Sofosbuvir-based direct-acting antivirals and changes in cholesterol and low density lipoprotein-cholesterol

Patient characteristics

Four hundred and eighty-seven CHC patients achieving SVR12 were included in the study (Table 1). The median age was 63 years, and 247 patients were male (50.7%). The two major genotypes (GT) are GT 1b (255 patients, 52.4%) and GT 2 (160 patients, 32.9%). Four hundred and fifty-one patients were treatment-naïve (92.6%), and 35 had HBV co-infection (7.2%). No patient received antiviral therapy for HBV, and neither developed HBV reactivation nor hepatitis flares during DAA therapy. Forty-one patients had HIV co-infection, who took anti-HIV drugs. The median log10 HCV RNA level was 6.18. One hundred and ninety-six patients had a baseline viral load < 800,000 IU/mL (40.3%). One hundred and one patients had a Fib-4 fibrosis stage of F3 (20.7%), and 54 patients, F4 (11.1%) (Table 1). The patient percentages of F0, F1, F2, and F3 were similar between SOF and non-SOF groups. F4 fibrosis is 13.3% in SOF group and 6.4% in non-SOF group.


Four hundred and ninety-five patients were treated with different DAA regimens. Four hundred and eighty-seven patients achieved SVR12. The SVR12 rates for SOF/VEL, SOF/LED, GLE/PIB, and ELB/GRA were 100% (124/124), 99.5% (206/207), 94.6% (122/129), and 100% (35/35), respectively (Table 2).

Table 2 Viral responses to different DAA regimens (n = 495).

Changes in TC and LDL-C at week 4

Three hundred and thirty patients achieving SVR12 were treated with SOF-based regimens (124 SOF/VEL and 206 SOF/LED), and 157 patients were treated with non-SOF-based (122 GLE/PIB and 35 ELB/GRA) with or without ribavirin (8 patients in SOF/VEL and 7 patients in SOF/LED) for 8 or 12 weeks as shown in Table 1 (DAA regimens). Ribavirin groups were treated for 12 weeks. At week 4, elevated TC (Fig. 2A) and LDL-C (Fig. 2B) were noted in patients treated with SOF/VEL (p < 0.001), SOF/LED (p < 0.001) and GLE/PIB (p < 0.001), but not in patients treated with ELB/GRA (TC, p = 0.176; LDL-C, p = 0.078). The elevations were sustained at SVR12 with SOF/VEL, SOF/LED and GLE/PIB (p < 0.001). However, the ELB/GRA group showed higher TC and LDL-C at SVR12 than baseline (TC, p = 0.023; LDL-C, p = 0.037).

Figure 2

Boxplots showing total cholesterol (TC) (A) and LDL-C (B) levels at baseline, week-4 and SVR12 during different DAAs treatment. Patient number: SOF/VEL (n = 124), SOF/LED (n = 206), GLE/PIB (n = 122) and ELB/GRA (n = 35). TC and LDL-C levels at baseline, week-4 and SVR12 were compared by Wilcoxon matched-pairs signed rank test.

Amplitudes of changes in TC and LDL-C between SOF- and non-SOF-based regimens

Amplitudes of changes in serum TC and LDL-C from baseline to week 4 (or SVR12) were expressed as Log10 [(Week 4 or SVR12)/Baseline] and shown at Y axis of Fig. 3. SOF-based regimens caused significantly larger amplitude of change in TC (Fig. 3A, p < 0.001) and LDL-C (Fig. 3B, p < 0.001) at week 4 compared to non-SOF-based regimens. These changes were not sustained at SVR12 (TC, p = 0.884; LDL-C, p = 0.475). The stratified analyses compared different two regimens and showed that there was no significant difference in log10 (Week4/Baseline) change of both TC (Fig. 3C, p = 0.361) and LDL-C (Fig. 3D, p = 0.248) between the two SOF-based regimens, SOF/VEL and SOF/LED. The statistically significant changes in TC and LDL-C were noted at these two-regimen comparisons: SOF/VEL vs GLE/PIB (TC, p = 0.001; LDL-C, p = 0.010), SOF/LED vs GLE/PIB (TC, p < 0.001; LDL-C, p < 0.001), and SOF/LED vs ELB/GRA (TC, p < 0.001; LDL-C, p = 0.011). The p value of TC at SOF/VEL vs ELB/GRA was 0.017, and that of LDL-C was 0.070. These data suggested that SOF was associated with the major inductor of higher week-4 lipid change.

Figure 3
figure 3

Boxplots showing TC and LDL-C ratios of week 4/baseline and SVR12/baseline in SOF-based and non-SOF-based DAA (TC in A; LDL-C in B) and in different DAA regimens (TC in C; LDL-C in D). The Y-axis scale is the value of log10[(Week 4 or SVR12)/Baseline]. The differences were compared by Mann–Whitney’s test.

Incidence comparisons of increased TC or LDL-C in SOF- and non-SOF-based regimens

To make TC and LDL-C elevations easy to understand, we classified week-4 TC and LDL-C changes to increases > 10% ([Week4/Baseline] > 1.1) and > 25% ([Week4/Baseline] > 1.25) by patient numbers (Table 3). The SOF-based regimens showed higher incidences of increases in TC and LDL-C > 10% (TC, p < 0.001; LDL-C, p < 0.001) or > 25% (TC, p = 0.003; LDL-C, p = 0.001) (Table 3). Relative risk (RR) of TC elevation > 10% for SOF-based regimens was 2.72-fold higher than non-SOF-based regimens (95% CI 1.84–4.02, p < 0.001), and that of LDL-C was 2.04 (95% CI 1.39–3.01, p < 0.001) (Table 4). RR of TC elevation > 25% for SOF-based regimens was 2.11-fold higher than non-SOF-based regimens (95% CI 1.28–3.47, p = 0.003), and that of LDL-C was 2.04 (95% CI 1.36–3.06, p = 0.001) (Table 4).

Table 3 The incidence of 10% or 25% increase in total cholesterol or LDL-C at week 4 in CHC patients treated with SOF- or non-SOF-based regimens (n = 487).
Table 4 The relative risk of total cholesterol and LDL-C ratio > 1.10 or 1.25 in CHC patients treated with DAA regimens at week 4 (n = 487).

There were no significant differences in week-4 TC and LDL-C elevations between two SOF regimens (SOF/VEL and SOF/LED) and between two non-SOF regimens (GLE/PIB and ELB/GRA) in either increase > 10% or > 25%. However, in TC > 10%, all SOF vs non-SOF (SOF/VEL vs GLE/PIB, SOF/VEL vs ELB/GRA, SOF/LED vs GLE/PIB, and SOF/LED vs ELB/GRA) showed significant differences in TC elevation. In LDL-C > 10%, SOF/LED caused significant higher risk in LDL-C elevation than GLE/PIB and ELB/GRA. In TC or LDL-C > 25%, SOF-based regimen still showed significant higher risk in some SOF vs non-SOF paired comparisons (SOF/VEL vs GLE/PIB and SOF/LED vs GLE/PIB). In TC or LDL-C > 25%, there are no difference in comparisons SOF/VEL vs ELB/GRA, and SOF/LED vs ELB/GRA. These statistics gave further evidence for SOF in worsened week-4 lipid profiles. The SOF-based lipid-elevation effects were not seen at SVR12 (Supplementary Table 1).

Multivariable logistic regression for possible confounders

The variables in Table 1, which affect SOF- and non-SOF-based statistics (p < 0.05) were subjected to multivariable logistic regression which evaluates confounders of HIV infection, WBC, platelet, DB, AST, creatinine, eGFR, hemodialysis and F4 status, and also classified into week 4/baseline > 1.10 and > 1.25 for TC and LDL-C as shown in supplementary Table 2 (sTable 2). SOF vs non-SOF still gave significant differences in TC and LDL-C at week 4/baseline either > 1.10 or > 1.25. Baseline WBC was negatively associated with TC elevation > 10% at week 4 (adjusted RR = 0.99, p = 0.033). Baseline AST was positively associated with LDL-C elevation > 25% at week 4 (adjusted RR = 1.01, p = 0.021). Hemodialysis was negatively associated with TC and LDL-C elevations either > 10% or > 25% (all with adjusted RR and p < 0.05). The influence of WBC, AST, and hemodialysis on TC and LDL-C during DAAs treatment is uncertain and requires further study to clarify relationship between them.

Chronic diseases-stratified analysis in SOF- and non-SOF groups

To determine whether chronic diseases affected TC and LDL-C during DAA treatment and at SVR12, we stratified SOF and non-SOF groups into disease subgroups including cardiovascular disease, hypercholesterolemia, diabetes mellitus, and chronic kidney disease (sTable 3). Patients with cardiovascular disease and chronic renal disease had higher percentage of patients taking non-SOF-based regimens (sTable 3, p values). The disease-stratified analysis showed that patients with hypercholesterolemia and diabetes mellitus did not have significant elevation of TC and LDL-C (> 10%) at week 4 (sTable 4) and SVR12 (sTable 5). Patients with cardiovascular disease showed elevated TC (p = 0.004) and LDL-C (p = 0.035) at week 4 (sTable 4) and elevated LDL-C (p = 0.027) at SVR12 (sTable 5). Patients with chronic kidney disease showed elevated LDL-C at week 4 (p = 0.040, sTable 4). These data suggest that patients with normal baseline TC and LDL-C contributed more to elevations of TC and LDL-C at week 4 than those with baseline hypercholesterolemia. It is known that diabetes mellitus patients are prone to have elevated blood cholesterol. Then we divided both SOF- and non-SOF groups into normal baseline cholesterol and baseline hypercholesterolemia subgroups. As shown in sTable 6, patients with normal baseline TC and LDL-C showed significant increases in TC (p < 0.001) and LDL-C (p = 0.001) at week 4, but the elevations were not sustained to SVR12 (sTable 7), consistent with data shown in Fig. 3A,B. SOF did not cause significant change in TC and LDL-C at week 4 (sTable 6) and SVR12 (sTable 7) in hypercholesterolemia subgroups.

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