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. 

In This Article

Results

Population Description

In all, 897 participants received a DAA treatment and 775 reached SVR. Seven hundred and thirty-seven participants did not have a history of liver-related events, 576 for AIDS-defining events, 742 for ischaemic events and 721 for NLNA cancers.

Median age (interquartile range, IQR) at treatment initiation was 53.1 (50.1–56.7) years and 577 (74.5%) were men. At time of HCV treatment initiation, 149 (27.9%) were cirrhotic, the median CD4 count was of 600 (402–831) cells/μL and 82 (12.6%) participants had a detectable HIV viral load (Table 1).

Events After SVR

After a median (IQR) follow-up of 3.0 (1.7–3.8) years, 48 deaths were observed, 11 due to liver causes, 10 NLNA cancers, six cardiovascular, one AIDS and 20 other causes. Twelve participants developed a liver-related event, six HCC, five liver decompensations and one liver-related death due to HCC. One AIDS-defining event (recurrent broncopneumopathy) was observed. Fifteen ischaemic events were observed, five deaths from cardiovascular causes, five with ischaemic heart disease, two strokes, two transient ischaemic attacks and one myocardial infarction. Finally, 27 NLNA cancers were observed, four non-melanoma skin, three anal, three breast, three lung, two melanoma, two nasopharynx/tongue, two pancreas, two prostate, one oesophagus and five others.

Liver-related Events

Overall, the incidence (95% confidence interval, 95% CI) of liver-related events per 1000 person-years (PY) was 5.9 (3.3–10.3). Incidence rates per 1000 PY were 1.9 (0.3–13.8), 7.7 (4.1–14.3) and 4.3 (0.6–30.7) for participants aged < 50 years, between 50 and 60 years and > 60 years, respectively. Men [7.0 (3.9–12.7)] and genotype 3 infected participants [19.5 (8.1–46.9)] seemed to have higher incidence rates than women [2.1 (0.3–15.0)] and participants infected by HCV genotype 1 [5.2 (2.3–11.5)] or others genotype [1.6 (0.2–11.7)], respectively. Participants with liver damage exhibited higher incidence rates of liver-related events: 16.0 (7.2–35.7) in cirrhotic participants, 15.4 (7.4–32.4) when liver stiffness value was > 12.5 kPa, 18.0 (8.1–40.1) when FIB-4 was > 3.25, and 13.5 (6.1–30.1) when platelets value was < 150 cells/μL. Finally, incidence of liver-related events per 1000 PY decreased with CD4 count: 29.1 (10.9–77.6) in participants with CD4 < 200 cells/μL vs. 7.2 (2.7–19.1) in those with CD4 between 200 and 500 cells/μL, and 3.0 (1.1–8.1) in those with CD4 > 500 cells/μL (Table 2).

When taking into account age and sex, cirrhosis [IRR = 12.2 (1.4–105.5)], liver stiffness value > 12.5 kPa [12.0 (1.5–93.2)] and CD4 count value [1.7 (0.4–7.7) and 9.7 (2.4–39.2), respectively, for participants with CD4 count between 200 and 500 cells/μL and < 200 cells/μL vs. participants with CD4 count > 500 cells/μL] were associated with increased incidence of liver-related events. HCV genotype 3 seemed to be associated with an increased incidence of liver-related events [3.0 (0.8–10.7)] compared with HCV genotype 1, but the association was not significant (Table 2; Figure 1).

Figure 1.

Cumulative probabilities of liver-related events according to cirrhosis status (A), liver stiffness value (B) and CD4 count (C) in participants reaching sustained virological response (SVR) after treatment with a direct-acting antiviral in the ANRS CO13 HEPAVIH cohort (n = 736)

Overall Mortality

After SVR, overall mortality rate was 22.2 (16.8–29.5) per 1000 PY. Mortality rates increased with age, being 5.7 (1.8–17.6), 25.5 (18.3–35.5) and 38.2 (20.6–71.1) per 1000 PY in participants aged < 50 years, between 50 and 60 years, and > 60 years, respectively. Mortality rates were 20.6 (14.7–28.8) in men and 27.7 (16.4–46.8) in women. Participants with liver damage had higher mortality rates after SVR [44.7 (28.5–70.0) in cirrhotic participants, 32.8 (20.1–53.5) when liver stiffness was > 12.5 kPa, and 32.2 (18.3–56.8) when FIB-4 was > 3.25]. But mortality rates decreased with CD4 count, being 45.1 (21.5–94.5), 30.1 (19.0–47.8) and 16.0 (10.5–24.3), for CD4 counts < 200 cells/μL, between 200 and 500 cells/μL, and > 500 cells/μL, respectively. Finally, participants with albumin < 40 g/L or GGT > 50 IU/L had higher mortality rates [30.6 (17.8–52.7) and 30.0 (22.4–40.2), respectively] (Table 2).

After taking into account age and sex, older age [IRR = 4.5 (1.4–14.5) between 50 and 60 years and 6.5 (1.8–23.7) after 60 years, compared with participants < 50 years], cirrhosis [IRR = 2.6 (1.3–5.4)], liver stiffness > 12.5 kPa [2.4 (1.3–4.6)], and GGT value > 50 IU/L [9.2 (2.2–38.0)] were associated with an increased risk of mortality after SVR. A trend for an increased risk according to CD4 count was also observed [1.5 (0.8–2.9) for CD4 between 200 and 500 cells/μL and 2.7 (1.1–6.4) for CD4 < 200 cells/μL compared with participants with CD4 count > 500 cells/μL) (Table 2; Figure 2).

Figure 2.

Cumulative probabilities of mortality according to age (A), cirrhosis status (B), liver stiffness value (C) and gamma-glutamyl transferase value (D) in participants reaching sustained virological response (SVR) after treatment with a direct-acting antiviral in the ANRS CO13 HEPAVIH cohort (n = 775)

Ischaemic Events

The incidence of ischaemic events per 1000 PY was 7.3 (4.4–12.2) and increased with age, being 1.9 (0.3–13.8) for those aged < 50 years, 8.5 (4.7–15.4) for those aged between 50 and 60 years, and 12.4 (4.0–38.6) for those aged > 60 years. The incidence was 6.4 (3.4–11.9) in men and 10.4 (4.3–24.9) in women. Current tobacco consumer had higher incidence per 1000 PY [10.5 (6.1–18.1) ] compared with never-consumer [3.1 (0.4–22.2)] and past consumer [3.5 (0.9–14.0)]. High total [13.7 (6.1–30.4)] and LDL [9.1 (4.9–16.9)] cholesterol incidence rates per 1000 PY were similar between cirrhotic [10.1 (3.8–27.0)] and non-cirrhotic [7.0 (3.3–14.7)] participants (Table 3).

After taking into account age and sex, total cholesterol value > 5 mmol/L was the only factor significantly associated with the incidence of ischaemic events (IRR = 3.6 (1.0–12.9) (Table 3; Figure 3a,b).

Figure 3.

Cumulative probabilities of ischaemic events according to cirrhosis status (A) and total cholesterol value (B) and of non-liver, non-AIDS-defining cancers according to cirrhosis status (C) and CD4 count (D) in participants reaching sustained virological response (SVR) after treatment with a direct-acting antiviral (DAA) in the ANRS CO13 HEPAVIH cohort (n = 742 and 721)

Non-liver-related Non-AIDS-defining Cancers

After SVR, the incidence of NLNA cancers was 13.7 (9.4–20.0) per 1000 PY. The incidence increased with age, being 7.9 (3.0–21.2), 15.5 (9.9–24.2) and 16.5 (6.2–44.0) per 1000 PY for those aged < 50 years, between 50 and 60 years, and > 60 years, respectively. Incidence rates per 1000 PY were similar between men [13.2 (8.5–20.4)] and women [15.7 (7.5–32.9)]. Cirrhotic participants [20.8 (10.4–41.6)], those with CD4 count between 200 and 500 cells/μL [27.0 (16.0–45.6)] and those with nadir CD4 count between 150 and 300 cells/μL [21.2 (10.6–42.3)] had higher incidence rates of NLNA cancers after SVR (Table 3).

After adjustment for age and sex, CD4 count was the only factor significantly associated with incidence of NLNA cancers after SVR [IRR = 2.8 (1.3–6.1) for CD4 between 200 and 500 cells/μL, and 0.7 (0.1–5.7) for CD4 < 200 cells/μL compared with those with CD4 > 500 cells/μL]. A trend for a significant association between cirrhosis and NLNA cancer incidence was observed [2.3 (0.9–6.3)] (Table 3; Figure 3c,d).

processing....