6. hiv antiretroviral resistance

05/03/2023 FACE CONSORTIUM 1

Viral load Monitoring Sensitisation meeting

29/4/16

Session 6 HIV ARV Resistance

ZAPPT


Introduction

• Drug resistance a significant obstacle in the fight against AIDS

• Resistance = poorer clinical outcomes

• What about transmitted resistance?


Big question….

• How seriously must we take resistance?


CDC Survey: DrugCDC Survey: Drug--Resistant HIV Resistant HIV Among Newly Diagnosed PatientsAmong Newly Diagnosed Patients

Prevalence of Drug Resistance (%)Prevalence of Drug Resistance (%)

1.31.33.03.0

1.71.7

7.77.7

10.710.7

2000 2000 (n=299)(n=299)

3.13.11.31.300>>2 drug class2 drug class2.82.80.80.800PIPI

8.48.42.12.10.40.4NNRTINNRTI

7.17.17.17.15.15.1NRTINRTI

14.514.58.88.85.55.5Resistance to:Resistance to:

Any drugAny drug

20032003--20042004(n=787)(n=787)

1999 1999 (n=239)(n=239)

1998 1998 (n=257)(n=257)

Bennett D, et al. 9th CROI, Seattle, 2002. Abstract 372.Bennett D, et al. 12th CROI. Boston, 2005. Abstract 674.


HIV drug resistance (HIV DR)

• It poses a significant threat to the success of national HIV programmes

• HIV DR results in more rapid VF among people receiving 1st line regimens and ↑ the need for 2nd line regimens more toxicity, adverse events, poorer adherence and ↑costs

Source : WHO “Consolidated guidelines on the use of ART for treating & preventing HIV infection - 30th June 2013 p.226


HIV drug resistance (HIV DR)

• Affects the ability to prevent HIV using ARV-based pre- or post-exposure prophylaxis or topical microbicides TasP will also be affected

• 1st case of PREP failure already reported

• Early warning indicators and surveys important too

Source : WHO “Consolidated guidelines on the use of ART for treating & preventing HIV infection - 30th June 2013 p.226


HIV DR Early Warning IndicatorsEWI %

1. Prescribing practices (% of initial ART prescriptions congruent with national/WHO guidelines)

100

2. Loss to follow-up (% of patients lost to follow-up at 12 months) <20

3. Loss to follow-up (% of patients lost to follow-up at 12 months) <20

4. On-time pill pickup (% of patients with 100% on-time drug pickups during the first 12 months of ART, or during a specified time period)

>90

5. On-time clinic appointment keeping (% of patients who attended all appointments on time during the first 12 months of ART, or during a specified time period)

>8

6. Drug supply continuity (% of clinics with antiretroviral drug supply continuity during a 12-month period)

100

7. Adherence as measured by pill count (% patient adherence to antiretroviral therapy by pill count or other standardized measure)

>90

8. Viral load suppression 12 months after ART initiation (% of patients with viral load <1000 at 12 months)

>70


WHO Early warning indicators

• Early warning indicators include: ART prescribing practices, drug supply continuity, adherence to ARV regimens, RIC, VL suppression

• Surveys of the following are important : acquired HIV drug resistance, pre-treatment drug resistance, transmitted drug resistance, resistance among < 18 months age


Types of drug resistance (DR)

Secondary (or acquired or induced)

Most common type of drug resistance,

and occurs when HIV continues to replicate in the presence of ART.

In order for this to happen, the level of the drug should be too low

to block viral replication, but high enough to exert a positive

selection pressure on the virus

Primary (or Transmitted) = TDR

Patients are sometimes primarily infected with

a resistant virus. The most common reason

is that a patient is infected by a partner (or a mother) who has

developed drug resistance

Source : HIV & TB Drug resistance 2013 p.2


Manifestations of Resistance

• Three types of resistance: – Clinical resistance: HIV multiplies rapidly in the

body even though one is taking ARVs. Manifests as higher viral load, lower CD4 count, or OIs

– Phenotypic resistance: HIV multiplies in a test tube when ARVs are added

– Genotypic resistance: The genetic code of HIV has mutations that are linked to drug resistance


• HIV drug resistance develops in patients via one of two major pathways :

Mechanisms of development of HIV drug resistance

Selective pressure (there are multiple

causes)

Transmission of drug

resistance Source : HIV & TB Drug resistance 2013 p.11


Pathways for the development of drug resistance

There are multiple causes for selective pressure (more than one

factor may contribute at the same time to the emergence of

resistance)


• Various mechanisms for the development of drug resistance have been identified

• These mechanisms differ between classes of drugs but also within a specific drug class

Mechanisms of development of HIV drug resistance


Why is HIV prone to develop resistance ?

• Mutations Occur During HIV Replication• Virion half-life = 30 minutes• Daily production = 109 – 1010 virions• RT incorporates the wrong nucleotide

once every 10,000 – 30,000 nucleotides• Approximately 1 mutation per viral copy• Higher viral replication = more frequent

mutations• Every single point mutation occurs daily

1. Coffin JM. Science. 1995;267:483-489.2. Wainberg MA et al. Science.1996;271:1282-1285. 3. Ho DD et al. Nature. 1995;373:123-126. 4. Wei X et al. Nature. 1995;373:117-122.


Induced Resistance Mechanism

• HIV infection characterized by high levels of virus production and turnover

• In chronic, untreated infection the total number of productively infected cells in lymphoid tissue is approx 107 to 108 cells

• Shorter half-life of infected cells• This number is relatively stable, reflecting the

balance between infection of new target cells and their clearance



• Second, HIV’s reverse transcriptase enzyme lacks a proof-reading function

• Allowing the virus to continually evolve leading to viral heterogeneity:

• Evade the immune response• Develop antiretroviral drug

resistance



• The more that HIV multiplies, the more mutations show up

• These mutations happen by accident

• The virus doesn’t “figure out” which mutations will resist medications or treatment


Combination therapy

• Effective combination therapy can block this selection process:

1. Multiple mechanisms are required for resistance to occur to all drugs in the regimen

2. Multiple drugs suppress viral replication more effectively than single agents. (in the absence of replication generation of new variants is arrested)


So………………

• How does resistance set in with HAART?Ans. If HIV continues to replication in the

presence of levels of drugs that are insufficient to block replication but sufficient to exert a positive selective pressure on variants with decreased drug susceptibility.

Worth noting – resistance is most often a consequence - not the cause – of initial treatment failure.


Primary Resistance

• ARV naïve patients are primarily infected with a virus resistant to ARVs

• HIV-2 intrinsically resistant to NNRTIs.• HIV-1 subtypes less susceptible to PIs &

NNRTIs• Some cases involve transmission of strains

from patients whom resistance developed during therapy


Cross Resistance

• Defined as resistance to drugs to which a virus has never been exposed

• Result of mutations that have been selected for by the use of another drug

• Always restricted to drugs within a given class of antiretroviral agents.


Resistant virus

Wild type virus

The evolution of HIV resistance

Wild virus predominant, ‘chance’ resistant virus

time


Resistant virus

Wild type virus

Effective ARV’s, ineffective, non-pathogenic crippled virus

Good adherence, high drug pressure



time


Resistant virus

Wild type virus


Decreased drug pressure as resistance develops



Crippled but pathogenic virus


time


Resistant virus

Wild type virus


Decreased drug pressure as resistance develops

Stop all drugs



Crippled but pathogenic virus


Rise of wild virus again, but large population of resistant virus

time


• Drug resistance will most likely only emerge in the presence of HAART if the virus is allowed to replicate in the presence of drugs eg sub-optimal adherence

Why is HIV prone to develop resistance ?

Insufficient drug pressure



3. Risk factors for development of HIV drug resistance

?a. The virus b. The hostc. The treatment


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http://www.google.co.za/url?sa=i&rct=j&q=patient+cartoon+pictures&source=images&cd=&cad=rja&docid=Vzh7Uz3Fznfe2M&tbnid=SEseJLLq6xkOnM:&ved=0CAUQjRw&url=http://www.colourbox.com/vector/vector-2616966&ei=S0-nUYqaJ4TZ0QWcoIGABg&psig=AFQjCNHCw8Bf7FdYTcmfuorEGPpCT8at0w&ust=1370005679486423

http://www.google.co.za/url?sa=i&rct=j&q=pills+cartoon+images&source=images&cd=&docid=g5iajTagjFai4M&tbnid=lrvEVsyhUs_NgM:&ved=0CAUQjRw&url=http://www.altham.com/html/child_safety_cartoons.html&ei=f0-nUdr4M4LX0QW3uoHoDg&psig=AFQjCNHLPMNi2HMKxQzAKs_X50mvnCIrEg&ust=1370005752563111


a. The Virus

• Extremely high rate of replication and lack of proof-reading ability make HIV particularly prone to development of resistance

• Note : The plasma viral load is higher in subtype C is generally higher than the other subtypes this subtype may be more prone to resistance but more data is needed.



Global distribution of HIV-1 subtypes

1.3 million

4.8 million

2 million

B 10%

A 12%

URF 4.2%

AG 6.7%

AE 3.1%

G 5%

D 3.6%

IAS July 2009, Cape Town

05/03/2023 FACE CONSORTIUM 30Dr Eric Hefer, May 2009 – SA HIV Clinicians Society

Subset = Clade


b. The Host

• Most factors ascribed to adherence issues • Definition of adherence :–the extent to which a patient follows a

prescribed treatment regimen. In HIV treatment, adherence levels greater than 90 to 95% are needed in order to prevent the emergence of drug resistance



Factors affecting adherence :

i. Demographics ii. Psychosocial and behavioural

characteristics iii. Health care administration and

deliveryiv. Medication characteristics

Source : HIV & TB Drug resistance 2013


i. Demographics – there is no consistent data showing that age, gender, socio-economic status or race are associated with poor adherence



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Factors affecting adherence :ii. Psychosocial/behaviour – psychiatric illness esp.

depression and alcoholism have lower adherence. Negative attitudes eg denialism also interfere with adherence some data also on poor social relationships, lack of involvement with friends and family, social isolation.chaotic lifestyles and living alone

• can be risk factors

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http://www.google.co.za/url?sa=i&rct=j&q=social+isolation&source=images&cd=&cad=rja&docid=l9XX9l88iWyXcM&tbnid=Kcu55ZFq8I7wyM:&ved=0CAUQjRw&url=/url?sa=i&rct=j&q=social+isolation&source=images&cd=&cad=rja&docid=l9XX9l88iWyXcM&tbnid=Kcu55ZFq8I7wyM:&ved=&url=http://socialistwebzine.blogspot.com/2012/02/how-social-isolation-kills.html&ei=a4KbUdbmI6OJ7Aan2IDwCg&psig=AFQjCNHLGTvbivzcCiY5WMmbv5toqTBu9A&ust=1369232363822723&ei=foKbUaHYHqiV0AXbp4GoBQ&psig=AFQjCNHLGTvbivzcCiY5WMmbv5toqTBu9A&ust=1369232363822723


iii. Health care administration and delivery – patient knowledge on : • Diagnosis• expected course of illness• correct dose of medication and • need to take medication continuously

• Studies have found that patients who know the names of their medication did better than those who did not



associated with a lower adherence


c. The treatment

• Three factors that can aid the development of resistance to cART:– 1.Poor potency eg sdNVP (historical)– 2. Wrong dose – sub-therapeutic doses can lead to

the rapid accumulation of resistance– 3. Drug-drug interactions esp. with

NNRTIs and PIs


Source : ttp://www.hivhotline.uct.ac.za

http://www.hivhotline.uct.ac.za/


Reasons for failure

• Non-adherence• Inadequate/inappropriate drugs

• Sub-optimal drug levels• Intrinsic drug resistance


Blown away

• Resistance is complex• > 200 mutations known to be involved• Some affect more than one drug• Some reverse resistance• A critical need for reliable, practical info on

resistance


Basic nomenclature of resistance

• HIV has an RNA genome and the RNA codes for all the proteins the virus needs to function. Each codon consists of 3 nucleotides and encodes for one particular amino acid (AA)

• Changes in the codon - a mutation - may cause encoding of a different AA and this is a mechanism that the HIV uses to develop resistance and to escape from the action of the ARVs



• This figure demonstrates 3 codons that code for AAs lysine (Lys), aspartic acid (Asp) and serine (Ser). If a mutation occurs in the second codon, and the G is replaced by an A, that codon no longer codes for Asp but rather asparagine (Asn), and this new AA may enable the HIV to escape the action of an ARV drug.


An example of a single nucleotide change leading to

a change in AA


• ‘wild type’ virus is a virus without any resistance mutations

• There is a standard manner in which resistance mutations are depicted in the scientific literature. The codon position of the AA is given with the amino acid of the ‘wild type’ virus before the codon position and the mutant AA after the codon position





M184V is the signature resistance mutation of lamivudine (3TC) where a

condon at position 184 in the viral genome, methionine (M) has been

replaced by Valine (V).


M184V

Wild-typeamino acid(consensus)

Codon (position)PR = 1-99 amino acids

RT = 1-560 amino acids

Mutant amino acid

Nomenclature


Facts

• Resistance is not an all or nothing phenomenon

• Generally it increases over time• Single mutations rarely produce complete

resistance, one exception M184V mutation in reverse transcriptase resulting in complete resistance to 3TC.


Viral Fitness

• Resistant viruses may display impaired viral fitness – Impaired fitness = ↓ replication efficiency, ↓ growth

• Many drugs retain residual antiviral activity despite presence of mutations – 3TC


Why is lamivudine(3TC) or emtricitabine (FTC) included as a first and second line drug ?

• Although both 3TC and FTC result in the rapid emergence of resistance, the mutation that they select for (M184V) has reduced viral fitness and actually confers increased susceptibility to both AZT and TDF. Hence 3TC and FTC remain useful for second-line therapy


So…..

• Resistance does not equal death• People rarely die on ARV’s, even with resistant

virus - Lancet 1999

• Decreasing resistance = lengthening life of drugs/ lengthening life of patients


Resistance testing

• Allows evaluation of the susceptibility of HIV to individual antiretroviral agents.

• Genotypic assays, detect the presence of resistance mutations

• Phenotypic assays, measure the susceptibility of the virus to various drugs in tissue-culture systems


Problems with resistance testing

• Tests are not available everywhere, expensive • Tests aren’t good at detecting “minority”

mutations (less than 20% of the virus population)

• Work better when the viral load is higher; if VL is very low tests might not work <400 copies/ml

• Test results can be difficult to understand.


New dx, ART naive

6. hiv antiretroviral resistance

Health & Medicine

Transcript of 6. hiv antiretroviral resistance