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ABCs of hepatitisSarah Doernberg, MD, MASAssociate Professor and Medical Director of Antimicrobial StewardshipDivision of Infectious Diseases, UCSF

Disclosures

§ Consultant: Genentech

Outline

§ Symptoms§ Hepatitis A § Hepatitis B§ Hepatitis C

Viral hepatitis manifestations

Acut

e • Fever• Fatigue• Anorexia• Nausea• Emesis• Abd pain• Clay-colored stool• Dark urine• Jaundice• Joint pain

Extra

inte

stin

al • Leukocytoclasticvasculitis

• Cryoglobulinemia• Arthritis• Optic neuritis• Transverse myelitis• Myocarditis• Aplastic anemia/red cell

aplasia• Lymphoma• Glomerulonephritis• Thyroid disease• Autoimmune

phenomena

Chr

onic • Cirrhosis

• Hepatic decompensation

• HCC


Outline: HAV

§ Epidemiology§ Pathogenesis§ Diagnosis§ Prevention

Which of these patients should receive HAV immunization?

A. A healthy 6 month-old infantB. A 25 year-old F who works at a day care centerC. A 55 year-old M who works in a burrito shopD. A 40 year-old F adopting an infant from EthiopiaE. A 33 year-old M working in a sewage treatment plant

Global HAV epidemiology, 2005

https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5507a1.htm#fig4

US HAV epidemiology

Vaccine

ACIP rec for universal pedsvaccination

https://www.cdc.gov/hepatitis/hav/havfaq.htm#general

• Recent major outbreaks among PWID and experiencing homelessness


HAV pathogenesisContamination of food, water or hands w/ HAV1. Fecal-oral2. Common source

Brief viremia

Replication in GI tract

Transported to liver (major replication site)

Shed from liver via bile to intestines

Exits body in feces

Shedding begins 2 weeks before symptoms and continues after resolution (wks to mths)

Incubation: 28 dd(15-50)

Can survive outside the body x months

https://www.cdc.gov/hepatitis/hav/havfaq.htm#generalhttps://commons.wikimedia.org/wiki/File:Uppergi.gif

HAV presentation and management

§ Self-limited, supportive care- sxs ~2 weeks

§ Kids can shed x mths§ Fulminant hepatitis rare

(<2%)- Risks: advanced age,

other liver disease

https://www.cdc.gov/hepatitis/resources/professionals/pdfs/ABCTable.pdf

0%

20%

40%

60%

80%

< 6 years 6-14 yrs > 14 yrs

Incidence of jaundice

HAV diagnosis

MMWR 2001;50[No. RR-2]; https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5304a1.htm

HAV prevention

Hyg

iene • Food/H20

precautions• Sanitation

Vacc

ine • Kids > 1 yo

• Travel• MSM• Homeless• Drug use• Clotting factors• Chronic liver dz• Adoption

Pass

ive

imm

unity • Pre-travel

• @ risk < 2wk• Can’t get

vaccine• Post exposure:

• Older age (>40!)

• Allergy• IC

https://www.cdc.gov/hepatitis/hav/havfaq.htm#general

Vaccine: lasts 20yInfection: lifelong immunity


Common HAV vaccination questions

§ Can a pt get doses from different manufacturers? Yes§ What if the second dose is delayed? Give ASAP; do not repeat dose #1. 1st

dose protects up to 10 yrs and can protect for travel§ Can it be given to immunocompromised patients? Yes§ Should I send HAV IgG before immunization? Not risky to revaccinate

immune pts but costly. Check in these groups:- Born/lived in high or intermediate endemicity regions- Those in groups w/ ↑ prevalence by ethnicity or behavior

- Adults > 40

§ Should I send serologic tests after immunization? Nohttps://www.cdc.gov/hepatitis/hav/havfaq.htm#generalhttps://www.cdc.gov/mmwr/preview/mmwrhtml/rr5507a1.htm

HAV summary

§ Spread via fecal-oral route§ No chronic phase§ Fulminant disease is rare, jaundice common§ Vaccine-preventable§ Hygiene is critical

Outline: HBV

§ Epidemiology§ Pathogenesis§ Screening, diagnosis, and test interpretation§ Treatment§ Prevention

US HBV epidemiology

• At least ~850K w/ chronic HBV in the US, may be up to 2 millionhttps://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

https://www.cdc.gov/hepatitis/hav/havfaq.htm


HBV prevalence worldwide

https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-to-travel/hepatitis-b

>350 million chronically infected2 billion have had infections

HBV transmission

§ Blood and bodily fluids (not breastmilk)- Survives outside the body x 7 days

§ Incubation: 1-4 mths§ Most common worldwide:

- Perinatal- Horizontal transmission in childhood

§ In the US:- Sex w/ infected partner- IDU

HBV natural history HBV case

§ New couple seeking care in your office

§ 39 year-old M, no medical issues

- Born in US, parents emigrated from Mongolia

- Does not know immunization history

§ 35 year-old F

- Severe RA failing therapy, rheumatologist planning rituximab

- Born in the US to US-born parents

§ No risky behaviors

B. Schwartz


Case, con’t. Which patient will you screen for HBV?

A. MaleB. FemaleC. Both patientsD. Neither patient

Who to screen (HBsAg)

§ High prevalence area- Born in regions with HBsAg prevalence ≥ 2%

- Born in US to parents from area with HBsAg prevalence ≥ 8%, if unvaccinated

- Born to HBsAg + mothers

§ High-risk activities- IDU, MSM, household contacts, sexual contacts

§ Prevention of transmission- Organ/blood/tissue donors, hemodialysis patients, pregnancy, needlestick

§ Risk of reactivation- Immunosuppression (test for HBcAb and HBsAb as well)

- HIV, HCV

Male

Female

Weinbaum CM et al. MMWR 2008; 57(RR08);1-20. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm

Acute HBV infection with recovery

Window period


Chronic HBV



HBV serologiesHBsAg HBsAb HBcAb IgM Total HBcAb HBV VL Interpretation- - - - - Susceptible

- + - - - HBV vaccinated

- + - + - “Resolved” infection

+ - + +/- +++ Acute infection

- - + +/- + Window

+ - - + ++ Chronic

+ - - +/- ++ Flare

- - - + +/- Multiple interpretations

Isolated HBcAb+

1. False positive2. Passive txsfer from maternal antibodies or IVIGàNo action

3. Resolved infection with very low-level HBsAb4. Window period/recovery fr acute infection (not yet made sAb)5. Occult chronic HBV with undetectable HBsAg

https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf

How to sort this out:• Check HBV DNAà#5 (not always +)• Repeat testing in 6 mths (addresses #2, #4)• Can also immunizeàresponse suggests #1; if not, #3

HBV reactivation

§ HBsAg+ or HBsAg- (HBcAb+)§ Inactive or resolved HBVàflare (↑ DNA and ALT)§ At risk (can also be spontaneous):

- Increased HBV replication during IS: Chemo, IS, transplants- Immune reconstitution

§ HIV+ and stop HBV antivirals§ HCV coinfection and treatment

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

Staging

B. Schwartz


Our male patient’s results

Characterize viral infection

Disease activity

Stage of disease

Comorbidities

HBV DNA: 130,000KHBeAg+, anti-HBe -

ALT > 2x ULN x 8 months

PT, Bili, Alb - wnlUltrasound: no HCC

Hep A, C, D IgG negative, HIV-, ETOH: minimal

B. Schwartz

What does that mean for our patient?

Chronic active

infection

Chronic hepatitis B infection*

Inactive carrier state

HBeAg+ HBeAg-10-20%/yr

precore mutation

• ↑ HBV DNA (> 20K)• Elevated ALT• Biopsy – inflam

• ↓ HBV DNA , (< 2K)• Normal ALT• Biopsy – no inflammation

Hepatic decompensationCirrhosis

HCC

*

* Must have HBsAg+ x 2, 6 months apart

1-5%/yr

2-5%/yr

3%/yr

0.4%/yr

B. Schwartz

Case, con’t: Which patient should receive HBV treatment?

A. MaleB. FemaleC. BothD. Neither

Treatment§ Immunological cure: Loss of HBsAg & HBV DNA suppression§ Virological cure: Currently impossible: covalently closed circular DNA

(cccDNA) still in hepatocytesàcan reactivate

Drug AE CommentsInterferon Flu-like sxs, mood, cytopenias, autoimmunity Fixed durationLamivudine Pancreatitis, lactic acidosis Risk of resistance

Telbivudine ↑CK, lactic acidosis, neuropathy

Entecavir Lactic acidosisAdefovir ARF, Fanconi sx, nephrogenic DI, lactic acidosis

Tenofovir Nephropathy, Fanconi sx, osteomalacia, lactic acidosis

Terrault NA et al. Hepatology 2016; 63(1):261-283


Which adults to treat

1. Immune-active:- HBeAg neg: HBV DNA > 2000 + (ALT > 2 ULN or +histology)

§ If not meeting criteria: Case-by-case basis- HBeAg pos: HBV DNA > 20,000

2. Cirrhosis + HBsAg3. Pregnancy + HBsAg + DNA > 2K4. Acute HBV-mediated decompensation5. Immune suppression planned- Risk-stratify by HBsAg and type of IS

Male

Female

Terrault NA et al. Hepatology 2016; 63(1):261-283

Who w/ HBV should be screened for HCC?

§ Populations:

- Asian M > 40 y/o, F > 50 y/o- Cirrhosis- Family history of HCC- Africans/African Americans > 20 y/o- Any > 40 y/o w/ persistent or intermittent ALT elevation

and/or HBV DNA > 2000

§ How to screen (similar recs for HCC screening in HCV):- Q6mth ultrasound +/- AFP- CT is not recommendedàhigh false +, radiation, cost

Heimbach JK et al. Hepatology 2018; 67(1):358-380

Prevention

§ Behavioral modification§ Immunization (recombinant HBsAg): Prevention & PEP

- Single Ag and combos available§ HBIG: 3-6 mth protection; used as PEP

- Unvaccinated or nonresponder w/ HBsAg+ exposure (+vaccine)- Infants born to HBsAg+ mothers- Certain transplant recipients

Mast EE et al. MMWR 2006; 55(16)

Who to vaccinate

§ All infants and unvaccinated kids (catch-up): w/i 24 hrs of birth§ Sexual risk: partners, STI testing, MSM, high-risk sexual behavior§ Blood/fluid risk: IDU, household contacts, HCW, incarcerated, DM§ At risk for complications: Liver disease, immunocompromised§ ESRD§ HIV§ Travelers to regions with high or intermediate levels of HBV§ Any adult seeking protection from HBV infection

Abara WA et al. Ann Intern Med. 2017;167(11):794-804.


Common HBV vaccination questions

§ Can you give doses from different manufacturers? Yes§ If you get off schedule, what do you do? Proceed with next dose, no

need to restart§ Are extra doses or giving to someone with HBV harmful? No§ Can it be given to immunocompromised patients? Yes§ How long does immunity last? > 20 years§ Should I screen for immunity before immunization? Yes, screen all

patients in high-risk groups; no need for infants/kids§ Should I send serologic tests after immunization? Only if it will change

management:

https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

• HCW• ESRD, HIV, immunocompromised

• Sexual partners• Infants of HBsAg+ moms

Case, con’t: 1 month after she completes her HBV vaccine series, your pt’s HBsAb is negative. What do you do next?

A. Recheck HBsAgB. Give 1 booster dose of the vaccineC. Give the whole series againD. Counsel her not to receive ritux

Management of vaccine nonresponse

§ If received the vaccine remotely:- Up to 60% lose detectable Ab over time (though still protected)- Challenge with 1 doseàamnestic response

§ If recent or no response above, give 2nd three-dose series- 15-25% will respond after dose #1, 30-50% after all three

§ Retest 1-2 mths later

§ If still no response:- Check HBsAg- Consider nonresponder (<5%)àPEP if exposed

https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html#diagnosis

HBV take-home

§ HBV is common worldwide; many patients should be screened

§ Vaccinate at-risk populations§ Select patients benefit from treatment


Outline: HCV

§ Epidemiology§ Pathogenesis§ Screening and diagnosis§ Treatment

- Pre-treatment evaluation- Treatment- Monitoring

HCV: A disturbing trend

• ~30,000 acute HCV annually in the US

• 2.7-3.9 million w/ chronic HCV

https://www.cdc.gov/hepatitis/statistics/2016surveillance/index.htm#tabs-6-6

HCV pathogenesis

https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm

Populations to screen

§ Ever injection drug use§ Intranasal illicit drug use§ All baby boomers (1945-1965)§ HIV+§ Before PrEP initiation§ Hemodialysis§ Incarceration§ Sxs/signs of hepatitis

§ Transplant or transfusion < 1992, clotting factors < 1987

§ Transplant from high-risk donor§ SOT donors§ HCWs§ Unregulated tattoo§ Children born to HCV+mothers

At least 1 time; Screen more frequently if risk is ongoing

https://w w w .uspreventiveserv icestaskforce.org /P age/D ocum ent/R ecom m endationS ta tem entF ina l/hepatitis-c-screen ing

https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm


https://w w w .cdc.gov/hepatitis /hcv/pdfs /hcv_graph.pdf

When to check HCV RNA:• Reexposure in HCV Ab + pt• Dx of HCV in immunocompromise• Dx of active versus cleared virus

after screening Ab• Antiviral therapy

How to test Case

§ 36M with well-controlled HIV, chronic HCV, and intermittent IV heroin abuse. His HCV has never been treated.

§ He states that he’s been clean for 8 months§ Patient wonders, “Can I qualify for one of those fancy new

hepatitis treatments that I keep hearing about?”

Bryn Boslett, MD

Who to treat?

§ Everyone with chronic HCV should be treated- Except limited life expectancy (12 mths) not reversible by treatment or

transplant

https://w w w .hcvgu ide lines.org /eva luate /w hen-w hom

What studies are necessary in pre-treatment assessment for a patient with HCV?

A. Hepatitis C genotypeB. Hepatitis C resistance testingC. FibroScan (transient elastography)D. All of the above


Things to know before starting

1) Degree of liver fibrosis2) Genotype3) History of prior treatment: Failed DAAs vs older agents4) Concomitant issues

-Comorbid conditions -Medications

Bryn Boslett, MD

What you need to know about genotypes

M essina JP e t a l. H epato logy. 2015; 61(1): 77–87.

• 7 genotypes• Many subtypes• Affects prognosis & Rx• GT1: 70% of US HCV

• 55% 1a• GT2: 15-20%• GT3: 10%

• Fibrosis progression• Remainder: Uncommon

Staging

Blood tests

• Indirect: Measure hepatic function but not extracellular matrix metabolism

• Direct: Reflex extracellular matrix turnover

Imaging

• Transient elastography (Fibroscan)

• Cross-sectional imaging not needed for staging

Biopsy

• Gold standard, rarely needed anymore

• Discordant results• Concern for

concurrent diagnosies

Case, con’t. Before initiating HCV therapy for the patient, what other information is needed?

A. Current antiretroviral therapyB. Psychiatric evaluationC. Evaluation for varicesD. At least three months of negative urine tox screens


NS5a NS5b ProteaseTarget Viral assembly and release Viral RNA polymerase Viral proteaseNaming “-asvir" “-buvir” “-previr”

Harvoni Ledipasvir SofosbuvirZepatier Elbasvir Grazoprevir

Epclusa Velpatasvir SofosbuvirMavyret Pibrentasvir Glecaprevir

Vosevi* Velpatasvir Sofosbuvir Voxilaprevir* = for treatment-experienced (including with NS5a inhibitors)

What are the options?

Kohli A et al. JAMA 2014;312(6):631-40. doi: 10.1001/jama.2014.7085.https://www.hcvguidelines.org/evaluate/resistance Bryn Boslett, MD

How to choose

1) Focus on comorbid conditions – some safety concerns2) Focus on other medications – look for interactions3) Focus on insurance requirements – what is covered4) Focus on duration and pill burden – less is more

Genotype 1

Regimen RBV? DurationGlecaprevir/Pibrentasvir (Mavyret) No 8a -12 wks

Elbasvir/Grazoprevir (Zepatier) +/-b 12 -16b wks

Ledipasvir/Sofosbuvir (Harvoni) +/-c 8d-12 wks

Velpatasvir/Sofosbuvir (Epclusa) No 12 wks

Bryn Boslett, MD; http://www.hcvguidelines.org/

a) AASLD/IDSA guidelines rec 12 wks if comp cirrhosis; 8 wks likely OK per Expedition 8 b) GT 1a needs NS5A RAS genotype à 16 wks + RBV if resistance presentc) RBV added if comp cirrhosis AND prior Peg-I/RBV failured) 8 weeks only if non-black, no HIV, HCV RNA < 6 million IU/mL

Genotype 3, including comp cirrhosis

Regimen RBV? DurationGlecaprevir/Pibrentasvir (Mavyret) No 8a-12 wks

Velpatasvir/Sofosbuvir (Epclusa) +/-b 12 wks

Bryn Boslett, MD; http://www.hcvguidelines.org/

a) AASLD/IDSA guidelines rec 12 wks if comp cirrhosis; does NOT include INF failures b) GT3 comp cirrhotic or treatment experienced, perform NS5a RAS testing: If Y93H, ribavirin recommended


Important Comorbidities

§ Renal disease- Avoid SOF for CrCL < 30- ELB/GRZ (Zepatier) or GLE/PIB (Mavyret) are ok for CrCl < 30 &

ESRD § GERD/Gastritis

- PPI not recommended with LDV or VEL (in Harvoni, Epclusa)§ Anemia

- If ribavirin-containing regimen is indicated§ HBV

- Risk for re-activation; sAg+ should be on HBV-active therapy

Bryn Boslett, MD

Most common drug interactions

§ Elbasvir/Grazoprevir (Zepatier) & Glecaprevir/Pibrentasvir(Mavyret) - Many interactions with HIV anti-retrovirals- Some contraindicated, esp ritonavir-boosted protease inhibitors

§ Ledipasvir and Velpatasvir (part of Harvoni and Epclusa) - ↓ drug levels w/ acid blocking meds (antacids, H2 blockers, PPIs)

§ Sofosbuvir with amiodarone- Black Box!

Bryn Boslett, MD

Resistance§ Resistance-associated substitutions (RAS): Amino acid change

associated with loss of antiviral susceptibility- Drug-class RAS- Drug-specific RAS

§ Associated with virologic failure§ Testing is drug-, genotype-, and treatment-history specific

- Most do not need it- GT1a: if considering Elbasvir/Grazoprevir (Zepatier)- GT3: if cirrhosis or prior IFN + Velpatasvir/sofosbuvir (Epclusa)

https://www.hcvguidelines.org/evaluate/resistance

Summary: Evaluation before therapy§ Stage fibrosis

§ Drug-drug interactions: https://www.hep-druginteractions.org/§ CBC, INR, LFTs, eGFR§ HCV GT and subtype§ NS5a RAS testing

- GT1a: if considering Zepatier- GT3: if cirrhosis or prior IFN failure + Epclusa

§ HCV RNA w/i 12 mths§ Pregnancy test if appropriate (ribavirin planned)§ If planning protease inhibitor:

- Child-Pugh scoreàcontraindicated if ≥7 or decompensated liver disease

§ HBsAg, anti-HBsAb, and anti-HBcAb- If positive, test for HBV DNAàtreat/prophylax or monitor closely, risk for reactivation

https://www.hcvguidelines.org/evaluate/monitoringBrynn Boslett, MD

https://www.hepatitis.va.gov/products/patient/sofosbuvir-simeprevir-handouts.asp

https://www.hcvguidelines.org/evaluate/monitoring


Monitoring

§ CBC, eGFR, LFTs at 4 weeks

- More frequent CBCs if on ribavirin- 10-fold ↑ in ALT without symptoms or ↑ ALT < 10-fold w/

sxsàdiscontinue

§ HCV VL at 4 weeks and 12 weeks post-treatment- If detectable at 4 weeks, recheck at 6

- Consider at 24 weeks post-treatment if at risk for failure§ If cirrhotic, needs ongoing HCC screening

§ HCV Ab may remain + àif concern for reinfection, test RNA; con’t to educate re: reinfection

https://www.hcvguidelines.org/evaluate/monitoring

Hepatitis C resources

§ https://www.hcvguidelines.org/§ https://www.hep-druginteractions.org/§ https://www.hepatitis.va.gov/products/patient/sofosbuvir-

simeprevir-handouts.asp- Up-to-date patient education handouts

§ https://www.hepatitisc.uw.edu/

HCV summary

§ The HCV epidemic is growing in the face of the opioid crisis§ Effective treatment is available now; genotype and fibrosis staging

inform treatment decisions§ Continue to monitor after treatment and educate on reinfection

Thank you!Questions?





HAV outbreaks§ 2017: Largest US outbreak since the vaccine (CA and others)§ Unusual strain usu seen in Mediterranean and S. Africa§ Disproportionately affected: Homeless and/or PWID§ Public health approach:

- Hygiene: Handwashing stations, toilet access- Vaccination campaigns State Cases Hospitalized Death

CA 688 449 (65%) 21 (3%)MI 692 564 (82%) 22 (3%)UT 146 80 (55%) 0

https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/Immunization/Hepatitis-A-Outbreak.aspxhttps://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm

HBV virus Phases of chronic HBV

Phase ALT HBV DNA

HBeAg Histology

Immune tolerant Normal ↑↑↑≥1 million

+ Minimalinflammation/fibrosis

HBeAg+ immune active

Elevated

↑↑≥20,000

+ Moderate to severe inflammation/fibrosis

Inactive Normal Low or neg<2000

Neg Minimal necroinflammation, variable fibrosis

HBeAg- immune active

Elevated

≥2000 Neg Mod to severe inflammation/fibrosis

https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/Immunization/Hepatitis-A-Outbreak.aspx


Perinatal infection course

IMMUNE TOLERANCE(10-30 years)

IMMUNE CLEARANCE

NON-REPLICATIVE PHASE

(Inactive carrier state)

HBV DNA

AST/ALT

Who not to treat and how to monitor

§ Immune-tolerant phase (except markedly abnl biopsy)§ Pregnancy + HBsAg + DNA ≤ 200K

§ Why not to treat:- May not have complications: Inactive carriers

- Not always effective- Can develop resistance- Side effects

§ Monitoring: q6 month ALT (q3 mth if recently stopped)

What to do after making dx of HCV

§ Evaluate comorbidities that accelerate disease (HAV, HIV, HBV, EtOH, obesity)

§ Reduce transmission- Drug use—no sharing paraphernalia

- Sexual counseling: Low but present risk

- Household precautions: Do not share razors or toothbrushes

https://w w w .cdc.gov/hepatitis /hcv/hcvfaq.h tm

APRI = AST to Platelet Ratio Index

§ ((AST/AST ULN)/platelet count) * 100§ > 0.7àpossible “significant fibrosis” (F2+ fibrosis)- Sn 77%, Sp 72%

§ >1.0àpossible cirrhosis (F4) - Sn 76% Sp. 72%

§ >2.0àprobable cirrhosis- Sn 46%, Sp 91%

Lin ZH et al. Hepatology. 2011.


FIB-4 (fibrosis 4)

§ (age*ALT)/(plt*√ALT)§ < 1.45 à low likelihood of advanced

fibrosis/cirrhosis- NPV 90%

§ > 3.25 à advanced fibrosis/cirrhosis- Sp 97%, PPV 65%

Sterling RK et. al. Hepatology 2006.

Direct Acting Agents

Adopted from Gane, E.J., et al. American Journal of Transplantation. 2014

“-PREVIR”GrazoprevirGlecaprevirVoxilaprevir

à “-ASVIR”Le

dipasvirVel

patasvirElb

asvirPib

rentasvir

“-BUVIR”Sofosbuvir

16 abcsofhepatitis doernberg - ucsf cme · lamivudinepancreatitis, lactic acidosis risk of...

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