HIV Drugs - Miller

Structure of HIV

Surrounding envelope made up of gp120 proteins connected by gp41 transmembrane components. Contains an inner envelope called a capsid that contains viral genomic RNA and enzymes necessary for replication.

Replication Cycle of HIV

Once HIV binds to CD4 cells the virus gets brought into the cell

The viral RNA is released and reverse transcribed into DNA

This viral DNA is integrated into the hosts DNA

The host DNA is then replicated and transcribed

Viral proteins are produced and lead to production of new Virion particles

PrEP

Pre-exposure prophylaxis

For HIV Negative persons

Begins before exposure

Long-acting Drugs that reduce chances of HIV infections

PEP

Post-Exposure Prophylaxis

For HIV negative persons

28 days of treatment

Reduces chances of HIV infection

ART

Antiretroviral therapy

In HIV positive patient

Lifelong treatment

Aims to reduce viral load and improve CD4 count

HIV and Drug resistance

HIV Reverse transcriptase is highly error prone —→ large error rate and a small genome. 10⁹ virions can be produced a day. Every mutation at every nucleotide probably occurs many times each day in untreated patients.

Incomplete therapeutic control

Can lead to drug resistant HIV mutations. NNRTIs are highly effective against HIV-1. Single mutation at reverse transcription codon 103 can confer high level resistance to NNRTIs.

Multi drug therapy is required. Combination therapy suppresses the replication and limits resistance.

MOA of NRTIs - Reverse Transcription

Reverse transcriptase converts viral RNA into proviral DNA

NRTIs prevent infection of NEW cells (prior to integration of viral DNA)

Nucleoside analogs require intracellular activation to triphosphates by viral thymidine kinase

Since NRTIs lack a 3’OH, DNA chain elongation is terminated - another nucleoside can not be added by polymerase.

In other words NRTIs competitively inhibit the incorporation of native nucleotides and prevent elongation of viral DNA.

Example PrEP combo

TDF and Emtricitabine (NRTIs)

NRTIs are prodrugs

NRTIs have selectivity for Cellular thymidine kinases which phosphorylate the drug. This is the rate limiting step of this pathway and is why increasing concentration of parent drug does not necessarily increase active drug.

TAF vs TDF

TAF if the prodrug of TDF. Both have an active diphosphate form (most drugs are triphosphate). TAF leads to lower plasma exposure and generally less toxicity.

AEs of Didanosine

Peripheral neuropathy

N/V/D

Pancreatitis

lactic acidosis

Hepatic Steatosis

Hyperlipidemia

Insulin resistance

Lipoatrophy

AEs of Stavudine

Peripheral Neuropathy

AEs of Zidovudine

N/V/D

Bone marrow suppression (anemia, neutropenia)

Lactic acidosis

Hepatic Steatosis

Hyperlipidemia

Insulin resistance

Lipoatrophy

AEs of abacavir

Hypersensitivity reactions (fever, rash, flu-like symptoms) can be fatal if drug is continues

AEs of Tenofavir

Nephrotoxicity (increased sCr)

NRTI class wide AEs

Lactic acidosis and Hepatic steatosis (fatty liver)

MOA of NNRTIs

Block reverse transcriptase activity by binding adjacent to the enzyme’s active site, thereby inducing a conformation chance at the active site.

NNRTI characeristics

Active against HIV-1 and HIV-2

Shar similar toxicities and resistance profiles

Unlike NRTIs they do not need to be phosphorylated

Metabolized by CYP450 system

Low genetic barrier to resistance, only need 1-2 mutations for resistance to occur

PK properties of Nevirapine

Meals does not effect AUC

Primarily metabolized by 3A4 > 2B6

Does not inhibit 3A4

PK properties of Efavirenz

Meals increase AUC

Primarily metabolized by 2B6 > 3A4

Inhibitor of 3A4

PK properties of Etravirine

Meals greatly increase AUC

Metabolized by 3A4, 2C9, 2C19, UGT

Does not inhibit CYP3A4

Class wide AEs of NNRTIs

Rash/dermatologic reactions involving mucous membranes - urgent

Hepatotoxicity - monitor LFTs

AEs of Efavirenz

Dizziness, drowsiness, insomnia, depression, psychosis, suicidal ideation. These effects can be minimized by taking drug on empty stomach at bedtime.

Not restricted during pregnancy but used to not be offered to pregnant women

AEs of Nevirapine

Hypersensitivity reactions - Flu-like symptoms, fever, jaundice, abdominal pain with or without rash

HIV integrase action

HIV integrase is an essential enzyme in viral replication

Integrase has no human homologue

The enzyme positions viral DNA ends for insertion into the hosts DNA

Inhibitors block this strand transfer

Which drugs are HIV integrase inhibitors

Raltegravir and elvitegravir

Dolutegravir

Bictegravir

Cabotegravir

MOA of HIV integrase inhibitors

They prevent covalent insertion of HIV DNA into the host chromosome

These drugs do not excise DNA that has already been integrated

Raltegravir and Elvitegravir have a low genetic barrier to drug resistance, so rapid resistance may evolve if used a monotherapies

They are metabolized in the liver, so monitor in patients with hepatic disease

Drug-Drug interaction of HIV Integrase Inhibitors

Reduced absorption when co-administered with divalent and trivalent cations (Fluoroquinolones and tetracyclines)

Should be administered at least 2 hours before or 6 hours after oral administration of products

Cobicistat

Pharmacokinetic enhancer aka a booster

It inhibits CYP450 enzymes and boosts the concentration of other drugs, including elvitegravir

It has no HIV activity - co administration only enhances concentration of other HIV drugs

HIV Protease Action - inhibit maturation

HIV encodes an essential aspartyl protease that is significantly different from human aspartyl proteases

HIV protease cleaves the viral polyproteins (RNA) into smaller proteins like reverse transcriptase, integrase, protease, and structural proteins. These smaller proteins are necessary for the virus to mature and become infectious.

Which Drugs are HIV Protease Inhibitors and what are they

All are reversible competitive inhibitors:

Saquinavir

Indinavir

Ritonavir (booster)

Iopinavir

Darunavir

Amprenavir

Nelfinavir

Tipranavir

D/Ds of Pis

All PIs are substrates of common drug-metabolizing enzymes like CYP3A4. Drugs that inhibit or induce these enzymes increase or decrease PI drug concentrations.

Ritonavir

Booster. Potent inhibition of drug-metabolizing enzymes increases the serum concentration and half-lives of other PIs

MOA of HIV PI

They are peptidomimetics (peptide mimics)

Some sites cleaved by HIV protease are unique compared to peptide sequences recognized by human proteases.

HIV PIs recognize these unique sites and mimic the transition state of the cleavage state in the viral polyprotein, binding to HIV protease competitively inhibiting it from producing the proteins necessary for HIV to mature

Class Wide AEs of PIs

GI Effects: Nausea, vomiting, diarrhea. Taking with food may reduce symptoms

Hepatotoxicity: potential for hepatitis

Metabolic: Associated with lipodystrophy, especially fat accumulation (lip hypertrophy) in the abdomen, breasts, and neck

Nephrotoxicity: Adequate fluid intake is recommended to prevent precipitation in the kidney or ureters. Stone concerns particularly apply to indinavir and atazanavir.

Lenacapavir

Capsid Inhibitor

Binds to the capsid proteins and prevents the delivery and disassembly of the capsid in the cell nucleus and the maturation of the capsid in new virus particles

Capsids

Protein shells that protect and package the HIV RNA and essential enzymes.

Characteristics of LENA

Long-acting SC or Oral

T1/2 is 8-12 weeks and 10-12 days respectively

No overlapping resistance with any approved HIV agents

High rates of virologic suppression in combination with other antiretroviral agents

Resistance to LEN is often associated with high fitness cost to the virus meaning mutations that inhibit LEN can make HIV less efficient at replicating.

Use with other active drugs for heavily treatment-experienced patients with multidrug resistant HIV-1

How does HIV-1 Bind to its target cell

gp120 binds to CD4 molecule which triggers a conformational change in gp120, allowing it to bind to the co-receptor CCR5 (on T-cell). The virus then firmly attaches to the host cell membrane via exposed gp41. Virus cell fusion occurs as gp41 undergoes further changes into a hairpin structure that draws the two membranes into proximity. This allows the viral capsid to enter the hosts cell cytoplasm.

Maraviroc (Selzentry)

Chemokine receptor antagonist (CCR5), blocks gp120 from binding, fusing, and entering the T-cell.

Disrupts the interaction between HIV-1 and gp120 and CCR5 receptors on uninfected cells.

Patients MUST have CCR5-tropic HIV-1

Chemokines

Some viruses use CCR5 as a co-receptor during viral attachment. Other viruses used CXCR4 as the co-receptor

Trofile Assay

A diagnostic test to determine if patient is eligible for CCR5 antagonist therapy. The assay determines if the patient’s virus uses CCR5, CXCR4, or both co-receptors

Maraviroc resistance

Forms via mutations in gp120

D/D interaction of Maraviroc

Maraviroc is a CYP3A4 substrate. Dose adjustment is necessary when administering with inducers or inhibitors of this enzyme.

AEs of maraviroc

Possible liver toxicity (black box warning)

Drug allergy (severe rash)

Ibalizumab (Trogarzo)

The first MAB to be approved for HIV-1

Humanized IgG4 CD4-directed post attachment inhibitor for heavily treatment experienced adults with multi-drug resistant HIV-1.

Does not block the binding of MHC molecules or the initiation of CD4+ cell immune responses

MOA of Ibalizumab

MAB binds to CD4 molecule and blocks post-attachment steps needed for entry. HIV cannot complete its entry into the cell.

Fostemsavir

HIV attachment inhibitor

Treatment options for heavily treatment-experienced adults with multi-drug resistant HIV-1.

Avoid with strong CYP3A4 inducers like rifampin

MOA of Fostemsavir

Administered as a prodrug. Metabolized into the active drug Temsavir by alkaline phosphatase. Binds to gp120 on the HIV virion preventing binding to CD4 receptors on host cells.

Enfuvirtide (Fuzeon)

Synthetic 36 amino acid peptide derived from HIV-1 envelope glycoprotein gp41.

Used as a salvage therapy for individuals who have advanced disease, are treatment experienced, and continue to show evidence of ongoing viral replications.

Administered as a SC injection

AE of enfuvirtide

Injection site reaction - pain, erythema, pruritic, and nodule formation

MOA of Enfuvirtide (Fuzeon)

Inhibits fusion of viral and cellular membranes by mimicking portions of GP41. Inhibits protein interactions needed for the “zipping” process responsible for viral fusion with cell membrane.