Antiretrovirals

Antiretroviral therapy is the most developed pharmacology in clinical virology. No other infection has produced as many drug classes, as much pharmacological knowledge, or as rich a public-health programme. Each drug class blocks a distinct step of the replication cycle, with its own mechanism, toxicity and barrier to resistance, and those three properties govern how regimens are chosen.

A brief history

The history of antiretroviral therapy is a history of combination. Zidovudine (AZT), licensed in 1987, was the first agent and the proof that the HIV replication cycle could be targeted, but it also showed that monotherapy fails: viraemia rebounded within months as resistance emerged. The breakthrough came with the HIV protease inhibitors and the recognition that three drugs targeting two or more steps of the cycle could suppress viral replication below the limit of detection. The introduction of indinavir-based triple therapy in 1996 produced one of the most dramatic collapses in disease-specific mortality in modern medicine.

The next two decades refined the principle. The non-nucleoside reverse transcriptase inhibitors (NNRTIs), first nevirapine then efavirenz, enabled once-daily dosing and, combined with generic tenofovir and lamivudine, the global scale-up of ART through the early 2000s. The integrase strand-transfer inhibitors arrived from 2007 (raltegravir, then elvitegravir, then dolutegravir in 2013), bringing higher potency, lower toxicity and, with dolutegravir and the later bictegravir, a much higher genetic barrier to resistance than the NNRTIs. By the late 2010s the World Health Organization had moved dolutegravir-based regimens to first line.

The current frontier is long-acting therapy. Cabotegravir and rilpivirine nanosuspensions, given by intramuscular injection every two months, were the first; the capsid inhibitor lenacapavir, dosed once every six months subcutaneously, is the most striking. Its pivotal Purpose 1 and Purpose 2 trials showed near-complete prevention of HIV acquisition in both cisgender women and men and gender-diverse people, the largest single jump in PrEP efficacy in the field’s history.

Drug classes

Six classes are in routine clinical use, each targeting a distinct step of the replication cycle.

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

NRTIs are nucleoside or nucleotide analogues that, once intracellularly phosphorylated to their triphosphate form, compete with natural dNTPs (deoxynucleoside triphosphates) for incorporation by reverse transcriptase and act as chain terminators. Their intracellular half-life, not their plasma half-life, drives the dosing interval. Class toxicity is mitochondrial (lactic acidosis, hepatic steatosis, lipoatrophy), historically severe with the earlier agents (d4T, ddI) and largely abated with modern ones.

Agent	Mechanism	Key toxicities	Notes
TDF (tenofovir disoproxil)	Nucleotide analogue chain terminator	Proximal tubulopathy (phosphate and potassium wasting), Fanconi syndrome, reduced bone density	Also active against hepatitis B virus (HBV); avoid below an eGFR (estimated glomerular filtration rate) of 50
TAF (tenofovir alafenamide)	Tenofovir prodrug, lower plasma tenofovir exposure	Much less renal and bone toxicity; greater weight gain and adverse lipids	The renal-sparing tenofovir option
3TC (lamivudine), FTC (emtricitabine)	Cytidine analogue chain terminators	Very low (rare pure red cell aplasia)	Both active against HBV; M184V emerges fast but cuts viral fitness and re-sensitises to AZT and tenofovir
ABC (abacavir)	Guanosine analogue chain terminator	HLA-B*5701 hypersensitivity, fatal on re-challenge	The alternative when tenofovir is contraindicated; no renal dose adjustment
AZT (zidovudine)	Thymidine analogue chain terminator	Anaemia, neutropenia, myopathy, lipoatrophy	Largely legacy; macrocytosis is expected and benign; needs full-blood-count monitoring

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

The NNRTIs are non-competitive allosteric inhibitors that bind a hydrophobic pocket on reverse transcriptase. They need no intracellular activation and have no activity against HIV-2. The class has a low genetic barrier to resistance: a single mutation (the classic K103N) confers high-level resistance, often with cross-resistance within the class, which is why the integrase inhibitors have displaced it from first line.

Agent	Mechanism	Key toxicities	Notes
EFV (efavirenz)	Non-competitive allosteric RT inhibitor	CNS (central nervous system) effects (vivid dreams, depression, rare psychosis), rash, gynaecomastia, dyslipidaemia, hepatitis	No HIV-2 activity; a 400 mg dose is non-inferior with better tolerability; no dose change with rifampicin
NVP (nevirapine)	As efavirenz	Hepatotoxicity, rash including Stevens-Johnson syndrome	Superseded for adult initiation

Protease inhibitors (PIs)

The PIs are peptidomimetic inhibitors of HIV-1 protease, blocking the maturational cleavage of the Gag and Gag-Pol polyproteins. They have a high genetic barrier, needing several stepwise mutations to fail, and require pharmacoenhancement (low-dose ritonavir, the “/r” suffix, or cobicistat) to reach effective concentrations. Class toxicities are metabolic (dyslipidaemia, insulin resistance) and gastrointestinal; all are CYP3A4 substrates and potent CYP3A4 inhibitors, the source of their abundant drug interactions.

Agent	Mechanism	Key toxicities	Notes
ATV/r (atazanavir/r)	Competitive HIV protease inhibitor	Benign unconjugated hyperbilirubinaemia, occasional cosmetic jaundice, rare nephrolithiasis; lower lipid impact than LPV/r	Requires gastric acidity (no proton-pump inhibitors (PPIs), take with food); contraindicated with rifampicin
DRV/r (darunavir/r)	As ATV/r	GI upset, rash, dyslipidaemia, rare hepatitis	The highest-barrier PI; contains a sulfonamide moiety (caution in sulpha allergy); contraindicated with rifampicin
LPV/r (lopinavir/r)	As ATV/r	Worst lipid and gastrointestinal profile of the class	The only PI safe with rifampicin, dose-doubled; has paediatric formulations

Integrase strand-transfer inhibitors (INSTIs)

INSTIs block the strand-transfer step that inserts proviral DNA into host chromatin. They are the most potent class, with viral loads falling faster than on any other anchor drug, and the modern agents are well tolerated, with weight gain and occasionally sleep disturbance the main signals. They chelate polyvalent cations in the gut, so antacid, iron and calcium dosing must be timed.

Agent	Mechanism	Key toxicities	Notes
DTG (dolutegravir)	Integrase strand-transfer inhibitor	Insomnia, headache, GI upset; a benign creatinine rise of ~30 µmol/L from reduced tubular secretion	High genetic barrier (R263K is rare and carries a fitness cost); safe in pregnancy and breastfeeding; double the dose with rifampicin or enzyme-inducing anticonvulsants
CAB-LA (cabotegravir long-acting)	INSTI, intramuscular nanosuspension	Injection-site reactions	Positioned for PrEP, not treatment; prior exposure can seed integrase resistance, so a diagnosed person needs integrase genotyping
RAL (raltegravir)	First-generation INSTI	Well tolerated	Lower genetic barrier than DTG; niche and selected paediatric use; prior exposure raises DTG-resistance risk (Q148H pathway)

Dolutegravir’s weight gain is understood as the unmasking of weight previously suppressed by untreated HIV and by efavirenz, so dolutegravir should not be stopped for weight gain. The 2018 Tsepamo neural-tube-defect signal was not confirmed in mature data, and dolutegravir is now used without restriction in pregnancy, breastfeeding and safe conception.

Capsid inhibitors

A new class with a single agent so far. Lenacapavir binds multiple sites on the HIV-1 capsid and disrupts uncoating, nuclear import and assembly. It is given as two subcutaneous abdominal injections every 26 weeks after an oral loading dose, and its resistance signature is the capsid N74D mutation (with M66I and others under monotherapy pressure). It is approved for highly treatment-experienced multidrug-resistant HIV and, on the strength of the Purpose trials, for PrEP.

Entry and attachment inhibitors

These agents are now rarely used, kept for multi-class salvage. Enfuvirtide is a 36-amino-acid peptide that binds the gp41 heptad-repeat 1 region and prevents fusion, given subcutaneously twice daily for multi-class salvage; HIV-2 is intrinsically resistant. Maraviroc is a small-molecule CCR5 antagonist, the only antiretroviral that targets a host protein, and needs a co-receptor tropism assay before use because it works only against R5-tropic virus. Fostemsavir (a gp120 attachment inhibitor) and ibalizumab (an anti-CD4 monoclonal antibody) are reserved internationally for multidrug-resistant salvage.

Special populations

Pregnancy and breastfeeding. A dolutegravir-based regimen is the choice throughout pregnancy, the earlier neural-tube-defect concern having been not confirmed at maturity of the Tsepamo cohort. Infant prophylaxis is stratified by maternal viral load: lower-risk infants receive a short nevirapine course, higher-risk infants extended dual prophylaxis with AZT and nevirapine, continued in breastfed infants until maternal viral suppression.

Renal impairment. Tenofovir disoproxil is contraindicated below eGFR 50; switch to abacavir unless HBV co-infection mandates TAF. Integrase and non-nucleoside RT inhibitors and protease inhibitors need no renal adjustment, but NRTI dose intervals lengthen with declining function (every 48 hours at eGFR 30 to 50, every 72 to 96 hours at 10 to 29, weekly below 10).

Hepatic impairment and HBV co-infection. Tenofovir is the backbone in HBV-positive patients, and it must not be stopped abruptly because a hepatitis flare may follow. Nevirapine is avoided, protease inhibitors can cause hepatitis, and hepatitis B surface antigen (HBsAg) status is part of every baseline workup.

Tuberculosis co-infection. The principal interaction is between rifampicin and the ART anchor: with dolutegravir, add a second 50 mg tablet twelve hours after the usual dose, continuing until two weeks after rifampicin ends. ART timing is CD4-driven (within two weeks if CD4 is below 50, by eight weeks if it is at or above 50, and deferred four to eight weeks in TB meningitis). Atazanavir/r and darunavir/r cannot be given with rifampicin (substitute rifabutin), while LPV/r is the rifampicin-tolerant PI when dose-doubled.

HIV-2. HIV-2 is intrinsically resistant to all NNRTIs and to enfuvirtide, and several protease inhibitors are less active against it. Regimens use two NRTIs with dolutegravir, and viral-load monitoring needs an HIV-2-validated assay.

Key drug interactions

A handful of interactions account for most of the day-to-day prescribing risk.

• Dolutegravir and rifampicin, the commonest ART-TB interaction: double dolutegravir to 50 mg twelve-hourly until two weeks past rifampicin.
• Dolutegravir and polyvalent cations (calcium, iron, magnesium, aluminium antacids): chelation lowers exposure, so give antacids at least six hours before or two hours after dolutegravir (calcium and iron with food are acceptable).
• Dolutegravir and enzyme-inducing anticonvulsants (carbamazepine, phenytoin, phenobarbital): double dolutegravir, or substitute valproate (avoiding it in pregnancy), lamotrigine, levetiracetam or topiramate.
• Efavirenz and rifampicin: no dose change is required.
• Boosted PIs and rifampicin: atazanavir/r and darunavir/r are contraindicated; switch to rifabutin or to double-dose LPV/r.
• Protease inhibitors and statins: simvastatin and lovastatin are contraindicated, atorvastatin only at low dose; pravastatin and fluvastatin are the safer choices.
• Atazanavir and proton-pump inhibitors: contraindicated, since atazanavir requires gastric acidity; antacids and H2-blockers need temporal separation.
• Boosted PIs and hormonal contraception: efficacy is reduced, so advise dual contraception, with an intrauterine device a favoured option.

Adverse effects and monitoring

Class-typical toxicities drive the routine monitoring schedule. Tenofovir disoproxil needs serum creatinine and eGFR at baseline, month three and month ten, then annually. AZT needs a full blood count at baseline and through the first months. Protease-inhibitor regimens warrant a fasting lipid profile at baseline and three-monthly. Dolutegravir needs no dedicated chemistry monitoring beyond noting the benign early creatinine rise of about 30 µmol/L. Weight, blood pressure and HbA1c should be tracked across the cohort, because long-term suppressed HIV carries an excess cardiovascular risk that ART does not fully reverse.

PrEP (Pre-Exposure Prophylaxis)

Pre-exposure prophylaxis (PrEP) is now available in several formulations. Daily oral tenofovir/FTC remains the most widely used PrEP and the default across all populations. An alternative event-driven 2-1-1 schedule (two tablets 2 to 24 hours before sex, then one at 24 hours and one at 48 hours) can also be recommended to men who have sex with men (MSM).

The dapivirine vaginal ring offers about a ~30% reduction in HIV acquisition.

Long-acting cabotegravir, intramuscular every two months after a loading dose, was shown in HPTN 083 and 084 to be non-inferior or superior to oral PrEP.

The newest agent, lenacapavir, given as a twice-yearly subcutaneous injection, is the most efficacious PrEP agent yet studied and the subject of the Purpose trials.

The Purpose 1 and Purpose 2 trials, conducted between 2021 and 2024, tested twice-yearly subcutaneous lenacapavir against daily oral PrEP in two distinct populations. They used a counterfactual comparison to a cross-sectionally estimated background HIV incidence, with daily F/TDF as an active-control arm, a design forced by the impossibility of a true placebo arm against an established preventive intervention.

Feature	Purpose 1 (NEJM 2024)	Purpose 2 (NEJM 2025)
Population	Cisgender adolescent girls and young women, 16 to 25 yr	Cisgender gay and bisexual men, trans women and men, gender-non-binary, 16+ yr (median 29)
Sites	28 sites in South Africa and Uganda (84% SA)	92 sites across the US, Brazil, Thailand, South Africa, Peru, Argentina, Mexico
Randomisation	2 : 2 : 1 lenacapavir vs F/TAF vs F/TDF	2 : 1 lenacapavir vs F/TDF
Sample size (modified intention-to-treat)	5,338	3,265
Lenacapavir arm, HIV infections	0 / 2,134 (0.00 per 100 person-years)	2 / 2,179 (0.10 per 100 person-years)
Incidence rate ratio (IRR) vs background	0.00 (100% reduction)	0.04 (96% reduction)
IRR vs daily F/TDF arm	0.00	0.11 (89% reduction)
Adherence to oral PrEP	Poor and declining (most below two doses/week by week 52)	Better (62% high adherence at week 52)
Key adverse event	Injection-site nodules (~64%)	Injection-site nodules (~63%), injection-site-reaction discontinuation 1.2%
Breakthrough N74D capsid resistance	None	Both breakthroughs developed capsid N74D

Two findings stand out. First, adherence is the central public-health finding of Purpose 1: in adolescent girls and young women in sub-Saharan Africa, daily oral PrEP, even with TAF, did not reduce acquisition versus background incidence because adherence was too low, and a twice-yearly injection bypasses the problem entirely.

Second, resistance is the central pharmacological finding of Purpose 2: both breakthroughs occurred while plasma lenacapavir was within the pharmacokinetic range, and both rapidly selected the N74D capsid mutation. Anyone seroconverting on lenacapavir PrEP must be assumed to have acquired infection during exposure, resistance genotyping must include the capsid region, and capsid inhibitors should not be used in the subsequent treatment regimen.

PEP (Post-Exposure Prophylaxis)

Post-exposure prophylaxis (PEP) is a 28-day course of triple antiretroviral therapy given after a discrete high-risk exposure, working on the principle that early, brief, full-dose ART can prevent established infection if started during the eclipse phase. Timing is decisive: start as soon as possible, and within 72 hours, beyond which biological efficacy is presumed lost; begin empirically without waiting for the source’s result, and stop only if the source proves HIV-negative.

Indications span occupational percutaneous injury, mucocutaneous exposure, non-occupational sexual exposure including sexual assault, and shared injecting equipment; per-act transmission risk is roughly ~0.3% for a percutaneous needlestick and ~1.4% for receptive anal intercourse, lower for other routes.

The workup covers source-patient testing where possible, baseline HIV, HBsAg and hepatitis C virus (HCV) antibody in the exposed person, a pregnancy test, and the sexual-assault forensic and emergency-contraception package where relevant; hepatitis B PEP (hepatitis B immunoglobulin, HBIG, plus accelerated vaccination) is considered separately if the source is HBsAg-positive and the exposed person is not immune.

Follow-up HIV testing is at 6 weeks and 3 months, with 6-month testing reserved for HCV-coinfected sources. The main driver of PEP failure is an incomplete course, so adherence counselling, barrier contraception and mental-health support (particularly after sexual assault) matter.

New drug development

HIV remains the most pharmacologically active area in clinical virology, and the principles its drug development teaches generalise. The pipeline is moving toward longer-acting, less-frequently-dosed agents (capsid and maturation inhibitors, long-acting NRTIs such as islatravir), broader genetic barriers in the integrase class (bictegravir already available internationally), and broadly neutralising antibodies for both prevention and cure. Long-acting injectables, by turning adherence from a daily-tablet problem into a clinic-visit problem, are reshaping not just HIV but the wider antiviral field.

South African context

South Africa runs one of the largest ART programmes in the world, and its public-sector practice has several distinctive features.

First-line regimen. The standard adult first line is the once-daily fixed-dose combination of tenofovir disoproxil, lamivudine and dolutegravir, TLD, used from 30 kg and 10 years including in pregnancy and breastfeeding where renal function is adequate (eGFR above 50). The historical efavirenz-based TEE regimen (TDF/FTC/EFV) has been phased out, with viral-load-independent transition to TLD. Efavirenz is retained transitionally only for patients already suppressed on it who start rifampicin. Practice now uses TLD 1 / TLD 2 / TLD 3 in place of “first / second / third line”: TLD 1 has never failed a dolutegravir-based regimen, TLD 2 is on TLD after an earlier failure (typically TEE), and TLD 3 is an individualised salvage regimen approved through the ARV Drug Resistance Committee (ADReC). Tenofovir can be recycled into TLD 2, because the M184V mutation that accompanies failure reduces viral fitness and modestly increases tenofovir susceptibility.

Paediatrics. The preferred regimen is ALD (abacavir, lamivudine, dolutegravir) from 2 kg and 37 weeks until about 30 kg or nine years, with a dispersible pALD formulation extending dolutegravir to neonates (the 10 mg dispersible tablet is not bioequivalent to the film-coated form; the dispersible 30 mg matches a 50 mg film-coated tablet). Preterm neonates below 2 kg receive AZT, lamivudine and nevirapine.

Agent positioning and access. TAF is reserved for HBV co-infection with reduced renal function. Atazanavir/r is the preferred second-line protease inhibitor, having displaced LPV/r; darunavir/r is accessed through ADReC for third line. The programme is built on the Department of Health Essential Medicines List: TLD, ALD, dispersible paediatric dolutegravir, atazanavir/r, LPV/r and the legacy NRTIs are EDL items dispensed through facility pharmacy, while agents not on the EDL (darunavir/r, raltegravir, TAF, cabotegravir-LA, lenacapavir, maraviroc, enfuvirtide) are accessed case-by-case through ADReC. Because the HLA-B*5701 allele is rare in Black African populations (under ~1%), routine HLA-B*5701 screening before abacavir is not part of public-sector practice, though it is recommended internationally in patients of non-African descent.

Reflex dolutegravir drug-level testing. A distinctive recent development is reflex drug-level testing as a gatekeeper before resistance genotyping. When the criteria for a drug-resistance test are met (in essence two consecutive viral loads at or above 1,000 copies/mL after nine months on dolutegravir with documented adherence intervention), the laboratory first measures a dolutegravir level on the specimen. If dolutegravir is undetectable, no genotype is performed: the result is treated as non-adherence and the patient returns to enhanced adherence counselling. Only when the level is detectable does the laboratory proceed to the full resistance test (reverse transcriptase, protease and integrase). The rationale is operational, since resistance testing is expensive and uninformative in the non-adherent, but it has changed how virological failure is investigated.

Prevention. Daily oral tenofovir/FTC PrEP is available through public-sector PrEP clinics; the dapivirine ring and long-acting cabotegravir are being introduced, and lenacapavir is not yet routine, with South African Health Products Regulatory Authority (SAHPRA) review anticipated. The capsid-resistance assay needed after a lenacapavir-PrEP seroconversion is not yet routine in South African virology laboratories. The PEP regimen is TLD, which has displaced the older, poorly tolerated AZT/3TC/lopinavir regimens. Lenacapavir PrEP access will move quickly as guidelines, formularies, generic competition and Sunlenca licensing evolve.

References and recommended reading

• National Department of Health, South Africa. National Consolidated Guidelines for the Prevention and Management of HIV in Adults, Adolescents, Children, Infants and Pregnant and Breastfeeding Women. 2026. The primary source for South African ART regimens, monitoring, special populations, the reflex dolutegravir drug-level testing workflow and the EDL/ADReC framework.
• Southern African HIV Clinicians Society. Adult Antiretroviral Therapy Guidelines, 2023 Update. Clinician-society guidance with broader pharmacological depth; a useful contrast on TAF positioning, the preferred protease inhibitor, and routine baseline viral load.
• Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology, 4th edition (Antiretroviral agents, Chapter 11). ASM Press; 2016. The textbook source for class mechanism, pharmacology and the principles of antiviral drug development; it predates cabotegravir-LA, lenacapavir, the resolution of the dolutegravir neural-tube-defect signal and the TLD rollout.
• Bekker L-G, Das M, Abdool Karim Q, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med 2024;391:1179 to 1192. The Purpose 1 trial.
• Kelley CF, Acevedo-Quiñones M, Agwu AL, et al. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. N Engl J Med 2025;392:1261 to 1276. The Purpose 2 trial.