HIV Antiretroviral Therapy

Mechanism of Action

The mechanisms of action of the significant classes of ART used in the treatment of HIV infection are as follows.

Nucleoside Reverse Transcriptase Inhibitors

NRTIs compete with natural deoxynucleotides for incorporation into a growing viral DNA chain. However, NRTIs lack a 3′-hydroxyl group on the deoxyribose moiety. This difference results in the incorporation of an NRTI, and the next incoming deoxynucleotide cannot form the 5′,3′ phosphodiester bond needed to extend the DNA chain. The result is a chain-termination event during DNA synthesis.

Non-Nucleoside Reverse Transcriptase Inhibitors

NNRTIs block reverse transcriptase by directly binding to the enzyme. Though NNRTIs do not incorporate into viral DNA, they inhibit the movement of RT protein domains that are essential for DNA synthesis.

Protease Inhibitors

PIs bind the HIV-1 protease and block the proteolytic cleavage of protein precursors required for viral particle production.

Fusion Inhibitors

Fusion inhibitors disrupt the binding, fusion, and entry of HIV virions into a human cell. Enfuvirtide binds to gp41 and disrupts membrane attachment.

Chemokine Receptor 5 Antagonist

Maraviroc blocks the chemokine receptor 5 (CCR5) on T cells, preventing viral attachment. CCR5 tropism testing is required before starting maraviroc. The effectiveness of HIV-1 entry inhibitors depends on viral co-receptor tropisms, making tropism determination clinically important.[22] 

Integrase Strand Transfer Inhibitors

Integrase inhibitors block integrase activity, preventing the viral genome from integrating into the host cell's DNA.

Attachment Inhibitor

Fostemsavir is an attachment inhibitor of HIV-1 that binds to the virus's gp120 protein, preventing it from attaching to and entering human CD4+ T cells. It is a prodrug that is converted to its active form, temsavir, in the body. This unique mechanism makes it helpful in treating patients with HIV that has become resistant to other antiviral drugs.[23]

Postattachment Inhibitors

This class is a monoclonal antibody (ibalizumab) that binds to CD4 and inhibits viral entry into the cell. It is the first monoclonal antibody approved for the treatment of HIV-1 infection.[24]

Pharmacokinetic Enhancers

Pharmacokinetic enhancers inhibit human cytochrome P450 3A (CYP3A) activity, increasing the plasma concentrations of other anti-HIV drugs.[25]

Capsid Inhibitors 

Capsid inhibitor lenacapavir binds directly to the HIV-1 capsid protein, interfering with viral replication.[26][27]

Administration

The standard of care is rapid initiation of ART to achieve and maintain sustained viral suppression and prevent mutation. As patients take these medications orally, there are now several options that combine 3 to 4 drugs into 1 pill for better patient compliance due to once-daily administration. This dosing increases both adherence and long-term effectiveness. Ibalizumab is an exception, as it is an injectable agent.[28]

Patients are tested and educated to take all of their medications correctly to reduce the risk of resistance and cross-resistance to related drugs. Medication adherence is often difficult due to adverse effects associated with an HIV regimen. Common barriers to adherence include trouble swallowing pills, a busy schedule (shift work), unstable living or housing situations, alcohol or drug use, fear of disclosing HIV status, and lack of insurance. Before starting an HIV regimen, strategies such as 7-day pillboxes, phone applications, and alarms should be in place. Addressing mental health and substance-use issues improves adherence, but neither is a contraindication to initiating ART; supportive services should be provided alongside treatment.[29][30]

Available Dosage Forms and Strengths

HIV antiretrovirals are primarily available as oral formulations. Common drugs are available in tablet formulations, including tenofovir disoproxil fumarate (150 mg, 200 mg, 250 mg, and 300 mg), tenofovir alafenamide (10 mg and 25 mg), emtricitabine (200 mg), and dolutegravir (10 mg, 25 mg, and 50 mg). Fixed-dose combination tablets include abacavir/dolutegravir/lamivudine and bictegravir/emtricitabine/tenofovir alafenamide. Novel formulations include intramuscular injections of cabotegravir (600 mg) and rilpivirine (900 mg). Lenacapavir is available as an oral tablet (300 mg) and as a subcutaneous injection (927 mg). Ibalizumab, an intravenous monoclonal antibody, is supplied as 200 mg/1.33 mL (150 mg/mL).

Adult Dosage

Recommended initial regimens for most individuals with HIV

Regimens are chosen based on efficacy, tolerability, toxicity profiles, and ease of use.

For individuals without prior use of cabotegravir long-acting injectable as PrEP, one of the following is recommended:

• Bictegravir/tenofovir alafenamide/emtricitabine (fixed-dose combination)

• Dolutegravir plus tenofovir alafenamide or tenofovir disoproxil fumarate plus emtricitabine or lamivudine

• Dolutegravir/lamivudine dual therapy, except in patients with:

  • HIV RNA >500,000 copies/mL

  • Hepatitis B virus coinfection

  • When ART initiation occurs before genotypic resistance testing for reverse transcriptase or hepatitis B testing is available

For individuals with a history of cabotegravir long-acting injectable use as PrEP, INSTI genotype resistance testing is recommended before starting ART. If ART must be initiated before genotype results are available, the recommended regimen is as follows:

• Darunavir boosted with cobicistat or ritonavir, plus tenofovir alafenamide or tenofovir disoproxil fumarate, plus emtricitabine or lamivudine.

Postexposure prophylaxis

• For HIV PEP, the CDC recommends a preferred 28-day regimen. The preferred regimens for adults and adolescents without contraindications are
  • Bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF)
  • Dolutegravir (DTG) plus (tenofovir alafenamide [TAF]) or tenofovir disoproxil fumarate [TDF]) plus (emtricitabine [FTC] or lamivudine [3TC])

Preexposure prophylaxis

The CDC has recommended the following options.

• Oral daily: Emtricitabine/tenofovir disoproxil fumarate (F/TDF), administered at a dosage of 200 mg/300 mg, is recommended for all individuals at risk through sexual exposure or injection drug use.
• Oral daily: Emtricitabine/tenofovir alafenamide (F/TAF), administered at a dosage of 200 mg/25 mg, is recommended for the prevention of HIV through sexual transmission except for those assigned female at birth who could get HIV through receptive vaginal sex, because F/TAF has not been studied in that subgroup.
• Injectable: Cabotegravir (CAB) 600 mg, administered as an intramuscular injection every 2 months after initial loading, is recommended for the prevention of sexually transmitted HIV among all individuals. The regimen consists of an initial dose, a second dose at 1 month, and dosing every 2 months thereafter.
• Injectable: In June 2025, the FDA approved lenacapavir (LEN) for injection, administered every 6 months, as HIV PrEP, based on randomized controlled trials (PURPOSE 1 and PURPOSE 2).[31][27][32]

Specific Patient Populations

Hepatic impairment: Guidance for treating HIV in patients with hepatic impairment is given below.

• Moderate or severe hepatic impairment: Regimens that are not recommended include efavirenz/TDF and TDF/lamivudine.[33][34] 
• Patients with Child-Pugh class B or C: Abacavir-containing regimens, including abacavir alone, abacavir/lamivudine, and dolutegravir/abacavir/lamivudine, are not recommended due to the abacavir component. Nevirapine is contraindicated, and the use of tenofovir alafenamide (TAF) is not recommended.[35] 
• General guidance: Abacavir and nevirapine are contraindicated in patients with hepatic impairment.

Renal impairment: Caution is warranted in patients receiving a tenofovir-containing regimen due to potential nephrotoxicity. The CDC's recommendations are as follows. 

• Creatinine clearance (CrCl) less than 30 mL/min: Elvitegravir, cobicistat, TDF, and emtricitabine should not be initiated. 
• Regimens not recommended: Efavirenz, TDF/emtricitabine, doravirine/TDF/lamivudine, efavirenz/TDF/lamivudine, and rilpivirine/TDF/emtricitabine.
• Recommended regimens: Use individual antiretroviral components and adjust doses based on creatinine clearance. It is advisable to change from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen.
• General guidance: Avoid any combination containing tenofovir due to the risk of potential nephrotoxicity; dolutegravir/lamivudine, abacavir/lamivudine, and dolutegravir/abacavir/lamivudine are not recommended. 

For patients on hemodialysis with CrCl less than 30 mL/min, the recommendations are as follows.

• TAF/emtricitabine: 1 tablet once daily; on hemodialysis days, administer after completion of dialysis.
• Bictegravir/TAF/emtricitabine: 1 tablet once daily; on hemodialysis days, administer after completion of dialysis.
• Elvitegravir/cobicistat/TAF/emtricitabine: 1 tablet once daily; on hemodialysis days, administer after completion of dialysis.
• Rilpivirine/TAF/emtricitabine: 1 tablet once daily; on hemodialysis days, administer after completion of dialysis.
• Darunavir/cobicistat/TAF/emtricitabine: 1 tablet once daily; on hemodialysis days, administer after completion of dialysis.[35]

Pregnancy considerations: The preferred regimen is INSTI-based therapy such as dolutegravir, emtricitabine, and tenofovir.[36] The combination of dolutegravir, emtricitabine, and TAF was associated with the lowest frequency of composite adverse pregnancy outcomes and neonatal deaths.[37] According to CDC guidelines, COVID-19 vaccination is strongly recommended for all pregnant patients with HIV infection.[38] Tenofovir alafenamide/emtricitabine plus dolutegravir, or TDF/emtricitabine plus dolutegravir, may be used as an alternative regimen if tenofovir alafenamide is not available.[13]

Breastfeeding considerations: Breastfeeding is not recommended for patients who are confirmed or presumed to have HIV infection. Infants exposed perinatally to HIV should receive postpartum antiretroviral prophylaxis to decrease the risk of perinatal transmission. Patients should be counseled that maternal ART reduces but does not eliminate the risk of HIV transmission to the infant. Therefore, mothers should use safe, affordable alternatives to infant feeding.[39] A 4-week zidovudine antiretroviral prophylaxis is frequently used in newborns whose mothers received ART during pregnancy and had adequate viral suppression 4 weeks before delivery. Higher rates of hematologic toxicity have been observed in infants who received zidovudine (ZDV) plus lamivudine (3TC) and other combination infant antiretroviral regimens (such as ZDV plus 3TC plus nevirapine [NVP]) than in those who received ZDV alone.[40] 

Another study evaluated zidovudine/lamivudine/NVP prophylaxis for high-risk neonates and did not significantly increase the risk of short-term toxicity compared with ZDV monotherapy.[41] Prevention of Pneumocystis jirovecii pneumonia requires prophylaxis with trimethoprim-sulfamethoxazole for infants delivered to mothers with HIV.[42]

Pediatric patients: INSTIs demonstrate greater efficacy and safety compared with NNRTIs and PIs. INSTI-based ART regimens are preferred for initial treatment in infants, children, and adolescents. Eligible patients should be transitioned to an INSTI-based regimen when possible. The following recommendations apply (see also the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection).

• For infants from birth to less than 30 days of age, preferred regimens include nevirapine plus zidovudine plus lamivudine or emtricitabine, or raltegravir plus zidovudine plus lamivudine or emtricitabine, provided that the infant has a body weight of 2 kg or more. Preterm infants with a postmenstrual age of 32 to 37 weeks should receive nevirapine plus zidovudine plus lamivudine or emtricitabine. In infants and children aged 30 days to less than 2 years, those with a body weight of less than 3 kg should continue nevirapine- or raltegravir-based regimens. Once the child reaches a body weight of 3 kg or more, transition to dolutegravir-based regimens is recommended. Options include dolutegravir plus abacavir with lamivudine or emtricitabine for patients negative for human leukocyte antigen B*57:01 (HLA-B*57:01), or dolutegravir plus zidovudine with lamivudine or emtricitabine.

• Children aged 3 months to 2 years or younger with a body weight of 6 kg to less than 25 kg may receive fixed-dose dolutegravir/abacavir/lamivudine if HLA-B*57:01–negative.

• For children aged 2 to 12 years or younger who are unable to swallow pills, preferred regimens include dispersible dolutegravir plus abacavir plus lamivudine (with a body weight of 6 kg to <25 kg, HLA-B*57:01–negative), dolutegravir film-coated tablets plus abacavir and liquid lamivudine or emtricitabine (≥25 kg, HLA-B*57:01–negative), dolutegravir plus emtricitabine plus tenofovir alafenamide (≥14 kg), or dolutegravir dispersible tablets plus zidovudine and liquid lamivudine or emtricitabine if abacavir is contraindicated. Children in this age group who can swallow pills and weigh 14 kg or more may receive bictegravir plus emtricitabine plus tenofovir alafenamide, or dolutegravir plus emtricitabine plus tenofovir alafenamide.

• Pediatric patients with a body weight of 25 kg or more who are HLA-B*57:01–negative may receive fixed-dose dolutegravir/abacavir/lamivudine. Testing for HLA-B*57:01 is mandatory before initiating abacavir to reduce the risk of hypersensitivity reactions. Regimen selection is guided by both weight and age. Liquid and dispersible formulations facilitate administration in young children and in individuals unable to swallow pills. Transition to INSTI-based regimens is recommended whenever clinically feasible.

Older patients: Diagnosis of HIV at later stages is more common in older adults. Early diagnosis, treatment, and counseling are vital to reduce the risk of secondary transmission. ART is recommended for all patients with HIV and is especially crucial for older individuals due to increased risks of non-AIDS complications and potentially reduced immune response. Compared to HIV-negative individuals, those with HIV have twice the risk of atherosclerotic cardiovascular disease (ASCVD), with diagnosis occurring nearly a decade earlier. The Panel on Antiretroviral Guidelines advises initiating at least a moderate-intensity statin in HIV-positive patients aged 40 to 75 years with a 10-year ASCVD risk of 5% to 20%. Polypharmacy is common; all medications should be regularly evaluated for appropriateness, potential interactions, and adverse effects. Drug–drug interactions between ART and other medications should be carefully monitored, especially when modifying regimens or adding new drugs, including long-acting injectables and on-demand therapies.

Older HIV-positive patients are more prone to adverse drug events, necessitating close monitoring of bone, kidney, metabolic, cardiovascular, cognitive, and hepatic health. HIV-related immunologic aging and inflammation can contribute to the development of comorbidities and frailty. Collaborative care among HIV specialists, primary care providers, and other clinicians is essential for optimizing outcomes and promoting adherence to clinical guidelines. Neurocognitive decline progresses faster in older HIV-positive individuals, with impairments affecting memory, attention, and executive function, which may impact treatment adherence and survival. Referral to specialists is recommended for significant cognitive issues. Mental health conditions, particularly anxiety and depression, are common; routine screening and appropriate management are essential. Due to the higher burden of age-related diseases in this population, additional medical and social support may be necessary to address both HIV and comorbidities (refer to the PDF on the website clinicalinfo.hiv.gov).

Adverse Effects

The adverse effects associated with HIV medications are mentioned below.

Nucleoside Reverse Transcriptase Inhibitors

The common adverse effects of NRTIs include lactic acidosis, mitochondrial toxicity, hepatic steatosis, myopathy, peripheral neuropathy, and pancreatitis, and these effects may vary depending on pharmacogenetic factors and preexisting comorbidities. Individual adverse effects are listed below.

• Abacavir: Hypersensitivity reaction, HLA-B*57:01–associated immunologically mediated reaction, possible association with myocardial infarction in observational cohorts.
• Emtricitabine: Cutaneous hyperpigmentation.[43]
• Lamivudine: Rash.
• Tenofovir disoproxil fumarate: Fanconi syndrome, elevated serum creatinine, reduction in bone mineral density, osteomalacia, and non-anion gap metabolic acidosis.[44]
• Tenofovir alafenamide: Dyslipidemia (hypertriglyceridemia, increased low-density lipoprotein [LDL] cholesterol, increased high-density lipoprotein [HDL] cholesterol).
• Zidovudine: Nausea, vomiting, and bone marrow suppression.
• Stavudine: Peripheral neuropathy, lipodystrophy, and lactic acidosis.[45]
• Didanosine: Peripheral neuropathy and pancreatitis.[46]
• Zalcitabine: Peripheral neuropathy.[47] 

Non-Nucleoside Reverse Transcriptase Inhibitors

The common adverse effects of NNRTIs include rash, Stevens-Johnson syndrome/toxic epidermal necrolysis, and hepatotoxicity. Individual adverse effects are listed below.

• Efavirenz: Neuropsychiatric adverse effects and dyslipidemia.[48]
• Nevirapine: Severe hepatotoxicity, rash, and Stevens-Johnson syndrome.[49][50]
• Rilpivirine: QT-interval prolongation, depression, suicidality, sleep disturbances, and inhibition of tubular creatinine secretion resulting in serum creatinine elevation without renal injury.
• Doravirine: Dizziness, sleep disorders, altered sensorium, depression, and weight gain.
• Etravirine: Rash and mild neuropsychiatric symptoms.[51]

Protease Inhibitors

PIs are associated with gastrointestinal intolerance (nausea, diarrhea), dyslipidemia (hypertriglyceridemia, elevated LDL cholesterol), hyperglycemia, insulin resistance, lipohypertrophy, hepatotoxicity, increased cardiovascular risk, and extensive drug–drug interactions. Individual adverse effects are listed below.

• Atazanavir: Indirect hyperbilirubinemia with jaundice, PR-interval prolongation, nephrolithiasis, and cholelithiasis.
• Darunavir: Rash, hepatotoxicity, and increased cardiovascular event risk (observational cohorts).
• Darunavir/Ritonavir: Dyslipidemia, gastrointestinal intolerance, and cardiovascular events.
• Indinavir: Nephrolithiasis.[52]
• Lopinavir/Ritonavir: Gastrointestinal intolerance and dyslipidemia.[53]

Integrase Strand Transfer Inhibitors

INSTIs are associated with allergic hypersensitivity reactions, weight gain, insomnia, and neuropsychiatric adverse effects (in predisposed individuals). Individual adverse effects are listed below.

• Dolutegravir: Inhibition of tubular creatinine secretion, and rare hepatotoxicity, insomnia, and depression.[54]
• Bictegravir: Weight gain, gastrointestinal intolerance, and inhibition of tubular creatinine secretion.
• Cabotegravir: Injection-site pain with intramuscular administration.
• Raltegravir: Stevens-Johnson syndrome (rare) and elevated creatine kinase.
• Elvitegravir/cobicistat: Nausea, diarrhea, and dyslipidemia (cobicistat-related).[55]

Fusion Inhibitors

• Enfuviritide: Injection-site reactions, infections, difficulty breathing, fever, blood in the urine, dark-colored urine, low blood pressure, neutropenia, chills and shivering, and cough.

Chemokine Receptor 5 Antagonist

• Maraviroc: Allergic reactions, hepatotoxicity, dizziness, and musculoskeletal symptoms.[56]

Postattachment Inhibitors

• Ibalizumab: Infusion-related reactions, rash, and anaphylaxis.

Attachment Inhibitors

• Fostemsavir: Elevation of hepatic transaminases (particularly in hepatitis B or C coinfection) and QT-interval prolongation.[57]

Capsid Inhibitors

• Lenacapavir: Subcutaneous injection-site reactions (erythema, induration, swelling, nodules).[27]

Pharmacokinetic Inhibitors

• Cobicistat: Inhibition of tubular creatinine secretion (increased serum creatinine without renal injury), gastrointestinal intolerance, dyslipidemia, and hepatotoxicity.[58]

Some long-term adverse effects of HIV medicines are peripheral neuropathy, hepatotoxicity, kidney failure, heart disease, diabetes/insulin resistance, hyperlipidemia, osteoporosis, suicidal ideation or depression, and nervous system deficits.[59][60]

Refer to Common and/or Severe Adverse Effects Associated with Antiretroviral Medications for more information.

Drug-Drug Interactions

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• Nephrotoxicity increases significantly when tenofovir disoproxil fumarate is administered with diclofenac or ibuprofen, and this combination should be avoided in patients with renal impairment. Tenofovir disoproxil fumarate concentrations increase markedly when it is coadministered with ritonavir-boosted atazanavir or ritonavir-boosted lopinavir, and renal function should be closely monitored.

• Tenofovir alafenamide: Exposure increases substantially when it is coadministered with cobicistat or ritonavir, an effect observed only in fixed-dose combinations. Tenofovir alafenamide exposure decreases markedly when coadministered with rifampin, carbamazepine, phenytoin, or St. John's wort, and coadministration is contraindicated.

• Zidovudine: The risk of cytopenias increases when zidovudine is coadministered with ganciclovir, ribavirin, or interferon-alpha; complete blood counts (CBCs) should be performed with close follow-up. Zidovudine concentrations increase when it is administered with methadone, and dose reduction may be necessary.

• Didanosine/stavudine (not used frequently in clinical practice): The risk of pancreatitis increases substantially when didanosine or stavudine is coadministered with ribavirin; this combination should be avoided. Didanosine exposure increases markedly when it is administered with tenofovir disoproxil fumarate, and this combination must not be used.

Non-Nucleoside Reverse Transcriptase Inhibitors

• Efavirenz: Efavirenz induces CYP3A4 and CYP2B6, thereby reducing concentrations of methadone, hormonal contraceptives, and several antipsychotics, necessitating dose modification or alternative therapy. Efavirenz concentrations increase when administered with ticlopidine or clopidogrel; therefore, monitoring for central nervous system toxicity is appropriate.

• Rilpivirine: Proton pump inhibitors markedly reduce rilpivirine absorption, and rilpivirine must not be coadministered with omeprazole, pantoprazole, or related medications. H2-receptor antagonists reduce rilpivirine exposure; an interval is required when using famotidine or ranitidine. The risk of QT prolongation increases when rilpivirine is coadministered with amiodarone or moxifloxacin; therefore, electrocardiogram (ECG) monitoring is appropriate.

• Etravirine: Etravirine induces CYP3A4, thereby decreasing concentrations of most PIs unless ritonavir or cobicistat boosting is used. Etravirine concentrations decrease markedly when it is administered with rifampin or carbamazepine, and coadministration is contraindicated.

• Doravirine: Doravirine exposure decreases substantially when it is administered with rifampin, carbamazepine, phenytoin, or St. John's wort, and coadministration is contraindicated.

Protease Inhibitors

• Ritonavir- and cobicistat-boosted PIs strongly inhibit CYP3A4, thereby increasing concentrations of benzodiazepines, statins, direct oral anticoagulants, and calcineurin inhibitors, potentially requiring dose modification or avoidance. In contrast, CYP3A4 inducers, including rifampin, phenytoin, carbamazepine, and St. John’s wort, markedly reduce PI exposure and therefore should not be coadministered.

• Atazanavir: Proton pump inhibitors significantly reduce atazanavir absorption, and coadministration with omeprazole at doses of 20 mg equivalents or greater should be approached with caution. Indirect hyperbilirubinemia increases when atazanavir is administered with indinavir, and this combination must be avoided.

• Darunavir: Darunavir concentrations decline precipitously when administered without ritonavir or cobicistat, necessitating boosting. Darunavir increases bleeding risk when it is administered with warfarin or direct oral anticoagulants, and the International Normalized Ratio or anticoagulation parameters require monitoring.

• Lopinavir/ritonavir: QT-interval and PR-interval prolongation increase when lopinavir/ritonavir is administered with sotalol, quinidine, or amiodarone, and coadministration should be avoided.

Integrase Strand Transfer Inhibitors

• Integrase inhibitors bind polyvalent cations via chelation. Magnesium, aluminum, calcium, and iron supplements reduce the absorption of dolutegravir, bictegravir, and raltegravir; therefore, dose separation is required.

• Bictegravir: Bictegravir exposure decreases substantially when it is administered with rifampin, and coadministration is contraindicated.

• Raltegravir: Raltegravir exposure decreases when it is coadministered with rifampin, necessitating dose adjustment.

• Cabotegravir: Cabotegravir exposure decreases when it is coadministered with rifampin, phenytoin, or carbamazepine; coadministration should be avoided. 

Chemokine Receptor 5 Antagonist

• Maraviroc: CYP3A4 inhibitors, including ritonavir, cobicistat, ketoconazole, and clarithromycin, increase maraviroc exposure and require a dose reduction. CYP3A4 inducers, including rifampin, rifapentine, carbamazepine, phenobarbital, and St. John's wort, decrease maraviroc exposure markedly, and coadministration is contraindicated. Postural hypotension increases when maraviroc is administered with amlodipine, losartan, or metoprolol, and blood pressure requires monitoring. Hepatotoxicity risk increases when maraviroc is administered with isoniazid or methotrexate, and hepatic function monitoring is needed.[56]

Fusion Inhibitor

• Enfuvirtide: Enfuvirtide does not undergo CYP-mediated metabolism and has no clinically meaningful pharmacokinetic interactions. With increasing use, interactions may be reported; therefore, it is always advisable to remain watchful for any drug-drug interactions.

Postattachment Inhibitor

• Ibalizumab: Ibalizumab does not undergo metabolism through CYP pathways, and ibalizumab has no clinically significant pharmacokinetic interactions. With increasing use, interactions may be reported; therefore, it is always advisable to remain watchful for any drug-drug interactions.

Attachment Inhibitor

• Fostemsavir: Fostemsavir concentrations decrease markedly when it is administered with rifampin, carbamazepine, phenytoin, phenobarbital, or St. John's wort, and coadministration is contraindicated. Fostemsavir exposure increases substantially when it is coadministered with ritonavir- or cobicistat-boosted PIs or azole antifungals, and monitoring for adverse effects is warranted. The risk of QT prolongation increases when fostemsavir is administered with dofetilide, amiodarone, quinidine, or moxifloxacin, and baseline and periodic ECG monitoring is advisable. Fostemsavir exposure increases when it is administered with cyclosporine, and monitoring for gastrointestinal and cardiac adverse effects is necessary.

• Strong inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort are contraindicated because they can suppress lenacapavir levels for prolonged periods due to the drug's exceptionally long half-life.

Capsid Inhibitor (Lenacapavir)

• Strong CYP3A inducers such as rifampin, carbamazepine, and phenytoin significantly decrease lenacapavir exposure; therefore, their combination is contraindicated because subtherapeutic levels can lead to virologic failure and resistance.

• Strong CYP3A, P-glycoprotein (P-gp), and uridine diphosphate–glucuronosyltransferase family 1 member A1 (UGT1A1) inhibitors, such as atazanavir/cobicistat or ketoconazole, significantly increase lenacapavir concentrations, and coadministration is not recommended due to the risk of toxicity from excessive accumulation.

• Lenacapavir is a moderate CYP3A inhibitor that raises exposure to CYP3A substrates such as midazolam. Clinicians should adjust doses or choose alternatives to prevent adverse reactions.

• Lenacapavir inhibits P-gp and BCRP, raising levels of transporter substrates such as digoxin and rosuvastatin; monitoring or dose adjustments are advised to avoid toxicity. When used with oral contraceptives containing levonorgestrel, lenacapavir increases hormone exposure through CYP3A inhibition; therefore, clinicians should monitor for hormone-related adverse effects.[61]

Contraindications

The contraindications associated with HIV medications are listed below.

• Abacavir: Patients with HLA-B*57:01, prior hypersensitivity reaction to abacavir, or moderate to severe hepatic impairment. [62]
• Emtricitabine: Patients with previously demonstrated hypersensitivity to any of the components of the product.
• Lamivudine: Patients with a previous hypersensitivity reaction to lamivudine.
• Tenofovir disoproxil fumarate: Previous hypersensitivity or a glomerular filtration rate of less than 50.
• Zidovudine: Patients who have had potentially life-threatening allergic reactions (eg, anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations.
• Efavirenz: Patients with clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the ingredients of this product; coadministration of efavirenz with elbasvir and grazoprevir is contraindicated.
• Etravirine: Patients with known hypersensitivity to etravirine.
• Nevirapine: Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C, respectively) and for use as occupational and nonoccupational PEP regimens. Women with a CD4 count greater than 250 or men with a CD4 count greater than 400 are at increased risk of hypersensitivity reactions. Hepatotoxicity is largely cholestatic but may also demonstrate a hepatocellular pattern. In some cases, clinically apparent hepatotoxicity occurs after the first 8 weeks of therapy and may be severe and fatal.[49]
• Rilpivirine: Contraindicated for coadministration with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, dexamethasone, St. John's wort, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole.
• Atazanavir: Contraindicated in patients with a history of clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any component of the formulation. Concurrent administration of drugs that are highly dependent on cytochrome P450 3A4 (CYP3A4) or UGT1A1 for clearance may result in increased plasma concentrations of the interacting drugs and serious, potentially life-threatening adverse events. When coadministered with strong CYP3A4 inducers, atazanavir exposure may be reduced, leading to loss of therapeutic efficacy.
• Darunavir: Coadministration is contraindicated with medications highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events.
• Fosamprenavir: Contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome) to any of the components of fosamprenavir or amprenavir, when coadministered with medications that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events. 
• Ritonavir: Contraindicated in patients with known hypersensitivity (eg, toxic epidermal necrolysis or Stevens-Johnson syndrome) to ritonavir or any of its components. Ritonavir is contraindicated with medications highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening reactions. Ritonavir is also contraindicated with potent CYP3A inducers, as significantly reduced lopinavir plasma concentrations may be associated with an increased risk of virologic failure, potential resistance, and cross-resistance.[63]
• Saquinavir: Contraindicated in patients with congenital long QT syndrome; refractory hypokalemia or hypomagnesemia; or concurrent administration of medications that increase saquinavir plasma concentrations and prolong the QT interval. It is also contraindicated in patients with complete atrioventricular block without an implanted pacemaker or in those at high risk of atrioventricular block. Additional contraindications include clinically significant hypersensitivity (eg, anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients; severe hepatic impairment; and concomitant use of drugs that are CYP3A substrates for which increased plasma concentrations may result in serious or life-threatening adverse reactions.
• Tipranavir: Contraindicated with concurrent administration of drugs highly dependent on CYP3A4 for clearance or potent CYP3A4 inducers due to increased risk of intracranial bleeding. Tipranavir is also contraindicated in moderate to severe hepatic impairment.[64]
• Enfuvirtide: Patients with known hypersensitivity to enfuvirtide or any of its components.
• Maraviroc: Contraindicated in patients with severe renal impairment or end-stage renal disease (creatinine clearance [CrCl] <30 mL/min) who are concurrently taking potent CYP3A inhibitors or inducers.
• Dolutegravir: Contraindicated in patients with a previous hypersensitivity reaction to dolutegravir or those receiving dofetilide because of the risk of elevated dofetilide plasma concentrations and severe, life-threatening events.
• Raltegravir: No contraindications are listed; however, hypersensitivity reactions are noted as a warning in the prescribing information.
• Ibalizumab: Contraindicated in patients with a history of hypersensitivity reactions.[65]
• Cobicistat: Concomitant use of cobicistat with atazanavir is contraindicated in patients dependent on CYP3A or UGT1A1 for drug clearance, when elevated plasma concentrations may result in severe, life-threatening events. Darunavir and cobicistat should not be coadministered with drugs highly dependent on CYP3A for clearance because of the risk of increased plasma concentrations and serious adverse events.

Monitoring

The following tests should be performed to monitor patients on HIV ART:

Initial Assessment (Start of Therapy)

• CD4 count
• HIV viral load
• Resistance testing
• HLA-B*57:01 testing for abacavir hypersensitivity [66]
• Tropism testing
• Hepatitis B serology
• Hepatitis C screening
• CBC with differential
• Basic chemistry 
• Alanine transaminase (ALT), aspartate transaminase (AST), and serum bilirubin
• Fasting lipid profile
• Fasting glucose and hemoglobin A1C
• Urinalysis
• Pregnancy test 

Every 3 to 6 Months

• CD4 count for the first 2 years of ART, or if viremia develops
• HIV viral load
• Basic chemistry
• ALT, AST,  and bilirubin
• CBC with differential if on zidovudine
• Fasting glucose and hemoglobin A1C should be checked if abnormal before

Every 6 Months

• CBC with differential
• Urinalysis if on bictegravir/emtricitabine/TAF or efavirenz/emtricitabine/TDF

Every 12 Months

• After 2 years, if the CD4 count is between 300 and 500, then every 12 months; if the CD4 count is greater than 500, monitoring is optional.
• Hepatitis B serology may be repeated unless the patient is immunized.
• Screen for hepatitis C in patients at risk.
• Fasting lipid profile
• Fasting glucose and hemoglobin A1C
• Urinalysis
• The QuantiFERON-TB test (interferon gamma release assay or IGRA) [67]

Treatment Failure or Modification

• CD4 count
• HIV viral load
• Resistance testing
• Hepatitis B serology
• Hepatitis C screening
• Basic chemistry
• ALT/AST/bilirubin
• CBC with differential
• Fasting lipid profile
• Fasting glucose and hemoglobin A1C
• Urinalysis
• Pregnancy test
• Tropism testing is required for maraviroc because it works exclusively as an entry inhibitor against CCR5-tropic HIV. The purpose of this testing is to confirm the absence of CXCR4-tropic or dual/mixed (non-CCR5) viruses, as their presence renders maraviroc largely ineffective against the entire viral population, making the drug contraindicated.[68]

Toxicity

Many HIV medicines have adverse effects and toxicity that may require supportive treatment, monitoring, and adjustment of the HIV regimen.[59]

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

NRTIs are characterized by mitochondrial toxicity, which can result in severe myopathy, hepatic failure, and potentially fatal lactic acidosis. When lactic acidosis is suspected, all NRTIs must be discontinued immediately and supportive management initiated.

• Zidovudine: Zidovudine causes dose-dependent bone marrow suppression, most commonly resulting in anemia and neutropenia. Toxicity may present more severely in overdose settings, including dosing errors in neonates.
• Stavudine: Stavudine has high mitochondrial toxicity and can cause severe lactic acidosis, hepatic steatosis, and painful peripheral neuropathy.
• Didanosine: Didanosine is associated with pancreatitis and peripheral neuropathy, and these reactions may be severe or life-threatening.
• Zalcitabine: Zalcitabine causes significant peripheral neuropathy with cumulative exposure.
• Abacavir: Abacavir can cause a potentially fatal hypersensitivity reaction linked to HLA-B*57:01. Immediate cessation is mandatory if symptoms develop.
• Lamivudine: Lamivudine is generally well tolerated, with rare cases of clinically relevant hypersensitivity or hepatotoxicity.
• Emtricitabine: Emtricitabine toxicity is uncommon, with cutaneous hyperpigmentation being the only notable drug-specific reaction.
• Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate may cause nephrotoxicity, including proximal tubular injury and Fanconi syndrome. It should be avoided in individuals with preexisting renal impairment.
• Tenofovir alafenamide: Tenofovir alafenamide has a lower nephrotoxicity rate but can cause dyslipidemia. Tenofovir is removed by hemodialysis with an extraction coefficient of about 54%.

Non-Nucleoside Reverse Transcriptase Inhibitors

NNRTIs frequently cause hepatic injury and severe dermatologic reactions. Certain drugs are associated with neuropsychiatric toxicity.

First-Generation Non-Nucleoside Reverse Transcriptase Inhibitors

• Nevirapine: Therapy with nevirapine is associated with significant transaminase elevations in 4% to 20% of patients and symptomatic elevations in 1% to 5% of patients. Among the more than 20 antiretroviral agents, NVP is perhaps the most common cause of serious, clinically apparent acute liver injury. The clinically apparent liver injury due to nevirapine is as high as 1%, with fatalities ensuing in approximately 0.1% of treated patients. The onset of injury typically occurs within the first 6 to 8 weeks of therapy. The presenting symptoms usually include abdominal pain and fatigue, followed by fever, rash, and jaundice. Most patients exhibit a cholestatic pattern of hepatic injury, but hepatocellular injury is also observed in severe cases. NVP hepatotoxicity can be severe and fatal, and cases requiring emergency liver transplantation have been reported. NVP should be promptly discontinued if serum aminotransferase levels rise to approximately 10 times the upper limit of normal, remain persistently above 5 times the upper limit of normal, or are accompanied by bilirubin elevations or hepatitis.[49] 

• Efavirenz: Overdoses of efavirenz present with neuropsychiatric symptoms, and management is supportive.

Second-Generation Non-Nucleoside Reverse Transcriptase Inhibitors

• Etravirine: Etravirine is associated with Stevens-Johnson syndrome and can cause hepatic enzyme elevations.
• Rilpivirine: Rilpivirine may prolong the QT interval at high concentrations and may worsen depressive symptoms in susceptible individuals.
• Doravirine: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with doravirine, and the drug should be discontinued immediately if these reactions occur.

Protease Inhibitors

These inhibitors have been associated with insulin resistance, type 2 diabetes, and lipodystrophy.

Integrase Strand Transfer Inhibitors

Weight gain is frequently observed after starting INSTI-containing regimens in ART-naive individuals. Bictegravir and dolutegravir produce the most significant increases in body weight, and INSTIs cause more weight gain than NNRTIs or boosted PIs. Further research is needed to identify predictors and determine the long-term metabolic or cardiovascular implications. INSTIs may worsen psychiatric symptoms. Central nervous system–related adverse events, including headache, insomnia, dizziness, and depression, have been reported and are usually mild. Because depression is common in individuals with HIV, close monitoring is advised when initiating these drugs, particularly in those with a history of depression or those receiving antidepressants or other psychotropic medications.[69]

Chemokine Receptor 5 Antagonist

• Maraviroc (entry inhibitor): Severe hepatotoxicity with allergic features, including fatal events, has been reported; if patients develop signs or symptoms of hepatitis (eg, elevated liver transaminases) with rash or systemic allergic reaction, maraviroc should be discontinued and hepatic laboratory parameters monitored.[56][70] 

Attachment Inhibitors

• Fostemsavir: In studies, administration at 4 times the recommended dose has prolonged the QTc interval; increases in hepatic transaminases have also been observed in individuals with coinfection with hepatitis B or C. Caution is advised when prescribing fostemsavir in patients with preexisting QTc prolongation or concomitant use of QT-prolonging drugs, and ECG and liver enzyme monitoring may be indicated. There is no known specific treatment for overdose with fostemsavir. An ECG should be obtained to measure the QTc interval, and the patient's clinical status should be monitored. If an overdose occurs, the patient should be monitored, and supportive therapy should be provided. 

Capsid Inhibitors

• Lenacapavir: Injection-site reactions with subcutaneous administration are frequent; improper administration has been associated with severe reactions, including necrosis and ulceration; correct subcutaneous abdominal injection technique should be ensured, and persistent nodules or induration should be evaluated.[69]

Postattachment Inhibitors

• Ibalizumab: Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported following infusions of ibalizumab. If anaphylaxis occurs, ibalizumab should be discontinued immediately, and appropriate anaphylaxis treatment should be initiated.

Immune reconstitution inflammatory syndrome (IRIS) is observed with the initiation of ART, particularly in HIV-infected patients who start treatment with a low CD4+ cell count and have an underlying opportunistic infection or malignancy. Key monitoring strategies include regular clinical evaluations for new or worsening symptoms; monitoring CD4+ cell counts and viral load to track immune recovery; and using specific tests, such as neuroimaging or chest x-rays, to assess for IRIS-related inflammation. In many cases, IRIS is self-limiting and only symptomatic treatment is required, in addition to treatment of the IRIS infection.[71][72] 

For individual drug-specific toxicity related to more recently approved drugs and multidrug regimens, especially in patients with hepatitis B, tuberculosis, or other opportunistic infections, consultation with a medical toxicologist and an infectious disease specialist is recommended. The National Poison Control Center should be contacted for the latest recommendations.

Enhancing Healthcare Team Outcomes

The management of patients with HIV is best achieved through an interprofessional team that includes physicians, nurse practitioners, physician assistants, infectious disease specialists, pharmacists (including infectious disease specialty pharmacists focused on antiretroviral therapy), and infectious disease nurses. The pharmacist should verify the selected regimen, assess for drug interactions, verify dosing, and assume responsibility for patient education. Nursing staff can initially assess treatment effectiveness and, in particular, patient compliance. They must also participate in patient education, as nonadherence can lead to therapeutic failure.

All healthcare team members must emphasize adherence when appropriate, and any concerns regarding the regimen or compliance must be communicated to the treating physician. All interprofessional team members are responsible for patient monitoring, including compliance, and must document any concerns in the patient's medical record and promptly notify the appropriate team members to initiate corrective action; this open communication is crucial to the success of ART. Historically, the term "highly active ART" referred to multidrug regimens. Today, the accepted term is ART.

Overwhelming data show that ART can improve survival and reduce the risk of opportunistic infections. Thus, healthcare professionals must understand these medications given their efficacy and potential adverse effects. Consultation with an infectious disease expert is recommended when there are uncertainties regarding ART. Infectious disease clinicians and other healthcare professionals play a key role in ensuring that adults and children with HIV receive safe and effective therapy. Infectious disease specialists and healthcare professionals are integral to the formulation of domestic and global policies to address infectious diseases and improve public health.[73]

Poor retention in HIV care is associated with increased morbidity and mortality and a greater risk of HIV transmission. The Patient-Centered HIV Care Model (PCHCM) incorporates community-based pharmacists with clinicians. PCHCM demonstrated that close collaborations between pharmacists and clinicians can improve the retention of patients with HIV and enhance patient outcomes.[74] A study suggests that community pharmacy–based administration of long-acting injectable ART is generally well received and represents a promising strategy to expand access to HIV treatment. However, real-world implementation remains constrained by operational barriers, including inadequate staffing, limited pharmacist training, insufficient private space for injections, and inconsistent reimbursement pathways.

Successful scale-up continues to depend on strong, bidirectional collaboration between HIV clinics and community pharmacies, which remains the central enabling factor for broader adoption.[75] Guidelines developed by organizations such as the CDC, FDA, and DHHS are essential for informing the implementation of evidence-based ART among healthcare professionals. Effective HIV management is best achieved through ongoing, collaborative efforts among physicians, infectious disease specialists, pharmacists, and nurses, who collectively tailor and optimize treatment for each patient. This interprofessional approach is crucial for rapid adaptation to updated protocols and the integration of newly approved medications to address the challenge of multidrug-resistant HIV. By leveraging each discipline's expertise, the risk of adverse drug events can be minimized while maintaining therapeutic effectiveness.