Dimas Alexandre Kliemann

Treatment of severe chromoblastomycosis with itraconazole and 5-flucytosine association

Chromoblastomycosis is a chronic human melanized fungi infection of the subcutaneous tissue caused by traumatic inoculation of a specific group of dematiaceous fungi through the skin, often found in barefooted agricultural workers, in tropical and subtropical climate countries. We report the case of a male patient presenting a slow-growing pruriginous lesion on the limbs for 20 years, mistreated over that time, which was diagnosed and successfully treated as chromoblastomycosis. Besides the prevalence of this disease, treatment is still a clinical challenge.

Polymorphisms and resistance mutations of hepatitis C virus on sequences in the European hepatitis C virus database

AIM To evaluate the occurrence of resistant mutations in treatment-naïve hepatitis C virus (HCV) sequences deposited in the European hepatitis C virus database (euHCVdb). METHODS The sequences were downloaded from the euHCVdb (https://euhcvdb.ibcp.fr/euHCVdb/). The search was performed for full-length NS3 protease, NS5A and NS5B polymerase sequences of HCV, separated by genotypes 1a, 1b, 2a, 2b and 3a, and resulted in 798 NS3, 708 NS5A and 535 NS5B sequences from HCV genotypes 1a, 1b, 2a, 2b and 3a, after the exclusion of sequences containing errors and/or gaps or incomplete sequences, and sequences from patients previously treated with direct antiviral agents (DAA). The sequence alignment was performed with MEGA 6.06 MAC and the resulting protein sequences were then analyzed using the BioEdit 7.2.5. for mutations associated with resistance. Only positions that have been described as being associated with failure in treatment in in vivo studies, and/or as conferring a more than 2-fold change in replication in comparison to the wildtype reference strain in in vitro phenotypic assays were included in the analysis. RESULTS The Q80K variant in the NS3 gene was the most prevalent mutation, being found in 44.66% of subtype 1a and 0.25% of subtype 1b. Other frequent mutations observed in more than 2% of the NS3 sequences were: I170V (3.21%) in genotype 1a, and Y56F (15.93%), V132I (23.28%) and I170V (65.20%) in genotype 1b. For the NS5A, 2.21% of the genotype 1a sequences have the P58S mutation, 5.95% of genotype 1b sequences have the R30Q mutation, 15.79% of subtypes 2a sequences have the Q30R mutation, 23.08% of subtype 2b sequences have a L31M mutation, and in subtype 3a sequences, 23.08% have the M31L resistant variants. For the NS5B, the V321L RAV was identified in 0.60% of genotype 1a and in 0.32% of genotype 1b sequences, and the N142T variant was observed in 0.32% of subtype 1b sequences. The C316Y, S556G, D559N RAV were identified in 0.33%, 7.82% and 0.32% of genotype 1b sequences, respectively, and were not observed in other genotypes. CONCLUSION HCV mutants resistant to DAAs are found in low frequency, nevertheless they could be selected and therapy could fail due resistance substitutions in HCV genome.

Incidence of hepatocellular carcinoma in patients with chronic liver disease due to hepatitis B or C and coinfected with the human immunodeficiency virus: A retrospective cohort study

AIM To assess the incidence of hepatocellular carcinoma (HCC) in chronic liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfected with human immunodeficiency virus (HIV). METHODS A retrospective cohort study was performed, including patients with chronic liver disease due to HBV or HCV, with and without HIV coinfection. Patients were selected in the largest tertiary public hospital complex in southern Brazil between January 2007 and June 2014. We assessed demographic and clinical data, including lifestyle habits such as illicit drug use or alcohol abuse, in addition to frequency and reasons for hospital admissions via medical records review. RESULTS Of 804 patients were included (399 with HIV coinfection and 405 monoinfected with HBV or HCV). Coinfected patients were younger (36.7 ± 10 vs 46.3 ± 12.5, P < 0.001). Liver cirrhosis was observed in 31.3% of HIV-negative patients and in 16.5% of coinfected (P < 0.001). HCC was diagnosed in 36 patients (10 HIV coinfected and 26 monoinfected). The incidence density of HCC in coinfected and monoinfected patients was 0.25 and 0.72 cases per 100 patient-years (95%CI: 0.12-0.46 vs 0.47-1.05) (long-rank P = 0.002), respectively. The ratio for the HCC incidence rate was 2.98 for HIV-negative. However, when adjusting for age or when only cirrhotic are analyzed, the absence of HIV lost statistical significance for the development of HCC. CONCLUSION In this study, the presence of HIV coinfection in chronic liver disease due to HBV or HCV showed no relation to the increase of HCC incidence.

Biochemical non-invasive assessment of liver fibrosis cannot replace biopsy in HIV-HCV coinfected patients

BACKGROUND AND RATIONALE The liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis. However, this method presents limitations. In addition, the non-invasive evaluation of liver fibrosis is a challenge. The aim of this study was to validate the fibrosis cirrhosis index (FCI) index in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, and compare to AST/ALT ratio (AAR), AST to platelet ratio index (APRI) and FIB-4 scores, as a tool for the assessment of liver fibrosis in coinfected patients. MATERIAL AND METHODS Retrospective cross sectional study including 92 HIV-HCV coinfected patients evaluated in two reference centers for HIV treatment in the Public Health System in Southern Brazil. Patients who underwent liver biopsy for any indication and had concomitant laboratory data in the 3 months prior to liver biopsy, to allow the calculation of studied noninvasive markers (AAR, APRI, FIB-4 and FCI) were included. RESULTS APRI < 0.5 presents the higher specificity to detect no or minimal fibrosis, whereas APRI > 1.5 presents the best negative predictive value and FCI > 1.25 the best specificity to detect significant fibrosis. The values of noninvasive markers for each Metavir fibrosis stage showed statistically significant differences only for APRI. In conclusion, until better noninvasive markers for liver fibrosis are developed and validated for HIV-HCV coinfected patients, noninvasive serum markers should be used carefully in this population.BACKGROUND AND RATIONALE The liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis. However, this method presents limitations. In addition, the non-invasive evaluation of liver fibrosis is a challenge. The aim of this study was to validate the fibrosis cirrhosis index (FCI) index in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, and compare to AST/ALT ratio (AAR), AST to platelet ratio index (APRI) and FIB-4 scores, as a tool for the assessment of liver fibrosis in coinfected patients. MATERIAL AND METHODS Retrospective cross sectional study including 92 HIV-HCV coinfected patients evaluated in two reference centers for HIV treatment in the Public Health System in Southern Brazil. Patients who underwent liver biopsy for any indication and had concomitant laboratory data in the 3 months prior to liver biopsy, to allow the calculation of studied noninvasive markers (AAR, APRI, FIB-4 and FCI) were included. RESULTS APRI < 0.5 presents the higher specificity to detect no or minimal fibrosis, whereas APRI > 1.5 presents the best negative predictive value and FCI > 1.25 the best specificity to detect significant fibrosis. The values of noninvasive markers for each Metavir fibrosis stage showed statistically significant differences only for APRI. In conclusion, until better noninvasive markers for liver fibrosis are developed and validated for HIV-HCV coinfected patients, noninvasive serum markers should be used carefully in this population.

HAART and liver: is it safe?

INTRODUCTION Liver disease caused by hepatitis C virus (HCV) is a major cause of morbidity in HIV patients. This study investigates the possibility that chronic HCV increases the risk of hepatotoxicity after highly active antiretroviral therapy (HAART) initiation. METHODOLOGY The data from 30 coinfected HIV/HCV and 35 HIV monoinfected patients between August 2008 and August 2010, since the start of HAART, were analyzed along with data from every three months, with clinical/laboratory evaluation until the end of twelve months. The aim of this study was to assess risk and incidence of hepatotoxicity in both groups. RESULTS Before the introduction of HAART, coinfected patients had higher average levels of transaminases than did the monoinfected group (p < 0.001). After initiation of HAART, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were higher in coinfected patients, regardless of type of HAART they received. Twenty-two (73%) of the coinfected patients had some degree of hepatotoxicity versus only seven (20%) of the monoinfected patients. No patient had severe hepatotoxicity. Risk of hepatotoxicity after HAART in a coinfected patient was 3.7 times higher than in a monoinfected patient (RR 3.7 [1.8-7.4], p < 0.001). CONCLUSIONS This study demonstrates that coinfected patients are at an increased risk for developing hepatotoxicity, but the clinical and immunological benefits of HAART are higher than the risk of hepatotoxicity and rarely justify discontinuation of therapy.

Immune restoration in human immunodeficiency virus and hepatitis C virus coinfected patients after highly active antiretroviral therapy

OBJECTIVE To evaluate the influence of hepatitis C virus on immunological and virological responses after highly active antiretroviral therapy initiation in human immunodeficiency virus/hepatitis C virus coinfected patients compared to monoinfected human immunodeficiency virus-infected patients. METHODS The study enrolled 65 human immunodeficiency virus-1-infected subjects who initiated highly active antiretroviral therapy and attended follow-up visits over 48 weeks from 2008 to 2010. They were grouped based on hepatitis C virus-RNA results. Virological and immunological responses were monitored at baseline and at the end of weeks 12, 24, 36, and 48. RESULTS There were 35 human immunodeficiency virus monoinfected and 30 human immunodeficiency virus/hepatitis C virus coinfected patients. In the present study human immunodeficiency virus/hepatitis C virus coinfection did not seem to influence CD4 T-lymphocytes recovery. There was no difference between the curves of CD4 T-lymphocytes raise of coinfected and monoinfected groups. CONCLUSION This prospective study confirms that hepatitis C virus infection does not seem to be associated with impaired CD4 T-lymphocytes recovery after HAART.

Genetic Barrier to Direct Acting Antivirals in HCV Sequences Deposited in the European Databank.

Background & Aims Development of resistance results from mutations in the viral genome, and the presence of selective drug pressure leads to the emergence of a resistant virus population. The aim of this study was to analyze the impact of genetic variability on the genetic barrier to drug resistance to DAAs. Methods The genetic barrier was quantified based on the number and type of nucleotide mutations required to impart resistance, considering full-length HCV NS3, NS5A and NS5B regions segregated by genotype into subtypes 1a, 1b, 2a, 2b and 3a. This study analyzeds 789 NS3 sequences, 708 sequences and 536 NS5B sequences deposited in the European Hepatitis C Virus Database, in the following resistance-associated positions: NS3: F43/I/L/S/V, Q80K/R, R155K/G, A156G/S/T and D168A/C/E/G/H/N/T/V/Y; NS5A: L/M28A/T/V, Q30E/H/R, L31F/I/M/V, H58D or P58S and Y93C/F/H/N/S; NS5B: S282P/R/T, C316H/N/Y, S368T, Y448C/H, S556G/R, D559R. Results Variants that require only one transversion in NS3 were found in 4 positions and include F43S, R80K, R155K/G and A156T. The genetic barrier to resistance shows subtypic differences at position 155 of the NS3 gene where a single transition is necessary in subtype 1a. In the NS5A gene, 5 positions where only one nucleotide change can confer resistance were found, such as L31M which requires one transversion in all subtypes, except in 0.28% of 1b sequences; and R30H, generated by a single transition, which was found in 10.25% of the sequences of genotype 1b. Other subtypic differences were observed at position 58, where resistance is less likely in genotype 1a because a transversion is required to create the variant 58S. For the NS5B inhibitors, the genetic barrier at positions conferring resistance was nearly identical in subtypes 1a and 1b, and single transitions or transversions were necessary in 5 positions to generate a drug-resistant variant of HCV. The positions C316Y and S556D required only one transition in all genotypes, Y448H and S556 G/N/R positions required only one transition for up to 98.8% of the sequences analyzed. A single variant in position 448 in genotype 1a is less likely to become the resistance variant 448H because it requires two transversions. Also, in the position 559D a transversion and a transition were necessary to generate the resistance mutant D559H. Conclusion Results revealed that in 14 out of 16 positions, conversion to a drug-resistant variant of HCV required only one single nucleotide substitutions threatening direct acting antivirals from all three classes.

Uso do score APRI na avaliação de doença hepática, após início de terapia antirretroviral, em pacientes portadores do HIV co-infectados com HCV versus monoinfectados por HIV

INTRODUCTION The impact of highly active antiretroviral therapy (HAART) on hepatic fibrosis progression in HIV and hepatitis C virus coinfected patients is not completely understood. Noninvasive hepatic fibrosis markers show great promise in determining liver fibrosis staging and monitoring disease progression. METHODS Twenty-four patients divided equally into two groups: 12 HIV-monoinfected and 12 with HIV/HCV coinfected patients, were followed from July 2008 to August 2009, after initiating HAART, with clinical, epidemiological and laboratorial assessments every 3 months and calculation of the aspartate aminotransferase to platelet ratio index (APRI). This study aimed to compare the progression of APRI, a noninvasive hepatic fibrosis marker, among populations with HIV and HIV/HCV coinfection. RESULTS No differences were observed between the groups regarding age, sex, measurement of CD4 and HIV viral load in all consultations, type of HAART and APRI before initiating HAART. Coinfected patients showed a significantly higher APRI than the monoinfected group in month 3 (0.57 ± 0.31 x 0.27 ± 0.105, p = 0.02) and 6 (0.93 ± 0.79 x 0.28 ± 0.11, p = 0.04). CONCLUSIONS In the present study, HAART was associated with APRI increases over six months follow-up in HIV/HCV coinfected patients, suggesting that these may be experiencing cumulative hepatotoxicity and immune reconstitution inflammatory syndrome after initiating antiretroviral drugs.

Relative validity of a food frequency questionnaire in patients coinfected with hepatitis C virus and human immunodeficiency virus

INTRODUCTION: Validation of food frequency questionnaires (FFQs) is recommended for accurate measurement of habitual food consumption. We assessed the relative validity of a FFQ in patients coinfected with hepatitis C virus and human immunodeficiency virus. METHODS: Each patient responded to a FFQ and three 24-hour food recalls. Pearsons correlation and weighted Kappa index analyses were performed to identify the FFQ relative validity and concordance. RESULTS: De-attenuated correlation coefficients ranged from 0.35 (vitamin B1) to 0.81 (selenium). The concordance index ranged from 0.07 (vitamin C) to 0.51 (calcium). CONCLUSIONS: The FFQ showed satisfactory relative validity for most nutrients.

Identification of hepatitis B virus A1762T/G1764A double mutant strain in patients in Southern Brazil

Infection by hepatitis B virus (HBV) is a worldwide public health problem. Chronic HBV infection with high viral replication may lead to cirrhosis and/or hepatocellular carcinoma. Mutant HBV strains, such as the HBV A1762T/G1764A double mutant, have been associated with poor prognosis and higher risk of the patient for developing cirrhosis and/or hepatocellular carcinoma. This study analyzed the presence of the HBV A1762T/G1764A double mutant in patients with chronic HBV and its association with clinical parameters such as viral load, aminotransferases, and HBV antigens. A total of 49 patients with chronic hepatitis B were included in the study, and the HBV A1762T/G1764A double mutant strain was detected in four samples (8.16%) by polymerase chain reaction followed by restriction fragment length analysis (PCR-RFLP). The viral load was not significantly different between patients with or without the double mutant strain (p=0.43). On the other hand, carriers of the HBV A1762T/G1764A double mutant had higher levels of ALT (p=0.0028), while AST levels did not differ between groups (p=0.051). In this study, 75% of the samples with the HBV A1762T/G1764A double mutation were HBeAg negative and anti-HBe positive, reflecting seroconversion even though they still displayed high viral loads. Our study has shown that the HBV A1762T/G1764A double mutant strain circulates in Brazilian patients, and is associated with elevated levels of ALT and HBeAg seroconversion.