9.2 HIV Pharmacotherapy, PrEP/PEP & Viral Hepatitis

HIV Pharmacotherapy, PrEP/PEP & Viral Hepatitis

Executive Summary: Antiretroviral therapy (ART) must be initiated in all individuals diagnosed with HIV immediately or as rapidly as possible, regardless of CD4 cell count, to reduce morbidity, mortality, and eliminate sexual transmission (Undetectable = Untransmittable [U=U]). Integrase Strand Transfer Inhibitor (INSTI)-based regimens form the cornerstone of modern initial therapy due to exceptional virologic potency, high genetic barriers to resistance, and minimal adverse effect profiles. In viral hepatitis, direct-acting antivirals (DAAs) achieve sustained virologic cure (>95%) in chronic Hepatitis C, while potent nucleos(t)ide analogues suppress Hepatitis B viral replication longitudinally.

1. Initial ART Regimens for Treatment-Naive Adults (DHHS Guidelines)

The Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents recommend that initial therapy for most people with HIV consist of an INSTI plus 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) (or 1 NRTI in a specific 2-drug regimen):

Preferred 3-Drug and 2-Drug Initial Regimens

2. Special ART Safety Principles, Toxicity Profiles & Drug Interactions

Abacavir (ABC) Hypersensitivity & HLA-B*5701 Testing

• Mechanism: Abacavir binds specifically within the antigen-binding groove of the HLA-B*5701 major histocompatibility complex (MHC) class I molecule, altering self-peptide presentation and triggering an uncontrolled, multi-organ cytotoxic T-cell hypersensitivity reaction (HSR).
• Clinical Presentation: Multi-system syndrome characterized by fever, maculopapular rash, gastrointestinal distress (nausea, vomiting, diarrhea, abdominal pain), severe fatigue/malaise, and respiratory symptoms (cough, dyspnea, pharyngitis). Symptoms typically manifest within the first 6 weeks of therapy and worsen with each dose.
• Absolute Rule: If a patient tests positive for HLA-B*5701, abacavir is ABSOLUTELY CONTRAINDICATED and should be documented as a lifetime severe drug allergy. If abacavir is discontinued due to suspected HSR, NEVER RECHALLENGE THE PATIENT, as immediate, life-threatening anaphylactic collapse and death can occur within hours.

Tenofovir Comparison: TAF vs. TDF

Both agents are prodrugs of tenofovir, which is phosphorylated intracellularly to tenofovir diphosphate, a potent competitive inhibitor of HIV reverse transcriptase and HBV DNA polymerase.

INSTI Polyvalent Cation Chelation Interactions

• Mechanism: Integrase Strand Transfer Inhibitors (bictegravir, dolutegravir, raltegravir) utilize catalytic coordination with two divalent magnesium ions ($Mg^{2+}$) within the integrase active site. When co-administered orally with polyvalent metal cations ($Al^{3+}, Mg^{2+}, Ca^{2+}, Fe^{2+}, Fe^{3+}, Zn^{2+}$) present in antacids, multivitamins, and mineral supplements, chelation complexes form in the GI tract, reducing INSTI absorption by up to 70–90% and precipitating virologic failure.
• Management Guidelines:
  • Antacids containing Aluminum / Magnesium: Administer INSTI at least 2 hours before or 6 hours after antacids.
  • Calcium or Iron Supplements: Dolutegravir and bictegravir can be taken simultaneously with calcium or iron supplements IF taken WITH FOOD. If taken on an empty stomach, separate by 2 hours before or 6 hours after.

3. Pre-Exposure Prophylaxis (PrEP) & Post-Exposure Prophylaxis (PEP)

Pre-Exposure Prophylaxis (PrEP)

Indicated for HIV-negative individuals at ongoing substantial risk of HIV acquisition through sexual contact or injection drug use.

PrEP Monitoring Protocol

• Baseline: Document negative HIV status within 7 days prior to initiation using a laboratory-based HIV-1/2 antigen/antibody immunoassay AND HIV-1 RNA qualitative/quantitative assay. Confirm HBV status (HBsAg); screen for STIs, renal function (eGFR, urine protein), and pregnancy.
• Follow-up: Repeat HIV-1 RNA and Ag/Ab testing every 3 months for oral PrEP (or every 2 months before each cabotegravir injection); monitor eGFR semi-annually (or annually if <50 years with eGFR >90 mL/min).

Post-Exposure Prophylaxis (PEP / nPEP)

• Timing Window: Must be initiated as urgently as possible within 72 hours of potential occupational (e.g., needlestick) or non-occupational (unprotected sexual encounter, shared needle, assault) exposure to HIV.
• Duration: Exactly 28 continuous days of triple-drug ART.
• Preferred Regimen: Dolutegravir (Tivicay 50 mg daily) OR Raltegravir (Isentress 400 mg BID) PLUS Truvada (FTC/TDF 200/300 mg daily). (Biktarvy is also widely used off-label as an STR option in clinic protocols).
• Follow-Up Testing: Baseline HIV test, repeat testing at 4–6 weeks and 3 months (12 weeks) post-exposure.

4. Viral Hepatitis: Chronic Hepatitis B (HBV) & Hepatitis C (HCV)

Chronic Hepatitis B Virus (HBV)

• Treatment Goals: Suppress HBV viral replication (HBV DNA), normalize ALT, prevent progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).
• First-Line Oral Antivirals (High Genetic Barrier to Resistance):
  • Entecavir (ETV): 0.5 mg PO once daily on an empty stomach (at least 2 hours before or after meals). Dose is 1 mg daily in lamivudine-refractory patients or decompensated cirrhosis. Requires renal dose reduction.
  • Tenofovir Disoproxil Fumarate (TDF): 300 mg PO daily with or without food. Indicated in lamivudine resistance and pregnancy.
  • Tenofovir Alafenamide (Vemlidy - TAF): 25 mg PO daily with food. Preferred in patients with underlying renal dysfunction (CrCl ≥ 15 mL/min) or osteoporosis.
• Black Box Warning: Severe acute exacerbations of hepatitis B have been reported in patients who discontinue anti-HBV therapy. Closely monitor hepatic function for several months following discontinuation.

Chronic Hepatitis C Virus (HCV) & Direct-Acting Antivirals (DAAs)

Direct-acting antivirals target specific non-structural viral proteins (NS3/4A protease, NS5A replication complex, and NS5B RNA polymerase) to achieve a Sustained Virologic Response at 12 weeks post-treatment (SVR12), which equates to virologic cure in >95% of patients.

┌────────────────────────────────────────────────────────────────────────┐
│                     PANGENOTYPIC DAA REGIMENS (HCV)                    │
├──────────────────────────────────┬─────────────────────────────────────┤
│ MAVYRET (Glecaprevir/Pibrentasvir│ EPCLUSA (Sofosbuvir/Velpatasvir)    │
│ • 3 tablets PO ONCE DAILY w/ food│ • 1 tablet PO ONCE DAILY w/ or w/o  │
│ • DURATION: 8 WEEKS (Naive, +/-  │ • DURATION: 12 WEEKS (Naive, +/-    │
│   compensated Child-Pugh A)      │   compensated Child-Pugh A)         │
│ • Safe in ANY renal function     │ • Avoid PPIs or take Epclusa w/ food│
│   (including Stage 5 CKD/HD)     │   4h before omeprazole ≤20 mg       │
│ • Check statin interactions!     │ • AMIODARONE STRICTLY CONTRAINDICATED│
└──────────────────────────────────┴─────────────────────────────────────┘

DAA Drug Interactions & Clinical Pearls

1. Black Box Warning (HBV Reactivation): All patients initiating DAA therapy must be screened for evidence of current or prior HBV infection (HBsAg and anti-HBc). DAA clearance of HCV allows latent HBV replication to surge, potentially precipitating fulminant hepatic failure. If HBsAg is positive, initiate concurrent anti-HBV therapy.
2. Amiodarone + Sofosbuvir Contraindication: Co-administration of sofosbuvir-containing regimens (Epclusa, Harvoni, Vosevi) with amiodarone causes severe, symptomatic bradycardia and fatal cardiac arrest. Amiodarone is strictly contraindicated.
3. Acid-Reducing Agents with Velpatasvir (Epclusa): Velpatasvir requires an acidic gastric environment for oral dissolution and absorption:
   • Antacids: Separate by at least 4 hours.
   • $H_2$-Receptor Antagonists (Famotidine): Administer simultaneously with Epclusa or 12 hours apart (dose $\le$ 40 mg BID equivalent).
   • Proton Pump Inhibitors (Omeprazole): Avoid if possible. If medically necessary, administer Epclusa with food 4 hours before omeprazole $\le$ 20 mg daily.
4. Statin Interactions with Protease Inhibitors (Glecaprevir / Mavyret): NS3/4A protease inhibitors inhibit OATP1B1/1B3 hepatic transporters and BCRP, dramatically increasing statin plasma concentrations. Simvastatin and high-dose atorvastatin are contraindicated; rosuvastatin must not exceed 10 mg daily.