HCV reinfection incidence among individuals treated for recent infection.

One challenge to HCV elimination through therapeutic intervention is reinfection. The aim of this analysis was to calculate the incidence of HCV reinfection among both HIV-positive and HIV-negative individuals treated for recent HCV infection (estimated infection duration <18 months). Individuals with recent HCV infection who achieved an end-of-treatment response in four open-label studies between 2004 and 2015 in Australia and New Zealand were assessed for HCV reinfection, confirmed by sequencing of the Core-E2 and/or NS5B regions. Reinfection incidence was calculated using person-time of observation. Exact Poisson regression analysis was used to assess factors associated with HCV reinfection. The cohort at risk for reinfection (n=120; 83% male; median age 36 years) was composed of HIV-positive men-who-have-sex-with-men (53%) and people who inject drugs (current 49%, ever 69%). Total follow-up time at risk was 135 person-years (median 1.08 years, range 0.17, 2.53). Ten cases of HCV reinfection were identified, for an incidence of 7.4 per 100 py (95% CI 4.0, 13.8). Reinfection incidence was significantly higher among participants who reported injection drug use at end of or post-treatment, irrespective of HIV status (15.5 per 100 py, 95% CI 7.8, 31.1). In adjusted analysis, factors associated with reinfection were older age (aIRR 5.3, 95% CI 1.15, 51.5, P=.042) and injection drug use at end of or post-treatment (aIRR 7.9, 95% CI 1.6, 77.2, P=.008). High reinfection incidence following treatment for recent HCV infection in individuals with ongoing risk behaviour emphasizes the need for post-treatment surveillance, harm reduction strategies and education in at-risk populations.

Regional challenges: evaluation of a hepatitis outreach programme using transient elastography (FibroScan) in Victoria.

BACKGROUND: Evaluation of an outreach programme using a mobile transient elastography (TE) device (FibroScan) to improve liver disease assessment in different clinical settings. AIMS: To evaluate a programme of liver fibrosis assessment by TE and to compare fibrosis scores between different sites and patient groups. METHODS: Prospective cohort study. TE was conducted at a tertiary hospital and during outreach clinics in three different settings: community clinics, clinics for people who use drugs (PWUD) and regional clinics in rural Victoria. All patients referred for TE at the participating locations were eligible during the study period. RESULTS: A total of 200 of 623 patients was assessed and evaluated during outreach sessions (regional 100; PWUD 18; community 82). While the majority of patients in community centres were infected with hepatitis B (68%), most patients in regional clinics and in PWUD settings had hepatitis C virus (HCV) (81 and 100%, respectively). Significantly more patients assessed at regional clinics and PWUD settings presented with severe fibrosis (F3-F4, F4): regional clinics 39%; PWUD 31%; tertiary 11%; community 7%, (P <0.001). Multivariable logistic regression analysis revealed that older age, alcohol consumption, male sex, increased alanine transferase levels, HCV infection and importantly, evaluation at regional sites were independently associated with severe fibrosis. CONCLUSIONS: A TE-based outreach programme allows for assessment of liver fibrosis in varied and regional populations. The finding that patients in regional settings and PWUD presented with more advanced fibrosis should prompt improvements in healthcare to improve access for these populations.

Adoptive T cell immunotherapy for treatment of ganciclovir-resistant cytomegalovirus disease in a renal transplant recipient.

Cytomegalovirus (CMV) is a significant cause of morbidity, mortality and graft loss in solid organ transplantation (SOT). Treatment options for ganciclovir-resistant CMV are limited. We describe a case of ganciclovir-resistant CMV disease in a renal transplant recipient manifested by thrombotic microangiopathy-associated glomerulopathy. Adoptive T cell immunotherapy using CMV-specific T cells from a donor bank was used as salvage therapy. This report is a proof-of-concept of the clinical and logistical feasibility of this therapy in SOT recipients.

Immunogenicity and safety of a two-dose live attenuated varicella vaccine given to adults following autologous hematopoietic stem cell transplantation.

BACKGROUND: Immunogenicity and safety of varicella vaccine (Varilrix(™) [Oka-RIT]; GlaxoSmithKline Vaccines) in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT) were assessed (September 2003 to September 2007; NCT00792623). METHODS: Two Oka-RIT doses were given at 4.5 and 6.5 months post transplantation. Humoral immune responses were assessed using an immunofluorescence assay (anti-varicella zoster virus [VZV] antibody; cutoff 1:4) after each vaccine dose. Solicited local (8 day) and general (43 day), unsolicited (until day 43) adverse events (AEs) after each vaccine dose and serious adverse events (SAEs) (until 17.5 months post dose 2) were recorded. RESULTS: Of 45 patients, 19 were included in the according to protocol cohort for immunogenicity; 15 patients had pre- and post-vaccination serum samples positive for anti-VZV antibodies. Vaccine responses (anti-VZV antibody titer ≥1:4 in seronegative patients, and ≥4-fold increase in anti-VZV antibody titer in seropositive patients) were elicited by only 2 patients 2 months post dose 1, and by a single patient 1.5 months post dose 2. Although no major safety signals were detected, any and Grade 3 solicited AEs that were causally related to vaccination were reported by 44.8% and 10.3% patients, respectively. During the 43-day follow-up period, 3 patients developed varicella-like rash (1 vaccine-type VZV). Beyond 43 days, herpes zoster was reported in 2 patients and wild-type varicella infection in 2 patients (1 was breakthrough infection). Four non-fatal SAEs were reported by patients and considered causally unrelated to vaccination. CONCLUSION: Oka-RIT was poorly immunogenic but safe when given to adults up to 6 months post autologous HSCT, and alternative strategies are required to prevent VZV-associated complications in these populations.

Hepatitis B serological changes following allogeneic bone marrow transplantation.

Hepatitis B (HBV) reverse seroconversion (RS) in immunocompromised patients with serological evidence of past HBV infection (hepatitis B surface antigen [sAg] negative, core antibody [cAb] positive) has been reported with increasing frequency following allogeneic hematopoietic stem cell transplant (allo-HSCT). We performed a retrospective review of serial HBV serological testing in patients who had undergone allo-HSCT at our center between 2000 and 2006. We identified 12 patients with serological evidence of past HBV, including 1 case of RS. Although 7 of these 12 patients had no changes in serological markers detected after transplantation, 5 of them had declining levels of hepatitis B surface antibodies [sAb], with 2 to < 10 IU/mL. The remaining 4 patients with past HBV had loss of antiHBcAb. An additional 14 patients developed isolated antiHBcAb post allo-HSCT in the setting of receiving HBV screened (HBsAg, antiHBcAb) negative donor stem cells. Monitoring of HBV serological markers (including antiHBsAb) and HBV DNA levels pre allo-HSCT in recipients and donors, and post allo-SCT in recipients, would allow early detection and treatment of RS and identify new acquisition of HBV.

Mycobacterium genavense duodenitis following allogeneic peripheral blood stem cell transplantation.

A 56-year-old man was diagnosed with Mycobacterium genavense duodenitis 21 months after an allogeneic peripheral stem cell transplant complicated by graft-versus-host disease requiring intense immunosuppression. This duodenitis responded to prolonged therapy with clarithromycin, ciprofloxacin, and rifabutin and reduction of immunosuppression.

Characteristics and treatment outcomes among HIV-infected individuals in the Australian Trial in Acute Hepatitis C.

BACKGROUND: The Australian Trial in Acute Hepatitis C (ATAHC) is a National Institutes of Health-funded prospective cohort study of the natural history and efficacy of treatment in individuals with recently acquired hepatitis C. Enrollment is open to both human immunodeficiency virus (HIV)-infected and -uninfected individuals. The aim of this article was to evaluate characteristics and virological outcomes among HIV-infected individuals enrolled in ATAHC. METHODS: Eligibility criteria included the first positive result of testing for anti-hepatitis C virus (HCV) antibody within 6 months and either clinical hepatitis diagnosed within the past 12 months or documented anti-HCV seroconversion within the past 24 months. RESULTS: Of the initial 103 patients enrolled, 27 (26%) were HIV infected. HIV-infected patients were more likely to be older, to have HCV genotype 1 infection and high levels of HCV RNA at baseline than were HCV-monoinfected patients. Sexual acquisition accounted for the majority (56%) of HCV infections among HIV-infected patients, compared with only 8% of HCV-monoinfected patients. The median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of pegylated interferon and ribavirin resulted in rates of undetectability of HCV RNA of 95%, 90%, and 80% at weeks 12, 24, and 48, respectively. Undetectability at week 4 was achieved in 44% of patients and yielded positive and negative predictive values for sustained virological response of 100% and 33%, respectively. CONCLUSIONS: Significant differences were demonstrated between HIV-infected and HIV-uninfected individuals enrolled in ATAHC. Treatment responses among HIV-infected individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high-risk individuals and early treatment for recently acquired HCV infection.

HCV treatment with pegylated interferon and ribavirin in patients with haemophilia and HIV/HCV co-infection.

Individuals with haemophilia are frequently infected with both human immunodeficiency virus (HIV) and hepatitis C virus (HCV); however, limited evidence is currently available regarding the efficacy of HCV treatment with pegylated interferon and ribavirin in this patient population. The aim of this study was to review HCV treatment outcomes in a cohort of patients with haemophilia and HIV/HCV co-infection. A retrospective, single centre review of 13 consecutive patients treated with pegylated interferon and ribavirin was performed. All patients were male with haemophilia A and a median age of 43 (range 27-62) at initiation of HCV therapy. Nine of 13 (69%) patients had genotype (gt1) 1 HCV (3 x gt3, 1 x gt4). Twelve of 13 (92%) were receiving ART, with a mean CD4+ count of 428 cells microL(-1) (range 175-928 cells microL(-1)) at initiation of HCV therapy. Six of 11 (55%) patients achieved EVR (3 x gt1, 2 x gt3, 1 x gt4) at 12 weeks, 4/13 (31%) had EOTR (2 x gt1, 2 x gt3) and 1/13 (8%) achieved sustained virological response (1 x gt1). Seven of 11 (64%) patients normalized ALT during therapy wherein mean ALT fell from 101 to 76 U L(-1). Only 1/13 (8%) patients discontinued therapy prematurely due to side effects. CD4+ cell counts and HIV viral load remained stable during HCV treatment, with a mean 437 cells microL(-1) and <50 copies mL(-1) at 48 weeks respectively. Patients in our cohort with haemophilia and HCV/HIV co-infection responded poorly to HCV treatment. Alternative HCV treatment strategies need to be considered in patients with haemophilia and HIV/HCV co-infection.

Prolonged use of tenofovir in HIV/hepatitis B virus (HBV)-coinfected individuals does not lead to HBV polymerase mutations and is associated with persistence of lamivudine HBV polymerase mutations.

OBJECTIVES: The aim of the study was to identify and characterize hepatitis B virus (HBV) polymerase gene mutations associated with ongoing HBV replication in HIV/HBV-coinfected individuals receiving tenofovir (TDF). METHODS: This retrospective cross-sectional study identified 28 HIV/HBV-coinfected individuals who had received TDF for at least 3 months. All patients had samples available while receiving TDF (on-TDF), and 24 also had samples available prior to treatment (pre-TDF). Case records were reviewed to obtain clinical and virological data at the times of sampling (+/-3 months). The HBV DNA of all samples was amplified using polymerase chain reaction (PCR), and the polymerase region of PCR-positive samples was sequenced and compared with reference HBV data. RESULTS: Of the pre-TDF samples, 15 of 24 (63%) were HBV PCR positive. Of the on-TDF samples, four of 28 (14%) were HBV PCR positive (mean time on TDF 13.5 months; range 3-23 months). Lamivudine (3TC)-resistance mutations were detected in three of four (75%) of these viraemic samples. The previously identified putative TDF-resistance mutations, rtA194T+rtL180M+rtM204V, were not detected in any individual. CONCLUSIONS: Unique mutations in the HBV polymerase gene associated with TDF resistance are rare in HIV/HBV coinfection. 3TC-resistance mutations persist and a significant proportion of patients are HBV PCR positive despite the addition of TDF.

Gram-negative organisms predominate in Hickman line-related infections in non-neutropenic patients with hematological malignancies.

BACKGROUND: Catheter-related blood stream infections (CRBSI) cause significant morbidity and mortality in patients with hematological malignancies. Previous studies have identified a predominance of gram-positive organisms causing CRBSI but they included both neutropenic and non-neutropenic patients with solid organ and hematological malignancies. The aim of our study was to evaluate the incidence and microbiological profile of CRBSIs in a specific cohort of patients with hematological malignancies in their non-neutropenic phase of illness. METHODS: A detailed retrospective review was done from January 2003 to December 2005 on all patients with hematological malignancies who had double-lumen non-antibiotic impregnated tunneled CVCs (Hickman catheters) inserted in our hospital to identify those fulfilling our criteria for CRBSI episodes. RESULTS: Amongst 273 evaluable patients, 61 developed CRBSI on 70 occasions. In contrast to previous studies, there was a predominance of gram-negative infections (68%). The majority (73%) of initial CRBSI episodes required catheter removal within 7 days of onset. Vancomycin and cefepime was the most common initial antibiotic regimen used. CONCLUSIONS: This study highlights the predominance of gram-negative infections in our cohort of non-neutropenic patients with underlying hematological malignancies who had Hickman catheters whose lines were not salvageable in the majority of cases. Empiric monotherapy with an antimicrobial agent with broad spectrum gram-negative cover needs to be given upfront pending results of the nature and sensitivity of organisms identified.

Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04.

The reactogenicity and safety of an experimental hepatitis B (HB) vaccine containing adjuvant system (AS04) was compared with a licensed vaccine in a phase III, single-blind, randomised study in healthy volunteers >or=15 years of age. A total of 1303 subjects were enrolled to receive either two doses of HB-AS04 (0, 6 months) or three doses of the comparator vaccine (0, 1, 6 months). Two doses of HB-AS04 elicited seroprotection rates close to 100% and two-fold higher GMTs than the comparator vaccine. Results showed that both vaccines were well tolerated and the general safety profile of HB-AS04 was similar to that of the comparator vaccine.

Guidelines for the use of antifungal agents in the treatment of invasive Candida and mould infections.

ABSTRACT Treatment of invasive fungal infections is increasingly complex. Amphotericin B deoxycholate has long been the mainstay of treatment. However, there has been increasing recognition of both the propensity for nephro-toxicity in haematology, transplant and intensive care patients as well as its adverse impact on morbidity and mortality. This has coincided with the availabilty of newer, and in certain settings, more effective antifungal agents. Although the newer agents clearly cause less nephrotoxicity than amphotericin B, drug interactions, hepatic effects and unique side-effects need to be considered. The spectrum of the newer triazoles and echinocandins varies, highlighting the importance of accurate identification of the causative organism where possible. Consensus Australian guidelines have been developed to assist clinicians with treatment choices by reviewing the current evidence for the efficacy, the toxicity and the cost of these agents.

Successful allogeneic stem cell transplant after invasive pulmonary zygomycosis.

We report the successful outcome of allogeneic stem cell transplant (SCT) in a patient with acute lymphoblastic leukaemia (ALL) and pulmonary zygomycosis diagnosed prior to transplant. The lesion was surgically excised and SCT proceeded with antifungal therapy, granulocyte transfusions and G-CSF support during the period of neutropenia.

Successful treatment of foscarnet-resistant herpes simplex stomatitis with intravenous cidofovir in a child.

A leukemic child developed recurrent herpes simplex virus lesions shortly after receiving a bone marrow transplant and while taking acyclovir. The isolate was resistant to acyclovir and foscarnet in vitro. The lesions responded to a course of cidofovir.

Human immunodeficiency virus-hepatitis C coinfection: swapping new problems for newer ones.

Recent successes in HIV therapy have uncovered other health problems for HIV-infected individuals. Hepatitis C has become an especially significant problem, partly due to its faster progression in an immunocompromised setting. In addition, the higher viral loads in coinfected patients likely result in more efficient perinatal and perhaps even sexual transmission. Therapy has largely been neglected, despite data suggesting its efficacy in HIV-HCV coinfected patients. Studies of combination interferon and ribavirin studies are lacking, although underway. A major concern is the potential inactivation of certain thymidine analogues by ribavirin. Some antiretroviral therapies, such as ritonavir, indinavir and nevirapine, may enhance liver toxicity in coinfected patients and should be avoided if possible. The role of chronic low-grade liver function abnormalities remains uncertain and requires further investigation.

Abnormal cervical cytology in bone marrow transplant recipients.

Particular human papillomavirus (HPV) subtypes are implicated in the genesis of abnormal cervical cytology and cervical cancer. While most immunocompetent hosts clear HPV infection with no sequelae, some develop premalignant cytological changes of whom a minority subsequently progress to overt carcinoma. Immunocompromised patients, such as renal allograft recipients and HIV-infected individuals, have a higher rate of cytological abnormalities. This is thought to be due to prolonged persistence of virus due to impaired clearance by the immune system. We undertook a retrospective review of the cervical cytology of all women who underwent BMT at two transplant centres and who had cervical smears performed between 1990 and 1998. The rate of cytological abnormalities was significantly higher than in the general population before BMT (age-adjusted odds ratio (OR) 2.2, P = 0.02) and after BMT (OR 7.0, P < 0.0001). After BMT, allogeneic recipients had a higher rate of abnormalities than did autologous patients (OR 2.6, P = 0.02) although only allogeneic recipients had a higher rate of abnormalities post-BMT compared to pre-BMT (allogeneic OR 6.8, P = 0.004). These observations suggest that pre-transplant disease and treatment factors increase the risk of cytologic abnormalities and that transplant-related factors such as conditioning therapy and immunosuppression further increase this risk. These data suggest that more frequent screening may be required in these at-risk groups, especially allogeneic recipients. Prospective studies are required to further evaluate cytological abnormalities and HPV shedding in these populations.

Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir.

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3-80.7) months. Herpes simplex virus antibody positive (HSV+) patients received aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6-19%) at 12 months, 32% (22-42%) at 24 months and 38% (27-50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20-46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. We conclude that 3-6 months of low-dose aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD.

Homopolymer mutational hot spots mediate herpes simplex virus resistance to acyclovir.

In the majority of cases, the mechanism underlying the resistance to acyclovir (ACV) of herpes simplex viruses (HSVs) is thymidine kinase (TK) deficiency. Plaque isolates from eight ACV-resistant (ACVr) clinical isolates from AIDS patients, of which five reactivated, were sequenced to determine the genetic lesion within the tk gene conferring resistance and whether this may have correlated with reactivation potential. Mutations were clustered within two homopolymer nucleotide stretches. Three plaque isolates (1737-14, 90-150-3, and 89-650-5) had insertion mutations within a stretch of 7 guanosines, while two isolates (89-063-1 and 89-353-1) had frameshift mutations within a stretch of 6 cytosines (a deletion and an insertion, respectively). Mutations resulted in premature termination codons, and the predicted 28- and 32-kDa truncated TK products were detected by Western blot analysis of virus-infected cell extracts. The repair of one homopolymer frameshift mutation (in isolate 1737-14) restored TK activity, demonstrating that this mutation is the basis of TK deficiency. Of the five reactivated isolates, four were TK deficient and contained frameshift mutations while the fifth retained TK activity because of its altered-TK or Pol- phenotype. These data demonstrate that the majority of ACVr clinical isolates contain frameshift mutations within two long homopolymer nucleotide stretches which function as hot spots within the HSV tk gene and produce nonfunctional, truncated TK proteins.