Alavian S M et al. that HIV infection is a risk factor for OHB (46). Indeed, many reports have indicated that HIV-infected patients are at a higher risk of HBV co-infection in many regions, as illustrated by HBsAg high prevalence in HIV-positive patients in comparison to HIV-negative patients (47, 48). The reported prevalence of OHB occult HBV among HIV- infected patients has ranged from 0 % to 89.5 %, mostly in anti-HBc positive patients, with a considerable number of other studies reporting results between these two ex- tremes (49-51) (Table 1). The variability between the stud- ies may be explained by fluctuations in HBV-DNAHBV DNA replication over time (even when these assays are validated with high specificity and quite high sensitiv- ity), HCV co-infection, or the impact of treatments that are active against both HIV and HBV, such as lamivudine and tenofovir. In addition, differences in risk factors for contracting HBV between the studied populations and regional differences in overall HBV prevalence may con- tribute to the observed differences in occult HBV preva- lence. Furthermore, such studies suffer from a lack of methodological standardization, limited sample sizes, and few prospective studies. Occult HBV infection clini- cal significance in HIV-infected patients remains unclear. HBV reactivation from occult to overt HBsAg infection can occur in immune suppression clinical setting (52), which underscores the potential clinical significance of occult HBV infection in HIV-positive persons. Apart from HCV in- fection influence on the prognosis of OHB and HIV, mul- tiple studies have reported an association between occult HBV infection and flare-ups of hepatic transaminases (49, 53, 54). One study found that these liver outbreaks were due to the restoration of adaptive HBV-specific immune response and innate nonspecific immune responses (55), although several other studies that compared the levels of liver enzymes in HIV patients with and without OHB were not able to confirm these response routes (51, 56-58). Longitudinal studies with longer periods of observation that examine other hepatic outcomes, such as hepatic fibrosis by liver biopsy and hepatocellular carcinoma, would provide more insight into occult HBV clinical im- pact in HIV-infected individuals. The literature generally advocates that, for individuals co-infected with HBV and HIV, HBsAg- positive patients should be treated if their HBV DNA, or aminotransferase levels increase, or if they experience significant hepatic fibrosis (59). Still, clear guidelines have yet to be established for occult HBV co- infection in HIV positive patients. 3.5. Cryptogenic Cirrhosis Several studies have also demonstrated the presence of HBV DNA in the serum or livers of patients with crypto- genic cirrhosis, who lack serologic markers for HBV and HCV (34, 60-63). The frequency of occult HBV infection in cryptogenic cirrhosis has ranged between 4.8 % and 40 % in various studies, depending on the prevalence of HBV in the study areas and the type of specimen studied (se- Occult Hepatitis B (OBH) in Clinical Settings rum or liver) (34, 60, 62, 64) (Table 1). OHB clinical features in these settings remain largely unknown. In the labora- tory, no association was found between the presence of OHB and demographic, biochemical (AST, ALT), or sero- logic features in cryptogenic cirrhotic patients, implying that none of these parameters were useful to distinguish OHB-positive from OHB negative patients. However, ob- servations showed that OHB frequency increased in an- ti-HBc positive patients isolates (regardless of anti-HBs positivity) (60-62, 64). Cirrhosis is generally considered as the most important risk factor for hepatocellular car- cinoma development; therefore, in addition to its pos- sible direct oncogenic properties, occult HBV infection may favor neoplastic transformation in infected patients through its contribution to cirrhosis. 3.6. Hepatocellular Carcinoma (HCC) Despite the strong association between HCC and sero- positivity of HBsAg, almost all clinical and epidemiologi- cal studies have observed HBsAg-seronegative patients affected by HCC and liver cirrhosis. A significant propor- tion of these patients were seropositive on anti-HBs and anti-HBc seropositive and seronegative foron antibodies against hepatitis C virus (anti-HCV), especially in areas where HBV infection was hyperendemic (35, 65-68). Sev- eral studies have reported HBV DNA detection in tumor- ous liver tissue of HBsAg- negative HCC patients, with prevalence rates ranging from 30 % to 80 % (36, 69) (Table 1). The major question that arises with this evidence is whether occult HBV infection alone causes HCC. The hy- pothesis that OHB occult hepatitis retains the same pro- oncogenic features,accelerates liver disease progression, and cirrhosis development (36) has been suggested by epidemiological and molecular studies and supported by animal models. Accordingly, experiments in animal mod- els demonstrated that both woodchucks and ground squirrels, once infected by woodchuck hepatitis virus and ground squirrel hepatitis virus, respectively, were at high risk of developing HCC after the apparent clearance of the virus (70, 71). Three longitudinal follow-up studies showed the role of OHB in HCC development (65, 72, 73). In follow-up pe- riods of 82.8 ± 32.6 months, eight out of nine patients who acquired HCC were OHB positive at the time of final follow-up (73). In a similar finding, in a period of 91.8 ± 48.5 months, four out of eight OHB positive cases had acquired HCC (72). However, one follow-up study found a negative correlation (74); specifically, only one of seven OHB and HCV co-infected patients whose HCV was not without HCV eradicated ion with interferon therapy de- veloped HCC during average periods of 58.6 ± 18.1 months. Future cohort studies must be performed to address this question. Mutational analysis in HBsAg-positive HCC ver- sus HBsAg-negative patients showed multiple genetic variants in different parts of the HBV genome and regula- tory regions (68, 75, 76); however, others did not find such 4 Published by Kowsar, © BRCGL 2012 Hepat Mon. 2012;12(8):e6126