Spontaneous hepatitis C virus clearance in HIV patients with chronic hepatitis C bearing IL28B-CC alleles using antiretroviral therapy Eugenia Vispo, Pablo Barreiro, Zulema Plaza, Jose Vicente Ferna´ndez-Montero, Pablo Labarga, Carmen de Mendoza, Rocı´o Sierra-Enguita, Ana Trevin˜o, Mariola Lopez and Vicente Soriano Background: A quarter of individuals acutely infected with hepatitis C virus (HCV) clear the virus spontaneously. Once chronic infection is established, HCV elimination generally can only be achieved using specific antiviral therapy, such as peg-interferonribavirin. Herein, we report a group of chronically HIV/HCV-coinfected patients that cleared HCV spontaneously while being treated only with antiretrovirals. Methods: Retrospective analysis of all HIV-infected individuals with positive HCV antibodies (HCV-Abs) and negative serum HCV-RNA seen during 2012 at a reference HIV clinic in Madrid. Results: From a total of 2366 HIV-infected individuals, 618 (26%) were HCV-Abþ, of whom 387 (62%) were positive for serum HCV-RNA. Individuals HCV-Abþ/HCVRNA-negative were grouped into two categories – those that had eliminated HCV following a course of antiviral treatment (n ¼ 198, 86%) and those who had cleared the virus spontaneously (n ¼ 33, 14%). Eight with spontaneous clearance were HBsAgþ and might have cleared HCV as a result of viral interference. However, six (24%) out of the remaining 25 did so after being serum HCV-RNAþ for longer than 6 months (median 5.6 years, range 1.3–12 years). All harbored alleles and had undetectable plasma HIV-RNA on HAART around the time of HCV clearance. Conclusion: Spontaneous HCV clearance may occur in a subset of chronically HIV/ HCV-coinfected patients on HAART harboring IL28B-CC. Given that antiretrovirals do not display any direct anti-HCV activity, recovery of innate immune responses could be responsible for these late HCV clearance episodes. Thus, periodic testing of serum HCV-RNA may be warranted in chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC alleles. ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2014, 28:1473–1478 Keywords: antiretroviral drugs, coinfection, hepatitis C, IL28B, liver, spontaneous clearance
Introduction Acute hepatitis C virus (HCV) infection progresses to chronicity in around a quarter of cases [1,2]. Following the acute phase of HCV replication, viremia often becomes undetectable within 12 weeks in patients with
self-limited infection [3], although a subset of patients depicts HCV replication for up to 1 year before definitive elimination [4,5]. Female sex, symptomatic acute hepatitis, and high peak of viremia are associated with spontaneous resolution of HCV infection [1,2,6]. More recently, polymorphisms at several host genes have been
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. Correspondence to Dr Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III. Calle Sinesio Delgado 10, Madrid 28029, Spain. Tel: +34 91 453 2500; fax: +34 91 733 6614; e-mail: [email protected] Received: 21 September 2013; revised: 4 January 2014; accepted: 24 February 2014. DOI:10.1097/QAD.0000000000000275
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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shown to influence the rate of spontaneous HCV clearance [2,7], single-nucleotide changes at interleukin (IL)28B alleles being the most important [2,8,9]. Finally, sexual exposure seems to be associated with a lower risk of chronicity than parenteral transmission, such as in haemophiliac individuals or injecting drug users, perhaps due to multiple inoculation episodes or larger size of the inoculum [10–12]. Once established for more than 6–12 months, HCV infection results in chronic inflammation and development of hepatic fibrosis in one-third of patients [13]. However, in the presence of some comorbidities, such as HIV coinfection, HCV-related liver disease progresses faster to cirrhosis and end-stage liver disease [13–15]. Overall, HIV/HCV-coinfected individuals respond less to standard therapy with peg-interferon-ribavirin and may experience more drug-related side effects, often as result of drug interactions with antiretrovirals [16]. Elimination of HCV-RNA from individuals with chronic hepatitis C has been reported occasionally, often accompanying hepatitis B or delta virus superinfections, and interpreted as a result of viral interference phenomena [12,17,18]. Herein, we report a group of chronically HIV/HCV-coinfected patients followed for long periods that experienced spontaneous HCV clearance while only being treated with antiretroviral drugs.
Patients and methods Study design This was a retrospective analysis of all HIV-infected individuals with positive HCVantibodies (HCV-Abs) and negative serum HCV-RNA seen during 2012 at a reference HIV clinic in Madrid, Spain, where around 2500 HIV-infected individuals are currently on regular follow-up. Data recording Main demographics (age, sex, alcohol intake, and BMI), hematologic variables (hemoglobin, leukocyte, and platelet counts), biochemistry [glucose, transaminases, gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, total cholesterol, low-density lipoprotein (LDL)cholesterol, triglycerides, and creatinine), HIV parameters (current and nadir CD4þ cell count, plasma HIV-RNA, current and prior antiretroviral drugs), hepatitis C markers (HCV genotype, HCV-RNA, prior peg-interferonribavirin therapy), and hepatitis B virus (HBV) serostatus were examined. HBsAg was tested using a commercial assay (HBV Architect, Abbott, Madrid, Spain). Viral load tests All specimens had been tested for viral load for either HIV or HCV as part of a routine clinical monitoring. Blood
was drawn before breakfast in all individuals, centrifuged and plasma stored frozen at 208C until testing, generally within 2 weeks. Commercial assays based on real-time PCR were used for measurement of both HIV-RNA and HCV-RNA (Roche, Barcelona, Spain). The lower limit of detection was 20 copies/ml and 15 IU/ml, respectively.
Hepatitis C virus genotyping This was performed using the commercial LiPA HCV genotype v2.0 assay (Innogenetics, Ghent, Belgium), which is a line probe assay that simultaneously detects sequences in the 50 untranslated (50 UTR) and core regions of the HCV genome. Interleukin 28B genotyping The rs12979860 single-nucleotide polymorphism was determined from DNA specimens collected from peripheral blood mononuclear cells using the 50 nuclease assay with allele specific TaqMan probes (ABI TaqMan allelic discrimination kit) and the ABI7900HT Sequence Detection System (Applied Biosystems, Carlsbad, California, USA). The results were reported as two categories: CC and CT/TT. Liver fibrosis assessment Transient elastometry (FibroScan; EchoSens, Paris, France) was performed by experienced operators using a single machine. Final liver stiffness values were reported as kiloPascals (kPa). Values less than 7.5 kPa were considered as equivalent to histologic Metavir stages F0– F1, values 7.5–9.4 kPa reflected F2, values 9.5–14.4 kPa were considered as F3, and values greater than 14.5 kPa were equivalent to F4 (cirrhosis) [19]. Statistical analysis Continuous variables are expressed as mean and SDs, whereas categorical variables are recorded as percentages. The Student’s t test was used for the comparison of continuous variables, whereas categorical variables were compared using the chi-square test. The SPSS version 17.0 software (SPSS Inc., Chicago, Illinois, USA) was used for calculations.
Results From a total of 2366 HIV-positive individuals seen during 2012 at our institution, 618 (26%) were HCV-Abþ. Table 1 summarizes the main characteristics of the whole study population, stratified by positive or negative for HCV-Abs. Briefly, 81% were men, with a mean age of 45 years. Injection drug use was recorded in one-quarter, whereas half were MSM. Less than 2% of MSM in this cohort acknowledged intravenous drug use. Overall, 5% were positive for HBsAg. Up to 96% of patients were on antiretroviral therapy and 86% had undetectable plasma HIV-RNA. The median CD4þ cell count was
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Spontaneous hepatitis C virus clearance in HIV Vispo et al.
1475
Table 1. Main characteristics of the study population. Variable N (%) Male sex [n (%)] Mean age [years (SD)] Risk group [n (%)] Intravenous drug use MSM Serum HBsAgþ [n (%)] Positive hepatitis delta virus antibody [n (%)] Antiretroviral therapy [n (%)] Mean CD4þ cell count [cells/ml (SD)] Undetectable plasma HIV-RNA [n (%)]
All
HCV-Ab pos
HCV-Ab neg
P
2366 1921 (81) 45 10
618 (26) 450 (73) 48 6
1718 (72) 1460 (85) 44 10
AIDS 2014, 28:1473–1478 Keywords: antiretroviral drugs, coinfection, hepatitis C, IL28B, liver, spontaneous clearance
Introduction Acute hepatitis C virus (HCV) infection progresses to chronicity in around a quarter of cases [1,2]. Following the acute phase of HCV replication, viremia often becomes undetectable within 12 weeks in patients with
self-limited infection [3], although a subset of patients depicts HCV replication for up to 1 year before definitive elimination [4,5]. Female sex, symptomatic acute hepatitis, and high peak of viremia are associated with spontaneous resolution of HCV infection [1,2,6]. More recently, polymorphisms at several host genes have been
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. Correspondence to Dr Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III. Calle Sinesio Delgado 10, Madrid 28029, Spain. Tel: +34 91 453 2500; fax: +34 91 733 6614; e-mail: [email protected] Received: 21 September 2013; revised: 4 January 2014; accepted: 24 February 2014. DOI:10.1097/QAD.0000000000000275
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
1473
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1474
AIDS
2014, Vol 28 No 10
shown to influence the rate of spontaneous HCV clearance [2,7], single-nucleotide changes at interleukin (IL)28B alleles being the most important [2,8,9]. Finally, sexual exposure seems to be associated with a lower risk of chronicity than parenteral transmission, such as in haemophiliac individuals or injecting drug users, perhaps due to multiple inoculation episodes or larger size of the inoculum [10–12]. Once established for more than 6–12 months, HCV infection results in chronic inflammation and development of hepatic fibrosis in one-third of patients [13]. However, in the presence of some comorbidities, such as HIV coinfection, HCV-related liver disease progresses faster to cirrhosis and end-stage liver disease [13–15]. Overall, HIV/HCV-coinfected individuals respond less to standard therapy with peg-interferon-ribavirin and may experience more drug-related side effects, often as result of drug interactions with antiretrovirals [16]. Elimination of HCV-RNA from individuals with chronic hepatitis C has been reported occasionally, often accompanying hepatitis B or delta virus superinfections, and interpreted as a result of viral interference phenomena [12,17,18]. Herein, we report a group of chronically HIV/HCV-coinfected patients followed for long periods that experienced spontaneous HCV clearance while only being treated with antiretroviral drugs.
Patients and methods Study design This was a retrospective analysis of all HIV-infected individuals with positive HCVantibodies (HCV-Abs) and negative serum HCV-RNA seen during 2012 at a reference HIV clinic in Madrid, Spain, where around 2500 HIV-infected individuals are currently on regular follow-up. Data recording Main demographics (age, sex, alcohol intake, and BMI), hematologic variables (hemoglobin, leukocyte, and platelet counts), biochemistry [glucose, transaminases, gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, total cholesterol, low-density lipoprotein (LDL)cholesterol, triglycerides, and creatinine), HIV parameters (current and nadir CD4þ cell count, plasma HIV-RNA, current and prior antiretroviral drugs), hepatitis C markers (HCV genotype, HCV-RNA, prior peg-interferonribavirin therapy), and hepatitis B virus (HBV) serostatus were examined. HBsAg was tested using a commercial assay (HBV Architect, Abbott, Madrid, Spain). Viral load tests All specimens had been tested for viral load for either HIV or HCV as part of a routine clinical monitoring. Blood
was drawn before breakfast in all individuals, centrifuged and plasma stored frozen at 208C until testing, generally within 2 weeks. Commercial assays based on real-time PCR were used for measurement of both HIV-RNA and HCV-RNA (Roche, Barcelona, Spain). The lower limit of detection was 20 copies/ml and 15 IU/ml, respectively.
Hepatitis C virus genotyping This was performed using the commercial LiPA HCV genotype v2.0 assay (Innogenetics, Ghent, Belgium), which is a line probe assay that simultaneously detects sequences in the 50 untranslated (50 UTR) and core regions of the HCV genome. Interleukin 28B genotyping The rs12979860 single-nucleotide polymorphism was determined from DNA specimens collected from peripheral blood mononuclear cells using the 50 nuclease assay with allele specific TaqMan probes (ABI TaqMan allelic discrimination kit) and the ABI7900HT Sequence Detection System (Applied Biosystems, Carlsbad, California, USA). The results were reported as two categories: CC and CT/TT. Liver fibrosis assessment Transient elastometry (FibroScan; EchoSens, Paris, France) was performed by experienced operators using a single machine. Final liver stiffness values were reported as kiloPascals (kPa). Values less than 7.5 kPa were considered as equivalent to histologic Metavir stages F0– F1, values 7.5–9.4 kPa reflected F2, values 9.5–14.4 kPa were considered as F3, and values greater than 14.5 kPa were equivalent to F4 (cirrhosis) [19]. Statistical analysis Continuous variables are expressed as mean and SDs, whereas categorical variables are recorded as percentages. The Student’s t test was used for the comparison of continuous variables, whereas categorical variables were compared using the chi-square test. The SPSS version 17.0 software (SPSS Inc., Chicago, Illinois, USA) was used for calculations.
Results From a total of 2366 HIV-positive individuals seen during 2012 at our institution, 618 (26%) were HCV-Abþ. Table 1 summarizes the main characteristics of the whole study population, stratified by positive or negative for HCV-Abs. Briefly, 81% were men, with a mean age of 45 years. Injection drug use was recorded in one-quarter, whereas half were MSM. Less than 2% of MSM in this cohort acknowledged intravenous drug use. Overall, 5% were positive for HBsAg. Up to 96% of patients were on antiretroviral therapy and 86% had undetectable plasma HIV-RNA. The median CD4þ cell count was
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Spontaneous hepatitis C virus clearance in HIV Vispo et al.
1475
Table 1. Main characteristics of the study population. Variable N (%) Male sex [n (%)] Mean age [years (SD)] Risk group [n (%)] Intravenous drug use MSM Serum HBsAgþ [n (%)] Positive hepatitis delta virus antibody [n (%)] Antiretroviral therapy [n (%)] Mean CD4þ cell count [cells/ml (SD)] Undetectable plasma HIV-RNA [n (%)]
All
HCV-Ab pos
HCV-Ab neg
P
2366 1921 (81) 45 10
618 (26) 450 (73) 48 6
1718 (72) 1460 (85) 44 10
