il punto sui regimi “nrti sparing” · what to start comparison of updated 2012-2014 guidelines...

Il punto sui regimi “NRTI sparing”

Andrea Antinori

INMI L. Spallanzani IRCCS, Roma

What to Start

Comparison of Updated 2012-2014 Guidelines Regimen

CNA-SIMIT 20131 DHHS 20132 IAS 20123 EACS 20134 BHIVA 20135 GESIDA 20146 CNS-ANRS 20137

EFV/TDF/FTC Preferred Preferred Recommended Recommended Preferred Preferred Preferred

EFV + ABC/3TC Preferred* Alternative Recommended* Recommended* Alternative* Alternative* Preferred*

NVP + TDF /FTC Alternative Acceptable Alternative Alternative Alternative Alternative Alternative

RPV+TDF/FTC Preferred* Alternative Alternative Recommended* Alternative* Preferred* Preferred*

ATV/r + TDF/FTC Preferred Preferred Recommended Recommended Preferred Preferred Preferred

ATV/r + ABV/3TC Preferred* Alternative Recommended* Recommended* Alternative* Preferred* Preferred*

DRV/r + TDF/FTC Preferred Preferred Recommended Recommended Preferred Preferred Preferred

DRV/r + ABV/3TC Preferred Alternative Alternative Recommended* Alternative* Alternative Alternative

LPV/r + TDF/FTC Alternative Alternative Alternative Alternative Alternative Alternative Alternative

LPV/r + ABV/3TC Alternative Alternative Alternative Alternative Alternative Alternative Alternative

RAL + TDF/FTC Preferred Preferred Recommended Recommended Preferred Preferred Alternative

EVG/COBI/TDF/FTC

Preferred Preferred Alternative Preferred Preferred

DTG+TDF/FTC Preferred Preferred Preferred

DTG+ABV/3TC Preferred Preferred Preferred

* Recommended/preferred only if HIV-RNA <100.000 c/mL

1. Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1, 2013 Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf; 2. DHHS Guidelines 2013 Available at http://aidsinfo.nih.gov/guidelines 3. ARV Treatment of Adult HIV Infection. 2012 Recommendation of the IAS-USA panel. JAMA 2012;308:387-402. 4. EACS Guidelines 2013. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf. 5. BHIVA Guidelines 2012-Updated 2013. HIV Medicine (2014), 15 (Suppl. 1), 1–85 6. GESIDA. Documento de consenso de Gesida/Plan Nacional sobre el SIDA respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana. Actualización enero 2014 7. CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf

http://aidsinfo.nih.gov/guidelines

http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf

3 Active Drugs—Not 2, Not 4—Have Been the Sweet Spot for Initial HIV Treatment

Studies With 2-Drug Strategies DMP-066

ACTG 5142

SPARTAN

ACTG 5162

RADAR

PROGRESS

A4001078

Studies With 4-Drug Strategies ACTG 5095

ACTG 5173

COL40263

None to date offers compelling evidence to move from 3-drug approach.

Sax PE, personal observation, 2014

A5142. Time to virological failure

Riddler SA, et al. N Engl J Med, 2008

Virologic failure was defined as a lack of suppression of plasma HIV-1 RNA by 1 log10 or rebound before week 32 or a lack of suppression to less than 200 copies per milliliter or rebound after week 32. Confirmation of suspected virologic failure was required within 4 weeks.

A5142. Summary of Resistance Mutations at the Time of Virologic Failure

Riddler SA, et al. N Engl J Med, 2008

PROGRESS

Virologic efficacy through week 96

Reynes J, et al. AIDS Res Hum Retroviruses, 2013

PROGRESS

Safety data through week 96

For subjects who had baseline and week 96 total bone mineral density measurements, the mean baseline total bone mineral density was similar between treatment groups (LPV/r +RAL=1.18 g/cm2, LPV/r+TDF/FTC=1.19 g/cm2, p=0.762). The LPV/r + TDF/FTC group had a statistically significant mean percent decrease from baseline to week 96 (–2.48%, p < 0.001). In contrast, the mean percent change from baseline for the LPV/r +RAL group was not statistically significant ( + 0.68%, p = 0.158). The mean percent decrease from baseline in total bone mineral density for the LPV/r + TDF/FTC group was statistically significantly greater compared to the mean percent change of the LPV/r +RAL group ( p < 0.001).

Reynes J, et al. AIDS Res Hum Retroviruses, 2013

IAC July 22, 2010: SPARTAN: THLBB204

8

SPARTAN. Study Design

ATV+RAL 300/400 mg BID (n = 63)

Screening/Enrollment

(2:1)

HIV RNA 5000 c/mLRandomization (N = 94) Stratified: HIV RNA < 100,000 c/mL vs. 100,000 c/mL

ATV+RTV 300/100 mg QD TDF/FTC 300/200 mg QD (n = 31)

Primary endpoint: • Determine the proportion of patients with HIV RNA < 50 c/mL at week 24 Secondary endpoints: • Change from baseline in CD4 cell counts at weeks 24, 48 & 96 • Safety through weeks 24, 48 & 96 • Assess pharmacokinetics of ATV+RAL experimental regimen


Response Rate (HIV RNA < 50 c/mL) through Week 24-CVR (NC = F)

CVR (NC = F) is a modified intent-to-treat analysis of confirmed virologic response where non-completers equal failure. Responders are: • Subjects who achieve and maintain confirmed response (2 consecutive on-treatment HIV RNA < 50 c/mL) through the visit week without intervening virologic rebound or discontinuation • Subjects who achieve resuppression (i.e., confirmed response after virologic rebound) at the visit week.

o

Weeks

o

o

n 0

20

40

60

80

100

B/L 4 8 12 16 20 24

n

n

n n n n n

o

o o

o

o

Pe

rce

nt

Re

spo

nd

ers

(9

5%

CI)

ATV+RAL (N = 63)

ATV+RTV + TDF/FTC (N = 30) o

74.6%

63.3%

IAC July 22, 2010: SPARTAN: THLBB204 10

SPARTAN. Safety through Week 24

Number of Patients n/N (%)

ATV+RAL ATV+RTV +TDF/FTC

AEs leading to DC* 4/63 (6.3) 0

Grade 2-4 treatment-related AEs† 19/63 (30.2) 10/30 (33.3)

Grade 3-4 AEs 16/63 (25.4) 6/30 (20.0)

Grade 3-4 total bilirubin abnormalities 38/63 (60.3) 14/30 (46.7)

Grade 4 total bilirubin abnormalities 13/63 (20.6) 0

PR mean change from BL‡ msec (SE)§ 17.6 (2.10) 4.9 (2.25)

QRS mean change from BL msec (SE)§ 8.9 (1.02) 3.6 (1.97)

*Included arrhythmia-1, jaundice-1, jaundice and ocular icterus-1, Lung cancer-1 †Grade 2-4 treatment-related AE hyperbilirubinemia occurred in 19% (12/63) of subjects on ATV+RAL and 16.7% (5/30) on ATV/RTV+TVD §The worst value in the visit window was used


† 8/11 VF subjects on ATV+RAL had a baseline HIV VL>250,000 † 4/8 VF subjects on ATV/RTV +TDF/FTC had a baseline HIV VL>250,000 * Criteria for resistance testing: (1) Subjects with HIV RNA ≥ 400 copies/mL at or after week 24 (2) Rebound to HIV RNA ≥ 400 at any time during the study (3) Discontinued before achieving viral suppression (HIV RNA <50) after week 8 with last HIV RNA ≥ 400 1 additional subject on ATV+RAL met criteria (2) with a wild type genotype and resuppressed at discontinuation visit **One subject developed phenotypic resistance to RAL (BCO > 1.5) without any genotypic evidence of RAL RAMs at week 24. Note: One additional patient at week 32 was found originally to have a major substitution (N155N/H mixture) to RAL at Week 32 but remained phenotypically sensitive to RAL. Subsequently, the contract reference lab changed the report to read "No RAL mutations detected".

SPARTAN Resistance through Week 24

No known RAL resistance mutation

n = 1**

IN gene could

not be amplified n = 1

ATV+RAL RNA > 400c/mL

n = 6*

ATV Resistance

n = 0

TDF/FTC Resistance

n = 0

ATV/RTV RNA > 400c/mL

n = 1*

ATV

Resistance n = 0

ATV+RAL CVR VF (HIV RNA >50 c/mL) N = 11†

IN Mutations: n = 1 Q148R+N155H+T97A

n = 1 Q148R n = 2 N155H

RAL Genotypic & Phenotypic

resistance n = 4

ATV/RTV+TDF/FTC CVR VF (HIV RNA >50 c/mL)

N = 8†

ACTG A5262: DRV/RTV + RAL Without NRTIs in Treatment-Naive Patients

• Single-arm study (N = 112) – RAL 400 mg BID +

DRV/RTV 800/100 mg QD

• Virologic failure: 16% at Wk 24; 26% at Wk 48

• VF associated with baseline VL > 100,000 c/mL

– HR 3.76 (95% CI: 1.52-9.31; P = .004)

• 5/25 VFs with genotypes had integrase mutations; all had baseline VL > 100,000 c/mL

Taiwo B, et al. CROI 2011. Abstract 551. Taiwo B, et al. AIDS, 2011

Time to VF by Baseline HIV-1 RNA Log rank P = .0002

Pro

bab

ility

of

No

t H

avin

g a

VF

1.0

0.8

0.6

0.4

0.2

0 1 12 24 36 48

Wks

HIV-1 RNA > 100,000 c/mL HIV-1 RNA ≤ 100,000 c/mL

HIV-1 RNA > 100,000 c/mL: n with VF: 0 2 10 4 5 n at risk: 49 48 46 35 31 HIV-1 RNA ≤ 100,000 c/mL: n with VF: 0 1 4 1 1 n at risk: 63 62 59 54 50

NEAT 001/ANRS 143 study design

• Phase III, randomised, open-label, multicenter, parallel-group, non-inferiority, strategic trial

• 78 sites, 15 countries (Austria, Belgium, Denmark, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden)

DRV+r 800+100 mg QD + TDF/FTC FDC QD

DRV+r 800+100 mg QD + RAL 400 mg BID

Minimum

Week 96 Randomisation 1:1 stratified by country and participation in virology/immunology substudy

HIV-1 ART-naïve ≥ 18 years

HIV-1 RNA > 1000 c/ml CD4 ≤ 500/mm3

HBs Ag negative No major IAS-USA resistance mutations

• Composite virological and clinical primary endpoint (6 components)

Raffi F, et al. CROI 2014, Boston (MA). Abst.84LB

• Primary endpoint : Time to failure, as the first occurrence of any of the following components:

Virological

– V1. change of treatment before W32 because of insufficient virologic response

• HIV-1 RNA reduction < 1 log10 c/ml by W18*

• or HIV-1 RNA ≥ 400 c/ml at W24*

– V2. HIV-1 RNA ≥ 50 c/ml at W32*

– V3. HIV-1 RNA ≥ 50 c/ml at any time after W32*

Clinical

– C1 death due to any cause

– C2. any new or recurrent AIDS defining event**

– C3. any new serious non AIDS defining event**

• All patients followed-up until last patient reached W96, events recorded until end of F-U

• Non-inferiority margin: absolute difference of at most 9% for the failure rate of RAL vs. TDF/FTC by W96 (estimated by Kaplan-Meier methods) in the ITT analysis

• Major secondary endpoints: safety, changes in CD4 and HIV RNA, genotypic resistance

NEAT 001/ANRS 143. Endpoints

* confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee


NEAT001/ANRS143. Primary analysis: time from randomisation to primary endpoint

Primary endpoint

* confirmed by a subsequent measurement

Estimated proportion reaching primary endpoint at W96 RAL: 17.4% vs TDF/FTC: 13.7%

Adjusted difference: 3.7% (95% CI: -1.1, 8.6%)

log rank p=0.12

0

0.25

0.50

0.75

1.00

Probability of reaching primary endpoint

402 395 393 361 350 340 331 215 90 12 400 384 375 347 329 317 308 211 90 11

0 8 18 32 48 64 80 96 112 128 144 Time (weeks)

RAL + DRV/r TDF/FTC + DRV/r

N at risk

RAL + DRV/r

TDF/FTC + DRV/r

N 401 404

N with primary endpoint 76 (19%) 61 (15%)

V1. Regimen change for insufficient response

< 1 log10 c/ml HIV RNA reduction W18*

1 0

HIV RNA ≥ 400 c/ml W24* 1 0

V2. HIV RNA ≥ 50 c/ml at W32*

27 28

V3. HIV RNA ≥ 50 c/ml after W32*

32 22

C1. Death 3 1

C2. AIDS event 5 3

C3. SNAIDS event 7 7


Overall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/r

Primary endpoint at W96 by baseline characteristics

n = 805

n = 530

n = 275

n = 123

n = 682

Overall

< 100,000 c/ml

> 100,000 c/ml

< 200/mm3

> 200/mm3

Baseline HIV-1 RNA

Baseline CD4+

17.4 %

7 %

36 %

39.0 %

13.6 %

13.7 %

7 %

27 %

21.3 %

12.2 %


10 0 -10 20 30

9

Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted

* Test for homogeneity

p = 0.09*

p = 0.02*

-1.1 8.6

-3.9 3.5

-0.05 19.3

4.7 30.8

-3.4 6.3


Virological failure during follow-up and resistance data

Protocol-defined virological failure change of any component of the initial randomised regimen before W32 because of confirmed insufficient virological response, defined as HIV-1 RNA reduction < 1 log10 copies/ml by W18 or HIV-1 RNA ≥ 400 copies/ml at W24 ; failure to achieve virological response by W32 (confirmed HIV-1 RNA ≥ 50 copies/ml at W32) ; confirmed HIV-1 RNA ≥ 50 copies/ml at any time after W32

According to the protocol, genotypic testing was carried out by local laboratories when patients had a single VL > 500 copies/ml at or after W32.

* 1 additional patient with T97A

RAL + DRV/r n=401

TDF/FTC + DRV/r n=404

Protocol-defined virological failure (PDVF), n 66 52

Number of PDVF who met criteria for genotype testing (HIV RNA > 500 copies/ml at or after W32)

33 9

Number of patients with single unconfirmed value of HIV RNA > 500 copies/ml at or after W32 (meeting criteria for genotype testing)

3 6

Genotype done, n 28/36 13/15

Major resistance mutations, n 5 0

NRTI 1 (K65R) 0

PI 0 0

INI 5 (N155H)* -


6.2

0

10

8

6

4

2

5.0

0.9

0.5

0.0 0.0

0.4 0.5

%

Grade 3-4 CK elevation

LDL-c Total chol: HDL-c ratio

Total cholesterol

RAL (n = 401) TDF/FTC (n = 404)

2

1.5

1

0.5

Grade 3-4 ALT elevation

Mean changes in fasting lipids at W96 from baseline (mmol/l)

Proportion with graded toxicity

p < 0.001

HDL-c

p = 0.02

0.1 0.2

p < 0.001 p = 0.7

3.0

1.0

Triglycerides

p = 0.49

0.3 0.2

0

NEAT 001/ANRS 143

Laboratory results at 96 wks


Creatinine clearance (eGFR, ml/min [Cockroft-Gault formula] Mean (95% CI) change from baseline

No grade 2-4 creatinine elevation in either arm

-15

-10

-5

0

5

0 4 8 12 18 24 32 32 48 64 80 96

Weeks


- 3.8

+ 0.9

p=0.02


NEAT 001/ANRS 143

Renal safety at 96 wks

A4001078. Maraviroc OD nucleoside analog-sparing regimen in treatment-naive patients

Conclusions: The virological activity and immunological benefit of once-daily MVC + ATV/r were confirmed. Indirect hyperbilirubinemia and associated signs were the most commonly reported Aes in both study treatment groups and were not associated with significant transaminase increases. No drug resistance occurred.

121 treatment-naive patients with CCR5-tropic HIV-1 (HIV-1 RNA >1000 copies/mL; CD4 cell count >100 cells/mm3) were randomized to receive either MVC 150 mg once daily (n = 60) or tenofovir emtricitabine (TDF/FTC) 300/200 mg once daily (n = 61) + ATV/r 300/100 mg once daily. Primary endpoint was proportion of patients with HIV-1 RNA >50 copies per milliliter at week 48.

Mills A, et al. J Acquir Immune Dedic Syndr, 2013

24 antiretroviral-naive R5 HIV-1–infected participants received maraviroc 150 mg and darunavir/ritonavir (DRV/r) 800/100 mg (MVC/DRV/r) once daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies per milliliter at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second phase empirical Bayes estimates were compared with decay rates from efavirenz (EFV) plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs, and EFV plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4, 12, 24, and 48. VF occurred in 3 of 24 participants {12.5% [95% confidence interval (CI): 2.7 to 32.4]} at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 [8.3% (95% CI: 1.0 to 27.0)]. The week 48 failures were 2 of the 4 participants (50%) with baseline VL >100,000 copies per milliliter. Week 96 VF rate was 2/20 [10% (95% CI: 1.2 to 31.7)]. Phase 1 decay was faster with MVC/DRV/r than reported for ritonavirboosted lopinavir plus 2NRTIs (P = 0.0063) and similar to EFV based regimens. Individual maraviroc trough concentrations collected between 20 and 28 hours post dose (n = 59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady state concentration was 128 ng/mL. Conclusions: MVC/DRV/r 150/800/100 mg once daily has potential for treatment-naive patients with R5 HIV-1.

Virologic response, early HIV-1 decay, and MRV PK with MRV plus DRV/r

Taiwo B, et al. J Acquir Immune Defic Syndr, 2013

Mora-Peris B, et al. JAC, 2013

MODERN Study

DRV/RTV Plus MVC vs DRV/RTV Plus FTC/TDF

• Randomized, double-blind, double-dummy, active-controlled study

ClinicalTrials.gov. NCT01345630.

DRV/RTV + MVC QD

FTC/TDF placebo QD

DRV/RTV + FTC/TDF QD

MVC placebo QD

n = 393

n = 398

Wk 48 Wk 96

Primary Endpoint

Secondary Endpoint

Primary endpoint: Proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Wk 48

ART-naive subjects HIV-1 RNA > 1000 c/mL

CD4 ≥ 100 cells/mm3

Tropism-proven CCR5 virus only

No resistance to DRV, TDF, FTC

MODERN Study (A4001095 Early Termination Investigator Letter) ClinicalTrials.gov. NCT01345630.

MODERN Study Wk 48 Results: DRV/RTV + MVC Inferior to DRV/RTV + TDF/FTC

Noninferiority Margin (95% CI) -10% (-17.7% to -6.1%)

HIV

-1 R

NA

<5

0 c

/mL

(%)

Virologic Failures DRV/RTV + MVC, 38 DRV/RTV + FTC/TDF, 13

Study terminated early due to inferior efficacy October 4, 2013, following Data Monitoring Committee recommendation

100

80

60

40

20

0

90

70

50

30

10

DVR/r + MVC (n = 393) DVR/r + FTC/TDF (n = 398)

72%

83%

DHHS 2014

Other Antiretroviral Strategies for Initial Therapy When Abacavir or Tenofovir Cannot Be Used

“In summary, the aggregate results from most of the studies with NRTI-sparing regimens—with the exception of the NEAT ANRS 143 study, which has not yet been published—demonstrate that these initial strategies either have lower efficacy or more side effects than their standard-of-care treatment comparators without affording the benefit of reduced pill burden or dosing frequency. An additional concern is that the two most favorable outcomes in studies thus far were seen with twice-daily LPV/r based regimens (in the PROGRESS and GARDEL trials); LPV/r is not considered a Recommended initial regimen because of its unfavorable lipid, tolerability and pill burden characteristics as compared to ATV/r and DRV/r.

PI/r monotherapy has been studied as an NRTI-sparing strategy, but mainly in the setting of regimen simplification in patients who have achieved viral suppression on an initial combination ART regimen. The results of clinical trials evaluating these regimens are discussed in the Regimen Switching in the Setting of Virologic Suppression section. As stated earlier, at this point, the Panel does not recommend any of these strategies for initial therapy except in patients in whom both TDF and ABC are contraindicated.”

Linee-guida CNA-SIMIT 2013

Regimi opzionali per l’inizio della cART

Summary

• Limited and heterogeneous studies

• Potency limitations at high viral load

• Plasma exposure and interaction may be critical

• Risk of selecting resistence for low genetic barrier components (NNRTI, INSTI)

• Safety benefit uncertain

il punto sui regimi “nrti sparing” · what to start comparison of updated 2012-2014 guidelines...

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