Live from 2016 CROI: Tuesday 23 February Coverage
Dr Christina Psomas is following closely the sessions at the 2016 CROI in Boston since Monday.
In this post she gives us an highlight of what was to be remembered among the several sessions presented on Tuesday 23 February.
"It is the second day of this exciting CROI in a cloudy Boston and the rhythm of the meeting is maintained; the auditorium was full for the plenary session this morning"....
John Mascola of the NIH did a brilliant presentation during the plenary session on "Harnessing antibodies for HIV-1 prevention and treatment". The concept of using antibodies against HIV-1 follows naturally from knowledge gained from many viral diseases. Antibodies can probably be used in prevention (Antibody Mediated Prevention/AMP or Passive Antibody Prevention/PAP), but we do not yet possess clinical data proving protection in human populations. The human monoclonal antibody VRC01 for instance, is a CD4 binding site antibody with preclinical data in a SHIV challenge model that should confer complete in vivo protection against infection. Questions that are still unanswered are the way the antibodies work, as well as if Fc-mediated effector functions (ADCC) are needed for protection. With foreseeable engineering e.g. potency and half-life, mAbs could play an important role in the prevention of HIV-1 infection in high-risk populations.
Antibodies can also be used as a treatment, in a complementary way to ART, in order to block viral entry, or to eliminate infected cells, having an impact on the cell-associated viral reservoir. Thus, mAbs may be used:
- During acute HIV-infection with ARV, to rapidly reduce viremia and limit seeding viral reservoir
- To maintain long-term viral suppression induced by ARV
- To reduce cell-associated viral reservoir.
Joe Eron developed "Where we are and where we are going in terms of antiretroviral therapy". Our goals of ART are really big, because we want to close the gaps and achieve 90-90-90, with more than 90% of viral suppression. In the "Real World", we have to improve diagnosis, treatment and retention to care, in order to achieve this objective. Shift to Integrase Inhibitor-based therapy since 2008 allowed the persistence of the initial ART, without early changes due to problems of intolerance. But we still need new drugs, because we have bigger goals (95%, 95%, 95% by year 2030), in order to close the gap of accessibility to treatment by all PLHIV, and face real hurdles (long-term toxicities, safety in pregnancy, specific populations like children and aging population, resistant virus). New agents should concern new targets (maturation or attachment inhibitors, translocation inhibitors, broadly neutralizing monoclonal antibodies) or new formulations (nanosuspensions).
The session 0-4 of Oral Abstracts or Complications from Head to Toe was really dynamic. Heidi M. Crane proposed a new CVD risk assessment in the CNICS cohort (5 sites across the US). The ASCVD score was compared to the Framingham, the ATP3 and the DAD risk scores, even all these scores except DAD were not developed for use among HIV-infected individuals. The addition of ARV medications in the DAD score did not improve discrimination or calibration compared to ASCVD that seems to work fairly well in HIV.
Felicia Chow described stroke incidence in the ALLRT (AIDS Clinical Trials Group Longitudinal Linked Randomized Trials) cohort, concerning populations of women and black HIV-infected participants. There is 15-80% higher risk of stroke associated with HIV infection after adjustment for traditional risk factors. Felicia demonstrated in her study a trend towards higher age-adjusted incidence rates of stroke in HIV-infected women compared to men, and non-Hispanic Blacks compared to Hispanic/other race. Concerning the risk factors, hypertension, elevated LDL and unsuppressed viral load were associated with greater risk of stroke, while overweight/obesity had a paradoxical protective effect on stroke risk.
In a double blind, randomized, 3-arm trial Meagan K. O'Brien studied the effect of 12 weeks of aspirin on immune activation and endothelial function of HIV-infected patients. Even if the effect on cyclooxygenase inhibition was identified, there was no evidence for an effect of aspirin on sCD14, sCD163, other immune markers, or endothelial function.
José Bernardino presented on behalf of the NEAT 001/ANRS 143 study participants the sub study of body composition changes on Darunavir/Ritonavir (DRV/r) + either Raltegravir (RAL) or Tenofovir/emtricitabine (TDF/FTC) as first line ART. The use of the nucleotide sparing regimen DRV/r + RAL tends to produce a higher increase in total and trunk fat mass than the TDF/FTC containing regimen at W96. Changes in body composition were associated with changes in leptin levels, and higher baseline leptin levels were associated with higher trunk, limb, and total body fat mass.
Alvaro Borges presented data of a large European-cohort (cohorte EuroSIDA), in order to determine factors independently associated with fractures and osteonecrosis. Only TDF between antiretrovirals (current or past exposure) was independently associated with fracture incidence; along with age, BMI >18, IV drug use, hepatitis C, history of fracture, osteonecrosis, of AIDS, recent non-AIDS cancer or recent cardiovascular disease are factors indepedently associated with fractures.
Finally, Robert Grant closed this session with his Late Breaker abstract concerning recovery of bone mineral density after stopping oral HIV pre-exposure prophylaxis of the iPrEx trial. The DXA substudy of bone mineral density (BMD) was conducted at 7 study sites, according to the following design:
Participants of the iPrEx trial recovered spine and hip BMD after PrEP use stopped, with a complete recovery among younger adults (<25 years) within 6 months after stopping PrEP, compared to older adults who recovered completely but in a longer periode of time.
The beautiful mind's session (session S-2 Symposium) begun with Magnus Glisslen's presentation concerning CSF and blood biomarkers of CNS HIV infection. The new neurologic nosologic entities of treated HIV-infected persons mainly concern mild neurocognitive impairment (30-60%), and not HAD (HIV-Associated Dementia) which is extremely rare in subjects on stable treatment. The usual CSF biomarkers are: CSF HIV-RNA (with symptomatic CSF escapes or asymptomatic ones called blips and due to immune activation), CSF neopterin (stable elevated levels under ART, correlated to low-level CSF viral load and associated with BBB dysfunction), CSF t-tau (marker of neuronal injury), and NFL. There are similarities and differences in neuropathology between HIV and Alzheimer's disease, with some common biomarkers (t-tau, p-tau, AB42). This is why NFL could be used in order to differentiate HAD from other pathologies, especially if there is axonal disruption due to aging. Moreover, blood NFL seems to be closely correlated to CSF NFL and can therefore be a peripheral marker of neuronal injury.
Beau Ances presented Neuroimaging of HIV in the Brain. Neuroimaging in treated patients may help evaluate the effects of HIV, Inflammation, aging and ART. T1 imaging can appreciate Grey Matter volume and thickness, while DTI (Diffusion, Tensor Imaging) and DBSI (Diffusion Basis Spectrum Imaging) studies white matter structure and connections. Functional Neuroimaging consists in MRS (Magnetic Resonance Spectroscopy) studying brain metabolites, ASL (Arterial Spin Labelling) evaluating the cerebral blood flow, et le resting State fMRI (rs-fc) evaluating the functional connections. According to the mechanism of HIV-related CNS injury (early vs chronic HIV infection, HIV replication, aging, ART neurotoxicity), we can choose adapted structural and functional neuroimaging methods, that can show changes even before subtle changes in neuropsychological performance testing.
Ronald Swanstrom demonstrated that the CNS is considered as an HIV reservoir because of its intrinsic characteristics (virus enters the CNS during an active process, trafficking in the infected CD4+ T cells and rests compartmentalized, can expand as clonal amplification or persist and evolve, is dependent on CD4+ T cell abundance), its localization (HIV persists in perivascular macrophages and microglia within the brain parenchyma), and consequences of its presence (traffic of immune cells into the CNS if inflammatory immune response --> pleocytosis).
Andrea Calcagno closed this mind's session with therapeutics of the CNS with HIV infection. Indeed, the beneficial effect of ART in the CNS is aready proven, but there is a balance of pros and cons among potential neurotoxicity of ART, neurocognitive sides effects, neuro-vascular damage, neurotargeted drugs (especially in PHI, CSF escape). Adjunctive therapies may be necessary adapted to each patient. Andrea finished with Arthur Conan Doyle's citation: "I am a brain, Watson. The rest of me is a mere appendix".
The whole conference assembly joined the ballroom B/C early in the evening (Special Session SS Oral Abstracts) , in order to learn from people who were there, people who lived the 2013-16 Ebola outbreak. Eugene Richardson, presented the unreported cases of asymptomatic infections in a village in Kono District that was one of four major district hotspots. He found that 25% of all infections were asymptomatic, that raise the crucial question of transmission of the Ebola virus from asymptomatic donors.
Jean-François Etard described the observed sequelae of Ebola virus disease in the 1268 surviving patients in Guinea. Survivors had a global clinical, biological, genetic, psychosocial, and socio-anthropological evaluation, according to a follow-up schedule over 24 months. Thus, this study identified a high frequency of clinical symptoms several months after discharge, with a long-term RNA positivity in semen, but the current number of positive semen is likely to be low.
The PREVAIL (Partnership for Research on Ebola Virus in Liberia) III study is a cohort study of survivors of Ebola Virus Infection in Liberia, initiated in June 2015. The objective was to follow the 1500 survivors and the 6000 close contacts, in order to detect long-term clinical sequelae. Overall, the burden of illness is high in both survivors and close contacts, with a bigger prevalence of ocular, musculoskeletal and neurologic complications in survivors. Detectable viral RNA in semen persists even one year after acute disease. This study is still ongoing, with multiple specialty substudies and a planned 5-year follow-up.
Finally, the PREVAIL I study proved the immunogenicity, as well as the good tolerance of 2 vaccine candidates of a phase 2 vaccine trial (VSVΔG-ZEBOV and ChAd3-EBO-Z vaccines), and the PREVAIL II study described the use of ZMappTM, a therapeutic agent against Ebola virus. This last study has been closed prior to reaching the desired sample size per arm, because of the extinction of the outbreak.
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Key words: 2016 CROI, 2016 CROI summary, CROI, Christina Psomas, Ebola, HIV, HIV cure, HIV persistence, HIV reservoirs, ISHEID