66.3 Chronic HIV Infection Management & Primary Care Integration

Antiretroviral Therapy (ART): Principles & Modern Regimens

Advances in antiretroviral therapy (ART) have transformed HIV from a fatal progressive immunodeficiency into a manageable, chronic medical condition. Modern primary care integration requires family physicians to manage both viral suppression and long-term cardiometabolic, oncologic, and infectious comorbidities.

Universal Initiation & The U=U Paradigm

• DHHS / WHO Recommendation: ART is recommended for all HIV-infected individuals, regardless of their CD4+ T-cell count, as soon as possible following diagnosis (including same-day "rapid start" ART), to decrease morbidity and mortality and prevent transmission.
• Undetectable = Untransmittable (U=U): Large-scale multicenter prospective studies (PARTNER 1, PARTNER 2, and Opposites Attract) proved conclusively that individuals with HIV who maintain a sustained plasma viral load of $<200\text{ copies/mL}$ (undetectable) on ART have ZERO risk of sexually transmitting HIV to their HIV-negative sexual partners. This paradigm eliminates stigma and promotes lifelong treatment adherence.

First-Line Antiretroviral Regimens

First-line initial regimens for ART-naive adults consist of a second-generation Integrase Strand Transfer Inhibitor (INSTI) with a high barrier to genetic resistance, combined with two Nucleoside Reverse Transcriptase Inhibitors (NRTIs), or a specific approved two-drug regimen:

                    FIRST-LINE INITIAL ART REGIMENS (DHHS GUIDELINES)

   Regimen Formulation               Components & Class Composition                Dosing & Clinical Advantages
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════════
   Biktarvy                          • Bictegravir (50 mg INSTI)                   • Single tablet once daily with or without food.
   (Single-Tablet Regimen)           • Tenofovir Alafenamide (TAF 25 mg NRTI)      • Extremely high barrier to resistance;
                                     • Emtricitabine (FTC 200 mg NRTI)               excellent renal and bone safety profile.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Triumeq                           • Dolutegravir (50 mg INSTI)                  • Single tablet once daily.
   (Single-Tablet Regimen)           • Abacavir (ABC 600 mg NRTI)                  • MANDATORY HLA-B*5701 SCREENING PRIOR
                                     • Lamivudine (3TC 300 mg NRTI)                  TO USE (prevents fatal hypersensitivity!).
                                                                                   • Contraindicated if patient has HBV coinfection.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Tivicay + Descovy or Truvada      • Dolutegravir (50 mg INSTI)                  • Two tablets once daily.
   (Multi-Tablet Regimen)            • PLUS [TAF 25 mg / FTC 200 mg] (Descovy)     • Rapid viral suppression; minimal CYP interactions;
                                       OR [TDF 300 mg / FTC 200 mg] (Truvada)        high resistance barrier.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Dovato                            • Dolutegravir (50 mg INSTI)                  • Single tablet once daily (TWO-DRUG REGIMEN).
   (Approved 2-Drug Regimen)         • Lamivudine (3TC 300 mg NRTI)                • STRICT RESTRICTIONS: Baseline viral load
                                                                                     must be < 500,000 copies/mL, no HBV coinfection,
                                                                                     and no prior M184V/I resistance mutations.
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════

Critical Pharmacological & Organ-Specific Considerations

1. Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF):
   • TDF (Older Formulation): High plasma circulating tenofovir concentrations cause proximal renal tubular dysfunction (Fanconi syndrome: hypophosphatemia, proteinuria, glycosuria, acute kidney injury) and progressive accelerated bone mineral density loss / osteomalacia.
   • TAF (Newer Formulation): A targeted prodrug that is taken up intracellularly into lymphoid cells and peripheral blood mononuclear cells before hydrolyzing into active tenofovir diphosphate. Plasma circulating tenofovir levels are 90% lower, resulting in significantly less renal tubular toxicity and minimal bone mineral density impact. However, TAF is associated with greater weight gain and mild lipid elevations compared to TDF.
2. Abacavir & The HLA-B*5701 Hypersensitivity Reaction:
   • Patients possessing the HLA-B*5701 allele (present in 5–8% of Caucasians) have an extreme risk of a life-threatening, multi-system hypersensitivity reaction (fever, rash, nausea, vomiting, dyspnea, hypotension).
   • Mandatory Rule: Every patient must be screened for HLA-B*5701 before initiating abacavir. If positive, abacavir is permanently contraindicated and documented as an allergy. Never rechallenge a patient suspected of abacavir hypersensitivity, as re-exposure can be rapidly fatal.
3. Coadministration with Polyvalent Cations:
   • Integrase inhibitors (bictegravir, dolutegravir) chelate divalent/trivalent cations ($Mg^{2+}, Al^{3+}, Ca^{2+}, Fe^{2+}$). Antacids, sucralfate, calcium, or iron supplements bind INSTIs in the gastrointestinal tract, dropping absorption by $>70%$. INSTIs must be taken at least 2 hours before or 6 hours after cation-containing antacids/supplements.

Laboratory Monitoring Schedule

• Baseline Evaluation: Plasma HIV-1 RNA viral load, CD4+ T-lymphocyte count, HIV genotype/resistance test (reverse transcriptase and protease, ± integrase), complete blood count, comprehensive metabolic panel (BUN, creatinine, eGFR, LFTs), fasting lipid profile, HbA1c, urinalysis with urine protein/creatinine ratio, HLA-B*5701 screen, Hepatitis A/B/C serologies, syphilis testing (RPR/VDRL), gonorrhea/chlamydia NAAT, and baseline IGRA/tuberculin skin test.
• Longitudinal Monitoring:
  • Plasma HIV RNA and CD4 count: Check 2 to 4 weeks after ART initiation/modification, then every 3 to 6 months until virologically suppressed ($<50\text{ copies/mL}$). Once suppressed for $>1–2$ years with CD4 $>300–500\text{ cells/}\mu\text{L}$, viral load can be monitored every 6 months, and routine CD4 monitoring may be optional.

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Opportunistic Infection (OI) Prophylaxis Protocol

Opportunistic infections correlate directly with the degree of cell-mediated immunosuppression quantified by the absolute CD4+ T-cell count:

                  OPPORTUNISTIC INFECTION PROPHYLAXIS PROTOCOL (DHHS / CDC)

   CD4+ Threshold       Target Pathogen                    First-Line Prophylactic Regimen              Alternative Regimens & Stopping Criteria
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════
   CD4 < 200 cells/μL   Pneumocystis jirovecii             • TMP-SMX (Bactrim) 1 Double-Strength        • Alternatives (Sulfa allergy / G6PD):
   (or CD4% < 14% or    Pneumonia (PJP)                      (DS) tablet PO once daily                    - Dapsone 100 mg daily (check G6PD!)
   oral thrush)                                            • Co-protects against Toxoplasma gondii      - Atovaquone 1500 mg daily with meals
                                                                                                          - Aerosolized Pentamidine 300 mg monthly.
                                                                                                        • DISCONTINUATION: Stop when CD4 > 200
                                                                                                          for ≥ 3 consecutive months on ART.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   CD4 < 100 cells/μL   Toxoplasma gondii Encephalitis     • TMP-SMX 1 DS tablet PO once daily          • Alternative: Dapsone 50 mg daily +
   (and positive        (Cerebral mass lesions, seizures)    (same regimen as PJP prophylaxis)            Pyrimethamine 50 mg/week + Leucovorin 25 mg/wk,
   Toxoplasma IgG)                                                                                        or Atovaquone 1500 mg daily.
                                                                                                        • DISCONTINUATION: Stop when CD4 > 200
                                                                                                          for ≥ 3 consecutive months on ART.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   CD4 < 50 cells/μL    Mycobacterium avium Complex (MAC)  • ROUTINE PRIMARY PROPHYLAXIS IS NO          • Primary prophylaxis with Azithromycin
                        (Disseminated fever, drenching       LONGER RECOMMENDED in patients who           1200 mg weekly is RESERVED ONLY for
                        night sweats, severe anemia,         IMMEDIATELY INITIATE ART.                    patients NOT on effective ART or with
                        hepatosplenomegaly)                                                               persistent viremia.
                                                                                                        • Stop when effective ART is initiated.
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════

Immune Reconstitution Inflammatory Syndrome (IRIS)

When ART is initiated in a patient with severe baseline immunosuppression (typically CD4 $<100\text{ cells/}\mu\text{L}$), rapid immune recovery and proliferation of pathogen-specific CD4 memory cells can trigger an exuberant, dysregulated hyperinflammatory response termed IRIS:

• Paradoxical IRIS: Exaggerated, paradoxical clinical worsening of a treated opportunistic infection (e.g., patient being treated for pulmonary tuberculosis suddenly develops high fevers, expanding infiltrates, and massive lymphadenopathy despite microbiological cure).
• Unmasking IRIS: Sudden, aggressive clinical presentation of a previously occult, subclinical, undiagnosed opportunistic pathogen (e.g., undiagnosed cryptococcal meningitis erupting with intracranial hypertension and cranial nerve palsies 2 weeks after ART start).
• Management Principles:
  • DO NOT STOP ART in most cases: Maintain antiretroviral therapy to ensure long-term immune restoration.
  • Treat the underlying opportunistic infection aggressively with specific antimicrobials.
  • For severe, life-threatening inflammation (e.g., CNS IRIS, tracheal compression, severe hypoxemic respiratory failure): Administer systemic corticosteroids (prednisone 0.5 to 1.0 mg/kg/day tapered over 2 to 6 weeks).
  • Exception / Timing Nuance: In acute cryptococcal meningitis, ART must be delayed for 2 to 6 weeks after initiating antifungal therapy (amphotericin B + flucytosine) because early ART initiation in cryptococcal CNS disease dramatically increases mortality from fatal cerebral edema.

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Primary Care Health Maintenance & Comorbidity Management

Because effective ART achieves normal life expectancies, individuals living with chronic HIV face non-AIDS chronic diseases driven by persistent low-grade immune activation, systemic inflammation, and antiretroviral metabolic effects.

Cardiovascular Disease & The REPRIEVE Trial Guidelines

Patients with HIV experience a 1.5- to 2-fold increased relative risk of atherosclerotic cardiovascular disease (ASCVD) compared to uninfected controls, even after adjusting for traditional risk factors.

• The Landmark REPRIEVE Trial (2023): Randomized over 7,700 individuals with HIV aged 40–75 with low-to-moderate 10-year ASCVD risk (median risk ~4.5%) to pitavastatin 4 mg daily versus placebo. Statin therapy resulted in a 35% relative reduction in major adverse cardiovascular events (MACE) and an 11% reduction in all-cause mortality.
• Updated Primary Care Guidelines: Clinicians should recommend moderate-intensity statin therapy (e.g., pitavastatin 4 mg daily, atorvastatin 20 mg daily, or rosuvastatin 10 mg daily) for all individuals with HIV aged 40 to 75 years with low-to-moderate ASCVD risk ($<20%$), independent of baseline LDL levels.
• Drug Interaction Alert: Simvastatin and lovastatin are STRICTLY CONTRAINDICATED with protease inhibitors (atazanavir, darunavir) and cobicistat/ritonavir boosters because CYP3A4 inhibition increases statin levels $>20$-fold, precipitating fatal rhabdomyolysis.

Cancer Screening Protocol in Chronic HIV

                      CANCER SCREENING RECOMMENDATIONS IN HIV

   Malignancy                  Target Population & Screening Protocol                            Clinical Rationale & Notes
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════════
   Cervical Cancer             • Begin cervical Pap smear at diagnosis or onset of               • Markedly increased incidence of
                                 sexual activity (no later than age 21).                           HPV persistence, CIN II/III,
                               • Screen annually for 3 consecutive normal results;                 and invasive cervical carcinoma.
                                 then co-testing (cytology + HPV) every 3 years.                 • AIDS-defining malignancy.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Anal Cancer                 • Consider Anal Cytology (Anal Pap) every 1–3 years for:          • ANCHOR Trial demonstrated that
                                 - Men who have sex with men (MSM)                                 treating biopsy-proven high-grade
                                 - Transgender women                                               squamous intraepithelial lesions (HSIL)
                                 - Women with history of cervical/vulvar HSIL                      with ablation reduces anal cancer by 57%.
                               • Abnormal anal cytology warrants High-Resolution Anoscopy (HRA).
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Breast & Colorectal         • Follow standard average-risk guidelines:                        • Same as general population.
     Malignancies              - Screening mammography starting at age 40 (USPSTF).
                               - Colorectal cancer screening from age 45 to 75.
   ───────────────────────────────────────────────────────────────────────────────────────────────────────────
   Hepatocellular Carcinoma    • Hepatic ultrasound ± serum alpha-fetoprotein (AFP)              • Accelerated progression from
                                 every 6 months in patients with cirrhosis or chronic HBV/HCV.     chronic hepatitis to cirrhosis in HIV.
   ═══════════════════════════════════════════════════════════════════════════════════════════════════════════════

Comprehensive Immunization Guidelines in Chronic HIV

Immunizations must be proactively updated, with strict precautions regarding live vaccines:

1. Pneumococcal Conjugate Vaccine: Single dose of PCV20 (Prevnar 20) alone, OR PCV15 followed by PPSV23 (Pneumovax 23) $\ge 8$ weeks later.
2. Hepatitis B Virus (HBV): Double-dose recombinant hepatitis B vaccine series (40 mcg at 0, 1, and 6 months) OR the 2-dose CpG-adjuvanted vaccine (Heplisav-B 20 mcg at 0 and 1 month). Check post-vaccination surface antibody (anti-HBs) titers 1–2 months after series completion; target anti-HBs $\ge 10\text{ mIU/mL}$.
3. Meningococcal Conjugate (MenACWY): 2-dose primary series administered 8 weeks apart, with a booster dose every 5 years throughout life.
4. Recombinant Zoster Vaccine (Shingrix): 2 doses separated by 2 to 6 months for all adults aged $\ge 19$ years with HIV, regardless of prior zoster history or CD4 count.
5. Human Papillomavirus (HPV): 3-dose series (0, 1–2, and 6 months) of recombinant 9-valent HPV vaccine through age 45 years.
6. Annual Influenza & COVID-19: Routine seasonal intramuscular inactivated influenza vaccine and updated COVID-19 mRNA vaccines.

[!CRITICAL] Live Attenuated Vaccine Prohibition Live attenuated vaccines (MMR, Varicella, Yellow Fever, oral typhoid, intranasal live influenza) are STRICTLY CONTRAINDICATED in any individual with HIV whose CD4+ T-cell count is $< 200\text{ cells/}\mu\text{L}$ (or CD4 percentage $<14%$). Administration of live replication-competent virus in this immunocompromised window can cause uncontrolled, fatal vaccine-strain disseminated infection.