepatitis C virus infection. Five patients received non-recommended antiretroviral drug regimens, according to the latest guidelines, with drug combinations including didanosine, stavudine, zidovudine, or dual antiretroviral combination therapy. In their follow-up 17 (47%) patients had adverse events related to hepatitis C virus treatment. Six patients required dose reduction in peginterferon, ribavirin, or both drugs due to severe side effects. Nine patients required erythropoiesis stimulating factors due to severe anemia and, 4 patients required treatment with granulocyte-colony stimulating factors due to severe neutropenia. One patient required discontinuation of peginterferon plus ribavirin therapy due to an acute decompensation of an advanced liver disease. At the end of follow-up, 16 (44%) patients achieved sustained virologic response, 18 (50%) had no sustained virologic response and, 2 (6%) patients died. Deaths were related with acute neurological deterioration and vascular disease. 3.2. Patients not starting anti-hepatitis C virus therapy A total of 77 (68%) patients did not start the therapy for hepatitis C virus. Twenty-two patients had absolute or relative medical contraindications for interferon therapy. These contraindications were: CD4 lymphocyte count less than 100 cells/μL (n = 3), advanced liver disease (n =1), heavy alcohol use (n=5), significant mental health illness (n =8), illegal substance abuse (n =3), and other treatment priority requirement (n =2). Fifty-five patients had barriers for not starting interferon therapy other than medical contraindications. Barriers in 15 patients were classified as provider barrier since a physician never proposed to patients a therapy for hepatitis C virus infection, and in 40 patients barriers were classified as patient barriers due to patient often missing appointments to the clinic or delaying to retrieve antiretroviral
drug medication (n = 22), patient unwillingness to initiate therapy due to fear of adverse effects (n = 10), or patients preferring to defer hepatitis C virus therapy at the time of study period (n=8) (Fig. 2). In patients with barriers the proportion of hepatitis C virus RNA quantification was 51%, and that of hepatitis C virus genotype testing was 67%. We compared the demographic and clinical characteristics of patients with barriers classified as provider (n = 15) or patient barriers (n = 40). More patients classified as provider barriers were receiving antiretroviral drug therapy than those classified as patient barriers (93% vs. 62%; p = 0.022); the remaining variables analyzed such as sex, age, education level, proportion of unemployment, civil status, hepatitis C virus genotype, hepatitis C virus RNA quantification, HIV RNA quantification and lymphocyte CD4 counts were distributed similarly in both groups. For comparison purposes we considered provider barriers and patient barriers as one group (n = 55) when comparing their characteristics to those patients starting hepatitis C virus treatment (n = 36). Univariate analysis showed that education degree, civil status, use of antiretroviral therapy and HIV viral load were associated with hepatitis C virus treatment status in patients with Hepatitis C virus and HIV co-infection (Table 3). We carried out a logistic regression analysis to determine the independent variables associated with patient not starting hepatitis C virus therapy. Socio-demographic variables such as education degree and civil status showed stronger association with hepatitis C virus therapy status than the use of antiretroviral therapy or HIV viral load, according to the Odds Ratios obtained (Table 4). Patients with no studies or primary studies and those with civil status single, separated or widower had the greatest barriers for starting hepatitis C virus therapy. 4. Discussion This cross-sectional study carried out in a referral hospital with integrated care for HIV and hepatitis C virus infections in Eastern Spain showed a low rate of hepatitis C virus evaluation and treatment in patients with HIV infection. Only 61% of patients had hepatitis C virus genotype identification and viral load quantification. Moreover, only onethird of patients received peginterferon plus ribavirin therapy for hepatitis C virus infection. Sustained virologic response was observed in 44% of such patients. Therefore, only 14% of the full cohort achieved
J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72 Table 1 Characteristics of 113 HIV/HCV-infected patients analyzed. Characteristic Age (years), median [IQR] Sex — no. (%) Male Female Education — no. (%) No education Primary studies Secondary studies University degree Unknown Unemployment — no. (%) Yes No Unknown Civil status — no. (%) Single Married/cohabitant Separated/widower Unknown Antiretroviral therapy — no. (%) Yes No Interferon plus ribavirin therapy — no. (%) Yes No CD4 cell count × 109/L, -median [IQR] HIV RNA (copies/mL), median [IQR] HIV RNA not detectable (%) HBsAg seropositive — no. (%) Yes No HCV RNA (copies/mL), median [IQR] HCV RNA (UI/mL) b 800,000 HCV genotype — no. (%) Genotype 1a/1b Genotype 2a/2b/2c Genotype 3 Genotype 4 Genotype 5 Unknown Aspartate aminotransferase (units/L), median [IQR] Alanine aminotransferase (units/L), median [IQR] Platelet count × 106/L, -median [IQR] APRI index, median [IQR] APRI index N 1.5 Liver biopsy — no. (%) Yes No Liver transient elastography (Fibroscan) — no. (%) Yes No
43.88 [41.55–47.63] 77 (68) 36 (32) 34 (30) 48 (42) 19 (17) 1 (1) 11 (10) 37 (33) 67 (59) 9 (8) 42 41 17 13
(37) (36) (15) (12)
86 (76) 27 (24) 36 (32) 77 (68) 437 [283–597.5] 50 [50–1,640] 64 (56) 1 (1) 112 (99) 1,470,000 [358,500–4,965,000] 30 (41) 48 (43) 2 (2) 18 (16) 15 (13) 1 (1) 28 (25) 46 [33–78.25] 58.50 [31–99.25] 170,000 [130,000–223,000] 0.75 [0.48–1.30] 22 (19) 13 (11) 100 (89)
24 (21) 89 (79)
sustained viral response for hepatitis C virus infection, with a significant proportion of patients suffering from severe adverse effects related to peginterferon plus ribavirin therapy. Among patients not treated for
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hepatitis C virus infection, the great proportion (55 out from 77 patients) had conditions other than medical contraindications to receive peginterferon plus ribavirin treatment. Those conditions were mostly patient barriers due to a lack of adherence to antiretroviral therapy, unwillingness to start treatment for hepatitis C virus infection, or preferring to defer therapy at the moment the study was carried out. The cause specific analysis for those barriers identified that patient socio-demographic characteristics were stronger predictors for physicians to refrain from starting hepatitis C virus therapy than other specific laboratory or clinical data. Moreover, lower education degree and civil status other than married or cohabitant were significant barriers to start therapy for hepatitis C virus infection in HIV-infected patients. Studies carried out in other countries showed that a minor proportion of patients with HIV infection received hepatitis C virus pre-treatment assessment for genotype characterization and viral load quantification with figures ranging from 33% to 57% [7,8]. In patients completing hepatitis C virus pre-treatment assessment the proportion of subjects starting therapy varied from 9% in US veterans [9] to 23%– 42% in US urban HIV clinics [7,8] and to 40% in a cross-sectional study carried out in Spain [10]. The proportion of patients who achieved sustained virologic response after starting treatment with peginterferon and ribavirin varied initially from 21% [7] up to 49% in most recent cohort series [11–13]. In pivotal clinical trials of patients with hepatitis C virus and HIV co-infection starting peginterferon plus ribavirin therapy the rate of sustained virologic response was observed in 27% to 40% [14,15]. The results observed in our study are in concordance to those described in the literature in terms of proportion of patients with completed evaluation for hepatitis C virus infection, treatment initiation and rate of sustained virologic response. As expected, patients treated with peginterferon and ribavirin suffered a significant number of major adverse effects, mainly hematologic toxicity. Nevertheless, the increasing rates of sustained virologic response observed in recent years are explained in part due to the greater proportion patients receiving full dose peginterferon and ribavirin facilitated by the use of hematopoietic growth factors [16]. A main objective of our study was to identify barriers to initiate therapy with peginterferon plus ribavirin in HIV-infected patients with hepatitis C virus infection. Approximately two third of patients were not eligible for peginterferon and ribavirin therapy due to absolute or relative medical contraindication or presence of patient or physician barriers. Several studies have pointed out that the main barriers to initiate therapy for hepatitis C virus infection are the presence of psychiatric illness, alcohol consumption or substance abuse [7,17–19]. The strategies used to overcome these barriers included the integration of hepatitis C virus treatment in mental health and addiction programmes [20–22]. However, in our study we identified only 16 patients out of 113 who were ineligible due to those factors. On the other hand, the vast majority of patients not treated for hepatitis C virus infection had barriers other than medical conditions that precluded treatment with peginterferon plus ribavirin. These conditions were in most cases patient related barriers due to the lack of adherence to HIV follow-up or unwillingness to start therapy. These conditions identified
Fig. 2. Provider and patient barriers for hepatitis C virus infection evaluation in patients with no contraindications for therapy.
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Table 2 Characteristics of patients that started treatment for hepatitis C virus infection. Characteristic Sex — no. (%) Male Female Age median [IQR] — year Education — no. (%) No education Primary studies Secondary studies University degree Unknown Unemployment — no. (%) Yes No Civil status — no. (%) Single Married/cohabitant Separated/widower Unknown Serum HCV RNA Median [IQR] — IU/mL N 800,000 IU/mL — no. (%) HCV genotype — no. (%) 1 2 3 4 5 Unknown Advanced liver disease Antiretroviral therapy — no. (%) None Any Combination antiretroviral therapy Didanosine + lamivudine + nevirapine Tenofovir + zidovudine + lamivudine + abacavir Tenofovir + abacavir + atazanavir/ritonavir Tenofovir + atazanavir/ritonavir Tenofovir + emtricitabine + efavirenz Tenofovir+emtricitabine+Fosamprenavir/ ritonavir Tenofovir + emtricitabine + lopinavir/ritonavir Tenofovir + lamivudine + nevirapine Tenofovir + lamivudine + lopinavir/ritonavir Tenofovir + nevirapine + lopinavir/ritonavir Tenofovir + efavirenz + lopinavir/ritonavir Stavudine + lamivudine + efavirenz Stavudine + lamivudine + nevirapine HIV-1 RNA Mean [IQR] — log10 copies/mL Undetectable HIV RNA (b50 copies/mL) — no. (%) CD4+ cells — no./mm3 Median [IQR] b200/mm3 — no. (%) Adverse events related to hepatitis C virus treatment Any Reduction in pegylated interferon dose Reduction in ribavirin dose Reduction in pegylated interferon and ribavirin dose Neutropenia requiring granulocyte-colony stimulating factor (G-CSF) therapy Anemia requiring erythropoiesis stimulating agents Liver disease decompensation requiring interferon and ribavirin discontinuation Outcome Sustained virological response No sustained virological response Deaths, not related with liver disease
Patients starting therapy for hepatitis C virus infection N = 36 22 (61) 14 (39) 45.33 [41.13–48.59] 4 (11) 17 (47) 11 (31) 1 (3) 3 (8) 10 (9) 26 (23) 8 (22) 23 (64) 4 (11) 1 (3) 865,661 [329,619–4,150,000] 26 (72) 18 (50) 1 (3) 6 (17) 8 (22) 1 (3) 2 (6) 5 (14) 4 (11) 32 (89) 1 (3) 1 (3) 1 (3) 1 (3) 14 (39) 1 (3) 3 (9) 3 (9) 2 (6) 2 (6) 1 (3) 1 (3) 1 (3) 50 [50–50] 27 (75)
463 [368–590] 0
17 (47) 3 (8) 1 (3) 2 (6) 4 (11) 9 (25) 1 (3)
16 (44) 18 (50) 2 (6)
Table 3 Factors associated with treatment status for HCV in patients co-infected with HIV/HCV, excluding those with absolute or relative medical contraindications. Characteristic, n (%)
Age group, years b40 ≥40 Gender Male Female Education No education or primary studies Secondary studies or university degree Civil status Single, separated or widower Married or cohabitant Unemployment No Yes Antiretroviral therapy No Yes CD4 lymphocyte cell count × 109/L b200 ≥200 HIV RNA (copies/mL) b50 ≥50 HCV genotype 1 or 4 2 or 3 HCV RNA (UI/mL) b800,000 ≥800,000 Aspartate aminotransferase (Units/L) b38 ≥38 Alanine aminotransferase (Units/L) b40 ≥40 Platelet count × 109/L b150,000 ≥150,000 APRI index b1.5 ≥1.5 Liver fibrosis stage 3–4 by liver biopsy or liver transient elastography N 11.8 kPa Yes No
Treated HCV Nontreated HCV P value patients (n = 36) patients (n = 55) 8 (22) 28 (78)
7 (13) 50 (87)
0.233
22 (61) 14 (39)
40 (73) 15 (27)
0.245
21 (58)
45 (82)
0.012
12 (33)
8 (14)
8 (22) 27 (75)
25 (45) 24 (44)
0.018
26 (23) 10 (9)
32 (58) 19 (35)
0.356
4 (11) 32 (89)
16 (28) 41 (72)
0.043
0 (0) 36 (100)
4 (7) 51 (93)
0.150
27 (75) 9 (25)
27 (49) 28 (51)
0.014
24 (67) 8 (22)
18 (33) 10 (18)
0.470
10 (28) 19 (53)
11 (20) 19 (35)
0.861
12 (34) 23 (66)
18 (33) 37 (67)
0.926
12 (34) 23 (66)
17 (31) 38 (69)
0.783
24 (67) 12 (33)
32 (58) 23 (42)
0.416
31 (86) 5 (14)
44 (82) 11 (18)
0.564 0.433
5 (14) 16 (44)
2 (4) 13 (24)
in our study have been found in other survey studies [7,19]. In addition, another significant proportion of patients was never proposed for therapy by clinicians for unknown reasons. In univariate and multivariate analyses we identified patient socio-demographic characteristics as a major determinant for starting treatment for hepatitis C virus infection. It has been reported that patient socio-demographic characteristics are explanatory variables that account for the direct relationship between education degree, patient social support and treatment willingness for hepatitis C virus infection [23]. In addition, a meta-analysis has shown a significant relationship between therapy adherence and practical, emotional and social support [24]. We used civil status as a surrogate measure of social support; living single, separated or widower were identified as significant barriers for hepatitis C virus therapy in our study. A creation of a comprehensive program of co-infection patient peergroup, and a home care system have improved treatment outcomes in other settings [25,26]. Moreover, it is well known that higher education degree is associated with better information and knowledge of the
J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72 Table 4 Univariate and multivariate analysis: association between socio-demographic and clinical characteristic with patients not starting treatment for HCV. Univariate analysis Characteristic
Odds 95% ratio confidence limits
Education 1 Secondary or university studies (reference group) No studies or 3.67 primary studies
and mental health problems to expand hepatitis C virus infection treatment to a larger population of HIV-infected patients co-infected with hepatitis C virus.
Multivariate analysis P value
Odds ratio
95% confidence limits
P value
1.26–10.67
0.017
4.53
1.36–15.16
0.014
1.23–8.53
0.017
4.81
1.54–14.99
0.007
Antiretroviral therapy Yes 1 (reference group) No 3.28
0.99–10.80
0.051
2.25
0.46–11.00
0.317
HIV RNA Not detectable 1 (reference group) ≥ 50 copies/mL 3.11
1.24–7.82
0.016
1.82
0.52–6.34
0.346
Civil status Married–cohabitant 1 (reference group) Single–separated– 3.24 widower
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5. Learning points • Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. • In this cross-sectional study carried out in a referral hospital with integrated care for hepatitis C virus and HIV co-infection only 61% of patients had appropriate evaluation for hepatitis C virus infection and only one-third of patients received therapy with peginterferon and ribavirin. Patients treated with peginterferon plus ribavirin showed a 44% sustained virologic response. • Logistic regression analysis identified patient socio-demographic characteristics as the main determinants related to initiation of hepatitis C virus treatment. • Patients with social disadvantages defined by lower education degree or civil status single, separated or widower will require a multidisciplinary model of health care to improve hepatitis C virus treatment initiation and success.
Author contributions disease. In fact, one study showed that many of the patients who decline treatment had based their decision as a consequence of a lack of enough knowledge about HCV disease. After improving hepatitis C virus infection knowledge, patients felt better satisfied with their care and more actively involved in their treatment [27]. Of note, economic factors were not a major barrier in our study since medication and treatment costs were covered by the Regional Health System. Other factors related to physician decision to start therapy for hepatitis C virus infection, in univariate analysis were, whether the patient was receiving antiretroviral therapy or had HIV viral load below the limit of detection. There is ample evidence that concurrent HIV infection accelerates the progression of fibrosis and liver-related morbidity and -mortality in HCV-infected patients [28]. Therefore, therapy for HIV infection should be started at earlier stages when coinfection with hepatitis C virus or hepatitis B virus is present (GESIDA) [29]. Although socio-demographic variables retained stronger explanatory association in the decision to start therapy for hepatitis C virus, the use of antiretroviral therapy should be considered in patients with hepatitis C virus infection when CD4 lymphocyte count is between 350 and 500 cells/μL. Our study has some limitations. Firstly it is a cross-sectional retrospective study where risk factors and disease outcome were ascertained at a single point in time. However, it was useful to define the service needs and hypothesis generation to address the burden of population requiring comprehensive care. Secondly, since variables were measured a single point in time, civil status and education could have changed in a minor proportion of patients along the observation period. However, patients earning higher education level or getting married or cohabitant would have tended to decrease the strength of association between lack of treatment, and lower education and social support. In spite of this bias, there was a clear direct association of these factors with the lack of hepatitis C virus treatment in multivariate analysis. In conclusion, our study points out the importance of sociodemographic characteristics of patients with hepatitis C virus and HIV co-infection to be eligible to start peginterferon plus ribavirin therapy. It is necessary to implement a multidisciplinary model of care to address patient information, social support and management of substance use
All the authors participated in the establishment of the research. JE, and RF conceived the research and participated in its design. JE performed the statistical analysis. JE wrote the initial draft of the manuscript, which JE, RF, FP, CA and CB edited. All authors read and approved the final manuscript. Conflict of interest Authors declare no conflict of interest. Acknowledgement This study was partly funded by an investigational grant from Roche Farma, España. References [1] Pérez Cachafeiro S, Del Amo J, Iribarren JA, Salavert Lleti M, Gutiérrez F, Moreno A, et al. Decrease in serial prevalence of coinfection with hepatitis C virus among HIV-infected patients in Spain, 1997–2006. Clin Infect Dis 2009;48:1467–70. [2] Qurishi N, Kreuzberg C, Lüchters G, Effenberger W, Kupfer B, Sauerbruch T, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 2003;362:1708–13. [3] Macías J, Berenguer J, Japón MA, Girón JA, Rivero A, López-Cortés LF, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology 2009;50:1056–63. [4] Rockstroh JK, Bhagani S, Benhamou Y, Bruno R, Mauss S, Peters L, et al. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med 2008;9: 82–8. [5] Berenguer J, Alvarez-Pellicer J, Martín PM, López-Aldeguer J, Von-Wichmann MA, Quereda C, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 2009;50:407–13. [6] Tural C, Tor J, Sanvisens A, Pérez-Alvarez N, Martínez E, Ojanguren I, et al. Accuracy of simple biochemical tests in identifying liver fibrosis in patients co-infected with human immunodeficiency virus and hepatitis C virus. Clin Gastroenterol Hepatol 2009;7:339–45. [7] Mehta SH, Lucas GM, Mirel LB, Torbenson M, Higgins Y, Moore RD, et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS 2006;20:2361–9. [8] Taylor LE. Delivering care to injection drug users coinfected with HIV and hepatitis C virus. Clin Infect Dis 2005;40(Suppl 5):S355–61.
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[9] Backus LI, Boothroyd DB, Phillips BR, Mole LA. Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus. J Viral Hepat 2006;13:799–810. [10] Maida I, Soriano V, Ramos B, Rios P, Gonzalez-Lahoz J, Nuñez M. Characteristics and prospects for hepatitis C therapy o fan HIV–HCV coinfected population followed at a reference HIV center. HIV Clin Trials 2005;6:329–36. [11] Martin-Carbonero L, Nuñez M, Mariño A, Alcocer F, Bonet L, Garcia-Samaniego J, et al. Indetectable hepatitis C virus RNA at week 4 as predictor of sustained virological response in HIV patients with chronic hepatitis C. AIDS 2008;22:15–21. [12] Valerio L, Yazdanpanah Y, Poizot-Martin I, Rosenthal E, Marimoutou C, Gastaut JA, et al. Baseline CD4 cell count and outcome of pegylated interferon plus ribavirin therapy in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2008;47:50–5. [13] Pineda JA, Mira JA, Gil I de L, Valera-Bestard B, Rivero A, Merino D, et al. Influence of concomitant antiretroviral therapy on the rate of sustained virological response to pegylated interferon plus ribavirin in hepatitisC virus/HIV-coinfected patients. J Antimicrob Chemother 2007;60:1347–54. [14] Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451–9. [15] Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438–50. [16] Behler CM, Vittinghoff E, Linn F, Chung RT, Peters MG, Robbins GK, et al. Hematologic toxicity associated with interferon-based hepatitis C therapy in HIV type 1-coinfected subjects. Clin Infect Dis 2007;44:1375–83. [17] Nunes D, Saitz R, Libman H, Cheng DM, Vidaver J, Samet JH. Barriers to treatment of hepatitis C in HIV/HCV-coinfected adults with alcohol problems. Alcohol Clin Exp Res 2006;30:1520–6. [18] McLaren M, Garber G, Cooper C. Barriers to hepatitis C virus treatment in a Canadian HIV–hepatitis C virus coinfection tertiary care clinic. Can J Gastroenterol 2008;22:133–7. [19] Cacoub P, Rosenthal E, Halfon P, Sene D, Perronne C, Pol S. Treatment of hepatitis C virus and human immunodeficiency virus coinfection: from large trials to real life. J Viral Hepat 2006;13:678–82.
[20] Huckans MS, Blackwell AD, Harms TA, Indest DW, Hauser P. Integrated hepatitis C virus treatment: addressing comorbid substance use disorders and HIV infection. AIDS 2005;19(Suppl 3):S106–15. [21] Edlin BR, Kresina TF, Raymond DB, Carden MR, Gourevitch MN, Rich JD, et al. Overcoming barriers to prevention, care, and treatment of hepatitis C in illicit drug users. Clin Infect Dis 2005;40(Suppl 5):S276–85. [22] Scheft H, Fontenette DC. Psychiatric barriers to readiness for treatment for hepatitis C Virus (HCV) infection among injection drug users: clinical experience of an addiction psychiatrist in the HIV–HCV coinfection clinic of a public health hospital. Clin Infect Dis 2005;40(Suppl 5):S292–6. [23] Gordillo V, del Amo J, Soriano V, González-Lahoz J. Sociodemographic and psychological variables influencing adherence to antiretroviral therapy. AIDS 1999;13:1763–9. [24] DiMatteo MR. Social support and patient adherence to medical treatment: a metaanalysis. Health Psychol 2004;23:207–18. [25] Clanon KA, Johannes Mueller J, Harank M. Integrating treatment for hepatitis C virus infection into an HIV clinic. Clin Infect Dis 2005;40(Suppl 5):S362–6. [26] Kresina TF, Bruce RD, Cargill VA, Cheever LW. Integrating care for hepatitis C virus (HCV) and primary care for HIV for injection drug users coinfected with HIV and HCV. Clin Infect Dis 2005;41(Suppl 1):S83–8. [27] Balfour L, Cooper C, Tasca GA, Kane M, Kowal J, Garber G. Evaluation of health care needs and patient satisfaction among hepatitis C patients treated at a hospital-based, viral hepatitis clinic. Can J Public Health 2004;95:272–7. [28] Pineda JA, García-García JA, Aguilar-Guisado M, Ríos-Villegas MJ, Ruiz-Morales J, Rivero A, et al. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology 2007;46:622–30. [29] Panel de expertos de Gesida y Plan Nacional sobre el Sida. Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with human immunodeficiency virus infection (update February 2009). Enferm Infecc Microbiol Clín 2009;27:222–35.
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Original article
Cross-sectional epidemiology of hepatitis C virus detection and treatment in HIV-infected patients Javier Ena a,⁎, Rosa F. Ruiz-de-Apodaca b, Francisco Pasquau a, Concepción Amador a, Concepción Benito a a b
Department of Internal Medicine, Hospital Marina Baixa, Villajoyosa, Alicante, Spain Department of Pharmacy, Hospital Marina Baixa, Villajoyosa, Alicante, Spain
a r t i c l e
i n f o
Article history: Received 7 February 2010 Received in revised form 5 July 2010 Accepted 18 August 2010 Available online 15 September 2010 Keywords: Hepatitis C virus Human immunodeficiency virus Cross-sectional studies
a b s t r a c t Background: Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. Methods: Cross-sectional study. In a HIV referral clinic we assessed the proportion of patients eligible for hepatitis C virus evaluation and treatment according to consensus guidelines. Results: We identified 134 patients with hepatitis C virus and HIV co-infection. Twenty-one patients were excluded from the analysis due to never attending the HIV clinic (n = 12) or having hepatitis C virus RNA not detectable (n = 9). In the remaining 113 patients, only 61% had identification of hepatitis C virus genotype and quantification of hepatitis C viral load. Thirty-six patients started peginterferon plus ribavirin, and 16 (44%) achieved sustained virologic response. Seventy-seven patients did not receive treatment for hepatitis C virus due to the presence of medical contraindications (n = 22), provider barriers (n = 15), or patient barriers (n = 40). Multivariate analysis identified lower education degree (odds ratio: 4.53; 95% confidence intervals: 1.36–15.16, p = 0.014) and patient civil status single, separated or widower (odds ratio: 4.81; 95% confidence intervals: 1.54–14.99, p = 0.007) as the independent determinants associated to not initiating therapy for hepatitis C virus infection in patients with barriers. Conclusion: A minor proportion of HIV-infected patients received appropriate assessment and treatment for hepatitis C virus infection. Social disadvantages require multidisciplinary models of health care to improve hepatitis C virus treatment initiation and success. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction In Spain, approximately 42% of individuals with human immunodeficiency virus are co-infected with hepatitis C virus [1]. The introduction of highly active antiretroviral therapy has led to a prolongation of the life span in HIV-infected patients leaving hepatitis C virus co-infection as one of the most significant factors influencing the overall survival of this population [2]. Although the mechanism of interaction between hepatitis C virus and HIV is not completely understood, it is well known that patients with HIV/HCV co-infection show a faster rate of fibrosis progression resulting in more frequent occurrences of cirrhosis, end-stage liver disease, and hepatocellular carcinoma [3]. The treatment for hepatitis C virus in co-infected patients is similar to that of hepatitis C virus mono-infection; i.e., a combination of peginterferon plus ribavirin
⁎ Corresponding author. Servicio de Medicina Interna, Hospital Marina Baixa, Av Alcalde Jaume Botella Mayor 7, Villajoyosa 03570, Alicante, Spain. Tel.: +34 96 6859957; fax: +34 96 6859900. E-mail address: [email protected] (J. Ena).
[4]. Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus [5]. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. The aim of this study was to describe the characteristics of HIV-infected patients with hepatitis C virus infection attending a referral HIV clinic in Spain, assessing barriers to initiate therapy with peginterferon plus ribavirin. 2. Patients and methods 2.1. Setting The Hospital Marina Baixa is a 280-bed institution belonging to the Regional Health System (Agencia de Salut de la Comunitat Valenciana). It provides coverage to a population of 210,000 habitants in the East Coast of Spain. The HIV clinic at the Hospital offers clinical care by infectious diseases specialists, pharmacysts and nurses to patients with HIV infection who are evaluated at a 3-month interval. In the year 2008 a cohort of 380 patients with HIV infection attended the clinic. HIV-
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.08.006
J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72
infected patients with hepatitis C virus infection receive an integrated care within the HIV clinic and the treatment cost is fully covered by the Regional Health System. 2.2. Study design A cross-sectional study was conducted in patients attending the HIV clinic between January and March 2009. 2.3. Patient identification Patients with hepatitis C virus and HIV co-infection were identified by means of clinical records review. In addition, we reviewed the HIV and HCV serology records of the Clinical Microbiology Laboratory and the hepatitis C virus dispensation records of the Pharmacy Department from January 2002 to January 2009. 2.4. Patient assessments We reviewed the clinical records to collect information on demographics, attendance records and laboratory data including baseline HIV RNA, CD4 lymphocyte cell count, use of antiretroviral therapy, HBsAg status, hepatitis C virus genotype, hepatitis C virus RNA quantification, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, liver biopsy and liver transient elastography. Prediction of advanced liver fibrosis was carried out using the APRI index (also known as aspartate transferase platelet ratio index) [6], results of liver biopsy, and liver transient elastography. Advanced liver fibrosis was considered when APRI index was greater than 1.5, when liver biopsy showed F3–F4 in METAVIR index, or when values obtained by liver transient elastography were above 11.8 kPa [4]. In patients treated for hepatitis C virus infection, laboratory data were collected before starting therapy; in those not treated, laboratory data were collected recent to the cross-sectional study (past 4 months). Patients follow-up was considered until sustained virological response was confirmed at 24 weeks after finishing hepatitis C virus treatment, or until treatment discontinuation occurred due to drug toxicity, virological failure or death. 2.5. Definitions of contraindications for interferon therapy Medical contraindications to interferon therapy were defined based on the clinical practice guidelines and recent recommendations of the Executive Committee of the European AIDS Clinical Society [4]. Subjects with the following conditions were excluded: an active HIV-related opportunistic infection or cancer; an absolute neutrophil count below 1500/mm [3]; a platelet count below 70,000/mm [3]; a hemoglobin level below 11 g/dL for women, or below 12 g/dL for men; a serum creatinine level more than 1.5 times the upper limit of normal; evidence of decompensated liver disease; severe psychiatric disease, especially depression; clinically significant coexisting medical conditions; and, for women, pregnancy or unwillingness to practice contraception. In addition, we considered absolute contraindications for interferon plus ribavirin therapy: current (past 30 days) heavy alcohol use (more than 40 g per day in men and more than 20 g per day in women), recent (past 6 months) injection drug use, CD4 cell count of less than 100 cells/μL, advanced liver disease defined as a Child–Pugh score of equal or greater than 7, and suicidal ideation or attempt in the past 6 months. Relative contraindications were defined as current moderate alcohol use (less than heavy use but not abstinent), current injection drug use without needle sharing, CD4 count from 100 to 199 cells/μL, and significant depressive symptoms. Additionally we considered as contraindications for interferon therapy those patients denying consent for treatment and physician conviction of poor patient compliance.
67
2.6. Statistical analysis Descriptive statistics were used to characterize the sample. To assess the determinants for those patients starting hepatitis C virus therapy compared to those who did not start the therapy for causes other than absolute or relative medical contraindications, we used Chi square test, Fisher exact test, odds ratios and 95% confidence intervals. Logistic regression analysis was used to assess independent determinats for not starting treatment for hepatitis C virus in patients with conditions other than medical contraindications compared with those patients who were treated with pegylated interferon plus ribavirin. Due to the small number of subjects we grouped education degree in two strata (low: no education or primary studies and high: secondary or university studies) and civil status in two strata (single–separated–widower and married– cohabitant). A P value of less than 0.05 was considered to indicate statistical significance. All analyses were carried out with the use of SPSS software for windows (release 15.0). 2.7. Ethical review The protocol was approved by the institutional review board of the Hospital Marina Baixa. Information obtained was recorded in such a manner that subjects cannot be recognized, directly or through identifiers linked to the subjects. The study was designed to identify opportunities to improve the health care of patients with hepatitis C virus and HIV co-infection. 3. Results We identified a total of 134 patients with HIV and hepatitis C virus co-infection after reviewing the Clinical Laboratory serology records, the Pharmacy Department dispensation records and the clinical records of patients attending the HIV clinic during the study period (Fig. 1). Twelve patients identified from the serology test register never attended the HIV clinic. Nine patients were hepatitis C virus antibody-positive but RNA negative, and as such, were excluded from the analysis. The remaining 113 co-infected patients were evaluated in detail (Table 1). This sample was predominantly male (68%). The median age was 43.88 years (Interquartile range: 41.55–47.63), 37% had never been married, 36% was currently married or cohabiting and 15% was separated or widower. Regarding education, 72% of patients had no education or primary studies. A total of 86 (76%) patients was receiving combination antiretroviral therapy and 64 had HIV viral load below the detection limit (50 copies/mL). Hepatitis C virus genotype assessment was carried out in 85 (75%) patients and hepatitis C virus viral load quantification was carried out in 73 (65%) patients and both in 69 (61%) patients. Approximately 56% of patients had unfavourable hepatitis C virus genotypes 1 or 4 for treatment. Regarding the determination of the degree of liver fibrosis, all patients had possibility for evaluation of APRI index but only 36 (32%) had liver biopsy (n = 13) or liver transient elastography (n = 24) carried out. A total of 22 patients had APRI index, liver biopsy or liver transient elastography results indicating advanced fibrosis. 3.1. Patients starting anti-hepatitis C virus therapy A total of 36 (32%) patients initiated anti-hepatitis C virus therapy. Patients received 180 μg of peginterferon alfa-2a subcutaneously weekly plus weighted-based ribavirin dosing (1000 mg per day for patients b75 kg, and 1200 mg per day for patients ≥75 kg). A safety assessment was performed in subjects at week 4 and every 12 weeks until the end of treatment. An efficacy assessment was performed at weeks 24, 48 and 60 with the use of a quantitative HCV RNA assay (Roche Cobas Amplicor 2.0). Treatment was maintained for 48 weeks in patients with virologic response (HCV RNA level of less than 60 IU/mL at a 24 week assessment). Sustained virologic response was confirmed at
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J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72
Fig. 1. Flow of patients included in the study.
week 60 in patients who completed anti-hepatitis C virus treatment. Treatment was discontinued if the patient developed drug intolerance or severe side effects to peginterferon or ribavirin or lack of virologic response. Twenty-six patients had HCV genotypes 1 or 4. The patients' main clinical characteristics are summarized in Table 2. Overall, most patients were married or cohabitant, with HIV viral load below the detection limit and had a mean CD4 cell count of 525/mm [3]. A total of 32 (89%) patients was on antiretroviral treatment when they started therapy for hepatitis C virus infection. Five patients received non-recommended antiretroviral drug regimens, according to the latest guidelines, with drug combinations including didanosine, stavudine, zidovudine, or dual antiretroviral combination therapy. In their follow-up 17 (47%) patients had adverse events related to hepatitis C virus treatment. Six patients required dose reduction in peginterferon, ribavirin, or both drugs due to severe side effects. Nine patients required erythropoiesis stimulating factors due to severe anemia and, 4 patients required treatment with granulocyte-colony stimulating factors due to severe neutropenia. One patient required discontinuation of peginterferon plus ribavirin therapy due to an acute decompensation of an advanced liver disease. At the end of follow-up, 16 (44%) patients achieved sustained virologic response, 18 (50%) had no sustained virologic response and, 2 (6%) patients died. Deaths were related with acute neurological deterioration and vascular disease. 3.2. Patients not starting anti-hepatitis C virus therapy A total of 77 (68%) patients did not start the therapy for hepatitis C virus. Twenty-two patients had absolute or relative medical contraindications for interferon therapy. These contraindications were: CD4 lymphocyte count less than 100 cells/μL (n = 3), advanced liver disease (n =1), heavy alcohol use (n=5), significant mental health illness (n =8), illegal substance abuse (n =3), and other treatment priority requirement (n =2). Fifty-five patients had barriers for not starting interferon therapy other than medical contraindications. Barriers in 15 patients were classified as provider barrier since a physician never proposed to patients a therapy for hepatitis C virus infection, and in 40 patients barriers were classified as patient barriers due to patient often missing appointments to the clinic or delaying to retrieve antiretroviral
drug medication (n = 22), patient unwillingness to initiate therapy due to fear of adverse effects (n = 10), or patients preferring to defer hepatitis C virus therapy at the time of study period (n=8) (Fig. 2). In patients with barriers the proportion of hepatitis C virus RNA quantification was 51%, and that of hepatitis C virus genotype testing was 67%. We compared the demographic and clinical characteristics of patients with barriers classified as provider (n = 15) or patient barriers (n = 40). More patients classified as provider barriers were receiving antiretroviral drug therapy than those classified as patient barriers (93% vs. 62%; p = 0.022); the remaining variables analyzed such as sex, age, education level, proportion of unemployment, civil status, hepatitis C virus genotype, hepatitis C virus RNA quantification, HIV RNA quantification and lymphocyte CD4 counts were distributed similarly in both groups. For comparison purposes we considered provider barriers and patient barriers as one group (n = 55) when comparing their characteristics to those patients starting hepatitis C virus treatment (n = 36). Univariate analysis showed that education degree, civil status, use of antiretroviral therapy and HIV viral load were associated with hepatitis C virus treatment status in patients with Hepatitis C virus and HIV co-infection (Table 3). We carried out a logistic regression analysis to determine the independent variables associated with patient not starting hepatitis C virus therapy. Socio-demographic variables such as education degree and civil status showed stronger association with hepatitis C virus therapy status than the use of antiretroviral therapy or HIV viral load, according to the Odds Ratios obtained (Table 4). Patients with no studies or primary studies and those with civil status single, separated or widower had the greatest barriers for starting hepatitis C virus therapy. 4. Discussion This cross-sectional study carried out in a referral hospital with integrated care for HIV and hepatitis C virus infections in Eastern Spain showed a low rate of hepatitis C virus evaluation and treatment in patients with HIV infection. Only 61% of patients had hepatitis C virus genotype identification and viral load quantification. Moreover, only onethird of patients received peginterferon plus ribavirin therapy for hepatitis C virus infection. Sustained virologic response was observed in 44% of such patients. Therefore, only 14% of the full cohort achieved
J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72 Table 1 Characteristics of 113 HIV/HCV-infected patients analyzed. Characteristic Age (years), median [IQR] Sex — no. (%) Male Female Education — no. (%) No education Primary studies Secondary studies University degree Unknown Unemployment — no. (%) Yes No Unknown Civil status — no. (%) Single Married/cohabitant Separated/widower Unknown Antiretroviral therapy — no. (%) Yes No Interferon plus ribavirin therapy — no. (%) Yes No CD4 cell count × 109/L, -median [IQR] HIV RNA (copies/mL), median [IQR] HIV RNA not detectable (%) HBsAg seropositive — no. (%) Yes No HCV RNA (copies/mL), median [IQR] HCV RNA (UI/mL) b 800,000 HCV genotype — no. (%) Genotype 1a/1b Genotype 2a/2b/2c Genotype 3 Genotype 4 Genotype 5 Unknown Aspartate aminotransferase (units/L), median [IQR] Alanine aminotransferase (units/L), median [IQR] Platelet count × 106/L, -median [IQR] APRI index, median [IQR] APRI index N 1.5 Liver biopsy — no. (%) Yes No Liver transient elastography (Fibroscan) — no. (%) Yes No
43.88 [41.55–47.63] 77 (68) 36 (32) 34 (30) 48 (42) 19 (17) 1 (1) 11 (10) 37 (33) 67 (59) 9 (8) 42 41 17 13
(37) (36) (15) (12)
86 (76) 27 (24) 36 (32) 77 (68) 437 [283–597.5] 50 [50–1,640] 64 (56) 1 (1) 112 (99) 1,470,000 [358,500–4,965,000] 30 (41) 48 (43) 2 (2) 18 (16) 15 (13) 1 (1) 28 (25) 46 [33–78.25] 58.50 [31–99.25] 170,000 [130,000–223,000] 0.75 [0.48–1.30] 22 (19) 13 (11) 100 (89)
24 (21) 89 (79)
sustained viral response for hepatitis C virus infection, with a significant proportion of patients suffering from severe adverse effects related to peginterferon plus ribavirin therapy. Among patients not treated for
69
hepatitis C virus infection, the great proportion (55 out from 77 patients) had conditions other than medical contraindications to receive peginterferon plus ribavirin treatment. Those conditions were mostly patient barriers due to a lack of adherence to antiretroviral therapy, unwillingness to start treatment for hepatitis C virus infection, or preferring to defer therapy at the moment the study was carried out. The cause specific analysis for those barriers identified that patient socio-demographic characteristics were stronger predictors for physicians to refrain from starting hepatitis C virus therapy than other specific laboratory or clinical data. Moreover, lower education degree and civil status other than married or cohabitant were significant barriers to start therapy for hepatitis C virus infection in HIV-infected patients. Studies carried out in other countries showed that a minor proportion of patients with HIV infection received hepatitis C virus pre-treatment assessment for genotype characterization and viral load quantification with figures ranging from 33% to 57% [7,8]. In patients completing hepatitis C virus pre-treatment assessment the proportion of subjects starting therapy varied from 9% in US veterans [9] to 23%– 42% in US urban HIV clinics [7,8] and to 40% in a cross-sectional study carried out in Spain [10]. The proportion of patients who achieved sustained virologic response after starting treatment with peginterferon and ribavirin varied initially from 21% [7] up to 49% in most recent cohort series [11–13]. In pivotal clinical trials of patients with hepatitis C virus and HIV co-infection starting peginterferon plus ribavirin therapy the rate of sustained virologic response was observed in 27% to 40% [14,15]. The results observed in our study are in concordance to those described in the literature in terms of proportion of patients with completed evaluation for hepatitis C virus infection, treatment initiation and rate of sustained virologic response. As expected, patients treated with peginterferon and ribavirin suffered a significant number of major adverse effects, mainly hematologic toxicity. Nevertheless, the increasing rates of sustained virologic response observed in recent years are explained in part due to the greater proportion patients receiving full dose peginterferon and ribavirin facilitated by the use of hematopoietic growth factors [16]. A main objective of our study was to identify barriers to initiate therapy with peginterferon plus ribavirin in HIV-infected patients with hepatitis C virus infection. Approximately two third of patients were not eligible for peginterferon and ribavirin therapy due to absolute or relative medical contraindication or presence of patient or physician barriers. Several studies have pointed out that the main barriers to initiate therapy for hepatitis C virus infection are the presence of psychiatric illness, alcohol consumption or substance abuse [7,17–19]. The strategies used to overcome these barriers included the integration of hepatitis C virus treatment in mental health and addiction programmes [20–22]. However, in our study we identified only 16 patients out of 113 who were ineligible due to those factors. On the other hand, the vast majority of patients not treated for hepatitis C virus infection had barriers other than medical conditions that precluded treatment with peginterferon plus ribavirin. These conditions were in most cases patient related barriers due to the lack of adherence to HIV follow-up or unwillingness to start therapy. These conditions identified
Fig. 2. Provider and patient barriers for hepatitis C virus infection evaluation in patients with no contraindications for therapy.
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Table 2 Characteristics of patients that started treatment for hepatitis C virus infection. Characteristic Sex — no. (%) Male Female Age median [IQR] — year Education — no. (%) No education Primary studies Secondary studies University degree Unknown Unemployment — no. (%) Yes No Civil status — no. (%) Single Married/cohabitant Separated/widower Unknown Serum HCV RNA Median [IQR] — IU/mL N 800,000 IU/mL — no. (%) HCV genotype — no. (%) 1 2 3 4 5 Unknown Advanced liver disease Antiretroviral therapy — no. (%) None Any Combination antiretroviral therapy Didanosine + lamivudine + nevirapine Tenofovir + zidovudine + lamivudine + abacavir Tenofovir + abacavir + atazanavir/ritonavir Tenofovir + atazanavir/ritonavir Tenofovir + emtricitabine + efavirenz Tenofovir+emtricitabine+Fosamprenavir/ ritonavir Tenofovir + emtricitabine + lopinavir/ritonavir Tenofovir + lamivudine + nevirapine Tenofovir + lamivudine + lopinavir/ritonavir Tenofovir + nevirapine + lopinavir/ritonavir Tenofovir + efavirenz + lopinavir/ritonavir Stavudine + lamivudine + efavirenz Stavudine + lamivudine + nevirapine HIV-1 RNA Mean [IQR] — log10 copies/mL Undetectable HIV RNA (b50 copies/mL) — no. (%) CD4+ cells — no./mm3 Median [IQR] b200/mm3 — no. (%) Adverse events related to hepatitis C virus treatment Any Reduction in pegylated interferon dose Reduction in ribavirin dose Reduction in pegylated interferon and ribavirin dose Neutropenia requiring granulocyte-colony stimulating factor (G-CSF) therapy Anemia requiring erythropoiesis stimulating agents Liver disease decompensation requiring interferon and ribavirin discontinuation Outcome Sustained virological response No sustained virological response Deaths, not related with liver disease
Patients starting therapy for hepatitis C virus infection N = 36 22 (61) 14 (39) 45.33 [41.13–48.59] 4 (11) 17 (47) 11 (31) 1 (3) 3 (8) 10 (9) 26 (23) 8 (22) 23 (64) 4 (11) 1 (3) 865,661 [329,619–4,150,000] 26 (72) 18 (50) 1 (3) 6 (17) 8 (22) 1 (3) 2 (6) 5 (14) 4 (11) 32 (89) 1 (3) 1 (3) 1 (3) 1 (3) 14 (39) 1 (3) 3 (9) 3 (9) 2 (6) 2 (6) 1 (3) 1 (3) 1 (3) 50 [50–50] 27 (75)
463 [368–590] 0
17 (47) 3 (8) 1 (3) 2 (6) 4 (11) 9 (25) 1 (3)
16 (44) 18 (50) 2 (6)
Table 3 Factors associated with treatment status for HCV in patients co-infected with HIV/HCV, excluding those with absolute or relative medical contraindications. Characteristic, n (%)
Age group, years b40 ≥40 Gender Male Female Education No education or primary studies Secondary studies or university degree Civil status Single, separated or widower Married or cohabitant Unemployment No Yes Antiretroviral therapy No Yes CD4 lymphocyte cell count × 109/L b200 ≥200 HIV RNA (copies/mL) b50 ≥50 HCV genotype 1 or 4 2 or 3 HCV RNA (UI/mL) b800,000 ≥800,000 Aspartate aminotransferase (Units/L) b38 ≥38 Alanine aminotransferase (Units/L) b40 ≥40 Platelet count × 109/L b150,000 ≥150,000 APRI index b1.5 ≥1.5 Liver fibrosis stage 3–4 by liver biopsy or liver transient elastography N 11.8 kPa Yes No
Treated HCV Nontreated HCV P value patients (n = 36) patients (n = 55) 8 (22) 28 (78)
7 (13) 50 (87)
0.233
22 (61) 14 (39)
40 (73) 15 (27)
0.245
21 (58)
45 (82)
0.012
12 (33)
8 (14)
8 (22) 27 (75)
25 (45) 24 (44)
0.018
26 (23) 10 (9)
32 (58) 19 (35)
0.356
4 (11) 32 (89)
16 (28) 41 (72)
0.043
0 (0) 36 (100)
4 (7) 51 (93)
0.150
27 (75) 9 (25)
27 (49) 28 (51)
0.014
24 (67) 8 (22)
18 (33) 10 (18)
0.470
10 (28) 19 (53)
11 (20) 19 (35)
0.861
12 (34) 23 (66)
18 (33) 37 (67)
0.926
12 (34) 23 (66)
17 (31) 38 (69)
0.783
24 (67) 12 (33)
32 (58) 23 (42)
0.416
31 (86) 5 (14)
44 (82) 11 (18)
0.564 0.433
5 (14) 16 (44)
2 (4) 13 (24)
in our study have been found in other survey studies [7,19]. In addition, another significant proportion of patients was never proposed for therapy by clinicians for unknown reasons. In univariate and multivariate analyses we identified patient socio-demographic characteristics as a major determinant for starting treatment for hepatitis C virus infection. It has been reported that patient socio-demographic characteristics are explanatory variables that account for the direct relationship between education degree, patient social support and treatment willingness for hepatitis C virus infection [23]. In addition, a meta-analysis has shown a significant relationship between therapy adherence and practical, emotional and social support [24]. We used civil status as a surrogate measure of social support; living single, separated or widower were identified as significant barriers for hepatitis C virus therapy in our study. A creation of a comprehensive program of co-infection patient peergroup, and a home care system have improved treatment outcomes in other settings [25,26]. Moreover, it is well known that higher education degree is associated with better information and knowledge of the
J. Ena et al. / European Journal of Internal Medicine 22 (2011) 66–72 Table 4 Univariate and multivariate analysis: association between socio-demographic and clinical characteristic with patients not starting treatment for HCV. Univariate analysis Characteristic
Odds 95% ratio confidence limits
Education 1 Secondary or university studies (reference group) No studies or 3.67 primary studies
and mental health problems to expand hepatitis C virus infection treatment to a larger population of HIV-infected patients co-infected with hepatitis C virus.
Multivariate analysis P value
Odds ratio
95% confidence limits
P value
1.26–10.67
0.017
4.53
1.36–15.16
0.014
1.23–8.53
0.017
4.81
1.54–14.99
0.007
Antiretroviral therapy Yes 1 (reference group) No 3.28
0.99–10.80
0.051
2.25
0.46–11.00
0.317
HIV RNA Not detectable 1 (reference group) ≥ 50 copies/mL 3.11
1.24–7.82
0.016
1.82
0.52–6.34
0.346
Civil status Married–cohabitant 1 (reference group) Single–separated– 3.24 widower
71
5. Learning points • Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. • In this cross-sectional study carried out in a referral hospital with integrated care for hepatitis C virus and HIV co-infection only 61% of patients had appropriate evaluation for hepatitis C virus infection and only one-third of patients received therapy with peginterferon and ribavirin. Patients treated with peginterferon plus ribavirin showed a 44% sustained virologic response. • Logistic regression analysis identified patient socio-demographic characteristics as the main determinants related to initiation of hepatitis C virus treatment. • Patients with social disadvantages defined by lower education degree or civil status single, separated or widower will require a multidisciplinary model of health care to improve hepatitis C virus treatment initiation and success.
Author contributions disease. In fact, one study showed that many of the patients who decline treatment had based their decision as a consequence of a lack of enough knowledge about HCV disease. After improving hepatitis C virus infection knowledge, patients felt better satisfied with their care and more actively involved in their treatment [27]. Of note, economic factors were not a major barrier in our study since medication and treatment costs were covered by the Regional Health System. Other factors related to physician decision to start therapy for hepatitis C virus infection, in univariate analysis were, whether the patient was receiving antiretroviral therapy or had HIV viral load below the limit of detection. There is ample evidence that concurrent HIV infection accelerates the progression of fibrosis and liver-related morbidity and -mortality in HCV-infected patients [28]. Therefore, therapy for HIV infection should be started at earlier stages when coinfection with hepatitis C virus or hepatitis B virus is present (GESIDA) [29]. Although socio-demographic variables retained stronger explanatory association in the decision to start therapy for hepatitis C virus, the use of antiretroviral therapy should be considered in patients with hepatitis C virus infection when CD4 lymphocyte count is between 350 and 500 cells/μL. Our study has some limitations. Firstly it is a cross-sectional retrospective study where risk factors and disease outcome were ascertained at a single point in time. However, it was useful to define the service needs and hypothesis generation to address the burden of population requiring comprehensive care. Secondly, since variables were measured a single point in time, civil status and education could have changed in a minor proportion of patients along the observation period. However, patients earning higher education level or getting married or cohabitant would have tended to decrease the strength of association between lack of treatment, and lower education and social support. In spite of this bias, there was a clear direct association of these factors with the lack of hepatitis C virus treatment in multivariate analysis. In conclusion, our study points out the importance of sociodemographic characteristics of patients with hepatitis C virus and HIV co-infection to be eligible to start peginterferon plus ribavirin therapy. It is necessary to implement a multidisciplinary model of care to address patient information, social support and management of substance use
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