Study Notes on Human Immunodeficiency Viruses and Acquired Immunodeficiency Syndrome

Understand the indications, mechanism of action of medications used to treat HIV.
Identify and evaluate the adverse effects, drug interactions, contraindications, and monitoring parameters for commonly used antiretroviral medications.
Summarize key contraindications for abacavir and maraviroc, including genetic and pharmacological factors that influence safety.
Define and apply prophylactic regimens for pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), including adjustments for special patient populations.

Routes of Transmission:
- Sexual
- Parenteral
- Perinatal
Hallmark of Untreated HIV: Profound depletion of CD4 T lymphocytes and severe immunosuppression, leading to significant risk of opportunistic infections, morbidity, and mortality.
HIV-1: Major retrovirus causing AIDS.
HIV-2: A less virulent strain of the retrovirus.

CD4+ T Lymphocyte Count (cells/mm³) (e.g., from 1200 to below 200):
- 0 - 3 weeks: Primary infection leads to acute symptoms and rapid depletion of CD4 count.
- Clinical Latency: Gradually reduced CD4 counts.
- Opportunistic Diseases: Significant decrease in CD4 below 200 increases the risk of opportunistic diseases.
  . HIV RNA Copies: Tracks viral load and the disease progression.

Components:
- HIV RNA: Genetic material of HIV.
- HIV Capsid: Core that contains HIV RNA.
- HIV Envelope: Outer surface containing spikes for binding to CD4 cells.
- HIV Enzymes: Proteins that carry out key steps in the HIV life cycle.
- HIV Glycoproteins: Protein spikes embedded in the HIV envelope.

Binding (Attachment): HIV binds to CD4 cell receptors.
Fusion: HIV envelope fuses with the CD4 cell membrane, allowing entry of the virus.
Reverse Transcription: HIV RNA is converted to viral DNA using reverse transcriptase.
Integration: Integrase enzyme incorporates HIV's viral DNA into the host's DNA.
Replication: Integrated viral DNA is transcribed and translated, producing new viral proteins.
Assembly: New HIV particles are formed and transport to the cell surface.
Budding: New immature HIV particles bud off from the host cell and mature into infectious viruses through protease cleavage.

Formerly known as Highly Active Anti-Retroviral Therapy (HAART) — now termed ART because all drugs used are highly active.
Distinct Classes:
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
- Protease Inhibitors
- Integrase Inhibitors
- Fusion Inhibitors
- CCR5 Inhibitors
- Capsid Inhibitors

Mechanism: Inhibit viral reverse transcriptase to prevent viral DNA formation.
Common Examples:
- Zidovudine (AZT): Used widely to prevent vertical transmission; may cause myelosuppression and myopathies.
- Lamivudine (3TC): Also active against hepatitis B; resistance can develop if used as a sole agent.
- Abacavir (ABC): Requires testing for HLA-B*5701 for hypersensitivity reactions; associated with lipid abnormalities.
- Tenofovir (both disoproxil fumarate and alafenamide): Pro-drugs that release tenofovir; major side effects include GI toxicity and renal dysfunction.
- Emtricitabine (FTC): Renally eliminated; can lead to hyperpigmentation in certain populations.

Mechanism: Bind non-competitively to reverse transcriptase leading to conformational change, can show resistance due to single mutations.
Notable Agents:
- Efavirenz (EFV): Side effects include sedation, depression, and vivid dreams.
- Nevirapine (NVP): Used to prevent mother-to-child transmission; may cause hepatotoxicity.
- Etravirine (ETR): Less side effects and improved efficacy for resistant viruses.
- Rilpivirine (RPV): Take with food, metabolized by CYP P450; contraindicated with high viral loads.
- Doravirine (DOR): Approved in 2018; fewer side effects and drug interactions.

Mechanism: Block the action of protease, leading to immature noninfectious virions.
Key Examples:
- Atazanavir (ATV): Risks include hyperbilirubinemia and drug interactions with acid-suppressive therapies.
- Darunavir (DRV): Risk of rash and liver toxicity.
- Ritonavir (RTV): Mostly used as a booster due to significant side effects; metabolizes many ARTs to enhance their effectiveness.

Mechanism: Inhibit integrase to prevent integration of viral DNA into the host genome.
Prominent Agents:
- Raltegravir: Fewer drug interactions and a long safety track record but has a low genetic barrier to resistance.
- Elvitegravir: Typically co-formulated with boosters; numerous drug interactions.
- Dolutegravir: High genetic barrier; associated with weight gain.
- Bictegravir: Utilized in Biktarvy and noted for high genetic barrier.
- Cabotegravir: Used in long-acting injectable form for PrEP.

Fusion Inhibitor: Enfuvirtide (T-20); SQ injection; common ADEs include injection site reactions and hypersensitivity.
CCR5 Antagonist: Maraviroc (MVC); must ensure virus uses this coreceptor, drug interactions with CYP 3A4.

Recommended to begin treatment immediately upon diagnosis confirmation.
START Trial: Multicenter trial evaluating immediate vs deferred ART in treatment-naïve populations.

Initial ART should generally consist of 2-3 drug regimens with at least one integrase inhibitor and two NRTIs.
Preferred Regimens:
- Bictegravir/TAF/FTC: First line.
- Dolutegravir + (Emtricitabine or Lamivudine) + Tenofovir.

Identified factors affecting adherence include psychiatric conditions, substance abuse, social instability, ADEs, missed visits, and the costs of therapy.

Pregnancy:
- ART should commence immediately to minimize risk of transmission to the fetus; avoid Efavirenz and carefully consider Dolutegravir's teratogenic risks.

Post-Exposure Prophylaxis (PEP): Highly effective if initiated soon after exposure in at-risk situations; generally consists of InSTI combined with 2 NRTIs.
Pre-exposure Prophylaxis (PrEP): Daily medications such as Tenofovir and Emtricitabine or long-acting options like Cabotegravir; HIV testing and renal function testing are crucial.

Adherence and misconception regarding “elite HIV controllers”; ensure HIV testing frequency and risks are managed effectively across populations, especially among those with HIV/HBV and HIV/HCV co-infections.

Consult CDC guidelines for further information on management and preventive measures regarding HIV/AIDS.