Anti-retroviral Drugs

Question 1

1. Name membrane fusion inhibitor(s) and describe how it interferes with the normal mechanism of HIV replication.

Answer 1

enfuvitide: competitively binds a specific region of gp41 and inhibits folding of HR1 and HR2 within gp41, disrupting membrane fusion (salvage regimen), includes a human target

1. Resistance through mutation in the region of gp41
2. Toxicity: injection site reactions

Question 2

1. Name entry inhibitor(s) and describe how it interferes with the normal mechanism of HIV replication.

Answer 2

maraviroc: inhibits attachment of the virus gp120 to the CCR5 co-receptor by changing its structure via allosteric binding, active in R5 virus and not X4 virus (viral tropism), is also a substrate of p450

1. Resistance: mutations that change gp120 that allow binding to CCR5, emergence of mixed tropic or CXCR4-tropic virus
2. Toxicity: host cell CCR5, important in immunity i.e. against West Nile, it blocked; hepatotoxicity, muscle pain, sleep disturbances and GI side effects

Question 3

1. Name nucleoside reverse transcriptase inhibitors(s) and describe how it interferes with the normal mechanism of HIV replication.

Answer 3

zidovudine (AZT), abacavir (ABC)- nucleoside analogues that lack a 3’OH on the ribose sugar so incorporation in to DNA by RT results in termination of the chain (must be phosphorylated by host enzymes in cytoplasm), lack of phosphorylation leads to increased absorbance of NRTIs relative to analogs,

1. Resistance: RT that discriminate against NRTIs during DNA synthesis or RT that promote hydrolytic removal of chain terminating NRTI
2. Toxicity: mitochondria from inhibition of mitochondrial DNA polymerase ; Zidovudine: bone marrow suppression

Question 4

4. Describe the clinical presentation and significance of the abacavir hypersensitivity syndrome and nucleoside reverse transcriptase inhibitor (NRTI) associated mitochondrial toxicity and lactic acidosis.

Answer 4

Abacavir: hypersensitivity syndrome (6%) HLA B*5701 marker: fever, rash, headache, nausea, abdominal pain, cough and SOB

NRTI: mitochondria from inhibition of mitochondrial DNA polymerase (high affinity for NRTIs) leading to depletion of key proteins (ETC), build up of lactate and triglycerides associated with severe academia, hepatic steatosis and fetal hepatomegaly

Question 5

1. Name nonnucleoside reverse transcriptase inhibitors(s) and describe how it interferes with the normal mechanism of HIV replication.

Answer 5

efavirenz: block RT activity by binding hydrophobic pocket allosteric site in p66, inducing a conformational change, do not require phosphorylation to be active
1. Resistance: single mutation in the NNRTI-binding pocket,

2. Toxicity:
   Class: rash, including life threatening dermatologic reactions (nevirapine); hepatotoxicity (nervaripine); all NNRTIs are P450 CYP3A4 substrates
   Efavirenz: CNS efficts including vivid dreams, feelings of disconnect, sleep disturbance and worsening of unrecognized or undertreated mental health disorders, teratogenicity

Question 6

1. Name protease inhibitors(s) and describe how it interferes with the normal mechanism of HIV replication.

Answer 6

i. Protease inhibitors: ritonavir, atazanavir- action by binding reversibly, with high affinity to the active site of protease, binding prevents protease cleavage of gag-pol; small doses of ritnovir is used to inhibit p450 metaoblism of lopinavir, co-formulation advantageous

1. Resistance: mutations impact binding with the protease pocket and cause cross-resistance among several drugs
2. Toxicity:
   Class: hepatotoxicity, GI upset and diarrhea, lipodystrophy (fat redistribution, fat atrophy, hyperlipidemia, insulin resistance)- atazanavir least so; all are p450 CYP3A4 substrates, most are inhibitors

Question 7

1. Name integrate inhibitor inhibitors(s) and describe how it interferes with the normal mechanism of HIV replication.

Answer 7

ii. Integrase inhibitor- raltegravir: inhibits one of the 3 main steps in the process known as strand transfer

1. Resistance: via mutations in the integrase gene and several different pathways
2. Toxicity: uncommonly ND, headache, no p450 CYP3A4 interactions

Question 8

2. Explain how phosphorylation of NRTIs can cause drug interactions among NRTIs.

Answer 8

Multiple drugs use the same phosphatase enzymes for activation, usually not used together (thymidine kinase has a higher affinity for AZT than stavudine, is antagonist to stavudine

Question 9

3. Explain the difference between genotypic and phenotypic resistance testing.

Answer 9

a. Genotypic v. phenotypic resistance: phenotypic testing (growth rate of HIV is compared to the rate of wild type virus) described by “fold” resistance; genotypic sequencing of the sample virus is compared to the wild type
b. Drug resistance frequency is affected by adherence

Question 10

5. Identify molecular reasons why combination drug therapy is more effective than monotherapy.

Answer 10

a. Combining suppresses viral replication at different points in life cycle
b. Combining nucleoside analogs with different bases increases the chances of drug incorporation by viral reverse transcriptase
c. Dual PI therapy takes advantage of positive drug interactions

Question 11

Name examples of 
NRTI
NNRTI
PI
Fusion inhibitor 
Integrase inhibitor

Answer 11

NRTI	Zidovudine, abacarvir
NNRTI	Efavirenz
Protease Inhibitor	Reitonavir, atazanavir
CCR5	Maraviroc
Integrase Inhibitor	raltegravir