The herpesviruses constitute a large family of double-stranded deoxyribonucleic acid (DNA) viruses unified by their capacity for lifelong latency in the host. This biological strategy has profound clinical consequences, as immunosuppression of any cause can reactivate latent virus and produce disease ranging from self-limited mucocutaneous lesions to life-threatening end-organ damage in vulnerable populations.
Herpesvirus Classification. The family Herpesviridae is divided into three subfamilies based on biological and genomic properties. The alphaherpesviruses include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV); these are characterized by rapid replication, a broad host range, and latency in sensory ganglia. The betaherpesviruses include cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and human herpesvirus 7 (HHV-7), which replicate more slowly and establish latency in hematopoietic cells and other tissue reservoirs. The gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), also designated human herpesvirus 8 (HHV-8), are lymphotropic and associated with malignant transformation.1 This classification matters clinically because antiviral drug spectra correspond closely to subfamily boundaries, with most licensed agents targeting alphaherpesviruses far more potently than betaherpesviruses or gammaherpesviruses.
Replication Cycle and Antiviral Targets. Herpesvirus replication follows a defined sequence that antivirals exploit at multiple steps. After cell entry via membrane fusion, the viral capsid is transported to the nucleus where the linear double-stranded DNA genome circularizes and transcription begins. Immediate-early genes encode regulatory proteins, early genes encode enzymes required for DNA replication including the viral DNA polymerase, and late genes encode structural proteins assembled into progeny virions.1 The viral thymidine kinase (TK), encoded by HSV-1, HSV-2, and VZV, is the primary target for acyclovir activation and is absent from CMV, explaining the class difference in acyclovir potency. Viral DNA polymerase is the final common target shared by acyclovir, ganciclovir, foscarnet, and cidofovir, though each interacts with the polymerase through distinct mechanisms and at different sites.2
Latency and Its Clinical Implications. Latency is established when the virus enters a transcriptionally restricted state in host cells, persisting as circular episomal DNA without productive replication. HSV-1 and HSV-2 establish latency in trigeminal and dorsal root ganglia respectively, with only latency-associated transcripts (LATs) expressed during quiescence. VZV becomes latent in cranial nerve and dorsal root ganglia following primary varicella infection, and reactivates as herpes zoster decades later, particularly when cell-mediated immunity declines with age or immunosuppression. CMV latency occurs in cluster of differentiation 34 (CD34)-positive hematopoietic progenitor cells and monocytes, with reactivation triggered by inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and other proinflammatory mediators encountered during transplantation, critical illness, or human immunodeficiency virus (HIV) disease progression.1 No currently available antiviral eradicates latent virus; therapy is therefore directed at suppressing active replication, reducing severity and duration of symptomatic episodes, and preventing end-organ damage in high-risk patients.
Acyclovir and valacyclovir cover HSV-1, HSV-2, and VZV (alphaherpesviruses) with minimal CMV activity. Ganciclovir and valganciclovir are agents of choice for CMV (betaherpesvirus). Foscarnet and cidofovir provide broader coverage including acyclovir-resistant HSV and ganciclovir-resistant CMV. No licensed agent reliably treats EBV or KSHV disease. CMV lacks viral TK, making it intrinsically resistant to acyclovir.
Acyclovir remains the prototype antiviral against which all herpesvirus agents are compared. Its elegant selectivity for virus-infected cells rests on a two-step activation mechanism that concentrates the active drug at precisely the site where it is needed, leaving uninfected host cells essentially unexposed to inhibitory concentrations.
Mechanism of Action. Acyclovir (acycloguanosine) is an acyclic nucleoside analogue of guanosine. Its selectivity depends on preferential phosphorylation by virus-encoded thymidine kinase (TK) present in herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV)-infected cells. Viral TK converts acyclovir to acyclovir monophosphate far more efficiently than cellular kinases convert the unphosphorylated drug, creating a concentration gradient of roughly 40- to 100-fold in infected versus uninfected cells. Cellular kinases then complete the conversion to acyclovir triphosphate, which inhibits viral deoxyribonucleic acid (DNA) polymerase through two mechanisms: competitive inhibition with deoxyguanosine triphosphate (dGTP) as the substrate, and obligate chain termination after incorporation into the growing viral DNA strand because the acyclic sugar lacks the 3'-hydroxyl group required for chain elongation.2 The selectivity for viral over cellular DNA polymerase is approximately 10- to 30-fold, making acyclovir exceptionally well tolerated even at high intravenous doses.
Clinical Spectrum. The clinical spectrum of acyclovir encompasses HSV-1, HSV-2, and VZV, with potency varying considerably across the three. HSV-1 and HSV-2 are the most susceptible, with 50% inhibitory concentration (IC50) values typically in the range of 0.1 to 1.6 micromolar. VZV is approximately 10-fold less susceptible, requiring higher drug exposures for clinical effect; this is reflected in the substantially higher acyclovir doses used for varicella and zoster (800 mg five times daily orally) compared with herpes simplex virus (HSV) (400 mg three times daily). Epstein-Barr virus (EBV) carries a viral TK of low activity, and acyclovir has minimal clinically meaningful effect on EBV disease despite some in vitro activity. Cytomegalovirus (CMV) lacks a viral thymidine kinase (TK) entirely and is therefore intrinsically resistant to acyclovir; the apparent benefit seen with high-dose oral acyclovir in some early CMV prophylaxis trials is now understood to reflect indirect immunological mechanisms rather than direct antiviral activity.2
Pharmacokinetics and Valacyclovir. Oral bioavailability of acyclovir is poor, ranging from 15% to 30%, and is saturable at higher doses due to limited intestinal absorption capacity. Valacyclovir, the L-valyl ester prodrug of acyclovir, was developed to overcome this limitation. After oral administration, valacyclovir is rapidly hydrolyzed by intestinal and hepatic valacyclohydrolase to acyclovir, achieving plasma concentrations three to five times higher than equivalent oral acyclovir doses and approximating those achieved with intravenous acyclovir at standard doses.5 Acyclovir distributes widely, achieving therapeutic concentrations in the cerebrospinal fluid (CSF) at approximately 50% of plasma levels, which is critical for the treatment of herpes simplex encephalitis (HSE). Renal excretion is the primary elimination route, largely unchanged, necessitating dose adjustment for creatinine clearance (CrCl) below 50 mL per minute. Intravenous acyclovir can precipitate in renal tubules if infused rapidly or in hypovolemic patients, and adequate hydration during intravenous infusion is essential to prevent crystalline nephropathy.
Resistance Mechanisms. Resistance to acyclovir in clinical practice is caused predominantly by mutations in the viral TK gene, which reduce TK activity or alter TK substrate specificity so that acyclovir is no longer efficiently phosphorylated. Less commonly, mutations in the viral DNA polymerase gene reduce acyclovir binding affinity. TK-null and TK-partial mutants retain pathogenicity and can cause severe, progressive, treatment-refractory mucocutaneous disease particularly in patients with advanced human immunodeficiency virus (HIV) infection or after hematopoietic stem cell transplantation (HSCT).8 Because TK is required for acyclovir activation but not for foscarnet or cidofovir activity, acyclovir-resistant HSV strains retain full susceptibility to both foscarnet and cidofovir, providing a clear therapeutic escape route. Phenotypic resistance testing (plaque reduction assay) takes 10 to 14 days and is the gold standard; genotypic testing for TK and polymerase mutations is faster and increasingly available in reference laboratories.
HSV encephalitis: IV acyclovir 10 mg/kg every 8 hours for 14-21 days. Neonatal HSV: IV acyclovir 20 mg/kg every 8 hours for 21 days (disseminated/CNS) or 14 days (skin/eye/mouth). VZV in immunocompromised: IV acyclovir 10-12 mg/kg every 8 hours. Valacyclovir 1 g three times daily approximates IV acyclovir for zoster in immunocompetent adults. All doses require renal dose adjustment when CrCl < 50 mL/min.
Cytomegalovirus (CMV) disease in immunocompromised patients remains one of the most challenging management problems in transplant and human immunodeficiency virus (HIV) medicine. The agents available for CMV treatment and prophylaxis carry significant toxicity profiles that require careful monitoring and dose management throughout the course of therapy.
Ganciclovir: Mechanism and Selectivity. Ganciclovir is an acyclic nucleoside analogue structurally related to acyclovir but with a key difference: it possesses a 3'-hydroxyl group on the acyclic side chain that allows for chain elongation after incorporation, making it a less obligate chain terminator than acyclovir. Of note, CMV encodes a viral phosphotransferase (the UL97 gene product) rather than a classical thymidine kinase, and UL97 phosphorylates ganciclovir to its monophosphate form. Cellular kinases complete the conversion to ganciclovir triphosphate, which then competitively inhibits CMV deoxyribonucleic acid (DNA) polymerase (the UL54 gene product) and is incorporated into elongating viral DNA, where it slows and eventually terminates replication. The selectivity of ganciclovir for CMV-infected cells is considerably lower than that of acyclovir for herpes simplex virus (HSV)-infected cells because the UL97 phosphotransferase, while preferring ganciclovir over host substrates, generates higher intracellular concentrations of ganciclovir triphosphate in CMV-infected cells relative to uninfected cells by only approximately 10-fold.2 This narrower selectivity index underlies ganciclovir's more significant toxicity profile compared with acyclovir.
Ganciclovir and Valganciclovir: Toxicity and Clinical Use. The dose-limiting toxicity of ganciclovir is myelosuppression, specifically neutropenia, which occurs in 15% to 40% of treatment courses and is the most common reason for dose reduction or drug discontinuation. Neutrophil nadirs typically occur within the first two weeks of therapy and are generally reversible on dose reduction or discontinuation. Thrombocytopenia and anemia occur less frequently. Granulocyte colony-stimulating factor (G-CSF) is used in practice to support absolute neutrophil count (ANC) during essential ganciclovir therapy when neutropenia is severe. Renal toxicity is mild relative to foscarnet or cidofovir, but dose adjustment for renal impairment is required because ganciclovir is eliminated unchanged by glomerular filtration and tubular secretion. Ganciclovir is teratogenic and potentially carcinogenic in animal studies; its use in pregnancy is reserved for life-threatening CMV disease where no safer alternative exists. Valganciclovir, the oral L-valyl ester prodrug, achieves systemic exposure equivalent to intravenous ganciclovir and has replaced oral ganciclovir for prophylaxis and maintenance therapy in transplant recipients and HIV patients with controlled CMV disease.3
Foscarnet: Mechanism and Spectrum. Foscarnet (phosphonoformic acid) is a pyrophosphate analogue that inhibits viral DNA polymerase by a mechanism entirely distinct from nucleoside analogues. Foscarnet binds directly to the pyrophosphate-binding site of the viral DNA polymerase, blocking pyrophosphate release during nucleotide incorporation and thereby halting chain elongation. It does not require intracellular phosphorylation and is therefore active against thymidine kinase (TK)-deficient acyclovir-resistant herpes simplex virus (HSV) strains and against UL97-mutant ganciclovir-resistant CMV strains, provided the polymerase itself remains susceptible. Foscarnet is active against all human herpesviruses including CMV, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), and human herpesvirus 6 (HHV-6), and retains activity against most ganciclovir-resistant CMV isolates carrying UL97 mutations.8 However, UL54 polymerase mutations that cause ganciclovir resistance can confer partial cross-resistance to foscarnet, and combined UL97 plus UL54 mutations produce high-level multidrug resistance that leaves cidofovir or combination therapy as the only options.
Foscarnet: Nephrotoxicity and Electrolyte Management. Foscarnet's major limitation is severe nephrotoxicity, occurring in up to 30% of patients. Renal injury results from direct tubular toxicity, precipitation in glomerular capillaries, and ionic disturbances caused by foscarnet chelating divalent cations. Vigorous saline prehydration with 500 to 1000 mL of normal saline before each infusion is mandatory and substantially reduces nephrotoxicity risk. Electrolyte disturbances are common and potentially severe: hypocalcemia (due to calcium chelation by foscarnet), hypomagnesemia, hypokalemia, and hypophosphatemia or hyperphosphatemia all occur and require careful monitoring with each infusion. Genital ulceration from high concentrations of foscarnet in urine is a distinctive adverse effect managed by maintaining adequate urine output and genital hygiene. Despite its toxicity profile, foscarnet remains a critical salvage option for drug-resistant herpesvirus infections in immunocompromised patients, and its lack of myelosuppression makes it the preferred CMV agent when ganciclovir-related neutropenia is severe.8
Ganciclovir/valganciclovir: CBC with differential twice weekly during induction, weekly during maintenance; serum creatinine twice weekly. Foscarnet: serum electrolytes (calcium, magnesium, potassium, phosphate) before every infusion; serum creatinine twice weekly; 500-1000 mL NS prehydration mandatory before each dose; monitor for genital ulceration.
Cidofovir and brincidofovir occupy a distinct niche in herpesvirus pharmacology, offering broad-spectrum deoxyribonucleic acid (DNA) virus coverage against cytomegalovirus (CMV), herpesviruses, and other DNA virus families extending well beyond the herpesvirus family. Their clinical utility is limited by significant toxicity for cidofovir and by a complex regulatory history for brincidofovir, but both agents remain important in the management of drug-resistant or refractory herpesvirus and poxvirus infections.
Cidofovir: Mechanism and Spectrum. Cidofovir is an acyclic nucleoside phosphonate, structurally unique in that it contains a phosphonate group that mimics nucleoside monophosphate. This design has a crucial consequence: unlike acyclovir and ganciclovir, cidofovir does not require viral thymidine kinase (TK) or UL97 (CMV-encoded phosphotransferase) for initial phosphorylation. Cellular enzymes convert cidofovir directly to cidofovir diphosphate, the active moiety, which then inhibits viral DNA polymerase by competing with deoxycytidine triphosphate (dCTP) and causing chain termination after incorporation. Because activation is entirely virus-independent, cidofovir retains full activity against TK-deficient acyclovir-resistant herpes simplex virus (HSV) strains and against UL97-mutant ganciclovir-resistant cytomegalovirus (CMV) strains, provided the viral DNA polymerase itself remains sensitive.8 The antiviral spectrum is broad, encompassing CMV, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), adenovirus, BK (BK polyomavirus), and orthopoxviruses including smallpox and mpox, making cidofovir one of the few licensed agents with documented activity across multiple DNA virus families.
Cidofovir: Nephrotoxicity and Mandatory Protocol. The clinical utility of cidofovir is severely constrained by dose-dependent nephrotoxicity. Cidofovir is concentrated in proximal tubular cells by the organic anion transporter 1 (OAT1), reaching intracellular concentrations that cause mitochondrial dysfunction, tubular apoptosis, and progressive renal failure. Nephrotoxicity occurs in 20% to 65% of patients depending on dose and hydration status, and can be irreversible if not recognized promptly. The mandatory coadministration of probenecid, a competitive OAT1 inhibitor, reduces cidofovir uptake into proximal tubular cells and substantially mitigates nephrotoxicity; probenecid 2 g is given orally three hours before each cidofovir dose and 1 g at two and eight hours after infusion. Aggressive intravenous saline preloading (1 liter of normal saline over one hour before cidofovir infusion) is also required. Despite these precautions, serum creatinine must be checked before every dose, and cidofovir must be withheld if creatinine rises by 0.3 mg per deciliter or more above baseline or if proteinuria reaches 2+ or greater on dipstick. Uveitis and ocular hypotony are distinctive adverse effects reported primarily in human immunodeficiency virus (HIV) patients receiving systemic cidofovir.9
Brincidofovir: Lipid Conjugate Design and Clinical Role. Brincidofovir (CMX001) is a lipid conjugate of cidofovir, linked via an ether lipid to improve oral bioavailability and reduce renal tubular uptake. The lipid conjugate enters cells via lipid transport pathways rather than through OAT1, dramatically reducing proximal tubular exposure and the associated nephrotoxicity that limits cidofovir. Inside the cell, phospholipases cleave the lipid moiety to release cidofovir, which is then phosphorylated to cidofovir diphosphate. Intracellular concentrations of cidofovir diphosphate achieved with brincidofovir exceed those from equivalent cidofovir doses because the lipid conjugate essentially bypasses the concentration-limiting renal extraction step and delivers drug directly to intracellular compartments.10 Brincidofovir received U.S. Food and Drug Administration (FDA) approval in June 2021 under the brand name Tembexa specifically for the treatment of smallpox (variola virus) as part of the U.S. strategic national stockpile preparedness initiative, and has been used in the context of mpox (monkeypox) outbreaks. The primary adverse effects are gastrointestinal: diarrhea, nausea, vomiting, and abdominal pain are frequent and can be treatment-limiting. Hepatotoxicity, including transaminase elevation, has been observed and requires monitoring. The absence of significant nephrotoxicity compared with cidofovir makes brincidofovir potentially attractive for immunocompromised patients with renal insufficiency, though its clinical role in herpesvirus infections beyond orthopoxviruses remains under investigation.
Every cidofovir infusion requires: (1) probenecid 2 g PO 3 hours before, then 1 g at 2 and 8 hours post-infusion; (2) 1 L NS IV over 1 hour pre-infusion; (3) serum creatinine and urine protein checked within 48 hours of each dose; (4) hold if creatinine rises ≥ 0.3 mg/dL above baseline or proteinuria ≥ 2+. Cidofovir is contraindicated if CrCl < 55 mL/min or if patient has pre-existing proteinuria ≥ 100 mg/dL.
The pharmacological management of herpesvirus infections is substantially modified by the clinical context in which they occur. Immunocompromised patients, pregnant women, and neonates each present distinct pharmacokinetic, virological, and safety considerations that require departure from standard outpatient treatment paradigms.
Immunocompromised Patients. In immunocompromised patients, herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections carry substantially greater morbidity than in immunocompetent hosts. Mucocutaneous HSV may progress to extensive necrotic ulceration rather than resolving in the typical 7 to 10 days seen in healthy individuals. VZV primary infection (varicella) and reactivation (zoster) can disseminate viscerally, causing pneumonitis, hepatitis, and encephalitis. The threshold for intravenous therapy is therefore lower: HSV encephalitis, disseminated HSV, and disseminated zoster in immunocompromised patients are managed with intravenous acyclovir 10 to 12 mg per kilogram every eight hours rather than oral regimens. Chronic suppressive therapy with valacyclovir or acyclovir is standard practice in solid organ transplant (SOT) recipients, hematopoietic stem cell transplant (HSCT) recipients, and patients with advanced human immunodeficiency virus (HIV) during the period of profound immunosuppression to prevent HSV and VZV reactivation.7 When acyclovir-resistant HSV or VZV is identified or strongly suspected based on lack of clinical response after five to seven days of adequate intravenous acyclovir, foscarnet is the agent of choice.
Pregnancy: Safety and Indications. Herpesvirus management in pregnancy requires balancing fetal risk from the infection itself against potential teratogenicity of antiviral drugs. Acyclovir and valacyclovir are classified as Pregnancy Category B agents based on animal safety data and extensive human experience from the Acyclovir in Pregnancy Registry, which found no increase in birth defects among over 1800 first-trimester exposures.4 Current guidelines support acyclovir and valacyclovir as safe and effective for primary genital herpes simplex virus (HSV) in pregnancy, varicella-zoster virus (VZV) pneumonia (which carries 40% maternal mortality if untreated), and disseminated herpesvirus infections. Suppressive valacyclovir therapy from 36 weeks gestation reduces the risk of HSV shedding and recurrent lesions at delivery, lowering the rate of cesarean delivery performed for active HSV disease.
Pregnancy: Congenital Infection and Antiviral Safety. Ganciclovir and foscarnet are generally avoided in pregnancy given teratogenic potential in animal models, reserving their use for maternal life-threatening cytomegalovirus (CMV) disease where benefit clearly outweighs risk. Congenital CMV (cCMV) represents the most common congenital viral infection globally, affecting approximately 0.5% to 1% of all live births; maternal primary CMV infection during pregnancy carries a transmission risk of 30% to 40%, while reactivation carries a lower but non-negligible risk of vertical transmission. The distinction between primary and non-primary maternal infection matters clinically because primary infection carries substantially higher rates of fetal transmission and symptomatic neonatal disease than does reactivation in a seropositive mother.11
Neonatal HSV: Emergency Management and Suppression. Neonatal HSV is a medical emergency carrying substantial mortality and neurological morbidity even with treatment. Neonates acquire herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2) most commonly through contact with maternal genital secretions at delivery (peripartum transmission), though intrauterine and postnatal acquisition also occur. Disease manifests as three overlapping syndromes: skin, eye, and mouth (SEM) disease; encephalitis; and disseminated disease involving liver, adrenal glands, lung, and central nervous system (CNS). All three forms require immediate high-dose intravenous acyclovir at 20 mg per kilogram every eight hours, with duration determined by syndrome: 14 days for SEM disease and 21 days for encephalitis or disseminated disease. High-dose acyclovir in neonates is well tolerated with adequate hydration, though neutropenia and nephrotoxicity require monitoring. Following completion of intravenous therapy, oral acyclovir suppression at 300 mg per square meter three times daily for six months significantly reduces HSV recurrence and improves neurodevelopmental outcomes in infants with CNS or disseminated disease, representing one of the most compelling evidence-based uses of long-term antiviral suppression in any population.6
Any neonate with skin vesicles, seizures, fever with CSF pleocytosis, or maternal history of genital HSV: empiric IV acyclovir 20 mg/kg q8h pending full evaluation including CSF HSV PCR, surface swabs (conjunctiva, nasopharynx, rectum), and liver function tests. Do not delay therapy for test results. Follow intravenous course with oral suppressive acyclovir 300 mg/m² TID for 6 months in CNS or disseminated disease.
Cytomegalovirus (CMV) disease in solid organ transplant recipients and human immunodeficiency virus (HIV)-infected patients with advanced immunodeficiency represents the most complex arena of herpesvirus pharmacology, requiring individualized decisions about prophylaxis strategy, viral load monitoring thresholds, treatment intensity, and the duration of secondary prophylaxis based on the patient's evolving immune status.
Risk Stratification and Prophylaxis Strategies in Transplant. In solid organ transplantation, the risk of CMV disease is determined primarily by the donor and recipient CMV serostatus at the time of transplant. The highest-risk combination is a CMV-seropositive donor organ transplanted into a CMV-seronegative recipient (D+/R-), carrying a 50% to 80% risk of CMV infection without prophylaxis and a 20% to 30% risk of end-organ disease. Seropositive recipients (R+), whether receiving D+ or D- organs, face reactivation risk of 10% to 30%, modulated substantially by the degree of immunosuppression, particularly T-cell-depleting agents such as antithymocyte globulin (ATG) and alemtuzumab. Two prophylaxis strategies have been validated: universal prophylaxis, in which all patients above a defined risk threshold receive valganciclovir or ganciclovir for a defined period (typically 3 to 6 months post-transplant), and pre-emptive therapy, in which CMV viral load is monitored regularly by polymerase chain reaction (PCR) and therapy initiated when viral load exceeds a predefined threshold, before symptoms develop. Universal prophylaxis reduces CMV disease incidence more consistently, but is associated with the phenomenon of late-onset CMV disease occurring after prophylaxis discontinuation, particularly in D+/R- recipients whose immune reconstitution may be incomplete at the time prophylaxis ends.7
CMV End-Organ Disease in Transplant Recipients. CMV end-organ disease in transplant recipients encompasses pneumonitis, gastrointestinal disease (esophagitis, colitis), hepatitis, retinitis, and neurological disease. CMV pneumonitis in hematopoietic stem cell transplant (HSCT) recipients carries the highest mortality, with rates of 50% or greater in the pre-antiviral era now reduced to 15% to 30% with aggressive pre-emptive strategies and combination therapy. CMV colitis presents as diarrhea, hematochezia, and abdominal pain; diagnosis requires tissue biopsy demonstrating CMV cytopathic effect (intranuclear owl-eye inclusions) or positive immunohistochemistry, as blood CMV PCR may be negative in isolated gastrointestinal disease. Treatment of CMV end-organ disease uses intravenous ganciclovir 5 mg per kilogram every 12 hours (induction) until symptoms resolve and viral load is undetectable, then transitioning to oral valganciclovir for maintenance. Duration of maintenance therapy in transplant recipients is individualized based on immune status and viral load trajectory, with a minimum of three months typically recommended for retinitis and other severe presentations.7
CMV Retinitis in HIV and Letermovir. CMV retinitis in human immunodeficiency virus (HIV)-infected patients historically caused blindness in up to 25% of individuals with acquired immunodeficiency syndrome (AIDS) before effective antiretroviral therapy (ART). The advent of ART has reduced CMV retinitis incidence dramatically, but it remains an important opportunistic infection in patients presenting with advanced untreated HIV with cluster of differentiation 4 (CD4) T-lymphocyte counts below 50 cells per microliter or in those who fail or cannot tolerate ART. Valganciclovir 900 mg twice daily for induction followed by 900 mg once daily for maintenance is the first-line regimen for CMV retinitis in HIV patients who can absorb oral medications. Intravitreal ganciclovir or foscarnet injections are used as adjunctive therapy for immediately sight-threatening zone 1 lesions (within 1500 micrometers of the optic disc or fovea) to achieve rapid local viral suppression before systemic therapy takes effect.9
Immune Reconstitution and Letermovir. Immune reconstitution inflammatory syndrome (IRIS) complicating CMV retinitis can paradoxically worsen retinal inflammation after ART initiation, sometimes requiring corticosteroids; this risk is one reason ART initiation is deferred for at least two weeks after starting CMV treatment in patients with active CMV retinitis. Letermovir, a UL56 (CMV terminase complex subunit) inhibitor approved in 2017 for CMV prophylaxis in CMV-seropositive hematopoietic stem cell transplant (HSCT) recipients, represents the first mechanistically novel CMV agent in decades and has no cross-resistance with ganciclovir, foscarnet, or cidofovir. Its absence of myelosuppression and favorable oral bioavailability make letermovir a particularly attractive prophylactic option in HSCT recipients, though its role in the treatment of established CMV disease in transplant or HIV populations remains under active clinical investigation.7
Consider genotypic resistance testing (UL97, UL54) when: CMV viral load fails to decline by at least 1 log10 after 2 weeks of adequate ganciclovir therapy; viral load rebounds after initial response; patient has prior ganciclovir exposure. UL97 mutations confer resistance to ganciclovir/valganciclovir; add or switch to foscarnet. UL54 mutations may cause cross-resistance to ganciclovir and foscarnet; cidofovir may retain activity. Combined UL97+UL54 high-level resistance: consider combination foscarnet plus ganciclovir or investigational agents.
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