CROI 2016 Report Back: Complications and Long term

outcomes of HIV and ART

AETC/Community Consortium Phyllis C. Tien, MD

Professor of Medicine, UCSF Staff Physician, SFVAMC

March 23, 2016

Financial Disclosures

• None to disclose

Narrowing the Gap in Life Expectancy for HIV+ versus HIV- Subjects

Kaiser cohort data from 1996-2011 evaluating life expectancy between HIV+ (n=25,768; 46% on ART at BL) and HIV- (n=257,600) subjects

• Mortality rate of 1,827 vs. 326 per 100,000 person-years, respectively • Abridged life tables were used to estimate years of life remaining at age 20

Marcus J, et al, CROI 2016. Boston, MA. Oral 54

Even with early ART initiation, a life expectancy gap remains between HIV+ and HIV- subjects. Mitigation of risk factors, like smoking, may further reduce the survival disparity.

Expected years of life remaining at age 20 (95% confidence interval)

HIV+ HIV- Difference P value

Overall 49.3 62.3 13.1 (11.5-14.6) <0.001

HIV+ and initiated ART with CD4 ≥500

54.5 62.3 7.9 (5.1-10.6) <0.001

+ No hepatitis B or C 55.4 62.6 7.2 (4.4-10.0) <0.001

+ No drug/alcohol abuse 57.2 63.8 6.6 (3.9-9.3) <0.001

+ No smoking 58.9 64.3 5.4 (2.2-8.7) <0.001

.

Mechanism of Action of Tenofovir Disoproxil Fumarate vs Tenofovir

Alafenamide

Switch to F/TAF associated with increases in eGFR over 48 wks;

minimal changes in F/TDF group

• TAF also associated with less proteinuria (urine protein and albumin creatinine ratio) and fewer protein markers of proximal tubulopathy (urine retinol-binding protein and beta2-microglobulin to creatinine ratio)

• Increases in those who did not switch.

Switch to F/TAF show increases in spine/hip BMD over 48 wks;

stable or decreased in F/TDF group

Recovery of hip BMD, by PrEP use and age

iPrEx / iPrEx Open Label Extension (OLE): BMD Analysis

BMD declined while on F/TDF but recovered completely after stopping F/TDF for PrEP

Grant R et al, CROI 2016. Boston, MA, Oral #48LB

*P<0.05; **P<0.001

DXA substudy of 498 subjects (median age 25; 446 MSM, 52 transgender women)

Recovery of spine BMD, by PrEP use and age

Age <25

Placebo

TFV-DP <16 at Week 24

TFV-DP ≥16 at Week 24 Ch

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Age ≥25

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T i m e S i n ce R a ndo m i z a t i o n

EuroSIDA: Impact of TDF Exposure on Risk of Fractures in HIV-Infected Pts

• Prospective analysis of 11,820 HIV-infected pts

• Followed from baseline (Jan 2004) to last visit or death to assess for fractures, femoral osteonecrosis

Borges AH, et al. CROI 2016. Abstract 46. Reproduced with permission.

TDF Exposure

Any Fracture (n=619)

IRR (95% CI)

Osteoporotic Fx* (n=132)

IRR (95% CI)

Univariate Multivariate† Multivariate†

Ever used vs never

used 1.71‡ (1.42-2.06) 1.40‡ (1.15-1.70) 1.10 (0.76-1.58)

On TDF vs not on TDF 1.38‡ (1.16-1.64) 1.25‡ (1.15-1.70) 1.12 (0.79-1.60)

Cumulative TDF

exposure/5 yrs 1.28‡ (1.13-1.50) 1.08 (0.94-1.25) 0.99 (0.69-1.43)

*Fracture of the spine, arm, wrist, or hip. †Adjusted for demographics, HIV-specific variables, and comorbidities. ‡P < .05; n=

Ofotokun et al CROI 2016 Oral Abstract 47

Single infusion of zoledronic acid prevents ART-induced bone resorption and blunts bone loss

Ofotokun et al CROI 2016 Oral Abstract 47

Ofotokun et al CROI 2016 Oral Abstract 47

Similar findings in the hip

CVD Risk Score Comparison in HIV+ Pts

Crane HM, et al. CROI 2016. Abstract 42.

Crane HM, et al. CROI 2016. Abstract 42.

Chow et al CROI 2016 Abstract #43

HIV viremia had greatest risk of stroke; trend toward women and blacks with increased risk

in ALLRT cohort

CROI 2016 Report Back: Hepatitis

AETC/Community Consortium Phyllis C. Tien, MD

Professor of Medicine, UCSF Staff Physician, SFVAMC

March 23, 2016

Current HCV DAA drugs

• GAPS in KNOWLEDGE – Use of DAAs in Acute HCV – NS5A RAVs and DAA treatment failures – Use of SOF/velpatasvir (investigational pangenotypic NS5A

DAA) in HIV/HCV – Impact of HCV cure; implications of persistent liver fibrosis

NS3

Protease

Inhibitors

NS5A Replication

Complex

Inhibitors

NS5B

Nucleoside

Inhibitors

NS5B

Nonnucleoside

Inhibitors

Other

FDA Approved DAA Agents (2011 – 2016)

Boceprevir Peginterferon

Telaprevir Ribavirin

Simeprevir Ledipasvir Sofosbuvir

Paritaprevir/r Ombitasvir Dasabuvir

Daclatasvir

Grazoprevir Elbasvir FDA approval dates: BOC=5/13/2011; TPV=5/23/2011; SIM=11/22/2013; LDV/SOF=10/9/2014; 3D=12/14/2014; DAC=7/24/2015; EBV/GPR=1/28/2016

Ledipasvir/Sofosbuvir for 6 wks in HIV with acute GT 1 and 4 HCV infection

Rockstroh JK et al CROI 2016 Boston MA Oral Abstract 154LB

-None with new NS5A RAVs at relapse -Higher baseline HCV RNA appears associated with relapse -For 3 with relapse, at tail end of acute HCV definition

Acute HCV definition defined as either: 1) HCV RNA+ & neg HCV ab/HCV RNA within last 6 months or 2) Incr ALT/AST >2.5 x ULN in past 6 mos with nl LFTs in past year.

Retreatment with LDV/SOF12 effective including in pts w/high level NS5A RAVs

Wilson E et al CROI 2016 Abstract #580

• Intent of SYNERGY study was to see if addition of DAA to LDV/SOF would allow shorter durations (6 or 4 weeks) of therapy.

• High level NS5A RAVs predict poor response to short course of 4 week therapy

• Retreatment with 12 weeks LDV/SOF effective in 90%

CAUTION: Mostly all Stage 0-2

Drug Interactions between Sofosbuvir/velpatasvir & boosted HIV regimens

Mogalian et al CROI 2016 Abstract #100

Effect of SOF/VEL on HIV ARVs: TFV AUC ~90% lower when administered as TAF; ~20 – 30% higher when administered as TDF

HCV Cure & Extrahepatic Comorbidities in HIV

Berenguer J et al CROI 2016 Boston, MA Abstract #611

Decreased cumulative incidence of renal events and DM in those with SVR

Significant liver fibrosis (defined by APRI >0.5) associated with worse neuropsychological testing performance

independent of HIV and HCV

Valcour V et al CROI 2016 Abstract #422

Statin dose & type and liver outcomes: Electronically retrieved cohort of HCV+ veterans (ERCHIVES)

• Atorva & Fluva associated with greater anti-fibrotic effect that other statin types

• Dose-dependent reduction in fibrosis progression & incident HCC

• Is this effect specific to HCV fibrosis?

Simon TG et al CROI 2016 Abstract #551

Atorvastatin therapy reduces liver fat measured by CT in patients with HIV

• Liver fat or steatosis is highly prevalent in HIV; obesity is major risk factor and possibly immune activation

• 12 month, randomized double-blind placebo controlled trial (n=37) • Change in BMI and visceral adipose tissue did not differ between the Atorva and

placebo group. • Change in LDL associated with change in liver fat (CAUTION: small sample size)

Lo et al CROI 2016 Abstract #553

For more info: Croiwebcasts.org • Monday, 2/22/16 Interactive Case-based

Workshop on HCV Treatment

• Tuesday, 2/23/16 Symposium “Global Impact of Hepatitis”

• Tuesday 2/23/16 Themed Discussion “Rants about HCV RAVs”

• Thursday 2/25 Oral Abstract “HCV: Curing the Patient but not the Population”

• Thursday 2/25 Themed Discussion “HIV effects on Liver Fibrosis and Steatosis”

US PrEP Demo Project: Real-World Outcomes

Changes in Renal Function Associated with FTC/TDF for PrEP Use

Open-label US PrEP Demo Project of 557 MSM and transgender women (TGW). Median age 33; baseline median Cr 0.92 / median eGFR 97 mL/min. Objective: evaluate changes in

renal function over 48 weeks

Liu A, et al. CROI 2016. Boston, MA. #867

-6

-4

-2

0

2

Screening 12 24 36 48

Mean change in eGFR over 48 weeks, %

Bars indicate standard error

Mea

n %

Ch

ange

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GFR

fro

m

bas

elin

e(m

l/m

in)

3 patients required interruption of FTC/TDF for PrEP due to elevated Cr; all 3 patients re-started FTC/TDF for PrEP

34 (7%) of patients had >25% eGFR loss from baseline; only 4 (0.8%) confirmed on repeat testing

TFV-DP levels ≥ 4 doses/wk were associated with declines of ~4 mL/min in eGFR, compared with those with lower adherence

New onset eGFR <70mL/min (n=59; 13%) was more common with baseline eGFR <90 mL/min, particularly in older adults; may warrant additional monitoring

FTC/TDF PrEP was associated with modest decline in eGFR and was non-progressive through Week 48. Older patients with baseline eGFR <90 mL/min more commonly experienced eGFR <70 mL/min

-2.8%

Week

Ofotokun et al CROI 2016 Oral Abstract 47

EuroSIDA: Association Between Use of Specific ARVs and Risk of Osteonecrosis

Borges AH, et al. CROI 2016. Abstract 46. Reproduced with permission.

*Race, previouis femoral necrosis at baseline, fracture, nadir CD4+ cell count, age, AIDS and non-AIDS-

defining malignancy, nonmalignant AIDS event.

TDF LPV/

RTV

SQV IDV ddI TDF LPV/

RTV

SQV IDV ddI

Ever Used ARV

0.5

5.0

1.99

1.75

1.97

1.77 1.70

1.42 1.39 1.55

1.39 1.43

.25 .25 .17 .20 .27 .051 .031 .015 .027 .013 P Value:

Adju

ste

d*

IRR

for

Oste

onecro

sis

(95%

CI)

Each ARV included in

separate model and adjusted

for all other variables*

Each ARV mutually adjusted for

use of the other ARVs and

adjusted for all other variables*

Slide credit: clinicaloptions.com