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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