|Year : 2020 | Volume
| Issue : 3 | Page : 154-161
The aspartate aminotransferase to platelet ratio index for assessing hepatic fibrosis in human immunodeficiency virus-hepatitis C virus coinfected patients: A local experience
Moirangthem Ratankumar Singh1, Pukhrambam Vedanti Devi1, Md Sadam Hussain1, Gayatri Devi Pukhrambam2
1 Department of Medicine, Jawaharlal Nehru Institute of Medical Sciences, Imphal, Manipur, India
2 Department of Pathology, Regional Institute of Medical Sciences, Imphal, Manipur, India
|Date of Submission||13-Jan-2021|
|Date of Acceptance||15-Jan-2021|
|Date of Web Publication||29-Apr-2021|
Pukhrambam Vedanti Devi
Department of Medicine, Jawaharlal Nehru Institute of Medical Sciences, Porompat, Imphal, Manipur
Source of Support: None, Conflict of Interest: None
Background: HCV infection is widespread among HIV infected populations because of their increased life expectancy with the advent of HAART. Hepatic fibrosis is one of the most robust prognostic factors used to predict HCV disease progression and clinical outcomes. This study's objective was to evaluate hepatic fibrosis using APRI in HIV-HCV co-infected individuals compared to HIV monoinfected.
Methods: A total of 120 HIV infected patients (mean age 41.7±10.0 years) was enrolled in a study conducted in JNIMS, Manipur from August 2017 to August 2019. Liver fibrosis was assessed by the APRI which signifies the presence and absence of significant fibrosis if APRI > 1.5 and APRI < 0.5 respectively. Correlation between hepatic fibrosis and immunological status was established. Statistical analysis was done using SPSS version 21.
Results: HIV-HCV co-infected patients had a higher abnormal mean AST level (114.18±150.19 IU/L) than HIV monoinfected (65.03±47.71 IU/L). The mean platelet count in HIV-HCV co-infected patients (106±38×103 cells/mm3) was lower than that of HIV monoinfected (207±80×103 cells/mm3). The mean APRI score in HIV-HCV co-infected patients (3.05±3.89) was higher than that in HIV monoinfected (1.02±1.38) indicating the presence of significant hepatic fibrosis in the co-infected group (p<.001).
Conclusion: A high AST level combined with thrombocytopenia (APRI score>1.5) is an indicator of hepatic fibrosis in HIV-HCV co-infected individuals. Our study demonstrates that HIV-HCV co-infected patients and HIV related advanced immunosuppression is associated with higher APRI. Because of its simple, non-invasive and less costly nature, APRI may be utilised for assessing hepatic fibrosis in resource-limited settings.
Keywords: AST, APRI, HIV-HCV co-infection, Hepatic fibrosis, Thrombocytopenia
|How to cite this article:|
Singh MR, Devi PV, Hussain MS, Pukhrambam GD. The aspartate aminotransferase to platelet ratio index for assessing hepatic fibrosis in human immunodeficiency virus-hepatitis C virus coinfected patients: A local experience. J Med Soc 2020;34:154-61
|How to cite this URL:|
Singh MR, Devi PV, Hussain MS, Pukhrambam GD. The aspartate aminotransferase to platelet ratio index for assessing hepatic fibrosis in human immunodeficiency virus-hepatitis C virus coinfected patients: A local experience. J Med Soc [serial online] 2020 [cited 2021 Aug 1];34:154-61. Available from: https://www.jmedsoc.org/text.asp?2020/34/3/154/315100
| Introduction|| |
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections are serious public health problems worldwide due to their high prevalence. Both these infections are significant health challenges in the modern world, causing damage to the resource-poor southeast Asian countries. HIV infection is fast becoming a major health hazard globally, with an estimated 38 million persons being infected. Worldwide, HCV accounts for approximately 71 million chronic infections, and 2.75 million persons are coinfected with HIV.
With the advent of highly active antiretroviral therapy (HAART) in 1996, HIV infection has become a chronic disease, with an increase in the life expectancy of HIV-infected patients worldwide. Further, HCV infection is widespread among HIV-infected populations because these two viruses share the same transmission routes.
In Manipur, HIV and HCV coinfection is common because of the increased number of intravenous drug users and being located in India's eastern international border. Most of the HIV/HCV cases in Manipur have a longer life than before after starting free HAART by National AIDS Control Organization (NACO) through the State AIDS Control Society since April 2004. However, the quality of life and survival of people living with HIV are threatened by HCV coinfection.
Chronic liver disease is the most common non-AIDS-related cause of death among individuals with HIV Type 1 infection. Recent data suggest that HIV can activate hepatic stellate cells and may be able to infect hepatocytes,, potentially leading to liver disease.
Coinfection with HIV and HCV is responsible for a large proportion of liver disease among HIV-infected individuals., HIV/HCV coinfected patients suffer from more liver-related morbidity and mortality, nonhepatic organ dysfunction, and overall mortality than HCV-monoinfected patients. HIV infection remains independently associated with advanced liver fibrosis and cirrhosis in patients with HIV/HCV coinfection, even in the potent HAART era.
HIV coinfection accelerates fibrosis progression among HCV-infected persons. Although control of HIV replication and restoration of the CD4 cell count may mitigate this to some extent, the effect is not entirely reversed. Thus, antiretroviral therapy is not a substitute for HCV treatment.
Before HCV therapy, liver disease severity must be assessed. An accurate assessment of fibrosis remains vital as the degree of hepatic fibrosis is one of the most robust prognostic factors used to predict HCV disease progression and clinical outcomes. Liver biopsy is the diagnostic standard, but this test is invasive and has limitations and complications.
Noninvasive tests to stage the degree of fibrosis in patients with chronic HCV infection include models incorporating indirect serum biomarkers (routine tests), direct serum biomarkers (components of the extracellular matrix produced by activated hepatic stellate cells), and vibration-controlled transient liver elastography.
The aspartate aminotransferase (AST) to platelet ratio index (APRI) incorporating readily available laboratory data is a validated marker of hepatic fibrosis among HCV-infected individuals with and without HIV infection., Using an APRI cutoff of >1.5, the sensitivity and specificity of APRI for biopsy-confirmed significant fibrosis are 41% and 95%, respectively. Furthermore, HIV and viral hepatitis are independently associated with increased APRI.
Certain studies have shown that APRI is highly predictive of significant fibrosis in HIV/HCV coinfection and could serve as a biopsy-sparing measure, making treatment more accessible for this population. Therefore, in low- and-middle-income countries and settings where treatment expands outside of specialty clinics, as happens in Manipur, the APRI is a generally available simple, cheap, noninvasive alternative to liver biopsy and other noninvasive tests for assessing liver disease severity before HCV therapy in HIV/HCV coinfected patients.
Certain studies concluded that, in HIV/HCV coinfected patients, a low CD4 count <250 cells/mm3 at biopsy was associated with a 5-fold increase in the presence of advanced liver fibrosis independent of both duration of HCV infection and other known risk factors.
This study's objective was to evaluate hepatic fibrosis in HIV/HCV coinfected patients compared to HIV-monoinfected using APRI score. We also evaluated the correlation of APRI score with CD4 count in the subgroup of patients having CD4 count <250 cells/mm3 to assess if any relationship exists between them in HIV-monoinfected and HIV/HCV coinfected patients.
| Material and Methods|| |
Study design and setting
A cross-sectional and descriptive study was done to evaluate hepatic fibrosis in 120 patients admitted in Medicine Ward or attended Medicine outpatient department (OPD) in Jawaharlal Nehru Institute of Medical Sciences (JNIMS), Porompat, Manipur, irrespective of socioeconomic status and who have consented for the study was conducted from August 2017 to August 2019.
Patients included in this study were (1) HIV-positive patients as per the NACO 2015 guidelines irrespective of their antiretroviral treatment status whose diagnosis of HIV is made with three ER (ELISA Rapid) using HIV test kits: Comb-AIDS: Principle – DOT Immunoassay, Tridot: Principle – Immunofiltration, and S. D Bioline HIV Yz3.A: Principle – Immunochromatography, (2) HIV/HCV coinfected patients whose diagnosis of HCV infection is made by the presence of anti-HCV antibodies (third-generation ELISA-Flaviscreen), (3) age >30 years but <75 years, and (4) those patients who give informed consent.
Critically ill patients, pregnant women, and patients with previously known or congenital hematological disorders were excluded from the study.
Determination of aspartate aminotransferase level
The AST level was determined by spectrophotometry with the VITROS 250 equipment using the quantitative analytical method.
Platelet count analysis
Platelet count was determined through full blood count testing with the Sysmex XS 800i analyzer (Sysmex Corporation, Transasia-India) which allows the analysis of levels and identifying human blood components by flow cytometry.
Evaluation of hepatic fibrosis
The evaluation of hepatic fibrosis was determined using the APRI score (aminotransferase divided by platelet ratio index), which is a noninvasive technique that measures blood parameters (indirect markers of fibrosis such as AST and platelet count). The APRI is defined as follows:
APRI score of <0.5 is taken as the cutoff to predict the absence of significant fibrosis.
APRI score of >1.5 is taken as the cutoff to predict the presence of significant fibrosis.
APRI score of 0.5–1.5 cannot classify patients as likely or unlikely to have significant fibrosis.
The AST upper limit of normal was taken as 40 IU/ml.
The CD4 lymphocyte count was determined by flow cytometry using the CyFlow Counter (Sysmex Corporation, Transasia-India), which allows quantitative and qualitative analysis by identifying and counting CD4+ T lymphocytes according to the manufacturer's instruction.
The statistical analyses were done using Microsoft Excel 2016. Descriptive statistics such as percentages, mean, and standard deviation were used. Analytical statistics: t-test, Chi-square test, and Fisher's exact test were used. The correlation coefficient established the relationship between hepatic fibrosis and the immunological status of the patients in this study. Correlation analysis was used to assess the association between the dependent (APRI score) and independent variables (CD4 cell count <250 cells/mm3). A significant value was considered at P <0.05.
The study's protocol was submitted to the Institutional Ethics Committee of JNIMS for approval, and informed consent was obtained from the patients before the beginning of the study.
| Results|| |
Characteristics of the study population
A cross-sectional study was conducted among 120 patients with HIV infection which included 55 patients with HIV-HCV coinfection attending Medicine OPD or admitted in Medicine Ward of JNIMS, Imphal, from August 2017 to August 2019. Most of the patients (62.5%) were males and males were significantly (P < 0.001) more among HIV-HCV coinfection (83.6%) than HIV only (44.6%) as shown in [Table 1].
|Table 1: Distribution of the patients by gender and age stratified by the presence or absence of hepatitis C virus coinfection|
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The study population's mean age was 41.7 ± 10.0 years ranging from 44.2 ± 8.4 years in HIV-HCV coinfected patients to 39.6 ± 10.9 years in HIV monoinfection. The most common age group in HIV monoinfection and HIV-HCV coinfection groups was 41–50 years, as shown in [Table 1].
The mean AST was 87.56 ± 109.84 IU/L (13–896) ranging from 114.18 ± 150.19 IU/L (13–896) in HIV-HCV coinfected patients to 65.03 ± 47.71 IU/L (16–287) in HIV monoinfected. AST was significantly (P < 0.05) increased among HIV-HCV coinfection group, as shown in [Table 2].
The mean platelet was 161 ± 82 × 103 cells/mm3 (30–400 × 103 cells/mm3) ranging from 106 ± 38 × 103 cells/mm3 (30–244 × 103 cells/mm3) in HIV-HCV coinfected patients to 207 ± 80 × 103 cells/mm3 (40–400 × 103 cells/mm3) in HIV monoinfected. Platelet counts were reduced significantly among HIV-HCV coinfection group (P < 0.001) as shown in [Table 2].
The mean CD4 count in this study was 239.78 ± 217.51 cells/mm3 (10–1280 cells/mm3) ranging from 186.82 ± 182.40 cells/mm3 (11–665 cells/mm3) in HIV-HCV coinfected patients to 284.58 ± 235.46 cells/mm3 (10–1280 cells/mm3) in HIV monoinfected patients. There is statistical proof that these two groups of patients have significantly different mean CD4 counts (P < 0.05), as shown in [Table 2]. There is a statistically significant relationship between the CD4 count and the type of infection (P < 0.05). More HIV-HCV coinfected patients are likely to have a CD4 count <250 cells/mm3 compared with HIV monoinfection, as shown in [Table 3].
|Table 3: CD4 count-wise distribution of the patients stratified by the presence or absence of hepatitis C virus coinfection|
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Evaluation of hepatic fibrosis outcomes
The mean APRI score in this study was 1.95 ± 2.99 (0.16–22.17) ranging from 3.05 ± 3.89 (0.27–22.17) in HIV-HCV coinfected patients to 1.02 ± 1.38 (0.16–10.81) in HIV-monoinfected patients. There is statistical proof that these two groups of patients have significantly different mean APRI scores (P < 0.001). The mean APRI score was higher among HIV-HCV coinfection group, as shown in [Table 2]. There is a statistically significant relationship between the APRI score and the type of infection (P < 0.001). More HIV-HCV coinfected patients are likely to have an APRI score >1.5 depicting significant hepatic fibrosis compared with HIV monoinfection, as shown in [Table 4].
|Table 4: Aspartate aminotransferase to platelet ratio index score-wise distribution of the total patients and the subgroup with CD4 <250 stratified by the presence or absence of hepatitis C virus coinfection|
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Effect of CD4 count on aspartate aminotransferase to platelet ratio index score
The mean CD4 count in this study was 239.78 ± 217.51 cells/mm3. There is a statistically significant relationship between the APRI score and the group of patients with CD4 count <250 cells/mm3 (P < 0.05). More HIV-HCV coinfected patients with CD4 count < 250 cells/mm3 are likely to have APRI score >1.5 depicting significant hepatic fibrosis compared with that of HIV monoinfection, as shown in [Table 4].
The HIV-HCV coinfected patients with CD4 count <250 cells/mm3 have a mean APRI score of 2.43 ± 2.19 and HIV-monoinfected patients with CD4 count <250 cells/mm3 have a mean APRI score of 0.95 ± 0.62. There is statistical proof that these two groups of patients have significantly different mean APRI scores (P < 0.001), as shown in [Table 5].
|Table 5: Mean aspartate aminotransferase to platelet ratio index scores and correlation between CD4 count and aspartate aminotransferase to platelet ratio index scores of the patients with CD4 <250 stratified by the presence or absence of hepatitis C virus coinfection|
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The correlation coefficient “r” established the relationship between hepatic fibrosis (APRI score) and the immunological status (CD4 count) of the patients. In HIV-HCV coinfected patients with CD4 count <250 cells/mm3, the correlation coefficient “r” is −0.117 and P > 0.05 which shows that the very low negative correlation is statistically insignificant as shown in [Table 5]. In HIV monoinfected patients with CD4 count <250 cells/mm3, the correlation coefficient “r” is −0.218 and P > 0.05, showing that the low negative correlation is statistically insignificant as shown in [Table 5]. Therefore, no definite correlation could be established between the hepatic fibrosis and immunological status of the patients in both the groups using the APRI score.
| Discussion|| |
All patients with HCV infection should be treated with direct-acting antiviral therapies. Even in HIV-HCV coinfection, HAART is not a substitute for HCV treatment. Although HAART can control HIV replication and restore the CD4 cell count, it does not entirely reverse the progression of accelerated liver fibrosis by HIV coinfection among HCV-infected persons.,
Despite the strong recommendation for treating nearly all HCV-infected patients, pretreatment assessment of a patient's understanding of treatment goals and education about adherence and follow-up are essential. Assessment of liver disease severity is necessary before therapy. Identifying patients with cirrhosis or advanced fibrosis is of particular importance, as the choice of treatment regimen and posttreatment prognosis depends on the stage of fibrosis. Assessment of the stage of fibrosis is not required in patients with clinical evidence of cirrhosis. Patients with advanced fibrosis and those with cirrhosis need continued posttreatment surveillance for hepatocellular carcinoma every 6 months by ultrasonography. Thus, the HCV treatment regimen and its duration, along with posttreatment surveillance, depend on the pretreatment assessed stage of liver fibrosis.
Therefore, we conducted this study to assess the stage of liver fibrosis using the APRI score in HIV-monoinfected and HIV-HCV coinfected patients and to see whether there is an association between the APRI score and the CD4 count in severely immunocompromised (CD4 <250 cells/mm3) patients in both the groups.
The mean age of the present study population was 39.6 ± 10.9 years for HIV group and 44.2 ± 8.4 years for HIV-HCV coinfection group. Hence, mean age was similar to that of Devi et al., who analyzed a total of 100 HIV-positive patients, symptomatic as well as asymptomatic (mean age was 39.8 ± 10.7 [7–80] years). Patients in the 41–50 age group were the most infected with 52.7% of HIV-HCV coinfected patients and 35.4% of HIV monoinfected patients. These figures are similar to those found in previous studies which found an average age of 48 (45–51) years old and 39.8 ± 10.7 (31–40) years old, respectively. Overall, out of the total 120 patients, 75 (62.5%) were males and 45 (37.5%) were females with a male-female ratio of 1.7:1. Males were significantly more among HIV-HCV coinfection than HIV monoinfection.
We found elevated mean AST level in HIV-HCV coinfected patients compared to HIV monoinfected (114.18 ± 150.19 IU/L vs. 65.03 ± 47.1 IU/L; P =0.014). The increase in AST levels in our study population when compared to the normal AST value, which ranges between 5 and 40 IU/L in healthy individuals could be explained by hepatic cytolysis since the liver is the main target organ for hepatic infections. The interaction between HIV gp120 and CCR5/CXCR4 coreceptors on hepatocytes through transforming growth factor -β1 is a key mediator in the process of liver fibrosis as it is one of the most profibrogenic cytokines. Our results are consistent with a previous study that found that HIV-HCV coinfected individuals have a high level of AST, ranging from 31 to 75 IU/L and the result of our study's elevated mean AST level in this coinfected group is even much higher.
Parinitha and Kulkarni et al. had reported in their study of hematological changes in 250 HIV patients and thrombocytopenia in 45 (18%) cases. In our study, the mean platelet was 161 ± 82 × 103 cells/mm3. Out of 120 patients, 63 (52.5%) have thrombocytopenia (platelet count <150 × 103 cells/mm3), of which 49 (77.8%) were HIV-HCV coinfected while 14 (22.2%) were HIV monoinfected. Thus, more HIV-HCV coinfected patients had thrombocytopenia than HIV monoinfection. This incidence could be explained by the ineffective platelet production and increased platelet destruction in HIV infection. Furthermore, HCV coinfection may aggravate the decrease of platelet count in chronic HIV-infected patients, and HIV infection would accelerate the decrease of platelet count induced by HCV infection. Sequestration of platelets in cirrhosis and portal hypertension and decreased thrombopoietin production in advanced liver disease may be responsible for thrombocytopenia observed in the HIV-HCV coinfected patients. Other mechanisms include chronic immune thrombocytopenic purpura associated with HCV infection and cryoglobulins and antiplatelet autoantibodies. Thus, both HIV and HCV viruses are known to be associated with a reduction of platelet counts, indicating that coinfection with HCV would aggravate the symptom of thrombocytopenia induced by chronic HIV infection.
HCV does not seem to have a major impact on the natural history of HIV infection. In studies before the HAART era, HCV coinfection had no effect on HIV progression. In the HAART era, Greub et al. first reported that, in a cohort of 3111 Swiss patients starting HAART, HCV seropositivity was associated with a higher risk of death or developing an AIDS-related illness. However, this finding may have been confounded by other factors, as two large American series encompassing more than 12,000 patients failed to confirm such an effect. It is unclear whether HIV-HCV coinfection is associated with impaired CD4+ cell recovery following HAART initiation. Individual studies reported conflicting results, while a meta-analysis found only a modest effect: the increase in CD4+ cells was 33 cells/mm3 less in coinfected patients. Small studies suggested a unique genotype effect: Genotype 3 seemed to be associated with HIV progression. The present study showed that mean CD4 is significantly lower in HIV-HCV coinfected group (186.82 ± 182.40 cells/mm3), and this group of patients are likely to have a CD4 count <250 cells/mm3 compared with HIV monoinfection. A previous study had interpreted that, irrespective of the duration of HIV infection when HCV is acquired, CD4+ cell counts were temporarily lower following HCV seroconversion, even when on cART. However, our finding is in contrast to a previous study that found a higher median CD4 count of 584 cells/mm3 (interquartile range: 396–775) in HIV-HCV coinfection.
Using the APRI scoring system, 61.8% of our study patients coinfected with HIV/HCV had statistically significant fibrosis (APRI >1.5) compared to only 20% HIV monoinfected. The mean APRI score in HIV-HCV coinfection group is higher than that in the HIV monoinfected group (3.05 ± 3.89 vs. 1.02 ± 1.38; P < 0.001). These results are similar to previous studies, and as expected, infection with both HIV and HCV had a synergistic effect on APRI. This is consistent with prior studies demonstrating the deleterious effect of HIV infection on the viral hepatitis-related liver disease., In the setting of viral hepatitis, HIV-associated immune dysregulation and increased gastrointestinal microbial translocation have also been implicated in promoting hepatic fibrosis., As shown by our findings, thrombocytopenia is common among patients with HIV-HCV coinfection and platelet count is used in APRI calculation. Higher APRI values in HIV-infected individuals may be due to HIV infection rather than underlying liver disease. However, this is not so as a previous study has shown that both viral hepatitis and HIV were independently associated with higher APRI values and that differences in platelets between the groups of patients with a different type of infection (HIV, HCV, or both) were not responsible for the associations with higher APRI values.
The decrease in CD4 count levels, due to HIV infection, leads to a reduction in the antifibrotic activity of NK cells, which leads to rapid progression of hepatic fibrosis in HIV-HCV coinfection. In our study, although most of the HIV-HCV coinfected patients having CD4 count <250 cells/mm3 have statistically significant APRI score >1.5 depicting significant fibrosis as compared to HIV monoinfection, the association between the fibrosis score using APRI and CD4 count was not statistically significant (P = 0.471). Our finding is similar to that of a previous study which concluded that APRI is less accurate in coinfected patients with low CD4 counts (<250 cells/mm3).
The present study was limited by a small sample size of 120 patients, those patients on HAART, and antitubercular therapy were not properly separated; alcoholics were not excluded, and certain tests such as liver biopsy and HIV viral load were not performed due to lack of facilities and expertise.
| Conclusion|| |
Our study demonstrates that HIV-HCV coinfected patients and HIV-related advanced immunosuppression is associated with higher APRI. However, there is no significant association between the low CD4 count and APRI. Because of its simple, noninvasive, and less costly nature, APRI may be utilized in resource-limited settings prior to HCV therapy to predict significant fibrosis in some patients with HIV-HCV coinfection although it appears to be less accurate in coinfected patients with low CD4 counts. Hence, further study in this population who are at increased risk for advanced liver disease is required.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]