Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-CoV-2.

A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this study was to explore certain clinical profiles involving severe immunosuppression that may help explain the prolonged persistence of viable viruses. We present three severely immunosuppressed cases (A, B, and C) with a history of lymphoma and prolonged SARS-CoV-2 shedding (2, 4, and 6 months), two of whom finally died. Whole-genome sequencing of 9 and 10 specimens from Cases A and B revealed extensive within-patient acquisition of diversity, 12 and 28 new single nucleotide polymorphisms, respectively, which suggests ongoing SARS-CoV-2 replication. This diversity was not observed for Case C after analysing 5 sequential nasopharyngeal specimens and one plasma specimen, and was only observed in one bronchoaspirate specimen, although viral viability was still considered based on constant low Ct values throughout the disease and recovery of the virus in cell cultures. The acquired viral diversity in Cases A and B followed different dynamics. For Case A, new single nucleotide polymorphisms were quickly fixed (13-15 days) after emerging as minority variants, while for Case B, higher diversity was observed at a slower emergence: fixation pace (1-2 months). Slower SARS-CoV-2 evolutionary pace was observed for Case A following the administration of hyperimmune plasma. This work adds knowledge on SARS-CoV-2 prolonged shedding in severely immunocompromised patients and demonstrates viral viability, noteworthy acquired intra-patient diversity, and different SARS-CoV-2 evolutionary dynamics in persistent cases.

Effects of Hepatitis C Virus (HCV) Eradication on Bone Mineral Density in Human Immunodeficiency Virus/HCV-Coinfected Patients.

BACKGROUND: Little is known about the effects of eradication of hepatitis C virus (HCV) on bone mineral density (BMD) and biomarkers of bone remodeling in human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: We prospectively assessed standardized BMD (sBMD) at the lumbar spine and femoral neck, World Health Organization BMD categories at both sites, and plasma concentrations of soluble receptor activator of NF-κß ligand (sRANKL), and osteoprotegerin (OPG) at baseline (the date of initiation of anti-HCV therapy) and at 96 weeks. RESULTS: A total of 238 patients were included. The median age was 49.5 years, 76.5% were males, 48.3% had cirrhosis, 98.3% were on antiretroviral therapy, median CD4+ cell count was 527 cells/µL, and 86.6% had HIV-1 RNA <50 copies/mL. The prevalence of osteoporosis at baseline at the lumbar spine (LS) and femoral neck (FN) was 17.6% and 7.2%, respectively. Anti-HCV therapy comprised pegylated interferon (peg-IFN) and ribavirin (RBV) plus 1 direct-acting antiviral in 53.4%, peg-IFN/RBV in 34.5%, and sofosbuvir/RBV in 12.2%. A total of 145 (60.9%) patients achieved sustained virologic response (SVR). No significant effect of SVR was observed on sBMD for the interaction between time and SVR either in the LS (P = .801) or the FN (P = .911). Likewise, no significant effect of SVR was observed in plasma levels of sRANKL (P = .205), OPG (P = .249), or sRANKL/OPG ratio (P = .123) for the interaction between time and SVR. No significant correlation was found between fibrosis by transient elastography, and LS and FN sBMD, at baseline and week 96. CONCLUSIONS: SVR was not associated with significant changes in BMD nor biomarkers of bone remodeling in HIV/HCV-coinfected persons.

Plasma IP-10 and IL-6 are linked to Child-Pugh B cirrhosis in patients with advanced HCV-related cirrhosis: a cross-sectional study.

We aimed to evaluate the association of plasma biomarkers linked to inflammation (bacterial translocation, inflammatory response, and endothelial dysfunction), coagulopathy, and angiogenesis with the severity of liver cirrhosis (assessed by the Child-Pugh-Turcotte score, CTP) and Child-Pugh B cirrhosis (CTP 7-9) in patients with advanced hepatitis C virus (HCV)-related cirrhosis. We carried out a cross-sectional study in 97 patients with advanced HCV-related cirrhosis (32 HCV-monoinfected and 65 HIV/HCV-coinfected). Plasma biomarkers were measured by ProcartaPlex multiplex immunoassays. The outcome variable was the CTP score and the Child-Pugh B cirrhosis (CTP 7-9). HIV/HCV-coinfected patients and HCV-monoinfected patients with advanced HCV-related cirrhosis had near-equivalent values of plasma biomarkers. Higher values of plasma biomarkers linked to an inflammatory response (IP-10, IL-8, IL-6, and OPG), endothelial dysfunction (sVCAM-1 and sICAM-1), and coagulopathy (D-dimer) were related to higher CTP values. The most significant biomarkers to detect the presence of Child-Pugh B cirrhosis (CTP 7-9) were IP-10 (p-value= 0.008) and IL-6 (p-value=0.002). The AUC-ROC values of IP-10, IL-6, and both biomarkers combined (IP-10+IL-6) were 0.78, 0.88, and 0.96, respectively. In conclusion, HIV infection does not appear to have a significant impact on the analyzed plasma biomarkers in patients with advanced HCV-related cirrhosis. However, plasma biomarkers linked to inflammation (inflammatory response and endothelial dysfunction) were related to the severity of liver cirrhosis (CTP score), mainly IP-10 and IL-6, which discriminated patients with Child-Pugh B concerning Child-Pugh A.

Polypharmacy and Drug-Drug Interactions in People Living With Human Immunodeficiency Virus in the Region of Madrid, Spain: A Population-Based Study.

BACKGROUND: Drug-drug interactions (DDIs) that involve antiretrovirals (ARVs) tend to cause harm if unrecognized, especially in the context of comorbidity and polypharmacy. METHODS: A linkage was established between the drug dispensing registry of Madrid and the Liverpool human immunodeficiency virus (HIV) DDI database (January 2017-June 2017). Polypharmacy was defined as the use of ≥5 non-HIV medications, and DDIs were classified by a traffic-light ranking for severity. RESULTS: A total of 22 945 people living with HIV (PLWH) and 6 613 506 individuals without HIV had received medications. ARV regimens were predominantly based on integrase inhibitors (51.96%). Polypharmacy was higher in PLWH (32.94%) than individuals without HIV (22.16%; P < .001); this difference was consistently observed across all age strata except for individuals ≥75 years. Polypharmacy was more common in women than men in both PLWH and individuals without HIV. The prevalence of contraindicated combinations involving ARVs was 3.18%. Comedications containing corticosteroids, quetiapine, or antithrombotic agents were associated with the highest risk for red-flag DDI, and the use of raltegravir- or dolutegravir-based antiretroviral therapy was associated with an adjusted odds ratio of 0.72 (95% confidence interval, .60-.88; P = .001) for red-flag DDI. CONCLUSIONS: Polypharmacy was more frequent among PLWH across all age groups except those aged ≥75 years and was more common in women. The detection of contraindicated medications in PLWH suggests a likely disconnect between hospital and community prescriptions. Switching to alternative unboosted integrase regimens should be considered for patients with risk of harm from DDIs.

Drug-related and psychopathological symptoms in HIV-positive men who have sex with men who inject drugs during sex (slamsex): Data from the U-SEX GESIDA 9416 Study.

OBJECTIVES: Sexualized intravenous drug use, also known as slamsex, seems to be increasing among HIV-positive men who have sex with men (MSM). Physical and psychopathological symptoms have previously been reported in this population, although research on the subject of slamsex is scarce. The objectives of our study were to describe the psychopathological background of a sample of HIV-positive MSM who engaged in slamsex during the previous year and to compare physical, psychopathological, and drug-related symptoms between these participants and those who engaged in non-injecting sexualized drug use. DESIGN AND METHODS: Participants (HIV-positive MSM) were recruited from the U-Sex study in 22 HIV clinics in Madrid during 2016-17. All participants completed an anonymous cross-sectional online survey on sexual behavior and recreational drug use. When participants met the inclusion criteria, physicians offered them the opportunity to participate and gave them a card with a unique code and a link to access the online survey. The present analysis is based on HIV-positive MSM who had engaged in slamsex and non-injecting sexualized drug use. RESULTS: The survey sample comprised 742 participants. Of all the participants who completed the survey, 216 (29.1%) had engaged in chemsex, and of these, 34 (15.7%) had engaged in slamsex. Participants who engaged in slamsex were more likely to have current psychopathology (depression, anxiety, and drug-related disorders) than participants who engaged in non-injecting sexualized drug use. In addition, participants who engaged in slamsex more frequently reported high-risk sexual behaviors and polydrug use and were more often diagnosed with sexually transmitted infections (STIs) and hepatitis C than those who did not inject drugs. Compared with participants who did not inject drugs, participants who engaged in slamsex experienced more severe drug-related symptoms (withdrawal and dependence), symptoms of severe intoxication (loss of consciousness), and severe psychopathological symptoms during or after slamsex (eg, paranoid thoughts and suicidal behaviors). CONCLUSION: Slamsex is closely associated with current psychiatric disorders and severe drug-related and psychiatric symptoms.

European mitochondrial haplogroups predict liver-related outcomes in patients coinfected with HIV and HCV: a retrospective study.

BACKGROUND: Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients. METHODS: We carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk. RESULTS: The study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups (p = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values. CONCLUSIONS: European mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

Genetic variants upstream of TNFAIP3 in the 6q23 region are associated with liver disease severity in HIV/HCV-coinfected patients: A cross-sectional study.

BACKGROUND: TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients. METHODS: A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2). RESULTS: Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively). CONCLUSIONS: Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.

Prognostic value of liver stiffness in HIV/HCV-Coinfected patients with decompensated cirrhosis.

BACKGROUND: Little is known about the utility of transient elastography (TE) for assessing the prognosis of patients with decompensated cirrhosis (DC). METHODS: We analyzed HIV/HCV-coinfected patients with DC who underwent TE as part of their routine follow-up between 2006 and 2015. We also calculated the liver stiffness spleen diameter-to-platelet score (LSPS), FIB-4 index, albumin, MELD score, and Child-Pugh score. The primary outcome was death. RESULTS: The study population comprised 65 patients. After a median follow-up of 32 months after the first TE, 17 patients had received anti-HCV therapy and 31 patients had died. The highest area under the receiver operating characteristic curve (AUROC) value for prediction of death was observed with albumin (0.695), followed by Child-Pugh score (0.648), both with P values < .05. Lower AUROC values were observed with MELD score (0.633), TE (0.618), LSPS score (0.595), and FIB-4 (0.569), all with P values > .05. In the univariate Cox regression analysis, albumin, FIB-4, Child-Pugh score, and MELD score, but not TE, were associated with death. In the multivariate analysis, albumin and Child-Pugh score were the only baseline variables associated with death. CONCLUSIONS: Our results suggest that TE is not useful for assessing the prognosis of HIV-infected patients with decompensated HCV-related cirrhosis. Albumin concentration and Child-Pugh scores were the most consistent predictors of death in this population group.

Prognostic Value of Transient Elastography in Human Immunodeficiency Virus-Infected Patients With Chronic Hepatitis C.

BACKGROUND: Our objective was to study the prognostic value of liver stiffness (LS) in HIV-infected patients with chronic hepatitis C (CHC). METHODS: We analyzed HIV-infected patients with compensated CHC and at least 1 determination of LS. The primary outcome was the occurrence of liver-related events (LRE), namely, decompensation or hepatocellular carcinoma, whichever occurred first. We selected patients without sustained viral response (SVR) or end-of-treatment response (ETR) during follow-up and allocated them to an estimation cohort (EC) and a validation cohort (VC). RESULTS: The study population comprised 1292 patients. After a median follow-up of 5.8 years, 90 patients experienced LRE and 73 died. In the subgroup of 957 patients without SVR or ETR, the area under the receiver operating characteristic curves (AUROCs) (95% confidence interval [CI]) of LS for prediction of LRE in the EC (n = 634) and the VC (n = 323) were 0.87 and 0.88, respectively. The best cutoff value of LS to rule out LRE in the EC was 12 kPa, with a negative predictive value of 98.3% in the EC and 98.2% in the VC. Per each 1 kPa and 5 kPa increase above 12 kPa, the hazard ratio of LRE (taking into account death as a competing risk) was 1.07 (95% CI, 1.05-1.08) and 1.38 (95% CI, 1.31-1.46), respectively. CONCLUSIONS: Liver stiffness is very accurate for predicting LRE in coinfected patients. Patients with an LS <12 kPa had a 98% probability of not developing LRE after a median follow-up of almost 6 years. Above the 12-kPa cutoff, the hazard of LRE increases proportionally with LS.

Soluble Adhesion Molecules in Patients Coinfected with HIV and HCV: A Predictor of Outcome.

BACKGROUND: Higher serum levels of adhesion molecules (sICAM-1 and sVCAM-1) are associated with advanced liver fibrosis in patients coinfected with human immunodeficiency virus and hepatitis C virus. We assessed the relationship between serum levels of adhesion molecules and liver-related events (LRE) or death, in coinfected patients. METHODS: We studied clinical characteristics and outcomes of 182 coinfected patients with a baseline liver biopsy (58 with advanced fibrosis) and simultaneous plasma samples who were followed for median of 9 years. We used receiver-operating characteristic (ROC) curves to calculate optimized cutoff values (OCV) of sICAM-1 and sVCAM-1, defined as the values with the highest combination of sensitivity and specificity for LRE. We used multivariate regression analysis to test the association between OCVs of sICAM-1 and sVCAM-1 and outcomes. The variables for adjustment were age, HIV transmission category, liver fibrosis, baseline CD4+ T-cell counts, antiretroviral therapy, and sustained virologic response (SVR). RESULTS: During the study period 51 patients had SVR, 19 had LRE, and 16 died. The OCVs for LRE were 5.68 Log pg/mL for sICAM-1 and 6.25 Log pg/mL for sVCAM-1, respectively. The adjusted subhazard ratio (aSHR) (95% confidence interval [CI]) of death or LRE, whichever occurred first, for sICAM-1 and sVCAM-1 > OCV were 3.98 ([1.14; 13.89], P = 0.030) and 2.81 ([1.10; 7.19], respectively (P = 0.030). CONCLUSIONS: Serum levels of sICAM-1 and sVCAM-1 can serve as markers of outcome in HIV/HCV-coinfected patients. Therapies targeting necroinflammatory damage and fibrogenesis may have a role in the management chronic hepatitis C.

Prediction of liver complications in patients with hepatitis C virus-related cirrhosis with and without HIV coinfection: comparison of hepatic venous pressure gradient and transient elastography.

BACKGROUND: Hepatic venous pressure gradient (HVPG) is the best indicator of prognosis in patients with compensated cirrhosis. We compared HVPG and transient elastography (TE) for the prediction of liver-related events (LREs) in patients with hepatitis C virus (HCV)-related cirrhosis with or without human immunodeficiency virus (HIV) coinfection. METHODS: This was a retrospective review of all consecutive patients with compensated HCV-related cirrhosis who were assessed simultaneously using TE and HVPG between January 2005 and December 2011. We used receiver operating characteristic (ROC) curves to determine the ability of TE and HVPG to predict the first LRE (liver decompensation or hepatocellular carcinoma). RESULTS: The study included 60 patients, 36 of whom were coinfected with HIV. After a median follow-up of 42 months, 6 patients died, 8 experienced liver decompensations, and 7 were diagnosed with hepatocellular carcinoma. The area under the ROC curve (AUROC) of TE and HVPG for prediction of LREs in all patients was 0.85 (95% confidence interval [CI], .73-.97) and 0.76 (95% CI, .63-.89) (P = .13); for HIV-infected patients, the AUROC was 0.85 (95% CI, .67-1.00) and 0.81 (95% CI, .64-.97) (P = .57); and for non-HIV-infected patients, the AUROC was 0.88 (95% CI, .75-1.00) and 0.77 (95% CI, .57-.97) (P = .19). Based on the AUROC values, 2 TE cutoff points were chosen to predict the absence (<25 kPa) or presence (≥40 kPa) of LREs, thus enabling correct classification of 82% of patients. CONCLUSIONS: Our data suggest that TE is at least as valid as HVPG for predicting LREs in patients with compensated HCV-related cirrhosis with or without concomitant HIV coinfection.