For HIV, there are 2 surrogate markers we can use:
- CD4 (Tcell) count
- Viral load
What is the CD4 count in a healthy person? Explain the significance of CD4 count.
Healthy person: 500-1200 cells/mm^3
Significance:
- Most important lab indicator of immune function in HIV pts
- Strongest predictor of disease progression
- Assess response to ART
- Assess need for initiating or discontinuing prophylaxis for opportunistic infections
For HIV, there are 2 surrogate markers we can use:
- CD4 (Tcell) count
- Viral load
Explain the significance of viral load
- Measures amount of virus in plasma
- Most important indicator of response to ART
- Useful in predicting clinical progression
After initiating ART, how often do you monitor CD4 count?
How would you define ‘adequate response to Tx’?
Assessed at baseline, then every 3-6 months AFTER ART initiation.
Once adequate response (↑ in CD4 count by 50-150 cells/mm^3 within first year of Tx) achieved, assess every 12 months.
After initiating ART, how often do you monitor viral load?
Measured BEFORE ART initiation.
Measured 2-4w (not later than 8w) AFTER Tx initiation/ modification.
Then measured every 4-8w until viral load suppressed.
What are the 2 types of ART combinations?
- 2 NRTIs + 1 INSTI
- 1 NRTI + 1 INSTI
Name the medications under ‘2 NRTIs + 1 INSTI’ (3)
- Tenofovir + emtricitabine + bictegravir
- Tenofovir + emtricitabine + dolutegravir
- Abacavir + lamivudine + dolutegravir [Triumeq]
Name the medications under ‘1 NRTI + 1 INSTI’
Emtricitabine + dolutegravir
What are the contraindications for 1 NRTI + 1 INSTI?
- HIV RNA > 500,000 copies/mL
- HBV co-infection
- Pt whose results of HIV genotypic resistance testing or HBV testing not available yet
Name all the NRTIs (TEALZ)
Tenofovir
Emtricitabine
Abacavir
Lamivudine
Zidovudine
MOA of NRTIs?
Inhibits reverse transcriptase, prevents HIV DNA replication
What are the disadvantages of NRTI?
- ADEs include mitochondrial toxicity (rare but serious)
s/sx: lactic acidosis, hepatic steatosis (fatty infiltrate), lipoatrophy (fat loss)
(Z > T = A = L) - Requires dose adjustment in renally impaired (except Abacavir)
What are the ADEs of lamivudine, emtricitabine, tenofovir, abacavir and zidovudine?
Which are the 2 with ADEs to take more note of?
Lamivudine: minimal toxicity, n/v/d
Emtricitabine: minimal toxicity, hyperpigmentation, n/d
Tenofovir: n/v/d, renal impairment, decrease in bone mineral density (TAF < TDF)
Abacavir: n/v/d, hypersensitivity rxn in pts with HLA-B5701 (must test for HLA-B*5701 before initiating Tx, discontinue if occurs), possible association with MI (do not use for pts with high CV risk)
Zidovudine: n/v/d, myopathy, bone marrow suppression (anaemia, neutropenia) → monitor full blood count while on Tx
Name all the INSTIs (BRED)
Bictegravir, Raltegravir, Elvitegravir, Dolutegravir
MOA of INSTIs?
Inhibits integrase enzyme from combining viral DNA with host cell DNA
What are the advantages of INSTIs?
- Bictegravir, Dolutegravir have good virologic effectiveness
- High genetic barrier to resistance (B, D > R, E)
- Generally well tolerated
What are the disadvantages of INSTIs?
(general ADEs, ADEs specific to bictegravir & dolutegravir and raltegravir and DDIs)
General ADEs: Weight gain, n/d, headache, depression (rare)
Bictegravir and Dolutegravir: ↑ SCr
Raltegravir: pyrexia, creatine kinase elevation (rhabdomyolysis)
DDIs: ↓ bioavailability with concurrent administration of polyvalent cations; Bictegravir, Dolutegravir and Elvitegravir are CYP3A4 substrates
Name the NNRTIs (ER)
Efavirenz, Rilpivirine
MOA of NNRTIs?
Also targets reverse transcriptase enzyme but at a different binding site than NRTIs
Advantages of NNRTIs?
- Long t1/2
- Less metabolic toxicity (hyperlipidemia, insulin resistance) than some PIs
Disadvantages of NNRTIs?
- Low genetic barrier to resistance
- Cross resistance among NNRTIs
- Skin rash, SJS (R < E)
- Potential for CYP450 DDIs (some are inducers, some inhibitors)
- QTc prolongation
ADEs of NNRTIs? (specific)
- Efavirenz: rash, hyperlipidemia, neuropsychiatric (dizziness, depression, insomnia, abnormal dreams, hallucination), ↑ in LDL-C and TGs, hepatotoxicity
- Rilpivirine: depression, headache
- Mixed CYP inducer/ inhibitor: Efavirenz CYP3A4 substrate, induces CYP2B6 and 2C19; Rilpivirine CYP3A4 substrate, oral absorption ↓ with ↑ gastric pH (use with PPIs contraindicated)
Name all the protease inhibitors (FRALD)
Fosamprenavir, Ritonavir, Atazanavir, Lopinavir, Darunavir
Advantages of PIs?
- High genetic barrier to resistance
- Resistance less common
Disadvantages of PIs? (ADEs and DDIs)
- ADEs: metabolic complications (dyslipidemia, insulin resistance), GI SEs (n/v/d), liver toxicity (esp with chronic hep B, C), lipohypertrophy, ↑ risk of osteopenia/ osteoporosis
- CYP3A4 inhibitors and substrates → potential DDIs
