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The unprecedented global scale of COVID‐19 globally has triggered a race to discover interventions to reduce associated morbidity and mortality and rapid release of research findings prior to any degree of critical review. As with previous novel infection outbreaks, antiretrovirals are just one drug class that has been held up as a potential strategy for prophylaxis and treatment with scant evidence and risk of harm. Here we summarize the evidence for antiretrovirals to treat COVID‐19 and, as a drug that has also been studied in HIV, hydroxychloroquine, and flag some of the pitfalls of using therapies that have not been evaluated robustly. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the paper is to present the outcomes of the HepHIV 2019 conference, held in Bucharest under the Romanian EU Presidency and focusing on challenges of timely and integrated testing and care. Methods: The conference programme was put together by the organizing committee. It consisted of invited talks and peer‐reviewed abstracts. Results: In all, 65 abstracts from 20 countries were presented during the conference, which had nearly 250 delegates, including high‐profile political representation. The conference highlighted the need to shift towards further disease integration because of the epidemiological characteristics of the hepatitis B (HBV), hepatitis C (HCV), HIV, sexually transmitted infection (STIs) and tuberculosis (TB) epidemics in the WHO European region. Integration should be a priority in the response to the epidemics to better reach key populations and to ensure better testing coverage. This relates to both the integration of services in shared care models and the integration of different settings and stakeholders in national strategies. Conclusions: The conference demonstrated the need for greater political support for the policy changes required to implement integration. Testing normalization efforts are key to maximizing the impact of integration efforts. The conference call to action can help to guide developments in testing and linkage‐to‐care interventions across the European region. [ABSTRACT FROM AUTHOR]

Objectives: Development of novel antiretrovirals aims at reducing long‐term toxicities. Tenofovir disoproxil fumarate (TDF) has been associated with potential nephrotoxicity. The aim of our study was to assess the impact of switching from TDF to tenofovir alafenamide (TAF) on functional nephropathy and lipid parameters in a real‐life setting. Methods: We retrospectively analysed data from 347 HIV‐infected patients switching from a TDF‐ to a TAF‐containing regimen between April and December 2016. Sociodemographic, clinical and laboratory data were collected at TDF‐to‐TAF switch, and at 3 and 6 months thereafter. Proteinuria and albuminuria were classified according to Kidney Diseases Improving Global Outcomes (KDIGO) guidelines. Results: At time of switch, moderately and severely increased proteinuria was detected in 32% and 8% of patients, respectively; however, urine dipstick analysis was negative in 84% and 42%, respectively. Moderately and severely increased albuminuria was found in 17% and 3% of patients, respectively. In patients with a urinary protein‐to‐creatinine ratio (UPCR) ≥ 150 mg/g, the mean value declined from 416 mg/g at baseline to 272 mg/g (P < 0.001) and 242 mg/g (P < 0.001) after 3 and 6 months, respectively. Patients with an albumin‐to‐creatinine ratio (UACR) ≥ 30 mg/g showed no significant decrease of albuminuria. Mean total cholesterol increased from 187 mg/dL at baseline to 202 (P < 0.001) and 208 mg/dL (P < 0.001) at 3 and 6 months, respectively, and mean low‐density lipoprotein (LDL) cholesterol increased from 114 mg/dL at baseline to 124 (P < 0.001) and 128 mg/dL (P < 0.001), respectively. As mean high‐density lipoprotein (HDL) cholesterol increased from 50 mg/dL at baseline to 54 (P < 0.001) and 57 mg/dL (P < 0.001) at 3 and 6 months, respectively, the LDL:HDL ratio remained stable. Conclusions: In an aging HIV‐infected cohort, proteinuria and albuminuria were common findings and were underdiagnosed via urine dipstick. Our real‐life data suggest that laboratory markers of moderately/severely increased proteinuria improved after TDF‐to‐TAF‐switch. Lipid profiles were not aggravated. Long‐term follow‐up is needed to determine the clinical benefit of the TDF‐to‐TAF switch. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to assess the regression of liver stiffness after successful direct‐acting antiviral (DAA) treatment in patients with hepatitis C virus (HCV) monoinfection and HCV/‐HIV coinfection. In addition, we aimed to identify factors associated with liver stiffness regression. Methods: We studied patients treated with interferon‐free DAA regimens with a sustained virological response at week 12 (SVR12) or 24 (SVR24) post‐treatment. Liver stiffness was assessed by transient elastography (TE) before the initiation and after the end of treatment (median 12 weeks). Results: Of 214 enrolled patients, 85 (40%) were HCV monoinfected and 129 (60%) HCV/HIV coinfected. Baseline median TE values were 7.8 kPa [interquartile range (IQR) 5.9–12.0 kPa] in mono‐infected patients and 10.7 kPa (IQR 7.8–17.0 kPa) in coinfected patients. Overall, the median TE value decreased from 10.1 to 6.8 kPa (n = 214; P < 0.0001). There was no difference between mono‐ and coinfected patients (−2.2 versus −3.3 kPa, respectively; P = 0.88), which was verified by an analysis of covariance (ANCOVA) adjusting for baseline TE values. Significant (≥ 30%) regression of liver stiffness was achieved by 45% of patients (54% with baseline TE ≥ 7.1 kPa). In multivariate analysis, a prior HCV treatment was a negative predictor of liver stiffness regression [odds ratio (OR) 0.31; P = 0.001]. A higher baseline TE value was positively associated with achieving a significant regression (OR 1.06; P = 0.02). HIV coinfection status, HCV genotype, age, sex, treatment duration, controlled attenuation parameter value, bilirubin concentration, platelet count and aspartate aminotransferase concentration were not associated with liver stiffness regression. Conclusions: Regression of liver stiffness after successful DAA treatment did not differ in patients with HCV monoinfection and those with HCV/HIV coinfection. Half of all patients achieved a significant (≥ 30%) regression. Prior treatment for HCV was a negative predictor for this endpoint, while a higher baseline TE value was positively associated with regression. [ABSTRACT FROM AUTHOR]

Objectives Studies have shown that hepatitis C virus ( HCV) RNA levels remain stable over time in HIV/ HCV-coinfected individuals taking combination antiretroviral therapy (c ART), while spontaneous clearance of HCV RNA during the persistent infection phase has been documented only rarely among those with the CC interleukin ( IL)-28B genotype. This study describes HCV RNA profiles and factors associated with changes over time in HCV RNA levels in the ESPRIT study. Methods HIV/ HCV-coinfected individuals positive for HCV RNA were included in the study. Follow-up was counted from the first HCV RNA positive test and censored at the initiation of interferon-based treatment. HCV RNA and IL-28B measurements were performed in the same reference laboratory. Random effects mixed models were used to analyse changes over time in HCV RNA. Results A total of 312 ESPRIT patients were included in the study (151 in the arm receiving subcutaneous recombinant IL-2 and 161 in the control arm). Most of the patients were white (89%) and male (76%), and they had a median of 5 HCV RNA measurements per person [interquartile range ( IQR) 3-6; range 1-9]. Median follow-up was 5 years ( IQR: 2−6 years). At baseline, 96% of patients were taking cART and 93% had undetectable HIV RNA. Mean HCV RNA levels decreased by 13% per year over the study period [95% confidence interval ( CI) 8-18%; P < 0.0001]. Baseline HCV RNA levels and the change over time in HCV RNA did not differ by randomization arm ( P = 0.16 and P = 0.56, respectively). Nine individuals spontaneously cleared HCV RNA during follow-up [ IL-28B genotypes: CC, five patients (56%); CT, four patients (44%)]. Conclusions HCV RNA levels decreased over time in this population with well-controlled HIV infection. Spontaneous clearance of HCV RNA was documented in five individuals with IL-28B genotype CC and four with the CT genotype. [ABSTRACT FROM AUTHOR]

Background The European AIDS Clinical Society ( EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. Guideline highlights The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment ( ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment ( START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (Pr EP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug−drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus ( HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. Conclusions The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview. [ABSTRACT FROM AUTHOR]

Objectives While idiopathic pulmonary arterial hypertension ( PAH) is a rare disease, it is seen more frequently in patients with HIV infection. The aim of this study was to evaluate the prevalence of pulmonary hypertension ( PH) in patients with HIV infection by echocardiographic screening. Methods Echocardiography and N-terminal of the prohormone brain natriuretic peptide measurement were used to examine the prevalence of PH prospectively in HIV-positive patients ( n = 374) during routine follow-up visits for HIV disease. Results In echocardiographic screening, PH was detected in a total of 23 of 374 HIV-infected patients (6.1%). Of these, three patients (13%) presented with symptoms of dyspnoea and fatigue, and diagnosis of PAH was confirmed by right heart catheterization. Patients with systolic pulmonary artery pressure ( sPAP) > 30 mmHg were more likely to be female, to have a history of injecting drug use and to originate from high-prevalence countries ( HPCs). Conclusions Echocardiographic screening detected PH in a substantial proportion of HIV-positive patients. Female gender, a history of injecting drug use and HPC origin were associated with a higher prevalence of HIV-associated PH. The relevance and long-term outcome of these findings need to be validated in follow-up studies, which are ongoing. [ABSTRACT FROM AUTHOR]

Objectives Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus deferred antiretroviral therapy ( ART) on liver fibrosis progression. Methods Sites in the Strategic Timing of AntiRetroviral Treatment ( START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline, and two noninvasive serum algorithms, APRI and FIB-4, were calculated. Demographic and liver-related information was collected for all START participants at baseline. Results A total of 230 participants were enrolled in the substudy (11.5% with hepatitis B or C virus coinfection), of whom 221 had a valid transient elastography ( TE) result. The median TE score was 4.9 kPa [interquartile range ( IQR) 4.3-6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval ( CI) 5.1-12.1%] had a TE score of > 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in multivariate analysis were higher alanine aminotransferase ( ALT) per 10 U/ L ( P = 0.045), higher log10 HIV RNA ( P < 0.001) and Hispanic/ Latino ethnicity ( P = 0.01). TE correlated weakly with noninvasive markers. Conclusions At baseline, significant liver fibrosis was observed in approximately 8% of participants, with higher ALT and HIV RNA the only clinical factors associated with increasing TE score. TE will be used annually to monitor fibrosis and evaluate the role of ART in further fibrosis progression. [ABSTRACT FROM AUTHOR]

Objectives Following resolution of hepatitis C virus ( HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV-1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. Methods All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA ≥ 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. Results Of 191 eligible patients, 35 [18.3%; 95% confidence interval ( CI) 12.8-23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users ( IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0-5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio ( OR) 0.44; 95% CI 0.20-0.99; P = 0.046] and older persons ( OR 0.51 per 10 years older; 95% CI 0.28-0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non- IDUs ( OR 6.58; 95% CI 1.48-29.28; P = 0.013). Conclusions Around 1 in 5 HIV-infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early. [ABSTRACT FROM AUTHOR]

Objectives The incidence of sexually transmitted hepatitis C virus ( HCV) reinfection is on the rise in HIV-infected men who have sex with men ( MSM). Data on natural history of acute hepatitis C and possible factors associated with spontaneous clearance are limited. The aim of this study was to analyse the outcome of HCV reinfections in HIV-positive MSM. Methods A retrospective analysis was carried out on patients with more than one sexually acquired HCV infection who were diagnosed at four major German HIV and hepatitis care centres. Reinfection was defined by genotype or phylogenetic clade switch, detectable HCV RNA after a sustained virological response ( SVR) or after spontaneous clearance ( SC). Results In total, 48 HIV-positive MSM were identified with HCV reinfection, among them 11 with a third episode and one patient with four episodes. At the first episode, 43 and five patients had an SVR and SC, respectively. The second episode was accompanied by a genotype switch in 29 patients (60%). Whereas 30 and nine patients showed an SVR and SC, respectively, eight patients developed chronic hepatitis. Neither HCV genotype switch nor interleukin-28 B genotype was associated with SC. However, SC rates at the second episode were higher for patients with SC at the first episode compared with patients without SC (60 vs. 14%, respectively; P = 0.03). Two patients with SC at the first episode were reinfected with the same genotype. Conclusions Multiple reinfections in HIV-infected MSM do occur, with or without genotype switch, and with prior SC of previous episodes. In this large case series, except for SC at the first episode, no factor was of value in clinical decision-making for early therapeutic intervention in acute HCV reinfection. [ABSTRACT FROM AUTHOR]

Objectives Because of the improved life expectancy provided by successful antiretroviral combination therapy, preventive health measures in HIV-infected patients have assumed increasing importance. To date, no data exist on rates of mucosal abnormalities detected by screening colonoscopy in > 50-year-old HIV-infected patients in Germany. The aim of this study was to obtain such data. Methods A screening colonoscopy was offered to 159 HIV-infected patients (age > 50 years) who presented for HIV standard of care visits at the infectious diseases out-patient clinic at the university hospital in Bonn over a 1-year period from February 2010. Pearson's χ2 test, Fisher's exact test and the Mann− Whitney U-test were used for statistical analysis. Results Fifty-one patients (32.1%) had undergone a screening colonoscopy in the past 10 years, and 45 patients (28.3%) were eventually screened in the observation period. The median age of the 96 screened patients (86% male and 14% female) was 58 years [interquartile range ( IQR) 54-64 years]. Overall, endoscopic abnormalities were found in 61% of patients. Histological examination showed tubular adenomas in 21.9% of patients, tubulovillous adenomas in 3.1% and serrated adenomas in 1%. Hyperplastic polyps were found in 15.6% of patients, a nonspecific colitis in 16.7% and diverticulosis in 12.5%. In four cases there was even an early-stage carcinoma (two anal, one rectal and one colon cancer). In univariate analysis, no significant differences with regard to immune status, highly active antiretroviral therapy, family history, personal risk factors or comedication were found between patients with dysplastic and normal mucosas. Conclusions The high acceptance rate of screening colonoscopy and the in comparison with the HIV-negative population comparably higher rate of abnormalities in this cohort of HIV-infected patients justify enhanced implementation of screening colonoscopy in clinical practice. [ABSTRACT FROM AUTHOR]

Objectives All HIV/hepatitis C virus ( HCV)-coinfected patients with chronic HCV infection and ≥ F2 fibrosis should be considered for HCV therapy. This study aimed to determine the rate of HCV treatment uptake among coinfected patients in Europe. Methods EuroSIDA patients with viraemic HCV infection were included in the study. Poisson regression was used to identify temporal changes and regional differences in HCV treatment uptake. Results A total of 1984 patients were included in the study, with a median follow-up time of 168 months [interquartile range ( IQR) 121-204 months]. To date, 501 (25.3%) HIV/ HCV-coinfected patients have received HCV therapy. Treatment incidence rose from 0.33 [95% confidence interval ( CI) 0.16-0.50] per 100 person-years of follow-up ( PYFU) in 1998 to 5.93 (95% CI 4.49-7.38) in 2007, falling to 3.78 (95% CI 2.50-5.07) in 2009. After adjustment, CD4 cell count > 350 cells/μL [incidence rate ratio ( IRR) 1.33 (95% CI 1.06-1.67) vs. CD4 count 200−350 cells/μL] and ≥ F2 liver fibrosis [ IRR 1.60 (95% CI 1.14-2.25; P = 0.0065) vs. < F2 fibrosis] were predictors of anti- HCV treatment initiation. However, 22% of patients who remain untreated for HCV, with fibrosis data available, had ≥ F2 fibrosis and should have been considered for treatment, while only 36% of treated patients had ≥ F2 fibrosis. Conclusions Although treatment incidence for HCV has increased, there remain a large proportion of patients indicated for treatment who have yet to be treated. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the use of raltegravir with unboosted atazanavir in combination with one nucleoside reverse transcriptase inhibitor ( NRTI) (lamivudine or emtricitabine) as a potentially well-tolerated once-daily (qd) maintenance regimen. Methods We compared the pharmacokinetics of raltegravir 400 mg twice daily (bid) with raltegravir 800 mg qd in HIV-infected patients ( n = 17) on unboosted atazanavir (600 mg qd) in combination with lamivudine or emtricitabine. Results The area under the plasma concentration vs. time curve for a dose interval t ( AUC0- t) of 800 mg qd divided by 2 was not significantly different from the AUC0- t of 400 mg bid ( P = 0.664) but the minimum concentration ( Cmin) was 72% lower with the qd regimen ( P = 0.002). The regimen was well tolerated and the viral load remained undetectable in all patients during the 6 weeks of the study follow-up. Conclusions A qd regimen of raltegravir 800 mg, atazanavir 600 mg and lamivudine or emtricitabine resulted in favourable pharmacokinetic profiles and good short-term safety and efficacy data. Larger phase IIb studies are needed to explore this novel regimen. [ABSTRACT FROM AUTHOR]

Objectives Infection with hepatitis C virus ( HCV) is a major cause of chronic liver disease. High HCV RNA levels have been associated with poor treatment response. This study aimed to examine the natural history of HCV RNA in chronically HCV/ HIV-coinfected individuals. Methods Mixed models were used to analyse the natural history of HCV RNA changes over time in HIV-positive patients with chronic HCV infection. Results A total of 1541 individuals, predominantly White (91%), male (73%), from southern (35%) and western central Europe (23%) and with HCV genotype 1 (58%), were included in the analysis. The median follow-up time was 5.0 years [interquartile range ( IQR) 2.8 to 8.3 years]. Among patients not on combination antiretroviral therapy ( cART), HCV RNA levels increased by a mean 27.6% per year [95% confidence interval ( CI) 6.1−53.5%; P = 0.0098]. Among patients receiving cART, HCV RNA levels were stable, increasing by a mean 2.6% per year (95% CI −1.1 to 6.5%; P = 0.17). Baseline HCV RNA levels were 25.5% higher (95% CI 8.8 to 39.1%; P = 0.0044) in individuals with HCV genotype 1 compared with HCV genotypes 2, 3 and 4. A 1 log HIV-1 RNA copies/mL increase in HIV RNA was associated with a 10.9% increase (95% CI 2.3 to 20.2%; P = 0.012) in HCV RNA. Conclusions While HCV RNA levels increased significantly in patients prior to receiving cART, among those treated with cART HCV RNA levels remained stable over time. [ABSTRACT FROM AUTHOR]

Objective The aim was to examine the long-term safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double-blind, randomized, controlled Phase III studies. Methods In STARTMRK, treatment-naïve patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK-1 and -2, highly treatment-experienced patients with multi-drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were ≤5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK. Results Hepatitis coinfection was present in 6% (34 of 563) of treatment-naïve patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment-experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug-related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2-4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV-1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK). Conclusion Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV-infected patients with HBV/HCV coinfection. [ABSTRACT FROM AUTHOR]

Objective To assess the effect of highly active antiretroviral therapy (HAART) on surrogate markers of lymphocyte apoptosis in HIV 1-infected individuals. Methods Ex vivo apoptosis was studied prospectively in 26 antiretroviral naive HIV-positive patients up to 12 weeks after sequential initiation of HAART [phase I: nucleoside reverse transcriptase inhibitor (NRTI), phase II: NRTI + protease inhibitor (PI)]. Apoptosis was assessed via CD95-, Apo2.7-expression and annexin-V-binding in peripheral CD4, CD8, B and NK-cells, and compared to changes in activation markers (HLA-DR, CD38) and viral loads. Results After introduction of HAART CD4-counts rose significantly mainly through cell redistribution, while activation markers decreased. Although Apo2.7 expression decreased throughout the study period, it was not possible to establish a correlation to the rise in CD4 cells. Unexpectedly, CD95 expression and annexin V binding were elevated during phase I of treatment without PI and began to decline only after the addition of a PI in phase II. Poor responders to antiretroviral therapy had significantly higher CD95 expression and annexin V binding in the initial phase of antiretroviral regimen. Conclusion These data show divergent effects of HAART on surrogate markers of apoptosis, when treatment is initiated sequentially with NRTIs first. Partial suppression of HIV replication during treatment without PI may be associated with increased rates of apoptosis. [ABSTRACT FROM AUTHOR]

Objectives To evaluate safety and efficacy of the protease inhibitor combination ritonavir/indinavir 100/800 mg twice daily plus 2–3 nucleoside reverse transcriptase inhibitors (NRTI) in antiretroviral-naive patients. Methods Within this open-label, uncontrolled multicentre trial, antiretroviral-naive patients (n = 57) with median baseline HIV-RNA of 308 000 copies/mL (range 170–3.01 million copies/mL) and median CD4 cell count of 50 cells/μL (range 0–853 cells/μL) were started on 2–3 NRTIs plus ritonavir/indinavir 100/800 mg twice daily. CD4 cell counts and HIV-RNA were determined at weeks 0, 4, 8, 12, 16, 20, 24 and 48. Statistical analysis was performed on treatment as well as intent-to-treat. Results Viral load decreased by a median of 3.79 log10 copies/mL (range 2.0–4.60 log10 copies/mL) until week 48. At week 48, 23/57 (40%, intent-to-treat) patients showed a viral load ≤ 80 copies/mL. In parallel, median CD4 cell counts increased by a median of 149 cells/μL (range -60–420 cells/μL). Median triglycerides and cholesterol increased from baseline 160 mg/dL (range 33–364 mg/dL) to 218 mg/dL (range 110–527 mg/dL) at week 48 and from 166 mg/dL (range 63–262 mg/dL) to 233 mg/dL (range 95–359 mg/dL), respectively. Twenty-seven of fifty-seven patients (47%) discontinued study medication, 19 (33%) due to nephrolithiasis. Two patients changed their antiretroviral regimen after failing virologically. Conclusion Ritonavir/indinavir 100/800 mg twice daily appears to be effective up to 48 weeks despite high baseline viraemia and low CD4 cell count in antiretroviral-naive patients. However, discontinuation due to adverse events, especially nephrotoxicity, is frequent and limits treatment duration. Therefore, extra hydration appears inevitable with this combination. [ABSTRACT FROM AUTHOR]

In a controlled, prospective study, the efficacy of ritonavir 200 mg twice daily (bid) in inhibiting the decrease of amprenavir plasma concentrations caused by co-administration of lopinavir was assessed. Twelve HIV-seropositive patients were enrolled, and nine patients completed the 28-day study. At day 14, plasma concentrations of amprenavir 600 mg bid and ritonavir 200 mg bid were determined over 12 h. At day 15, lopinavir 400 mg bid was added. At day 28, plasma concentrations of amprenavir, ritonavir and lopinavir were assessed. Co-administration of lopinavir was found to decrease the amprenavir concentration, determined as the median area under the curve over 12 h (AUC12), by 25% (AUC12 24.9 microg/h/mL vs. 18.5 microg/h/mL; P<0.01), despite the presence of ritonavir 200 mg bid. Eight participants discontinued the study regimen during the first 6 weeks because of adverse gastrointestinal events. In conclusion, gastrointestinal tolerance of a regimen containing an increased dose of ritonavir 200 mg bid was low, while the regimen did not prevent a decrease of amprenavir and possibly lopinavir plasma concentrations. [ABSTRACT FROM AUTHOR]

Objective To determine the long-term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs). Design and methods In an open-label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients (n = 93) with a high median baseline HIV-1 RNA level of 210 000 copies/mL (range 17 000–2 943 000) and a median CD4 cell count of 195 copies/µL (range 4–656 copies/µL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4-week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures. Results HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks. Conclusions Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load. [ABSTRACT FROM AUTHOR]

Background and Aims: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH., Methods: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC)., Results: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis., Conclusions: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes., Methods: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression., Results: Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%-17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%-55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%-5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6-17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2-2.1), liver-related death (2.9, 1.6-5.0) and HCC (6.3, 2.5-16.0)., Conclusion: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Several cohorts have shown that long-term tenofovir-containing combination antiretroviral therapy (cART) leads to higher HBsAg seroclearance rates in HIV/HBV coinfected patients vs HBV-monoinfected patients under tenofovir disoproxil fumarate (TDF)-based therapy. We have analysed data on determinants of HBsAg loss in a retrospective multicentric cohort of 359 HIV/HBV coinfected patients. Median CD4 T-cell count at baseline was 359/ul (321-404), CDC stage was C in 20% (n = 70). Most patients (68%) were ART-naïve when TDF- or tenofovir alafenamide (TAF)-containing cART was initiated (baseline). After a median follow-up of 11 years HBsAg loss had occurred in 66/359 (18%) patients. However, patients with stage CDC C (P ≤ .001), lower CD4 gain (P = .043) and not receiving TDF/FTC (P = .008) were less likely to lose HBsAg. Long-term TDF-containing cART appears to achieve higher rates of HBsAg seroclearance compared to published data for HBV monoinfected subjects. However, late presentation for HIV and poor immune recovery significantly impair HBV seroconversion rates., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

There is an ongoing global hepatitis C virus (HCV) epidemic mainly related to high-risk behaviour in persons who inject drugs (PWID) and in HIV-infected men who have sex with men (MSM) which continues to fuel the HCV epidemic. Treatment of HCV infection with direct antiviral therapy (DAA) has been very successful in the last decade. Main obstacles for HCV elimination are HCV reinfections observed in PWID and HIV-infected MSM. We present here an HIV-infected MSM patient who has been reinfected thrice with HCV. The virus which was investigated from his last reinfection episode reveals transmission of a newly acquired HCV protease inhibitor (PI) resistance, despite not having been exposed to HCV-PIs during his last DAA therapy., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Severe hepatic steatosis shows a high prevalence and contributes to morbidity and mortality in human immunodeficiency virus (HIV) infected patients. Known risk factors include obesity, dyslipidaemia and features of metabolic syndrome. Fibroblast growth factor 21 (FGF-21) is involved with hepatic glucose and lipid metabolism. This study aimed to evaluate FGF-21 as a biomarker for severe hepatic steatosis in non-obese HIV-infected patients., Methods: This is a prospective, cross-sectional, monocentric study including HIV-infected out-patients. Hepatic steatosis was measured via controlled attenuation parameter (CAP) using FibroScan 502 touch (ECHOSENS, France). Severe hepatic steatosis was defined at CAP ≥ 253 dB/m. Peripheral blood samples were collected and plasma was analysed for FGF-21. Demographic and clinical characteristics were collected from patient's health records., Results: In total, 73 non-obese HIV-monoinfected patients were included in this study. Prevalence of severe hepatic steatosis was 41%. Patients with severe hepatic steatosis showed significantly higher levels of FGF-21. Univariate analysis revealed FGF-21, BMI, hyperlipidaemia, ALT levels and arterial hypertension as significant, while multivariate analysis showed only FGF-21, arterial hypertension and ALT levels as significant independent risk factors for severe hepatic steatosis., Conclusion: This study presents FGF-21 as an independent and stronger predictor of severe hepatic steatosis than blood lipids in HIV-infected patients. Moreover, arterial hypertension and ALT levels predict severe steatosis even in non-obese HIV-monoinfected patients. Furthermore, this study supports existing metabolic risk factors and expands them to non-obese HIV-infected patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Twelve weeks of the pangenotypic direct-acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL-3 approval study. However, presence of resistance-associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response., Aim: To assess the efficacy and safety of SOF/VEL ± ribavirin (RBV) and the impact of NS5A RASs and RBV use on treatment outcome in HCV GT3 infection in a real-world setting., Methods: In this multicentre cohort study, GT3 patients from ten treatment centres across Germany were included. Sustained virological response was assessed 12 weeks after end-of-treatment (SVR12) in modified intention-to-treat (mITT) and per-protocol analysis (PP). NS5A RASs were tested by population-based sequencing., Results: A total of 293 GT3 patients were included. The median age was 48 years, 70% were male, 25.3% were cirrhotic, 9.2% were HCV/HIV co-infected and 21.8% were treatment-experienced, including 4.1% with DAA experience. Baseline NS5A RASs (Y93H, A30K, L31M) were detected in 11.2%. RBV was added in 5% of noncirrhotic and 58.9% of cirrhotic patients, respectively. SVR12 rates for SOF/VEL±RBV were 95.9% (mITT) and 99.5% (PP), respectively. Only 1 virological relapse occurred in a cirrhotic patient previously treated with SOF/RBV. No treatment-related major adverse events occurred., Conclusion: Twelve weeks of SOL/VEL±RBV was safe and highly efficient in HCV GT3 across a diverse patient population. Baseline NS5A RASs were rarely observed and presence did not seem to impact SVR, regardless of the use of RBV., (© 2018 John Wiley & Sons Ltd.)

Background & Aims: In the last decade, several outbreaks of sexually acquired acute hepatitis C (HCV) infection have been described in HIV-positive men who have sex with men (MSM). The aims of this study were to determine whether there has been an increase in the number of acute HCV infections in different parts of Europe., Methods: HCV seroconversion was defined as an HCV-antibody test change from negative to positive within the observation period in EuroSIDA. Binomial regression was performed to determine factors associated with being tested for HCV and HCV seroconversion., Results: A total of 223 HCV seroconversions were observed from 16,188 tests [1.38% (95%CI 1.20-1.56)] among 5736 patients between 2002 and 2013. Overall the odds of acquiring HCV infection increased by 4% per year (OR 1.04 [95%CI 0.99-1.09]; P = 0.10). Overall 63.2% (141/223) of all seroconversions were seen among MSM. Similar patterns were observed across all European regions (P = 0.69, test for interaction) and HIV transmission risks groups (P = 0.69, test for interaction). In multivariate analysis, North, South and East Europe had higher odds of HCV seroconversion compared with Western Europe [OR 1.90 (1.28-2.81), 1.55 (0.99-2.45) and 1.86 (1.21-2.84); P = 0.0014, P = 0.058 and P = 0.0044 respectively]., Conclusions: Within EuroSIDA a significant increase in HCV seroconversions can be observed after accounting for increased levels of testing for HCV in recent years. This highlights the need for increased HCV prevention efforts among HIV-positive persons in Europe., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: The efficacy and safety of triple therapy combining boceprevir (BOC) or telaprevir (TVR) with pegylated interferon-alfa and ribavirin (PegIFN/RBV) has rarely been investigated in human immunodeficiency virus/hepatitis C virus (HIV/HCV) genotype 1-coinfected patients with cirrhosis., Methods: We conducted a European (France, Italy, Germany, Netherlands) multicentre study of triple therapy in cirrhotic HIV/HCV GT1-coinfected patients., Results: Fifty-nine patients (47 TVR, 12 BOC) were studied. Median CD4 cell count was 457 (293-578)/mm(3), and HIV viral load was <50 copies/ml in 93% of patients. The HCV genotype was GT1a (78%) or GT1b (13%). Previous PegIFN/RBV therapy had resulted in non-response (73%) or relapse (12%), and 15% of patients were treatment-naïve. The sustained virological response rate at week 12 (SVR12) was 53% overall (57% with TVR, 36% with BOC). A baseline HCV-RNA level <800 000 IU/ml tended to be associated with SVR12 (65 vs 42%, P = 0.11). In multivariate analysis, a virological response at week 4 after BOC or TVR initiation was significantly associated with SVR12 (P = 0.040). Early discontinuation of triple therapy was frequent (n = 26, 44%), because of non-response/breakthrough (65%) or adverse events (AEs) (35%). Three patients died. Severe anaemia (<9 g/dl) occurred in 14 patients (25%), leading to RBV dose reduction (22%), erythropoietin use (56%) or blood transfusion (14%). In multivariate analysis, lack of RBV dose reduction was significantly associated with severe AEs (P = 0.006)., Conclusions: More than half of HIV/HCV GT1-coinfected patients with cirrhosis achieved a SVR12. To avoid unnecessary adverse effects, therapy should be discontinued if no response is obtained at week 4., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The development of direct acting antivirals (DAAs) against the hepatitis C virus (HCV) has revolutionized treatment paradigms for HCV in HIV co-infected subjects. In the era of DAAs, HIV/HCV co-infected patients have the same cure rates of over 90% with interferon (IFN)-free DAA combinations. Therefore, guidelines no longer separate mono- and co-infected subjects. Indications for HCV therapy and DAA drug selection have become the same for all patients. The only special consideration in HIV/HCV co-infected subjects is the need to check for drug-drug interactions between HIV and HCV drugs, especially HIV and HCV protease inhibitors which have a high risk of clinically significant drug interactions. Because of the faster progression of fibrosis and the higher risk of hepatic decompensation in co-infected subjects, even with combination antiretroviral (ART) therapy, the availability of modern HCV treatments needs to be extended and HCV therapy should be discussed in all co-infected patients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

With the licensing of the first hepatitis C (HCV) protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC), cure rates for chronic HCV infection will substantially improve. Human immunodeficiency virus- chronic hepatitis C (HIV-HCV) co-infected patients are in urgent need for these new drugs, because they are facing both severe liver disease and lower response rates than HCV monoinfected patients. The currently available efficacy data are however, limited to two phase II trials. Fortunately, TVR and BOC appear to be able to improve cure rates in co-infected patients. A major challenge for clinicians will be the management of drug-drug interactions of antiretroviral drugs and new PI. As HCV PI are also metabolized by the cytochrome P450 3A4 system interactions are probable as well with non-nucleoside reverse transcriptase inhibitors as with HIV PI. To our knowledge, TVR can only be safely used with one protease inhibitor, boosted atazanavir, and also with efavirenz (EFV), although this combination requires TVR dose adjustments. Boceprevir should not be combined with HIV PI and should not be combined with EFV. The approval of TVR and BOC will create new chances of cure also for HIV-HCV co-infected patients. However, the decision who to treat or not has to be taken carefully on the basis of fibrosis stage and previous treatment outcomes. In addition, HIV therapy needs to be optimized according to the available drug-drug interaction data., (© 2012 John Wiley & Sons A/S.)

Background: An ongoing HCV epidemic currently affects a growing proportion of HIV-positive men who have sex with men (MSM) in Europe. Recently in the North-Rhine region of Germany, we have observed an increase in acute HCV infections of genotype 4 (HCV-4)., Aims: To characterize the current spread of HCV-4 among German MSM using a molecular epidemiological approach., Methods: Patient characteristics and sera were collected for HIV-positive MSM diagnosed with acute HCV-4 infections in the North-Rhine region (n=14), Hamburg (n=14), Frankfurt (n=4) and Berlin (n=4). Part of the HCV NS5B region (436 bp) was amplified, sequenced and compared with HCV-4 sequences from HIV-positive Dutch, English and French MSM (n=50) as well as unrelated HCV risk groups (n=61)., Results: NS5B sequences were obtained from 35/36 (97%) of German cases, all of which were HCV subtype 4d (HCV-4d). The phylogenetic analysis of HCV sequences revealed two MSM-specific HCV-4d clusters of 71 and 12 sequences. All except one of the German MSM belonged to a large MSM-specific HCV cluster containing MSM from all four different European countries. None of the HCV-4 strains circulating among injecting drug users or in HCV-4 endemic areas were part of the MSM-specific clusters., Conclusions: HCV rapidly spreads among European HIV-positive MSM through a joint international transmission network, separate from that of injecting drug users. In order to contain this epidemic, non-parenteral routes of transmission, such as unsafe sex, must be taken into consideration and prevention measures should be refocused accordingly.

Background: Hepatitis C virus (HCV) infection is associated with multiple extrahepatic manifestations. It is unclear to what extent extrahepatic manifestations occur in HIV/HCV coinfection., Methods: We prospectively assessed cross-sectional frequencies of autoimmune manifestations in HIV/HCV-coinfected patients (n=98), HIV-mono-infected (n=45) and HCV-mono-infected patients (n=78). Diagnostic vasculitis scores, HCV and HIV loads, CD4 cell counts, thyroid-, cardiolipin-, non-organ-specific tissue antibodies (nuclear, smooth muscle, anti-liver-kidney-microsome, neutrophil-cytoplasmic) and cryoglobulins were determined., Results: Synergistic effects of HCV and HIV infection were observed with respect to the prevalence of antibodies against thyroglobulin (HCV infection 15.4%, HIV infection 8.8%, HIV/HCV coinfection 30.6%; P<0.001) and cardiolipin antibodies (HCV infection 9.0%, HIV infection 31%, HIV/HCV coinfection 46%; P<0.001). Cryoglobulinemia type III, was significantly associated with HCV infection (HCV, 25.6%; HIV/HCV, 20.4%) but not with HIV infection (4.4%, P<0.05). Rheumatoid factor was commonly detected in patients with HCV infection (48%), but occurred considerably less frequently in patients with HIV infection (4.4%) or HIV/HCV coinfection (9.5%, P<0.01)., Conclusion: HIV coinfection appears to differentially modulate the frequency of HCV-related autoimmunity. However, autoimmunity is rarely accompanied by clinical manifestations.

Severe anaemia is a frequent complication in advanced HIV infection. In our study we investigated the interaction between cytokine network, HIV infection and erythropoietin (Epo) response with increasing anaemia levels. No correlations could be established between circulating tumour necrosis factor (TNF)-alpha and any of the examined parameters. However, a negative correlation was found between haemoglobin values and soluble TNF receptor levels (sTNF-R-I: r = -0.54; P < 0.001; sTNF-R II: r = -0.47; P < 0.001) as well as interleukin-6 levels (r = -0.29; P < 0.01). In contrast, no significant increase in log[Epo], counterbalancing haemoglobin decline and paralleling the rise in sTNF receptors, was found. In patients classified as stage III, according to the Centers for Disease Control (CDC) classification, the erythropoietin response was significantly more impaired than in patients from CDC groups I and II (P < 0.01). The results of this study suggest that similar to its action in vitro, activation of the TNF/TNF-R system may impair erythropoietin production in HIV-associated anaemia. Due to the brief half-life of TNF-alpha, this activation is particularly reflected by elevations of soluble TNF receptor levels.