What it is:"Viral hepatitis" is not one disease, it's five unrelated viruses (A, B, C, D, E) that all happen to attack the liver. The letter tells you almost nothing about severity and everything about how you catch it, whether it becomes chronic, and whether you can cure or only suppress it.
The core problem:HAV is a fecal-oral, self-limited nuisance you prevent. HBV is a blood/sexual/perinatal virus that integrates into the liver and, once chronic, you manage for life. HCV used to be the same story as HBV, but modern direct-acting antivirals (DAAs) actually cure it in 8 to 12 weeks.
What you do about it:HAV, prevent with vaccine or immune globulin, then support through it. HBV, decide who needs suppressive therapy using DNA and ALT thresholds. HCV, test everyone once, treat almost everyone who's positive, confirm cure at 12 weeks.
Ask three questions for any hepatitis virus: (1) How does it spread?(2) Does it go chronic?(3) Can you cure it or only suppress/prevent it?HAV never goes chronic, so question 3 doesn't apply, you just prevent it. HBV goes chronic and you suppress it (rarely cure). HCV goes chronic in most people but you now cure it in nearly everyone. Hold onto that grid and the whole chapter organizes itself.
Delta hepatitis (HDV) only exists as a co-infection riding along with HBV, and hepatitis E behaves like a nastier HAV. Board and practice questions live almost entirely in A, B, and C, so that's where this document lives too.
| Hepatitis A | Hepatitis B | Hepatitis C | |
|---|---|---|---|
| Route | Fecal-oral (contaminated food/water, person-to-person) | Blood, sexual contact, perinatal | Blood (injection drug use dominates), less often sexual or perinatal |
| Goes chronic? | Never.Lifelong immunity after | Yes, especially if acquired perinatally or in early childhood | Yes, in up to 85%of acute infections |
| Endpoint of disease | Full recovery, no liver damage | Cirrhosis, decompensation, hepatocellular carcinoma (HCC) | Cirrhosis (30% risk of end-stage liver disease over 10 years), HCC (1-2%/year once cirrhotic) |
| Can you cure it? | N/A, self-limited | Rarely. Nucleos(t)ide analogs suppress, don't eradicate | Yes.8-12 weeks of DAAs cures the large majority |
| Vaccine exists? | Yes (Havrix, Vaqta, Twinrix) | Yes (part of routine infant schedule) | No.High mutation rate defeats vaccine development |
HAV = prevent it. HBV = suppress it. HCV = cure it.If a question asks about a "vaccine-preventable" hepatitis with no chronic phase, it's A. If it asks about a virus you manage indefinitely with antivirals but rarely clear, it's B. If it asks about a virus with a defined cure endpoint (SVR), it's C.
The clinical behavior of each virus traces straight back to how it interacts with the hepatocyte and the immune system. Understanding this explains why HAV disappears, HBV persists, and HCV mutates its way around cure attempts (until DAAs changed the math).
HAV is a small RNA virus that replicates in hepatocytes but doesn't integrate into the genome and doesn't establish a reservoir. The immune system mounts a vigorous cytotoxic T-cell response that clears infected hepatocytes completely. That's exactly why it never becomes chronic and why one infection confers lifelong immunity, the immune system has seen the whole virus and destroyed every copy of it. The disease has three phases: an incubation period averaging 28 days(range 15-50), an acute hepatitis phase lasting around 2 months, and a convalescence period. Some patients feel unwell for up to 9 months, but nearly everyone has resolved clinically within 6 months, and most within 2.
HBV is a DNA virus, and after infecting a hepatocyte it forms a stable minichromosome (covalently closed circular DNA) that persists inside the nucleus essentially indefinitely. This is the mechanistic reason HBV can never be fully eradicated with current drugs, you can shut down replication and viral protein output, but the archived template stays put and can reactivate if immune control lapses (this is exactly why an isolated anti-HBc-positive patient who becomes immunosuppressed needs to be watched for reactivation). Liver injury in HBV is largely immune-mediated, the immune system attacking infected hepatocytes causes as much or more damage than the virus itself, which is why some patients tolerate high viral loads with minimal liver injury (immune-tolerant phase) while others with lower viral loads have brisk inflammation.
HCV is an RNA virus with an error-prone polymerase, so within a single infected person it exists as a swarm of closely related variants (quasispecies). That constant antigenic drift is why the immune system usually fails to clear it (driving the 85% chronic progression rate) and why no vaccine exists, by the time you'd mount a durable antibody response the dominant viral variant has already changed. It's also why treatment had to evolve into multi-drug DAA combinations that hit several distinct viral proteins (NS3/4A protease, NS5A, NS5B polymerase) simultaneously, hitting the virus from several angles at once closes the escape routes that monotherapy left open.
Every treatment decision in this chapter maps back to viral biology. HAV needs no antiviral because the host clears it alone. HBV drugs (nucleos(t)ide analogs) block the reverse transcriptase step so new virus can't be made, but they cannot touch the cccDNA archive, hence "suppression, not cure," and lifelong therapy. HCV DAAs hit multiple distinct steps in a single replication cycle, so resistance can't easily emerge in the short treatment course, hence "cure," not suppression.
All three acute infections can look identical on exam, and in all three, the majority of infected people don't look sick at all. That overlap is exactly why serology, not symptoms, makes the diagnosis.
| Hepatitis A | Hepatitis B | Hepatitis C | |
|---|---|---|---|
| Symptomatic? | >70% symptomatic(adults). Kids <6 usually asymptomatic | ~70% anicteric/subclinical, especially younger patients | ~70% asymptomatic even in acute infection |
| If symptomatic | Fever, jaundice, scleral icterus, hepatomegaly; less often splenomegaly, rash, arthralgia | Jaundice, dark urine, pale/clay stool, abdominal pain, fatigue, fever, chills, anorexia, pruritus | Same nonspecific picture: fatigue, anorexia, weakness, jaundice, abdominal pain, dark urine (in the ~1/3 who have any symptoms) |
| ALT/AST | Often >1000 IU/L, ALT>AST | 1000-2000 IU/L, ALT>AST | Highly variable, can reach ~1000 IU/L, ALT>AST |
| Bilirubin | Elevated, rises after the aminotransferases | Can be normal or elevated | Elevated, rises after the aminotransferases |
| Diagnostic test | IgM anti-HAV | IgM anti-HBc (+) and HBsAg (+) | HCV RNA detectable/quantifiable; antibody reactive within 12 weeks of exposure |
~70% is the magic asymptomatic figure for both HBV and HCV.That's exactly why universal screening (not symptom-triggered testing) is the strategy for both, and why so many people don't find out they're infected until decades later when cirrhosis or HCC shows up.
IgM anti-HAVis the acute-infection marker. It's detectable 5 to 10 days before symptoms even start, so by the time a patient walks in jaundiced, the test is already positive. There's no equivalent of the HBV serology maze here, IgM anti-HAV positive plus a compatible clinical picture (acute fatigue, abdominal pain, anorexia, intermittent nausea/vomiting, jaundice or transaminase elevation) is the diagnosis.
HBsAgis the most abundant of the three HBV surface antigens and appears at the onset of clinical symptoms. The single most important cutoff to memorize: HBsAg persisting past 6 monthsdefines chronic infection, and chronic infection is what carries the long-term risk of cirrhosis, decompensation, and HCC.
| HBsAg | Total anti-HBc | IgM anti-HBc | Anti-HBs | Interpretation |
|---|---|---|---|---|
| - | - | - | - | Susceptible, never exposed, never vaccinated |
| - | + | - | + | Past infection, resolved. No further management unless the patient starts immunosuppressive therapy or chemo |
| - | - | - | + | Immune from vaccination(only valid if drawn 1-2 months after the 3rd dose) |
| + | + | + | - | Acute infection |
| + | + | - | - | Chronic infection, needs further workup |
| - | + | - | Isolated core antibody.Resolved infection or false positive; if the patient is immunocompromised, check HBV DNA directly |
Think of it as three questions. HBsAg= "is virus present right now?" Anti-HBc(especially IgM) = "has the immune system ever seen this virus, and how recently?" Anti-HBs= "is the patient protected?" Vaccination only ever produces anti-HBs (never anti-HBc, because the vaccine contains no core antigen), which is exactly how you distinguish vaccine-induced immunity from immunity earned by surviving a real infection.
The workflow is two steps and the order matters. Anti-HCV antibodyis the initial screening test. If it's reactive, that only tells you the person was exposed at some point, it does not distinguish current infection from a past infection that already cleared (spontaneously or with treatment). Anyone antibody-positive needs confirmatory HCV RNAtesting to prove the virus is actually replicating right now. In acute infection, HCV RNA turns positive fast (1-2 weeks post-exposure) and climbs quickly, well before the antibody test converts (up to 12 weeks).
Universal, one-time screening: all adults ≥18, plus every pregnant patient at every pregnancy. On top of that, periodic re-testing for ongoing risk: people who inject drugs or share any drug-preparation equipment, patients on maintenance hemodialysis, sexually active MSM with HIV, and MSM starting HIV PrEP.
There is no antiviral treatment for HAV.Management is entirely supportive, and corticosteroids are specifically not recommended. Everything you actually do for HAV happens before exposure or immediately after it.
Three inactivated vaccines are licensed: Havrix, Vaqta,and Twinrix(the combination product that also contains hepatitis B surface antigen). A single dose gets ≥94% seroconversion, which is genuinely excellent for a vaccine, though the full series is still what's recommended for durable protection. Side effects are mild: injection-site soreness/warmth, headache, malaise.
Universal vaccination starts at 1 year of age. Beyond the routine schedule, vaccinate: any unvaccinated child 2-18, international travelers to countries with high or intermediate HAV endemicity (Canada, Western Europe, Japan, Australia, and New Zealand are exceptions, no higher risk than the US), MSM, people who inject or don't inject drugs, people with occupational exposure risk (research work with HAV or HAV-infected primates), anyone with chronic liver disease (including existing HBV or HCV infection), household or babysitting-level contacts of a recent international adoptee from a high/intermediate endemicity country (within 60 days of arrival), and honestly, anyone who wants immunity can get it.
People over 40, anyone immunocompromised, and anyone with chronic liver disease planning travel are specifically called out as higher-risk-for-bad-outcome groups who should be prioritized for vaccination.
Ig provides temporary passive immunity and is used when vaccination isn't an option, or alongside vaccination for extra coverage. It works best given during the incubation period, before the virus has had time to establish infection.
| Indication | Dose |
|---|---|
| Postexposure prophylaxis, or short-term preexposure prophylaxis (≤5 months) | 0.02 mL/kg IM, single dose |
| Longer-duration preexposure prophylaxis | 0.06 mL/kg IM, single dose |
HAV vaccine can be co-administered with Ig. For someone already exposed and unvaccinated, Ig is specifically indicated if they're over 40, have an underlying medical condition, if there's limited experience with the vaccine in that population, or if the vaccine is contraindicated, and combined vaccine plus Ig is often the preferred approach for the best protection. For last-minute travelers (departure in ≤2 weeks) heading to a high or intermediate-risk country who are older, immunocompromised, or have chronic liver disease, give bothIg and vaccine together.
Anaphylaxis to Ig has been reported specifically in patients with IgA deficiency. Ask about this before giving immune globulin.
Vaccination is the single most effective HBV prevention strategy and the US built a comprehensive vaccination program around it. Passive immunity via HBIGcovers postexposure situations. The goal of immunizing against HBV isn't just stopping acute illness, it's preventing the short window of viremia that leads to transmission, clinical disease, and (the part that matters most) chronic infection.
Who gets the HBV vaccine:all infants; unvaccinated adults 19-59 with diabetes (60+ at clinician discretion); sex partners of HBsAg-positive people; sexually active people not in a long-term monogamous relationship (>1 partner per 6 months); MSM; STD clinic patients; people with HIV; current or recent injection drug use; household contacts of chronic HBV, plus staff/clients of institutions for the developmentally disabled; healthcare and public-safety workers with blood exposure risk; dialysis/ESRD patients (predialysis, peritoneal, and home dialysis included); correctional facility inmates; international travelers to areas with HBsAg prevalence ≥2%; anyone with chronic HCV or chronic liver disease (alcoholic liver disease, cirrhosis, fatty liver, autoimmune hepatitis); and really, any unvaccinated adult who wants it, no specific risk factor required.
Common vaccine side effects differ slightly by product: single-antigen vaccines cause more nausea/dizziness and fever/headache, combination vaccines more fever, injection-site erythema, and vomiting. Heplisav-B's most common reactions within 7 days are injection-site pain, fatigue, and headache.
The goals of chronic HBV therapy are to suppress viral replicationand prevent progression to cirrhosis and HCC, plus prevent reactivationin patients whose infection is currently inactive. Treatment decisions weigh age, HBV DNA level, ALT level, and whether cirrhosis is already present.
Anyone with cirrhosis (compensated or decompensated) and HBV DNA >2000 IU/mL gets treated, full stop, regardless of ALT. Outside of cirrhosis, treatment criteria hinge on active disease: HBV DNA >2000 IU/mL andALT ≥2x the upper limit of normal and/or histologic evidence of liver disease (moderate or greater fibrosis on biopsy or noninvasive testing). Below those thresholds, with any detectable DNA under 2000, treatment becomes a judgment call weighing age, family history of HCC, prior HBV treatment, and extrahepatic manifestations.
Regardless of whether drug therapy is started, every chronic HBV patient should be counseled to avoid alcohol, get vaccinated against HAV if not already immune, and take steps to prevent transmission, and their sexual and household contacts should be vaccinated against HBV.
Two families of agents are approved: the immune-mediating agents, interferon-alfa and pegylated interferon-alfa, and the nucleos(t)ide analogs, lamivudine, telbivudine, adefovir, entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. None of these clear the cccDNA reservoir described above, which is exactly why HBV therapy is typically indefinite rather than a fixed course like HCV.
HCV splits into six major genotypes (numbered 1 through 6, each with lettered subtypes like 1a and 1b). In the US, genotype 1 (1a and 1b) dominates, followed by genotypes 2 and 3. Older interferon-based regimens cared enormously about genotype and duration varied wildly; modern pangenotypic DAAs have flattened a lot of that complexity, but genotype 3 and decompensated cirrhosis are still where regimen choice gets narrower.
Treatment is recommended for essentially all HCV-infected people. The only population where treatment isn't currently recommended is patients with a life expectancy under 12 months from a non-liver cause. Cure is defined as sustained virologic response (SVR), meaning HCV RNA is undetectable at least 12 weeks after finishing therapy. Patients who achieve SVR will still test antibody-positive forever (the antibody test doesn't revert), which does not mean they're immune to reinfection.
Before starting therapy, check: HCV RNA, CBC, liver function tests, INR, GFR, HIV antigen/antibody, hepatitis B serologies, and anti-HAV (so you know whether to vaccinate against A and/or B at the same visit).
Patients who are treatment-naive, have no history or suspicion of HCC, haven't had a liver transplant, and have no HIV or active HBV infection can go straight to a simplified pathway, whether or not they have compensated cirrhosis (no cirrhosis and compensated cirrhosis are treated similarly, just with more monitoring if cirrhotic):
Glecaprevir/pibrentasvir3 tablets by mouth daily with food for 8 weeks, or
Sofosbuvir/velpatasvir1 tablet by mouth daily (with or without food) for 12 weeks.
Recheck HCV RNA and LFTs 12 weeks after finishing therapyto confirm SVR and resolution of hepatic inflammation.
| Regimen | GT1a | GT1b | GT2 | GT3 | GT4 | GT5/6 |
|---|---|---|---|---|---|---|
| Glecaprevir/pibrentasvir | Yes | Yes | Yes | Yes | Yes | Yes |
| Sofosbuvir/velpatasvir | Yes | Yes | Yes | Yes* | Yes | Yes |
| Ledipasvir/sofosbuvir | Yes | Yes | No | No | Yes | Yes |
| Elbasvir/grazoprevir | No | Yes | No | No | Yes | No |
*Compensated cirrhosis with GT3 is an alternative use for sofosbuvir/velpatasvir, requiring NS5A resistance-associated substitution (RAS) testing beforehand.
Glecaprevir/pibrentasvir is pangenotypic, it's the "works everywhere" 8-week option and is why it's the default in the simplified pathway. Ledipasvir/sofosbuvir has a genotype 2/3 blind spot, don't reach for it there. Elbasvir/grazoprevir is the narrowest, useful basically only in genotype 1b and 4, and it specifically requires baseline NS5A resistance testing, if the Y93 RASis present, switch to something else.
Carbamazepine, phenobarbital, phenytoin, oxcarbazepine, rifampin, and St. John's wortare potent enzyme/transporter inducers that are expected to cause HCV treatment failurewhen combined with any DAA regimen. This is a screen-every-time interaction check, not a dose adjustment problem, these combinations should generally be avoided outright during HCV therapy.
| Product | Population / Use | Dose | Schedule |
|---|---|---|---|
| Hepatitis A vaccines | |||
| Havrix | Age 1-18 | 720 ELISA units (0.5 mL) | 2 doses, 0 and 6-12 months |
| Havrix | Age ≥19 | 1440 ELISA units (1 mL) | 2 doses, 0 and 6-12 months |
| Vaqta | Age 1-18 | 25 units (0.5 mL) | 2 doses, 0 and 6-18 months |
| Vaqta | Age ≥19 | 50 units (1 mL) | 2 doses, 0 and 6-18 months |
| Twinrix (HAV+HBV combo) | Age ≥18 | 720 ELISA units (1 mL) | 3 doses: 0, 1, 6 months |
| Twinrix, accelerated | Age ≥18 | 720 ELISA units (1 mL) | 4 doses: 0, day 7, day 21-30, + 12 months |
| Hepatitis A immune globulin (Ig) | |||
| Ig | Postexposure prophylaxis, or preexposure ≤5 months | 0.02 mL/kg IM | Single dose |
| Ig | Preexposure, longer stays | 0.06 mL/kg IM | Single dose |
| Hepatitis B chronic therapy (indefinite unless otherwise indicated) | |||
| Entecavir, tenofovir DF, tenofovir AF | Preferred nucleos(t)ide analogs, high barrier to resistance | Per renal function; once daily | |
| Lamivudine, telbivudine, adefovir | Older agents, lower barrier to resistance | Once daily | |
| Peg-interferon-alfa / interferon-alfa | Immune-mediating option, finite course | Subcutaneous, per product | |
| Hepatitis C, treatment-naive, no or compensated cirrhosis | |||
| Glecaprevir/pibrentasvir | All genotypes | 3 tablets by mouth daily, with food | 8 weeks |
| Sofosbuvir/velpatasvir | All genotypes | 1 tablet by mouth daily, with or without food | 12 weeks |
| Hepatitis C, decompensated cirrhosis (CTP B/C) | |||
| Ledipasvir/sofosbuvir | With ribavirin, per protocol | Extended course, specialist-managed | |
| Sofosbuvir/velpatasvir | With ribavirin, per protocol | Extended course, specialist-managed | |
A patient who looks "cured" on serology (HBsAg negative, anti-HBc positive, with or without anti-HBs) still has the cccDNA archive sitting in their hepatocytes. Starting immunosuppressive therapy or chemotherapy removes the immune pressure holding that archive in check, and reactivation can follow. This is exactly why the "isolated anti-HBc positive" and "resolved infection" rows of the serology table both carry the same caveat: if the patient is about to be immunosuppressed, don't just file the old labs away, check HBV DNA and reassess.
These patients have fewer safe options and more monitoring needs than the simplified treatment-naive pathway. They often need ribavirinadded to their DAA backbone, and the only regimens carried forward into this population are ledipasvir/sofosbuvirand sofosbuvir/velpatasvir. Everything else on the genotype table above assumes compensated liver function; decompensation changes the entire calculus and these patients need specialist-level, on-treatment monitoring plus continued post-treatment follow-up for their underlying liver disease.
Adherence is a crucial driver of SVR across all HCV regimens, but it's called out as especially important in genotype 1infection. Missed doses give the quasispecies swarm described above more room to select for resistant variants across a short treatment window, so counseling on strict daily dosing (with food when required) is not optional patient education, it's part of the cure strategy.
| Parameter | When | Watching for |
|---|---|---|
| ALT/AST, bilirubin | At presentation for any acute hepatitis, then trended | Severity and trajectory of hepatocellular injury |
| HBsAg | At diagnosis, then at 6 months | Persistence past 6 months confirms chronic HBV infection |
| HBV DNA, ALT | Periodically in chronic HBV, more often if untreated but active | Whether treatment criteria are newly met (DNA >2000 IU/mL with ALT ≥2x ULN, or any cirrhosis) |
| HCV RNA | To confirm active infection after a positive antibody test; again 12 weeks after finishing therapy | Current infection vs past cleared infection; SVR (cure) confirmation |
| LFTs | 12 weeks post-HCV therapy, alongside HCV RNA | Resolution of hepatic inflammation, confirms the cure is "real" clinically, not just virologically |
| HIV Ag/Ab, HBV serologies, anti-HAV | Baseline, before starting HCV therapy | Coinfections that change regimen eligibility; gaps in HAV/HBV immunity to close with vaccination |