What are the current Indian National AIDS Control Organisation recommendations for first‑line and second‑line antiretroviral therapy in treatment‑naïve HIV‑positive adults, including the preferred regimen, alternatives for renal impairment, monitoring schedule, treatment‑failure criteria, and special considerations for tuberculosis co‑infection and pregnancy?

Antiretroviral Therapy Guidelines in India

First-Line Regimen for Treatment-Naïve Adults

The National AIDS Control Organisation (NACO) of India recommends tenofovir disoproxil fumarate (TDF) 300 mg + lamivudine (3TC) 300 mg + dolutegravir (DTG) 50 mg as a fixed-dose combination, administered once daily, as the preferred first-line regimen for all treatment-naïve HIV-positive adults. 1, 2, 3

Rationale for DTG-Based Regimen

• DTG-based regimens achieve virological suppression (HIV RNA <1,000 copies/mL) in >99% of patients at 6 months, demonstrating superior efficacy compared to older NNRTI-based regimens. 2
• DTG has a high genetic barrier to resistance, reducing the risk of treatment failure even with suboptimal adherence. 1, 3
• At 24 weeks, 86.8% of Indian patients achieved HIV RNA <50 copies/mL on DTG + TDF/3TC, with mean CD4 count increases of 143 cells/µL from baseline. 3

Alternative First-Line Regimen (When DTG Unavailable)

• TDF 300 mg + 3TC 300 mg + efavirenz (EFV) 600 mg once daily was the previous standard first-line regimen and remains an acceptable alternative when DTG is contraindicated or unavailable. 1, 4
• EFV 400 mg (reduced dose) combined with TDF/3TC maintains virological suppression in >97% of patients who switch from EFV 600 mg, with lower rates of neuropsychiatric adverse events. 4

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Special Populations and Modifications

Renal Impairment

• Avoid TDF or adjust the dose when creatinine clearance is <60 mL/min to prevent nephrotoxicity; consider switching to tenofovir alafenamide (TAF) if available, though TAF is not yet widely accessible in the Indian public health system. 1, 5
• Monitor estimated glomerular filtration rate (eGFR), urinalysis, glycosuria, and proteinuria at baseline, after any regimen change, and every 6 months once HIV RNA is stable. 5

Tuberculosis Co-Infection

• For patients receiving rifampin-based TB therapy, use DTG 50 mg twice daily (not once daily) + TDF/3TC, as rifampin reduces DTG levels by approximately 50%. 5, 1
• Alternative for TB co-infection: EFV 600 mg + TDF/3TC once daily, which has fewer drug-drug interactions with rifampin. 1, 5
• Initiate ART within 2 weeks of starting TB treatment in patients with CD4 <50 cells/µL to reduce mortality. 5
• In patients with CD4 ≥50 cells/µL, start ART within 2–8 weeks of TB treatment initiation to balance efficacy with immune reconstitution inflammatory syndrome (IRIS) risk. 5
• Delay ART for 4–6 weeks in cryptococcal meningitis after beginning antifungal therapy to minimize severe IRIS. 5

Pregnancy

• DTG + TDF/3TC is the preferred regimen during pregnancy for maternal health and prevention of vertical transmission. 5, 1
• If a protease inhibitor is required, use darunavir 600 mg + ritonavir 100 mg twice daily (once-daily dosing is insufficient during pregnancy). 5
• Initiate ART immediately in all pregnant individuals, regardless of CD4 count or viral load. 5

Hepatitis B Co-Infection

• All regimens must include TDF (or TAF if available) plus 3TC or emtricitabine (FTC) to provide dual activity against HIV and HBV. 5, 1
• Do not discontinue lamivudine or tenofovir abruptly, as this can precipitate HBV flares. 5

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Baseline Testing and Monitoring Schedule

Required Baseline Tests (Do Not Delay ART While Awaiting Results)

• HIV-1 RNA viral load, CD4 count, genotypic resistance testing (reverse transcriptase, protease, integrase), HLA-B*5701 (only if abacavir is being considered), hepatitis A/B/C serology, complete blood count, comprehensive metabolic panel, fasting lipid profile, glucose, pregnancy test (if applicable), and urinalysis for glucose and protein. 6, 1, 7
• HLA-B*5701 testing is mandatory only if abacavir is planned; otherwise, start ART on the day of diagnosis. 6

Monitoring Schedule After ART Initiation

• HIV RNA viral load at 4–6 weeks after starting ART, then every 3 months until <50 copies/mL for 1 year, then every 6 months as long as suppression is maintained. 1, 7
• CD4 count every 6 months until >250 cells/µL for 1 year with viral suppression, then monitoring can be discontinued if CD4 >500 cells/µL for 2 years. 6, 7
• Renal function (eGFR, urinalysis) and hepatic function (ALT, AST) every 6 months for patients on TDF or DTG. 1, 3

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Treatment Failure Criteria and Second-Line Regimens

Virological Failure Definition

• Confirmed HIV RNA >1,000 copies/mL on two consecutive measurements at least 4 weeks apart, despite adherence counseling. 1, 2

Second-Line Regimen After NNRTI-Based First-Line Failure

• Switch to DTG + two active NRTIs (preferably TDF/3TC if not used in first-line, or zidovudine/lamivudine if TDF was used). 1
• DTG-based second-line regimens are superior to boosted protease inhibitor regimens in patients failing NNRTI-based first-line therapy. 1

Second-Line Regimen After InSTI-Based First-Line Failure

• Switch to boosted darunavir/ritonavir (600/100 mg twice daily) + two active NRTIs guided by resistance testing. 1, 5
• Perform genotypic resistance testing before switching to identify active agents. 1

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Common Adverse Events and Management

DTG-Related Adverse Events

• Headache (18%), pyrexia (14%), vomiting (6.4%), and upper respiratory tract infections (6%) are the most common adverse events. 3
• Neuropsychiatric symptoms (insomnia, depression) occur in <5% of patients and usually resolve within 4–8 weeks. 3
• Hepatotoxicity (3.2%) and cutaneous reactions (2.4%) may require temporary discontinuation; in 93% of cases, DTG can be safely reintroduced. 2

TDF-Related Adverse Events

• Nephrotoxicity (proximal renal tubular dysfunction) and decreased bone mineral density are the primary concerns. 5, 2
• One patient (0.4%) required permanent discontinuation due to TDF-induced nephrotoxicity in a cohort of 249 Indian patients. 2

EFV-Related Adverse Events

• Neuropsychiatric adverse events (dizziness, vivid dreams, depression, suicidality) occur in 10–20% of patients on EFV 600 mg. 4, 8
• Reducing EFV dose to 400 mg decreases neuropsychiatric adverse events while maintaining virological efficacy. 4

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Opportunistic Infection Prophylaxis

Pneumocystis Pneumonia (PCP) Prophylaxis

• Initiate trimethoprim-sulfamethoxazole (TMP-SMX) 960 mg daily (or 480 mg daily if 960 mg not tolerated) when CD4 <200 cells/µL, and continue until CD4 rises above 200 cells/µL for at least 3 consecutive months. 6

Mycobacterium Avium Complex (MAC) Prophylaxis

• Primary MAC prophylaxis is not recommended when effective ART is started promptly, as early ART reduces MAC incidence sufficiently. 6

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Key Pitfalls to Avoid

• Do not delay ART initiation while awaiting baseline laboratory results (except HLA-B*5701 if abacavir is planned); start treatment on the day of diagnosis. 6
• Do not use DTG once daily in patients receiving rifampin; increase to 50 mg twice daily or switch to EFV-based regimen. 5, 1
• Do not prescribe TDF to patients with creatinine clearance <60 mL/min without dose adjustment, as this leads to avoidable nephrotoxicity. 5, 1
• Do not switch regimens based solely on low CD4/CD8 ratio when viral suppression is maintained; this parameter does not guide treatment decisions. 7
• Confirm virological failure with repeat testing and reinforce adherence counseling before switching regimens, as poor adherence is the most common cause of detectable viral load. 1