# HIV - Antiretroviral Therapy Principles

## Epidemiology and Virology

### Current State

Approximately 39 million people are living with HIV globally, with approximately 1.2 million in the United States. New diagnoses in the US have been declining to approximately 30,000 annually, with the Ending the HIV Epidemic initiative targeting a 90 percent reduction by 2030. Untreated HIV has a median progression time to AIDS of 8 to 10 years, with death occurring within 2 to 3 years of developing AIDS. With effective antiretroviral therapy, however, patients who achieve and maintain virologic suppression with adequate adherence now have near-normal life expectancy. The principle of U=U, Undetectable equals Untransmittable, represents one of the most consequential public health messages in HIV medicine, establishing that viral suppression below 200 copies per milliliter effectively eliminates sexual transmission risk.

### HIV Virology Relevant to ART

HIV-1 is the cause of the global pandemic, while HIV-2, largely confined to West Africa, is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors. The viral lifecycle provides multiple targets for antiretroviral intervention: attachment and entry are targeted by CCR5 antagonists, attachment inhibitors, and post-attachment inhibitors; fusion by enfuvirtide; reverse transcription by NRTIs and NNRTIs; integration by integrase strand transfer inhibitors; protease-mediated processing by protease inhibitors; and capsid assembly by the novel agent lenacapavir. The extraordinary viral replication rate of 10 to the ninth to 10 to the tenth virions per day, combined with the error-prone reverse transcriptase that lacks proofreading capability, generates a high mutation rate that inevitably drives resistance development without fully suppressive therapy. The latent reservoir, consisting of integrated proviral DNA within resting CD4-positive memory T cells, is established within days of infection and represents the fundamental barrier to HIV cure.

## When to Start ART

### Universal Treatment

The current standard of care is to treat all persons with HIV regardless of CD4 count, as endorsed by the DHHS, IAS-USA, and WHO guidelines. The evidence base for universal treatment was established by the START trial in 2015, which demonstrated a 57 percent reduction in serious AIDS and non-AIDS events with immediate ART at any CD4 count compared to deferring treatment until the CD4 count fell below 350. The TEMPRANO trial in 2015 reinforced these findings in a high-TB-burden setting, showing a 44 percent reduction in severe morbidity with early ART. Rapid ART initiation, defined as same-day or within seven days of diagnosis, improves linkage to care, sustained engagement, and time to viral suppression. The exceptions to immediate ART initiation are cryptococcal meningitis, where ART should be deferred four to six weeks to minimize the risk of immune reconstitution inflammatory syndrome, and TB meningitis, where ART should be deferred two to eight weeks.

## Antiretroviral Drug Classes

### NRTIs (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors)

NRTIs form the backbone of most ART regimens, typically used as a dual NRTI backbone combined with an anchor agent from another class. Tenofovir disoproxil fumarate (TDF) is associated with renal tubular toxicity including Fanconi syndrome and bone mineral density loss, requiring dose adjustment for renal impairment. Tenofovir alafenamide (TAF), a prodrug formulation, produces less renal and bone toxicity than TDF but is associated with higher lipid levels and is preferred in most clinical settings. Emtricitabine (FTC) is well-tolerated and has activity against hepatitis B virus, with a risk of HBV flare upon discontinuation. Abacavir (ABC) requires HLA-B*5701 testing before initiation, as 3 to 8 percent of the population carries this allele, and its presence absolutely contraindicates abacavir use due to the risk of a potentially fatal hypersensitivity reaction. Some studies have suggested an association between abacavir and cardiovascular risk, though this remains debated. Lamivudine (3TC) is similar to emtricitabine and interchangeable in most settings. The preferred NRTI backbone is TAF/FTC or TDF/FTC, with ABC/3TC as an alternative when the patient is HLA-B*5701 negative.

### NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)

NNRTIs bind non-competitively to reverse transcriptase at an allosteric site. Efavirenz causes CNS side effects including vivid dreams and dizziness, carries a teratogenicity concern though the actual risk is low, and has a low genetic barrier to resistance with a single K103N mutation conferring high-level resistance. Rilpivirine must be taken with a meal of at least 500 kilocalories, cannot be used when the viral load exceeds 100,000 or the CD4 count is below 200 due to higher rates of virologic failure, and is incompatible with proton pump inhibitors and requires spacing with H2 blockers. Doravirine is a newer NNRTI with fewer CNS effects, a favorable lipid profile, no food requirement, a higher genetic barrier than efavirenz or rilpivirine, and retained activity against the K103N mutation. As a class, NNRTIs have fallen from first-line status due to their lower genetic barrier compared to integrase inhibitors.

### Protease Inhibitors (PIs)

Darunavir boosted with ritonavir or cobicistat is the only protease inhibitor that remains in current recommended first-line regimens, possessing a high genetic barrier to resistance requiring 10 to 11 mutations for full resistance to boosted darunavir. The class is associated with gastrointestinal side effects and metabolic complications including dyslipidemia and insulin resistance. Ritonavir and cobicistat serve as pharmacokinetic boosters through CYP3A4 inhibition, creating a substantial drug interaction potential that requires careful medication review. Atazanavir, used less commonly now, causes unconjugated hyperbilirubinemia and nephrolithiasis.

### INSTIs (Integrase Strand Transfer Inhibitors)

Integrase inhibitors have become the current first-line anchor agents for ART. Dolutegravir (DTG) has a high genetic barrier to resistance, once-daily dosing, excellent tolerability, and minimal drug interactions, though weight gain, particularly in Black women, and rare insomnia are recognized concerns. The initial signal of neural tube defects from Botswana was not confirmed in larger studies, and DTG is now considered safe in pregnancy. Bictegravir (BIC) is available only as the fixed-dose combination BIC/TAF/FTC (Biktarvy) and has a similar profile to dolutegravir with once-daily, single-tablet dosing. Cabotegravir (CAB) is a long-acting injectable administered intramuscularly every two months, combined with rilpivirine long-acting for treatment as Cabenuva, after an oral lead-in period. Raltegravir, the first-generation INSTI, has a lower genetic barrier and requires twice-daily dosing, making it less preferred. Elvitegravir requires cobicistat boosting and has a lower genetic barrier, excluding it from current first-line recommendations.

### Novel Agents

Lenacapavir is the first-in-class capsid inhibitor, administered as an ultra-long-acting subcutaneous injection every six months. It is currently approved for highly treatment-experienced patients with multidrug-resistant HIV, and the PURPOSE 1 trial demonstrated 100 percent efficacy in cisgender women for PrEP, heralding a potential paradigm shift in HIV prevention. Fostemsavir is an attachment inhibitor that binds gp120 and is reserved for treatment-experienced patients. Ibalizumab is a post-attachment inhibitor monoclonal antibody targeting CD4, administered intravenously every two weeks for multidrug-resistant HIV. Islatravir is an NRTI with an ultra-long half-life currently under development for treatment and PrEP combinations.

<image>A comprehensive diagram of the HIV viral lifecycle showing each step targeted by antiretroviral drug classes. Start with a free HIV virion approaching a CD4+ T cell. Show: (1) Attachment/binding to CD4 and CCR5/CXCR4 co-receptors (label: attachment inhibitors, CCR5 antagonists, post-attachment inhibitors), (2) Fusion of viral and cell membranes (label: fusion inhibitors), (3) Reverse transcription of RNA to DNA in cytoplasm (label: NRTIs, NNRTIs), (4) Integration of proviral DNA into host genome (label: INSTIs), (5) Transcription and translation of viral proteins (no current drug target), (6) Protease cleavage of polyproteins (label: PIs), (7) Capsid assembly and budding (label: capsid inhibitors/lenacapavir). Use a circular cell diagram with numbered steps and drug class boxes connected by arrows. Include representative drug names for each class. Medical illustration style with molecular detail.</image>

## Recommended Initial ART Regimens (DHHS 2024)

### Preferred Regimens

| Regimen | Components | Dosing | Key Considerations |
|---|---|---|---|
| BIC/TAF/FTC (Biktarvy) | Bictegravir + tenofovir alafenamide + emtricitabine | 1 tablet daily | Most prescribed initial regimen; single-tablet; high genetic barrier |
| DTG + TAF/FTC | Dolutegravir + tenofovir alafenamide + emtricitabine | 2 pills daily | DTG available separately; flexible backbone options |
| DTG/3TC (Dovato) | Dolutegravir + lamivudine | 1 tablet daily | Two-drug regimen; avoid if HBV co-infection, VL >500,000, or pre-resistance testing |
| DTG + TDF/FTC | Dolutegravir + tenofovir disoproxil fumarate + emtricitabine | 2 pills daily | TDF: monitor renal function and bone density |
| CAB + RPV LA (Cabenuva) | Cabotegravir LA + rilpivirine LA IM | q2 months (after oral lead-in) | Long-acting injectable; requires viral suppression first |

The preferred initial ART regimens include bictegravir/TAF/emtricitabine (Biktarvy), a single-tablet regimen dosed once daily that has become the most prescribed initial regimen in the United States. Dolutegravir combined with TAF/emtricitabine or TDF/FTC represents a two-pill regimen with DTG available as a single agent. Dolutegravir/lamivudine (Dovato) is a two-drug regimen that should not be used in patients with HBV co-infection, those with a viral load above 500,000, or before resistance testing results are available.

### Rapid-Start Considerations

Rapid ART initiation at the first visit, even before genotype results are available, is appropriate for most patients. Preferred rapid-start regimens include BIC/TAF/FTC or DTG plus TAF/FTC, selected for their high genetic barrier to resistance, which makes transmitted INSTI resistance unlikely. Exceptions to immediate ART initiation include suspected INSTI resistance from prior PrEP use with non-adherence and established opportunistic infections requiring specific timing of ART.

### Special Populations

In pregnancy, a DTG-based regimen is preferred throughout, with growing data supporting BIC/TAF/FTC. Efavirenz and cobicistat-boosted regimens should be avoided. In HBV co-infection, the regimen must include TAF or TDF plus FTC or 3TC to provide dual HBV-active agents, and discontinuation risks HBV flare. In TB co-infection, DTG should be dosed at 50 milligrams twice daily with rifampin due to enzyme induction, or an efavirenz-based regimen can be used, while protease inhibitors are contraindicated with rifampin. In chronic kidney disease, TAF is preferred over TDF, TDF should be avoided when eGFR is below 60, and 3TC and FTC dosing require adjustment.

## Monitoring on ART

### Viral Load

The goal of ART is viral suppression below 50 copies per milliliter, which most patients achieve by 8 to 12 weeks with a maximum target of 24 weeks. Monitoring should occur at 4 weeks, then every 4 to 8 weeks until suppression is achieved, then every 3 to 6 months. Virologic failure is defined as a viral load above 200 copies per milliliter on two consecutive measurements.

### CD4 Count

CD4 monitoring occurs at baseline and then every 3 to 6 months until the count exceeds 350 for two years with sustained viral suppression, at which point routine monitoring can be discontinued. The CD4 nadir is more prognostic than the current CD4 count for predicting the degree of immune reconstitution.

### Drug Resistance Testing

Genotype testing should be performed at diagnosis, as baseline resistance is present in 15 to 20 percent of treatment-naive patients in the United States. Repeat genotyping is indicated at virologic failure, performed while the patient remains on the failing regimen to maintain the drug pressure necessary for resistance detection. Integrase resistance testing is not routine at baseline, as transmitted INSTI resistance remains below 1 percent, though it is increasing.

### Metabolic Monitoring

Fasting lipids and glucose or HbA1c should be checked at baseline and annually. Renal function monitoring is particularly important with TDF-containing regimens, with BMP and urinalysis every 6 to 12 months. Bone density assessment with DXA should be considered in postmenopausal women, men over 50, and patients on TDF. Weight monitoring is essential given the recognized association between INSTI use and weight gain, which is more pronounced with DTG than BIC, in Black women, and with TAF-containing regimens.

<image>A monitoring timeline infographic for patients initiating ART. Create a horizontal timeline from "ART initiation" to "Year 2+" with key monitoring milestones marked. At baseline: "HIV genotype, viral load, CD4, CBC, CMP, lipids, HbA1c, HBV/HCV serologies, RPR, STI screening, HLA-B*5701 (if ABC planned), urinalysis, pregnancy test." At 2-4 weeks: "Viral load (confirm response), tolerability assessment." At 3 months: "Viral load, CD4, renal function." At 6 months: "Viral load (confirm suppression <50), CD4, lipids, renal function." At 12 months: "All baseline labs repeated." After year 1 with suppression: "Viral load q6 months, CD4 can be discontinued after >350 x 2 years, metabolic monitoring annually." Include icons for each test type and color-code by frequency. Professional clinical monitoring schedule format.</image>

## Drug Interactions

### Key Interactions

Rifampin is a powerful CYP3A4 and UGT1A1 inducer that requires doubling the DTG dose to 50 milligrams twice daily. Protease inhibitors are contraindicated with rifampin, and rifabutin should be substituted when a PI-based regimen is necessary. Proton pump inhibitors are contraindicated with rilpivirine, and dolutegravir-containing regimens require separation from antacids by 2 hours before or 6 hours after dosing. DTG inhibits the organic cation transporter OCT2, increasing metformin levels and necessitating a maximum metformin dose of 1,000 milligrams daily. Protease inhibitors boosted with ritonavir or cobicistat dramatically increase statin levels, contraindicating simvastatin and lovastatin and requiring low-dose atorvastatin or dose-limited rosuvastatin. Direct oral anticoagulant levels are significantly altered by ritonavir and cobicistat, requiring avoidance or extreme caution. Divalent cations including calcium, iron, magnesium, and aluminum chelate integrase inhibitors and require separation by 2 to 6 hours depending on the specific INSTI.

## Antiretroviral Resistance

### NRTI Resistance

The M184V mutation is the most common NRTI resistance mutation, conferring high-level resistance to lamivudine and emtricitabine but paradoxically increasing susceptibility to TDF and AZT while reducing viral fitness. This observation supports the strategy of maintaining lamivudine in a failing regimen for its residual benefit. The K65R mutation confers TDF resistance and is less common with TAF. Thymidine analog mutations accumulate with AZT and d4T exposure and produce a pattern of cross-resistance.

### INSTI Resistance

Resistance to DTG and BIC is rare due to their high genetic barrier. Key INSTI mutations include Q148H/K/R with secondary mutations leading to DTG and BIC resistance, R263K selected by BIC, and G118R. Resistance is considerably more common with first-generation INSTIs raltegravir and elvitegravir.

## Key Clinical Pearls

- Treat ALL patients with HIV immediately -- rapid ART initiation (same day when possible) improves outcomes and reduces transmission
- U=U (Undetectable = Untransmittable): viral suppression <200 copies/mL effectively eliminates sexual transmission (PARTNER 1/2, HPTN 052 studies)
- BIC/TAF/FTC (Biktarvy) and DTG-based regimens are the current standard of care for initial ART -- high genetic barrier, well-tolerated, once-daily
- Always check HLA-B*5701 before prescribing abacavir and HBV serology before ART initiation (HBV flare risk on ART discontinuation)
- INSTI-associated weight gain is a real clinical concern, particularly with DTG; monitor and counsel patients
- Lenacapavir (q6-month injection) represents a paradigm shift for both treatment and prevention of HIV
- Drug interactions with boosted PIs (ritonavir/cobicistat) are extensive and dangerous -- always check interaction databases (Liverpool HIV Drug Interactions website)

## References
1. INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection (START). *N Engl J Med*. 2015;373(9):795-807.
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. DHHS. Updated 2024.
3. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. *Clin Infect Dis*. 2020;71(6):1379-1389.
4. Rodger AJ, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive ART (PARTNER 2). *Lancet*. 2019;393(10189):2428-2438.
5. Segal-Maurer S, DeJesus E, Engel LC, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. *N Engl J Med*. 2022;386(19):1793-1803.