Prediction-based classification for longitudinal biomarkers

Assessment of circulating CD4 count change over time in HIV-infected subjects on antiretroviral therapy (ART) is a central component of disease monitoring. The increasing number of HIV-infected subjects starting therapy and the limited capacity to support CD4 count testing within resource-limited settings have fueled interest in identifying correlates of CD4 count change such as total lymphocyte count, among others. The application of modeling techniques will be essential to this endeavor due to the typically nonlinear CD4 trajectory over time and the multiple input variables necessary for capturing CD4 variability. We propose a prediction-based classification approach that involves first stage modeling and subsequent classification based on clinically meaningful thresholds. This approach draws on existing analytical methods described in the receiver operating characteristic curve literature while presenting an extension for handling a continuous outcome. Application of this method to an independent test sample results in greater than 98% positive predictive value for CD4 count change. The prediction algorithm is derived based on a cohort of $n=270$ HIV-1 infected individuals from the Royal Free Hospital, London who were followed for up to three years from initiation of ART. A test sample comprised of $n=72$ individuals from Philadelphia and followed for a similar length of time is used for validation. Results suggest that this approach may be a useful tool for prioritizing limited laboratory resources for CD4 testing after subjects start antiretroviral therapy.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS326 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

The Influence of Abacavir and Other Antiretroviral Agents on Virological Response to HCV Therapy Among Antiretroviral-Treated HIV-Infected Patients.

BACKGROUND: It remains unclear if certain antiretroviral medications, particularly abacavir, compromise response to HCV therapy. Such data could inform the selection of appropriate antiretrovirals in HIV/HCV-coinfected patients. The aim of this study was to determine if use of abacavir, as well as other antiretrovirals, was associated with reduced response to pegylated interferon (PEG-IFN) plus ribavirin. METHODS: A cohort study was performed among antiretroviral-treated HIV/HCV-coinfected patients initiating PEG-IFN plus ribavirin between January 2001 and June 2007 at six sites in the United States. Abacavir and other antiretrovirals represented exposures of interest. Study outcomes included an early virological response (\u3e or =2 log IU/ml decrease in HCV viral load at 12 weeks) and sustained virological response (undetectable HCV viral load 24 weeks after treatment discontinuation). RESULTS: Among 212 patients, 74 (35%) received abacavir. For patients infected with HCV genotype 1 or 4, no differences were observed between abacavir users and non-users in early virological response (26 [40%] versus 53 [44%]; adjusted odds ratio [OR] 1.00; 95% confidence interval [CI] 0.50-2.00) or sustained virological response (8 [13%] versus 13 [12%]; adjusted OR 1.34; 95% CI 0.50-3.62). Among genotype 2 and 3 patients, rates of early virological response (7 [78%] versus 16 [89%]; OR 0.44; 95% CI 0.05-3.76) and sustained virological response (3 [33%] versus 8 [44%]; OR 0.63; 95% CI 0.12-3.32) were also similar between abacavir users and non-users. No association was found between other antiretrovirals and a lack of early or sustained response. CONCLUSIONS: Use of abacavir or other antiretroviral medications was not associated with reduced early or sustained virological response rates

Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification

Luis Montaner and colleagues retrospectively apply a potential capacity-saving CD4 count prediction tool to a cohort of HIV patients on antiretroviral therapy

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA–positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART

Randomized, Controlled Trial of Therapy Interruption in Chronic HIV-1 Infection

BACKGROUND: Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms. METHODS AND FINDINGS: Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1–8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4–8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen. CONCLUSION: Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted

HPLC-based purification and isolation of potent anti-HIV and latency reversing Daphnane Diterpenes from the medicinal plant Gnidia sericocephala (Thymelaeaceae)

Despite the success of combination antiretroviral therapy (cART), HIV persists in low- and middle-income countries (LMIC) due to emerging drug resistance and insufficient drug accessibility. Furthermore, cART does not target latently-infected CD4+ T cells, which represent a major barrier to HIV eradication. The “shock and kill” therapeutic approach aims to reactivate provirus expression in latently-infected cells in the presence of cART and target virus-expressing cells for elimination. An attractive therapeutic prototype in LMICs would therefore be capable of simultaneously inhibiting viral replication and inducing latency reversal. Here we report that Gnidia sericocephala, which is used by traditional health practitioners in South Africa for HIV/AIDS management to supplement cART, contains at least four daphnane-type compounds (yuanhuacine A (1), yuanhuacine as part of a mixture (2), yuanhuajine (3), and gniditrin (4)) that inhibit viral replication and/or reverse HIV latency. For example, 1 and 2 inhibit HIV replication in peripheral blood mononuclear cells (PBMC) by >80% at 0.08 g/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal effective concentration (EC50) of 0.03 M without cytotoxicity. Both 1 and 2 also reverse HIV latency in vitro consistent with protein kinase C activation but at 16.7-fold lower concentrations than the control prostratin. Both 1 and 2 also reverse latency in primary CD4+ T cells from cART-suppressed donors with HIV similar to prostratin but at 6.7-fold lower concentrations. These results highlight G. sericocephala and components 1 and 2 as anti-HIV agents for improving cART efficacy and supporting HIV cure efforts in resource-limited regions.SUPPLEMENTARY MATERIAL : TABLE S1: Anti-HIV replication activity of the positive control efavirenz using the in vitro deCIPhR assay: TABLE S2: Anti-HIV replication activity of G. sericocephala root extracts using the in vitro deCIPhR assay: TABLE S3: Cytotoxicity of G. sericocephala root extracts using the in vitro deCIPhR assay; FIGURE S1: 1H NMR data of yuanhuacine A (1), acquired on a Bruker Avance III HD 500 MHz NMR spectrophotometer with Prodigy Probe, the compound dissolved in deuterated chloroform (CDCl3): FIGURE S2: 13C NMR data of yuanhuacine A (1), acquired on a Bruker Avance III HD 500 MHz NMR spectrophotometer with Prodigy Probe, the compound dissolved in deuterated chloroform (CDCl3): FIGURE S3: The DEBT NMR data of yuanhuacine A (1), acquired on a Bruker Avance III HD 500 MHz NMR spectrophotometer with Prodigy Probe, the compound dissolved in deuterated chloroform (CDCl3).Funding was provided by the South African Department of Science and Innovation (DST/CON 0031/2019), Canadian Institutes for Health Research (CIHR PJT-153057) (I.T.) and the New Frontiers in Research Fund—Explorations (NFRFE-2018-01386) (I.T.). This work was also supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) (I.T.; N.G.), a DELTAs African Initiative [grant # DEL-15-006]. The DELTA African Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Welcome Trust [grant # 107752/Z/15/Z] and the UK government. This work was also supported by grants to L.J.M.: Beyond Antiretroviral Treatment (BEAT)-HIV Delaney Collaboratory Grants UM1AI126620 and UM1AI64570. It was also supported by the Robert I. Jacobs Fund of the Philadelphia Foundation; Penn Center for AIDS Research Grant P30 AI 045880; and the Herbert Kean. The APC was funded by University of Pretoria and Deaprtment of Science and Innovation.https://www.mdpi.com/journal/virusesam2023Chemistr

The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial

The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01(B) vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01(B)_2 group, N=64) or 3 (F4/AS01(B)_3 group, N=62) doses of F4/AS01(B) or placebo (control group, N=64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4(+) T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01(B)_2 and control group (0.073 log(10)copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01(B)_3 and control group (-0.096 log(10)copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4(+) T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01(B) recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01(B)_2 group: angioedema). F4/AS01(B) induced polyfunctional F4-specific CD4(+) T-cells, but had no significant impact on F4-specific CD8(+) T-cell and anti-F4 antibody levels.F4/AS01(B) had a clinically acceptable safety profile, induced F4-specific CD4(+) T-cell responses, but did not reduce HIV-1 VL, impact CD4(+) T-cells count, delay ART initiation, or prevent HIV-1 related clinical events

Safety, Tolerability, and Efficacy of Raltegravir in a Diverse Cohort of HIV-Infected Patients: 48-Week Results from the REALMRK Study

The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race

Preliminary Acceptability of a Home-Based Peripheral Blood Collection Device for Viral Load Testing in the Context of Analytical Treatment Interruptions in HIV Cure Trials: Results from a Nationwide Survey in the United States

Frequent viral load testing is necessary during analytical treatment interruptions (ATIs) in HIV cure-directed clinical trials, though such may be burdensome and inconvenient to trial participants. We implemented a national, cross-sectional survey in the United States to examine the acceptability of a novel home-based peripheral blood collection device for HIV viral load testing. Between June and August 2021, we distributed an online survey to people with HIV (PWH) and community members, biomedical HIV cure researchers and HIV care providers. We performed descriptive analyses to summarize the results. We received 73 survey responses, with 51 from community members, 12 from biomedical HIV cure researchers and 10 from HIV care providers. Of those, 51 (70%) were cisgender men and 50 (68%) reported living with HIV. Most (>80% overall) indicated that the device would be helpful during ATI trials and they would feel comfortable using it themselves or recommending it to their patients/participants. Of the 50 PWH, 42 (84%) indicated they would use the device if they were participating in an ATI trial and 27 (54%) also expressed a willingness to use the device outside of HIV cure studies. Increasing sensitivity of viral load tests and pluri-potency of the device (CD4 count, chemistries) would augment acceptability. Survey findings provide evidence that viral load home testing would be an important adjunct to ongoing HIV cure-directed trials involving ATIs. Survey findings may help inform successful implementation and uptake of the device in the context of personalized HIV care

La communication politique et le confessionnalisme au liban : le cas des élections legislatives de 2009

In a Middle Eastern context where the Sunni-Shia conflict is becoming more and more obvious, we ask ourselves if the political communications and electoral speeches of the Future Movement and of Hezbollah do reflect the sectarian division and the Sunni-Shia conflict in Lebanon. This thesis on “political communication and confessionalism in Lebanon: the 2009 parliamentary elections” proposes theoretical concepts of political communication, an overview of the Lebanese context between the elections of 2005 and 2009 and a study of the Sunni-Shia conflict through the discourse analysis of the leaders of both parties each considered representing a community in its majority.The qualitative and quantitative discourse analysis, divided into four categories, namely: the campaigns‟ launching study, the crises study, the diachronic study and the elections closing study, based on several selection criteria such as the date, context, nature and the leader who is delivering the speech, aims to identify the communication elements that would reflect sectarian tensions and an eventual Sunni-Shia conflict that geopolitical analysis tend to confirm.Le liban est un pays multicommunautaire, ce qui a conduit, depuis 1920, à de nombreux conflits intercommunautaires, non religieux, entre des groupes qui s'arrachent le pouvoir. ces conflits opposaient souvent les chrétiens qui ont, pour la plupart, une vision pro-occidentale d'une part aux musulmans qui sont plus orientés vers les pays arabes d'autre part.toutefois, il semblerait que plusieurs phénomènes de l'histoire contemporaine du liban aient modifié cette dualité chrétienne-musulmane. l'assassinat de rafik hariri, leader sunnite, en février 2005 en plein coeur de beyrouth et la guerre israélienne sur le hezbollah, parti chiite par excellence en juillet-août 2006 auraient changé le visage du conflit, pour en faire un conflit sunnite-chiite. un conflit qui règnerait non seulement sur le liban mais sur toute la région du moyen-orient.ayant pour objectif d'étudier ce conflit sous l'angle de 'la communication politique et le confessionnalisme au liban', plus particulièrement le cas des élections législatives de 2009 ; nous étudierons essentiellement les discours politiques des deux partis représentant les communautés sunnite et chiite afin de pouvoir en ressortir les éventuelles tensions intercommunautaires après avoir établit le cadre théorique et le contexte de notre projet de recherche