Download Contending with Evolution and Escape by HIV

Principles and reality of HIV drug resistance
in sub-Saharan Africa
Doug Richman
INTEREST WORKSHOP
8 May 2015
CLINICAL DATA DURING SIXTEEN WEEKS OF INH THERAPY
WEEKS OF TREATMENT
PRE
RX
2
180
4
6
8
10
12
14
16
100
BODY
90
WT.
TEMP
98.6
70
++
+
ROENTGEN
CHANGES
IMPR.
NO CHANGE
WORSE
X
200
SPUTUM
WT.
100 (GM)
GAFFKY
COUNT
V
0
0
4+
SPUTUM CULT.
4+
4+
4+
4+
4+
3+
ISONIAZID
SENSITIVE
SL
RESISTANT INT
HIGH
ISONIAZID
MG./DAY
150
0
PRE
RX
2
4
6
8
10
12
14
16
Coates et al, The Clinical Significance... N Engl J Med 248:1085, 1953
INH SUSCEPTIBILITY OF ISOLATES FROM PATIENTS WITH
PULMONARY TB TREATED WITH INH MONOTHERAPY
100
NEGATIVE
PERCENTAGE OF CASES
80
SENSITIVE
SLIGHT
60
INTERMEDIATE
40
“RESISTANT”
20
HIGH
0
0
2
4
6
8
10
12
14
16
WEEKS OF TREATMENT
Coates et al, The Clinical Significance... N Engl J Med 248:1083, 1953
PREEXISTENCE OF DRUG RESISTANT MUTANTS OF TB
Number
of plates
Colonies
per plate
(actual)
Prevalence
of resistance
mutants
99.101,
106,107
1 in 5 x 104
Inoculum*
per plate
Drug
conc.
4
5 x 106
µg./ml.
INH† 1.0
4
5 x 107
SM‡ 2.0
55, 59
64,70
1 in 1 x 106
100
1 x 108
INH 1.0
SM 2.0
No growth
<1 in 1 x 1010
* Number of viable, bacterial units from a seven to 10 day old vigorously
growing, well dispersed H37Rv culture in liquid medium (ST).
† Isoniazid
‡ Streptomycin
Cohn et al, J Clin Invest 38:1349, 1959
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) replication with antiviral
therapy.
 Drug resistance is a major factor
contributing to the failure of antiretroviral
therapy.
Diversity of RNA Virus
Populations
 RNA viruses constitute a quasispecies.
 Genetically distinct viral variants evolve
from an initial monoclonal or
oligoclonal virus inoculum.
 Variants are generated due to errorprone nature of RT.
Drug-Resistant Mutants Preexist
in Untreated Patients
 The HIV genome contains 104
nucleotides.
 The mutation rate of HIV is ~3 x 10-5
nucleotides/ replication cycle.
 ~1011 virions are generated by 107 - 108
rounds of replication each day.
Preexisting Drug Resistance
Mutations
 Single mutants produced daily
 Isolated from treatment-naive patients or
those infected before antiretroviral drug
availability
 Double mutants less common
 3 or more specific resistance mutations
in the same genome rare
Rapid Turnover of Viral
Quasispecies
 Most of the virus population in plasma is
cleared and replaced each day.
 Rapid turnover allows rapid emergence of drugresistant variants under selective pressure.
 Resistant variants may be replaced by residual
wild-type virus if selective pressure is removed.
 Resting latently infected cells may continue 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

Acquired resistance following nonsuppressive treatment
(secondary resistance)

Transmitted resistance
(primary resistance)
• Both mechanisms are too prevalent.
• Prevention strategies for these two mechanisms
are completely different.
Plaque reduction (%)
AZT Susceptibility of Sequential Isolates
of HIV-1 From a Patient Administered AZT
Larder, Darby
and Richman,
Science 1989; 243:1731.
0
A036C
(11 mos)
A036D
(20 mos)
A036B
(2 mos)
50
100
0.001 0.01
0.1
1
AZT (µM)
10
HCSUS:
Prevalence of HIV Drug Resistance
 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
Proportion With
Phenotypic Resistance
 HCSUS population
78%
70%
51%
42%
31%
14%
 Resistance less common
 Patients cared for by the
most experienced
providers
Any NRTI NNRTI PI
Drug
>2
3
Drug Classes
Richman et al, AIDS 18:1393, 2004
Transmission of Drug-Resistant HIV
in Treatment-Naïve Patients
IC50 >10-fold increase via PhenoSense HIV (ViroLogic)
Phenotypic Resistance
(% patients)
NNRTI
14
PI
NRTI
1995
1996
1997
1998
1999
2000
(n=11)
(n=56)
(n=101)
(n=97)
(n=90)
(n=23)
Little SJ, et al. N Engl J Med. 2002;347:385-394
450
90
80
70
60
50
40
30
R2 = 0.97
20
400
50,000
350
300
40,000
250
30,000
200
150
20,000
100
10,000
10
50
0
0
2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
60,000
Patient-months of ARV Exposure
100
Decreasing resistance despite increased
ARV exposure in BC, 1997-2008
Increasing proportion of VL levels
<50 c/mL in BC, 2000-2008
Annual Incidence of Resistance (N)
Percentage of patients with pVL <50 copies/mL
Improved Virologic Outcomes Concomitant
with Decreasing Incidence of Drug Resistance
0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Gill VS, et al. CID (2010) 50:98-105
Year
15
How did this reduction in resistance with
more expanded treatment happen?
 Better drugs
 More potent and better half-lives
(TDF/FTC, better PIs, integrase inhibitors)
 More tolerable and less toxic (thymidine
analogues are history)
 Fixed dose combinations
 Better monitoring of failure and then use
of drug resistance testing and better drugs
for treatment failure
GENEVA/DAKAR, 12 DECEMBER 2002
- HIV Treatment Access Coalition (ITAC)
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.
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”
25,0
% of Patients with Acquired HIVDR
20,7
20,0
15,0
15,0
11,1
10,0
7,2
5,0
0,0
6 to 11
12 to 23
24 to 35
≥36
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
25,0
23,5
21,6
% of Patients wth Drug Resistance
21,6
20,0
20,0
17,3
15,9
15,0
10,5
10,0
NRTI
8,2
7,2
6,7
5,0
NNRTI
PI
4,2
3,7
Multi-Class
2,0
0,0
0,1
6 to 11
0,1
12 to 23
0,0
24 to 35
≥36
Months on ART
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
% of Patients with Transmitted HIVDR
7,0
6,6
6,0
5,0
4,0
Total HIVDR
4,0
NNRTI
PI
2,8
3,0
2,0
NRTI
3,5
Multi-Class
2,0
2,1
1,4
1,0
1,0
1,2
0,6
0,0
<5 years
≥5 years
Time Since ART Availability
Figure 3. Changes in rates of transmitted HIVDR according to time since ART availability
Stadeli and Richman, Antiviral Therapy 18(1):115-23, 2013
Pham et al,
AIDS, 2014
Cost of continuing a regimen failing
as defined by virologic criteria
M184V + other NRTI mutation
M184V or wild type
Percent of Patients
100
80
60
40
20
0
0–8 9–16 17–24 25–32 33–40 41–48
Weeks
n = 39
34
28
24
20
16
♦ 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 crossresistance to all RTIs
Melby T, et al. 8th CROI; 2001; Chicago, Ill. Abstract 448
Rapid accumulation of DRMs when first-line ART is
continued despite virological failure
Longitudinal genotyping analysis at first detection of VF (t1) and 6-12
months after (t2)
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
How much will resistance impact the benefits of the
antiretroviral rollout in resource-limited countries?
Access to antiretroviral therapy has been a
remarkable achievement with a dramatic
impact on almost 12 million individuals in
resource-limited countries; however,
 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).
Say NO To CRAP Therapy
Continued Replication under Antiviral
Pressure
 Continued replication in the presence of drug will likely
lead to further evolution of the viral population.
 In theory, further evolution can result in a more fit, drugresistant viral population that may remain enriched in the
patient, even in the absence of drug pressure.
 This should be prevented by discontinuing the direct
acting antiviral if a patient has a confirmed increase in
HCV RNA levels while adhering to therapy.
FCHR-HCV DRAG
Stuart Ray
Prevention of acquired drug resistance
requires addressing the causes
 The patient
 adherence
 The prescribing care provider
 selecting an optimal regimen
 counseling the patient
 The drugs
 Potency
 tolerability
 pharmacokinetics
Additional factors specific to LMIC that
contribute to the emergence of HIV
drug resistance
 Suboptimal Regimens
 Thymidine analogues
 Insufficient second-line and salvage regimens
 Failure of methods and resources to monitor
viral loads
 Drug distribution (stock-outs)
 Perinatal PMTC rather than treating pregnant
women with ART (option B+)
Summary
 The principles of HIV drug resistance are well
established (Darwinian evolution).
 The mistakes and lessons learned in the
developed world are being recapitulated in low
and middle income countries.
 Prevention of further increases in drug resistance
 Better regimens
 Avoid stockouts
 Monitor viral load
 Interventions to improve adherence and
reduced risk behaviors