Biological therapies for rheumatoid arthritis: beyond TNF‐α blockade

Biological therapies represent one of the major advances in the treatment of rheumatoid arthritis in the past decade. The tumour necrosis factor alpha (TNF‐α) inhibitors have started marketing in most Asian countries. Despite having a higher efficacy than conventional disease‐modifying antirheumatic drugs (DMARDs), the anti‐TNF‐α agents are not successful in all patients with rheumatoid arthritis. Moreover, short‐term and long‐term complications such as tuberculous infection and lymphoma are still a major concern. Recent studies have demonstrated that several non‐TNF‐α biologics such as rituximab, abatacept and tocilizumab are effective in patients with refractory rheumatoid arthritis, including those who are not responsive to the TNF‐α inhibitors. This article updates the clinical data on the recently developed non‐TNF‐α biological agents in rheumatoid arthritis.     

A snapshot of virological presentation and outcome of immunosuppression‐driven HBV reactivation from real clinical practice: Evidence of a relevant risk of death and evolution from silent to chronic infection

The study was undertaken in order to provide a snapshot from real clinical practice of virological presentation and outcome of patients developing immunosuppression‐driven HBV reactivation. Seventy patients with HBV reactivation were included (66.2% treated with rituximab, 10% with corticosteroids and 23.8% with other immunosuppressive drugs). Following HBV reactivation, patients received anti‐HBV treatment for a median (IQR) follow‐up of 31(13‐47) months. At baseline‐screening, 72.9% of patients were HBsAg‐negative and 27.1% HBsAg‐positive. About 71.4% had a diagnosis of biochemical reactivation [median (IQR) HBV DNA and ALT: 6.9 (5.4‐7.8) log IU/mL and 359 (102‐775) U/L]. Moreover, 10% of patients died from hepatic failure. Antiviral prophylaxis was documented in 57.9% and 15.7% of HBsAg‐positive and HBsAg‐negative patients at baseline‐screening (median [IQR] prophylaxis duration: 24[15‐33] and 25[17‐36] months, respectively). Notably, HBV reactivation occurred 2‐24 months after completing the recommended course of anti‐HBV prophylaxis in 35.3% of patients. By analysing treatment outcome, the cumulative probability of ALT normalization and of virological suppression was 97% and 69%, respectively. Nevertheless, in patients negative to HBsAg at baseline‐screening, only 27% returned to HBsAg‐negative status during prolonged follow‐up, suggesting the establishment of chronic infection. In conclusion, most patients received a diagnosis of HBV reactivation accompanied by high ALT and 10% died for hepatic failure, supporting the importance of strict monitoring for an early HBV reactivation diagnosis. Furthermore, HBV reactivation correlates with high risk of HBV chronicity in patients negative for HBsAg at baseline‐screening, converting a silent into a chronic infection, requiring long‐term antiviral treatment. Finally, a relevant proportion of patients experienced HBV reactivation after completing the recommended course of anti‐HBV prophylaxis, suggesting the need to reconsider proper duration of prophylaxis particularly in profound immunosuppression.     

Interferon‐α/β for treatment of chronic hepatitis C infection in the era of direct‐acting antiviral agents

Type I interferons (IFN‐α/β), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN‐free regimen combining oral direct‐acting antiviral agents (DAA) will be approved soon for genotype 1 patients. Here, we discuss the role of IFN‐α/β in the forthcoming “era of DAA” with consideration of limitations and concerns about IFN‐free therapies. First, the therapeutic efficacy of first‐generation DAA varies among the different subtypes. While the rate of sustained virological response (SVR) is 60–90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAA. Second, there is concern about the emergence of drug‐resistance resulting from inappropriate use of DAA. The clinical significance of pre‐existing resistant variants has not been elucidated. Drug resistance may affect the efficacy of next‐generation treatments. An IFN and ribavirin backbone in combination with DAA is an effective measure to prevent the emergence of drug resistance and/or to suppress pre‐existing resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN‐free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first‐generation DAA, low‐dose IFN maintenance therapy is a treatment option until the next‐generation therapy with pan‐genotypic potency and high genetic barrier become available.     

A new method of concentrating hepatitis B virus (HBV) DNA and HBV surface antigen: an application of the method to the detection of occult HBV infection

Background The risk of post‐transfusion hepatitis B virus (HBV) infection has been reduced after the implementation of HBV nucleic acid amplification technology (NAT). However, the problem of HBV DNA‐positive and HBV surface antigen (HBsAg)‐negative occult HBV infections remains to be solved. This is in part due to the HBV DNA load being too low to detect these occult HBV infections using mini‐pool NAT. In Japan, the assay for the antibody against the HBV core antigen (anti‐HBc) has not completely excluded occult HBV infection. To solve this problem, we have developed a new method of concentrating HBV DNA and HBsAg simultaneously to increase the sensitivity of detection tests. Methods Virus concentration is achieved by the enhancement of the agglutination of viruses using poly‐L‐lysine in the presence of a bivalent metal. Poly‐L‐lysine‐coated magnetic beads are used to shorten the time of each step of the concentration procedure. Seventy‐seven anti‐HBc‐positive and HBsAg‐negative donations were examined. HBsAg and anti‐HBc were tested by enzyme immunoassay (EIA) (AxSYM; Abbott) and haemagglutination inhibition test (Japanese Red Cross), respectively. Results HBV surface antigen and HBV DNA levels were concentrated up to four‐ to sevenfold. Using this method, 35 of the 77 anti‐HBc‐positive and HBsAg‐negative donors were HBV DNA‐positive by individual NAT and a further five donors became HBV DNA‐positive by HBV concentration. Twenty‐seven of 40 occult HBV infections became HBsAg‐positive by HBsAg concentration. Conclusion Our new method of concentrating HBV and HBsAg increased the sensitivities of EIA and HBV NAT, and enabled us to detect 27 of 40 occult HBV infections by HBsAg EIA.     

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.     

Tolerability and efficacy of anti‐HBV nucleos(t)ide analogues in HBV‐DNA‐positive cirrhotic patients with HBV/HCV dual infection

Summary. We evaluated tolerability and virological and clinical impact of anti‐Hepatitis B Virus (HBV) nucleos(t)ide analogues in cirrhotic patients with HBV/Hepatitis C Virus (HCV) coinfection. The virological and clinical course of 24 consecutive HBsAg/HBV‐DNA/anti‐HCV‐positive patients with cirrhosis was compared with that of 24 HBsAg/HBV‐DNA‐positive, anti‐HCV‐negative cirrhotic patients, pair‐matched for age (±5 years), sex, HBeAg/anti‐HBe status and Child‐Pugh class. Patients in both groups were previously untreated with oral antiviral agents at enrolment and were treated for at least 24 months (range 24–54). At the 12th and 18th month of treatment, HBV‐DNA was negative in 21 (87.5%) and 23 (95.8%) patients with hepatitis B and C and in 20 (83.3%) and 22 (91.6%) in patients with isolated HBV; all patients in both groups were HBV‐DNA‐negative at month 24 and at subsequent observations. Treatment was well tolerated by all patients in both groups. At the last observation (for co‐infected patients, median 44 months and range 24–54; for mono‐infected patients, median 40 months and range 24–54), a deterioration in Child class was observed in eight (47%) of 17 patients in patients with both HBV and HCV who were HCV‐RNA‐positive at baseline, but in none of seven HCV‐RNA‐negative patients in the same group, and in one patient (4.2%) in the mono‐infected patients. Reactivation of HCV infection was relatively infrequent (12.5% of cases) and never associated with a clinical deterioration. Treatment with nucleotides in HBsAg/HBV‐DNA/anti‐HCV‐positive patients with cirrhosis showed a favourable virological effect in all cases, but a favourable clinical result only in the HCV‐RNA‐negative at baseline.     

Experience with anti‐tumor necrosis factor‐α therapy in India

Aims: To review the Indian experience with anti‐tumor necrosis factor (TNF)‐α therapy. Methods: ‘PubMed’ and ‘IndMED’ were searched for Indian studies on anti‐TNF‐α therapy. Data were compiled and analysed. Results: Data on infliximab from 176 patients from five different series were collated. One hundred and forty‐seven had ankylosing spondylitis (AS), nine had polyarticular juvenile idiopathic arthritis (JIA), 12 had rheumatoid arthritis (RA), six had undifferentiated spondyloarthropathy, one had inflammatory bowel disease‐related spondyloarthritis and one had psoriatic arthritis. Thus, 155/176. (88%) had spondyloarthropathy (SpA). No screening for latent tuberculosis was done in any of the studies. One series comprising 108 cases of AS, used 3 mg/kg infliximab infusions (instead of 5 mg/kg) at 8‐weekly intervals with omission of the 2‐week and 6‐week doses. All others with SpA (n = 47) followed the standard protocol: 171/176 patients had a significant improvement. Reactivation tuberculosis developed in 5/47 (10.6%) SpA patients treated with standard doses of infliximab. This amounted to 56 times increased risk compared to baseline (0.187%). None of the 129 patients treated with 3 mg/kg infusions of infliximab developed reactivation tuberculosis (AS ?108, RA ?12, JIA ?9). The lone study on etanercept showed good efficacy in 40 patients with RA. However, seven serious adverse events occurred. Conclusions: Infliximab showed expected efficacy in SpA, RA and JIA. Reactivation tuberculosis developed in 10.6% of the SpA group treated with standard regimen. Patients treated with lower doses of infliximab which included a large subgroup of SpA patients and those with RA or JIA did not develop tuberculosis.     

Advantage of IFN‐β/α2b same‐day administration for ribavirin‐intolerant patients with chronic hepatitis C

Aim: Although interferon (IFN)/ribavirin is the mainstream combination treatment for chronic hepatitis C in patients with a high viral load, ribavirin is problematic for women of childbearing age and patients with anemia. Therefore we needed to establish a new regimen without ribavirin. Methods: We devised a new regimen (same‐day β/α2b) to administer IFN‐β and α2b on the same‐day, and compared it with IFN‐α2b alone and IFN‐α2b plus ribavirin. The cases were 36 patients (26.1%) in whom ribavirin could not be used (young women, anemia, etc.) among 138 patients who underwent IFN treatment after ribavirin release. Results: The percentages of patients withdrawing due to side‐effects were 6.8%, 18.8% and 17.0% in the treatment with same‐day β/α2b, IFN‐α2b alone and IFN‐α2b plus ribavirin groups, respectively. In genotype 1b, the sustained viral response (SVR) was 28.6% (4/14), 13.6% (3/22) and 25.0% (8/32) with a high viral load, and 91.7% (11/12), 27.3% (3/11) and 57.1% (4/7) with a low viral load for the respective groups. According to a study on viral half‐life during the early phase of IFN therapy, there was no difference among the regimens of same‐day IFN‐β/α2b, β alone, α2b alone and twice‐daily treatment with IFN‐β. Same‐day β/α2b treatment showed a significantly higher SVR rate in moving type patients with a genotype 1b/high viral load. Conclusions: Same‐day β/α2b treatment resulted in few cases where therapy was discontinued and showed a high SVR rate. This regimen is especially appropriate in cases where ribavirin has been deemed unsuitable.     

Identified OAS3 gene variants associated with coexistence of HBsAg and anti‐HBs in chronic HBV infection

The underlying mechanism of coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen antibody (anti‐HBs) is still controversial. To identify the host genetic factors related to this unusual clinical phenomenon, a two‐stage study was conducted in the Chinese Han population. In the first stage, we performed a case‐control (1:1) age‐ and gender‐matched study of 101 cases with concurrent HBsAg and anti‐HBs and 102 controls with negative HBsAg and positive anti‐HBs using whole exome sequencing. In the second validation stage, we directly sequence the 16 exons on the OAS3 gene in two dependent cohorts of 48 cases and 200 controls. Although, in the first stage, a genome‐wide association study of 58,563 polymorphism variants in 101 cases and 102 controls found no significant loci (P‐value ≤ .05/58563), and neither locus achieved a conservative genome‐wide significance threshold (P‐value ≤ 5e‐08), gene‐based burden analysis showed that OAS3 gene rare variants were associated with the coexistence of HBsAg and anti‐HBs. (P‐value = 4.127e‐06 ≤ 0.05/6994). A total of 16 rare variants were screened out from 21 cases and 3 controls. In the second validation stage, one case with a stop‐gained rare variant was identified. Fisher’s exact test of all 149 cases and 302 controls showed that the rare coding sequence mutations were more frequent in cases vs controls (P‐value = 7.299e‐09, OR = 17.27, 95% CI [5.01‐58.72]). Protein‐coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti‐HBs in patients with chronic HBV infection in Chinese Han population.     

IL‐28B (IFN‐λ3) and IFN‐α synergistically inhibit HCV replication

Genetic variation in the IL‐28B (interleukin‐28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon‐α and ribavirin. However, the mechanisms by which polymorphisms in the IL‐28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN‐λs and IFN‐α on HCV RNA replication. The anti‐HCV effect of IFN‐λ3 and IFN‐α in combination was also assessed. Changes in gene expression induced by IFN‐λ3 and IFN‐α were compared using cDNA microarray analysis. IFN‐λs at concentrations of 1 ng/mL or more exhibited concentration‐ and time‐dependent HCV inhibition. In combination, IFN‐λ3 and IFN‐α had a synergistic anti‐HCV effect; however , no synergistic enhancement was observed for interferon‐stimulated response element (ISRE) activity or upregulation of interferon ‐ stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN‐λ3‐induced gene expression occurred later and lasted longer than that induced by IFN‐α. In addition, although the genes upregulated by IFN‐α and IFN‐λ3 were similar to microarray analysis, interferon‐stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN‐α and IFN‐λ3 in combination showed synergistic anti‐HCV activity in vitro. Differences in time‐dependent upregulation of these genes might contribute to the synergistic antiviral activity.     

Safety and efficacy of faldaprevir in combination with pegylated interferon α‐2b and ribavirin in Japanese patients with genotype‐1 chronic hepatitis C virus infection

Aim

We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α‐2b and ribavirin (PegIFNα‐2b/RBV) in Japanese patients with HCV genotype‐1 infection.

Methods

Treatment‐naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response‐guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα‐2b/RBV for 24 or 48 weeks (RGT). Response‐guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment‐experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα‐2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα‐2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post‐treatment (SVR12) was a secondary end‐point.

Results

All except one patient experienced drug‐related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment‐naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively.

Conclusions

In treatment‐naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα‐2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV, with at least comparable efficacy. In treatment‐experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV. Clinicaltrials.gov NCT01579474.

     

Interferon α2–Thymosin α1 Fusion Protein (IFNα2–Tα1): A Genetically Engineered Fusion Protein with Enhanced Anticancer and Antiviral Effect

Human interferon α2 (IFNα2) and thymosin α1 (Tα1) are therapeutic proteins used for the treatment of viral infections and different types of cancer. Both IFNα2 and Tα1 show a synergic effect in their activities when used in combination. Furthermore, the therapeutic fusion proteins produced through the genetic fusion of two genes can exhibit several therapeutic functions in one molecule. In this study, we determined the anticancer and antiviral effect of human interferon α2–thymosin α1 fusion protein (IFNα2–Tα1) produced in our laboratory for the first time. The cytotoxic and genotoxic effect of IFNα2–Tα1 was evaluated in HepG2 and MDA-MB-231 cells. The in vitro assays confirmed that IFNα2–Tα1 inhibited the growth of cells more effectively than IFNα2 alone and showed an elevated genotoxic effect. The expression of proapoptotic genes was also significantly enhanced in IFNα2–Tα1-treated cells compared to IFNα2-treated cells. Furthermore, the HCV RNA level was significantly reduced in IFNα2–Tα1-treated HCV-infected Huh7 cells compared to IFNα2-treated cells. The quantitative PCR analysis showed that the expression of various genes, the products of which inhibit HCV replication, was significantly enhanced in IFNα2–Tα1-treated cells compared to IFNα2-treated cells. Our findings demonstrate that IFNα2–Tα1 is more effective than single IFNα2 as an anticancer and antiviral agent.     

Recombinant human interferon α-2b (rh IFNα-2b) therapy for steroid resistant idiopathic thrombocytopenic purpura (ITP)

The efficacy of recombinant human interferon α-2b (rh IFNα-2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases. Forty-one patients treated with rh IFNα-2b three times a week, six of 18 (33.3%) in the low dose group (150 × 10⁴IU: 3 MIU) and four of 20 (20.0%) in the high dose group (300 × 10¹⁰IU: 3 MIU) responded with platelet counts increasing to above 50 × 10⁹/L. Because of the exacerbation of thrombocytopenia and nasal bleeding, treatment was discontinued within 2 weeks in three patients out of 41 cases. On the other hand, six of nine patients (66.7%) treated with 3 MIU of IFNα-2b once a week for 8 weeks showed satisfactory response. Treatment with either administration schedule did not result in sustaining platelet counts above 50 × 10⁹/L for a long time after treatment. The results indicate that once a week administration schedule of rh IFNα-2b is more efficacious for platelet counts increasing for short period in patients who failed to respond to steroid and other medications than other schedules. The maintenance of this treatment schedule will allow sustained increased platelet levels, resulting in relief of bleeding tendency, while also being cost effective in comparison with other IFN treatment schedules and achieving better patient compliance without flu-like symptoms. © 1996 Wiley-Liss, Inc.     

‘It's magic stuff’: The experiences of patients with ankylosing spondylitis taking anti‐TNF‐α medication

Introduction: Several studies have identified the efficacy of anti‐tumour necrosis factor‐alpha (anti‐TNF‐α) treatment in ankylosing spondylitis (AS). However, few studies have explored the perceptions of patients taking this new medication. The aim of this study was to explore the impact of anti‐TNF‐α on the quality of life of people with AS. Methods: A qualitative approach was adopted to provide a holistic understanding of participants' views and experiences in the context of their overall lives. Semi‐structured interviews were undertaken and transcribed verbatim. Data were analysed using thematic analysis. Ethical approval and informed consent were obtained. Results: Eight people participated and described a significant improvement in their physical and psychological status, leading to a more positive outlook on their life. Specific areas highlighted were employment, activities of daily living, hobbies and relationships with partners and family, some of which are not captured by current AS‐specific outcome measures. Negative aspects of anti‐TNF‐α use were described as the inconvenience of monitoring and issues relating to travelling abroad. All participants expressed concern about the possibility of being withdrawn from treatment and the perceived impact this would have on their lives. Conclusions: Anti‐TNF‐α treatment has a positive impact on the lives of people with AS, such that a major concern is being withdrawn from treatment, highlighting the need to provide tailored support to people being withdrawn from treatment. To capture the full impact of anti‐TNF‐α treatment, further consideration needs to be given to the choice of appropriate outcome measures. Copyright © 2008 John Wiley & Sons, Ltd.     

Real-world efficacy and safety of Ledipasvir + Sofosbuvir and Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir combination therapies for chronic hepatitis C: A Turkish experience

Background/AimsThis study aimed to evaluate the real-life efficacy and tolerability of direct-acting antiviral treatments for patients with chronic hepatitis C (CHC) with/without cirrhosis in the Turkish population.Material and MethodsA total of 4,352 patients with CHC from 36 different institutions in Turkey were enrolled. They received ledipasvir (LDV) and sofosbuvir (SOF)±ribavirin (RBV) ombitasvir/paritaprevir/ritonavir±dasabuvir (PrOD)±RBV for 12 or 24 weeks. Sustained virologic response (SVR) rates, factors affecting SVR, safety profile, and hepatocellular cancer (HCC) occurrence were analyzed.ResultsSVR12 was achieved in 92.8% of the patients (4,040/4,352) according to intention-to-treat and in 98.3% of the patients (4,040/4,108) according to per-protocol analysis. The SVR12 rates were similar between the treatment regimens (97.2%–100%) and genotypes (95.6%–100%). Patients achieving SVR showed a significant decrease in the mean serum alanine transaminase (ALT) levels (50.90±54.60 U/L to 17.00±14.50 U/L) and model for end-stage liver disease (MELD) scores (7.51±4.54 to 7.32±3.40) (p<0.05). Of the patients, 2 were diagnosed with HCC during the treatment and 14 were diagnosed with HCC 37.0±16.0 weeks post-treatment. Higher initial MELD score (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.22–2.38; p=0.023]), higher hepatitis C virus (HCV) RNA levels (OR: 1.44, 95% CI: 1.31–2.28; p=0.038), and higher serum ALT levels (OR: 1.38, 95% CI: 1.21–1.83; p=0.042) were associated with poor SVR12. The most common adverse events were fatigue (12.6%), pruritis (7.3%), increased serum ALT (4.7%) and bilirubin (3.8%) levels, and anemia (3.1%).ConclusionLDV/SOF or PrOD±RBV were effective and tolerable treatments for patients with CHC and with or without advanced liver disease before and after liver transplantation. Although HCV eradication improves the liver function, there is a risk of developing HCC.     

HBV/HDV co‐infection in the Western Brazilian Amazonia: an intriguing mutation among HDV genotype 3 carriers

HDV infection still remains a serious public health problem in Amazonia. There are few data regarding the biomolecular aspects of HBV/HDV co‐infection in this region. We studied 92 patients HBsAg⁺/anti‐HDV IgG⁺ followed at the Hepatitis Referral Centers of Porto Velho (RO), Rio Branco and Cruzeiro do Sul (AC), Brazil, from March 2006 to March 2007 for whom the HDV and/or the HBV genotype could be determined. The HDV genotype could be determined in 90 patients, while the HBV genotypes could be positively determined in 74. HBV subgenotype F2 is the most prevalent (40.2%), followed by the subgenotypes A1 (15.2%) and D3 (8.7%), while 16.4% were other subgenotypes or genotypes, 4.3% were discordant and 15.2% were unamplifiable. Surprisingly, HDV genotype 3 (HDV‐3) was found in all of the HBV/HDV‐infected patients that could be genotyped for HDV, confirming that HDV‐3 can associate with non‐F HBV genotypes. However, a HDV‐3 mutant was found in 29.3% of patients and was more frequently associated with non‐F HBV genotypes (P < 0.001) than were nonmutant strains, suggesting that the mutation may facilitate association of HDV‐3 with non‐F HBV genotypes.