STEPTRACKERMICROBIOLOGY + PHARMACOLOGY | ANTIRETROVIRALS | HIGH-YIELD REVIEW

HIV Antiretrovirals

Combination ART — usually two NRTIs plus an integrase inhibitor — suppresses HIV to undetectable levels. Know each class by its step in the life cycle and its signature toxicity.

FOCUS ON
Standard regimen: 2 NRTIs (tenofovir + emtricitabine or lamivudine) + an integrase inhibitor (bictegravir, dolutegravir). NRTIs (nucleoside analogs, need phosphorylation, chain terminators): tenofovir (TDF → kidney, bone; TAF less), emtricitabine/lamivudine (also HBV), abacavir (hypersensitivity → test HLA-B*57:01), zidovudine (macrocytic anemia, myopathy; perinatal). NNRTIs (bind RT allosterically, no activation): efavirenz (vivid dreams, CNS, teratogen concerns), nevirapine (hepatotoxicity, SJS), rilpivirine. Protease inhibitors (-navir, boosted with ritonavir/cobicistat): lipodystrophy, hyperglycemia, CYP3A4 inhibition, indinavir stones. Integrase inhibitors (-tegravir): weight gain, ↑ CK, neural tube concern (dolutegravir early, minor). Entry: maraviroc (CCR5), enfuvirtide (gp41), ibalizumab, lenacapavir (capsid).
CLASS · DRUG
MECHANISM
TOXICITY
NOTES
Tenofovir (TDF, TAF)
Nucleotide RT inhibitor
TDF: proximal tubulopathy (Fanconi), ↓ bone density · TAF less
Also treats HBV · PrEP
Emtricitabine · lamivudine
Cytidine analogs
Well tolerated
Also HBV — stopping can flare hepatitis
Abacavir
Guanosine analog
Hypersensitivity (fever, rash, GI, respiratory) — fatal on rechallenge; possible MI risk
Test HLA-B*57:01 first
Zidovudine (AZT)
Thymidine analog
Macrocytic anemia, neutropenia, myopathy, lactic acidosis
Newborn prophylaxis after HIV ⁺ birth
NRTI class effect
Inhibit mitochondrial DNA polymerase γ (older drugs: stavudine, didanosine)
Lactic acidosis, hepatic steatosis, peripheral neuropathy, pancreatitis, lipoatrophy
Mitochondrial toxicity
Efavirenz
NNRTI: binds RT away from active site; no phosphorylation needed
Vivid dreams, insomnia, depression, rash; false ⁺ cannabinoid test
CYP inducer
Nevirapine · rilpivirine · doravirine
NNRTIs
Nevirapine: hepatotoxicity (women with high CD4), SJS · rilpivirine: needs acid (no PPIs)
Single mutation → resistance (low barrier)
Protease inhibitors
Darunavir, atazanavir, lopinavir (-navir): block cleavage of gag-pol polyprotein
Hyperlipidemia, insulin resistance, lipodystrophy (fat redistribution), GI upset · atazanavir: indirect hyperbilirubinemia; indinavir: kidney stones
Boosted by ritonavir/cobicistat (CYP3A4 inhibition) → many interactions; rifampin contraindicated
Integrase inhibitors
Bictegravir, dolutegravir, raltegravir, cabotegravir (-tegravir): block strand transfer
Weight gain, insomnia, ↑ CK; ↑ creatinine (dolutegravir/bictegravir block secretion)
High barrier to resistance · chelated by antacids · cabotegravir injectable (PrEP, treatment)
Maraviroc
CCR5 antagonist on host cell
Hepatotoxicity
Only for CCR5-tropic virus (tropism assay)
Enfuvirtide · ibalizumab · lenacapavir
gp41 fusion inhibitor · anti-CD4 mAb · capsid inhibitor
Injection-site reactions (enfuvirtide)
Salvage therapy; lenacapavir twice-yearly PrEP
Pregnancy & perinatal
ART throughout pregnancy, IV zidovudine at delivery if viral load high
Infant zidovudine ± others
Undetectable load → transmission < 1%
Prevention
PrEP: TDF/FTC or TAF/FTC daily, cabotegravir every 2 months · PEP: 3-drug ART within 72 h for 28 days
Check HIV, HBV, kidney function
Undetectable = untransmittable

Mechanism — NRTI vs NNRTI

NRTINucleoside analog
→
Host kinases phosphorylate
→
Competes at RT active site, no 3′-OH → chain stops
NNRTINot a nucleoside
→
Binds pocket near active siteAllosteric, no activation
→
HIV-1 onlyHIV-2 resistant

Signature toxicities

DRUG
TOXICITY
BEFORE STARTING
Abacavir
Hypersensitivity
HLA-B*57:01
Tenofovir DF
Kidney, bone
Creatinine, phosphate
Zidovudine
Anemia, myopathy
CBC
Efavirenz
CNS, dreams
Psychiatric history
Protease inhibitors
Metabolic, interactions
Lipids, glucose, drug list
Integrase inhibitors
Weight gain
—

How it's tested

COMMON CONFUSIONA rise in creatinine on dolutegravir or bictegravir (or cobicistat) reflects blocked tubular secretion, not true loss of GFR.
THE TRAPRifampin with protease inhibitors or many integrase inhibitors slashes their levels — use rifabutin or adjust ART for HIV-TB coinfection.
YOUR APPROACHLife-cycle step → class → drug → pre-start test (HLA-B*57:01, HBV status, kidney) → toxicity and interactions.

If you see… think…

Fever, rash and dyspnea 2 weeks into ART, HLA-B*57:01 ⁺ → abacavir hypersensitivity
Glycosuria, hypophosphatemia on ART → tenofovir DF (Fanconi)
Macrocytic anemia on ART → zidovudine
Vivid nightmares on ART → efavirenz
Buffalo hump, high triglycerides, hyperglycemia → protease inhibitors
Kidney stones on ART → indinavir
Drugs ending in -tegravir → integrase inhibitors
Drug requiring a tropism test → maraviroc (CCR5)
HBV flare after stopping an HIV drug → tenofovir, lamivudine, emtricitabine
Booster used to raise protease inhibitor levels → ritonavir or cobicistat (CYP3A4)