Treatment failure and PI monotherapy

Bonaventura ClotetIrsicaixa Foundation

HIV Clinical UnitHospital Universitari “Germans Trias i Pujol”

Badalona, Catalonia

• Transparency declaration

• I have served during the past 2 years as a consultant on advisory boards or participated in speakers’ bureaus or conducted clinical trials with BMS, Abbott, Gilead, Janssen, Merck and ViiV

Principles of HIV treatment

Toxicity Tolerability

Maximal, lifelong, and continuous suppression of HIV replicationPrevent resistancePromote immune recoveryPrevent transmission

Regimen adherence considerations

Goal of therapy

Convenience

EfficacyMinimum requirement

Patient Cost1

SOURCE: Antiretroviral Treatment of Adult HIV Infection. 2012 Recommendations of the International Antiviral Society – USA Panel, July 25, 2012

Antiretroviral therapy, 27 years of continuous improvement,30 drugs, 6 classes…

1981 1990 2000 2010

2008

2007

2005

2003

2001

1999

1998

1997

1996

1987

1992

1991

1983

AIDS,

1st

cases Didanosine

Zalcitabine

Zidovudine

Stavudine, Lamivudine, saquinavir, ritonavir, indinavir

Delavirdine

Nevirapine, nelfinavir

Efavirenz, abacavir, amprenavir

Lopinavir/r

Emtricitabine

Tipranavir

Maraviroc, raltegravir, darunavir

Etravirine

Tenofovir

2002

2004

Enfuvirtide, fosamprenavir, atazanavir

Rilpivirine

2012

Trizivir* Atripla* Eviplera*

NRTIs

NNRTIs

PIs

Fusion inhibitor

CCR5 inhibitor

Integrase inhibitor

* STR (single tablet regimen)

1981

HIV

discovery

2013

2014

Elvitegravir

Dolutegravir

Stribild*

1920

s

Modified from F Raffi

TAF, 744-Cabotegravir

Triumeq*

2015

?

TAF (Tenofavir alafenamida) NRTI

Doravirine (MK-1439) NNRTI

DRV/COBI PI

GSK 744 Cabotegravir, Integrasa Inhibidor long acting (LA)

TMC 278 LA

BMS-663068 Entry Inhibidor

CENICRIVIROC (CVC)-CCR5/CCR2 antagonist

GENERICS

2015

2015 2020 2025 2030 2035 2040 2045

Antiretroviral therapy, the future……………..

2030

End of AIDS

Epidemic ?

0%

Modified from J.Montaner

Patent Expiry dates: 2014-2019

In 11 years (2015-2026) many drugs will be available as individual generics, but co-formulated versions will still maintain the patent

2014: ZDV, 3TC, NVP, EFV, RTV, Combivir – already generic

2016: ABC, LPV/r (soft-gel)

2017: TDF, ATV/r, DRV/r

2019: ETR, ABC/3TC (Kivexa)

2024: TDF/FTC (Truvada)

2025: raltegravir

2026: TDF/3TC/EFV (Atripla), TDF/FTC/RPV (Complera), dolutegravir

Ref: Medecins Sans Frontieres 2014: Untangling the web of ARV price reductions

The Highest the BL VL

The longest it takes to

reach VL<50 c/ml

To maintain viral suppression

how much potency and how many

drugs are required?

3 or 2 drugs?

BL VL matters?

78

77

76

STARTMRK RAL (n=281)

CASTLE ATV + RTV (n=440)

ABT 730 LPV/r qd (n=333)

CASTLE LPV/r (n=443)

84

82THRIVE EFV (n=538)

76ABT 730 LPV/r bid (n=331)

86

GS-102 STRIBILD (n=348)

90GS-103 STRIBILD (n=353)

87GS-103 ATV + RTV (n=355)

86

GS-102 ATRIPLA (n=352)

84ARTEMIS DRV + RTV (n=343)

83ECHO RPV (n=346)

76GS-903 EFV (n=299)

82STARTMRK EFV (n=282)

80GS 934 EFV (n=244)

78ARTEMIS LPV/r (n=346)

SPRING-2 DTG (n=242) 89

SINGLE DTG (n=414) 88

SPRING-2 RAL (n=169)

88

82STaR EFV (n=392)

86STaR RPV (n=394)

86THRIVE RPV (n=340)

83ECHO EFV (n=344)

65KLEAN LPV/r (n=444)

66KLEAN FPV/r (n=434)

Pivotal ART studies, VL <50 c/mL, 48 weeks ITT, by NRTIs

81SINGLE EFV (n=419)

QDMRK RAL BID (n=388) 89

EFV ZDV 3TC

006 Study

64%

Dec 1999

Modified from E Ribera

83.6%

In high BL

VL>100K

The 4 rules to have a

successful anti-HIV therapy

• No baseline resistance mutations

• Good adherence >95% (less number of

pills or STR better….but consider cost

and co-packaging alternatives)

• No PK interactions with other drugs

• No significant toxicities

If fulfilled…..100% should achieve and

maintain VL<40

How can we reduce drug burden?

• Reduced dosing of individual drugs

• PI monotherapy

• Class-sparing strategies

• Dual therapy including 3TC

How can we reduce drug burden?

• Reduced dosing of individual drugs

• PI monotherapy

• Class-sparing strategies

• Dual therapy including 3TC

Boosted PI monotherapy

Gathe JC, et al. WAC 2004; MoOrB1057; Gathe JC, et al. IAS 2007; WEPEB034; Cameron DW, et al. J Infect Dis 2008;198:234–40; Arribas JR, et al. J Acquir Immune Defic Syndr 2005;40:280–7; Pulido F, et al. AIDS 2008;22:F1–9; MacArthur RD, et al. IAC 2006;TUAB0102; EACS 2009 PS4/5; Wilkin TJ, et al. J Infect Dis 2009;199:866–71; Vernazza P, et al. AIDS 2007;21:1309–15; Karlström O, et al. J Acquir Immune Defic Syndr 2007;44:417–22; EACS 2009; PS4/6; IAS 2009; Bierman WF, et al. AIDS 2009;23:279–91

Boosted PI monotherapy

Scenario Trial PI

NaïveIMANI I, II

MONARK

LPV/rInduction - maintenance MO-613

Simplification

OK pilot

OK04

KALMO

IMANI III

ACTG-5201

ATARITMO

Karlstrom et al

OREY

ATV/RTV

MONOI

MONETDRV/RTV

Monotherapy: later looks better...

1. Delfraissy JF, et al. AIDS 2008;22:385–93; 2. Cameron DW, et al. J Infect Dis 2008;198:234–40;

3. Arribas J, et al. J Acquir Immune Defic Syndr 2005;40:280–7

Discontinued

On study, HIV-1 RNA >400

On study, HIV-1 RNA 50–400

On study, HIV-1 RNA <50

.

MONARK1

Initial therapy

M03-6132

Induction/Maintenance

0

20

40

60

80

100

0 16 32

Wk

48 0 16 32 48 64 80 96

Wk Wk

36 4812

OK043

Simplification

0 24

Pa

tie

nts

(%

)

DRV/RTV Monotherapy:

Noninferior or not noninferior?

87.5 92.0ITT Analysis

94.199

MONOI 48 Wks[2]

92.1 90.7

Switch (Intensification With NRTIs) Allowed

DRV/RTV Mono

80.6

MONET 96 Wks[1]

DRV/RTV Mono

DRV/RTV + 2 NRTIs

Lower

limit of

90% CI:

-9.1

TLOVR, S = F

74.8 = -5.8% (-16.0% to +4.4%)

129127

DRV/RTV + 2 NRTIs

= +1.4%

(-5.5% to +8.3%)

129127

PP Analysis (Switches allowed)

Lower

limit of

90% CI:

-11.2

DRV/RTV Mono

DRV/RTV + 2 NRTIs

DRV/RTV Mono

DRV/RTV + 2 NRTIs

1. Rieger A, et al. AIDS 2010. Abstract THLBB209. 2. Katlama C, et al. AIDS. 2010;24:2365-2374.

Mono not noninferior

Mono noninferior

Mono noninferior

Mono not

noninferior

113112

102 102

100

80

60

40

20

0

100

80

60

40

20

0

100

80

60

40

20

0

100

80

60

40

20

0

Pa

tie

nts

Me

etin

g

Prim

ary

En

dp

oin

t /%

)P

atie

nts

Me

etin

g

Prim

ary

En

dp

oin

t /%

)

DRV/r BID and

with NRTIs

Introduction

Results show

non-inferiority

Non inferiority

Non demonstrated

PLoS One. 2012;7(5):e37442

92 patients followed for a median of 73wks.

Treatment failure at 48 wks:-Per protocol 9.8%

RESULTS

VF: 9 (9.8%) patients; 4 (44.4%) reported poor adherence. All were re-

suppressed

OT: 77 (83.7%) patients

Full dataset analysis: 77 (81.1%) patients

Blips: 17 (18.5%), no VF.

No factors associated with VF PLoS One. 2012;7(5):e37442

• DRV/r monotherapy appears to be safe and effective in

patients with sustained viral suppression in routine clinical

practice.

• Monotherapy with DRV/r is associated with a low rate of

VF. In addition, as in clinical trials, viral resuppression is

achieved in almost all patient experiencing VF, mainly by

reintroducing NRTIs or other antiretroviral regimens.

•In clinical practice, VF to DRV/r monotherapy is not

associated to DRV-resistance development

• With the possible exception of patients previously

receiving LPV/r, DRV/r monotherapy does not seem to

confer a clear benefit in the management of dyslipidemia.

CONCLUSIONS

PLoS One (2013); 8(7): e70201

STUDY MONOKAL

Methods:

•Single centre cross-sectional, exploratory, case-control study.

•pVL <50 copies/mL.

•Primary endpoint: The proportion of patients with complete virological

suppression (HIV RNA <1 copy/mL) in CSF.

•Secondary endpoints:

-The proportion of patients with neurocognitive impairment (NCI),

defined by performing at least 1 SD below the standardized mean in at

least 2 neurocognitive areas.

-Differences on neurocognitive status in terms of GDS, which is a

validated method to study compositely impairment on neurocognitive

functioning.

Objective: to compare the presence of HIV replication in CSF and the

neurocognitive performance in patients who had been receiving LPV/r-

based standard HAART (LPV/r-HAART) or LPV/r-MT for at least 96 weeks.

PLoS One (2013); 8(7): e70201

Of 162 potential candidates, 37 patients agreed to participate

RESULTS

PLoS One (2013); 8(7): e70201

Patients with complete CSF-virological suppression

(RNA HIV <1 copy/mL)

LPV/r-MT group LPV/r-HAART group0

20

40

60

80

100 p= 0.601

14 (82.4%)

16 (94.1%)

% o

f pat

ient

s

• The proportion of patients with HIV-1 RNA <1 copy/mL in CSF in the LPV/r-MT group was similar to

LPV/r-HAART group.

• 3 patients on LPV/r-MT had determinations of CSF HIV-1 RNA of 1, 75 and 120 copies/mL.

• 1 patient on LPV/r + ABC/3TC ( LPV/r-HAART group) had a CSF HIV RNA of 2 copies/mL.

PLoS One (2013); 8(7): e70201

THERAPEUTIC DRUG MONITORING

0 10 20 30 400.1

1

10

100

1000

10000

100000Plasma

CSF

TPD

LP

V c

on

cen

trati

on

(n

g/m

L)

Measured CSF concentrations exceeded the 50% IC50 for WT HIV-

1 (0.69 mg/ml) by a median 32.2-fold (IQR: 16.4-45.4)

PLoS One (2013); 8(7): e70201

PERCENTAGES OF SUBJECTS WITH NCI

•In the LPV/r-MT group: 7 (41%) patients with NCI while in LPV/r-HAART group: 10 (59%)

patients with NCI (p=0.48).

•When patients with possible confounding comorbidities were excluded, the results were

similar (p=0.43).

•Considering neurocognitive functioning, values were mildly better in MT group. In total

sample, GDS was 0.23 in MT group and 0.46 in HAART group (p=0.025), and in non-

comorbities sample 0.25 and 0.5 (p=0.04), respectively.

Whole sample Non-comorbidities sample0

20

40

60

80

100 LPV/r-MT

LPV/r-ART

7 (41%)

10 (59%)

6 (46%)

8 (61%)

p=0.48 p=0.43

Pat

ients

with N

CI,

%

PLoS One (2013); 8(7): e70201

CONCLUSIONS

• The proportion of patients with complete viral suppression

(HIV-1 RNA <1 copy/mL) was similar between LPV/r-MT

and LPV/r-HAART.

• Although the difference was not statistically significant,

there were fewer patients with NCI in the LPV/r-MT group.

• Neurocognitive functioning proved to be slightly better in

patients on LPV/r-MT compared to LPV/r-HAART.

• This study suggests that in patients receiving LPV/r-MT

for a long time, CSF HIV replication is completely

suppressed in most of them. Additionally, the use of

LPV/r-MT does not appear to be associated with worse

neurocognitive functioning. PLoS One (2013); 8(7): e70201

RESULTS

Outcomes of patients according to cumulative survival analysis

Similar percentage of patients on LPV/r and DRV/r who were free of VF at 48 and 96 weeks

(HR=1.0, 95% CI 0.6–1.8; P=0.962).

Occurrence of blips, CD4+ nadir <100 cells/mm3, prior failure with PIs or a duration of

virological suppression <24 weeks were not associated to VFJ Antimicrob Chemother (2014) (In press)

RESULTS

Outcomes of patients according to cumulative survival analysis

•LPV/r free of TF at 48 and 96 weeks: 76% (95% CI 71%–81%) and 59% (95% CI 53%–65%),

respectively.

•DRV/r free of TF at 48 and 96 weeks: 86% (95% CI 76%–88%) and 68% (95% CI 59%–75%),

respectively.

•Patients on LPV/r had a 1.5-fold greater risk (95% CI 1.1–2.1; P=0.012) of TF.

•TF was not associated with any of the other factors J Antimicrob Chemother (2014) (In press)

Safety

• AEs were registered as the main reason for the discontinuation (23.6% of patients on LPV/r and 7.5% of patients on DRV/r).

• The most frequent AE leading to treatment discontinuation were GI disturbances (43.8%) and dyslipidaemia (38.2%)

• The AEs were usually mild and none was Grade 3–4.

• Patients on LPV/r were at significantly greater risk than those on DRV/r of experiencing AE leading to a discontinuation of treatment (HR=2.3, 95% CI 1.3–3.9; P=0.003).

• No cases of HIV-related encephalopathy or other serious CNS AEs

RESULTS

J Antimicrob Chemother (2014) (In press)

CONCLUSIONS

• Monotherapy with LPV/r or DRV/r seems to be safe and

effective in HIV-1-infected patients with sustained viral

suppression in clinical practice.

• Better tolerability and convenience of administration

suggest that DRV/r might be the preferred option for PI

monotherapy.

• The proper selection of candidates for PI monotherapy is

mandatory in order to minimize the risk of failure

J Antimicrob Chemother (2014) (In press)

New Microbiol 2015 (ACCEPTED 2015)

OBJECTIVE

• To evaluate changes in BMD by dual-energy X-ray absorptiometry

(DXA) in HIV-infected patients after 1, 2, or 3 years since the switch

from triple ART to PI monotherapy (LPV/r or DRV/r).

New Microbiol 2015 (in revision)

METHODS

• A single-centre longitudinal study including 46 HIV-infected patients.

• Inclusion criteria:

– Treatment with PI monotherapy (LPV/r BID or DRV/r QD) for at

least 1 year

– Triple ART at the moment of the switch to the PI monotherapy

– DXA scan close to the date of the switch to the PI monotherapy

(from 4 months before to 2 months after starting the

monotherapy).

• Exclusion criteria:

– Concomitant treatment for osteoporosis/osteopenia

(bisphosphonates), or secondary causes of low bone

mineralization (testosterone deficit, thyroid disease) during the

monotherapy

– Any change or interruption of the treatmentNew Microbiol 2015 (in revision)

RESULTS

Median percentage of change from baseline in Bone mineral density in total

femur and lumbar spine.

•In the one-year group, the median percentage of change was 0.20 (IQR, -2.29 to 2.08,

p=0.910) in total femur BMD and -0.08 (IQR, -5.55 to 4.32, p=0.955) in lumbar spine BMD

•There were no significant changes in two- or three-year groups

New Microbiol 2015 (in revision)

CONCLUSIONS

• Treatment with PI monotherapy (both LPV/r and DRV/r)

during 1, 2, or 3 years leads to the stabilization of BMD

in patients with long-term virological suppression.

• Prospective comparative studies are necessary

New Microbiol 2015 (in revision)

Rules for a succesful switch to

PI Monotherpay

• Nadir CD4 > 200/mm3 (ideally > 300/mm3)

• Low proviral DNA at the time of switching

• No baseline resistances to PIs (no primary

resistances)

• No treatment failures to any PI based

approach

How can we reduce drug burden?

• Reduced dosing of individual drugs

• PI monotherapy

• Class-sparing strategies

• Dual therapy including 3TC

Study PI/r + 3TC armPI component

Comparator arm

First line GARDEL LPV/r LPV/r + 3TC + NRTI

Switch OLE LPV/r LPV/r + 3TC/FTC + NRTI

SALT ATV/RTV ATV/RTV + 2 NRTI

ATLAS DRV/RTV or LPV/r

DRV/RTV or LPV/r

MOBIDIP DRV/RTV or LPV/r

DRV/RTV or LPV/r

PI/r + LAMIVUDINE (3TC)

GARDEL: Study design

Phase III, randomized, international , controlled, open-label study

• Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US.

DT:LPV/r 400/100mg BID+ 3TC 150 mg BID(n=217)

TT:LPV/r 400/100mg BID+ 3TC or FTC and a third investigator-selected NRTI in fixed-dose combination(n=209)

ARV- naive patients,

18 years

HIV-1 RNA >1000 copies/ml

No IAS-USA defined NRTI or PI resistance at screening*

HB(s)Ag negative

(N = 426)

Stratified by screening HIV-1 RNA (≤ or > 100,000 copies/mL)

Wk 48 primary endpoint

*Defined as > 1 major or > 2 minor LPV/r mutations) LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S

Wk 24 interim analysis

Cahn, Lancet Inf. Dis, 2014

Viral load <50 copies/mL at week 48 (ITTe)

(p= 0.171, difference +4.6% [CI95%:-2.2% to +11.8%])

Viral load <50 copies/mL at week 48 (ITTe), baseline VL

> 100.000 copies/mL

(p= 0.145, difference +9.3% [CI95%:-2.8% to +21.5%])

CD4 increase from BL to W48

310330350370390410430450470490510530550570

BSL W4 W12 W24 W36 W48

DT TT

+ 227 cells/mm3

+ 217 cells/mm3

p=0.625

DT(n=214)

TT(n=202)

P[IC95%]

HIV – RNA < 50 copies/mL (n; %)

189 (88.3%) 169 (83.7%) 0.171[-2.2% ; +11.8%]

HIV – RNA >50 copies/mL (n; %)

10 (4.7%) 12 (5.9%)0.720

[-6.1%; +3.5%]

No Virologic data at week 48 windowReasons:Discontinued studydue to adverse eventor death

2 (0.9 %)* 10 (4.9 %)**0.03

[-7.8%; -3.0%]

Discontinued studyfor other reasons***

13 (6.1%) 11 (5.4%)0.948

[-4.3; +5.6]

Virologic Outcome at W48

*** (Non compliance with study procedures, consent withdrawal, adherence, opportunistic infection, lost to follow-up, pregnancy)

* 1 death: Sepsis, 1 nephrotic syndrome ** 2 Rash, 3 anemia, 5 GI intolerance

Protocol-Defined Virologic Failure and Emergent Resistance Mutations

Number of patients, n (%)DT

(N=214)TT

(N=202)

Confirmed virological failures 10 (4.6 %) 12 (5.9 %)*

HIV-1 RNA at failure (copies/ml)(median-IQR)

236(183-17,687)

1027(123-4,880)

Never suppressed 2 8

Rebounders 8 4

Primary PI RAMs 0 0

NRTI RAMs (M184V) 2 0

*p=0.72

PDVF: 2 measurements of HIV-1 RNA at least 1 week apart>400 copies/mL at week 24 > 50 copies/mL at week 48

Emergent resistance mutations, in samples successfully amplified:DT: 2 out of 5 both M184V TT: 0 out of 8

Rolon et al: IAC 2014; Abstr WePe 080

• Our results demonstrate that DT with LPV/r+3TC was non-inferior to triple therapy after 48 weeks of treatment, regardless of baseline viral load.

• The DT regimen showed fewer discontinuations due to safety and tolerability .

• Virologic failure, occurring at similarly low levels in both treatment arms, did not result in PI resistance development, preserving a wide range of drugs for 2nd line ARV therapy.

• These results suggest that a dual LPV/r+3TC regimen warrants further clinical research and consideration as a potential therapeutic option for ARV naïve subjects.

GARDEL: conclusions

OLE:Study design

Randomization 1:1

LPV/r BID + 3TC/FTC QD + NRTI (TT)

LPV/r BID + 3TC/FTC QD (DT)

48 weeks

• 48-week multicenter, prospective, randomized, open-label, non-inferiority trial (n:250)

• Eligibility criteria

HIV-infected patients with plasma HIV-1 RNA < 50 copies/ml

for ≥ 6 months on TT with LPV/r + 3TC/FTC + NRTI and

no resistance to LPV/r or 3TC/FTC

• Primary endpoint:

- Proportion of patients free of therapeutic failure at 48 weeks, in the m-ITT

population defined as two consecutive viral load measurements >= 50

copies/ml, death, progression to new AIDS defining disease, loss to follow-

up or change or

Difference (95% CI)-0.6% (-6.9% to + 8.1%)

Primary endpoint

0.8%3.3%3.4% 2.5% 2.5%2.5%

91.5% 90.9%

1.7% 0.8%

Resistance mutationsDT

(n=118)TT

(n=121)

Patients with protocol-defined virologicfailure*

3 3

Patients with virological failure and VL> 500 copies/mL

2 0

Patients with blip 12 12

Patients with any detectable viral load (>50 copies /mL)

15 15

*Protocol defined VF: 2 consecutive VL >50 copies/mL

DT(n=118)

TT(n=121)

Patients analyzed for resistance 1/3 0/3

Patients with data available 1/3 -

Patients with resistance to ARV regimen

1 (103N and 184V) -

How can we reduce drug burden?

• Reduced dosing of individual drugs

• PI monotherapy

• Class-sparing strategies

• Dual therapy including 3TC

Dual therapy under investigation

PI/r + integrase inhibitor

PI/r + CCR5 inhibitor

PI/r + 3TC/FTC

PI/r + NNRTI

Integrase inhibitor + NNRTI

Integrase Inhibitor + 3TC/FTC