1. ARV Resistance

2. Learning Objectives Define drug resistance
Identify factors that influence drug resistance.
Identify strategies for minimizing development of drug resistance.
Identify strategies for responding to detection of moderate to high levels of drug resistant HIV.

3. Impact of drug resistance
Why is it important to measure drug resistance?
How does it impact the success of large-scale treatment programs?
Transition to next section. Note that we will try to answer these questions.

4. What is ARV drug resistance?
Drugs no longer block virus replication
Cause:
Mutations in the viral genome
One or more:
Specific for an antiviral drug OR
Affecting related drugs (cross-resistance)
How much resistance? Which drugs?
Depends on type and number of mutations
Present definition of drug resistance and its causes:
Reduced susceptibility of the virus to a specific antiviral drug (drug is less effective in blocking virus replication)
Caused by mutations in the viral genome, generally located in the gene encoding the protein targeted by the antiviral drug
Mutations can be specific for an antiviral drug or lead to reduced susceptibility to related drugs (cross-resistance)
Magnitude of resistance imparted depends on mutations
In some cases (e.g. 3TC or nevirapine) a single mutation may result in a completely resistant virus (low genetic barrier drugs)
In some cases multiple mutations are needed (e.g. lopinavir or darunavir) to reduce drug activity (high genetic barrier drugs)
Accumulation of mutations may result in increase in the level of resistance (AZT or PIs)

5. Types of drug resistance
Acquired drug resistance
Develops when patients interrupt their treatment, do not take it according to prescription, or the drugs are not absorbed properly
Transmitted drug resistance
People are infected from others who had HIV drug resistance and that carry resistant

6. EXPLAIN Globally, there are an estimated 36
EXPLAIN Globally, there are an estimated 36.9 million adults and children living with HIV, as measured in In Malawi, there are approximately 980,000 PLWHIV with an estimated 50% on ART.

7. HIV Drug Resistance - unavoidable
HIV DR is an inevitable consequence of ART, influenced by:
Ability of regimens to suppress replication completely
Adherence and tolerability of regimens
"Genetic barrier" to resistance
Relative fitness of resistant variant(s)
Pharmacokinetics (IQ)
Availability/continuity of drug supply
Removal of barriers to access to care
Therefore, efforts to minimize HIV DR should be focused on these factors
Emphasize that while it is impossible to eliminate or completely prevent drug resistance, it is possible and necessary to minimize drug resistance. Barriers = transportation, costs.

8. Need for population-based therapies1
Need for rapid scale-up
Limitations in health infrastructure, trained personnel, facilities, lab capacity, drug transport and storage 2
Need for standardized simplified treatment protocols
Regimen selection not by clinicians but by national policy—first-line and second-line regimens
Present information on the need to have an effective but limited set of treatment options when resources are scarce:
Rapid scale-up of antiretroviral therapy is an international priority.
Many countries have targeted coverage for 80% of individuals in need of treatment.
Making this scale-up more challenging are infrastructure limitations.
Given these constraints, the public health approach to extend ART rapidly to the maximum number of people relies on standardized simplified treatment protocols, standardized management approaches, and decentralized service delivery.
The decision on an effective first-line regimen (usually one NNRTI and two NRTIs) and a second-line regimen (usually a PI boosted by ritonavir and two NRTIs) is made at the national level, because there is not the money, equipment, facilities, or people to support individually-prescribed regimens. Regimen selection is based on the unique challenges (availability, cost) of that country.

9. Need to maintain effectiveness1
Limited number of regimens available 2
Need to minimize drug resistance
Present the importance of minimizing drug resistance given the factors previously described: With standardized simplified treatment protocols across a large number of people, the emergence and spread of drug resistance can have extensive and costly consequences. At the national level, you can minimize drug resistance by carefully monitoring it and by promoting adherence to the recommended regimen.

10. Drug resistance and HIV
evolves rapidly within human body
has a high replication rate
has a high mutation rate 
Resistant strains can emerge within days if drug pressure is not sufficient to suppress replication.
Resistant strains persist indefinitely and can re-emerge if same drugs are stopped and restarted.
Present factors related to this virus in particular that lead to drug resistance in a population.

11. Review Why is it important to measure drug resistance?
How does it impact the success of large-scale treatment programs?

12. Factors that influence development of drug resistance
What regimens influence drug resistance?
What patient factors influence drug resistance?
What public health approaches influence drug resistance?
Transition to next section. Note that we will try to answer these questions.

13. In which conditions is DR more likely?
Treatment with <3 drugs
Inappropriate selection of drugs
Adding one drug to a failing regimen
Interruption of treatment (even for a few days)
Prolonging a failing regimen

14. Virus related factors influencing resistance
High replication rate of HIV
Turnover of 10 billion virions daily
Frequent errors made during replication
High mutation rate
20 million mutations daily
Latent reservoirs of HIV
Enable drug resistant HIV to hide for years
ARV resistance, once it develops, is probably life-long, since resistant HIV can hide in latent cellular reservoirs, which can be activated many years later. Once a patient is resistant to an ARV drug, that drug will probably be ineffective in the future. HIV does not “forgive” treatment errors or non- adherence.

15. Resistance can develop quickly, depending on the viral load
Days Before Mutation Arises
300,000
0.1
30,000 1
3,000 10
300
100 30
1,000
Siliciano, 2002

16. Drug related factors influencing resistance
Inadequate potency (strength)
Drug interactions leading to suboptimal drug levels
Inadequate durability of drug potency (e.g., dual therapy)
Poor tolerability
Inconvenience of regimen
Viral escape depends on the rate of residual viral replication, which is increased if there is: Inadequate potency, e.g. mono and dual therapy. With a more potent regimen, there is decreased replication and decreased chance to develop drug resistance mutations.
what are the drug interactions to be concerned with here?

17. Adequate Drug Levels are Crucial to Control HIV Replication
High drug levels delay or prevent development of resistance.
Low drug levels encourage viral replication, ARV resistance, viral rebound and ultimate clinical deterioration.

18. Mutations and Resistance
For certain ARVs, only one mutation is needed to stop the drug from working.
For other ARVs, multiple, step-wise mutations must occur before the drug loses affect.
some arvs are stronger than others and may require slightly less strict adherence than others. however, still aim for 95% for all

19. In which conditions is DR less likely?
Medication Factors:
All patients treated with 3 or more drugs
Use of appropriate drug regimens
Can reliably suppress HIV replication to levels of <50 copies/ml
Use of fixed-dose combinations to support adherence

20. In which conditions is DR less likely?
Systems Factors:
Limited number of regimens
Trained personnel, low turnover
Supervision and monitoring
Adequate lab services
Drug supply and delivery systems

21. In which conditions is DR less likely?
Patient Factors:
Adherence to treatment regimen
Avoiding interruption of treatment, even if only a few days
Regular follow-up (going to clinic)
Staying on uninterrupted first-line ART as long as possible

22. Programmatic factors affecting patient adherence
Cost of treatment to patient (not only money, but time)
Distance patient must travel to get treatment
Supply interruptions
Availability of second-line regimens for patients whose first-line regimens fail
Timing of use of second-line regimens
Present information on factors that are associated with avoiding widespread drug resistance.

23. Discussion What regimens influence drug resistance?
What patient factors influence drug resistance?
What public health approaches influence drug resistance?

24. Reflection What regimens do we use in our country?
What systematic and programmatic challenges do we face?
Ask participants to write their own answers to these questions in the blank space on their handouts.

25. Minimizing drug resistance
What can countries do to minimize or suppress drug resistance?
Transition to next section. Note that we will try to answer these questions.

26. Strengthen existing programmes that minimize HIV DR
Support for adherence and follow-up  THIS IS YOU!
Removal of barriers to ART access
Drug supply continuity at the individual, ART site, and national levels

27. Monitor early warning indicators
Routine collection of medical and pharmacy records
Monitor for factors associated with HIV DR prevention or emergence
Extent to which prescribing practices meet national and international guidelines
% of patients still on first-line; % lost to follow-up
% patients with timely medication pick up and clinical follow- up
Drug supply continuity at site
Adherence and viral load  THIS IS YOU!

28. HIV DR Early Warning Indicators (EWIs)
Proportion lost to follow-up during the first 12 months of ART
Prescribing practices
Patient retention on first-line ART
Site-level ART Program Function
Drug supply continuity
On-time ARV drug pick up
Present: This side shows ix different recommended EWIs (in red) and two additional EWIs (in blue). These blue ones are good, but need good infrastructures in place to gather the data.
Emphasize:
On time pickup: % of ART patients picking up prescribed ARV drugs on time (before previous drugs run out)
Drug supply: ART stops, substitutions, and switches due to ARV shortages during a specified period OR % of months during a year with no antiretroviral drug stock outages
Viral load 6 months
ART appointment-keeping
Pill count/ adherence

29. Key Messages Impact of HIV Drug Resistance
Factors that Influence Development of Drug Resistance
How to Minimize Drug Resistance