Antiretroviral Therapy for HIV-1 - Eisenhower

Life Cycle of HIV and Drug Targets

1. Entry

2. Cytoplasmic Transport and Nuclear Import

3. Reverse Transcription

4. Integration

5. Transcription

6. Translation

7. Assembly

8. Budding and Maturation

Core Principles of ARV Regimen Selection

High potency - fully suppresses HIV in plasma to decrease risk of replication and drug resistance, and prevent transmission

High Barrier to Resistance - resistance is possible with all drug classes and cross-resistance within a drug class often occurs. Newer drugs in classes may be developed to require mutations that are less likely to occur in order to become resistant

Individualization/Tolerance - consider treatment and prevention treatment, comorbidities, ARV-related toxicities, resistance testing, potential for drug interaction, barriers to care, and preferences

Goals of HIV Therapy

Suppress HIV RNA to levels below detectable limit

Maintain viral suppression to reduce HIV-related morbidity and mortality including opportunistic infections, transmission, and non-AIDS medical events

Which drugs are Integrase Strand Transfer Inhibitors (INSTIs)

End in -gravir

Bictegravir

Cabotegravir

Dolutegravir

Elvitegravir

Raltegravir

General Info about INSTIs

First line regimens often include an INSTI due to high barrier resistance

Common AEs of INSTIs

Nausea

Diarrhea

Abdominal pain

Headache

Insomnia

Dizziness

Somnolence

Fatigue

Abnormal Dreams

Cabotegravir

INSTI

Oral of LA Injectable

Space PO from polyvalent cations

Take with food

Rare AE of INSTI

SJS

Myopathy

Rhabdomyolysis

Redistribution of body fat

Dolutegravir

INSTI

Space from Antacids, cations, sucralfate, iron, calcium, buffered medications

Risk of hepatotoxicity

Elvitegravir

INSTI

Take with food

Bictegravir

INSTI

Space from Al/Mg antacids

Can take with calcium or iron on empty stomach, space if not.

Do not co-administer with sucralfate

Which Drugs are Protease Inhibitors (PIs)

Atazanavir

Darunavir

Fosamprenavir

Indinavir

Lopinavir/Ritonavir

Nelfinavir

Ritonavir (booster)

Saquinavir

Tipranavir

General Info on Protease inhibitors

Often boosted with ritonavir or cobicistat (darunavir)

Administration of PIs

Oral

Most are given with food, except lopinavir/ritonavir/ and fosamprevnair tablets

Once or twice daily dosing

Common AEs of PIs

N/V/D

Dyslipidemia

Headache

Abdominal pain

Rash

Peripheral Neurologic symptoms - atazanavir

Rare side effects of PIs

SJS and skin reactions

Lipodystrophy

Cardiac conduction abnormalities

Hyperbilirubinemia and hepatotoxicity - atazanavir

Hemophilia

Allergy Alert for PIs

use fosamprenavir, tipranavir, darunavir with caution if history of sulfonamide allergy

Which Drugs are Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine

Efavirenz

Etravirine

Nevirapine

Rilpivirine

Doravirine

General info on NNRTIs

Historically given with 2 NRTIs but INSTI based regimens have mostly replaced these.

More likely to be given with an INSTI as a 2 drug regimen for treatment

Administration of NNRTIs

Oral or injectable - rilpivirine

Take on an empty stomach - efavirenz

Take with meal - rilpivirine

Common AEs of NNRTIs

N/V/D

Rash

Dyslipidemia

QT prolongation

Abnormal Dreams

Depressive disorder (rilpivirine)

Rare side effects of NNRTIs

SJS and skin reactions

IRIS

Hepatotoxicity - nevirapine (CD4 >250 in f, >400 in men)

Serious depression

Nervous system symptoms

Increased TGs and cholesterol

Lipodystrophy

Which drugs are Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Abacavir

Didanosine

Emtricitabine

Lamivudine Stavudine

Tenofovir alafenamide (TAF)

Tenofovir disoproxil fumarate (TDF)

Zidovudine

TDF vs TAF

TDF - 1st generation

TAF - next generation prodrug. Considered more effective with less risk of renal and bone toxicities than TDF

Administration of NRTIs

Oral

Common AEs of NRTIs

Nausea/Vomiting

Headache

Fatigue

Rare AEs of NRTIs

Peripheral neuropathy

Lactic acidosis

Hepatotoxicity

Anemia - zidovudine (may inc MCV and lead to macrocytic anemia)

Abacavir Pearl

Must complete HLA B*5701 testing prior to initiation due to potential of hypersensitivity reactions

What drugs are Nucleoside Reverse Transcriptase Translocation Inhibitors (NRTTI)

Islatravir (Idvynso)

General info on Islatravir

Newly approved to be given with Doravirine in a fixed dose combination for HIV-1 treatment

Administration of Islatravir

Once daily by mouth with or without food

Common AEs of Islatravir

Diarrhea

Dizziness

Headache

Fatigue

Abdominal Distention

Headache

Increased Weight

Contraindication of Islatravir

Co-administration with Lamivudine or emtricitabine which may decrease its effectiveness

Co-administration of strong CYP3A enzyme inducers may decrease effectiveness of IDYNSO

What drugs are CCR5 Co-Receptor Antagonists

Maraviroc (Selzentry)

General info on Maraviroc

Indicated for only CCR5-tropic HIV-1

Ineffective for dual/mixed CXCR4-tropic HIV-1

Given to treatment-experienced or treatment naive patients

CYP3A4 substrate

Dose adjustment for severe renal impairment or ESRD (end stage renal disease)

Administration of Maraviroc

Oral twice daily

Administered in combination with other ARV

Common AEs of Maraviroc

Pyrexia (fever)

Dizziness

rash

URTI

Bronchitis, cough

Flatulence, bloating

Abdominal pain and distention

GI atonic and hypomotility

Rare side effects of Maraviroc

Hepatotoxicity accompanied by rash and systemic allergic reaction

SJS and other hypersensitivity reactions

Myocardial Ischemia and/or infarction

What dursg are Fusion Protein inhibitors

Enfuvirtide

General info for Enfuvirtide

Indicated for treatment-experienced patients with HIV-1 replication despite ongoing ARV

No dose adjustments needed for renal or hepatic impairment

Administration of Enfuvirtide

Reconstitute vial with sterile water from kit

Twice daily SC injection, first one is supervised

Administered with other ARV

AEs of Enfuvirtide

Injection site reactions

Diarrhea/nausea

Fatigue

Rare side effects of Enfuvirtide

Injection site reaction (pain, discomfort, erythema, nodules, cysts, ecchymosis)

Post injection bleeding

Hypersensitivity

Pneumonia

Immune reconstitution inflammatory syndrome (IRIS)

Immune reconstitution inflammatory syndrome (IRIS)

Paradoxical response that involves unmasking or worsening of infections. May occur if ART is immediately initiated before resolution of cryptococcal meningitis or meningeal TB.

Most likely to be ART naive with less CSF inflammation presentation.

Reduce risk by delaying initiation of ART and assessing whether CSF is sterile in setting of cryptococcus

May be challenging to differentiate treatment failure from IRIS

IRIS can also reactivate HBV associated liver diseases

What Drugs are CD4 directed Post attachment HIV-1 Inhibitors

Ibalizumab-uiyk (Trogarzo)

General Info for Ibalizumab

Indicated for heavily treatment experienced adults with multi-drug-resistant HIV-1 failing their current ARV regimen

Limited Data

Administration of Ibalizumab

IV infusion

Administered in combination with other ARV

Common AEs of Ibalizumab

Nausea/Diarrhea

Dizziness

Rash

Rare side effect of Ibalizumab

IRIS

What drug is a HIV-1 Capsid Inhibitor

Lenacapavir (Sunlenca, Yeztugo)

General info for Lenacapavir

Sunlenca: is indicated for heavily treatment experienced adults with multidrug resistant HIV-1 whose current ARV regimen is failing due to resistance, intolerance, or safety issues

Yeztugo: indicated for PrEP

Administration for Lenacapavir

Initiation is oral tablets

Maintenance is SC injection administered by a provider

Administered in combo with other ARV

Not studied in ESRD or severe hepatic impairment

Dosing schedule is provided for delayed or missed doses

Common AE of lenacapavir

Injection site reactions

Nausea

Headache

Rare AEs of lenacapvir

IRIS (Sunlenca)

Injection site reaction - nodules and indurations

Co-administration with strop CYP3A4 inducers is contraindicated (Sunlenca)

Dosage modification are needed if administered with moderate or strong CYP3A4 inducers (Yeztugo)