2. Introductory Case: Abebech
Abebech is a 35 year old woman with HIV
infection, whom you have been following,
presents with a CD4 count of 180 cells/mm3. She
is otherwise doing fine. She delivered a healthy
baby less than 6 months ago for which she
received peri-partum single-dose nevirapine for
prevention of mother-to-child-transmission
(PMTCT). You have access to viral load (HIV-1
RNA) and resistance testing:
• The viral load is 100,000 copies/ml
• The genotype test shows mutations at K103N
3. Which of the followings are true about
Abebech?
1. She has an induced resistance to NVP at the time of
PMTCT
2. She can successfully be treated with the Ethiopian first-
line regimens
3. The resistance to NVP is recognized to exist by the
presence of genetic mutations at K103N.
4. No other drug should be used from NNRTI class as a
substitute for NVP
Introductory Case: Abebech Cont. (2)
4. 4
Unit Learning Objectives
Explain the mechanism of how antiretroviral resistance
develops
Describe the various ways of identifying resistance
Identify basic considerations for choosing the next
regimen
Describe the role of the pharmacist in reducing the risk
of resistance emergence
5. 5
Background
ARV drug resistance is a major challenge to
treatment programs for both developed and
developing countries.
Transmission of drug-resistant HIV strains is
documented and is associated with a suboptimal
virologic response to initial antiretroviral therapy.
6. 6
What is HIV Resistance?
HIV reproduces very quickly, making billions of
new viruses every day.
As HIV often makes errors while reproducing,
each new generation of viruses differs slightly
from the one before.
Some changes to the structure of the virus can
improve its ability to reproduce.
Viruses which are able to reproduce in the
presence of ARVs are said to be resistant
strains.
7. 7
Types of Resistance
1. Induced
High rate of HIV replication and high mutation rate
result in a complex and diverse mixture of drug
susceptible and resistant viruses (viral quasi
species)
This may make the virus less susceptible to ARVs
8. 8
Types of Resistance (2)
2. Primary
Patients infected with drug resistant HIV strain
Subtypes of HIV may be less susceptible to certain
ARVs
9. 1. She has an induced resistance to NVP at the
time of PMTCT
TRUE
At the time of Single dose NVP administration for
PMTCT purpose, most likely the virus was
induced to be resistant to it
Introductory Case: Abebech Cont.
10. 10
How Does Resistance Develop?
Resistance results from changes in the genetic
information (mutations) in the virus
When these mutations occur in the presence of
low levels of medications:
The drug resistant virus grows faster and better than
the drug susceptible virus
The drug resistant virus replaces the drug susceptible
virus in the patient
14. 14
Why does resistance develop in a treatment
naïve individual?
Inadequate ARV levels in the blood
Drug-drug interactions
Drug-food interactions
Non-adherence
Inadequate potency of a regimen OR individual
drugs
For example using only 2 drugs rather than 3 drugs in
an ARV regimen
15. 15
Consequences of Resistance
Drug resistance limits current drug regimen
effectiveness and future options
ART combinations fail
The disease progresses
16. 2. She can successfully be treated with the
Ethiopian first-line regimens
FALSE
Abebech can not be treated with the Ethiopia first-
line regime which contains either NVP or EFV.
She should be initiated on second-line drugs
containing PIs.
Introductory Case: Abebech Cont.
17. 17
How can you recognize resistance?
Failure of therapy defined by
Clinical criteria of disease progression
Falling CD4 Count
Virologic failure:
Resistance Testing is the best way to detect
resistance
18. 18
Resistance Testing
Two types of resistance testing
Genotyping
• Detects drug resistant mutations on the virus genome
that make the virus resistant to certain ARVs
• Less expensive
• Usually can be completed in 1-2 weeks
Phenotyping
• Measures the ability of viruse to grow in the presence
of various concentrations of ARVs
• More expensive
• Usually takes 2-3 weeks to complete
19. 19
Genotyping
Identifies mutations
Does not measure susceptibility of virus to drugs
Cannot easily be related directly to phenotypic
resistance
May not be useful to select/adjust drug therapy
20. 20
How to Identify a Mutation in HIV?
“M” is the “wild
type” amino acid
“184” is the
codon position
M 184 V
“V” is the mutant
amino acid
M184V indicates a mutation in codon 184 of the reverse transcriptase gene leading
to a valine for methionine substitution in the reverse transcriptase enzyme.
21. 21
Phenotyping
Measures susceptibility of virus to drugs (IC50)
Drug susceptibility more useful for drug therapy
modifications than mutation presence
Needed to establish the effect on a given
genotype and the resulting phenotype
22. 3. The resistance to NVP is recognized to exist by
the presence of genetic mutations at K103N.
TRUE
After genotyping, if mutations such as K103N
occurs, suggesting drug-resistance for NVP
Introductory Case: Abebech Cont.
23. 23
Suspect Resistance in the
Setting of Treatment Failure
Due to HIV’s high transcription error rate + high
level of replication, mutant HIV variants
constantly generated
The variants often contain mutations that confer
variable levels of resistance to antiretroviral
agents
Poor adherence or suboptimal regimens can
lead to resistance and ‘viral breakthrough’
24. 24
Considerations for the next regimen
Resistance testing is not currently an option in
Ethiopia
Key Points to consider in cases of treatment
failure:
Potential for cross resistance
Resistance is not an all or nothing phenomenon
Make empirical choices
25. NRTI Resistance
Mutations Selected by Comment
TAMs (41, 67, 70,
210, 215, 219)
AZT , d4T Reduce activity of
all NRTIs
M184V 3TC Reduces activity
of ddI, FTC, 3TC;
increases activity
of AZT
K65R, 74V ddI, TDF, ABC Protects against
TAMS
27. Tale of Two Mutations
184V 103N
Induction 3TC or FTC NVP or EFV
Requirement > 3 wks Rx single dose
Increase resistance
3TC
NNRTI
1000 fold
------------
------------
1000 fold
Cross-resistance 3TC/FTC NNRTI
Fitness Decreased No change
Collateral effect ↑ AZT, d4T activity No benefit
Utility of Drug Great None
28. Comparison between Resistances on
NNRTIs and PIs
NNRTI PI
Effectiveness Excellent Excellent
Failure Single mutation
leads to class
resistance
Requires
multiple
mutations
Options in class None* Many
Continued use
with failure
No benefit Increasing PI
mutations
*Etravirine could be an option but not available in Ethiopia
29. 29
Cross-Resistance
Resistance to one drug can cause resistance to
others of the same class
NRTI: partial cross-class resistance
NNRTI: complete cross-class resistance
PI: partial cross-class resistance
• Partly overcome by ritonavir boosting
30. 30
Cross Resistance: Nucleoside Analogues
Cross resistance exists between
ZDV and D4T
3TC and FTC
Susceptibility to ZDV, D4T and TDF is
increased with 3TC resistance
Tenofovir requires the accumulation of a number
of mutations before it’s effectiveness is affected
It is not associated with cross resistance to
nucleosides
31. 31
Cross Resistance: Nucleoside Analogues (2)
3TC resistance is caused by a single mutation
May lead to cross-resistance against ABC and DDI
DDI can still be used as it is less affected by
mutations developed by 3TC, ZDV and D4T
High level resistance to both ZDV and 3TC =
resistance to abacavir
32. 32
Cross Resistance: Nucleoside Analogues (3)
What does this mean for a second line
nucleoside backbone?
If 3TC was used in the initial regimen, do not use it
again
If not used in the first line regimen, use ZDV with
caution
ABC+ DDI should be used with caution
• Especially in the presence of long-standing failure
The nucleoside backbone of DDI + TDF should retain
activity against resistant strains
33. 33
Cross resistance: NNRTIs
Emerges quickly
Caused by a single mutation
Development of resistance to one NNRTI will
lead to resistance of all other NNRTIs
Do not sequence if failure has occurred
Risk of resistance when stopping an NNRTI
34. 34
Cross resistance: PIs
Some mutations are selected for only by certain
protease inhibitors (Nelfinavir)
Considerable overlap
PIs with activity after failure of an initial PI
include lopinaivr/r or atazanavir/r
35. 35
Cross Resistance: PIs (2)
What implications does resistance have on a
choice of PI for the 2nd line regimen?
A ritonavir boosted component is recommended
LPV/r preferable to NFV due to their effectiveness
36. 4. No other drug should be used from NNRTI class
as a substitute for NVP
TRUE
Since there is a cross-resistance within NNRTs,
hence, in case where there is resistance to NVP,
there will also be resistance to EFV.
Introductory Case: Abebech Cont.
37. 37
Reducing the Risk of Resistance
Involve patients in adherence plan
Involve families and friends of the patients
Educate patients
ARVs are not like other medications
Drug interactions
Provide medication counseling
Patient needs to know where to go for help
38. 38
Reducing the Risk of Resistance (2)
Prevent
drug-drug interactions
drug-food interactions
Suppress viral load
The lower the viral load after starting treatment, the
longer it will be controlled
Take care when changing to new drugs
39. 39
Reducing the Risk of Resistance (3)
Need for new combinations:
Rising viral load
Failing health
Switch early
40. 40
Infection with Drug-resistant HIV
Transmission of drug-resistant virus
Widespread use of ARVs
Pregnancy
Becoming infected with a drug-resistant strain
may seriously limit a person’s treatment options
Similar to developing resistance while taking
treatments
Narrows down the range of drugs that the patient
benefits
41. 41
Selection of Drug-resistant HIV-1
During Therapy to Reduce MTCT
With ARV drugs or drug regimens that do not
fully suppress viral replication there may be:
Selection for pre-existing resistant viral populations
Development of new mutations
Results:
Decrease ARV effectiveness of future treatment that
contains the same drug, or drugs within the same
class
Benefit greatly outweighs the risk
42. 42
Selection of Drug-resistant HIV-1
During Therapy to Reduce MTCT (2)
ZDV-resistant virus not selected by short-course
ZDV in treatment-naïve pregnant women
With longer courses, it is selected & transmitted
3TC-resistant strain is selected in ~40% of
women after 2 months of ZDV + 3TC
Nevirapine-resistant strain is selected in mothers
and infants
Decays rapidly in mothers
Resistant virus appears prominent in milk
43. 43
Minimize Emergence of
Viral Resistance
Never prescribe ARVs in the absence of
adherence counseling and support
Never prescribe mono-therapy or dual therapy
Ensure optimal serum drug concentrations
Avoid drug interactions
Diagnose and manage malabsorption
If ARV medications are to be discontinued, stop
all drugs at the same time
Possible exception: NNRTIs
44. Role of Pharmacists in Delaying HIV
Resistance
Pharmacists can play an important role in
delaying the occurrence of HIV resistance by:
Involving patients as active participant in their
adherence plan.
Involving their families/friends to assist them in
minimizing barriers to medication adherence.
Providing medication counseling and act as a
resource to assist patients with adverse effects to
prevent discontinuation of therapy.
Educating patients about potential drug-interactions
leading to resistance.
45. 45
Key Points
Resistance develops when HIV mutants emerge
which can reproduce in the presence of a drug
Resistance is an important reason why HIV
drugs fail
More missed doses means resistance is more
likely
Drug interactions and poor absorption can also
contribute to resistance
46. 46
Key Points (2)
Virus populations can develop resistance to
more than one drug; this is why combination
therapy may fail
Continuing on failing drugs encourages
resistance
Cross-resistance occurs because some drugs
share resistance mutations
Pharmacists play important role in prevention
and early detection of HIV resistance through
patient education.
Editor's Notes
Notes:
Step 1: Unit Introduction and Learning Objectives
Step 2: HIV Resistance to ARVs
Step 3: Key Points and Unit Summary
Notes:
Ethiopia can learn from the experiences of the developed countries, i.e., proper initiation of potent regimens, incorporation of culturally appropriate adherence training and maintenance programs, and synchronization with drug resistance surveillance and monitoring initiatives.
WHO recommends that countries planning to implement ART programs should concurrently introduce HIV drug resistance surveillance systems. This will allow countries to detect potential drug resistance at the population level and to modify recommended treatment regimens accordingly.
Testing for resistance to ARVs is not currently a possibility in Ethiopia. Principles of resistance will be useful when choosing a second line regimen.
Notes:
Some of these errors produce viruses which are defective and so can't reproduce themselves well. Over time these 'less fit' viruses will die off.
Researchers estimate that every possible error that might appear in HIV's structure occurs once every day if virus production is not being suppressed. This means the seeds for a drug resistant crop of viruses are being sown every day, and these viruses will be the ones which grow best when a patient starts taking anti-HIV treatment.
Notes:
You can see why if any of these mutations can confer some selective advantage to the virus, such as a decrease in its susceptibility to an ARV, the corresponding species will overtake the others. The rapidity of this process depends on the level of the selective advantage conferred by the mutation, prevalence of the mutation within the virus population and the level of drug at the site of HIV replication.
Combination therapy (HAART) can block the development of resistance for two reasons.
First: Multiple mechanisms (each requiring different mutations) are required for resistance to occur to all drugs in the regimen. Even if a small number of variants with the potential for resistance to individual agents exist before treatment, it is highly unlikely that some of those variants are able to resist all the drugs. HAART targets these multiple mechanisms.
Second: Multiple ARV agents suppress viral replication better than single agents. In the absence of viral replication, the generation of new variants is arrested. If a patient is taking HAART, the virus can only replicate if the levels of the drug are insufficient (poor absorption, non-adherence, etc)
Notes:
Some subtypes of HIV-1 can be less susceptible to protease inhibitors and NNRTIs than the subtype B strains that are available in the US and Europe. More information is needed on this subject.
Non-B subtypes are dominant in Africa and Asia.
Notes:
Resistance can emerge whenever HIV continues to reproduce whilst anti-HIV drugs are being taken. HIV can develop resistance to all available anti-HIV drugs, but if they are taken together in a combination, resistance can be delayed. This is because together, the drugs are able to exert a much more powerful effect on HIV, and because it’s much more difficult to emerge for an HIV population which is resistant to all of the drugs in the combination, rather than to only one drug.
Some mutations (or changes) in the virus allow certain viruses to resist the effects of one or another antiretroviral drug
Each infected person has a mixture of viruses, some of which are resistant to some medications
Notes:
This slide is a schematic showing that some HIV variants will still be stopped with HAART, but other HIV variants will continue replicating. In many resistant viruses, the wild type virus will usually be suppressed but other variants are not.
When a resistant virus assumes the role of predominate viral type it will cause the viral load to increase. An increased viral load may be the first indication of resistance. (While the resistant virus is predominating the ARV continues to control the drug susceptible population which in over time becomes smaller and smaller).
Notes:
This slide shows that when a patient is adherent, the drug blood levels are high enough to keep all virus variants suppressed. However, once doses of medications are missed, the plasma drug level falls to a level that allows the drug resistant virus to overgrow the drug-sensitive virus.
From this slide you can see the role that ADHERENCE plays in the control of HIV. Missing even one dose of ARV can allow escape of virus and promote resistance. In order for ARV to be effective the patient must adhere to more than 90% of the doses of medication or resistance is likely.
Notes:
Some potential causes of the development of drug resistance in a patient naïve to therapy include:
Inadequate ARV levels in the blood, which can be attributed to:
Drug-drug interactions (which may decrease the amount of drug in the blood to below the levels which inhibit viral replication)
Drug-food interactions (which may decrease drug absorption and lead to low levels of drug at the site where HIV replication occurs)
Non-adherence to the dosage schedule
Another example would be a patient with a large amount of virus in their blood who would need a very potent regimen to control viral replication. In this situation, the three drug regimen would have to be very potent, in addition to the nucleoside backbone, if using a protease inhibitor Lopenavir/r or SQV/r would be a better choice than nelfinavir due to their potency.
Notes:
In general, most of the failure in the first 24 weeks of treatment using recommended HAART regimens is due to lack of adherence or lack of potency, and most late failures that follow good viroloigc response are due to resistance.
Clinical criteria of disease progression
New or recurrent OI
Do not confuse with immune reconstitution syndrome
Onset or recurrent WHO Stage III condition
Falling CD4 Count
Fall of >50% from the peak
Return to baseline or below
Virologic failure:
Failure of viral load to become undetectable (failure to suppress)
Reappearance of detectable virus after a period of undetectability (loss of virologic control)
Less than one log (10-fold) decrease in viral load from baseline after 8-12 weeks of ART
Note:
As genotyping and phenotyping assays are not currently available in Ethiopia, this curriculum will not focus on the mutations that may be observed, rather with practical applications derived from these assays to assist with choosing second line regimens.
Notes:
Genotyping assays detect drug resistance mutations that are present in the relevant viral genes (reverse transcriptase and protease).
Certain genotyping assays involve sequencing of the entire reverse transcriptase and protease genes, whereas others use probes to detect selected mutations that are known to confer drug resistance. Interpretation of test results requires knowledge of the mutations that are selected for by different ARV drugs and of the potential for cross resistance to other drugs.
Note:
So here, we see that a mutation has occurred for the amino acid encoded at position 184.
Notes:
Recombinant phenotyping assays involve insertion of the reverse transcriptase and protease gene sequences derived from patient plasma HIV RNA into the backbone of a laboratory clone of HIV either by cloning or by in vitro recombination.
Replication of the recombinant virus at different drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference HIV strain.
Drug concentrations that inhibit 50% and 90% of viral replication IC 50 and IC 90 (the median inhibitory concentration) are calculated and the ratio of the IC50 of test and reference viruses is reported as the fold increase in IC50 (fold resistance).
Interpretation of phenotyping assay results is complicated by the lack of information regarding the specific resistance level (fold increase in IC50) that is associated with drug failure, although clinically significant fold increase cutoffs are now available for some drugs. Again, consultation with a specialist can be helpful for interpreting test results.
Notes:
Due to HIV’s high transcription error rate + high level of replication, mutant HIV variants are constantly generated
These variants often contain mutations that confer variable levels of resistance to antiretroviral agents
Poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’
Notes:
Key Points to consider when choosing a new regimen in the event of treatment failure in order to increase the likelihood of treatment success and minimize the risk of cross resistance:
Potential for cross resistance exists in all ARV classes
Resistance is not an all or nothing phenomenon and generally increases over time. Exceptions are resistance to 3TC and NNRTIs which occur after a single mutation.
Make empirical choices to provide a regimen with as much antiviral activity as possible
Notes:
NRTI Resistance
AZT resistance: is associated with the mutations at reverse transcriptase codons 41, 67, 70, 215, and 219. Those codons at 41, 215, and 219 are most important. Three to 6 mutations result in 100-fold decrease in sensitivity.
3TC Resistance: rapid development of resistance, and a single point mutation (M184V) is sufficient for loss of effectiveness. That is due to specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine (M) residue to either isoleucine or valine (V).
d4T resistance: In vivo d4T resistance is mediated primarily by thymidine analogue mutations (TAMs) (e.g. 41L, 67N, 70R, 210W, 215Y/F, 219Q/E). As with ZDV, the M184V mutation associated with 3TC resistance appears to increase susceptibility to d4T.
DDI resistance: mutations at reverse transcriptase codon 74 are most important. It causes 5 to 26 fold decrease in didanosine susceptibility. Additional mutations at codons 184, 65, 135, and 200 also have been associated with resistance.
TDF resistance: Susceptibility is decreased in patients with three or more TAMs that include 41L and 210W mutations. Susceptibility is increased with 184V mutations, which is why 184-high level 3 TC resistance increase activity of TDF.
ABC resistance: ABC selects primarily for 74V, and to a lesser extent K65R and 115F. The 184V mutation does not significantly decrease ABC susceptibility unless there are TAMS.
Notes:
For some drugs (NNRTIs and 3TC), a single mutation causes high-level resistance. This can lead to failure of certain drugs very quickly – such drugs are said to have low genetic barrier for resistance.
For others (NRTIs and PIs), many mutations must occur for high-level resistance to occur. Resistance to these drugs occurs more slowly – while such drugs are said to have high genetic barrier for resistance.
Notes:
Currently, a newer analogue, Etravirine (ETV) from the NNRTI class, has been approved; however this drug is not available in Ethiopia.
Notes:
Once resistance to one drug has emerged, this virus population may also be resistant to drugs a patient has not yet taken. This is called cross-resistance.
Notes:
Resistance to AZT and 3TC may mean resistance to abacavir. Abacavir can probably be used after the development of resistance to 3TC, providing that three or less TAMs are present (maybe in the setting of recent failure)
There is now substantial evidence of cross resistance between AZT and d4T, with both drugs causing ‘AZT-associated’ mutations or TAMs. d4T after ZDV, or ZDV after d4T, may be less effective if TAMs have developed.
TAMs reduce the antiviral activity of both d4T and AZT.
Notes:
There is a significant degree of cross-resistance between some nucleoside analogues, which can lead to problems in selecting pairs of nucleoside analogues for use in combination therapy for someone who has already received extensive nucleoside treatment.
ZDV resistance occurs less frequently when the drugs are paired with 3TC, although there is wide variation in the frequency of thymidine analogue mutations in patients experiencing failure of first-line therapy (<1% - 30%).
Where nucleoside analogues have been used as the backbone of the first regimen, data on resistance patterns have the following implications for sequencing of nucleoside analogues (NRTIs):
3TC resistance may lead to cross-resistance against abacavir and ddI, and vice versa. Where a 3TC-containing regimen is used as first-line treatment, it is highly likely that 3TC resistance will emerge if the regimen fails. Resistance to d4T or AZT is far less likely to emerge (< 10% of patients), and one study suggests no loss of sensitivity to these drugs in people without genotypic resistance, suggesting that these drugs can be used again later.
However, DDI can be used after the development of resistance to 3TC (it is not affected by 3TC resistance), and is not seriously affected by the development of AZT and d4T-associated mutations (thymidine analogue mutations, or TAMs). It is clear that there is considerable cross-resistance among the NRTIs. However, multi-nucleoside resistance mutations may not blunt the effectiveness of all NRTIs. Researchers investigated the effectiveness of NRTIs against multi-nucleoside resistant virus in the test tube and found that ddI response was less affected than 3TC, d4T or AZT (ddI has proven to be effective in the presence of multiple nucleoside analogue mutations), suggesting that ddI may be a more attractive candidate than other NRTIs for `recycling' in a salvage regimen if such mutations are present.
Notes:
When D4T or ZDV +3TC are used as part of the first-line regimen, nucleoside cross-resistance may compromise the potency of alternative dual nucleoside components in the second line regimen, especially in the presence of long-standing virological failure. In this situation, it is necessary to make empirical alternative choices with a view to providing as much antiviral activity as possible.
If 3TC was used in the initial regimen, do not use it again. Where a 3TC-containing regimen is used as first-line treatment, it is highly likely that 3TC resistance will emerge if the regimen fails. This precludes the use of FTC as well.
Despite the emergence of resistance to AZT, there is evidence that people who take AZT as part of their first antiretroviral regimen have a better chance of viral suppression when they switch to a regimen containing d4T, compared with people who start with d4T and switch to AZT.
Given the cross resistance between D4T and ZDV, second line regimens that might offer more activity include TDF/DDI or ABC/DDI. The issue of cost and drug hypersensitivity with ABC, however, remain. Furthermore, high-level ZDV/3TC co-resistance confers diminished susceptibility to ABC.
Tenofovir can be compromised by multiple nucleoside analogue mutations but often retains activity against nucleoside resistant viral strains.
Notes:
Among people on combinations containing non-nucleoside reverse transcriptase inhibitors (NNRTIs, e.g. efavirenz, nevirapine, delavirdine), resistance readily emerges to the NNRTIs if HIV is not quickly and fully suppressed to very low levels.
This is because a single mutation can confer high level resistance to an NNRTI. Consequently, NNRTIs should only be used as part of powerful combinations containing at least three anti-HIV drugs which can reduce HIV levels below the limits of detection.
Risk of resistance when stopping an NNRTI: The NNRTIs have a long half-life - which means that the body clears these drugs slowly. This means that if a patient stops taking all the drugs at the same time, low levels of the NNRTIs may remain in blood after the other drugs have gone. This can put them at increased risk of NNRTI resistance.
When considering stopping a regimen which includes an NNRTI, consider staggering the discontinuation of the drugs.
Notes:
Example of certain protease inhibitors:
If Nelfinavir is used as the initial PI, it selects mutations that are not cross resistant to other PIs. With the acquisition of additional mutations, other PIs will become less susceptible.
There is considerable overlap between combinations of mutations in HIV strains that develop resistance to PIs.
This explains the wide cross resistance that is observed within this drug class.
Along with mutations to additional PIs (L10I, M36I, I54V, A71V) the afore mentioned mutations are likely to predict poor response to all currently available PIs. However, lopinavir often retains activity after failure with other PIs.
Notes:
Answer: NFV can be considered as an alternative for the PI component of the 2nd line regimen if a ritonavir enhanced PI is not available, if a cold chain is not secure or if there is a clinical contraindication to the use of another PI. The role and availability of other PIs cannot be fully specified at the moment.
Ritonavir boosted regimens may overcome low level resistance. This may be especially important for the second line regimen when some nucleoside mutations exist.
Notes:
Suppress viral load: Keep viral load under control by excellent adherence to treatment – counsel the patient to take the treatment as prescribed.
People whose viral load falls and remains below 50 copies when they start treatment are at a lower risk of developing resistance than people whose viral load does not fall that low. The current standard is for anti-HIV treatment to use three drugs.
In the absence of viral load tests, the signs that treatment is failing will be:
Falling CD4 cell count (where CD4 testing is available)
Return of symptoms, indicating that the immune system is declining once again
Take care when changing to new drugs: merely adding a single new drug to a combination which is not keeping viral load fully suppressed can allow resistance to that drug to emerge rapidly, because the impact of that one drug is unlikely to be enough to stop HIV reproducing.
Notes:
It wastes that drug. If a combination is unable to fully suppress HIV, the patient should be switched to a regimen with all new drugs, if possible to give the best chance that the new combination will work.
Where resources allow, the replacement drugs should be chosen with help from a test to detect whether the virus is resistant to particular drugs.
If drugs are being switched because of adverse effects, and the patient’s viral load is suppressed, this does not present the same risk of resistance emerging. In this situation, just a single drug may be changed.
Notes:
The speed at which resistance develops to different anti-HIV drugs is variable. HIV needs only one mutation to become fully resistant to 3TC, to efavirenz and to nevirapine. This simple change (just a single mutation) can happen easily, even at quite low levels of viral load rebound.
Full resistance to the other drugs may require a particular pattern of several mutations to emerge. This will take a little longer and will happen only if these drugs are taken while there is ongoing HIV reproduction. In other words, this will be more of a risk if a patient continues to take the drugs while their viral load is rebounding. The higher the viral load rebounds, the greater the risk that a drug-resistant pattern of mutations will develop.
For this reason, a rising viral load should signal the need to consider changing to a new combination, so long as there are options to switch to. However, regular viral load monitoring may not be possible in some settings.
Notes:
Transmission of drug-resistant virus:
With the widespread use of anti-HIV drugs in many parts of the world and the accompanying problem of drug resistance, it’s become more common for people who contract HIV to be infected with a drug-resistant strain.
This can happen either through sexual transmission, through contact with infected blood (for example through injecting drugs), or from an HIV-positive mother to her baby.
Pregnant women that receive ARV therapy during pregnancy may transmit resistant virus to their babies.
Whether someone who is already HIV-positive can become infected a second time with a drug-resistant strain is much less clear. Though there is some evidence that it may occur, it’s difficult to know how great the risk is.
There are currently no data to indicate that drug-resistant viruses are more virulent than non-resistant viruses.
There is currently no evidence that drug-resistant viruses are more transmissible than non-resistant viruses.
Notes:
Selection of resistant viral populations:
More likely to rapidly occur with drugs in which a single mutation is associated with development of drug resistance; i.e. 3TC (with and without concomitant ZDV treatment) and Nevirapine.
Virus containing drug resistant mutations decreases in amount once antiretroviral drug prophylaxis is discontinued, and wild type virus dominates. However, the mutant virus may remain present in an individual at very low levels.
It is unknown if such low-level drug resistance would affect the efficacy of the antiretroviral prophylaxis regimen if used in a subsequent pregnancy.
The WHO concluded that the benefit of decreasing mother–to-child HIV transmission with these antiretroviral drug prophylaxis regimens greatly outweighs concerns related to development of drug resistance.
Notes:
Short course is begun at 36 weeks.
Long course is started at 28 weeks.
Drug-resistant virus in infants: unclear if transmitted or selected by postnatal treatment.
Mutations in infant differed from those in mothers, suggesting selection in infants or transmission of minor genetic variant.
Notes:
Providers can play an important role in delaying the occurrence of HIV resistance through good prescribing practices and assisting patients in achieving adherence.
Mono-therapy or dual therapy may be used for PMTCT or for post-exposure prophylaxis only but should not be used as HAART therapy.
Adherence is the responsibility of the provider. Irresponsible prescripion practice results in non-adherence and resistance.
Factors that will contribute to adherence and decrease resistance:
Pre-prescribing
Patient education
Psychosocial support
Demonstration of likely success by adherence to care
Verbalized understanding of HIV, ARV and adherence
Non-chaotic lifestyle
*MOST EXPERTS RECOMMEND STAGGERING DISCONTINUATION OF NNRTI BASED REGIMEN (STOP NRTI BACKBONE 7-14 DAYS AFTER STOPPING NNRTI)
Notes:
Pharmacists can play an important role in delaying the occurrence of HIV resistance by assisting patients in remaining adherent to their regimens:
Involve patients as active participant in their adherence plan. Identify possible barriers to adherence prior to starting medication.
Involve their families/friends to assist them in minimizing barriers to medication adherence.
Educate patients on the importance of adherence in the prevention of resistance.
Antiretroviral therapy is not like other medications. Other medications (not antibiotics) will not become less effective over time if a dose is missed, example: if the dose of an antihypertensive is missed, their blood pressure may go up slightly and then will come back down again once therapy is restarted.
Be aware of concomitant medications and treatments and their potential to interact with ARV therapies.
Help patients to understand how drug interactions can lead to antiviral resistance and treatment failure.
Provide medication counseling and act as a resource to assist patients with side effects to prevent discontinuation of therapy .
If the patient experiences problems, they must know who to go to for advice. Can they ask questions of the pharmacist or should they go to their doctor? Where can they go in the evening?
The goal is to help them successfully continue on their medications, to overcome initial side effects and stay on their regimen for a long while.
