Association of serum lipid profile with liver fibrosis in HCV‑coinfected HIV patients on suppressive anti‑retroviral therapy
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- Published online on: August 13, 2024 https://doi.org/10.3892/br.2024.1834
- Article Number: 146
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Copyright: © Srisopa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease in individuals living with human immunodeficiency virus (HIV) (PLWH) under anti-retroviral therapy (ART) (1,2) due to shared common routes of transmission. Worldwide, ~2.3 million individuals are estimated to be coinfected with HIV and HCV (2). A cohort study of the Asia HIV observational database reported ≤15.2% of HCV coinfection in HIV-infected individuals (3) and studies in Thai PLWH have also suggested a high prevalence of 4-11% (4-7). This coinfection causes a higher risk of progressive hepatitis and accelerates the progression to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) (1,2,8). HIV infection causes hepatitis C-mediated liver fibrosis by direct and indirect mechanisms. HIV directly activates hepatocytes, hepatic stellate cells and Kupffer cells, which cooperatively participate in inflammation and fibrogenesis in the liver. HIV infection also causes microbial translocation, indirectly inducing liver injury, impaired HCV immune responses and fibrogenesis (2). While studies support the pathological effects of coinfection in both HIV- and HCV-mediated disease progression, advancements in the management of HIV-infected patients with ART in the past decade (1,2) and the use of direct-acting antivirals (DAAs) for chronic HCV infection adds more complexity to the treatment and care of chronic liver disease caused by HIV and HCV coinfection.
Previous studies have indicated significant liver fibrosis and multiple risk factors for the severity and progression of liver diseases in PLWH, including age, sex, CD4+ cell count, CD4+/CD8+ ratio, HIV RNA levels, alcohol consumption, diabetes mellitus and HCV coinfection (4,9-11). Although studies in HCV-infected patients have demonstrated various clinical conditions associated with liver fibrosis and progression to HCC either before or after the DAA era, such as age, duration of infection, diabetes mellitus and alcohol consumption (12,13), the progression of chronic hepatitis C in PLWH may be more advanced and complicated (14). Moreover, studies have indicated glucose and lipid abnormalities associated with commonly used anti-retroviral (ARV) drug regimens in PLWH (15,16). However, disordered glucose and lipid metabolism in HCV-coinfected patients with HIV under ART remains to be elucidated. The present study aimed to examine the prevalence and associated clinical features of liver fibrosis in Thai patients coinfected with HIV and HCV under suppressive ART. In particular, metabolic markers in this patient group were determined. The present study provided data supporting the development of diagnosis, treatment and care for HCV-coinfected PLWH.
Materials and methods
Study population, clinical data and laboratory investigation
A retrospective cross-sectional study was conducted on 105 patients coinfected with HIV and HCV attending Bamrasnaradura Infectious Diseases Institute (Thailand) between November 2016 and December 2017. As shown in Fig. 1, the patients were aged >20 years, with documented HIV and HCV infection and blood samples and clinical data were available (Table I). Patients with documented hepatitis B virus (HBV) infection, active opportunistic infections (OIs) and who regularly consumed alcohol, herbal medicine, paracetamol and steroid medications were excluded from the study. All subjects provided written informed consent. The study protocol was reviewed and approved by the Human Ethics Committee No. 3, Thammasat University (approval no. 070/2560) and the Bamrasnaradura Infectious Diseases Institute (approval no. R005/60). The patients were previously characterized and the distribution and clinical significance of HCV genotypes in the present study group were reported in a previous study (17).
 | Table ICharacteristics of Thai patients coinfected with HIV and HCV according to the presence of significant liver fibrosis assessed by FIB-4 score and APRI (n=105). |
Clinical data and laboratory investigation
Data collected from the medical records of the patients included age, sex, HIV infection diagnosis, duration of HIV infection, currently used ARV drugs, duration of ART, duration of HCV infection, HCV and HBV infection diagnosis, pretreatment HCV viral load, HCV genotypes, current HCV treatment status and OIs. Data collected from a screening questionnaire included weight, height, alcohol consumption, steroid and paracetamol drug intake and herbal medicine use. All patients underwent clinical examination and blood samples were subjected to testing for HIV viral load (Roche Molecular Diagnostics); CD4+ cell count (BD Biosciences); platelet count (Beckman Coulter, Inc.); liver function tests, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (Roche Diagnostics); fasting blood sugar (FBS); and serum lipid levels, including cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) (Roche Diagnostics).
Sustained virologic response (SVR) was defined as negative HCV RNA at 6 months after completing HCV treatment (18). Liver fibrosis was evaluated by fibrosis score-4 (FIB-4), which was classified into class 1 (≤1.45), class 2 (1.46-3.25) and class 3 (>3.25) (19,20) and AST-to-platelet ratio index (APRI), which was classified into class 1 (≤0.5), class 2 (0.51-1.5) and class 3 (>1.5) (21). Abnormal levels of FBS were defined as ≤110 mg/dl (22-24). According to the National Cholesterol Education Program, Adult Treatment Panel III guidelines (24), lipid profile abnormalities included hypercholesterolemia, defined as cholesterol levels ≥200 mg/dl; hypertriglyceridemia, defined as TG levels ≥150 mg/dl; high LDL cholesterol, defined as ≥130 mg/dl; and low HDL cholesterol, defined as <40 mg/dl in men and <50 mg/dl in women (24). Metabolic markers, including TG/HDL ratio and TG-glucose index, were also determined to predict cardiometabolic disease. In the present study, the cut-off values of TG/HDL ratio were 2.6 for men and 1.7 for women, while those of TG-glucose index were 9.2 (25,26).
Statistical analysis
Data are presented as the mean ± standard derivation, median (range) and percentages. The χ2 and Fisher's exact tests were used to determine the association between categorical variables and liver fibrosis, as assessed by FIB-4 score and APRI, whereas the Mann-Whitney U test was used to analyze the association between liver fibrosis or HCV therapy and continuous variables. The level of statistical significance was set at P<0.05. Univariate and multivariate logistic regression was performed to determine the risks for liver fibrosis. Odds ratio (OR) with 95% confidence interval (CI) values and P-values were calculated. P<0.05 was considered to indicate a statistically significant difference. The statistical analysis was performed using SPSS version 15.0 (SPSS Inc.).
Results
The present study was conducted on 105 patients with HIV and HCV coinfection according to the flow diagram in Fig. 1. The study consisted of 95 (90.5%) male and 10 (9.5%) female patients, with median ages of 46 (27-67) years and 47 (34-61) years, respectively. The mean CD4+ cell count was 566±2.66 cells/ml and 91% (93/102) of patients had undetectable levels of HIV viral load (<20 copies/ml). The majority of patients (99/100) were on ART, 78% (78/100) on 2 nucleoside reverse transcriptase inhibitors (2NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), 7% (7/100) on 2NRTIs and protease inhibitors (PIs). and 15% (15/100) on other antiretroviral drugs. Only 1% (1/100) of the patients were naïve to ART. The median duration of ART was 9 (2-20) years. In this patient group (Table I), the prevalence of patients coinfected with HCV genotypes 1, 3 and 6 were 54.8% (40/73), 37% (27/73) and 8.2% (6/73), respectively and 90.1% (64/71) of the patients had pretreatment HCV viral load >5.0 log IU/ml (17). A total of 51% (51/100) of the patients were on HCV therapy with 35% (35/100) achieving SVR, 7% (7/100) not achieving SVR and 9% (9/100) currently receiving treatment. The prevalence of patients having significant liver fibrosis assessed by FIB-4 scores >1.45 was 53.3% and by APRI >0.5 was 63.8%. The rates of patients with abnormal levels of FBS were 23.1% (24/104), whereas those with hypercholesterolemia, hypertriglyceridemia, high LDL and low HDL cholesterol were 17% (17/100), 33.3% (34/102), 22.8% (23/101) and 36.4% (36/99), respectively. In the present study group, the median values of metabolic markers, TG/HDL ratio and TG-glucose index, were 2.62 (0.48-23.94) and 4.69 (4.3-5.66) respectively. The rates of patients at risk for cardiometabolic diseases with a TG/HDL ratio >2.6 for men and 1.7 for women were 53.1% (51/96). However, no patients with a TG-glucose index >9.2 were observed.
The characteristics of the patients according to the presence of significant liver fibrosis are shown in Table I. The majority of characteristics of the patients with and without significant liver fibrosis, as evaluated by FIB-4 score and APRI, were similar. However, age and CD4+ cell count were significantly associated with liver fibrosis, as assessed by FIB-4 scores (P=0.008 and P=0.027, respectively); and HCV treatment status, cholesterol and LDL levels were associated with liver fibrosis, as assessed by APRI (P<0.001, P=0.050 and P=0.001, respectively). The data were consistent with the univariate and multivariate analyses of risk factors for significant liver fibrosis in the present study group (Table II). Multivariate analysis indicated that patients aged >50 years had an 11.4 times higher risk (P=0.001) and those with a CD4+ cell count <350 cells/µl had a 5.7 times higher risk (P=0.017) for liver fibrosis, as assessed by FIB-4 scores, than those aged ≤40 years and with a CD4+ cell count ≥350 cells/µl respectively. Univariate and multivariate analyses indicated that patients naïve to HCV treatment had 7.5 times (P=0.001) and 5.4 times (P=0.003) higher risks than those with SVR, respectively. Similarly, patients who were on HCV treatment had 15.3 times (P=0.015) and 12.7 times (P=0.033) higher risks than patients with SVR, respectively. Notably, the univariate analysis indicated that patients developing hypercholesterolemia, high HDL and high LDL cholesterol had lower risks than those with normal levels (OR 0.3, 95% CI 0.1-0.9, P=0.037; OR 0.4, 95% CI 0.2-0.9, P=0.041; OR 0.2, 95% CI 0.1-0.5, P=0.001, respectively). However, only patients with high LDL cholesterol remained at a lower risk (OR 0.1, 95% CI 0.3-0.8, P=0.029) according to multivariate analysis adjusted for sex, age, CD4+ cell count, ARV treatment, HCV genotypes, pretreatment HCV viral load, HCV treatment, FBS and a lipid panel.
| Table IIUnivariate and multivariate analyses of risks for liver fibrosis in Thai patients coinfected with HIV and HCV (n=105). |
Analysis by the Mann-Whitney U test, shown in Table III, indicated significantly higher levels of AST in patients with moderate and advanced liver fibrosis, as assessed by FIB-4 scores (P=0.004 and P<0.001, respectively) and APRI (both P<0.001) and higher levels of ALT were detected in patients with moderate and advanced liver fibrosis, as assessed by APRI (both P<0.001), than those without fibrosis. Patients with moderate and advanced fibrosis evaluated by FIB-4 scores were significantly older than those without liver fibrosis (P<0.031 and P<0.001, respectively). Consistent with the univariate and multivariate analyses, considerably lower levels of cholesterol, HDL and LDL were observed in the patients with advanced liver fibrosis, with a FIB-4 score >3.25 and APRI >1.5 (all P<0.05).
| Table IIIMedian levels of lipid profiles, age, CD4+ cell count and liver enzymes stratified by FIB-4 scores and APRI in Thai patients coinfected with HIV and HCV. |
As univariate and multivariate analyses indicated a significant association of HCV treatment status with liver fibrosis evaluated by APRI, laboratory parameters, including lipid profiles, age, CD4+ cell count and liver enzymes stratified by HCV treatment status were analyzed by the Mann-Whitney U test (Table IV). The data showed that there was no significant difference between the median ages and CD4+ cell counts in the SVR and with naïve to HCV treatment or non-SVR patient groups. The SVR group had significantly higher median levels of liver enzymes, AST and ALT and liver fibrosis, as determined by FIB-4 and APRI, than those in the naïve to HCV treatment or non-SVR patient groups (P<0.001, P<0.001, P=0.047 and P<0.001, respectively), indicating that the therapy achieving SVR had improved liver pathology. Consistent with the lower levels of lipids, cholesterol, HDL and LDL observed in the patients with advanced liver fibrosis, median levels of cholesterol and LDL in patients in the naïve to treatment or non-SVR groups were significantly lower than those observed in the SVR group (P=0.031 and P=0.039, respectively). These data may suggest an involvement of lipid metabolism in liver fibrosis in patients with HIV and HCV coinfection.
| Table IVMedian levels of lipid profiles, age, CD4+ cell count, liver enzymes and liver fibrosis markers stratified by status of HCV therapy in patients coinfected with HIV and HCV. |
Discussion
HCV coinfection is well-established as a major risk for the progression of chronic liver disease in PLWH (1,2,10,27). The present study was conducted on Thai patients coinfected with HIV and HCV mostly on long-term suppressive ART. A total of 51% of the present study group underwent HCV therapy with an SVR rate of 35%. The data indicated the high prevalence of patients developing significant liver fibrosis and the relatively high rates of those with abnormally high levels of FBS, lipid profiles, which were total cholesterol, TG, LDL and HDL and TG/HDL in the present study group. Previous studies have indicated that, in the era of ART, HCV/HIV coinfection accelerates the progression of hepatitis to advanced chronic liver disease and HCC and can cause higher liver-related mortality (8,14,28,29). Moreover, the commonly used ARV drugs in PLWH are associated with impaired FBS and abnormal lipid profiles, contributing to increasing risks for diabetes and cardiovascular disease (15,16). Thus, the present study group has the potential to develop advanced liver disease and metabolic disorders. However, metabolic alterations in PLWH who are coinfected with HCV appear to be more complicated. In the present study, clinical features associated with significant liver fibrosis, particularly metabolic profiles, in patients coinfected with HIV and HCV mostly on suppressive ART were investigated.
Similar to previous studies on HCV- or HIV-infected patients (4,10,12,13), clinical features associated with significant liver fibrosis in this HCV and HIV-coinfected patient group were identified. While patients aged >50 years and with a CD4+ cell count <350 cells/µl exhibited a high risk for significant liver fibrosis, as assessed by FIB-4 scores, patients naïve to or receiving HCV treatment carried a high risk for liver fibrosis, as determined by APRI. Notably, the analysis also indicated a significant association of lipid levels with liver fibrosis evaluated by APRI. Patients who developed hypercholesterolemia, high HDL and high LDL levels had lower risks for liver fibrosis than those with normal levels, which was consistent with the significant reduction of lipid levels in more advanced liver fibrosis observed in the patients with FIB-4 scores >3.25 and APRI >1.5 compared with those without liver fibrosis. In addition, the data indicated that HCV treatment achieving SVR significantly increased the levels of lipids, cholesterol and LDL, in this HIV/HCV patient group. This was similar to the findings of previous studies indicating lower serum levels of total cholesterol, LDL, HDL and TG in HCV-monoinfected patients compared with those in negative subjects (30,31). The previous epidemiological study indicated that HCV infection might cause hypolipidemia regardless of host factors, including age, nutrition and hepatic damage (31). The involvement of hypolipidemia with the outcome of liver transplantation has also been demonstrated in a patient group with high rates of HCV infection (32). Therefore, the association of lipid levels with liver fibrosis in HCV-coinfected PLWH observed in the present study was possibly due to HCV coinfection and the status of HCV treatment.
Initially, the present study observed the relatively high prevalence of patients at risk for cardiometabolic diseases, as indicated by lipid profile abnormalities and TG/HDL ratio, which was consistent with a previous study in PLWH (16). However, the present data indicated no association between the abnormally high TG/HDL ratio and significant liver fibrosis as evaluated by FIB-4 and APRI. In addition, the logistic regression analysis indicated a negative association of lipid levels, cholesterol, HDL and LDL, with liver fibrosis as assessed by APRI. Indeed, HCV infection is closely associated with host lipid metabolism (33). Serum lipids serve roles in HCV virion circulation and entry into hepatocytes (33). The virus also employs different types of lipids to facilitate virion production and assembly (33). The inverse relationship between lipid levels and liver fibrosis observed in the present study may reflect the disruption of lipid metabolism caused by hepatic damage during HCV infection. While it has been reported that commonly used ARV drug regimens cause an increase in serum lipid levels in PLWH (16), the mechanisms underlying HCV infection-mediated host lipid metabolism in PLWH on suppressive ART require further clarification.
The limitations of the present study include that it contained a limited number of subjects, which may affect the statistical significance of the variables tested. Clinical data were obtained from retrospective medical reviews and the drug regimens used for hepatitis C therapy were unavailable. However, as the data collection was performed at a time when HCV therapy in Thailand was performed based on the clinical practice guidelines for the management of chronic hepatitis C 2015, all treated HCV-infected patients were likely to have received a combination of pegylated interferon and ribavirin (34). Thus, the present study provides data before the use of DAA therapy in Thailand.
In conclusion, the present cross-sectional study detected the high prevalence of liver fibrosis in HCV-coinfected PLWH, evaluated by non-invasive markers, FIB-4 scores and APRI. The analysis indicated that age, CD4+ cell count, HCV treatment and lipid profiles, including cholesterol, HDL and LDL, were significantly associated with liver fibrosis. Notably, the reduction of serum lipid levels was significantly associated with the severity of chronic liver disease. Long-term monitoring for clinical outcomes related to lipid metabolism, particularly in patients starting DAA therapy, is warranted.
Acknowledgements
Not applicable.
Funding
Funding: The present study was supported by the Thailand Science Research and Innovation Fundamental Fund fiscal year 2022 (grant no. 2493097) and the Thammasat University Research Unit in Diagnostic Molecular Biology of Chronic Diseases related to Cancer (DMB-CDC). Somkid Srisopa is a recipient of the Research Grant for Graduate Studies from the National Research Council of Thailand (fiscal year 2018, contract no. 7/2561).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
CA contributed to funding acquisition, resources, supervision, study design, data analysis, manuscript preparation, review and editing. SS performed experimental work, data collection and analysis and manuscript preparation. DP contributed to the statistical analysis. SS and CA confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The protocol of the present study was reviewed and approved by the Human Ethics Committee no. 3, Thammasat University (approval no. 070/2560) and Bamrasnaradura Infectious Diseases Institute (approval no. R005/60), Thailand.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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