ID Clinical Case Conference14 April, 2003 Munshi Moyenuddin, M.D. Ph.D. Fellow, Infectious Diseases WFU Baptist Medical Center
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
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.
Physical Exam • Ht- 5’8’’, 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
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
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.
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 <50, CD4-250 (8/99) • VL remained <50, 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 <50, CD4-260
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 <50 and CD4 >250 • 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
Labs (contd) • Amylase- 103, lipase- 22, lactate- 1.3 • CD4- 220, VL- <50 • Pt continued to work, was tolerating food, gained back 3-lb wt, abd pain continued • Good compliance with meds • Rept HBV DNA (12/02)- <0.01 pg/ml.
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.
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
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.
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 <5-yrs of age and in 80% of <20 yrs of age with chr HBV.
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.
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 2002;123:1084).
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 1998;28:231). • 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).
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).
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 1992;103: 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.
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 1994;106 : 1000)
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; 73:1498; NEJM 2002;347:168). • 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 +
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; 21:77) • Other hepatotrophic stimuli, such as environmental toxins, are likely to act synergistically in the multistep pathogenesis of HCC.
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.
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 2001;20:3674). • Hepatitis B x (HBx) protein, encoded by many integrated sequences, has transactivating function (J Virol 1987;61:3448).
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 1990;87:2970). • Overexpression of the large HBs protein can cause liver cancer in transgenic mice (Cell 1989;59:1145).
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 1994;9:3335). • 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.
Molecular mechanism of HBV-associated liver cancer • Mice expressing the HBx protein under authentic promoter control exhibited HCC development (J Hepatology 1999;31:123). • 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 1998;188:341).
Screening for HCC • HCC may have a long asymptomatic stage lasting 2-yrs or longer in Alaskan Eskimos (Lancet 1982;2:889). • 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 1985;89:259).
Screening for HCC • Using alpha-fetoprotein (AFP) as a screening method, small HCC (tumors with a diameter of <5 cm) were found in 37 to 59% of pts with HCC (Hepatology 2000;32:842; J Gastroenterol Hepatol 1994;9:361). • Periodic screening utilizing both AFP and ultrasound, small tumors were detected in 57 and 83% respectively with HCC (Hepatology 1995;22:432; Cancer 1985;56:660).
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).
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 (<200 ng/ml) are at higher risk of HCC than those with a single increased value (Hepatology 2000;32:842) • 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 1991;36: 1787; Am J Gastroenterol 1992;87:991).
Screening for HCC • Studies suggested that DCP and AFP are complimentary and result in a higher sensitivity than either test alone (Cancer 1998;82:1643; Am J Gastroenterology 1999;94:650) • Ultrasound (US) is more sensitive than AFP for small HCC. • The combination of US and AFP appears to be superior to either alone (Hepatology 1995:22:432).
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 1995;22:432; Cancer 1996;78:977) • Periodic testing can detect HCC at a resectable stage in >50% of the instances.
Screening for HCC • Evidence suggests that carriers with low risk of HCC could be screened with AFP, and those at high risk (men >45 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.
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 1997;158:5692).
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; 196:1105).
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.