The role of cohorts studies in current treatment guidelines development: the Italian experience. Andrea Antinori INMI L Spallanzani IRCCS, Roma

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1 The role of cohorts studies in current treatment guidelines development: the Italian experience Andrea Antinori INMI L Spallanzani IRCCS, Roma

2 INITIATING THERAPY

3 When to start ART? Guidelines Update Clinical category CD4 cells/mm 3 WHO 13 1 DHHS 13 2 IAS-USA 12 3 EACS 13 4 CNA-SIMIT 12 5 BHIVA 12 6 GESIDA 13 7 CNS-ANRS 13 8 AIDS-defining or symptoms Any value Treat (AI) Treat (AI) Treat (AI) Treat Treat (AI) Treat (AI) Treat (AI) Treat (AI) Pregnancy Any value Treat (AI) Treat (AI) Treat (AI) Treat Treat (AI) Treat (AI) Treat (AI) Treat (AI) HBV, HCV Any value Treat HBV (AIII) Treat (AI-II) Treat (AII/CIII) Treat or consider only if CD4 <500/mm 3 Treat (AI-II) Treat or consider only if Treat (AII) Treat (AIII) CD4 <500/mm 3 Other clinical conditions Any value TB HIVAN HIVAN HIVAN, Malignancies, HAND HIVAN, Malignancies, HAND, CVD HIVAN, Malignancies, HAND HIVAN, Malignancies, HAND, CVD Malignancies Asymptomatic <350 Treat (AI) Treat (AI) Treat (AI) Treat Treat (AI) Treat (AI) Treat (AI) Treat (AI) Asymptomatic Treat (AII) Treat (AII) Treat (AI) Consider treatment Treat (AII) Generally defer Treat (BI) Treat (AII) Asymptomatic >500 Defer Treat as moderate (BIII) Treat as moderate (BIII) Consider treatment Treat only on individual basis (AII/BIII) Generally defer Treat as moderate (BIII) Treat as moderate (BIII) Prevent sexual transmission Any value Treat (AI) Treat (AI-II) Consider treatment Treat PHI (BIII) Consider treatment Treat (AI-II) Consider (GPP) Treat (AI-II) Treat (AI/BIII) 1. WHO consolidated guidelines onthe use of antiretroviral drugs for treating and preventing HIV infection. June DHHS Guidelines 2013 Available at 3. ARV Treatment of Adult HIV Infection Recommendation of the IAS-USA panel. JAMA 2012;308: EACS Guidelines Available at 5. Linee Guida Italiane sull utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1, Available at: 6. BHIVA Guidelines Avalilable at: 7. 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 CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

4 Current treatment guidelines for HIV infection are derived using a variety of different approaches. Those that use the GRADE system do not generally recommend the initiation of cart for asymptomatic individuals with a CD4 cell count above 350 cells/ml, unless the individual wishes to take cart to prevent onward transmission. The evidence to support the earlier initiation of cart derives from observational studies (with potential for significant bias). The findings from these studies are often inconsistent, the evidence may be indirect to the question of interest, and the observational studies may fail to capture all important outcomes. This should question a decision to rate revised recommendations as based on strong evidence. Use of more stringent criteria, such as those proposed by the GRADE approach, would likely reach the conclusion that the evidence is insufficient to make firm recommendations. Sabin CA, et al. AIDS, 2013

5 Risk of clinical progression or death for deferring cart at CD4 level than Cohort N. partecipants AIDS or Death Consistency Death alone Consistency NA-ACCORD (N Engl J Med, 2009) ART-CC/When to start (Lancet, 2009) 17,517 n.a. n.a. Deferred cart at CD : HR 1.69 ( ) 24,444 Deferred cart to CD4 lower than : HR 1.28 ( ) yes Deferred cart to CD4 lower than : HR 1.13 ( ) yes no HIV-CAUSAL (Ann Intern Med, 2011) 20,971 Compared with initiating cart at CD4 cell count threshold 500/mm3, HR for 350/mm 3 threshold:1.38 ( ) yes Compared with initiating cart at CD4 cell count threshold 500/mm 3, HR for 350/mm3 threshold:1.01 ( ) no CASCADE (Arch Intern Med, 2011) 9,455 In CD4 stratum , cart initiation associated with ahr: 0.75 ( ) no In CD4 stratum , cart initiation associated with ahr: 0.51 ( ) yes

6 START Design HIV-infected adults, ART-naive with CD4+ cell counts > 500 cells/mm 3 Early ART Group Immediately initiate ART N=2,000 Deferred ART Group Defer ART until CD4+ <350 cells/mm 3 or symptoms develop N=2,000 Primary endpoint: Serious AIDS & serious non-aids disease

7 Changing Criteria for Antiretroviral Therapy Initiation in DHHS Guidelines CD4+Count, cells/mm > 500 Offer if VL > 20K Offer if VL > 55K Consider if VL 100K Consider in certain groups* Consider Treat Offer if VL > 20K Consider if VL > 55K Consider if VL 100K Consider in certain groups* Treat Treat < 200 or symptomatic Offer if VL > 20K Offer, but controversy exists Offer after discussion with patient Treat Treat Treat Treat Treat Treat Treat Treat Treat *Pregnant women, patients with HIV-associated nephropathy, and patients with HBV that requires treatment. 50% of panel members recommended starting antiretroviral therapy; 50% of members viewed treatment as optional. Wilkin T, et al. Available at:

8 The higher risk of OD/death in DC patients was associated with living longer with uncontrolled HIV replication even at higher CD4 cell counts. DC patients had HIV RNA levels 400 copies/ml for most of the follow-up time when their CD4 cell counts were 350 cells/l, and this uncontrolled viral replication even at these higher CD4 cell counts was associated with an increased risk of OD/death. The SMART Study Group, J Iinfect Dis, 2008

9 The effect of HIV infection and its treatment on inflammation and immunosenescence Many of the T cell characteristics associated with immunosenescence including thymic dysfunction, T cell activation, and a reduced T cell regenerative potential are more common among individuals who fail to exhibit robust CD4+ T cell gains during therapy than among those who achieve a normal CD4+ T cell count. Because a low CD4+ T cell count on therapy is a consistent proximal predictor of non-aids morbidity, these observations collectively suggest that HIV-associated immunosenescence contributes to persistent immunodeficiency and the early onset of age-associated diseases The persistent inflammation during therapy is probably due to a number of factors, including ongoing HIV production (if not HIV replication), increased copathogen load (particularly CMV, but likely other herpesviruses as well), translocation of lipopolysaccharide (LPS) across a damaged gut mucosa, loss of T regulatory cells and other immunoregulatory cells, and the irreversible fibrosis of the thymus and lymphoid infrastructure Deeks SG, Annu Rev Med, 2011

10 What to Start: Comparison of Guidelines Regimen CNA-SIMIT DHHS IAS EACS BHIVA 2012 GESIDA 2013 CNS-ANRS 2013 EFV/TDF/FTC Preferred (A1) Preferred Recommended Recommended Preferred Preferred Preferred ATV/r + TDF/FTC Preferred (A1) Preferred Recommended Recommended Preferred Preferred Preferred DRV/r + TDF/FTC Preferred (A1) Preferred Recommended Recommended Preferred Preferred Preferred RAL + TDF/FTC Preferred (A1) Preferred Recommended Recommended Preferred Preferred Alternative EFV + ABC/3TC Preferred (A1)* Alternative Recommended* Recommended** Alternative** Preferred** Preferred** ATV/r+ABV/3TC Preferred (A1)* Alternative Recommended* Recommended** Alternative** Preferred** Preferred** RPV+TDF/FTC Preferred (A1)# Alternative Alternative Recommended# Preferred# Preferred# LPV/r + TDF/FTC Preferred (B1) Alternative Alternative Alternative Alternative Preferred Alternative LPV/r + ABV/3TC Preferred (B1) Alternative Alternative Alternative Alternative Preferred Alternative NVP + TDF /FTC Preferred (B1) Acceptable Alternative Alternative Alternative Preferred Alternative EVG/COBI/TDF/FTC Preferred Alternative DTG+TDF/FTC Preferred DTG+ABV/3TC Preferred * ABV/3TC preferred as A1 only if HIV-RNA < c/ml ** Use of abacavir + lamivudine as NRTI backbone is recommended only if baseline viral load less than 100,000 copies/ml. # Rilpivirine, only if VL < c/ml 1. Linee Guida Italiane sull utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1, Available at: 2. DHHS Guidelines 2013 Available at 3. ARV Treatment of Adult HIV Infection Recommendation of the IAS-USA panel. JAMA 2012;308: EACS Guidelines Available at 5. BHIVA Guidelines Avalilable at: 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 CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

11 Pre-ART high-level viremia is an independent factor of reduced virological response Baseline HIV-RNA ranges Relative Hazard to achieve HIV-RNA<50 copies/ml Crude Adjusted b K a K - 100K 0.66 < < K - 300K 0.43 < < K - 500K 0.38 < <0.001 >500K 0.29 < <0.001 a Reference range. b Adjusted for: gender, age, pre-haart CD4 cell count, transmitted drug resistance, calendar year, third drug (PI vs. NNRTI). Santoro et al. Antivir Therapy, 2013

12 Linee-guida CNA-SIMIT 2012 Regimi raccomandati per l inizio della terapia ARV in presenza di HIV-RNA > copie/ml.

13 Linee-guida CNA-SIMIT 2012 Regimi raccomandati per l inizio della terapia ARV in presenza di HIV-RNA < copie/ml.

14 Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or TDF/FTC, Even For High BL VL HIV-1 RNA < 50 c/ml at Wk 48 by FDA Snapshot Analysis (%) In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG, including with high BL HIV-1 RNA n/ N = / / / / / / 38 0 < 100k 100K- 250K- < 250K 500K Baseline HIV-1 RNA (c/ml) Eron J, et al. Glasgow Abstract P / 18 > 500K ABC/3TC TDF/FTC 64 18/ 28 In pooled analysis (SPRING-2 and SINGLE), high response rates with ABC/3TC or TDF/FTC at low and high BL HIV-1 RNA levels Proportion Free of Protocol-Defined Virologic Failure Group (events/n) ABC/3TC, 100K (10/537) ABC/3TC, > 100K (21/210) TDF/FTC, 100K (19/623) TDF/FTC, > 100K (31/285) Data from both studies and both INSTIs pooled Wk

15 Efficacy predictors - viral load 100,000 Meta-analysis/systematic review on 40,124 pts, treatment-naïve HIV-1+ adults, prospective design, 48 weeks duration, ITT efficacy analysis Efficacy % (SD) r 2 (%) Multivariable analysis Coeff 95% CI p p group Placebo Yes 67 (13) 7.9 Ref No 57 (15) , Pills per day , -0.8 <0.001 <0.001 Third drug class NNRTI 64 (11) 47.6 Ref <0.001 INSTI 81 (5) , PI (boosted) 65 (11) , NRTI 43 (17) , <0.001 PI (no RTV) 43 (11) , CCR5+/-PI 58 (7) , INSTI+PI 54 (18) , NNRTI+PI 43 (8) , Lee FJ, et al. 7 th IAS, Kuala Lumpur, Abst. WEAB0104

16 CHANGING THERAPY

17 High rates of treatment modification or interruption in the first years of ART 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. Abgrall S, et al. The ART Cohort Collaboration, AIDS, 2013

18 Danish HIV Cohort Study. Rates of switch to simpler and less toxic regimens have increased between 1997 and 2009 The rates of modifications due to virological failure, toxicity and other reasons have dropped substantially, while the rate of simplifications has increased. IR per 100 PYFU of first treatment modification by year of cart initiation Helleberg M, et al. Antiviral Therapy, 2013

19 HOW TO CONTINUE AFTER VIROLOGICAL SUPPRESSION: STRATEGIES FOR OPTIMIZING cart 1. A reduction of daily doses and pill burden, but still in a triple cart regimen (management simplification); 2. A reduction in the number of ARV drugs: schematic simplification (de-intensification); 3. Other switching strategies with a triple drug combination, not included in the above conditions. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update July 2012.

20 Probability of treatment failure in patients receiving LPV/r monotherapy (n=224) d Arminio Monforte A, et al. Antiviral Therapy, 2013

21 DHHS 2013 Management of Patients with Virologic Failure

22 Time to virologic rebound according to the T0 viral load (VL) Viral rebound defined as confirmed or last available viral load >50 copies/ml. In treated patients monitored by RealTime, a VL of copies/ml and, to a lesser extent, RNA detection >40 copies/ml predict rebound >50 and >400 copies/ml independently of other recognized determinants. The goal of HAART may need to be revised to a lower cutoff than 50 copies/ml. Doyle T, et al. Clin Infect Dis, 2012

23 Resistance to different ARV drug classes by plasma viremia ranges Santoro M, et al. in press

24 Relative rates of switch after failure (from VL copies/ml) Calendar year Current VL, copies/ml Unadjusted RR (95% CI) p-value Adjusted* RR (95% CI) p-value (1.09, 11.68) (1.39, 15.01) (3.91, 27.77) < (4.75, 33.82) <.001 Calendar year Current VL, copies/ml Unadjusted RR (95% CI) p-value Adjusted* RR (95% CI) p-value (0.96, 5.49) (1.45, 8.42) (1.00, 5.28) (1.95, 10.46) <.001 *gender, mode of HIV transmission, nationality, current CD4 count, drugs currently received and clinical site. Cozzi-Lepri A, et al. IWHOD, 2013

25 Linee-Guida CNA-SIMIT 2012 Raccomandazioni per la gestione del fallimento virologico in rapporto alla viremia

26 THANKS FOR ATTENTION