ARV  therapy:  From  Our  Roots  Comes  Our  Growth  

Calvin Cohen, MD, MSc Research Director, CRI New England

Harvard Vanguard Medical Associates Harvard Medical School

Boston, USA This activity is supported by an educational grant from:

Lessons  Learned  

Three  an(virals  leads  to  durable  suppression  

If  three  are  good,  are  four  be7er?  

ZDV/3TC/EFV  vs  ZDV/3TC/ABC/EFV  

Adapted  from  Gulick  R,  et  al.  45th  ICAAC;  December  16-­‐19,  2005;  Washington,  D.C.,  Abstract  H-­‐416a.  

Adapted  from  Markowitz  M  et  al.  18th  CROI;  Boston  MA;  Feb  27-­‐Mar  2  2011.  Abst  148LB  

Our  2013  An=retroviral  Library:  Currently  Approved  (in  the  US)  

NRTIs  •  Abacavir  

•  Didanosine  •  Emtricitabine  •  Lamivudine  •  Stavudine  •  Tenofovir  

•  Zidovudine  

PIs  •  Atazanavir  •  Darunavir  

•  Fos-­‐Amprenavir  •  Indinavir  •  Lopinavir  •  Nelfinavir  •  Ritonavir  

•  Saquinavir  •  Tipranavir  

NNRTIs  •  Delavirdine  •  Efavirenz  •  Etravirine  

•  Nevirapine  (XR)  •  Rilpivirine   Entry  inhibitors  

• Maraviroc  

Integrase  inhibitors  •  Raltegravir  

•  Elvitegravir*  •  Dolutegravir  

Fusion  Inhibitors  •  Enfuvirtide  

PK  booster  •  Cobicistat*  

*Only  available  coformulated  with  TDF/FTC  

Suppression:    How  Many  Drugs  are  Op=mal?  

•  One  – Boosted  PI  Monotherapy  

•  Two  – Boosted  PI  and  one  more  ARV  – And  Other  approaches…  

•  Three  – The  current  Standard  of  Care  –  Two  NRTIs  +  a  3rd  ARV  

• More?  

Cahn  P  et  al.  14th  EACS;  Brussels,  Belgium;  October  16-­‐19,  2013.  Abst.  LBPS7/6.  

Dual  Therapy  (DT):    LPV/r  400/100  mg  BID  +  3TC  150  mg  BID  

(n=217)  

Triple  Therapy  (TT):    LPV/r  400/100  mg  BID  +  3TC  or  FTC    

and  a  third  inves=gator-­‐selected  NRTI  in  fixed-­‐dose  combina=on  (n=209)  

ARV-­‐  naive  pa=ents  ≥18  years  

HIV  RNA  >1,000  copies/mL  No  IAS-­‐USA  defined  NRTI  or  PI  

resistance  at  screening  HB(s)Ag  nega=ve  

(N=426)  

Stra=fied  by  Screening  HIV  RNA  

(≤  or  >  100,000  copies/mL)  

Week  24  Interim  Analysis  

Week  48  Primary  Endpoint  

Cahn P et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. LBPS7/6.

0%  

10%  

20%  

30%  

40%  

50%  

60%  

70%  

80%  

90%  

100%  

BSL   W4   W8   W12   W24   W36   W48  

DT   TT  

Per

cent

Pat

ient

s

P=0.171,  difference  +4.6%    [Cl  95%:  -­‐2.2%  to  +11.8%]  

88.3 83.7

Week  

 VL  <50  copies/mL  (ITTe)  

Preferred  Regimens:    Regimens  with  op=mal  and  durable  efficacy,  favorable  tolerability  and  toxicity  profile,  and  ease  of  use

NNRTI:          EFV/TDF/FTC    

EFV  –  cau(on  for  women  given  risk  of  birth  defects  when  EFV  used  in  first  trimester  

PI:          ATV/r  +  TDF/FTC            DRV/r  (once  daily)  +  TDF/FTC  

ATV/r  should  not  be  used  in  pa(ent  who  require  >20  mg  omeprazole  equivalent    per  day  

Int:          RAL  +  TDF/FTC   RAL  dosing  BID

2013  DHHS  Guidelines:    What  to  Start:  Four  Preferred  

Available  at:  h7p://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.  Revision    February  12,  2013  

Preferred  Regimens:    Regimens  with  op=mal  and  durable  efficacy,  favorable  tolerability  and  toxicity  profile,  and  ease  of  use

NNRTI:          EFV/TDF/FTC    

EFV  –  cau(on  for  women  given  risk  of  birth  defects  when  EFV  used  in  first  trimester  

PI:          ATV/r  +  TDF/FTC            DRV/r  (once  daily)  +  TDF/FTC  

ATV/r  should  not  be  used  in  pa(ent  who  require  >20  mg  omeprazole  equivalent    per  day  

Int:          RAL  +  TDF/FTC            EVG/cob/TDF/FTC          DTG  +  TDF/FTC  or  ABC/3TC  

RAL  dosing  BID

Nov  2013  DHHS  Guidelines:    What  to  Start:  Seven  Preferred  

Available  at:  h7p://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.  Revision    February  12,  2013  

www.clinicaltrials.gov  

The  START  Study  

•  Sample  Size  Increased  in  2013  to  4,600  –  addi(onal  n=600  >35  years  old  –  Enrolled  >4,400  as  of  Oct  2013  

•  Hypothesis:  early  ART  reduces  rate  of  primary  endpoint  by  28.8%  –   43%  for  AIDS  events;  24%  for  non-­‐AIDS  events    

Early  ART  group  Ini=ate  ART  immediately    following  randomiza=on  

N=2,300  

Deferred  ART  group  Defer  ART  un=l  the  CD4  count  declines  to  <350  cells/mm3  or  

 AIDS  develops  N=2,300

 

ART  Naïve  HIV-­‐infected  individuals    Confirmed  CD4  count  >500  cells/mm3  

Even  Just  to  Prevent  HIV  Transmission  

•  Though  we  know  how  HIV  is  transmi7ed…    

3,5  

1,7  

0  0  

1  

2  

3  

4  

5  

6  

Unprotected  RAI**  

Protected  RAI**  

Exclusively  fella=o  

Percen

t  

Preven=ng  HIV  Transmission  Safer  Sex:  the  HOT  Study  

"   Cohort  study  of  MSM  •  N  =  439  •  Six  month  observa(on  period  •  Oral  sex:  No  HIV  infec(ons  observed  despite  lack  of  condom  use  (94%)  

"   Conclusions:  •  Rate  of  transmission  via  oral  sex  is  lowest      

•  Not  zero:  <0.8%  

*     HIV  incidence  determined  in  repeat  testers  **  RAI  =  recep=ve  anal  intercourse  

Adapted  from  Page-­‐Shafer  K,  et  al.  XIV  Intl  AIDS  Conference,  Barcelona  2002,  #4872;      Balls  et  al.  We  PpC2072,  Bangkok  2004  

D:A:D:    Predic=ng  Cardiovascular  Disease  Risk  in  HIV  

*Full  D:A:D  CVD  predic=on  model  included  age,  gender,  systolic  BP,  smoking  status,  family  history  of  CVD,  diabetes,  total  cholesterol,  HDL,  CD4  count,  cumula=ve  exposure  to  PIs  and  NRTIs,  and  current  use  of  ABC.  Reduced  model  omits  ARV.  

Friis-Moller N, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS1/3.

Risk  factor   Per  unit   D:A:D  Full*  

Age   ln     22.0  

Sex   1.37  

Diabetes   1.96  

Smoking    current  /  former  

2.25  /  1.24  

Total  and  HDL  cholesterol   ln   2.58  /  0.61  

Systolic  BP    (#:  if  treated)  

ln     4.59  

Family  History  CVD   1.37  

SPIRIT  NCEP:  Categorical  Analysis  of  LDL  

22%

17%

45%

29%

42%

48%

37%

33%

22%

22%

15%

24%

11%

10%

3%

11%

4%

3%

1%

2%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Week 24

Baseline

Week 24

Baseline

<100 mg/dLOptimal 100 to 129 mg/dL Optimal/ Above Optimal 130 to 159 mg/dL Borderline High 160 to 189 mg/dL High ≥190 Very High

RPV

/FTC

/TD

F Im

med

iate

Sw

itch

PI/r+

2NR

TIs

At Week 24, P<0.001 for comparison between groups (Cochran-Mantel-Haenszel Row Mean Score test using modified ridit scores)

Tebas  P,  et  al.  IDSA  2013.  San  Francisco,  October  2-­‐2,  Abstract  672  

<5.5 mmol/L 5.5 to 7.16 mmol/L 7.2 to 8.8 mmol/L 8.9 to 10.5 mmol/L >10.6mmol/L

SPIRIT  Categorical  Analysis  of  Total  Cholesterol:HDL  Ra=o  

RPV

/FTC

/TD

F Im

med

iate

Sw

itch

PI/r

+ 2N

RTI

s

At Week 24, P<0.001 for comparison between groups (Cochran-Mantel-Haenszel Row Mean Score test using modified ridit scores)

Tebas  P,  et  al.  IDSA  2013.  San  Francisco,  October  2-­‐2,  Abstract  672  

D:A:D:    Predic=ng  Cardiovascular  Disease  Risk  in  HIV  

*Full  D:A:D  CVD  predic=on  model  included  age,  gender,  systolic  BP,  smoking  status,  family  history  of  CVD,  diabetes,  total  cholesterol,  HDL,  CD4  count,  cumula=ve  exposure  to  PIs  and  NRTIs,  and  current  use  of  ABC.  Reduced  model  omits  ARV.  

Friis-­‐Moller  N,  et  al.  14th  EACS;  Brussels,  Belgium;  October  16-­‐19,  2013.  Abst.  PS1/3.  

Risk  factor   Per  unit   D:A:D  Full*  

Age   ln     22.0  

Sex   1.37  

Diabetes   1.96  

Smoking    current  /  former  

2.25  /  1.24  

Total  and  HDL  cholesterol   ln   2.58  /  0.61  

Systolic  BP    (#:  if  treated)  

ln     4.59  

Family  History  CVD   1.37  

CD4  cell  count   2-­‐fold  higher   0.89  

Abacavir    -­‐  current   1.47  

PI    -­‐  cum.  exposure   year   1.05  

NRTI  –  cum.exposure   year   1.03  

ACTG  5224s:  Biomarkers  of  Inflamma=on  High  Sensi=vity  CRP  

McComsey  G,  et  al.  19th  CROI;  Sea7le,  WA;  March  5-­‐8,  2012.  Abst.  835.  

STaR  Virologic  Suppression  at  Weeks  48  &  96  by  Baseline  HIV-­‐1  RNA  Stra(fied  by  100,000  c/mL  –  Snapshot  Analysis  

7.6  

0  -­‐12%   12%  

Favours  EFV/FTC/TDF  

Favours  RPV/FTC/TDF  

7.2  1.1   13.4  

0.2   15.1  

W48  

W96  

0  

10  

20  

30  

40  

50  

60  

70  

80  

90  

100  

<100k  

Baseline  HIV-­‐1  RNA,  c/mL  

231/  260  

204/  250  

205/  260  

178/  250  

HIV-­‐1  RNA,  <50  c/m

L  (%

)  

89  

82   79  

71  

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

W48   W48  W96   W96  

STaR:    Adverse  Events  Leading  to  Discon=nua=on  of  Study  Drug  through  Week  96  

RPV/FTC/TDF  (n=394)  

EFV/FTC/TDF  (n=392)  

Discon=nua=ons*  Due  to  Adverse  Event  (AE),  n  (%)   12  (3.0%)   43  (11.0%)  

AE  leading  to  discon=nua=on  in  >1  subject  in  either  arm  

   Nervous  System  Disorders  

         Dizziness   0   6  (1.5%)  

   Psychiatric  Disorders  

       Abnormal  Dreams   0   5  (1.3%)  

       Insomnia   1  (0.3%)   4  (1.0%)  

       Depression   0   8  (2.0%)  

       Suicidal  Idea=on   0   3  (0.8%)  

       Nightmare   0   2  (0.5%)  

   GI,  General,  Skin  Disorders  

         Diarrhea     0     2  (0.5%)  

         Fa=gue   0   2  (0.5%)  

         Pyrexia   0   2  (0.5%)  

         Toxic  Skin  Erup=on   0   2  (0.5%)  

33 Cohen  C,  et  al.  EACS  Brussels  2013,  LBPE7/17  

Time  to  Suicidality,  primary  analysis  

Hazard ratio (95% CI) 2.28 (1.27 to 4.10), p=0.006

47  events/5817  PY*      (8.08/  1000  PY)  

15  events/4099  PY*      (3.66/1000  PY)  

Mollan  K,  et  al.  IDWeek  2013.  San  Francisco,  CA.  #670.  

Awempted/Completed    Suicide,  2ndary  

analysis  

Death  Compe=ng  Risk    

Mollan  K,  et  al.  IDWeek  2013.  San  Francisco,  CA.  #670.  

Overall  Grade  2-­‐4  CNS  adverse  events  were  significantly  decreased  by  Week  4  and  also  at  Week  12  (P<0.001)  

UK  Mul=center  Study  ATR  to  EPA  Switch  due  to  CNS  toxicity  (Week12)  

Nelson  M,  et  al.  ICAAC  2013.  Denver,  CO.  #H-­‐672b  

Propor=on  of  individual  Grade  2-­‐4  CNS  Adverse  Events  

80

70

60

50

40

30

20

10

0

Prop

ortio

ns (%

)

Week 4 Baseline

Week 12

P=0.008

P=0.029

P=0.001

P=0.021

P=0.005

P=0.008

P=0.564

P=0.003

P=0.034

P<0.001

Each  CNS  adverse  event,  except  headache,  showed  sta(s(cally  significant  improvement  (P<0.05)    

-12% +12%

-1.1 4.1 9.2

4.2 10.3 -1.9

-1.6 3.6 8.8

5.1 9.4 0.7

2.5 7.4 12.3

Differences in Percentages (95% CI)

1.1 7.2 13.4

9.5 17.3 1.7

-20 -15 -10 -5 0 5 10 15 20

Efficacy:  Newer  Treatments  Outperform  EFV  Favours  EFV     Favours  Comparator  

GS-1021 (STB vs. ATR) N=700 88% vs. 84% (Snapshot)

GS-102/103/1042 (STB vs. ATR) N=1124 89% vs. 84% (Snapshot)

STaR3 (CPA vs. ATR) N=786 86% vs. 82% (Snapshot) 89% vs. 82% (Snapshot) BLVL ≤100,000 cpm

STARTMRK4 (RAL vs. EFV) N=566 86% vs. 82% (ITT, NC=F) 71% vs. 61% (ITT, NC=F)

SINGLE5 (DTG vs. ATR) N=833 88% vs. 81% (Snapshot)

Week 48: Non-inferiority shown

Week 48 (Pooled): Statistically significant higher VL response

Week 48: Non-inferiority shown

Week 48: Statistically significant higher VL response

Week 48: Non-inferiority shown

Week 48: Statistically significant superior VL response

Week 240: Statistically significant higher VL response

1. Sax P, et al. Lancet 2012;379:2429–38 2. Ward D, et al. ICAAC 2012; San Francisco, CA. Oral H-555 3. Cohen C, et al. HIV-11 2012; Glasgow. O425; Data on File

4. Rockstroh J, et al. IAC 2012; Washington, DC. LBPE019 5. Walmsley S, et al. ICAAC 2012; San Francisco, CA. Oral H-556b 6. Cohen C, et al. JAIDS 2012;60:33-42

Study  102/103  –  Through  Week  144  Renal  Events  Leading  to  Study  Drug  Discon=nua=on  

Clumeck  N,  et  al.  14th  EACS;  Brussels,  Belgium;  October  16-­‐19,  2013.  Abst.    LBPS7/2.  Wohl  D,  et  al.  ICAAC  2013.  Denver,  CO.#H-­‐672a  

Onset  (Week)  

STB  –  Study  102  (n=348)  

0-­‐24  

Proximal  Renal  Tubulopathy  

Isolated  Rise  in  Crea=nine  

Onset  (Week)  

STB  –  Study  103  (n=355)  

0-­‐24   24-­‐48   48-­‐96   96-­‐144  

Proximal  Renal  Tubulopathy   0   0   0     0  

Isolated  Rise  in  Crea=nine   2  (0.6%)   +2  (0.6%)   0   +1  (0.3%)  

48-­‐96  

+1  (0.3%)  

0  2  (0.6%)  

4  (1.1%)  

24-­‐48  

0  

0   +1  (0.3%)  

0  

96-­‐144  

1.Rockstroh  JK,  et  al.  HIV-­‐11  2012;  Glasgow.  0424              2.Rockstroh  JK,  et  al.  JAIDS  2013,  e-­‐published  

Incidence/Prevalence  of  Common  Gastrointes=nal  AEs  Study  102  –  Week  144  

STB (n=348) ATR (n=352)

Diarrhea   Nausea  

Weeks   Weeks  

Pa=en

ts  with  AE  (%

)  

6% 5% 4% 5%

4% 5% 4% 4%

48 96 144 48 96 144

4%  

3%  

7%  

6%  

Wohl  D,  et  al.  ICAAC  2013.  Denver,  CO.#H-­‐672a  

Taken  from:  Fischl  M,  et  al.  CROI  2000,  Abstract  71  

The  evolu=on  of  ART:  simpler,  well  tolerated  regimens  1996  

d4T+3TC+IDV  10  /  Q8h  

1998  

AZT/3TC+EFV  5  /  BID  

2000  

AZT/3TC/ABC  1  /  BID  

2003  

TDF+FTC+EFV  3  /  QD  

2004  

TDF/FTC+EFV    

ABC/3TC+EFV  

2  /  QD  

2006  

TDF/FTC/EFV  1  /  QD  

2011  

TDF/FTC/RPV  1  /  QD  

2012  

TDF/FTC/EVG/Cobi  1  /  QD  

Hicks  C,  et  al.  EACS  2007.  Madrid.  Poster  P5.7/01  

Vera  J,  Aragão  F.  HIV11,  Glasgow,  UK  2012  #P5c  

The  Future:  More  ARVs,  More  FDCs  and  STRs  

van  Sighem  A,  et  al.  CROI  2010.  Abstract  526  

Stalemate?  Or  the  Cure?  

“…may  HIV  flow  from  our  blood  Into  our  history  books..”  

-­‐  William  Jefferson  Clinton  10th  Retrovirus  Conf.  Boston  2003