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Mortality trends in HIV: HIV Outpatient Study (HOPS) . Palella FJ et al. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; Abstract 872.. The big picture of hepatitis. Damage to liver cells caused by inflammation or cell deathCan be caused by infections, drug toxicity, poisoning, biliary tract obstructionIf persists, can lead to progressive scarring of the liver (cirrhosis) and end-stage liver dysfunction.
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1. Hepatitis and HIV Co-Infection Sandra G. Gompf, MD, FACP, FIDSA
Associate Professor, Infectious Diseases and International Medicine
University of South Florida College of Medicine
2. Mortality trends in HIV: HIV Outpatient Study (HOPS) The HIV Outpatient Study (HOPS) included 5561 participants treated at 2 public, 4 university, and 2 private clinics from 1996 to 2002.1 Rates of death due to nonopportunistic causes and nonopportunistic illnesses contributing to death (as a percentage of all deaths) were calculated. Nonopportunistic illnesses were categorized based on disease, including pulmonary, hepatic, renal, and cardiovascular. Patients were followed for a median of 35.3 months.
Overall death and opportunistic infection rates remained low through the seventh year of highly prevalent HAART usage in the HOPS; the proportion of deaths attributable to nonopportunistic illness increased and was positively associated with the number of years having received antiretroviral therapy (ART). Of 473 deaths included in this analysis, the proportion of all primary and secondary causes of deaths that were nonopportunistic illnesses increased over time from 45.7% in 1996 to 71.7% in 2002 (P <.0001 for trend). For the calendar years 2000, 2001, and 2002, the most frequent nonopportunistic illnesses cited as contributing to death, as a percentage of all deaths in this 3-year period were: hepatic (35.6%), pulmonary (22.7%), cardiovascular (17.2%), and renal (9.8%).
Reference
1. Palella FJ, Baker R, Moorman AC, Chmiel J, Wood K, Holmberg SD, and the HOPS Investigators. Mortality and morbidity in the HAART era: changing causes of death and disease in the HIV Outpatient Study. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; February 8-11, 2004; San Francisco, Calif. Abstract 872.
The HIV Outpatient Study (HOPS) included 5561 participants treated at 2 public, 4 university, and 2 private clinics from 1996 to 2002.1 Rates of death due to nonopportunistic causes and nonopportunistic illnesses contributing to death (as a percentage of all deaths) were calculated. Nonopportunistic illnesses were categorized based on disease, including pulmonary, hepatic, renal, and cardiovascular. Patients were followed for a median of 35.3 months.
Overall death and opportunistic infection rates remained low through the seventh year of highly prevalent HAART usage in the HOPS; the proportion of deaths attributable to nonopportunistic illness increased and was positively associated with the number of years having received antiretroviral therapy (ART). Of 473 deaths included in this analysis, the proportion of all primary and secondary causes of deaths that were nonopportunistic illnesses increased over time from 45.7% in 1996 to 71.7% in 2002 (P <.0001 for trend). For the calendar years 2000, 2001, and 2002, the most frequent nonopportunistic illnesses cited as contributing to death, as a percentage of all deaths in this 3-year period were: hepatic (35.6%), pulmonary (22.7%), cardiovascular (17.2%), and renal (9.8%).
Reference
1. Palella FJ, Baker R, Moorman AC, Chmiel J, Wood K, Holmberg SD, and the HOPS Investigators. Mortality and morbidity in the HAART era: changing causes of death and disease in the HIV Outpatient Study. Presented at: 11th Conference on Retroviruses and Opportunistic Infections, 2004; February 8-11, 2004; San Francisco, Calif. Abstract 872.
3. The big picture of hepatitis Damage to liver cells caused by inflammation or cell death
Can be caused by infections, drug toxicity, poisoning, biliary tract obstruction
If persists, can lead to progressive scarring of the liver (cirrhosis) and end-stage liver dysfunction
4. Causes of hepatitis in the HIV + patient Drugs
HAART
Metabolic complications
Treatment of opportunistic infection
Viral pathogens
Hepatitis A, B, C
CMV
Overlap is common HAART-older PIs
Metabolic complications-mitochondrial dysfunction
Treatment of opportunistic infection-azole antifungalsHAART-older PIs
Metabolic complications-mitochondrial dysfunction
Treatment of opportunistic infection-azole antifungals
5. Drug-induced hepatotoxicity, besides HAART trimethoprim-sulfamethoxazole, antituberculars, azole antifungals
anabolic steroids
acetaminophen
statins & fibrates
6. HAART-induced hepatotoxicity Elevated transaminases mostly with PIs, but also w/ NNRTIs
May be related to “hyperimmunity” or “immune restoration syndrome”
Often subsides over several months
HIV/HCV+ are 3-5-fold more likely to develop severe transaminitis
7. Viral Hepatitis in HIV + patients Acute viral hepatitis be severe or fatal
Acute viral hepatitis can add to liver damage already present from other causes
E.g. Acute hepatitis A on chronic hepatitis C may be deadly
8. Viral Hepatitis Overview
9. GBV-C infection: the role ofHepatitis G may reduce mortality in late HIV
may reduce HIV viral loads
10. Hepatitis A & HIV, in brief role seems significant
35 HIV+ with acute HAV
80% treatment interrupted X ~ 2 months
25% lost efficacy on resuming HAART
safe, effective VACCINE available
11. Hepatitis C Transmitted via IVDU/blood, less often sex (more likely for MSM)
In U.S., 4 million HCV+ ? 85% chronic
If chronic ? 20% cirrhotic @ 20 years
Once cirrhotic ? 25% hepatocellular CA
(0.5% of total HCV+)
Alcohol & HIV worsen prognosis
Usually no symptoms
sometimes fatigue, RUQ ache, difficulty concentrating
12. Hepatitis C 6 Genotypes
1, 2, & 3 are commonest in US/W Europe
~75% Genotype 1
~25% “Non-1”
Most are 2 & 3
4 occurs less often
African Americans less likely to have sustained response to treatment
SVR 28% AA vs. 52% Cauc
13. Hepatitis C Like HIV, antigenic variation occurs
? Hepatitis C antibody is not protective
? no vaccine
Unlike HIV & HBV, does not integrate into the host genome
? eradication is possible / more likely with treatment
14. Sources of Infection for Persons with Hepatitis C 30-50% HIV+ have chronic HCV
HIV/HCV:
IVDU 90%
hemophilia 8%
MSM 4-8%
Sexual/household exposure to HCV+ contact
Sexual transmission in monogamous couples ~ 1-5%
razors
Multiple sex partners
Sexual practices that may damage mucosa
Birth to HCV-infected mother
Acute maternal infection during pregnancy
Vietnam-era veterans (~7% vs. 2% general US pop.)Sexual/household exposure to HCV+ contact
Sexual transmission in monogamous couples ~ 1-5%
razors
Multiple sex partners
Sexual practices that may damage mucosa
Birth to HCV-infected mother
Acute maternal infection during pregnancy
Vietnam-era veterans (~7% vs. 2% general US pop.)
15. Sources of Infection for Persons with Hepatitis C Sexual/household exposure to HCV+ contact
Sexual transmission in monogamous couples ~ 1-5%
Razors
Multiple sex partners
Sexual practices that may damage mucosa
Birth to HCV-infected mother
Acute maternal infection during pregnancy
Vietnam-era veterans (~7% vs. 2% general US pop.) Sexual/household exposure to HCV+ contact
Sexual transmission in monogamous couples ~ 1-5%
razors
Multiple sex partners
Sexual practices that may damage mucosa
Birth to HCV-infected mother
Acute maternal infection during pregnancy
Vietnam-era veterans (~7% vs. 2% general US pop.)Sexual/household exposure to HCV+ contact
Sexual transmission in monogamous couples ~ 1-5%
razors
Multiple sex partners
Sexual practices that may damage mucosa
Birth to HCV-infected mother
Acute maternal infection during pregnancy
Vietnam-era veterans (~7% vs. 2% general US pop.)
16. HIV/HCV Co-infection is associated with Rapid Progression to Cirrhosis Soto, et al. J Hepat 1997
compared 547 HIV- with 116 HIV+
all with chronic hepatitis C
Incidence of cirrhosis
HIV-
2.6% (mean HCV duration 23.2 years)
HIV+
14.9% (mean HCV duration 6.9 years)
17. Other interactions between Hepatitis C & HIV chronic HCV is more likely in advanced HIV (low CD4 & high HIV viral load)
high HCV viral load predicts progression to AIDS regardless of HIV viral load
chronic HCV blunts CD4 response to HAART
cirrhosis suppresses immunity
May affect total CD4
18. Diagnosing HCV in HIV Do not rely on transaminases! There is no correlation between transaminase levels and disease severity.
HCV ELISA antibody screening
+Antibody means “infected at some point”, need to determine if active or chronic infection
in advanced HIV, may be falsely negative
HCV RNA PCR confirms or excludes active disease
+Viral load means “active hepatitis”
19. Diagnosing HCV in HIV HCV ELISA antibody (low-threshold, sensitive)
If + (or advanced HIV)? HCV RNA quantitative PCR.
If HCV ELISA or RNA PCR -, no further intervention.
If HCV RNA PCR + ? active hepatitis is present…
20. Doc, I have chronic hepatitis, now what? STOP ALL ETHANOL
Genotyping is helpful in predicting response to therapy
1 is more refractory to treatment
Non-1 are very responsive
Rule out other causes of liver disease if liver enzymes are abnormal
Autoimmune hepatitis, biliary disease, hemochromatosis
21. Look for complications of chronic hepatitis Liver biopsy? Gold standard in evaluating hepatitis and cirrhosis—how “close” to cirrhosis is your patient?
1% serious bleed
Fibrosure™(blood) & Fibroscan ™ (liver stiffness) not validated in HIV yet, but non-invasive measures of fibrosis
Sonogram – screen for other liver disease, CA
Alpha-fetoprotein alone is not enough to screen out CA
FIBROSURE™ uses a combination of six serum biochemical markers plus age and gender in a patented algorithm to determine the degree of liver fibrosis and the level of ongoing necroinflammatory activity. BioPredictive is currently researching clinical use of this test for other disease populations, including hepatitis B, HIV-HCV, and alcoholic and non-alcoholic steato hepatitis (NASH).
FIBROSCAN ™ (transient elastography) measures liver stiffness & correlates w/ fibrosis.FIBROSURE™ uses a combination of six serum biochemical markers plus age and gender in a patented algorithm to determine the degree of liver fibrosis and the level of ongoing necroinflammatory activity. BioPredictive is currently researching clinical use of this test for other disease populations, including hepatitis B, HIV-HCV, and alcoholic and non-alcoholic steato hepatitis (NASH).
FIBROSCAN ™ (transient elastography) measures liver stiffness & correlates w/ fibrosis.
22. Look for complications of chronic hepatitis Extra-hepatic manifestations of Hepatitis C
Mixed cryoglobulinemia (rash, joint pain)
Membranous glomerulonephritis (proteinuria)
These may be reasons to treat BUT:
extrahepatic manifestations may differ in HIV-HCV
may or may not improve
23. Talking to your patient: Benefits & goals of treating chronic hepatitis C in HIV Viral eradication (“sustained viral remission”, SVR)
Delay progression of fibrosis
Prevent/delay bad clinical outcomes of cirrhosis
Liver decompensation
Hepatocellular carcinoma
Death
Improve tolerance and effectiveness of HAART
Allows aggressive antiretroviral drug therapy
Enhance immune reconstitution?
24. Note bene:Which hepatitis drugs are which?? PEG aINF 2b
Schering-Plough
PEG-Intron A ™
ribavirin (Rebetol™)
PEG aINF 2a
Roche
Pegasys™
ribavirin (Copegus™) lamivudine
Epivir-HBV™, 50mg
Epivir™, 150mg (HIV)
adefovir, Hepsera™
entecavir, Baraclude™
telbivudine, Tyzeka™ Schering’s interferon, entecavir, adefovir, & telbivudine not indicated in HIV
Those highlighted in red are rx that are FDA approved for use in HIV
Schering’s interferon, entecavir, adefovir, & telbivudine not indicated in HIV
Those highlighted in red are rx that are FDA approved for use in HIV
25. Talking to your patient: Benefits & goals of treating chronic hepatitis C in HIV In studies, sustained viral remission w/ newer treatments: PEG ?IFN + ribavirin
Genotype 1 & 4 (~ 30 - 70 % SVR)
Genotype 2 & 3 (>80% SVR)
HIV disease is not worsened by ?IFN or ribavirin
26. Talking to your patient: Risks, problems, & adverse effects of treating chronic hepatitis C in HIV
There’s still more to talk about…..
27. Hepatitis C Treatment Toxicities Pegylated aINF 2a or 2b
flu-like symptoms
depression/suicidal
fatigue, dizziness
anorexia, nausea/diarrhea
bone marrow suppression
immune suppression, infection
autoimmune disease
thyroid, diabetes
hair loss, oral ulcers
pulmonary fibrosis
Ribavirin
anemia/hemolysis
dose dependent
2.5-3g ? within 4 weeks
erythopoietin
bone marrow depression
embryocidal / Category X
teratogenic for up to 6 months after treatment
FDA Ribavirin Pregnancy Registry
28. Talking to your patient: Whom NOT to treat Major contraindications:
pregnant or planning to be
untreated/severe depression or psych disease
significant ischemic cardiovascular disease
decompensated cirrhosis before/during treatment
hemoglobinopathies (thalassemia/sickle cell)
significant asthma, lung disease
malignancy
end-stage renal disease
29. Talking to your patient: Whom to delay or re-consider treating Relative contraindications:
untreated depression or psych disease
“street” drug or ethanol abuse
uncontrolled diabetes or thyroid disease
seizure disorders
infections
poor ADHERENCE (predicts poor adherence to treatment, BIRTH CONTROL, follow-up visits)
30. Talking to your patient: Best odds and best reasons to treat Stable HIV disease with intact immune function
(to eradicate virus, delay cirrhosis/CA)
Advanced hepatic fibrosis
(to delay cirrhosis/CA)
Starting HAART
(to limit HAART interruptions & improve response )
31. Talking with your patient: Which to treat first? HIV or HCV? CD4 < 350 ? treat HIV
Higher risk of HIV morbidity/mortality
Lower HCV response to tx
CD4 > 350 ? treat HCV
HCV response is better @ higher CD4s
lower pressure to start HAART
possibly avoid HAART interruptions due to hepatotoxicity
32. Talking to your patient: Other Issues ex-IVDU & needle aversions…
“Needle fixation”
Ritual of injecting
Injection = euphoric experience
Risk of recidivism
33. Ribavirin interacts with HAART
34. Other HAART considerations with Hepatitis C
35. Treatment of HCV in HIV+ PEG aINF 2a (fixed 180 mcg) or 2b (wgt-based) subcutaneously every week X 48 weeks
+
Ribavirin 800mg PO daily (up to 1200mg for genotype 1 or 4) X 48 weeks
If HCV undetectable @ 12 weeks ? continue
if not, D/C
If HCV undetectable @ 48 weeks ? repeat @ 72 weeks
if still undetectable ? SVR!!
36. Prescreening and Monitoring during Treatment Prescreening tests:
serum or urine ß HCG
serum TSH
serum ANA
iron, ferritin
HAV & HBV serology
CBC & differential
PT, PTT
fasting blood glucose, lytes, creatinine, liver enzymes
Monitoring:
Monthly
CBC & diff (& @ 2 weeks of start)
lytes, FBS, creatinine, liver enzymes
serum or urine ß HCG
@ 12, 48, & 72 weeks
HCV RNA PCR
Every 12 weeks
serum TSH
37. Managing adverse effects Avoid dose reductions where possible
Moderate depression – MH care, reduce PEG; D/C if severe or suicidal
Neutropenia & thrombocytopenia
G-CSF 300 mcg SC TIW to keep ANC > 750
ANC < 750: reduce PEG
ANC > 750: hold PEG, resume at lower dose once over 750
PLT < 50K: reduce PEG; at < 25K, D/C PEG
Anemia
Erythropoietin alfa 40K IU SC weekly if Hgb <12 mg/dL
Reduce RBV if Hgb <10 mg/dL, D/C if < 8 mg/dL
38. The future of HIV/HCV? Longer courses of pegylated INF + ribavirin
72 weeks
maximum ribavirin dose
Improved SVR, reduced relapse
AST-to-platelet ratio index (APRI) may prove useful as a non-invasive marker for fibrosis
39. Key points about HCV/HIV
40. Hepatitis B Hepatitis B
sex, perinatal, IVDU, blood
>300,000/year in U.S.
Only 25% symptomatic: acute jaundice, elevated liver enzymes, fatigue, NVD
Lifetime risk up to 100% if risks (avg U.S. 5%)
10% become chronic ? cirrhosis/CA in 20-30 yrs
Ethanol, HIV, other hepatitis viruses
Over 1 million have chronic HBV in US
Relative risk of HBV from needle stick in HCW is 30%, vs. HIV 3%
Over 1 million have chronic HBV in US
Relative risk of HBV from needle stick in HCW is 30%, vs. HIV 3%
41. Hepatitis B & HIV acute HBV may be more severe
~10% of HIV+
5-6x > chronicity than HBV+
impaired cell-mediated immunity can cause chronicity
HIV/HBV 19x > liver deaths than HBV+
8x > liver deaths than HIV+
42. Hepatitis B & HIV 7 genotypes (data evolving)
A commonest in HIV/HBV/U.S.– 75%
may respond best
G least common – 25%
marker of rapid fibrosis
efavirenz exposure
duration of HIV Chronic hepatitis B does not change mortality
Chronic hepatitis B does not change mortality
43. Serology & Mutations in Chronic HBV HBsAg HBsAb HBeAg HBV DNA
+ - +* +
*Pre-core protein/core promoter mutation
don’t express HBeAg, DNA ??
severe inflammation ?cirrhosis
longer duration of disease?older
more resistant to therapy
non-A genotypes, Asia/Europe Mutations prevents expression of eAg, poorer immune control/greater inflammatory responseMutations prevents expression of eAg, poorer immune control/greater inflammatory response
44. Serology & Mutations in Chronic HBV YMDD mutation = lamivudine resistance
1000x rise in resistance
Up to 90% resistance @ 4 years lamivudine
Mutations in RT region of HBV DNA pol
YMDD motif = tyrosine, methionine, aspartic acid, aspartic acid
2 forms: M ? valine or M ? isoleucine
45. Hepatitis B & HIV: “Occult” HBV Isolated HBcAb + and DNA low level +:
HBsAg HBsAb HBV DNA
- - +
commoner in HIV+ Chronic hepatitis B does not change mortality
Chronic hepatitis B does not change mortality
46. Hepatitis B & HIV: “Occult” HBV may account for acute flare in:
HAART initiation/immune reconstitution
With immune suppression (CD4? or chemo-therapy)
Should get HBV vaccine
Poor anamnestic response
Chronic hepatitis B does not change mortality
Chronic hepatitis B does not change mortality
47. Therapies for Chronic HBV in HIV+ First line:
lamivudine (Epivir™)—NOT Epivir-HBV™
emtricitabine (Emtriva™, off-label for HBV)
inhibit HBV DNA pol
YMDD resistance with lamivudine
15% @ 1 yr
30-40% @ 2 yr
70-90% @ 4 yrs
emtricitabine is equivalent, delayed resistance/may overcome YMDD
48. Therapies for Chronic HBV in HIV+ Unlike HAART, combination therapy is no better than sequential monotherapy in HBV
lamivudine = tenofovir/lamivudine
sequencing or combo depends on HIV & HAART
49. Therapies for Chronic HBV in HIV+ Second line: interferon
PEG aINF 2a x 48 wk
~30% SVR
Roche, 1st PEG FDA approved for HIV/HBV, 2005
Schering PEG aINF 2b used off-label?, more data for HIV/HCV but not HIV/HBV
50. Therapies for Chronic HBV in HIV:Other agents? adefovir (Hepsera™) –NO
dosing for HBV is too low to suppress HIV
promotes tenofovir resistance
entecavir (Baraclude™)–CAUTION
may be associated with M184V (FDA MedWatch 2/2007) Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
51. Therapies for Chronic HBV in HIV:Other agents? telbivudine (Tyzeka™)—maybe??
nucleoside analog
alternative to lamivudine, tenofovir pre-HAART?
may have additive benefit with other agents—combination therapy?
no HIV-1 activity, no apparent NRTI antagonism in vitro
but no data in HIV+ Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
52. When to treat & with what Ready for HAART?
lamivudine & emtricitabine/tenofovir backbones
indefinite tx
FLARES with stopping meds or onset of YMDD resistance — USE CAUTION Not ready for HAART?
Consider PEG aINF 2a + ribavirin x 48 weeks
advanced fibrosis
HIV/HBV/HCV
improves fibrosis
may clear virus
Consider earlier HAART w/ HBV-active agents… Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
53. Earlier HAART…? 79 HBsAg+ (39 also HBeAg+)
37% lamivudine experienced
58% lamivudine & tenofovir experienced
Followed on HAART that included HBV agents
@ 52 wks, undetectable HBV PCR was most likely in those with greater CD4 increases & undetectable HIV ? will starting HAART earlier be beneficial? Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
Famciclovir
-modest to good HBV DNA suppression
-improvement in ALT/histology is more significant
-may achieve HBeAg - in 40%
-better in combo w/ lamivudine
-possible consideration in future
54. Treatment options for lamivudine-resistant HBV (YMDD mutants) emtricitabine may still work in YMDD+
tenofovir (off-label for HBV)
entecavir with caution?
telbivudine??
consider PEG aINF 2a + ribavirin
expectant management
55. What about the patient with end-stage liver disease? Liver transplantation may be a viable option in selected HIV+ individuals
Experimental, outcomes ~ non-HIV+
good HIV control
good adherence/compliance
HCV recurrence is common in new liver
Re-treatment may need to be longer In recent years, several research teams have found that outcomes of liver transplantation in HIV positive patients are nearly as good as those in HIV negative people. However, in HIV positive and negative individuals alike, HCV infection typically recurs in the new liver following the procedure.
In recent years, several research teams have found that outcomes of liver transplantation in HIV positive patients are nearly as good as those in HIV negative people. However, in HIV positive and negative individuals alike, HCV infection typically recurs in the new liver following the procedure.
56. Hepatitis A, B, C & HIV Prevention is KEY
Screen & vaccinate early
Lower CD4s will lower antibody response
CD4 < 200 ~15-40% antibody
CD4 >500 ~ 90% antibody
Counsel about risk factors
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