Download Antiretroviral resistance

ANTIRETROVIRAL
RESISTANCE
Jennifer Fulcher, MD, PhD
Outline
• What is antiretroviral resistance?
 Review HIV-1 life cycle and antiretroviral drug targets
 Define antiretroviral resistance
 Prevalence of antiretroviral resistance
• How does antiretroviral resistance occur?
 Mechanism of antiretroviral resistance
• How do we address antiretroviral resistance?
 Treatment considerations of antiretroviral resistance
 Prevention of antiretroviral resistance
History of antiretroviral therapy
1st antiretroviral
drug approved
by FDA (NRTI
class)
1981
1987
1st cases of
opportunistic
infections
described
Term AIDS
described by
CDC (1982)
Next class of
antiretroviral drugs
approved by FDA
(NNRTI class)
1995
1st protease
inhibitor
antiretroviral
drug approved
by FDA (PI
class)
New class of antiretroviral
drugs approved by FDA
(fusion & entry inhibitor
class)
1997
Combination
ART started
“drug
cocktails”
2003
2007
New class of
antiretroviral
drugs approved
by FDA (INSTI
class)
Why do we have to use combination
antiretroviral therapy?
HIV virus (viral load)
This virus has
become resistant to
the drug used
one drug therapy
combination therapy
Time
What is antiretroviral therapy resistance?
• Resistance means that the virus has mutated so that
certain drugs are no longer effective.
• Resistance is caused by mutations that occur in the HIV virus 
these mutations can cause resistance to one antiretroviral drug or
to many antiretroviral drugs
• Anytime HIV is able to multiply mutations can occur
antiretroviral drug
HIV
BLOCKS VIRUS
antiretroviral drug
HIV
mutation
RESISTANCE
HIV-1 life cycle
New virus
matures and
leaves cell
Virus binds
to and
enters cell
Host cell machinery
produces viral
proteins to make new
virus
Virus genetic material turned into
DNA that integrates into host genome
Modified from Nature Reviews Genetics 5, 52-61 (January 2004)
Classes of antiretroviral therapy
Reverse transcriptase inhibitors
(NRTIs or NNRTIs)
Virus genetic material turned into
DNA that integrates into host genome
Modified from Nature Reviews Genetics 5, 52-61 (January 2004)
Classes of antiretroviral therapy
Protease inhibitors
(PIs)
New virus
matures and
leaves cell
Modified from Nature Reviews Genetics 5, 52-61 (January 2004)
Classes of antiretroviral therapy
Integrase inhibitors
(INSTIs)
Virus genetic material turned into
DNA that integrates into host genome
Modified from Nature Reviews Genetics 5, 52-61 (January 2004)
Classes of antiretroviral therapy
Fusion and entry inhibitors
Virus binds
to and
enters cell
Modified from Nature Reviews Genetics 5, 52-61 (January 2004)
How does resistance happen?
• HIV reverse transcriptase is
very error prone – it makes at
least one mistake every time it
makes a new HIV virus
• Some mistakes don’t affect
the virus, but some of those
mistakes are in a place that
blocks antiretroviral drug
activity
• “mistake” = mutation
How does resistance happen?
• Virus without mutations is the most fit and will dominate
when no drugs are present
• However, when ARVs are present, mutations that block
antiretroviral drug activity provide an advantage to the
virus
• The virus that doesn’t have mutations will be blocked by
antiretroviral drugs and will no longer grow
• The virus that has mutations that affects antiretroviral
drug activity will continue to grow despite presence of the
drugs  these viruses are resistant
How does resistance happen?
Selective pressure from the drug allows the
mutant (resistant) virus to grow
http://www.natap.org/2006/HIV/071906_02.htm
How does resistance happen?
HIV
antiretroviral drug
antiretroviral drug
antiretroviral drug
BLOCKS
VIRUS
How does resistance happen?
• Antiretroviral drug resistance can also be transmitted
from one person to another at the time of HIV infection
• So, a person who has not yet taken antiretroviral drugs can have
resistance
Transmitted drug resistance in persons with acute/early HIV-1 in San Francisco, 2002-2009. PLoS One. 2010;5:e15510
How common is resistance?
• On average, it is estimated that 20-38% of people on
ARVs will develop resistance during therapy
• About 5 to 20% of virus that is transmitted has
resistance to at least one antiretroviral drug
What factors contribute to resistance?
• Resistance occurs when drug levels in the body are not
adequate to stop replication of the virus
 Medication adherence
 Medication absorption
 Drug-drug interactions
 Transmitted resistance
When do we suspect resistance?
1. If a patient has an increasing viral load while on ART
then we suspect there may be resistance
- This assumes the patient has been adherent in taking their
HIV medications
2. All patients are screened for resistance prior to starting
ART for the first time
- Transmitted resistance can occur about 5-20% of the time
How do we test for resistance?
• HIV Genotype Test
• This test determines the genetic sequence of the HIV virus in the
patient’s blood which is then compared to a database to identify if
mutations are present.
Blood sample taken
from patient
HIV genetic sequence
identified
Patient’s HIV
sequence is
compared to HIV
database (Stanford,
IAS-USA) then report
made which tells
which resistance
mutations are
present
Not all mutations are created equal
• Some mutations cause loss of activity for an entire class
of drugs; while some mutations only cause loss of activity
for a single drug
NRTIs
• Emtriva®
(emtricitabine)
• Epivir® (3TC,
lamivudine)
• Retrovir® (AZT,
zidovudine)
• Videx-EC® (ddI,
didanosine)
• Viread® (tenofovir)
• Zerit® (d4T,
stavudine)
• Ziagen® (abacavir)
PIs
NNRTIs
• Edurant® (rilpivirine)
• Intelence®
(etravirine)
• Rescriptor®
(delavirdine)
• Sustiva® (efavirenz)
• Viramune®
(nevirapine)
•
•
•
•
•
•
•
•
•
Aptivus® (tipranavir)
Crixivan® (indinavir)
Invirase® (saquinavir)
Kaletra® (lopinavir +
ritonavir)
Lexiva®
(fosamprenavir)
Norvir® (ritonavir)
Prezista®(darunavir)
Reyataz®
(atazanavir)
Viracept® (nelfinavir)
INSTIs
• Isentress®
(raltegravir)
• Tivicay®
(dolutegravir)
• (elvitegravir)
Not all drugs are created equal
Low barrier to resistance
High barrier to resistance
• Some drugs easily
• Some drugs are more
develop resistance; often
a single mutation is
enough to cause
resistance
 Reverse transcriptase
inhibitors (NRTIs,
NNRTIs)
“durable” and need
multiple mutations to
cause resistance
 Protease inhibitors
What do we do if there is resistance?
1. Discuss with patient why resistance may have
developed.
2. Change HIV medications to a regimen that does not
include drugs to which HIV is resistant.
- often we have to change to an entirely new class of drugs to
avoid
resistance
- the drugs to which the HIV was resistant can not be used in
future regimens
3. Continue to monitor the patient’s viral load for response
to the new medications and development of any further
resistance
What can patients do to protect against
resistance?
1. Take all HIV medications
regularly.
2. If doses are frequently
missed, talk to the doctor
immediately to discuss
strategies to improve
adherence.
3. If adherence is a problem, it
may be best to not take any
HIV medications until reasons
for non-adherence have been
addressed.
Summary & Review
• HIV reverse transcriptase is error-prone which leads to
mutations when the virus replicates
• Some mutations affect the activity of antiretroviral drugs
 resistance
• Resistance occurs when people have inadequate
amounts of antiretroviral drugs because this allows for
some replication (leading to mutations) and also selects
for the resistant virus
• Resistance mutations can affect only one drug, or can
affect an entire class of drugs
• Classes of drugs have different “barriers” to resistance
Summary & Review
• Factors that contribute to resistance are:
• medication adherence
• medication absorption
• drug-drug interactions
• transmitted adherence
• Treatment and prevention of resistance involves selecting
a new regimen that avoids drugs to which the virus is
resistant
• Underlying factors that led to resistance must be
addressed in order to both treat resistance and prevent
further resistance