Why Is Acyclovir Given to Cancer Patients?

Cancer patients often receive treatments that weaken their immune system, making them vulnerable to infections. One significant concern is the reactivation of latent viruses, which can cause complications during therapy. To mitigate these risks, antiviral medications like acyclovir are prescribed as a preventative measure due to their effectiveness against specific viruses that threaten immunocompromised individuals.

Immunosuppression in Oncology

Cancer treatments, particularly chemotherapy and radiation, suppress the immune system by targeting rapidly dividing cells, including essential components of immune defense. This suppression increases susceptibility to opportunistic infections, as the body’s ability to fight pathogens diminishes. The extent of immunosuppression varies based on cancer type, treatment regimen, and individual factors such as age and baseline immune function.

Certain chemotherapeutic agents, including cyclophosphamide, methotrexate, and fludarabine, cause profound lymphocyte depletion, particularly affecting T and B cells. This reduction in immune surveillance raises the risk of infections that a healthy immune system would typically control. Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy can lead to prolonged immune dysfunction, sometimes lasting months or years. The degree of immunosuppression is often measured by absolute neutrophil count (ANC) and CD4+ T-cell levels, with thresholds below 500 cells/µL and 200 cells/µL, respectively, indicating heightened infection risk.

Corticosteroids, frequently used in oncology to manage inflammation, nausea, and treatment-related side effects, further weaken immune responses by inhibiting cytokine production and impairing phagocytic function. Patients on prolonged steroid therapy, especially at doses exceeding 20 mg of prednisone (or equivalent) per day for more than two weeks, face an increased risk of opportunistic infections, necessitating prophylactic interventions.

Herpesvirus Reactivation in Cancer

Latent herpesviruses can become clinically significant in cancer patients, as these viruses persist in a dormant state and may reactivate under immunosuppressive conditions. Among the most concerning are herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV), all of which can lead to serious complications.

HSV-1 and HSV-2 reactivation is common in oncology settings, often causing painful oral or genital ulcerations. In severe cases, HSV can disseminate, leading to complications such as herpetic esophagitis or encephalitis. A study in Clinical Infectious Diseases found that among hematologic malignancy patients, HSV reactivation exceeded 60% in those not receiving antiviral prophylaxis, highlighting the burden of HSV-related morbidity in this population.

VZV, responsible for varicella (chickenpox) and herpes zoster (shingles), poses a risk, particularly in hematologic cancer patients and those undergoing HSCT. Reactivation can present as localized dermatomal eruptions or progress to disseminated disease, which carries a mortality rate approaching 20% in immunocompromised patients if untreated. Neurological complications such as postherpetic neuralgia and VZV vasculopathy further underscore the need for timely intervention.

EBV reactivation presents additional challenges, particularly in post-transplant lymphoproliferative disorder (PTLD). This condition arises when unchecked EBV replication leads to aberrant B-cell proliferation, potentially progressing to lymphoma. EBV DNAemia—detectable viral DNA in the bloodstream—is a predictive marker for PTLD development, and preemptive antiviral or immunomodulatory strategies may be necessary in high-risk cases.

Mechanism of Acyclovir in Viral Replication

Acyclovir selectively inhibits herpesvirus replication by targeting viral DNA synthesis. Its structural similarity to guanosine, a nucleoside required for DNA polymerization, allows it to act as a chain terminator when incorporated into viral DNA, halting replication.

Once administered, acyclovir undergoes phosphorylation by viral thymidine kinase (TK), an enzyme produced by herpesviruses but not found in significant amounts in uninfected mammalian cells. This activation ensures acyclovir remains largely inactive in non-infected cells, minimizing toxicity. Cellular kinases then add two additional phosphate groups, converting acyclovir monophosphate into its active triphosphate form.

The active acyclovir triphosphate competes with endogenous deoxyguanosine triphosphate (dGTP) for incorporation into the growing viral DNA strand. Once integrated, it causes premature termination of DNA elongation, preventing further nucleotide addition. Additionally, acyclovir triphosphate inhibits viral DNA polymerase more effectively than host polymerases, further reducing viral replication. Studies have shown that HSV DNA polymerase has a 100-fold higher affinity for acyclovir triphosphate compared to mammalian DNA polymerase, reinforcing its targeted antiviral activity.

Viral Management Considerations During Treatment

Preventing herpesvirus complications in cancer patients requires carefully timed antiviral administration, with acyclovir being a primary option due to its well-documented efficacy. Prophylactic use is recommended for high-risk individuals, including those undergoing HSCT or intensive chemotherapy. Guidelines from the Infectious Diseases Society of America (IDSA) suggest initiating acyclovir prophylaxis in seropositive patients at doses ranging from 400 mg orally twice daily to 800 mg three times a day, depending on risk factors and treatment intensity. For patients unable to take oral formulations or at risk for severe infections, intravenous dosing at 5 mg/kg every eight hours is often preferred.

Despite its efficacy, acyclovir therapy requires careful monitoring, particularly in individuals with renal impairment. Since the drug is primarily excreted unchanged by the kidneys, dose adjustments are necessary for patients with reduced creatinine clearance to prevent nephrotoxicity. Crystalluria, where acyclovir precipitates in renal tubules, has been reported in high-dose intravenous therapy, emphasizing the importance of adequate hydration. A minimum urine output of 75-100 mL/hour is often recommended to reduce this risk. Additionally, drug resistance, though uncommon, has been documented in immunocompromised populations, with mutations in the viral thymidine kinase gene rendering standard acyclovir therapy ineffective. In such cases, alternative agents like foscarnet or cidofovir may be required.