|Year : 2019 | Volume
| Issue : 2 | Page : 219-224
Characteristics of treatment-naïve HBV-infected individuals with HIV-1 coinfection: A cross-sectional study from South India
John Paul Demosthenes1, Jaiprasath Sachithanandham1, Gnanadurai John Fletcher1, Uday George Zachariah2, George Mathew Varghese3, Hubert Darius John Daniel1, Lakshmanan Jeyaseelan4, Priya Abraham1, Rajesh Kannangai1
1 Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||14-Jan-2019|
|Date of Decision||13-Jun-2019|
|Date of Acceptance||30-Sep-2019|
|Date of Web Publication||19-Nov-2019|
Dr. Rajesh Kannangai
Department of Clinical Virology, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Purpose: Human immunodeficiency virus-1 (HIV-1) and hepatitis B virus (HBV) coinfection has become a major health problem across the globe. The increased life expectancy of HIV-1 patients due to antiretroviral therapy has led to the emergence of liver disease as a major mortality factor among them. The purpose of the study was to examine the baseline characteristics of HBV in treatment-naïve HBV/HIV coinfection from southern India compared to monoinfected individuals. Materials and Methods: The study was cross sectional in design, and samples were examined from 80 HIV-1, 70 HBV and 35 HBV/HIV-coinfected individuals using chemiluminescent microparticle immunoassay, real-time polymerase chain reaction and flow cytometry assays. Results: There was a significant increase in HBV DNA (P = 0.0001), higher hepatitis B e antigen percentage difference (P = 0.027) and lower CD4 counts (P = 0.01) among the HBV/HIV-coinfected individuals, but no difference in the HIV-1 viral load compared to HIV-1-monoinfected individuals. Also, the aspartate aminotransferase levels, prothrombin time and the international normalised ratio were significantly high among coinfected individuals. Conclusion: These findings conclude that HIV-1 coinfection can have serious implications on the outcome of HBV-related liver disease. To the contrary, HBV infection had no consequence on the progression of HIV-1 disease but distinctly lowered CD4+ T-cells.
Keywords: Aspartate aminotransferase to platelet ratio index, CD4 T cell, fibrosis-4, hepatitis B virus, human immunodeficiency virus-1, viral load
|How to cite this article:|
Demosthenes JP, Sachithanandham J, Fletcher GJ, Zachariah UG, Varghese GM, John Daniel HD, Jeyaseelan L, Abraham P, Kannangai R. Characteristics of treatment-naïve HBV-infected individuals with HIV-1 coinfection: A cross-sectional study from South India. Indian J Med Microbiol 2019;37:219-24
|How to cite this URL:|
Demosthenes JP, Sachithanandham J, Fletcher GJ, Zachariah UG, Varghese GM, John Daniel HD, Jeyaseelan L, Abraham P, Kannangai R. Characteristics of treatment-naïve HBV-infected individuals with HIV-1 coinfection: A cross-sectional study from South India. Indian J Med Microbiol [serial online] 2019 [cited 2019 Dec 14];37:219-24. Available from: http://www.ijmm.org/text.asp?2019/37/2/219/271168
| ~ Introduction|| |
Worldwide, around 370 million people are infected with hepatitis B virus (HBV), and the majority of the cases occur in the endemic regions of Africa and Asia. India harbours the second largest population of chronic hepatitis infection (hepatitis B surface antigen [HBsAg] prevalence of 2% to 7%) of the world. Globally, approximately 35.3 million are infected with human immunodeficiency virus-1 (HIV-1), of which about 10% is coinfected with HBV., India with third largest HIV-1 infected population has around 2.1 million people living with HIV-1 National AIDS Control Organization, 2015–2016, and among them, approximately 7%–9% individuals are coinfected with HBV.
HIV-1 and HBV are transmitted by sexual and parenteral routes, which cannot be eradicated from the infected individuals with current therapies. Since both the viruses are transmitted through common routes, coinfection is common. HBV infection leads to chronic liver disease and leads to the development of cirrhosis and hepatocellular carcinoma (HCC). HBV/HIV-coinfected individuals have high HBV viral load and have increased risks for liver cirrhosis and HCC., HBV/HIV coinfection can complicate the diagnosis of HBV due to spontaneous loss of hepatitis B surface antibody and reactivation of HBV replication., Management of HBV/HIV coinfection is further complicated by the emergence of mutations leading to resistance to therapy for few antiretroviral drugs. HIV-1 status is assessed and monitored by CD4 lymphocyte count and percentage and quantification of HIV-1 RNA levels. The progression of HBV infection is diagnosed and monitored by HBsAg and hepatitis B e antigen (HBeAg) status, HBV DNA levels, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and platelet count. Effective introduction of antiretroviral therapy has reduced the deaths due to HIV-1-related illness, but hepatic failure has become the major cause of death. As the survival of HIV-1 patients is prolonged due to effective ART, the burden of coinfection is bound to increase in HBV-endemic areas.
There are conflicting reports about the effect of HBV on HIV-1 disease progression. It is very important to study the natural history of the disease in coinfected individuals for better management, as the liver disease takes prominence among all the other AIDS-related illness. Furthermore, the rate of disease progression varies from person to person, with many factors such as viral subtypes, human leucocyte antigen genotype and host immune responses playing a very important role. In this study, we compared the baseline characteristics of HBV in HIV-1/HBV coinfected and monoinfected individuals.
| ~ Materials and Methods|| |
This cross-sectional study was carried out at the Department of Clinical Virology in a tertiary care hospital in South India from 2014 to 2017. Written informed consent was obtained from all study participants following approval from the Institutional Review Board. Blood samples were collected from 80 HIV-1-infected individuals who had come for routine CD4 + T-cell, HIV-1 or HBV viral load estimations. Blood samples were also collected from 70 HBsAg positive, HIV-1 Ag/Ab and HCV Ab-negative individuals and 35 coinfected individuals for HIV-1 Ag/Ab and HBsAg-positive individuals but who were HCV-Ab negative. Patients were classified as coinfected if they were HIV-1 Ag/Ab and HBsAg positive. The individual data on ALT, AST, prothrombin time (PT) and platelet count were taken from the individuals' medical record for analysis.
All 185 study participants recruited for this study were treatment naïve for both HBV and HIV-1 at the time of sample collection.
Three mL of whole blood samples were collected in a sterile K2 ethylenediaminetetraacetic acid vacutainer (Beckton Dickinson, New Jersey, USA) for CD4 estimation from serologically confirmed HIV-1 monoinfected and coinfected individuals. Samples for CD4 estimation were collected between 8 am and 10 am to avoid diurnal variation. In parallel, 8 mL of blood samples were collected for estimation of HBsAg, HBeAg, HIV-1 RNA and HBV DNA viral load estimation. Plasma was separated and stored in multiple aliquots at −60°C until testing. The CD4+ T-cell enumeration was done using flow cytometry (BD FACS Count CD4 Reagents, San Jose, USA). CD4+ T-cell enumeration was performed on all samples from HIV-1 monoinfected and coinfected but not on HBV-monoinfected individuals.
Both the HBsAg and HBeAg were analysed using a chemiluminescent microparticle immunoassay. A quantitative HBsAg assay (Abbott ARCHITECT, GmbH, Wiesbaden, Germany) and qualitative HBeAg assay (Abbott ARCHITECT, GmbH, Wiesbaden, Germany) were performed on all HBV monoinfected and coinfected samples. Samples with a concentration higher than the linear range of the HBsAg assay were diluted to evaluate the absolute concentration. The assays were performed as per manufacturer's instructions.
Quantification of human immunodeficiency virus-1 RNA
HIV-1 RNA viral load quantification was performed on all plasma samples from HIV-1 monoinfected and coinfected individuals by TaqMan-based real-time polymerase chain reaction (PCR) using Abbott real-time PCR (Abbott Molecular Inc., Des Plaines, IL, USA). Nucleic acid extraction was done using 850 μL of plasma by the Abbott m2000sp sample preparation system using magnetic particle technology and amplification/detection by m2000rt instrument, with a lower limit of detection as <40 copies/mL.
Quantification of hepatitis B virus DNA
Quantification of HBV DNA was performed on all plasma samples from HBV monoinfected and coinfected individuals using Abbott real-time HBV Assay (Abbott Molecular Inc., Des Plaines, IL, USA) with a linear range of 1.00 log10 IU/mL–9.00 log10 IU/mL. The results can also be reported in IU/mL or log copies/mL using a conversion factor of 3.41 (1 IU = 3.41). The lower limit of detection was calculated as 1.43 log10 IU/mL of HBV DNA using primary reference material (National Institute for Biological Standards and Control 97/750).
Liver fibrosis score calculator
The AST to platelet ratio index (APRI) was calculated for all HBV-monoinfected and HBV/HIV-coinfected individuals using the formula: APRI = ([AST/upper limit of normal]/platelet count [109/l]) ×100. The 40 U/L of AST was used as the upper limit of the normal rate. The fibrosis-4 (FIB-4) index is a noninvasive alternative method to determine liver FIB. It is calculated by the formula: FIB 4 = (Age × AST)/(platelet count × [square root of ALT]).
The statistical analysis for the continuous variables like age, CD4+ T-cell count, HIV-1 and HBV viral load was done using independent t-test (Stata, version 13.1, StataCorp, College Station, TX, USA). HBsAg, ALT and AST levels were analysed using the Mann–Whitney rank sum test (MedCalc Statistical Software version 14.8.1 (MedCalc Software bvba, Ostend, Belgium). To analyse the categorical variable like HBeAg and gender, Fischer's exact test was applied MedCalc Statistical Software version 14.8.1 (MedCalc Software bvba, Ostend, Belgium). Samples which were below the limit of detection (<40 copies/mL) for HIV-1 were taken as 39 copies/mL for statistical analysis for all the viral loads.
| ~ Results|| |
The median age of the HBV-monoinfected, HIV-1-monoinfected and HBV/HIV-coinfected groups were 37.5, 39 and 40, respectively, without any significant difference. The study population was predominantly male with 75.7%, 53.7% and 71.4% in HBV-monoinfected, HIV-1-monoinfected and HBV/HIV-coinfected groups, respectively. There was no statistically significant gender difference among the study groups.
The median viral load in HIV-1-monoinfected group was 4.76 log10 copies/mL (interquartile range [IQR] 3.87–5.19 log10 copies/mL). Among the coinfected group of 35 individuals, the median HIV-1 viral load copies were 4.59 log10 copies/mL (IQR 3.94–5.68 log copies/mL) [Figure 1]a. There was no significant difference in the HIV-1 viral load between the two groups.
|Figure 1: Box plot showing the median viral load level among (a) human immunodeficiency virus-1 monoinfection versus hepatitis B virus/human immunodeficiency virus coinfection, (b) hepatitis B virus monoinfection versus hepatitis B virus/human immunodeficiency virus coinfection|
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The median HBV DNA levels were 3.15 log10 IU/mL (IQR 2.5–4.48 log10 IU/mL) in the HBV-monoinfected group. In the coinfected group of 35, the median HBV viral load was 5.94 log10 IU/mL with the IQR between 3.48 and 8.30 log10 IU/mL. The difference was statistically significant (P = 0.0003) [Figure 1]b. In the coinfected group, 65.7% had high HBV viral load (>20,000 IU/mL) compared to 28.6% in the HBV-monoinfected group (P = 0.0001).
The CD4 + T-cell count was lower in the HBV/HIV-coinfected group with 182 cells/μL (IQR 55–329 cells/μl) when compared to HIV-1-monoinfected group having 383 cells/μL (IQR 152–592 cells/μl). The difference was statistically significant (P = 0.011) [Figure 2].
|Figure 2: Box plot showing the median count of CD4 cells among human immunodeficiency virus-1 monoinfection and hepatitis B virus/human immunodeficiency virus coinfection|
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The median HBsAg level in the monoinfected group was log103.58 IU/mL (IQR log103.10–4.25 IU/mL) while among the coinfected group, it was log103.90 IU/mL (IQR log103.31–4.89 IU/mL) (P = 0.065) [Figure 3]a. Among the HBV/HIV-coinfected patients, 17 (48.5%) were HBeAg positive, and in HBV-monoinfected group, only 18 (25.7%) were positive for HBeAg and this difference in the proportion was significant (P = 0.02) [Figure 3]b.
|Figure 3: Box plot showing the median hepatitis B surface antigen values (a) and the proportion of hepatitis B e antigen status (b) among hepatitis B virus monoinfection and hepatitis B virus/human immunodeficiency virus coinfection|
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On comparison with HBeAg status, there was no significant change in the levels of HBsAg, HBV viral load, AST and ALT levels among HBeAg-negative HBV/HIV-coinfected individuals and HBV-monoinfected individuals. In the HBeAg-positive group, there was a substantial increase in the median HBV DNA viral load in the HBV/HIV-coinfected group and HBV-monoinfected group (log108.72 IU/mL vs. log106.23 IU/mL) (P = 0.0423). However, other serological markers tested showed no significance [Table 1].
|Table 1: Virological and biochemical characteristics of hepatitis B virus-monoinfected and hepatitis B virus/human immunodeficiency virus-coinfected individuals|
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In patients where both AST level and platelet counts were available, the APRI score was calculated. This was available for 57 of the 70 HBV-monoinfected individuals, 40 HIV-1-monoinfected individuals and 35 HBV/HIV-coinfected individuals. The median APRI score for the HBV-monoinfected group was 0.32, 0.37 for HIV-1-monoinfected and 0.70 for the HBV/HIV-coinfected group. There is a statistically significant increase in APRI score in the HBV/HIV-coinfected group compared to the monoinfected group (P = 0.0098). Likewise, the FIB-4 score was also calculated for all the study groups, and the difference was statistically significant between HBV-monoinfected and HBV/HIV-coinfected group. All the data on the different markers tested among the three groups are shown in [Table 2].
|Table 2: Comparison of median values and interquartile range of liver enzymes and markers of liver fibrosis among hepatitis B virus, human immunodeficiency virus-1-monoinfected and hepatitis B virus/human immunodeficiency virus-coinfected individuals|
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The PT and international normalized ratio (INR) were available for 55 HBV-monoinfected, 24 HIV-1-monoinfected and 23 HBV/HIV-coinfected group. The PT and INR values were compared among the three groups: the HBV, HIV-1 and HBV/HIV coinfected and the PT values were 10.8, 10.8 and 11.6, respectively. Moreover, the INR values were 1.01, 1 and 1.06, respectively. There was a statistically significant difference between HBV-, HIV-1-monoinfected group compared with HBV/HIV-coinfected group as shown in [Table 2].
| ~ Discussion|| |
There are many factors that influence the course of HIV-1 and HBV infection. The progression of the disease depends on age and the immune status of the infected individual. There are reports which clearly indicate that progression to AIDS is rapid in older individuals irrespective of the mode of infection. Bai et al. has related patients' age as one of the key factors predicting the outcome of chronic hepatitis. Here, in our study, there was no significant difference in the median age between the study populations.
CD4+ T-cell count is one of the reliable markers for the measurement of treatment response and disease progression among HIV-1-infected individuals. In this study, we found a statistically significant reduction in CD4+ T-cell count in HBV/HIV-coinfected individuals compared to HIV-1-monoinfected individuals. One of the reasons for this could be HBV superinfection in individuals with HIV-1 infection. Similar to our findings, a study from Ghana done on HIV treatment-naïve patients has found a significant decrease in CD4+ T-cell count in HBV/HIV-coinfected patients. Also, a study from Kolkata has associated decreased CD4+ T-cell count to HBV in patients with non-HIV chronic hepatitis B infection. Another possible reason might be the HBV genotype, a study among the HBV/HIV-coinfected individuals from India has associated HBV genotype/D with lower CD4 count among HBV/HIV-coinfected individuals. It is not clear whether the reduction in the CD4 is due to genotype D or the low CD4 count favours HBV Type D. Although we have not genotyped HBV in this study, a study was done previously in the same population which reported that genotype D is the predominant HBV genotype in southern India. A similar study among the HIV/HCV coinfection reports that chronic immune activation may be one of the factors for the reduction in the CD4+ T-cell counts. Chang et al. in their study on HBV/HIV coinfection observed that HBV-specific CD4+ T-cell response was reduced in the HBV/HIV-coinfected group. A retrospective study of pregnant women with HIV-1 in Italy has concluded that HBV has a significant influence on the reduction of CD4 response, but these women were on ART. There is an adverse effect on CD4 and deferred immune response in HBV/HIV-coinfected individuals by HBV in an Ethiopian cohort study. In our study, 54% of the coinfected individuals have a CD4 count <200 cells/μL, which is similar to a study done in Kolkata which reported 50% of the patients in their study population had <200 CD4 cells/μL.
Prevention of opportunistic infections is important among HIV-1-infected individuals as CD4+ T-cell count decreases. In our study, the HIV-1 viral loads between the coinfected and monoinfected individuals were not significantly different, but the CD4 count was significantly lower in the coinfected individuals. This would imply that coinfected individuals could progress to HIV-1-related illness faster than monoinfected individuals. And the frequency of getting an opportunistic infection escalates as the CD4+ T-cell count lowers. HIV-1-infected individuals with low CD4 count place them at a higher risk of getting cancers, of which liver cancer is the most frequently observed because of coinfection with HBV. In this study, the frequency of tuberculosis was higher in coinfected individuals (28.5%) as compared with HIV-1 monoinfected (15%).
The study also showed a marginal median increase in the HBsAg levels (P = 0.065) with significantly higher HBV DNA copies, in the coinfected group (P = 0.0003) compared to HBV-monoinfected group indicating active HBV replication. The HBsAg levels were high in HBV/HIV-coinfected group compared to the HBV-monoinfected group, but it was not statistically significant. The reason for this is because of the high variance observed among the coinfected group. There was also a significantly higher number of HBeAg-positive individuals among the coinfected population, compared to the HBV-monoinfected group. It is apparent that HIV-1 has a profound influence on the natural history and disease progression of HBV. This has been shown by an increased HBV viral load and a higher proportion of HBeAg positivity which indicates a weakening in nature and magnitude of the immune response against HBV. These findings reaffirm the published report on HBV/HIV treatment-naive population.
Although liver biopsy remains the gold standard for diagnosing fibrosis, APRI and FIB-4 are the most commonly used noninvasive methods to determine liver fibrosis. The use of APRI score as a surrogate marker for liver fibrosis is common; frequently, it has been used as a predictor of liver-related mortality in HCV  and alcoholic liver disease. A study done in the US has evaluated and used APRI as an additional noninvasive marker for predicting liver fibrosis in children. In our study, we found that the median APRI score was significantly higher (P = 0.009) in the coinfected group compared to HBV monoinfected. The FIB-4 index with a cut-off of >1.05 is more appropriate for screening significant fibrosis as per Li et al. The median FIB-4 score values were higher in the coinfected group. A study from Tanzania also showed similar results. APRI and FIB-4 score along with measurement of liver enzymes would be a good indicator of liver damage. In our study population, there was a median increase in the liver enzymes in the coinfected group, indicating acute injury to the liver in this group, compared with the monoinfected group. This finding was also supported by the INR values of patients in each group.
One of the limitations of the study is nonavailability of infection timeline for HBV/HIV among coinfected individuals, which plays a significant role in disease progression. Nevertheless, comparing with HBV-monoinfected individuals, there is definitely an increased sign of liver damage in individuals coinfected with HIV-1. This suggests that HIV-1 may play a role in the pathogenesis of coinfected individuals.
| ~ Conclusion|| |
This study done on treatment-naive South Indian population gives baseline characteristics of HBV/HIV-coinfected individuals in comparison with HBV- and HIV-1-monoinfected individuals. This study also demonstrated the influence of HIV-1 infection on the disease progression of HBV as observed by the HBV markers and liver function tests compared to HIV-1. The possible explanation for the effect of HBV on the lowering of CD4+ T-cells among the HBV/HIV-coinfected group may be due to the levels of the cytokines, chronic immune activation and the apoptotic pathways associated with these infections. A prospective longitudinal study on the immunological profile of HBV/HIV coinfection may give a better understanding of the intrinsic mechanism involved in the disease pathogenesis.
Financial support and sponsorship
This study was financially supported by Fluid research grant (IRB Min. No. 8797 dated 19.03.2014) and Clinical Virology Department Research Funds, Christian Medical College, Vellore - 632 004, Tamil Nadu, India. The published work is a part of the Ph.D. thesis of M John Paul Demosthenes, under The Tamil Nadu Dr M.G.R. Medical University.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]