Viral Hepatitis and HIV/AIDS - Lecture Notes PDF

Viral hepatitis and HIV/AIDS Dr Samson Wong Department of Microbiology Learning objectives u Basic virology of the hepatitis viruses (hepatitis A to E) and human immunodeficiency viruses (HIV). u Epidemiology and transmission of the different types of viral hepatitis and HIV infection. u Clinical...

Viral hepatitis and HIV/AIDS Dr Samson Wong Department of Microbiology Learning objectives u Basic virology of the hepatitis viruses (hepatitis A to E) and human immunodeficiency viruses (HIV). u Epidemiology and transmission of the different types of viral hepatitis and HIV infection. u Clinical courses of viral hepatitis and HIV infection. u HIV infection versus AIDS; AIDS-defining illnesses. u Principles of diagnosis and management of viral hepatitis and HIV infection. u Principles of prevention of viral hepatitis and HIV infection. Viral hepatitis What is hepatitis? u Hepatitis. u Inflammation of the liver. u Hepatocellular injuries. Causes of hepatitis u “Classical” viral hepatitis agents. u Hepatitis A, B, C, D, E viruses. u Hepatotropic viruses (hepatitis viruses A to E) that have a specific affinity for the liver. u Liver damage occurring as a result of other systemic infections. u e.g. yellow fever virus, cytomegalovirus (CMV), EpsteinBarr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus (HSV), Leptospira. u Chemicals, drugs, alcohols, toxins. u Autoimmune diseases. Clinical presentations of viral hepatitis u Asymptomatic. u Self-limited acute hepatitis. uNausea, vomiting, abdominal pain, fever, jaundice, teacoloured urine, hepatomegaly. u Fulminant hepatitis. u Chronic hepatitis with chronic liver disease and complications. ue.g. cirrhosis, hepatocellular carcinoma. Transmission of viral hepatitis u Enteric (faeco-oral). u Foodborne, waterborne, person-to-person (including oral sex). u Parenteral. u Vertical transmission (congenital, perinatal). u Horizontal transmission. uTransfusion (blood and blood products) and transplantation. u Uncommon nowadays because of screening for HBV and HCV. uSexual. uInjection drug use. uHealthcare-related (HBV, HCV). u Patient-to-patient, patient-to-provider, provider-to-patient. u Contaminated drugs, instruments, environment. May result in outbreaks. Hepatitis A virus (HAV) u Family Picornaviridae. u Genus Hepatovirus. u Non-enveloped, single-stranded RNA virus. u Relatively stable in: u Acid (pH 1.0 for 2 hours). u Heat (60ºC for 1 hour). u Destroyed by: u Boiling water for 5 minutes. u Chlorine (sodium hypochlorite), ultraviolet irradiation. u Food: >85ºC for 1 minute. Harrison TJ, Dusheiko Gm, Zuckerman AJ. Hepatitis viruses. In: Zuckerman AJ, Banatvala JE, Pattison JR, Griffiths PD, Schoub BD (ed). Principles and Practice of Clinical Virology, 5th edition. 2004. John Wiley & Sons. Hepatitis A transmission u Faeco-oral transmission. u Potential for outbreaks. u Water. u Food (e.g. shellfish, oysters, other contaminated food). uLargest foodborne outbreak of hepatitis A: Shanghai, 1988; >300,000 cases reported, 47 (0.015%) fatal. u Person-to-person, including sexual acts. uOutbreaks often reported among male homosexuals. uHong Kong, 8·2016 to 2017: increased incidence among HIV+ male homosexuals. u Clinical course. u Acute hepatitis. u Case-fatality <0.5%. Course of acute hepatitis A Karayiannis P, Thomas HC. Enterically transmitted viral hepatitis: hepatitis A and hepatitis E. In: Dooley JS, Lok A, Burroughs AK, Heathcote J (ed). Sherlock’s Diseases of the Liver and Biliary System, 12th edition. Wiley-Blackwell, 2011. Hepatitis B virus (HBV) u Family Hepadnaviridae. u Genus Orthohepadnavirus. u Enveloped, double-stranded DNA virus. u 3 morphological forms under electron microscopy. u42 nm Dane particles; enveloped complete virions. u HBcAg in the core, HBsAg in the envelope. u22 nm spherical particles; made up of HBsAg; most numerous. u22 nm diameter tubular/filamentous particles; variable length (can be >200 nm); made up of HBsAg. Harrison TJ, Dusheiko Gm, Zuckerman AJ. Hepatitis viruses. In: Zuckerman AJ, Banatvala JE, Pattison JR, Griffiths PD, Schoub BD (ed). Principles and Practice of Clinical Virology, 5th edition. 2004. John Wiley & Sons. Target of protective immunity Cobb BR, Valsamakis A. Chronic hepatitis B, C, and D. Microbiol Spectr 2016;4(4). doi: 10.1128/microbiolspec.DMIH2-0025-2015. HBV antigens and DNA of diagnostic importance HBcAg HBsAg HBeAg HBV DNA Name Significance Core antigen • Antibodies (anti-HBc) indicate history of infection. • Antibodies generally persist life-long. • On surface of viral envelope and circulating. • Indicates active infection (acute and chronic). • Antibodies (anti-HBs) are protective. • A truncated derivative of HBcAg. • A marker of high viral replication activity. • Correlates with greater infectivity. • Positive in 5–40% of HBV carriers. Surface antigen e antigen Hepatitis B virus DNA • Circulating in blood. • Indicates active infection (acute and chronic). • Quantification possible. Hepatitis B transmission u Infectivity depends on viral load and HBeAg status. u Stable in environment for at least 7 days. u Vertical transmission. u Mother HBeAg positive: 80–90%. u Mother HBeAg negative: 10–20%. u Main routes of transmission. u Highly endemic areas: mainly perinatal infection during delivery. (In utero transmission rare; <2%.) u Low endemicity areas: sexual or injection drug use (needle-sharing) in adolescence and adults. u Other routes: household (non-sexual), occupational or healthcare exposure. Hepatitis B u Manifestation and course depends on age of infection. u Acute infections. u Can be asymptomatic or symptomatic. u Chronic infections. u HBsAg positive for ≥6 months. u Can be asymptomatic (inactive carriers) or symptomatic (chronic active hepatitis). u May flare up in previously asymptomatic patients, e.g. superinfection by other hepatitis viruses, immunosuppressive therapy. u Infection in infants: ~90% becomes chronic. u Infection in children <5 years: ~30% becomes chronic. u Infection in adults: 2–6% becomes chronic. u 15–20% progress to cirrhosis/hepatocellular carcinoma. u The most important cause of hepatocellular carcinoma in Hong Kong. Acute hepatitis B Lok ASF. Hepatitis B. In: Dooley JS, Lok A, Burroughs AK, Heathcote J (ed). Sherlock’s Diseases of the Liver and Biliary System, 12th edition. Wiley-Blackwell, 2011. Chronic hepatitis B Lok ASF. Hepatitis B. In: Dooley JS, Lok A, Burroughs AK, Heathcote J (ed). Sherlock’s Diseases of the Liver and Biliary System, 12th edition. Wiley-Blackwell, 2011. Hepatitis C virus (HCV) u “Non-A, non-B (NANB) hepatitis”. u Family Flaviviridae. u Genus Hepacivirus. u Enveloped, single-stranded, positive sense, RNA virus. u Stable for days on environmental surfaces. Hepatitis C u Acute infection symptomatic in 20–30%. u Chronic infection occurs in 50–70%. u No significant impact by age of infection. u 20–30% progress to chronic active hepatitis or cirrhosis. u Transmission. u Blood and body fluids (transfusion, injection drug use, nosocomial, etc.) u Less efficient: sexual, vertical. Course of HCV infection Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet 2008;372:321–332. Hepatitis D virus (HDV) u The “delta agent”. u Genus Deltavirus. u A “defective virus”; requires HBsAg coat for transmission. u Single-stranded, negative sense, RNA virus. u HDAg (delta antigen) surrounded by HBsAg envelope. u Transmission: same as HBV. u Prevalence in HBV-positive individuals: 0–60%. u Co-infection (with HBV) or superinfection (in someone already infected with HBV). u Prone to cause fulminant hepatitis (80%), especially in superinfection. Hepatitis E virus (HEV) u Family Hepeviridae. u Genus Hepevirus. u Single-stranded, positive sense, RNA virus. u 4 different species (A to D). u Species A: causes most of the human infections. u Species C: rats, wild rodents, other mammals. u Transmission. u Waterborne: often causes outbreaks. u Foodborne: animal reservoir, especially pigs. Consumption of raw/undercooked pig liver or offal. u Person-to-person transmission: faeco-oral; transplantation. Hepatitis E u Acute hepatitis. u Commonest. u Mortality 0.07–0.6%; up to 15–25% in pregnant women (especially third trimester). u Chronic hepatitis. u Can occur in immunocompromised individuals (e.g. organ transplant recipients, haematological malignancies, advanced HIV). Course of acute hepatitis E Aggarwal R, Krawczynski K. Hepatitis E. In: Feldman M, Friedman LS, Brandt LJ (ed). Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th edition. Elsevier, 2011. Diagnosis of viral hepatitis u Clinical suspicion. u Clinical manifestations. u Epidemiology, e.g. u High-risk food. u Outbreak situation. u High-risk behaviours: e.g. sexual exposure, injection drug use. u Serology. u Commonest method for diagnosis. u Antibody detection. u Nucleic acid amplification. u PCR/RT-PCR of faeces, blood, etc. for viral DNA/RNA. Serological diagnosis u Hepatitis A. u Anti-HAV IgM: recent infection or immunization (persists 3–6 months). u Anti-HAV IgG: past infection or immunization. u Hepatitis B. u A panel of antigens and antibodies. u Hepatitis C. u Anti-HCV IgG antibodies. u Hepatitis D. u Simultaneous coinfection or superinfection with HBV. u Anti-HDV. u Hepatitis E. u IgM: recent infection. u IgG: past infection. Hepatitis B serology HBsAg Total anti-HBc IgM anti-HBc Anti-HBs – – – – Never infected or vaccinated; susceptible. + – – – Early acute infection; transient (up to 18–21 days) after vaccination. + + + – Acute infection. – + + – Acute resolving infection. – + – + Past infection; recovered; immune (protected). + + – – Chronic infection. – + – – False positive; past infection; low-level chronic infection; passive transfer to infant born to HBsAgpositive mother. – – – + Response to vaccine; immune if antibody >10 mIU/mL; passive transfer after HBIG. HBsAg HBeAg Anti-HBc IgM Anti HBc IgG Anti-HBs Interpretation = HBV infection: acute or chronic = High levels of HBV replication and infectivity = Recent HBV infection = Recovered or chronic HBV infection = Immunity to HBV infection Treatment of viral hepatitis u Supportive treatment. u Specific antiviral treatments. u HBV. u e.g. (lamivudine), entecavir, tenofovir, adefovir, telbivudine. u HCV. u Interferon-alpha + ribavirin. u Direct-acting antivirals (DAA) since 2011. >1 agent used in combination, e.g. sofosbuvir, dasabuvir, simeprevir, daclatasvir, ledipasvir, velpatasvir, voxilaprevir. u HDV: interferon-alpha, bulevirtide. u HEV: ribavirin. u Liver transplantation in fulminant liver failure. Prevention of viral hepatitis u Interruption of the routes of transmission. u Food and water hygiene, personal hygiene. Sanitation. u Injection drug users. u Prevention of nosocomial transmission (needlestick and other sharps injuries; contamination of instruments, environment, and drugs). u Prevention of sexual transmission (barrier methods). u Vaccines available for: u HAV. u HBV. u HEV (in some countries). u Post-exposure prophylaxis. u HAV. u Vaccination ± immunoglobulin. u HBV. u Hepatitis B immunoglobulin (HBIG), vaccination. Hepatitis A vaccine u Inactivated vaccine. u Single or in combination with hepatitis B vaccine. u Efficacy >90%. Hepatitis B vaccine u First generation vaccines: plasma-derived. u Current vaccines: recombinant HBsAg. u Single or in combination with other vaccines. u Part of childhood immunization programme in most countries. u Mandatory for healthcare workers. Hepatitis B post-exposure prophylaxis Centre for Health Protection. Recommendations on the postexposure management and prophylaxis of needlestick injury or mucosal contact to HBV, HCV and HIV. 2014. Available at:: http://www.chp.gov.hk/files/pdf/recommendations_on_postexposure_management_and_prophylaxis_of_needlestick_injury_or_mucosal_contact_to_hbv_hcv_and_hiv_ eng_r.pdf Hepatitis C exposure u No recommendations for post-exposure prophylaxis. u If source is positive, monitor recipient at baseline, 6 weeks, and 6 months after exposure. u Liver function. u Serology (antibody seroconversion). u RT-PCR for HCV RNA. u Early initiation of treatment if seroconverts. Hepatitis E vaccine u Recombinant viral capsid protein. u Licensed in some countries, e.g. China. HIV and AIDS In 2022: • 39.0 million [33.1 million–45.7 million] people globally were living with HIV. • 1.3 million [1 million–1.7 million] people became newly infected with HIV. • 630 000 [480 000–880 000] people died from AIDS-related illnesses. https://aidsinfo.unaids.org/ People living with HIV https://aidsinfo.unaids.org/ https://aidsinfo.unaids.org/ HIV/AIDS in Hong Kong Up to 30/6/2023: 11830 HIV cases, 2441 AIDS cases. 82% males, 18% females. https://www.aids.gov.hk/english/surveillance/cumhivaids.jpg Cumulative (1984–3/2023): Sexual = 79.8% (homosexual = 41.8%, heterosexual = 32.1%, bisexual = 5.9%) Injection drug use = 3.2% https://www.aids.gov.hk/english/surveillance/stdaids/std23q1.pdf Basic virology of HIV u Family Retroviridae. u Genus Lentivirus. u Single-stranded, positive sense, RNA virus. u Retroviruses. u RNA genome → RNA-dependent DNA polymerase (reverse transcriptase) → viral DNA. u Human immunodeficiency virus types 1 and 2. u HIV-1: global. u HIV-2: mainly in west Africa. u Cell receptor: CD4. u Co-receptors: chemokine receptors, e.g. CXCR4, CCR5, others. Transmission of HIV u Parenteral transmission through blood and body fluids (especially genital secretions). u Transfusion and transplantation. u Less common nowadays because of screening. u Sexual. u Injection drug use. u Vertical (perinatal; breastfeeding; less often congenital). u Occupational (needlestick and sharps injuries). u Risk related to the viral load in source and type/extent of injury. Immunology of HIV infection u Target cells u CD4+ helper-inducer T lymphocytes. u Also infects monocytes, macrophages, lymphoid tissues, neural cells. u Results in progressive depletion of CD4+ T cells, deterioration in adaptive immune system, especially cell-mediated immunity. u Relationship between viral load and clinical outcome and risk of transmission. u Predisposition to: u Common infections. u Opportunistic infections. u Cancer formation. Riedel S, Hobden JA, Miller S, Morse SA, Mietzner TA, Detrick B, Mitchell TG, Sakanari JA, Hotez P, Mejia R. Jawetz, Melnick, & Adelberg’s Medical Microbiology. 28th ed, 2019. McGraw Hill. Clinical presentations of HIV infection u Stages of infection. uPrimary infection. uDissemination to lymphoid organs. uLatency (2–15 years). uElevated HIV expression. uClinical disease. uDeath. u Clinical disease. uAcute (primary) HIV syndrome. u Fever, skin rash, enlarged lymph nodes, pharyngitis, myalgia, arthralgia, etc. uAsymptomatic stage. uOpportunistic infections. uDisease involvement of almost any system, e.g. nervous, cardiovascular, gastrointestinal, blood, skin, endocrine. uCancers. Acquired immunodeficiency syndrome (AIDS) u AIDS = an advanced stage of HIV infection where the immune system is severely compromised. u Without treatment, appears 8–10 years (median) after initial infection. u Definition. u Documented HIV infection + presence of AIDS-defining illness. u In some countries (e.g. USA): CD4+ cell count <200/µL. AIDS-defining illnesses (ADI) u Bacterial infections, multiple or recurrent (only among children aged <13 years) u Kaposi sarcoma u Candidiasis of bronchi, trachea, lungs, oesophagus u Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex (<13 years old) u Cervical cancer, invasive u Lymphoma, Burkitt u Coccidioidomycosis, disseminated or extrapulmonary u Lymphoma, immunoblastic u Lymphoma, primary, of brain u Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary u Cryptococcosis, extrapulmonary u Cryptosporidiosis, chronic intestinal (>1 month’s duration) u Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month u Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary u Cytomegalovirus retinitis (with loss of vision) u u Encephalopathy, HIV-related Mycobacterium, other species or unidentified species, disseminated or extrapulmonary u Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month) u Pneumocystis jirovecii pneumonia u Pneumonia, recurrent u Progressive multifocal leukoencephalopathy u Salmonella septicaemia, recurrent u Toxoplasmosis of brain, onset at age >1 month u Wasting syndrome attributed to HIV u Histoplasmosis, disseminated or extrapulmonary u Isosporiasis, chronic intestinal (>1 month’s duration) AIDS-defining illness u Example of local modification: u Talaromycosis (penicilliosis; Talaromyces (Penicillium) marneffei infection) considered to be an ADI in Southeast Asia. u Commonest ADI in Hong Kong (up to 2023 Q1) u Pneumocystis jirovecii pneumonia = 44.0% u Tuberculosis = 22.3% u Other fungal infections = 8.7% u Talaromycosis (penicillioisis) = 6.6% u Cytomegalovirus disease = 5.2% https://www.aids.gov.hk/english/surveillance/stdaids/std23q1.pdf Diagnosis of HIV infection u Culture of virus. u Not routinely performed. u Serology. u Mainly by enzyme immunoassays (EIA). u HIV-1 p24 antigen + anti-HIV antibodies (IgG + IgM) + differentiation of HIV-1 from HIV-2 (antibodies). u Nucleic acid amplification. u Not generally used for screening and initial diagnosis. u Useful for quantification of viral load. u Detection of resistance to antivirals. u Additional information. u CD4+ lymphocyte count. u Opportunistic infections. HIV self-testing u e.g. OraQuickTM. https://www.fda.gov/consumers/consumer-updates/facts-about-home-hiv-testing https://brightonsexualhealth.com/advice/oraquick-hiv-self-test-results/ Management of HIV infections u Anti-retroviral therapy (ART). u A combination of drugs (usually 3) is always necessary (highly active anti-retroviral therapy [HAART]). u Goals: u Reduce viral load, thereby reducing HIV-associated morbidity and prolongs survival. u Prevention of opportunistic infections: chemoprophylaxis. u Primary chemoprophylaxis. u Secondary chemoprophylaxis. Anti-retroviral agents Groups Examples Nucleoside reverse transcriptase Abacavir, didanosine, emtricitabine, lamivudine, inhibitors (NRTI) stavudine, zidovudine Nucleotide reverse transcriptase Tenofovir inhibitors (NtRTI) Non-nucleoside reverse transcriptase Efavirenz, etravirine, nevirapine, rilpivirine inhibitors (NNRTI) Protease inhibitors (PI) Atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir Integrase inhibitors (INSTI) Dolutegravir, elvitegravir, raltegravir, bictegravir, cabotegravir Fusion inhibitor (FI) Enfuvirtide CCR5 co-receptor antagonist Maraviroc Attachment inhibitor Fostemsavir (prodrug of temsavir) Monoclonal antibody entry inhibitor Ibalizumab Prevention of HIV infection u Behavioural modifications (e.g. sexual [barrier methods], injection drug use). u Screening of blood products and organ donors. u Prevention of mother-to-child transmission (ART treatment for pregnant women). u Infection control and occupational safety. u Post-exposure prophylaxis. u Pre-exposure prophylaxis. Risk of transmission after needlestick injury u HBV, e antigen positive up to 30% u HBV, e antigen negative 1–6% u HCV 1.8% u HIV 0.3% Further reading (ebooks available through HKU Libraries) u Ryan JY (ed). Sherris & Ryan’s Medical Microbiology. 8th edition. McGraw Hill Education, 2022. u Riedel S, Hobden JA, Miller S, Morse SA, Mietzner TA, Detrick B, Mitchell TG, Sakanari JA, Hotez P, Mejia R. Jawetz, Melnick, & Adelberg’s Medical Microbiology. 28th ed, 2019. McGraw Hill. u Levinson W, Chin-Hong P, Joyce EA, Nussbaum J, Schwartz B. Review of Medical Microbiology and Immunology: A Guide to Clinical Infectious Diseases. 17th edition. McGraw-Hill Education, 2022. u Centre for Health Protection. Recommendations on the postexposure management and prophylaxis of needlestick injury or mucosal contact to HBV, HCV and HIV. 2014. http://www.chp.gov.hk/files/pdf/recommendations_on_postexposu re_management_and_prophylaxis_of_needlestick_injury_or_mucos al_contact_to_hbv_hcv_and_hiv_eng_r.pdf