Advancing pharmacogenetic testing in a tertiary hospital: a retrospective analysis after 10 years of activity.

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice.

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.

Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients.

Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB variants in patients with hypercholesterolemia. Index patients (n = 825) with clinically suspected FH were analyzed using next-generation sequencing. In total, 40% of the patients presented a variant in LDLR, APOB, PCSK9 or LDLRAP1, with 12% of the variants in APOB. These variants showed frequencies in the general population lower than 0.5% and were classified as damaging and/or probably damaging by 3 or more predictors of pathogenicity. The variants c.10030A>G;p.(Lys3344Glu) and c.11401T>A;p.(Ser3801Thr) were characterized. The p.(Lys3344Glu) variant co-segregated with high low-density lipoprotein (LDL)-cholesterol in 2 families studied. LDL isolated from apoB p.(Lys3344Glu) heterozygous patients showed reduced ability to compete with fluorescently-labelled LDL for cellular binding and uptake compared with control LDL and was markedly deficient in supporting U937 cell proliferation. LDL that was carrying apoB p.(Ser3801Thr) was not defective in competing with control LDL for cellular binding and uptake. We conclude that the apoB p.(Lys3344Glu) variant is defective in the interaction with the LDL receptor and is causative of FH, whereas the apoB p.(Ser3801Thr) variant is benign.

Analytical validation of a laboratory-development multigene pharmacogenetic assay.

OBJECTIVE: The implementation of pharmacogenetics (PGx) in clinical practice is an essential tool for personalized medicine. However, clinical laboratories must validate their procedures before being used to perform PGx studies in patients, in order to confirm that they are adequate for the intended purposes. METHODS: We designed a validation process for our in-house pharmacogenetic PCR-based method assay. RESULTS: The concordance to reference, repeatability and reproducibility was 100%. Sensitivity and specificity were 100% for the detection of variant diplotypes in CYP2C9, CYP3A5, TPMT, DPYD and UGT1A1 genes. The sensitivity was lower in the detection of CYP2C19 variants due to a limitation in the design that prevents the detection of CYP2C19 *2/*10 diplotype. CONCLUSIONS: The success of implementing clinical pharmacogenetic testing into routine clinical practice is dependent on the precision of genotyping. Limitations must be bearing in mind to guarantee the quality of PGx assays in clinical laboratory practice. We provided objective evidence that the necessary requirements in our laboratory-development assay were fulfilled.

Familial hypercholesterolemia: A single-nucleotide variant (SNV) in mosaic at the low density lipoprotein receptor (LDLR).

BACKGROUND AND AIMS: Familial hypercholesterolemia is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes. The objective of this article was the molecular characterization of a patient with hypercholesterolemia. METHODS AND RESULTS: Genetic analysis of DNA from peripheral blood and saliva was performed by NGS, Sanger sequencing and pyrosequencing technologies. NGS analysis detected the pathogenic variant LDLR:c.1951G > T:p.(Asp651Tyr) in 9%-12% of reads. The presence of the variant was confirmed by pyrosequencing analysis. The variant found was functional characterized using an in vitro model (CHO-ldlA7 cells). Activity and expression of cell surface LDLR were measured by flow cytometry. Colocalization LDLR-Dil-LDL was detected by immunofluorescence. The LDLR activity showed 80% uptake, 50% binding and 53% expression of cell surface LDLR regarding wild type. CONCLUSIONS: Herein, we report the first case of a mosaic single nucleotide variant affecting the LDLR gene in a patient with familial hypercholesterolemia. As it has been described for other pathologies, mosaicism could be underestimated in FH and its detection will improve with the introduction of NGS technologies in the diagnostic routine.

Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia: A case report.

RATIONALE: Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events. PATIENT CONCERNS: We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia. DIAGNOSIS: Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. Sanger sequencing was used to confirm the presence of the variants of interest. The genetic analysis showed a pathogenic heterozygous mutation in LDLR [exon 6:c.902A>G:p(Asp301Gly)], as well as a loss-of-function heterozygous variant in PCSK9 [exon1:c.137 G>T:p.(Arg46Leu)]. The genetic analysis of the index case's mother revealed compound heterozygosity for 2 different mutations in LDLR [c.902A>G:p.(Asp301Gly); c.1646G>T:p.(Gly549Val)] in exon 6 and in exon 11, respectively, and the same loss-of-function variant in PCSK9 that had been found in her daughter [(PCSK9:exon1:c.137G>T:p.(Arg46Leu)]. The maternal grandfather of the index case presented the same genetic variants as his granddaughter. INTERVENTIONS: The index case did not receive any specific treatment for hypercholesterolemia. The loss-of-function variant in PCSK9 protected her from higher LDL-cholesterol levels, provided she kept partial activity of the LDLR. In her mother, instead, a PCSK9 inhibitor was tried but failed to achieve lipid control. The reason for this may be the complete absence in LDL receptor activity. LDL apheresis was started afterwards, resulting in adequate lipid level control. OUTCOMES: To the date, the index case has achieved to maintain adequate total and LDL-cholesterol levels without any other intervention. She has had no known cardiovascular complication. LESSONS: Loss-of-function mutations in PCSK9 could protect from developing more severe forms of hypercholesterolemia. The finding of these mutations (LDLR-PCSK9) in three consecutive generations could imply an adaptive mechanism against the development of hypercholesterolemia.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as "uncertain significant variants", and therefore, carry out cascade family screening.

A new variant (c.1A>G) in LDLRAP1 causing autosomal recessive hypercholesterolemia: Characterization of the defect and response to PCSK9 inhibition.

BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a rare disorder caused by mutations in LDLRAP1, which impairs internalization of hepatic LDL receptor (LDLR). ARH patients respond relatively well to statins or the combination of statins and Ezetimibe, but scarce and variable data on treatment with PCSK9 inhibitors is available. We aimed to identify and characterize the defect in a hypercholesterolemic patient with premature cardiovascular disease and determine the response to lipid-lowering treatment. METHODS AND RESULTS: Gene sequencing revealed a homozygous c.1A > G:p.? variant in LDLRAP1. Primary lymphocytes were isolated from the ARH patient, one control and two LDLR-defective subjects, one LDLR:p.(Cys352Ser) heterozygote and one LDLR:p.(Asn825Lys) homozygote. The patient had undetectable full-length ARH protein by Western blotting, but expressed a lower-than-normal molecular weight peptide. LDLR activity was measured by flow cytometry, which showed that LDL binding and uptake were reduced in lymphocytes from the ARH patient as compared to control lymphocytes, but were slightly higher than in those from the LDLR:p.(Cys352Ser) heterozygote. Despite the analogous internalization defect predicted in ARH and homozygous LDLR:p.(Asn825Lys) lymphocytes, LDL uptake was higher in the former than in the latter. LDL-cholesterol levels were markedly reduced by the successive therapy with Atorvastatin and Atorvastatin plus Ezetimibe, and the addition of Evolocumab biweekly decreased LDL-cholesterol by a further 39%. CONCLUSIONS: The LDLRAP1:c.1A > G variant is associated with the appearance of an N-terminal truncated ARH protein and to reduced, although still significant, LDLR activity in lymphocytes. Residual LDLR activity may be relevant for the substantial response of the patient to Evolocumab.

A new variant in PHKA2 is associated with glycogen storage disease type IXa.

Glucogenosis type IX is caused by pathogenic variants of the PHKA2 gene. Herein, we report a patient with clinical symptoms compatible with Glycogen Storage Disease type IXa. PYGL, PHKA1, PHKA2, PHKB and PHKG2 genes were analyzed by Next Generation Sequencing (NGS). We identified the previously undescribed hemizygous missense variant NM_000292.2(PHKA2):c.1963G > A, p.(Glu655Lys) in PHKA2 exon 18. In silico analyses showed two possible pathogenic consequences: it affects a highly conserved amino acid and disrupts the exon 18 canonical splice donor site. The variant was found as a "de novo" event.

Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting: The MENTE Study.

BACKGROUND: Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF. PATIENTS AND METHODS: A multicenter, cross-sectional study was performed on markers of renal tubular function and bone turnover in hepatitis B virus-monoinfected patients on long-term treatment with Entecavir or Tenofovir (the MENTE study). The analyzed parameters were: retinol-binding protein/creatinine, neutrophil gelatinase-associated lipocalin/creatinine, excretion of phosphates, uric acid excretion, glomerular filtrate, protein/creatinine, albumin/creatinine, serum creatinine, phosphate, CTX, P1NP, vitamin D, and parathormone. RESULTS: A total of 280 patients (ETV: 89, TDF: 69, control: 122) were included in this study. The TDF group was associated with altered levels of retinol-binding protein (RBP)/creatinine (TDF 25% vs. 7% ETV and control; P<0.001). Protein/creatinine, uric acid excretion, P1NP1, and parathormone were higher in the TDF group. The proportion of patients with serum phosphate <2.5 mg/dL was higher in both the ETV and the TDF groups compared with the control. The multivariate analysis showed that the use of TDF was independently associated with a higher risk of altered excretion of RBP/creatinine (4.4; interquartile range: 1.4 to 14; P=0.013). CONCLUSIONS: We found an independent association between TDF use and altered RBP excretion. This finding indicates subclinical tubular damage. Because tubular dysfunction can precede the decline of renal function, close monitoring of RBP levels in patients with CHB on nucleos(t)ide analog treatment must be performed for early detection of TDF-related renal toxicity. In this study, these differences in tubular function were not associated with concomitant changes in markers of bone turnover.

Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting.

INTRODUCTION: Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (Ctrough) in the clinical setting, the effect of UGT1A1*28 and concomitant antiretrovirals. METHODS: A total of 86 patients, from Turin, Italy, and Madrid, Spain, were included in the analysis. Blood samples were obtained 10-14 hours postdose. Genotyping for UGT1A1*28 was conducted by sequencing. RESULTS: High interpatient and intrapatient variabilities were observed; 13 patients had ≥3 samples available, and the median coefficient of variation was 128 (64-265). Coadministration of RAL with atazanavir (ATV, n = 9) resulted in higher raltegravir Ctrough, 517 (307-2706) ng/mL when compared with patients not receiving ATV (n = 77) 223 (95-552; P = 0.02). UGT1A1*28 did not influence RAL plasma exposure. DISCUSSION: We have documented large intersubject and intrasubject variabilities in RAL plasma concentrations and confirmed the interaction with ATV. Further studies are required to better understand the mechanisms that influence the pharmacokinetics of RAL.

Plasma raltegravir exposure influences the antiviral activity and selection of resistance mutations.

Raltegravir (RAL) resistance is associated with the selection of integrase mutations at positions 92, 143, 148, and/or 155. A substantial proportion of RAL failures, however, occurs in the absence of these changes. An examination of RAL plasma concentrations may help in interpreting this observation. All early RAL virological failures seen at 22 clinics in Spain during 2009 were identified. HIV integrase sequences and RAL plasma trough concentrations (C(t)) were examined. A total of 106 patients experiencing virological failure on RAL were identified. Only the earliest sample on failure was examined. Integrase sequences could be obtained for 89 (84%), of whom 30 (33.7%) depicted primary RAL resistance mutations (15 N155H, eight Q148H/R, three Y143R, one E92Q, and three more than one of them). Another nine (10.1%) patients showed only secondary changes. The remaining 50 RAL early failures (56.2%) did not select any integrase change. RAL C(t) could be measured in 66 patients at failure and in 21 of them before failure. In a control group of 37 patients with viral suppression on RAL, detectable plasma levels were seen in all cases, with greater median RAL C(t) than in failures, either at the time of viral rebound (p<0.001) or before it (p=0.055). Moreover, median C(t) at the time of failure was greater in patients selecting primary RAL resistance mutations than in the rest of the failures (p<0.001). Undetectable RAL C(t) was seen only in patients failing RAL without integrase resistance mutations (64.1% of them). RAL failures in the absence of integrase resistance mutations mainly reflect poor drug compliance.

Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.

BACKGROUND: A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rs1127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia. RESULTS: A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR. CONCLUSIONS: This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.

Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus-coinfected patients treated for chronic hepatitis C.

The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.

Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction.

BACKGROUND: Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD. METHODS: TFV accumulation was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4(+) cells and monocyte-derived macrophages (MDMs). Substrate specificity was confirmed by cepharanthine (ABCC10 inhibitor) and small interfering RNA (siRNA) studies. Fourteen SNPs in ABCC10 were genotyped in human immunodeficiency virus-positive patients with KTD (n = 19) or without KTD (controls; n = 96). SNP and haplotype analysis was performed using Haploview. RESULTS: TFV accumulation was significantly lower in HEK293-ABCC10 cell lines than in parental HEK293 cells (35% lower; P = .02); this was reversed by cepharanthine. siRNA knockdown of ABCC10 resulted in increased accumulation of TFV in CD4(+) cells (18%; P = .04) and MDMs (25%; P = .04). Two ABCC10 SNPs (rs9349256: odds ratio [OR], 2.3; P = .02; rs2125739, OR, 2.0; P = .05) and their haplotype (OR, 2.1; P = .05) were significantly associated with KTD. rs9349256 was associated with urine phosphorus wasting (P = .02) and ß2 microglobulinuria (P = .04). CONCLUSIONS: TFV is a substrate for ABCC10, and genetic variability within the ABCC10 gene may influence TFV renal tubular transport and contribute to the development of KTD. These results need to be replicated in other cohorts.

Impact of IL28B polymorphisms on response to peginterferon and ribavirin in HIV­hepatitis C virus-coinfected patients with prior nonresponse or relapse.

IL28B polymorphisms predict treatment response in chronic hepatitis C. However, no information exists in prior treatment failures. A total of 62 HIV/hepatitis C virus (HCV) patients who completed retreatment with peginterferon-α/ribavirin were examined, of whom 25 (40%) had been cured. Predictors of response [odds ratio, OR (95% confidence interval, CI)] were HCV genotypes 2/3 [16.1 (2.7-90.9)], prior relapse [9.6 (1.5-62.4)] and ribavirin plasma trough concentrations at week 4 [4.9 (1.3-18.4)]. IL28B-CC only predicted response in prior nonresponders carrying HCV genotypes 1/4 [25.1 (1.9-337)].

Short communication: use of serum bilirubin levels as surrogate marker of early virological response to atazanavir-based antiretroviral therapy.

Given that atazanavir (ATV) increases bilirubin in an exposure-dependent manner, we tested whether bilirubin levels could be used as a surrogate of virological response to ATV-based regimens in 182 patients. Bilirubin increases of ≥0.7 mg/dl were independently associated with early virological response with an odds ratio of 5.2 (95% confidence interval 2.2-11.9). Total bilirubin, a nonexpensive, simple, and widely available parameter, might be used as a surrogate of virological response to ATV-based regimens, especially in areas with limited resources where HIV-RNA testing is not available.

Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients.

INTRODUCTION: Knowledge of drug interactions is vital to maximize antiretroviral efficacy and avoid drug-related toxicities. Treatment of co-morbidities has become a difficult task in HIV-infected individuals because pharmacokinetic and/or pharmacodynamic interactions are common when other medications are prescribed along with antiretroviral agents. AREAS COVERED: This article provides an update of the most relevant drug interactions that occur between antiretroviral agents and other drugs. The article additionally revisits how these drug interactions can be prevented from occurring as well as how they can be managed. EXPERT OPINION: Interactions between antiretrovirals and other drugs are frequent in clinical practice. The most common are those affecting drug metabolism due to induction or inhibition of the CYP450, leading to abnormal drug exposure. It is by this mechanism that most HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and maraviroc often interact with other medications. In contrast, nucleoside reverse transcriptase inhibitors and some integrase inhibitors, which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions, although nucleoside analogs might be involved in some pharmacodynamic interactions.

Noncirrhotic portal hypertension in HIV infection.

PURPOSE OF REVIEW: Liver disease in the HAART era is one of the leading causes of morbidity and mortality in HIV-infected individuals in Western countries. Even if the majority of cases rely on identifiable causes (viral hepatitis, steatohepatitis, alcohol abuse, drug toxicity, etc.), the cause of liver abnormalities remains unknown for a subset of patients, some of whom present with noncirrhotic portal hypertension (NCPH). RECENT FINDINGS: In 2006, the first reports of NCPH in HIV-infected patients attracted special attention. Typically, individuals unaware of any underlying liver illness presented with variceal bleeding, occasionally fatal. Interestingly, severe portal hypertension occurred in the absence of liver function impairment in most cases. Liver biopsy revealed a distinctive histological feature characterized by massive absence of portal veins along with focal obliteration of small portal veins. After extensive ruling out of other causes, the role of antiretroviral toxicity (particularly didanosine exposure) emerged as the major contributor to this condition. Other potential factors could be an enhanced microbial translocation from the gut and prothrombotic conditions. SUMMARY: NCPH is an uncommon condition, although increasingly being reported in HIV-infected individuals. It generally presents as a clinical episode of decompensated portal hypertension, generally with gastrointestinal bleeding. Long-lasting HIV infection and prolonged antiretroviral exposure are universally recognized in these patients. The involvement of didanosine has been highlighted in most series. Removal of this drug and prevention of variceal bleeding episodes are currently the most effective prophylactic and therapeutic interventions.

Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial.

BACKGROUND: Raltegravir has demonstrated good antiviral activity and safety profile in twice-daily (bid) dosing. However, its long terminal elimination half-life might allow once-daily (qd) administration. METHODS: Consecutive HIV-infected individuals at our clinic under protease inhibitor (PI)-based regimens with plasma HIV-RNA <50 copies/mL for > 24 weeks were invited to replace PIs with raltegravir. Patients were randomly assigned to raltegravir 800 mg qd, 400 mg bid, or twice daily for the first 3 months and then once daily. RESULTS: A total of 222 patients completed 24 weeks of follow-up on raltegravir (149 once-daily arm, 35 twice-daily arm, and 38 twice-daily to once-daily arm). At inclusion, mean CD4+ count was 574±308 cells/µL. Within 24 weeks, 13 (5.9%) patients experienced virological failure: 12 (6.4%) in the once-daily arms, and 1 (2.9%) in the twice-daily arm (P = .18). The rate of virological failure was 16.2% (12/74) in patients with prior nucleoside reverse transcriptase inhibitor (NRTI) resistance but only 0.7% (1/148) in the rest (P < .001). CONCLUSION: A switch from PIs to raltegravir in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression, as long as prior NRTI resistance had not been selected. No significant differences were seen when comparing raltegravir twice daily or once daily in this context, although once-daily dosing tended to perform less well.