Effectiveness, treatment completion and safety of sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir + dasabuvir in patients with chronic kidney disease: an ERCHIVES study.

BACKGROUND: Chronic kidney disease (CKD) was a relative contraindication to hepatitis C virus (HCV) treatment in the interferon/ribavirin era. AIM: To determine the efficacy, tolerability and safety of sofosbuvir/ledipasvir (SOF/LDV) and paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens in persons with CKD. METHODS: We identified persons initiated on a SOF/LDV or PrOD regimen from October 30, 2014 to April 30, 2016. We excluded those with missing HCV genotype or eGFR values. We determined treatment completion and sustained virologic response (SVR) rates, and proportion developing worsening renal function or grade 3/4 haematologic toxicity. RESULTS: Among 13 663 persons on SOF/LDV±ribavirin, 14% and 1% persons had CKD Stage 3 and 4-5 respectively, 67.8% completed treatment, 98.2% achieved SVR. Treatment completion or SVR rates did not decline with advanced CKD or ribavirin administration. Among 3961 persons on PrOD±ribavirin, 9% and 3% persons had CKD Stage 3 and 4-5, respectively, 74.0% completed treatment and 98.2% achieved SVR. A decrease in treatment completion rates was seen in CKD stage 4-5 and those on ribavirin, but this did not impact SVR rates. A >10 mL/min/1.73 m2 drop in eGFR from baseline was observed in 30%-38% of persons with baseline eGFR ≥60 mL/min/1.73 m2 , but in only 0%-6% with CKD4-5. Grade 3/4 anaemia was more frequent in persons with CKD4-5, but ribavirin co-administration did not appear to affect this. CONCLUSIONS: SOF/LDV and PrOD achieved high SVR rates in CKD population. Treatment completion rates were lower than expected. A decline in eGFR and development of anaemia were observed in a substantial proportion of persons, but the clinical implications remain unclear.

Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A.

BACKGROUND: Mild, transient alanine aminotransferase (ALT) elevations were seen in Phase I studies of caspofungin and cyclosporin A (CsA). METHODS: We conducted a retrospective chart review at four sites to characterize the hepatic safety in patients receiving > or =1 day of both drugs over a 20-month period. Investigators assessed reasons for discontinuing concomitant therapy and the presence/etiology of any hepatotoxicity. RESULTS: Forty patients receiving concomitant therapy for 1-290 days (median 17.5 days) were identified. Although common, liver enzyme abnormalities were frequently attributed to other comorbidities or medications. ALT and/or aspartate aminotransferase (AST) elevations occurred in 14 patients (35%). Five had AST elevations at least possibly related to caspofungin/CsA, but none were >3.6 times the normal upper limit. No ALT elevations were related to caspofungin/CsA. Two of 4 patients had discontinuation of therapy because of hepatotoxicity possibly related to caspofungin/CsA. No serious adverse events occurred because of caspofungin. CONCLUSIONS: These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin/CsA.

Assessment of markers of hepatitis C virus infection in a Japanese adult population.

Latent-class analysis was used to evaluate the usefulness of markers of hepatitis C virus (HCV) infection in characterizing the true, underlying infection in a community-based Japanese population. Antibodies to HCV were detected in 24%, HCV RNA in 22%, and HCV core protein in 19% of stored serum samples from 372 adults. A 2-class model suggested that positive results for any 2 virus markers defined the current HCV infection class, with an estimated prevalence of 22% (95% confidence interval, 18%-26%). The sensitivity for detection of current HCV infection was highest for anti-HCV (97%) and was more moderate for HCV RNA (91%) and HCV core protein (85%). The specificity for each marker was > or =96%. In general, the association between demographic factors and current HCV infection status was strengthened by use of latent-class analysis that combined data for markers of HCV infection, when compared with results of logistic regression analysis for each marker separately.

Do HIV type 1 RNA levels provide additional prognostic value to CD4(+) T lymphocyte counts in patients with advanced HIV type 1 infection?

Our objective was to assess whether HIV-1 RNA levels provide additional prognostic information beyond CD4(+) T lymphocyte counts in the prediction of subsequent HIV-1 disease progression among patients with advanced HIV-1 disease. In a nested case-control study conducted in patients with baseline CD4(+) T lymphocyte counts < 300 cells/mm(3) and receiving nucleoside reverse transcriptase inhibitors, 102 patients who progressed to an AIDS-defining event or death were matched within 10 CD4(+) T lymphocyte cells/mm(3) to patients who did not progress. The relationship between plasma HIV-1 RNA levels and HIV-1 disease progression was studied using conditional logistic regression analysis, which adjusts for the matching by baseline CD4(+) T lymphocytes. We observed a 0.10 log(10) copies/ml difference in baseline HIV-1 RNA levels between cases and their matched controls (p = 0.027). The relative risk for HIV-1 disease progression increased with increasing baseline HIV-1 RNA levels (odds ratio [OR] for a 3-fold higher HIV-1 RNA level, 1.42; 95% confidence interval [CI], 1.08--1.86), and remained important when also controlling for clinical status at baseline and CD4(+) T lymphocytes at 2 months (p = 0.038). Higher baseline HIV-1 RNA levels were associated with HIV-1 disease progression among patients with a baseline CD4(+) T lymphocyte count of 100 cells/mm(3) or greater (OR, 1.80; 95% CI, 1.15--2.81), but not among patients with a baseline CD4(+) T lymphocyte count < 100 cells/mm(3) (OR, 1.09; 95% CI, 0.73--1.63). We concluded that HIV-1 RNA levels predict subsequent HIV-1 disease progression independent of CD4(+) T lymphocyte counts. The magnitude and importance of the prognostic information contained in the HIV-1 RNA levels appear to depend on the CD4(+) T lymphocyte counts.

Diffusive properties of immature articular cartilage.

The diffusive properties of immature bovine articular cartilage were determined using two different-sized, uncharged solutes (glucose 180 Da, and dextran 10k Da). Radioactively tagged glucose and dextran were diffused into the cartilage for transport times of 5, 15, and 60 min, and the diffusion and partition coefficients were calculated by fitting the experimental data to a one-dimensional diffusion model. The diffusion and partition coefficients for the two solutes averaged 6.08 +/- 2.19 and 5.09 +/- 2.51 (x 10(-6) cm2/s) and 0.712 +/- 0.149 and 0.615 +/- 0.120, respectively. Both coefficients were significantly greater for glucose compared to the larger dextran. While no statistical differences could be found in the diffusive properties of these solutes in immature cartilage compared to their diffusive properties in mature cartilage, there was some evidence that the larger dextran solute might diffuse faster in the earlier time periods. Finally, the bulk fluid contents between the two types of cartilage were not different even though the immature tissue was significantly thicker (1.6 times) than the mature tissue. Our results indicate that the solute diffusion properties of articular cartilage, at least with respect to uncharged solutes, do not change during skeletal maturation.

Effect of proteoglycan removal on solute mobility in articular cartilage.

Transport of nutrients, cytokines, pharmacologic agents, and matrix components through articular cartilage is critical for the viability and structural integrity of the tissue. To understand the role of the extracellular matrix in regulating this process, we measured the diffusivity of three uncharged solutes of different molecular size (glucose, MW 180; inulin, MW 5000; dextran, MW 70,000) into intact cartilage and cartilage that had its proteoglycan (PG) component removed. Solute diffusivity was measured by performing transient (nonsteady state) one-dimensional diffusion tests using radiolabelled solutes. Compared to intact cartilage, the diffusivity of glucose was unchanged after PG removal, inulin was unchanged but dextran increased by 1.7 times after 71% PG removal, and both inulin and dextran increased by 1.6 and 2.0 times, respectively, after 93% PG removal. The diffusivities of inulin and dextran were inversely proportional to the PG content. While no change was found in the tissue's bulk fluid content, PG depletion resulted in an increase in fluid content in the upper regions of the tissue and a decrease in the lower regions. These results indicate that in intact tissue small uncharged solutes have free mobility through the inter-molecular and intra-molecular PG volumes, larger molecules have limited intra-molecular mobility, and very large molecules are excluded from the intra-molecular space.

The predictive value of changes in serologic and cell markers of HIV activity for subsequent clinical outcome in patients with asymptomatic HIV disease treated with zidovudine.

OBJECTIVE: To determine if serologic marker responses to zidovudine treatment during the first year of antiretroviral therapy could predict subsequent HIV disease progression independently of absolute CD4 lymphocyte responses. METHODS: We conducted a case-control study in patients with asymptomatic HIV disease, who were initiating zidovudine therapy in a randomized, prospective trial. A total of 102 patients who progressed to AIDS or advanced AIDS-related complex and 177 randomly selected controls matched by baseline CD4 cell count and duration of follow-up had serum samples (from prior to and at 8, 16, 32 and 48 weeks of zidovudine treatment) assayed for acid-disassociated HIV p24 antigen, beta 2-microglobulin (beta 2M), neopterin, soluble interleukin (IL)-2 receptor, soluble CD4 protein and soluble CD8 protein. RESULTS: Median time to event for cases was 20.2 months; median follow-up on study was 35.4 months for controls. After controlling for absolute CD4 count at baseline, increased baseline serum concentrations of HIV p24 antigen, beta 2M, neopterin, and soluble IL-2 receptor were highly predictive of increased risk of HIV disease progression. In a multiple logistic regression model, controlling for baseline marker values, change in beta 2M consistently added independent value to change in CD4 count in predicting subsequent risk of disease progression. CONCLUSIONS: Monitoring serum immunologic markers, in particular beta 2M, in addition to absolute CD4 lymphocyte counts prior to and within the first 4 months after initiating dideoxynucleoside therapy can increase the accuracy of estimations of subsequent long-term risk of clinical HIV disease progression. This information may be useful to clinicians and patients who are making decisions about initiating or changing antiretroviral therapy.

Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. The NIAID AIDS Clinical Trials Group.

OBJECTIVE: To compare the safety and efficacy of continuing zidovudine therapy with that of zalcitabine alone or zalcitabine and zidovudine used together. DESIGN: A randomized, double-blind, controlled trial. SETTING: AIDS Clinical Trials units and National Hemophilia Foundation sites. PATIENTS: 1001 patients with symptomatic human immunodeficiency (HIV) disease and 300 or fewer CD4 cells/mm3 or asymptomatic HIV disease and 200 or fewer CD4 cells/mm3 who had tolerated zidovudine therapy for 6 months or more. INTERVENTION: Patients were randomly assigned to receive zidovudine, 600 mg/d; zalcitabine, 2.25 mg/d; or zidovudine, 600 mg/d, and zalcitabine, 2.25 mg/d. MEASUREMENTS: The primary end point was time to disease progression or death. RESULTS: The median follow-up time was 17.7 months. The estimated 12-month event-free rates were 70%, 67%, and 73%, respectively, for the zidovudine, zalcitabine, and combination groups (P = 0.26). A trend analysis showed significantly lower progression rates for combination therapy compared with zidovudine therapy as the pretreatment CD4 cell count increased (P = 0.027). For patients with 150 or more CD4 cells/mm3, those receiving combination therapy were less likely to have disease progression or to die than were those receiving zidovudine (relative risk, 0.51; 95% CI, 0.28 to 0.93; P = 0.029). We observed no difference between the zalcitabine and zidovudine groups (relative risk, 0.74; CI, 0.40 to 1.36; P = 0.33). For patients with 50 to 150 CD4 cells/mm3 or fewer than 50 CD4 cells/mm3, we found no differences among the treatment groups (P = 0.69 and P = 0.57, respectively). Severe toxic effects occurred less frequently among patients with 150 or more CD4 cells/mm3. CONCLUSIONS: We found no overall benefits of zalcitabine used alone or with zidovudine. However, a trend analysis suggested a better outcome for combination therapy compared with zidovudine as the pretreatment CD4 cell count increased.

Standardized microtiter assay for determination of syncytium-inducing phenotypes of clinical human immunodeficiency virus type 1 isolates.

A standardized assay in 96-well microtiter plates for syncytium-inducing (SI) human immunodeficiency virus type 1 phenotype detection using MT-2 cells has been developed. SI variants were found in 67% of the patients with advanced human immunodeficiency virus disease. The occurrence of the SI phenotype increased with lower CD4+ counts. There was no association between p24 antigenemia and the SI phenotype.

Serum p24 antigen level as an intermediate end point in clinical trials of zidovudine in people infected with human immunodeficiency virus type 1. Aids Clinical Trials Group Virology Laboratories.

Serum p24 antigen levels were examined in subjects from three clinical trials of zidovudine to determine whether the pattern of change in serum p24 antigen during the first 8-16 weeks of therapy was associated with human immunodeficiency virus type 1 (HIV-1) disease progression or death. Among 406 patients with AIDS and a first episode of Pneumocystis carinii pneumonia, 65% had measurable pretreatment concentrations of serum p24 antigen (> or = 10 pg/mL). Changes during treatment were not associated with reduced mortality. In 637 mildly symptomatic patients, 24% had measurable concentrations, and changes were marginally associated with increased time until more advanced disease. Among 683 asymptomatic patients, 18% had measurable concentrations, and changes were not associated with increased time until progression. Despite the small number of clinical events and the low rate of serum p24 antigen positivity in the latter two studies, pretreatment serum p24 antigen levels were predictive of clinical outcome; subsequent measurements appear to be of limited use in evaluating zidovudine therapy.

Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group.

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.

Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group.

A standardized antiviral drug susceptibility assay for clinical human immunodeficiency virus type 1 (HIV-1) isolates has been developed for use in clinical trials. The protocol is a two-step procedure that first involves cocultivation of patient infected peripheral blood mononuclear cells (PBMC) with seronegative phytohemagglutinin-stimulated donor PBMC to obtain an HIV-1 stock. The virus stock is titrated for viral infectivity (50% tissue culture infective dose) by use of serial fourfold virus dilutions in donor PBMC. A standardized inoculum of 1,000 50% tissue culture infective doses per 10(6) cells is used in the second step of the procedure to acutely infect seronegative donor PBMC in a 7-day microtiter plate assay with triplicate wells containing zidovudine (ZDV) concentrations ranging from 0 to 5.0 microM. The ZDV 50% inhibitory concentrations (IC50) for reference ZDV-susceptible and ZDV-resistant HIV-1 isolates ranged from 0.002 to 0.113 microM and from 0.15 to > 5.0 microM, respectively. Use of this consensus protocol reduced interlaboratory variability for ZDV IC50 determinations with reference HIV-1 isolates. Among eight laboratories, the coefficient of variation ranged from 0.85 to 1.25 with different PBMC protocols and was reduced to 0.39 to 0.98 with the standardized assay. Among the clinical HIV-1 isolates assayed by the standardized drug susceptibility assay, the median ZDV IC50 increased gradually with more ZDV therapy. This protocol provides an efficient and reproducible means to assess the in vitro susceptibility to antiretroviral agents of virtually all clinical HIV-1 isolates.

Selecting pedigrees for linkage analysis of a quantitative trait: the expected number of informative meioses.

With evidence of segregation at a major locus for a quantitative trait having been found, a logical next step is to select a subset of the pedigrees to include in a linkage study to map the major locus. Ideally this subset should include much of the linkage information in the sample but include only a fraction of the pedigrees. We previously described a strategy for selecting pedigrees for linkage analysis of a quantitative trait on the basis of a pedigree likelihood-ratio statistic. For quantitative traits controlled by a major locus with a rare dominant allele, the likelihood-ratio strategy extracted nearly all the information for linkage while typically requiring marker data on only about one-third of the pedigrees. Here, we describe a new strategy to select pedigrees for linkage analysis on the basis of the expected number of potentially informative meioses in each pedigree. We demonstrate that this informative-meioses strategy provides an efficient and more general means to select pedigrees for a linkage study of a quantitative trait.