Download Dr deOliveira - Will Drug Resistance Jeopardize the

Will Drug Resistance Jeopardize the
National HIV Drug Resistance
Programme?
Prof. Tulio de Oliveira
Africa Centre for Health and Population Studies, University of KwaZulu-Natal,
South Africa
Research Department of Infection, University College of London (UCL), U.K.
Southern African Treatment Resistance Network (SATuRN)
AWACC
“19 – 20 November 2015”
http://www.bioafrica.net/saturn/
Question 1: Will drug resistance jeopardize the
National HIV treatment?
A) Yes
B) Maybe
C) No
D) No idea
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SATuRN Vision
Develop advanced yet affordable HIV & TB drug
resistance diagnostics, implement it at primary
health care clinics in resource limited settings and
create a collaborative system for surveillance,
research and capacity building.
SURVEILLANCE
& RESEARCH
ADVANACED
DIAGNOSTICS
COLLABORATION &
CAPACITY BUILDING
What is the SATuRN?
a network consisting of biomedical scientists, clinicians,
epidemiologists and public health experts
SATuRN managed at the Africa
Centre/UKZN and and the SA-MRC
CURRENT PARTNERS includes 24 partners
in southern Africa
DIAGNOSTIC, DATABASE AND RESEARCH
More info at www.bioafrica.net
Collaborators & implementation sites
info at www.bioafrica.net/saturn/
De Oliveira et al. Nature 2010
Libin et al. Bioinformatics 2013
Manasa et al. Database 2014
Surveillance of Drug Resistance Mutations (SDRM)
in treatment naïve patients?
No. TDR was detected in 2010.
2011 and 2012 both had 18
participants with any SDRM,
4.7% and 7.1% respectively
The majority of the mutations
were NNRTI (103, 106), which
provide resistance to EFV.
Manasa et al., CROI & HIVDR 2015
Manasa et al. ARHR, in review
Question 2: Is transmission of drug resistance
increasing?
A) Yes
B) No
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Question 3: Will individuals with resistance to 1/3
drugs on fixed dose combination suppress on
ART?
A) Yes
B) No
C) More research need to see the long term
effects
D) A & C
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Transmitted drug resistance and
suppression.
Germany: Overall prevalence of TDR remained stable at a rather
high level (12%).
No significant differences in the frequency of virologic failure
were identified during first-line cART between patients with
TDR and fully-active cART, patients with TDR and non-fully
active cART and patients without TDR.
Overall, TDR prevalence in Uganda was relatively low (i.e <
10%) and its presence did not always imply treatment failure.
Zu Knyphausen et al. 2014
Lee et al. 2014
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Virological failure and drug resistance?
Adult*
2010-2013
(n=516)
Children*
2011-2013
(n=108)
High-level of resistance
on patients failing 1st line
Estimates of HIVDR
prevalence
87%
84.3%
Estimates of HIVDR to >= 2
drugs
82%
70.5%
Long time on failure give
rise to potential for
transmission.
GSS for the standard 2nd line
regimen <2, suggesting a
compromised regimen
17%
7%
Viral suppression after
genotype
69%
Results
Non-fixed dose
combination.
60%
Average time on therapy
47 months
39 months
Average time on failing
regimen
27 months
20 months
*Approximately 15% of Adults and 35% children failing
regimen after 24 months
Manasa et al. ARHR 2010
Manasa et al. PLoS One 2013
Pillay et al. AIDS Res Ther 2014
Question 4: Which of the factors are involved in
the development of failure and drug resistance?
A) Adherence
B) Poor absorption
C) Toxicities
D) Social issues
E) All of the above.
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Virological failure and drug resistance?
Sergio Carmona and Wendy Stevens (NHLS) presented data
from the Global Fund survey, including analysis of
resistance in pre-treatment populations, patients failing
NNRTI-based regimens and patient failing PI-based
regimens
– Acquired HIVDR 1L: 793 sequences; median time on
ART 36 mo; 96% with drug resistance ~ 4% WT.
– 92% of the patients with drug resistance to 1st line
susceptible to 2nd line!
Carmona, HIV Drug Resistance National
Workgroup, NICD, Oct 2015.
Gene sequencing in the clinic: HIV resistance testing
Many ‘resistance mutations’ have been defined for HIV - these are changes in viral
protein sequence that are associated with decreased susceptibility to specific drugs
Mutations in the reverse transcriptase gene associated with resistance to nucleoside and nucleotide reverse transcriptase inhibitors
IAS-USA 2008
Question 5: Why most of patients with resistance
to first line will be susceptible to second line?
A) No cross resistance between TDF and
AZT
B) Potent PI inhibitor (LPV/r)
C) A & B
D) None of the above
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EARNEST Trial design
HIV positive adolescents / adults (n=1200)
1st line NNRTI-based regimen >12m; > 90% adherence last 1m
Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria
RANDOMIZE
PI + 2-3 NRTIs
(NRTIs according to local
standard of care)
PI + RAL
(12 wk induction)
PI + RAL
PI
(Monotherapy)
FOLLOW-UP FOR 144 WEEKS
Primary outcome at week 96:
Good HIV disease control – defined as all of:
 Alive and no new WHO4 events from 0-96 weeks AND
 CD4 cell count > 250 cells/mm3 at 96 weeks AND
 VL<10,000 c/ml OR >10,000 c/ml without PI res. mutations at 96 weeks
Paton N et al. NEJM 2014
Hypothesis
The efficacy of NRTIs is likely to be compromised by
cross-resistance from multiple mutations arising during
first-line therapy, and the drugs carry well-recognized
risks of toxic effects.
We hypothesized that combining a boosted
protease inhibitor with raltegravir, a heat-stable
integrase inhibitor, to create a second-line regimen
with two completely new drug classes that
would not be compromised by resistance selected
from first-line therapy would sufficiently increase
efficacy and decrease toxicity to justify the increased
cost of the regimen.
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Primary endpoint at 96 weeks
Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96
•
•
•
Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono+: 56%
Risk diff (95% CI): PI/RAL – PI/NRTI:
+4.2% (-2.4%,+10.8%; P=0.21)
Risk diff (95% CI): PImono+ – PI/NRTI:
-4.1% (-10.8%, +2.6%; P=0.23)
P<0.0001
P=0.08
Paton N et al., IAS 2013; WELBB02
Second line failure and
resistance?
• Many publications show that <25% of the patients
failing second line therapy develop high-level
resistance to PIs.
• The majority without resistance will suppress if
adherence is increased.
• Patients failing second line with resistance have
access to third line regimens in South Africa.
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Conclusion
I believe that the NDoH have done a great job on
establishing new treatment guidelines.
These involved recently change of the first, second and
third line regimens. Furthermore, the use of FDC and
TDF in first line and AZT in the second line allowed that
cross-resistance not to become a problem.
Low levels of PI resistance in second line failure suggest
that patients will suppress with better adherence support.
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Question 1: Will drug resistance jeopardize the
National HIV treatment?
A) Yes
B) Maybe
C) No
D) No idea
E) None of the above.
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More info: www.bioafrica.net/saturn
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