Q3 LONG ANSWER 10M ★ High-yield

Discuss antiretroviral therapy — classes of drugs, first-line regimens, adverse effects, monitoring and treatment failure.

General Medicine · Final Professional

Principles

Antiretroviral therapy (ART) uses a combination of at least three drugs from two or more classes to achieve durable suppression of viral replication. Combination therapy is essential because HIV has a high mutation rate and monotherapy inevitably selects resistance.

Goals of therapy:

1. Maximal and durable suppression of viral load to undetectable levels

2. Restoration and preservation of immune function (rising CD4 count)

3. Reduction of HIV-related morbidity and mortality, and prolongation of life

4. Prevention of transmission — sexual, vertical and parenteral (U = U: undetectable equals untransmittable)

Current policy is "test and treat" — ART for ALL people living with HIV, at any CD4 count, as soon as possible after diagnosis, with same-day initiation where feasible.

Classes of Antiretroviral Drugs

Class	Mechanism	Examples	Key adverse effects
NRTI (nucleoside/nucleotide reverse transcriptase inhibitors)	Chain termination of the growing DNA strand	Tenofovir (TDF/TAF), lamivudine (3TC), emtricitabine, abacavir, zidovudine	Lactic acidosis and mitochondrial toxicity (class effect); tenofovir — renal tubular dysfunction and reduced bone density; zidovudine — anaemia and myopathy; *abacavir — hypersensitivity (HLA-B5701)**
NNRTI (non-nucleoside)	Direct non-competitive binding to reverse transcriptase	Efavirenz, nevirapine, rilpivirine, doravirine	Efavirenz — CNS effects (vivid dreams, dizziness, depression); nevirapine — rash including SJS/TEN, and hepatotoxicity; low genetic barrier to resistance; no activity against HIV-2
INSTI (integrase strand transfer inhibitors)	Block integration of viral DNA into host genome	Dolutegravir, bictegravir, raltegravir	Best tolerated class; weight gain, insomnia, headache; high genetic barrier (dolutegravir, bictegravir)
PI (protease inhibitors)	Prevent cleavage of viral polyprotein → immature non-infectious virions	Ritonavir-boosted lopinavir, atazanavir, darunavir	Metabolic — dyslipidaemia, insulin resistance, lipodystrophy; gastrointestinal upset; numerous drug interactions via CYP3A4
Entry / fusion inhibitors	Block gp41 fusion or CCR5 co-receptor	Enfuvirtide, maraviroc	Injection site reactions; maraviroc requires tropism testing
Post-attachment / capsid inhibitors	Newer agents for multidrug-resistant disease	Ibalizumab, lenacapavir	Specialist use

First-line Regimen

The current preferred first-line regimen in India and internationally is two NRTIs plus an integrase inhibitor — in practice tenofovir + lamivudine + dolutegravir (the "TLD" fixed-dose combination), provided free through NACO's ART centres.

Why dolutegravir-based therapy displaced efavirenz: greater potency with rapid viral suppression, a high genetic barrier to resistance, better tolerability, fewer drug interactions, and availability as a single fixed-dose tablet once daily, which improves adherence.

Alternatives are used where dolutegravir or tenofovir is unsuitable — for example abacavir or zidovudine in renal impairment, and efavirenz- or protease inhibitor-based regimens in specific circumstances.

Special situations:

Tuberculosis co-infection: rifampicin induces metabolism of dolutegravir and protease inhibitors — dolutegravir dose frequency is increased, or rifabutin substituted. ATT is started first, with ART added after 2–8 weeks depending on CD4 count, and deferred longer in TB meningitis because of fatal IRIS risk.
Pregnancy: ART for all pregnant women; dolutegravir-based regimens are now recommended throughout pregnancy.
Hepatitis B co-infection: use a tenofovir plus lamivudine/emtricitabine backbone, which treats both viruses; never stop these abruptly because of the risk of hepatitis B flare.
Renal impairment: avoid or dose-adjust tenofovir disoproxil; TAF is less nephrotoxic.

Monitoring

Parameter	Purpose	Frequency
HIV viral load	The primary measure of treatment success — target undetectable (< 50 copies/mL) by 6 months	Baseline, 6 months, then 6–12 monthly
CD4 count	Immune recovery; guides prophylaxis	Baseline, then periodically until stable and suppressed
Adherence assessment	The strongest determinant of outcome	Every visit
Renal function, urinalysis	Tenofovir toxicity	Baseline and periodically
Liver function	Nevirapine, PI toxicity, viral hepatitis	Baseline and periodically
CBC	Zidovudine anaemia	Baseline and periodically
Fasting glucose and lipids	PI and INSTI metabolic effects	Baseline and annually
Weight and blood pressure	INSTI-associated weight gain, cardiovascular risk	Every visit

Adherence

Adherence above 95% is required for durable viral suppression — this is the central message to the patient and the commonest reason for failure. Barriers in the Indian context include stigma and non-disclosure, travel to ART centres, migration for work, alcohol use, pill burden, side effects, and treatment fatigue. Strategies: fixed-dose single-tablet regimens, counselling at every visit, treatment supporters, linkage to community groups, and tracking of missed appointments.

Treatment Failure

Type	Definition
Virological failure	Viral load > 1000 copies/mL on two consecutive measurements ≥ 3 months apart, with adherence support in between — the earliest and most sensitive indicator
Immunological failure	Failure of CD4 to rise, or fall to baseline or below, on therapy
Clinical failure	New or recurrent WHO stage 4 condition after 6 months of therapy

Approach to suspected failure — in order:

1. Assess adherence first — poor adherence, not resistance, is the commonest cause. A repeat viral load after intensive adherence counselling resolves many cases.

2. Review drug interactions, malabsorption, and dosing errors.

3. Genotypic resistance testing where available, to guide the switch.

4. Switch to a second-line regimen — conventionally two new NRTIs with a ritonavir-boosted protease inhibitor (or dolutegravir if not previously used); third-line regimens use darunavir with newer agents.

Never add a single drug to a failing regimen — this is functional monotherapy and rapidly selects further resistance.

Key Adverse Effects to Counsel About

Immune reconstitution inflammatory syndrome in the first weeks (see the separate answer).
Lipodystrophy — peripheral fat loss with central accumulation and buffalo hump (older agents, especially stavudine, now withdrawn).
Metabolic — dyslipidaemia, insulin resistance, and increased cardiovascular risk; weight gain with integrase inhibitors and TAF, an increasingly recognised problem.
Renal and bone toxicity with tenofovir disoproxil.
Hypersensitivity to abacavir — fever, rash, gastrointestinal and respiratory symptoms; never rechallenge, as re-exposure can be fatal; prevented by HLA-B*5701 screening.
Lactic acidosis and hepatic steatosis — a rare but life-threatening NRTI class effect.
Drug interactions — with rifampicin, antiepileptics, statins, antacids and calcium/iron (which chelate dolutegravir and must be separated in time), and hormonal contraceptives.

DANGER / REMEMBER

Never interrupt or stop ART casually — during admission, surgery, or when a patient is nil by mouth. Interruption allows viral rebound, immune decline and, with drugs of differing half-lives, selects resistance. If the oral route is unavailable, seek specialist advice for alternative formulations rather than simply omitting doses. Equally, never add one drug to a failing regimen.

NEEDS VERIFICATION

First-line and second-line regimens, dolutegravir dosing with rifampicin, and the viral load threshold defining failure — confirm against the current NACO national ART guidelines, which are revised periodically.

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