Therapy-naive Patients Research Articles

Clinical Use of HIV Integrase Inhibitors: A Systematic Review and Meta-Analysis

BackgroundOptimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings.MethodsMEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted.Results48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59–0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11–0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89–2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir.ConclusionIn first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment.

HIV neuropathy in pre-HAART patients and it′s correlation with risk factors in Central India

Peripheral neuropathy (PN) is the most common neurological complication of human immunodeficiency virus (HIV) infection and often goes unrecognized. This ailment has a significant debilitating impact on the quality of life of HIV/acquired immunodeficiency syndrome (AIDS) patients. HIV-associated sensory neuropathy (HIV-SN) is the most common PN in HIV infected patients. In India, although HIV has emerged as a public health menace, the burden of HIV-SN has not yet been well-defined. We used the Brief Peripheral Neuropathy Screening (BPNS) tool, validated by the AIDS Clinical Trial Group (ACTG) and carried out a cross-sectional study to determine the prevalence of HIV-SN and its associated factors among highly active antiretroviral therapy (HAART) naive HIV patients. HIV-SN is defined as the presence of neuropathic symptoms and at least an abnormal perception of vibrations of a 128 Hz tuning fork on the great toe or abnormal ankle reflexes or both. Out of 75 patients studied, 40% had clinical HIV-SN and nerve conduction study (NCS) confirmed its presence in all of them. In patients with neuropathy, the mean hemoglobin was 10.76 g/dl (P < 0.0001), mean serum albumin 2.7 g/dl (P < 0.001), mean body mass index (BMI) 17.18 kg/m 2 (P < 0.0001), and mean CD4 T-cell count was 497/μl; whereas, in patients not having neuropathy the same values were 12.81 g/dl, 3.64 g/dl, 20.22 kg/m 2 , and 678/μl, respectively. Patients recall and clinical chart review showed that, 40% had symptoms even prior to HAART initiation. HIV-SN is more common among pre-HAART patients with low level of hemoglobin, serum albumin, BMI, and CD4 T-cell count. Hence, it is found that neuropathy can be prevented by improving immune as well as nutritional status of HIV infected patients. So, BPNS, being a simple diagnostic tool should therefore be routinely applied to screen the neuropathy, to minimize the negative impact it has on the quality of life in patients with HIV infection.

Negative Regulation of Hepatitis C Virus Specific Immunity Is Highly Heterogeneous and Modulated by Pegylated Interferon-Alpha/Ribavirin Therapy

Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-β and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-α/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern before, during and after PegIFN-α/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-γ production in therapy-naive chronic HCV patients was associated with higher HCV-RNA loads, which suggests that protective antiviral immunity is controlled by IL-10. In addition, as a consequence of PegIFN-α/ribavirin therapy, negative regulation of especially HCV-specific IFN-γ production by TGF-β and IL-10 changed dramatically. Our findings emphasize the importance of negative regulation for the dysfunctional HCV-specific immunity, which should be considered in the design of future immunomodulatory therapies.

Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients

We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) as a marker for CYP3A induction. Plasma 4β-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4β-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4β-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4β-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.

Can immunotherapy be useful as a "functional cure" for infection with Human Immunodeficiency Virus-1?

Immunotherapy aims to assist the natural immune system in achieving control over viral infection. Various immunotherapy formats have been evaluated in either therapy-naive or therapy-experienced HIV-infected patients over the last 20 years. These formats included non-antigen specific strategies such as cytokines that stimulate immunity or suppress the viral replication, as well as antibodies that block negative regulatory pathways. A number of HIV-specific therapeutic vaccinations have also been proposed, using in vivo injection of inactivated virus, plasmid DNA encoding HIV antigens, or recombinant viral vectors containing HIV genes. A specific format of therapeutic vaccines consists of ex vivo loading of autologous dendritic cells with one of the above mentioned antigenic formats or mRNA encoding HIV antigens.This review provides an extensive overview of the background and rationale of these different therapeutic attempts and discusses the results of trials in the SIV macaque model and in patients. To date success has been limited, which could be explained by insufficient quality or strength of the induced immune responses, incomplete coverage of HIV variability and/or inappropriate immune activation, with ensuing increased susceptibility of target cells.Future attempts at therapeutic vaccination should ideally be performed under the protection of highly active antiretroviral drugs in patients with a recovered immune system. Risks for immune escape should be limited by a better coverage of the HIV variability, using either conserved or mosaic sequences. Appropriate molecular adjuvants should be included to enhance the quality and strength of the responses, without inducing inappropriate immune activation. Finally, to achieve a long-lasting effect on viral control (i.e. a “functional cure”) it is likely that these immune interventions should be combined with anti-latency drugs and/or gene therapy.

High rate of K65R for antiretroviral therapy-naive patients with subtype C HIV infection failing a tenofovir-containing first-line regimen

We sought to determine the rate of the K65R mutation in patients receiving tenofovir (TDF)-based antiretroviral therapy (ART) with subtype C HIV infection. Retrospective cohort study. All patients initiated on stavudine (d4T) with lamivudine (3TC) or TDF with 3TC and a nonnucleoside reverse transcriptase inhibitor at McCord Hospital in Durban, South Africa had their charts reviewed. All patients with virologic failure, defined as a viral load more than 1000 copies/ml after 5 months of a first ART regimen, had genotypic resistance testing performed prospectively using a validated in-house assay. Important resistance mutations were selected based upon published mutations in subtype B virus in the Stanford HIV Drug Resistance database. A total of 585 patients were initiated on TDF-containing first-line ART from 3 August 2010 to 17 March 2011. Thirty-five (6.0%) of these patients had virologic failure and 23 of 33 (69.7%) of the virologic failure patients had the K65R mutation. The median (interquartile range) for the baseline CD4 cell count was 105 cells/μl (49-209) and viral load at virologic failure was 47 571 copies/ml (20 708-202 000). During the same period, 53 patients were initiated on d4T-containing regimens. Two (3.8%) of these patients had virologic failure and one of the virologic failure patients had the K65R mutation. Preliminary data show very high rates (>65%) of K65R for patients failing TDF-based first-line regimens at McCord Hospital with few additional nucleoside reverse transcriptase inhibitor mutations compared with subtype B. These rates may reflect faster in-vivo selection, longer time on a failing regimen or transmitted drug resistance.

Transmitted Antiretroviral Drug Resistance and Thumb Subdomain Polymorphisms Among Newly HIV Type 1 Diagnosed Patients Infected with CRF01_AE and CRF07_BC Virus in Guangdong Province, China

The aim of this study was to elucidate the prevalence of transmitted drug-resistant (TDR) mutations and reverse transcriptase (RT) thumb subdomain polymorphisms in CRF01_AE and CRF07_BC virus among newly diagnosed, therapy-naive HIV-1 patients in Guangdong Province, China. One hundred and sixty-four samples were collected in the Guangzhou Eighth People's Hospital. The entire protease gene and 300 codons of the entry part of the reverse transcriptase were amplified and sequenced. Furthermore, genotypic drug resistance, polymorphisms, and their phylogeny were analyzed. According to eligibility criteria, seven samples were excluded, and 119 of 157 (75.8%) samples (84 CRF01_AE and 35 CRF07_BC) were amplified and sequenced successfully. The prevalence of TDR identified in the present study was 6.7% [8/119, 95% confidence interval (CI) 1.8-11.6%]. Three major resistance mutations, K103N, M184V, and Y188L, each of which caused more than one drug resistance, appeared in only two patients; the prevalence [1.7 % (2/119)] was relatively low. Until now, this is the first observation of the five newly identified accessory mutations, V35T, K43E, V60I, K122E, and E203D, and seven thumb subdomain polymorphisms, A272P, K277R, K281R, T286A, E291D, V292I, and I293V, in the RT gene in China. These findings provide useful information for guidance on the antiretroviral therapy (ART) policy in China where therapeutic options are still limited.

A Randomized Controlled Trial of Highly Active Antiretroviral Therapy Versus Highly Active Antiretroviral Therapy and Chemotherapy in Therapy-Naive Patients With HIV-Associated Kaposi Sarcoma in South Africa

The optimal approach to HIV-associated Kaposi sarcoma (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized that survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes. We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naive patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine, and nevirapine (Triomune; CXT arm received Triomune plus bleomycin, doxorubicin, and vincristine every 3 weeks. When bleomycin, doxorubicin, and vincristine were not available, oral etoposide (50-100 mg for 1-21 days of a 28-day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence, and quality of life. Fifty-nine subjects were randomized to HAART and 53 to CXT; 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference, 27%; 95% confidence interval, 9%-43%; P = 0.005). At 12 months, 77% were alive (no survival difference between arms; P = 0.49), 82% had HIV viral load <50 copies per milliliter without difference between the arms (P = 0.47); CD4 counts and quality-of-life measures improved in all patients. HAART with chemotherapy produced higher overall KS response over 12 months, whereas HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and human herpes virus-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.

Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice

Guidelines state that the CCR5-inhibitor Maraviroc should be prescribed to patients infected with R5-tropic HIV-1 only. Therefore, viral tropism needs to be assessed phenotypically or genotypically. Preliminary clinical trial data suggest that genotypic analysis in triplicate is associated with improved prediction of virological response by increasing the detection of X4-tropic variants. Our objective was to evaluate the impact of triplicate genotypic analysis on prediction of co-receptor usage in routine clinical practice. Samples from therapy-naive and therapy-experienced patients were collected for routine tropism testing at three European clinical centres. Viral RNA was isolated from plasma and proviral DNA from peripheral blood mononuclear cells. Gp120-V3 was amplified in a triplicate nested RT-PCR procedure and sequenced. Co-receptor usage was predicted using the Geno2Pheno[coreceptor] algorithm and analysed with a false-positive rate (FPR) of 5.75%, 10%, or an FPR of 20% and according to the current European guidelines on the clinical management of HIV-1 tropism testing. A total of 266 sequences were obtained from 101 patient samples. Discordance in tropism prediction for the triplicates was observed in ten samples using an FPR of 10%. Triplicate testing resulted in a 16.7% increase in X4-predicted samples and to reclassification from R5 to X4 tropism for four cases rendering these patients ineligible for Maraviroc treatment. In conclusion, triplicate genotypic tropism testing increases X4 tropism detection in individual cases, which may prove to be pivotal when CCR5-inhibitor therapy is applied.

Long-Term Safety and Efficacy and Association between Baseline Treatment History and Postbaseline Relapses in Multiple Sclerosis Patients Treated with Natalizumab in the TYSABRI(R) Observational Program (TOP) (P04.134)

Objective: Evaluate long-term safety, efficacy, and associations between baseline treatment history and postbaseline annualized relapse rate (ARR) in multiple sclerosis (MS) patients treated with natalizumab. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) study is an open-label, multinational, observational study assessing long-term outcomes in relapsing-remitting MS patients in the postmarketing setting in Europe, Australia, and Canada. Design/Methods: As of June 2011, 3484 patients from 15 countries were enrolled. Incidence of serious adverse events (SAEs) was analyzed. ARR and Expanded Disability Status Scale (EDSS) scores were assessed. Associations between baseline therapy and postbaseline ARR were analyzed using negative binomial regression for 5 baseline groups: therapy naive (n=337), interferon (IFN) only (n=1626), glatiramer acetate (GA) only (n=288), switched between GA and IFN in either order (n=595), or immunosuppressant (IS) use (n=487). Results: - 53]) natalizumab infusions. Overall, 5.1% of patients experienced ≥1 SAE; infections (1.1%) and hypersensitivity reactions (0.7%) were most frequent. Seven cases of progressive multifocal leukoencephalopathy (PML) occurred after 35, 29, 28, 26, 24, 24, and 12 natalizumab infusions. Three of them were previously exposed to mitoxantrone. Overall, the mean EDSS score was 3.5 at baseline and 3.4 after 3 years. ARR was significantly decreased regardless of baseline treatment history; mean ARR decreased (n=3458) from baseline (1.98) to postbaseline (0.28; P Conclusions: The overall incidence and type of SAEs reported in TOP are consistent with natalizumab9s known safety profile. EDSS scores were stable and ARR was significantly reduced after 3 years of natalizumab therapy. ARRs were lowest in therapy-naive patients and highest in patients with prior IS. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.

Long-Term Antiretroviral Treatment Outcomes in Seven Countries in the Caribbean

To report long-term HIV treatment outcomes in 7 Caribbean countries. Observational cohort study. We report outcomes for all antiretroviral therapy (ART) naive adult patients enrolled on ART from program inception until study closing for cohorts in Barbados, the Dominican Republic, Haiti, Jamaica, Martinique, Trinidad, and Puerto Rico. Incidence and predictors of mortality were analyzed by time-to-event approaches. A total of 8203 patients were on ART from 1998 to 2008. Median follow-up time was 31 months (interquartile range: 14-50 months). The overall mortality was 13%: 6% in Martinique, 8% in Jamaica, 11% in Trinidad, 13% in Haiti, 15% in the Dominican Republic, 15% in Barbados, and 24% in Puerto Rico. Mortality was associated with male gender [hazard ratio (HR), 1.58; 95% confidence interval (CI): 1.33 to 1.87], body weight (HR, 0.85 per 10 pounds; 95% CI: 0.82 to 0.89), hemoglobin (HR, 0.84 per g/dL; 95% CI: 0.80 to 0.88), CD4 cell count (0.90 per 50 CD4 cells; 95% CI: 0.86 to 0.93), concurrent tuberculosis (HR, 1.58; 95% CI: 1.25 to 2.01) and age (HR, 1.19 per 10 years; 95% CI: 1.11 to 1.28). After controlling for these variables, mortality in Martinique, Jamaica, Trinidad, and Haiti was not significantly different. A total of 75% of patients remained alive and in care at the end of the study period. Long-term mortality rates vary widely across the Caribbean countries. Much of the difference can be explained by disease severity at ART initiation, nutritional status, and concurrent tuberculosis. Earlier ART initiation will be critical to improve the outcomes.

The new standard of HCV therapy: Treatment in therapy-naive patients †

The new standard of HCV therapy: Treatment in therapy-naive patients †

Adjuvant PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) or Gemcitabine Followed by Chemoradiation in Pancreatic Cancer: A Randomized Phase II Trial

Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and β=.10, the study was to enroll 51 patients per arm. A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

InactivatingPSMB5Mutations and P-Glycoprotein (Multidrug Resistance-Associated Protein/ATP-Binding Cassette B1) Mediate Resistance to Proteasome Inhibitors: Ex Vivo Efficacy of (Immuno)Proteasome Inhibitors in Mononuclear Blood Cells from Patients with Rheumatoid Arthritis

Bortezomib (BTZ), a registered proteasome inhibitor (PI) for multiple myeloma, has also been proposed as a potential antirheumatic agent. Its reported side effects, however, make it unappealing for long-term administration, and resistance may also develop. To overcome this, second-generation PIs became available. Here, we investigated whether a novel class of peptide epoxyketone-based PIs, including carfilzomib, N-((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (ONX0912), and (S)-3-(4-methoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (ONX0914), might escape two established BTZ-resistance mechanisms: 1) mutations in the proteasome β5 subunit (PSMB5) targeted by these PIs, and 2) drug efflux mediated by ATP-binding cassette transporters. THP1 myeloid sublines with acquired resistance to BTZ (54- to 235-fold) caused by mutations in the PSMB5 gene displayed marked cross-resistance but less pronounced cross-resistance to carfilzomib (9- to 32-fold), ONX0912 (39- to 62-fold), and ONX0914 (27- to 97-fold). As for ATP-binding cassette transporter-mediated efflux, lymphoid CEM/VLB cells with P-glycoprotein (Pgp)/multidrug resistance 1 overexpression exhibited substantial resistance to carfilzomib (114-fold), ONX0912 (23-fold), and ONX0914 (162-fold), whereas less resistance to BTZ (4.5-fold) was observed. Consistently, β5 subunit-associated chymotrypsin-like proteasome activity was significantly less inhibited in these CEM/VLB cells. Ex vivo analysis of peripheral blood mononuclear cells from therapy-naive patients with rheumatoid arthritis revealed that, although basal Pgp levels were low, P-glycoprotein expression compromised the inhibitory effect of carfilzomib and ONX0914. However, the use of P121 (reversin 121), a Pgp transport inhibitor, restored parental cell inhibitory levels in both CEM/VLB cells and peripheral blood mononuclear cells. These results indicate that the pharmacologic activity of these PIs may be hindered by drug resistance mechanisms involving PSMB5 mutations and PI extrusion via Pgp.

Personalizing HIV Therapy, Mission Impossible?

Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naive patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance. This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations.

Preclinical and First-In-Human Phase I Clinical Evaluation of Stampidine, a Potent Anti-HIV Pharmaceutical Drug Candidate

The rationally designed novel anti-HIV drug candidate Stampidine exhibited (a) remarkable subnanomolar to low nanomolar in vitro ARV potency against genotypically and phenotypically NRTI-resistant primary clinical HIV isolates, non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 isolates, clinical non-B subtype HIV- 1 isolates (subtypes A, C, F, and G) originating from South America, Asia, and sub-Saharan Africa with resistance to stavudine, adefovir and tenofovir, as well as recombinant HIV clones containing common patterns of RT mutations responsible for NRTI resistance such as multiple TAMs plus M184V, multiple TAMs plus T69 insertion, and Q151 complex (b) favorable, safety profile in mice, rats, dogs, and cats, and (c) promising prophylactic in vivo anti-retroviral activity in Hu-PBL-SCID mice as well as therapeutic anti-retroviral activity in FIV-infected domestic cats. Notably, in a placebo-controlled Phase I study involving 30 therapy-naive adult HIV-infected adult patients, formulated GMP- grade oral Stampidine capsules did not cause dose-limiting toxicity at single dose levels ranging from 5 to 25 mg/kg. Taken together, the presented favorable preclinical and early clinical safety/activity profile of Stampidine warrants its further development as a new anti-HIV drug candidate.

Lopinavir Plasma Concentrations and Serum Lipids in Therapy Na&amp;#239;ve HIV-Patients: A Sub Analysis of the FREE Study

Antiretroviral therapy in HIV patients is known for its negative effect on the cardiovascular system. One of the major adverse events in patients on lopinavir is increasing lipids. Hyperlipidaemia together with chronic inflammation by HIV-infection itself makes these patients prone for cardiovascular diseases.The purpose of this study (a sub study within the FREE-study) was to determine if higher plasma lopinavir (LPV) concentrations lead to increase of serum lipids. Plasma drug concentrations were analysed up to week 24 in a prospective cohort of HIV antiretroviral therapy naive patients who started on a regimen of zidovudine, lamivudine and ritonavir-boosted lopinavir (FREE study). Prospectively we measured plasma lopinavir concentrations from baseline to week 24 in 72 naive HIV-patients starting on lopinavir (59 males and 13 females). A total of 210 samples were analysed, with at least 2 samples in every patient. Mean LPV trough concentration was 4.3 mg/L (± 2.1). The median intra-subject variation in LPV level was 38% (range 4% - 111%). Serum lipids were not correlated to LPV plasma concentrations possibly due to the wide intra-individual variability in LPV trough levels. Monitoring of plasma lopinavir and subsequent dose adjustment of LPV will not be useful to prevent hyperlipidaemia in HIV-patients treated with lopinavir.

Longitudinal Assessment of Interleukin 7 Plasma Levels in HIV-Infected Patients in the Absence of and Under Antiretroviral Therapy

Cross-sectional studies in HIV-positive patients have suggested that interleukin 7 (IL-7) may increase in parallel to CD4 decline during the natural course of HIV infection. We tested this hypothesis in a longitudinal study examining the evolution of IL-7 and CD4 counts in 2 different scenarios. IL-7 and CD4 counts were regularly monitored in 30 drug-naive patients during a follow-up period of 46 ± 14 months in the absence of therapy and in 42 patients who started highly active antiretroviral therapy and maintained undetectable viremia for 2 years. Multivariate linear regression analysis was used to ascertain what factors were associated with IL-7 variations during follow-up. In antiretroviral therapy-naive patients, CD4 counts significantly decreased (P < 0.0001), whereas plasma HIV-RNA and IL-7 levels remained fairly stable. In patients on highly active antiretroviral therapy, CD4 counts significantly increased (P < 0.0001) and IL-7 tended to decrease (P = 0.1). There was no correlation between CD4 and IL-7 variations either in the naive or in the treated population. The only parameter significantly associated with IL-7 variation during follow-up was its baseline level that showed a negative correlation. In HIV patients with low or moderate degree of immunodeficiency, CD4 counts and plasma IL-7 levels do not evolve in parallel, suggesting that other factors different from CD4 counts must be involved in the upregulation of IL-7 observed in HIV infection.

The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia

AbstractIdentification of patients at risk of early disease progression is the mainstay of tailored management in chronic lymphocytic leukemia (CLL). Although application of established biomarkers is limited by intrinsic detection/readout complexities, abnormality of κ and λ serum-free light chain ratio [sFLC (κ/λ)] was proposed as a straightforward prognosticator in CLL. By analyzing 449 therapy-naive patients, we show that an abnormal sFLC(κ/λ), along with CD38, ZAP-70, IGHV mutations, cytogenetics and stage, independently predicts treatment-free survival (TFS) but becomes prognostically irrelevant if the cumulative amount of clonal and nonclonal FLCs [sFLC(κ + λ)], a variable associated with cytogenetic risk, exceeds the threshold of 60.6 mg/mL. Patients with sFLC(κ + λ) above cut-off displayed a poorer TFS outcome, irrespective of sFLC(κ/λ). Only ZAP-70, cytogenetics, stage, and TFS remained associated with sFLC(κ + λ) in a multivariate model. By assigning 1 point each for these variables, the 3-year probability of TFS was 94.8%, 84.5%, 61.6%, and 21.1% for patients scoring 0, 1, 2, and 3 + 4, respectively (P < .0001). These data, and the demonstration that monoclonal and polyclonal B cells concur to FLC synthesis in tumor tissues, suggest that sFLC(κ/λ) and sFLC(κ + λ) mirror distinct biologic processes in CLL. sFLC(κ + λ) assessment represents a sensitive and cost-effective tool for identifying CLL patients requiring early treatment.

Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis

To examine blood B cell subsets in patients with rheumatoid arthritis (RA) prior to B cell depletion therapy and to assess their potential as predictors of clinical response to rituximab (RTX). Blood B cell subsets were assessed by flow cytometry in 208 RA patients included in an RTX retreatment study (assessed prior to RTX treatment) and in 47 age-matched controls. Expression of BAFF receptor (BAFF-R) on B cells and serum B cell biomarkers was also measured. B cell subsets and BAFF-R expression were compared between RA patient and control populations. Univariate and multivariate analyses were performed to identify baseline factors associated with a European League Against Rheumatism response 24 weeks after 1 cycle of RTX. Mean ± SD counts of both CD27- naive and CD27+ memory B cells were decreased in RA patients (188.6 ± 121.4/mm(3)) compared with controls (257.3 ± 154.1/mm(3)) (P = 0.001) and were partially restored in patients treated with methotrexate (MTX) plus anti-tumor necrosis factor compared with patients treated with MTX alone. Within the CD27+ memory B cells, the CD27+IgD- switched memory subtype was selectively decreased, irrespective of treatment. The frequency of CD27+ memory B cells correlated inversely with levels of several B cell activation biomarkers in RA. Serum BAFF level and BAFF-R expression was comparable in RA patients and controls. A low baseline CD27+ memory B cell frequency was associated with a greater clinical response to RTX (odds ratio 0.97 [95% confidence interval 0.95-0.99], P = 0.0015). In B cell depletion therapy-naive RA patients, a low frequency of CD27+ memory B cells correlated with levels of serum B cell activation biomarkers and may predict response to RTX. These results suggest that low memory B cell frequency may be indicative of a B cell-driven RA subtype that is more sensitive to B cell depletion therapy.