Does choice of antiretroviraldrugs matter for inflammation?

Cristina Mussini

Pp prevalence was higher in cases than controls in all age strata (all p-values <0.001)

Pp prevalence seen cases aged 41-50 was similar to that observed among controls

aged 51-60 controls (p=0.282)

Poly-patology prevalence in cases and

controls, stratified by age categories

Pp 3.9% 9.0% 20.0% 46.9% Pp 0.5% 1.9% 6.6% 18.7%

Guaraldi G. et al Clin Infect Dis. 2008 ;47:250-7

HIV: chronic inflammatory disease

• Untreated HIV infection• Inflammation and activation is driven by HIV replication.

• Treated HIV infection• low-level HIV replication

• microbial translocation

• viral coinfections (eg, cytomegalovirus or HCV infection)

• comorbidities

• lifestyle factors (tobacco, alcohol use, low physical activity)

Why is chronic inflammation harmful?

HIV-associated risk factors likely amplify the same

inflammatory pathways associated with CVD in the

general population

Deeks et al NEJM 12

Treated HIV disease associated with increased

aortic inflammation (FDG-PET)

Tissue inflammation predicted by sCD163

Subramanian/Grinspoon, JAMA, 2012

HIV- HIV+

Untreated patients with undetectable viral loads (HIV controllers) had a higher carotid intima-media thickness(IMT) than the HIV-seronegative persons. Carotid IMT was comparable in the HIV controllers and untreatedHIV noncontrollers.

PY Hsue 2009

Will early ART normalize immune

function and health?

Lower But Persistently Abnormal Immune

Activation with Very Early ART (RV254)

• Thai study of HIV+ individuals dx very early during acute HIV infection

• Compared to high-risk HIV- controls and ART-suppressed HIV+ who initiated

during chronic HIV infection

Chronic HIV on ART

HIV-uninfected

Utay, CROI 2015, #47

: 12 days

: 16 days

: 18 days

Estimated Duration

of HIV Infection

10

8

6

4

2

0

Cum

ula

tive P

erc

ent

With E

vent

0 6 12 18 24 30 36 42 48 54 60

Month

Deferred ART

Immediate ART

1.8% vs 4.1% in deferred vs immediate arms experienced serious AIDS or non-

AIDS related event or death: HR = 0.43 (95% CI: 0.30 to 0.62); P < .001

START: No Difference in Cardiovascular Outcomes with Early vs. Delayed ART

START, NEJM, 2015 and Baker, CROI 2016, #41

Cardiovascular

Events(Early vs. Delayed):

HR 0.84 (0.4-1.8)

P=0.65

Small Artery Elasticity

(higher better)

Also no difference in

pulmonary fn. decline

(Base FEV1 96% pred)

(Kunisaki, EACS, 2015)

How can we measure chronicinflammation?

The biomarker most

strongly associated with

mortality risk

was IL-6, despite

HIV suppression in a cohort

of cART-treated men.

CROI 2018

CROI 2018

IL6, D-Dimer or T-cells: which best predict events or explain benefits of early ART?

Abstract 74 CROI 2018

What about antiretroviral drugs

Raltegravir leads to a faster CD4:CD8 ratio normalization

What about new strategies

39978 patients in the ART-CC collaboration followed for 15

years after starting ART

22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

BMC Med. 2018;16:79

The effect was present at 12 months

…maintained at 24 months

Quiros-Roldan et al. BMC Infectious Diseases 2018

Could it be discontinuation of tenofovir?

Quiros-Roldan et al. BMC Infectious Diseases 2018

Maybe it could be different discontinuingabacavir ?

Quiros-Roldan et al. BMC Infectious Diseases 2018

Why does it happen?

A. Chéret Lancet Infect Dis 2015

At month 24, HIV-DNA loads were similar between groups (2·35

[IQR 2·05–2·50] log10 per 106 PBMC in the intensive cART

group vs 2·25 [1·71–2·55] in the standard cART group; p=0·21).

JAC 2010

Fletcher et al., PNAS 2104

Compared with concentrationsin PBMCs, the IC concentration

of TFV-DB, FTC-TP, ATV, DRV and EFV was lower in

the lymphatic tissue (LT) compartment, particularly in the

lymph node.

714 determinations of ARV drug concentrations in plasmaand 592 analyte determinations for IC drug concentrationsin PBMCs and in mononuclear cells (MNCs) from the LN,ileum, and rectum were performed.

PK of INSTIs in Lymphoid Tissue

In lymph nodes, only EVG/COBI achieved a median IQ > 1

Evaluation of INSTI levels in lymph nodes (LN) in HIV+ participants administered DTG (n=11), EVG/COBI (n=17), or RAL (n=6) with NRTIs

Fletcher C, et al. CROI 2018. Boston, MA. Oral 27

44

Lymph Node Inhibitory Quotient (IQ)

DTG, dolutegravir; EVG/COBI, elvitegravir/cobicistat; pbIC90, protein-binding corrected 90% inhibitory concentration; RAL, raltegravir

1.50

0.430.28

5

4

3

2

1

0LN

In

tra

ce

llula

r C

on

ce

ntr

atio

n:

pbIC

90

Ratio

DTG EVG RAL

‡

• LN and gut-associated lymphoid tissue are the principal sites of HIV replication and where the latent pool of virus is maintained

Further studies are needed to determine whether lower concentrations create conditions that allow persistent viral production

Samples analyzed• DTG: 13/17• EVG/COBI: 19/25• RAL: 4/6

Conclusions

Inflammation is one of the main cause of SNAEs.

Concerning inflammatory biomarkers, CD4:CD8 ratio seems to be the easiest to be performed in clinical practice.

There are not definitive data to indicate that one drug is better than the other.

We still lack a lot of data on what is going on in PLWHIV in tissues different than blood, thus new strategies should be adopted with caution.