Identification of two novel subtypes of hepatitis C virus genotype 8 and a potential new genotype successfully treated with direct acting antivirals.

BACKGROUND: Hepatitis C virus (HCV) has a high genetic diversity and is classified into 8 genotypes and over 90 subtypes with some endemic to specific world regions. This could compromise direct-acting antiviral (DAA) efficacy and global HCV elimination. METHODS: We characterised HCV subtypes 'rare' to the UK (non-1a/1b/2b/3a/4d) by whole genome sequencing via a national surveillance programme. Genetic analyses to determine the genotype of samples with unresolved genotypes were undertaken by comparison with ICTV HCV reference sequences. RESULTS: Two HCV variants were characterised as being closely related to the recently identified genotype 8 (GT8), with >85% pairwise genetic distance similarity to GT8 sequences and within the typical inter-subtype genetic distance range. The individuals infected by the variants were UK residents originally from Pakistan and India. In contrast, a third variant was only confidently identified to be more similar to GT6 compared to other genotypes across 6% of the genome and was isolated from a UK resident originally from Guyana. All three were cured with pangenotypic DAAs (Sofosbuvir + Velpatasvir or Glecaprevir + Pibrentasvir) despite the presence of resistance polymorphisms in NS3 (80 K/168E), NS5A (28 V/30S/62L/92S/93S) and NS5B (159F). CONCLUSIONS: This study expands our knowledge of HCV diversity by identifying two new GT8 subtypes and potentially a new genotype.

COVID-19 mortality among people with diagnosed HIV compared to those without during the first wave of the COVID-19 pandemic in England.

OBJECTIVES: We describe COVID-19 mortality among people with and without HIV during the first wave of the pandemic in England. METHODS: National surveillance data on adults (aged ≥ 15 years) with diagnosed HIV resident in England were linked to national COVID-19 mortality surveillance data (2 March 2020-16 June 2020); HIV clinicians verified linked cases and provided information on the circumstances of death. We present COVID-19 mortality rates by HIV status, using negative binomial regression to assess the association between HIV and mortality, adjusting for gender, age and ethnicity. RESULTS: Overall, 99 people with HIV, including 61 of black ethnicity, died of/with COVID-19 (107/100 000) compared with 49 483 people without HIV (109/100 000). Compared to people without HIV, higher COVID-19 mortality rates were observed in people with HIV of black (188 vs. 122/100 000) and Asian (131 vs. 77.0/100 000) ethnicity, and in both younger (15-59 years: 58.3 vs. 10.2/100 000) and older (≥ 60 years: 434 vs. 355/100 000) people. After adjustment for demographic factors, people with HIV had a higher COVID-19 mortality risk than those without (2.18; 95% CI: 1.76-2.70). Most people with HIV who died of/with COVID-19 had suppressed HIV viraemia (91%) and at least one comorbidity reported to be associated with poor COVID-19 outcomes (87%). CONCLUSIONS: In the first wave of the pandemic in England, COVID-19 mortality among people with HIV was low, but was higher than in those without HIV, after controlling for demographic factors. This supports the strategy of prioritizing COVID-19 vaccination for people with HIV and strongly encouraging its uptake, especially in those of black and Asian ethnicity.

PrEP use and unmet PrEP-need among men who have sex with men in London prior to the implementation of a national PrEP programme, a cross-sectional study from June to August 2019.

BACKGROUND: Access to prevention options, including HIV pre-exposure prophylaxis (PrEP), remains a public health priority for gay, bisexual, and other men who have sex with men (MSM), especially in London. We describe PrEP use in a London community sample of MSM before the introduction of a national PrEP programme in October 2020. METHODS: From June-August 2019, MSM aged ≥ 18 recruited from London commercial venues were asked to self-complete a sexual health questionnaire and provide an oral fluid sample for anonymous HIV antibody testing. Descriptive analyses of demographic characteristics, service engagement and outcomes, as well as sexual risk and prevention behaviours were examined in the survey population and in those reporting current PrEP use. We performed sequential, multivariate analyses examining current PrEP use in MSM of self-perceived HIV-negative/unknown status with identified PrEP-need defined as the report of condomless anal sex (CAS) in the last three months, or the report of CAS (in the last year) with an HIV-positive/unknown status partner not known to be on HIV treatment, in reflection of UK PrEP guidelines. RESULTS: One thousand five hundred and thirty-fifth questionnaires were completed across 34 venues, where 1408 were analysed. One in five MSM of self-perceived HIV-negative/unknown status reported current PrEP use (19.7%, 242/1230). In men with PrEP-need, 68.2% (431/632) did not report current use. Current PrEP use was associated with age (aOR: 3.52, 95% CI: 1.76-7.02 in men aged 40-44 vs men aged 18-25) and education (aOR: 1.72, 95% CI: 1.01-2.92 in men with ≥ 2 years/still full-time vs no/ < 2 years of education since age 16). CONCLUSION: Among MSM in London, PrEP use is high but there is indication of unmet PrEP-need in men of younger age and lower levels of post-16 education. National programme monitoring and evaluation will require continued community monitoring to guide interventions ensuring equitable PrEP access and uptake in those who could most benefit from PrEP.

Real world SOF/VEL/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy.

Sustained viral response (SVR) rates for direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection routinely exceed 95%. However, a small number of patients require retreatment. Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is a potent DAA combination primarily used for the retreatment of patients who failed by DAA therapies. Here we evaluate retreatment outcomes and the effects of resistance-associated substitutions (RAS) in a real-world cohort, including a large number of genotype (GT)3 infected patients. 144 patients from the UK were retreated with SOF/VEL/VOX following virologic failure with first-line DAA treatment regimens. Full-length HCV genome sequencing was performed prior to retreatment with SOF/VEL/VOX. HCV subtypes were assigned and RAS relevant to each genotype were identified. GT1a and GT3a each made up 38% (GT1a n = 55, GT3a n = 54) of the cohort. 40% (n = 58) of patients had liver cirrhosis of whom 7% (n = 4) were decompensated, 10% (n = 14) had hepatocellular carcinoma (HCC) and 8% (n = 12) had received a liver transplant prior to retreatment. The overall retreatment SVR12 rate was 90% (129/144). On univariate analysis, GT3 infection (50/62; SVR = 81%, p = .009), cirrhosis (47/58; SVR = 81%, p = .01) and prior treatment with SOF/VEL (12/17; SVR = 71%, p = .02) or SOF+DCV (14/19; SVR = 74%, p = .012) were significantly associated with retreatment failure, but existence of pre-retreatment RAS was not when viral genotype was taken into account. Retreatment with SOF/VEL/VOX is very successful for non-GT3-infected patients. However, for GT3-infected patients, particularly those with cirrhosis and failed by initial SOF/VEL treatment, SVR rates were significantly lower and alternative retreatment regimens should be considered.

Transmission of hepatitis C virus in HIV-positive and PrEP-using MSM in England.

We sought to characterize risk factors and patterns of HCV transmission amongst men who have sex with men (MSM). MSM with recently acquired HCV (AHCV) were prospectively recruited ('clinic cohort') between January and September 2017. Clinical data and risk behaviours were identified and blood obtained for HCV whole genome sequencing. Phylogenetic analyses were performed, using sequences from this cohort and two other AHCV cohorts, to identify transmission clusters. Sixteen (40.0%) men in the clinic cohort were HIV-negative MSM. HIV-negative MSM were younger than HIV-positive MSM; most (81.3%) had taken HIV PrEP in the preceding year. Eighteen men (45.0%) reported injection drug use; most (34, 85.0%) reported noninjection drug use in the last year. Most in both groups reported condomless anal sex, fisting and sex in a group environment. Few (7, 17.5%) men thought partners may have had HCV. There were 52 sequences in the HCV genotype 1a phylogeny, 18 from the clinic cohort and 34 from other AHCV cohorts; 47 (90.4%) clustered with ≥1 other sequence. There were 7 clusters of 2-27 sequences; 6 clusters contained HIV-negative and HIV-positive MSM and 1 cluster only HIV-positive MSM. Four of these clusters were part of larger clusters first described in 2007. PrEP-using MSM are at risk of HCV, sharing similar risk factors to HIV-positive MSM. Phylogenetics highlights that PrEP-using and HIV-positive MSM are involved in the same HCV transmission networks. Few men demonstrated HCV awareness and risk reduction strategies should be expanded.

Immunopathological characterization of human cutaneous leishmaniasis lesions caused by Leishmania (Viannia) spp. in Amazonian Brazil.

American cutaneous leishmaniasis (ACL) is a chronic infectious disease caused by different protozoan species of Leishmania, and it is endemic in both tropical and subtropical countries. Using immunohistochemistry, we investigate the density of CD68+, lysozyme+, CD1a+, factor XIIIa+, CD4+, CD8+, CD56+, interferon (IFN)-γ+, and inducible NO synthase (iNOS+) cells. These cells were analyzed from 22 biopsy samples obtained from the lesions of ACL patients, whose infection was caused by Leishmania (Viannia) spp. Histopathological analysis showed dense mononuclear inflammatory infiltration in the dermis, which was composed of lymphocytes, macrophages, plasma cells, and discrete tissue parasitism. Granulomatous reactions were also present in the majority of cases. The density of the activated macrophages was higher than that of inactivated macrophages in the lesions. The density of Langerhans cells (CD1a+) was lower than that of dermal dendrocytes (factor XIIIa+). The density of CD8+ T lymphocytes was higher than that of CD4+ T lymphocytes. The cellular density of these immunological markers in relation to the species of Leishmania demonstrated that L. (Viannia) sp. lesions had higher IFN-γ expression than that Leishmania (Viania) braziliensis lesions. The evaluation of these markers, according to disease progression, did not reveal any significant differences. L. (Viannia) sp. infection leads to a favorable immune response in the host, as predominantly represented by lysozyme+, factor XIIIa+, CD8+ T cells, and the expression of (IFN)-γ+ at the lesion site.

A comparison of seminal hepatitis C virus (HCV) RNA levels during recent and chronic HCV infection in HIV-infected and HIV-uninfected individuals.

BACKGROUND: We aimed to characterize seminal hepatitis C virus (HCV) RNA dynamics in human immunodeficiency virus (HIV)-positive men with acute HCV infection given its potential role in sexual transmission of HCV. METHODS: Men with acute HCV infection (duration, ≤12 months) or chronic HCV infection (duration, >12 months) were prospectively recruited. Paired semen and blood samples were assayed for HCV RNA levels. Results were analyzed using χ(2), Fisher exact, Mann-Whitney U, and Kruskal-Wallis tests. RESULTS: Eighteen men (27.3%) had acute HCV and HIV coinfection, 22 (33.3%) had chronic HCV infection and HIV coinfection, and 26 (39.4%) had chronic HCV monoinfection. HCV RNA was detected in semen specimens from 29 of 66 men (43.9%). The median HCV RNA level in blood was 4.0 log IU/mL higher than that in semen. HCV RNA levels were correlated in semen and blood (r(2) = 0.142). Neither HIV positivity nor acute HCV infection was associated with an increased frequency of seminal HCV RNA detection. Among men with acute HCV and HIV coinfection, the median HCV RNA level in blood specimens from those with seminal HCV RNA was higher than that in blood specimens from those without seminal HCV RNA (P = .001). Seminal HCV RNA was detected in ≥1 sample for 26 of 35 men (74.3%) attending follow up. CONCLUSIONS: HCV RNA was detected in semen during both acute and chronic HCV infection. This was unaffected by HIV positivity or the phase of HCV infection. Elevated seminal HCV RNA levels could contribute to sexual transmission of HCV, but other factors, including high-risk behaviors, may be the main drivers for HCV transmission in HIV-infected individuals.

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.

Sexually transmitted hepatitis C infection: the new epidemic in MSM?

PURPOSE OF REVIEW: Increasing evidence has emerged for permucosal transmission of hepatitis C amongst HIV-infected MSM. RECENT FINDINGS: A rising incidence of acute hepatitis C virus (HCV) in HIV-infected MSM has been observed since 2000 in Europe, Australia, USA and Asia. Transmission appears to occur through the permucosal rather than the more usual parenteral route. Although often multifactorial, permucosal risk factors can be classified as behavioural (sexual practices and mucosally administered drugs) and biological (HIV and sexually transmitted infections). This review will describe the epidemiology of HCV infection in this cohort. Current and future treatment strategies will also be outlined in the context of novel, orally bioavailable, directly acting antiviral therapies. SUMMARY: An improved understanding of HCV epidemiology will allow implementation of more effective public health interventions to limit onward transmission of HCV.