35.HIVAntretrovirals

8/12/2019 35.HIVAntretrovirals

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35. HIV Antiretroviral Agents

Dr. Gail Skowron, 4/1/2013

OBJECTIVES

1. HIV STRUCTURE AND DRUG TARGETS

a. 2 single stranded RNA moleculesb. Reverse Transcriptase enzyme

c. GP120 envelope protein

d. All are targets of antiretrovirals

2. HIV LIFECYCLE AND DRUG TARGETS

Each step in the life cycle is listed and any drugs targeting that step are listed below each step.

Bolded steps have underlined drug targets, with existing therapy names and the year they wereintroduced if it was mentioned.

I am maintaining her color coding from lecture, as follows:

DHHS PREFERRED use in Treatment-Nave Patients

DHHS ALTERNATIVE use in Treatment-Nave Patients

DHHS ACCEPTABLE use in Treatment-Nave Patients

RARELY used or of historical importance

PMTCT = Prevention of Mother-To-Child Transmission

Treatment naive = never been treated before

She emphasized that we should know all the details about all drugs HIGHLIGHTED IN AQUA first, and also

and learn as much as possible about those HIGHLIGHTED IN YELLOW.


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CD4 binding

Co-receptor binding - CCR5 or CXCR4 = CCR5 antagonist

Maraviroc (2007-2008)

Fusion = Fusion inhibitor

Enfuvirtide

Only injectable and used 2x day

Not often used

Reverse transcription (vRNA to vDNA) = Reverse transcriptase inhibitor NucleoSide Analogues

Emtricitabine

Lamivudine

Abacavir

Zidovudine (AZT)

NucleoTide Analogues

Tenofovir

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

Efavirenz

Rilpivirine Nevirapine

Etravirine

Formation of DS vDNA (DNA DNA)

Integration of DS vDNA into host cell DNA = Integrase inhibitors

Raltegravir (2007-2008)

Elvitegravir (2012)

Transcription (vRNA genome and mRNA)

Translation of viral proteins

Protein processing = Protease inhibitors

Amprenavir

Lopinavir

Atazanavir

Fos-Amprenavir

Tipranavir

Darunavir

Assembly

Release


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3. CLINICAL GUIDELINES FOR ANTIRETROVIRAL THERAPY

a. Use 3 drugs active against the patients virus

Because reverse transcriptase is error prone, 1/10,000 BPs have a mutation... which is

the total amount of BPs in HIV


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This means that virtually every time HIV replicates it has at least 1 mutation

The incidence of mutation means that random point mutations easily form which can

confer resistance on the HIV, so monotherapy DOES NOT WORK for HIV

Monotherapy was only effective for 6 months - at first used just AZT

Bitherapy is also not a permanent solution

b. Start and stop all at once

c. Evaluate risk:benefit ratio

d. Simpler regimens promotes better adherence and improved virologic response Better adherence = better response

If you do not keep to your regimen, HIV quickly becomes resistant to one or all of the

drugs you are taking - these are NOT drugs you can forget to take for a few days

There are only 27 potential drugs, and once you have resistance to a drug, you can no

longer use this drug and that is eliminated as a possibility

e. The best regimen is the one the patient will take

Some drugs work for some people and not others you have to play around with the

drugs that work best for each patient

For example, some patients end up on their 6th or 7th regimen because 1-5 werent

working

4. PHARMACOLOGIC PRINCIPLES OF ANTIRETROVIRAL USE

a. Mechanism of action

b. Pharmacokinetics

Dosage forms: intravenous, subcutaneous, oral, inhalation, topical

Bioavailability: drugs and prodrugs

Tissue distribution

Metabolism and dose adjustment

Many agents are metabolized by the hepatic cytochrome P450 system and may

either inhibit or induce metabolism of other P450 metabolized drugs (both for Hand for other diseases)

This some unpredicted drug interactions

ALWAYS LOOK UP DRUG INTERACTIONS and know that there may be

UNPREDICTED reactions because there is not always good data for each drug

combination

c. Side effects: HIV-Associated Lipodystrophy Syndrome

Changes in fat distribution

Subcutaneous fat wasting - D Drugs - AZT

Lipoatrophy: sunken cheeks, sunken temples

Fat accumulation - Protease Inhibitors

Intra-abdominal fat Localized

Breast enlargement Buffalo hump

Metabolic complications

Dyslipidemia

Insulin resistance

Diabetes mellitus

d. Drug interactions, including boosting***

Exploitation of drug interactions to increase efficacy or metabolism of HIV drugs

Use medscape to LOOK UP DRUG INTERACTIONS


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For example: simvastatin is contraindicated for ritonavir there are certain drugs you

NEVER use with antiretroviral regimens

e. Combination strategies (fixed dose combinations) ***

***These areas are unique to HIV drugs, and she did not talk about these in reference to antivirals for

other viruses.

f. Refer to: Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults &

Adolescents

Last update 12 Feb 2013 276 pages

There are 3 categories for drugs:

Preferred regimens: regimens with optimal and durable efficacy, favorable

tolerability and toxicity profile and ease of use these are for non-pregnant patie

Alternative regimens: regimens that are effective and tolerable, but have potent

disadvantages when compared with preferred regimens an alternate regimen

may be the preferred regimen for some patients

Here, to make things easy, she is ONLY FOCUSING on those drugs used for INITIAL therapy, not those use

specifically for drug-experienced people who have developed resistances.

Note that we are NOT responsible for the 3-letter abbreviations for the names, just the names themselves. As

mentioned above, the focus is on PREFERRED drugs and less so on ALTERNATIVE/ACCEPTABLE drugs.

We also do not need to know the specific names of mutations that confer resistance.

She has a very detailed handout and suggested to use it if it helps, but not if it doesnt.

5. NUCLEOSIDE ANALOGUE AND NUCLEOTIDE ANALOGUE

a. Mechanism of Action

Reverse transcriptase inhibitors Two mechanisms of action:

Competitive inhibition: e.g. azidothymidine (as AZT-TP) competes with dTTP

Chain termination: once AZT-TP is incorporated into the growing DNA chain,

natural dNTP cannot be added

b. Pharmacokinetics

Target = viral reverse transcriptase

Plasma half-life of parent compound may be short, intracellular triphosphate (active dru

has longer half-life than parent compound

The parent compound is NOT the active compound the active compound has a

longer half life than the parent - around 12 hours When they originally measured the plasma half life, they used the parent

compound and ended up overdosing people with AZT and horrible side effec

None have significant effect on CYP450 metabolism

c. Mechanism of resistance

Single or multiple base-pair mutations in reverse transcriptase

d. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1 infected Adults and

Adolescents

Two nucleoside analogues form the cornerstone of triple combination therapy

Preferred for Initial Therapy


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Tenofovir + emtricitabine = Truvada

Formulated in a single pill

Alternative

Abacavir + lamivudine = Epzicom

Formulated in a single pill

Acceptable

Zidovudine + lamivudine = Combivir

e. Adverse Side Effects Lactic acidosis, hepatic fat deposition

Very rare now

Still have a black box warning, however

Peripheral neuropathy

Can be permanent

Lipoatrophy, increase lipids

Pancreatitis

Mostly attributable to the d-drugs ddC (zalcitabine), ddI (didanosine) and d4T

(stavudine):

Used extensively in the past

All have fallen out of favor due to these side effects

Now we use better-tolerated drugs

f. List of Drugs

Tenofovir (TDF) - WE SHOULD KNOW EVERYTHING LISTED BELOW FOR THIS

DRUG

MOA: A nucleoTide analogue

Tenofovir disoproxil fumarate is the prodrug of tenofovir

DOSING: 10-50 hour intracellular half-life

Dont have to remember this number, but know its LONG

Dosed 1x day

METABOLISM: Renal excretion

SIDE EFFECTS: inc creatinine, proteinuria, dec bone density

These were discounted early on

RESISTANCE: K65R (location of codon that confers resistance)

OTHER: Active vs Hepatitis B.

Monitor HBV/HIV coinfected pts after stopping TDF for post-treatment

exacerbation of hepatitis

If you have a patient with both HBV and HIV, chose an agent active

against, both but be careful if you stop your HIV therapy because then H

might flare

COMBO DRUGS:

Truvada (Emtricitabine + Tenofovir)

Atripla (Emtricitabine + Tenofovir + Efavirenz)

Emtricitabine (FTC) AND Lamivudine (3TC)

These two drugs are analogues

MOA: A nucleoSide analogue

DOSING: Dosed 1x day

METABOLISM: Renal excretion

SIDE EFFECTS: Few, extremely well-tolerated


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RESISTANCE: M184V, RAPIDLY DEVELOPS

If you skip this pill at all, you will get resistance

Both drugs share a single codon that confers resistance

OTHER: Active vs Hepatitis B

Monitor HBV/HIV coinfected pts after stopping TDF for post-treatment

exacerbation of hepatitis

COMBO DRUGS:

Truvada (Emtricitabine + Tenofovir) Atripla (Emtricitabine + Tenofovir + Efavirenz)

Abacavir (ABC)



METABOLISM: Metabolized by alcohol dehydrogenase in the liver

SIDE EFFECTS: Hypersensitivity reaction in 5%

Fever, rash, fatigue, GI or respiratory symptoms

Usually occurs within first 6 weeks of therapy

DANGER! Rechallenging(i.e. stopping the med because of the

hypersensitivity reaction and then restarting it later) severehypotension and death

We can screen for this with HLA-B*5701 testing if you are negative, you

wont get this syndrome we only give the drug to those negative for

HLA-B*5701

COMBO DRUG: Epzicome (Abacavir + lamivudine)

Zidovudine (AZT)- first drug ever tested for HIV



This is the achilles heel of the drug

METABOLISM: glucuronidated in the liver SIDE EFFECTS: anemia, granulocytopenia, nausea

Used give 2500mg with severe side effects, some of which are permane

Now, give 600mg/day with less side effects

OTHER:

Excellent CNS penetration- 60% of plasma this is important because

can be used to treat patients with HIV-dementia or cognitive symptoms

Important component of PMTCT

Available for IV use during labor and delivery (the only antiretrov

that has an IV form)

Given to infant after birth COMBO DRUG: Combivir (Zidovudine + lamivudine)

Fixed dose combinations - most commonly given as a combination pill

Truvada

Emtricitabine + Tenofovir

1 pill/day

Epzicom

Abacivir + lamivudine

1 pill/day

Combivir


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Zidovudine + lamivudine

1 pill/day

6. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

Use NNRTIs because no one ever uses the full name.

a. Mechanism of action: Inhibit reverse transcriptase at a different site

b. Use: Potent inhibitors of HIV-1 NOT HIV-2 (remember this!)

c. Adverse Side Effects Rash is a side effect common to the class, may be severe

d. Resistance

Low genetic barrier to resistance= single point mutation causes resistance (efaviren

& nevirapine)

e. List of Drugs

Efavirenz KNOW EVERYTHING BELOW FOR THIS - It is a very popular drug!

MOA: Inhibit reverse transcriptase

DOSING: 1x day

METABOLISM: induces some P450 enzymes, inhibits others

SIDE EFFECTS: CNS or psychiatric symptoms in 50% (dizziness, impaired

concentration, somnolence, abnormal dreams, insomnia)

Generally resolve in 2-4 weeks.

May improve with dosing at bedtime (QHS)

Fatty foods inc absorption (so dont eat with fatty foods)

Rash in 27%, generally mild to moderate

RESISTANCE: K103N (single mutation)

OTHER: Do not give during 1st trimester of pregnancy

Now, we recommend NOT to start this during the first trimester of

pregnancy or to get pregnant if you are on it However, if you get pregnant while taking it, most doctors will not have y

stop the drug, because usually by the time you find out you are pregnan

the window of opportunity for serious birth defects has passed and its to

late

COMBO DRUG: Atripla

Tri-therapy in 1 pill

Emtricitabine + tenofovir + efavirenz

PREFERRED DHHS regimen for naive patients

One pill, once a day!

Rilpivirine MOA: Inhibit reverse transcriptase, active against mutations caused by first

generation pills

DOSING: 1x day

Take with a 500 calorie meal this makes it hard for people with certain

eating habits

Avoid acid reducing agents

SIDE EFFECTS: compared to EFV (ATRIPLA), fewer discontinuations for CNS

adverse effects, fewer lipid effects, fewer rashes

OTHER: Not recommended in patients with pre-Rx HIV RNA >100,000 copies/m


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COMBO DRUG: Complera (Tenofovir + Emtricitabine + Rilpirvirine), 1x day

Nevirapine

MOA: Inhibit reverse transcriptase

DOSING

2x day for generic

1x day for for Viramune

METABOLISM: Induces P450 metabolism

SIDE EFFECTS: Rash: greater severity than others in the category related to CD4 count

time of drug initiation

Elevated transaminases

OTHER:

Avoid in women with CD4 > 250, men with CD4 > 400


Give 3 doses to newborn

COMBO DRUG: 2 NRTI + Nevirapine

Etravirine(Treatment Experienced ONLY)

MOA: Inhibit reverse transcriptase DOSING: 2x day

METABOLISM: Hepatic, many drug interactions

SIDE EFFECTS: Rash, nausea, no CNS side effects

RESISTANCE:

2nd generation NNRTI, fully active vs. K103N virus (which is resistant to

EFV, NVP)

Resistance requires multiple NNRTI mutations, Y181C is a key mutation

Mutation in Y181C confers resistance to the entire class of drugs

OTHER:

Avoid in women with CD4 > 250, men with CD4 > 400


Give 3 doses to newborn

Approved for treatment-experienced patients only

COMBO DRUG: In combination with protease inhibitor

7. PROTEASE INHIBITORS

a. Mechanism of action:Target viral protease

The HIV makes a big polyprotein strand when it transcribes from RNA

This polyprotein must be cleaved into active proteins/enzymes

Inhibits proteolysis of gag and gag-pol proteins Renders progeny virions non-infectious

b. Metabolism: all protease inhibitors inhibit P450 metabolism

c. Boosting: Ritonavir

Small doses of ritonavir inhibit P450 metabolism, which increases the trough and AUC

a second PI

Because all these drugs have short half lives, they used to have to be dosed every 8-1

hours adding tiny doses of ritonavir prolongs the half-life of these drugs and allows the

to be taken less often

When you add ritonavir, you get a higher Cmax and Cmin (trough) and this extends the


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half-life

d. Resistance

Boosted PIshave a low rate of resistance in breakthrough virions due to high trough

concentrations

e. DHHS Guidelines for Initial Therapy

2 NRTI (or NRTI + NtRTI) plus:

Preferred

Atazanavir/rtv: 2 pills once daily

Darunavir/rtv: 2 pills once daily

Alternative

Fos-amprenavir/rtv: once and twice daily regimens

Lopinavir/rtv: 2 pills twice a day

f. Resistance Mutations

Mutations that confer resistance to these drugs is very complex

These genes can accumulate many different mutations

g. List of Drugs

Atazanavir

MOA: Target viral protease


Take with food

Proton pump inhibitors (PPIs), H2 blockers (H2B) and antacids reduce

absorption - complex guidelines for acid reducing agents

METABOLISM: If given with TDF, must use boosted ATV/rtv

SIDE EFFECT: Indirect (unconjugated) hyperbilirubinemia

Due to inhibition of UDP-glucuronosyl transferase (UGT)

Dose related, higher rate with RTV boosting

No medical consequence

OTHER: Part of preferred regimen for PMTCT (just added)

COMBO DRUGS: Atazanavir/rtv: 2 pills once daily


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Darunavir


SIDE EFFECT: Nausea, diarrhea, headache, skin rash

RESISTANCE: Active against viruses that are resistant to multiple other

protease inhibitors (2nd generation PI)

OTHER: Contains sulfa moiety use with caution in patients with severe sulf

allergy

COMBO DRUGS: Darunavir/rtv: 2 pills once daily Fos-Amprenavir


Prodrug of amprenavir with greater bioavailability

DOSING: Used to be many pills a day, now there is a formulation that is 2 pills,

day

OTHER: Contains sulfa moiety use with caution in patients with severe sulf

allergy

COMBO DRUGS: Fos-amprenavir/rtv: 2 pills, 2x daily

Lopinavir/Ritonavir(always co-formulated!) = Kaletra

MOA: Target viral protease DOSING: 400 mg lopinavir + 100 mg ritonavir, 2x day

Fixed dose combination pill (tablet)

200 mg plus 50 mg = 2 pills twice a day

May be given as 4 pills once a day (but this may worsen side

effects)

The 200 mg ritonavir/day is higher than other boosted PIs (which

are 100 mg/day) this worse side effects

SIDE EFFECTS: diarrhea, nausea, hyperlipidemia

OTHER: Part of preferred regimen for PMTCT - most important drug!

COMBO DRUGS: Kaletra

8. CCR5 ANTAGONIST

a. Mechanism of Action:

There are 2 types of virus, one that is CXCR4 and one that is CCR5

This drug only blocks those that bind CCR5


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b. List of Drugs (only 1)

Maraviroc

MOA: CCR5 Antagonist

Only active against R5 virus

Must send tropism test before starting (Trofile detects >.3% of X4

virus)


RESISTANCE:

Amino acid substitutions/deletions in the V3 loop of the HIV-1 envelope

(gp120) allows virus to continue to bind to CCR5 receptor

Tropism shift emergence of X4 or dual/mixed-tropic virus that is not

inhibited

No cross-resistance with other classes because its a brand new class

SIDE EFFECT: generally well-tolerated orthostatic hypotension, especially in

patients with renal or hepatic dysfunction

COMBO DRUGS:

9. HIV INTEGRASE INHIBITORS = INTEGRASE STRAND TRANSFER INHIBITORS (INSTI)


13/15

a. Mechanism of Action

There is a pre-integration complex that forms

They block 3 processing and strand transfer

b. List of Drugs

Raltegravir

MOA: Binds to pre-integration complex

DOSING: 2x day

METABOLISM: not a substrate, inhibitor, or inducer of CYP3A4 primarily

metabolized by glucuronidation via UGT

SIDE EFFECTS: well-tolerated, rarely increase CPK, rash (possibly severe)

RESISTANCE: lower barrier to resistance compared to boosted PIs use with 2

other fully active agents & give to a patient that will take it as directed

COMBO DRUG: Use with 2 other fully active agents

Elvitegravir (plus cobicistat aka cobi)

MOA: Binds to pre-integration complex

DOSING: 1x day

METABOLISM: metabolized by CYP3A4, coformulated with a CYP3A4

inhibitor, cobicistat which boosts

RESISTANCE: cross-resistance with raltegravir

COMBO DRUG: Stribild = coformulated with tenofovir + emtricitabine + cobicist

(the QUAD pill) LOTS OF drug interactions

OTHER: Drug interactions due to CYP3A4 inhibition by cobicistat

SUMMARY

REVIEW QUIZ


14/15

1. What is the mechanism of action for Tenofovir?

A. nucleoside analogue

B. nucleotide analogue

C. protease inhibitor

D. reverse transcriptase inhibitor

E. CCR5 antagonist

2. Which strain of HIV is resistant to Tenofovir?A. K65R

B. K60R

C. K65P

D. M184V

E. K103N

3. What is the mechanism of action for Emtricitabine and Lamivudine?





E. CCR5 antagonist

4. What strain is resistant to Emtricitabine and Lamivudine?

A. K65R

B. K60R

C. K65P

D. M184V

E. K103N

5. What is the mechanism of action for Efavirenz?





E. CCR5 antagonist

6. Which strain is resistant to Efavirenz?

A. K65R

B. K60R

C. K65PD. M184V

E. K103N

7. What is the mechanism of action for Atazanavir?





E. CCR5 antagonist


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8. What is the mechanism of action for Darunavir?





E. CCR5 antagonist

ANSWERS:

1. B. nucleotide analogue

2. A. K65R

3. A. nucleoside analogue

4. D. M184V

5. D. reverse transcriptase inhibitor

6. E. K103N

7. C. protease inhibitor

8. C. protease inhibitor

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35.HIVAntretrovirals

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