Comprehensive Study Guide: Gender-Affirming Medicine, Infectious Diseases, and Bone Health

Antiviral Pharmacotherapy for Herpes, Hepatitis, and CMV

• Mechanism of Action (MOA) for Herpesvirus Drugs:     * These agents target the viral polymerase.     * They incorporate themselves into the DNA strand during synthesis, leading to elongation inhibition and termination of the strand.

• Key Antiviral Agents and Bioavailability Profiles:     * Acyclovir:         * Characterized by a polar hydroxyl group, which limits its oral bioavailability.         * Functions as a classic chain terminator.         * The newly incorporated non-natural nucleotide lacks a $3'$ hydroxyl group, making the DNA strand unable to undergo further elongation.         * Must be bioactivated via host kinases to function.         * Direct usage of acyclovir triphosphate is impossible due to the high polarity of the group.     * Valacyclovir:         * A prodrug of acyclovir.         * Attaches a more lipophilic group to the end side chain to improve absorption/bioavailability.     * Ganciclovir:         * Contains two hydroxyl groups, which increases polarity and prevents ready absorption.         * Available as intravenous (IV) only.     * Valganciclovir:         * A prodrug of ganciclovir with higher bioavailability due to the addition of a large non-polar group.     * Famicyclovir:         * Possesses the highest bioavailability among the listed agents.         * It is metabolized into penciclovir.

• Antiviral Spectrum of Activity Table:     * HCMV (Human Cytomegalovirus):         * Acyclovir: $-$         * Ganciclovir: $+$         * Famiciclovir: $-$     * HSV (Herpes Simplex Virus):         * Acyclovir: $+$         * Ganciclovir: $+$         * Famiciclovir: $+$     * VZV (Varicella Zoster Virus):         * Acyclovir: $+$         * Ganciclovir: $+$         * Famiciclovir: $+$

• Hepatitis C Viral (HCV) Inhibitors:     * Velpatasvir (NS5A Inhibitor):         * Highly synergistic when combined with sofosbuvir.     * Sofosbuvir (NS5B Inhibitor):         * Acts as an RNA polymerase chain terminator.         * Requires bioactivation via kinases specifically within the hepatocyte.     * General MOA for HCV agents: Inhibition of RNA-dependent RNA polymerase.

Biology of Bone Remodeling and Calcium Homeostasis

• Daily Calcium Turnover:     * The whole-body daily calcium turnover should ideally result in no net loss.     * Equilibrium is reached when dietary intake equals the amount excreted.     * Bone serves as the primary deposition site for the body's calcium.     * The kidneys perform massive reabsorption of calcium daily, excreting very little relative to the filtered load.

• Hormonal Regulation of Calcium Homeostasis:     * Parathyroid Hormone (PTH):         * Increases renal calcium reabsorption.         * Stimulates calcium release from the bone.         * The net result is an increase in plasma calcium levels.     * Calcitriol (Active Vitamin D):         * Increases calcium absorption in the intestines.         * Inhibits the production of PTH.         * The net result is an increase in plasma calcium levels but a decrease in PTH.     * Calcitonin:         * Secreted in increased concentrations in response to high plasma calcium.         * Inhibits calcium release from the bone.         * Inhibits renal calcium reabsorption (increasing urinary excretion).         * Inhibits the production of PTH.         * The net result is a decrease in plasma calcium concentrations.

• Bone Mineral Density (BMD) and Aging:     * Peak BMD is reached in the $20s$ for both males and females, after which it declines.     * Females experience a precipitous decline in BMD following menopause.     * As BMD declines with age, the incidence of bone fractures increases; this is significantly more pronounced in female populations.

Pathophysiology and Mechanisms of Osteoporosis

• Osteoporosis Definition:     * Characterized by the loss of BMD in spongy trabecular bone.     * Leads to microfractures, collapse of vertebrae, and an increased risk of complete fractures.     * Females are more vulnerable due to the decline in estrogen and progesterone post-menopause.     * Molecularly, osteoclast-mediated bone dissolution exceeds the rate of osteoblast-mediated bone production.

• Mechanical Forces and Bone Formation:     * Mechanical bending force (active exercise) moves fluid through Haversian canals and canaliculi.     * Fluid flow is sensed by osteocytes through cellular protrusions and integrin binding.     * Osteocytes sense microdamage, which initially activates osteoclasts, followed by osteocyte-mediated inhibition of those osteoclasts and subsequent stimulation of osteoblast development.

• Biochemical Signaling Pathways:     * RANK/RANKL: Osteoclast development is stimulated by RANK binding to RANK Ligand (RANKL).     * Osteoprotegerin (OPG): Inhibits this binding and induces osteoclast apoptosis.     * Sclerostin:         * A cytokine released by osteocytes that inhibits osteoblast development.         * Mechanical fluid flow (exercise) inhibits sclerostin release, allowing for osteoblast development.         * Sclerostin inhibits the WNT signaling pathway.     * WNT Signaling: Promotes osteoblast proliferation, differentiation, and survival while decreasing osteoclast formation.     * PTH Interaction: PTH blocks the production of sclerostin by osteocytes.

Pharmacologic Treatment of Bone Disorders

• Postmenopausal Osteoporosis Contributors:     * Declining estrogen, reduced physical activity, reduced intestinal calcium absorption, and reduced calcitriol production.

• Hypoestrogenic States vs. Estrogen/SERM Therapy:     * Hypoestrogenic Conditions: Stimulate RANKL production and reduce OPG expression, maturing more osteoclasts.     * Estrogen and Selective Estrogen Receptor Modulators (SERMs):         * Inhibit osteoblast apoptosis.         * Increase OPG levels to inhibit osteoclast differentiation/survival.         * Stimulate calcitriol production.

• SERMs (e.g., Raloxifene):     * Non-steroidal compounds with tissue-selective activity.     * Goal: Act as an estrogen agonist in beneficial tissues (bone, liver) and an antagonist in potentially harmful tissues (breast, endometrium, vasculature).

• Denosumab:     * A monoclonal antibody that binds to RANKL, preventing it from binding to RANK.     * Promotes apoptosis of mature osteoclasts (antiresorptive).     * Warning: Discontinuation causes a rebound effect with abrupt changes in bone remodeling.

• PTH Analogs (Teriparatide and Abaloparatide):     * Inhibit OPG and increase RANKL when continuous, but intermittently administered, they increase BMD and reduce fracture risk.     * Increase bone formation by inhibiting sclerostin.

• Romosozumab:     * Anti-sclerostin monoclonal antibody (anabolic agent).     * Increases WNT signaling by inhibiting sclerostin, leading to decreased osteoclast formation and increased osteoblast activity.

• Vitamin D (Calcitriol):     * Precursor is cholesterol; requires heat and sunlight to create provitamin $D_3$.     * Requires renal function ($1-\alpha$ hydroxylase enzyme) for final bioactivation.

• Bisphosphonates:     * Pyrophosphate analogs with high affinity for bone mineral (hydroxyapatite).     * Inhibit Farnesyl diphosphate synthase (FPPS) in osteoclasts, which is necessary for protein prenylation and cell survival.     * Generational Differences: Third-generation bisphosphonates have higher binding affinity for hydroxyapatite and the active site of FPPS than second-generation drugs.

Factors Contributing to Bone Density Loss

• GERD Medications (e.g., Prilosec/PPIs): Inhibit calcium absorption from the GI tract.

• Aromatase Inhibitors (Breast Cancer): Decrease estrogen levels.

• Thiazolidinediones (TZDs for Diabetes): Trigger stem cell differentiation into adipocytes instead of osteoblasts.

• Long-term Glucocorticoids (e.g., Prednisone):     * Causes low blood calcium.     * Decreases GI calcium absorption.     * Increases urinary calcium excretion.     * Depresses osteoblast formation.

• GnRH Agonists/Antagonists: Decrease estrogen levels.

• Depo-MPA: Contributes to bone density loss.

Clinical Assessment and Screening for Osteoporosis

• Diagnostic Gold Standard: Dual-energy X-ray absorptiometry (DXA) of the lumbar spine and hip.

• Scoring Definitions:     * Z-Score: BMD compared to an age-, sex-, and ethnicity-matched reference population.     * T-Score: BMD compared to a young-adult reference population of the same sex (e.g., comparing a $60$-year-old to a $20$-year-old).

• Bone Mass Classification (T-Scores):     * Normal: $-1.0$ and above (within $1$ SD of the mean).     * Low Bone Mass (Osteopenia): Between $-1.0$ and $-2.5$.     * Osteoporosis: $-2.5$ and below or the presence of an incident fracture (hip, vertebral, or forearm).

• Screening Recommendations (BHOF):     * Women aged $\geq 65$.     * Men aged $\geq 70$.     * Postmenopausal women and men aged $50-69$ with clinical risk factors.     * Adults aged $\geq 50$ with a history of adult-age fracture.

• Vertebral Fracture Imaging Criteria:     * Women $\geq 65$ if T-score $\leq -1.0$ (femoral neck).     * Women $\geq 70$ and Men $\geq 80$ if T-score $\leq -1.0$ (lumbar spine, total hip, or femoral neck).     * Men aged $70-79$ if T-score $\leq -1.5$.     * Height loss > 1.5 inches in women $\geq 70$.

Non-Pharmacologic Management and Supplemental Calcium/Vitamin D

• Lifestyle Interventions:     * Weight-based and resistance exercise.     * Smoking cessation and limiting alcohol (ETOH) consumption.     * Fall prevention (utilizing Beers List and STOPP criteria).

• Recommended Daily Intake for Calcium and Vitamin D:     * Ages 19-50 (Men & Women): $1000\,mg$ Calcium / $400-600\,units$ Vitamin D.     * Men Age 50-70: $1000\,mg$ Calcium / $800-1000\,units$ Vitamin D.     * Women $\geq 51$ and Men $\geq 71$: $1200\,mg$ Calcium / $800-1000\,units$ Vitamin D.

• Calcium Supplementation Details:     * Calcium Carbonate: Requires an acidic environment; take with food; PPIs reduce absorption; more constipating.     * Calcium Citrate: Acid-independent absorption; better tolerated; fewer drug-drug interactions (DDIs).     * Dosing Tip: Limit individual doses to $500-600\,mg$ at a time for optimal absorption.

• Dietary Sources (approx. Ca content):     * Milk/Yogurt: $300\,mg$.     * Almond Milk: $450\,mg$.     * Cheese: $200\,mg$.     * Tofu (firm): $250\,mg$.     * Add $250\,mg$ for baseline "daily other" intake.

Detailed Antiresorptive and Anabolic Medication Profiles

• Bisphosphonates Safety and Administration:     * Contraindications: Esophageal delay abnormalities, hypocalcemia, inability to sit upright for $30$ minutes ($60$ minutes for Ibandronate).     * Renal thresholds: Not recommended if CrCl < 35\,mL/min (Alendronate, Zoledronic acid) or CrCl < 30\,mL/min (Risedronate, Ibandronate).     * Adverse Effects: Osteonecrosis of the jaw and atypical femur fractures.     * Administration: Take with a full glass of water $30$ minutes before eating ($60$ minutes for Ibandronate); no NSAIDs for flu-like symptoms after Zoledronic acid (use APAP).

• Denosumab Considerations:     * Indicated for osteoporosis and prevention for patients on aromatase inhibitors or androgen deprivation therapy.     * Monitor serum calcium weekly for the first month if eGFR < 30\,mL/min/1.73\,m^2.

• Anabolic Therapy (Teriparatide/Abaloparatide):     * Use is generally restricted to $24$ months.     * Can cause hypercalciuria and hypercalcemia.

• Raloxifene (SERM):     * Contraindicated in patients with a history of VTE or during pregnancy.     * Reduces breast cancer risk but only prevents vertebral fractures.

Sexual Health, Stigma, and Expedited Partner Treatment (EPT)

• The 5 Ps of Sexual History:     * 1. Partners     * 2. Practices     * 3. Protection     * 4. Past history of STIs     * 5. Pregnancy Intentions

• At-Risk Populations: Adolescents, young adults, men who have sex with men (MSM), pregnant women, and Black, Native American, and Hispanic communities.

• Expedited Partner Treatment (EPT):     * A harm-reduction strategy where providers treat the sexual partners of patients diagnosed with specific STIs without examining the partner.     * Prescription Requirements:         * Prescriber name, address, and phone number.         * Date of issue.         * Patient name and Date of Birth (DOB).         * Patient address (Partner address is not required).         * Best practice: Indicate "EPT" on the script.         * No refills allowed; requires signature, quantity, and name of drug.         * Note: DEA number is not required for EPT.

Immunizations: Varicella, Zoster, HPV, and MPox

• Varicella (Varivax):     * Live attenuated virus; SubQ administration.     * Two-dose series: Dose 1 at $12-15$ months; Dose 2 at $4-6$ years.

• Shingles (Shingrix - RZV):     * Recombinant Zoster Vaccine; intramuscular.     * Two-dose series given $2-6$ months apart.     * Recommended for all adults $\geq 50$ (even if they had chickenpox or the previous Zostavax) and immunocompromised adults $\geq 19$.

• Human Papillomavirus (HPV - Gardasil 9):     * 9-valent recombinant vaccine ($6, 11, 16, 18, 31, 33, 45, 52, 58$).     * Targets females and males aged $9-45$.     * Doses:         * Before $15^{th}$ birthday: 2 doses ($6-12$ months apart).         * After $15^{th}$ birthday: 3 doses ($0, 1-2, 6$ months).

• MPox Virus:     * Treatment: Supportive care, pain management, and Tecovirimat.     * Prevention: JYNNEOS vaccine (2-dose SubQ, $4$ weeks apart).

Pharmacotherapy of Viral Hepatitis (A, B, and C)

• Hepatitis A (HAV):     * Fecal-oral transmission. Treatment is supportive.     * Vaccine is inactivated whole-cell, IM, 2 doses at least $6$ months apart.

• Hepatitis B (HBV):     * Serology Meanings:         * HBsAg (+): Infectious (acute or chronic).         * HBsAb (+): Recovery/Immunity from infection or vaccination.         * HBcAb (+): Previous or ongoing infection (core antibody).         * IgM HBcAb (+): Recent acute infection.     * Treatment: Interferons (curative, no resistance) or Nucleotide Analogs (indefinite therapy).

• Hepatitis C (HCV):     * FIB-4 Score Algorithm: Uses age, AST, ALT, and platelets.         * < 1.45: Treat in Primary Care.         * $1.45-3.25$: Perform Fibroscan; if $F0-F2$, treat in Primary Care.         * > 3.25 or Fibroscan $F3-F4$: Refer to Hepatology (Cirrhosis suspected).     * Agents:         * NS3/4A Protease Inhibitors: "-previr" (e.g., Glecaprevir).         * NS5A Inhibitors: "-asvir" (e.g., Pibrentasvir, Velpatasvir).         * NS5B Polymerase Inhibitors: "-buvir" (e.g., Sofosbuvir).     * Regimens: Mavyret (8 weeks with food) or Epclusa (12 weeks).

Management of HIV: Initiation, Regimens, and Special Populations

• Initiation: Start ART at diagnosis regardless of CD4 count.

• Regimen Design: Typically 2 NRTIs ("backbone") + a Base (INSTI, PI, or NNRTI).     * Backbone: Abacavir or Tenofovir + Lamivudine or Emtricitabine.     * First-Line choice: Tenofovir + Lamivudine/Emtricitabine + Dolutegravir/Bictegravir.

• Standard Regimens:     * Biktarvy (TAF/FTC/BIC): Low resistance risk; do not use with rifamycins.     * Dovato (DTG/FTC): 2-drug regimen; not for viral loads > 500,000 or HBV co-infection.     * HLA-B*5701 Testing: Required before using Abacavir.

• TDF vs. TAF:     * TDF: Higher bone/renal toxicity; converts to TFV in plasma.     * TAF: Safer; stays in lymphocytes; better for kidney/bone.

• Renal thresholds: TDF not for eGFR < 60\,mL/min; TAF not for eGFR < 30\,mL/min.

HIV Prevention: PrEP and PEP Strategies

• PrEP Drugs: TDF, TAF, FTC, and Cabotegravir.

• PEP Drugs: TAF, TDF, FTC, DTG, and BIC.

• Long-Acting Cabotegravir:     * Gluteal injection; $2$-inch needle for BMI > 30\,kg/m^2.     * If injection is missed by > 7 days, bridge with oral cabotegravir for $28$ days.

• Lenacapavir (LEN):     * SQ injection (2 injections at least $4$ inches apart every $6$ months).     * Avoid with strong P-gp or CYP3A4 inhibitors (Rifampin, Carbamazepine, St. John's Wort).

• Post-Exposure Prophylaxis (PEP):     * Must start within $72$ hours of exposure (ineffective at $\geq 73$ hours).     * Duration: $4$ weeks; 3-drug regimen preferred.

Management of Herpesviruses and Cytomegalovirus (CMV)

• HSV-1 (Orofacial): Docosanol (OTC), Topical Penciclovir ($q2h \times 4\,days$), or Valacyclovir ($2\,g\,q12h \times 1\,day$).

• HSV-2 (Genital): Valacyclovir $1\,g\,BID$ for initial; $1\,g\,QD$ for suppression if < 10 outbreaks/year.

• Varicella Zoster (Shingles): Initiation within $72$ hours of rash; Valacyclovir $1\,g\,TID \times 7\,days$.

• CMV Dosing:     * Pediatrics: IV Ganciclovir ($6\,mg/kg\,q12h$) for $6$ weeks, then oral Valganciclovir ($16\,mg/kg\,BID$) for $6$ months.     * Pregnancy: Valacyclovir $8\,g/day$ for mothers with primary CMV in the $1^{st}$ trimester.

Public Health Surveillance and Population Health

• Definition: The ongoing, systemic collection, analysis, and implementation of health-related data.

• Goals: Describe needs for prevention, characterize at-risk populations, and measure intervention impact.

• Population Health: The assessment of health determinants and outcomes within specific groups.