Antiretroviral (ARV) drug interactions arise from predictable pharmacokinetic mechanisms: inhibition or induction of cytochrome P450 (CYP) enzymes, modulation of uridine diphosphate-glucuronosyltransferase (UGT) enzymes, and alteration of drug transporter activity. Understanding the mechanistic basis of these interactions allows clinicians to anticipate, quantify, and manage them without memorizing every individual combination.
The cytochrome P450 3A4 (CYP3A4) enzyme metabolizes the majority of currently approved antiretrovirals and a vast proportion of all drugs used in clinical medicine. CYP3A4 inhibition by ritonavir and cobicistat is the basis of pharmacokinetic boosting, but the same mechanism raises plasma concentrations of any co-administered CYP3A4 substrate — producing interactions spanning statins, immunosuppressants, benzodiazepines, opioids, direct oral anticoagulants (DOACs), and antifungals. CYP3A4 induction by efavirenz, nevirapine, and rifampin decreases plasma concentrations of CYP3A4 substrates, potentially reducing efficacy of co-administered drugs to subtherapeutic levels. Rifampin is the strongest clinically available CYP3A4 inducer and reduces the area under the concentration-time curve (AUC) of most protease inhibitors (PIs) by 75 to 90%, entirely negating the pharmacokinetic boosting strategy. The magnitude of CYP3A4 interactions scales with the inhibitor or inducer potency and the fraction of the victim drug metabolized by CYP3A4 (fm CYP3A4) — drugs with high fm CYP3A4 (greater than 0.9) are most sensitive to interaction.1
Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is the primary elimination pathway for raltegravir (RAL) and contributes substantially to dolutegravir (DTG) and bictegravir (BIC) clearance. Atazanavir (ATV), which inhibits UGT1A1 to produce its characteristic unconjugated hyperbilirubinemia, also raises raltegravir plasma concentrations by approximately 41% through UGT1A1 inhibition; this interaction is not clinically harmful but illustrates the breadth of UGT-mediated interactions. Rifampin strongly induces UGT1A1, reducing raltegravir AUC by approximately 40% and dolutegravir AUC by approximately 54% — the basis for the recommendation to double the dolutegravir dose to 50 mg twice daily when co-administered with rifampin. UGT isoforms UGT1A3 (uridine diphosphate glucuronosyltransferase 1A3) and UGT2B7 (uridine diphosphate glucuronosyltransferase 2B7) contribute to the metabolism of other ARVs and are subject to induction by rifamycins and by some anticonvulsants.2
Drug transporters mediate several clinically important ARV interactions distinct from CYP metabolism. P-glycoprotein (P-gp), an adenosine triphosphate (ATP)-binding cassette efflux transporter expressed in the intestinal epithelium, blood-brain barrier, and renal tubule, limits absorption and central nervous system (CNS) penetration of many ARVs and is inhibited by ritonavir and cobicistat. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3) mediate hepatic uptake of some statins and are inhibited by several PIs, raising statin concentrations independently of CYP3A4 inhibition; rosuvastatin, which is not CYP3A4-metabolized, is subject to OATP1B1-mediated interaction with lopinavir/ritonavir (LPV/r), raising its concentrations approximately 2-fold. Organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATE1 and MATE2-K) mediate renal secretion of creatinine; inhibition by cobicistat and dolutegravir produces the predictable serum creatinine rise that is an artifact of tubular secretion blockade rather than nephrotoxicity.2
Pharmacodynamic interactions, though less common than pharmacokinetic ones, are clinically relevant in antiretroviral therapy. Additive or synergistic ARV combinations are the basis of effective combination antiretroviral therapy (cART), but pharmacodynamic antagonism can occur — the most important historical example being the combination of zidovudine (ZDV) and stavudine (d4T), both thymidine analogues that compete for the same intracellular phosphorylation pathway and are therefore pharmacodynamically antagonistic and should never be co-administered. Additive nephrotoxicity from tenofovir disoproxil fumarate (TDF) co-administered with other nephrotoxic agents (non-steroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, amphotericin B, cidofovir) increases the risk of proximal tubular injury beyond that of TDF alone. Additive QTc prolongation from certain ARVs (particularly atazanavir and lopinavir/ritonavir) with other QTc-prolonging drugs requires monitoring in patients with cardiac risk factors.2
For any new drug added to an ARV regimen, ask: (1) Is it a CYP3A4, UGT1A1, or P-gp substrate, inhibitor, or inducer? (2) What is its fm CYP3A4 — the higher it is, the more sensitive it is to inhibitors and inducers. (3) Does the ARV regimen contain a booster (ritonavir or cobicistat)? If yes, assume all CYP3A4-sensitive drugs will be affected. (4) Is the ARV an inducer (efavirenz, nevirapine, tipranavir/r)? If yes, assume all CYP3A4 and UGT1A1 substrates will be reduced. Online tools (University of Liverpool HIV Drug Interactions Checker, AIDSinfo interaction database) should be used for all complex regimen decisions.
Certain drug classes generate antiretroviral (ARV) interactions of sufficient clinical magnitude that subtherapeutic ARV concentrations, treatment failure, or serious co-medication toxicity result without appropriate management. These interactions span the most commonly prescribed drug classes in the populations in which human immunodeficiency virus (HIV) is prevalent, making their recognition a core clinical competency.
Rifamycin co-treatment for tuberculosis (TB) represents the highest-stakes ARV interaction scenario because both conditions require immediate treatment and the rifamycins, particularly rifampin, are the most potent cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) inducers in clinical use. Rifampin reduces protease inhibitor (PI) area under the concentration-time curve (AUC) by 75 to 90% regardless of pharmacokinetic boosting, making all PI-based regimens contraindicated with rifampin. Among NNRTIs, efavirenz is the only acceptable option with rifampin: efavirenz 600 mg daily maintains adequate plasma concentrations in most patients despite approximately 26% AUC reduction; the 800 mg dose is sometimes recommended for patients above 60 kg based on pharmacokinetic modeling, though clinical outcome data supporting this dose increase are limited. Among INSTIs, dolutegravir 50 mg twice daily is the preferred strategy for HIV/tuberculosis (HIV/TB) co-treatment in most guidelines: rifampin reduces dolutegravir AUC by approximately 54% via UGT1A1 and CYP3A4 induction, and dose-doubling restores adequate trough concentrations. Rifabutin is a weaker CYP3A4 inducer than rifampin and can be used with PI-based regimens (at a reduced dose of 150 mg every other day or three times weekly), INSTIs at standard doses, and NNRTIs without dose adjustment, making it the preferred rifamycin in resource-rich settings where ARV flexibility is available.23
Acid-suppressing agents interact with ARVs whose absorption depends on gastric acidity. Rilpivirine (RPV) absorption decreases by approximately 76% with concurrent proton pump inhibitor (PPI) use because rilpivirine requires an acidic environment for dissolution and absorption; PPIs raise gastric pH throughout the day regardless of timing relative to the dose, making the combination absolutely contraindicated with no circumvention possible through dose separation. Histamine-2 (H2) receptor antagonists (H2RAs) raise gastric pH transiently and can be used with rilpivirine if administered at least 12 hours before or at least 4 hours after the rilpivirine dose. Atazanavir (ATV) unboosted also requires gastric acidity and cannot be co-administered with PPIs at any dose; boosted atazanavir tolerates PPIs at doses equivalent to omeprazole 20 mg or less when administered at least 12 hours before atazanavir. The clinical implication is that PPI-dependent patients — common in populations with gastroesophageal reflux disease — should be directed toward regimens that do not contain rilpivirine or unboosted atazanavir, with dolutegravir- or bictegravir-based regimens being the most appropriate alternatives.3
Methadone and buprenorphine are the pharmacological cornerstones of opioid use disorder (OUD) treatment, and their interactions with ARVs are clinically consequential because OUD and HIV co-infection are prevalent. Efavirenz reduces methadone plasma concentrations by 50 to 60% through CYP3A4 and cytochrome P450 2B6 (CYP2B6) induction, inducing opioid withdrawal symptoms within days to weeks of efavirenz initiation; patients must be warned and methadone dose escalation coordinated with the methadone clinic before starting efavirenz-containing regimens. Nevirapine similarly reduces methadone concentrations by approximately 46%. Lopinavir/ritonavir also reduces methadone AUC by approximately 50% through combined CYP3A4 induction (tipranavir-mediated) and UDP-glucuronosyltransferase (uridine diphosphate-glucuronosyltransferase, UDP-GT) induction. Buprenorphine/naloxone interactions with ARVs are more modest: atazanavir raises buprenorphine concentrations modestly through CYP3A4 inhibition, potentially increasing sedation, while efavirenz decreases buprenorphine concentrations by approximately 50%, occasionally precipitating withdrawal. Dolutegravir- and bictegravir-based regimens have minimal interactions with methadone or buprenorphine and are strongly preferred for patients on opioid substitution therapy.3
Efavirenz reduces methadone concentrations by 50 to 60% via CYP3A4 and CYP2B6 induction, precipitating opioid withdrawal within days of initiation. This interaction is predictable and preventable: contact the methadone clinic before starting efavirenz, warn the patient about withdrawal symptoms, and arrange dose escalation in advance. If efavirenz is unavoidable in a methadone-maintained patient, pre-emptive dose increases of 20 to 40% at initiation are commonly required. Dolutegravir-based regimens are strongly preferred to avoid this interaction entirely.
Anticonvulsants that are potent CYP3A4 and UGT1A1 inducers — carbamazepine, phenytoin, phenobarbital, and oxcarbazepine — reduce plasma concentrations of essentially all ARVs to a clinically significant degree. Carbamazepine reduces dolutegravir AUC by approximately 49%, raltegravir AUC by approximately 49%, and elvitegravir AUC substantially when boosted with cobicistat; carbamazepine concentrations are simultaneously elevated by some boosted PI regimens. The preferred approach for patients requiring anticonvulsants is to use non-inducing agents where clinically appropriate: levetiracetam, lamotrigine (with caution in boosted PI regimens, which reduce lamotrigine glucuronidation), lacosamide, and pregabalin have minimal cytochrome P450 (CYP) interactions and are preferred in patients on ARV therapy. When inducing anticonvulsants cannot be avoided, dolutegravir 50 mg twice daily is the preferred integrase strand transfer inhibitor (INSTI) strategy, following the same principle as rifampin co-treatment.3
Hormonal contraceptives are affected by ARV interactions through CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT)-mediated changes in estrogen and progestin metabolism. Efavirenz and nevirapine reduce ethinyl estradiol concentrations by 40 to 55% and norethindrone by approximately 18%, potentially compromising efficacy of combined oral contraceptive pills (COCPs); alternative or additional contraceptive methods are recommended for women on efavirenz- or nevirapine-containing regimens who rely on hormonal contraception for pregnancy prevention. Boosted PI regimens have variable effects: lopinavir/ritonavir reduces ethinyl estradiol by approximately 42%, while other boosted PIs have more modest effects. Etonogestrel implants, which rely on CYP3A4-mediated metabolism for clearance, may have reduced efficacy with enzyme-inducing ARVs; copper and levonorgestrel-releasing intrauterine devices (IUDs) are the safest contraceptive options in women on ARVs with significant hormonal interactions. Dolutegravir, bictegravir, and raltegravir have no clinically significant interactions with combined hormonal contraceptives and are preferred when contraceptive interactions are a concern.3
Antiretroviral toxicity has evolved substantially over three decades: the most severe toxicities of early antiretroviral (ARV) regimens — lactic acidosis, severe lipoatrophy, and life-threatening hypersensitivity — are now rare with modern agents. Current toxicity concerns center on renal and bone effects of tenofovir-containing regimens, metabolic consequences of integrase inhibitors and boosted PIs, hepatotoxicity in patients with viral hepatitis co-infection, and immune reconstitution inflammatory syndrome in the setting of advanced immunodeficiency.
Tenofovir disoproxil fumarate (TDF) nephrotoxicity manifests across a spectrum from subclinical proximal tubular dysfunction to overt Fanconi syndrome. TDF is concentrated in proximal tubular cells via organic anion transporter 1 (OAT1)-mediated uptake, where it inhibits mitochondrial deoxyribonucleic acid (DNA) polymerase gamma, impairing mitochondrial function and producing proximal tubule injury. The full clinical picture of TDF-associated Fanconi syndrome includes normoglycemic glucosuria, phosphaturia with hypophosphatemia, aminoaciduria, uricosuria, and tubular proteinuria (beta-2 microglobulin, alpha-1 microglobulin); in severe cases, progressive renal impairment with an estimated glomerular filtration rate (eGFR) decline occurs. Risk factors for TDF nephrotoxicity include baseline renal impairment, older age, low body weight, diabetes mellitus, concomitant nephrotoxic drugs, and co-administration with boosted PIs or cobicistat — the latter two raise proximal tubular TDF concentrations by inhibiting MRP2 (multidrug resistance-associated protein 2)-mediated tubular efflux. Tenofovir alafenamide (TAF), which delivers the active metabolite tenofovir diphosphate (TFV-DP) to lymphocytes at 90% lower plasma tenofovir concentrations, substantially reduces proximal tubular exposure and is associated with significantly less nephrotoxicity and bone mineral density loss than TDF in head-to-head clinical trials.8
Bone mineral density (BMD) loss occurs with initiation of any antiretroviral regimen, reflecting an immune reconstitution effect as well as direct drug toxicity. TDF is consistently associated with greater BMD loss than TAF or abacavir-containing regimens: a meta-analysis of switch trials found an average BMD increase of 1 to 2% at the spine and hip when patients switched from TDF- to TAF-based regimens. The mechanism involves TDF-driven increase in bone resorption markers and suppression of bone formation markers, likely mediated by proximal tubular phosphate wasting and secondary hyperparathyroidism as well as direct osteoblast toxicity. Patients on long-term TDF-containing regimens, particularly postmenopausal women, older men, and those with additional osteoporosis risk factors, should have periodic dual-energy X-ray absorptiometry (DEXA) scanning and adequate calcium and vitamin D supplementation. Integrase inhibitor-associated weight gain, discussed in Module 2, may paradoxically confer modest BMD benefit through increased mechanical loading, partially offsetting ARV-related bone loss.8
Hepatotoxicity from ARV agents occurs through several distinct mechanisms. Nevirapine-associated hepatotoxicity is the most severe and occurs through an immune-mediated hypersensitivity mechanism that is concentrated in patients with higher cluster of differentiation 4 (CD4) counts at ARV initiation — women with CD4 above 250 cells/mm³ and men with CD4 above 400 cells/mm³ are at highest risk, limiting nevirapine use as initial therapy in these patients. Hepatotoxicity from tipranavir/ritonavir, including decompensated cirrhosis and hepatic failure, has been reported in patients with underlying hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection and limits its use. Atazanavir rarely causes hepatocellular injury distinct from its uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)-mediated unconjugated hyperbilirubinemia, which is benign and does not reflect hepatotoxicity. In patients with underlying HBV or HCV co-infection, nearly any ARV-associated hepatotoxicity risk is amplified; regular hepatic monitoring every 3 to 6 months is appropriate in patients with viral hepatitis co-infection starting ARV therapy, particularly in the first 12 weeks of treatment.5
Cardiovascular risk attributable to ARV therapy has been extensively studied, with the D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) cohort providing the most comprehensive longitudinal data. Abacavir (ABC) use has been associated with increased myocardial infarction risk in several large observational studies, with a relative risk approximately 1.7 to 1.9-fold compared with non-users; the biological mechanism remains debated, with proposed contributions from endothelial activation, platelet aggregation, and systemic inflammation. The association is most pronounced in patients with pre-existing high cardiovascular risk, and current guidelines recommend avoiding abacavir in patients with high cardiovascular risk (10-year risk above 20% by Framingham criteria) when alternative backbones are available. Lopinavir/ritonavir has been independently associated with myocardial infarction risk in the D:A:D cohort, as have older indinavir-based regimens no longer in clinical use. Modern integrase strand transfer inhibitor (INSTI)-based regimens with TAF or TDF backbones have more favorable cardiovascular risk profiles than older protease inhibitor (PI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in available comparative data.10
Immune reconstitution inflammatory syndrome (IRIS) occurs in 10 to 25% of patients initiating ART with advanced immunodeficiency (CD4 below 100 cells/mm³), typically within 4 to 8 weeks. Two forms exist: unmasking IRIS (previously subclinical infection becomes apparent as immune function recovers) and paradoxical IRIS (known treated infection worsens despite effective antimicrobial therapy). Most common precipitants: Mycobacterium tuberculosis, Mycobacterium avium complex (MAC), Cryptococcus neoformans, cytomegalovirus (CMV), and hepatitis B and C. Cryptococcal IRIS carries the highest mortality risk; lumbar puncture and ICP management are essential. Management: continue ART and antimicrobials; corticosteroids for severe non-cryptococcal IRIS; therapeutic LP for cryptococcal IRIS-associated raised ICP. The START and TEMPRANO trials confirmed that earlier ART initiation at higher CD4 counts substantially reduces IRIS risk.
The pharmacological management of human immunodeficiency virus (HIV) in pregnancy serves two simultaneous goals: maintaining viral suppression in the pregnant person to preserve their health, and reducing HIV ribonucleic acid (RNA) viral load to prevent mother-to-child transmission (MTCT) of HIV. These goals are aligned — durable viral suppression to below the limit of detection is the single most effective intervention for MTCT prevention, achieving transmission rates below 1% in resource-rich settings.
All persons with HIV who are pregnant or planning pregnancy should initiate or continue antiretroviral (ARV) therapy regardless of cluster of differentiation 4 (CD4) count or viral load. Early initiation — ideally before conception or as early as possible in the first trimester — is associated with the lowest rates of MTCT and the best maternal outcomes. Among INSTIs, dolutegravir is now recommended throughout pregnancy including at conception by the Department of Health and Human Services (DHHS) and World Health Organization (WHO) guidelines following reassessment of the neural tube defect signal: the most recent analyses from the Tsepamo study in Botswana show neural tube defect (NTD) rates with periconceptional dolutegravir of approximately 0.19%, not significantly different from background rates in most analyses. Raltegravir retains an important role as an integrase strand transfer inhibitor (INSTI) alternative in pregnancy with the most extensive historical safety data; twice-daily dosing is maintained throughout pregnancy as pharmacokinetic studies show adequate trough concentrations despite modest third-trimester reduction in raltegravir exposure.7
Among nucleoside reverse transcriptase inhibitor (NRTI) backbones in pregnancy, tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC) is the preferred backbone in most guidelines, supported by the largest body of safety and efficacy data in pregnant populations and its dual activity against hepatitis B virus (HBV) — important in regions where HBV co-infection is prevalent. Tenofovir alafenamide (TAF) has less pregnancy pharmacokinetic data than TDF; TAF plasma concentrations are approximately 30% lower in the third trimester than postpartum, and while clinical data are accumulating, most guidelines still recommend TDF over TAF for pregnancy where TAF is not specifically indicated by renal or bone concerns. Abacavir/3TC is an acceptable alternative in human leukocyte antigen B*57:01 (HLA-B*57:01)-negative patients but lacks the HBV coverage of TDF-containing regimens. Zidovudine (ZDV) retains a specific role in MTCT prevention: intrapartum intravenous (IV) ZDV is administered to HIV-positive persons in labor with viral load above 1,000 copies/mL or unknown viral load to reduce transmission risk at delivery, regardless of the oral ARV regimen being maintained.67
Several ARV agents are specifically avoided or restricted in pregnancy. Efavirenz has historically carried a pregnancy category D designation due to neural tube defects in primate studies and isolated case reports in humans; current DHHS guidelines have de-escalated this concern and accept efavirenz use throughout pregnancy, including in the first trimester, when no preferred alternative is available — however, it remains a non-preferred agent when alternatives exist. Atazanavir carries a risk of severe neonatal hyperbilirubinemia and kernicterus due to uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) inhibition crossing the placenta; monitoring of neonatal bilirubin is required if atazanavir is used near term. Lopinavir/ritonavir oral solution contains propylene glycol and ethanol and is contraindicated in neonates; the tablet formulation is acceptable but requires dose escalation in the second and third trimesters due to reduced lopinavir/ritonavir (LPV/r) exposure during pregnancy. Cabotegravir-rilpivivirine long-acting injectable antiretroviral therapy (ART) is not recommended in pregnancy: safety data are absent, and the prolonged pharmacokinetic tail of both agents — particularly rilpivirine detectable for years after the last injection — makes rapid discontinuation impossible if adverse effects emerge.6
Intrapartum and neonatal prophylaxis strategies depend on maternal viral load at delivery. For persons with viral load below 50 copies/mL at 36 weeks' gestation, intrapartum ZDV infusion is not required and cesarean section is not recommended on HIV grounds; vaginal delivery carries equivalent MTCT risk to cesarean section when the maternal viral load is undetectable. For persons with viral load above 1,000 copies/mL or unknown viral load at delivery, intrapartum IV ZDV plus elective cesarean section at 38 weeks is recommended, reducing MTCT risk by approximately 50% compared with vaginal delivery with detectable viremia. Neonatal prophylaxis with ZDV syrup for 4 to 6 weeks is standard for all infants born to HIV-positive mothers; dual or triple prophylaxis (ZDV plus nevirapine plus 3TC) is recommended for infants born to mothers with viral load above 1,000 copies/mL or those who received no prenatal ART.7
Renal and hepatic impairment alter antiretroviral (ARV) pharmacokinetics through reduced drug clearance, altered protein binding, and changes in first-pass metabolism and biliary excretion. Most modern ARVs require little or no dose adjustment across the spectrum of renal impairment, but important exceptions exist — particularly for fixed-dose combinations whose individual components have differing renal thresholds, and for agents with predominant renal elimination.
Among nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), lamivudine (3TC), and zidovudine (ZDV) are renally eliminated and require dose adjustment at reduced eGFR. TDF should not be initiated when eGFR is below 60 mL/min/1.73m² in patients not already receiving TDF; tenofovir alafenamide (TAF) may be used down to eGFR of 15 mL/min/1.73m² and is preferred over TDF when available in patients with chronic kidney disease (CKD).4 FTC and 3TC require interval extension below eGFR 50 mL/min/1.73m²; in dialysis patients, both may be administered after each hemodialysis session to compensate for dialytic removal. Abacavir is hepatically metabolized and requires no renal dose adjustment at any eGFR level, making abacavir/3TC (with 3TC dose-adjusted) or abacavir/3TC a reasonable backbone option in patients with advanced CKD who are human leukocyte antigen B*57:01 (HLA-B*57:01)-negative. All NRTIs are partially removed by hemodialysis; dosing should generally occur after dialysis sessions to minimize removal of the administered dose.8
Fixed-dose combinations impose specific eGFR thresholds based on their least-renally-tolerant component. Biktarvy (bictegravir/TAF/FTC) is not recommended below eGFR 15 mL/min/1.73m² due to the FTC component; Genvoya (elvitegravir/cobicistat/TAF/FTC) is not recommended below eGFR 30 mL/min/1.73m² due to the cobicistat component — the FTC renal threshold is lower but the combination is restricted by cobicistat. Descovy (TAF/FTC) is not recommended below eGFR 15 mL/min/1.73m². Truvada (TDF/FTC) carries TDF's threshold of eGFR 60 mL/min/1.73m² for initiation and requires dose adjustment (interval extension to every 48 hours) at eGFR 30 to 49 mL/min/1.73m². For patients on dialysis, individualized regimens built from component ARVs rather than fixed-dose combinations are often necessary, with dosing adjusted for dialysis schedules and dialytic clearance of individual drugs.8
INSTIs generally require no renal dose adjustment because their primary elimination is hepatic (UGT1A1 and CYP3A4) rather than renal. Dolutegravir, raltegravir, and bictegravir can all be used without dose modification at any eGFR level, including in dialysis patients, based on pharmacokinetic and safety studies showing adequate and consistent plasma concentrations across the spectrum of renal impairment. The cobicistat-associated serum creatinine rise — an artifact of multidrug and toxin extrusion protein 1 (MATE1) inhibition rather than true glomerular filtration rate (GFR) reduction — must not be misinterpreted as worsening renal function in patients receiving cobicistat-containing regimens; the estimated eGFR by cystatin C (which is not secreted by the tubule) or measured GFR by inulin clearance provides a more accurate reflection of true GFR in cobicistat-treated patients when the distinction is clinically important.8
Hepatic impairment alters ARV pharmacokinetics most significantly for agents with high hepatic extraction and extensive first-pass metabolism. Among PIs, darunavir and lopinavir are extensively hepatically metabolized and require monitoring in moderate hepatic impairment (Child-Pugh B); both are contraindicated in severe hepatic impairment (Child-Pugh C) due to substantially elevated and unpredictable drug exposures. Tipranavir/ritonavir is contraindicated in any degree of clinically significant hepatic impairment due to its hepatotoxicity risk, particularly in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection. Among integrase strand transfer inhibitors (INSTIs), raltegravir pharmacokinetics are not substantially altered by hepatic impairment and it is the preferred integrase strand transfer inhibitor (INSTI) in Child-Pugh C disease. Dolutegravir area under the concentration-time curve (AUC) increases approximately 1.5-fold in Child-Pugh B but remains acceptable; it is not recommended in Child-Pugh C due to insufficient data. Abacavir is contraindicated in moderate to severe hepatic impairment due to its dependence on hepatic alcohol dehydrogenase and UDP-glucuronosyltransferase (uridine diphosphate-glucuronosyltransferase, UDP-GT) for elimination.5
Hepatitis B virus (HBV) co-infection in human immunodeficiency virus (HIV)-positive patients requires careful ARV selection because several ARVs with anti-HBV activity — TDF, TAF, FTC, and 3TC — must be included in the regimen to prevent HBV-related hepatic complications. Discontinuation of TDF or TAF in HBV co-infected patients without simultaneous coverage by an alternative anti-HBV agent can precipitate severe HBV flares with acute hepatic decompensation and, rarely, liver failure. Entecavir, an oral HBV antiviral without anti-HIV activity, selects for the methionine-to-valine substitution at codon 184 (M184V) resistance mutation in HIV when used without a suppressive ARV regimen; it should never be used as anti-HBV monotherapy in persons with HIV without a fully suppressive ARV backbone. Patients with HIV/hepatitis B virus (HIV/HBV) co-infection should be managed with TDF/FTC or TAF/FTC plus a third ARV agent, ensuring HBV coverage is maintained throughout any regimen switches.9
The aging of the human immunodeficiency virus (HIV)-positive population, driven by the success of modern antiretroviral (ARV) therapy, has created a new clinical challenge: managing HIV as a chronic condition in persons with accumulating comorbidities, polypharmacy, and age-related pharmacokinetic changes. Simultaneously, HIV/tuberculosis (HIV/TB) co-treatment remains the most pharmacologically complex scenario in infectious disease practice, requiring synthesis of multiple interaction management strategies simultaneously.
Older persons living with HIV (PLWH), defined variably as those above 50 or 60 years, experience accelerated aging phenotypes including earlier onset of cardiovascular disease, osteoporosis, neurocognitive impairment, frailty, and malignancy compared with age-matched HIV-negative individuals. The mechanisms are multifactorial: chronic immune activation and inflammation driven by residual HIV replication even at undetectable viral loads, cumulative ARV toxicity, and the direct effects of long-standing immunodeficiency on end-organ health. Pharmacokinetic changes of aging relevant to ARV management include reduced renal function (necessitating lower estimated glomerular filtration rate (eGFR) thresholds for tenofovir disoproxil fumarate (TDF) use and more careful monitoring of renally-cleared agents), reduced hepatic blood flow and cytochrome P450 (CYP) enzyme activity (modestly increasing exposure to hepatically-metabolized ARVs), and reduced albumin concentrations (affecting protein binding of highly-bound agents such as PIs). The polypharmacy burden in older PLWH is substantial: a median of 8 to 12 concurrent medications is common in patients above age 60, dramatically increasing the probability of clinically relevant drug interactions and adverse effects.10
The HIV/TB co-treatment synthesis requires simultaneous management of the rifampin-ARV interaction, the risk of immune reconstitution inflammatory syndrome (IRIS), overlapping hepatotoxicity from both ARV and antitubercular regimens, and optimization of both treatment durations. The preferred approach in most resource-rich settings is: (1) initiate tuberculosis (TB) treatment with standard four-drug therapy (isoniazid, rifampin, pyrazinamide, ethambutol); (2) initiate ARV therapy within 2 weeks for patients with cluster of differentiation 4 (CD4) below 50 cells/mm³ (to minimize IRIS risk from delayed treatment) and within 8 to 12 weeks for those with CD4 above 50 cells/mm³ (allowing TB treatment to establish some control before immune reconstitution); (3) use dolutegravir 50 mg twice daily as the integrase strand transfer inhibitor (INSTI) with rifampin, or switch to rifabutin 150 mg three times weekly to allow standard-dose dolutegravir and more flexible ARV choices. Hepatotoxicity monitoring every 2 to 4 weeks during the intensive phase of TB treatment plus ARV initiation is essential, as overlapping hepatotoxic potential from isoniazid, pyrazinamide, rifampin, and some ARVs creates a high-risk hepatotoxicity window. Paradoxical tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) remains common (15 to 20% of HIV/TB co-treated patients) and is managed with non-steroidal anti-inflammatory agents for mild cases and corticosteroids for severe or life-threatening presentations.311
Cardiovascular risk management in PLWH integrates standard risk factor modification with HIV-specific considerations. The 10-year cardiovascular risk in PLWH is approximately 1.5 to 2-fold higher than in HIV-negative individuals of the same age and sex after adjustment for traditional risk factors, attributable to chronic immune activation, residual low-level viremia, and effects of certain ARV agents on lipid metabolism and endothelial function. Statin therapy in PLWH requires attention to drug interactions: rosuvastatin and pravastatin are the safest choices with boosted protease inhibitor (PI)-containing regimens; atorvastatin may be used at reduced doses; simvastatin and lovastatin are contraindicated. Low-dose aspirin for primary cardiovascular prevention follows the same risk-benefit framework as in HIV-negative populations but may interact with ritonavir-boosted regimens through cytochrome P450 2C9 (CYP2C9)-mediated effects on aspirin metabolism. Smoking cessation is the highest-impact modifiable cardiovascular risk factor in PLWH and should be addressed at every clinical encounter; the cytochrome P450 induction by tobacco smoke (CYP1A2) has minimal interaction with currently approved ARVs. Blood pressure control and glycemic management in PLWH are addressed using the same targets and agents as in the general population, with awareness of the interaction profiles of any antihypertensives or antidiabetic agents added to a regimen already containing ARVs.1011
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