Drug Resistance

KITSO AIDS Training Program

Lecture 8: ARV Resistance and Treatment Failure delivered by

Dr. Daniel J. Baxter, ACHAP

Learning Objectives • Know the importance of drug resistance as a cause of treatment failure. • Understand the principles of ARV drug resistance. • Know the main causes of ARV drug resistance.

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Drug Resistance • Resistance reduces the ability of a drug, or combination of drugs, to block or reduce the replication of HIV. • As a result, viral load increases and CD4 count or CD4% decreases.

Treatment Failure • ARV resistance is an important cause of treatment failure, which almost always means virologic failure. • Treatment (i.e., virologic) failure occurs when viral load is not suppressed to < 400 initially, or after being initially suppressed, the viral load later becomes detectable. 4

Treatment Failure (2) • Treatment (virologic) failure can be thought of as falling into two general categories: – Subtherapeutic blood/tissue levels of

ARV(s). – ARV resistance. 5

Treatment Failure (3) • Causes of treatment failure due to subtherapeutic blood levels of ARVs: – Non-adherence. – Drug-drug interactions. – Poor absorption (e.g., ddI, NFV). – Gastroenteritis. – Incorrect level of ARV (e.g., pediatric

calculations, d4T/ddI dose in adults). – Inadequate potency or durability of ARV regimen.

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Treatment Failure (4) If viral replication due to subtherapeutic ARV levels persists, ARV resistance will eventually develop.

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How does drug resistance occur? (1) • HIV drug resistance is a consequence of viral replication in the presence of ARV drugs. • Reverse transcriptase is a very error prone enzyme and thus causes many mutations (on average, 1 mutation per life cycle). • These mutations are completely random and by chance.

HIV Mutations May Affect: • Virulence - the ability of the virus to invade a cell. • Viral fitness - the ability of the virus to compete with wild type virus. • Response to ARVs, that is, ARV resistance. • Immune response: HIV may escape antibody and CD8 immune control.

How does drug resistance occur? (2) • Faster viral replication leads to a higher chance of HIV mutations, some of which can cause resistance to the ARV drugs. • Once mutations make HIV resistant to one ARV drug, it can then quickly develop other mutations which can cause resistance to related ARV drugs, including an entire class of drugs – e.g., if replication is allowed to persist, resistance

to AZT can extend to other NRTIs and thus limit future treatment options.

To Minimize the Chance of Resistance • Treatment failure must be

addressed promptly.

• Patients should not be kept on a failing regimen for much more than a month!

Factors Leading to Resistance (1) • VIRUS related • DRUG related

• PATIENT related One or more of these factors can lead to ARV resistance in a given patient.

Factors Leading to Resistance (2)  High replication rate  High mutation rate – resistance  Latent reservoirs of HIV

Virus

Drug

Patient  Adherence