Antiretrovirals

Quick revision

HIV is never treated with one drug: current guidelines build a regimen from an integrase strand transfer inhibitor plus two nucleoside/nucleotide reverse transcriptase inhibitors, because combining agents from different classes closes off the escape routes any single drug leaves open to HIV's fast-mutating reverse transcriptase.

• The DHHS adult and adolescent guidelines recommend an oral second-generation integrase strand transfer inhibitor (INSTI) plus two NRTIs — bictegravir/tenofovir alafenamide/emtricitabine or dolutegravir plus TAF/FTC, TDF/FTC or TDF/lamivudine — as initial therapy for most people with HIV. (8)
• NRTIs (e.g. tenofovir, emtricitabine, lamivudine, abacavir) are chain terminators: they lack the 3'-hydroxyl group DNA synthesis needs to keep extending, so viral DNA synthesis stops once one is incorporated. (7)
• NNRTIs (e.g. efavirenz, nevirapine, rilpivirine, doravirine) bind reverse transcriptase directly at a site away from the active centre and block the enzyme's conformational movement rather than terminating the growing DNA chain. (7)
• Protease inhibitors (e.g. darunavir, atazanavir, lopinavir) block the HIV protease that cleaves precursor polyproteins into mature structural and enzymatic proteins, so virions assembled in their presence are immature and non-infectious. (7)
• Integrase strand transfer inhibitors (e.g. dolutegravir, bictegravir, raltegravir, cabotegravir) block integrase from inserting the reverse-transcribed viral DNA into the host genome. (7)
• Abacavir carries an FDA-mandated HLA-B*5701 screening requirement: patients who test positive for that allele are at materially higher risk of a multi-organ hypersensitivity reaction and abacavir is contraindicated for them, and once hypersensitivity is suspected in anyone, abacavir is stopped for good. (3)
• Tenofovir disoproxil fumarate and tenofovir alafenamide both carry renal and bone-density warnings; acute renal failure, Fanconi syndrome and decreases in bone mineral density are described in their labelling. (2)
• Darunavir, like most HIV protease inhibitors used today, is not given alone: its own label states it must be co-administered with low-dose ritonavir (or cobicistat) as a pharmacokinetic booster to reach adequate plasma concentrations. (5)

Overview

Antiretroviral therapy (ART) is built around a principle that has held since the mid-1990s: HIV is treated with a combination regimen, not a single drug. Standard therapy uses three medications drawn from at least two antiretroviral classes, targeting different steps of the replication cycle at once. This is not a dosing convenience — it is a direct response to how fast HIV's reverse transcriptase makes copying errors, which lets drug-resistant variants emerge under the selective pressure of a single agent far faster than they would against two or three simultaneously. (7)

The classes in routine use each interrupt a different stage. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) both act on reverse transcriptase, but by different mechanisms — one by terminating the growing DNA chain, the other by binding an allosteric site and freezing the enzyme's motion. Protease inhibitors act later, blocking the cleavage step that turns a newly budded, structurally immature virion into an infectious one. Integrase strand transfer inhibitors act in between, stopping the reverse-transcribed viral DNA from being spliced into the host cell's own genome. A smaller group of entry and attachment inhibitors, plus a fusion inhibitor and a capsid inhibitor, acts earliest of all, before the virus gets inside the cell or before its genetic material is even uncoated. (7)

Current DHHS guidance for adults and adolescents starting therapy recommends an INSTI-based regimen — an integrase inhibitor plus two NRTIs — as the preferred starting point for most people with HIV, reflecting durable virologic efficacy and a comparatively favourable tolerability profile relative to older NNRTI- or protease-inhibitor-based regimens. A small number of specifically studied two-drug regimens, such as dolutegravir plus lamivudine, are now also used in selected patients, but this is a defined exception built on its own trial evidence rather than a general retreat from combination therapy. (8)

Two toxicities recur across this field of otherwise very different drugs and are worth holding in mind together. Abacavir hypersensitivity is an immunologically mediated, potentially fatal multi-organ reaction strongly associated with the HLA-B*5701 allele, and it is managed by pre-treatment genetic screening plus permanent discontinuation if it is ever suspected — not by dose adjustment. Tenofovir, in either its older disoproxil fumarate form or the newer, lower-dose alafenamide prodrug, carries a renal and bone-density signal that is monitored with baseline and periodic labs rather than screened for genetically. Both are class-defining safety issues that a student is expected to be able to name, not generic antiviral side effects. (3) (2)

Classification and drug examples

Antiretrovirals are grouped by the step of the HIV replication cycle each class interrupts. The five classes below cover the drugs in routine combination regimens; a smaller set of newer entry, attachment, post-attachment and capsid inhibitors is reserved mainly for multidrug-resistant disease and is noted rather than covered drug-by-drug here.

Mechanism of action

HIV's replication cycle offers several distinct points a drug can interrupt: reverse transcription of viral RNA into DNA, integration of that DNA into the host genome, and the protease-mediated maturation of newly assembled virions, plus entry and fusion steps before any of that begins. Each antiretroviral class targets one of these steps, and combining classes closes off more escape routes than any single class could alone, which is why standard therapy is built from at least two classes rather than one.

Molecular target

Reverse transcriptase (NRTIs, NNRTIs), integrase (INSTIs), protease (PIs), and viral entry/fusion/capsid machinery (entry, fusion and capsid inhibitors)

Pharmacodynamic effect

Virustatic — suppresses ongoing replication and new infection of cells rather than eliminating latently infected cells, which is why ART is lifelong rather than curative

Effect kinetics

Viral load falls over days to weeks of adherent therapy; rebound occurs within weeks of stopping or of resistance developing

1. NRTIs terminate the growing viral DNA chain

   NRTIs are analogues of the natural deoxynucleotides but lack the 3'-hydroxyl group DNA polymerisation needs to add the next nucleotide, so once reverse transcriptase incorporates one, chain elongation stops. (7)

2. NNRTIs jam reverse transcriptase from an allosteric site

   NNRTIs bind a pocket near, but distinct from, the enzyme's catalytic site and block the conformational flexibility reverse transcriptase needs to function, without being incorporated into the DNA chain themselves. (7)

3. INSTIs block integration of viral DNA into the host genome

   After reverse transcription, the pre-integration complex normally uses viral integrase to splice viral DNA into host chromosomal DNA; INSTIs bind integrase and block the strand-transfer step specifically. (7)

4. Protease inhibitors block maturation of the budding virion

   Newly assembled virions bud from the cell containing long Gag and Gag-Pol polyprotein precursors that must be cleaved by HIV protease into individual structural and enzymatic proteins; protease inhibitors block that cleavage, leaving immature, non-infectious particles. (7)

5. Entry, fusion and capsid inhibitors act earliest or latest of all

   CCR5 antagonists block the co-receptor step of attachment, fusion inhibitors block gp41-mediated membrane fusion before the viral core enters the cell, and capsid inhibitors like lenacapavir bind the capsid protein to disrupt multiple later steps including uncoating and assembly. (7)

Spectrum of activity

Antiretrovirals are active against HIV-1 (and, for some agents, HIV-2) specifically, not against other retroviruses or unrelated viral families; "spectrum" here means which HIV strains and resistance patterns a given class still reaches, rather than a list of unrelated organisms the way an antibacterial spectrum works.

Major clinical uses

Pharmacokinetics

• This page gives no dose regimens by design. Regimen selection and dose adjustment depend on treatment history, resistance testing, renal and hepatic function, pregnancy, and concomitant medications, and belong in a current prescribing reference or the DHHS guidelines used by the treating clinician.
• Cytochrome P450 and UGT drug-interaction potential is a major practical differentiator within this field: protease inhibitors and several NNRTIs are strong CYP3A4 substrates or modulators, while INSTIs interact mainly through UGT1A1 metabolism and, for the whole class, through chelation with polyvalent cations. (5) (4)

Adverse effects

Common

• Gastrointestinal upset: Nausea, diarrhea and headache are commonly reported across most oral antiretrovirals, including BIKTARVY. (1)
• Neuropsychiatric symptoms with efavirenz: Dizziness, abnormal dreams, insomnia and, less commonly, hallucination or euphoria occur in roughly half of patients, usually most pronounced in the first one to two weeks. (6)
• Insomnia, fatigue and headache with dolutegravir: The most common adverse reactions of at least moderate intensity reported with TIVICAY. (4)

Serious adverse effects

• Abacavir hypersensitivity reaction: A multi-organ syndrome typically involving two or more of fever, rash, gastrointestinal symptoms, constitutional symptoms and respiratory symptoms; can occur even in HLA-B*5701-negative patients, though at much lower frequency. Screen for HLA-B*5701 before starting; discontinue abacavir immediately if hypersensitivity is suspected and never rechallenge with abacavir or any abacavir-containing product. (3)
• Renal impairment and Fanconi syndrome with tenofovir: Acute renal failure and Fanconi syndrome have been reported with tenofovir disoproxil fumarate, particularly with concurrent nephrotoxic drugs. Baseline and periodic monitoring of renal function is part of routine care with any tenofovir-containing regimen. (2)
• Decreased bone mineral density with tenofovir: Decreases in bone mineral density have been observed in both HIV-infected and HIV-uninfected individuals taking tenofovir disoproxil fumarate; osteomalacia associated with renal tubular injury has also been reported. Bone monitoring is considered in patients with a history of pathologic fracture or risk factors for bone loss. (2)
• Severe acute hepatitis B exacerbation after stopping an HBV-active antiretroviral: Patients coinfected with HIV and HBV who discontinue emtricitabine- or tenofovir-containing regimens (or BIKTARVY as a whole) can experience severe, sometimes fatal, hepatitis B flares. HBV status is tested before starting and hepatic function is monitored closely for several months after any such regimen is stopped. (1) (2)
• Hypersensitivity and hepatotoxicity with dolutegravir: Hypersensitivity reactions with rash, constitutional findings and sometimes organ dysfunction including liver injury have been reported; patients with underlying hepatitis B or C may be at increased risk of transaminase elevation. Discontinue promptly if hypersensitivity is suspected; monitor liver enzymes in HBV/HCV-coinfected patients. (4)
• Serious psychiatric symptoms with efavirenz: Severe depression, suicidal ideation and other serious psychiatric symptoms have been reported. Immediate medical evaluation is recommended for new or worsening severe psychiatric symptoms. (6)

Drug-specific effects

• Abacavir: The only antiretroviral in routine use with a labelled pharmacogenomic contraindication (HLA-B*5701 positivity) rather than a purely clinical one. (3)
• Darunavir (boosted): Must always be co-administered with ritonavir or cobicistat and with food; unboosted use is not an approved option. (5)
• Efavirenz: The class-defining neuropsychiatric adverse-effect profile among NNRTIs, distinct from the largely renal/bone concerns of the NRTI backbone drugs. (6)

Contraindications, precautions and interactions

Contraindications

• Abacavir: known HLA-B*5701-positive status, or a prior hypersensitivity reaction to abacavir. (3)
• BIKTARVY: coadministration with dofetilide (risk of serious cardiac effects) or rifampin (reduces bictegravir concentrations, risking treatment failure and resistance). (1)

Precautions

• HIV/HBV coinfection requires caution around stopping any emtricitabine- or tenofovir-containing regimen because of the risk of severe hepatitis B exacerbation. (2) (1)
• Pre-existing renal impairment is a caution for tenofovir-containing regimens, given the drug's renal elimination and nephrotoxicity signal. (2)
• TRUVADA for PrEP requires confirmed HIV-negative status immediately before starting and retesting at least every three months during use, because undetected acute infection risks selecting drug-resistant HIV-1 variants. (2)

Drug interactions

• Polyvalent cation-containing antacids, laxatives, sucralfate, or iron/calcium supplements: Reduce dolutegravir absorption; dosing must be separated by two hours before or six hours after. (4)
• Rifampin and other strong CYP3A/UGT1A1 inducers: Can reduce bictegravir or dolutegravir concentrations enough to risk virologic failure. (1)
• Other CYP3A4 substrates: Ritonavir- or cobicistat-boosted protease inhibitors have extensive CYP3A4-mediated interaction potential with many other drug classes. (5)

Resistance mechanisms

Comparison tables

High-yield exam pearls

• HIV is never treated with monotherapy, and outside a few specifically studied two-drug regimens, not with two drugs from one class either. (7) HIV's error-prone reverse transcriptase generates resistance mutations constantly; combining classes with different resistance pathways is what keeps a regimen durable.
• Abacavir hypersensitivity is screened for genetically (HLA-B*5701), not managed by dose reduction. (3) It is one of the few antiretroviral toxicities with a mandated pre-treatment pharmacogenomic test rather than a purely clinical monitoring plan.
• Boosted protease inhibitors are always given with ritonavir or cobicistat. (5) Unboosted PI regimens are not an approved option for agents like darunavir — the booster is required to reach adequate plasma exposure, not optional for tolerability.
• Second-generation INSTIs (bictegravir, dolutegravir) have a much higher genetic barrier to resistance than first-generation raltegravir. (8) (7) This is why current guidelines favour bictegravir- or dolutegravir-based regimens as initial therapy.
• Stopping an emtricitabine- or tenofovir-containing regimen in a patient coinfected with HBV can trigger a severe hepatitis flare. (2) (1) Both drugs are also active against HBV, so withdrawing them removes HBV suppression as well as HIV suppression, and hepatic function needs monitoring for months afterward.

Common exam traps

• Trap: Assuming any two-drug HIV regimen is inadequate. Actually: Specifically studied two-drug regimens such as dolutegravir/lamivudine are now guideline-supported for selected patients — the general rule against under-treating HIV is about resistance barrier and trial evidence, not an absolute drug count. (8)
• Trap: Treating ritonavir as primarily an antiretroviral in modern regimens. Actually: At the low doses used today, ritonavir functions mainly as a CYP3A4-inhibiting pharmacokinetic booster for another protease inhibitor, not as the regimen's antiviral backbone. (5)
• Trap: Assuming abacavir hypersensitivity cannot occur in an HLA-B*5701-negative patient. Actually: The label explicitly notes hypersensitivity reactions have occurred in patients who do not carry the allele, so a negative test lowers but does not eliminate the risk, and any suspected reaction still means permanent discontinuation. (3)
• Trap: Assuming NNRTIs work the same way as NRTIs because both act on reverse transcriptase. Actually: NRTIs are incorporated into the growing DNA chain and terminate it; NNRTIs are not incorporated at all and instead bind an allosteric pocket that blocks the enzyme's necessary conformational change. (7)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. Why is HIV treated with combination antiretroviral therapy rather than a single drug?

   • Because no single antiretroviral is potent enough to suppress viral load
   • Because HIV's error-prone reverse transcriptase generates resistance mutations quickly, and combining classes closes off more resistance pathways than any one class can alone
   • Because combination pills are easier to manufacture
   • Because single-drug regimens are more expensive
   Show answer

   Answer: Because HIV's error-prone reverse transcriptase generates resistance mutations quickly, and combining classes closes off more resistance pathways than any one class can alone

   HIV's high mutation rate under drug pressure means a single agent is quickly overcome by resistant variants; combining agents from different classes with different resistance pathways is what keeps suppression durable. (7)

2. What distinguishes the mechanism of NNRTIs from NRTIs?

   • NNRTIs terminate the DNA chain like NRTIs but at a different nucleotide
   • NNRTIs bind an allosteric pocket on reverse transcriptase and block its conformational change, without being incorporated into the DNA chain
   • NNRTIs act on integrase rather than reverse transcriptase
   • NNRTIs and NRTIs have an identical mechanism
   Show answer

   Answer: NNRTIs bind an allosteric pocket on reverse transcriptase and block its conformational change, without being incorporated into the DNA chain

   NRTIs are incorporated into viral DNA and terminate the chain because they lack a 3'-hydroxyl group; NNRTIs instead bind an allosteric site and block the enzyme's necessary movement without becoming part of the DNA. (7)

3. Before starting abacavir, which test is specifically required by the drug's labelling?

   • CD4 count only
   • HLA-B*5701 genetic testing
   • Liver biopsy
   • Tropism testing
   Show answer

   Answer: HLA-B*5701 genetic testing

   Abacavir carries a labelled requirement for HLA-B*5701 screening because patients who carry the allele are at markedly higher risk of a serious multi-organ hypersensitivity reaction. (3)

4. Why must darunavir be co-administered with ritonavir or cobicistat?

   • To improve its taste
   • To boost darunavir's plasma exposure via CYP3A4 inhibition, which is required to achieve the intended antiviral effect
   • Because darunavir has no antiviral activity alone
   • To reduce pill burden
   Show answer

   Answer: To boost darunavir's plasma exposure via CYP3A4 inhibition, which is required to achieve the intended antiviral effect

   The PREZISTA label states darunavir must be co-administered with ritonavir (or cobicistat) and food to achieve the desired antiviral effect; boosting is required, not optional. (5)

5. Which class does dolutegravir belong to, and what is a key drug-interaction concern with it?

   • Protease inhibitor; interacts with grapefruit juice
   • Integrase strand transfer inhibitor; polyvalent cation-containing products (antacids, iron, calcium) reduce its absorption
   • NNRTI; interacts with St John's wort only
   • Fusion inhibitor; no significant interactions
   Show answer

   Answer: Integrase strand transfer inhibitor; polyvalent cation-containing products (antacids, iron, calcium) reduce its absorption

   Dolutegravir is an INSTI, and its label specifies separating dosing from cation-containing antacids, supplements or laxatives by two hours before or six hours after to avoid reduced absorption. (4)

6. What can happen if a patient coinfected with HIV and hepatitis B stops a tenofovir- or emtricitabine-containing regimen?

   • Nothing of clinical significance
   • A severe, sometimes fatal, acute exacerbation of hepatitis B
   • Immediate HIV cure
   • Improved renal function only
   Show answer

   Answer: A severe, sometimes fatal, acute exacerbation of hepatitis B

   Both drugs are active against HBV as well as HIV; stopping them removes HBV suppression and can trigger a severe hepatic flare, so hepatic function is monitored closely for months afterward. (2) (1)

Frequently asked questions

References

1. BIKTARVY (bictegravir, emtricitabine, and tenofovir alafenamide) — prescribing information DailyMed, U.S. National Library of Medicine
2. TRUVADA (emtricitabine and tenofovir disoproxil fumarate) — prescribing information DailyMed, U.S. National Library of Medicine
3. ZIAGEN (abacavir) — prescribing information DailyMed, U.S. National Library of Medicine
4. TIVICAY (dolutegravir) — prescribing information DailyMed, U.S. National Library of Medicine
5. PREZISTA (darunavir) — prescribing information DailyMed, U.S. National Library of Medicine
6. SUSTIVA (efavirenz) — prescribing information DailyMed, U.S. National Library of Medicine
7. HIV Antiretroviral Therapy StatPearls Publishing / NCBI Bookshelf, 2026
8. What to Start: Initial Combination Antiretroviral Regimens for the Antiretroviral-Naive Patient Panel on Antiretroviral Guidelines for Adults and Adolescents, U.S. Department of Health and Human Services (clinicalinfo.HIV.gov)

Related drug classes

• Hepatitis antivirals
• Antiherpes and other DNA-virus antivirals

Back to the Antivirals, antifungals and antiparasitics classification · Pharmacology Study Corner