Showing papers by "Chloe Orkin published in 2010"

Analysis of Memory B Cell Responses and Isolation of Novel Monoclonal Antibodies with Neutralizing Breadth from HIV-1-Infected Individuals

Abstract: Background: The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine.Methods and Findings: We immortalized IgG(+) memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity.Conclusions: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

Comparison of Changes in Bone Density and Turnover with Abacavir-Lamivudine versus Tenofovir-Emtricitabine in HIV-Infected Adults: 48-Week Results from the ASSERT Study

Abstract: Background. Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. Methods. In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir- emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. Results. A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir-emtricitabine group, -3.6%; P= 6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >= 6% in the hip; 15% vs 5% had a loss of >= 6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P Conclusions. This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Late diagnosis in the HAART era: proposed common definitions and associations with mortality.

Abstract: Objective: To identify a definition of presentation after clinical or immunological disease progression that will reliably identify an individual at high risk of mortality over the first 3 months after HIV diagnosis and that can be adopted as a basis for comparing over time and regions.Design: An observational cohort study.Methods: Individuals seen for the first time at a UK Collaborative HIV Cohort study clinic from 1996 to 2006 were identified. Two immunological (CD4 cell count < 200 cells/mu l and CD4 cell count <50 cells/mu l) and two clinical (AIDS and severe/moderate AIDS) criteria for presentation with advanced HIV disease were compared, as well as combinations of them. The predictive ability of each diagnosis for identifying individuals who died in the first 3 months after HIV diagnosis was assessed.Results: Fifteen thousand seven hundred and seventy-four patients were included, of whom 1495 (9.5%), 4231 (26.8%), 1523 (9.7%) and 379 (2.4%) had a CD4 cell count below 50 cells/mu l, CD4 cell count below 200 cells/mu l, AIDS or severe/moderate AIDS at diagnosis; CD4 cell counts were unavailable for 2264 (14.4%) patients. Two hundred and six (1.3%) patients died within the first 3 months. Sensitivities of the individual criteria ranged from 18.0% (severe/moderate AIDS) to 50.5% (CD4 cell count < 200 cells/mu l) with specificities ranging from 73.5% (CD4 < 200 cells/mu l) to 97.8% (severe/moderate AIDS). Combinations of clinical and immunological criteria increased the sensitivity but decreased the specificity.Conclusion: We propose that presentation with 'advanced HIV disease' is presentation with a CD4 cell count below 200 cells/mu l or AIDS, whereas 'late' presentation is defined as presentation when the CD4 cell count is below that when treatment should be initiated (currently CD4 cell count < 350 cells/mu l or AIDS). (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Excellent immunological recovery following CODOX-M/IVAC, an effective intensive chemotherapy for HIV-associated Burkitt's lymphoma.

Abstract: OBJECTIVE AND DESIGN : To retrospectively describe the recovery of cellular immunity and the clinical outcome of 30 patients with HIV-associated Burkitt's lymphoma (HIV-BL), who were treated with the intensive chemotherapy CODOX-M/IVAC and HAART as part of their standard care. PATIENTS AND METHODS : Seventy-three percent of the patients had high-risk disease, defined by stage, performance status, extranodal sites and lactate dehydrogenase. The median CD4 cell count at diagnosis of HIV-BL was 171/ml (range: 4-848) and the plasma HIV viral load was undetectable in five of 29 patients. RESULTS : Nine patients died during treatment (disease progression, three; toxicity, five; central nervous system lesion not biopsied, one). Response rate was 70% (complete response/complete response uncertain, 17; partial response, 4). After a median follow-up of 22 months (range: 6-72), 18 patients remain alive without disease progression. The 3-year overall survival and event-free survival were 52 and 75%, respectively. Viral load was undetectable in 88% and CD4 cell count more than 200/ml in 58% of patients assessed 6 months after completing chemotherapy, and in 87 and 80% at 12 months, respectively. CONCLUSION : The intensive regimen CODOX-M/IVAC, a feasible and effective chemotherapy, is associated with an excellent immunological recovery in patients with HIV-BL on HAART.

Discordant responses on starting highly active antiretroviral therapy: suboptimal CD4 increases despite early viral suppression in the UK Collaborative HIV Cohort (UK CHIC) Study

Abstract: Objectives Patients starting highly active antiretroviral therapy (HAART) may have a suboptimal CD4 increase despite rapid virological suppression. The frequency and the significance for patient care of this discordant response are uncertain. This study was designed to determine the incidence of a discordant response at two time-points, soon after 6 months and at 12 months, and to determine the relationship with clinical outcomes. Methods Data obtained in the UK Collaborative HIV Cohort Study were analysed. A total of 2584 treatment-naive patients starting HAART with HIV viral load (VL)>1000 HIV-1 RNA copies/mL at baseline and <50 copies/mL within 6 months were included in the analysis. Patients were classified at either 6–10 (midpoint 8) months or 10–14 (midpoint 12) months as having a discordant (CD4 count increase <100 cells/μL from baseline) or concordant response (CD4 count increase ≥100 cells/μL). Results Discordant responses occurred in 32.1% of patients at 8 months and in 24.2% at 12 months; 35% of those discordant at 8 months were concordant at 12 months. A discordant response was associated with older age, lower baseline VL, and (at 12 months) higher baseline CD4 cell count. In a multivariate analysis it was associated with an increased risk of death, more strongly at 12 months [incidence rate ratio (IRR) 3.35, 95% confidence interval (CI) 1.73–6.47, P<0.001] than at 8 months (IRR 2.08, 95% CI 1.19–3.64, P=0.010), but not with new AIDS events. Conclusions Discordant responders have a worse outcome, but assessment at 12 months may be preferred, given the number of ‘slow’ responders. Management strategies to improve outcomes for discordant responders need to be investigated.

Prospective epidemiological study of the prevalence of human leukocyte antigen (HLA)-B*5701 in HIV-1-infected UK subjects

Abstract: Objectives Human leukocyte antigen (HLA)-B*5701 is strongly associated with developing a hypersensitivity reaction to abacavir (ABC) in White and Hispanic subjects Across the UK, limited data exist on HLA-B*5701 prevalence in HIV-1-infected subjects We determined HLA-B*5701 prevalence in the general HIV-1-infected population and in specific ethnic groups, particularly Black Africans who, in general, exhibit greater genetic diversity We also compared HLA-B*5701 results obtained from local laboratories with those from a central provider Design and methods Multi-centre, observational study All HIV-1-infected adult individuals receiving care at participating centres were eligible, irrespective of treatment status or prior exposure to ABC Subjects provided samples for HLA-B*5701 assessment by both local (blood) and central laboratories (buccal swabs) HLA-B*5701 prevalence was adjusted to represent the ethnic group composition of the general UK population, and by main ethnic group Results From eight UK centres, 1494 subjects [618 (41%) White, 770 (52%) Black] were recruited Eighty-nine per cent of Black subjects reported an immediate country of origin in Africa Overall adjusted HLA-B*5701 prevalence was 455% [95% confidence interval (CI) 349% to 560%] Among White subjects, prevalence was 793% (CI 580% to 1006%) Among Black subjects, only two (both Ugandan) were HLA-B*5701 positive giving a rate of 026% (CI 007% to 094%) Conclusions HLA-B*5701 prevalence was similar to previously reported rates in White HIV-infected subjects but considerably lower than that reported in Black HIV-1-infected subjects, as a result of the large proportion of Black African subjects

Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations

Abstract: ObjectiveEffective antiretroviral therapy (ART) has transformed the care of people with HIV, but it is important to monitor time trends in indicators of treatment success and antic future changes.MethodsWe assessed time trends from 2000 to 2007 in several indicators of treatment success in the UK Collaborative HIV Cohort (CHIC) Study, and using national HIV data from the Health Protection Agency (HPA) we developed a model to project future trends.ResultsThe proportion of patients on ART with a viral load 50 copies/mL rose fromz 118 (0.7%) to 857 (1.9%). Projections to 2012 suggest sustained high levels of success, with a continued increase in the number of patients who have failed multiple drugs but a relatively stable number of such patients experiencing viral loads > 50 copies/mL. Numbers of deaths are projected to remain low.ConclusionsThere have been continued improvements in key indicators of success in patients with HIV from 2000 to 2007. Although the number of patients who have ETCF is projected to rise in the future, the number of such patients with viral loads > 50 copies/mL is not projected to increase up to 2012. New drugs may be needed in future to sustain these positive trends.

Long-Term Probability of Detecting Drug-Resistant HIV in Treatment-Naive Patients Initiating Combination Antiretroviral Therapy

Abstract: Background. Robust long-term estimates of the risk of development of drug resistance are needed for human immunodeficiency virus (HIV)-infected patients starting combination antiretroviral therapy (cART) regimens currently used in routine clinical practice.Methods. We followed a large cohort of patients seen in 1 of 11 HIV clinics in the United Kingdom after starting cART with nucleoside reverse-transcriptase inhibitors and either a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Survival analysis was employed to estimate the incidence of virological failure and of detected drug resistance.Results. Seven thousand eight hundred ninety-one patients were included; 6448 (82%) started cART with an NNRTI and 1423 (17%) with a PI/r. The cumulative risk of virological failure by 8 years was 28%. The cumulative probabilities of detecting any mutation, >= 1 major nucleoside reverse-transcriptase inhibitor International AIDS Society-United States of America (IAS-USA) mutation, >= 1 major NNRTI IAS-USA mutation (in those starting an NNRTI), and >= 1 major PI IAS-USA mutation (in those starting a PI) were 17%, 14%, 15%, and 7%, respectively, by 8 years. The probability of detecting PI mutations in people who started PI/r-based regimens was lower than that of detecting NNRTI mutations in those starting NNRTI-based regimens (adjusted relative hazard, 0.36; 95% confidence interval, 0.26-0.50; P < .001). The risk of detecting nucleoside resistance did not vary according to whether an NNRTI or a PI/r was used in the regimen (adjusted relative hazard, 1.00; 95% confidence interval, 0.80-1.26; P = .98).Conclusions. In patients who started modern cART in clinical practice in the United Kingdom, virological failure by 8 years was relatively common and was paralleled by an appreciable risk of resistance detection, although the detection rate of class-specific resistance was lower for those who started a PI/r-based regimen.

An epidemiologic study to determine the prevalence of the HLA-B*5701 allele among HIV-positive patients in Europe.

Abstract: OBJECTIVES HLA-B*5701 is a major histocompatibility complex class I allele associated with an immunologically-mediated hypersensitivity reaction to abacavir. The objectives of this study were to evaluate HLA-B*5701 prevalence among European, HIV-1-infected patients and to compare the local and central laboratory screening results. METHODS Data were combined from six multicentre, prospective studies involving 10 European countries in which HIV-1-infected patients (irrespective of treatment experience or previous HLA-B*5701 screening), >or=18 years of age, were evaluated for HLA-B*5701 carriage, determined by the central and local laboratory methods. RESULTS A total of 9720 patients from 272 centres were included in the analysis. The overall estimate of HLA-B*5701 prevalence in Europe was 4.98%, with country-specific estimates ranging from 1.53 to 7.75%. HLA-B*5701 prevalence was highest in the self-reported white population (6.49%) and lowest in the black population (0.39%). Local laboratory results had a high specificity (99.9%) and sensitivity (99.2%) when compared with the central laboratory results. CONCLUSION This study supports data from previous studies regarding the prevalence of HLA-B*5701 in the HIV population and the variation of HLA-B*5701 prevalence between different racial groups. The high specificity and sensitivity of local laboratory results, suggests that clinicians can be confident in using local laboratories for pretreatment HLA-B*5701 screening. However, it is essential that local laboratories participate in HLA-B*5701-specific quality assurance programs to maintain 100% sensitivity. In HIV-infected patients, pretreatment HLA-B*5701 screening may allow more informed decisions regarding abacavir use and has the potential to significantly reduce the frequency of abacavir-related hypersensitivity reactions and costs associated with managing these reactions.

The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

Abstract: Objective:To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. Design:A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Results:Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41–0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22–0.37) for less than 100 cells/μl, 0.33 (0.25–0.44) for 100 to less than 200 cells/μl, 0.38 (0.28–0.52) for 200 to less than 350 cells/μl, 0.55 (0.41–0.74) for 350 to less than 500 cells/μl, and 0.77 (0.58–1.01) for 500 cells/μl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49–0.67) for less than 1 year since initiation to 0.21 (0.14–0.31) for 5 years or more (P value for trend <0.001). Conclusion:We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Factors influencing lopinavir and atazanavir plasma concentration

Abstract: BACKGROUND The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration. METHODS Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake. RESULTS Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54). CONCLUSIONS This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.

Neutralization activity in a geographically diverse East London cohort of human immunodeficiency virus type 1-infected patients: clade C infection results in a stronger and broader humoral immune response than clade B infection.

Abstract: The array of human immunodeficiency virus (HIV) subtypes encountered in East London, an area long associated with migration, is unusually heterogeneous, reflecting the diverse geographical origins of the population. In this study it was shown that viral subtypes or clades infecting a sample of HIV type 1 (HIV-1)-positive individuals in East London reflect the global pandemic. The authors studied the humoral response in 210 treatment-naive chronically HIV-1-infected (>1 year) adult subjects against a panel of 12 viruses from six different clades. Plasmas from individuals infected with clade C, but also plasmas from clade A, and to a lesser degree clade CRF02_AG and CRF01_AE, were significantly more potent at neutralizing the tested viruses compared with plasmas from individuals infected with clade B. The difference in humoral robustness between clade C- and B-infected patients was confirmed in titration studies with an extended panel of clade B and C viruses. These results support the approach to develop an HIV-1 vaccine that includes clade C or A envelope protein (Env) immunogens for the induction of a potent neutralizing humoral response.

Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: The STALWART study

Abstract: Background: The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4 + counts compared to no therapy. Methodology: Participants not on continuous ART with $300 CD4 + cells/mm 3 were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4 + counts, HIV RNA, and HIV progression events were collected monthly. Principal Findings: A total of 267 participants were randomized. At week 32, the mean CD4 + count was 134 cells greater in the IL-2 alone group (p,0.001), and 133 cells greater in the IL-2 plus ART group (p,0.001) compared to the no therapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group assigned to no therapy experienced an opportunistic event or died (HR 5.84, CI: 0.59 to 43.57; p = 0.009). Conclusions: IL-2 alone or with peri-cycle HAART increases CD4 + counts but was associated with a greater number of opportunistic events or deaths compared to no therapy. These results call into question the immunoprotective significance of IL-2-induced CD4 + cells. Trial Registration: ClinicalTrials.gov NCT00110812

ARTEMIS: 192-week efficacy and safety of once-daily darunavir/ritonavir (DRV/r) vs lopinavir/r (LPV/r) in treatment-naïve HIV-1-infected adults

Abstract: ARTEMIS was a Phase III, randomised, open-label study assessing efficacy and safety of DRV/r 800/100mg qd versus LPV/r 800/200mg total daily dose (qd or bid) in treatment-naive HIV-1-infected adults. At 96 wks, DRV/r demonstrated non-inferiority and superiority to LPV/r in virological response. Wk 192 results are reported. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P3 Cite this article as: Orkin et al.: ARTEMIS: 192-week efficacy and safety of once-daily darunavir/ritonavir (DRV/r) vs lopinavir/r (LPV/r) in treatment-naive HIV-1-infected adults. Journal of the International AIDS Society 2010 13(Suppl 4):P3. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113031/

Switching from Kivexa + efavirenz to Atripla reduces total cholesterol in hypercholesterolemic subjects: final results of a 24-week, randomized study

Abstract: Dyslipidemia in persons with HIV contributes significantly to cardiovascular (CV) risk. Abacavir (ABC) has been shown to increase lipid levels and some cohort studies have suggested an association between ABC use and myocardial infarction (MI). Comparative data suggested Truvada (TDF/FTC) has a lesser effect on lipid parameters than Kivexa [KVX]. We investigated the change in fasting lipid parameters in hypercholesterolemic subjects switching from KVX + Efavirenz [EFV] to Atripla [ATR]. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P80 Cite this article as: Moyle et al.: Switching from Kivexa + efavirenz to Atripla reduces total cholesterol in hypercholesterolemic subjects: final results of a 24-week, randomized study. Journal of the International AIDS Society 2010 13(Suppl 4):P80. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113087/