Joe Sasadeusz

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. Bone Marrow Transplantation (2000) 25, 657–664.

A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naïve individuals in Thailand

Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is associated with considerable liver disease morbidity and mortality. Emerging HIV epidemics in areas of high HBV endemicity such as Asia are expanding the population with HIV/HBV coinfection. Limited randomized trial data exist to support current guidelines for HBV combination therapy in HIV/HBV coinfection. The objective of this prospective randomized clinical trial was to compare the strategy of HBV monotherapy with lamivudine (LAM) or tenofovir disoproxil fumarate (TDF) versus HBV combination therapy with LAM/TDF in antiretroviral‐naïve HIV/HBV‐coinfected subjects in Thailand. Thirty‐six HIV/HBV‐coinfected subjects initiating highly active antiretroviral therapy (HAART) were randomized to either LAM (arm 1), TDF (arm 2), or LAM/TDF (arm 3) as HBV‐active drugs within HAART. At week 48, time‐weighted area under the curve analysis revealed that the median HBV DNA reduction from baseline was 4.07 log10 c/mL in arm 1, 4.57 log10 c/mL in arm 2, and 4.73 log10 c/mL in arm 3 (P = 0.70). HBV DNA suppressed to <3 log10 c/mL in 46% in arm 1, 92% in arm 2, and 91% in arm 3 (P = 0.013, intent‐to‐treat analysis). HBV‐resistant changes were detected in two subjects, both in arm 1. Hepatitis B e antigen (HBeAg) loss was observed in 33% of HBeAg‐positive subjects, and 8% experienced hepatitis B surface antigen loss. Hepatic flare was observed in 25% of subjects. Conclusion: LAM monotherapy resulted in a greater proportion of subjects with HBV DNA >3 log10 c/mL at week 48 and in early resistance development. This study confirms current treatment guidelines that recommend a TDF‐based regimen as the treatment of choice for HIV/HBV coinfection, but does not demonstrate any advantage of HBV combination therapy in this short‐term setting. (HEPATOLOGY 2008.)

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.

Immune Reconstitution Hepatitis in HIV and Hepatitis B Coinfection, Despite Lamivudine Therapy as Part of HAART

Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection occurs commonly. The introduction of antiretroviral therapy can result in immune reconstitution hepatitis. We describe 2 coinfected patients who developed clinical flares of HBV disease, despite the inclusion of lamivudine, a drug with anti-HBV activity, in their HAART regimens. Potential strategies to manage individuals with HBV/HIV coinfection are discussed.

Reduced Hepatitis B Virus (HBV)-Specific CD4+ T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy

ABSTRACT Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronically infected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4+ and CD8+ T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers (n = 34) were studied, including individuals never treated for HBV infection (n = 7), HBV-infected individuals receiving anti-HBV therapy (n = 13), and HIV-1-HBV-coinfected individuals receiving anti-HBV therapy (n = 14). CD4+ and CD8+ HBV-specific T-cell responses were more frequently detected and the CD8+ T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBV-specific T-cell response and HBV viral load. HBV-specific CD4+ and CD8+ T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8+ T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4+ T-cell responses were significantly reduced in HIV-1-HBV-coinfected individuals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.

Effect of Baseline CD4 Cell Count on the Efficacy and Safety of Peginterferon Alfa-2a (40KD) Plus Ribavirin in Patients With HIV/Hepatitis C Virus Coinfection

Objective:The impact of baseline CD4 status on hepatitis C virus (HCV) treatment response among patients with HIV/HCV coinfection was investigated using data from a randomized study of peginterferon alfa-2a (40KD) + ribavirin (Peg-IFN/RBV). Methods:Of 860 patients treated with conventional interferon alfa-2a + ribavirin (IFN/RBV), peginterferon alfa-2a (40KD) + placebo (Peg-IFN), or Peg-IFN/RBV for 48 weeks, 857 patients had baseline CD4 data available and were included in the analysis. Efficacy and safety were analyzed according to baseline CD4 status as absolute cell count and proportion of total lymphocytes. Results:Sustained virologic response (SVR) rates were highest with Peg-IFN/RBV across all CD4 strata. With Peg-IFN/RBV, SVR rates were independent of baseline CD4 in genotype 2/3 patients, but in genotype 1 patients, they tended to be higher with higher CD4 or CD4%. Frequencies of adverse events (AEs) and serious AEs were similar among treatment arms and CD4 strata. Withdrawal and dose reduction rates attributable to safety were highest with CD4 <200 cells/μL. Conclusions:Peg-IFN/RBV could be effective and well tolerated in HIV/HCV-coinfected individuals with stable HIV. With Peg-IFN/RBV, response tended to increase with higher CD4 counts in genotype 1; however, because of the paucity of patients with CD4 <200 cells/μL, these data require corroboration.

Antiviral chemotherapeutic agents against respiratory viruses: where are we now and what's in the pipeline?

Purpose of review The emergence of severe acute respiratory syndrome in late 2002 and the recent outbreaks of avian influenza in Asia are timely reminders of the ever present risks from respiratory viral diseases. Apart from influenza, there are no vaccines and very few antiviral chemotherapeutic agents available for the prevention and treatment of respiratory viral infections—the most common cause of human illness. If the current H5N1 avian influenza outbreak ever assumes the role of a pandemic, formidable technical difficulties relating to the properties of the agent, itself, will ensure that vaccines will only become available after a significant lead time and then only to a relatively small percentage of the population. The use of existing antivirals could be critical in limiting the initial spread of a pandemic, although their use in the control of epidemics caused by nonpandemic viruses has not been evaluated. It is against this background that a review of recent developments in respiratory antivirals has been undertaken. Recent findings The late 1990s were a period of unprecedented activity in the development of new and much superior antivirals for the treatment of influenza infections. However, during the past 2 to 3 years and largely for commercial reasons, there has been a decline in interest in their further development by major drug companies. This situation may soon change with the possible advent of new pandemic viruses, and moves are afoot in several countries to consider the stockpiling of antivirals. The neuraminidase inhibitors zanamivir and oseltamivir, and the M2 inhibitors amantadine and rimantadine, remain the only options for controlling respiratory disease caused by influenza viruses, although the latter two could not be used against very recent H5N1 strains. There are several other neuraminidase inhibitors in development. Compounds with activity against other respiratory viruses, notably rhinoviruses, are also in development, many based on a newer knowledge of viral protein structure and function (rational drug design). Summary The following is an overview of recent papers on the further development of neuraminidase inhibitors against influenza viruses and on recent development of newer antivirals against RSV and rhinoviruses. Where possible, comparisons are made with existing antivirals. For considerations of space, this review has been structured around stages in the replication cycle of significant respiratory viruses that have been traditionally used as targets for inhibition.

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

ABSTRACT

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. Bone Marrow Transplantation (2001) 28, 393–397.

Combination HBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HIV/HBV coinfected individuals.

Objectives:To determine if highly active antiretroviral therapy (HAART) with combination anti-hepatitis B virus (HBV) therapy compared to HAART with HBV monotherapy leads to greater HBV DNA suppression in an HIV/HBV coinfected cohort. Design:A cross-sectional analysis of 122 HIV/HBV coinfected patients from Australia and the United States. Methods:Univariate analysis and ordinal logistic regression were used to determine factors associated with an HBV DNA less than 100 IU/ml. Results:The majority of patients were on HAART (85%), had an HIV RNA less than 50 copies/ml, a median CD4 cell count of 438 cells/μl, and had prior or current lamivudine therapy (98%). The majority (89%) of those on HAART were on HBV-active drugs including 54% on tenofovir (TDF) with either lamivudine (LAM) or emtrictabine (FTC), 34% receiving LAM or FTC monotherapy, and 12% on TDF monotherapy. Only 4% of patients in the combination (TDF + LAM/FTC) group had HBV DNA greater than 20 000 IU/ml compared to 54% in the group on no HBV-active therapy, 31% in the LAM or FTC monotherapy group, and 30% in the TDF monotherapy group (P < 0.0001). In an ordinal logistic regression model, monotherapy with either TDF or LAM remained independently associated with higher HBV DNA. Conclusion:These data suggest that there may be an advantage to using TDF in combination with LAM or FTC in HIV/HBV coinfection, particularly in the setting of previous LAM experience. Continued prospective follow-up in this study will confirm whether the advantage is sustained longer-term.