Receiving Protease Inhibitors Research Articles

PHF19 before and post induction treatment possess favorable potency of reflecting treatment response to protease inhibitors, event-free survival, and overall survival in multiple myeloma patients

ABSTRACT Objective Plant homeodomain finger protein 19 (PHF19) regulates hematopoietic stem cell differentiation and promotes multiple myeloma (MM) progression. This study intended to explore the potency of PHF19 at baseline and post induction treatment in estimating treatment response to protease inhibitors and survival in MM patients. Methods This retrospective study screened 69 MM patients who received protease inhibitors with bone marrow (BM) samples available at both baseline and post induction treatment. Twenty healthy BM donors were included as healthy controls (HCs). PHF19 in plasma cells from BM was quantified by reverse transcription-quantitative polymerase chain reaction. Results PHF19 at baseline and post induction treatment in MM patients were increased than in HCs. In MM patients, PHF19 was declined post induction treatment. Elevated PHF19 at baseline and post induction treatment were correlated with renal impairment, beta-2-microglobulin ≥5.5 mg/L, t (4; 14), higher international staging system (ISS) stage, and higher revised ISS (R-ISS) stage. Concerning treatment response, PHF19 at baseline and post induction treatment were negatively associated with complete response and overall response rate. Notably, abnormal PHF19 (above 95% quantile value of PHF19 in HCs) at baseline and post induction treatment were linked with shortened event-free survival (EFS) and overall survival (OS). After adjustment, abnormal PHF19 post induction treatment was independently related to shortened EFS (hazard ratio = 2.474) and OS (hazard ratio = 3.124). Conclusion PHF19 is aberrantly high and declines post induction therapy, which simultaneously reflects unfavorable treatment response to protease inhibitors as well as shorter EFS and OS in MM patients.

Factors associated with immunological non-response after ART initiation: a retrospective observational cohort study

BackgroundAmong people living with HIV (PLHIV) on antiretroviral therapy (ART), the mortality of immunological non-responders (INRs) is higher than that of immunological responders (IRs). However, factors associated with immunological non-response following ART are not well documented.MethodsWe obtained data for HIV patients from the National Free Antiretroviral Treatment Program database in China. Patients were grouped into IRs (CD4 cell count ≥ 350 cells/μl after 24 months’ treatment), immunological incomplete responders (ICRs) (200–350 cells/μl) and INRs (< 200 cells/μl). Multivariable logistic regression was used to assess factors associated with immunological non-response.ResultsA total of 3900 PLHIV were included, among whom 2309 (59.2%) were IRs, 1206 (30.9%) ICRs and 385 (9.9%) INRs. In multivariable analysis, immunological non-response was associated with being male (2.07, 1.39–3.09), older age [40–49 years (vs. 18–29 years): 2.05, 1.29–3.25; 50–59 years: 4.04, 2.33-7.00; ≥ 60 years: 5.51, 2.84–10.67], HBV co-infection (1.63, 1.14–2.34), HCV co-infection (2.01, 1.01–4.02), lower CD4 + T cell count [50–200 cells/μl (vs. 200–350 cells/μl): 40.20, 16.83–96.01; < 50 cells/μl: 215.67, 85.62-543.26] and lower CD4/CD8 ratio (2.93, 1.98–4.34) at baseline. Compared with patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) based regimens, those receiving protease inhibitors (PIs) based regimens were less likely to be INRs (0.47, 0.26–0.82).ConclusionsWe found a sizable immunological non-response rate among HIV-infected patients. Being male, older age, coinfection with HBV and HCV, lower CD4 + T cell count and lower CD4/CD8 ratio are risk factors of immunological non-response, whereas PIs-based regimens is a protective factor.

Potential drug-drug interactions due to concomitant medicine use among people living with HIV on antiretroviral therapy in Australia.

We quantified concomitant medicine use and occurrence of potential drug-drug interactions in people living with HIV in Australia who are treated with antiretroviral therapy (ART). In this cohort study using dispensing claims of a 10% random sample of Australians, we identified 2230 people dispensed ART between January 2018 and December 2019 (mean age 49.0years, standard deviation 12.0years, 88% male). We examined concomitant medicine use by identifying nontopical medicines dispensed within 90-days of any antiretroviral medicine dispensing during a 12-month follow-up period. For every antiretroviral and nonantiretroviral pair, we identified and classified possible drug-drug interactions using the University of Liverpool HIV drug interactions database. A total of 1728 (78%) people were dispensed at least 1 and 633 (28%) 5 or more unique medicines in addition to ART in a 12-month period; systemic anti-infectives and medicines acting on the nervous system were the most common (68% and 56%, respectively). Among comedicated people, 1637 (95%) had at least 1 medicine combination classified as weak interactions, 558 (32%) interactions requiring close monitoring/dose adjustment and 94 (5%) that should not be coadministered. Contraindication or interactions requiring close monitoring/dose adjustment were more common among people receiving protease inhibitors (50-73% across different antiretrovirals), non-nucleoside reverse transcriptase inhibitors (35-64%), people using single-tablet combinations containing elvitegravir (30-46%) and those using tenofovir disoproxil (26-30%). Concomitant medicine use is widespread among people living with HIV in Australia. Despite a relatively low prevalence of contraindicated medicines, almost a third received medicines that require close monitoring or dose adjustment.

Long-term follow-up of HIV-1 multi-drug-resistant treatment-experienced participants treated with etravirine, raltegravir and boosted darunavir: towards drug-reduced regimen? ANRS CO3 Aquitaine Cohort 2007–2018

To assess the efficacy of raltegravir, etravirine and darunavir/ritonavir (TRIO regimen) in treatment-experienced patients with human immunodeficiency virus-1 (HIV-1) infection by describing the proportion of patients who experienced virological failure (VF) at Week 24. The secondary objectives were to assess the HIV-1 plasma viral load (pVL) after Week 24, the proportion of patients who were receiving dual therapy or monotherapy at the last visit, and the number of deaths. Patients from the ANRS CO3 Aquitaine Cohort who were prescribed the TRIO regimen between February 2007 and September 2018 were classified into two groups based on their pVL at study inclusion: the virological failure group (VFG; pVL >50 copies/mL) and the virologically suppressed group (VSG; pVL <50 copies/mL). The impact of baseline pVL and genotypic susceptibility score (GSS) on VF was analysed. In total, 184 patients were enrolled in this study, with 123 (66.8%) in the VFG and 61 (33.2%) in the VSG. The median length of follow-up was 7.5 (interquartile range 4.1-9.6) years, and 29 (15.8%) patients died. Thirty-seven (25.5%) patients experienced VF at Week 24, including 32/145 (32.7%) in the VFG and 5/47 (10.6%) in the VSG (P<0.01). Resistance-associated mutations were detected in integrase, reverse transcriptase and protease for 7/37 (18.9%), 3/37 (8.1%) and 1/37 (2.7%) patients, respectively. High pVL and GSS at baseline were independently associated with VF. At the last visit, 76/184 (41.3%) patients were still receiving the TRIO regimen, while 55/184 (29.9%) were receiving dual therapy and 1/184 (0.5%) was receiving protease inhibitor monotherapy. Among the 56 patients receiving dual therapy or monotherapy, 51 (96.2%) had pVL <50 copies/mL. Despite a high level of mutation resistance at baseline, long-term virological follow-up was favourable and one-third of patients were eligible for drug-reducing strategies.

Drug Resistance, Rather than Low Tenofovir Levels in Blood or Urine, Is Associated with Tenofovir, Emtricitabine, and Efavirenz Failure in Resource-Limited Settings.

The high cost of viral load (VL) testing limits its use for antiretroviral therapy (ART) adherence support. A low-cost lateral flow urine tenofovir (TFV) rapid assay predicts pre-exposure prophylaxis breakthroughs, but has not yet been investigated in HIV treatment. We therefore evaluated its utility in a pilot cross-sectional study of TFV-containing ART recipients at an increased risk of virologic failure (VF). Participants who had a treatment interruption ≥30 days or had ≥1 episode of viremia (VL ≥400 copies/mL) in the previous year were recruited from a public health setting in Cape Town, South Africa. Self-reported adherence data were collected, the urine TFV assay performed, and concurrent TFV-diphosphate analyzed in dried blood spots. VL testing was done concurrently and, if viremic, genotypic HIV drug resistance testing was performed. Of 48 participants, 18 (37.5%) had VL (>400 copies/mL) at the time of the study, including 16 of 39 receiving efavirenz (EFV), 2 of 6 receiving protease inhibitors, and 0 of 3 receiving dolutegravir. Resistance testing succeeded in 17/18, of which 14 had significant mutations compromising ≥2 agents of the current EFV-based regimen. Of these 14, all had detected urine TFV. Urine TFV was undetectable in two out of three without regimen-relevant resistance; p = .02. In participants on EFV-based regimens returning to care, VF was largely due to viral resistance, where detectable urine TFV had 100% sensitivity (14/14 participants) in predicting resistance. Conversely, when undetectable, the urine-based assay could be used to preclude participants with poor adherence from undergoing costly HIV drug resistance testing.

Contribution of APOA5, APOC3, CETP, ABCA1 and SIK3 genetic variants to hypertriglyceridemia development in Mexican HIV-patients receiving antiretroviral therapy.

To investigate the impact of single nucleotide polymorphisms (SNPs) from APOA5, APOC3, CETP, ATP binding cassette transporter A1 and SIK3 genes in the development of hypertriglyceridemia in HIV patients under antiretroviral therapy. A case-control study was developed. Leukocytic genomic DNA was extracted and genotyping for SNPs rs662799, rs964184, rs5128, rs2854116, rs2854117, rs3764261, rs4149310, rs4149267 and rs139961185 was performed by real time-PCR using TaqMan allelic discrimination assays, in Mexican mestizo patients with HIV infection, with hypertriglyceridemia (>1.7 mmol/L) under antiretroviral therapy. Genetic variants were also investigated in a control group of normolipidemic HIV patients (≤ 1.7 mmol/L). Haplotypes and gene interactions were analyzed. A total of 602 HIV patients were genotyped (316 cases and 286 controls). Age and antiretroviral regimen based on protease inhibitors were associated with hypertriglyceridemia (P = 0.0001 and P = 0.0002. respectively). SNP rs964184 GG genotype in APOA5 gene exhibited the highest association with hypertriglyceridemia risk (OR, 3.2, 95% CI, 1.7-5.8, P = 0.0001); followed by SNP rs139961185 in SIK3 gene (OR = 2.3; (95% CI, 1.1-4.8; P = 0.03 for AA vs. AG genotype; and APOC3 rs5128 GG genotype, (OR, 2.2; 95% CI, 1.1-4.9; P = 0.04) under codominant models. These associations were maintained in the adjusted analysis by age and protease inhibitors based antiretroviral regimens. This study reveals an association between rs964184 in APOA5; rs5128 in APOC3 and rs139961185 in SIK3 and high triglyceride concentrations in Mexican HIV-patients receiving protease inhibitors. These genetic factors may influence the adverse effects related to antiretroviral therapy.

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation

Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25). Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group. Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

Genomic instability in people living with HIV

The increased life expectancy of people living with HIV (PLWH) receiving antiretroviral treatment (ART) has transformed HIV infection into a chronic disease. However, patients may be at risk of accelerated aging and the accumulation of cellular damage, which may trigger the development of cancer. We evaluated genomic instability in HIV-positive individuals with different viral loads receiving antiretroviral treatment (ART) and in HIV ART-naïve individuals. We included 67 participants divided into four groups: group 1 (n = 24) HIV patients receiving reverse-transcriptase inhibitors (tenofovir/ emtricitabine/ efavirenz and abacavir/ lamivudine/ efavirenz), group 2 (n = 22) HIV patients receiving protease inhibitors combined with other antiretroviral drugs (tenofovir/ emtricitabine with ritonavir/ atazanavir or lopinavir/ ritonavir, and darunavir/ ritonavir/ raltegravir), group 3 (n = 13) HIV ART-naïve patients, and group 4 (n = 8) healthy individuals (controls). Nuclear abnormalities in buccal mucosal samples (micronuclei, binucleated cells, nuclear buds, karyorrhexis, karyolysis, and pyknosis) were quantified. Simultaneously, blood samples were taken to quantify CD4+, CD8+, and HIV viral load. There was a significant age difference between HIV ART-naïve patients and receiving ART groups. Infection time was longer in HIV patients with ART than in ART-naïve patients. There were no differences in sex, smoking, alcohol consumption, or number of micronucleated cells between the study groups. We found higher frequencies of binucleated cells and nuclear buds in HIV patients, HIV ART-naïve, and HIV ART patients compared to the control group. We found a positive correlation between nuclear buds and CD4/CD8 ratio in the HIV ART-naïve group. In conclusion, PLWH showed increased genomic instability. The CD4/CD8 ratio affects the numbers of nuclear buds and binucleated cells. These findings are pertinent to mechanisms of damage and possible strategies to mitigate carcinogenesis in PLWH.

Incidence and impact of low-level viremia among people living with HIV who received protease inhibitor- or dolutegravir-based antiretroviral therapy

ObjectivesThe impact of very low-level viremia (VLLV) and low-level viremia (LLV) are rarely investigated among people living with HIV (PLWH) receiving dolutegravir- vs protease inhibitor (PI)-based antiretroviral therapy (ART). MethodsVirally suppressed PLWH receiving long-term PI-containing ART were included in this study. The incidences of developing VLLV (plasma HIV RNA load (PVL) 20–49 copies/ml), LLV (PVL 50–999 copies/ml), and virological failure (any PVL ≥ 1000 copies/ml) were compared between those switched to dolutegravir-based ART and those remaining on PI-containing ART. ResultsA total of 183 PLWH were switched to dolutegravir-based regimens and 309 remained on PI-containing regimens. The incidences of VLLV and LLV were 26.5 and 13.2 per 100 person-years of follow-up in the dolutegravir group, respectively, and 17.1 and 7.0 per 100 person-years of follow-up in the PI group; there were no statistically significant differences after adjusting for confounders. The rate of virological failure was 1.3 per 100 person-years of follow-up in the dolutegravir group and 1.9 per 100 person-years of follow-up in the PI group (p = 0.32). Neither VLLV nor LLV was related to subsequent virological failure. ConclusionsAmong virally suppressed PLWH, the risk of developing VLLV or LLV were similar between those switched to dolutegravir-based therapy and those who continued PI-based therapy. VLLV and LLV were not associated with subsequent virological failure.

Adipocytokine dysregulation, abnormal glucose metabolism, and lipodystrophy in HIV-infected adolescents receiving protease inhibitors

BackgroundLipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We evaluated risk factors, adipocytokine levels, insulin resistance, and lipid profiles in HIV-infected adolescents with different lipodystrophy types. MethodsA cross-sectional study was conducted in 80 perinatally HIV-infected adolescents receiving PI-based highly active antiretroviral therapy for ≥ 6 months. Patients underwent oral glucose tolerance tests and measurements of high-molecular-weight (HMW) adiponectin, leptin, resistin, insulin, and lipids. They were classified into 3 groups based on the clinical findings: no lipodystrophy, isolated lipoatrophy, and any lipohypertrophy (isolated lipohypertrophy or combined type). ResultsOf the 80 patients (median age, 16.7 years), 18 (22.5%) had isolated lipoatrophy, while 8 (10%) had any lipohypertrophy (four with isolated lipohypertrophy, and four with the combined type). In a multivariate analysis, longer exposure to stavudine (OR: 1.03; 95% CI, 1.01–1.06; p = 0.005) and indinavir (OR: 1.03; 95% CI, 1.01–1.06; p = 0.012) were associated with lipoatrophy, while longer exposure to didanosine (OR: 1.04; 95% CI, 1.01–1.08; p = 0.017) and indinavir (OR: 1.10; 95% CI, 1.00–1.21; p = 0.045) were associated with any lipohypertrophy. Leptin levels were highest in the any-lipohypertrophy group and lowest in the isolated-lipoatrophy group (p = 0.013). HMW adiponectin levels were significantly lowest in the any-lipohypertrophy group and highest in the no-lipodystrophy group (p = 0.001). There were no significant differences in the levels of resistin among the three groups (p = 0.234). The prevalence of insulin resistance (p = 0.002) and prediabetes/diabetes (p < 0.001) were significantly highest in the any-lipohypertrophy group. Patients with lipoatrophy and those without lipodystrophy had comparable degrees of insulin resistance (p = 0.292). In multiple linear regression analysis, adjusted for age, sex, and waist-height ratio, HMW adiponectin levels were associated with Matsuda index (β = 0.5; p = 0.003) and quantitative insulin sensitivity check index (QUICKI) (β = 40.1; p = 0.010) and almost significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.054). Leptin and resistin levels were not associated with HOMA-IR, Matsuda index, or QUICKI (all p > 0.05). ConclusionsAbnormal glucose metabolism and dysregulation of adipocytokines were common in the HIV-infected adolescents with lipohypertrophy and the combined type. Preventive screening for cardiovascular diseases caused by metabolic alterations should be routinely performed.

Correlation Between Duration Of Protease Inhibitor Therapy With Insulin Resistance In HIV Patients

Abstract Metabolic diseases related to Human Immunodeficiency Virus (HIV) caused an increase in the workload of health services. Prevalence of HIV infection in Indonesian provinces varied considerably, ranging from less than 0.1% to 4%. Several studies have analyzed the correlation between insulin resistance and the usage of antiretroviral drugs, especially protease inhibitors. The main mechanism that responsible for insulin resistance is related to glucose transporter inhibition (GLUT4). This study objective is to assess the correlation between prolonged administration of protease inhibitors and insulin resistance in patients with that have diagnosed with HIV. Method. This research is an observational research using a cross-sectional design. The study was carried at the POSYANSUS Polyclinic at H. Adam Malik General Hospital in August - December 2019. The study sample were 34 HIV-treated patients receiving protease inhibitor ARV therapy. The study was analysed using chi square. Results. The characteristics of the study subjects had the most frequent age range at the age of 34 - 49 years (54.3%), men (71.4%) and women (28.6%). The longest use of antiretroviral drugs is most in the 6-12 months group (60%). Insulin resistance number in this study was 13 people (37.1%). The average HOMA-IR value of the study subjects was 2 (0.8-16.5), fasting blood sugar levels were 86 (70-283) mg / dl, fasting insulin levels were 9.1 (4.1-79.4) (µU / ml)., urea levels of 20.88 ± 9.7 mg / dl and creatinine levels of 0.81 ± 0.15 mg / dl. There was a significant correlation between the duration of ARV treatment with insulin resistance (p = 0.018; OR 7.65) Conclusion. There is a significant correlation between the duration of ARV treatment with insulin resistance. The longer Protease Inhibitor was used, the bigger insulin resistance.

Adjustment of Immunosuppression for Liver Transplant Recipients Infected with HCV and Treated with Paritaprevir / Ritonavir - Ombitasvir/ Dasabuvir and Ribavirin

Introduction. Eradication rates of hepatitis C virus (HCV) infection is likely to rise after liver transplantation (LT). We aimed to evaluate the clinical role of a simple method for calcineurin inhibitors (CNI) adjustment in post-LT patients receiving paritaprevir / ritonavir / ombitasvir / dasabuvir and ribavirin (3D scheme). Material and Methods. We included post-LT adult patients between 2014 and 2017. All selected subjects had at least a 12-month follow-up receiving a stable dose of a CNI. All patients had HCV-1 infection, no liver cirrhosis and received the 3D scheme for 24 weeks. Serial blood concentration measurements of immunosuppressant drugs were obtained. CNI dose was adjusted since 3D scheme initiation and during follow-up until adequate levels were obtained. Results. A total of 10 LT patients (mean age 58.7 ± 11.26 years, 60 % women), out of LT 22, received the 3D regime. Tacrolimus was used in 9 patients: four patients received a dose of 0.5 mg every 10 days and 5 received doses of 0.25 mg every 5 days (mean levels, 9.07 ± 5.56 ng/mL). The trough concentration (Ctrough) was 2 ng / mL and the maximum concentration (Cmax) was 30 ng / mL. Only one patient was treated with cyclosporine (mean blood levels of 152.85 ± 54.55 ng / mL). All cases exhibited a sustained viral response. Discussion and Conclusions. It is possible to adjust CNI in LT patients under the 3D regime, with high response rates. Low CNI doses are required to avoid toxicity and side effects in HCV patients receiving protease inhibitors.

10-year outcome of temporary structured treatment interruption (STI) among HIV-1-infected patients: An observational study in a single medical center

Lifelong antiretroviral therapy (ART) is recommended for HIV-1 infected patients but may lead to intolerance or poor adherence. Structured treatment interruption (STI) is a strategy for drug holiday or to boost HIV-specific immunity. But the long-term outcome of STI was never reported in literature. This is a single-center observational study. We followed the HIV-infected patients who already had a stable viral suppression and voluntarily started temporary STI with a fixed 12-week interval after counseling, evaluation and education. HIV-1-specific T cell response was also measured in some patients. Totally 34 HIV-infected patients received temporary STI since July, 2006. 18 patients completed 10-year follow-up. All patients received protease inhibitors (PI)-based ART before and during temporary STI. The patients received temporary STI with a period of 36-85 weeks. All of them reached viral suppression after 12 weeks of restarting continuous ART. No viral rebound or opportunistic disease was recorded during follow-up. No adverse event or comorbidity was attributed to STI. The plasma viral load (PVL) at the end of STI was significantly lower than baseline PVL in patients with a longer duration of STI (≤36 weeks vs. >36 weeks, P=0.005). The T cell response study revealed that cyclically increased HIV-1-specific T cell response after starting STI in patients with baseline CD4+ count >350/μL. Temporary STI may not lead to worse long-term outcome among highly selected patients. The policy may partially control viral replication through reminding the HIV-1 specific T cell immunity.

The Evaluation of Medication Adherence in Patients Infected With HCV Receiving Protease Inhibitors: A Pilot Study.

Adherence to treatment is essential for hepatitis C cure. Studies show the complexity of the treatment due to side effects, many pills, and rigor in the schedules. The aim of this study was to evaluate the adherence to treatment with protease inhibitor in patients with hepatitis C. It is a longitudinal, observational, prospective pilot study with patients with hepatitis C genotype 1. Bimonthly consultations and biweekly calls for 20 weeks were performed. Evaluation methods for adherence were Measure of Adherence to Treatment score, patient report, count pills, and sustained virological response. Twenty-two patients were enrolled. Mean age was 54.0 ± 8.72 years; 50% were men, educational level was 7.9 ± 3.89 years for the study, and intake of pills was 2.2 ± 1.60 per day. Adverse events reported were fatigue (90.9%), muscular pain (72.7%), and nausea (68.2%). In total, 71.4% of patients took 100% of medications and were classified as having a high degree of adherence to treatment. The sustained virological response was not significant in relation to the high or low adherence degree. Measure of Adherence to Treatment score is a good instrument to measure adherence to protease inhibitor treatment. The adherence of patients undergoing long-term and complex treatments improves when the multidisciplinary team follows up every 7-15 days. The patient's access to the team through additional phone calls or medical/nursing appointment is essential to improve adherence.

Lipid profile and renal safety of tenofovir disoproxil fumarate-based anti-retroviral therapy in HIV-infected Chinese patients

BackgroundTenofovir disoproxil fumarate (TDF) is an important component of antiretroviral therapy (ART) that has been widely used. The aim of this study was to observe the long-term impact of TDF-based ART on lipid metabolism profiles and renal functions in Chinese patients. Methods414 and 124 HIV-infected, ART-naïve patients who initiated TDF-based regimens and non-TDF regimens respectively were retrospectively included. Demographic characteristics and clinical information of each patient was collected. Changes of lipid profiles and renal function, as well as the risk factors of hyperlipidemia and renal dysfunction were analyzed. ResultsAfter 96 weeks of ART, HIV viral loads were undetectable in 97.34% (403/414) of patients exposed to TDF. The plasma total cholesterol (TCH) increased from 3.97 ± 0.83 mmol/L to 4.53 ± 0.87 mmol/L (P < 0.001), which did not show a significant difference comparing with non-TDF exposed group. By contrast, the plasma triglyceride (TG) levels increased, but were still lower than that in the non-TDF exposed group (0.26 ± 1.24 vs. 0.89 ± 1.78, P < 0.001). The mean estimated glomerular filtration rate (eGFR) decreased from 127.29 ± 24.04ml∙min−1∙1.73 m−2 at baseline to 118.84 ± 22.74 ml∙min−1∙1.73 m−2(P < 0.001) in the TDF exposed group, while it increased in the non-TDF exposed group. In the TDF group, high body mass index (BMI) (OR = 1.13, P = 0.01), high baseline TG (OR = 2.33, P<0.001) and receiving protease inhibitors (PIs) (OR = 7.58, P < 0.001) were associated with hypertriglyceridemia after ART, while high baseline TCH predicted hypercholesterolemia (OR = 3.58, P < 0.001). MSM (OR = 0.22, P = 0.02) and baseline eGFR (OR = 0.90, P < 0.001) was associated with renal dysfunction after ART. ConclusionsTDF-based regimens are of good therapeutic effect among Chinese people. These regimens showed a better plasma lipid profile but mild renal dysfunction as compared to non-TDF based regimens. Patients with high BMI, high baseline TG, high baseline TCH and low baseline eGFR should be closely monitored when using TDF-based ART.

Study of Hepatitis Eradication Receiving Protease Inhibitor Administration

Study of Hepatitis Eradication Receiving Protease Inhibitor Administration

933. Serum Albumin Is Associated With Higher Inflammation and Carotid Atherosclerosis in Treated HIV Infection

BackgroundLower serum albumin has recently been associated with cardiovascular disease and non-AIDS malignancies in HIV. This analysis explores the associations between serum albumin and markers of inflammation and atherosclerosis.MethodsWe conducted a nested study within in the SATURN-HIV trial in which 147 HIV+ adults on stable antiretroviral therapy (ART), were virally suppressed, and had an LDL-cholesterol level <130 mg/dL were randomized to 10 mg daily rosuvastatin or placebo. Measures of serum albumin, carotid intima media thickness (IMT, surrogate marker of atherosclerosis), inflammation, T-cell and monocyte immune activation were assessed at baseline, 24, 48, and 96 weeks later. Spearman correlations and linear-mixed effects models with random intercept and slope were conducted to assess associations with albumin.ResultsMean age was 45 years, 80% were male, 69% were African American, and 46% were receiving protease inhibitors. Mean serum albumin was not significantly different between the groups at any time points (4.05–4.08 g/dL in statin arm vs. 4.01–4.11 g/dL in placebo arm, P = 0.08–0.35). Low serum albumin significantly correlated with elevated levels of interleukin-6 (IL6), d-dimer, fibrinogen, and high sensitivity C-reactive protein (hsCRP) at all time points (P ≤ 0.04). Low serum albumin also correlated with higher inflammatory monocytes (CD14+CD16+) at week 24 and week 96 (P ≤ 0.03) but not with markers of T-cell activation at any time point (P ≥ 0.10). Lower baseline albumin significantly predicted larger changes in IMT (P = 0.03), IL6, d-dimer, tumor necrosis factor-α receptor 1, fibrinogen, and hsCRP (P ≤ 0.02) over 96 weeks. After adjusting for age, gender, smoking, body mass index, vascular cell adhesion molecule and creatinine clearance, every 1 g/dL decrease in albumin remained associated with a 0.5 mm increase in IMT over 96 weeks (P = 0.05).ConclusionLower serum albumin in controlled HIV is associated with higher markers of chronic inflammation, hypercoagulation, and monocyte activation, which could explain the prior observation that albumin predicts non-AIDS events in HIV. Our findings suggest that serum albumin may predict progression of carotid atherosclerosis independent of traditional risk factors.Disclosures G. A McComsey, Gilead: Consultant, Consulting fee and Research support. Merck: Consultant, Consulting fee and Research support. Viiv: Consultant, Consulting fee and Research support. Roche: Research Contractor, Research support. Astellas: Research Contractor, Research support.

The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: a randomised, placebo-controlled, double-blind trial

Whether ongoing virus replication occurs in HIV-infected individuals on antiretroviral therapy (ART) is unclear; therefore, whether residual virus replication is a barrier to achieving a cure for HIV is also unknown. We aimed to establish whether ART intensification with dolutegravir would reveal or affect residual virus replication in HIV-infected individuals on suppressive treatment. In this randomised, placebo-controlled, double-blind trial, we enrolled HIV-infected adults (aged 18 years and older) receiving combination ART (at least three agents) for at least 3 years from the Alfred Hospital and Melbourne Sexual Health Centre, Melbourne, VIC, Australia. Eligible participants had fewer than 50 copies per mL HIV-1 plasma RNA for more than 3 years and fewer than 20 copies per mL at screening and two CD4 counts higher than 350 cells per μL in the previous 24 months including screening. Participants were randomly assigned (1:1) to receive 50 mg oral dolutegravir or placebo once a day for 56 days in addition to background ART. Follow-up was done at days 1, 3, 7, 14, 28, 56, and 84. The primary outcome was the change from baseline in frequency of 2-long terminal repeat (2-LTR) circles in peripheral blood CD4 cells at day 7. This trial is registered with ClinicalTrials.gov, number NCT02500446. Between Sept 21, 2015, and Sept 19, 2016, 46 individuals were screened for inclusion. 40 were eligible for inclusion and were randomly assigned to the dolutegravir (n=21) or placebo group (n=19). All enrolled participants completed the study procedures and no individuals were lost to follow up. All participants were on suppressive ART with 12% receiving protease inhibitors and the others non-nucleoside reverse transcriptase inhibitors. Median 2-LTR circles fold-change from baseline to day 7 was -0·17 (IQR -0·90 to 0·90) in the dolutegravir group and -0·26 (-1·00 to 1·17) in the placebo group (p=0·17). The addition of dolutegravir to pre-existing ART regimens was safe and there were no treatment discontinuations or treatment-related serious adverse events. Our findings show that in HIV-infected individuals on modern suppressive ART regimens, residual replication is rare, if at all present, and was not recorded in blood after dolutegravir intensification. Because tissue biopsies were not done we cannot exclude the possibility of residual virus replication in tissue. Strategies other than ART alone are needed to eliminate HIV persistence on treatment. ViiV Healthcare.

Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India.

Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000 copies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0– 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (P < .001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (P = .006).CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.

Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience.

AIMTo evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital.METHODSAll patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12).RESULTSA total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR.CONCLUSIONThe SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.