Hepatocellular carcinoma in a patient with human immunodeficiency virus and hepatitis B virus coinfection: an emerging problem?

Abstract: Infections with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) have similar risk factors and routes of transmission. It is estimated that 64 to 84% of HIV-infected individuals have positive markers for anti-HBc antibodies, with the chronic HBV infection rate approaching 16%. There is, however, a paucity of information on HBV/HIV coinfection, and its clinical implications remain unclear. We review the literature and report our recent experience with a 44-year-old man with HBV/HIV coinfection who developed metastatic hepatocellular carcinoma despite quiescent HBV and HIV disease courses. Highly active antiretroviral therapy has revolutionized HIV disease. As a result, morbidity and mortality from other underlying chronic, non-HIV-related diseases, such as the HBV infection and hepatocellular carcinoma reported here, will likely continue to increase in the HIV-infected patient population.

Key Words: coinfection, hepatitis B virus, hepatocellular carcinoma, human immunodeficiency virus

**********

The World Health Organization estimates that 400 million people worldwide are hepatitis B virus (HBV) carriers and that 1.25 million people have chronic HBV infection in the United States. (1-3) Infections with HBV and human immunodeficiency virus (HIV) have similar risk factors and routes of transmission. Among HIV-infected patients, 64 to 84% are known to have positive markers for anti-HBc antibodies, (4,5) and the rate of chronic HBV infection is approximately 16% in HIV-infected patients. (6) The interaction between HBV and HIV is complex and its implications remain unclear. There have been reports that demonstrate a more rapid progression of HIV disease in these coinfected patients, whereas others do not detect such progression. (7-9) In addition, there appears to be mounting evidence for a prolonged period of a high rate of viral replication in HBV carriers who are HIV-infected, although it is not yet known how this translates into a risk of developing HBV-associated complications such as hepatocellular carcinoma. (9)

Hepatocellular carcinoma (HCC) is a highly malignant tumor, and HBV chronic carriers have a 100- to 233-fold increased risk of developing HCC. (10,11) Although there is clear evidence that HCC occurs after a shorter period of hepatitis C virus (HCV) infection and at a younger age in HCV/HIV coinfected patients, (12) there is a paucity of information on HBV/HIV coinfection as it relates to HCC. Immunodeficiency-associated tumors such as Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer are virus-induced or at least virus-related. Many have hypothesized that HIV may act as a cofactor in accelerating the development of HBV-associated HCC, but there have been no reports demonstrating a greater risk of HCC in this subgroup of patients. (13-16)

Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of HIV disease. Opportunistic infections and the progression to acquired immunodeficiency syndrome (AIDS) have markedly declined with the widespread use of HAART. Consequently, other underlying chronic diseases, such as viral hepatitis, are now playing an increasing role in morbidity and mortality of HIV-infected patients. For example, Martin-Carbonero et al (17) recently reported that chronic viral liver disease represented 45% of the causes of in-hospital deaths among HIV-infected individuals. We recently encountered a patient with HBV/HIV coinfection who developed metastatic HCC despite quiescent HBV and HIV disease courses.

Case Report

A 44-year-old man presented to his primary physician with a 3-month history of flu-like symptoms, fatigue, chills, low-grade fevers, and a right-sided fullness and pain. He also complained of a 20-lb weight loss. Nausea and vomiting were experienced without hematemesis, dysphagia, odynophagia, or early satiety. He reported occasional loose stools but denied melena, hematochezia, and steatorrhea. Medical history was significant for HIV disease since 1984 but without an AIDS-defining illness. The polymerase chain reaction HIV-RNA tests had shown undetectable levels for over 4 years and his CD4 count had been consistently over 300 cells/[micro]L (normal, 237-1,130 cells/[micro]L). HBV was diagnosed a few years before the HIV diagnosis. Hepatitis B surface antigen was positive but the HBV-DNA was negative, consistent with an inactive carrier state, for as far back as 7 years. HCV antibody was negative and the liver function tests had also remained normal.

Initial physical examination by the primary care physician revealed a large, hard, palpable liver. A computed tomographic scan was obtained that showed major abnormalities; there was a large heterogeneous mass measuring 6 cm that appeared to be originating from the posterior wall of the duodenum (Fig. 1A). Furthermore, diffuse foci of decreased attenuation were noted within the liver, with the largest lesion measuring 5.5 cm (Fig. 1B). His vital signs were unremarkable during our consultation, and the physical examination was notable for marked hepatomegaly with liver edge palpable approximately 9 cm below the costophrenic angle. There was no evidence of jaundice, ascites, peripheral edema, spider angiomata, asterixis, palmar erythema, or lymphadenopathy. Aside from HIV and HBV infections, he had a history of Wolff-Parkinson-White syndrome. Medications included atenolol 50 mg/d, flecainide 50 mg twice per day, lamivudine 150 mg combined with zidovudine 300 mg (Combivir; GlaxoSmithKline, Research Triangle Park, NC) one tablet twice per day, and efavirenz (Sustiva; Bristol-Myers Squibb Co., Princeton, NJ) 600 mg daily. He had a 20-pack-year smoking history, which he quit 4 years earlier, and he denied heavy alcohol intake or dependence. The patient admitted to intravenous drug use in the 1970s. No one in his family was known to suffer from liver disease.

Complete blood count revealed normal white blood cell and platelet counts and hemoglobin and hematocrit of 12.8 g/dL (normal, 13.8-17.0 g/dL) and 37.2% (normal, 40-50%), respectively. Basic chemistry panel and coagulation panel were unremarkable. Liver function test showed the following: total bilirubin, 0.30 mg/dL (normal, 0.2-1.3 mg/dL); total protein, 7.4 g/dL (normal, 6.3-8.2 g/dL); albumin, 3.5 g/dL (normal, 3.5-5.1 g/dL); alkaline phosphatase, 236 U/L (normal, 38-126 U/L); aspartate aminotransferase, 134 U/L (normal, 15-46 U/L); alanine aminotransferase, 51 U/L (normal, 21-72 U/L); and lactate dehydrogenase, 1,140 U/L (normal, 313-618 U/L).

Other serologic tests were obtained and an upper endoscopy was performed to determine whether or not the large extrahepatic mass was located in the duodenal wall or in the extraduodenal space. Duodenal erosions were noted on upper endoscopy; there was no evidence of an intraluminal mass or a notable extrinsic compression. Biopsies of the duodenal erosions showed focal mild acute and chronic inflammation without atypia. Endoscopic ultrasound was then performed, which showed that the extrahepatic mass was a large, well-circumscribed lesion located outside the duodenal wall, measuring 6.4 X 5.6 cm at its largest dimensions (Fig. 2). The lesion was adjacent to the inferior vena cava, but no invasion was seen. A prominent lymph node was present next to the mass in addition to several hypodense lesions in the liver. Aspirate and core samples were obtained and sent for cytology, histology, and flow cytometry.

The cytologic, histologic, and immunohistochemical findings of the fine-needle aspiration specimen were consistent with HCC (Fig. 3). The aspirate was highly cellular, with large cohesive clusters, trabeculae, and individual cells. The cells were large and pleomorphic and contained abundant eosinophilic cytoplasm and macronucleoli. Multinucleated forms were present and atypical mitoses were also identified. Histochemical stains demonstrated periodic-acid Schiff-positive, diastase-sensitive, cytoplasmic granules. The tumor was positive for low-molecular-weight cytokeratin, pan-cytokeratin, and vimentin on immunohistochemical staining, with negative monoclonal carcinoembryonic antigen. HBV-DNA was 4.76 pg/mL (normal, <0.01 pg/mL), which correlated to approximately 714,000 copies/mL. HCV antibody was negative. CD4 was 343 cells/[micro]L and polymerase chain reaction HIV-RNA again demonstrated an undetectable level. [alpha]-Fetoprotein tumor marker was elevated at 3,175 ng/mL (normal, 0-15 ng/mL). Significant laboratory test results are summarized in Table 1.

For palliation of his symptomatic right hepatic lobe mass, the patient underwent a successful selective chemoembolization of multiple tumors in the right inferior hepatic lobe with injections of doxorubicin 50 mg and lipoidal 15 mL (Fig. 4). Subsequent radiologic studies, unfortunately, demonstrated interval enlargement of the mass within the caudate and right lobes of the liver, with the caudate lobe mass now measuring 5.8 X 6.8 cm X 5.7 cm. This enlarging caudate lobe was exerting a mass effect on the adjacent duodenum and pancreas. The right lobe of the liver also showed interval progression of tumor burden with infiltration of the majority of the lobe. Interval development of ascites and portal venous thrombosis extending into the splenic and superior mesenteric veins were seen, as well as extraluminal compression of the inferior vena cava by tumor. Omental thickening and peritoneal implants were also noted. After 3 months of palliative care for this rapidly progressing HCC, he died.

Discussion

This case demonstrates that non-HIV diseases, in the era of expanded use of HAART, will assume an increasing role in morbidity and mortality of HIV-infected patients. It is well established that HIV/HCV and HBV/HCV coinfections lead to a more aggressive course in the development of HCC. (6,12,18,19) Lower CD4 counts are associated with increased prevalence in cirrhosis, although HCV infection does not seem to alter the natural history of HIV disease in most of these patients. (20) Some advocate that HBV, along with HCV, should not be considered an opportunistic infection but as a companion infection in patients with HIV infection or AIDS. (2) There are studies suggesting that HIV infection enhances HBV replication while decreasing the associated liver injury, but others have concluded differently. (21) In general, patients with controlled or early HIV infection have a milder HBV infection, and those patients with advanced AIDS have more severe HBV disease. (2) Although it remains unclear whether HIV alters the natural history of HBV, it appears that HBV/HIV-coinfected patients tend to have higher HBV-DNA levels, lower spontaneous hepatitis B early antigen seroconversion rates, and more severe liver disease. (21-23)

Chronic HBV infection accounts for the greatest portion of HCC in Asia and Africa but only accounts for 15 to 20% of HCC cases in the United States. (24) Male gender, family history of HCC, older age, presence of cirrhosis, and coinfection with HCV increase the risk for developing HCC in chronic HBV infection. (25) Clinical impact of HBV/HIV coinfection and their joint influence on the pathogenesis of HCC remain complex and unanswered. Although HIV possibly acts as a cofactor in accelerating the development of HBV-associated HCC, there are no clear indications of a greater risk of HCC in HIV-positive persons with HBV coinfection compared with those carrying HBV alone. (14-16) Interestingly, Tanaka et al (26) reported a case of HCC in an HIV-infected patient who had no evidence of viral hepatitis infection, cirrhosis, alcohol abuse, or other risk factors for chronic liver disease, suggesting that HIV infection alone may predispose an individual to HCC. This predisposition, if real, is likely linked to HIV's immunosuppressive effect and to its subsequent interference with immunemediated tumor surveillance. (15)

[FIGURE 1 OMITTED]

The HBV X protein, a 17-kDa protein that functions as a transcriptional transactivator of a variety of viral and cellular promoter/enhancer elements, is commonly implicated in HBV infection and development of HCC. (27-29) This has been a topic of intense research. Gomez-Gonzalo et al (28) and others (30,31) have shown that HBV X protein induces ongoing HIV replication, leading to a faster progression to AIDS in HIV/HBV coinfected patients. The worsening immunosuppression may then create a state of tolerance with high levels of HBV replication, diminished viral clearance, progressive hepatic injury, and ultimately HCC, if direct cytotoxicity is the predominant mechanism of HBV-related hepatic damage. (2)

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

Reappearance of HBV in newly HIV-infected patients and in patients who developed AIDS has been reported, even in patients who were previously immune (hepatitis B surface antibody-positive status). (32-35) The reactivation phenomenon in AIDS cases has been explained by both B-cell dysfunction and reduction in CD4 lymphocytes. (32,34) Therefore, many have recommended that the primary consideration in HBV/HIV coinfected patients should be control and treatment of HIV rather than HBV. Once HIV is under good control, individuals with active replication and significant fibrosis on biopsy are the ones most likely to benefit from HBV therapy with interferon; the exact role of lamivudine in treating coinfected patients is not known. (2,36) Treatment of HIV with HAART, however, can be accompanied by significant consequences in the presence of HBV coinfection. Exacerbation of HBV infection and deaths from liver failure caused by immune reconstitution during HAART have been reported. (37)

Our patient had HIV infection for over 18 years, and his HIV disease was well-controlled for at least the past 4 years, evidenced by undetectable viral load and the absence of progression to AIDS. It appears that his non-HIV disease was the cause of death. His situation may have represented reactivation of HBV in the setting of HIV disease, in spite of many years of quiescent HBV/HIV coinfection. Furthermore, this patient's HIV treatment regimen, containing lamivudine (in Combivir), could also have introduced YMDD mutants. His HCC presented suddenly and progressed rapidly.

Conclusion

This case report summarizes a patient with HBV/HIV coinfection who developed metastatic HCC despite quiescent HBV and HIV disease courses. The advent of HAART has revolutionized and dramatically improved the prognosis of HIV disease. As a result, morbidity and mortality from other underlying chronic, non-HIV-related diseases, such as the HBV infection and HCC reported here, will likely continue to increase in the HIV-infected patient population.

Table 1. Summary of significant laboratory results (a)

                                                        Reference
Test                                 Result               value

HAV IgG                                 +
HAV IgM                                 -
HBsAg                                   +
HBsAb                                   -
HBc IgG                                 +
HBc IgM                                 -
HBeAg                                   +
HBeAb                                   -
HBV-DNA (pg/ml)              4.76 (~714,000 copies/ml)    <0.01
HCV Ab                                  -
HDV IgG                                 -
HDV IgM                                 -
[alpha]-Fetoprotein (ng/ml)           3,175                0-15
PCR HIV-RNA                             -
CD4 (cells/[micro]l)                    343              237-1,130

(a) HAV, hepatis A virus: Ig, immunoglobulin; HBsAg, hepatitis B surface
antigen; HBsAb, hepatitis B surface antibody; HBc, hepatitis B conc;
HBeAg, hepatitis B early antigen; HBeAb, hepatitis B early antibody;
HCV, hepatitis C virus; HDV, hepatitis D virus; PCR, polymerase chain
reaction; HIV, human immunodeficiency virus; + positive, -, negative.

Accepted March 3, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9704-0401

References

1. Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination--Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 1991;40(RR-13):1-25.

2. Befeler AS, Di Bisceglie AM. Hepatitis B. Infect Dis Clin North Am 2000;14:617-632.

3. Coleman PJ, McQuillan GM, Moyer LA, et al. Incidence of hepatitis B virus infection in the United States, 1976-1994: estimates from the National Health and Nutrition Examination Surveys. J Infect Dis 1998;178:954-959.

4. Hadler SC, Judson FN, O'Malley PM, et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163:454-459.

5. Scharschmidt BF, Held MJ, Hollander HH, et al. Hepatitis B in patients with HIV infection: relationship to AIDS and patient survival. Ann Intern Med 1992;117:837-838.

6. Ockenga J, Tillmann HL, Trautwein C, et al. Hepatitis B and C in HIV-infected patients: prevalence and prognostic value. J Hepatol 1997;27:18-24.

7. Eskild A, Magnus P, Petersen G, et al. Hepatitis B antibodies in HIV-infected homosexual men are associated with more rapid progression to AIDS. AIDS 1992;6:571-574.

8. McDonald MI, Hamilton JD, Durack DT. Hepatitis B surface antigen could harbour the infective agent of AIDS. Lancet 1983;2:882-884.

9. Gilson RJ, Hawkins AE, Beecham MR, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS 1997;11:597-606.

10. Alka S, Hemlata D, Vaishali C, et al. Hepatitis B virus surface (S) transactivator with DNA-binding properties. J Med Virol 2000;61:1-10.

11. Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet 1981;2:1129-1133.

12. Garcia-Samaniego J, Rodriguez M, Berenguer J, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol 2001;96:179-183.

13. Brockmeyer N, Barthel B. Clinical manifestations and therapies of AIDS associated tumors. Eur J Med Res 1998;3:127-147.

14. Holmberg SD. Possible cofactors for the development of AIDS-related neoplasms. Cancer Detect Prev 1990;14:331-336.

15. Schulz TF, Boshoff CH, Weiss RA. HIV infection and neoplasia. Lancet 1996;348:587-591.

16. Smukler AJ, Ratner L. Hepatitis viruses and hepatocellular carcinoma in HIV-infected patients. Curr Opin Oncol 2002;14:538-542.

17. Martin-Carbonero L, Soriano V, Valencia E, et al. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retroviruses 2001;17:1467-1471.

18. Cheney CP, Chopra S, Graham C. Hepatitis C. Infect Dis Clin North Am 2000;14:633-667.

19. Chiaramonte M, Stroffolini T, Vian A, et al. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 1999;85:2132-2137.

20. Bonacini M, Puoti M. Hepatitis C in patients with human immunodeficiency virus infection: diagnosis, natural history, meta-analysis of sexual and vertical transmission, and therapeutic issues. Arch Intern Med 2000;160:3365-3373.

21. Housset C, Pol S, Carnot F, et al. Interactions between human immunodeficiency virus-1, hepatitis delta virus and hepatitis B virus infections in 260 chronic carriers of hepatitis B virus. Hepatology 1992;15:578-583.

22. Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999;29:1306-1310.

23. Bodsworth N, Donovan B, Nightingale BN. The effect of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men. J Infect Dis 1989;160:577-582.

24. Di Bisceglie AM, Carithers RL Jr, Gores GJ. Hepatocellular carcinoma. Hepatology 1998;28:1161-1165.

25. Lok AS, McMahon BJ. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34:1225-1241.

26. Tanaka T, Imamura A, Masuda G, et al. A case of hepatocellular carcinoma in HIV-infected patient. Hepatogastroenterology 1996;43:1067-1072.

27. Cromlish JA. Hepatitis B virus-induced hepatocellular carcinoma: possible roles for HBx. Trends Microbiol 1996;4:270-274.

28. Gomez-Gonzalo M, Carretero M, Rullas J, et al. The hepatitis B virus X protein induces HIV-1 replication and transcription in synergy with T-cell activation signals: functional roles of NF-kappaB/NF-AT and SP1-binding sites in the HIV-1 long terminal repeat promoter. J Biol Chem 2001;276:35435-35443.

29. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--Summary of a workshop. Gastroenterology 2001;120:1828-1853.

30. Twu JS, Chu K, Robinson WS. Hepatitis B virus X gene activates kappa B-like enhancer sequences in the long terminal repeat of human immunodeficiency virus I. Proc Natl Acad Sci U S A 1989;86:5168-5172.

31. Barak O, Aronheim A, Shaul Y. HBV X protein targets HIV Tat-binding protein 1. Virology 2001;283:110-120.

32. Vento S, di Perri G, Luzzati R, et al. Clinical reactivation of hepatitis B in anti-HBs-positive patients with AIDS. Lancet 1989;1:332-333 (letter).

33. Lazizi Y, Grangeot-Keros L, Delfraissy JF, et al. Reappearance of hepatitis B virus in immune patients infected with the human immunodeficiency virus type 1. J Infect Dis 1988;158:666-667 (letter).

34. Altfeld M, Rockstroh JK, Addo M, et al. Reactivation of hepatitis B in a long-term anti-HBs-positive patient with AIDS following lamivudine withdrawal. J Hepatol 1998;29:306-309.

35. Perrillo RP. Acute flares in chronic hepatitis B: The natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-1022.

36. Mai AL, Yim C, O'Rourke K, et al. The interaction of human immunodeficiency virus infection and hepatitis B virus infection in infected homosexual men. J Clin Gastroenterol 1996;22:299-304.

37. Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997;349:995-996 (letter).

RELATED ARTICLE: Key Points

* Hepatocellular carcinoma will be an emerging problem facing an increasing number of hepatitis B virus and human immunodeficiency virus coinfected individuals.

* We review the literature and report our recent experience with a 44-year-old man with hepatitis B virus and human immunodeficiency virus coinfection who developed metastatic hepatocellular carcinoma despite quiescent hepatitis B virus and human immunodeficiency virus disease courses.

* Routine serologic monitoring to detect active hepatitis B virus replication and an aggressive hepatocellular carcinoma screening practice, even in inactive carrier-state patients, may be warranted in hepatitis B virus and human immunodeficiency virus co-infected individuals.

LCDR Chris B. Hyun, MC, USNR, and CDR Walter J. Coyle, MC, USN

From the Gastroenterology Division, Department of Internal Medicine, Naval Medical Center, San Diego, CA.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the U.S. Department of the Navy, the U.S. Department of Defense, or the United States Government.

Reprint requests to LCDR MC, USNR Chris B. Hyun, MD, c/o Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-1005. Email: [e-mail]