PATIENT 5

• Rudo is a 17 year old girl from

Mkoba 4.
• She got raped at 11 and
contracted HIV
• What could be the cause of the high viral load
• She has been on the first line • What other information would you need to
regimen for 5 years ask
• What would be your course of action
• However, her Viral Load has
been high of late
 ANTIRETROVIRAL
TREATMENT RESISTANCE
– THE HIV CASE
LEARNING OUTCOMES
• By the end of the lesson you should be able to
• Describe the ART regimens used in the country
• Describe how ART develops
• Describe methods on how to reduce the incidences of ART
LESSON OUTLINE
• The mechanisms of ART
• Resistance in 1st , 2nd and 3rd line therapy
• Causes of ART resistance
• Challenges and future prospects
HIV DRUG RESISTANCE
https://www.youtube.com/watch?v=wtfJf9YdK-w
DRUG MECHANISM OF ACTION
https://
www.youtube.com/
watch?
v=IOXEAAHmzT4
HIV Life Cycle – and Mechanism of Action
https://www.youtube.com/watch?v=IOXEAAHmzT4
DRUG CLASSES
Drug Class - MOA Examples
CCR5 antagonists.
Post-attachment inhibitors.

Fusion inhibitors
Nucleoside reverse transcriptase inhibitors (NRTIs)

Protease Inhibitors

Non-nucleoside reverse transcriptase inhibitors

(NNRTIs)

Integrase strand transfer inhibitors (INSTIs)

 ANTIRETROVIRAL DRUGS IN HIV – The
Zim Scenario
• First Line Regimen
• 2nd line Regimen
• 3rd line Regimen

• ARVs are usually given as drug combinations from different drug classes
• This is a bid to reduce Drug Resistance by the virus
• Drug Resistance is when the drug is no longer effective in keeping the viral load suppressed.
• These regimen are always changing because of new evidence (WHO and local data), national pool of resistance
noticed, availability of drugs (a good number of drugs are donor funded)
• The regimens also differ with age groups

Key Documents for Zim: EDLIZ, ZIM ART Guidelines 2016,

https://www.who.int/publications/i/item/9789240031593
CAUSES OF ART
RESISTANCE
• Mutations that occur during
copying of viral genetic material
– low fidelity of RT and High
replication rate of HIV
• The mutation can affect the
target site for drug action leading
to drug inactivation
• If virus is partially supressed, the
mutant HIVirus can then multiply
to levels that render the drug
useless for effective viral
suppression
CAUSES OF PARTIAL SUPPRESSION –
SUBOPTIMAL DOSES
• Poor adherence
• Poor
pharmacokinetics –
low drug absorption,
hyperactive drug
elimination, drug-drug
interaction
• Treatment
interruption
How does resistance develop?

Social/personal issues
Poor potency Regimen issues
Wrong dose Toxicities
Poor adherence
Host genetics
Poor absorption Insufficient drug level
Rapid clearance Viral replication in the
presence of drug
Poor activation

Drug interactions Resistant virus

PRETREATMENT DRUG RESISTANCE
• One can be inoculated with an already drug
resistant strain
• Vertical transmission from mother to child
– nearly ½ of newly diagnosed infants have
NNRTI resistance
• Horizontal transmission – up to 10% of
adults starting HIV treatment have NNRTI
resistance
• Previous treatment – Mothers initiated on
PMTCT later develop drug resistance
• Using a drugs that were used for PrEP
GENETIC BARRIER TO RESISTANCE
• This can be defined as the number
of mutations that are needed to
confer resistance to a drug
• The higher the GB the more
mutations needed before the
virus becomes resistant to the
drug
• NNRTIs have lower GBR and
therefore require strict adherence
• PIs however have higher GBR and
therefore that longer for
resistance to occur
 CROSS RESISTANCE
• In most cases, resistance
developing in one drug also
translates to resistance to
most drugs in the same class
• In other cases the resistance
developed in one drug only
affects the drug in another
class for a short period of
time – this will be partial
cross resistance

https://www.youtube.com/watch?v=QEEqz-
hitxA
REDUCING DRUG RESISTANCE
• Increasing adherence
• Increasing availability of drugs and systems that support that
• Reducing pill load
• Combining drug classes
• Increasing drug novelty
• Increasing HIV Drug resistance monitoring – Genotypic and
Phenotypic (https://www.youtube.com/watch?v=Xz9kpWLaw0A)
• Salvaging
Challenges in tackling Drug Resistance
• Adherence counselling is employed but how do you monitor
adherence practices?
• Drug resistance testing
• Newer classes of Drugs
• Tailor made drug combinations and dosing
SUMMARY
• HIV or other viral infections are develop drug resistance with time
• This drug resistance comes about as a result of different factors
including suboptimal dosing, replication rate of virus and fidelity of
the viral replication mechanisms
• Increasing Viral Load suppression methods is the current best way to
reduce HIV drug resistance