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Abstract

Background: The burden of chronic viral hepatitis among people living with human immunodeficiency virus (PLWH) and its association with liver disease in Nigeria has been seldom explored. Our objective was to compare characteristics in PLWH with and without significant liver fibrosis/cirrhosis, examining its association with viral hepatitis and other risk factors. Methods: Cross-sectional study among PLWH with and without significant fibrosis/cirrhosis (transient elastography ≥ 9.3 kPa) between July 2018 and August 2022. Data were compared between participant groups and logistic regression used to determine association between chronic viral hepatitis and significant fibrosis/cirrhosis. Results: Five hundred and thirty-seven participants (34.3% male), median age 46 years, 22.2% with significant fibrosis/cirrhosis were analyzed. Seroprevalence of hepatitis B virus (HBV) was 11.2% and hepatitis C virus (HCV) 5.7%. Male sex, diabetes, HBV, and HCV were associated with significant fibrosis/cirrhosis, while ART for >5 years was associated with reduced risk. Conclusion: The chronic hepatitis viruses are associated with significant liver fibrosis/cirrhosis in PLWH in Nigeria, highlighting the importance of viral hepatitis awareness, screening, and treatment in HIV programs to reduce the risk of liver disease.

Plain Language Summary

Hepatitis B and C infection and liver disease in people with HIV infection in Nigeria

People living with human immunodeficiency virus (HIV) infection who have hepatitis B or C infection have a higher chance of developing advanced liver disease than those who do not have either of the hepatitis infections. This finding highlights the importance of awareness, screening, and treatment of the hepatitis viruses in HIV programs in order to reduce the risk of liver disease in this population.

Keywords

liver fibrosis liver disease HCV HBV HIV fibroscan Nigeria

Background

Following the success of antiretroviral treatment (ART), liver disease has become an important cause of morbidity and mortality in people living with the human immunodeficiency virus (HIV) (PLWH). While overall death rates have declined, there has been a corresponding increase in the proportion of deaths due to liver disease and other non-AIDS-related causes.¹ Liver disease is now the most common non-AIDS-related cause of death among PLWH in Europe and the United States, accounting for up to 14% of all deaths and 50% of all in-hospital deaths.^2,3

Liver fibrosis and cirrhosis are common in PLWH in sub-Saharan Africa and other low- and middle-income countries, occurring in about 9% to 17%.^4–6 In high-income countries, the most common causes of liver fibrosis and cirrhosis in PLWH are chronic viral hepatitis B and C (HBV and HCV), nonalcoholic fatty liver disease (NAFLD), and excess alcohol.⁷ Among PLWH co-infected with HBV and HCV, rates of liver fibrosis are up to 5 times higher than in those with HIV alone.^8,9 Progression of liver fibrosis is also faster in those with HIV/HCV co-infection than in those with HCV alone.^10,11 In persons with HIV/HBV co-infection, liver fibrosis has been shown to progress in about 30% despite effective ART and HBV and HIV virological suppression.^12,13

In Nigeria, there is a high prevalence of HBV and HCV among PLWH (7.8% and 4.7%, respectively).¹⁴ Results from one study showed that HBV infection was associated with advanced liver fibrosis in PLWH in Nigeria.⁹ In contrast, chronic HCV has not been well characterized, neither has its association with liver disease been well described in PLWH in Nigeria because of the lack of virological testing to confirm active infection in most studies.^15,16 Chronic HCV prevalence rates ranging from 6% to 8.2% have been reported from the few studies that used confirmatory virological testing.^17,18 Triple infection has also been reported, with a prevalence ranging from 0.6% to 2.5% in Nigeria.^14,16,19 High rates of both HCV and HBV in PLWH in Nigeria put persons with HIV at substantial risk of liver fibrosis and other liver complications.¹⁴ Several other local factors exist in Nigeria that can exacerbate that risk including fatty liver, hyperlipidemia, consumption of alcohol and herbs, cigarette smoking, and HBV/hepatitis D virus (HDV) co-infection.^20–22

Our objective was to compare demographic, clinical, and laboratory characteristics in PLWH with and without significant liver fibrosis/cirrhosis in Nigeria. We also examined the association between viral hepatitis co-infection and significant liver fibrosis/cirrhosis, particularly chronic HCV, which has not been reported in this setting.^9,23

Methods

This cross-sectional study was conducted among PLWH in Nigeria who were enrolled in a longitudinal study examining the epigenomic biomarkers of HIV-associated hepatocellular carcinoma (HCC) in Nigeria (grant number U54CA221205).²⁴ Participants included in this analysis were from 2 HIV control groups without HCC: (i) participants with HIV without HCC or significant liver fibrosis/cirrhosis (transient elastography [TE] < 9.3 kPa); (ii) participants with HIV with significant fibrosis/cirrhosis (TE ≥ 9.3 kPa). The TE cutoff for significant liver fibrosis/cirrhosis (≥9.3 kPa) was chosen from a previous validation study that was conducted in a population of predominantly black Americans.²⁵ Participants were recruited from the Gastroenterology and HIV clinics of 2 large tertiary hospitals located in the southwestern and northcentral regions of Nigeria, between July 2018 and August 2022. They were included in this analysis if they were: (a) documented HIV seropositive and (b) >18 years. Exclusion criteria were: (a) clinical and/or radiological evidence of HCC, other liver diseases such as autoimmune hepatitis, cholestatic liver diseases, or other primary or secondary malignancy; (b) unable to consent; and (c) currently pregnant. Ethical approval was received from the Health Research Ethics Committees of College of Medicine, University of Lagos, Lagos (approval number CMUL/HREC/01/18/326) and Jos University Teaching Hospital, Jos (approval number JUTH/DCS/ADM/127/XXVII/629), and all participants provided written informed consent.

Sampling Technique and Sample Size Determination

Convenience sampling technique was used, in which all consecutively presenting and consenting participants attending the HIV clinics were enrolled if they fulfilled the eligibility criteria.

Data Collection

All study participants were provided with information about the study and asked to sign an informed consent. At enrollment, participants underwent a physical exam by the study physician and laboratory testing for HIV (using enzyme-linked immunosorbent assay and western blot), complete blood count, comprehensive chemistry panel including albumin, total bilirubin, aspartate transaminase (AST) and alanine transaminase (ALT); viral serology including hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) and HCV antibody (anti-HCV) using Lumi Quick diagnostics rapid test kits, and alpha-fetoprotein. Plasma samples were also collected for methylomic analysis. Patients who were confirmed HIV seropositive also had CD4+ T cell count (flow cytometry (Partec GmbH, Munster, Germany), and HIV RNA (Roche Ampliprep TaqMan, Roche Diagnostics Germany; lower limit of detection of 20 copies/mL) testing performed and were referred immediately to the HIV care and treatment clinic at their respective institutions for further treatment and care. Confirmatory HBV and HCV viral load testing on stored specimens was performed on all HBsAg and anti-HCV positive participants using the Cepheid GeneXpert^® system.

The HIV clinics of the 2 hospitals provided comprehensive care and treatment services to participants with HIV infection based on Nigerian guidelines.²⁶ Participants were evaluated every 3 to 6 months in the clinic and at each visit were provided with ART, counseling and support to encourage medication adherence. All participants are initiated on ART immediately after diagnosis. The preferred ART regimen at the time of study was the combination of tenofovir, lamivudine, and dolutegravir according to Nigerian guidelines, which most study participants were receiving.²⁶ Participants diagnosed with HBV and/or HCV infection with clinical, laboratory, or radiological evidence of liver abnormalities, such as features of decompensated liver disease or HCC, are typically referred to the Gastroenterology clinic for additional evaluation.

Data included in this analysis included: age, sex, weight (kilograms), height (meters), highest educational level, marital status, consumption of local herbs and alcohol, tobacco use, family history of HCC, history of diabetes (self-reported), duration of ART, and ART regimen. The following laboratory data were included: platelet count, ALT, AST, HBsAg, anti-HCV, HIV RNA, HBV DNA, HCV RNA, and TE score.

Statistical Analysis

Data were analyzed using R Statistical software version 4.1.2. Baseline characteristics were described using the median and interquartile range (IQR) for continuous variables such as age, and counts and percentages for categorical variables such as sex. Body mass index (BMI) was calculated as weight (kilograms)/height² (meters²) (kg/m²). The outcome variable was the presence or absence of significant liver fibrosis/cirrhosis, which was defined as TE ≥ 9.3 or <9.3 kPa, respectively.²⁵ We also analyzed the data using a lower cutoff for advanced fibrosis/cirrhosis of TE ≥ 7.6 kPa, which was chosen from a previous validation study.²⁷ We compared participants with and without significant liver fibrosis/cirrhosis using the Mann-Whitney U test for continuous variables, and the χ2 test or Fisher's exact test for categorical variables. For logistic regression, we dichotomized age (>50 vs ≤50 years), BMI (≥25 vs <25 kg/m²), and duration of ART (>5 vs ≤5 years). Univariate logistic regression was performed to evaluate the unadjusted associated factors for significant liver fibrosis/cirrhosis. Thereafter, we performed multivariable logistic regression to determine the factors that were independently associated with significant liver fibrosis/cirrhosis after adjusting for clinically significant predictors (BMI, duration of ART, HBsAg) and variables with a univariate P-value of <.2 (age, sex, consumption of herbs or alcohol, diabetes and viremic HCV [defined as anti-HCV seropositivity and HCV RNA > 10 IU/mL]). We presented results in tables as odds ratios and corresponding 95% confidence intervals.

Results

Characteristics of the Study Participants

Five hundred and thirty-seven participants of which 119 (22.2%) with significant liver fibrosis/cirrhosis (TE ≥ 9.3 kPa), and 418 (77.8%) without significant liver fibrosis/cirrhosis (TE < 9.3 kPa) were included in this analysis. The median age was 46 years (IQR = 40, 53), 34.3% were male and median duration of ART was 10.8 years (IQR = 5.6, 13.5). The majority were married (347 of 537, 64.6%), 362 of 534 (67.8%) had at least secondary school education, while 8 of 503 (1.6%) reported a family history of HCC. Fifty-seven of 507 (11.2%) were HBsAg seropositive, 59 of 502 (11.8%) were anti-HCV seropositive and 28 of 489 (5.7%) had viremic HCV (Table 1). Participants with significant liver fibrosis/cirrhosis were older than those without (48 vs 46 years), and consumed herbs (29.7% vs 15.4%) and alcohol (25.2% vs 13.7%) more frequently than those without. More participants with significant fibrosis/cirrhosis had viremic HCV infection (15 of 93 [16.1%]) than those without (13 of 396 [3.3%]), however, the frequency of HBsAg seropositivity was similar in those with and without significant fibrosis/cirrhosis. Diabetes was more common in those with significant fibrosis/cirrhosis (11 of 118 [9.3%] vs 8 of 412 [1.9%]). ALT and AST were higher in those with significant liver fibrosis/cirrhosis (25 vs 15 U/L and 44 vs 29 U/L, respectively).

Table 1.

Demographic, Clinical and Laboratory Characteristics of the Participants.

Variables	n	Overall	TE ≥ 9.3 kPa	TE < 9.3 kPa	P-value
Total participants	537		119 (22.2)	418 (77.8)
Demographic
Age, median (IQR)	537	46 (40, 53)	48 (41, 56)	46 (40, 52)	.02*
Male versus female (n, %)	537	184 (34.3)	54 (45.4)	130 (31.1)	.005*
BMI (kg/m²), median (IQR)	532	25.1 (22.1, 29)	24.7 (21.9, 28.8)	25.3 (22.1, 29)	.28
Clinical
Herb consumption, yes vs no (n, %)	533	99 (18.6)	35 (29.7)	64 (15.4)	<.001*
Alcohol consumption, yes vs no (n, %)	536	87 (16.2)	30 (25.2)	57 (13.7)	.004*
Current tobacco use, yes vs no (n, %)	534	20 (3.7)	5 (4.2)	15 (3.6)	.96
Family history HCC, yes vs no (n, %)	503	8 (1.6)	3 (2.8)	5 (1.3)	.5
Diabetes (self-report), yes vs no (n, %)	530	19 (3.6)	11 (9.3)	8 (1.9)	<.001*
Duration of ART (years), median (IQR)	490	10.8 (5.6, 13.5)	9.8 (2.6, 13.7)	10.9 (6.6, 13.5)	.25
Laboratory
HBsAg positive (n, %)	507	57 (11.2)	16 (15.5)	41 (10.1)	.17
HBV viral load, median (IQR)	48	0 (0, 10)	0 (0, 11.5)	0 (0, 10)	.86
Anti-HCV positive (n, %)	502	59 (11.8)	26 (26)	33 (8.2)	<.001*
Anti-HCV+/RNA > 10 IU/mL (n, %)	489	28 (5.7)	15 (16.1)	13 (3.3)	<.001*
HIV viral load, median (IQR)	425	20 (20, 40)	20 (10, 40)	20 (20, 40)	.62
Platelet, median (IQR)	402	233 (190, 287)	232 (167, 292)	234 (194, 284)	.2
Alanine transaminase, median (IQR)	491	17 (10, 27)	25 (13, 43)	15 (9, 23)	<.001*
Aspartate transaminase, median (IQR)	493	31 (24, 43)	44 (31, 75)	29 (23, 39)	<.001*

Viral load, alanine transaminase, and aspartate transaminase reported in IU/mL, platelet count reported in *1000/µL.

*Significant variables.

Abbreviations: ART, antiretroviral therapy; BMI, body mass index; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IQR, interquartile range; n, number of records available for that variable; TE, transient elastography.

Factors associated with significant liver fibrosis/cirrhosis (TE ≥ 9.3 kPa). In multivariable analyses, factors independently associated with significant liver fibrosis/cirrhosis were male sex, diabetes, ART use, HBsAg seropositivity, and viremic HCV infection after adjusting for known risk factors for significant liver fibrosis/cirrhosis. ART use for more than 5 years reduced the odds of significant liver fibrosis/cirrhosis by 50%. HBsAg seropositivity and viremic HCV infection increased the odds by greater than 2 and 7 times, respectively. Age, BMI, and consumption of herbs or alcohol were not associated with significant liver fibrosis/cirrhosis after adjusting for other risk factors (Table 2). Using the lower TE cutoff value of ≥7.6 kPa obtained from a prior validation study,²⁷ only HBV and HCV were associated with liver fibrosis/cirrhosis, while ART use for more than 5 years reduced the risk of liver fibrosis/cirrhosis by 40%.

Table 2.

Factors Associated With Significant Liver Fibrosis/Cirrhosis.

Variable^a	Univariate analysis		Multivariable analysis
	OR (95% CI)	P-value	OR (95% CI)	P-value
Age > 50 vs ≤50	1.5 (1.0, 2.3)	.04	1.4 (0.8, 2.4)	.24
Male vs female	1.8 (1.2, 2.8)	.004	1.8 (1.02, 3.2)	.04*
BMI ≥ 25 vs <25 kg/m²	0.8 (0.5, 1.2)	.34	0.9 (0.5, 1.6)	.8
Herb consumption	2.3 (1.4, 3.7)	<.001	1.6 (0.8, 3.1)	.2
Alcohol consumption	2.1 (1.3, 3.5)	.003	2.0 (0.9, 4.2)	.06
Diabetes (self-report)	5.2 (2.1, 13.7)	<.001	5.3 (1.6, 18.4)	.006*
ART use > 5 years	0.6 (0.4, 0.9)	.028	0.5 (0.3, 0.95)	.03*
HBsAg seropositive	1.6 (0.9, 3.0)	.125	2.2 (1.1, 4.5)	.02*
Anti-HCV/RNA > 10 IU/mL	5.7 (2.6, 12.6)	<.001	7.2 (3.1, 17. 1)	<.001*

^aAll variables with P-values of <.2 on χ² test or Fisher's exact test or were clinically significant were entered into the multivariable analysis.

*Significant variables.

Abbreviations: ART, antiretroviral therapy; BMI, body mass index; CI, confidence interval; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; OR, odds ratio.

Discussion

In this study, we compared demographic, clinical, and laboratory characteristics in PLWH with and without significant liver fibrosis/cirrhosis, examining more closely the associations between viral hepatitis co-infection and significant liver fibrosis/cirrhosis.

To our knowledge, this is the first study from Nigeria and one of the few from Africa to report an association between chronic HCV infection confirmed with molecular testing, and significant liver fibrosis/cirrhosis in PLWH. Most studies to date have only measured and reported the prevalence of antibodies to HCV which does not distinguish between active and past infection. In this study, 6% had chronic HCV. Our data is similar to 2 other Nigerian studies^17,18 of PLWH where virologic testing was also performed, and higher than that reported in the general Nigerian population,²⁸ where only anti-HCV serological testing was performed. HCV has been reported to be highly prevalent (8%-28%) in other at-risk groups such as those with HCC or chronic liver disease,^15,24,29,30 though in these studies, molecular testing was not done. The high prevalence of chronic HCV in this study may be explained by the shared routes of transmission of HCV and HIV which may include contaminated blood, needle sharing, scarification, and sexual activity.^31,32 In this study, HCV increased the odds of significant liver fibrosis/cirrhosis more than 7 times. Other studies from outside Africa have also reported a strong association between HCV and significant liver fibrosis/cirrhosis in patients with HIV infection, using different TE cutoffs (≥7.1 and ≥9.4 kPa, respectively).^33,34 Globally, direct-acting antiviral (DAA) therapy for the treatment of HCV has been available since 2013, resulting in cure rates of over 90%, regression of liver fibrosis, and improved survival.^35–37 In Nigeria, DAA agents are available, however, access is limited because the drugs are mostly paid for out of pocket.³⁸ This data emphasizes need for more widespread access to DAA in Nigeria. Expansion of health insurance access and availability of government subsidies for HCV laboratory testing and treatment are some of the ways to help mitigate high costs.

In this study, we also found that chronic HBV infection increased the odds of liver fibrosis in PLWH, similar to several other studies from African settings.^6,9 Chronic inflammation from HBV leads to repeated injury and activation of the fibrogenic pathways, resulting in chronic activation of fibrogenesis. This leads to increased synthesis and decreased degradation of fibrogenic collagen, resulting in its deposition in the extracellular matrix that surrounds the lobules, which is the hallmark of fibrosis.³⁹ Interestingly, HBsAg seropositivity was independently associated with fibrosis despite high rates of HBV viral suppression and a relatively long duration of ART (median 11 years) that included 2 active HBV agents. Fibrosis regression has been reported widely among PLWH with HBV on long-term ART in African and non-African settings.^6,40,41 Vinikoor et al⁴¹ reported a reduction in the prevalence of significant fibrosis from 14% to 6.7% and cirrhosis from 2.2% to 1.1% following a year of ART in persons with HIV and HIV/HBV from Zambia.⁴¹ However, other studies have reported fibrosis progression in up to 30% of patients with HIV/HBV co-infection despite effective ART,⁴² and persistently higher rates of fibrosis during follow up compared to those with HIV alone.¹² In Nigeria, and other countries with high HBV prevalence, HBV infection is frequently acquired in early childhood, thus predating HIV infection.⁴³ It is therefore possible for fibrosis to already be present at the time of HIV acquisition, and this may progress despite effective ART. While some studies have reported an independent association between HBV viremia and liver fibrosis, others have reported only associations with HIV-related factors such as, HIV viremia, and low CD4T cell counts, particularly before and early after ART initiation.^9,12,13 This suggests multiple factors play a role in fibrosis progression which may differ according to stage of HBV and HIV infection, and is something that requires further evaluation. Nevertheless, it is clear that the large majority benefit from HBV active ART, and thus immediate screening of PLWH for HBV, treatment with HBV active ART and assessment for liver damage remain a priority in this population as well as a search for more effective HBV therapies to improve outcomes in these people.⁴³

In this study, we report other factors that were associated with fibrosis/cirrhosis, although only when the higher cutoff of 9.3 kPa was used. The association between male sex and liver fibrosis has been reported in other studies in the general population and in PLWH.^41,44,45 Studies show that, independent of age, younger women, with viral hepatitis but without HIV infection, have less severe liver fibrosis than age-matched male peers.^46–48 This may be due to the protective effect of estrogen in younger women via its suppression of the secretion of tumor necrosis factor-alpha and other cytokines that are involved in fibrogenesis.^46,47,49,50 Other studies have found no association between male sex and liver cirrhosis.^6,9,51 Different participant characteristics, such as higher rates of overweight/obesity and consumption of herbs in our study, may explain some of the discrepancy in findings.

Diabetes, albeit not very common and self-reported, was also independently associated with significant liver fibrosis/cirrhosis in this population. Diabetes has been reported commonly as a risk factor for fibrosis in several other studies both in persons with and without HIV.^52,53 Insulin resistance is associated with progression of hepatic fibrosis, and is a central component of NAFLD in diabetes.⁵⁴ Several mechanisms have been proposed including genetic factors, hepatic fat accumulation, alterations in energy metabolism, and inflammatory signals derived from various cell types.⁵⁴ Hyperglycemia stimulates the hepatic stellate cells which are involved in fibrogenesis.⁵⁵ Our data, although preliminary, suggests that persons with diabetes may benefit from more routine targeted liver fibrosis screening particularly if other risk factors are present.⁵⁶

Our study had some limitations. A relatively small number of participants were included and were recruited from only 2 tertiary centers in Nigeria which may limit generalizability to other settings. Participants with and without liver fibrosis were intentionally enrolled and this could have introduced bias. The TE cutoffs used in this study to distinguish between those with and without significant fibrosis/cirrhosis were based on a previous validation study that was conducted in a population of predominantly black Americans, and reported a sensitivity of 86% for TE ≥ 9.3 kPa for the diagnosis of significant fibrosis/cirrhosis.²⁵ It is possible that some participants with more advanced stages of fibrosis could have been included in the TE < 9.3 kPa group. However, to account for this possibility, we repeated the analysis with a lower TE cutoff (from another validation study) and viral hepatitis remained associated with significant fibrosis/cirrhosis. Despite these limitations, our study has significant value that addresses research gaps in Africa, including the strong association of chronic hepatitis C with significant liver fibrosis/cirrhosis.

Conclusion

Chronic viral hepatitis (HCV and HBV) are associated with liver fibrosis in PLWH in Nigeria, while long-term ART use may reduce this risk. Strategies to improve HBV and HCV awareness and screening among Nigeria PLWH and promote access to treatment among those who are co-infected, are all critical to prevent further transmission, reduce morbidity, and mortality associated with these infections.

Footnotes

Acknowledgements

We thank Professor Folasade Ogunsola for her contributions to this work.

Author Contribution

OL, EO, AA, WA, FA, GI, AS, RM, LH, and CH conceptualized and designed the study. EO, GK, MO, MD, PD, DN, OL, and EO collected the data. EO, GO, HA, OO, BJ, IK, AC, and CH analyzed and interpreted the data. EO and CH drafted the work. All authors critically revised the manuscript for important content. All the authors approved the final version of the manuscript, including the authorship.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Division of Cancer Prevention, National Cancer Institute, grant no.: NIH/NCI U54CA221205 (PI Robert Murphy, Lifang Hou).

Ethical Statement

This study was approved by the Health Research Ethics Committees of the College of Medicine, University of Lagos, Lagos, Nigeria (approval number CMUL/HREC/01/18/326) on March 12, 2018 and Jos University Teaching Hospital, Jos, Nigeria (approval number JUTH/DCS/ADM/127/XXVII/629) on November 27, 2017. All participants provided written informed consent prior to enrollment in the study.

ORCID iD

Emuobor Odeghe

References

Palella

Jr Baker

Moorman

, et al. HIV Outpatient Study Investigators. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43(1):27-34, doi:10.1097/01.qai.0000233310.90484.16

Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group; Smith

Sabin

Lundgren

, et al. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D study. AIDS. 2010;24(10):1537-1548, doi:10.1097/QAD.0b013e32833a0918. Erratum in: AIDS. 2011;25(6):883.

Martín-Carbonero

Soriano

Valencia

García-Samaniego

López

González-Lahoz

. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retroviruses. 2001;17(16):1467-1471. doi:10.1089/08892220152644160

Perazzo

Cardoso

Yanavich

, et al. Predictive factors associated with liver fibrosis and steatosis by transient elastography in patients with HIV mono-infection under long-term combined antiretroviral therapy. J Int AIDS Soc. 2018;21(11):e25201. doi:10.1002/jia2.25201

Vinikoor

Mulenga

Siyunda

, et al.; International Epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA). Association between hepatitis B co-infection and elevated liver stiffness among HIV-infected adults in Lusaka, Zambia. Trop Med Int Health. 2016;21(11):1435-1441, doi:10.1111/tmi.12764

Stabinski

Reynolds

Ocama

, et al.; Rakai Health Sciences Program. High prevalence of liver fibrosis associated with HIV infection: a study in rural Rakai, Uganda. Antivir Ther. 2011;16(3):405-411.

Price

Thio

. Liver disease in the HIV-infected individual. Clin Gastroenterol Hepatol. 2010;8(12):1002-1012.

Xie

Han

Qiu

, et al. Prevalence of hepatitis B and C viruses in HIV-positive patients in China: a cross-sectional study. J Int AIDS Soc. 2016;19(1):20659.

Hawkins

Agbaji

Ugoagwu

, et al. Assessment of liver fibrosis by transient elastography in patients with HIV and hepatitis B virus coinfection in Nigeria. Clin Infect Dis. 2013;57(12):e189-e192.

10.

Benhamou

Bochet

Martino

V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30(4):1054-1058.

11.

Bonnard

Lescure

Amiel

, et al. Documented rapid course of hepatic fibrosis between two biopsies in patients coinfected by HIV and HCV despite high CD4 cell count. J Viral Hepat. 2007;14(11):806-811.

12.

Rivera

Machenry

Okpokwu

, et al. HBV co-infection is associated with persistently elevated liver stiffness measurement in HIV-positive adults: a 6-year single-centre cohort study in Nigeria. Antivir Ther. 2021;26(6-8):106-116. doi:10.1177/13596535211058262

13.

Iacob

Luminos

Benea

, et al. Liver fibrosis progression in a cohort of young HIV and HIV/HBV co-infected patients: a longitudinal study using non-invasive APRI and Fib-4 scores. Front Med (Lausanne). 2022;9:888050. doi:10.3389/fmed.2022.888050

14.

Nnakenyi

Uchechukwu

Nto-Ezimah

. Prevalence of hepatitis B and C virus co-infection in HIV positive patients attending a health institution in southeast Nigeria. African Health Sci. 2020;20(2):579-586. doi:10.4314/ahs.v20i2.5

15.

Newton

Oghene

Okonko

. Anti-HCV antibody among newly diagnosed HIV patients in Ughelli, a suburban area of Delta State Nigeria. African Health Sci. 2015;15(3):728-736. doi:10.4314/ahs.v15i3.5

16.

Ladep

Agaba

Agbaji

, et al. Rates and impact of hepatitis on human immunodeficiency virus infection in a large African cohort. World J Gastroenterol. 2013;19(10):1602-1610. doi:10.3748/wjg.v19.i10.1602

17.

Agwale

Tanimoto

Womack

, et al. Prevalence of HCV coinfection in HIV-infected individuals in Nigeria and characterization of HCV genotypes. J Clin Virol. 2004;31(Suppl 1):S3-S6, doi:10.1016/j.jcv.2004.09.001 doi:10.1016/j.jcv.2004.09.001

18.

Agbaji

Thio

Meloni

, et al. Impact of hepatitis C virus on HIV response to antiretroviral therapy in Nigeria. J Acquir Immune Defic Syndr. 2013;62(2):204-207. doi:10.1097/QAI.0b013e31827ce536

19.

Anyanwu

NCJ

Sunmonu

Mathew

. Viral hepatitis B and C co-infection with human immunodeficiency virus among adult patients attending selected highly active anti-retroviral therapy clinics in Nigeria's capital. J Immunoassay Immunochem. 2020;41(2):171-183. doi:10.1080/15321819.2019.1705852

20.

Lesi

Soyebi

Eboh

. Fatty liver and hyperlipidemia in a cohort of HIV-positive Africans on highly active antiretroviral therapy. J Natl Med Assoc. 2009;101(2):151-155. doi:10.1016/s0027-9684(15)30828-2

21.

Nwokediuko

Osuala

Uduma

Alaneme

Onwuka

Mesigo

. Pattern of liver disease admissions in a Nigerian tertiary hospital. Niger J Clin Pract. 2013;16(3):339-342. doi:10.4103/1119-3077.113458

22.

Ifeorah

Bakarey

Adeniji

Onyemelukwe

. Seroprevalence of hepatitis B and delta viruses among HIV-infected population attending anti-retroviral clinic in selected health facilities in Abuja, Nigeria. J Immunoassay Immunochem. 2017;38(6):608-619.

23.

Iruolagbe

Ohanador

Amene-Imananagha

Abubakar

Jessica

Obianemmie

. Prevalence of liver-fibrosis using FIB-4 in HIV-patients on anti-retroviral therapy in Nigeria and CD4 and TNF as predictors. AJRIMPS. 2019;6(4):1-9.

24.

Davwar

Okeke

Duguru

, et al. Hepatocellular carcinoma presentation and prognosis among Nigerian adults with and without HIV. PLoS ONE. 2023;18(3):e0282539. doi:10.1371/journal.pone.0282539

25.

Kirk

Astemborski

Mehta

, et al. Assessment of liver fibrosis by transient elastography in persons with hepatitis C virus infection or HIV-hepatitis C virus coinfection. Clin Infect Dis. 2009;48(7):963-972. doi:10.1086/597350

26.

National Guidelines for HIV Prevention, Treatment and Care by National AIDS and STIs control programme, Federal Ministry of Health Nigeria 2020. Accessed May 15, 2023. National HIV Treatment Guideline 21.04.2021.cdr (prepwatch.org).

27.

Miailhes

Pradat

Chevallier

, et al. Proficiency of transient elastography compared to liver biopsy for the assessment of fibrosis in HIV/HBV-coinfected patients. J Viral Hepat. 2011;18(1):61-69. doi:10.1111/j.1365-2893.2010.01275.x

28.

Onyekwere

Hameed

. Hepatitis B and C virus prevalence and association with demographics: report of population screening in Nigeria. Trop Doct. 2015;45(4):231-235. doi:10.1177/0049475514560211

29.

Emokpae

Adejumol

Abdu

Sadiq

. Serum alpha-fetoprotein level is higher in hepatitis C than hepatitis B infected chronic liver disease patients. Niger Med J. 2013;54(6):426-429. doi:10.4103/0300-1652.126302

30.

Okonkwo

Nwosu

Ukah

Okpala

Ahaneku

. The clinical and pathological features of hepatocellular carcinoma in Nnewi, Nigeria. Niger J Med. 2011;20(3):366-371.

31.

Deng

Liang

Cai

, et al. Transmission networks of hepatitis C virus among HIV/HCV-coinfected patients in Guangdong, China. Virol J. 2022;19(1):117. doi:10.1186/s12985-022-01849-4

32.

Okafor

Ugwu

Okoroiwu

. Hepatitis C virus infection and its associated factors among prisoners in a Nigerian prison. BMC Gastroenterol. 2020;20(1):360. doi:10.1186/s12876-020-01504-8

33.

Brescini

Orsetti

Gesuita

, et al. Evaluating liver fibrosis by transient elastometry in patients with HIV-HCV coinfection and monoinfection. Hepat Mon. 2014;14(8):e15426. doi:10.5812/hepatmon.15426

34.

Androutsakos

Schina

Pouliakis

Kontos

Sipsas

Hatzis

. Causative factors of liver fibrosis in HIV-infected patients. A single center study. BMC Gastroenterol. 2020;20(1):91.

35.

Lledó

Carrasco

Benítez-Gutiérrez

, et al. Regression of liver fibrosis after curing chronic hepatitis C with oral antivirals in patients with and without HIV coinfection. AIDS. 2018;32(16):2347-2352.

36.

Quaranta

Ferrigno

Tata

, et al. Liver function following hepatitis C virus eradication by direct acting antivirals in patients with liver cirrhosis: data from the PITER cohort. BMC Infect Dis. 2021;21(1):413.

37.

Corma-Gómez

Morano

Téllez

, et al.; RIS-HEP13 and GEHEP 011 study groups. HIV infection does not increase the risk of liver complications in hepatitis C virus-infected patient with advanced fibrosis, after sustained virological response with direct-acting antivirals. AIDS. 2019;33(7):1167-1174.

38.

Boeke

Adesigbin

Agwuocha

, et al. Initial success from a public health approach to hepatitis C testing, treatment and cure in seven countries: the road to elimination. BMJ Glob Health. 2020;5(12):e003767. doi:10.1136/bmjgh-2020-003767

39.

Acharya

Chouhan

Weiskirchen

. Cellular mechanisms of liver fibrosis. Front Pharmacol. 2021;12:671640. doi:10.3389/fphar.2021.671640

40.

Marcellin

Gane

Buti

, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-475.

41.

Vinikoor

Sinkala

Chilengi

, et al.; IeDEA- Southern Africa. Impact of antiretroviral therapy on liver fibrosis among human immunodeficiency virus-infected adults with and without HBV coinfection in Zambia. Clin Infect Dis. 2017;64(10):1343-1349. Erratum in: Clin Infect Dis. 2017;65(8):1431-1433. doi:10.1093/cid/cix122

42.

Boyd

Bottero

Miailhes

, et al. Liver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with tenofovir disoproxil fumarate in France: a prospective cohort study. J Int AIDS Soc. 2017;20(1):21426. doi:10.7448/IAS.20.1.21426

43.

Lui

Wong

Yang

Sheng

Lee

. Current practice and recommendations for management of hepatitis B virus in people living with HIV in Asia. HIV Med. 2023;24(10):1035-1044. doi:10.1111/hiv.13545

44.

Villa

Owusu

Smith

, et al. Liver steatosis and fibrosis in people with human immunodeficiency virus in West Africa and the relationship with hepatitis B virus coinfection. Hepatol Commun. 2022;6(11):3036-3051. doi:10.1002/hep4.2000

45.

Nah

Cho

Kim

Chu

Kwon

Cho

. Prevalence of liver fibrosis and associated risk factors in the Korean general population: a retrospective cross-sectional study. BMJ Open. 2021;11(3):e046529.

46.

Villa

Vukotic

Cammà

, et al. Reproductive status is associated with the severity of fibrosis in women with hepatitis C. PLoS ONE. 2012;7(9):e44624.

47.

Di Martino

Lebray

Myers

, et al. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology. 2004;40(6):1426-1433.

48.

Xiong

Yang

, et al. Influence of gender and reproductive factors on liver fibrosis in patients with chronic hepatitis B infection. Clin Transl Gastroenterol. 2019;10(10):e00085.

49.

Rogers

Eastell

. The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. Bone. 2001;29(1):30-34.

50.

Tacke

Weiskirchen

. Update on hepatic stellate cells: pathogenic role in liver fibrosis and novel isolation techniques. Expert Rev Gastroenterol Hepatol. 2012;6(1):67-80.

51.

Jaquet

Wandeler

Nouaman

, et al. Alcohol use, viral hepatitis and liver fibrosis among HIV-positive persons in West Africa: a cross-sectional study. J Int AIDS Soc. 2017;20(1):21424.

52.

Park

Kwon

Sohn

, et al. Risk of liver fibrosis in patients with prediabetes and diabetes mellitus. PLoS ONE. 2022;17(6):e0269070. doi:10.1371/journal.pone.0269070

53.

Vuille-Lessard

Lebouché

Lennox

, et al. Nonalcoholic fatty liver disease diagnosed by transient elastography with controlled attenuation parameter in unselected HIV monoinfected patients. AIDS. 2016;30(17):2635-2643. doi:10.1097/QAD.0000000000001241

54.

Fujii

Kawada

, Japan Study Group of Nafld Jsg-Nafld. The role of insulin resistance and diabetes in nonalcoholic fatty liver disease. Int J Mol Sci. 2020;21(11):3863, doi:10.3390/ijms21113863

55.

Paradis

Perlemuter

Bonvoust

, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34(4 Pt 1):738-744.

56.

Rinella

Neuschwander-Tetri

Siddiqui

, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323

Hepatitis B and C Virus Co-Infection and Their Association With Liver Disease in Persons With HIV in Nigeria

Abstract

Plain Language Summary

Keywords

Background

Methods

Sampling Technique and Sample Size Determination

Data Collection

Statistical Analysis

Results

Characteristics of the Study Participants

Discussion

Conclusion

Footnotes

Acknowledgements

Author Contribution

Declaration of Conflicting Interests

Funding

Ethical Statement

ORCID iD

References