1. UZ-UCSF ANNUAL RESEARCH DAY
A5354/Early ART to Limit Infection and Establishment of Reservoir [EARLIER]
UZ-UCSF ANNUAL RESEARCH DAY
05 MAY 2017
W. Samaneka
MBChB, MSc
For ACTG Team

2. Background
Current evidence suggests that ART instituted early during acute HIV infection (AHI) is key to containing HIV reservoir establishment --its critical role in achieving HIV remission (Ananworanich et al 2015)
ART initiation at different stages of AHI could predict magnitude and characteristics of HIV-reservoirs, quality and quantity of HIV specific immune responses.
This knowledge will inform future immune -based strategies to eliminate latently infected cells.

3. Natural History of Untreated HIV Infection
Stages: Viral transmission 2-3 weeks; Acute retroviral syndrome 2-3 weeks; recovery and seroconversion 2-4 weeks; Asymptomatic chronic HIV infn Av 8 year
Precipitous decline in CD4, high concetration of HIV RNA.
Initial “burst” during acute infection and decline to a “set point” as a result of seroconversion and development of immune response.
An, Ping et al. Trends in Genetics , Volume 26 , Issue 3 ,

4. Clinical Symptoms of AHI
The majority of people infected by HIV develop a flu-like illness within a month or two after the virus enters the body. This illness, known as a primary or acute HIV infection, may last for a few weeks. Possible signs and symptoms include:
Fever
Headache
Muscle aches
Rash
Chills
Sore throat
Mouth or genital ulcers
Swollen lymph glands, mainly on the neck
Joint pain
Night sweats
Diarrhea
Häggström M. Wikiversity Journal of Medicine 1 (2)

5. Usual Course of Treated HIV Infection
Viral Setpoint
Start
ART
Stop
ART

6. Potential Course with Interventions
Stop
ART
Stop
ART

7. Stages of Acute HIV Infection (Fiebig Staging)
RNA
P24 Antigen 4
Possible presence
of P24 Antigen 3 2  Y
Specific EIA
Present on
Western Blot 1 
Plasma Viral RNA (copies/mL) Y Y
This is another representation of the Fiebig stages. This system has helped us better understand the effect of early treatment at different stages. But we should also keep in mind that there is variability between people.
This time, we show the tests that are able to detect the infection.
Stage 1: Only HIV RNA (around 10 days after infection)
Stage 2: HIV RNA and p24 antigen (around 15 days after infection)
Stage 3: HIV RNA, p24 antigen and specific enzyme immuno-assay (EIA) (around 21 days after infection)
Stage 4: The HIV infection starts to appear on the Western Blot (around 25 days after infection)
Days following HIV Transmission
Adapted from CUREiculum

8. Establishing the Latent Reservoir
Naïve CD4+ T cell
HIV
Latent Reservoir
Activated CD4+ T cell
Once HIV enters an immune cell (blue cell) it integrates into the cell’s DNA, the cell’s control center for reproducing itself. It hijacks the replication process, getting the cell to make more virus particles instead of more cells. Most cells realize that they are infected (yellow cell) so will die or send out a chemical signal to be killed. But sometimes, these cells turn into resting memory cells.
Long lived memory cells, (which are CD4 T cells) help the body fight off foreign invaders they have already seen. Long lived memory cells act like police patrolling with a most wanted list
Cell
Death
Cell
Survival
Resting Memory
CD4+ T cell
Adapted from D. Persaud and CUREiculum

9. HIV Reservoirs Stevenson. Scientific American 299, 78 - 83 (2008)
When the immune cell is on patrol but has not recognized a familiar pathogen, it is “resting” or “not activated” or reproducing itself; the cells aren’t sending out any signals for destruction. During this time HIV appears not to be doing anything either. The rest of the immune system can’t see it because it is hiding inside the body’s own cell. ARV’s can’t find it either, for the same reason. Not only are these cells hard to find because they aren’t sending out signals. They are also hard to find because there are very few of these reservoir cells in the body
Stevenson. Scientific American 299, (2008)

10. Why is Early ART Important?
One of the most effective ways to contain the HIV reservoir, preserve immunity and reduce immune activation
May optimize responses to immune-based interventions aimed at achieving HIV remission
Is essential to prevent sexual transmission of HIV during acute infection
May be a critical step in clinical research towards HIV cure
Adapted from CUREiculum

11. A5354:Early ART to Limit Infection and Establishment of Reservoir (EARLIER)
Will enroll 150 participants identified during acute HIV infection at ACTG sites.
Fiebig stage-classification to characterize the progression from HIV-1 exposure to seroconversion at time of ART initiation.
50 Fiebig I/II
50 Fiebig III/IV
50 Fiebig V

12. A5354/EARLIER Participants will be offered immediate ART (within 48hr)
Single tablet regimen (EVG/COB/FTC/TAF)
Will evaluate reservoir size after 1 year of ART across a variety of body compartments.

13. Objectives
To assess how starting ART as soon as the infection is found affects the amount of HIV-1 in blood and how well the body fights the HIV-1 infection.
To measure the amount of HIV-1 DNA (genetic material for HIV-1) seen in CD4+ T-cells (infection-fighting cells in blood) after 48 weeks of ART
To assess how early treatment for HIV affects the numbers of HIV-1 infection fighting cells (CD4+ and CD8+ T-cells) in blood

14. Eligibility Criteria 18 years and above
Appropriate documentation from medical records of diagnosis of acute HIV-1 infection (AHI) within 7 days prior to enrollment.[Referrals from prevention trials]
Ability and willingness to initiate ART at enrollment.

15. Important Exclusion Criteria
Positive HIV-1 antibody test ≥90 days prior to study entry.(outreach.. CAB)
AHI diagnosis within 60 days after receiving any investigational ARV or HIV-1 vaccine or immune prophylaxis for HIV-1 infection
Initiation of ARVs for PREP and PEP within 60 days prior to diagnosis of AHI

16. Study Status Enrolling (Jan 27, 2017) 27/150 enrolled
Pari CRS target enrolment 15 participants.

17. Site readiness JREC, MRCZ and MCAZ approvals Awaiting RCZ approval
Webinar training done
Target activation date May 2017

18. Acknowledgements NIAID Gilead Sciences UZ-UCSF leadership
Prof JG Hakim
CAB
ACTG Team

19. THANK YOU