Antiretrovirals — Questions

Long-acting antiretroviral PrEP (pre-exposure prophylaxis) delivers inhibitory drug concentrations for weeks to months from a single administration, converting adherence from a daily-tablet problem into a clinic-visit problem.

Available agents:

• Long-acting injectable cabotegravir (CAB-LA): an integrase strand-transfer inhibitor formulated as a nanosuspension; given by intramuscular injection at month 0 and month 1 (the loading doses), then every 8 weeks. HPTN 083 (men who have sex with men, transgender women) and HPTN 084 (cisgender women in sub-Saharan Africa) showed superiority to daily oral TDF/FTC (tenofovir disoproxil fumarate/emtricitabine).
• Dapivirine vaginal ring: a monthly silicone ring delivering a non-nucleoside reverse transcriptase inhibitor (NNRTI) locally to the vaginal mucosa; modest (~30%) efficacy.
• Lenacapavir: first-in-class capsid inhibitor; two subcutaneous abdominal injections every 26 weeks, with brief oral loading. Purpose 1 and Purpose 2 showed near-complete prevention.

Key practical considerations:

• Confirm HIV-negative status before each administration. A single sub-therapeutic antiretroviral can select resistant virus if given during unrecognised acute infection.
• Oral lead-in. A brief oral course of the active drug before the first injection confirms tolerability before committing to a long-acting agent.
• Injection-site reactions occur in around 60% with both CAB-LA and lenacapavir; usually self-limiting nodules, rarely causing discontinuation.
• Pharmacokinetic (PK) tail. Prolonged sub-therapeutic concentrations follow the last dose; exposure during this tail may fail to prevent infection yet still select resistance. Counsel on cessation, bridging with oral PrEP if risk continues.
• Breakthrough infection and resistance. Purpose 2 demonstrated capsid N74D in both breakthroughs; HPTN 083/084 demonstrated integrase resistance in CAB-LA-exposed seroconverters. Resistance genotyping must include the relevant region (capsid for lenacapavir; integrase for cabotegravir).
• LEVI syndrome: delayed and blunted seroconversion under long-acting PrEP that fails to prevent infection.
• Programmatic implementation. Cold-chain logistics, trained injectors, reliable patient recall systems and supply security determine whether long-acting PrEP succeeds at scale.
• Cost and access. Lenacapavir in particular is currently expensive; access is the live policy issue in South Africa and globally.

The dapivirine vaginal ring is a flexible silicone ring containing 25 mg of dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). Worn continuously for one month then replaced, it gives slow, sustained local release at the cervicovaginal mucosa.

Evidence base. Two large randomised trials, ASPIRE (MTN-020) and The Ring Study (IPM-027), tested the ring in over 4,500 sub-Saharan African women and showed an approximately 27 to 31% reduction in HIV acquisition compared with placebo. Efficacy was clearly adherence-dependent: the most consistent users achieved a reduction of over 50%, while efficacy was lower in younger women whose adherence was typically poorer. The open-label extensions HOPE and DREAM showed greater real-world reductions, likely reflecting selection of more motivated users.

Regulatory status. The World Health Organization in 2021 recommended the dapivirine ring as a prevention option for women at substantial risk of HIV who are unable or unwilling to use oral pre-exposure prophylaxis (PrEP). Several countries, including South Africa, have approved it.

Strengths:

• Women-controlled: inserted and managed privately, valuable where partner dynamics constrain consistent pill-taking.
• Local delivery: minimal systemic exposure, no significant drug interactions, no renal monitoring.
• Long-acting: monthly replacement, no daily-pill burden.
• Continuous protection: no need to anticipate exposures.
• Acceptable to most trial participants.

Limitations:

• Modest efficacy compared with newer long-acting agents: around 30% in trials versus 96 to 100% with lenacapavir and superior efficacy with cabotegravir.
• HIV-1 only: HIV-2 is intrinsically resistant to NNRTIs.
• Only for women.
• Provides no contraceptive effect: dual prevention requires an additional method.
• Insertion technique and acceptability vary; some women find the device uncomfortable or culturally unacceptable.
• Public-sector uptake has been limited globally.

Place in current practice. The ring is a niche tool, for women who reject or cannot reliably take daily oral PrEP and cannot access long-acting injectables. Long-acting cabotegravir (CAB-LA) and lenacapavir have reduced its prominence, but its user-control and minimal systemic profile retain value in specific contexts.

Pre-exposure prophylaxis (PrEP) is antiretroviral medication taken by HIV-negative people at substantial risk, to prevent acquisition. It is a cornerstone of biomedical HIV prevention.

Principle. Maintain inhibitory drug concentrations at exposure sites so encountered virus cannot establish productive infection. iPrEx, CAPRISA 004, Partners PrEP and TDF2 showed daily oral tenofovir/emtricitabine reduces acquisition in proportion to adherence (~70% with consistent use, over 90% with detectable drug levels).

Available agents:

• Daily oral TDF/FTC (tenofovir disoproxil fumarate/emtricitabine): the workhorse of public-sector PrEP globally; available through dedicated PrEP clinics in South Africa.
• Event-driven oral PrEP (2-1-1): TDF/FTC dosed before and after sexual contact, suitable for men who have sex with men with predictable, infrequent exposures.
• Dapivirine vaginal ring: a women-controlled monthly silicone ring; ~30% efficacy in trials.
• Long-acting cabotegravir (CAB-LA): intramuscular injection every two months after a loading dose; superior to daily oral PrEP in HPTN 083 and 084.
• Twice-yearly subcutaneous lenacapavir: the most efficacious PrEP agent yet studied; near-complete prevention in Purpose 1 (cisgender women, 100%) and Purpose 2 (men and gender-diverse people, 96%).

Target populations. Those at substantial risk of HIV acquisition: sex workers, men who have sex with men, transgender people, serodiscordant couples (until the partner is virally suppressed), adolescent girls and young women in high-prevalence settings, and people who inject drugs.

Considerations before initiation. Confirm HIV-negative status (and re-test at each visit); baseline renal function (for TDF-based PrEP); hepatitis B surface antigen (HBsAg, for ongoing tenofovir coverage); pregnancy is not a contraindication. Counsel on the requirement for adherence and on safer-sex practice during the start-up period.

Synergy with treatment as prevention. PrEP complements rather than replaces antiretroviral therapy (ART) for the HIV-positive partner. A virally suppressed partner does not transmit (undetectable equals untransmittable, U=U); PrEP protects against exposures from people not on suppressive ART.

Limitations and emerging issues. Adherence is the main challenge for oral PrEP, particularly in adolescent girls and young women. Long-acting agents address adherence but introduce specific issues: injection-site reactions, pharmacokinetic-tail resistance risk if discontinued, and the long-acting early viral inhibition (LEVI) phenomenon. Drug-resistance selection is rare on PrEP but possible if started during unrecognised acute infection. Access to the newest agents, lenacapavir in particular, is currently constrained by cost and supply.

Concern over dolutegravir (DTG) in pregnancy arose from a safety signal that attenuated as the data matured.

The 2018 Tsepamo signal. In May 2018 the Tsepamo birth-outcomes surveillance in Botswana reported an apparent excess of neural-tube defects (NTDs) in women on dolutegravir at conception: ~0.94% in DTG-exposed pregnancies versus ~0.12% in the unexposed (4 NTDs in 426 DTG-exposed births).

The initial response. The World Health Organization (WHO) issued interim guidance cautioning against DTG in women of child-bearing potential without effective contraception. National programmes, including South Africa’s, adjusted recommendations accordingly. Women of child-bearing potential who could not commit to reliable contraception were considered for non-DTG regimens during the period of uncertainty.

Subsequent evolution. As the cohort accrued more women and longer follow-up, the NTD signal attenuated. By the early 2020s the DTG-exposed NTD prevalence had fallen to ~0.19% versus ~0.11% in the unexposed, no longer statistically significant, and corroborated by independent data. It is now considered most likely a chance finding inflated by ascertainment bias in the small early dataset.

Current recommendations:

• DTG is the first-line antiretroviral throughout pregnancy and in women of child-bearing potential, without restriction.
• Effective contraception is no longer required specifically for NTD concerns (general prevention of mother-to-child transmission (PMTCT) and reproductive-health principles still apply).
• Conception on a DTG-containing regimen is supported as safe.
• Routine pre-conception folate intake (5 mg daily in resource-rich settings, or as locally available) remains recommended, in line with general pre-conception care.

Significance. The episode carried a real cost: women may have been switched to less effective or less tolerated regimens during the uncertain period, illustrating the limits of early signal detection in small cohorts and the value of prospective birth-outcomes surveillance.

Why DTG is preferred. Its high genetic barrier, rapid viral-load reduction and good tolerability make it the regimen of choice in women of child-bearing potential. Vertical transmission on maternal DTG-based regimens is at or below WHO elimination thresholds once maternal suppression is achieved.

Lenacapavir is the first approved member of a new antiretroviral class, the capsid inhibitors.

Mechanism. Lenacapavir binds multiple sites on the HIV-1 capsid hexamer interface, disrupting capsid function at three stages of replication:

• Early post-entry: interferes with uncoating, reverse transcription and nuclear import of the pre-integration complex.
• Capsid stability: alters uncoating kinetics, exposing the genome prematurely or in the wrong cellular location.
• Late assembly: disrupts capsid lattice assembly during virion morphogenesis, producing immature, non-infectious particles.

This multi-step mechanism underlies its very high potency (picomolar half-maximal inhibitory concentration, IC₅₀) and high genetic barrier, since multiple, often costly, mutations are required to escape.

Long-acting early viral inhibition (LEVI) syndrome describes the atypical clinical-laboratory picture that occurs when HIV is acquired despite long-acting antiretroviral PrEP, when the PrEP agent partially suppresses but does not abolish very early viral replication. The PrEP fails to prevent infection but profoundly distorts the early course of infection.

Mechanism. Inhibitory concentrations of a long-acting agent at the moment of acquisition suppress (without eradicating) the first rounds of viral replication. The infection establishes, but the viraemia is blunted and intermittent and the host humoral response is delayed and weakened in step with reduced antigenic stimulus.

Diagnostic implications:

• Antibody assays (including fourth-generation Ag/Ab combos) may be negative or only weakly reactive for weeks to months, well beyond the usual 2 to 4 week diagnostic window.
• HIV RNA is often detectable, but at very low levels, sometimes intermittently positive and negative on serial testing.
• Fiebig staging is distorted; patients may sit in early Fiebig stages for prolonged periods.
• Risk of missed or delayed diagnosis: a person continuing PrEP with intermittent low-level viraemia may be mistaken for an adherent PrEP user with assay noise. Routine 4th-gen testing for breakthrough monitoring is inadequate.
• Risk of drug-resistance selection: sub-therapeutic exposure to a single antiretroviral (ARV) class for weeks drives selection of resistance mutations (capsid N74D for lenacapavir; integrase mutations for cabotegravir).

Management implications:

• High suspicion in any long-acting PrEP user with seroconversion-like symptoms or any positive HIV nucleic-acid test, however low.
• Confirm by HIV RNA / nucleic-acid amplification test (NAAT) rather than relying on serology.
• Switch to a treatment regimen that avoids the implicated PrEP-agent class.
• Resistance genotyping including the relevant region (capsid for lenacapavir; integrase for cabotegravir).
• Specialist consultation: LEVI is an emerging clinical pattern requiring centralised expertise.

Progression implications. The natural history under LEVI is not fully characterised. Reservoir seeding and chronic infection still occur, but at a different rhythm. Long-term virological and immunological outcomes are an active area of study.

Dolutegravir (DTG) is a second-generation integrase strand-transfer inhibitor that has become the anchor of first-line antiretroviral therapy (ART) worldwide and the keystone of the South African ART programme.

Class and mechanism. DTG is an integrase strand-transfer inhibitor (INSTI). It binds the integrase active site and blocks the strand-transfer step that inserts proviral DNA into host chromatin; without integration, productive infection cannot proceed.

Pharmacology:

• Standard adult dose: 50 mg once daily, orally.
• Bioavailable with or without food (food slightly delays absorption without impairing efficacy).
• Metabolism via UGT1A1 (major) and CYP3A4 (minor); minimal renal elimination.
• Plasma half-life around 14 hours, supporting once-daily dosing.
• High genetic barrier: the R263K resistance mutation arises rarely and carries a measurable fitness cost.

Key interactions:

• Rifampicin (a strong UGT1A1/CYP3A4 inducer): add a second 50 mg tablet twelve hours after the TLD dose, until two weeks past rifampicin.
• Polyvalent cations (Ca²⁺, Fe²⁺, Mg²⁺, Al³⁺) chelate DTG in the gut; time antacids at least six hours before or two hours after DTG, though calcium and iron with food can be co-administered.
• Enzyme-inducing anticonvulsants (carbamazepine, phenytoin, phenobarbital) also need dose doubling; valproate, lamotrigine or levetiracetam are preferred.
• Metformin: DTG raises its levels; cap metformin (typically 2 g/day).

Adverse effects:

• Common but mild: insomnia, headache, mild gastrointestinal (GI) upset.
• Creatinine artefact: DTG inhibits tubular creatinine secretion (OCT2/MATE1) without affecting true glomerular filtration rate (GFR). A rise of up to about 30 µmol/L in the first weeks is benign; investigate only larger or later rises.
• Weight gain, well-recognised, but now understood as unmasking of weight previously suppressed by HIV and efavirenz (EFV); DTG should not be switched off for weight gain alone.
• Pregnancy and women of child-bearing potential: the 2018 Tsepamo neural-tube-defect signal has not been confirmed in mature data; DTG is used without restriction in pregnancy, breastfeeding and safe conception.
• Rare hepatitis and hypersensitivity.

Role in the South African ART programme. Dolutegravir was rolled out as the anchor of the TLD (tenofovir / lamivudine / dolutegravir) fixed-dose combination from 2019 to 2020, replacing the efavirenz-based TEE regimen. TLD is now the first-line regimen for adults and adolescents from 30 kg and 10 years, including in pregnancy. The paediatric equivalent ALD (abacavir / lamivudine / dolutegravir) and the dispersible pALD formulation extend the regimen down to neonates of 2 kg and 37 weeks’ gestational age. DTG sits on the public-sector Essential Medicines List and is delivered through routine facility pharmacy without specialist authorisation.

Resistance. DTG monotherapy or low-adherence dolutegravir-based therapy occasionally selects the R263K mutation (low-level resistance, fitness cost) or, with prior INSTI exposure, the Q148H pathway (higher-level resistance). Recent South African practice introduces reflex DTG drug-level testing as a gatekeeper before resistance genotyping in patients meeting virological failure criteria: undetectable DTG implies adherence failure rather than true resistance.

South African post-exposure prophylaxis (PEP) is a 28-day course of TLD, started as soon as possible after exposure with an upper limit of 72 hours.

Begin empirically (the source’s HIV result is not required before starting) and stop only if the source proves HIV-negative on confirmed testing. A single tenofovir dose, cabotegravir injections, a seven-day triple-dose course, and withholding PEP on the basis of hepatitis B vaccination are all wrong. Baseline HIV, hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (anti-HCV) testing of the exposed person is part of the workup; consider separately the need for hepatitis B virus (HBV) PEP (hepatitis B immunoglobulin plus accelerated vaccination) if the source is HBsAg-positive and the exposed person is not immune.

M184V confers high-level resistance to lamivudine and emtricitabine while reducing replicative fitness and re-sensitising the virus to zidovudine; it also modestly increases tenofovir susceptibility.

It does not affect dolutegravir, spares neither lamivudine nor emtricitabine, and does not abolish the whole nucleoside reverse transcriptase inhibitor (NRTI) class. This is why lamivudine is recycled into second-line regimens: the residual selective pressure on M184V helps suppress the virus and preserves NRTI activity in the backbone.

Vivid dreams, depression, dizziness and mood changes are typical central nervous system (CNS) effects of efavirenz, most marked in the first weeks and usually improving thereafter.

They are not encephalopathy demanding immediate cessation, virological failure, nucleoside-analogue mitochondrial toxicity or a rifampicin interaction. Take at night to mitigate; severe psychosis or persistent severe mood disturbance warrants switching.

Simvastatin (and lovastatin) are heavily CYP3A4-metabolised, so boosted protease inhibitors (PIs) raise their concentrations to a level that risks rhabdomyolysis, making them contraindicated.

Atorvastatin may be used at low dose, and pravastatin, fluvastatin and rosuvastatin are the safer choices.

Atazanavir inhibits UGT1A1, producing a benign indirect (unconjugated) hyperbilirubinaemia occasionally visible as scleral icterus or jaundice.

Normal aminotransferases exclude drug-induced hepatitis; the picture is not obstructive cholestasis, haemolysis or sepsis-related cholestasis. It is a cosmetic effect, not liver injury, does not require discontinuation, and is sometimes used as a marker of adherence.

Polyvalent cations (calcium, aluminium, magnesium, iron) chelate dolutegravir in the gut, so the antacid must be separated by at least six hours before or two hours after the dose.

Stopping, dose-doubling, co-administering or switching to a proton-pump inhibitor are all wrong: proton-pump inhibitors do not address the chelation, and calcium or iron taken with food may be co-administered.

Seroconversion on lenacapavir pre-exposure prophylaxis (PrEP) mandates resistance genotyping that includes the capsid region, since breakthrough virus selects the capsid N74D signature (M66I and Q67H are also reported).

Standard reverse-transcriptase, protease or integrase genotyping alone would miss the relevant resistance, and deferring or omitting testing is inappropriate; the capsid assay is not yet routine in South African virology laboratories, and capsid inhibitors should be avoided in the subsequent regimen.

Rifampicin induces UGT1A1 and CYP3A4 and substantially reduces dolutegravir exposure, so dolutegravir is doubled with a supplementary 50 mg tablet twelve hours after the TLD dose.

The supplementary dose continues until two weeks past the rifampicin so that enzyme induction has waned. Leaving TLD unchanged underdoses dolutegravir, while switching to a protease inhibitor, halving the dose or stopping antiretrovirals are all inappropriate.

Dolutegravir inhibits tubular secretion of creatinine via OCT2 and MATE1 without altering true glomerular filtration rate (GFR), so a rise of up to about 30 µmol/L in the first weeks is expected and benign.

This asymptomatic early rise is neither acute tubular necrosis, pre-renal injury, tenofovir-induced Fanconi syndrome nor HIV-associated nephropathy. Investigate only larger rises, those occurring later, or those accompanied by tubular wasting, proteinuria or symptoms.

Boosted protease inhibitors reduce the efficacy of hormonal contraception, so dual contraception is advised, with an intrauterine device a favoured option.

The interaction lowers contraceptive hormone levels rather than raising protease-inhibitor levels or causing hyperkalaemia, and separating the dosing times does not overcome it.

Proton-pump inhibitors suppress gastric acid enough to drop atazanavir levels below therapeutic, so they are contraindicated.

Atazanavir is absorbed only in an acidic stomach and must be taken with food; H2-receptor blockers and antacids need careful temporal separation. Loperamide, metformin, paracetamol and amoxicillin carry no comparable interaction.

Dolutegravir binds the active site of integrase and blocks the strand-transfer step that splices proviral DNA into host chromatin, so without integration the provirus cannot be transcribed.

It does not act on reverse transcription, protease-mediated maturation, capsid uncoating or co-receptor-mediated fusion. Dolutegravir (DTG) has a high genetic barrier: R263K arises rarely and carries a fitness cost.

Protease inhibitors block cleavage of the Gag and Gag-Pol polyproteins, so the structural proteins stay uncleaved and the resulting virions are non-infectious.

They act at maturation, not at reverse transcription, integration, uncoating or fusion. All protease inhibitors (PIs) in clinical use require pharmacoenhancement with low-dose ritonavir (the “/r” suffix) or cobicistat.

Purpose 2 showed a large reduction in HIV acquisition, about 96% versus background incidence and about 89% versus daily F/TDF (emtricitabine/tenofovir disoproxil fumarate).

Across 3,265 participants in the US, Brazil, Thailand, South Africa, Peru, Argentina and Mexico, there were 2 infections in the 2,179-participant lenacapavir arm, both developing the capsid N74D resistance mutation. The trial was neither futile nor placebo-equivalent, and incidence was lower, not higher, on lenacapavir.

In South African practice, tenofovir disoproxil fumarate (TDF) is avoided once the estimated glomerular filtration rate (eGFR) falls below 50 mL/min/1.73 m².

TDF is renally cleared and causes proximal tubular injury and reduced bone mineral density. The usual substitute is abacavir; TAF/FTC (tenofovir alafenamide/emtricitabine) is reserved for hepatitis B virus (HBV) co-infection with reduced renal function.

Abacavir hypersensitivity is strongly linked to the HLA-B*5701 allele, presenting within the first six weeks with fever, rash, gastrointestinal, respiratory and constitutional symptoms.

Re-challenge after a recognised reaction is contraindicated and can be fatal. It is not Stevens-Johnson syndrome (linked instead to HLA-B*15:02), drug-induced lupus, first-dose anaphylaxis or interstitial nephritis. The allele is rare in Black African populations (under 1%), so routine HLA-B*5701 screening is not part of South African public-sector practice.

Purpose 1 recorded 0 infections among 2,134 women in the lenacapavir arm, a 100% reduction versus background incidence and the highest pre-exposure prophylaxis (PrEP) efficacy yet recorded.

Among 5,338 women across South African and Ugandan sites, participants were randomised 2:2:1 to twice-yearly subcutaneous lenacapavir, daily F/TAF (emtricitabine/tenofovir alafenamide) or daily F/TDF (emtricitabine/tenofovir disoproxil fumarate). Efficacy was not modest, inferior or absent, and the trial was not halted for safety; it also illustrated the adherence problem with daily oral PrEP in this population.

TLD is the once-daily fixed-dose tablet of tenofovir disoproxil 300 mg, lamivudine 300 mg and dolutegravir 50 mg.

The paediatric equivalent ALD substitutes abacavir for tenofovir, and the older efavirenz-based regimen was TEE (tenofovir, emtricitabine, efavirenz); the lopinavir/ritonavir and darunavir/ritonavir options name protease inhibitors, not the current first-line third agent.

Nevirapine’s defining safety signals are hepatotoxicity and severe rash, the latter including Stevens-Johnson syndrome, both most likely in the first weeks of initiation.

Anaemia and neutropenia belong to zidovudine, renal tubular injury and Fanconi syndrome to tenofovir, mitochondrial neuropathy and lactic acidosis to the older nucleoside analogues, and central nervous system (CNS) effects to efavirenz. These signals moved South African practice away from nevirapine in adult initiation; residual uses are the preterm neonatal regimen and infant prophylaxis for HIV-exposed infants.

The non-nucleoside reverse transcriptase inhibitors have a low genetic barrier: a single mutation such as K103N confers high-level, often class-wide resistance, which is why they were displaced from first line.

Boosted protease inhibitors and second-generation integrase inhibitors (dolutegravir) have high barriers needing several stepwise mutations, and tenofovir resistance also requires accumulation.

Zidovudine is retained for the preterm neonatal regimen (AZT/3TC/NVP) and for renal failure with concurrent abacavir hypersensitivity (AZT/3TC/DTG).

It is not indicated by HIV-2 status, patient preference, routine needlestick prophylaxis or hepatitis B co-infection alone. Anaemia and neutropenia are the watchpoints (monitor full blood count during the first months); macrocytosis is expected and benign.