Pharmacology · Antiviral Pharmacology

ARV Interactions, Toxicity, and Special Populations

Interaction mechanisms, toxicity syndromes, and clinical decision rules

The two dominant ARV interaction frameworks operate in opposite directions — CYP3A4 inhibition by ritonavir and cobicistat raises co-administered drug concentrations (explaining why simvastatin and lovastatin are absolutely contraindicated with any boosted PI regimen), while CYP3A4 induction by efavirenz, nevirapine, and rifampin lowers them (explaining methadone withdrawal and oral contraceptive failure in patients on these agents).
Rifampin presents the most clinically consequential drug interaction in ART because it reduces boosted PI AUC by 75–90%, making all boosted PI regimens contraindicated — the preferred approach for HIV/TB co-treatment is either dolutegravir 50 mg twice daily (dose-doubled to overcome rifampin induction) or switching from rifampin to the weaker inducer rifabutin to allow standard ARV dosing.
TDF nephrotoxicity targets the proximal tubule via OAT1-mediated drug accumulation — the resulting Fanconi syndrome produces glucosuria without hyperglycemia, phosphaturia, and proteinuria; risk is amplified by concurrent ritonavir or cobicistat through inhibition of MRP2-mediated tubular efflux, and the threshold to switch from TDF to TAF is eGFR below 60 mL/min or significant osteoporosis risk.
IRIS occurs in 10–25% of patients who start ART with CD4 below 100 cells/mm³, typically within 4–8 weeks, as recovering immune function mounts an inflammatory response against previously subclinical infections — cryptococcal IRIS carries the highest mortality because of raised intracranial pressure requiring therapeutic lumbar punctures, and corticosteroids are avoided in cryptococcal IRIS due to risk of worsening fungal disease.
Dolutegravir is now the recommended INSTI throughout pregnancy including at conception, following updated analyses showing the neural tube defect signal was smaller than initially reported — raltegravir remains the alternative with the most established long-term pregnancy safety data, and intrapartum intravenous ZDV is still given when viral load exceeds 1,000 copies/mL at delivery regardless of the oral ART regimen.

Abbreviations: ARV = antiretroviral · CYP = cytochrome P450 · IRIS = immune reconstitution inflammatory syndrome · MTCT = mother-to-child transmission · TB = tuberculosis · UGT1A1 = uridine diphosphate glucuronosyltransferase 1A1 · eGFR = estimated glomerular filtration rate · PPI = proton pump inhibitor · ICP = intracranial pressure · OAT1 = organic anion transporter 1

ARV Interaction Framework

Inhibitors — Boosted PI Regimens

CYP3A4 Inhibitors

Ritonavir and cobicistat block CYP3A4 → raise concentrations of all CYP3A4 substrates
Simvastatin/lovastatin absolutely contraindicated — CYP3A4 inhibition raises levels up to 50-fold → rhabdomyolysis
Tacrolimus/cyclosporine: dramatic concentration rise — transplant patients require extreme dose reduction and frequent monitoring
DOACs rivaroxaban and apixaban: contraindicated — major bleeding risk from elevated drug exposure
Rifabutin: reduce to 150 mg every other day when co-administered with boosted PIs

Inducers — NNRTIs and Rifamycins

CYP3A4 Inducers

Lower concentrations of CYP3A4 substrates — may cause treatment failure for co-administered drugs
Rifampin: reduces boosted PI AUC 75–90% — contraindicated with all boosted PI regimens
Rifampin reduces dolutegravir AUC ~54% → dose-double to 50 mg twice daily to compensate
Efavirenz/rifampin combination: efavirenz AUC reduced ~26% — acceptable; increase efavirenz dose if needed
Efavirenz/nevirapine: lower methadone 50–60%; lower oral contraceptives 40–55% — counsel patients

Key Interaction Pair

Rifamycins + ARVs

Rifampin: contraindicated with all boosted PIs — induction overwhelms pharmacokinetic boosting
Preferred approach: use dolutegravir 50 mg twice daily, OR switch rifampin to rifabutin
Rifabutin (weaker inducer): usable with boosted PIs (reduce rifabutin dose), INSTIs (standard dose), NNRTIs (standard dose)

Key Interaction Pair

Acid Suppression + ARVs

PPIs: absolutely contraindicated with rilpivirine (suppresses acid all day — cannot overcome with timing)
PPIs: contraindicated with unboosted atazanavir — requires gastric acid for absorption
H2 blockers: acceptable with rilpivirine if separated by 12 h before or 4 h after
DTG and BIC: no acid-dependent absorption — preferred in PPI-dependent patients

Key Interaction Pair

Methadone + ARVs

Efavirenz reduces methadone 50–60% via CYP3A4/2B6 induction → opioid withdrawal within days of starting
Nevirapine: similar reduction (~46%) — same clinical risk
Coordinate with methadone prescriber before starting efavirenz or nevirapine
Dolutegravir and bictegravir: no significant methadone interaction — preferred in all patients on methadone maintenance

Key ARV Toxicity Syndromes

NRTI Toxicity

TDF Renal and Bone Toxicity

OAT1 transporter concentrates TDF in proximal tubular cells → mitochondrial injury → Fanconi syndrome
Fanconi triad: glucosuria without hyperglycemia, phosphaturia, proteinuria
Risk amplified by cobicistat/ritonavir — both inhibit MRP2 tubular efflux, further raising intracellular TDF
TDF causes greater bone mineral density loss than TAF or abacavir — monitor in osteoporosis-risk patients
Switch to TAF when eGFR <60 mL/min or significant osteoporosis risk

Hepatotoxicity and Cardiovascular Risk

Hepatotoxicity by Agent

NevirapineImmune-mediated; highest risk in women with CD4 >250 and men with CD4 >400 at initiation — avoid in these groups
AtazanavirUGT1A1 inhibition → unconjugated hyperbilirubinemia, scleral icterus — benign, not true hepatotoxicity
AbacavirAssociated with 1.7–1.9-fold increased MI risk — avoid in patients with high cardiovascular risk scores
Monitor liver function in HBV/HCV co-infected patients during ART initiation

IRIS — Immune Reconstitution Inflammatory Syndrome

Occurs in 10–25% of patients starting ART with CD4 below 100 cells/mm³ — typically within 4–8 weeks of ART initiation. Two forms: unmasking IRIS (subclinical infection becomes clinically apparent) and paradoxical IRIS (previously diagnosed and treated infection worsens). Most common precipitants: TB, MAC, Cryptococcus, CMV retinitis.

Cryptococcal IRIS carries the highest mortality — raised intracranial pressure is the primary mechanism and requires therapeutic lumbar puncture; corticosteroids worsen outcomes in cryptococcal IRIS and should not be used. For severe non-cryptococcal IRIS, corticosteroids are appropriate. Continue ART through IRIS — ART interruption worsens outcomes.

HIV in Pregnancy — Key Rules

Preferred Agents

Preferred Regimen in Pregnancy

Dolutegravir: now recommended throughout pregnancy including at conception — NTD signal largely resolved by updated data
Raltegravir: preferred INSTI alternative — most established pregnancy safety data of any INSTI
NRTI backbone: TDF/FTC preferred — most safety data; dual HBV activity
Intrapartum IV ZDV: give if viral load >1,000 copies/mL or unknown VL at delivery — regardless of oral ART regimen

Agents to Avoid

Contraindicated or Non-Preferred in Pregnancy

Cabotegravir-rilpivirine long-acting injectable: contraindicated — no adequate safety data; prolonged PK tail if must stop
Atazanavir near term: neonatal hyperbilirubinemia risk — monitor neonatal bilirubin closely
Efavirenz: non-preferred but acceptable when no suitable alternative is available
Lopinavir/ritonavir oral solution: contraindicated in neonates — propylene glycol and ethanol excipients

Dose Adjustments — Organ Impairment

Kidney Disease

Renal Impairment

TDF: avoid if eGFR <60 mL/min — switch to TAF
TAF: safe down to eGFR ≥15 mL/min; not recommended below 15 as part of Biktarvy
Abacavir: no renal dose adjustment required — hepatic metabolism only
INSTIs (DTG, BIC, RAL): no dose adjustment at any eGFR including dialysis
Cobicistat/dolutegravir creatinine artifact: use cystatin C-based eGFR for true GFR assessment
Genvoya (EVG/COBI/TAF/FTC): not recommended below eGFR 30 — cobicistat component

Liver Disease

Hepatic Impairment

Darunavir and lopinavir: contraindicated in Child-Pugh C hepatic impairment
Raltegravir: preferred INSTI in Child-Pugh C — UGT1A1 metabolism minimally affected by liver disease
Dolutegravir: AUC increases 1.5-fold in Child-Pugh B — not recommended in Child-Pugh C
Abacavir: contraindicated in moderate-to-severe hepatic impairment — relies on hepatic metabolism via alcohol dehydrogenase and UGT
Tipranavir: contraindicated in any clinically significant hepatic impairment

HIV/TB Co-treatment — Timing and Drug Selection

Start TB treatment first. Start ART within 2 weeks if CD4 below 50 cells/mm³; within 8–12 weeks if CD4 at or above 50 cells/mm³. For drug selection: use dolutegravir 50 mg twice daily with rifampin, or switch rifampin to rifabutin 150 mg three times weekly to allow standard-dose dolutegravir. Monitor liver function every 2–4 weeks during the intensive phase of TB treatment.

Paradoxical TB-IRIS occurs in 15–20% of patients — treat with NSAIDs for mild cases, corticosteroids for severe cases. Do not interrupt ART. The mortality benefit of early ART (within 2 weeks) in patients with CD4 below 50 is substantial and outweighs the IRIS risk.

Suggested References

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