Body & Soul Research update, 25 October 2016
Updates from BHIVA conference on... Cure breakthrough or not? Long acting retrovirals what do they offer? When to start treatment asap post diagnosis?
Media reports of HIV cure breakthrough? Sunday Times 2 October: brink of an HIV cure HIV undetectable in blood of first man to have completed trial One of 50 (only 39 recruited to date) BUT don t hold your breath...
What do we mean by an HIV cure? Sterilising Cure INFECTIOUS DISEASE MODEL the Berlin patient Aviraemia; no transmission; no replication competent virus; no detectable HIVinfected cells Functional Cure ie remission CANCER MODEL No disease progression No CD4 cell loss No transmission But...no agreed duration
What is latent HIV? HIV infects CD4+ cells some become resting memory cells or reservoirs Major reservoirs: Dormant memory Tcells in lymph nodes and blood Macrophages and dendritic cells (other types of immune system cells) in lymph nodes, the gut and central nervous system
If size matters...the hypothesis towards remission The longer people live with untreated HIV the larger the pool of latently infected cells If ART is started immediately around the time of diagnosis will it be possible to push the reservoir below a threshold, enabling viral control off therapy (treatment)?
Where we are now We don t understand the pathological consequences (potential harm) We are starting to understand the role of ART (but without control groups can not be sure) There is an interplay between host immunity and random reactivation We are starting to develop predictors, but need more to understand the mechanism Important Virological remission is real We must put all of this in the setting of excellent ART and outcomes to balance risk vs benefits
What happens if people treated early stop therapy? What happens if people treated early in PHI stop therapy? VISCONTI study identified 14 individuals treated in Acute infection for average 3.5 years who stopped ART and controlled viraemia for years after stopping They did not share the same protective HLA alleles Virus could be grown in vitro from blood samples Did they control because their level of viral reservoir was below a certain threshold?
RIVER TRIAL is in early stages Research in Viral Eradication of HIV Reservoirs (RIVER) CHERUB collaboration: five universities, NIHR funding People infected within last six months Fewer HIV infected cells in the body Theory: easier to completely remove HIV & stop ARVs
How does it work? Kick and kill strategy using 4 drug combination ARV Raltegravir used because fast acting 22 weeks standard ARVs, then 4 drug ARV alone OR + Vaccination to improve immune responses + Vorinostat Vorinostat activates cells infected with HIV (10 rounds in 28 days) HIV cells can be spotted by immune system/arv treatment
When will we know if it works? Tests will continue for next five years NOT yet recommending stopping ARTs RIVER first study results 2018: are all traces of HIV DNA gone? BUT real test will be stopping ARTs Berlin patient bone marrow transplant only cure so far recognised Wait and see
RIVER research to sum up what we know We don t understand pathological (potentially harmful) consequences We are beginning to understand the role of ART but we ethically can not have comparison control groups Virological remission is real so we are keen to explore.. BUT It is important to put this into the context of excellent ART when considering risk vs benefits
Long acting treatment with retrovirals Research from Professor Saye Khoo University of Liverpool
Long acting retrovirals Why long-acting? Potency, delivery, pharmacology Long-acting Antiretrovirals for Treatment rilpivirine cabotegravir other agents PreP Real-life challenges
Why long acting? Improve adherence, convenience (work, travel, etc) Fragile populations Psychological benefit, pill fatigue etc Improves bioavailability PK smoothing, reduced variability Eliminates food effects and gut-based DDIs, improve GI tolerability Public health benefits community VLs, transmissions
Long acting Antiretrovirals Monthly injections v daily dosage How to control the daily drug delivery? Who is this suitable for? What drugs have been trialed? What other issues are there?
Real-life challenges Injection issues: needle fatigue consistency of injections - children, low BMI, gender-based differences Pharmaceutical: formulations? variability BMI, gender, pharmacogenetic, scalability, affordability implementation and health system capacity
Real life challenges - contd Patient problems: lead-in, lead-out, bridging scenarios/missed dosing/managing DDIs New Clinical Events: eg pregnancy, contraception, - epilepsy, TB, liver/renal failure, cardiac event, cancer, surgery etc PreP: is there a prevention target? stopping PreP?
Long-Acting Antiretrovirals - Summary Potential for treatment and prevention Generally high acceptance in research But who for? adherence, co-morbidities? Real-life challenges? more data on women needed DDIs cannot necessarily be imputed from oral dosing studies
Testing and treatment of HIV within 24 hours Is it viable? Dr Nneka Nwokolo 56 Dean Street, Chelsea and Westminster Hospital
2015 statistics show massive progress in UK 88,000 people in the UK accessed treatment 84,800 are on treatment 79,800 are virally suppressed
How has this happened? Newer ARVs from existing classes with better tolerability Newer ARV classes Better evidence base (START,TasP and Cure studies) Better accessibility (generics) Life expectancy approaching normal
Standards today are New HIV diagnosis timeline is as follows: Baseline tests, then appointment within 2 weeks: VL, CD4, resistance test, Human Leukocyte Antigen (HLA); hepatitis screens, haematology and biochemistry; vaccination status; STI screening Adjustment period Start treatment according to baseline bloods and guidelines
Are patients ready to start? Should they? I m ready to start today or Is it safe? I don t want to be infectious or What about resistance? I want modern once a day treatment I want to preserve my immune system Will this lead to cure? Are patients being pressurised?
What research is there about treatment on diagnosis immediate starting of ARVs? Haiti study Real world San Francisco RAPID programme Real world 56 Dean Street experience
Dean Street experience All patients seen in medical appointment within 2 weeks All patients offered ART at 1st appointment 26 (23%) did not start at 1st visit - 18 declined immediate treatment - (6 lost to follow-up; no info on 2) Data on 87 (77%)
Positive results at Dean Street High acceptability of immediate testing Fast viral load suppression 85% VL <200 at 16 weeks 99% VL <200 at 24 weeks (1 individual with High retention at 24 weeks Success!
Challenges to same day ART initiation Service capacity Acceptability to clinicians Acceptability to patients Infrastructure pharmacy capacity, health adviser support
Summary International guidelines recommend treatment for all individuals with HIV Early treatment particularly valuable in limiting reservoir in acute infection and preventing transmission In some settings early treatment associated with significant improvements in linkage to care
Conclusions from Dean Street research Starting ART at diagnosis is challenging but feasible Acceptable to patients Parallel rather than serial interventions Retention in care in UK is excellent, early treatment may reinforce this
Still to be considered final thoughts Much more research needed into test and treat within 24 hours Age profile? Women? Heterosexual? Dean Street is MSM, urban user group Ethics? What do you think?