9.1 Antiretroviral Therapy and Management of HIV-1 Infection

Antiretroviral Therapy and Management of HIV-1 Infection

The pharmacotherapeutic management of Human Immunodeficiency Virus Type 1 (HIV-1) infection has transformed from palliative multi-tablet regimens into highly potent, well-tolerated, once-daily single-tablet regimens and long-acting injectables. Achieving and sustaining virologic suppression halts disease progression, restores immunologic architecture, eliminates the risk of sexual transmission (Undetectable = Untransmittable [U=U]), and prevents opportunistic complications.

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Principles of Antiretroviral Therapy and HHS Guidelines Framework

The United States Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents recommends initiating antiretroviral therapy (ART) in all individuals diagnosed with HIV-1 infection, regardless of CD4+ T-lymphocyte cell count, to reduce morbidity, mortality, and transmission risk. Therapy should be started as soon as possible after diagnosis, including immediate ("rapid start" or "same-day") initiation upon clinical presentation, provided the patient is ready and contraindications are excluded.

Core Goals of Antiretroviral Therapy

• Maximal and Durable Virologic Suppression: Reduction of plasma HIV-1 RNA below the lower limit of clinical detection (<50 copies/mL, or <20 copies/mL depending on the commercial assay platform).
• Quantitative and Qualitative Immune Restoration: Expansion of functional CD4+ T-cell counts, restoration of pathogen-specific cellular immunity, and reduction of chronic systemic immune activation and systemic inflammation.
• Prevention of Transmission: Suppression of plasma viral load to undetectable levels prevents sexual transmission to seronegative partners.
• Preservation of Future Regimen Options: Minimizing drug toxicity, maximizing regimen durability, and preventing the selection of drug-resistant viral quasispecies.

Baseline Pre-Treatment Laboratory and Clinical Evaluation

Prior to initiating or modifying ART, a structured laboratory evaluation is essential:

1. HIV Disease Markers: Plasma HIV-1 RNA viral load (quantitative RT-PCR) and CD4+ T-lymphocyte count with percentage.
2. Genotypic Resistance Testing: Evaluation of the reverse transcriptase (RT) and protease (PR) genes to detect transmitted drug resistance. Genotypic integrase strand transfer inhibitor (INSTI) resistance testing should be added if transmitted INSTI resistance is suspected or if rapid ART is initiated before test turnaround.
3. Hepatitis Serologies: Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and total hepatitis B core antibody (anti-HBc). Identifying chronic HBV co-infection dictates the mandatory inclusion of a dual-active NRTI backbone (TDF/FTC, TAF/FTC, or TDF + 3TC). Hepatitis C virus (HCV) antibody with reflex RNA quantification.
4. Safety and Metabolic Markers: Serum creatinine, estimated creatinine clearance (CrCl via Cockcroft-Gault) or eGFR (CKD-EPI), urinalysis with urine albumin-to-creatinine or protein-to-creatinine ratio, hepatic transaminases, total bilirubin, fasting lipid profile, and fasting blood glucose or hemoglobin A1c.
5. Specialized Pre-Treatment Screens:
   • HLA-B*5701 Screening: Mandatory prior to prescribing any regimen containing abacavir (ABC). A positive test indicates high risk for an immune-mediated hypersensitivity reaction and permanently contraindicates abacavir.
   • Coreceptor Tropism Assay: Required prior to initiating the CCR5 coreceptor antagonist maraviroc to confirm exclusive R5-tropic viral populations.
   • Pregnancy Testing: In individuals of childbearing potential to guide drug selection and teratogenicity discussions.

                    HIV-1 Replication Cycle and Pharmacological Targets

1. Attachment & Binding ──► gp120 binds host CD4 receptor
                             [Target: Fostemsavir (gp120 attachment inhibitor)]
                             [Target: Ibalizumab (CD4-directed post-attachment mAb)]
                                      │
2. Coreceptor Interaction ─► gp120 interacts with host CCR5 or CXCR4 coreceptor
                             [Target: Maraviroc (CCR5 antagonist)]
                                      │
3. Viral Fusion ──────────► gp41 conformational change mediates membrane fusion
                             [Target: Enfuvirtide (Fusion inhibitor)]
                                      │
4. Uncoating & Transport ─► Capsid cone disassembles; proviral complex enters nucleus
                             [Target: Lenacapavir (Multi-stage Capsid inhibitor)]
                                      │
5. Reverse Transcription ─► Viral RNA transcribed into double-stranded cDNA
                             [Target: NRTIs (Competitive chain terminators)]
                             [Target: NNRTIs (Allosteric non-competitive RT inhibitors)]
                                      │
6. Proviral Integration ──► Integrase inserts viral cDNA into human chromosome
                             [Target: INSTIs (Catalytic Mg2+ chelators: BIC, DTG, CAB, RAL)]
                                      │
7. Transcription/Translation► Host RNA polymerase transcribes viral mRNAs; polyproteins made
                                      │
8. Assembly & Maturation ─► Viral protease cleaves Gag/Gag-Pol polyproteins into mature units
                             [Target: Protease Inhibitors (DRV, ATV boosted with RTV/COBI)]
                             [Target: Lenacapavir (Capsid assembly interference)]

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Antiretroviral Drug Classes, Mechanisms, and Molecular Targets

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

NRTIs serve as the foundational backbone of multi-agent ART regimens. They are purine or pyrimidine nucleoside (or nucleotide) analogues that require intracellular triphosphorylation (or diphosphorylation in the case of tenofovir) by host cellular kinases to become active.

• Molecular Mechanism: The active triphosphate metabolite competitively binds to the catalytic site of HIV-1 reverse transcriptase in competition with endogenous deoxynucleotide triphosphates (dNTPs). Because NRTIs lack a 3'-hydroxyl (-OH) group on the ribose ring, incorporation into the elongating viral cDNA chain terminates phosphodiester bond formation, resulting in immediate chain termination.
• Mitochondrial Toxicity Class Effect: Older NRTIs (didanosine, stavudine, zidovudine) inhibited host mitochondrial DNA polymerase-gamma, producing lactic acidosis, hepatic steatosis, lipoatrophy, and peripheral neuropathy. Modern NRTIs (TAF, TDF, FTC, 3TC, ABC) exhibit weak affinity for DNA polymerase-gamma, virtually eliminating clinical lactic acidosis.

Tenofovir Formulations: TDF versus TAF

Tenofovir is an acyclic nucleotide diester analogue of adenosine monophosphate. Because it already carries a single phosphate group, it requires only two intracellular phosphorylation events to form tenofovir diphosphate (TFV-DP).

Abacavir (ABC) and HLA-B*5701 Hypersensitivity

Abacavir is a carbocyclic guanosine analogue. Its clinical deployment is governed by immunogenetics:

• HLA-B*5701 Hypersensitivity Reaction (HSR): Approximately 5–8% of Caucasian individuals carry the MHC Class I allele HLA-B*5701. Abacavir binds non-covalently within the antigen-binding cleft (specifically the F-pocket) of the HLA-B*5701 molecule, altering the shape and chemical properties of the antigen-binding groove. This causes self-peptides to be perceived as foreign, triggering an uncontrolled, polyclonal CD8+ T-cell and cytokine storm.
• Clinical Presentation: Symptoms typically emerge within the first 6 weeks of therapy and involve at least two of the following organ groups: fever, rash (maculopapular or urticarial), gastrointestinal distress (nausea, vomiting, diarrhea, abdominal pain), constitutional symptoms (malaise, severe fatigue), and respiratory symptoms (dyspnea, pharyngitis, cough).
• Mandatory Policy: Screening for HLA-B*5701 is mandatory prior to initiating abacavir. A positive result must be permanently documented in the medical record, and abacavir must never be administered. If abacavir HSR is suspected clinically, the drug must be stopped immediately and never rechallenged. Rechallenging abacavir following an HSR can precipitate fatal anaphylactoid shock within hours.
• Cardiovascular Risk: Several observational cohorts (e.g., the D:A:D study) reported an association between recent abacavir use and increased risk of acute myocardial infarction (MI), potentially mediated by platelet hyperreactivity and endothelial dysfunction. HHS guidelines advise caution when prescribing abacavir to individuals with high underlying cardiovascular risk.

Emtricitabine (FTC) and Lamivudine (3TC)

Emtricitabine (fluorinated cytosine analogue) and lamivudine (cytosine analogue) are pharmacologically interchangeable in triple-drug therapy:

• Both exhibit benign safety profiles, minimal protein binding, and renal elimination.
• Resistance Profile (The M184V/I Mutation): A single nucleotide transition in the reverse transcriptase gene causes a methionine-to-valine (M184V) or methionine-to-isoleucine (M184I) substitution at codon 184 within the conserved catalytic YMDD motif. M184V confers complete, high-level (>1,000-fold) cross-resistance to both 3TC and FTC. However, M184V severely impairs viral replicative fitness, reduces viral viral load capacity, and hypersensitizes the virus to tenofovir and zidovudine. Consequently, lamivudine or emtricitabine is frequently retained in second-line salvage regimens to maintain the M184V fitness handicap.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTIs are non-competitive, allosteric inhibitors of reverse transcriptase that bind directly to an adjacent hydrophobic pocket ("NNRTI pocket"). This induces a three-dimensional spatial rearrangement of the polymerase catalytic site, blocking nucleotide polymerization.

• Efavirenz (EFV): Historically a cornerstone of therapy, efavirenz is now an alternative due to neuropsychiatric toxicities. More than 50% of patients experience central nervous system (CNS) adverse effects within the first 1–2 weeks of therapy, including abnormal vivid dreams, nightmares, dizziness, insomnia, depersonalization, severe depression, and suicidal ideation. These effects are accentuated in CYP2B6 slow metabolizers (e.g., CYP2B6*6 allele). Administration on an empty stomach at bedtime mitigates peak drug levels and daytime somnolence. Efavirenz has a low genetic barrier to resistance; a single K103N mutation confers complete class cross-resistance to first-generation NNRTIs.
• Rilpivirine (RPV): A second-generation diarylpyrimidine NNRTI with conformational flexibility that tolerates certain RT mutations.
  • Administration Requirements: Rilpivirine requires an acidic gastric environment for oral dissolution and absorption; co-administration with proton pump inhibitors (PPIs) is strictly contraindicated. H2-receptor antagonists must be taken at least 12 hours before or 4 hours after rilpivirine, and antacids separated by 2 hours before or 4 hours after. Rilpivirine must be taken with a substantial meal (at least 500 kcal, with fat content); nutritional protein shakes or fasting states lead to suboptimal absorption and virologic failure.
  • Clinical Cutoffs: In treatment-naive patients, rilpivirine has higher rates of virologic failure and emergent NNRTI/NRTI resistance (specifically E138K + M184I) when baseline HIV-1 RNA exceeds 100,000 copies/mL or baseline CD4+ count is <200 cells/mm3. Therefore, oral rilpivirine is recommended only for patients with baseline viral load <100,000 copies/mL and CD4 >200 cells/mm3.
• Doravirine (DOR): A next-generation NNRTI designed to overcome common NNRTI resistance. Doravirine maintains full in vitro antiviral activity against viral isolates harboring K103N, Y181C, or G190A mutations. It can be taken with or without food, exhibits no clinically significant interaction with gastric acid-reducing agents (PPIs, H2RAs, antacids), and produces a favorable, neutral lipid profile.

Protease Inhibitors (PIs) and Pharmacokinetic Boosting

HIV-1 protease is an aspartyl protease enzyme that cleaves the large Gag and Gag-Pol polyprotein precursors into individual structural core proteins (p24, p17, p7) and essential functional enzymes (reverse transcriptase, integrase, protease). Protease inhibitors competitively bind the active enzymatic catalytic pocket, arresting polyprotein processing and yielding immature, non-infectious virions.

Pharmacokinetic Enhancers (Boosting Agents)

All modern PI regimens require pharmacological boosting with either ritonavir (RTV) or cobicistat (COBI):

• Ritonavir (100 mg daily): A protease inhibitor that is a potent, irreversible mechanism-based inhibitor of hepatic and intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. Boosting increases PI area under the curve (AUC) and maintains trough levels well above the protein-binding-corrected IC50 throughout the dosing interval. Ritonavir also induces CYP1A2, CYP2C9, CYP2C19, and glucuronosyltransferases (UGT), creating complex drug-drug interactions.
• Cobicistat (150 mg daily): A structural analogue of ritonavir that lacks intrinsic antiretroviral activity. It is a selective, mechanism-based inhibitor of CYP3A and P-glycoprotein, with fewer broad inducing properties. Cobicistat also inhibits renal tubular creatinine secretion via multidrug and toxin extrusion protein 1 (MATE1), causing an artifactual, benign increase in serum creatinine of 0.1 to 0.15 mg/dL without reducing true glomerular filtration.

Key Protease Inhibitor Agents

• Darunavir (DRV): The preferred PI due to its high genetic barrier to resistance. Darunavir forms extensive hydrogen bonds with the backbone atoms of the protease enzyme active site; multiple primary protease mutations (e.g., V32I, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V) are required before phenotypic resistance occurs. Contains a sulfonamide moiety; caution is warranted in patients with severe sulfa allergies. Boosted darunavir (DRV/r or DRV/c) is a favored option when adherence is questionable or when ART must begin prior to genotype results.
• Atazanavir (ATV): An azapeptide PI boosted with ritonavir or cobicistat. Inhibits hepatic UGT1A1, leading to benign, indirect (unconjugated) hyperbilirubinemia and clinical scleral icterus in up to 30–50% of patients (phenotypically mimicking Gilbert syndrome). Also associated with nephrolithiasis and cholelithiasis. Requires acidic gastric pH for optimal dissolution; co-administration with PPIs requires strict dose limitations and timing separation.
• Metabolic Derangements of Boosted PIs: Class-wide adverse effects include dyslipidemia (hypertriglyceridemia, elevated LDL), peripheral insulin resistance, new-onset diabetes mellitus, and visceral lipodystrophy (central adiposity, dorsocervical fat pad accumulation ["buffalo hump"]).

Integrase Strand Transfer Inhibitors (INSTIs)

INSTIs represent the primary cornerstone of modern initial ART. Following reverse transcription in the host cytoplasm, the viral integrase enzyme processes the 3' ends of proviral cDNA (3'-end processing) and escorts the pre-integration complex into the nucleus.

• Mechanism of Action: INSTIs bind specifically to the pre-assembled intasome complex and chelate two essential catalytic divalent magnesium ions ($Mg^{2+}$) within the integrase active site. This selectively inhibits the strand transfer reaction, preventing covalent insertion of proviral DNA into the host genome.
• First-Generation INSTIs (Raltegravir [RAL], Elvitegravir [EVG]): Have a low genetic barrier to resistance. A single primary amino acid substitution at positions Y143, Q148, or N155 confers extensive cross-resistance between raltegravir and elvitegravir.
• Second-Generation INSTIs (Dolutegravir [DTG], Bictegravir [BIC], Cabotegravir [CAB]): Characterized by prolonged binding half-lives (dissociation half-life >50–70 hours) and deeper structural penetration into the catalytic pocket. They have a high genetic barrier to resistance; virologic failure with emergent resistance is exceptionally rare in treatment-naive individuals. Dolutegravir retains activity against many viral strains carrying single first-generation INSTI mutations.
• Class Adverse Effects & Pharmacological Pearls:
  • Renal Secretion Inhibition: Both dolutegravir and bictegravir inhibit the basolateral organic cation transporter 2 (OCT2) and apical MATE1 transporters in the proximal renal tubule. This causes a benign, non-progressive rise in serum creatinine (typically 0.1 to 0.2 mg/dL) within the first 2 to 4 weeks of therapy due to blockade of tubular creatinine secretion, with no change in true glomerular filtration rate (GFR).
  • Polyvalent Cation Binding: INSTIs possess metal-chelating pharmacophores. Co-administration with polyvalent cations ($Al^{3+}$, $Mg^{2+}$, $Ca^{2+}$, $Fe^{2+}$) found in antacids, laxatives, and mineral supplements precipitates insoluble complexes, reducing INSTI bioavailability by up to 70–80%. Cation-containing antacids must be taken at least 2 hours before or 6 hours after INSTIs. (Dolutegravir and bictegravir can be taken simultaneously with calcium or iron supplements if taken with food).
  • Weight Gain & Neuropsychiatric Effects: Second-generation INSTIs are associated with greater body weight increases than NNRTIs or PIs (amplified when combined with TAF). Rare neuropsychiatric adverse events include insomnia, vivid dreams, headache, and mood changes.

Entry and Capsid Inhibitors

For patients with multidrug-resistant (MDR) HIV-1 or extensive treatment experience, novel mechanistic classes target distinct steps of viral entry and structural assembly:

• Maraviroc (MVC): Small-molecule chemokine coreceptor antagonist that binds allosterically to the host CCR5 coreceptor, preventing gp120 binding. It has zero activity against CXCR4-tropic or dual/mixed (D/M) tropic viruses. A molecular or phenotypic tropism assay (Trofile) is legally and clinically mandatory prior to prescribing; maraviroc is indicated only if pure R5 tropism is confirmed.
• Fostemsavir: An oral prodrug of temsavir, which binds directly to the viral envelope glycoprotein gp120 adjacent to the CD4 binding pocket. This locks gp120 into a closed conformation, preventing viral attachment to host CD4 receptors regardless of CCR5 or CXCR4 tropism. Indicated for heavily treatment-experienced patients with multidrug resistance.
• Ibalizumab: A recombinant humanized IgG4 monoclonal antibody administered as an intravenous infusion every 14 days. Binds epitope domain 2 of the host CD4 receptor, inducing steric hindrance that prevents post-attachment conformational changes required for coreceptor interaction and viral entry, without causing CD4 immunosuppression or depletion.
• Lenacapavir: A first-in-class, multi-stage selective capsid inhibitor. Lenacapavir binds to the interface between adjacent capsid protein (p24) hexamers, disrupting three independent phases: (1) inhibition of capsid disassembly during uncoating, (2) inhibition of nuclear translocation of viral pre-integration complexes, and (3) disruption of capsid core assembly and maturation. Formulated as a subcutaneous injection administered once every 6 months (following an oral initiation lead-in). Approved for heavily treatment-experienced adults with MDR HIV failing their current regimen.

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Initial Recommended Regimens for Most People with HIV

HHS guidelines recommend that an initial regimen for an ART-naive individual consist of two NRTIs combined with a second-generation INSTI possessing a high genetic barrier to resistance, or a specific two-drug regimen in qualified individuals.

Critical Restrictions for the Two-Drug Regimen (Dolutegravir / Lamivudine)

The landmark GEMINI-1 and GEMINI-2 clinical trials proved that dolutegravir/lamivudine is non-inferior to a standard 3-drug regimen (DTG + TDF/FTC) in treatment-naive individuals. However, DTG/3TC is contraindicated unless the following four criteria are strictly fulfilled:

1. Baseline HIV-1 RNA must be < 500,000 copies/mL: Patients with viral loads $\ge 500,000\text{ copies/mL}$ were excluded from initial regulatory trials; higher baseline viremia increases the risk of virologic failure.
2. Absence of Chronic Hepatitis B Co-infection: Documented negative HBsAg. Lamivudine is the only HBV-active agent in Dovato; using 3TC as HBV monotherapy rapidly selects for the M204V/I reverse transcriptase resistance mutation in HBV within months, leading to hepatitis flare and loss of HBV control. A tenofovir-containing dual-active backbone is mandatory for HIV/HBV co-infection.
3. No Known Pre-Existing Resistance: Resistance testing must document absence of the M184V/I mutation and INSTI resistance mutations.
4. Not Recommended for Rapid Start: If ART is initiated before baseline viral load, resistance genotype, or HBV serology results are confirmed, DTG/3TC must not be chosen; a 3-drug regimen (e.g., BIC/TAF/FTC) must be used instead.

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Long-Acting Injectable Antiretroviral Therapy

Long-acting injectable antiretroviral therapy represents an alternative for individuals struggling with daily oral pill fatigue or stigma.

Cabotegravir and Rilpivirine (CAB + RPV, Cabenuva)

Cabenuva combines an extended-release suspension of cabotegravir (INSTI) and rilpivirine (NNRTI) administered via separate gluteal intramuscular (IM) injections.

• Indications and Eligibility:
  • Approved solely as a replacement maintenance regimen for individuals who have achieved stable virologic suppression (plasma HIV-1 RNA < 50 copies/mL) for at least 3 to 6 months on an oral regimen.
  • Must have no history of virologic failure and no known or suspected baseline resistance to either cabotegravir or rilpivirine.
  • Must have documented negative chronic hepatitis B infection (unless an additional oral HBV active agent is continued).
• Dosing Protocols:
  • Oral Lead-in (Optional): Daily oral cabotegravir (30 mg) plus oral rilpivirine (25 mg) for approximately 28 days to assess tolerability prior to initiating long-acting depots. Patients may also proceed directly to injection without an oral lead-in.
  • Monthly Injections: Cabotegravir 400 mg IM (2 mL) + Rilpivirine 600 mg IM (2 mL) once monthly.
  • Every-2-Month Injections: Cabotegravir 600 mg IM (3 mL) + Rilpivirine 900 mg IM (3 mL) once every 2 months (following two monthly initiation loading doses).
• Predictors of Virologic Failure on CAB/RPV: Pooled multivariable regression analyses from the ATLAS, FLAIR, and ATLAS-2M trials identified three baseline factors that synergistically increase the risk of virologic failure:
  1. Proviral RPV Resistance Mutations: Presence of at least two archived NNRTI resistance mutations.
  2. HIV-1 Subtype A6/A1: Viral strains endemic to Russia and Eastern Europe carrying specific integrase polymorphisms (L74I).
  3. Body Mass Index (BMI) $\ge 30\text{ kg/m}^2$: Thick subcutaneous adipose tissue impairing intramuscular gluteal depot penetration; requires a longer 2-inch needle to guarantee true intramuscular deposition.

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Biomedical HIV Prevention: PrEP and PEP

Biomedical prevention encompasses pre-exposure prophylaxis (PrEP) for seronegative individuals at ongoing risk, and post-exposure prophylaxis (PEP) following isolated high-risk exposures.

                               HIV Prevention Decision Pathway

Is there an acute, isolated high-risk exposure within the last 72 hours?
   ├──► YES ──► Post-Exposure Prophylaxis (PEP)
   │             - Initiate immediately within 72 hours (ideally <2 hours)
   │             - Prescribe full 28-day 3-drug regimen: [TDF/FTC or TAF/FTC] + [DTG or BIC]
   │             - Baseline HIV testing, repeated at 4-6 weeks and 3 months
   │
   └──► NO  ──► Pre-Exposure Prophylaxis (PrEP) Evaluation for Ongoing Risk
                 - Screen: Negative HIV Ag/Ab test AND HIV-1 RNA within 1-2 weeks
                 - Assess exposure route, renal function (CrCl), and HBV status
                 │
                 ├─► Receptive Anal Sex, PWID, or Receptive Vaginal Sex?
                 │    ├── TDF/FTC (Truvada) PO daily [CrCl ≥ 50 mL/min; all populations]
                 │    └── Cabotegravir (Apretude) 600 mg IM q2 months [all populations]
                 │
                 └─► Exclusively Receptive Anal Sex (Cisgender Men & Transgender Women)?
                      └── TAF/FTC (Descovy) PO daily [CrCl ≥ 30 mL/min; NOT for vaginal sex]

Pre-Exposure Prophylaxis (PrEP)

1. Oral TDF/FTC (Truvada): Approved for all adults and adolescents weighing $\ge 35\text{ kg}$ at risk from sexual exposure (men who have sex with men [MSM], transgender individuals, heterosexual men and women) or injection drug use (PWID). Requires baseline estimated $\text{CrCl} \ge 50\text{ mL/min}$. Reaches maximal protective mucosal tissue concentrations in rectal tissue within 7 days, but requires approximately 20 days of daily dosing to achieve protective concentrations in cervicovaginal tissue and blood.
2. Oral TAF/FTC (Descovy): Approved for individuals at risk from sexual exposure, excluding individuals at risk from receptive vaginal sex. The DISCOVER trial evaluated Descovy only in cisgender MSM and transgender women; pharmacokinetic differences in female genital tract tissue leave its efficacy unproven for receptive vaginal exposures. Sparing of bone and renal biomarkers; approved for estimated $\text{CrCl} \ge 30\text{ mL/min}$.
3. Long-Acting Injectable Cabotegravir (Apretude): Cabotegravir 600 mg (3 mL) intramuscular gluteal injection administered every 2 months (after two monthly initiation injections). The HPTN 083 (MSM/transgender women) and HPTN 084 (cisgender women) trials demonstrated superior efficacy of injectable cabotegravir over daily oral TDF/FTC, largely driven by overcoming real-world adherence barriers. Approved for all at-risk populations $\ge 35\text{ kg}$.
4. Twice-Yearly Subcutaneous Lenacapavir (Yeztugo): FDA-approved for PrEP on June 18, 2025 for adults and adolescents weighing $\ge 35\text{ kg}$, making it the first HIV prevention option dosed only every 6 months (two subcutaneous abdominal injections of 927 mg, preceded by oral loading doses on days 1 and 2). PURPOSE 1 (cisgender women in sub-Saharan Africa) and PURPOSE 2 (MSM, transgender and gender-diverse people) showed near-complete prevention of incident HIV, with superiority over daily oral TDF/FTC. Counsel on injection-site nodules, and note that lenacapavir's long pharmacologic tail requires a plan to cover the period after the last injection if PrEP is stopped. The same molecule, marketed as Sunlenca, is used for multidrug-resistant HIV treatment — do not interchange the indications or dosing.
5. PrEP Diagnostic Safety Protocol: Clinicians must confirm a non-reactive HIV status using a laboratory-based HIV-1/2 antigen/antibody immunoassay and a quantitative HIV-1 RNA viral load assay within 1 to 2 weeks prior to starting or restarting PrEP. Starting PrEP during acute, unrecognized HIV infection provides incomplete ART (monotherapy or dual NRTI therapy), selecting for drug-resistant mutations (such as M184V or INSTI mutations).

Post-Exposure Prophylaxis (PEP)

PEP is indicated for occupational (needlestick, mucosal splash) or non-occupational (unprotected intercourse, condom rupture, sexual assault, needle sharing) exposures to blood or body fluids from an individual known or suspected to have HIV.

• Timing Window: PEP must be initiated as rapidly as possible, ideally within 2 hours and no later than 72 hours post-exposure. Beyond 72 hours, animal models and clinical data demonstrate a lack of efficacy, as viral integration and systemic dissemination have already occurred.
• Regimen Duration & Composition: A full 28-day course of a potent 3-drug regimen is required:
  • Preferred: Tenofovir (TDF or TAF) + Emtricitabine (or Lamivudine) PLUS Dolutegravir (50 mg once daily) OR Bictegravir (as part of co-formulated Biktarvy) OR Raltegravir (400 mg twice daily).
• Follow-up Monitoring: Baseline HIV testing of the exposed individual; repeat testing at 4 to 6 weeks and 3 months post-exposure using a 4th-generation antigen/antibody assay. If the source individual is confirmed to be HIV-negative via a 4th-generation assay, PEP can be discontinued immediately.

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Immune Reconstitution Inflammatory Syndrome (IRIS)

Immune Reconstitution Inflammatory Syndrome (IRIS) is an exaggerated hyper-inflammatory response directed against viable or dead pathogen antigens following the initiation or re-introduction of ART.

Pathophysiology and Classification

As ART suppresses viral replication, rapid expansion and redistribution of memory CD4+ T-lymphocytes occurs, restoring cellular immune reactivity. In the presence of high microbial antigen burdens, this reconstituted immune system mounts an inflammatory response characterized by high circulating concentrations of interferon-gamma, interleukin-6, and TNF-alpha.

• Unmasking IRIS: ART is initiated in a patient with an occult, subclinical, undiagnosed infection. The recovering immune response reveals the disease with aggressive, atypical inflammation (e.g., rapid cavitation of subclinical tuberculosis, florid cutaneous lesions, or sudden lymphadenitis).
• Paradoxical IRIS: ART is initiated in a patient receiving treatment for an established opportunistic infection. Despite microbiological control and virologic suppression, the patient experiences severe clinical worsening of original symptoms (e.g., expanding tuberculomas, enlarging lymph nodes, recrudescent fever, worsening pulmonary infiltrates).

Clinical Management of IRIS

• Do NOT Stop ART: In the vast majority of cases, ART should be continued while aggressive antimicrobial therapy directed against the underlying opportunistic pathogen is optimized.
• Anti-Inflammatory Interventions: Non-steroidal anti-inflammatory drugs (NSAIDs) for mild localized inflammation. For moderate-to-severe, debilitating, or organ-threatening IRIS (e.g., central nervous system tuberculomas, severe pulmonary compromise), systemic corticosteroids (prednisone 1 to 2 mg/kg/day or IV dexamethasone equivalent) should be administered and tapered over 2 to 6 weeks.

Timing of ART Initiation in Acute Opportunistic Infections

Balancing early ART (to restore immunity and prevent new AIDS-defining events) against delayed ART (to prevent fatal IRIS) represents a critical clinical decision:

                                Timing of ART in Acute Opportunistic Infections

                ┌────────────────────────────────────────────────────────┐
                │ Acute Opportunistic Infection Diagnosed & Therapy Begun│
                └───────────────────────────┬────────────────────────────┘
                                            │
                 Is the infection Cryptococcal Meningitis or TB Meningitis?
                                            │
                       ┌────────────────────┴────────────────────┐
                       ▼ YES                                     ▼ NO
     ┌───────────────────────────────────┐     ┌───────────────────────────────────┐
     │    CENTRAL NERVOUS SYSTEM OIs     │     │      NON-CNS / SYSTEMIC OIs       │
     │ Cryptococcal Meningitis:          │     │ - Pneumocystis Pneumonia (PCP)    │
     │   DELAY ART for 2 to 6 WEEKS      │     │ - Disseminated MAC                │
     │ TB Meningitis:                    │     │ - Candidiasis, CMV, Histoplasma   │
     │   DELAY ART for 4 to 8 WEEKS      │     │ - Bacterial Sepsis, Diarrheal OIs │
     │                                   │     │                                   │
     │ Rationale: Swelling inside fixed  │     │ Rationale: Early ART within       │
     │ cranium causes fatal herniation.  │     │ 2 WEEKS reduces death and AIDS.   │
     └───────────────────────────────────┘     └───────────────────────────────────┘

1. Standard Recommendation for Most Opportunistic Infections:
   • For non-CNS infections, including Pneumocystis jirovecii pneumonia (PCP), gastrointestinal infections, and systemic fungal or bacterial infections: Initiate ART within 2 weeks of starting OI therapy.
   • Randomized trials (ACTG A5164) demonstrated that initiating ART within 14 days resulted in a 50% reduction in AIDS progression and mortality compared to delaying ART until OI therapy concluded, with no increase in adverse events.
2. The Cryptococcal Meningitis Exception (Strict Delay):
   • Delay ART for at least 2 to 6 weeks following the start of antifungal therapy.
   • In the randomized Cryptococcal Optimal ART Timing (COAT) trial, early ART initiation (within 7 to 14 days) led to a significantly higher 26-week mortality (45% vs 30%) compared to delayed ART (initiated at 5 weeks). In the non-expandable cranial vault, early immune reconstitution provokes acute neuro-inflammation and cerebral edema, precipitating catastrophic intracranial hypertension and brain herniation.
3. Tuberculous Meningitis:
   • In CNS tuberculosis, immediate ART is similarly associated with severe intracranial adverse events. Guidelines advise delaying ART for 4 to 8 weeks after starting antituberculous therapy, accompanied by adjunctive high-dose dexamethasone.