HIV Lifecycle and Therapeutics

high

You want your CD4 count to be _________

low

You want your HIV Viral Load Test to be _________

HIV

is a retrovirus that infects and causes the depletion of CD4+ helper T-cells of the immune system

gp120 and gp41

What the 2 structural components that make up the HIV envelope that play an essential role in HIV entry into the host cell?

HIV Life Cycle

1. Attachment

2. Fusion

3. Reverse Transcription

4. Nuclear Transport and capsid disassembly

5. Integration

6. New viral mRNA transcription

7. New viral protein translation

8. Capsid Assembly

9. Budding

10. New Virus Release

viral entry and hijacking of host cell

Attachment

Fusion

Reverse Transcription

Nuclear Transport and capsid disassembly

Integration

Viral replication using host cell and subsequent release

New viral mRNA transcription

New viral protein translation

Capsid Assembly

Budding

New Virus Release

• Maximally and durably suppress plasma HIV RNA (suppression of viral load);

• Restore and preserve immunologic function;

• Reduce HIV-associated morbidity and prolong the duration and quality of survival; and

• Prevent HIV transmission

What are the treatment goals of Antiretroviral therapy (ART)?

≥ 2 drugs from 2 or more drug classes (an INSTI anchor drug plus a 2-drug NRTI backbone)

To achieve viral suppression with ART you use:

untransmittable

Undetectable means ___________.

200

A viral load remaining below _________ copies/mL means it is undetectable.

Biktarvy

bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF)

Triumeq

Dolutegravir (DTG), Abacavir (ABC), Lamivudine (3TC)

Dovato

dolutegravir (DGT) /lamivudine (3TC)

INSTI + 2 NRTIs

Biktarvy

INSTI + 1 NRTI

Dovato

INSTI + 2 NRTIs

Triumeq

Tivicay

Dolutegravir (DTG)

Descovy

emtricitabine (FTC) /tenofovir alafenamide (TAF)

Truvada

emtricitabine (FTC) /tenofovir (TDF)

Abacavir

What HIV drug has a PgX issue associated with HLA-B*5701?

ssRNA

Each HIV-1 virus contains 2 copies of:

HIV reverse transcriptase

results in a copy of linear, viral double-strand dsDNA being generated from viral ssRNA. Host nucleotide building blocks are used.

HIV RT

lacks a proofreading function, meaning it makes frequent mistakes (mutations) when copying its RNA. This high mutation rate helps the virus develop drug resistance and evade the immune system.

Nucleoside/tide reverse transcriptase inhibitors (NRTIs)

act as chain terminators

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

these bind to HIV reverse transcriptase enzyme and inhibit the function of the enzyme

NRTIs

-require additional structure editing in body to become ACTIVE drug

-considered PRODRUGS

-all are chain terminators

DDIs with NRTIs

Minimal with NRTI use; not subject to first-pass metabolism, not metabolized by CYPs

Mitochondrial tox of NRTIs

due to the use of NRTIs can manifest as one of the following: myopathy, lipoatrophy, neuropathy, and lactic acidosis with or without hepatic steatosis

post tx acute exacerbation of Hep B Virus (HBV)

What is the BBW with NRTIs?

NRTI meds

Emtricitabine (FTC)

Lamivudine (3TC)

Tenofovir disoproxil fumarate (TDF)

Tenofovir Alafenamide (TAF)

Abacavir

Tenofovir disoproxil fumarate (TDF)

-can cause renal and bone toxic effects related to high plasma tenofovir concentrations

-CI in CKD if CrCl < 60

-CI in Osteoporosis

Tenofovir alafenamide (TAF)

-is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations.

-Better safety profile.

-CI in CKD if CrCl < 30

ZIAGEN Abacavir (ABC

-associated with a drug hypersensitivity syndrome in approximately 8% of those starting the drug

-FDA recommends genetic screening for HLA-B*57:01 before starting any patient on any abacavir-containing regimen.

-also associated with an increased risk of ischemic cardiovascular events, including myocardial infarction

NNRTIs

-are not prodrugs

-they are not chain terminators

-they bind at an allosteric site of HIV RT, and block enzyme function

Rash usually develops within the first few weeks of therapy and resolves with continued treatment

What is the most common AEs associated with all NNRTs?

Efavirenz

• Should be taken on empty stomach -preferably at bedtime—Risk of increased adverse effects when taken with food due to increased efavirenz exposure.

• Neuropsychiatric side-effects such as dizziness, depression, and abnormal dreams are common. Avoid in patients with psychiatric illness or dementia.

• QTc prolongation

• PGx issue with CYP2B6 IM or PM phenotypes -dose reductions recommended

Rilpivirine

• Must be taken with food

• QTc prolongation

• The use of oral rilpivirine with any proton pump inhibitor (PPI) or CYP3A4 inducers is contradicted

Doravirine

• Newest member of NNRTIs, significantly fewer and less severe CNS adverse events when compared to efavirenz.

• Can be taken with or without food.

• A more favorable lipid profile, lower incidence of rash.

HIV Integrase Strand Transfer Inhibitors (INSTIs)

"-tegravir"

-are highly effective, tolerable, have minimal drug interactions (there are exceptions), and demonstrated limited adverse effects in clinical trials used for drug approval

-second line therapy

INSTIs

• Raltegravir (RAL)

• Elvitegravir (EVG)

• Bictegravir (BIC)

• Dolutegravir (DTG)

• Cabotegravir (CBG) newest

INSTI class adverse effects

• Multiple recent analyses have found that starting or switching to an integrase strand transfer inhibitor (INSTI), especially dolutegravir or bictegravir, leads to more weight gain than starting or continuing an NNRTI or boosted protease inhibitor (PI).

• It is important to note that this weight change tends to plateau within 6 to 12 months after the switch and does not happen in all individuals.

Protease Inhibitors (PIs)

"-navir"

-are all peptide analogs that competitively inhibit active site of HIV-protease

First generation PIs

• Poor bioavailability

• High metabolic clearance

• Suboptimal PK; they required high doses to be taken several times a day.

• Resistance; patients quickly developed resistance to them.

• Most have ben discontinued or are no longer used.

Atazanavir (ATV) and Darunavir (DRV)

What are the PIs that are commonly used?

Ritonavir

is a PI that is used as a PL enhancer (booster)

HIV protease Inhibitors Class Adverse Effects

-interpatient variability in Pharmacokinetics

-significant first-pass metabolism by CYP3A4 is common but can be mitigated with a PK enhancer

-GI AEs (D, N, V)

-hyperlipidemia

70%

About _____ of pts receiving protease inhibitors experience hyperlipidemia. Which commonly requires statins, fibrates, omega-3 fatty acids

rosuvastatin, atorvastatin, and pitavastatin

What are the preferred statins in ppl with HIV, including ppl taking an HIV protease inhibitor and/or PK booster

Darunavir (DRV)

-The incidence of rash in persons taking this are approximately 10%, with most cases involving mild to moderate severity.

-should be taken with food and a PK enhancer.

Atazanavir (ATV)

-Is an inhibitor of the drug metabolizing enzyme UGT1A1 -this can lead to benign jaundice, which improves with switching to an alternate antiretroviral medication.

-should be taken with food and a PK enhancer

TYBOST (Cobicistat) and (NORVIR) Ritonavir

-PK enhancers are Inhibitors of CYP3A4; it "protects" the co-administered HIV protease inhibitor drug from metabolism by CYP3A4

-Result of its use: increase plasma concentration of other co-administered Pis without the risk of causing resistant mutations in the HIV virus

attachment in HIV entry

HIV gp120 attaches to the host CD4 receptor

co-receptor binding in HIV entry

-Following attachment, HIV gp120 interacts with a host chemokine co-receptor

-The HIV co-receptor binding (CCR5 or CXCR4) depends on the HIV subtype (R5 or X4). HIV Tropism.

fusion in HIV entry

Activation of the gp41 fusion machinery, generating the necessary momentum for the formation of a fusion pore and HIV-host cell membrane fusion

tropism

The type of coreceptor recognized by HIV-gp120 will determine the type of CD4 cell that the virus will be able to infect, also known as the _________ of the virus.

HIV Entry Inhibitors (Salvage Therapy) classes

• Attachment inhibitors (newest!)

• CD4 post-attachment inhibitors

• CCR5 co-receptor antagonists

• Fusion inhibitors

HIV Entry Inhibitors

-are second-line agents that prevent HIV-1 cellular entry by binding a cellular target.

-Commonly referred to as Salvage Therapy or Rescue Therapy.

-refractory pts

- indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations

-used in combo with other HIV-1 antiviral agents

RUKOBIA (Fostemsavir)

-attachment inhibitor

-s an oral prodrug that is hydrolyzed to the active form Temsavir, which binds to the HIV gp120 envelope, blocks interaction with CD4 receptor

-Common AEs: N/D

-AEs of Concern: QTc prolongation and liver enzyme elevation

SELZENTRY (maraviroc)

-is unique in that this drug was the first available in clinical practice to interact with a component of the human immune system rather than HIV itself.

-oral drug used in combo antiretroviral tx of adults infected with only CCR5-tropic HIV1

-test genotype or phenotype assay prior to use

-dose reduction with CYP3A4 inhibitors

-dose increase with CYP3A4 inducers

hepatotoxicity

What is the BW for maraviroc (Selzentry)?

TROGARZO (Ibalizumab-uiyk)

-CD4 post-attachment inhibitor

-First-in-class monoclonal antibody for HIV approved in 2018

-Indicated for HIV-1 infection in heavily treated adults with multidrug-resistant infection failing their current antiretroviral therapy regimen. -Salvage therapy

-Administered IV; infusion every two weeks.

-Used in combination regimens

lenacapavir (Sunlenca)

-FDA approved first in class capsid inhibitor that targets HIV-1 at multiple stages of the HIV-1 lifecycle

-used in combo with other ARTs for the tx of HIV-1 infection in heavily tx experienced adults with multidrug resistant HIV-1 infection failing their current ATV regimen due to resistance, intolerance, or safety considerations

-available as 300 mg tabs and as a single dose vial for SQ injection

CYP3A

Concomitant administration of SUNLENCA is contraindicated with

strong _________ inducers.

12 mo +

Residual concentrations of SUNLENCA may remain in the systemic circulation of patients for up to:

SC lenacapavir

has shown zero infections in a phase 3 trial when used as PrEP

YEZTUGO (lenacapavir)

-First and Only FDA-Approved HIV Prevention Option Offering 6 Months of Protection.

-Same as SUNLENCA, but indication differs

-injection is indicated for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents (>35kg) who are at risk for HIV-1 acquisition.

-injections/tabs day 1: tablets day 2; injections every 6 mo

-closest thing we have to a HIV vaccine $$$ (28k per yr)

BW of YEZTUGO (lenacapavir)

Individuals must be tested for HIV-1 infection prior to initiating YEZTUGO, and with each subsequent injection of YEZTUGO, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of YEZTUGO by individuals with undiagnosed HIV-1 infection. Do not initiate YEZTUGO unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving YEZTUGO must transition to a complete HIV-1 treatment regimen.

PrEP (Pre-exposure prophylaxis)

-is used by people who are HIV negative and at high risk of being exposed to HIV through sex or injection drug use.

-If you have HIV, PrEP medicine is not for you!

PrEP drugs

-emcitibine/tenofovir disoproxil fumarate (Truvada)

-emtricitabine/tenofovir alafenamide (Descovy)

-cabotegravir (Apretude)

BW for PrEP drugs (EXCEPT Apretude)

Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected individuals who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF) and/or tenofovir alafenamide (TAF) and may occur with discontinuation of DESCOVY or TRUVADA. Hepatic function should be monitored closely in these individuals who discontinue DESCOVY or TRUVADA. If appropriate anti-hepatitis B therapy may be warranted.