Abstract Background and Aims Refractory lupus nephritis (LN) is defined as either no response to standard of care (SOC), i.e., failure to improve within 3–4 months or not achieving partial response within 12 months or complete response after 2 years of treatment. This condition is characterized by poor outcome, is often life-threatening, and represents a relatively unexplored clinical setting. A dysregulation of CD38 expression has been reported in Systemic lupus Erythematosus, and highly expressing CD38 plasma cells relegated in bone marrow niches inaccessible to conventional and biological agents could represent a source of repowering of the immune dysregulation. The efficacy and safety of daratumumab, a monoclonal antibody specifically directed at CD38, given without any other immunosuppressant or agents targeting B-cell-activating factor, were assessed in a discrete cohort of patients with refractory LN, in whom both SOC and rescue treatments had failed. Method Six patients (1 male and 5 females) aged 41.3 years (range 20 to 61 years) were treated with Daratumumab monotherapy. The treatment protocol consisted of 16 mg/kg daratumumab administered intravenously weekly for 8 weeks, then every two weeks 8 more times, and lastly monthly for 8 times. All patients had failed previous treatments with both SOC including either mycophenolate mofetil or cyclophosphamide-azathioprine, and rescue therapies including Rituximab, Ocrelizumab, Belimumab, and iv IgG. Results One out of six patients did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients continued to be treated (total treatment maximum 22 infusions) and reached a 12-month observation. Renal biopsy performed before daratumumab administration revealed a class IV LN in 1 patient, class V LN in 1 patient, class III+V LN in 1 patient and class IV+V LN in the other 2. Three patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 g per 24 h to 0.59 g per 24 h, 0.9 g per 24 h and 0.8 g per 24 h (P = 0.0010) at 3 months, 6 months and 12 months, respectively, was observed. The mean value of serum Creatinine (sCr) decreased from 2.3 to 1.5 mg/dl. The mean value of sCr decreased from 2.3 mg dl−1 to 1.5 mg/dl (P = 0.98) at 12 months. C3 and C4 levels increased from 72.8 (range, 0–99) to 101.6 (range, 78.0–135) mg/dl (P = 0.16) and from 9.4 (range, 5–14) to 20.4 (range, 13–30) mg/dl (P = 0.0182), respectively. A decrease in IgG mean levels from 971.7 mg dl−1 (range, 251–1546) to 512.3 mg/dl (range, 88–957), 481.7 (range, 84–878) mg/dl and 508.4 mg/dl (range, 192–685) at 3 months, 6 months and 12 months, respectively, was observed. Improvement of clinical symptoms was paralleled by seroconversion of anti-double-stranded DNA antibodies (p = 0.03), significant decrease in interferon-gamma values (p = 0.0006), BMCA-B-cell maturation antigen (p = 0.0005) and soluble CD163 levels (p = 0.045), and IL 10 levels (p = 0.0006). Clinical remission was substantiated by improvement of SLEDAI-2K score (p = 0.03). Daratumumab was generally well tolerated. Conclusion These data suggest that Daratumumab administered alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) is highly effective in refractory LN. The multifaced effects of Daratumumab on the inflammatory burden and the interferon gamma profile could provide a restoration of the immune balance.

Abstract Background and Aims Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. Method This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome Results The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. Conclusion In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

Cancer is a leading cause of death in people with chronic kidney disease (CKD). The incidence of CKD in patients with cancer is higher than in the non-cancer population. Across various populations, CKD is associated with an elevated risk of cancer incidence and cancer death compared with people without CKD, although the risks are cancer site-specific. The potential mechanisms for the increased risk of cancer observed in CKD, include patient factors, disease, and treatment factors. CKD has also a major impact on the treatment of cancer patients. The kidney is the primary route of elimination of many anticancer drugs. Dosing of anticancer agents according to kidney function is essential to avoid undertreatment and toxicity. Because of the systemic exclusion of patients with severe kidney dysfunction from clinical cancer trials, data are lacking to guide dosing of anticancer drugs in patients with chronic kidney disease. As a consequence, many therapies are denied to CKD patients due to their possible toxicities. An orchestrated effort by all stakeholders is required to fill the knowledge gap and improve the outcome of cancer patients with kidney dysfunction.

Abstract Background and Aims The aim of this prospective study is to investigate the long term safety and efficacy of intesified B-cell depletion therapy (IBCDT) in patients with active lupus nephritis (LN), in comparison to a conventional immunosuppresant therapy, followed by a 3 year maintenence micophenolate mofetil (MMF) regimen. Method Thirty patients were administered an IBCDT (4 weekly rituximab [RTX] 375 mg/m2 and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide [CYC], 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/d by the third month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2 to 3 g/d, whereas 10 were given the Euro Lupus CYC. MMF (1-2 g/daily) or azathioprine (AZA, 1-2 mg/kg/day) were given for > 3 years as a maintenance therapy. Results At 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC (P = 0.03); the dose of oral prednisone was lower in the IBCDT group (mean ± SD 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d, P < 0.01) or CYC group (7.5 ± 9.0 mg/d, P < 0.01). Mean follow-up after treatment was 44.5 months (interquartile range [IQR] 36-120 months), 48.6 months (IQR 36-120 months), and 45.3 (IQR 36-120 months) for IBCDT, MMF, and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the 3 groups. Conclusion In biopsy-proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by >3-year maintenance either MMF or AZA regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.

Abstract Background and Aims A considerable number of patients with high clinical suspicion for cryoglobulinaemic vasculitis either show negative results for the detection of cryoglobulins or show only trace amounts which cannot be characterized for composition. We aimed at establishing whether the failure to detect or the detection of trace amounts of cryoglobulin with conventional methods either identifies a peculiar subset of low level cryoglobulinaemia (from now on hypocryoglobulinaemia) or represents a separate entity. Method Using a modified precipitation technique in hypo-ionic medium, we prospectively identified between 2008 and 2021 237 patients (median age 60.8 years [22-97], 137 females) having <0.5% cryocrit and clinical suspicion of autoimmune disorder Results 54 out of 237 patients (22.7%) had a history of HCV infection. 169 out of 237 patients (71%) had an established underlying disease, while 68 patients (28.6%) (median age 62.9 years [29-93], 35 females) did not show either laboratory markers or clinical symptoms consonant with an underlying aetiology. These 68 cases with only trace amounts of cryoglobulins were defined as having a putatively idiopathic hypocryoglobulinaemia. Nineteen of these 68 patients (27.9%) had a history of HCV infection. Twenty-four patients out of 68 (35.3%) were positive for rheumatoid factor (RF), while 25 (36.7%) patients had signs of complement consumption, and 36 (52.9%) had increased inflammatory indexes. Seven patients only had arthralgia and constitutional symptoms while 61 out of 68 (89.7%) presented with at least one of the three cardinal signs of cryoglobulinaemic vasculitis including skin lesions, peripheral nerve involvement, and glomerulonephritis. Seventy-five percent of the subjects had type III hypocryoglobulins. In patients with hypocryoglobulinaemia the histologic features of glomerulonephritis (also examined by electron microscopy) resembled those of mixed cryoglobulinaemia-associated glomerulonephritis Conclusion In conclusion, hypocryoglobulins are often polyclonal and are mainly unrelated to HCV infection. Patients who present high clinical suspicion for vasculitis, especially glomerulonephritis and yet test negative for cryoglobulinaemia detected by standard techniques, could require deeper investigation even in the absence of HCV infection, RF activity or signs of complement consumption.

Abstract Background and Aims Rituximab (RTX) has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Method Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Results Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Conclusion Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Introduction: In Brazil, the majority of the population relies on the public health care system (PHCS). Due to funding restrictions, PHCS has some limitations, as a large part of the budget must be designated to basic health needs, a priority condition in a developing country. In the last years, some initiatives were developed in order to mitigate this condition and improve public access to specialized health care, including the treatment of intestinal failure (IF). Methods: A model of public-private partnership (PPP) was developed, involving the Federal Government (FG) and Hospital Sirio-Libanes (HSL), a private hospital considered a center of excellence. By this model, HSL is responsible for the development and management of specialized medical programs not available in the PHCS, in exchange for fiscal incentives. Results: In 2009, a project named PROADI-SUS was initiated between the FG and HSL. This partnership was responsible for the development of a pediatric liver transplant program, which performed more than 1000 pediatric liver transplants, promoted research activity and diffusion of medical education to other centers. Due to the scarce of intestinal rehabilitation centers in Brazil, and the absence of a pediatric multivisceral transplant team, by the end of 2016 the same strategy was utilized to develop a program specialized in the treatment of IF in the PHCS. The program was instituted in a pediatric public hospital (Hospital Menino Jesus), and due to the complexity of IF patients, improvements were performed in several areas of the hospital, benefiting not only the IF patients, but the general population. Medical resources not available in the public hospital are obtained in the private hospital; transplants are performed in the private hospital and as soon as the patient is stable, the post-operative is followed by the same team in the public hospital. The intestinal rehabilitation center is now receiving patients from all over Brazil, and has started to teach and support other public hospitals in order to disseminate the treatment of intestinal failure through the country. Conclusion: The association of a private center of excellence with the public system, through a PPP, promoted a significant improvement in the treatment of IF in the Brazilian PHCS. In the next years, the dissemination of the knowledge acquired with this PPP will permit the creation of new public intestinal rehabilitation centers, benefiting more patients of the public system.

Background An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. Methods This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry. Results Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P <0.001); P203Q+S210R (17.4% [4/23] in HCC vs 0% [0/110] in non-HCC, P=0.001). Both mutations reside in trans-membrane C-terminal domain critical for HBsAg-secretion. In in-vitro experiments, P203Q, S210R and P203Q+S210R significantly reduced the ratio [secreted/intracellular HBsAg] compared to wt at each time-point analysed (P <0.05), supporting an impaired HBsAg-secretion. Furthermore, P203Q and P203Q+S210R increased the percentage of cells in S-phase compared to wt, indicating cell-cycle progression (P203Q:26±13%; P203Q+S210R:29±14%; wt:18%±9, P <0.01. Additionally, S210R increased the percentage of cells in G2/M-phase (26±8% for wt versus 33±6% for S210R, P <0.001). Conclusions Specific mutations in HBsAg C-terminus significantly correlate with HBV-induced HCC. They hamper HBsAg-secretion and are associated with increased cellular proliferation, supporting their involvement in HCC-development. The identification of viral genetic markers associated with HCC is critical to identify patients at higher HCC-risk that may deserve intensive liver monitoring, and/or early anti-HBV therapy.

Introduction: HBsAg plays a critical role in mediating HBV-induced hepatocellular carcinoma (HCC).

Introduction: HBsAg/HDAg interaction is critical for HDV morphogenesis and replication.

Background and Aims: Every year globally WHO reports nearly 20 million Hepatitis E virus (HEV) infections. The disease has potential to cause massive epidemics. The reservoir of HEV during interepidemic period in India is not well characterized, with evidences of deficient zoonotic links. Further, the sporadic cases usually lack history of contact with clinically overt HEV patients. In the present context the occurrence of subclinical HEV as a possible reservoir of infection in endemic region was evaluated. Methods: Blood samples were collected from 67 apparently-healthy individuals and 10 acute viral hepatitis (AVH) patients during two HEV outbreaks in North India. The serum samples were tested for anti-HEV IgM, IgG, HEV-IgG avidity-index, HEV viral-load and conventional-PCR followed by sequencing and phylogenetic analysis. Results: A total of 14 (20.89%) apparently-healthy individuals showed presence of both anti-HEV IgM and IgG. Based on HEVIgG avidity-index, 9 apparently-healthy individuals (64.28%) had secondary-exposure, 4 (28.57%) had primary-exposure, while one patient had intermediate-avidity. Subclinical subjects with primaryexposure had significantly higher anti-HEV IgM index as compared to secondary-exposure. Viral-load in clinically jaundiced patients was significantly higher as compared to subclinical subjects (p < 0.0001). Phylogenetic analysis showed HEV sequences retrieved from subclinical individuals (Genotype 1a) clustered along with AVH patients reported in the same outbreak suggesting matched origin. The significantly low viral-load in subclinical subjects hints towards the dose dependency for progression of clinical manifestation. Conclusions: We document subclinical passage of HEV occurs without producing clinically overt hepatitis goes un-noticed which, in turn helps maintaining the virus in nature possibly leading to its endemicity.

Background: To define HBsAg-mutations correlated with different serum HBV-DNA levels in HBV chronically-infected drug-naive patients.Methods: This study included 187 patients stratified into the following ranges of serum HBV-DNA: 12-2000 IU/ml, 2000-100,000 IU/ml, and > 100,000 IU/ml. HBsAg-mutations were associated with HBV-DNA levels by applying a Bayesian-Partitional-Model and Fisher-exact test. Mutant and wild-type HBV genotype-D genomes were expressed in Huh7 cells and HBsAg-production was determined in cell-supernatants at 3 days-post-transfection.Results: Specific HBsAg-mutations (M197T,-S204N-Y206C/H-F220L) were significantly correlated with serum HBV-DNA < 2000 IU/ml (posterior-probability>90%, P < 0.05). The presence of Y206C/H and/or F220L was also associated with lower median (IQR) HBsAg-levels and lower median (IQR) transaminases (for HBsAg: 250[115-840] IU/ml for Y206C/H and/or F220L versus 4300[640-11,838] IU/ml for wild-type, P = 0.023; for ALT:28[21-40] IU/ml versus 53[34-90] IU/ml, P < 0.001). These mutations were localized in the HBsAg C-terminus, known to be involved in virion and/or HBsAg secretion. The co-occurrence of Y206C + F220L was found significant by cluster-analysis, (P = 0.02). In addition, in an in-vitro model Y206C + F220L determined a 2.8-3.3 fold-reduction of HBsAg-amount released in supernatants compared to single mutants and wt (Y206C + F220L = 5,679 IU/ml; Y206H = 16,305 IU/ml; F220L = 18,368 IU/ml; Y206C = 18,680 IU/ml; wt = 14,280 IU/ml, P < 0.05).Conclusions: Specific HBsAg-mutations (compartmentalized in the HBsAg C-terminus) correlated with low-serum HBV-DNA and HBsAg-levels. These findings can be important to understand mechanisms underlying low HBV replicative potential including the inactive-carrier state. (C) 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S490-S490 Free communication (oral) presentations O654 PREVALENCE OF CHLAMYDIA AND MYCOPLASM GENITAL INFECTIONS IN WOMEN AGED <20 YEARS VERSUS ≥20 YEARS M. Giovannini, M. GiovanniniSearch for more papers by this authorK. Marino, K. MarinoSearch for more papers by this authorC. Fabiani, C. FabianiSearch for more papers by this authorR. Longo, R. LongoSearch for more papers by this authorG. Cappiello, G. CappielloSearch for more papers by this authorA. Spanò, A. SpanòSearch for more papers by this authorV. Spina, V. SpinaSearch for more papers by this author M. Giovannini, M. GiovanniniSearch for more papers by this authorK. Marino, K. MarinoSearch for more papers by this authorC. Fabiani, C. FabianiSearch for more papers by this authorR. Longo, R. LongoSearch for more papers by this authorG. Cappiello, G. CappielloSearch for more papers by this authorA. Spanò, A. SpanòSearch for more papers by this authorV. Spina, V. SpinaSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61084-4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S490-S490 RelatedInformation

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S639-S639 Poster presentations M338 REVIEW OF CASES OF ASCUS, LSIL, HSIL HPV-CORRELATED: EXPERIENCE OF S.PERTINI HOSPITAL'S SERVICE OF COLPOSCOPY FROM 1/1/2008 TO 31/12/2011: TREATMENT AND FOLLOW UP O. Oliviero, O. OlivieroSearch for more papers by this authorT. Canino, T. CaninoSearch for more papers by this authorK. Marino, K. MarinoSearch for more papers by this authorL. Mantenuto, L. MantenutoSearch for more papers by this authorG. Pontani, G. PontaniSearch for more papers by this authorR. Longo, R. LongoSearch for more papers by this authorD. Tedeschi, D. TedeschiSearch for more papers by this authorM. Giovannini, M. GiovanniniSearch for more papers by this author O. Oliviero, O. OlivieroSearch for more papers by this authorT. Canino, T. CaninoSearch for more papers by this authorK. Marino, K. MarinoSearch for more papers by this authorL. Mantenuto, L. MantenutoSearch for more papers by this authorG. Pontani, G. PontaniSearch for more papers by this authorR. Longo, R. LongoSearch for more papers by this authorD. Tedeschi, D. TedeschiSearch for more papers by this authorM. Giovannini, M. GiovanniniSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61529-XAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S639-S639 RelatedInformation

How the overlap between the hepatitis B virus (HBV) reverse transcriptase (RT) and HBV S antigen (HBsAg) genes modulates the extent of HBV genetic variability is still an open question, and was investigated here. The rate of nucleotide conservation (≤1% variability) followed an atypical pattern in the RT gene, due to an overlap between RT and HBsAg (69.9% nucleotide conservation in the overlapping region vs 41.2% in the non-overlapping region; P<0.001), with a consequently lower rate of synonymous substitution within the overlapping region [median(interquartile range)dS=3.1(1.5-7.4) vs 20.1(10.6-30.0); P=3.249×10(-22)]. The most conserved RT regions were located within the YMDD motif and the N-terminal parts of the palm and finger domains, critical for RT functionality. These regions also corresponded to highly conserved HBsAg domains that are critical for HBsAg secretion. Conversely, the genomic region encoding the HBsAg antigenic loop (where immune-escape mutations are localized) showed a sharp decrease in the extent of conservation (40.6%), which was less pronounced in the setting of human immunodeficiency virus (HIV)-driven immune suppression (48.8% in HIV-HBV co-infection vs 21.5% in mono-infected patients; P=0.020). In conclusion, the overlapping reading frame and the immune system appear to have shaped the patterns of RT and HBsAg genetic variability. Highly conserved regions in RT and HBsAg may deserve further attention as novel therapeutic targets.