Introduction
The virus causing hepatitis B is a circular, partial dual-stranded DNA virus [Figure 1], is a member of the family Hepadnaviridae which causes illness ranging from acute self-resolving hepatitis to chronic disease including fulminant hepatitis or chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma (HCC). Globally, the prevalence of Hepatitis B virus (HBV) infection remains a serious public health issue. Annually, 296 million people are chronically infected by HBV, causing 820,000 deaths.[1] In India with a population of over 1.21 billion people, the world’s second most populous country accounts for over 40 million people carrying the virus and almost half a million people dying from it annually.[1] Human immunodeficiency virus (HIV) belongs to the Genus Lentivirus (family Retroviridae) and possess, two types of isolates: HIV-1 and HIV-2. Globally, HIV-1 is the most common cause of AIDS, whereas HIV-2 is prevalent in some parts of Western and Central Africa.[2] The incidence of HBV infection is higher in patients with HIV due to the nearly identical routes of transmission. HIV/HBV co-infection is one of the most significant burdens faced by HIV-positive individuals. Worldwide, there were 37.9 million (32.7–44.0 million) HIV-positive individuals at the end of 2018. As of 2017, there were an estimated 2.14 million HIV-positive individuals in India (1.59–28.39 million).[3] Among them, those co-infected with chronic HBV infections chronic hepatitis B (CHB) were estimated to be 5%–20%.[4]
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Figure 1: HBV structure. HBV: Hepatitis B virus, HBcAg: Hepatitis B core antigen, HBsAg: Hepatitis B surface antigen
With the implementation of anti-retroviral therapy (ART), life expectancy has improved in HIV-positive individuals leading to liver disease-associated mortality becomes a major cause of death in HIV-positive individuals, among all causes of death associated with liver disease.[5] HIV and HBV can both be transmitted through similar routes; for example, by injection drug use, through sexual contact, during pregnancy or childbirth.[6] The HIV virus affects the natural history of HBV infection in a significant way through increasing HBV replication and DNA levels and decreasing HBV e-antigen hepatitis B e antigen (HBeAg) seroconversion in HIV/HBV co-infected patients. As a result, the liver fibrosis (FIB) advances rapidly, and the chances of developing cirrhosis decompensation, end-stage liver disease, and HCC also increase.[7] In addition to the complicated host-viral immune interaction, viral factors such as genotypes of the HBV have a significant impact on the clinical outcome of this co-infection.[8]
HIV/HBV co-infection complicates the immune response of the host, as well as the progression of both diseases and treatment outcome. Several researches have been undertaken around the world that have demonstrated that infection with HIV has a major impact on the natural history of HBV. HIV-HBV infection epidemiology and clinical implications are discussed in this article.
Epidemiology
The HBV and the HIV are among the top 10 causes of infectious disease mortality worldwide. Worldwide, approximately 35.3 million people are infected with HIV.[9] HIV infection affects about 1% of persons living with HBV (2.7 million people). As of 2020, according to the WHO estimates, 5%–20% of HIV-infected people are chronically infected with HBV (CHB).[10]
Prevalence of Hepatitis B Virus-Human Immunodeficiency Virus Co-Infection in Asia
Co-infection rates are the highest in regions where HBV and HIV endemicity are high, such as in the Indian subcontinent, sub-Saharan Africa, and South-east Asia are among them.[11–13] As hepatitis B is endemic to China, with a prevalence rate of 6.89%,[14] Chinese estimates suggest hepatitis B surface antigen (HBsAg) seropositivity ranges from 4.4% to 12.5% among HIV-positive individuals.[15–19] In Japan, HBV prevalence rate is 1% among general population and HIV-HBV co-infection ranges from 3.2% to 11.9% in HIV-positive individuals.[20–22] Iran with a HBV prevalence of 1.7% has also been reported to have a high rate of HBV-HIV co-infections.[23] Iran has been found to have an HBV infection rate between 1.8% and 28.6% among HIV-infected people.[24–27] Pakistan has been reported to have a prevalence of HBV of 3%–5% in general and 10%–20% in populations at high risk while HIV/HBV co-infection ranges from 3.4% to 10.4% in Pakistan’s HIV-positive individuals.[28–31] Further the study by The Therapeutics Research, Education, and AIDS Training Asia HIV Observational Database reported that, among 7455 HIV patients in 21 adult HIV treatment facilities in 12 countries in Asia Pacific, 10.5% were co-infected with both HBV and HIV.[31]
Co-Infection of Hepatitis B Virus and Human Immunodeficiency Virus in India
It has been reported that the overall prevalence of HBsAg positivity in India ranges between 2% and 8% in most studies.[32,33] With few studies conducted in India, a relatively high prevalence of co-infection of HBV-HIV (7%–14%) has been reported.[34–37]
Researchers in Eastern India reported a prevalence of HIV-HBV infection of 5.8% among 1331 HIV-positive patients. Another study in the region documented 11.3% co-infection with HIV and HBV among 320 HIV-positive patients. HIV-HBV co-infection was found to be present in 2.9% of 863 HIV-positive patients from Northern India. While a study conducted in Southern India shows 9% prevalence of HIV-HBV co-infection in 1100 HIV-positive patients. According to a study conducted in the eastern part of India, 5.8% prevalence of HIV-HBV among 1331 HIV patients was revealed.[38] Another study conducted in the region found that 11.3% of 320 HIV-positive patients had both HBV and HIV co-infection.[39] A study from Northern India found that the prevalence of HIV-HBV co-infection was 2.9% in 863 HIV-positive patients.[40] While a South Indian study found that HBV-HIV is present in 9% of 1100 HIV-positive patients.[41]
Clinical Implications among Human Immunodeficiency Virus/Hepatitis B Virus Co-Infected Patients
Infection with HIV compromises innate and adaptive immune responses against HBV, which is reflected in how the disease develops and progresses.[42] HIV may cause liver damage through a number of mechanisms that have not been fully elucidated. HBV-related hepatotoxicity seems to be exacerbated by HIV-induced immunodeficiency.[6] The natural course of HBV/HIV coinfection is more complex than that of HBV mono-infection and the risk of worsening of the disease is increased.[43] The risk of chronic hepatitis B (CHB) progression is five-fold higher with HIV-HBV co-infection, and mortality is two-fold higher with HIV-HBV co-infection, compared with HBV mono-infection.[44] Studies continue to report that with HIV-HBV co-infections, overall mortality, liver associated mortality, and hospital utilization rates and the risk of HCC are higher than in HBV mono-infected individuals.[45–50] HIV-infected individuals with HCC were found to have lower CD4 T cell counts and high HBV DNA levels.[51,52] HCC has been observed to progress more aggressively in co-infected patients with younger age at diagnosis, extrahepatic disease, and shorter survival rates.[53] HCC and liver disease in patients with HIV-HBV coinfection are strongly associated with liver FIB severity and cirrhosis.[54] When considering initiating treatment in co-infected patients, factors such as HIV infection, liver disease severity, probability of certain reactions, and potential adverse events must be considered.[55]
HIV/HBV co-infected patients face several challenges in terms of therapeutic management-such as antiviral medications are less effective than those prescribed to those with mono-infection. It is a constant concern that viral resistance and subsequent viral failure will arise and drugs with dual activity may simplify the treatment process but are more challenging to manage when resistance emerges to HIV or HBV.[56] In HIV-infected patients with chronic hepatitis B, lamivudine and tenofovir should be used as a first-line ARV regimen, according to the WHO guidelines.[10] In the case of lamivudine, virological resistance develops rapidly as a result of its sole use as an active agent. The use of lamivudine as an active agent results in rapid virological resistance.[57] Approximately 90% of co-infected individuals develop HBV resistance with lamivudine after 4 years of treatment.[58]
Diagnosis of Human Immunodeficiency Virus/Hepatitis B Virus Co-Infection
Serological
Because of alteration of natural history of infection, it is obvious to do accurate screening, diagnosis, and treatment of patients with HIV/HBV co-infection, for which a thorough understanding of the current diagnostic tests is necessary. HBV is primarily diagnosed by detecting the HBV antigens, HBsAg being the signature of this infection. Algorithm for serological classification of HBV is given in Table 1. If HBsAg remains positive for over 6 months, CHB virus infection is suspected. CHB develops during various phases, which affect the amounts and the sources of HBsAg when the immune system is tolerant to the disease, the HBsAg levels are high, whereas when the immune system is inactive, they are low.[59,60] It is considered a cure if a qualitative test for HBsAg reveals seroclearance (excluding occult HBV infection), regardless of whether antibodies are present or not.[61,62]
Table 1: Serological marker-based assessment of hepatitis B virus infection
A HBsAg level of <100 IU/ml in Asian patients whose HBeAg status is negative is indicative of spontaneous HBsAg sero-clearance within 6–8 years.[63] HBsAg levels are useful for predicting and monitoring the progress of a patient’s response to therapy with peginterferon while the HBeAg level determines a patient’s phase of chronic HBV infection.[64–66] In some individuals with negative HBsAg, the IgG antibodies against HBc are positive, such individuals often have detectable HBV DNA in the liver, as well as in the serum, such an infection is referred to as occult HBV.[67–69] Chemotherapy or immunosuppressive therapy can reactivate infection in HBsAg-negative, anti-HBc-positive patients with HBsAg reoccurrence.[68] Before the advent of HBV DNA testing, HbeAg and anti-HBe were used to show viral replication and infectivity.[66]
Anti-HBc immunoglobulin M (IgM) core antibody test for HBV determines the case of acute hepatitis B, this is often the only indication which is detected during the acute phase of hepatitis B when HBsAg is not detectable. Chronic hepatitis B patients who suffer severe flare-ups of the disease can also be found to have anti-HBc positive.[69] A positive anti-HBc IgG test, however, may indicate recent or past HBV infection. Anti-HBc positivity and a negative result for HBsAg in patients with cryptogenic HCC could indicate HBV infection or possible occult HBV infection.[70] In this infection, noninvasive tests such as the FIB-4 index and transient elastography can be useful.[71]
Molecular detection
Monitoring and detecting circulating HBV infection as well as assessing treatment response rely heavily on detection and quantification of the virus in plasma or serum.[72] HBV DNA titers are extremely variable clinically, from as high as 10 to the power 10 copies/ml during acute HBV infection[73] while patients with chronic HBV infection with HBeAg negative or those undergoing antiviral therapy or those with occult HBV infection, have low level of viremia.[74]
HBV DNA levels in patient specimens are likely to vary greatly, and the HBV genome itself has a wide range of variability. In combination, these factors make the development of HBV
DNA assays are difficult. Till date, there are eight genotypes of HBV (A to H) identified by sequence divergence of over 8% in the genome.[75–77] Each genotype of HBV has a characteristic geographical distribution.
The ability to screen for infectious agents, especially viruses, genetically has been enhanced by several nucleic acid amplification techniques (NAT), such as polymerase chain reaction (PCR), ligase chain reaction, loop-mediated isothermal amplification (LAMP), nucleic acid sequence-based amplification (NASBA), transcription-mediated amplification (TMA), and rolling circle amplification (RCA) etc.
The primary focus of genomic amplification-based tests remains the diagnosis of infectious diseases. This is because NAT combines the advantages of direct detection of the organisms with a higher sensitivity than traditional enzyme immunoassay-based antigen detection method.
The most preeminent detection of HBV DNA is the measurement of viral load using nucleic acid amplification method, which detect the virus, indicates how active the virus is at replication and the viral load of the patient. The most common HBV DNA assays in use are real-time PCR tests with detection limits of 10–20 IU/ml. As a result of issues with nondetection of HBsAg due to diagnostic-escape mutations in the epitopes or low antigen levels, it has become increasingly clear how important it is to use robust molecular biology tools in HBV monitoring. In addition to this, the advancement of molecular diagnostics for HBV has also resulted in greater efficiency and accuracy and detection of occult HBV cases.[78,79]
In the area of molecular diagnosis, the most preeminent detection of HBV DNA is the measurement of viral load, which indicates how active the virus is at replication. The most common HBV DNA assays in use are real-time PCR tests with detection limits of 10–20 IU/ml. As a result of issues with nondetection of HBsAg due to diagnostic-escape mutations in the epitopes or low antigen levels, it has become increasingly clear how important it is to use robust molecular biology tools in HBV monitoring. In addition to this, the advancement of molecular diagnostics for HBV has also resulted in greater efficiency and accuracy.[78,79]
In the field of molecular methods, amplification of HBV DNA can be accomplished by thermal cycling technologies, such as PCR, NASBA, qPCR, or isothermal amplification, TMA, LAMP, RCA etc.
Treatment
HIV-HBV co-infection is most commonly treated with HBV-active ART, which usually includes two NRTI, either lamivudine or emtricitabine in combination with tenofovir.[80] The nucleoside analogue lamivudine inhibits the reverse transcriptase enzyme activity of HBV and HIV, thereby suppressing their replication. According to studies, lamivudine is effective for co-infected patients and significantly lowers HBV DNA levels. Similarly, Tenofovir alafenamide (TAF) also appears to reduce negative effects on renal function and bone mineral density, while maintaining high levels of viral suppression, both in HIV and in HBV.[81] TAF has higher intracellular concentrations in PBMCs and hepatocytes than plasma, resulting in reduced dosing and toxicity as compared to disoproxil fumarate (TDF). A switch from a TDF to a TAF-containing regimen showed similar high levels of HBV virological control in HIV-HBV co-infection.[82,83]
WHO’s updated adult HIV treatment guidelines for 2016 recommend using integrase strand transfer inhibitors (INSTI) as part of first-line regimens.[80] Three INSTI drugs have now become widely used, including dolutegravir (DTG), raltegravir (RAL), and Elvitegravir/Cobicistat (EVG/c). The study of individuals coinfected with HIV and HBV or hepatitis C virus (HCV) (n = 324, 11% of total) found that they were more likely to suffer liver enzyme flares due to immune reconstitution inflammatory syndrome (IRID).[84] DTG was associated with fewer liver enzyme elevations in HIV- and HBV/HCV-positive individuals in comparison to RAL in ART naive individuals.[85]
Hepatitis B virus drug resistance
After 1 year of treatment with lamivudine for chronic hepatitis B, the emergence of drug-resistant HBV is a major concern, with an incidence of 14%–36%.[86] After 2, 3, and 4 years of treatment, this frequency increases to 38%, 49%, and 66%, respectively.[87] HBV that is lamivudine resistant is characterized by amino acid changes in the reverse transcriptase domain. Lamivudine resistance is associated with substitution of methionine by either isoleucine or valine within the YMDD motif (rtM204I/V mutants). In the case of a breakthrough of those drug-resistant HBV mutants, the viral levels rebound to baseline,[88] this will lead to a reduction in hepatitis B e antigen loss (HBeAg),[89] a high rate of relapses of serum alanine transaminase levels, and deteriorating liver histology.[90] Thus, the emergence of viral resistance is one of the most critical issues affecting patient outcomes when they are treated for chronic hepatitis B.
Conclusion
Co-infection with HIV and HBV is common all over the world. HIV-positive patients with co-infection with HBV and HIV continue to be at considerable risk for liver-related problems and deaths unrelated to AIDS. Co-infection of HBV-HIV is more likely to progress and complicate the disease and should be closely monitored and treated. In HBV co-infected patients, co-infection with HIV and HBV led to a faster progression of the disease, on the other hand, coinfected individuals are more likely to experience reverse seroconversion or reactivation for HBV infection. For better preventive or therapeutic measures, more research and attention are needed in this area.
Financial support and sponsorship
This study was financially supported by ICMR (HIV/50/207/09/2020 ECD-11/ICMR).
Conflicts of interest
There are no conflicts of interest.
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