Doug Richman Latsis  Symposium  

ETH  Zurich  3  July  2015

Lessons learned from HIV: treatment

4+ 4+ 4+ 4+4+ 4+ 3+

2 4 6 8 10 12 14 16

90

70

X

V

0

2 4 6 8 10 12 14 16

150

0

100

200

100

0

98.6

BODYWT.

180

PRERX

PRERX

GAFFKYCOUNT

ROENTGENCHANGES

SPUTUM CULT.

ISONIAZIDSENSITIVE

RESISTANT

ISONIAZIDMG./DAY

SL

INTHIGH

SPUTUMWT.

(GM)

TEMP

+++

NO CHANGEWORSE

IMPR.

WEEKS OF TREATMENTCLINICAL DATA DURING SIXTEEN WEEKS OF INH THERAPY

Coates et al, The Clinical Significance... N Engl J Med 248:1085, 1953

2 4 6 8 10 12 14 1600

20

40

60

80

100NEGATIVE

SENSITIVE

“RESISTANT”

SLIGHT

INTERMEDIATE

HIGH

PER

CEN

TAG

E O

F C

ASE

S

WEEKS OF TREATMENTCoates et al, The Clinical Significance... N Engl J Med 248:1083, 1953

INH SUSCEPTIBILITY OF ISOLATES FROM PATIENTS WITHPULMONARY TB TREATED WITH INH MONOTHERAPY

Colonies Prevalence Number Inoculum* Drug per plate of resistance of plates per plate conc. (actual) mutants

µg./ml. 4 5 x 106 INH† 1.0 99.101, 1 in 5 x 104

106,107 4 5 x 107 SM‡ 2.0 55, 59 1 in 1 x 106

64,70 100 1 x 108 INH 1.0 No growth

HIV-‐1  Drug  Resistance  is  the  RESULT  and  the  CAUSE  of  drug  failure  

§  Emergence  of  drug-‐resistant  virus  is  an  inevitable  consequence  of  the  failure  to  fully  suppress  HIV-‐1  (HCV,  HBV,  influenza  virus,  TB,  etc)  replicaQon  with  anQmicrobial  therapy.  

 §  Drug  resistance  is  a  major  factor  contribuQng    to  the  failure  of  anQretroviral  therapy.  

Diversity of RNA Virus Populations

§ RNA  viruses  consQtute  a  quasispecies.  § GeneQcally  disQnct  viral  variants  evolve  from  an  iniQal  monoclonal  or  oligoclonal  virus  inoculum.  

§ Variants  are  generated  due  to  error-‐prone  nature  of  RT.  

Drug-Resistant Mutants Preexist in Untreated Patients

§  The  HIV  genome  contains  104  nucleoQdes.  

§  The  mutaQon  rate  of  HIV  is  ~3  x  10-‐5  nucleoQdes/  replicaQon  cycle.  

§  ~1011  virions  are  generated  by  107  -‐  108  rounds  of  replicaQon  each  day.  

Preexisting Drug Resistance Mutations

§  Single  mutants  produced  daily  §  Isolated  from  treatment-‐naive  paQents  or  those  infected  before  anQretroviral  drug  availability  

§ Double  mutants  less  common  §  3  or  more  specific  resistance  mutaQons  in  the  same  genome  rare  

Rapid Turnover of Viral Quasispecies

§ Most  of  the  virus  populaQon  in  plasma  is  cleared  and  replaced  each  day.  

§  Rapid  turnover  allows  rapid  emergence  of  drug-‐resistant  variants  under  selecQve  pressure.  

§  Resistant  variants  may  be  replaced  by  residual  wild-‐type  virus  if  selecQve  pressure  is  removed.  

§  ResQng  latently  infected  cells  may  conQnue  to  harbor  drug-‐resistant  provirus.  

HIV-1 infection and a model of the distribution of viral quasispecies in the era of antiretroviral therapy

Metzner, Future Virology 1:377, 2006

HIV  drug  resistance  is  generated  by    one  of  two  major  mechanisms  

•  Both mechanisms are too prevalent. •  Prevention strategies for these two mechanisms

are completely different.

§     Acquired  resistance  following  non-‐          suppressive  treatment    

         (secondary  resistance)    §     Transmi_ed  resistance                (primary  resistance)  

A036D (20 mos) A036C

(11 mos)

A036B (2 mos)

AZT Susceptibility of Sequential Isolates of HIV-1 From a Patient Administered AZT

Plaq

ue re

duct

ion

(%) 0

50

100 0.001 0.01 0.1 1 10

AZT (µM)

Larder, Darby and Richman, Science 1989; 243:1731.

HCSUS: Prevalence of HIV Drug Resistance §  HCSUS population

§  Representative as possible to all HIV-positive persons receiving medical care in early 1996

§  1080 samples with HIV RNA >500 copies/mL

§  Resistance more common §  Lowest CD4 count nadir §  Higher HIV RNA §  More access to care

§  Resistance less common §  Patients cared for by the

most experienced providers

0

20

40

60

80

100

Prop

ortio

n W

ith

Phen

otyp

ic R

esis

tanc

e

Any NRTI NNRTI PI >2 3

78% 70%

31%

42% 51%

14%

Richman et al, AIDS 18:1393, 2004

Drug Drug Classes

14

0

5

10

15

Transmission of Drug-Resistant HIV in Treatment-Naïve Patients

Little SJ, et al. N Engl J Med. 2002;347:385-394

1995 1996 1997 1998 1999 2000 (n=11) (n=56) (n=101) (n=97) (n=90) (n=23)

Phen

otyp

ic R

esis

tanc

e (%

pat

ient

s)

IC50 >10-fold increase via PhenoSense HIV (ViroLogic)

NNRTI

PI

NRTI

15

The Good News

§  HIV  drug  resistance  is  not  maintained  in  the  environment  or  transmi_ed  by  fomites.  

§  HIV  drug  resistance  is  not  selected  for  or  maintained  in  animal  reservoirs.  

§  HIV  drug  resistance  is  not  maintained  or  spread  on  plasmids  or  other  geneQc  exchange  mechanisms,  as  for  anQbioQcs.  

§  Be_er  anQretroviral  drugs  have  reduced  HIV  drug  resistance  in  resource-‐rich  countries.  

16

0

10,000

20,000

30,000

40,000

50,000

60,000

0

50

100

150

200

250

300

350

400

450

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Patie

nt-m

onth

s of

AR

V Ex

posu

re

Ann

ual I

ncid

ence

of R

esis

tanc

e (N

)

Year

Increasing proportion of VL levels

How  did  this  reducQon  in  resistance  with  more  expanded  treatment  happen?  

§  Be_er  drugs  §  More  potent  and  be,er  half-‐lives  (TDF/

FTC,  be,er  PIs,  integrase  inhibitors)    §  More  tolerable  and  less  toxic  (thymidine  

analogues  are  history)  §  Fixed  dose  combinaDons  

§  Be_er  monitoring  of  failure  and  then  use  of  drug  resistance  tesQng  and  be_er  drugs  for  treatment  failure  

18

The  Bad  News  

§  With  the  roll-‐out  of  anQretroviral  drug  treatment  in  low  and  middle  income  countries  which  has  proven  to  be  a  dramaQc  accomplishment,  the  mistakes  made  in  rich  countries  have  been  recapitulated.  

Aimed to boost efforts to provide access to antiretroviral drugs that have saved hundreds of thousands of lives in Europe and the US to the growing number of people with HIV/AIDS in low and middle income countries who need them.

GENEVA/DAKAR, 12 DECEMBER 2002 - HIV Treatment Access Coalition (ITAC)

Joep Lange the then president of the IAS: “if we can get cold Coca Cola to every remote corner of Africa, it should not be impossible to do the same with drugs”

7.2  

11.1  

15.0  

20.7  

0.0  

5.0  

10.0  

15.0  

20.0  

25.0  

6  to  11   12  to  23   24  to  35   ≥36  

%  of  P

atients  with

 Acq

uired  HIVDR  

Months  on  ART  Figure  1.    Changes  in  rates  of  acquired  HIVDR  to  any  drug  class  according  duration  of  treatment.  HIVDR=human  immunodeficiency  virus  drug  resistance.  ART=antiretroviral  therapy.  

                                                 Stadeli  and  Richman,  Antiviral  Therapy  18(1):115-‐23,  2013      

   

4.2  

8.2  

20.0  

21.6  

6.7  

10.5  

17.3  

23.5  

0.1   0.1   0.0  

2.0  

3.7  

7.2  

15.9  

21.6  

0.0  

5.0  

10.0  

15.0  

20.0  

25.0  

6  to  11   12  to  23   24  to  35   ≥36  %  of  P

atient

s  wth

 Drug  Res

istanc

e  

Months  on  ART  

NRTI  

NNRTI  

PI  

Multi-‐Class  

Figure  2.    Distribution  of  acquired  HIVDR  to  individual  drug  classes  according  to  time  on  antiretroviral  therapy      

                                                                                 Stadeli  and  Richman,  Antiviral  Therapy  18(1):115-‐23,  2013      

4.0  

6.6  

2.0  

2.8  

2.1  

3.5  

0.6  

1.4  

1.0  1.2  

0.0  

1.0  

2.0  

3.0  

4.0  

5.0  

6.0  

7.0  

0.0

0.5

1.0

1.5

2.0

2.5

No PDR (n=2404)

PDR and fully-active ART

(n=52)

PDR and partially-active ART (n=123)

Virological failure Acquired drug-resistance

Multivariate analysis Pretherapy drug resistance (PDR) defined using IAS-USA list and Stanford hivdb algorithm

P

Cost of continuing a regimen failing as defined by virologic criteria

♦ CNA3005: ZDV/3TC/ABC vs. ZDV/3TC/IDV ♦ “First genotype”

performed at time of rebound ♦ “Last genotype”

performed prior to changing ART ♦ Early breakthrough with

wild type or M184V ♦  Increasing NRTI mutations

associated with cross-resistance to all RTIs

Melby T, et al. 8th CROI; 2001; Chicago, Ill. Abstract 448

0 20 40 60 80

100

0–8 9–16 17–24 25–32 33–40 41–48 Weeks

Perc

ent o

f Pat

ient

s

M184V + other NRTI mutation M184V or wild type

39 34 28 24 20 16 n =

0%

20%

40%

60%

80%

100%

BL t1 t2 BL t1 t2 BL t1 t2

NRTIs Truvada NNRTIs

Prop

ortion

 of  v

iruses

High  resistanceIntermediate  resistanceFully  susceptible

Predicted viral drug susceptibility

Barth  et  al.  IDRW  2010  

Rapid accumulation of DRMs when first-line ART is continued despite virological failure

RE Barth et al.

©2011 International Medical Press6 Page numbers not for citation purposes

ART regimen Baseline resistance Drug resistance profiles at t1a and t2b TAMs/K65R, n

CBV/NVPc None K103N, E138Q, M184V, T215NSY 1 TAM CBV/NVPc None K103N, M184I, G190A 0 CBV/NVPc NA M41L, A98G, K103N, E138A, M184V, T215FS T215F 2 TAMs CBV/NVP NA V106A, M184V, F227L 0 CBV/NVP NA K103N, V106Ma, E138A, F227La 0 CBV/NVP None A62Va, K101Ea, K103Na, K103S, V106Ma, M184V, G190A 0 CBV/EFVc E138A V106M, E138A, M184V, T215F, F227L, M230L 1 TAM CBV/EFVc None K103N, V108I, M184V, T215F, M230L 1 TAM CBV/EFVc None D67N, K70R, K103N, M184V, T215FI, K219Q, P225H 4 TAMs CBV/EFVc None K101Q, K103N, M184V, T215Y, M230L 1 TAM CBV/EFV None K101P, K103N K103S, M184V 0 CBV/EFV NA D67N, V90I, K103N, V106Ma, E138A 1 TAM CBV/EFV NA D67N, K70E, V106M, M184V, G190A 1 TAM CBV/EFV NA K103N, E138G, M184V 0 d4T/3TC/NVP K70E K65R, K70E, A98G, K103N, Y181C K65R d4T/3TC/NVP NA K103N, Y181C, M184V 0 d4T/3TC/NVP None K101E, V108I, Y181C, M184V 0 d4T/3TC/NVP V90I K65R, M184V, G190A K65R d4T/3TC/NVP None K65R, K101Ea, V108I, Y181C, M184V K65R d4T/3TC/NVP None K101E, K103Na, M184V, G190A 0 d4T/3TC/NVP None K103R, V179D, Y181Ca, M184V, Y188L 0 d4T/3TC/NVP None A62Va, K65R, T69d, K103N, V106Ma, Y181C, G190RSa, K219R K65R d4T/3TC/EFV None L74V, V75La, K103N, V108I, M184V, M230L, L234I 0 d4T/3TC/EFV None K65R, L100I, K103N, T215I K65R d4T/3TC/EFV None K65R, K101E, G190S K65R d4T/3TC/EFV V106M, M184V, G190A D67N, K101E, V106M, M184V, G190A, T215Y, K219R 2 TAMS

Table 2. Drug resistance profiles in individual patients

aMutations found at first detection of virological failure (t1) but no longer detectable after 6 or 12 months of ongoing viraemia (t2). bThe mutations in bold are the mutations that were only observed at t2. Mutations depicted in italics are drug resistance mutations that are not listed in IAS list. Arrows indicate a change of mutation at one locus between t1 and t2. cPatient was a child. ART, antiretroviral therapy; CBV, combivir; d4T, stavudine; EFV, efavirenz; NA, not available; NVP, nevirapine; TAM, thymidine analogue mutation; 3TC, lamivudine. n, number of observed TAMS per patient.

0

20

40

60

80

100

120

NRTI NNRTI Total

Num

ber o

f mut

atio

ns

Drug resistance according to drug class

02468

101214161820

M184V K103N TAMs K65R

Num

ber

of m

utat

ions

Specific drug resistance mutations

Baseline t1 t2

A B

Figure 2. Accumulation of drug resistance over time

NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitors; TAM, thymidine analogue mutation; t1, first detection of virological failure; t2, after 6 or 12 months of ongoing viraemia.

Steep increase in TAMs (+250%) and K65R (+100%) NNRTI susceptibility is already lost at first detection of VF

Precedes WHO-defined failure criteria

Barth et al. Antiviral Therapy 2012

Longitudinal genotyping analysis at first detection of VF (t1) and 6-12 months after (t2)

How much will resistance impact the benefits of the antiretroviral rollout in resource-limited countries?

§  We have been using suboptimal regimens for treatment and for MTCT.

§  We are assessing failure by clinical or CD4 endpoints.

§  We are not optimally monitoring virologic failure in individuals or resistance in populations (both acquired and transmitted).

Access to antiretroviral therapy has been a remarkable achievement with a dramatic impact on almost 12 million individuals in resource-limited countries; however,

Prevention of acquired drug resistance requires addressing the causes

§  The  paQent  §  adherence  

§  The  prescribing  care  provider  §  selecQng    an  opQmal  regimen  §  counseling  the  paQent  

§  The  drugs  §  Potency  §  tolerability  §  pharmacokineQcs  

AddiQonal  factors  specific  to  LMIC  that  contribute  to    the  emergence  of  HIV  

drug  resistance  

§  SubopQmal  Regimens  §  Thymidine  analogues  §  Insufficient  second-‐line  and  salvage  regimens  

§  Failure  of    methods  and  resources  to  monitor  viral  loads    

§  Drug  distribuQon  (stock-‐outs)  §  Perinatal  PMTC  rather  than  treaQng  

pregnant  women  with  ART  (opQon  B+)  

Summary  

§  The  principles  of  HIV  drug  resistance  are  well  established  (Darwinian  evoluQon).  

§  The  mistakes  and  lessons  learned  in  the  developed  world  are  being  recapitulated  in  low  and  middle  income  countries.  

§  PrevenQon  of  further  increases  in  drug  resistance    §  Be_er  regimens  § Avoid  stockouts  § Monitor  viral  load  §  IntervenQons  to  improve  adherence  and  reduced  risk  behaviors