Chatper 26. HIV

What kind of virus is HIV?

• ssRNA retrovirus

• uses CD4 T-helper cells as hosts to replicate

What is the preferred drug class to treat HIV?

antiretroviral therapy (ART)

How are lab values affected if HIV continues to replicate?

• viral load increases

• CD4 count decreases

When the CD4 count falls below ________, the immune system of patients with HIV can no longer ward off opportunistic infections (OIs).

<200 cells/mm^3

How is HIV infection spread?

infected body fluids make contact with mucus membranes or open wounds

i.e. unprotected sex, sharing injection equipment, pregnancy/childbirth/breastfeeding

What is another term for mother-to-child transmission of HIV?

vertical transmission

• Occurs with pregnancy, childbirth, or breastfeeding

CDC recommendations for HIV testing

• Once for all patients aged 13-64 years old

• Annually for patients with hx of other STIs and......

• hepatitis or tuberculosis

• Those that engage in high-risk activities (sex w multiple partners, sharing drug equipment)

How does acute HIV infection present?

flu-like symptoms

How is AIDS diagnosed?

CD4 count <200cells/mm^3

OR an AIDs-defining condition is present

• OIs [Opportunistic Infections]

• Kaposi's sarcoma (and other cancers)

• HIV wasting syndrome [debilitating condition with loss of fat, muscle, appetite]

What are treatment options to stimulate appetite in HIV wasting syndrome?

• Dronabinol

• Megestrol

How long after HIV infection can antibodies be detected in most people?

4 to 12 weeks post-infection

Diagnostic screening for HIV

a) Initial Screening

(HIV-1/-2 antigen/antibody immunoassay) (test for p24 antigens or hiv1/2 antibodies)

b) Confirmatory testing if reactive

(HIV-1/-2 antibody differentiation immunoassay)

• if indeterminate/negative = HIV-1 nucleic acid test (quantifies viral load) -> RNA testing

• if positive = HIV diagnosis and subtype confirmed

What at-home test detects the presence of HIV antibodies and provides immediate results?

OraQuick In-Home HIV Test

If one gets a positive result with the OraQuick test, what should they do?

Follow up with a confirmatory laboratory test

How soon can testing for HIV testing be done and why?

• 3 months after exposure

• sooner can lead to false negative d/t lag in antibody production

Drugs that act at Binding and Attachment (HIV attaches to CD4 receptor + co-receptor (CCR5/CXCR4) on surface of host CD4 T cell)

• Maraviroc (CCR5 antagonist)

• Fostemsavir (attachment inhibitor)

• Ibalizumab-uiyk (post-attachment inhibitor)

Drugs that Act on Fusion (HIV viral envelope fuses w/ cell membrane and enters, releasing inner capsid containing viral RNA and enzymes)

• Enfuvirtide (fusion inhibitor)

No class

Drugs that act on Reverse Transcription (HIV RNA -> HIV DNA by reverse transcriptase (enzyme))

• NRTIs (e.g. emtricitabine)

• NNRTIs (e.g. rilpivirine)

Drugs that act on Nuclear Import (HIV capsid transported into cell nucleus through nuclear pore)

• Lenacapavir (capsid inhibitor)

Drugs that act on Integration (inside nucleus, integrase (enzyme) inserts HIV DNA into host cell DNA)

• INSTIs (e.g. bictegravir, dolutegravir)

Drugs that act on Transcription/Translation (Host cell machinery transcribes/translates DNA into HIV RNA and long-chain proteins aka the HIV building blocks)

• None

Drugs that act on Assembly (new HIV rna/proteins/enzymes (incl. protease) assemble at the cell surface)

• lenacapavir (capsid inhibitor)

Drugs that act on Budding and Maturation (immature virus pinches off cell. Protease breaks up long viral protein chains, forming capsid and a mature virus that can infect other cells)

• PIs (e.g. darunavir)

• Lenacapavir (capsid inhibitor)

What is the most important indicator of ART response?

HIV viral load (tells how much HIV RNA is in blood)

• A high VL after starting ART indicates nonadherence or drug resistance

Compared to HIV VL being the most important indicator of ART Response, what is the other routine lab test to use?

CD4 Count

• Major indicator of immune fx to determine needs for OI ppx

Dovato

Dolutegravir/lamivudine

One pill, Once daily regimens

• Biktarvy

• Dovato

Biktarvy Components

Bictegravir / emtricitabine / TAF

Tivicay

Dolutegravir

Truvada

Emtricitabine/TDF

Descovy

Emtricitabine/TAF

Two pills, Once daily regimens

Tivicay + Truvada OR

Tivicay + Descovy

What tests should be done initially after HIV diagnosis, prior to starting treatment?

• Hepatitis B and C

• Pregnancy

• HLA-B*5701 (if using abacavir)

• Tropism assay (if using maraviroc)

ART treatment goals

• undetectable viral load

• restoring/preserving immune function

• reducing HIV-associated morbidity (i.e. OIs)

• preventing transmission

Guideline recommended treatment for most patients includes what class? and why?

INSTI-based regimens (most contain 2 NRTIs and 1 INSTI)

• Must start as soon as possible to maintain undetectable VL AND preserve immune function to reduce morbidity and transmission

What 2 drugs are interchangeable in an INSTI-based regimen? why mention this?

emtricitabine and lamivudine

• should not be used together

What drugs usually make up the NRTI backbone in most HIV regimens?

Truvada (em/TDF) or Descovy (em/TAF)

What drug is a first-line option but is an exception to the typical regimen makeup?

Dovato (dolutegravir/lamivudine)

it contains 1 INSTI and 1 NRTI

When should dovato not be used?

In treatment-naive patients if:

HIV RNA >500,000 copies/mL, HBV coinfection (or unknown), or HIV resistance genotypic testing not performed

When should Biktarvy, Dovato, Truvada, and Descovy not be used?

if CrCl <30 mL/min (fixed dose combinations offer little flexibility)

All can be given separately to control dosing except Biktarvy to allow renal dose adj

How does one make an alternative ART regimen?

1 "base" plus 2 NRTIs

Base = PI, NNRTI, INSTI

Backbone = 2 NRTIs

Alternative ART Regimen Choices

PI-Based (boosted w/ cobicistat or ritonavir)

• darunavir or atazanavir

NNRTI-Based

• Efavirenz, rilpivirine, or doravirine

INSTI-Based

• Elvitegravir (only available in combo products)

• Raltegravir

NRTI backbone (2 drugs, 1 from each row)

• TDF or TAF or abacavir PLUS

• Emtricitabine or lamivudine

Complete Regimen Examples

• rilpivirine + TDF + emtricitabine

• raltegravir + TAF + emtricitabine

True or false - breastfeeding can increase risk of transmission of HIV to child

true (replace with formula or banked pasteurized milk)

If a pregnant patient is already taking ART, they generally continue that treatment during pregnancy. For treatment-naive patients, what should they be initiated on preferentially?

2 NRTIs (abacavir/lamivudine, TAF/entricitabine) plus INSTI (dolutegravir preferred) or boosted PI (darunavir preferred)

IV zidovudine purpose?

Drug is given during the time of delivery for perinatal transmission prophylaxis if it is a new diagnosis of HIV, high viral load (>1000 copies/mL), or HIV status unknown

• Prevents perinatal HIV transmission

• Administer during LABOR and DELIVERY

Immune reconstitution inflammatory syndrome (IRIS) definition

Paradoxical worsening of underlying condition after ART is started

• (symptoms of underlying condition become unmasked)

What can appear during IRIS? and howto treat?

OIs, autoimmune conditions, and some cancers (Kaposi's sarcoma)

• MUST: Continue ART and treat unmasked condition (anti-infectives for causative pathogens)

NRTIs

Zidovudine (retrovir)

Lamivudine (Epivir)

Abacavir (Ziagen)

Tenofovir disoproxil fumarate (Viread)

Tenofovir alafenamide (Vemlidy) - TAF is usually in combos for HIV; can be single entity product for HBV known as Vemlidy

Emtricitabine (Emtriva)

Name Tip/REMEMBER —> Z LATTE

---

Abacavir (Ziagen)

Emtricitabine (Emtriva)

Lamivudine (Epivir)

Zidovudine (retrovir)

Tenofovir disoproxil fumarate (Viread)

Tenofovir alafenamide (Vemlidy)

MOA of NRTIs?

Competitively inhibit reverse transcriptase enzyme

• Prevents conversion of HIV RNA to DNA

Are all NRTIs renally or hepatically cleared? What is the exception?

renally

• Abacavir = exception (hepatic)

Which NRTIs can be given once daily?

• TDF and TAF

• Abacavir and Lamivudine

Warning for all NRTIs

Lactic acidosis and hepatomegaly with steatosis; Boxed Warning for zidovudine

Common side effects = nausea, diarrhea

Unique side effect of emtricitabine?

hyperpigmentation of palms of hands and soles of feet

Boxed Warning associated with Emtricitabine, lamivudine, and tenofovir products

These are boxed warnings for HBV and HIV Co-infections:

Severe acute HBV exacerbations can occur if discontinued

Lamivudine: doses for HVB will NOT treat HIV (co-infected need higher doses) do not use Epivir-HBV for HIV (contains lower dose of lamivudine than what is needed for HIV)

Boxed Warning associated with Abacavir

risk for hypersensitivity reaction (HSR)

• screen for HLA-B*5701 allele before starting (CI if has allele)

• Patients must carry card indicating that HSR is an emergency (fever, rash, NVD, dyspnea, cough)

• never re-challenge patients with hx of HSR

Risks associated with Tenofovir formulations (higher with TDF vs TAF)

higher with TDF

• renal impairment (incl. acute renal failure and Fanconi syndrome [renal tubular inj and electrolyte abnormality])

• decreased BMD (consider calcium, vit D supps; DEXA scan)

Higher with TAF

• TAF associated with lipid abnormalities [monitor lipids if switching from TDF to TAF

Zidovudine Laboratory effects/safety issues

• hematologic toxicity: neutropenia and anemia

• macrocytosis (high MCV) sign of adherence

INSTIs

Bictegravir (only in Biktarvy combo)

Cabotegravir (Apretude, Cabenuva combo)

Raltegravir (Isentress, Isentress HD)

Elvitegravir (Combos Genvoya and Stribild)

Dolutegravir (Tivicay)

B CRED (or another way to remember = generics end with -tegravir)

INSTI MOA

Block integrase enzyme, preventing HIV DNA from inserting into host cell DNA

What is the only INSTI that is given twice daily?

Isentress (NOT the HD one)

What is the dosing for MOST of INSTIs?

• remember: ends with “-tegravir”

• All are dosed ONCE DAILY

  • Exception: Isentress (twice daily)

Renal cutoffs for INSTIs

CrCl <70: Dont start Stribild (elvitegravir)

CrCl <50: d/c Stribild (elvitegravir)

CrCl <30: Dont start Biktarvy or Genvoya

What is the ONLY indication for Cabotegravir extended-release IM injection (Apretude)?

Pre-exposure prophylaxis (PrEP)

Side Effects of all INSTI

• weight gain

• insomnia

• rare risk of depression/Suicidal Ideation in pts with pre-existing psych conditions

Which INSTIs increase SCr (inhibit tubular secretion) with no effect on GFR?

Bictegravir, dolutegravir

Which INSTIs increase CPK, cause myopathy and rhabdo, and have HSR?

Raltegravir, Dolutegravir

HSR = hypersensitivity reaction (syndrome of rash, fever, symptoms of an allergic reaction)

Which INSTI can cause hepatotoxicity? and what risk factors?

Dolutegravir

• especially if co-infection with hepatitis B or C

Which INSTI causes injection site reactions?

Cabotegravir

• this is the same for apretude and cabenuva (ONLY INJECTIONS)

Specific counseling point for INSTI for patients taking it? Instructions?

How long should an INSTI be separated from polyvalent cations (Al, Ca, Mg, or Fe):

Take INSTI 2 hours before or 6 hours after [decreases INSTI absorption]

dolutegravir and bictegravir can be taken with calcium or iron if also taken with food

NNRTIs

Rilpivirine (Edurant; Complera, Odefsey, Juluca, and Cabenuva combos)

Efavirenz (Symfi (Lo) combo)

Doravirine (Pifeltro; Delstrigo combo)

Etravirine (Intelence)

Nevirapine

REDEN (All generics contain “-vir-” in them)

Side effects associated with NNRTIs

• Hepatotoxicity and severe rash

• Rash (SJS/TEN) -> highest risk w nevirapine

NNRTI MOA

non-competitively inhibit reverse transcriptase enzyme (prevent conversion of HIV RNA to HIV DNA)

Ripilvirine Side Effects

• Oral: take with meal and water (DO NOT sub w/ protein drink)

• Oral: requires acidic environment for absorption (NO PPIs, separate from H2RAs/antacids)

• Depression

• Increased SCr, no GFR effect

• DO NOT USE if initial viral load >100,000 copies/mL and/or CD4 count <200 cells/mm^3 (higher failure rate)

• Cabenuva (IM): injection site rxns

How should Ripilvirine be separate from acid reducers?

NEEDS AN ACIDIC GUT TO WORK

• PPIs: DO NOT USE

• H2RAs: Take H2RA 12 hrs before or 4 hours after

• Antacids: take antacid 2 hrs before or 4 hrs after

Efavirenz side effects

• Psych (depression, SI)

• CNS effects (impaired concentration, abnormal dreams, confusion) -> resolves 2-4 weeks in most patients

• Increased total cholesterol and triglycerides

Why are NNRTIs subject to drug interactions?

Major CYP 3A4 substrates

(ripilvirine and doravirine: do not use w strong inducers)

efavirenz and etravirine moderate 3A4 inducers

Protease Inhibitors

• Atazanavir (Reyataz; combo Evotaz)

• Darunavir (Prezista; combo Symtuza and Prezcobix)

• Fosamprenavir

• Lopinavir/ritonavir (Kaletra)

• Tipranavir (Aptivus)

ritonavir technically a PI, but only used as booster

Remember: ALL protease Inhibitors end in “-navir”

PIs MOA

Inhibit HIV protease enzyme, leads to preventing mature virus produced during budding and maturation

All PIs are recommended to take with what and which ones require renal dose adjustments?

• Booster, such as ritonavir or cobicistat

• none require renal dose adj

Which PI needs an acidic gut for absorption?

Atazanavir (separate from antacids and H2RAs)

avoid PPIs if unboosted; take boosted at least 12 hrs

• after PPI (dose should not exceed omeprazole 20mg or equivalent)

Unique side effect of atazanavir

Reversible hyperbilirubinemia (jaundice/scleral icterus "bananavir") -> does NOT require discontinuation [reversible]

Side Effects of All PIs

• Metabolic Syndrome

- decreased HDL; increased LDL and TG

- increased BG; Insulin resistance

- abdominal adiposity

• Hepatic dysfunction

- inc. LFTs, hepatitis, exacerbation of hepatic disease

• Hypersensitivity rxns

- rash (SJS/TEN)

- angioedema

- bronchospasm, anaphylaxis

• Diarrhea, nausea

• Major 3A4 substrates (and most are strong inhibitors)

- avoid strong CYP3A4 inducers (will dec. PI concentrations)

Which PIs should take caution with sulfa allergy?

Darunavir (and fosamprenavir, tipranavir)

Which PI can cause a disulfiram reaction with metronidazole?

Lopinavir/Ritonavir (Kaletra) oral solution contains 42% alcohol

PK Boosters (Enhancers)

• Ritonavir (Norvir; in paxlovid and kaletra)

• Cobicistat (Tybost; combos Genvoya, Stribild, Symtuza)

MOA/purpose of PK Boosters

Ritonavir and cobicistat are inhibitors of CYP3A4

• INCREASES (boosts) ART level and therapeutic effect

Ritonavir dosing

100 to 200 mg PO with food AND with boosted drug once or twice daily

Cobicistat dosing

150 mg daily with boosted drug AND with food

Is booster or treatment dosing lower?

booster

Are ritonavir and cobicistat interchangeable?

no

• do not use together

Drugs that are contraindicated/should be avoided with PK Boosters and PIs

• Alpha 1a blockers (alfuzosin, silodosin, tamsulosin)

• Amiodarone, dronedarone

• Anticoagulants/antiplatelets (apixaban, rivroxaban, ticagrelor)

• Azoles (voriconazole, posaconazole, itraconazole, isavuconazole)

• Hep C PIs (grazoprevir, glecaprevir)

• Lovstatin and simvastatin [use pita, ator, or rosuvastatin to treat HLD]

• PDE-5 inhibitors for pulmonary htn (sildenafil, tadalafil)

• Strong 3A4 inducers (PSPORCS)

• systemic, inhaled, and intranasal steroids (except beclomethasone)

CCR5 antagonist MOA and Drug

Maraviroc (selzentry)

(blocks HIV from binding CD4 cell in virus strains that use CCR5 co-receptor)

Which HIV drug must you have tropism assay results prior to starting?

Maraviroc

• determines if HIV strain infecting patient can only bind CCR5 co-receptor

• will not work if strain can bind CXCR4 or mixed (HIV will still enter CD4 wall)

Which drug is an attachment inhibitor?

Fostemsavir

Which drug is a post-attachment inhibitor and route?

ibalizumab-uiyk (trogarzo)

Route: IV

Which drug is a fusion inhibitor given SC?

Enfuvirtide (Fuzeon)

injection site rxns

Lenacapavir brand

Sunlenca

MOA/Class: Capsid Inhibitor

Biktarvy

Bictegravir/emtricitabine/TAF

Cabenuva

Cabotegravir/rilpivirine

Triumeq

Dolutegravir/abacavir/lamivudine