- Email: [email protected]
Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France
+Model
ARTICLE IN PRESS
CLINRE-1007; No. of Pages 3
Clinics and Research in Hepatology and Gastroenterology (2017) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
LETTER TO THE EDITOR
Spontaneous clearance of chronic hepatitis C virus infection in HIVpositive patients, southeastern France KEYWORDS Hepatitis C virus; Chronic infection; Spontaneous clearance; HIV; HCV genotype 4; Cirrhosis
To the Editor, Spontaneous clearance of hepatitis C virus (HCV) is very rare event at the chronic stage of infection, in contrast with what occurs at the acute stage. Indeed, its frequency was reported to range between only 0.11 and 0.74/100 patientyears [1—3]. Some associated factors have been identified among which infection with hepatitis B virus or Delta agent, immunosuppressive therapy withdrawal or CD4-cell count increase in HIV-infected patients, and liver transplantation or hepatocellular carcinoma occurrence [1,4,5]. Bulteel et al. recently described chronic HCV infections in 13,318 patients, mostly HCV-monoinfected patients, during the 1994—2013 period in Scotland [1]. In this study and two other previous large series [1—3], only 1/50 patients who experienced spontaneous clearance of chronic HCV infection was HIV-positive [1—3]. Based on our clinical records, before September 2015, 197 HIV-positive patients in our center had chronic HCV infection as defined by two positive HCV RNA testing more than 6 months apart and no HCV RNA negative testing. Among them, during one year between September 2015 and August 2016, 18 patients had a HCV RNA testing but did not receive anti-HCV therapies (whereas 47 were administered anti-HCV direct acting agents, 45 were not evaluated virologically, and 88 had been lost to follow-up or had died). We identified spontaneous HCV RNA disappearance in 2 of these 18 HIV-positive HCVchronically-infected patients.
The first case-patient is a 63-year-old woman, former injection drug user (IDU), diagnosed with HIV and HCV in 1987 and 1995, respectively. Liver biopsy performed in 2003 showed cirrhosis. The patient received multiple antiretroviral combination therapies, and, since June 2011, tenofovir-disoproxil fumarate/darunavir/ritonavir. Between 2009 and 2016, plasma HIV-RNA levels ranged between 2.15 log10 copies/mL and undetectability (Abbott Diagnostics assays). Mean CD4-cell counts increased from 662 cells/mm3 during the 2009—2010 period to 1,012 cells/mm3 during the 2015—2016 period (Fig. 1). The patient was treated only once for her infection with a HCV of genotype 4d [6]. She received pegylated-interferon/ribavirin between November 2005 and May 2007, but she did not respond to this treatment. Transaminases were normal during the 2011—2016 period, no alanine aminotransferase flares being observed. HCV RNA titer dropped from 4.6 to 1.07 log10 IU/mL between June 2013 and April 2014, reached undetectability in March 2016, and remained undetectable four months later (Abbott assays; detection threshold = 12 IU/mL). In March 2016, HAV, HBV and HEV PCR testing were negative, and HBV serology indicated past-resolved infection. The second patient, also a former IDU, is a 47-year-old woman diagnosed with HIV and HCV in 1989. She received multiple antiretroviral therapies and, since January 2014, tenofovir/emtricitabine/rilpivirine. Between 2012 and 2016, HIV RNA was undetectable and mean CD4-cell count was 325 cells/mm3 . HCV genotype is 4c. HCV-RNA load was ≈ 6 log10 during the 2001—2005 period, 3.5 log10 in December 2012, then detectable below the detection threshold in January 2014. Thereafter, it was weakly detectable (1.3 log10 ) in May 2014, undetectable in March 2016, but again weakly detectable (2.5 log10 ) in July 2016. Despite HCV reinfection could not be ruled out because low HCV loads hampered genotyping, it is unlikely due to the short time between collection of blood specimens that successively showed HCV RNA undetectability then positivity and the absence of documented risk factor and elevated transaminases. Transaminases indeed normalized between December 2011 and March 2014 then remained < 35 IU/L up to Year 2016. Between October 2013 and March 2014, hydroxychloroquine was administered to treat rheumatoid arthritis. Titers of antinuclear auto-antibodies (1/800) and anti-smooth muscle
http://dx.doi.org/10.1016/j.clinre.2017.04.005 2210-7401/© 2017 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Algoud M, et al. Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France. Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.04.005
+Model CLINRE-1007; No. of Pages 3
ARTICLE IN PRESS
2
Letter to the editor
Figure 1 (b).
Evolution of serum HCV RNA level, alanine aminotransferase level and CD4-cell count in case-patients no. 1 (a) and 2
auto-antibodies (1/640) were elevated, but thereafter reached normal values. Transient elastrography showed Metavir grade F1 fibrosis in September 2015. HAV and HEV RNA were negative in March 2016 and HBV serology was negative in July 2016. In previous studies that focused on HIV-infected people, periods of follow-up were undetermined, and spontaneous clearance of chronic HCV infection occurred in 3/466 HIV-positive patients (0.64%) in Stenkvist et al.’s study conducted in 2010 in Sweden [5], and in 6/387 HIV-positive patients (1.6%) in Vispo et al.’s study conducted in 2012 in Spain [4]. Our two patients were HCV-infected for a long time (> 20 years). Both were women, which was previously associated with a greater rate of spontaneous chronic hepatitis C resolution in HCV-monoinfected patients [1] but only involved 2/9 cases from Stenkvist et al.’s and Vispo et al.’s studies [4,5]. HCV genotype 4 found in our two case-patients was involved in 17% of infections in our HIV/HCV cohort and in the 18 patients evaluable here between September 2015 and August 2016, and it was reported in 2/8 cases (25%) in Stenkvist et al.’s and Vispo et al.’s studies [4,5]. Otherwise, hepatitis B surface antigen was absent from the serum of our two cases and was not mentioned in cases of spontaneous clearance of chronic HCV infection in Stenkvist et al.’s and Vispo et al.’s studies [4,5]. One of the two present casepatients was cirrhotic, as 17—33% of HIV-positive patients
in previous studies [4,5]. Finally, spontaneous clearance of chronic HCV infection can be followed by virological rebound [3,7]. This was observed here in case-patient no. 2, who could be, during longer follow-up, eventually spontaneously cured of HCV. Of note, before HCV RNA reached undetectability, he received for 6 months hydroxychloroquine, which was suggested in a few studies to have in vitro and in vivo efficiency against HCV [8]. Overall, spontaneous chronic hepatitis C resolution is a rare event in HIV-infected patients. Notwithtstanding, previous findings warrant to monitor HCV RNA in chronicallyinfected HIV-positive patients who are still untreated with anti-HCV direct acting agents, and to gain a better knowledge of the determinants of spontaneous chronic hepatitis C resolution.
Authors’ contributions MA and PC wrote the manuscript; MA, SA and PC performed virological analyses and analyzed data; HTD, AM and DBF provided and analyzed the clinical data.
Disclosure of interest The authors declare that they have no competing interest.
Please cite this article in press as: Algoud M, et al. Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France. Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.04.005
+Model CLINRE-1007; No. of Pages 3
ARTICLE IN PRESS
Letter to the editor
Acknowledgments We are grateful to Line Meddeb for helping with data collection.
References [1] Bulteel N, Partha SP, Forrest E, Stanley AJ, Innes H, Mills PR, et al. Factors associated with spontaneous clearance of chronic hepatitis C virus infection. J Hepatol 2016;65(2):266—72. [2] Watanabe H, Saito T, Shinzawa H, Okumoto K, Hattori E, Adachi T, et al. Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: a population-based cohort study. J Med Virol 2003;71(1):56—61. [3] Scott JD, McMahon BJ, Bruden D, Sullivan D, Homan C, Christensen C, et al. High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives. Clin Infect Dis 2006;42(7):945—52. [4] Vispo E, Barreiro P, Plaza Z, Fernandez-Montero JV, Labarga P, de Mendoza C, et al. Spontaneous hepatitis C virus clearance in HIV patients with chronic hepatitis C bearing IL28B-CC alleles using antiretroviral therapy. AIDS 2014;28(10):1473—8. [5] Stenkvist J, Nystrom J, Falconer K, Sonnerborg A, Weiland O. Occasional spontaneous clearance of chronic hepatitis C virus in HIV-infected individuals. J Hepatol 2014;61(4): 957—61. [6] Colson P, Borentain P, Dhiver C, Benhaim S, Gerolami R, Tamalet C. Recombinant hepatitis C viruses that might hamper accurate genotype classification and choice of treatment with direct-acting agents, southeastern France. Hepatology 2016;63(4):1400—2. [7] Kaung A, Sundaram V, Tran TT. Spontaneous clearance of hepatitis C virus in a patient co-infected with hepatitis C virus and human immunodeficiency virus: a case report. J Gastrointestin Liver Dis 2014;23(3):325—7. [8] Helal GK, Gad MA, Abd-Ellah MF, Eid MS. Hydroxychloroquine augments early virological response to pegylated interferon plus
3 ribavirin in genotype-4 chronic hepatitis C patients. J Med Virol 2016;88(12):2170—8.
Maxime Algoud a Hervé Tissot-Dupont c Amélie Menard c Danielle Botta-Fridlund d Sarah Aherfi a,b Philippe Colson a,b,∗ a Institut hospitalo-universitaire (IHU) Méditerranée infection, Assistance publique—Hôpitaux de Marseille, centre hospitalo-universitaire Timone, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, 19/21, boulevard Jean-Moulin, 13385, Marseille cedex 05, France b Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE) UM63 CNRS 7278 IRD 198 Inserm U1095, Aix-Marseille University, 27, boulevard Jean-Moulin, 13385, Marseille cedex 05, France c IHU Méditerranée infection, pôle des maladies infectieuses et tropicales clinique et biologique, service de maladies infectieuses, 19/21, boulevard Jean-Moulin, 13385, Marseille cedex 05, France d Service d’hépato-gastro-entérologie, centre hospitalo-universitaire Timone, 264, rue Saint-Pierre, 13385, Marseille cedex 05, France ∗
Corresponding author. Institut hospitalo-universitaire (IHU) Méditerranée infection, Assistance publique—Hôpitaux de Marseille, centre hospitalo-universitaire timone, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, 19/21, boulevard Jean-Moulin, 13385 Marseille cedex 05, France. E-mail address: [email protected] (P. Colson)
Please cite this article in press as: Algoud M, et al. Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France. Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.04.005
ARTICLE IN PRESS
CLINRE-1007; No. of Pages 3
Clinics and Research in Hepatology and Gastroenterology (2017) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
LETTER TO THE EDITOR
Spontaneous clearance of chronic hepatitis C virus infection in HIVpositive patients, southeastern France KEYWORDS Hepatitis C virus; Chronic infection; Spontaneous clearance; HIV; HCV genotype 4; Cirrhosis
To the Editor, Spontaneous clearance of hepatitis C virus (HCV) is very rare event at the chronic stage of infection, in contrast with what occurs at the acute stage. Indeed, its frequency was reported to range between only 0.11 and 0.74/100 patientyears [1—3]. Some associated factors have been identified among which infection with hepatitis B virus or Delta agent, immunosuppressive therapy withdrawal or CD4-cell count increase in HIV-infected patients, and liver transplantation or hepatocellular carcinoma occurrence [1,4,5]. Bulteel et al. recently described chronic HCV infections in 13,318 patients, mostly HCV-monoinfected patients, during the 1994—2013 period in Scotland [1]. In this study and two other previous large series [1—3], only 1/50 patients who experienced spontaneous clearance of chronic HCV infection was HIV-positive [1—3]. Based on our clinical records, before September 2015, 197 HIV-positive patients in our center had chronic HCV infection as defined by two positive HCV RNA testing more than 6 months apart and no HCV RNA negative testing. Among them, during one year between September 2015 and August 2016, 18 patients had a HCV RNA testing but did not receive anti-HCV therapies (whereas 47 were administered anti-HCV direct acting agents, 45 were not evaluated virologically, and 88 had been lost to follow-up or had died). We identified spontaneous HCV RNA disappearance in 2 of these 18 HIV-positive HCVchronically-infected patients.
The first case-patient is a 63-year-old woman, former injection drug user (IDU), diagnosed with HIV and HCV in 1987 and 1995, respectively. Liver biopsy performed in 2003 showed cirrhosis. The patient received multiple antiretroviral combination therapies, and, since June 2011, tenofovir-disoproxil fumarate/darunavir/ritonavir. Between 2009 and 2016, plasma HIV-RNA levels ranged between 2.15 log10 copies/mL and undetectability (Abbott Diagnostics assays). Mean CD4-cell counts increased from 662 cells/mm3 during the 2009—2010 period to 1,012 cells/mm3 during the 2015—2016 period (Fig. 1). The patient was treated only once for her infection with a HCV of genotype 4d [6]. She received pegylated-interferon/ribavirin between November 2005 and May 2007, but she did not respond to this treatment. Transaminases were normal during the 2011—2016 period, no alanine aminotransferase flares being observed. HCV RNA titer dropped from 4.6 to 1.07 log10 IU/mL between June 2013 and April 2014, reached undetectability in March 2016, and remained undetectable four months later (Abbott assays; detection threshold = 12 IU/mL). In March 2016, HAV, HBV and HEV PCR testing were negative, and HBV serology indicated past-resolved infection. The second patient, also a former IDU, is a 47-year-old woman diagnosed with HIV and HCV in 1989. She received multiple antiretroviral therapies and, since January 2014, tenofovir/emtricitabine/rilpivirine. Between 2012 and 2016, HIV RNA was undetectable and mean CD4-cell count was 325 cells/mm3 . HCV genotype is 4c. HCV-RNA load was ≈ 6 log10 during the 2001—2005 period, 3.5 log10 in December 2012, then detectable below the detection threshold in January 2014. Thereafter, it was weakly detectable (1.3 log10 ) in May 2014, undetectable in March 2016, but again weakly detectable (2.5 log10 ) in July 2016. Despite HCV reinfection could not be ruled out because low HCV loads hampered genotyping, it is unlikely due to the short time between collection of blood specimens that successively showed HCV RNA undetectability then positivity and the absence of documented risk factor and elevated transaminases. Transaminases indeed normalized between December 2011 and March 2014 then remained < 35 IU/L up to Year 2016. Between October 2013 and March 2014, hydroxychloroquine was administered to treat rheumatoid arthritis. Titers of antinuclear auto-antibodies (1/800) and anti-smooth muscle
http://dx.doi.org/10.1016/j.clinre.2017.04.005 2210-7401/© 2017 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Algoud M, et al. Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France. Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.04.005
+Model CLINRE-1007; No. of Pages 3
ARTICLE IN PRESS
2
Letter to the editor
Figure 1 (b).
Evolution of serum HCV RNA level, alanine aminotransferase level and CD4-cell count in case-patients no. 1 (a) and 2
auto-antibodies (1/640) were elevated, but thereafter reached normal values. Transient elastrography showed Metavir grade F1 fibrosis in September 2015. HAV and HEV RNA were negative in March 2016 and HBV serology was negative in July 2016. In previous studies that focused on HIV-infected people, periods of follow-up were undetermined, and spontaneous clearance of chronic HCV infection occurred in 3/466 HIV-positive patients (0.64%) in Stenkvist et al.’s study conducted in 2010 in Sweden [5], and in 6/387 HIV-positive patients (1.6%) in Vispo et al.’s study conducted in 2012 in Spain [4]. Our two patients were HCV-infected for a long time (> 20 years). Both were women, which was previously associated with a greater rate of spontaneous chronic hepatitis C resolution in HCV-monoinfected patients [1] but only involved 2/9 cases from Stenkvist et al.’s and Vispo et al.’s studies [4,5]. HCV genotype 4 found in our two case-patients was involved in 17% of infections in our HIV/HCV cohort and in the 18 patients evaluable here between September 2015 and August 2016, and it was reported in 2/8 cases (25%) in Stenkvist et al.’s and Vispo et al.’s studies [4,5]. Otherwise, hepatitis B surface antigen was absent from the serum of our two cases and was not mentioned in cases of spontaneous clearance of chronic HCV infection in Stenkvist et al.’s and Vispo et al.’s studies [4,5]. One of the two present casepatients was cirrhotic, as 17—33% of HIV-positive patients
in previous studies [4,5]. Finally, spontaneous clearance of chronic HCV infection can be followed by virological rebound [3,7]. This was observed here in case-patient no. 2, who could be, during longer follow-up, eventually spontaneously cured of HCV. Of note, before HCV RNA reached undetectability, he received for 6 months hydroxychloroquine, which was suggested in a few studies to have in vitro and in vivo efficiency against HCV [8]. Overall, spontaneous chronic hepatitis C resolution is a rare event in HIV-infected patients. Notwithtstanding, previous findings warrant to monitor HCV RNA in chronicallyinfected HIV-positive patients who are still untreated with anti-HCV direct acting agents, and to gain a better knowledge of the determinants of spontaneous chronic hepatitis C resolution.
Authors’ contributions MA and PC wrote the manuscript; MA, SA and PC performed virological analyses and analyzed data; HTD, AM and DBF provided and analyzed the clinical data.
Disclosure of interest The authors declare that they have no competing interest.
Please cite this article in press as: Algoud M, et al. Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France. Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.04.005
+Model CLINRE-1007; No. of Pages 3
ARTICLE IN PRESS
Letter to the editor
Acknowledgments We are grateful to Line Meddeb for helping with data collection.
References [1] Bulteel N, Partha SP, Forrest E, Stanley AJ, Innes H, Mills PR, et al. Factors associated with spontaneous clearance of chronic hepatitis C virus infection. J Hepatol 2016;65(2):266—72. [2] Watanabe H, Saito T, Shinzawa H, Okumoto K, Hattori E, Adachi T, et al. Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: a population-based cohort study. J Med Virol 2003;71(1):56—61. [3] Scott JD, McMahon BJ, Bruden D, Sullivan D, Homan C, Christensen C, et al. High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives. Clin Infect Dis 2006;42(7):945—52. [4] Vispo E, Barreiro P, Plaza Z, Fernandez-Montero JV, Labarga P, de Mendoza C, et al. Spontaneous hepatitis C virus clearance in HIV patients with chronic hepatitis C bearing IL28B-CC alleles using antiretroviral therapy. AIDS 2014;28(10):1473—8. [5] Stenkvist J, Nystrom J, Falconer K, Sonnerborg A, Weiland O. Occasional spontaneous clearance of chronic hepatitis C virus in HIV-infected individuals. J Hepatol 2014;61(4): 957—61. [6] Colson P, Borentain P, Dhiver C, Benhaim S, Gerolami R, Tamalet C. Recombinant hepatitis C viruses that might hamper accurate genotype classification and choice of treatment with direct-acting agents, southeastern France. Hepatology 2016;63(4):1400—2. [7] Kaung A, Sundaram V, Tran TT. Spontaneous clearance of hepatitis C virus in a patient co-infected with hepatitis C virus and human immunodeficiency virus: a case report. J Gastrointestin Liver Dis 2014;23(3):325—7. [8] Helal GK, Gad MA, Abd-Ellah MF, Eid MS. Hydroxychloroquine augments early virological response to pegylated interferon plus
3 ribavirin in genotype-4 chronic hepatitis C patients. J Med Virol 2016;88(12):2170—8.
Maxime Algoud a Hervé Tissot-Dupont c Amélie Menard c Danielle Botta-Fridlund d Sarah Aherfi a,b Philippe Colson a,b,∗ a Institut hospitalo-universitaire (IHU) Méditerranée infection, Assistance publique—Hôpitaux de Marseille, centre hospitalo-universitaire Timone, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, 19/21, boulevard Jean-Moulin, 13385, Marseille cedex 05, France b Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE) UM63 CNRS 7278 IRD 198 Inserm U1095, Aix-Marseille University, 27, boulevard Jean-Moulin, 13385, Marseille cedex 05, France c IHU Méditerranée infection, pôle des maladies infectieuses et tropicales clinique et biologique, service de maladies infectieuses, 19/21, boulevard Jean-Moulin, 13385, Marseille cedex 05, France d Service d’hépato-gastro-entérologie, centre hospitalo-universitaire Timone, 264, rue Saint-Pierre, 13385, Marseille cedex 05, France ∗
Corresponding author. Institut hospitalo-universitaire (IHU) Méditerranée infection, Assistance publique—Hôpitaux de Marseille, centre hospitalo-universitaire timone, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, 19/21, boulevard Jean-Moulin, 13385 Marseille cedex 05, France. E-mail address: [email protected] (P. Colson)
Please cite this article in press as: Algoud M, et al. Spontaneous clearance of chronic hepatitis C virus infection in HIV-positive patients, southeastern France. Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.04.005