Use of contraindicated antiretroviral drugs in people with HIV/HCV coinfections receiving HCV treatment with direct-acting antivirals-Results from the EuroSIDA study.

OBJECTIVES: Our objective was to determine whether antiretroviral drugs (ARVs) were used according to the European AIDS Clinical Society (EACS) guidelines for people with HIV/hepatitis C virus (HCV) coinfection treated with direct-acting antivirals (DAAs) between 30 November 2014 and 31 December 2019 in the pan-European EuroSIDA study. METHODS: At each publication date of the EACS guidelines, plus 3 and 6 months, we calculated the number of people receiving DAAs with potential and actual ARV contraindications ('red shading' in the EACS guidelines). We used logistic regression to investigate factors associated with using contraindicated ARVs. RESULTS: Among 1406 people starting DAAs, the median age was 51 years, 75% were male, 57% reported injected drug use as an HIV risk, and 76% were from western Europe. Of 1624 treatment episodes, 609 (37.5%) occurred while the patient was receiving ARVs with potential contraindications; among them, 38 (6.2%; 95% confidence interval [CI] 4.3-8.2) involved a contraindicated ARV (18 non-nucleoside reverse transcriptase inhibitors), 16 involved protease inhibitors, and four involved integrase strand transfer inhibitors. The adjusted odds of receiving a contraindicated ARV were higher (3.25; 95% CI 1.40-7.57) among participants from east/central east Europe (vs. south) and lower (0.22; 95% CI 0.08-0.65) for 2015-2018 guidelines (vs. 2014). In total, 29 of the 32 (90.6%) patients receiving a contraindicated ARV and 441 of the 461 (95.7%) with potential ARV contraindications experienced a sustained virological response ≥12 weeks after stopping treatment (SVR12; p = 0.55). CONCLUSION: In this large heterogenous European cohort, more than one-third of people with HIV/HCV coinfection received DAAs with potential ARV contraindications, but few received a contraindicated ARV. Use of contraindicated ARVs declined over time, corresponding to the increased availability of ARV therapy regimens without interactions with DAA across Europe. Participants who received a contraindicated DAA and ARV combination still had a high rate of SVR12.

BK polyomavirus associated progressive multifocal leukoencephalopathy in a person living with HIV.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the white matter central nervous system occurring in immunocompromised patients particularly those with T cell deficiency such as in HIV, haematological and solid organ malignancies and those taking immunomodulatory medications. PML is caused by JC virus however in rare cases BK virus has been isolated in the cerebral spinal fluid of patients presenting with PML. In this case we describe a 49 year old man who presented to the emergency department with a 2 week history of progressive right sided weakness and dysarthria. His background history included HIV diagnosed in 2005, he had not engaged with care in the past 2 years and had not been taking anti-retroviral therapy (ART). Other past medical history included untreated hepatitis C. His CD4 count was 90 (11%) cells/mm3 on admission and his HIV viral load VL) was 141,000 copies/ml. Magnetic resonance imaging(MRI) showed a hypointense lesion on T1, hyperintense on T2 and FLAIR without diffusion restriction and without mass effect. A lumbar puncture was performed which confirmed JC virus was positive (PCR <50 copies/ml) and also revealed BK virus was positive (PCR 46,511 copies/ml). The patient was commenced on tenofovir alafenamide fumarate/emtricitabine/darunavir/cobicistat in combination with dolutegravir 50mg twice daily. On day 40 post commencement of ART the patient was readmitted with worsening of his right arm weakness and dysarthria. A repeat MRI was performed which showed the hyperdense lesion on T2 and FLAIR appeared slightly larger with some slight enhancement with gadolinium contrast but no other features suggesting PML immune reconstitution inflammatory syndrome (IRIS). The CD4 count had increased to 141(17%) and HIV VL had decreased to 85 copies/ml. A clinical diagnosis of PML IRIS was made and the patient was commenced on prednisolone 30mg BD which lead to an initial improvement in symptoms. Interestingly in this case, both JC virus and BK virus were detected in the CSF of this patient with the level of JC virus being too low to quantify. BK virus was not detectable on peripheral serum sampling suggesting that BK virus is replicating in the CNS independent of other body sites. There have been 5 case reports in the literature of BK virus as the cause of PML. Testing for BK virus should be considered in patients presenting with signs and symptoms of PML and encephalitis particularly when no other cause is found.

Successful Treatment of Cryptococcal Meningitis and Cryptococcoma with Isavuconazole in a Patient Living with HIV.

We describe the successful use of isavuconazole for treatment of an HIV-positive patient with cryptococcal meningitis following induction therapy with liposomal amphotericin B and flucytosine. Because the Cryptococcus neoformans isolate from cerebrospinal fluid had a borderline minimum inhibitory concentration of 8 mg/L, initial consolidation therapy was given with a daily dose of fluconazole 1200 mg based on area under the curve to minimum inhibitory concentration modelling data. Toxicity, and the radiological emergence of a cryptococcoma in the setting of immune reconstitution inflammatory syndrome, prompted a therapeutic switch to isavuconazole. Subsequent imaging after 19 weeks of isavuconazole shows a significant reduction in cryptococcoma size from 11 mm to complete resolution. The patient remains well after 210 days of therapy with a view to completion of treatment after 1 year.

Virtual HIV pre-exposure prophylaxis outpatient service in the era of COVID-19.

In the midst of the COVID-19 pandemic, health care providers have had to rapidly change how they deliver care to patients. We discuss how we are delivering a virtual HIV pre-exposure prophylaxis (PrEP) service during this time; challenges faced; challenges expected and goals for the coming months.

High rates of unprotected anal sex and use of generic direct-acting antivirals in a cohort of MSM with acute HCV infection.

The role of condomless anal intercourse (CAI) as a driver for the epidemic of hepatitis C in MSM is still debated. Timely access to direct-acting antivirals (DAA) could represent an essential strategy to tackle this. Case notes of MSM diagnosed with acute hepatitis C (AHC) between July 2016 and June 2017 in a sexual health clinic in London were included. Behavioural data on sexual practices and STI monitoring in the 6 months prior to AHC diagnosis were collected. DAA routes of access and timing from AHC diagnosis to start of treatment were analysed. A total of 60 individuals were enrolled (median age 39 years, IQR = 33-46, 62% HIV co-infected, 72% genotype 1a). CAI was reported by 97%, drug use prior to or during sex by 73%; 46% was diagnosed with a rectal STI and 29% with syphilis. About 37% did not report any HCV risk factors other than condomless anal sex. About 36% had a new rectal STI in the 6 months following AHC. About 82% accessed DAA treatment and median time from AHC to DAA start was 278 days for those following the NHS standard of care route, 132 days for those accessing DAA via participation in trials and 114 for those who had self-sourced DAA online (P < 0.0011). SVR12 was achieved in 100% of the patients who received DAA treatment.In conclusion, CAI is a significant risk factor for HCV acquisition in MSM, irrespective of their HIV status. Rapid and wider access to treatment with DAA could represent a powerful strategy to reduce onward transmission and risk of reinfection in MSM.

Evolution of a pre-exposure prophylaxis (PrEP) service in a community-located sexual health clinic: concise report of the PrEPxpress.

Screening and treatment of sexually transmissible infections, including HIV, are free in the UK nations; pre-exposure prophylaxis (PrEP) became free in England in October 2017 through the PrEP Impact trial. Doctor-led PrEP clinics started at 56 Dean Street in September 2015, with the drug purchased privately at full price. The service was expanded to other staff to support initiation and monitoring of increasing numbers of attendees purchasing PrEP from online pharmacies. Nonetheless, when the clinic was given a target of 1700 for the PrEP Impact trial, it was clear this could not be achieved in a timely manner through 56 Dean Street alone. To prepare for the trial, all staff with HIV testing competencies were trained in good clinical practice and trial-specific procedures, and a patient group directive was approved to facilitate nurse prescribing and dispensing. Electronic pro formas to capture eligibility for starting or continuing PrEP were adapted for the Dean Street Express clinic, with some information collected directly from service users using touch screens. These interventions, together with an update to the 2016 information leaflet developed by the community, enabled enrolment and follow-up of 1700 participants in 4 months. PrEP advice and monitoring were easily accommodated in the 56 Dean Street sexual health service, but did require additional training and approval for nurse prescribing and dispensing drug in order to achieve the target, which still fell short of the demand.

Pharmacokinetics and pharmacodynamics of the nucleoside sparing dual regimen containing rilpivirine plus darunavir/ritonavir in treatment-naïve HIV-1-infected individuals.

BACKGROUND: We aimed at investigating the antiviral activity and the pharmacokinetics of the dual antiretroviral (ARV) combination of rilpivirine plus darunavir/ritonavir 25/800/100 mg once-daily in naïve HIV-1-infected individuals (NHII) with different baseline viral loads. SETTINGS: Pharmacokinetic/pharmacodynamics study in ARV-naïve HIV-infected individuals. METHODS: The primary endpoint was the number of NHII with HIV-RNA < 40 copies/mL at week 48. Secondary endpoints included rilpivirine/darunavir/ritonavir pharmacokinetics, HIV-RNA decay, and changes in ECG QT interval. RESULTS: Thirty-six individuals were enrolled, 18 with a baseline viral load < 100,000 copies/mL (group A) and 18 with a baseline viral load > 100,000 copies/mL (group B). All but 1 (HIV-RNA = 63 copies/mL) subjects achieved viral load < 50 copies/mL by week 36, and all at week 48. Median (range) HIV-RNA reduction (Log10 copies/mL) was 1.3 (0.6-1.9) over the first week, with no differences between groups A and B. Geometric mean and 95%CI rilpivirine Cmax, Ctrough, AUC were 183 (165-239), 114 (104-109) ng/mL, 2966 (2704-3820) ng h/mL. No QTcF interval changes were recorded. CONCLUSIONS: rilpivirine/darunavir/ritonavir could be efficacious, with limited short-term toxicity in ARV-naïve patients. Although rilpivirine was co-administered with ritonavir, its exposure was within ranges measured during phase III trials.

Chronic Hepatitis E as a cause for cryptogenic cirrhosis in HIV.

Chronic Hepatitis E infection (HEV) is reported in immunocompromised patients. A 45-year-old HIV-infected man had no cause found for a persistent transaminitis which predated commencement of antiretroviral therapy. Hepatic elastography and liver biopsy revealed cirrhosis. In 2010, he tested positive for HEV IgM/IgG antibodies. Plasma HEV RNA was detected. Archived samples revealed HEV viraemia since 2000. A 24-week course of pegylated interferon was commenced and HEV RNA became undetectable at week 4 until week 27 post treatment cessation. Chronic HEV infection should be considered in HIV patients as a cause for unexplained transaminitis and cryptogenic liver cirrhosis.

Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.

UNLABELLED: Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. CONCLUSION: Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.

Early proteomic analysis may allow noninvasive identification of hepatitis C response to treatment with pegylated interferon α-2b and ribavirin.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection represents a significant disease burden worldwide. Approximately 170 million people are chronically infected. HCV can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current standard treatment with pegylated interferon and ribavirin is suboptimal and up to 60% of patients fail to respond. Week 4 and 12 HCV RNA is used as a marker of response with nonresponders at 12 weeks discontinuing treatment. Earlier identification of nonresponders using novel biomarkers would be beneficial in preventing unnecessary toxicities and cost. This study profiled the proteomic response to treatment in HCV patients within the first 24 h using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS). METHODS: Serum from 25 HCV infected individuals during the initial 24 h of treatment was profiled using SELDI-TOF MS. Arrays were analyzed on the ProteinChip Reader and time-of-flight spectra were generated. Peak detection was performed by Biomarker Wizard software and analyzed using BioConductor packages. RESULTS: Significant differences were seen between the proteomic profiles of responders and nonresponders to treatment. Overall 70 peaks differentiated responders from nonresponders. A random forest classifier identified a panel of 20 peaks, which differentiated responders from nonresponders with 87.4% accuracy. The CM10 chip revealed 16 peaks identifying genotype 1 responders from nonresponders. CONCLUSION: This study identifies early proteomic spectra as potential predictors of HCV treatment response using SELDI-TOF MS. This illustrates the importance of early biomarkers in the prediction of response within the first 24 h, which may aid in tailoring HCV treatment regimens.

Early viral and peripheral blood mononuclear cell responses to pegylated interferon and ribavirin treatment: the first 24 h.

OBJECTIVES: This study explored gene expression differences in predicting response to pegylated interferon (IFN-PEG) and ribavirin (RBV) in hepatitis C infection. Current treatment for hepatitis C virus (HCV) with IFN-PEG alpha-2a/b and RBV is an expensive regimen with frequent significant side-effects where less than 60% of patients ultimately achieve a sustained virological response. Responders and nonresponders may not be identified for up to 6 months post-treatment. This dichotomy may be because of differences in the molecular genetic response. METHODS: Peripheral blood mononuclear cell samples were obtained from a cohort of 31 infected individuals within the first 24 h of treatment and the extracted RNA was hybridized to genome expression microarrays. Hepatitis C viral kinetics was also examined in these patients. The ability of differentially regulated genes to predict response to therapy was assessed with treatment outcome. RESULTS: Distinct patterns of gene expression distinguished responders from nonresponders to HCV treatment. The ultimate response to treatment with IFN-PEG and RBV was observed within the first 24 h of treatment by a greater drop in viral load (mean HCV RNA decline of 1.92+/-1.26 log10 IU/ml) in responders compared with nonresponders (P<0.007). Induced genes achieved maximal response within 12 h of therapy which coincided with a rapid decline in HCV RNA between 12 and 24 h. This study revealed that peripheral blood mononuclear cell metallothionein 2A, CCRL2, tumour necrosis factor-alpha-induced protein 6 (TNFAIP6) and IFN-induced protein with tetratricopeptide repeats 2 expression predicted viral treatment response to therapy verified by quantitative real time polymerase chain reaction. CONCLUSION: This study has identified a noninvasive gene microarray pattern and a set of verified genes to be predictive of hepatitis C patient response to IFN-PEG and RBV treatment within the first 24 h. The potential of this noninvasive diagnostic approach and identified genes as biomarkers of response to treatment warrants further investigation.