ID Clinical Case Conference 14 April, 2003

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ID Clinical Case Conference14 April, 2003

• Munshi Moyenuddin, M.D. Ph.D.
• Fellow, Infectious Diseases
• WFU Baptist Medical Center

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A 46 y/o white male with abdominal pain, nausea,
vomiting

• HIV diagnosed in 1991. No complications/ no
  medical care for 5-yrs.
• Presented on 2/28/96 with oral/esophageal
  candidiasis.
• CD4-10, VL-49,939
• Wbc-2.1, ANC-1400, Hg-11.2, plt-30, Cr-0.6,
  TB-0.9, AP-159, AST-62, Alb-3.7, ALT-21

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H P (contd)

• PMH Hospitalization- none, STD- none,
  Bronchopneumonia in 1995- treated with
  doxycycline, no h/o liver disease or jaundice
• Medications- none
• Allergies- none
• SHx- gay male, NC native, restaurant manager,
  smoker-1ppd, denied ETOH, no pets.

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Physical Exam

• Ht- 58, wt-112.5 lb, T-98, P-78, BP-114/74
• Gen- thin white male, no distress
• Skin- facial seborrhea
• HEENT- moderate oropharyngeal candidiasis
• Chest- scattered rhonchi, L-nipple ring
• Abd- unremarkable, no organomegaly
• Anorectum- external hemorrhoid
• Ext- no edema

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Labs treatment

• CMV IgG , Toxo IgG -, RPR
• Anti-HCV -, Anti-HBc ,
• Anti-HBs -, HBsAg
• Treatment started with AZT ddI, also,
  fluconazole and TMP/SMX.
• VL- 5030 in 6-months
• AZT was changed to d4T, continue ddI
• VL- 2487, crixivan was added.
• 2-years on treatment VL-100,785 CD4-90

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Treatment course

• Episode of fever with RUQ pain with gas.
• CT abdomen pelvis- no mass or stone
  low-density lesions in kidneys, likely cysts no
  liver lesion, enlargement of the portal vein with
  associated collaterals the spleen was mildly
  enlarged large hiatal hernia.
• Abd pain was resolved with antacid.
• Subsequently, no GI complaints.

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Labs and course of treatment

• Genotype- RT mutations 215, 41 PI mutations 36,
  71, 77
• Crixivan was stopped,EFV and HU were added to d4T
  and ddI (3/99)
• VL lt50, CD4-250 (8/99)
• VL remained lt50, developed peripheral neuropathy,
  ddI dose was decreased
• On 9/01 ddI HU were d/cd and 3TC was added to
  d4T and EFV
• VL remained lt50, CD4-260

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Labs treatment course

• HBV DNA 4.37 pg/ml (1 pg 150,000 copies)
• TB- 0.7, AP- 159, AST- 43, ALT 24
• VL remained lt50 and CD4 gt250
• Viread was added to 3TC, d4T, EFV (on 6/02)
• After 6-months, pt developed abd pain, nausea, wt
  loss of 9-lbs in 3-months.
• Alb- 4.2, TB- 0.8, AP- 238, AST- 61, ALT-39, Hg-
  14.1, plt- 186

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Labs (contd)

• Amylase- 103, lipase- 22, lactate- 1.3
• CD4- 220, VL- lt50
• Pt continued to work, was tolerating food, gained
  back 3-lb wt, abd pain continued
• Good compliance with meds
• Rept HBV DNA (12/02)- lt0.01 pg/ml.

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Labs (contd)

• CT abd pelvis (on 2/03)- multifocal enhancing
  masses within the R L hepatic lobes with tumor
  thrombus in the portal vein. The largest lesion
  measured about 8x8.6 cm.
• Liver bx (2/03)- hepatocellular carcinoma.

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Topics of Discussion

• Natural Course of Chr HBV infection.
• Prognosis of Chr HBV infection
• HBV Carrier State and HCC
• Aims of Treatment of Chr HBV
• Molecular Mechanisms of HBV-associated Liver
  Cancer
• Screening for HCC
• Prevention of HCC Associated with Chr Hepatitis

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Natural Course of chr. HBV inf

• Determined by the interplay between virus
  replication and the host immune response.
• Outcome depends upon the severity of liver
  disease at the time HBV replication is arrested.
• Two phases 1) Early replicative phase with
  active liver disease.
• 2) Late or nonreplicative phase with remission of
  disease.
• In perinatally acquired inf, there is an
  additional immune tolerance phase.

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Natural course of chr HBV inf

• Replicative phase Immune tolerance In the
  initial phase of perinatally acquired inf, high
  level of HBV replication without active liver
  disease (Hepatology 1992 15 770).
• This phase lasts 10 to 30 yrs with very low rate
  of HBeAg clearnce (Gastroenterology 1987 92
  1839).
• Studies found HBeAg in 90 of children lt5-yrs of
  age and in 80 of lt20 yrs of age with chr HBV.

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Natural Course of chr HBV inf

• Replicative phase Immune clearance Occurs
  during 2nd and 3rd decade of life.
• HBeAg clearance increases 10 to 20 annually.
• HBeAg seroconversion is frequently accompanied by
  increased ALT due to immune mediated lysis of
  hepatocytes (Gastroenterology 1993 105 1141).
• Exacerbation may be associated with IgM anti-HBc
  and increase in AFP.

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Natural Course of chr HBV inf

• Late or nonreplicative phase Pts are usually
  HBeAg negative and anti-HBe positive.
• May remain HBsAg positive with undetectable HBV
  DNA.
• Some pts become HBsAg negative. Annual rate of
  HBsAg clearance is 0.5 to 2 in western pts and
  0.1 to 0.8 in asian pts.
• A study of 218 pts over 62 months showed, of 189
  pts who were not cirrhotic at the time of HBsAg
  clearance, 3 developed cirrhosis and 3 developed
  hepatocellular carcinoma (2 had concurrent HCV or
  HDV) (Gastroenterology 20021231084).

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Natural Course of chr HBV inf

• Clearance of HBsAg does not preclude development
  of cirrhosis or HCC.
• In a series of 55 pts who cleared HBsAg,
  complications developed in 33 (11 HCC, 6
  cirrhosis, 1 fulminant liver failure) during a
  follow-up of 23 months (Hepatology 199828231).
• Pts may be infected with a mixture of wild-type
  virus and HBV variants with deletion in pre-S1
  region, associated with reduction in HBsAg
  synthesis (Hepatology 2000 32 116).

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Prognosis of chr HBV infection

• The estimated 5-year rates of progression in
  endemic areas are
• Chronic hepatitis to cirrhosis- 12 to 20
• Compensated cirrhosis to hepatic decompensation-
  20 to 23
• Compensated cirrhosis to hepatocellular
  carcinoma- 6 to 15
• (J Hepatol 1994 21 656 Hepatology 1995 21
  77).
• A study in chinese pts, the life-time risk of a
  liver-related death has been estimated at 40 to
  50 in men and 15 in women (Hepatology 1982 2
  215).

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Prognosis of chr HBV infection

• Pts with a prolonged replicative phase have a
  worse prognosis mostly due to cirrhosis and HCC.
• This was illustrated in a study of 98 pts with
  positive HBsAg cirrhosis (Gastroenterology
  1992103 1630).
• The 5-yr survival rate was significantly lower in
  pts with HBeAg.
• Clearance of HBeAg was associated with a 2.2-fold
  decrease in death rate.

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HBV carrier state and HCC

• A study of HBV carriers (HBsAg ) in Taiwan over
  4-yrs showed the relative risk of HCC was 223
  times that of noncarriers (Lancet 1981 2 1129).
• A prospective study of HBV carriers in North
  America showed, the incidence of new cases of HCC
  was 0.47 per year (Hepatology 1995 22 432).
• In a series of 317 HBV carrier in Canada, 16-yrs
  follow-up revealed no cases of HCC (Gastroenterol
  1994106 1000)

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HBV Carrier state and HCC

• The risk of HCC is much higher in pts who are
  HBeAg compared to those who are HBsAg but
  HBeAg (Anticancer Res 1991 11 2063 Br J
  Cancer 1996 731498 NEJM 2002347168).
• One of the largest study included 11,893
  Taiwanese men and were followed for 10-yrs, HCC
  was significantly higher in those who were both
  HBsAg HBeAg

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HBV Carrier state and HCC

• The risk of developing HCC is substantially
  greater in HBV pts who have cirrhosis.
• In one series, HCC occurred in 9 of such pts
  within a 6-yr period (Hepatology 1995 2177)
• Other hepatotrophic stimuli, such as
  environmental toxins, are likely to act
  synergistically in the multistep pathogenesis of
  HCC.

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Aims of treatment of chr HBV

• Sustained suppression of HBV replication.
• Remission of liver disease.
• The end-points to assess treatment response
  include-
• Normalization of ALT level
• Undetectable HBV DNA
• Loss of HBeAg
• Improvement of liver histology.

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Molecular Mechanisms of HBV-associated Liver
Cancer

• In cases of human HCC, integrated HBV DNA
  sequences can be found and viral proteins are
  expressed from the integrations.
• An altered expression of oncogenes and tumor
  suppressor genes is found in the HBV-infected
  liver (Oncogene 2001203674).
• Hepatitis B x (HBx) protein, encoded by many
  integrated sequences, has transactivating
  function (J Virol 1987613448).

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Molecular Mechanisms of HBV-associated Liver
Cancer

• Integration of HBV sequences often leads to
  carboxy-terminal truncation of the middle
  hepatitis B surface protein (HBs).
• This truncation yields a protein (MHBs) that can
  transactivate the transcription of a variety of
  genes (Proc Natl Acad Sci USA 1990872970).
• Overexpression of the large HBs protein can cause
  liver cancer in transgenic mice (Cell
  1989591145).

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Molecular Mechanisms of HBV-associated Liver
Cancer

• One of the transactivator sequences (HBx or
  MHBs) could be found in 81 of HBV-related HCC
  (Oncogene 199493335).
• HBx can transactivate a variety of targets
  including cellular genes and viral regulatory
  elements.
• HBx either complex with or alter the DNA binding
  of transcription factors.

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Molecular mechanism of HBV-associated liver cancer

• Mice expressing the HBx protein under authentic
  promoter control exhibited HCC development (J
  Hepatology 199931123).
• A study of immunepathogenesis of HCC demonstrated
  that continuous induction of HBV-specific T-cells
  and their migration into the liver fuels a chr
  inflammatory process which may cause
  hepatocarcinogenesis (J Exp Med 1998188341).

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Screening for HCC

• HCC may have a long asymptomatic stage lasting
  2-yrs or longer in Alaskan Eskimos (Lancet
  19822889).
• In the majority of pts, the cancer begins as a
  single tumor that is often encapsulated.
• The doubling time of HCC has been estimated to
  range from 2 to 12 months with a median of
  4-months (Gastroenterol 198589259).

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Screening for HCC

• Using alpha-fetoprotein (AFP) as a screening
  method, small HCC (tumors with a diameter of lt5
  cm) were found in 37 to 59 of pts with HCC
  (Hepatology 200032842 J Gastroenterol Hepatol
  19949361).
• Periodic screening utilizing both AFP and
  ultrasound, small tumors were detected in 57 and
  83 respectively with HCC (Hepatology
  199522432 Cancer 198556660).

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Screening for HCC

• Asymptomatic chr HBV Carrier with normal ALT and
  minimal or absent liver disease can develop HCC.
• The optimal age to initiate periodic screening is
  not known.
• The sensitivity of AFP test depends on the cutoff
  level. If a level of 20 ng/ml is used (normal
  level 8-12 ng), the sensitivity for small HCC
  ranges from 50 to 75 (Hepatology 2000 32 842).

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Screening for HCC

• AFP levels that rise in a step-like manner
  strongly suggest the presence of HCC.
• Persons with persistent mild elevation of AFP
  (lt200 ng/ml) are at higher risk of HCC than those
  with a single increased value (Hepatology
  200032842)
• Other markers that have been shown to be elevated
  in small HCC include des-gamma carboxy
  prothrombin (DCP), serum-gamma glutamyl
  transferase isoenzyme II, and alpha-L-fucosidase
  (Dig Dis Sci 199136 1787 Am J Gastroenterol
  199287991).

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Screening for HCC

• Studies suggested that DCP and AFP are
  complimentary and result in a higher sensitivity
  than either test alone (Cancer 1998821643 Am J
  Gastroenterology 199994650)
• Ultrasound (US) is more sensitive than AFP for
  small HCC.
• The combination of US and AFP appears to be
  superior to either alone (Hepatology 199522432).

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Screening for HCC

• Studies utilizing US and AFP, involving pts with
  cirrhosis due to HBV or HCV, screening every
  6-months appeared superior to yearly screening in
  the detection of small HCC.
• No difference between screening every 3 or
  6-months (Hepatology 199522432 Cancer
  199678977)
• Periodic testing can detect HCC at a resectable
  stage in gt50 of the instances.

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Screening for HCC

• Evidence suggests that carriers with low risk of
  HCC could be screened with AFP, and those at high
  risk (men gt45 yrs, cirrhosis, FHx of HCC) with
  AFP and US.
• Carriers can experience long-term survival after
  resection of small HCC.
• Screening with AFP alone has been shown to detect
  HCC early in some carriers from endemic areas.

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Prevention of HCC Associated with Chr Hepatitis

• A persistent immune responses against HBsAg are
  involved in the development of chr hepatitis
  leading to HCC.
• Studies demonstrated that Fas ligand (FasL), one
  of the major cytocidal molecules produced by CTLs
  plays an important role in the pathogenesis of
  HCC (J Immunol 1995 154 3806)
• Administration of soluble Fas that neutralizes
  FasL rescues mice from the fatal disease (J
  Immunol 19971585692).

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Prevention of HCC associated with Chr. Hepatitis

• Using an animal model of chr hepatitis that
  induces HCC, a recent study demonstrated that
  neutralization of the activity of Fas-ligand
  prevented hepatocyte apoptosis, proliferation,
  liver inflammation, and the development of HCC (J
  Exp Med 2002 1961105).

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Prevention of HCC associated with Chr Hepatitis

• The results provide a rationale for developing a
  therapy for hepatitis using anti-FasL antibody or
  inhibitors for the Fas signal transduction
  pathway.
• This is the first demonstration that amelioration
  of chr inflammation by treatment caused reduction
  of cancer development.