Occult HBV infection in HIV‐infected adults and evaluation of pooled NAT for HBV

The study aimed to determine the prevalence of occult hepatitis B virus infection among HIV‐infected persons and to evaluate the use of a pooling strategy to detect occult HBV infection in the setting of HIV infection. Five hundred and two HIV‐positive individuals were tested for HBV, occult HBV and hepatitis C and D with serologic and nucleic acid testing (NAT). We also evaluated a pooled NAT strategy for screening occult HBV infection among the HIV‐positive individuals. The prevalence of HBV infection among HIV‐positive individuals was 32 (6.4%), and occult HBV prevalence was 10%. The pooling HBV NAT had a sensitivity of 66.7% and specificity of 100%, compared to HBV DNA NAT of individual samples. In conclusion, this study found a high prevalence of occult HBV infection among our HIV‐infected population. We also demonstrated that pooled HBV NAT is highly specific, moderately sensitive and cost‐effective. As conventional HBV viral load assays are expensive in resource‐limited settings such as India, pooled HBV DNA NAT might be a good way for detecting occult HBV infection and will reduce HBV‐associated complications.     

HLA‐C and KIR combined genotype as new response marker for HBeAg‐positive chronic hepatitis B patients treated with interferon‐based combination therapy

Current treatment for chronic hepatitis B infection (CHB) consists of interferon‐based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA‐C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA‐C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa‐2a + adefovir. Genotyping of killer immunoglobin‐like receptors (KIRs) was performed by SSP‐PCR. One SNP in HLA‐C (rs2308557) was significantly associated with combined response in HBeAg‐positive CHB patients (P = 0.003). This SNP is linked to the HLA‐C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA‐C2 was observed significantly more often in HBeAg‐positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1‐C2 predicted response independent of HBV genotype and ALT at baseline. HLA‐C and KIR genotype is strongly associated with response in HBeAg‐positive CHB patients treated with interferon‐based therapy. In combination with other known response markers, HLA‐C/KIR genotype could enable the selection of patients more likely to respond to interferon‐based therapy.     

Incidence and risk factors for incomplete HBV DNA suppression in HIV/HBV‐co‐infected patients initiating tenofovir‐based therapy

Suppression of hepatitis B virus (HBV)‐DNA to undetectable levels is an important goal for HIV/HBV‐co‐infected patients receiving anti‐HBV‐active antiretroviral therapy (ART), and current guidelines recommend that this outcome should be reached by 1 year of treatment. However, the proportion of patients that fail to achieve an undetectable HBV DNA at this time point and its determinants remain unknown in clinical practice. The objective of this study was to determine the incidence and risk factors for incomplete HBV suppression following 1 year of tenofovir‐based ART. We performed a cohort study among tenofovir‐treated HIV/HBV‐co‐infected patients. Patients had HBV viraemia, initiated tenofovir‐based ART and had HBV DNA measured at 1 year of therapy. The primary outcome was incomplete HBV suppression (HBV DNA ≥2.6 log IU/mL) at 1 year. Logistic regression determined odds ratio (ORs) of incomplete HBV suppression for risk factors of interest. Among 133 patients, 54% (95% CI, 46–63%) had incomplete HBV suppression at 1 year. Incomplete suppression was associated with higher baseline HBV DNA (OR, 1.46 per log IU/mL increase; 95% CI, 1.1–1.94) and detectable HIV viraemia at 1 year (OR, 2.52; 95% CI, 1.19–5.32). Among 66 patients with suppressed HIV RNA at 1 year, 28 (42%) failed to achieve an undetectable HBV DNA. Failure to suppress HBV DNA by 1 year occurred in a sizeable proportion of tenofovir‐treated HIV/HBV‐co‐infected patients. Higher HBV DNA and detectable HIV viraemia were risk factors for incomplete HBV suppression.     

KIR2DL3 and the KIR ligand groups HLA‐A‐Bw4 and HLA‐C2 predict the outcome of hepatitis B virus infection

Killer immunoglobulin‐like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA‐KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty‐seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA‐A‐Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA‐C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA‐A‐Bw4 and HLA‐C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.     

Eighteen‐month lamivudine prophylaxis on preventing occult hepatitis B virus infection reactivation in patients with haematological malignancies receiving immunosuppression therapy

This study evaluated the long‐term efficacy and safety of an 18‐month lamivudine prophylaxis in 68 HBsAg‐negative/anti–HBc‐positive patients with oncohaematological disease. All 68 consecutive HBsAg‐negative/anti–HBc‐positive patients with an oncohaematological disease and naïve for chemotherapy observed from April 2008 to December 2012 at 2 Hematology Units in Naples were treated with lamivudine for 18 months after stopping chemotherapy and monitored for HBsAg at months 1 and 3 during chemotherapy and then every 3 months after its discontinuation. During follow‐up, 13 (19.1%) of the 68 patients died of complications related to their oncohaematological disease, and 3 (4%) showed a virological HBV reactivation (retroconversion to HBsAg positivity) 1‐7 months after the discontinuation of lamivudine prophylaxis (2 treated for chronic lymphocytic leukaemia and one for Waldenstrom's disease); of these, 2 showed a biochemical reactivation. Comparing the demographic and clinical characteristics of the 3 patients with a virological HBV reactivation to the 65 without, the former were older (median age and range: 67 years [75‐78] vs. 61 [24‐88]; P = .05) and were less frequently treated for B‐cell non‐Hodgkin lymphoma (B‐NHL) (0 vs. 70.7%, P = .03). In conclusion, a 18 months of lamivudine prophylaxis was effective in preventing HBV reactivation in HBsAg‐negative/anti–HBc‐positive patients treated for B‐NHL. However, in patients with chronic and severe immunodepression, such as those with chronic lymphocytic leukaemia and Waldenstrom's disease, prophylaxis should be continued for an indefinite period.     

Interferon for treatment of breakthrough infection with hepatitis B virus mutants developing during long-term lamivudine therapy

Background: We aimed to treat patients with chronic hepatitis B on long-term treatment with lamivudine who developed lamivudine-resistant hepatitis B virus (HBV) mutants along with clinical relapses. Methods: Of 217 patients with chronic hepatitis B who had been treated with lamivudine for 1–6 years, 23 (11%) developed lamivudine-resistant hepatitis B virus (HBV) mutants. Seven of them, including 1 whose case was previously reported, received interferon (IFN) daily for 4 weeks and then two or three times a week thereafter to cope with exacerbation of hepatitis. We investigated the efficacy of this IFN therapy in 6 patients, excluding the 1 previously reported. Results: In 4 patients, HBV DNA decreased to below the detectable limit of the branched DNA assay (<0.7 MEq/ml) accompanied by normalization of transaminase levels. During IFN therapy, 2 patients seroconverted to antibody to hepatitis B e antigen (HBeAg) and showed normalized transaminase levels. Interferon was required in 7 of the 111 (6%) patients with chronic hepatitis B who were positive for HBeAg, but in none of the 106 who were positive for antibody to HBeAg (P = 0.014). Conclusions: The efficacy of IFN in controlling virological breakthroughs and exacerbation of hepatitis by infection with lamivudine-resistant HBV mutants in patients with HBeAg-positive chronic hepatitis B could enhance the versatility of lamivudine, which may have to be given to them indefinitely. Received: December 11, 2001 / Accepted: May 17, 2002 Reprint requests to: F. Suzuki Editorial on page 988     

Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation

AIM: To analyze the effectiveness and safety of lamivudine treatment in patients with chronic HBV infection undergoing hemodialysis or after kidney transplantation, and to study the frequency of tyrosine - methionine - aspartate - aspartate (YMDD) mutation occurrence after lamivudine treatment. METHODS: We analyzed 91 patients with chronic hepatitis B, among whom, 16 patients underwent hemodialysis, 7 patients had kidney transplantation and 68 patients had normal function of kidney. The hemodialysis patients were treated by lamivudine 300 mg/wk. patients after kidney transplantation and patiente with normal function of kidney were treated with lamivudine 100 mg/d. Therapy lasted for 12 mo. HBV-DNA, HBsAg, HBeAg and anti-HBe, and anti-HCV antibodies were assessed in sera of patients. The analysis was performed before and 6 mo after the end of lamivudine treatment. Before, during and after the lamivudine therapy, the number of erythrocytes, leukocytes, platelets and hemoglobin concentration, ALT and AST activity, as well as bilirubin, urea and creatinine concentrations were analyzed in sera from patients. RESULTS: After the 12-mo lamivudine treatment, elimination of HBV - DNA was observed in 56% patients undergoing hemodialysis and in 53% patients with normal kidney function. Only 1 from 7 (14%) kidney-transplanted patients eliminated HBV-DNA. Furthermore, HBeAg elimination was observed in 36% hemodialysis patients, in 51% patients with normal function of kidneys and in 43% kidney transplanted patients. Among the patients undergoing dialysis, no YMDD mutation was found after 12 mo of therapy, while it was detected in 9 patients (13%) with normal function of kidney and in 2 kidney-transplanted patients (29%, P<0.006). We did not observe significant side effecte of lamivudine treatment in studied patiente. CONCLUSION: Effectiveness of lamivudine therapy in dialysis patients is comparable with that in patiente with normal function of kidney. Lamivudine treatment is well tolerated and safe in patiente with renal insufficiency undergoing hemodialysis and kidney-transplantation. However, in the latter group, high incidence of YMDD mutation after lamivudine treatment was observed.