Combination antiviral and anti-CMV immunoglobulin therapy for CMV infection: A case-control study.

Antiviral drugs decrease the pain and enhance the resolution of acute herpes zoster lesions in immunocompetent patients [1-6]. However, the effect of antiviral therapy on postherpetic neuralgia (PHN) remains controversial. Whereas some studies reported a lower incidence of prolonged pain with antiviral therapy [4], others found no benefit with respect to prolonged pain [5]. In an attempt to improve patient comfort and long-term outcome with respect to PHN, combinations of different drugs have also been evaluated [5-7]. Anecdotal reports have suggested that electroacupuncture may be helpful in the management of herpes-related pain [8,9]. Clinical experience with a novel form of electroanalgesia known as percutaneous electrical nerve stimulation (PENS) in the treatment of patients with acute herpes zoster suggested that it is effective in decreasing herpes-related pain and is associated with rapid resolution of the cutaneous lesions (Craig WF, Taylor SM, Fort Worth Center for Pain Management, personal communication, 1997). Therefore, we designed this clinical study to compare PENS therapy with a standard antiviral regimen with respect to the severity of the associated pain, impact on the patient's physical activity and quality of sleep, resolution of the herpes lesions, and incidence and severity of PHN. Methods After obtaining institutional review board approval and written, informed consent, 50 adult patients (27 female and 23 male) with the recent acute onset (<72 h) of herpes zoster lesions were administered one of two different treatment modalities according to a randomized, single-blind study design. Exclusionary criteria included known hypersensitivity to the antiviral drugs, preexisting neurological impairment, women who were pregnant or nursing, any previous experience with acupuncture-like therapies, the presence of the zoster rash for >72 h, or secondary complications from the viral infection. The patients were randomly assigned using a computer-based program to either the control group (which received famciclovir 500 mg three times a day for 1 wk) or the experimental group (which received PENS therapy for 30 min three times a week for 2 wk). The PENS therapy consisted of the placement of 32-gauge stainless steel acupuncture-like needle probes into the soft tissue to a depth of 1-2 cm at dermatomes one level above and below the cutaneous lesions (Figure 1 and Figure 2). The needle probes were connected to a low-output (5 mAmp) electrical generator and stimulated at frequencies ranging from 4 to 100 Hz. Patients in both treatment groups were evaluated daily by a physician (HEA) not involved in either the famciclovir or PENS treatments. The patients were instructed not to use any topical medications or systemic treatments during the 2-wk study period.Figure 1: The "arc" montage was applied initially when the lesions were wet during the first week of therapy, consisting of bipolar leads connected to needle probes placed in the soft tissues at one dermatomal level above and below the acute lesions. Each lead was connected to a pair of needles, alternating the positive (+) and the negative (-) electrode positions as shown.Figure 2: The "vertical" montage was applied after the lesions became crusted during the second week of therapy, consisting of bipolar leads stimulating across the dermatomal region from C4 to C7. Each lead was connected to a pair of needles, alternating the positive (+) and the negative (-) positions as shown.Before receiving the study treatments, all patients were asked to assess their baseline degree of pain, level of physical activity, and quality of sleep using three separate 100-mm visual analog scales (VAS), with 0 = minimal (lowest) to 100 = maximal (highest). All patients were instructed to return to the medical center daily during the 2-wk study period to assess the appearance of their cutaneous lesions and to complete the pain, physical activity, and quality of sleep VASs. At the end of the study period, all patients were asked to complete a global assessment questionnaire to evaluate the change in pain, physical activity, and quality of sleep using the VASs. The assessment of the cutaneous lesions was performed by a blind observer and included: 1) location of the rash; 2) severity of the rash (i.e., number of the lesions in the involved dermatomes) using the following classification system: mild (<25), moderate (25-50), or severe (> 50); 3) the last day that new lesions appeared; 4) the first day without any new lesions; 5) the first day with full crusting of the lesions; and 6) the time to complete healing of the lesions. All patients were contacted at 3-, 6-, and 9-mo intervals to inquire about the presence of pain in a dermatomal pattern corresponding to the level of the acute lesions (i.e., PHN). The severity of the PHN pain was quantified using the 100-mm pain VAS. Changes in the VAS scores were analyzed by using analysis of variance, with t-tests used to determine intergroup differences and Bonferroni's adjustment for multiple comparisons. Analysis of discrete data was performed using the chi squared test, with P values <0.05 considered statistically significant. Results The two treatment groups were similar with respect to demographic characteristics, including the location and severity of the herpetic lesions (Table 1). The PENS group experienced more rapid resolution of the vesicles and complete healing of the lesions (Table 2). The VAS pain scores were consistently lower in the PENS group during the 2-wk observation period (Table 3). On the global assessment questionnaire, the percent decrease in the VAS pain score was 67% in the PENS group compared with 45% in the control group (P < 0.05). The percent improvement in the VAS physical activity and quality of sleep scores (78% vs 60% and 55% vs 37%, respectively) was also greater in the PENS- versus famciclovir-treated patients at the end of the second week. The older patients (>or=to50 yr) were more likely to develop PHN symptoms, and PENS therapy was associated with a decrease in the severity of pain at 3 and 6 mo in this subpopulation (Table 2). However, no differences in PHN symptoms were apparent at the 9-mo follow-up assessment period.Table 1: Demographic Characteristics of Patients with Acute Herpes Zoster Receiving Antiviral Drug (Control) or PENS TherapyTable 2: Effect of Antiviral Drug (Control) or PENS Therapy on Resolution of Acute Herpes Zoster Lesions and the Incidence and Severity of Postherpetic NeuralgiaTable 3: Effect of Antiviral Drug (Control) or PENS Therapy on Pain Scores, Physical Activity, and Quality of Sleep in Patients with Acute Herpes ZosterDiscussion This comparative study suggests that PENS, a novel, nonpharmacologic analgesia technique, may be a viable alternative to antiviral drugs for the treatment of acute herpes zoster lesions. The use of PENS therapy provided pain relief, increased physical activity, and an improved quality of sleep that compared favorably with a standard antiviral therapy. In this preliminary study, PENS therapy was also more effective than famciclovir in preventing PHN-related pain symptoms 3 and 6 mo after resolution of the cutaneous lesions. Although this study can be criticized because it did not include a placebo (or sham) group, the benefits of antiviral therapy have been firmly established during the acute phase of the illness, and other investigators [4] have suggested that it would be unethical to include a placebo treatment group. The outcome assessments were blinded because the physician making the assessment was unaware of the treatment that the patients were receiving. Furthermore, the small cutaneous needle puncture sites (0.2 mm) produced by the PENS probes were not apparent to the individual performing the clinical assessments. Nevertheless, future studies should include a sham PENS group that receives the antiviral therapy in combination with the needle probes but without electrical stimulation. Unfortunately, the inclusion of a sham PENS group would not blind the patients because it does not mimic the sensation provided by the electrical stimulation associated with PENS therapy. The improved physical activity and quality of sleep during the second week of treatment in the PENS group may be secondary to the decrease in the intensity of pain. Although the mechanism of PENS-induced analgesia is not known, it may be related to both neural modulation produced by the electrical stimulus [10] and an increase in endogenous morphine-like substances (e.g., dynorphins, endorphins, enkephalins) within the central nervous system [11]. Using a rat model for studying electroacupuncture, Chen et al. [12] reported that an alternating 2-Hz and 15-Hz pattern of electrical stimulation was more effective than a fixed frequency of stimulation at either 2 Hz or 100 Hz in producing experimental analgesia. In a clinical study, Han et al. [11] reported that low-and high-frequency electrical stimulation resulted in increased cerebrospinal fluid levels of met-enkephalin and dynorphin, respectively. Further studies are clearly needed to determine the precise central nervous system mechanism(s) of PENS-induced analgesia. Because herpes zoster is caused by a reactivation of the varicella virus residing in the sensory ganglia and spinal cord after the primary viral infection, the beneficial effects of PENS therapy may also be related to electrical stimulation of the involved peripheral sensory nerves. The electrical current can produce localized vasodilation and may stimulate the release of antiinflammatory mediators at the site of injury. Further studies evaluating the efficacy of PENS therapy in immunosuppressed patients would be helpful in understanding the basis for its apparent analgesic and antiinflammatory activity. However, PENS therapy should be evaluated as a supplement to antiviral therapy in this high-risk patient population. In conclusion, PENS therapy is a unique nonpharmacologic approach to treating immunocompetent patients with acute herpes zoster that compared favorably with standard antiviral drug therapy in this preliminary study.

An Assessment of Herpesvirus Co-infections in Patients with CMV Disease: Correlation with Clinical and Virologic Outcomes

Human Cytomegalovirus and Kidney Transplantation: A Clinician's Update

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are important causes of acute neurologic illness. Although the role of acyclovir in treating HSV encephalitis is clear, the role of antiviral therapy in HSV meningitis remains controversial. In this retrospective observational study, we reviewed the charts of all patients with cerebrospinal fluid specimens positive for HSV-1 or HSV-2 by polymerase chain reaction between July 2000 and November 2012. Patients' charts were reviewed for demographic data, clinical presentation, treatment, and clinical outcomes. Forty-two patient-episodes were clinically classified as meningitis. In 6 episodes (14.3%), patients with meningitis received no antivirals, whereas the remaining episodes were treated with an oral antiviral (n = 11 [26.2%]), combination intravenous and oral therapy (n = 22 [52.4%]), or intravenous acyclovir alone (n = 3 [7.1%]). Six patients had recurrent episodes of meningitis and all recovered without any neurologic sequelae. Neurologic outcomes were significantly improved with antiviral therapy in immunocompromised patients with herpes meningitis (P < .05), but not in the 27 patient-episodes among immunocompetent patients (P = 1.0), as no neurologic sequelae were noted in this group. Most patients with HSV meningitis rapidly improve, but immunocompromised hosts have more neurologic sequelae and may benefit from antiviral therapy. Our data suggest symptomatic treatment alone for immunocompetent patients with HSV meningitis, avoiding the cost and side effects of prolonged intravenous acyclovir therapy; in contrast, immunocompromised patients had improved outcomes and would therefore benefit from antiviral therapy.

This Month in Gastroenterology

BACKGROUND:Chronic hepatitis C virus infection represents a more frequent cause of liver cirrhosis and hepatocellular carcinoma. Statins, inhibit HCV replication in vitro, enhance the antiviral effect of the already known antiviral drugs and reduce their resistance.AIM:To determine the impact of additional therapy (treatment with Atorvastatin 20 mg) to the standard antiviral therapy (pegylated interferon alpha-peg-IFN α and ribavirin) on achieving sustained virological response (SVR).MATERIAL AND METHODS:In the study which is comparative, open-label, prospective-retrospective, 70 patients diagnosed with chronic hepatitis C virus infection who met criteria for treatment with standard antiviral therapy combined with anti-lipemic therapy (Atorvastatin 20 mg) were included. Patients in the study were divided into two groups: one group of 35 patients receiving combination therapy (Atorvastatin + peg-IFN α + Ribavirin) and another group of 35 patients received only standard antiviral therapy. Those parameters were followed in all patients: genotyping, quantification of the virus, histological assessment of liver inflammation and fibrosis degree (before starting treatment), the presence of steatosis, laboratory analysis: hematology, liver, lipid and carbohydrate status, insulin blood level (the calculation of HOMA-IR) and body mass index (BMI) calculation. The overall treatment of the patients depends from the virus genotype, thus, patients with genotype 1 and 4 received 48 weeks standard antiviral therapy, but patients with genotypes 2 and 3 received 24 weeks of antiviral therapy. SVR was considered an undetectable level of HCV RNA levels 24 weeks after completion of antiviral therapy. The results were statistically analysed, and all results for p < 0.05 were considered statistically significant.RESULTS:Combination therapy leads to a slightly higher percentage of SVR (85.71%) in patients with chronic hepatitis C versus standard therapy (74.29%), but in a group of patients with genotype 3 this rate of SVR amounting to 95.83%. Combination therapy leads to significant improvement of lipid and glucose status after treatment, and in terms of side effects, there was no appearance of serious adverse events that would be a reason for discontinuation of the therapy.CONCLUSION:Combination therapy Atorvastatin + pegylated interferon alpha + Ribavirin leads to high rate of SVR of 95.83% in patients with chronic hepatitis C, genotype 3. Statins can be used safely in patients with chronic hepatitis C.

Detection of the potentiality before the actuality: Measurement of T-cell proliferation before cell division occurs.

Cytomegalovirus Infection

Herpes simplex virus (HSV) and cytomegalovirus (CMV) infections are commonly seen in immunocompromised patients, particularly in patients with HIV. However, fulminant CMV infection and concurrent infection with HSV and CMV in non-HIV patients are quite rare. We present the case of a 72-year-old HIV-negative man with a history of oropharyngeal carcinoma in remission and recent treatment of immune thrombocytopenic purpura with high-dose steroids who was transferred from an outside hospital for Ear Nose and Throat (ENT) evaluation of a non-healing buccal ulcer. During initial presentation, the patient was found to be febrile with acute hypoxic respiratory failure and a chest x-ray suggestive of bacterial pneumonia, though he failed to improve with broad-spectrum antibiotic therapy. He underwent esophagogastroduodenoscopy for dysphagia, which revealed a discrete ulcer positive for CMV. Biopsy of his buccal lesion was ultimately positive for HSV-1 and HSV-2. The patient’s clinical status improved significantly following the initiation of antiviral therapy.It is important to consider CMV infection in the setting of persistent fever, respiratory distress, or dysphagia in the non-HIV infected patient, especially in the setting of prolonged steroid use. CMV and HSV infection can occur simultaneously at distinct sites in the body, and CMV infection may predispose to HSV reactivation due to its long term effect on cell-mediated immunity. Early recognition of opportunistic infections and initiation of antiviral therapy in immunocompromised patients can greatly affect length of hospital stay, morbidity, and, ultimately, mortality.

Over the past several years, there have been advances in the diagnosis and treatment of cutaneous viral diseases in elderly patients. Herpes zoster is caused by reactivation in adults of the varicella-zoster virus (VZV) that causes chickenpox in children. For many years, aciclovir was the gold standard of antiviral therapy for the treatment of herpes zoster. Famciclovir and valaciclovir are newer antivirals, which offer less frequent administration. Postherpetic neuralgia (PHN) refers to pain lasting 2 months or more after an acute attack of herpes zoster. The pain may be constant or intermittent. The treatment of established PHN may include topical anaesthetics, analgesics, tricyclic antidepressants and anticonvulsants, and nonpharmacological therapy may be used to complement such treatment. Therapeutic strategies to prevent PHN include the use of oral corticosteroids, nerve blocks, and treatment with standard antiviral therapy. The three most recently discovered human herpes viruses (HHV-6, HHV-7 and HHV-8), in common with the other members of the family, may cause a primary infection, establish latent infection in a specific set of cells in their host, and then reactivate if conditions of altered immunity develop. These viruses have been associated with an array of disorders, which are important for the clinician to recognise. Cytomegalovirus (CMV) is a member of the herpesvirus family that is very prevalent worldwide. More than 80% of primary infections and 20% of reactivation-producing symptoms occur in transplant populations. Treatment options include intravenous administration of ganciclovir, foscarnet or cidofovir. Herpes simplex virus (HSV) most commonly affects the genital and perioral regions. In the elderly, HSV infection is typically manifest at the vermilion border of the lip. The main concern of recurrent herpes labialis in the elderly is related to potential autoinoculation of the eye or genital area. Treatment with aciclovir, famciclovir or valaciclovir is indicated for these infections. Molluscum contagiosum is caused by a poxvirus, which produces cutaneous lesions that appear as small, firm, umbilicated papules. Immunocompromised patients often do not respond to the usual destructive therapies, and intravenous or topical cidofovir may be useful in these patients.

CMV Infection after Transplant from Cord Blood Compared to Other Alternative Donors: The Importance of Donor-Negative CMV Serostatus

recommendation (should be done, but did not reach the essential level); c, depended on the conditions; and d, disapproval (deleted, unreasonable, unnecessary, incompatible with national conditions, inoperatable, not assessable, and no need to include this item in the consensus).

This systematic review does not demonstrate any significant effects of amantadine on all-cause mortality or liver-related morbidity composite outcome and on adverse events in patients with hepatitis C; however, the median trial duration was 12 months, with a median follow-up of six months, which is not long enough to assess the composite outcome sufficiently. Overall, we did not see an effect of amantadine on failure to achieve a sustained virological response. Subgroup analyses demonstrated that the combination of amantadine plus interferon-alpha and ribavirin seems to increase the number of patients achieving a sustained virological response. This finding may be caused by both systematic errors (bias) and risks of random errors (play of chance), but it could also be real. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine for patients with chronic hepatitis C will show strong benefits. Therefore, it is probably advisable to wait for the results of trials assessing other direct-acting antiviral drugs. In the absence of convincing evidence of benefit, the use of amantadine is justified in the context of randomised clinical trials assessing the effects of combination therapy. We found a lack of evidence on other aminoadamantanes than amantadine.

Although many studies have shown that cytomegalovirus (CMV) infection is an exacerbating factor in patients with ulcerative colitis (UC), there is no valid method to distinguish CMV infection requiring therapy from that disappearing without therapy. The aim of this study was to describe whether or not the endoscopic feature of a large ulcer predicts the necessity of antiviral therapy against CMV infection in active UC patients with positive mucosal viral assay. Active UC patients in whom CMV infection was detected by mucosal polymerase chain reaction (PCR) assay were enrolled in this prospective observational clinical study. Patients with a large ulcer (ulcerated group) were treated with antiviral and UC therapy. Patients without a large ulcer (non-ulcerated group) were treated with only UC therapy. We prospectively evaluated the clinical and endoscopic findings in all of the patients 2 months after starting this protocol, and observed their outcomes during one year. In the ulcerated group (n=10), 3 patients still had active disease at 2 months and underwent colectomy. Although the other 7 patients achieved remission at 2 months, 4 of the 7 patients had a flare-up, and the remaining 3 patients maintained remission. All of the patients in the non-ulcerated group (n=10) attained remission without antiviral therapy at 2 months, and maintained remission. In active UC patients with positive CMV DNA by mucosal PCR assay, the absence of a large ulcer suggests latent CMV infection, and requires no antiviral therapy.

JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2.