Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure.

BACKGROUND & AIMS: Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT). METHODS: We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated. RESULTS: A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H. CONCLUSIONS: We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. IMPACT AND IMPLICATIONS: There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Hodgkin Lymphoma after Disseminated Mycobacterium genavense Infection, Germany.

Mycobacterium genavense infection, a rare nontuberculous mycobacteria infection, occurs in heavily immunocompromised patients (i.e., those with advanced HIV disease, genetic disorders, or acquired immunologic disorders and those undergoing immunosuppressive therapy). We report a case of disseminated M. genavense infection preceding Hodgkin lymphoma in a patient without obvious risk factors for this infection.

Sexual Health in HIV-Positive Men Under Stable Antiretroviral Therapy During a 12-Month Period.

BACKGROUND: Sexual health is becoming increasingly important for many HIV-positive men undergoing highly effective antiretroviral therapy (ART) but remains frequently unaddressed in routine clinical consultation. AIM: To comprehensively evaluate sexual health in male patients with HIV on stable ART over a 12-month period. METHODS: The prospectively registered cohort study comprising 87 HIV-positive men on stable ART (median age: 43 years) was conducted between 2011 and 2015 at a university hospital. Patients were enrolled from the outpatient infectious disease unit and underwent an extensive andrological workup to assess parameters of sexual health (questionnaires, sex hormones, ultrasound, 2-glass urine test including semen analysis with microbiological and viral diagnostics). The study period per patient lasted 12 months. OUTCOME: The primary endpoint was the impact of chronic HIV infection on sexual health. RESULTS: Although, on average, sexual health was fine at baseline, 56% of the patients reported erectile dysfunction, 28% experienced reduced libido, 5% had hypogonadism, 36% showed at least 1 atrophic testicle with a volume of <10 ml, 8% suffered bacterial sexually transmitted infections, 35% had seminal inflammation, and up to 47% showed reduced sperm quality. Sexual satisfaction was linked to mental health (12-Item Short Form Health Survey questionnaire) and International Index of Erectile Function scores. During the study period, the collected parameters on sexual health were generally stable. However, 35% of patients had new sex partners (median: 5 partners), 7% had fathered a child or were planning procreation, 47% reported changed libido, 17% suffered bacterial sexually transmitted infections in the urogenital tract, 16% revealed a positive HIV viral load in blood, 11% had a positive HIV viral load in semen, and 28% were treated for andrological disorders. CLINICAL IMPLICATIONS: Sexual ill-health exists in about one third of patients. This manifests itself in sexual dysfunction, sexually transmitted infections, urogenital tract inflammation, and abnormal sperm parameters, all of which require adequate counseling and therapy. STRENGTH AND LIMITATIONS: The strength of this study is its comprehensive analysis of male sexual health over a 12-month period of stable ART treatment. Limitations are a heterogeneous patient cohort and a rather small percentage of patients with a positive HIV viral load in blood or semen, which prevented multivariate risk analysis. CONCLUSION: Our study provides evidence that sexual health should be actively taken into account in the routine consultation by infectious disease specialists, and an interdisciplinary approach is desirable in the case of symptoms or signs of sexual ill-health. Pilatz A, Maresch CC, Discher T, et al. Sexual Health in HIV-Positive Men Under Stable Antiretroviral Therapy During a 12-Month Period. J Sex Med 2021;18:284-294.

Treatment outcomes in hepatitis C virus genotype 1a infected patients with and without baseline NS5A resistance-associated substitutions.

BACKGROUND&AIMS: The presence of baseline resistance-associated substitutions (RASs) reduced sustained virologic response (SVR) rates in chronic hepatitis C virus (HCV) genotype 1a infected patients treated with Elbasvir/Grazoprevir (EBR/GZR). This study aimed to evaluate the frequency of NS5A RASs and treatment outcomes in patients for whom EBR/GZR was intended. METHODS: We sequenced NS5A in 832 samples from German genotype1a-infected DAA-naïve patients population-based, which were collected in the European Resistance Database. Treatment outcomes and clinical parameters were evaluated in 519 of these patients retrospectively. RESULTS: Overall, 6.5% of patients harbored EBR-specific NS5A RASs at baseline, including Q30H/R (3.3%), L31M (1.8%), Y93H (1.6%) and other individual variants. Antiviral treatment, including EBR/GZR, was initiated in 88% of patients. In the absence of RASs, the majority of patients received EBR/GZR for 12 weeks (57%) and the SVR rate was 97% compared to 99% SVR achieved using other DAA regimens (LDV/SOF±RBV, G/P, PrOD+RBV, VEL/SOF). Various regimens were used in the presence of RASs and SVR rates were high following treatment with LDV/SOF (100%), G/P (83%), PrOD/RBV (100%), VEL/SOF (100%), SMV/SOF (100%) and EBR/GZR+RBV for 16 weeks (100%). However, two patients received EBR/GZR for 16 weeks without RBV and one relapsed. CONCLUSIONS: EBR/GZR treatment with or without RBV for 12 or 16 weeks according to a baseline RAS analysis was highly effective with ≥97% SVR in patients with genotype 1a. EBR/GZR without RBV should be avoided in patients with RASs. High SVR rates were also achieved using other 8 or 12 weeks DAA regimens.

Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.

BACKGROUND: Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE: To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN: Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING: 10 university and 11 academic hospitals in Germany. PATIENTS: 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION: Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS: The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS: 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS: Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION: Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE: Roche Pharma and Lundbeck.

Neurosyphilis manifesting with unilateral visual loss and hyponatremia: a case report.

BACKGROUND: Syphilis is called the chameleon of the diseases due to its variety of its clinical presentations, potentially affecting every organ of the body. Incidence of this ancient disease is once again on the increase worldwide. CASE PRESENTATION: We here report an unusual case of neurosyphilis manifesting with unilateral visual loss and hyponatremia. The patient also had primary syphilitic lesions and was concomitantly diagnosed with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection. Treatment with ceftriaxone and prednisolone, completely resolved the hyponatremia and visual acuity was partially restored. CONCLUSION: Awareness of syphilis as a differential diagnosis is important as previously unreported presentations of neurosyphilis can arise, especially in HIV infected patients.

Influence of gender on cytokine induced depression and treatment: Gender aspects of IFN-α-induced depression.

BACKGROUND: Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. METHODS: Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. RESULTS: We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. CONCLUSIONS: Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

The Presentation, Diagnosis, and Treatment of Sexually Transmitted Infections.

BACKGROUND: The reported incidence of sexually transmitted infections (STIs) in Germany is rising. For example, the number of new reported cases of syphilis rose from 3034 in 2010 to 4410 in 2012. METHODS: This review is based on pertinent articles retrieved by a selective search in MEDLINE, and on guidelines and systematic reviews from Germany and abroad. RESULTS: We discuss sexually transmitted infections presenting with genital, anal, perianal, or oral ulcers, urethritis, cervicitis, urethral or vaginal discharge, or genital warts. We also discuss sexually transmitted infection with HIV and the hepatitis C virus (HCV). Acquired sexually transmitted infections elevate the risk of transmission of other sexually transmitted infections; thus, patients presenting for the diagnosis or treatment of any kind of sexually transmitted infection should be evaluated for others as well. For most of these diseases, treatment of the patient's sexual partner(s) is indicated. Diagnostic nucleic acid amplification techniques are over 90% sensitive and specific and are generally the best way to detect the responsible pathogen. Factors impeding effective treatment include antibiotic resistance (an increasing problem) and the late diagnosis of HIV and HCV infections. CONCLUSION: Sexually transmitted infections are common around the world, and any such infection increases the patient's risk of contracting other types of sexually transmitted infection. Molecular genetic diagnostic techniques should be made widely available.

Magnetic Resonance Imaging of the Lung as an Alternative for a Pregnant Woman with Pulmonary Tuberculosis.

We report a case of a pregnant 21-year-old woman with pulmonary tuberculosis in which magnetic resonance imaging of the lung was used to assess the extent and characteristics of the pathological changes. Although the lung has been mostly ignored in magnetic resonance imaging for many decades, today technical development enables detailed examinations of the lung. The technique is now entering the clinical arena and its indications are increasing. Magnetic resonance imaging of the lung is not only an alternative method without radiation exposure, it can provide additional information in pulmonary imaging compared to other modalities including computed tomography. We describe a successful application of magnetic resonance imaging of the lung and the imaging appearance of post-primary tuberculosis. This case report indicates that magnetic resonance imaging of the lung can potentially be the first choice imaging technique in pregnant women with suspected pulmonary tuberculosis.

Semen quality in HIV patients under stable antiretroviral therapy is impaired compared to WHO 2010 reference values and on sperm proteome level.

OBJECTIVES: To investigate semen quality in HIV patients under stable antiretroviral therapy (ART) compared with WHO 2010 reference values and on the sperm proteome level. DESIGN: Between 2011 and 2013, we prospectively enrolled 116 HIV-positive men without hepatitis B or C co-infections from our outpatient department for infectious diseases. METHODS: Patients received a comprehensive andrological work-up. Complete semen analysis was performed according to WHO 2010 recommendations, with each semen variable of the study population being compared with the WHO reference group (n~2000). Correlation analysis was done to investigate the influence of HIV surrogate parameters on semen quality. Two-dimensional gel electrophoresis and subsequent protein identification was performed to determine any differences in the sperm protein composition of the 15 HIV-positive patients and that of 15 age-matched healthy men. RESULTS: Median values of all assessed semen parameters were within a normal range. However, for each semen variable, about 25% of patients had values below the fifth percentile of the WHO 2010 reference group. Disease-related parameters (CD4þ cell count, viral load, CDC stage, duration of disease, duration of ART, number and type of antiretroviral drugs) were not significantly correlated with any sperm parameter. Sperm proteome analysis identified 14 downregulated proteins associated with sperm motility and fertility. CONCLUSION: This is the first study that compares all standard semen parameters in HIV positive patients under ART to WHO 2010 reference values. It provides evidence of impaired conventional semen parameters and altered sperm protein composition. Finally, HIV surrogate parameters are not suitable for predicting semen quality.

Variable ratio of hepatitis C virus RNA to viral core antigen in patient sera.

Quantification of hepatitis C virus (HCV) core antigen and RNA in serum samples leads to a highly variable ratio of both. It is not clear whether this is due to the inaccuracy of RNA quantification or whether both are independent parameters in a certain range. We established a real-time reverse transcription (RT)-PCR for HCV RNA that combines very high sensitivity with a large dynamic range and minimal standard deviations. The assay was calibrated with the first international standard, 96/790, and the international genotype panel for HCV from the National Institute of Biological Standardisation and Control. A linear readout was obtained between 200 and 5 x 10(7) IU/ml. The detection limit was 80 IU/ml, the reproducibility was <0.05 log, and the standard error within one run was <0.01. Comparison of the method with the Roche Monitor competitive RT-PCR revealed its high accuracy. The core protein concentration was determined within a range from 1.5 to 400 pg/ml by using the preliminary trak-C assay from Ortho Clinical Diagnostics. Correlating the HCV RNA levels with core antigen concentrations in 197 serum samples from 23 interferon-treated patients, a average ratio of 7,900 IU of HCV RNA per pg of core antigen was estimated, but the variability of this ratio exceeded largely the variability of the two assays, ranging from 50 to 20,000 IU/pg. Theoretically, HCV should contain ca. 43,000 IU of RNA/pg core. In conclusion, the core antigen assay seems to detect, in addition to complete virions, RNA-free core protein structures, which enhances its sensitivity (98% in this group). The variable ratio of RNA and core protein is not mainly due to standard deviations of quantification but could be an additional parameter for treatment follow-up and state of viral replication.