Antiviral Prophylaxis for Select at Risk Patients

To determine the effectiveness and safety of viral vaccines in patients with hematologic malignancies. The primary outcome was the incidence of infection. Secondary outcomes were mortality, incidence of complications, severe viral infection, hospitalization, immune response, and adverse effects.

Databases searched were the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL (June 2010). In addition, reference lists of relevant articles, abstracts from scientific meetings, and contacted vaccine manufacturers were used.

Randomized, controlled trials (RCTs) evaluating viral vaccines in patients with hematologic malignancies were included. No exclusion criteria were stated.

A total of 565 references were retrieved.

Relative risk (RR) was used for binary data, and mean difference (MD) was used for continuous data. The fixed-effect model was used in meta-analyses. Two authors (first and second authors) independently reviewed titles and abstracts of references retrieved from the searches and selected all potentially relevant studies. Copies of these articles were obtained and reviewed independently by the same authors against predefined inclusion criteria. The authors were not blinded to the names of the trial authors, institutions, or journal of publication. All disagreements about the selection of studies were resolved by consensus.

Interventions evaluated included heat-inactivated varicella-zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials), and inactivated poliovirus vaccine (IPV) (one trial).

• The final study sample included eight RCTs.
• Three hundred five patients were in intervention groups and 288 were in control groups.  
• Sample sizes across studies ranged from 25 to 182.
• Patients of all ages with hematologic malignancies, including acute and chronic leukemias, lymphomas (Hodgkin and non-Hodgkin), and myelomas, were included. Trials evaluating all forms of viral vaccines, including influenza, varicella, hepatitis A, hepatitis B, measles, mumps, rubella, and poliomyelitis, were included in the review. The control interventions could be placebo vaccine, no vaccine, an alternative form of vaccine, or alternative dosing regimens or schedules.

Patients were undergoing the active treatment phase of care.

The VZV vaccine might reduce herpes zoster compared with no vaccine (relative risk [RR] = 0.54; 95% confidence interval [CI] [0.3, 1.0]; p = 0.05). Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported a severity score of zoster that favored vaccination (MD = 2.6; 95% CI [0.94, 4.26]; p = 0.002). Two RCTs compared inactivated influenza vaccine with no vaccine and reported a lower risk of lower respiratory infections (RR = 0.39; 95% CI [0.19, 0.78]; p = 0.008) and hospitalization (RR = 0.17; 95% CI [0.09, 0.31]; p < 0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without reinduction chemotherapy (one trial). The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplantation (SCT) found no significant difference in seroconversion.

Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. Local adverse effects occur frequently.

The quality of evidence is low.

Further high-quality RCTs are needed.

To examine the effects of interventions for the prevention, treatment, or both, of herpes simplex virus (HSV) in patients receiving treatment for cancer.

• Databases searched were Cochrane Oral Health Group’s Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT, SIGLE, and LILACS.
• Keywords searched were neoplasm, cancer, bone marrow transplant, herpes simplex or herpes labialis, and mucositis herpetic.
• All randomized, controlled trials (RCTs) compared interventions for the prevention or treatment or both of HSV infection in people being treated for cancer.  Published and unpublished studies were included in the searches.
• Articles were excluded if they were not RCTs, did not involve patients with cancer, and did not meet the inclusion criteria.

Forty studies were initially reviewed.

• After excluding studies due to the exclusion criteria, 17 studies remained for analysis.
• The sample size across studies ranged from 21 to 151.
• The majority of studies were conducted in patients with hematologic malignancies.  Only one study included patients with solid tumors.

• Acyclovir was more effective than placebo in the prevention of herpes infections whether given orally (relative risk [RR] = 0.11; 95% CI [0.05, 0.24]) or intravenously (IV) (RR = 0.24; 95% CI [0.07, 0.86]). No differences were found in effectiveness between oral or IV use or between adults and children.
• Valaciclovir appeared to be as effective as acyclovir in two relatively small trials for prophylaxis. In one trial comparing prostaglandin E to placebo, placebo was more effective in prevention than prostaglandin. In terms of herpes treatment, there were only two studies found and reported. Acyclovir was more effective than placebo in terms of time to healing (p = 0.01) and the duration of viral shedding was lower with acyclovir (p = 0.00008) compared to placebo.

The evidence suggested that acyclovir may be beneficial for the prevention and treatment of herpes infection in this patient population; however, the risk ratios were relatively small, suggesting limited benefit.  Valaciclovir may also be effective; however, few studies have reported this particular agent, so firm conclusions cannot be drawn. Prostaglandin E appears to have no benefit for the prevention of herpes infection in this group of patients. The degree of immunocompromised patients in study samples was not discussed, and sample sizes varied across studies, suggesting limited ability to truly generalize the findings provided here.  Acyclovir was more effective than placebo in the prevention of herpes infections whether given orally (RR = 0.11; 95% CI [0.05, 0.24]) or IV (RR = 0.24; 95% CI [0.07, 0.86]). No differences were found in effectiveness between oral or IV use or between adults and children. Valaciclovir appeared to be as effective as aciclovir in two relatively small trials for prophylaxis.

Fifteen trials evaluated the effect for prevention of herpes infection, and two trials evaluated herpes treatment.

STUDY PURPOSE: Evaluate the efficacy of lamivudine prophylaxis  (100 mg daily) on HBsAg seropositive patients with breast cancer undergoing chemotherapy.

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: Medline, Embase, and the Cochrane databases

INCLUSION CRITERIA: (a) Types of studies: randomized controlled cohort, retrospective comparative case series, and prospective, controlled, non-randomized studies; (b) studies that included a lamivudine prophylaxis group and a group that did not receive lamivudine prophylaxis; and (c) all patients received chemotherapy and were HBsAg sero-positive.

EXCLUSION CRITERIA: Patient populations were excluded if: (a) the study did not measure HBV reactivation/flare as a specific outcome; (b) the patients did not receive chemotherapy; (c) patients had HIV co-infection; (d) patients had hepatitis D virus, hepatitis C virus, or other liver diseases; (e) there was no lamivudine prophylaxis and non-prophylaxis group; and (f) there was insufficient analytic information available.

TOTAL REFERENCES RETRIEVED: 16

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two independent reviewers retrieved and evaluated studies using a validated tool for scoring the quality of the study. Meta-analysis was performed using Review Manager Software 5.0.

• FINAL NUMBER STUDIES INCLUDED: 6 
• TOTAL PATIENTS INCLUDED IN REVIEW: 499
• SAMPLE RANGE ACROSS STUDIES: 20-169
• KEY SAMPLE CHARACTERISTICS: Sample consisted of  Asian female patients with breast cancer who were hepatitis HBsAg seropositive and treated with 4-6 cycles of chemotherapy (AC, AC + T, or CAF).

PHASE OF CARE: Active anti-tumor treatment

Lamivudine prophylaxis significantly reduced the risk of HBV reactivation in HBsAg seropositive patients (RR = 0.23, 95% CI [0.13, 0.39], p < 0.00001); the risk of hepatitis (RR = 0.2, 95% CI [0.08, 0.47], p =0.002); the rate of overall chemotherapy disruptions (RR = 0.36, 95% CI [0.21, 0.64], p = 0.0004); and the rate of delay of eight days or greater between cycles in those patients who completed chemotherapy (RR = 0.42, 95% CI [0.21, 0.82], p = 0.01).

Lamivudine 100 mg daily used as prophylaxis for HBsAg-seropositive patients undergoing chemotherapy significantly reduces the risk of hepatitis B reactivation and prevents chemotherapy delays.

• Limited number of studies included
• Exclusively Asian population, which is a population that has a high prevalence of hepatitis B carriers
• Only 1 of the 6 studies was a RCT.

Lamivudine 100 mg daily is recommend to prevent hepatitis B reactivation in patients who are HbsAg seropositive. There is no consensus on timing and duration of lamivudine prophylaxis. Some experts recommend lamivudine should be started at least one week before initiation and be continued until at least six weeks after the chemotherapy.

STUDY PURPOSE: To determine the risk of hepatitis B virus (HBV) reactivation with or without antiviral prophylaxis, and the effectiveness of prophylaxis

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 26
• TOTAL PATIENTS INCLUDED IN REVIEW: 2,079
• SAMPLE RANGE ACROSS STUDIES: 6–258 patients
• KEY SAMPLE CHARACTERISTICS: Included patients with chronic HBV and resolved HBV

PHASE OF CARE: Active antitumor treatment

Risk for HBV reactivation without prophylaxis ranged from 4%–68% (median = 25%) and with prophylaxis ranged from 0.9%–31.4% (median = 4.1%). Among 13 studies comparing reactivation risk between patients who did and did not receive HBV prophylaxis, the pooled odds ratio [OR] was 0.12 (95% confidence interval [CI] [0.06, 0.22]).

HBV prophylaxis can help reduce the odds of HBV reactivation in patients with solid tumors undergoing chemotherapy.

• High heterogeneity among studies prevented an analysis of risk of reactivation in individuals without prophylaxis.
• Only one RCT
• Small effect size, although statistically significant

HBV prophylaxis may reduce the chance of patients with a history of HBV experiencing reactivation when undergoing chemotherapy for solid tumors. The authors of this article noted that guidelines regarding HBV screening vary. While the American Society of Clinical Oncology (ASCO) recommends screening for individuals at high risk, the Centers for Disease Control and Prevention (CDC) and others recommend screening all patients receiving immunosuppressive therapy. The findings here provide some support for broad HBV screening and the appropriate use of HBV prophylaxis; however, this analysis had multiple limitations. Further study is warranted to determine the screening, prophylaxis, and cost-effectiveness benefits of these actions.

STUDY PURPOSE: To determine the effect of prophylactic or preemptive treatment with lamivudine for patients with breast cancer who were hepatitis B surface antigen positive on the following: (a) the rate of hepatitis B virus (HBV) reactivation, which was defined as an increase in HBV DNA levels more than 10 times or an absolute increase of HBV DNA levels that exceeded 1×109 copies/ml; (b) incidence of hepatitis, which was defined as greater than a three times increase in alanine aminotransferase (ALT) that exceeded the upper limit of normal range (ULN) or an absolute increase of ALT of more than 100 u/l; (c) rate of chemotherapy disruption, which was defined as either a premature termination of chemotherapy or a delay of more than eighty days of chemotherapy between cycles; and (d) overall mortality. Secondary outcomes included incidence of HBV-related hepatitis, rate of HBV-related chemotherapy disruption, HBV-related mortality, occurrence of YMDD mutations, and withdrawal hepatitis.

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 6
• TOTAL PATIENTS INCLUDED IN REVIEW = 430
• SAMPLE RANGE ACROSS STUDIES: 43–50 patients (median range)
• KEY SAMPLE CHARACTERISTICS: Patients with breast cancer undergoing systemic chemotherapy who were HBV carriers (HBsAg)

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care

An early preemptive strategy is superior to a therapeutic strategy in decreasing the incidence of HBV reactivation, HBV-related hepatitis, and the rate of chemotherapy disruption in patients with breast cancer.

• Limited search
• High heterogeneity

In this study, 16% of patients who were HBsAg positive undergoing chemotherapy for breast cancer developed overt hepatitis. Using a preemptive strategy of prescribing lamivudine at the commencement of chemotherapy decreased the rate of hepatitis to 2.2%. The authors noted that, as level III evidence, the AASLD (American Association for the Study of Liver Diseases) recommends that HBV carriers receiving cancer chemotherapy or immunosuppressive therapy with a baseline HBV DNA of less than 2,000 iu/ml should start antiviral therapy at the commencement of treatment and continue it for six months after the completion of chemotherapy or immunosuppressive therapy.

To provide a guide for the use of antimicrobial agents for chemotherapy-induced fever and neutropenia in patients with cancer. The patient population targeted included adult and pediatric patients with neutropenia.

For this guideline document, the IDSA Standards and Practice Guidelines Committee reconvened many members of their original guideline panel, together with additional experts, in the management of patients with fever and neutropenia. The committee included experts in infectious diseases, oncology, and hematopoietic stem cell transplantation (HSCT) in both adult and pediatric patients. The literature was reviewed and graded according to a systematic weighting of the level and grade of the evidence for making a recommendation.

Patients were undergoing the active treatment phase of care.

Antibiotic Prophylaxis 

Fluoroquinolone prophylaxis should be considered for high-risk neutropenic patients (patients expected to have absolute neutrophil counts (ANCs) of 100 cells/mm³ or lower for more than seven days. Levofloxacin and ciprofloxacin are the agents that have been evaluated the most and are generally equivalent, although levofloxacin is preferred for patients at risk for oral mucositis-related invasive viridans group streptococcal infection (B-1). The addition of a gram-positive active agent to fluoroquinolone prophylaxis is not recommended (A-1). Antibacterial prophylaxis is not indicated for low-risk patients anticipated to be neutropenic for less than seven days (A-III). 

Antifungal Prophylaxis

Patients at high risk for candida infection, such as recipients of allogeneic HSCT and patients with acute leukemia undergoing intensive chemotherapy, should be treated with antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin (A-I). Patients aged 13 years or older who are undergoing intensive chemotherapy for acute leukemia or myelodysplastic syndrome who are at high risk for aspergillus infection may be treated with posaconazole for antifungal prophylaxis (B-I). Prophylaxis against aspergillus infection is not effective in recipients of pre-engraftment HSCTs, but it is recommended for patients with a prior history of invasive aspergillosis (A-III), anticipated neutropenia of at least two weeks (C-III), or a prolonged period of neutropenia prior to transplantation (C-III). Antifungal prophylaxis is not recommended for patients with an anticipated duration of neutropenia of less than seven days (A-III). 

Antiviral Prophylaxis

Herpes simplex virus–positive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I). Annual influenza vaccination is recommended for all patients being treated for cancer (A-II). The optimal timing has not been established, but serologic responses may be best between chemotherapy cycles (more than seven days after the last treatment) or more than two weeks prior to the start of therapy (B-III). 

Colony-Stimulating Factors

Colony-stimulating factors are recommended for prophylaxis against neutropenia when the anticipated risk of fever and neutropenia is 20% or greater.

Prevention of Catheter-Related Bloodstream Infections

Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine are recommended for all central venous catheter insertions (A-I). 

Hand Hygiene

Hand hygiene is the most effective means of preventing infection in the hospital (A-II).

Environment

HSCT recipients should be in private rooms (B-III). Patients with neutropenia do not need to be placed in single-patient rooms. Allogeneic HSCT recipients should be in rooms with more than 12 air exchanges, high-efficiency particulate absorption filtration, and positive pressure (A-III). Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III). 

Isolation and Barrier Precautions

No specific protective gear (gowns, gloves, or masks) are necessary during the routine care of neutropenic patients. Standard barrier precautions should be used for all patients when contact with body fluids is anticipated.

Food

In general, food should be well cooked. Well-cleaned uncooked fruits and vegetables are acceptable.

Skin and Oral Care

Daily showers are recommended to maintain skin integrity (expert opinion). Patients should brush their teeth two times per day or more with a regular toothbrush, and flossing can be performed if it can be performed without trauma (expert opinion). Patients with mucositis should rinse their mouths with sterile water, saline, or sodium bicarbonate rinses four to six times per day (expert opinion). Menstruating immunocompromised women should avoid tampons (expert opinion). Rectal thermometers, enemas, suppositories, and rectal examinations are contraindicated for patients with neutropenia (expert opinion).

This was a comprehensive guideline developed by the Infectious Diseases Society of America (IDSA) to guide clinicians in the care of patients with chemotherapy-induced neutropenia and in the management of febrile neutropenia. The full guide can be located at http://cid.oxfordjournals.org/content/52/4/e56.full.

PURPOSE: To provide guidance for the clinical practice of preventing and treating infection in patients with cancer

PHASE OF CARE: Multiple phases of care

One thousand one hundred sixty-two publications were retrieved. No method of study quality evaluation or results were reported.

The combination of evidence- and consensus-based recommendations and the differentiation between them are not clearly stated. For vascular access device prevention of infection, the guidelines only address antimicrobial-coated catheters and not any other aspect of management.

The guidelines provide a comprehensive reference to assess patient risk of infection and expert recommendations regarding interventions aimed at the prevention and treatment of infection in patients with cancer. They do not discuss long-term survivorship issues in this area.

RESOURCE TYPE: Consensus-based guideline

PHASE OF CARE: Multiple phases of care

Not provided

The influenza vaccine is recommended in patients with active malignancy undergoing chemotherapy, patients with acute leukemia after chemotherapy, and all patients during maintenance treatment. Insufficient evidence exists for acyclovir prophylaxis for preventing herpes simplex virus (HSV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV) reactivation. The guidelines provide an algorithm for hepatitis B virus (HBV) reactivation prophylaxis, including screening, monitoring, and intervention based on positive HSs antigen and units of HBc DNA identified. Primary antiviral prophylaxis with nucleoside analogues for hepatitis B are effective in reducing risk. The guidelines identify risk factors for HBV reactivation:

• Treatment with anthracyclines
• Treatment with steroids (greater than 10–20 mg daily or equivalent for four weeks or more)
• Treatment with monoclonal antibodies
• Breast cancer or malignant lymphoma

• Limited search documentation

These guideline add to the body of evidence recommending influenza vaccination in patients undergoing cancer treatment. This guideline does not recommend other routine prophylaxis and does provide suggestions regarding specific agents for prophylaxis according to individual patient risk factors based on disease, history, and treatment type.