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Rapid detection of lamivudine-resistant hepatitis B virus polymerase gene variants.

The amino acid substitution from methionine to valine or isoleucine at the YMDD (tyrosine, methionine, aspartate, aspartate) motif of the HBV polymerase gene is the main mutation responsible for resistance to lamivudine treatment. Detection of emerging HBV variants by direct sequencing of the HBV genome is excessively time-consuming for studying large numbers of clinical samples. The aim of the study was to analyse the emergence of lamivudine-resistant HBV genotypes by means of restriction fragment length polymorphism (RFLP) of the PCR product generated from a fragment of domain C of the polymerase gene, in clinical samples from patients receiving treatment. The results with this method were compared with those obtained with a direct sequencing technique. In total, 139 serum samples were studied from 37 patients with chronic hepatitis B, obtained at pre-treatment and at 9, 12, 18 and 24 months of treatment. Variants were detected by cleavage of the products of the three PCRs with the following enzymes: FokI (identifies the normal variant, YMDD, and the mutant variant YVDD), SspI (identifies the mutant variant, YIDD) and Alw44I (identifies the variant, YVDD). The digested fragments were separated by electrophoresis in 3% agarose gel. Of the 139 serum samples analysed, the wild-type YMDD sequence was detected in 106 (76%), the YVDD variant in 20 (15%) and the YIDD variant in 13 (9%) cases. The non-mutated variant, YMDD, was detected in all the pre-treatment samples. After 9 months of treatment the mutant variant was detected in four of 37 serum samples analysed (11%) (two YVDD and two YIDD). At 12 months, 12 of the 37 serum samples (32%) showed mutations in the YMDD sequence (seven YVDD and five YIDD). Among the 16 serum samples obtained at 18 months, nine had the YMDD variant (56%) (seven YVDD and two YIDD). At 24 months, variants in the YMDD sequence were detected in eight of the 12 patients treated (66%) (four YVDD and four YIDD). HBV genotypes were confirmed by direct sequencing, with consistent results. In 45% of cases, the emergence of HBV variants was not associated with ALT breakthrough. The PCR-RFLP assay used in this study, in perfect concordance with direct sequencing, is an accurate method for genotyping lamivudine-resistant HBV variants. Since it is a rapid low-cost technique, PCR- RFLP is suitable for large-scale screening of these polymorphisms in clinical samples.

Antiviral Agents↗

The simple model versus the super model: translating experimental traumatic brain injury research to the bedside.

Despite considerable investigation in rodent models of traumatic brain injury (TBI), no novel therapy has been successfully translated from bench to bedside. Although well-described limitations of clinical trails may account for these failures, several modeling factors may also contribute to the lack of therapeutic translation from the laboratory to the clinic. Specifically, models of TBI may omit one or more critical, clinically relevant pathophysiologic features. In this invited review article, the impact of the limited incorporation of several important clinical pathophysiologic factors in TBI, namely secondary insults (i.e., hypotension and/or hypoxemia), coma, and aspects of standard neurointensive care monitoring and management strategies (i.e., intracranial pressure [ICP] monitoring and ICP-directed therapies, sedation, mechanical ventilation, and cardiovascular support) are discussed. Comparative studies in rodent and large animal models of TBI (which may, in some cases, represent super models) are also presented. We conclude that therapeutic breakthroughs will likely require a multidisciplinary approach, involving investigation in a range of models, including clinically relevant modifications of established animal models, along with development and application of new innovations in clinical trial design.

Animals↗

Implications of antimicrobial resistance in the empirical treatment of community-acquired respiratory tract infections: the case of macrolides.

Macrolide resistance among pneumococci is increasing worldwide and is associated with increasing macrolide use. Recent studies show that use of macrolides and azalides increases nasopharyngeal carriage of both macrolide-resistant and penicillin-resistant pneumococci. Carriage of a resistant pneumococcus may foster dissemination. The clinical relevance of in vitro resistance has been debated. However, recent data from a matched case-control study showed that 18 (24%) of 76 patients had breakthrough bacteraemia with an erythromycin-resistant pneumococcus while taking a macrolide, whereas none of the 136 matched controls with an erythromycin-susceptible pneumococcal bacteraemia was taking a macrolide (P = 0.0000001). Moreover, five (24%) of 21 patients bacteraemic with the low-level resistant M phenotype and none of the 40 matched controls were taking a macrolide (P = 0.00157). These data indicate that macrolide resistance due to both the efflux and the methylase mechanisms is clinically relevant. Furthermore, they favour guidelines for the empirical treatment of outpatients with community-acquired pneumonia that recommend high-dose oral amoxicillin and reserve coverage of atypical pathogens for selected high-risk populations.

Animals↗

Indications for nonoperative management of ureteroceles.

PURPOSE: Ureteroceles have traditionally been managed surgically. We report our indications and outcomes of nonoperative management of ureteroceles in a select cohort. MATERIALS AND METHODS: We identified prospectively for nonoperative management 11 females and 2 males with ureteroceles associated with hydronephrosis or multicystic dysplasia (MCD). Patients presented with either a febrile urinary tract infection (3) or prenatal hydronephrosis (10). All patients were evaluated with renal and bladder ultrasound, voiding cystourethrography and mercaptoacetyltriglycine-3 furosemide renography. Two subgroups were identified, consisting of 10 duplex system upper pole ureteroceles associated with nonobstructed functional systems and 3 ureteroceles associated with a completely nonfunctional single system (2) or duplex (1) kidneys with or without MCD. Median followup was 41 months (range 13 months to 8 years). RESULTS: Of the 13 patients 9 required no surgical intervention. Of these 9 patients 3 had either a nonfunctional upper pole moiety (1) or MCD (2) that involuted, and 6 had good function of the upper pole segments relative to the lower pole without high grade obstruction on furosemide renography. Mean upper pole relative to lower pole differential function as determined by isotope renogram in these 6 patients was 40.8% (range 28% to 65%) and median drainage half-time was 5.3 minutes (4.5 to 19.3). On sonography, hydronephrosis improved in all 6 cases, with 5 (83%) decreasing to grade 0 (3) or I (2). Of these 6 cases of duplex system ureteroceles 5 had associated ipsilateral lower pole reflux of grade III (2) or IV (3). Reflux resolved in all cases. Surgery was necessary for progressive obstruction 1 patient and for breakthrough urinary tract infection in 3. The mean upper pole differential function in the operative group of 24.3% was lower than that of the nonoperative group. The initial median drainage half-time was 12.5 minutes (range 6.9 to 20). There was no significant difference between the nonoperative and operative groups in regard to hydronephrosis grade, reflux grade or ureterocele size. CONCLUSIONS: Furosemide renography can identify a select subgroup of patients with ureteroceles who are candidates for nonoperative management. Ureteroceles with nonobstructed duplex systems have better preservation of renal function and a high rate of natural resolution of hydronephrosis and reflux. Ureteroceles associated with MCD or completely nonfunctioning upper pole moieties may never require surgical management.

Female↗

Micro-endodontic nonsurgical retreatment.

Clinicians frequently encounter endodontically treated teeth that are failing. The vast majority of these cases can be predictably retreated nonsurgically. Integration of specific technology, coupled with breakthrough techniques, are described and powerfully demonstrated. This article is designed for the dental team whose vision is to preserve strategic teeth and create endodontic excellence for its patients.

Adult↗

Report of a Scientific Working Group on Serious Adverse Events following Mectizan(R) treatment of onchocerciasis in Loa loa endemic areas.

The occurrence of Serious Adverse Experiences (SAEs) following Mectizan(R) treatment of onchocerciasis in Loa loa endemic areas has been increasingly reported over the past decade. These SAEs include a severely disabling, and potentially fatal, encephalopathy, which appears to correlate with a high load of L. loa microfilariae (> 30,000 mf/ml).Previous consultations organized by the Mectizan(R) Donation Program (MDP) in 1995 and 1999 have developed useful "case" definitions of encephalopathic SAEs following Mectizan(R) treatment and have summarized available evidence on its pathogenesis and optimal clinical management. At both meetings, the need for better understanding of the pathogenesis of the encephalopathy was emphasized, including the need for biological and autopsy specimens from the affected cases.Following a recommendation at the Joint Action Forum of the African Programme for Onchocerciasis Control in December 2001, the MDP, on behalf of the Mectizan(R) Expert Committee, organized a Scientific Working Group on L. loa associated SAEs following Mectizan(R) treatment in May 2002. The present report includes the background, new evidence, conclusions and recommendations from that Scientific Working Group. The following points represent a summary of the present status:1. Although there are more and better quality clinical and epidemiological data on L. loa, the pathogenesis of the Mectizan(R)-related L. loa encephalopathy remains obscure.2. Very limited progress has been made in research on the pathogenesis of encephalopathy, because of the lack of specimens from cases, and the lack of animal models.3. There has been no particular breakthrough in terms of the medical management of patients with L. loa encephalopathy; however, a favorable outcome usually results from prompt general nursing and nutritional care which remain the major interventions.The main recommendations for future actions are as follows:1. Validate and update the mapping of L. loa with a combination of remote sensing and RAPLOA techniques.2. Conduct an expert analysis of the apparent clustering of encephalopathic SAEs reported so far.3. Investigate a possible "pre-treatment" scheme with high-dose albendazole in L. loa endemic communities at high risk of encephalopathic SAEs if treated with Mectizan(R); this study will be conducted in collaboration with WHO/TDR.4. Establish a post of Loiasis Technical Advisor for research and operational support in Cameroon, to conduct population surveys and to facilitate better data collection from SAE cases, including postmortem studies as appropriate.5. Investigate the possibility of developing an animal model of L. loa encephalopathy; this activity would be linked to the above-mentioned research agenda in Cameroon.6. Investigate the best care model for encephalopathic SAEs, including identification of early warning signs and therapeutic interventions.7. Develop further models for health education messages needed for community compliance with Mectizan(R) treatment, and family support for SAE cases.8. Conduct research studies on the safety of combination therapy of Mectizan(R) and albendazole in areas co-endemic for L. loa and lymphatic filariasis (LF) with coordination from the relevant technical bodies that oversee these issues.The above recommendations will be implemented through a continuing collaboration between the interested parties represented at the Scientific Working Group, involved in onchocerciasis control and/or the Global Programme to Eliminate Lymphatic Filariasis.

Journal Article↗

Noninvasive monitoring of hypertensive breakthrough of cerebral autoregulation in a patient with acute ischemic stroke.

BACKGROUND AND PURPOSE: We describe the first documentation of hypertensive breakthrough of cerebral autoregulation in a patient with acute stroke with transcranial Doppler sonography. CASE DESCRIPTION: A 55-year-old patient with acute left hemispheric stroke was treated with moderate hypothermia. He died of transtentorial herniation 4 days after admission. Static cerebral autoregulation (sCA) of the unaffected hemisphere was evaluated 6 times during this period and always found to be intact. A bolus application of epinephrine resulted in a hypertensive episode (mean arterial pressure (MAP) 135 mm Hg); hypertensive breakthrough of cerebral autoregulation was evident when MAP exceeded approximately 110 mm Hg. Interestingly, no such breakthrough was evident during testing of sCA, even when MAP reached 120 mm Hg. CONCLUSIONS: Our observation suggests that (1) the pace of the MAP increase is crucial for the occurrence of a hypertensive breakthrough of the cerebral autoregulation and (2) the disturbance of cerebral autoregulation is potentially longer as previously assumed.

Blood Pressure Monitoring, Ambulatory↗

Efficacy and safety of 17alpha-hydroxyprogesterone caproate in hormone replacement therapy.

The aim of the present study was to evaluate the efficacy (in terms of induction of uterine bleeding) and safety (in terms of absence of endometrial hyperplasia) of 17alpha-hydroxyprogesterone caproate (17alpha-HPC) in a therapeutic regimen for hormonal replacement after menopause. Fifty postmenopausal patients received hormone replacement therapy (HRT) for 24 weeks. The treatment regimen consisted of standard estrogen replacement therapy at commonly prescribed doses for the prevention of climacteric symptoms and 341 mg of 17alpha-HPC every 30 days. Enrolled women were told to expect withdrawal bleeding 7-10 days after the administration of 17alpha-HPC. Forty-eight patients completed the trial. In 91.7% of cases, patients experienced the expected pattern, i.e., strict withdrawal bleeding exclusive of any other form of bleeding. Breakthrough bleeding and/or other forms of abnormal bleeding affected only four women. At the 6th month none of the endometrial samplings motivated by endometrial thickness >10 mm and evidence of heterogeneous echogenicity (two cases) was positive for carcinoma. No biopsies had to be performed at the end of the 12th month of treatment. No serious adverse effect where recorded during the study period. In conclusion, our data show the efficacy and safety of 17alpha-HPC in HRT.

17 alpha-Hydroxyprogesterone Caproate↗

Cerebrovascular hemodynamics in arteriovenous malformation complicated by normal perfusion pressure breakthrough.

Catastrophic hyperemic states are known complications after the treatment of certain types of intracranial arteriovenous malformations (AVMs). A case is presented in which a large AVM was preoperatively embolized and later resected. There was clear intra- and postoperative evidence of edema and hemorrhage, which resulted in a fatal outcome. Regional cerebral blood flow (rCBF) data from this patient obtained with single photon emission computed tomography (SPECT) both before and after embolization were compared with data from four patients with similar size supratentorial AVMs treated and studied in a similar protocol who did not develop perfusion breakthrough. Pretreatment hemispheric rCBF was significantly reduced in this patient's ipsilateral hemisphere (50 ml/100 g/min) compared to the control group mean (83 +/- 9.5 ml/100 g/min). A similar relative depression was found in the contralateral hemisphere. After therapeutic embolization, the ipsilateral rCBF increased by 33 ml/100 g/min and the contralateral hemispheric rCBF increased by 30 ml/100 g/min; this embolization-induced increase in rCBF was significantly higher than in the control group. Acetazolamide, known to increase rCBF in normal tissue by 35 +/- 3%, resulted in a 56% augmentation of ipsilateral hemispheric flow before embolization in the reported patient vs. a 22 +/- 10% increase for the control group. Postembolization, this hyperresponsiveness to acetazolamide remained unchanged. It is possible that these hemodynamic derangements may indicate a dissociation between the vasoconstrictive and vasodilatory reactivity in chronically hypoperfused territories adjacent to AVMs such that pharmacological or metabolic stimuli may induce further vasodilation, but sudden redistribution of large volumes of flow will not promote protective vasoconstriction.

Aged↗

[The cerebrocardiac syndrome].

The authors describe case histories of patients with brain involvement--extensive brain strokes with blood breakthrough to the ventricles. The development of myocardial lesions (from extensive hemorrhages to the heart muscle till the development of large myocardial infarction) attests to the possibility of centrally caused disorders of coronary circulation. It is necessary to note that the development of myocardial lesion is masked, as a rule, by the clinical picture of a grave brain stroke and is not adequately detectable at ECG studies. It is believed that the development of hemorrhages in the myocardium is consequent on the reperfusion syndrome, whereas formation of myocardial infarction is the result of the spasm of the coronary arteries.

Adult↗

[New methods of oral rehabilitation. Combination preprosthetic surgical operations with endosseous screw implants].

New methods developed in 1987 by the author are described which make the setting of titanium screw implants also possible in extreme cases of mandibular and maxillary atrophy. We describe the first time the posterior mandibular sandwich procedure after lateralization of the alveolar nerve which is a new preprosthetic method even without setting of implants. The anterior mandibular sandwich procedure is a new combination of the Schettler-method 1976 and the placement of titanium implants with interpositioning of autologous as well as lyophilized sterilized bone or lyo-cartilage. A new development is the Le Fort I-osteotomy of the extremely atrophic maxilla with total removal of the mucosa from the floor of the sinus and its obliteration using bicortical iliac crest bones fixed by titanium screw implants (Sailer, 1989). Simultaneously the intermaxillary relation is corrected and a submucous vestibuloplasty performed. Another new method is the vertical maxillary sandwich procedure designed for the extreme narrow alveolar ridge; the method fills a gap of conventional preprosthetic procedures and can be used with bank bone and bank cartilage, but also together with titanium screw implants placed extraorally into iliac crest grafts which are squeezed between the maxillary alveolar lamellae. The bucco-labial bony lamella is pedicled to the submucous tissues and to the periosteum, a submucous vestibuloplasty is always performed. The new methods are a breakthrough in preprosthetic surgery which allow the setting of long implants in cases of severe mandibular and maxillary atrophy. Fixed and hybrid suprastructures are now possible in these cases. The aesthetic aspects are convincing.(ABSTRACT TRUNCATED AT 250 WORDS)

Alveolar Bone Loss↗

Pilot study on the safety and efficacy of intravenous natural beta-interferon therapy in patients with chronic hepatitis C unresponsive to alpha-interferon.

BACKGROUND: Since a large fraction of patients affected by chronic hepatitis C do not respond to alpha-interferon therapy, we planned a pilot study of intravenous beta-interferon therapy in Italian patients non responsive to several courses of alpha-interferon. METHODS: Ten Italian patients with chronic hepatitis C were treated intravenously with beta-interferon to assess the biochemical and virological responses. Each patient received intravenously 6 MU of beta-interferon daily for 7 days a week for a period of 2 months; in responders, this treatment was followed by intramuscular beta-interferon administration 6 MU three times a week for an additional 8 weeks. RESULTS: All the patients were infected by the genotype 1b of hepatitis C virus and had a high serum concentration of HCV-RNA (4.1 +/- 3.3 x 10(7) copies/ml). During intravenous therapy, 4 patients (40%) showed a complete return to normal of alanino-aminotransferase and 3 cases became HCV-RNA negative. During intramuscular beta-interferon administration, two patients breakthrough. At the end of the follow-up (six months after the end of the treatment) two patients only showed return to normal of alanino-aminotransferase, but one of them remained HCV-RNA positive. CONCLUSIONS: These results indicate that even genotype 1b of hepatitis C virus can be suppressed by intravenous beta-interferon therapy, as previously described in similar cases in Japan. The rate of sustained biochemical and virologic response was, however, low, suggesting that further studies are needed to define the best regimen to achieve eradication of hepatitis C virus infection.

Adult↗

Spontaneous pneumothorax: consecutive treatment of a series of 45 cases. Preliminary results of using therapeutic videothoracoscopy.

The appearance of procedures derived from video assisted thoracoscopy (VAT) has fostered new breakthroughs in the treatment of spontaneous pneumothorax. Our early experience with a study protocol using this technique is described. Patients admitted to our hospital in 1995 with a diagnosis of spontaneous pneumothorax were enrolled consecutively. Diagnosis was based on symptoms and pneumothorax was quantified by measuring the interpleural distance observed on the chest film. The initial treatment was pleural drainage; VAT was ordered in cases of recurrence, when lung reexpansion failed or when air leakage was persistent. Forty-five cases (30 men, 15 women) are reported. Mean age was 29 years. Eleven (24%) patients had had earlier pleural drainage but were suffering recurrences. The right side was involved in 14 (54%) cases. Initial treatment was pleural drainage and in 32 cases no other treatment was given. VAT was performed on 11 patients. In 1 (9%) patient the procedure became a minithoracotomy, or video-assisted thoracoscopic surgery. In 2 patients conventional thoracotomy was performed. Mean time the procedure lasted was 80 min. Mean follow-up was 3 months. There were no recurrences among patients treated with VAT and surgery. Our initial experience demonstrates that VAT is the technique of preference for the definitive treatment of spontaneous pneumothorax. There is less postoperative pain, increased comfort, no noteworthy morbidity, shorter postoperative hospital stays and prompt return to normal activity for the patient; these advantages lead us to choose this treatment over open surgery.

Adolescent↗

[Parenteral contraceptive drugs: depot progestins].

Depot progestins as injectables, implantables or vaginal rings are suitable for contraception in those female patients, in which risk factors (e.g. cardiovascular risk) exclude the use of estrogen-progestin mixtures. In this paper the mode of action, indications, contraindications, advantages and disadvantages of the various methods using depot-progestins are discussed. Injectables contain either medroxyprogesterone acetate or norethistronenantate; both steroids are released slowly within a limited time interval (2 to 4 months) out of a depot. The major effect is a change of the cervical mucus. Side-effects are disturbances of the menstrual cycle (e.g. breakthrough bleedings) as well as an amenorrhea after frequent use (up to 50% of all cases). The subdermal implantables (Norplant 2 or 5) release levonorgestrel out of a depot over a time period of at least 5 years. Steroid plasma levels are lower than in those patients using a progestin-only pill. Side-effects of implantables are disturbances of the menstrual cycle (e.g. breakthrough bleeding); in patients who desire to conceive a child or suffer from undesirable side-effects the implantables can be removed at every time. The progestin releasing vaginal rings are in a stage of controlled clinical trials. The advantages depend on ethe easy mode of administration (implantation or removal). Side-effects are also breakthrough bleedings.

Administration, Intravaginal↗

Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.

Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.

Anticonvulsants↗

Molecular basis of steroid-resistant nephrotic syndrome.

The identification of the underlying gene defect in some cases of steroid resistant nephrotic syndrome (SRNS) has recently led to a critical breakthrough in the understanding of the pathogenesis of nephrotic syndromes. The more severe form of hereditary nephrotic syndromes is the congenital nephrotic syndrome of the Finnish type (CNF). The causative gene, NPHS1, encodes a novel protein, nephrin which is a transmembrane protein belonging to the immunoglobulin superfamily specifically expressed in the podocyte at the slit diaphragm. Using a positional cloning approach, our group identified a gene, NPHS2, involved in a specific entity of familial SRNS characterized by early onset, complete steroid-resistance, rapid progression to ESRD and no recurrence after renal transplantation. NPHS2 encodes a novel membrane protein named podocin localized at the cytoplasmic part of the slit diaphragm. Familial autosomal dominant cases of primary FSGS have been described in adulthood. Two corresponding genes have been mapped to date, one to 19q13 and the second to 11q21-22. The former has been identified as ACTN4, the gene encoding the actin-binding protein, a-actinin 4. Other genes involved in the slit-diaphragm or the nephrotic syndrome are CD2-associated protein (CD2AP), FAT1, WT1, LMX1B, SMARCAL1. Altogether, these data demonstrate the pivotal role of the podocyte in the development and the maintenance of the glomerular filtration barrier and the crucial role of the genetic factors in the development of SRNS.

Actinin↗

Characterisation of metal-chelate methacrylate monoliths.

Monoliths are attractive stationary phases for purification of large biomolecules like proteins because of their flow-unaffected properties. Isolation of histidine containing proteins to high purity can be efficiently performed using metal-chelate interactions within a single chromatographic step. In this work, we investigated properties of commercial metal-chelate methacrylate monoliths-Convective Interaction Media (CIM). Analytical CIM disk monolithic columns and CIM 8 ml monolithic columns were used for purification of tumor necrosis factor-alpha (TNF-alpha) analog LK-801 and green fluorescence protein with 6 histidine tag (GFP-6His). In both cases, purity over 90% was achieved. Dynamic binding capacity at 10% of breakthrough was around 17-18 mg/ml for LK-801 and around 30 mg/ml for GFP-6His. Adsorption isotherm revealed that the maximal capacity is achieved at protein concentration above 60 microg/ml. Dynamic binding capacity and resolution were found to be flow unaffected.

Adsorption↗

Genetic evolution of GB virus C/hepatitis G virus (GBV-C/HGV) under interferon pressure.

The epidemiology and clinical features of chronic GBV-C/HGV infection have largely been explored, but there is little information about the mechanisms enabling GBV-C/HGV to cause persistent infection. Since analysis of the genomic variation of GBV-C/HGV under interferon pressure might provide some insight into this issue, we analyzed the nucleotide sequence variation of the 5'NC and NS3 regions in GBV-C/HGV isolates obtained sequentially from seven patients co-infected with HCV and treated with interferon. A reduction of GBV-C/HGV-RNA serum level below the detection limit of the RT-PCR assay was observed during treatment in all patients, but upon interferon withdrawal, viral RNA remained undetectable in only two patients. Among the five patients who did not clear GBV-C/HGV-RNA, viral strains emerging after treatment were identical to those present at baseline in three cases. In a further case, in whom GBV-C/HGV-RNA re-emerged during therapy (breakthrough episode), several mutations appeared in relapse samples. In the remaining patient, with a mixed infection before therapy, only one of the two GBV-C/HGV strains present at baseline was detected upon treatment withdrawal. These data raise the possibility that positive selection may act over GBV-C/HGV genome during interferon therapy, and contribute to persistence of infection with this virus.

Base Sequence↗