Publications
321 results found
Herath S, Le Heron A, Colloca S, et al., 2016, Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors, Vaccine, Vol: 34, Pages: 4378-4385, ISSN: 1873-2518
In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains. The C57BL/6 strain showed the lowest range of responses compared to the other strains and, very few responses were seen to the same peptide pool in all three strains of mice. In CBA and BALB/c mice there were significant differences in IFNγ production dependent on the adenoviral vector used. Our results suggest that employing a single strain of mouse may underestimate the efficacy and efficiency of vaccine products.
Hoffmann M, Pantazis N, Martin GE, et al., 2016, Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection, PLOS Pathogens, Vol: 12, ISSN: 1553-7366
The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.
Martin GE, Pantazis N, Hoffmann M, et al., 2016, Exhaustion of activated CD8 T cells predicts disease progression in primary HIV-1 infection, Journal of the International AIDS Society, Vol: 19, Pages: 32-32, ISSN: 1758-2652
LAU RKW, JENKINS P, CAUN K, et al., 2016, TRENDS IN SEXUAL-BEHAVIOR IN A COHORT OF HOMOSEXUAL MEN - A 7 YEAR PROSPECTIVE-STUDY, INTERNATIONAL JOURNAL OF STD & AIDS, Vol: 3, Pages: 267-272, ISSN: 0956-4624
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LAU RKW, HILL A, JENKINS P, et al., 2016, 8 YEAR PROSPECTIVE-STUDY OF HIV-INFECTION IN A COHORT OF HOMOSEXUAL MEN - CLINICAL PROGRESSION, IMMUNOLOGICAL AND VIROLOGICAL MARKERS, INTERNATIONAL JOURNAL OF STD & AIDS, Vol: 3, Pages: 261-266, ISSN: 0956-4624
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- Citations: 7
Joachim A, Bauer A, Joseph S, et al., 2016, Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial., PLOS One, Vol: 11, ISSN: 1932-6203
BACKGROUND: A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA). METHODS: Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart. RESULTS: The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding antibodies to subtype C Env (included in HIV-DNA and protein boost), subtype B Env (included only in HIV-DNA) and CRF01_AE Env (included only in HIV-MVA) were significantly boosted by the CN54rgp140/GLA-AF immunizations. Functional antibodies detected using an infectious molecular clone virus/peripheral blood mononuclear cell neutralization assay, a pseudovirus/TZM-bl neutralization assay or by assays for antibody-dependent cellular cytotoxicity (ADCC) were not significantly boosted. In contrast, T-cell proliferative responses to subtype B MN antigen and IFN-γ ELISpot responses to Env peptides were significantly enhanced. Four volunteers not primed with HIV-DNA and HIV-MVA before the CN54rgp140/GLA-AF immunizations mounted an antibody response, while cell-mediated responses were rare. After the two Env subtype C protein immunizations, a trend towards higher median subtype C Env binding antibody titers was found in vaccinees who had received HIV-DN
Thornhill J, Inshaw J, Kaleebu P, et al., 2016, Enhanced normalisation of CD4/CD8 ratio with earlier antiretroviral therapy at Primary HIV Infection., Journal of Acquired Immune Deficiency Syndromes, Vol: 73, Pages: 69-73, ISSN: 0894-9255
BACKGROUND: Total CD4 T-cell counts predict HIV disease progression, but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker of immune dysfunction, a prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite ART, recovery of CD4/CD8 ratio in chronic HIV infection is incomplete; we hypothesize enhanced CD4/CD8 ratio recovery with earlier treatment initiation in recently infected individuals. METHODS: CD4 count and CD4/CD8 ratio were analyzed using data from two cohorts: SPARTAC trial, and the UK HIV Seroconverters Cohort where Primary HIV infection (PHI) was defined as within 6 months from estimated date of infection. Using time-to-event methods and Cox proportional hazard models we examined the effect of CD4/CD8 ratio at seroconversion on disease progression (CD4<350 cells/mm/ART initiation), and factors associated with time from ART initiation to CD4/CD8 normalization (ratio >1.0). FINDINGS: Of 573 seroconverters, 482 (84%) had abnormal CD4/CD8 ratios at HIV seroconversion. Individuals with higher CD4/CD8 ratio at seroconversion were significantly less likely to reach the disease progression end point (aHR [95% CI] = 0.52 [0.32, 0.82], p=0.005). The longer the interval between seroconversion and ART initiation (HR [95% CI] =0.98 per month increase [0.97, 0.99], p<0.001) the less likely CD4/CD8 ratio normalization. ART initiation within 6 months from seroconversion was significantly more likely to normalize (HR [95% CI] =2.47 [1.67, 3.67], p<0.001) than those initiating later. INTERPRETATION: The majority of individuals presenting in PHI have abnormal CD4/CD8 ratios. The sooner ART is initiated in PHI the greater the probability of achieving normal CD4/CD8 ratio.
Quinn K, Bouliotis G, Doyle N, et al., 2016, A first-in-human study, in HIV-positive men, of the novel HIV-fusion inhibitor C34-PEG4-Chol, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 18-18, ISSN: 1464-2662
May MT, Gill MJ, Wittkop L, et al., 2016, Mortality of treated HIV-1 positive individuals according to viral subtype in Europe and Canada: collaborative cohort analysis, AIDS, Vol: 30, Pages: 503-513, ISSN: 0269-9370
Objectives: To estimate prognosis by viral subtype in HIV-1-infected individuals fromstart of antiretroviral therapy (ART) and after viral failure.Design: Collaborative analysis of data from eight European and three Canadiancohorts.Methods: Adults (N>20 000) who started triple ART between 1996 and 2012 andhad data on viral subtype were followed for mortality. We estimated crude andadjusted (for age, sex, regimen, CD4þ cell count, and AIDS at baseline, period ofstarting ART, stratified by cohort, region of origin and risk group) mortality hazardratios (MHR) by subtype. We estimated MHR subsequent to viral failure defined astwo HIV-RNA measurements greater than 500 copies/ml after achieving viralsuppression.Results: The most prevalent subtypes were B (15 419; 74%), C (2091; 10%), CRF02AG(1057; 5%), A (873; 4%), CRF01AE (506; 2.4%), G (359; 1.7%), and D (232; 1.1%).Subtypes were strongly patterned by region of origin and risk group. During 104 649person-years of observation, 1172/20 784 patients died. Compared with subtype B,mortality was higher for subtype A, but similar for all other subtypes. MHR for A versus Bwere 1.13 (95% confidence interval 0.85,1.50) when stratified by cohort, increased to1.78 (1.27,2.51) on stratification by region and risk, and attenuated to 1.59 (1.14,2.23)on adjustment for covariates. MHR for A versus B was 2.65 (1.64,4.28) and 0.95(0.57,1.57) for patients who started ART with CD4þ cell count below, or more than, 100cells/ml, respectively. There was no difference in mortality between subtypes A, B and Cafter viral failure.Conclusion: Patients with subtype A had worse prognosis, an observation which maybe confounded by socio-demographic factors.
Herath S, Le Heron A, Colloca S, et al., 2015, Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag–pol–nef antigen, Vaccine, Vol: 33, Pages: 7283-7289, ISSN: 1873-2518
Hurst J, Hoffmann M, Pace M, et al., 2015, Immunological biomarkers predict HIV-1 viral rebound after treatment interruption, Nature Communications, Vol: 6, Pages: 1-9, ISSN: 2041-1723
Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of ‘post-treatment control’ (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication.
Hoehn KB, Gall A, Bashford-Rogers R, et al., 2015, Dynamics of immunoglobulin sequence diversity in HIV-1 infected individuals, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 370, ISSN: 0962-8436
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- Citations: 19
Jose S, Quinn K, Dunn D, et al., 2015, Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation, HIV Medicine, Vol: 17, Pages: 368-372, ISSN: 1464-2662
ObjectivesNo randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development.MethodsIn a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART.ResultsOf 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL.ConclusionsWe found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL.
Hamlyn E, Stoehr W, Cooper DA, et al., 2015, The effect of short-course antiretroviral therapy initiated in primary HIV-1 infection on interleukin-6 and D-dimer levels, AIDS, Vol: 29, Pages: 1355-1361, ISSN: 0269-9370
Objective: Interruption of antiretroviral therapy (ART) in chronic HIV disease is associated with increased mortality, predicted by elevations in interleukin-6 (IL-6) and D-dimer. The effect of ART interruption in primary HIV-1 infection on these biomarkers is unknown.Methods: Plasma samples from 200 HIV seroconverters enrolled in the Short Pulse Anti-Retroviral Therapy At HIV Seroconversion trial of deferred ART (standard of care) – 12 or 48 week ART (ART12 or ART48, respectively) – were analysed for IL-6 and D-dimer at weeks 0, 12, 16, 48, 52, 60 and 108 after randomization. Changes in log10 levels from weeks 0 to 12 were analysed using linear regression, as were changes from baseline to 4 weeks after stopping ART. Areas under the biomarker–time curves (AUC) to week 108 were adjusted for baseline values, and compared across all arms.Results: Median (inter-quartile range) baseline IL-6 and D-dimer were 1.45 (0.88, 2.41) pg/ml and 0.34 (0.20, 0.50) mg/l, respectively. At week 12, D-dimer levels were significantly lower among treated compared to untreated individuals (P < 0.001), whereas IL-6 levels were similar (P = 0.23). Within 4 weeks from stopping ART, IL-6 and D-dimer levels rose by 22 and 18%, reaching pre-ART levels. Over 108-week follow-up, there was no difference between arms in IL-6 AUC (P = 0.53), but D-dimer AUC was significantly lower for ART12 and ART48 compared to standard of care (overall P = 0.008).Conclusion: Stopping ART in primary HIV-1 infection leads to inflammatory biomarker rebound to pre-treatment levels. However, over 108-week follow-up, we found no evidence that biomarker levels were higher for those interrupting ART, compared to those remaining ART-naïve, and D-dimer levels were significantly lower.
Huntington S, Thorne C, Newell M-L, et al., 2015, Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy, AIDS, Vol: 29, Pages: 801-809, ISSN: 0269-9370
Objective: The objective of this study is to assess whether pregnancy is associated with an increased risk of liver enzyme elevation (LEE) and severe LEE in HIV-positive women on antiretroviral therapy (ART).Design: Two observational studies: the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC).Methods: Combined data from UK CHIC and NSHPC were used to identify factors associated with LEE (grade 1–4) and severe LEE (grade 3–4). Women starting ART in 2000–2012 were included irrespective of pregnancy status. Cox proportional hazards were used to assess fixed and time-dependent covariates including pregnancy status, CD4+ cell count, drug regimen and hepatitis B virus/hepatitis C virus (HBV/HCV) coinfection.Results: One-quarter (25.7%, 982/3815) of women were pregnant during follow-up, 14.2% (n = 541) when starting ART. The rate of LEE was 14.5/100 person-years in and 6.0/100 person-years outside of pregnancy. The rate of severe LEE was 3.9/100 person-years in and 0.6/100 person-years outside of pregnancy. The risk of LEE and severe LEE was increased during pregnancy [LEE: adjusted hazard ratio (aHR) 1.66 (1.31–2.09); severe LEE: aHR 3.57 (2.30–5.54)], including in secondary analyses excluding 541 women pregnant when starting ART. Other factors associated with LEE and severe LEE included lower CD4+ cell count (<250 cells/μl), HBV/HCV coinfection and calendar year.Conclusion: Although few women developed severe LEE, this study provides further evidence that pregnancy is associated with an increased risk of LEE and severe LEE, reinforcing the need for regular monitoring of liver biomarkers during pregnancy.
Knudsen ML, Ljungberg K, Tatoud R, et al., 2015, Alphavirus Replicon DNA Expressing HIV Antigens Is an Excellent Prime for Boosting with Recombinant Modified Vaccinia Ankara (MVA) or with HIV gp140 Protein Antigen, PLOS One, Vol: 10, ISSN: 1932-6203
Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells andantibodies. Studies in humans have shown that DNA vaccines are safe, but their immuno-genicity needs further improvement. As a step towards this goal, we have previously dem-onstrated that immunogenicity is increased with the use of an alphavirus DNA-launchedreplicon (DREP) vector compared to conventional DNA vaccines. In this study, we investi-gated the effect of varying the dose and number of administrations of DREP when given asa prime prior to a heterologous boost with poxvirus vector (MVA) and/or HIV gp140 proteinformulated in glucopyranosyl lipid A (GLA-AF) adjuvant. The DREP and MVA vaccine con-structs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three ad-ministrations of 0.2μg DREP induced lower HIV-specific T cell and IgG responses than theequivalent number of immunizations with 10μg DREP. However, the two doses were equal-ly efficient as a priming component in a heterologous prime-boost regimen. The magnitudeof immune responses depended on the number of priming immunizations rather than thedose. A single low dose of DREP prior to a heterologous boost resulted in greatly increasedimmune responses compared to MVA or protein antigen alone, demonstrating that a mere0.2μg DREP was sufficient for priming immune responses. Following a DREP prime, T cellresponses were expanded greatly by an MVA boost, and IgG responses were also expand-ed when boosted with protein antigen. When MVA and protein were administered simulta-neously following multiple DREP primes, responses were slightly compromised comparedto administering them sequentially. In conclusion, we have demonstrated efficient primingof HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the prim-ing effect depends on number of primes administered rather than dose.
Roberts HE, Hurst J, Robinson N, et al., 2015, Structured observations reveal slow HIV-1 CTL escape., Plos Genetics, Vol: 11, Pages: e1004914-e1004914, ISSN: 1553-7404
The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL escape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN-γ ELISpot and longitudinal HIV-1 gag, pol, and nef sequence data were used to study the timing and prevalence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero respectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two years.
White PJ, Fox J, Weber J, et al., 2014, How Many HIV Infections May Be Averted by Targeting Primary Infection in Men Who Have Sex With Men? Quantification of Changes in Transmission-Risk Behavior, Using an Individual-Based Model, Journal of Infectious Diseases, Vol: 210, Pages: S594-S599, ISSN: 1537-6613
In the United Kingdom, human immunodeficiency virus (HIV) transmission among men who have sex with men(MSM) is not under control, despite readily available treatment, highlighting the need to design a cost-effectivecombination prevention package. MSM report significantly reduced transmission risk behavior following HIVdiagnosis. To assess the effectiveness of HIV diagnosis in averting transmission during highly infectious primaryHIV infection (PHI), we developed a stochastic individual-based model to calculate the number of HIVtransmissionevents expected to occur from a cohort of recently infected MSM with and those without the behaviorchanges reported after diagnosis. The model incorporates different types of sex acts, incorporates condom use,and distinguishes between regular and casual sex partners. The impact on transmission in the 3 months afterinfection depends on PHI duration and testing frequency. If PHI lasts for 3 months and testing is performedmonthly, then behavior changes after diagnosis would have reduced estimated transmission events by 49%–52%,from 31–45 to 15–23 events; a shorter duration of PHI and/or a lower testing frequency reduces the number ofinfections averted. Diagnosing HIV during PHI can markedly reduce transmission by changing transmissionriskbehavior. Because of the high infectivity but short duration of PHI, even short-term behavior change cansignificantly reduce transmission. Our quantification of the number of infections averted is an essential componentof assessment of the cost-effectiveness of strategies to increase detection and diagnoses of PHI.
Thornhill J, Inshaw J, Oomeer S, et al., 2014, Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection, Journal of the International AIDS Society, Vol: 17, ISSN: 1758-2652
Introduction: Despite normalization of total CD4 counts, ongoing immune dysfunction is noted amongst those on antiretroviraltherapy (ART). Low CD4/CD8 ratio is associated with a high risk of AIDS and non-AIDS events and may act as a marker of immunesenescence [1]. This ratio is improved by ART although normalization is uncommon (7%) [2]. The probability of normalizationof CD4 count is improved with immediate ART initiation in primary HIV infection (PHI) [3]. We examined whether CD4/CD8 ratiosimilarly normalized in immediate vs. deferred ART at PHI.Methods: Using data from the SPARTAC trial and the UK Register of HIV Seroconverters, we examined the effect of ART withtime (continuous) from HIV seroconversion (SC) on CD4/CD8 ratio (]1) adjusted for sex, risk group, ethnicity, enrolment froman African site and both CD4 count and age at ART initiation. We also examined that effect by dichotomizing HIV duration at ARTinitiation (ART started within six months of SC: early ART; ART initiatedsix months after SC: deferred). We also considered timeto CD4 count normalization (]900 cells/mm3).Results: In total, 353 initiated ART with median (IQR) 97.9 (60.5, 384.5) days from estimated seroconversion; 253/353 early ART,100 deferred ART. At one year after starting ART, 114/253 (45%) early ART had normalized CD4/8 ratio, compared with 11/99(11%) in the deferred group, whilst 83/253 (33%) of early ART had normalized CD4 counts, compared with 3/99 (3%) in thedeferred group. Individuals initiating within six months of PHI were significantly more likely to reach normal ratio than thoseinitiating later (HR, 95% CI 2.96, 1.755.01, pB0.001). The longer after SC ART was initiated, the reduced likelihood of achievingnormalization of CD4/CD8 ratio (HR 0.98, 95% CI 0.960.99 for each 30-day increase). CD4 count at ART initiation was alsoassociated with normalization, as expected (HR 1.002, 95% CI 1.0011.002, pB0.001). There was an association betweennormal CD4/CD8 ratio and being virally suppr
The HIV-CAUSAL Collaboration, 2014, Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries, AIDS, Vol: 28, Pages: 2461-2473, ISSN: 0269-9370
Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis.Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, had CD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting.Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90–1.63) for tuberculosis, 2.61 (1.05–6.49) for MAC, 1.17 (0.34–4.08) for CMV retinitis, 1.18 (0.62–2.26) for PML, 1.21 (0.83–1.75) for HSV, 1.18 (0.87–1.58) for Kaposi sarcoma, 1.56 (0.82–2.95) for NHL, 1.11 (0.56–2.18) for cryptococcosis and 0.77 (0.40–1.49) for candidiasis.Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries.
Williams JP, Hurst J, Stoehr W, et al., 2014, HIV-1 DNA predicts disease progression and post-treatment virological control., eLife, Vol: 3, Pages: 1-16, ISSN: 2050-084X
In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials.
Hamlyn E, Fidler S, Stoehr W, et al., 2014, Interleukin-6 and D- dimer levels at seroconversion as predictors of HIV-1 disease progression, AIDS, Vol: 28, Pages: 869-874, ISSN: 0269-9370
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Frater J, Ewings F, Hurst J, et al., 2014, HIV-1-specific CD4<SUP>+</SUP> responses in primary HIV-1 infection predict disease progression, AIDS, Vol: 28, Pages: 699-708, ISSN: 0269-9370
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Huntington S, Thorne C, Anderson J, et al., 2014, Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naive women, BMC Infectious Diseases, Vol: 14, Pages: 1-5, ISSN: 1471-2334
BackgroundShort-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started.MethodsData were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression.ResultsIn adjusted analyses, ART-naïve (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS.ConclusionsIn this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman’s health.
McKay PF, Cope AV, Mann JFS, et al., 2014, Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen, PLOS One, Vol: 9, ISSN: 1932-6203
Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNApoxvirus-proteinstrategy in mice and rabbits, administering MVA and protein immunizations either sequentially orsimultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/2GLA-AF adjuvant) andeither co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. TheDNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to theboost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccinecomponents. Moreover, a high proportion of the total mucosal IgG (20 – 50%) present in the vaginal vault of thesevaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccinemodality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIVCN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene productexpressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA andGLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequentialvaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit ofthe condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced,an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF.
Lacabaratz C, Wiedemann A, Boucherie C, et al., 2013, A Phase I/II Trial of Preventive HIV Vaccination with DNA and Poxviral-Vector in Healthy Subjects EV03/ANRS VAC20: Cytokine Production by T Cells, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A174-A175, ISSN: 0889-2229
Stoehr W, Fidler S, McClure M, et al., 2013, Duration of HIV-1 Viral Suppression on Cessation of Antiretroviral Therapy in Primary Infection Correlates with Time on Therapy, PLoS ONE, Vol: 8, ISSN: 1932-6203
Objective: A minority of HIV-1 positive individuals treated with antiretroviral therapy (ART) in primary HIV-1 infection(PHI) maintain viral suppression on stopping. Whether this is related to ART duration has not been explored.Design: And Methods: Using SPARTAC trial data from individuals recruited within 6 months of seroconversion, wepresent an observational analysis investigating whether duration of ART was associated with post-treatment viraemiccontrol. Kaplan-Meier estimates, logistic regression and Cox models were used.Results: 165 participants reached plasma viral loads (VL) <400 copies/ml at the time of stopping therapy (ART stop).After ART stop, 159 experienced confirmed VL ≥400 copies/ml during median (IQR) follow-up of 167 (108,199)weeks.Most participants experienced VL rebound within 12 weeks from ART stop, however, there was a suggestion of ahigher probability of remaining <400 copies/ml for those on ART >12 weeks compared to ≤12 weeks (p=0.061).Cumulative probabilities of remaining <400 copies/ml at 12, 52 and 104 weeks after ART stop were 21%(95%CI=13,30), 4% (1,9), and 4% (1,9) for ≤12 weeks ART, and 32% (22,42), 14% (7,22), and 5% (2,11) for >12weeks.In multivariable regression, ART for >12 weeks was independently associated with a lower probability of being≥400 copies/ml within 12 weeks of ART stop (OR=0.11 (95%CI=0.03,0.34), p<0.001)). In Cox models of time to VL≥400 after 12 weeks, we only found an association with female sex (OR=0.2, p=0.001).Conclusion: Longer ART duration in PHI was associated with a higher probability of viral control after ART stop.
Weber J, Tatoud R, 2013, Testing times for HIV, BMJ-BRITISH MEDICAL JOURNAL, Vol: 347, ISSN: 1756-1833
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Weber J, Porter K, Babiker A, 2013, Short-Course Antiretroviral Therapy in Primary HIV Infection REPLY, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 368, Pages: 2036-2037, ISSN: 0028-4793
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Yager N, Robinson N, Brown H, et al., 2013, Longitudinal analysis of an HLA-BM*51-restricted epitope in integrase reveals immune escape in early HIV-1 infection, AIDS, Vol: 27, Pages: 313-323, ISSN: 0269-9370
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- Citations: 2
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