Archive for April, 2006

Original Article -Variant of Hepatitis B Virus with Primary Resistance to Adefovir

Source: N Engl J Med 27 Apr 2006 vol.354 N.17 p.1807-1812

Brief Report

Oliver Schildgen, Ph.D., Hueseyin Sirma, M.D., Anneke Funk, Ph.D., Cynthia Olotu, M.S., Ulrike C. Wend, Heinz Hartmann, M.D., Martin Helm, Jürgen K. Rockstroh, M.D., Wulf R. Willems, M.D., Hans Will, Ph.D., and Wolfram H. Gerlich, Ph.D.


The reverse-transcriptase inhibitor lamivudine (Zeffix, GlaxoSmithKline) is often used to treat chronic infection with hepatitis B virus (HBV) until resistance develops. Treatment may then be switched to the reverse-transcriptase inhibitor adefovir (Hepsera, Gilead), which has a lower frequency of resistance. Here, we describe three cases of primary adefovir resistance that were sensitive to tenofovir (Viread, Gilead). All three cases involved a rare HBV variant with a valine at position 233 of the reverse-transcriptase domain instead of isoleucine (rtI233V), as in the wild-type virus. This HBV variant also displayed resistance to adefovir and sensitivity to tenofovir in vitro.

Source Information

From the Institute of Medical Microbiology and Immunology and the Department of Medicine I, University of Bonn, Bonn (O.S., J.K.R.); the Heinrich-Pette-Institut, Hamburg (H.S., A.F., C.O., H.W.); the Institute of Medical Virology, University of Giessen, Giessen (U.C.W., W.R.W., W.H.G.); the Practice for Gastroenterology and Hepatology, Herne (H.H.); and the Practice Abelein/Helm, Nuremberg (M.H.) — all in Germany.

Drs. Schildgen and Sirma contributed equally to the article. Drs. Will and Gerlich contributed equally to the article.

Address reprint requests to Dr. Gerlich at the Institute of Medical Virology, Frankfurterstr. 107, D 35392 Giessen, Germany, or at
FREE ACCESS – Full Text of this Article  www.nejm.og


April 27, 2006 at 12:20 am Leave a comment

HIV/AIDS REVIEW ARTICLE – HIV-Associated Renal Diseases and Highly Active Antiretroviral Therapy–Induced Nephropathy

Source: Clin Infect Dis 15 May 2006 Vol.42 N.10 p.1488-1495

J. Röling,1 H. Schmid,2 M. Fischereder,2 R. Draenert,1 and F. D. Goebel1

Departments of 1Infectious Diseases and 2Nephrology, Medizinische Poliklinik, Ludwig Maximilians Universität, University of Munich, Munich, Germany

Renal disease is becoming an increasingly prevalent entity in human immunodeficiency virus (HIV)–infected patients; it occurs in a variety of clinical settings and is associated with histopathological changes.

HIV-related renal impairment can present as acute or chronic kidney disease; it can be caused directly or indirectly by HIV and/or by drug-related effects that are directly nephrotoxic or lead to changes in renal function by inducing metabolic vaculopathy and renal damage. Acute renal failure is frequently caused by the toxic effects of antiretroviral therapy or nephrotoxic antimicrobial substances used in the treatment of opportunistic infections. Chronic renal disease can be caused by multiple pathophysiological mechanisms, leading to HIV-associated nephropathy, a form of collapsing focal glomerulosclerosis, thrombotic microangiopathy, and various forms of immune complex glomerulonephritis. The increase in life expectancy and alteration of lipid metabolism due to receipt of highly active antiretroviral therapy are expected to result in an increased prevalence of diabetes and hypertension and, thus, to secondary diabetic and hypertensive renal damage. Antiretroviral agents, such as indinavir and tenofovir, have been associated with nephrotoxic drug effects that have been shown to be reversible in most cases. In this article, we review the current knowledge about acute and chronic HIV-associated renal disease, metabolic alterations and related nephropathies, and toxic drug effects of combination antiretroviral pharmacotherapy.

April 26, 2006 at 12:58 am Leave a comment

HIV/AIDS MAJOR ARTICLE – Impact of Hepatitis C Virus Coinfection on Response to Highly Active Antiretroviral Therapy and Outcome in HIV-Infected Individuals: A Nationwide Cohort Study

Source: Clin Infect Dis 15 May 2006 Vol.42 N.10 p.1481-1487

Nina Weis,1 Bjarne Ø. Lindhardt,2 Gitte Kronborg,1 Ann-Brit E. Hansen,2 Alex L. Laursen,6 Peer B. Christensen,3 Henrik Nielsen,4 Axel Møller,5 Henrik T. Sørensen,7,8 and Niels Obel3

1Department of Infectious Diseases, Hvidovre Hospital, and 2Department of Infectious Diseases, Rigshospitalet, Copenhagen, 3Department of Internal Medicine, Odense University Hospital, Odense, 4Department of Infectious Diseases, Aalborg Hospital, Aalborg, 5Department of Internal Medicine, Kolding Hospital, Kolding, 6Department of Infectious Diseases, Skejby Hospital, and 7Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; and 8Department of Epidemiology, Boston University, Boston, Massachusetts

Background. Coinfection with hepatitis C virus (HCV) in human immunodeficiency virus (HIV) type 1–infected patients may decrease the effectiveness of highly active antiretroviral therapy. We determined the impact of HCV infection on response to highly active antiretroviral therapy and outcome among Danish patients with HIV-1 infection.

Methods. This prospective cohort study included all adult Danish HIV-1–infected patients who started highly active antiretroviral therapy from 1 January 1995 to 1 January 2004. Patients were classified as HCV positive (positive HCV serological test and/or HCV PCR results [443 patients {16%}]), HCV negative (consistent negative HCV serological test results [2183 patients {80%}]) and HCV-U (never tested for HCV [108 patients {4%}]). The study end points were viral load, CD4+ cell count, and mortality.

Results. Compared with the HCV-negative group, overall mortality was significantly higher in the HCV-positive group (mortality rate ratio, 2.4; 95% confidence interval [CI], 1.9–3.0), as was liver disease–related mortality (mortality rate ratio, 16; 95% CI, 7.2–33). Furthermore, patients in the HCV-positive group had a higher risk of dying with a prothrombin time <0.3, from acquired immunodeficiency syndrome–related disease, and if they had a history of alcohol abuse. Although we observed no difference in viral load between the HCV-positive and HCV-negative groups, the HCV-positive group had a marginally lower absolute CD4+ cell count.

Conclusions. HIV-HCV–coinfected patients are compromised in their response to highly active antiretroviral therapy. Overall mortality, as well as mortality from liver-related and acquired immunodeficiency syndrome–related causes, is significantly increased in this patient group.

April 26, 2006 at 12:56 am Leave a comment


Source: Clin Infect Dis 15 May 2006 Vol.42 N.10 p.1449-1454

Kevin P. High, Section Editor

Victor Valcour1 and Robert Paul2

1Hawaii AIDS Clinical Research Program and the Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu; and 2Department of Psychiatry and Human Behavior, Brown Medical School, Providence, Rhode Island

Human immunodeficiency virus (HIV) infection in older patients is becoming increasingly common as seropositive individuals live longer because of long-term antiretroviral treatment. Simultaneously, the development and expression of dementia among HIV-infected patients is evolving in the era of highly active antiretroviral therapy (HAART) and immune reconstitution. How long-term HAART interacts with chronic HIV infection and advanced age with regard to cognition is not fully understood. This article provides an overview of HIV cognitive impairment as it relates to aging and presents some emerging issues in the field. Particular emphasis is placed on describing the changing landscape of HIV-related cognitive impairment and discussing possible concerns regarding the long-term effects of antiretroviral treatment. A brief discussion of potential adjunctive therapies to reduce cognitive symptoms associated with HIV infection in older individuals is provided.

April 26, 2006 at 12:53 am Leave a comment

BRIEF REPORT – The Poor Prognosis of Central Nervous System Cryptococcosis among Nonimmunosuppressed Patients: A Call for Better Disease Recognition and Evaluation of Adjuncts to Antifungal Therapy

Source: Clin Infect Dis 15 May 2006 Vol.42 N.10 p.1443-1447

Ismail Zafer Ecevit,1 Cornelius J. Clancy,1,3 Ilona M. Schmalfuss,2,3 and M. Hong Nguyen1,3

Departments of 1Medicine and 2Radiology, University of Florida College of Medicine, and 3Veteran's Affairs Medical Center, Gainesville, Florida

We describe 9 nonimmunosuppressed patients with central nervous system cryptococcosis. Morbidity and mortality were high, especially among patients with cerebral infarcts. This was attributed to delayed diagnosis and apparent sequelae of overwhelming host immune responses. We present clues suggesting the diagnosis. Increased recognition and timely diagnosis of this condition may improve outcomes.

April 26, 2006 at 12:50 am Leave a comment

MAJOR ARTICLE – Diagnosis of Invasive Aspergillosis Using a Galactomannan Assay: A Meta-Analysis

Source: Clin Infect Dis 15 May 2006 Vol.42 N.10 p.1417-1727

Christopher D. Pfeiffer,1 Jason P. Fine,2 and Nasia Safdar1

Departments of 1Medicine and 2Biostatistics, University of Wisconsin Medical School, Madison, Wisconsin

Background. A double-sandwich enzyme-linked immunosorbent galactomannan assay has been approved for surveillance for invasive aspergillosis in immunocompromised patients. We undertook a meta-analysis to assess the accuracy of a galactomannan assay for diagnosing invasive aspergillosis.

Methods. Studies of the galactomannan assay that used the European Organization for Research and Treatment of Cancer or similar criteria as a reference standard and provided data to calculate sensitivity and specificity were included. Pooled sensitivity and specificity and summary measures of accuracy, Q* (the upper left-most point on the summary receiver-operating characteristic curve), mean D (a log odds ratio), and Youden index were calculated. Subgroup analyses were performed to explore heterogeneity.

Results. Twenty-seven studies from 1966 to 28 February 2005 were included. Overall, the galactomannan assay had a sensitivity of 0.71 (95% confidence interval [CI], 0.68–0.74) and specificity of 0.89 (95% CI, 0.88–0.90) for proven cases of invasive aspergillosis. The Youden index, mean D, and Q* were 0.54 (95% CI, 0.41–0.65), 2.74 (95% CI, 21.12–3.36), and 0.80 (95% CI, 0.74–0.86), respectively, indicating moderate accuracy. Subgroup analyses showed that the performance of the test differed by patient population and type of reference standard used. Significant heterogeneity was present.

Conclusions. The galactomannan assay has moderate accuracy for diagnosis of invasive aspergillosis in immunocompromised patients. The test is more useful in patients who have hematological malignancy or who have undergone hematopoietic cell transplantation than in solid-organ transplant recipients. Further studies with attention to the impact of antifungal therapy, rigorous assessment of false-positive test results, and assessment of the utility of the test under nonsurveillance conditions are needed.

Received 8 November 2005; accepted 19 December 2005; electronically published 14 April 2006.
Presented in part: 43rd Annual Meeting of the Infectious Diseases Society of America, San Francisco, California, 6–9 October 2005 [abstract 284].

April 26, 2006 at 12:48 am Leave a comment

Update: Guillain-Barré Syndrome Among Recipients of Menactra® Meningococcal Conjugate Vaccine — United States, October 2005–February 2006

Source: MMWR April 7, 2006 v.55 N.13 p.364-366

In October 2005, a possible association between Guillain-Barré Syndrome (GBS) and receipt of meningococcal conjugate vaccine (i.e., meningococcal polysaccharide diphtheria toxoid conjugate vaccine [Menactra®])* (MCV4) was reported (1). GBS is a serious neurologic disorder involving inflammatory demyelination of the peripheral nerves. At the time of the first report, five confirmed cases of GBS after receipt of MCV4 had been reported to the Vaccine Adverse Events Reporting System (VAERS). During the 4 months since, three additional confirmed cases of GBS have been reported. This report describes two of these recent cases and provides additional data collected through February 2006. Because available evidence neither proves nor disproves a causal relation between MCV4 and GBS, further monitoring and studies are ongoing within VAERS and the Vaccine Safety Datalink (VSD). CDC continues to recommend use of MCV4 for persons for whom vaccination is indicated (1); the additional reported cases have not resulted in any change to that recommendation.

Case Reports

Brief clinical and epidemiologic descriptions of two of the newly reported cases follow. The third case is undergoing detailed clinical investigation but meets the provisional case definition for GBS.†

Case 1. On August 8, 2005, a male aged 19 years from Arizona was vaccinated with MCV4. Approximately 25 days later, he experienced numbness and tingling in his hands and feet, followed by weakness in his legs, difficulty running, and decreased dexterity in his hands. In the month before neurologic symptom onset, he had no defined episode of respiratory or gastrointestinal illness. He had traveled to Mexico twice during the preceding 3 months. Electrophysiology studies revealed a diffuse neuropathic process with both demyelinating and axonal features, consistent with GBS. Testing for Epstein-Barr virus capsid IgG and IgM antibodies was negative. Testing for cytomegalovirus IgG and IgM antibodies also was negative, as were serologic studies for hepatitis A, B, and C to rule out other probable causes of GBS. The patient was treated with intravenous immunoglobulin. At follow-up examination 8 weeks after onset, he had fully recovered.

Case 2. On November 4, 2005, a male aged 17 years from Ohio received MCV4. Eleven days later, he experienced numbness and tingling in his right foot, followed by the same symptoms in the left foot, which progressed proximally during the next 5 days. He also described a neck hyperextension injury sustained while playing sports 2 days before the start of sensory symptoms and sore throat and congestion 1 day before sensory symptoms. He had no gastrointestinal illness during the 6 weeks before hospital admission, which occurred 6 days after symptom onset. Cervical spine radiographs revealed no fractures; magnetic resonance imaging (MRI) of the spine revealed mild enhancement along the surface of distal cord and lumbar nerve roots, consistent with GBS. Nerve conduction studies also were consistent with GBS. Polymerase chain reaction (PCR) assays for enterovirus were negative, as were tests for Mycoplasma pneumoniae IgG and IgM. The patient was treated with intravenous immunoglobulin. At follow-up examination 2 weeks after admission, he had completely recovered.

In the two cases described in this report, the period from MCV4 vaccination to symptom onset was less than 6 weeks. This is the time window of elevated risk noted for GBS after administration of certain other vaccines (2).

To determine whether the reporting rate of GBS after MCV4 vaccination was higher than the expected incidence rate of GBS for the appropriate age group population, the reporting rate was calculated by dividing the eight confirmed GBS cases with onset within 6 weeks of vaccination by the number of vaccine doses distributed as provided by the manufacturer (approximately 3.77 million doses of MCV4 were distributed during March 2005–February 2006). The eight cases were divided by the 3.77 million distributed doses to provide the reporting rate for GBS after MCV4. The expected incidence rate of GBS was estimated from a multistate hospital discharge database (Health Care Utilization Project).§ For the years 2000–2003, the incidence rate of GBS among persons aged 11–19 years was estimated to be 1.4 per 100,000 population per year or 0.17 per 100,000 population during a 6-week period. Therefore, the ratio of the reporting rate of GBS after MCV4 vaccination to the expected incidence rate was 1.4 (95% confidence interval = 0.7–2.8), suggesting that the occurrence of eight cases of GBS within 6 weeks of MCV4 administration is similar to what might be expected to occur by chance alone.

As part of the investigation, other possible causes of GBS, such as Campylobacter jejuni, were assessed. C. jejuni is a leading cause of gastroenteritis globally and the most frequent antecedent pathogen in GBS (3). No evidence of C. jejuni was observed in any of the eight cases reported; however, many C. jejuni infections are asymptomatic. No serum samples from GBS cases reported after MCV4 vaccination were available for testing. To further assess the possibility that C. jejuni was a precipitating cause, unpublished data were collected and analyzed from all five state health departments involved in initial GBS case reports to VAERS (Arizona, New Jersey, New York, Ohio, and Pennsylvania). Despite an expected seasonal peak of GBS cases from June to October 2005 (CDC, unpublished data, 2005), none of the involved states reported outbreaks of C. jejuni during this period.

Reported by: Center for Biologics Evaluation and Research, Food and Drug Admin. Arizona State Health Dept. New Jersey Dept of Health and Senior Svcs. New York State Dept of Health. Columbus City Health Dept, Columbus, Ohio. Pennsylvania Dept Health. Immunization Safety Office, National Immunization Program; National Center for Infectious Diseases; F Soud, PhD, EIS Officer, CDC.

Editorial Note:

In October 2005, CDC and the Food and Drug Administration (FDA) alerted health-care providers about a possible association between GBS and MCV4 and encouraged reporting of adverse events to VAERS (1). Since that time, three additional confirmed cases of GBS with onset within 6 weeks of MCV4 vaccination have been reported. However, even with these reported cases, the reported incidence remains similar to the expected incidence. In addition, three other cases of GBS have been reported, with symptom onsets at >6 weeks (107 days, 116 days, and 125 days) after vaccination with MCV4; these three cases were not included in calculation of GBS rates. Because VAERS is a voluntary reporting system, the completeness of reporting of GBS remains unknown. Only three cases were reported since October 2005, suggesting that MCV4 might not be causally related to GBS. The background incidence rate of GBS is one to two cases per 100,000 population. However, the timing of onset of neurologic symptoms within 2–5 weeks of vaccination is still a concern.

Additional preliminary data from VSD,¶ a collaborative project between CDC and eight managed care organizations in the United States, have not identified GBS cases in MCV4 recipients. However, VSD has a limited ability to detect rare health events such as GBS. To further evaluate any potential risk, additional controlled studies of GBS after MCV4 are being planned.

The case definition developed for the initial investigation has been refined by an extended working group of the Brighton Collaboration,** an international voluntary collaboration of scientists. The Clinical Immunization Safety Assessment Network,†† in collaboration with CDC, continues to research and conduct standardized clinical evaluation of affected vaccinees to better understand the pathophysiology of select adverse events after vaccination, such as GBS. In response to the evaluation of the reported cases to VAERS, Sanofi Pasteur and FDA updated the Menactra vaccine package insert to list previous GBS as a contraindication and provide a warning of the temporal relation between GBS and MCV4 (4).

In October 2005, CDC recommended continuing use of MCV4 for persons for whom vaccination is recommended; the additional cases reported in this update do not affect that recommendation (1). In December 2005, the Global Advisory Committee on Vaccine Safety also recommended no change in MCV4 vaccination policies (5).

The Advisory Committee on Immunization Practices has recommended that persons with a history of GBS should not be vaccinated with MCV4 unless they are at elevated risk for meningococcal disease (6). Persons at elevated risk for meningococcal disease include first-year college students living in dormitories, military recruits, travelers to areas in which meningococcal disease is hyperendemic or epidemic, microbiologists who are routinely exposed to isolates of Neisseria meningitidis, patients with anatomic or functional asplenia, and patients with terminal complement deficiency. Information regarding the current investigation should be shared with adolescents and caregivers before MCV4 vaccination. A Vaccine Information Statement and fact sheet noting the information on the reported GBS cases is available at An updated fact sheet for health-care workers is available at CDC continues to recommend that health-care workers and any other persons aware of adverse events associated with MCV4 or any other vaccination report to VAERS cases of GBS or any other clinically significant adverse events. Reports may be submitted securely online at or by fax at 877-721-0366. Reporting forms and additional information is available at telephone, 800-822-7967.


1- CDC. Guillain-Barré syndrome among recipients of Menactra® meningococcal conjugate vaccine—United States, June–July 2005. MMWR 2005;54:1023–5.

2- Schonberger LB, Bergman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barré syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol 1979;110: 105–23.

3- Takawashi M, Koga M, Yokoyama K, Yuki N. Epidemiology of Campylobactor jejuni isolated from patients with Guillain-Barré and Fisher syndrome in Japan. J Clin Microbiol 2005;43:335–9.

3- Food and Drug Administration. Meningococcal (sero groups A,C,Y, and W 135) polysaccharide toxoid conjugate vaccine, Menactra®. Available at

4- World Health Organization. Conjugate meningococcal vaccine and Guillain-Barré Syndrome. Wkly Epidemiol Rec 2006;2:13–20.

5- CDC. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005;54(No. RR-7):1–21.

* Sanofi Pasteur (Swiftwater, Pennsylvania).

† Available at

§ Available at

¶ Available at

** Information available at

†† Available at

April 19, 2006 at 6:31 pm Leave a comment

Older Posts


April 2006
« Mar   May »

Posts by Month

Posts by Category