LIVE OF THE CROI 2018: MONDAY, MARCH 5, 2018
Christina Psomas, MD, PhD is our “grand reporter”
Harold W. Jaffe (Centers for Disease Control and Prevention, Atlanta, GA, USA) did an overview of the early days of AIDS during the Monday Plenary Session (PL-1). Lessons learned from this epidemic better prepared the world to respond to emerging infectious disease threats. The International Health Regulations and the Global Health Security Agenda provide a framework from global health preparedness. Disease detection is facilitated by the application of new data analytic tools to electronic health records and social media data, and new genetic techniques help us better understand the spread of infectious diseases. Yet human behaviour is difficult to change and ending the AIDS epidemic as a public health threat will be hard.
JoAnna L. Flynn (University of Pittsburgh, Pittsburgh, PA, USA) talked about pathogenesis of tuberculosis that remains a major problem worldwide. More than 2 billion people are infected with TB, which accounts for about 9 millions new cases and 1.5 million deaths per year. Current problems consist of outdated diagnostics, long drug treatment, drug resistance, poor efficacy of vaccine and poor access to health care. In terms of trying to understand TB, the granuloma is the pathological hallmark of TB, the host-response to infection that tries, but is not always sufficient to contain to contain that infection. There is heterogeneity in granulomas both in composition and function. Novel technologies and improved animal models have led to new insights regarding what might trigger reactivation (SIV, CD4 depletion, TNF neutralization, CD8 depletion). Inflammation and high bacterial burden granuloma can account for risk of reactivation of TB. On the other hand, primary infection provides much more robust protection (fewer and smaller granulomas, killing M. tuberculosis more efficiently) than boosted BCG vaccination. New vaccines may have to mimic TB to be protective (CMV-based vaccines seem to be promising).
Jean-Michel Molina inaugurated the Oral Abstract ART Session (O-02) sharing the W48 results of the Phase 3 randomized Gilead 380-1844 study, regarding efficacy and safety results of switching B/F/TAF (50/200/25 mg) from dolutegravir (DTG)-containing regimen DTG/ABC/3TC in HIV-infected virologically suppressed adults (Abstract 22). The primary endpoint was virologically outcome at W48. 563 participants were randomized 1:1 to switch to B/F/TAF once daily or continue current regimen and demonstrated non-inferiority according to primary endpoint (1.1% switching to B/F/TAF and 0.4% continuing DTG/ABC/3TC had HIV-1 RNA > or =50 c/mL, difference 0.7%; 95%CI -1.0% to 2.8%, p=0.62). No treatment emergent resistance was observed in either arm and adverse events were comparable between arms. The lipid, bon and renal safety profiles were comparable through 48 weeks of treatment, with the exception of a small decrease in triglycerides seen in the B/F/TAF group.
Diana Gibb (MRC Clinical Trials Unit at UCL, London, United Kingdom) presented results about Raltegravir intensification of first-line ART on IRIS on behalf of the REALITY trial team (Abstract 23). 1805 ART-naive HIV-infected adults/adolescents/children > or = 5y with CD4<100 cells/uL were randomised to initiate ART (2NRTI+NNRTI) with or with our 12 weeks RAL (Std+RAL or Std). Immunologic and virology baseline characteristics were similar between arms (first CD4 and retrospective VL on stored plasma at week 4). Mean change in log10 VL at week 4 was -3.4 in Std+RAL vs -2.7 in Std (p<0.001; 42.8% vs 14.5 < 50 c/mL respectively). All cause mortality was similar between arms at all time points. Fatal/non-fatal IRIS-compatible events occurred in 89 (9.9%) Std+RAL vs 86 (9.5%) Std patients (p=0.79), and IRIS events of known or unknown aetiology were not significantly different between regimens. Risk of fatal/non-fatal IRIS was independently higher in those with lower pre-ART CD4 (p< 0.001), older individuals (p=0.004) and those with TB at ART initiation (p=0.01). Despite faster VL decline on ART with 12 W of raltegravir in severely immunocompromised patients, they found no evidence supporting higher rates of IRIS. Lower CD4 pre-ART was confirmed to identify those at higher risk of death and IRIS, in whom an enhanced antibiotic prophylaxis would be useful.
Monica Gandhi (University of California San Francisco, San Francisco, CA, USA) showed results of the ACTG A5257 three-arm study comparing ATV/r, DRV/r and RAL-based regimens in naive participants, in terms of evaluation of hair ARV levels (higher long-term exposure) comparatively to virological outcomes (Abstract 24). Hair and viral load data were available for 2192 person-visits among 599 participants followed for a median of 217 weeks. Rates of virology failure by two years were 26%, 6%, and 3% for those with hair levels in the lowest, middle and highest tertiles, respectively. Lower hair ARV levels strongly predicted higher risk of VF (HR 1.69, p<0.001) for every 2-fold decrease in hair level), which remained consistent for each drug individually and when adjusted for self-reported adherence. The hazard of VF with hair ARV levels in the lowest tertile was 6.8 times that with levels in the highest tertile. Correlations between self-reported adherence and hair levels were weak.
Jose R Castillo-Mancilla (University of Colorado, Denver, Aurora, CO, USA) described how tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) that is an objective marker of cumulative adherence and TDF exposure, can also be a predictor of viral suppression (Abstract 25). A total of 1,198 person-visits from 532 participants were analyzed. TFV-DP was lower in Blacks vs Whites (p=0.002) and Hispanics (p=0.002); in non-boosted vs boosted regimens (p=0.003) and in NNRTI-based vs PI-based (p=0.006) and vs multiclass-based (p=0.02) regimens. TFV-DP in DBS was a stronger predictor of virologic suppression in HIV-infected individuals on TDF-based therapy than self-reported adherence. The aOR of virology suppression after adjusting for clinical and biological characteristics of participants was 76.5 for a TFV-DP concentration > or = 1850 fmol/punch (75th percentile of daily dosing, 7 doses/wk) compared to <350 fmol/punch (< 2doses/wk).Participants displayed higher tenofovir exposure than observed in HIV-negative volunteers, influenced by unique patient characteristics including race, BMI, ART class and pharmacologic booster.
Randolph P. Matthews (Merck Research Laboratories, North Wales, PA, USA) presented PK data from a clinical trial examining daily administration of MK-8591 (novel nucleoside reverse transcriptase translocation inhibitor) in healthy subjects (Abstract 26). After multiple daily dosing, MK-8591 was generally well tolerated up to 5 mg daily for 6 weeks. MK-8591-TP PBMC levels are above the level projected for efficacy after a single dose of 0.25 mg, while levels in tissue samples appear above the level projected for efficacy at steady state.
Courtney V. Fletcher (University of Nebraska Medical Center, Omaha, NE, USA) showed results of a comparative PK study of integrase inhibitors (INSTI) in 34 participants of clinical studies of lymphoid tissue (LT) compartments in the University of Minnesota (Abstract 27). While in PBMCs the IQ values for all INSTI were 6-fold or more above the protein binding corrected IC90-95 (pbIC90-95), in LT median IQ values were less than those in PBMCs except for EVG in the ileum and rectum. In lymph nodes (LN), only EVG achieved IQ values greater than 1 (meaning LN concentrations > or = pbIC90-95). These clinical data on INSTI penetration are consistent with the in vitro model prediction of IntraCellular bioavailability using human Lymphatic Endothelial Cells (EVG>DTG>RAL) and suggest that these lower LN INSTI concentrations create conditions allowing persistent viral production.
The “Stop It Now” Symposium begun with Jonah Sacha’s (Oregon Health & Science University, Portland, OR, USA) presentation about mechanisms of early CD8+ T cell control (Abstract 48). While the critical role of CD8+ T cells in containing viral infections is well known, the ability to elicit HIV-protective T celle responses with conventional approaches has remained elusive. Even if the importance of antiviral CD8+ T cells in HIV has already been proved, vaccine-induced Tcm CD8+ T cell responses give rise to an anamnestic immune response that arrives “too late” at the site of infection with “too little” magnitude to prevent irreversible establishment of the persistent viral reservoir. CMV as a vaccine vector for HIV may elicit unconventional T cell responses, namely MHC-E restricted CD8+ T cells that are necessary for protection against HIV/SIV, but not TB. The new paradigm introduced by Jonah Sacha was that of a vaccine-elicited immunity consisting of TEM (effector memory T cells), that may prevent, abort or even provide early complete control of HIV infection, especially with HIV-specific HLA-E restricted CD8+ T cells.