Differences in clinical features of HIV/HCV co-infected individuals compared with HCV mono-infected individuals in Southern Thailand

Objectives HIV/HCV co-infection is associated with more aggressive liver than HCV mono-infection. However, there are limited data in Thailand. This study was done to compare demographic data, basic laboratory results and hepatic �brosis between HIV/HCV co-infected patients and HCV mono-infected patients in a major tertiary care center in Southern Thailand. Methods This was a cross-sectional single center 2-year retrospective study of HCV-treatment-naïve HIV/HCV co-infected patients and HCV mono-infected patients in Songklanagarind Hospital in Southern Thailand. The records of demographic data, basic laboratory results and hepatic �brosis information were noted from all eligible patients. Results Data from 151 treatment-naïve HCV infected patients during the years 2018-2019 were collected. 51(34%) patients had HIV/HCV co-infections. Genotype 3a was predominant in HCV mono-infected patients(51%), while genotype 1a was predominant in HIV/HCV co-infected patients(35%). The median BMI in HCV mono-infected patients was higher than in HIV-HCV co-infected patients(23.1, IQR 20.3-24.8 vs 20.7, IQR 18.9-22.1, p<0.001). In multivariate analysis, HIV/HCV co-infected patients had higher alcohol consumption(AOR 24.9, p< 0.001), higher rates of unsafe sex(AOR 18.6, p=0.004) and MSM (AOR 8.48, p=0.006), and higher percents of genotype 1a(AOR 8.48, p=0.006) and HCV-RNA(AOR 2.3, p=0.035), while HIV/HCV co-infected individuals were less likely to be married (AOR 0.02, p<0.001), had higher median BMI(AOR 0.82, p=0.02), a higher rate of hepatic steatosis as assessed by controlled attenuation parameter (CAP)(AOR 0.98, p=0.02) and hepatic �brosis as assessed by FibroScan 502(AOR 0.91, p<0.001) than HCV mono-infected patients. In HIV/HCV co-infected individuals, hepatic �brosis as evaluated by liver stiffness measurement was not correlated with level of CD4 in our study. Conclusions HIV/HCV co-infected individuals were associated with genotype 1a, unsafe sex, single status and low BMI, while HCV mono-infected individuals were associated with high CAP and high hepatic �brosis. Large-scale cohort studies are needed to con�rm these results, especially hepatic �brosis in this era of high-fat food consumption.


Introduction
Hepatitis C virus (HCV) infection is a global public health concern, with approximately 70 million infected patients worldwide in 2019 (1).Infected individuals will eventually develop chronic hepatitis, cirrhosis and hepatocellular carcinoma resulting in liver-related mortality (2).The prevalence of HCV infection and its particular genotype varies between different countries and regions.In Thailand, recent surveys in 7 of Thailand's 76 provinces found approximately 759,000 anti-HCV + individuals and 357,000 who had viremic HCV infection (3,4), with genotype 3a predominant (36.4%).For genotypic distribution in Thailand, genotype 3 was predominant in southern Thailand, while, genotype 6 was more common in the North than the other regions (5).
Human immunode ciency virus is also a major global public health problem.Thirty-ve million people are estimated to be infected worldwide with nearly 520,000 in Thailand(6).HIV and HCV share a common route of transmission and thus co-infection is not uncommon, and among the 35 million HIV-infected individuals worldwide, 4-5 million (11-14%) are co-infected with HCV.The prevalence of HIV/HCV co-infection depends on the mode of acquiring HIV infection, with approximately 50% of patients acquiring their HIV infection through intravenous drug use (IVDU) and 5-20% through men who have sex with men (MSM) (7,8).An HIV/HCV co-infected patient is mainly characterized by a faster progression to liver cirrhosis that may lead to hepatic decompensation or the development of hepatocellular carcinoma (HCC) at a younger age (9).In addition, HIV/HCV co-infection results in higher mortality rates, especially in patients with low CD4 counts and high HIV viral loads (10)(11)(12).
To date there are limited data on HIV/HCV co-infections in Thailand, which is a problem because knowing genotype distributions and the rate of hepatic brosis in HCV-infected individuals with or without an HIV co-infection are essential for guiding optimal treatment regimens.To help ll this knowledge gap, in this study we aimed to evaluate demographic data, basic laboratory results and hepatic brosis among HIV/HCV co-infected individuals compared to HCV mono-infected individuals in Southern Thailand.

Study procedure
Demographic and laboratory data of HIV/HCV co-infected patients and HCV mono-infected patients who visited Songklanagarind Hospital, Hatyai, Thailand during 2018-2019 were collected retrospectively from medical records.Age, sex, ethnicity, marital status, and physician-reported HCV risk factors were collected.Liver biopsies are not routinely done at our hospital, so noninvasive brosis measurements by both a scoring system and liver stiffness measurements from a FibroScan 502 were used for evaluation of hepatic brosis.Hepatic steatosis was measured by controlled attenuation parameter (CAP).Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count levels were obtained from the same year as the initial HCV genotype testing and used to calculate APRI and FIB-4 brosis scores.The equations for APRI and FIB-4 were as follows: APRI = (AST/upper limit of normal)/platelet count (expressed as platelets × 109/L) × 100 (13,14)

Statistical analysis
We determined correlations of hepatic brosis by both liver stiffness measurement and brosis scores among the HIV/HCV co-infected study patients.Demographic and laboratory differences between HCV mono-infected and HIV/HCV co-infected individuals were examined using the Pearson Chi squared test for categoric variables and the Student's t-test or Wilcoxon rank sum test in cases of non-normal distribution for continuous variables.Stepwise logistic univariate regression analysis was used to investigate correlates of HIV/HCV co-infection among HCV-infected individuals.Variables with a p-value < 0.05 were included in the model.Univariate and multivariate linear regression models with an increased brosis score as a continuous variable were also evaluated.The Akaike Information Criterion (AIC) was used as a measure of relative-goodness-of-t to discriminate among various estimated models.Our nal set of models was based on a combination of AIC goodness-of-t as well as inclusion of clinically relevant variables, for which we used adjusted odds ratios (AOR).All analyses were performed using SPSS for Windows (Statistical Package for the Social Sciences, version 21.0, Armonk, New York, NY, USA), and GraphPad Prism, version 5.
Advanced brosis was demonstrated by both brosis score as APRI stage 3 (23.8%),FIB-4 stage 3 (31.1%)and by liver siffness measurement as Fibroscan 502 in which the median = 12 kPa.Liver steatosis was also evaluated by the same instrument in which the mean CAP = 207.1 dB/m.

Discussion
Our study found that the main risk factors for HIV/HCV co-infection were intravenous drug use and MSM, which is consistent with studies from Western countries on HIV/HCV co-infection (16,17).
In this study, we also evaluated brosis severity in both HCV mono-infection and HIV/HCV co-infection patients.Surprisingly, we found more severe hepatic brosis by both brosis scores (APRI and FIB-4) and liver brosis measured by FibroScan in HCV mono-infected individuals than in HIV/HCV co-infection individuals, ndings which are in contrast to most studies (18,19).As this was a cross-sectional study, however, we could not examine hepatic brosis progression, and a higher brosis stage in HCV monoinfection patients could not be directly associated with more aggressive brosis progression.Therefore, long term follow-up studies are required for determining hepatic brosis progression rates.A possible explanation for this nding may be that a high percentage of mono-infected individuals in this study were infected with HCV genotype 3a (51%) which is the strain most associated with rapid brosis progression (20)(21)(22).Our study also found higher BMIs and CAP scores in mono-infected individuals than in co-infected individuals, which may re ect a higher degree of liver steatosis leading to aggressive liver brosis progression (23).
Several limitations of this study should be noted.First, our sample size was small compared to the scale of HIV/HCV co-infection in Thailand.Second, all participants came from a single hospital in Songkhla province and thus there may be generalization issues.Third, some demographic data such as educational status could not be obtained and may have lead to some bias.Regardless of these potential limitations, we believe that our nding of strong associations between HIV/HCV co-infection with IVDU and MSM is valid, given similar ndings in previously published epidemiological research (24,25).In addition, this was a cross-sectional retrospective study which limited our ability to examine disease duration, which may be important as our mono-infection group was signi cantly older than the coinfection group which could indicate a longer disease duration leading to more severe hepatic brosis in mono-infected individuals.

Conclusion
HIV/HCV co-infected individuals were associated with genotype 1a, unsafe sex, single status and low BMI, while HCV mono-infected individuals were associated with high CAP and high levels of hepatic brosis.Large-scale cohort studies with follow up hepatic brosis assessment is required to better understand the rate of hepatic brosis progression.