Risk of Severe Clinical Events After Sustained Virological Response Following Direct-Acting Antiviral Therapy in HIV and Hepatitis C Virus Coinfected Participants

Mathieu Chalouni; Linda Wittkop; Firouzé Bani-Sadr; Karine Lacombe; Laure Esterle; Camille Gilbert; Patrick Miailhes; David Zucman; Marc Antoine Valantin; Sylvie Brégigeon-Ronot; Philippe Morlat; Eric Billaud; Lionel Piroth; Alissa Naqvi; Philippe Sogni; Dominique Salmon

Disclosures

HIV Medicine. 2021;22(9):791-804.

Abstract and Introduction

Abstract

Objectives: Sustained virological response (SVR) decreases the risk of hepatitis C virus (HCV)-related events. Nevertheless, a substantial risk of events persists. We estimated incidences and identified factors associated with severe clinical events after SVR following treatment with a direct-acting antiviral (DAA) in HIV/HCV-coinfected patients.

Methods: Participants from the ANRS CO13 HEPAVIH were included if they reached SVR. Incidence rates of overall mortality, liver-related events, AIDS-defining events, ischaemic events and non-liver non-AIDS-defining cancers (NLNA) were estimated. Factors associated with the risk of those events were identified using Poisson models adjusted on age at SVR and sex.

Results: In all, 775 participants were included. Incidence rates (95% confidence interval) of liver-related events, overall mortality, AIDS-defining events, ischaemic events and NLNA cancers per 1000 person-years were 5.9 (3.3–10.3), 22.2 (16.8–29.5), 0.6 (0.1–4.5), 7.3 (4.4–12.2) and 13.7 (9.4–20.0), respectively. For all events, incidence rates were higher in cirrhotic than in non-cirrhotic participants. Cirrhosis, liver stiffness and CD4 count were associated with liver-related events. Factors associated with overall mortality were age, cirrhosis, liver stiffness and gamma-glutamyl transferase (GGT). For ischaemic events and NLNA cancers, associated factors were total cholesterol and CD4 count, respectively.

Conclusions: After SVR following a DAA treatment, liver-related and AIDS-defining events were observed less frequently than NLNA cancers. Severity of liver disease was associated with the risk of liver-related events and of overall mortality but not with ischaemic events and NLNA cancers. Factors reflecting HIV infection were associated with NLNA cancers and liver-related events.

Introduction

Hepatitis C virus (HCV) infection is associated with several liver-related and non-liver-related complications and with mortality.^[1–4] Indeed, notably, due to chronic inflammation, endothelial damage and lipid accumulation, HCV infection increased the risk of ischaemic events and of non-liver-related cancers due to up-regulation of oncogenic signals and down-regulation of tumour suppressive signals.^[5] Since 2014 and the availability of direct-acting antivirals (DAAs) for the treatment of HCV chronic infection, the course of HCV disease has been largely modified. Direct-acting antivirals allow a sustained virological response (SVR) to be reached in more than 95%, in both HCV-monoinfected^[6] and HIV/HCV-coinfected^[7,8] patients. A SVR after anti-HCV treatment is associated with a reduction in risk of liver and non-liver-related complications related to HCV infection.^[9–13] However, a risk of HCV-related events remains despite SVR, especially for cirrhotic patients.^[14–17] In addition, historically, HIV coinfection negatively impacted the natural history of HCV infection, with a faster progression of liver fibrosis and a higher risk of HCV-related complications.^[1,18] The emergence of antiretroviral therapies substantially decreased the impact of HIV infection on the course of HCV history.^[19,20] In HIV/HCV-coinfected patients, few studies were conducted to identify factors associated with the risk of HCV-related events in participants who reached SVR, and especially for non-liver-related events. Our aim was to estimate incidence rates of HCV-related events, overall mortality, liver-related events, ischaemic events and non-liver-related non-AIDS-defining (NLNA) cancers and of AIDS-defining events, and to identify factors associated with the risk of these events, using an exploratory method, in HIV/HCV-coinfected participants who reached SVR. Despite that the effect of HCV infection on the natural history of HIV has not been clearly demonstrated, AIDS-defining events were studied as our population was at risk and could present specific risk factors for this event.

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Next Section

Abstract and Introduction
Population and Methods
Results
Discussion
References

Table 1. Baseline characteristics of participants from the ANRS CO13 HEPAVIH cohorts who reached sustained virological response (SVR) following treatment with a direct-acting antiviral (DAA) ^a
Characteristics	N	Median (IQR) or n (%)
Age (years)	775	53.1 (50.1–56.7)
Men	774	577 (74.5)
BMI (kg/m²)	740	22.2 (20.3– 24.7)
< 18.5		67 (9.1)
18.5–25.0		509 (68.8)
25.0–30.0		135 (18.2)
≥ 30.0		29 (3.9)
Alcohol consumption	760
Never		195 (25.7)
Past		206 (27.1)
Current		359 (47.2)
Tobacco consumption	756
Never		132 (17.5)
Past		153 (20.2)
Current		471 (62.3)
Time since first positive HCV serology (years)	746	18.3 (12.8–22.3)
Means of HCV contamination	694
Drug use		435 (62.7)
Sexual		121 (17.4)
Transfusion		55 (7.9)
Unknown		78 (11.2)
Other		5 (0.7)
HCV genotype	766
1		415 (54.2)
3		109 (14.2)
Others		242 (31.6)
Cirrhosis	535	149 (27.9)
Liver stiffness (kPa)	593	7.9 (5.7–13.5)
< 7.1		263 (44.4)
7.1–9.5		93 (15.7)
9.5–12.5		74 (12.5)
≥ 12.5		163 (27.5)
FIB–4	564	1.9 (1.3–3.0)
< 1.45		172 (30.5)
1.45–3.25		261 (46.3)
≥ 3.25		131 (23.2)
HIV CDC stage	767
1		329 (42.9)
2		211 (27.5)
3		227 (29.6)
CD4 count (cells/μL)	763	600.0 (402.0–831.0)
> 500		489 (64.1)
200–500		218 (28.6)
≤ 200		56 (7.3)
CD4 count nadir (cells/μL)	667	410.0 (255.0–598.0)
Undetectable HIV^e ral load	653	571 (87.4)
ARV treatment	775	761 (98.2)
Platelets (cells/μL)	576	185.0 (139.0–223.0)
Albumin (g/L)	455	42.0 (39.0–44.4)
Gamma-glutamyl transferase (GGT) (IU/L)	766	85.0 (43.0–155.0)
Total cholesterol (mmol/L)	592	4.3 (3.6–5.2)
HDL cholesterol (mmol/L)	650	1.2 (0.9–1.5)
LDL cholesterol (mmol/L)	640	2.5 (1.8–3.1)
Arterial hypertension	775	401 (51.7)

Abbreviations: ARV, antiretroviral; BMI, body mass index; CDC, Centers for Disease Control and Prevention; HCV, hepatitis C virus; IQR, interquartile range.

Table 2. Incidence rates of liver-related events and overall mortality in participants from the ANRS CO13 HEPAVIH cohort who reached sustained virological response following treatment with a direct-acting antiviral.
Characteristics	Liver-related event (n = 736)			Overall mortality (n = 775)
Characteristics	Incidence (95% CI)^a	IRR (95% CI)^b	P-value	Incidence (95% CI)^a	IRR (95% CI)	P-value
Overall	5.9 (3.3–10.3)	-	-	22.2 (16.8–29.5)	-	-
Age (years)			0.26			< 0.01
< 50	1.9 (0.3–13.8)	Ref.		5.7 (1.8–17.6)	Ref.
50–60	7.7 (4.1–14.3)	4.1 (0.5–31.9)		25.5 (18.3–35.5)	4.5 (1.4–14.5)
≥ 60	4.3 (0.6–30.7)	2.6 (0.2–41.7)		38.2 (20.6–71.1)	6.5 (1.8–23.7)
Sex			0.17			0.53
Men	7.0 (3.9–12.7)	Ref.		20.6 (14.7–28.8)	Ref.
Women	2.1 (0.3 15.0)	0.3 (0.1–2.3)		27.7 (16.4–46.8)	1.2 (0.7 2.3)
BMI (kg/m²)						0.40
< 18.5	-	-		33.8 (14.1–81.3)	Ref.
18.5–25	-	-		21.2 (14.8–30.3)	0.7 (0.3–1.9)
≥ 25	-	-		21.3 (16.0 28.5)	0.5 (0.1–1.5)
Alcohol consumption			0.89			0.13
Never	4.3 (1.1–17.0)	Ref.		21.9 (12.1–39.6)	Ref.
Past	5.1 (1.7–15.9)	1.0 (0.2–6.2)		12.9 (6.5–25.9)	0.6 (0.2–1.6)
Current	7.3 (3.5–15.4)	1.3 (0.3–6.8)		29.1 (20.2–41.9)	1.3 (0.7–2.7)
Tobacco consumption						0.13
Never	-	-		21.9 (12.1–39.6)	Ref.
Past	-	-		12.9 (6.5–25.9)	0.6 (0.2–1.6)
Current	-	-		29.1 (20.2–41.9)	1.3 (0.7–2.7)
HCV genotype			0.07			0.56
1	5.2 (2.3–11.5)	Ref.		18.0 (11.9–27.4)	Ref.
3	19.5 (8.1–46.9)	3.0 (0.8–10.7)		36.8 (19.8–68.5)	1.5 (0.7–3.5)
Others	1.6 (0.2–11.7)	0.3 (0.1–2.7)		24.7 (15.2–40.4)	1.3 (0.7–2.4)
Cirrhosis			0.02			0.01
No	1.0 (0.1–6.9)	Ref.		13.3 (7.9–22.5)	Ref.
Yes	16.0 (7.2–35.7)	12.2 (1.4–105.5)		44.7 (28.5–70.0)	2.6 (1.3–5.4)
Liver stiffness (kPa)			< 0.01			< 0.01
< 12.5	0.9 (0.1–6.3)	Ref.		12.0 (7.1–20.3)	Ref.
≥ 12.5	15.4 (7.4–32.4)	12.0 (1.5–93.2)		32.8 (20.1–53.5)	2.4 (1.3–4.6)
FIB–4			-			0.10
< 1.45	Ref.	-		8.9 (3.3–23.6)	Ref.
1.45–3.25	-	-		19.8 (11.7–33.4)	2.1 (0.6–7.4)
≥ 3.25	18.0 (8.1–40.1)	-		32.2 (18.3–56.8)	3.6 (1.0–13.0)
Platelets (cells/μL)			-			0.48
< 150	13.5 (6.1–30.1)	Ref.		26.0 (15.1–44.8)	Ref.
≥ 150	-			16.0 (9.9–25.7)	0.8 (0.4–1.6)
Albumin (g/L)			0.20			0.12
≥ 40	2.5 (0.6–9.9)	Ref.		30.6 (17.8–52.7)	Ref.
< 40	7.6 (2.4–23.5)	3.3 (0.6–19.9)		14.1 (8.0–24.9)	0.5 (0.2–1.2)
Gamma-glutamyl transferase (IU/L)			0.36			< 0.01
< 50	3.2 (0.8–12.8)	Ref.		4.5 (1.5–14.1)	Ref.
≥ 50	7.0 (3.8–13.1)	1.9 (0.4–8.9)		30.0 (22.4–40.2)	9.2 (2.2–38.0)
CD4 count (cells/μL)			0.01			0.09
≥ 500	3.0 (1.1–8.1)	Ref.		16.0 (10.5–24.3)	Ref.
200–500	7.2 (2.7–19.1)	1.7 (0.4–7.7)		30.1 (19.0–47.8)	1.5 (0.8–2.9)
< 200	29.1 (10.9–77.6)	9.7 (2.4–39.2)		45.1 (21.5–94.5)	2.7 (1.1–6.4)
Nadir CD4 (cells/μL)						0.36
< 150	-	-		23.1 (13.1–40.7)	Ref.
150–300	-	-		31.1 (18.0–53.5)	1.4 (0.4–1.7)
≥ 300	-	-		18.8 (12.5–28.3)	0.8 (0.6–3.0)
HIV^e viral load			0.90			0.38
Undetectable	4.0 (1.8–8.9)	Ref.		19.5 (13.7–27.7)	Ref.
Detectable	4.7 (0.7–33.4)	1.1 (0.1–9.5)		31.0 (14.8–65.1)	1.5 (0.6–3.3)
Total cholesterol (mmol/L)						0.99
< 5.0	-	-		22.6 (15.4–33.2)	Ref.
≥ 5.0	-	-		24.1 (13.4–43.5)	1.0 (0.5–2.1)
HDL cholesterol (mmol/L)						0.57
< 1.0	-	-		18.2 (10.1–32.8)	Ref.
≥ 1.0	-	-		20.8 (13.9–31.0)	1.2 (0.6–2.6)
LDL cholesterol (mmol/L)						0.89
< 1.4	-	-		22.5 (13.1–38.8)	Ref.
≥ 1.4	-	-		19.1 (12.6–29.0)	1.1 (0.5–2.2)
Hypertension						0.89
Yes	-	-		19.3 (12.4–29.9)	Ref.
No	-	-		24.9 (17.2–36.1)	1.0 (0.6–1.9)

Abbreviations: BMI, body mass index; CI, confidence interval; HCV, hepatitis C virus; HDL, high-density lipoprotein; IRR, incidence rate ratio; LDL, low-density lipoprotein.
^aIncidence per 1000 person years (PY) (95% confidence interval).

Table 3. Incidence rates of ischaemic events and non-liver-related non-AIDS-defining (NLNA) cancers in participants from the ANRS CO13 HEPAVIH cohort who reached sustained virological response following treatment with a direct-acting antiviral
Characteristics	Ischaemic event (n = 742)			NLNA cancers (n = 721)
Characteristics	Incidence (95% CI)^a	IRR (95% CI)	P-value	Incidence (95% CI)^a	IRR (95% CI)	P-value
Overall	7.3 (4.4–12.2)	-	-	13.7 (9.4–20.0)	-	-
Age (years)			0.17
< 50	1.9 (0.3–13.8)	Ref.		7.9 (3.0–21.2)	Ref.	0.40
50–60	8.5 (4.7–15.4)	4.3 (0.6–33.4)		15.5 (9.9–24.4)	2.0 (0.7 5.7)
≥ 60	12.4 (4.0–38.6)	6.0 (0.6–56.0)		16.5 (6.2–44.0)	2.0 (0.5–8.2)
Sex						0.75
Men	6.4 (3.4–11.9)	Ref.	0.49	13.2 (8.5–20.4)	Ref.
Women	10.4 (4.3–24.9)	1.5 (0.5–4.4)		15.7 (7.5–32.9)	1.2 (0.5–2.8)
BMI^d (kg/m²)			0.18			0.53
< 18.5	14.6 (3.6–58.3)	Ref.		14.2 (3.6–56.8)	Ref.
18.5–25	8.1 (4.5–14.7)	0.6 (0.1–2.7)		15.0 (9.5–23.5)	1.2 (0.3–5.3)
≥ 25	2.1 (0.3–15.1)	0.1 (0.1–1.6)		8.6 (3.2–22.9)	0.7 (0.1–3.7)
Alcohol consumption			0.44			0.88
Never	8.5 (3.2–22.7)	Ref.		11.4 (4.7–27.4)	Ref.
Past	3.5 (0.9–14.0)	0.4 (0.1–2.3)		12.4 (5.9–26.0)	1.2 (0.3–3.6)
Current	9.4 (4.9–18.0)	1.0 (0.3–3.4)		14.0 (8.1–24.1)	1.3 (0.4–3.7)
Tobacco consumption			0.10			0.19
Never	3.1 (0.4–22.2)	Ref.		22.2 (10.6–46.5)	Ref.
Past	2.3 (0.3–16.4)	0.8 (0.1–13.6)		7.0 (2.3–21.7)	0.3 (0.1–1.2)
Current	10.5 (6.1–18.1)	3.8 (0.5–30.5)		12.7 (7.7–21.1)	0.5 (0.2–1.4)
Cirrhosis			0.66			0.10
No	7.0 (3.3–14.7)	Ref.		8.2 (4.1–16.4)	Ref.
Yes	10.1 (3.8–27.0)	1.3 (0.4–4.5)		20.8 (10.4–41.6)	2.3 (0.9–6.3)
CD4 count (cells/μL)						0.02
≥ 500	-	-		9.3 (5.3–16.4)	Ref.
200–500	-	-		27.0 (16.0–45.6)	2.8 (1.3–6.1)
< 200	-	-		7.1 (1.0–50.7)	0.7 (0.1–5.7)
CD4 count (cells/μL)			0.29
≥ 500	7.7 (4.1–14.3)	Ref.		-	-
< 500	5.6 (2.1–14.8)	0.5 (0.1–1.9)		-	-
Nadir CD4 (cells/μL)						0.31
< 150	-	-		10.5 (6.0–18.5)	Ref.
150–300	-	-		21.2 (10.6–42.3)	2.0 (0.8–4.9)
≥ 300	-	-		15.7 (7.5–32.9)	1.5 (0.6–3.7)
HIV viral load			0.48			0.65
Undetectable	4.7 (2.2–9.8)	Ref.		12.5 (7.9–19.9)	Ref.
Detectable	9.1 (2.3–36.5)	1.8 (0.4–8.8)		9.4 (2.4–37.8)	0.7 (0.2–3.1)
Total cholesterol (mmol/L)			0.05
< 5.0	4.6 (1.9–11.1)	Ref.		-	-
≥ 5.0	13.7 (6.1–30.4)	3.6 (1.0–12.9)		-	-
HDL cholesterol (mmol/L)			0.28
< 1.0	5.4 (1.7–16.6)	Ref.		-	-
≥ 1.0	8.1 (4.2–15.6)	2.3 (0.5–11.0)		-	-
LDL cholesterol (mmol/L)			0.12
< 1.4	1.9 (0.3–13.2)	Ref.		-	-
≥ 1.4	9.1 (4.9–16.9)	5.1 (0.7–40.1)		-	-
Hypertension			0.37
Yes	8.1 (4.0–16.1)	Ref.		-	-
No	6.7 (3.2–14.0)	0.6 (0.2–1.8)		-	-

Abbreviations: BMI, body mass index; CI, confidence interval; HDL, high-density lipoprotein; IRR, incidence rate ratio; LDL, low-density lipoprotein.
^a Incidence per 1000 person-years (95% confidence interval).

Authors and Disclosures

Mathieu Chalouni¹, Linda Wittkop^1,2, Firouzé Bani-Sadr³, Karine Lacombe^4,5, Laure Esterle¹, Camille Gilbert¹, Patrick Miailhes⁶, David Zucman⁷, Marc Antoine Valantin⁸, Sylvie Brégigeon-Ronot⁹, Philippe Morlat^1,10, Eric Billaud¹¹, Lionel Piroth^12,13, Alissa Naqvi¹⁴, Philippe Sogni^15,16 and Dominique Salmon^16,17, for the ANRS CO13 HEPAVIH Cohort Study Group*

¹University of Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, Bordeaux, France
²Department of Public Health, CHU de Bordeaux, Bordeaux, France
³Department of Internal Medicine, Clinical Immunology and Infectious Diseases, Robert Debre Hospital, University Hospital, Reims, France
⁴INSERM Pierre Louis Institute of Epidemiology and Public Health, IPLESP, Sorbonne University, Paris, France
⁵Infectious Diseases Department, Saint-Antoine Hospital, APHP, Paris, France
⁶Department of Infectious and Tropical Diseases, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
⁷Internal Medicine Unit, Hopital Foch, Suresnes, France
⁸Inserm, Department of Infectious Diseases, Pierre Louis Institute of Epidemiology and Public Health, Pitie-Salpetriere Hospital, Sorbonne University, AP-HP, Paris, France
⁹Clinical Immunohematology Department, Marseille Public University Hospital System (AP-HM), Sainte-Marguerite Hospital, Aix-Marseille University, Marseille, France
¹⁰Department of Internal Medicine and Infectious Diseases, Saint Andre Hospital, Bordeaux University Hospital, Bordeaux, France
¹¹Infectious Disease Unit, CHU Nantes, CIC 1413 INSERM, COREVIH, Pays de la Loire, Nantes, France
¹²Infectious Diseases Department, Dijon University Hospital, Dijon, France
¹³University of Bourgogne-Franche- Comte, Dijon, France
¹⁴Infectious Diseases Department, Nice University Hospital, Archet Hospital, Nice, France
¹⁵Hepatology Department, APHP, Cochin Hospital, INSERM U-1223 and ICD, Pasteur Institute, Paris University, Paris, France
¹⁶Paris University, Paris, France
¹⁷Infectious and Tropical Diseases Department, AP-HP Centre, Cochin Hospital, Hotel Dieu, Paris, France

Correspondence
Linda Wittkop, 146 rue Leo Saignat, CS61292, 33076 Bordeaux cedex, France. Email: linda.wittkop@u-bordeaux.fr

*Listed in the Acknowledgements.

Conflict of Interest
KL has received funding grants from Gilead, MSD, Abbie, Viiv Healthcare and Janssen; has been on advisory boards for Gilead, MSD, Abbvie, ViiV Healthcare and Janssen; and taken part in training and educational activities for Gilead, MSD, Abbvie, ViiV Healthcare and Janssen. PM reports personal fees and non-financial support from MSD, non-financial support from Gilead, and non-financial support from VIIV Health Care, outside the submitted work.

Author Contributions
MC, LW, PS and DS were investigators of the study. LW, LE, PS and DS secured the funding for the study. LW, FB-S, KL, PM, DZ, MV, SBR, PM, EB, LP, AN, PS and DS were responsible for data collection, and LE and CG for data curation. MC and LW were responsible for the analysis. All authors contributed to the development of the study design and establishment of the analysis. MC led on preparing the manuscript. All authors critically reviewed and approved the final version of the manuscript.