Iniziare la terapia per poi personalizzarla: valutare ‘il presente’ a

360 gradi

Andrea Antinori9 Maggio 2014

Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag.

When to start cART? 2012-2014 Guidelines Update

1. WHO consolidated guidelines onthe use of antiretroviral drugs for treating and preventing HIV infection. June 20132. 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. 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; 6. BHIVA Guidelines 2012-Updated 2013. HIV Medicine (2014), 15 (Suppl. 1), 1–857. 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 20148. CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

NA-ACCORDMid-point life expectancy estimates at age 20 years in three

calendar periods, overall and by characteristics

Samji H, et al. PLoS One, 2014

Life expectancy estimates for the general population at age 20 years in 2009 were59.7 and 57.0 years for men and 63.9 and 61.7 years for women, in Canada and the U.S., respectively.

Higher CD4 Count at ART Initiation Predicts Greater Long-Term Likelihood of CD4 Count Normalization

• Progressively higher CD4 counts at ART initiation were associated with greater long-term CD4 gains, greater likelihood of achieving CD4 > 750 (“normalization”), increased unadjusted survival rates, higher CD4 at death, and decreased likelihood of deaths from both AIDS and non-AIDS causes.

Palella F, et al. CROI 2014; Boston (MA). Abst.#560.

Med

ian

CD4

coun

t, ce

lls/m

m3

≥ 500350-499200-34950-199< 50

HIV Outpatient Study (HOPS)

Relationship between current CD4 and AIDS-defining illness with a CD4 count ≥500 cells/μL

Relationship with current viral load and antiretroviral treatment.

COHERE. A total of 12,135 ADIs occurred at a CD4 count of ≥200 cells/μL among 207,539 persons with 1,154,803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0–21.1 per 1000 PYFU) with current CD4 200-349 cells/μL to 4.1 per 1000 PYFU (95% CI, 3.6–4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/μL. Persons with a current CD4 of 500–749 cells/μL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10–1.32).

Mocroft A, et al. Clin Infect Dis, 2013

SPARTAC Trial

Primary end point according to interval between seroconversion and randomization

The SPARTAC Trial Investigators, N Engl J Med, 2013

366 HIV individuals with PHI.Primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation.

Value of viremia copy years in deciding optimal timing of ART initiation in adults with HIV

Figure. Adjusted hazard ratios for the effect of initiation vs. deferring ART on time from SC to AIDS/death by a) viremia copy years pooling CD4 stratum, b) viremia copy years with CD4<350 cells/mm3and c) viremia copy years with CD4≥350 cells mm3

Pooling CD4 strata, hazard ratios for the effect of initiating ART on time from seroconversion to AIDS/death decreased as VCYyear increased, with a 63% reduced risk of AIDS/death for those initiating ART when VCY exceeded 100,000. At CD4<350 cells/mm3, there was an overall reduction in the risk of AIDS/death in all VCY groups (all HR < 1) for those initiating vs. deferring ART with no evidence that this benefit varied by VCY (p=0.78). At CD4 ≥ 350 there was a trend for increasing benefit of initiation vs. deferral with increasing VCY, with the largest benefit seen in the VCY ≥ 100,000 c/mL group (HR, 95% CI= 0.56, 0.35-0.90, p(heterogeneity) = 0.16).Results were qualitatively similar for CD4 strata ≥ 500 cells mm3.

Using 2011 CASCADE data of individuals with well estimated dates of HIV seroconversion, we created a sequence of ‘trials’ in which individuals were classified as initiating or deferring ART.6497 individuals contributed ≥1 baseline ‘trial’; 3089 (48%) initiated ART and 293 (5%) acquired AIDS/died.

Olson AD, et al. CROI 2014, Boston (MA). Abst.#558

Four opportunities for HIV prevention

The four stages of infection risk are listed at the top of the fi gure. Potential interventions during each stage arelisted within each box. The timeline for the intervention is listed in the arrows below the intervention boxes.STD=sexually transmitted diseases. ART=antiretroviral therapy. PrEP=pre-exposure prophylaxis. TDF/FTC=tenofovir disoproxil fumarate co-formulated with emtricitabine. PEP=post-exposure prophylaxis.

Cohen MS, et al. Lancet, 2013

DHHS 2014Initiating Antiretroviral Therapy in Treatment-Naive Patients

(Last updated May 1, 2014; last reviewed May 1, 2014)

Nodata

The Continuum of HIV Care in Various SettingsEngagement in HIV Care

• To achieve a reduction in HIV transmission, HAART programs must ensure the effectiveness and quality of a cascade of services from testing and referral to care to ensuring ongoing adherence to HAART2

• Large US cohorts have found that women, IVDU, younger and non-white patients were less likely to achieve virologic suppression, and may require targeted outreach along the cascade of care4,5,6

1. Adapted from CDC, MMWR 2011;60:1618-16232. Adapted from Nosyk B, et al. CROI 2013; Atlanta, GA. #1029

3. Costagliola D, et al. CROI 2013; Atlanta, GA. #1030

4. Althoff K, et al. CROI 2013; Atlanta, GA. #10265. Novak R, et al. CROI 2013; Atlanta, GA. #1032a 6. Horberg M, et al. CROI 2013; Atlanta, GA. #1033

*US ≤200 copies/mL, BC and France < 50 copies/mL

0%

20%

40%

60%

80%

100%

HIV-infected

HIV-diagnosed

Linked toHIV care

Retained inHIV care

On ART Suppressedviral load*

100 100 100

8086

81

62

79

41

56

74

3645

60

28 32

52

1,178,350 ~11,000 149,900

941,950

725,302

480,395426,590

328,475

United States1

British Columbia, Canada2

France3

10

The model of HIV continuum of care

Birger RB et al. Clin Infect Dis, 2014

1. Acutely infected individuals flow into asymptomatic undiagnosed.

2. Asymptomatic individuals either receive a diagnosis before progressing to AIDS or do not.

3. Tested, ineligible individuals eventually become eligible as their CD4 counts drop, but may be lost to follow up before attaining eligibility.

4. Tested-eligible individuals can be lost to follow-up or not linked to treatment, or be linked to treatment and then either be virologically suppressed or not suppressed.

5. Unsuppressed individuals move into a dead-end AIDS post-antiretroviral therapy compartment.

6. Undiagnosed and unlinked individuals progress to AIDS–never treated, from which they either die or present for treatment

What to Start: Comparison of Updated 2012-2014 GuidelinesRegimen CNA-SIMIT 20131 DHHS 20142 IAS 20123 EACS 20134 BHIVA 20135 GESIDA 20146 CNS-ANRS 20137

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

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

NVP + TDF /FTC Alternative Not recommended Alternative Alternative Alternative Alternative Alternative

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

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

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

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

RAL+ABV/3TC Preferred Alternative Recommended Alternative Preferred Alternative

EVG/COBI/TDF/FTC Preferred Recommended Alternative Preferred Preferred

DTG + TDF/FTC Preferred Recommended Preferred

DTG + ABV/3TC Preferred Recommended Preferred

* Only if HIV-RNA <100.000 c/mL; # Only if HIV-RNA <100.000 c/mL and CD4 >200 cell/mm3.

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 2014 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), 1–856. 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 20147. CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

ABC/3TC vs. TDF/FTC: primary virologic endpoint(High viral load stratum at DSMB action)

Hazard Ratio

1 5-4 Favors TDF/FTCFavors ABC/3TC

ABC/3TC vs. TDF/FTC with

EFV

ATV/r HR 2.22 (95% CI, 1.19, 4.14)

HR 2.46 (95% CI 1.20, 5.25)

Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB.

ACTG 5202 ABC/3TC vs TDF/FTC high viral load stratum

Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or TDF/FTC, Even for High BL VL

• In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG, including with high BL HIV-1 RNA*

Eron J, et al. Glasgow 2012. Abstract P204.

< 100k 100K - < 250K 250K - 500K > 500K0

20

40

60

80

100

HIV

-1 R

NA

< 50

c/m

L at

Wk

48 b

y FD

A Sn

apsh

ot A

naly

sis

(%)

86

n/N =

88

225/257

91

306/335

36/42

82

72/88

81

13/16

76

29/38

72

13/18

64

18/28

Baseline HIV-1 RNA (c/mL)

TDF/FTCTDF/FTCABC/3TCABC/3TC

*Pooled data from both INSTIs.

DTG 50 mg QD

(%)

DRV/r800/100 mg

QD (%)

Baseline ≤100,000 c/mL

ABC/3TC at Day 1 TDF/FTC at Day 1

8988

Snapshot at 48 weeks by baseline HIV-1 RNA and NRTI background therapy

DTG-based therapy showed statistical superiority in subjects with baseline HIV-1 RNA >100,000 c/mL overall and comparable efficacy independent of NRTI backbone through all viral load strata

Adapted from Clotet B, et al. Lancet, 2014

Baseline >100,000 c/mL

ABC/3TC at Day 1TDF/FTC at Day 1

9294

6050403020100–10–20

FavoursDRV/r

FavoursDTG

n

134228

2597

8886

6771

Difference in proportion (DTG–DRV/r; unadjusted)

Linee-guida CNA-SIMIT 2013Regimi raccomandati per l’inizio della cART

DHHS 2014 – What to start(Last updated May 1, 2014; last reviewed May 1, 2014)

Rating of Recommendations: A = Strong; B = Moderate; C = OptionalRating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohortstudies with long-term clinical outcomes; III = Expert Opinion

What data do we have in treatment-naive patients ?

NVP

ARTEMIS 6,7

LPV/r

EFV

DRV/r

ACTG 51422

Sierra-Madero3

EVG/c‡

Study 102* 11

ArTen12

DTG

STARTMRK

1

ECHO15

THRIVE16

2NN14

ATV/r

CASTLE,4,5ACTG 520213

Stud

y 103

10

PI

NNRTI

INSTI

RALSPRING19

SINGLE20

Adapted from: 1. Lennox JL, et al. Lancet 2009;374:796−806; 2. Riddler SA, et al. NEJM 2008;358:2095–106; 3. Sierra-Madero J, et al. JAIDS 2010;53:582–8; 4. Molina J-M, et al. Lancet 2008;372:646–55; 5. Molina J-M, et al. JAIDS 2010;53:323–32; 6. Ortiz R, et al. AIDS 2008;22:1389–97; 7. Mills AM, et al. AIDS 2009;23:1679─88; 8. Martínez E, et al. CROI 2013; Oral presentation 772; 9. Gallant JE, et al. JID 2013 [Epub ahead of print]; 10. DeJesus E, et al. Lancet 2012;379:2429–38; 11. Sax PE, et al. Lancet 2012;379:2439–48; 12. Soriano V, et al. Antivir Ther 2011;16:339–48; 13. Daar ES, et al. Ann Intern Med 2011;154:445–56; 14. van Leth F, et al. Lancet 2004;363:1253–63; 15. Molina J-M, et al. Lancet 2011;378:238–46; 16. Cohen CJ, et al. Lancet 2011;378:229–37; 17. European Medicines Agency http://www.ema.europa.eu (Accessed Apr 2013) 18. ATRIPLA SmPC Available at: http://www.ema.europa.eu Last updated 12/02/2013 (Accessed Apr 2013); 19. Raffi F, et all. Lancet Infect Dis. 2013 Nov;13(11):927-35; 20 Walmsley S et all. 52 ICAAC, September 9-12, 2012 H-556b; 21. Feinberg J et al. 52 ICAAC, September 9-12, 2012, H-1464a.

FLAMINGO 21

ATADAR8

RPV

ACTG52

57* ACTG5257 *

Virologic Suppression at Wk 48 by Baseline HIV-1 RNA

1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet. 2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract H1464a.

≤ 100,000 c/mL> 100,000 c/mL

SPRING-2[4]

3020100-20 -10

Difference, % (DTG-RAL) and 95% CI

In favor of RAL In favor of DTG

≤ 100,000 c/mL> 100,000 c/mL

SINGLE[4]

3020100-20 -10

Difference, % (DTG-EFV) and 95% CI

In favor of DTGIn favor of EFV

Study 102[2]

FLAMINGO[5]

≤ 100,000 c/mL> 100,000 c/mL

3020100-20 -10

Difference , % (DTG-DRV/RTV) and 95% CI

In favor of DTGIn favor of DRV/RTV

40

≤ 100,000 c/mL> 100,000 c/mL

Difference, % (EVG/COBI-EFV) and 95% CI

In favor of EFV In favor of EVG/COBI

Study 103[3]

-15 -10 -5 5 10 150

≤ 100,000 c/mL > 100,000 c/mL

Difference, % (EVG/COBI-ATV/RTV) and 95% CI

In favor of ATV/RTV In favor of EVG/COBI

≤ 100,000 c/mL> 100,000 c/mL

STARTMRK[1]

3020100-20 -10

Difference, % (RAL-EFV) and 95% CI

In favor of EFV In favor of RAL

-15 -10 -5 5 10 150

ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count

Cohen CJ, et al. AIDS. 2013;27:939-950.

HIV

-1 R

NA

< 50

cop

ies/

mL

(%)

By Baseline CD4+ Count (cells/mm3)

84

71

≤ 100k

Rilpivirine Efavirenz

8076

> 100k -≤ 500k

56

71

< 50

6975

50 -< 200

81 7985

79

200 - < 350

≥ 350

By Baseline HIV-1 RNA (copies/mL)

0

20

40

60

80

100

0

20

40

60

80

100

n = 368 329 249 270 n = 34 36 194 175 313 307 144 164

65

73

69 83

> 500k

STaR: EPA vs. ATR – Week 96 EPA Maintains Significant Difference in Virologic

Suppression vs. ATR at Low BLVL Through 96 Weeks

BLVL = Baseline Viral Load

BL HIV-1 RNA

≤100,000 c/mL

>100,000 c/mL

7.6

Baseline HIV-1 RNA, c/mL

231/260231/260

204/250204/250

107/134107/134

116/142116/142

205/260

178/250

102/134

106/142

0-12% 12%

FavoursATR

FavoursEPA

7.21.1 13.4

0.2 15.1W48

W96 p=0.046p=0.046

-11.1 -1.8 7.5

-8.7 1.5 11.6W48

W96p=0.78p=0.78

Cohen C, et al. EACS 2013; Brussels, Belgium. #LBPE7/17

HAART regimen patients (N=15,602) in VA cohorts evaluating the adherence and hospitalisation impact of receiving single-tablet regimen [STR (n=6,191)] or multiple tablet regimen [MTR; ≥2 tablets/day (n=9,411)] from Jan 2006 - July 2012 Adherence* results•At a threshold of ≥95%, a significantly higher proportion of STR vs. MTR patients were adherent (75.0% vs. 55.7%, P<0.001)•At 80% threshold STR vs. MTR: 90.0% vs. 77.5%, P<0.001•After adjusting for covariates at study entry, STR patients were two times significantly more likely to be adherent compared to MTR patients [Odds ratio** (95% CI): ≥ 80%=2.16 (1.92,2.43); ≥95%=1.98(1.81,2.17)]

Rao GA, et al. ICAAC 2013. Denver, CO. #H-1464Rao GA, et al. ICAAC 2013. Denver, CO. #H-1464

VA Study: STR vs. MTRAdherence Results

*Calculated using pharmacy claims data [medication possession ratio (MPR)] = [sum of days supply to all HAART regimen components (excluding days of last fill)/last fill date-first fill date] X 100%;**Odds ratio adjusted for covariates at study entry: age, race, geographic region, Charlson comorbidity index, mental health disorders, drug/alcohol abuse disorders, index year, treatment-naïve status, undetectable viral load

Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with OD vs BID regimens.

Antiretroviral therapy adherence rate, virological response, and pill burden. Area of circle is proportional to the sample size. Blue, once-daily regimens; orange, twice-daily regimens.

Meta-analysis of randomized controlled trials. RCTs comparing once daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study quality was rated using the Cochrane risk-of-bias tool.Nineteen studies met inclusion criteria (N = 6312 adult patients).

Nachega JB, et al. Clin Infect Dis, 2014

ACTG 5257Primary Endpoint Analyses at Wk 96

• Regimens equivalent in time to VF

Landovitz R, et al. CROI 2014, Boston (MA). Abst.#85

Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV

– In part due to high proportion of pts with hyperbilirubinemia

Considering both efficacy and tolerability, RAL superior to either boosted PI

DRV/RTV superior to ATV/RTV

Virologic Failure Tolerability Failure Composite Endpoint

Difference in 96-Wk Cumulative Incidence (97.5% CI)

0-10 10 20

ATV/RTV vs RAL3.4% (-0.7 to 7.4)

DRV/RTV vs RAL5.6% (1.3 -9.9)

ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3)

0-10 10 20

ATVRTV vs RAL15% (10-20)

DRV/RTV vs RAL7.5% (3.2-12.0)

ATV/RTV vs DRV/RTV7.5% (2.3-13.0)

Favors RAL

Favors DRV/RTV

Favors RAL

0-10 10 20

ATV/RTV vs RAL13% (9.4-16.0)

DRV/RTV vs RAL3.6% (1.4-5.8)

ATV/RTV vs DRV/RTV9.2% (5.5-13.0)

Favors RAL

Favors DRV/RTV

NEAT001/ANRS143. First Line RAL+DRV+RTV is Non-Inferior to FTC/TDF+DRV+RTV

Results: Primary endpoint incidence over 96 weeks was 17.4 % (RAL) vs. 13.7 % (FTC/TDF); adjusted absolute difference was 3.7% (non-inferior), upper 95% CI of 8.6% was below the pre-specified 9% margin.

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

RAL+ DRV+RTV

FTC/TDF +DRV+RTV

N 401 404

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

V1. Regiment 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

*Confirmed by a subsequent measurement

Primary EndpointPrimary Endpoint at Week 96 by

Baseline Characteristics

RAL+ DRV+RTV

FTC/TDF +DRV+RTV

Overall n = 805 17.4% 13.7%

Baseline HIV-1 RNA

<100,000 c/ml n = 530 7% 7%

≥100,000 c/ml n = 275 36% 27%

Baseline CD4+

<200/mm3 n = 123 39.0% 21.3%

≥200/mm3 n = 682 13.6% 12.2%

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

-10 0 10 20 30

-3.4 6.3

4.7 30.8

-0.05 19.3

-3.9 3.5

-1.1 8.6

Difference in Estimated Proportion(95% CO) RAL – FTC/TDF; Adjusted

9

p = 0.09*

p = 0.02*

• In planned subgroup analysis the outcome for patients with low CD4 (<200/mm3) RAL+DRV+RTV was inferior to FTC/TDF+DRV+RTV

• Comparable safety• Genotypic resistance: RAL (n=5) FTC/TDF (n=0)

ENCORE1A reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with TDF/FTC

during 48 weeks in ART-naive adults with HIV-1 infection 630 patients (efavirenz 400=321; efavirenz 600=309).

32% were women; 37% were African, 33% were Asian, and 30% were white.

The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4.75 log10 copies per mL (IQR 0.88).

The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI −2.1 to 5.79).

Encore1 Study Group, Lancet, 2014

High rates of treatment modification or interruption in the first years of ART

Abgrall S, et al. The ART Cohort Collaboration, AIDS, 2013

21,801 patients from 18 cohorts in Europe and North America starting ART.

Stacked Cumulative Incidence Functions of class change, substitution addition of drugs within class, switch to nonstandard regimen, interruption and death, estimated using competing risk methods.

Figures below the graph are the estimated cumulative incidence of each event at 1, 2 and 3 years, with 95% Cis.

Linee-guida CNA-SIMIT 2013Ottimizzazione della cART

Il termine ottimizzazione della cART è utilizzato per indicare strategie finalizzate al miglior risultato possibile, attraverso switch terapeutici anche differenti fra loro e con scopi e razionali diversi, ma sempre in condizioni di soppressione virologica (HIV-RNA < 50 copie/mL).

Sono immaginabili tre principali modalità di ottimizzazione:

•Riduzione del numero di farmaci antiretrovirali;•Riduzione del numero di dosi/somministrazioni e di compresse giornaliere, ma sempre ricorrendo ad uno schema di triplice terapia;•Altre strategie di ottimizzazione, che ricorrono ad uno schema di triplice terapia, non necessariamente inquadrabili nel razionale del precedente punto.

Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1. Novembre 2013

Simplification of ARV therapy to a single tablet regimen consisting of EFV/FTC/TDF

De Jesus E, et al. J Acquir Immune Defic Syndr, 2009

Percentage of patients with virologic response vs. HIV-1 RNA thresholds for the time to loss of virologic response (TLOVR) analysis. Black-shaded columns are patients randomized to the single tablet regimen of EFV/FTC/TDF; gray-shaded columns are patients randomized to SBR.

Efavirenz and chronic neuropsychiatric symptoms

In 32 patients treated with EFV and matched controls, symptoms of depression, anxiety and stress were assessed by the Depression Anxiety and Stress Scale (DASS). Mean duration of the last ARV regimen was 14+5 months for EFV group and 24+14 months in the control group.

In the EFV group, 19 patients (58%) reported unusual dreams in the past 7 days compared with 10 (32%) in the control group (P=0.049). No significant differences were observed with regard to quality of sleep, number of awakenings per night or fatigue.

Rihs TA, et al. HIV Med, 2006

Switching to RPV/FTC/TDF was non-inferior* to remaining on PI+RTV+2NRTIs for 24 weeks (difference 3.8, 95% CI [-1.6, 9.1]). Similar rates of virologic suppression were also seen with 48 weeks of treatment with RPV/FTC/TDF

SPIRIT. Virologic Suppression at Weeks 24 and 48 FDA Snapshot Analysis – ITT Population

RPV/FTC/TDF (immediate switch, Day 1 to W48)RPV/FTC/TDF (immediate switch, Day 1 to W48)

CD4 count change (cells/mm3): Week 24, RPV/FTC/TDF immediate switch +20, PI+RTV+2NRTIs +32, RPV/FTC/TDF delayed switch -7. Week 48, RPV/FTC/TDF immediate switch +10

Prop

ortio

n of

Sub

ject

s, %

(HIV-1 RNA <50 c/mL)(HIV-1 RNA <50 c/mL)

RPV/FTC/TDF (immediate switch, Day 1 to W24)RPV/FTC/TDF (immediate switch, Day 1 to W24)

PI+RTV+2NRTIs (delayed, Day 1 to W24)PI+RTV+2NRTIs (delayed, Day 1 to W24)

0.95.4

RPV/FTC/TDF (delayed switch, W24 to W48)RPV/FTC/TDF (delayed switch, W24 to W48)

92.1

1.36.65 5

93.789.9

0102030405060708090

100

Virologic Suppression Virologic Failure

No Data

FDA Snapshot at 24 Weeks FDA Snapshot at 48 Weeks

STRATEGY-PI Study

Switching to E/C/F/TDF from PI+RTV+FTC/TDF resulted in significantly higher rates of virological suppression

Arribas J, et al. CROI 2014, Boston (MA). Abst.551LB

Primary end point: FDA Snapshot <50 copies/mL at 48 wks

The puzzle of emerging HIV-associated conditions (HANA)

from High KP, et al. J Acquir Immune Defic Syndr, 2012

Metabolic disease in HIV infection

Recent trials investigating the effects of antiretroviral therapy on lipids

Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco, and genetics) and HIV-specifi c and ART-specific contributors (including chronic inflammation and immune activation)

Lake JE & Currier JS. Lancet Infect Dis, 2013

SPIRIT

Change in fasting lipids from baseline to week 24 and week 48

Palella F, et al. AIDS, 2014

A5257. INSTI produced a more favorable lipid profile than ATVr or DRVr

Following ART initiation, fasting TG, non-HDL-C, and calculated LDL-C increased in the 2 RTV boosted PI arms, and decreased or remained stable in the RAL arm.All pairwise comparisons between the ATV/RTV or DRV/RTV arm and the RAL arm showed greater increases with ATV/RTV or DRV/RTV treatment compared to RAL; no differences between ATV/RTV and DRV/RTV treatment were apparent.As-treated and sensitivity analyses excluding subjects on lipid lowering agents did not change results.

Mean of changes from Baseline in Fasting Lipid Profile (mg/dL) Over Time.

Ofotokun I, et al. CROI 2014, Boston (MA). Abst.#746

Change from Baseline in Fasting Lipids Study 102 and 103 – Week 96

0

5

10

15

20

25

0.0

0.2

0.4

0.6

Med

ian

Ch

ang

e at

W

k 96

(mg

/dL

)

(mm

ol/L

)

Total Cholesterol

LDL HDL Triglycerides

ATV/r + TVDSTB

(P=0.001)*

(P=0.064)*

(P=0.002)*

* STB vs ATR

(P=0.003)^

0

5

10

15

20

25

0.0

0.2

0.4

0.6

Med

ian

Chan

ge a

t W

k 96

(mg/

dL) (mm

ol/L)

ATR

12

18

8

12

16

11

68

54

8

16

^ STB vs ATV/r+TVD

No difference in change in TC to HDL ratio at Week 48 or 96

D:A:D: MI rate Stratified by cumulative exposure to any ATV, ATV with ritonavir, and ATV without ritonavir

The rate of MI varied from 2.80 (95% CI: 2.6, 23.0)/1000 PYFU in those with no exposure to ATV to 2.0 (1.2, 3.2)/1000 PYFU in those with >3 years exposure.

MI r

ate/

100

PYRS

(95%

CI)

Years of exposure

Any ATVPYFU 37005

ATV with RTVPYFU 31232

ATV without RTVPYFU 9611

d’Arminio Monforte A, et al. CROI 2012; Poster#823.

ARV Alteration of renal function (generally not treatment-limiting)

Treatment-limiting renal disease

TDF • Tubular dysfunction• Rapid eGFR decline • Proteinuria (non-glomerular)• Incident CKD

• AKI (rare)• Tubulo-interstitial nephritis (rare)• Tubular disease/FS (uncommon)• CKD with progressive eGFR decline

ATV/r • Inhibition of creatinine secretion• Tubular dysfunction• Rapid eGFR decline• Incident CKD

• AKI (rare)• Tubulo-interstitial nephritis (rare)• Nephrolithiasis (uncommon)• CKD with progressive eGFR decline

LPV/r • Incident CKD/CKD progression • None reportedCOBI/EVG • Inhibition of creatinine secretion • AKI (rare)

• Tubular disease/FS (uncommon)

COBI/ATV • Inhibition of creatinine secretion • AKI (rare)• Tubular disease/FS (uncommon)

DTG • Inhibition of creatinine secretion • None reported

RPV • Inhibition of creatinine secretion • None reported

ARV’s and the kidney

Post F, 2013

D:A:D Study. ARV Exposure (Per Year) and Incidence Rate Ratios of ceGFR ≤70 and CKD From eGFR >90

• Cumulative TDF (aIRR 1.18 [1.12-1.25] per year) and ATV/r (1.19 [1.09-1.32]) use were independently associated with increased rates of ceGFR ≤70 from eGFR >90, but not with CKD (eGFR <60), whereas lopinavir/r (LPV/r) use was associated with both endpoints (1.11 [1.05-1.17]) and 1.22 [1.16-1.28] respectively. Inconsistent trends were seen with abacavir use.

Ryom L, et al. J Infect Dis, 2013

AgeFamily history

ART Diabetes

HIV Hypertension

Hepatitis C

Ethnicity

KD Risk

= Modifiable= Non-modifiable

Risk factors for kidney disease in the HIV-positive population

Gupta et al. Clin Infect Dis 2005;40:1559–85.

Decreased CD4 cell count Increased viral load

D:A:D Non-ARV Predictors of Advanced CKD/ESRD

Gender female vs male

Ethnicity African vs Caucasian

HIV transmission IDU vs MSM

Prior AIDS yes vs no

HBV pos vs neg

HCV pos vs neg

Hypertension yes vs no

Diabetes yes vs no

Prior CVE yes vs no

Smoking non vs current

eGFR per 10 ml/min lower

Age per 10 years higher

CD4 per doubling

CD4 Nadir per 100 cells/mm3 higher

VL per log10 higher

Univariate Multivariate

0.25 0.5 1 2 4 8Advanced CKD/ESRD IRR (95%CI)

Poisson regression model adjusted for gender, ethnicity, HIV transmission group, enrolment cohort, Prior AIDS, HBV status*, HCV status*, smoking status*, hypertension*, diabetes*, cardiovascular events (CVE)*, baseline year, eGFR, age, current CD4 count*, CD4 Nadir, HIV-1 viral load (VL)*, and use of TDF, ATV/r, ATV, LPV/r, other PI/r and IND.

Incidence rate-ratio, IRR. *time-updated.

Ryom L, et al. AIDS, 2014

Lower chance to maintain viral suppression after switching to PI/r monotherapy

Mathis S., et al. PLoS One, 2011

PIVOT. PI/r monotherapy switch strategy for long-term HIV management

Patients were randomised to maintain ongoing triple therapy (OTT) or switch to a PI monotherapy strategy (PIm) using a ritonavir boosted PI (physician drug choice) with prompt re-introduction of NRTIs if unable to maintain VL suppression <50 copies/ml.

Primary outcome: loss of future drug options, defined as new intermediate/high level resistance to ≥1 drug to which the patient’s virus was considered to be sensitive at trial entry

Secondary outcomes: included serious disease complications (AIDS, serious non-AIDS, all-cause death), total grade 3/4 adverse events and neurocognitive function change (annual 5-test battery).

Analysis: all analyses done as ITT. Tested hypothesis of non inferiority of PIm on the primary outcome, margin 10%.

We randomised 587 patients who were followed for a median (maximum) of 44 (59) months; 2.7% withdrew or were lost-to follow up. In PIm, 80% selected DRV/r, 14% LPV/r, 7% other PI/r at randomisation.

Paton N, et al. CROI 2014; Abst.#550LB

More than 1 year of sustained viral suppression before switching to PI/r mono is related to lower risk of VF

Guiguet M, et al. AIDS, 2012

1. EACS guidelines version 6.0, 2011. 2. Thompson MA, et al. JAMA. 2012;308(4):387-402. 3. DHHS guidelines, 2014. Italian Guidelines (National AIDS Commission, Ministry of Health-SIMIT), 20131. EACS guidelines version 6.0, 2011. 2. Thompson MA, et al. JAMA. 2012;308(4):387-402. 3. DHHS guidelines, 2014. Italian Guidelines (National AIDS Commission, Ministry of Health-SIMIT), 2013

Guidelines Differ about PI/r Monotherapy Recommendations

Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag.