Emanuela Messina

Non-invasive fibrosis biomarkers - APRI and Forns - are associated with liver stiffness in HIV-monoinfected patients receiving antiretroviral drugs.

HIV‐monoinfected patients are susceptible to liver injury by different factors and may develop liver fibrosis, which requires adequate clinical management in terms of therapy and disease monitoring. We aimed to evaluate the presence of liver fibrosis identified by transient elastography (TE), its relationships with indirect biochemical markers [the aspartate aminotransferase/platelet ratio index (APRI), the Forns index and FIB‐4] and its predictive factors in HIV‐monoinfected patients receiving antiretroviral therapy (ART).

Dynamic of Mixed HCV Infection in Plasma and PBMC of HIV/HCV Patients Under Treatment With Peg-IFN/Ribavirin.

AbstractThe extent of mixed hepatitis C virus (HCV) genotype in different compartments (plasma and peripheral blood mononuclear cell, PBMC) and possible association with treatment efficacy in HIV/HCV coinfected patients remains to be unknown.The objective of this study was to elucidate the frequency of mixed genotype infection (MG), its profile in different compartments during anti-HCV treatment, and the possible influence of different genotypes on the response rate.The compartmentalization of HCV population was investigated by next-generation sequencing in 19 HIV/HCV coinfected patients under anti-HCV treatment with peginterferon/ribavirin (P–R). Ten individuals were nonresponder (NR) or relapser (RE) to P–R treatment and 9 had a sustained virological response (SVR).Eleven/nineteen (58%) patients had MG in plasma compartment. Ten or 12 patients infected by a difficult to treat genotype (DTG) 1 or 4 as dominant strain, had an MG, whereas only 1/7 individuals infected by easy to treat genotype (ETG) harbored a mixed genotype, P = 0.006. HCV–RNA was more frequently detected in PBMC of NR (10/10) than in those of SVR (5/9), P = 0.032. Mixed genotype infection was detected in 6/15 (40%) PBMC-positive cases and was not associated with P–R treatment response. By multivariate analysis, MG in plasma samples was the most important viral factor affecting the treatment response (P = 0.0237).Detection of MG in plasma of HIV/HCV coinfected patients seems to represent the major determinant of response to P–R treatment. This finding may have important clinical implication in light of the new therapeutic approach in HIV/HCV coinfected individuals suggesting that combination treatment with direct acting antivirals could be less effective in MG.

TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype

AIM To evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner’s scoring system. Patients were genotyped for TM6SF2 E167K (rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males (73.6%), the median age was 40.7 years and the immunological condition good (median CD4+ cells/mm3 = 505.5). RESULTS The 17 patients with the TM6SF2 E167K variant, compared with the 150 with TM6SF2-E/E, showed higher AST (P = 0.02) and alanine aminotransferase (P = 0.02) and higher fibrosis score (3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCV-genotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167K in non-3 HCV genotypes. No association between the TM6SF2 E167K variant and severe liver necroinflammation was observed. CONCLUSION In HIV/HCV coinfection the TM6SF2 E167K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.

Pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus-coinfected patients with liver cirrhosis

Objectives: To evaluate the plasma trough concentrations (Ctrough) of dolutegravir and rilpivirine used in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus (HCV)-coinfected patients with liver cirrhosis. Virological efficacy and safety of both ART and anti-HCV therapy were assessed. Patients and methods: A prospective observational study in HIV/HCV-coinfected patients with liver cirrhosis on ART with dolutegravir plus rilpivirine and treated with simeprevir plus sofosbuvir (±ribavirin) was conducted. Dolutegravir, rilpivirine, GS-331007 (sofosbuvir metabolite) and simeprevir Ctrough were evaluated with a validated HPLC method at anti-HCV treatment baseline and weeks 2 and 4. Geometric means were calculated to summarize Ctrough values. Results: Twelve patients were evaluated: 75% were males and the median (IQR) age was 53 (53–55) years. All patients were Child–Pugh stage A, except one who was stage B. The geometric mean (95% CI) of Ctrough of rilpivirine and dolutegravir did not change between baseline and week 4 (P = 0.654 and P = 0.268, respectively), with corresponding overall values of 135 (102–177) and 1357 (970–1897) ng/mL. The overall geometric mean (95% CI) of GS-331007 and simeprevir Ctrough was 370 (268–512) and 2537 (1569–4101) ng/mL, respectively, without significant variation between weeks 2 and 4 (P = 0.643 and P = 0.179, respectively). All patients completed anti-HCV treatment, achieving sustained virological response. All but two patients maintained undetectable HIV-RNA up to post-treatment week 24. Conclusions: Dolutegravir and rilpivirine Ctrough appeared not to be affected by concomitant treatment with simeprevir plus sofosbuvir in these HIV/HCV-coinfected patients with liver cirrhosis, supporting the use of this antiretroviral regimen in this setting.

Reversion of naturally occurring high-level resistance mutations to NS3 protease inhibitors in two treatment-naive individuals infected with hepatitis C virus

4 however, this is not consistent with the effectiveness of the therapy on P. falciparum. Another hypothesis is the natural or induced drug resistance of the parasite, which has not previously been reported in quartan malaria, except for one case of chloro-quine resistance in Indonesia, 5 while artemisinin resistance has been reported only in P. falciparum on the Thai–Cambodian border, and in unconfirmed reports from South America and some African countries. 6 A positive molecular biology test for P. malariae and a normal lumefantrine blood level would confirm this hypothesis: both tests could not be done in our case as this suspicion arose 38 days later, when samples were no longer available. A third possibility is the ineffectiveness of arte-mether/lumefantrine against the particularly long-lasting schizo-gonic pre-erythrocytic phase of P. malariae. Our patient had a minimum incubation period of 8 days for his P. falciparum malaria episode and of 54 days for P. malariae, so that P. falcip-arum may have been treated before P. malariae had appeared in his blood. In this case, the use of a longer-acting compound, such as mefloquine or piperaquine, or one with liver-stage activity, such as atovaquone/proguanil, might be preferable. Several hypotheses on possible biological interactions between P. malariae and other malaria parasites in mixed infections can be made, regarding respective disease suppression: the resolution of P. falciparum infection may have allowed the clinical manifestation of P. malariae, but the possible intervention of antimalarial drugs in these mechanisms has yet to be tested. Moreover, the presence of HIV infection in this patient must be taken into account. Although it is debated whether HIV coinfection can lead to the worsening of clinical malaria, the production of antibodies to P. falciparum is reduced in HIV-infected patients and other aspects of the antimalarial immune response, such as antigen-stimulated cell proliferation and the production of certain cytokines, are impaired. 7 We can not exclude HIV infection-related immune deficiency as a cofac-tor in P. malariae reappearance, particularly in an individual who has probably lost his semi-immunity to the parasite. In such travellers , the importance of malaria prophylaxis should not be underestimated, since their risk of infection as well as of severe disease may be increased. However, our case raises the problem of treating mixed infections also with the latest antimalarials and highlights the fact that P. malariae, in spite of its lower incidence and lower patho-genicity, deserves more attention. The …

Distribution of natural resistance to NS3 protease inhibitors in hepatitis C genotype 1a separated into clades 1 and 2 and in genotype 1b of HIV-infected patients

Naturally occurring resistance-associated variants (RAVs) within the protease domain of hepatitis C virus (HCV) genotype (G) 1a separated into clades 1 and 2, and G1b were investigated in 59 HIV/HCV coinfected patients. RAVs were detected in 10/23 G1a/clade 1 and 1/19 G1b (p 0.0059). A similar frequency of RAVs was found when comparing G1a/clade 2 and G1b (p 0.1672). A cross-resistance to the macrocyclic compounds simeprevir and paritaprevir was detected in two G1a/clade 2 and 1 G1b sequences and none of G1a/clade 1 sequences. The simultaneous characterization of subtype and natural RAVs by population analysis of the NS3 domain by may add important information for anti-HCV treatment strategies including protease inhibitors.

Cannabinoid receptor 2-63 RR variant is independently associated with severe necroinflammation in HIV/HCV coinfected patients

Objective This is the first study to analyze the impact of the rs35761398 variant of the CNR2 gene leading to the substitution of GLN (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with ARG (R) on the clinical presentation of chronic hepatitis in HIV/HCV coinfected patients. Methods Enrolled in this study were 166 consecutive HIV/HCV coinfected patients, naïve for HCV treatment. A pathologist unaware of the patients’ condition graded liver fibrosis, necroinflammation (Ishak) and steatosis. All patients were screened for the CB2 rs35761398 polymorphism. Results Of the 166 HIV/HCV coinfected patients, 72.9% were males, 42.5% were infected with HCV-genotype-3 and 60.2% had been intravenous drug users. The median age was 40.6 years and the immunological condition good (median CD4+ cells/mm3 = 507, IQR: 398.0–669.5). Thirty-five (21.1%) patients were naive for ART and 131(78.9%) were on ART. The CB2-RR variant was detected in 45.8% of patients, QR in 38.6% and QQ in 15.7%. Patients with CB2-RR showed a necroinflammation score (HAI) ≥9 more frequently than those with CB2-QQ or CB2-QR (32.9% vs. 11.5% and 14.1%, respectively, p≤0.001). In the multivariate analysis, the CB2-RR variant (p = 0.03) and liver fibrosis were both identified as independent predictors of the entity of liver necroinflammation (p = 0.0001). Conclusion This study shows interesting interplay between the CB2-RR variant and liver necroinflammation in chronic hepatitis patients with HIV/HCV coinfection, an observation of clinical value that coincides with the interest in the use of the CB2 agonists and antagonists in clinical practice emerging from the literature.

Marked Decrease in Lymphocyte Count in HIV/Hepatitis C Virus (HCV)-Coinfected Patients with Advanced Liver Disease during Anti-HCV Treatment with Direct-Acting Antiviral Regimens Including Ribavirin

Marked Decrease in Lymphocyte Count in HIV/Hepatitis C Virus (HCV)–Coinfected Patients With Advanced Liver Disease During Anti-HCV Treatment With DirectActing Antiviral Regimens Including Ribavirin TO THE EDITOR—We read with interest the report from Harrington and colleagues showing a reduction in lymphocyte count during interferon-free anti–hepatitis C virus (HCV) treatment with direct-acting antiviral (DAA)–based regimens containing ribavirin compared with ribavirinsparing regimens [1].Although a reduction of lymphocyte count was recorded, the cases of severe lymphopenia were small and no association between lymphopenia and infections was observed. Moreover, despite a decrease of absolute CD4 count in human immunodeficiency virus (HIV)– coinfected patients, none of them developed opportunistic infections [2]. The use of ribavirin in DAA-based regimens is suggested especially in patients with liver cirrhosis [3, 4],who are at higher risk of infections [5]. Moreover, infectious complications have a worse outcome in HIV-coinfected subjects [6]. The data reported from Harrington and colleagues derived from 3 clinical trials of ombitasvir/paritaprevir/ritonavir plus dasabuvir or ledipasvir/sofosbuvir, where a low proportion of patients with advanced liver disease treated with ribavirin-containing regimens was included (approximately 20% with liver cirrhosis in the ION-2 and in the TURQUOISE-I studies [overall 66 patients with liver cirrhosis] and 11%– 16% with advanced liver fibrosis in the PEARL-4 study [38 patients]) [2, 7–8]. Among them, 12 patients with liver cirrhosis were coinfected with HIV [2]. We report our experience with DAAbased regimens including ribavirin in HIV/HCV-coinfected patients with liver cirrhosis (n = 59) or advanced liver fibrosis (n = 12). Seventy-one patients have been treated since January 2015; 41 of them completed treatment and 23 reached posttreatment week 4. The major characteristics are summarized in Table 1. A reduction in the absolute lymphocyte count was observed at treatment week 4 compared to baseline, with median change of −100 (interquartile range [IQR], −400 to 100) cells/μL (relative change: −9% [IQR, −19% to 5%]), and confirmed at week 12, with a median change of −500 (IQR, −700 to −200) cells/μL (relative count change: −25% [IQR, −36% to −13%]). At post-treatment week 4, lymphocyte count almost returned to baseline values (change: −100 [−400 to 300] cells/μL). One patient developed grade 3 lymphopenia, which resolved after treatment completion. A reduction in absolute CD4 count was recorded at week 4 (−61 [IQR, −138 to 26] cells/μL) and 12 (−125 [IQR, −204 to −70] cells/μL), with almost complete recovery at post-treatment week 4 (change from baseline: –13 [IQR, −78 to 52] cells/μL). No variation in CD4 relative count was observed (median: −0.5% at week 4, 1.2% at week 12). Despite the reduction in absolute lymphocyte count, absolute neutrophil count remained stable up to 12 weeks (median: 400 cells/ μL and 0 cells/μL at weeks 4 and 12, respectively). Four (6%) patients experienced a bacterial infection (1 severe infection, 4 mild infections; no opportunistic infections) between baseline and post-treatment week 4; all completely recovered after antibiotic therapy. No treatment discontinuations due to infection were recorded. We observed a marked reduction in absolute lymphocyte count, associated with a reduction in absolute CD4 count, during ribavirin-containing anti-HCV therapy in HIV-coinfected patients with advanced liver disease. These data suggest careful monitoring of these patients during

Sustained virological response after ten days of triple anti-hepatitis C virus (HCV) therapy with telaprevir plus pegylated interferon and ribavirin in an HIV/HCV co-infected cirrhotic woman

The introduction of first-generation protease inhibitors for the treatment of chronic hepatitis C in subjects infected with hepatitis C virus (HCV) genotype 1 has significantly improved the sustained virological response (SVR) rate. As liver cirrhosis reduces the probability of achieving SVR, current guidelines discourage response-guided therapy in cirrhotic patients. We report the first case of a cirrhotic woman with chronic HCV and HIV co-infection achieving virological response after an ultra-short course of therapy. A 40-year-old HIV/HCV co-infected woman with compensated liver cirrhosis was treated with anti-HCV triple therapy containing telaprevir plus pegylated interferon and ribavirin. Baseline plasma HCV RNA was 3.6 log IU/ml and transaminases were within the normal range. She harboured IL28B rs12979860C/C alleles. Ten days after starting therapy, the patient stopped treatment because of mild anorexia and nausea. Virological response was detected at treatment discontinuation and was maintained up to 24 weeks. This case describes an unexpected SVR after a 10-day course of antiviral therapy in a cirrhotic HIV/HCV co-infected woman presenting positive predictive factors for a response (low viral load, IL28B genotype). Nonetheless, there is no evidence to suggest a shorter duration of treatment in this subset of patients.

Contents Vol. 93, 2017

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wis. M. Dietel, Berlin P. Dufour, Strasbourg M.S. Ernstoff , Buff alo, N.Y. M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buff alo, N.Y. M.J. Kelley, Durham, N.C. L. Kumar, New Delhi P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buff alo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buff alo, N.Y. D. Santini, Rome A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Zurich M.S. Tallman, New York, N.Y. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buff alo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief