Comprehensive Pharmacotherapy Reference Guide
Based on: NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections v1.2026 (March 11, 2026) | IDSA Guidelines
SECTION 1: OVERVIEW, MICROBIOLOGY & PATHOPHYSIOLOGY
1.1 Overview
- HSV (Herpes Simplex Virus) and VZV (Varicella Zoster Virus) are alpha-herpesviruses that establish lifelong latency in sensory ganglia after primary infection.
- In immunocompromised oncology patients, these viruses are a major cause of morbidity due to reactivation, not primary infection in most adults.
- Reactivation risk is directly proportional to the degree and duration of immunosuppression.
1.2 Key Distinctions: HSV-1, HSV-2, and VZV
| Feature | HSV-1 | HSV-2 | VZV |
|---|---|---|---|
| Primary Disease | Oral/labial herpes, encephalitis | Genital herpes | Varicella (chickenpox) |
| Reactivation | Cold sores, esophagitis, pneumonitis, encephalitis | Genital lesions, perianal ulcers | Herpes zoster (shingles), disseminated VZV |
| Latency Site | Trigeminal ganglia | Sacral ganglia | Dorsal root/cranial nerve ganglia |
| Oncology Relevance | Mucositis-trigger, esophagitis in HCT | Perianal/rectal ulcers in neutropenic pts | Zoster reactivation in allo-HCT, myeloma, CLL, CAR-T |
SECTION 2: RISK STRATIFICATION (NCCN INF-1 & INF-3, v1.2026)
2.1 NCCN Infection Risk Categories (INF-1)
| RISK LEVEL | DISEASE / THERAPY EXAMPLES | HSV/VZV PROPHYLAXIS |
| LOW | • Standard chemotherapy for solid tumors • Anticipated neutropenia < 7 days | • No prophylaxis needed • EXCEPTION: Give if prior HSV episode (treat during active therapy/neutropenia) |
| INTERMEDIATE | • Autologous HCT • Lymphoma (heterogeneous) • Multiple myeloma • CLL • Purine analogs (fludarabine, clofarabine, nelarabine, cladribine) • Anticipated neutropenia 7–10 days • CAR T-cell therapy [NEW v1.2026] | HSV: Consider during active therapy + possibly longer per immunosuppression VZV: Consider ≥6–12 months after autologous HCT or CAR T-cell therapy [NEW v1.2026] |
| HIGH | • Allogeneic HCT (including cord blood) • Acute leukemia (induction & consolidation) • Alemtuzumab therapy • Moderate-to-severe GVHD • Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) • Anticipated neutropenia > 10 days | HSV: Entire active therapy + neutropenia Alemtuzumab: minimum 2 months post- alemtuzumab AND until CD4 ≥ 200 cells/mcL VZV: ≥ 1 year after allogeneic HCT Proteasome inhibitors: during active therapy |
💎 CLINICAL PEARL: Letermovir (used for CMV prophylaxis post-allo-HCT) has NO activity against HSV or VZV. Always ensure separate HSV/VZV prophylaxis is maintained when letermovir is used (NCCN INF-4 footnote q).
💎 CLINICAL PEARL: CAR T-cell therapy was added in NCCN v1.2026 as an intermediate-risk indication for VZV prophylaxis (at least 6–12 months post-CAR-T). Flag all CAR-T patients for VZV prophylaxis review.
⚠ PHARMACIST WATCHOUT: In HCT recipients, prophylaxis is ONLY indicated if either the donor OR the recipient is seropositive for the virus. Always check donor and recipient serologies before initiating or discontinuing prophylaxis.
SECTION 3: CLINICAL PRESENTATIONS, SIGNS & SYMPTOMS
3.1 HSV in Oncology Patients
| SYNDROME | SIGNS & SYMPTOMS | ONCOLOGY PEARLS |
| Orolabial (HSV-1) | Vesicular/ulcerative lesions at lips/oral mucosa Pain, tingling, burning prodrome May present as severe mucositis overlapping with chemo-induced mucositis | Can mimic or worsen chemo-induced mucositis Assess oral cavity DAILY in neutropenic patients HSV may colonize mucositis ulcers |
| Esophagitis | Odynophagia (painful swallowing) Dysphagia, chest pain May lack classic skin lesions | NCCN FEV-6 update v1.2026: Esophagitis workup now requires HSV AND CMV diagnostics Initial therapy guided by clinical findings (eg, perioral HSV) |
| Encephalitis / CNS | Fever, headache, AMS, seizures Focal neurologic deficits MRI: temporal lobe involvement (HSV-1) | EMERGENCY — high mortality without treatment CSF PCR (HSV-1/2) is diagnostic test of choice IV acyclovir 10 mg/kg q8h — do not delay for results |
| Disseminated Cutaneous | Widespread vesicular eruption Hepatitis, pneumonitis possible High fever, severe illness | IV acyclovir required Isolate patient Can be fatal in profoundly immunocompromised patients |
| Genital/Perianal (HSV-2) | Painful ulcers at genitals, perianal area In neutropenic: may be atypical, deep, non-healing Proctitis, urinary retention possible | Perianal ulcers in neutropenic pts are an oncologic emergency Differential: CDiff colitis, CMV colitis, neutropenic colitis Swab and PCR testing |
3.2 VZV in Oncology Patients
| SYNDROME | SIGNS & SYMPTOMS | ONCOLOGY PEARLS |
| Dermatomal Zoster | Painful vesicular rash in 1–3 dermatomes Prodrome: burning/shooting pain before rash (1–5 days) Postherpetic neuralgia (PHN) risk post-resolution | Most common VZV presentation in hem/onc Bortezomib/carfilzomib (proteasome inhibitors) → especially high risk Start treatment within 72h of rash onset |
| Disseminated VZV | Vesicular rash crossing >3 dermatomes OR involving organs Fever, hepatitis, pneumonitis, encephalitis High mortality in HCT patients | IV acyclovir REQUIRED — not oral Airborne + contact precautions May lack typical dermatomal distribution |
| Primary Varicella (Chickenpox) | Generalized pruritic vesicular rash in various stages Fever, malaise Rare in adults (most immune) | Can be fatal in the immunocompromised VZV immunoglobulin (VariZIG) for post-exposure prophylaxis in seronegative patients IV acyclovir for treatment |
| Zoster Ophthalmicus | Rash involving V1 (ophthalmic) branch of CN V Hutchinson’s sign: vesicle on nose tip Eye pain, photophobia | URGENT Ophthalmology consult Risk of keratitis, uveitis, blindness Oral valacyclovir preferred if mild; IV if severe/disseminated |
| Ramsay Hunt Syndrome | Facial nerve palsy + auricular vesicles Ear pain, hearing loss, vertigo | VZV reactivation in CN VII geniculate ganglion Treat as dermatomal VZV |
⚠ PHARMACIST WATCHOUT: In neutropenic patients, typical vesicular skin lesions may be ABSENT or atypical. A high index of suspicion is required. Consider HSV/VZV PCR even for non-classic presentations.
💎 CLINICAL PEARL: Postherpetic neuralgia (PHN) after VZV can be severe and debilitating — early treatment initiation (within 72h) significantly reduces PHN risk. Alert the team about timing.
SECTION 4: DIAGNOSIS & LABORATORY EVALUATION
4.1 Diagnostic Workup
| TEST | INDICATION / SPECIMEN | COMMENTS |
| PCR (HSV/VZV DNA) | Vesicle swab, CSF, BAL, biopsy tissue, blood GOLD STANDARD | Most sensitive and specific test Can differentiate HSV-1 vs HSV-2 vs VZV CSF PCR for CNS disease |
| Tzanck Smear | Vesicle base scraping Rapid bedside test | Quick but low sensitivity Does NOT differentiate HSV vs VZV Cannot replace PCR |
| Viral Culture | Vesicle swab, CSF, bronchial washings | Takes days; less sensitive than PCR Useful for resistance testing (if needed) |
| Serology (IgG/IgM) | Serum — primarily for screening/seroprevalence | NOT useful for acute diagnosis in immunocompromised Seropositive IgG confirms prior exposure (relevant for prophylaxis decisions in HCT) |
| Skin Biopsy | Atypical/unusual lesions | Includes histology + immunostaining + PCR For disseminated or atypical presentations |
| Endoscopy + Biopsy | Esophagitis workup | NCCN FEV-6 v1.2026: Esophageal evaluation now requires HSV AND CMV diagnostics Biopsy with immunostaining |
| MRI Brain / LP | Suspected HSV encephalitis — CNS symptoms | MRI: temporal lobe hyperintensity on FLAIR CSF: PCR for HSV; elevated WBCs Start empiric IV acyclovir BEFORE results |
4.2 Key Laboratory Cutoffs & Baseline Labs
- Renal Function (SCr, BUN, eGFR/CrCl): CRITICAL before starting acyclovir/valacyclovir — all require renal dose adjustments.
- CBC with differential: Assess ANC, lymphocyte count, CD4 count (relevant for alemtuzumab patients — prophylaxis until CD4 ≥ 200 cells/mcL).
- LFTs (AST/ALT, bilirubin): Baseline before antivirals — monitor for hepatotoxicity.
- Electrolytes (Na, K, Mg, Phos): Especially important with IV foscarnet — causes severe electrolyte disturbances.
- Urinalysis + urine output: High-dose IV acyclovir requires adequate hydration and urine output monitoring to prevent crystal nephropathy.
🔴 CRITICAL: Before initiating IV acyclovir: HYDRATE the patient. Inadequate hydration causes acyclovir crystal nephropathy and acute kidney injury (AKI). Monitor SCr every 24–48h during high-dose IV therapy.
💎 CLINICAL PEARL: CD4 count cutoff for stopping alemtuzumab-related prophylaxis: CD4 ≥ 200 cells/mcL (NCCN INF-3). Never stop prophylaxis based on ANC alone in these patients.
SECTION 5: DIFFERENTIAL DIAGNOSIS
5.1 Differential for Mucocutaneous Lesions in Oncology Patients
| CONDITION | KEY FEATURES | HOW TO DIFFERENTIATE |
| HSV Mucositis/Esophagitis | Vesicular → ulcerative oral/esophageal lesions; focal; oral cold sores | HSV PCR swab; endoscopy + biopsy for esophageal |
| Chemo-induced Mucositis | Diffuse erythema/ulcers; temporally related to chemo (5–14 days) | Clinical; lack of HSV PCR positivity; responds to supportive care only |
| CMV Esophagitis/Colitis | Esophageal ulcers; linear lesions; diarrhea; fever; post-HCT | CMV PCR (blood + tissue); endoscopy biopsy — owl-eye inclusion bodies |
| Oral Candidiasis (Thrush) | White plaques on buccal mucosa; removable; may be painless | KOH prep; clinical; responds to antifungals — NOT antivirals |
| Aphthous Ulcers | Painful ulcers — round/oval, white base, erythematous halo | HSV PCR negative; no viral prodrome; no vesicles |
| VZV Zoster vs. Other Vesicular Rash | Dermatomal vesicular rash with pain; linear distribution | PCR from vesicle swab; Tzanck smear (cannot distinguish HSV vs VZV) |
| Drug Reaction / TEN / SJS | Widespread blistering; may involve mucous membranes; medication history | Drug causality review; biopsy; negative viral PCR; dermatology consult |
| GVHD (Skin/Oral) | Post-allo-HCT; lichenoid changes, erythema, desquamation; oral changes | Clinical context (allo-HCT); biopsy; negative HSV/VZV PCR |
| Neutropenic Enterocolitis / Perirectal Infection | Perirectal pain/tenderness; in neutropenic patients; may ulcerate | Can co-exist with HSV-2! PCR swab of perirectal area; CT abdomen/pelvis |
⚠ PHARMACIST WATCHOUT: CRITICAL: HSV esophagitis and CMV esophagitis can COEXIST in immunocompromised patients. Always send BOTH HSV and CMV diagnostics with esophageal biopsies (NCCN FEV-6 v1.2026).
SECTION 6: PHARMACOTHERAPY — DOSING, RENAL ADJUSTMENTS & MONITORING
NCCN v1.2026 — NCCN FEV-C v1.2026 — All dosing below is for ADULT patients with NORMAL renal function unless specified. Consult package insert for pediatric dosing and obesity adjustments.
NCCN v1.2026 — Acyclovir and valacyclovir dosing based on IDEAL BODY WEIGHT (IBW). Critical for obese patients — do not use actual body weight for IV dosing!
6.1 First-Line Antivirals: Acyclovir & Valacyclovir
ACYCLOVIR (Zovirax) — IV and Oral
| INDICATION | DOSE (NCCN FEV-C v1.2026) | ROUTE / DURATION |
| HSV Prophylaxis | 400–800 mg PO BID | Oral; duration per risk (INF-3) |
| VZV Prophylaxis (allo-HCT) | 400–800 mg PO BID | Oral; ≥1 year post-allo-HCT |
| Post-VZV Exposure Prophylaxis | 800 mg PO 5 times daily | Oral; started promptly after exposure |
| HSV Treatment (Significant Mucocutaneous) | 5 mg/kg IV every 8 h | IV; 7–10 days |
| VZV Treatment (Single Dermatomal) | 800 mg PO 5 times daily OR 10 mg/kg IV every 8 h | PO or IV; 7–10 days |
| Disseminated HSV/VZV or Encephalitis | 10 mg/kg IV every 8 h | IV; MINIMUM 14–21 days for encephalitis |
Acyclovir Renal Dose Adjustments (Adult)
| CrCl (mL/min) | Oral 200–800 mg | IV 5 mg/kg | IV 10 mg/kg |
| ≥ 50 | No adjustment | 5 mg/kg q8h | 10 mg/kg q8h |
| 25–50 | No adjustment | 5 mg/kg q12h | 10 mg/kg q12h |
| 10–25 | Reduce dose/frequency | 5 mg/kg q24h | 10 mg/kg q24h |
| < 10 (inc. HD) | 200 mg q12h | 2.5 mg/kg q24h | 5 mg/kg q24h — dose after HD |
🔴 CRITICAL: IV Acyclovir requires infusion over ≥ 60 MINUTES to prevent renal tubular precipitation. Do NOT push. Hydrate with 500–1000 mL NS before/during therapy. Monitor urine output, SCr every 24–48h.
💎 CLINICAL PEARL: Acyclovir dosing based on IDEAL BODY WEIGHT (IBW). For obese patients, use IBW + 40% of excess weight (adjusted BW) — NOT actual body weight.
⚠ PHARMACIST WATCHOUT: High-dose acyclovir can cause neurotoxicity (tremors, myoclonus, confusion, hallucinations) — especially with renal impairment. This is under-recognized. If new neuro symptoms develop in a patient on IV acyclovir, check levels/dose.
VALACYCLOVIR (Valtrex) — Oral [PREFERRED over oral acyclovir per NCCN v1.2026]
| INDICATION | DOSE (NCCN FEV-C v1.2026) | NOTES |
| HSV/VZV Prophylaxis | 500 mg PO BID | Preferred over oral acyclovir for VZV (NCCN v1.2026) |
| HSV Treatment | 1 g PO BID | [Updated NCCN FEV-C v1.2026] |
| VZV Treatment | 1 g PO TID | [Updated NCCN FEV-C v1.2026] Preferred over oral acyclovir for VZV |
Valacyclovir Renal Dose Adjustments
| CrCl (mL/min) | Prophylaxis (500 mg BID) | VZV Treatment (1g TID) |
| ≥ 50 | 500 mg BID — no adjustment | 1 g TID — no adjustment |
| 30–49 | 500 mg BID | 1 g BID |
| 10–29 | 500 mg daily | 1 g daily |
| < 10 (HD) | 250 mg daily (post-HD) | 500 mg daily (post-HD) |
🔴 CRITICAL: Valacyclovir at high doses can cause Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (TTP/HUS) in severely immunocompromised patients. This is a rare but FATAL complication. Monitor platelets and schistocytes in HCT patients on high-dose valacyclovir.
6.2 Famciclovir
| INDICATION | DOSE (NCCN FEV-C v1.2026) | NOTES |
| HSV or VZV Prophylaxis | 250 mg PO BID | Note: NCCN states ‘No data for oncologic-related prophylaxis’ — use valacyclovir or acyclovir preferentially |
| HSV Treatment | 250 mg PO TID | Renal adjustment required at CrCl < 60 mL/min |
| VZV Treatment | 500 mg PO TID | Renal adjustment required at CrCl < 60 mL/min |
⚠ PHARMACIST WATCHOUT: Famciclovir: NCCN explicitly states ‘No data for oncologic-related prophylaxis.’ Do not recommend famciclovir as first-line for prophylaxis in oncology patients. Use acyclovir or valacyclovir.
6.3 Foscarnet — Second-Line / Acyclovir-Resistant HSV/VZV
NCCN v1.2026 — Foscarnet is the drug of choice for acyclovir-resistant HSV and VZV (NCCN FEV-C 2 of 4)
| INDICATION | DOSE (NCCN FEV-C v1.2026) | NOTES |
| Acyclovir-Resistant HSV | 40 mg/kg IV every 8–12 h for 7–10 days | [Updated NCCN FEV-C 2 of 4, v1.2026] |
| Acyclovir-Resistant VZV | 40 mg/kg IV every 8–12 h | ID consult strongly recommended |
🔴 CRITICAL: Foscarnet is HIGHLY NEPHROTOXIC and causes severe ELECTROLYTE disturbances (hypocalcemia, hypomagnesemia, hypo/hyperphosphatemia, hypokalemia). PRE-HYDRATE with 500–1000 mL NS. Monitor electrolytes BID minimum during induction. Never give without IV hydration protocol. QTc prolongation risk with hypocalcemia.
💎 CLINICAL PEARL: Foscarnet does NOT cause myelosuppression (unlike ganciclovir) — this makes it preferred in patients with concurrent thrombocytopenia or neutropenia from chemotherapy.
⚠ PHARMACIST WATCHOUT: Penile/genital/oral ulcerations are a known local toxicity of foscarnet from drug concentration in urine. Ensure adequate hydration and urine dilution. This complication is often missed.
SECTION 7: PROPHYLAXIS DECISION ALGORITHM (NCCN INF-3 v1.2026)
7.1 Step-by-Step Prophylaxis Decision Framework
| STEP | QUESTION | ACTION |
| 1 | What is the overall infection risk category? | Classify as LOW / INTERMEDIATE / HIGH using NCCN INF-1 criteria |
| 2 | Is the patient seropositive for HSV or VZV? (HCT patients: check donor serology too) | Check HSV IgG, VZV IgG serology. In HCT: if EITHER donor or recipient is seropositive → prophylaxis indicated |
| 3 | Does patient have a history of prior HSV episodes? (for low-risk patients) | Even LOW risk patients: if prior HSV episode → give prophylaxis during active therapy |
| 4 | What antiviral to use? | Preferred: Valacyclovir 500 mg PO BID (preferred over oral acyclovir per NCCN v1.2026). Alternative: Acyclovir 400–800 mg PO BID |
| 5 | How long to continue prophylaxis? | LOW: During active therapy only (if prior HSV) INTERMEDIATE: HSV = active therapy ± longer; VZV = ≥6–12 months post-autologous HCT or CAR-T HIGH Allo-HCT: HSV = active therapy; VZV = ≥1 year HIGH Alemtuzumab: HSV/VZV = min. 2 months post-dose AND until CD4 ≥200 cells/mcL HIGH Proteasome inhibitors: During active therapy |
| 6 | Are there renal impairment concerns? | Adjust acyclovir/valacyclovir dose per CrCl (see dosing tables). Reassess renal function regularly. |
| 7 | Is patient on letermovir for CMV prophylaxis? | Letermovir has NO HSV/VZV activity! Continue acyclovir/valacyclovir separately — do not substitute. (NCCN INF-4 footnote q) |
7.2 Special Populations: Prophylaxis Duration Quick Reference
| POPULATION | HSV PROPHYLAXIS DURATION | VZV PROPHYLAXIS DURATION | PREFERRED AGENT |
| Autologous HCT | During active therapy | ≥ 6–12 months post-transplant | Valacyclovir 500 mg BID |
| CAR T-cell therapy [NEW v1.2026] | During active therapy | ≥ 6–12 months post-CAR-T | Valacyclovir 500 mg BID |
| Allogeneic HCT | Active therapy + engraftment period | ≥ 1 year post-transplant | Acyclovir 400–800 mg BID or Valacyclovir 500 mg BID |
| Alemtuzumab | Min. 2 months + until CD4 ≥ 200/mcL | Same — until CD4 ≥ 200/mcL | Valacyclovir 500 mg BID |
| Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) | During active therapy | During active therapy | Acyclovir 400 mg BID or Valacyclovir 500 mg BID |
| Acute leukemia (induction) | Active therapy + neutropenia period | Active therapy + neutropenia period | Acyclovir 400–800 mg BID or Valacyclovir 500 mg BID |
| CLL / Lymphoma / Myeloma | Consider during active therapy | Consider depending on immunosuppression degree | Valacyclovir 500 mg BID preferred |
💎 CLINICAL PEARL: Proteasome inhibitors (bortezomib/carfilzomib/ixazomib) — VZV reactivation risk is HIGH. Antiviral prophylaxis is MANDATORY during active therapy. This is one of the most commonly missed prophylaxis indications in practice.
💎 CLINICAL PEARL: For GVHD patients requiring significant immunosuppression escalation: reassess and extend prophylaxis duration. VZV reactivation risk remains elevated throughout active immunosuppression for GVHD.
SECTION 8: TREATMENT OF ACTIVE HSV/VZV DISEASE
8.1 Treatment Decision Framework
| SCENARIO | FIRST-LINE THERAPY | ROUTE / DOSE | DURATION |
| Mild oral HSV (on prophylaxis already) | Increase prophylaxis dose or switch to treatment dose valacyclovir | Valacyclovir 1 g PO BID | 7–10 days |
| Significant mucocutaneous HSV | IV Acyclovir | 5 mg/kg IV q8h (IBW) | 7–10 days |
| Mild-moderate dermatomal VZV | Valacyclovir (preferred per NCCN v1.2026) | 1 g PO TID | 7–10 days; start within 72h of rash |
| Severe/disseminated VZV or immune-compromised zoster | IV Acyclovir | 10 mg/kg IV q8h (IBW) | 7–10+ days until stable, then step down to oral |
| HSV/VZV Encephalitis | IV Acyclovir — DO NOT DELAY | 10 mg/kg IV q8h (IBW) | 14–21 days MINIMUM |
| Acyclovir-Resistant HSV or VZV | Foscarnet (drug of choice — NCCN FEV-C 2/4) | 40 mg/kg IV q8–12h | 7–10 days; ID consult required |
| Primary Varicella (seronegative patient) | IV Acyclovir (hospitalized) or high-dose oral valacyclovir (mild) | IV: 10 mg/kg q8h; OR Valacyclovir 1g PO TID | 7–10 days or until lesions crusted |
8.2 Post-Exposure Prophylaxis for VZV (Seronegative Patients)
- VariZIG (Varicella Zoster Immune Globulin): Preferred for VZV-seronegative immunocompromised patients with significant VZV exposure — give within 96 hours of exposure (10 days if VariZIG unavailable).
- Acyclovir post-exposure prophylaxis: 800 mg PO 5 times daily (NCCN FEV-C 1/4) — alternative if VariZIG not available.
- Significant exposure: household contact, prolonged face-to-face contact with active varicella/zoster.
🔴 CRITICAL: If an oncology patient with NO VZV immunity is exposed to active chickenpox or disseminated zoster — this is a MEDICAL EMERGENCY. Notify the team IMMEDIATELY. Patient must be removed from exposure, isolation initiated, and VariZIG given within 96h.
SECTION 9: MONITORING PARAMETERS & LAB CUTOFFS
9.1 Antiviral Monitoring Table
| DRUG | BASELINE LABS | ONGOING MONITORING | KEY PARAMETERS / THRESHOLDS |
| Acyclovir (IV) | SCr, BUN eGFR/CrCl Electrolytes Wt (for IBW dosing) | SCr every 24–48h (IV) Urine output ≥ 100 mL/h Neuro checks CBC if prolonged use | Hold/reduce if SCr increases >50% from baseline Maintain urine output ≥ 1–2 mL/kg/h Neurotoxicity: new tremors, myoclonus, confusion → check dose/renal function Infuse over ≥ 60 min (not faster) |
| Valacyclovir (PO) | SCr, CrCl CBC (baseline) | SCr monthly (outpatient) Platelet count in HCT patients | Adjust dose at CrCl < 50 mL/min TTP/HUS: platelets ↓, schistocytes on smear, rising LDH → STOP immediately — ID/hem consult TTP/HUS risk highest in BMT/SCT patients at high doses |
| Foscarnet (IV) | SCr/CrCl CMP (electrolytes) CBC Mg, Ca, Phos ECG (QTc) | SCr every 24–48h Electrolytes BID (induction) Ca, Mg, K, Phos BID QTc monitoring I&O | Hypocalcemia → QTc prolongation → TdP risk Mg goal: ≥ 0.8 mEq/L Replace all electrolytes aggressively Nephrotoxicity: dose-reduce at CrCl < 50 mL/min Maintain SCr < 1.5x baseline Pre-hydrate with 500–1000 mL NS before each dose |
| Famciclovir (PO) | SCr/CrCl | SCr monthly | Adjust at CrCl < 60 mL/min NOT recommended for oncologic prophylaxis (no data — NCCN) |
SECTION 10: VACCINATION — RZV (Recombinant Zoster Vaccine) IN ONCOLOGY
10.1 Recombinant Zoster Vaccine (RZV/Shingrix) — NCCN INF-7 & INF-8
| PARAMETER | DETAILS | ONCOLOGY-SPECIFIC NOTES |
| Vaccine Type | Recombinant (non-live) adjuvanted subunit vaccine — SAFE in immunocompromised | Live zoster vaccine (ZVL/Zostavax) is CONTRAINDICATED in immunocompromised patients |
| Dosing Schedule (General Adults) | 2 doses given 2–6 months apart (standard schedule) | In high-risk patients ≥18 years: 2nd dose can be given 1–2 months after 1st if expedited schedule beneficial |
| After Autologous HCT | 50–70 days after autologous HCT (NCCN INF-8) | 2 doses total; consider after immune reconstitution |
| After Allogeneic HCT | May be considered after allogeneic HCT (NCCN INF-8) | Timing depends on GVHD status and immunosuppression; avoid during active GVHD treatment |
| Indication Thresholds (General) | Recommended for adults ≥50 years; also for adults ≥18 years at increased risk for herpes zoster | Patients on proteasome inhibitors, purine analogs, CAR-T, allo-HCT are all ≥18 year risk-group eligible |
| Prior ZVL (Live) Vaccine History | Give RZV at least 2 months after last ZVL dose (NCCN INF-7) | ZVL is being phased out — most patients will be RZV-naïve |
| CONTRAINDICATION | Do NOT give live VZV vaccine during chemotherapy or active immunosuppression (GVHD treatment) — NCCN INF-7 | Only the varicella live vaccine is a concern — RZV (Shingrix) is recombinant and can be given in appropriate candidates |
💎 CLINICAL PEARL: RZV (Shingrix) is non-live — it is SAFE in immunocompromised patients. This is a key distinction from the old live Zostavax. RZV has ~90% efficacy in immunocompetent adults and remains effective in oncology populations.
⚠ PHARMACIST WATCHOUT: Vaccination should be TIMED appropriately — avoid giving during peak immunosuppression (eg, induction chemo, acute GVHD treatment). Optimal response requires some residual immune function. Discuss timing with the oncology team.
SECTION 11: SUPPORTIVE CARE & ANCILLARY MANAGEMENT
11.1 Pain Management (Zoster/PHN)
- Acute zoster pain: Consider scheduled acetaminophen, NSAIDs (if renal/GI safe), opioids for severe pain, gabapentin/pregabalin for neuropathic component.
- Postherpetic neuralgia (PHN): First-line agents: gabapentin, pregabalin, tricyclic antidepressants (amitriptyline/nortriptyline), topical lidocaine patches. Second-line: opioids for refractory cases.
- Topical capsaicin (high-concentration) or nerve blocks: Specialty pain management for refractory PHN.
11.2 Ophthalmology & ENT Considerations
- Zoster ophthalmicus (V1): Urgent ophthalmology consultation — risk of keratitis, anterior uveitis, retinitis, glaucoma, blindness.
- Oral antiviral adequate for mild-to-moderate; IV acyclovir for severe or disseminated with ocular involvement.
- Ramsay Hunt Syndrome: ENT consultation; may require steroid co-therapy (prednisolone 1 mg/kg/day tapered) in addition to antivirals — discuss with oncology team given steroid risks.
11.3 Infection Control Precautions
| INFECTION | PRECAUTION TYPE | DURATION |
| Active Varicella (chickenpox) | AIRBORNE + CONTACT precautions | Until all lesions crusted (typically 7–10 days) |
| Disseminated Zoster | AIRBORNE + CONTACT precautions | Until all lesions crusted |
| Localized Dermatomal Zoster (contained, covered) | CONTACT precautions (standard precautions if fully covered) | Until all lesions crusted |
| Oral/labial HSV (recurrent cold sores) | Standard precautions; contact if extensive lesions | Until lesions crusted/healed |
⚠ PHARMACIST WATCHOUT: Healthcare workers who are NOT immune to VZV should NOT care for patients with active varicella or disseminated zoster. Ensure proper staff assignment to avoid nosocomial transmission.
SECTION 12: ANTIVIRAL RESISTANCE — RECOGNITION & MANAGEMENT
12.1 Recognizing Acyclovir-Resistant HSV/VZV
- Suspect acyclovir/valacyclovir resistance if lesions WORSEN or fail to improve after 7–10 days of adequate antiviral therapy.
- Most common in severely immunocompromised patients: allo-HCT, AIDS, long-term antiviral use.
- Mechanism: Thymidine kinase (TK) mutation → cannot phosphorylate acyclovir → no active drug.
- Cross-resistance: TK-deficient strains are cross-resistant to acyclovir, valacyclovir, famciclovir, ganciclovir.
- NOT cross-resistant to: Foscarnet (different mechanism — pyrophosphate analog, does not require TK) and Cidofovir.
Acyclovir-Resistant HSV/VZV Management
- Confirm resistance — viral culture with susceptibility testing or PCR-based genotyping.
- Obtain Infectious Disease consultation (NCCN strongly recommends ID consult for resistant infections).
- Switch to Foscarnet: 40 mg/kg IV q8–12h for 7–10 days (NCCN FEV-C 2/4, updated v1.2026).
- Alternative: Cidofovir (for HSV, with probenecid and IV hydration) — limited data.
- Monitor closely for foscarnet-related nephrotoxicity and electrolyte disturbances.
💎 CLINICAL PEARL: Foscarnet is the drug of choice for BOTH acyclovir-resistant HSV AND ganciclovir-resistant CMV. Memorize this — it frequently comes up in complex HCT patients with multiple viral reactivations.
🔴 CRITICAL: Do NOT continue acyclovir or valacyclovir in a patient with proven or highly suspected acyclovir-resistant HSV/VZV — it is ineffective and delays appropriate therapy.
SECTION 13: KEY CLINICAL TRIALS & EVIDENCE BASE
| TRIAL | POPULATION | INTERVENTION | COMPARATOR | KEY RESULTS / RELEVANCE |
| Boeckh et al. 2006 (Blood) | Allo-HCT recipients | Long-term acyclovir 800 mg BID PO | Placebo | Significant reduction in VZV disease after allo-HCT. Foundation for ≥1-year VZV prophylaxis recommendation (NCCN reference 1, FEV-C) |
| Oxman et al. 2005 (NEJM) — Shingles Prevention Study | Adults ≥60 years (immunocompetent) | Live zoster vaccine (ZVL) | Placebo | 51% reduction in herpes zoster burden, 67% reduction in PHN. Established basis for zoster vaccination (now superseded by RZV) |
| ZOE-50 / ZOE-70 (NEJM 2015–2016) — RZV Trials | Adults ≥50 yrs (ZOE-50) and ≥70 yrs (ZOE-70) | RZV (Shingrix) 2-dose series | Placebo | ≥90% efficacy against herpes zoster. ~89% reduction in PHN. Basis for RZV preferred over ZVL (NCCN INF-7) |
| Solano-Iturri et al. RZV in Allo-HCT | Allo-HCT recipients (adults) | RZV 2-dose series post-HCT | Placebo/historical control | RZV immunogenic and well-tolerated post-allo-HCT. Supports consideration of RZV in post-HCT setting (NCCN INF-8) |
| Erard et al. — Valacyclovir vs. Acyclovir (HCT) | HCT recipients | Valacyclovir 500 mg PO BID | Acyclovir 400 mg PO BID | Valacyclovir non-inferior to acyclovir for HSV/VZV prophylaxis with better bioavailability. Basis for preference of valacyclovir in NCCN v1.2026 (FEV-C update) |
| Tomblyn et al. 2009 — BBMT Guidelines | HCT recipients globally | Guideline compilation — acyclovir/valacyclovir prophylaxis | N/A (guideline) | Global HCT infection prevention framework. Referenced by NCCN FEV-C for CMV/HSV prophylaxis dosing (NCCN reference 5, FEV-C 4/4) |
SECTION 14: PHARMACIST WATCHOUTS — ROUNDS, TUMOR BOARD & CHEMO REVIEW
14.1 Chemotherapy Review Checklist — HSV/VZV Prophylaxis
| ✓ | ITEM TO VERIFY | WHY IT MATTERS |
| ☐ | Is antiviral prophylaxis ordered for all intermediate/high-risk patients? | Frequently omitted — especially in bortezomib regimens and CAR-T |
| ☐ | Is the dose of acyclovir/valacyclovir appropriate for the patient’s renal function (CrCl)? | Renal dosing errors are common — especially as nephrotoxic chemo affects CrCl |
| ☐ | Is acyclovir IV being infused over ≥60 minutes with adequate hydration? | Rapid infusion → crystal nephropathy → AKI |
| ☐ | For allo-HCT on letermovir (CMV prophylaxis): Is separate HSV/VZV antiviral also ordered? | Letermovir has NO HSV/VZV coverage — this gap is a critical safety issue |
| ☐ | Has VZV prophylaxis duration been reassessed in patients > 1 year post-allo-HCT? | VZV reactivation can occur beyond 1 year, especially with chronic GVHD/ongoing IST |
| ☐ | Has RZV vaccination status been reviewed and documented for eligible patients? | Pre-chemotherapy vaccination or post-HCT vaccination planning per NCCN INF-7/8 |
| ☐ | If patient is on CAR T-cell therapy: Has VZV prophylaxis (6–12 months) been initiated? | NEW NCCN v1.2026 update — VZV prophylaxis added for CAR-T population |
| ☐ | For patients receiving alemtuzumab: Is CD4 count being monitored? Prophylaxis continues until CD4 ≥ 200 cells/mcL | Stopping too early is a common error — CD4, not ANC, drives the decision |
| ☐ | For HCT patients on high-dose valacyclovir: Are platelets and LDH being monitored for TTP/HUS? | Rare but life-threatening — can be confused with GVHD thrombocytopenia or drug toxicity |
| ☐ | For patients receiving foscarnet: Are electrolytes (Ca, Mg, K, Phos) and renal function being monitored BID during induction? | Foscarnet electrolyte disturbances are severe and life-threatening — hypocalcemia → TdP |
14.2 Drug Interactions — Key HSV/VZV Antiviral Interactions in Oncology
| ANTIVIRAL | INTERACTING DRUG | INTERACTION | MANAGEMENT |
| Acyclovir / Valacyclovir | Nephrotoxic chemo (cisplatin, ifosfamide, MTX) | ↑ Risk of combined nephrotoxicity and AKI | Monitor SCr closely; hydrate aggressively; consider dose-holding if AKI develops |
| Acyclovir / Valacyclovir | Probenecid | ↑ Acyclovir levels (↓ tubular secretion) | Monitor for toxicity; may be used intentionally to boost levels |
| Acyclovir | Mycophenolate (MMF) — HCT GVHD patients | Both renally cleared — potential for ↑ MPAG levels | Monitor renal function; space doses if possible |
| Foscarnet | Nephrotoxic drugs (aminoglycosides, amphotericin B, cisplatin) | Additive nephrotoxicity — HIGH RISK | Avoid combination if possible; if needed — aggressive hydration, close monitoring q24h |
| Foscarnet | QTc-prolonging agents (fluoroquinolones, azoles, ondansetron) | Additive QTc prolongation through hypocalcemia mechanism | ECG monitoring; aggressive calcium/magnesium repletion; avoid combination when possible |
| Acyclovir (high-dose) / Foscarnet | Cyclosporine / Tacrolimus (post-HCT) | Additive nephrotoxicity; ↑ calcineurin inhibitor levels in renal impairment | Monitor CNI levels more frequently when starting/stopping antivirals; adjust CNI dose if renal function changes |
SECTION 15: CLINICAL PEARLS SUMMARY — QUICK REFERENCE FOR ROUNDS
| # | CLINICAL PEARL |
| 1 | NCCN v1.2026 NEW: CAR T-cell therapy added as intermediate-risk indication — give VZV prophylaxis for ≥6–12 months post-CAR-T. Flag all CAR-T patients. |
| 2 | Letermovir (CMV prophylaxis) has ZERO activity vs. HSV/VZV. ALWAYS co-prescribe separate HSV/VZV antiviral in allo-HCT patients on letermovir. |
| 3 | Valacyclovir is NOW preferred over oral acyclovir for both HSV and VZV treatment per NCCN FEV-C v1.2026 update. Use Valacyclovir 1g PO BID (HSV) or 1g PO TID (VZV). |
| 4 | Alemtuzumab patients: Stop HSV/VZV prophylaxis ONLY when CD4 ≥ 200 cells/mcL — NOT based on ANC or neutrophil recovery. |
| 5 | Proteasome inhibitors (bortezomib, carfilzomib, ixazomib): VZV reactivation is MANDATORY to prophylax against. Frequently omitted in practice — always verify. |
| 6 | IV Acyclovir: Dose based on IDEAL BODY WEIGHT (not actual weight in obese patients). Infuse over ≥ 60 minutes. Hydrate aggressively. Monitor SCr every 24–48h. |
| 7 | Acyclovir-resistant HSV/VZV: Foscarnet 40 mg/kg IV q8–12h is the drug of choice. Does NOT require thymidine kinase activation. ID consult required. |
| 8 | Foscarnet: Most dangerous antiviral for electrolytes. Causes hypocalcemia, hypomagnesemia, hypophosphatemia, hypokalemia → QTc prolongation → TdP. Mandatory BID electrolyte monitoring + aggressive replacement. |
| 9 | TTP/HUS with high-dose valacyclovir: Rare but FATAL in immunocompromised patients. Watch for: falling platelets, rising LDH, microangiopathic hemolytic anemia (schistocytes). Stop immediately if suspected. |
| 10 | NCCN FEV-6 v1.2026: Esophagitis workup NOW requires BOTH HSV AND CMV diagnostics. Never work up one without the other in immunocompromised patients. |
| 11 | Famciclovir: NCCN states ‘No data for oncologic-related prophylaxis’ — do NOT recommend it as first-line for prophylaxis in hem/onc patients. Prefer acyclovir or valacyclovir. |
| 12 | Acyclovir neurotoxicity is under-recognized: Tremors, myoclonus, confusion, agitation — especially with renal impairment. Check dose and renal function before attributing to other causes. |
| 13 | RZV (Shingrix) is NON-LIVE and SAFE in immunocompromised patients. Time vaccination appropriately — avoid peak immunosuppression. Check if patient has received 2-dose series. |
| 14 | VZV-seronegative patient with significant VZV exposure = MEDICAL EMERGENCY in oncology. Remove from exposure, isolate, give VariZIG within 96h (or acyclovir 800mg 5x/day if VariZIG unavailable). |
| 15 | HCT-specific: In HCT recipients, HSV/VZV prophylaxis is indicated only if EITHER donor OR recipient is seropositive. Always check BOTH donor and recipient serologies before initiating prophylaxis. |
SECTION 16: MEDICATION QUICK REFERENCE — CLASS, MOA & CLINICAL PEARLS
| DRUG (Brand) | CLASS / BRIEF MOA | CLINICAL PEARLS / SIDE EFFECTS / COUNSELING |
| Acyclovir (Zovirax) | Synthetic purine nucleoside analog. Requires TK for activation → inhibits HSV/VZV DNA polymerase. Selective for infected cells. | • Dose by IBW (IV); infuse ≥60 min; hydrate aggressively • Renal dose adjustment (see table) • SE: Nephrotoxicity (crystals), neurotoxicity (high dose), N/V • Neurotoxicity: tremor, myoclonus, confusion — under-recognized • Counsel: Take with food; maintain hydration • Weak CMV activity — NOT sufficient for CMV prophylaxis • NCCN: Prophylaxis 400–800 mg PO BID; Encephalitis 10 mg/kg IV q8h |
| Valacyclovir (Valtrex) | L-valine ester prodrug of acyclovir. 3–5x higher bioavailability. Same MOA as acyclovir post-conversion. | • PREFERRED over oral acyclovir for HSV or VZV per NCCN v1.2026 • Treatment: HSV 1g PO BID; VZV 1g PO TID [NCCN FEV-C update v1.2026] • Prophylaxis: 500 mg PO BID • Renal dose adjustment required at CrCl < 50 • HIGH DOSE WARNING: TTP/HUS risk in immunocompromised — monitor CBC + smear • SE: Headache, N/V, renal (at high doses) • Counsel: Take with or without food; adequate hydration |
| Famciclovir (Famvir) | Prodrug of penciclovir. Requires TK activation → inhibits viral DNA polymerase. | • NCCN: No data for oncologic prophylaxis — NOT first-line in hem/onc • Can be used for treatment (not recommended over valacyclovir) • Treatment: HSV 250 mg TID; VZV 500 mg TID • Renal adjustment at CrCl < 60 mL/min • SE: Headache, N/V, diarrhea • Counsel: Take with or without food |
| Foscarnet (Foscavir) | Inorganic pyrophosphate analog. Directly inhibits viral DNA polymerase WITHOUT requiring TK activation. Active vs. TK-mutant (acyclovir-resistant) strains. | • Drug of choice: Acyclovir-resistant HSV/VZV (NCCN FEV-C 2/4) • Drug of choice: Ganciclovir-resistant CMV • Acyclovir-resistant HSV/VZV: 40 mg/kg IV q8–12h x 7–10 days [Updated NCCN v1.2026] • PRE-HYDRATE 500–1000 mL NS before each dose • SE: Nephrotoxicity, electrolyte disturbances (hypoCa, hypoMg, hypoPhos, hypoK) • Monitor Ca/Mg/K/Phos BID minimum during induction • QTc prolongation from hypocalcemia → TdP risk • Genital/oral ulceration from urinary drug concentration • Does NOT cause myelosuppression (advantage over ganciclovir) • ID consult strongly recommended |
| VariZIG (VZV Immunoglobulin) | Passive immunization — pre-formed VZV-specific IgG antibodies. Provides immediate but temporary protection (3–4 weeks). | • Indicated: VZV-seronegative immunocompromised patient with significant VZV exposure • Give WITHIN 96 hours of exposure (up to 10 days if 96h window missed) • Dose: 125 units/10 kg, maximum 625 units IM • SE: Injection site pain, headache, rarely allergic reaction • Does NOT prevent infection with certainty — monitor for symptoms • NOT a substitute for vaccination • Counsel: Monitor for signs of VZV infection for 28 days post-exposure |
| RZV/Shingrix (Recombinant Zoster Vaccine) | Adjuvanted recombinant subunit vaccine (glycoprotein E + AS01B adjuvant). Stimulates cell-mediated and humoral immunity. NON-LIVE — safe in immunocompromised. | • NCCN INF-7: Recommended for adults ≥50 years and ≥18 years at increased risk for HZ • 2 doses — standard: 2–6 months apart; expedited: 1–2 months apart (in ≥18 yr high risk) • Post-autologous HCT: Start at 50–70 days (NCCN INF-8) • After previous ZVL live vaccine: Wait ≥2 months before giving RZV • Common SE: Injection site reactions (pain, swelling), systemic (fever, fatigue, myalgia) — may be more pronounced than other vaccines • NOT interchangeable with live zoster vaccine (ZVL/Zostavax) • Counsel: Systemic reactions common after 2nd dose; take acetaminophen for comfort; does not protect against chickenpox (primary varicella) |
Reference Sources: NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections v1.2026 (March 11, 2026) | IDSA Guidelines | Clinical pharmacology references | Key clinical trials cited in NCCN FEV-C, INF-3, INF-7, INF-8 footnotes.
FOR EDUCATIONAL USE ONLY. All clinical decisions must be individualized. Not a substitute for clinical judgment, institutional guidelines, or patient-specific considerations. Verify drug dosing with current package inserts and institutional resources.