Antiviral prophylaxis for varicella zoster in immunocompromised patients (excluding haematological malignancies)
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the effectiveness of antiviral agents as prophylaxis against VZV reactivation in immunosuppressed patients.
Background
Varicella‐zoster virus (VZV) is a common herpesvirus that causes chicken pox and shingles. The former is a reflection of primary infection and, by adulthood, many (particularly in temperate climates) would have had prior exposure to VZV. VZV remains latent within the host; a declining VZV‐specific host immunity allows for spontaneous reactivation, with shingles being the most common manifestation (Gilden 2004). Although commonly regarded as a benign childhood illness, prior to the VZV vaccination campaign in 1995, VZV and associated complications previously resulted in 11,000 to 13,000 hospitalisations and 100 to 150 deaths each year in the United States (Reynolds 2008). Varicella vaccine and a herpes zoster vaccine have been developed as preventative therapies but guidelines and uptake of these vaccines vary between countries.
Antiviral agents are used as prophylaxis against other herpesviruses. Antiviral agents are now commonly used for prevention of recurrent genital herpes (Diaz‐Mitoma 1998; Fife 2008), caused by herpes simplex virus, including at obstetric delivery (Hollier 2009). Antiviral prophylaxis has also been shown to reduce cytomegalovirus (CMV) disease and CMV‐associated mortality in solid‐organ transplants (Hodson 2009).
Description of the condition
Reactivation of latent infection usually manifests as herpes zoster. This is commonly associated with post‐herpetic pain (neuralgia) which may be debilitating. Other complications include herpes ophthalmicus, optic neuritis, pneumonitis, hepatic dissemination, central nervous system vasculopathy, radiculitis and meningoencephalitis (Cohen 2008; Gilden 2004). Disseminated disease may result in severe morbidity and death.
Reactivation disease is particularly common in immunocompromised patients such as allogeneic haematopoietic stem cell transplantation (HSCT) recipients, solid organ transplant recipients, those on immunosuppressants and patients infected with human immunodeficiency virus (HIV) (Weller 1995). In a retrospective review of solid‐organ transplants, the overall incidence of herpes zoster was 8.6% (Gourishankar 2003). In the immunocompromised host, the burden of disseminated VZV disease is compounded by the risk of transplant failure, both leading to considerable morbidity and mortality
As disseminated VZV is a highly contagious disease, the potential for patient‐to‐patient transmission in hospital facilities where other immunocompromised patients are managed may also increase the risk to other patients (Adler 2008).
Description of the intervention
Antivirals such as aciclovir, an inhibitor of viral thymidine kinase, and more recently the analogues valaciclovir and famciclovir, have been used for the early treatment of varicella and herpes zoster. Aciclovir has been found to reduce the incidence of VZV disease after allogeneic HSCT (Boekch 2006; Ljungman 1986; Selby 1989). Antiviral therapy for herpesviruses including prevention of VZV in patients with haematological malignancy are discussed in a separate Cochrane review (Trelle 2009). Although antiviral prophylaxis may reduce the rate of viral disease whilst on prophylaxis, the adverse effects of antiviral agents and development of antiviral resistance need to be considered.
How the intervention might work
Antivirals may reduce the frequency and severity of reactivation disease and the potential for severe complications, thereby reducing patient morbidity and mortality.
Why it is important to do this review
VZV is a common disease associated with significant morbidity. In high‐income countries there are increasing numbers of patients with immunosuppression at risk of reactivation VZV disease during the course of cancer treatment and following organ transplantation (Weller 1995). Additionally, the global HIV pandemic, particularly in low‐income countries, has resulted in an ever‐growing group of severely immunocompromised individuals. Exploring the evidence for and against antiviral prophylaxis in these groups would assist in their long‐term management.
Objectives
To evaluate the effectiveness of antiviral agents as prophylaxis against VZV reactivation in immunosuppressed patients.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) of any type of antiviral agent.
Types of participants
Immunosuppressed children or adults (for example, due to HIV/AIDS, solid organ transplant recipients or those receiving anti‐lymphocyte antibodies).
Patients with underlying haematological malignancies, such as acute leukaemia, bone marrow transplant recipients or stem‐cell transplant recipients and those with graft versus host disease are included in a separate Cochrane review (Trelle 2009).
Types of interventions
We will only include trials that include the use of other medications or interventions if all participants had equal access to such medications or interventions.
We will exclude trials comparing only two or more medications without a placebo comparison group.
Types of outcome measures
Attempts will be made to obtain data on at least one of the following outcome measures:
Primary outcomes
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Clinical evidence of VZV disease.
Secondary outcomes
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All‐cause mortality.
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VZV‐related mortality.
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Other viral infections (including herpes simplex).
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Development of resistance.
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Adverse effects including renal dysfunction, allergies.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue) which includes the Cochrane Acute Respiratory Infections (ARI) Group and Airways Group's Specialised Trials Registers; MEDLINE (1966 to present); and EMBASE (1974 to present). The following search strategy will be used to search MEDLINE and CENTRAL. The MEDLINE search will be combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE (Lefebvre 2008).
MEDLINE (Ovid)
1 Herpes Zoster/
2 Herpesvirus 3, Human/
3 varicella zoster virus.tw,nm.
4 (human herpesvirus 3 or human herpes virus 3).tw.
5 Chickenpox/
6 (chicken pox or chickenpox).tw.
7 herpes zoster*.tw.
8 shingles.tw.
9 varicella*.tw.
10 zoster.tw.
11 or/1‐10
12 exp Antiviral Agents/
13 antiviral*.tw,nm.
14 acyclovir/ or ganciclovir/
15 aciclovir.tw,nm.
16 acyclovir.tw,nm.
17 valacyclovir.tw,nm.
18 valgancyclovir.tw,nm.
19 famiciclovir.tw,nm.
20 famciclovir.tw,nm.
21 cidofovir.tw,nm.
22 foscarnet.tw,nm.
23 brivudin.tw,nm.
24 or/12‐23
25 Antibiotic Prophylaxis/
26 (prophylax* or prevent* or protect*).tw.
27 or/25‐26
28 27 and 11 and 24
Searching other resources
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Proceedings of relevant major conferences (including, but not limited to, Interscience Conference of Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Infectious Diseases Society of America, European Congress of Clinical Microbiology and Infectious Diseases, and American Society of Transplant Physicians).
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The list of references in identified studies and major reviews.
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Contact with researchers active in the field and primary authors of identified relevant trials for details of unpublished trials.
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Contact with manufacturers of the study drugs (including GlaxoSmithKline, Sandoz, Alphapharm, Novartis Pharmaceuticals) for additional published or unpublished trials.
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There will be no language or publication restrictions.
Data collection and analysis
Selection of studies
Two review authors (CCC, RJM) will independently review literature searches to identify potentially relevant trials for full review. We will conduct searches of bibliographies and texts to identify additional studies. From the full text using specific criteria, the same two review authors will independently select trials for inclusion. We will exclude studies which only include patients with underlying haematological malignancies (such as acute leukaemia, bone marrow transplant recipients or stem‐cell transplant recipients and those with graft versus host disease) as these will be included in a separate Cochrane review (Trelle 2009). In the event of studies with mixed underlying conditions, the same two review authors will selectively include data pertaining to those without haematological malignancies. If the data cannot be separated, these studies will be discussed but we will not analyse the data. We will measure agreement using kappa statistics. We will resolve disagreement by discussions with the other review authors (ACC, MS).
Data extraction and management
We will review trials that satisfy the inclusion criteria and the following information will be recorded: study setting, year of study, source of funding, patient recruitment details (including number of eligible subjects), inclusion and exclusion criteria, other symptoms, randomisation and allocation concealment method, numbers of participants randomised, blinding (masking) of participants, care providers and outcome assessors, dose and type of intervention, duration of therapy, co‐interventions, numbers of patients not followed up, reasons for withdrawals from study protocol (clinical, side‐effects, refusal or other), details of side‐effects of therapy, and whether intention‐to‐treat analyses were possible. We will extract data based on the outcomes described previously. We will request further information from the trial authors where required.
Assessment of risk of bias in included studies
In order to assess the risk of bias, two review authors (CCC, RJM) will independently assess the quality of the studies included in the review according to the domain‐based evaluation recommended by the Cochrane Collaboration (Higgins 2008).
Adequate sequence generation?
Yes (low‐risk of bias), if the investigators describe a random component in the sequence generation process such as: referring to a random numbers table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation.
No (high‐risk of bias), if the investigators describe a non‐random component in the sequence generation process.
Unclear, if insufficient information about the sequence generation process to permit judgement of 'Yes' or 'No'.
Allocation concealment
Yes (low‐risk of bias), if participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation.
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Central allocation (including telephone, web‐based and pharmacy‐controlled randomisation).
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Sequentially numbered drug containers of identical appearance.
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Sequentially numbered, opaque, sealed envelopes.
No (high‐risk of bias), if participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on the following.
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Using an open random allocation schedule (for example, a list of random numbers).
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Assignment envelopes were used without appropriate safeguards (for example, if envelopes were unsealed or nonopaque or not sequentially numbered).
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Alternation or rotation.
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Date of birth.
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Case record number.
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Any other explicitly unconcealed procedure.
Unclear, if insufficient information to permit judgement of 'Yes' or 'No'.
Blinding of participants, personnel and outcome assessors
Yes (low‐risk of bias), if any one of the following occurred.
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No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
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Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
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Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.
No (high‐risk of bias), if any one of the following occurred.
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No blinding, or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.
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Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.
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Either participants or some key study personnel were not blinded, and the non‐blinding of others likely to introduce bias.
Unclear, if any one of the following occurred.
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Insufficient information to permit judgement of ‘Yes’ or ‘No’.
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The study did not address this outcome.
Incomplete outcome data
Yes (low‐risk of bias), if any one of the following occurred.
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No missing outcome data.
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Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).
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Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.
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For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.
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For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.
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Missing data have been imputed using appropriate methods.
No (high‐risk of bias), if any one of the following occurred.
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Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.
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For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate.
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For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size.
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‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation;
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Potentially inappropriate application of simple imputation.
Unclear, if any one of the following occurred.
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Insufficient reporting of attrition/exclusions to permit judgement of ‘Yes’ or ‘No’ (for example, number randomised not stated, no reasons for missing data provided).
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The study did not address this outcome.
Selected outcome reporting
Yes (low‐risk of bias), if any of the following: the study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
No (high‐risk of bias), if any one of the following: not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (for example, subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear, if insufficient information to permit judgement of 'Yes' or 'No'.
Other potential threats to validity
Yes (low‐risk of bias), if the study appears to be free of other sources of bias.
No (high‐risk of bias), if there is at least one important risk of bias. For example, the study:
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had a potential source of bias related to the specific study design used; or
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stopped early due to some data‐dependent process (including a formal‐stopping rule); or
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had extreme baseline imbalance; or
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has been claimed to have been fraudulent; or
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had some other problem.
Unclear, if there may be a risk of bias, but there is either:
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insufficient information to assess whether an important risk of bias exists; or
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insufficient rationale or evidence that an identified problem will introduce bias.
Measures of treatment effect
Studies reporting risk ratios (RR) and odds ratios (OR) will be compared separately using the Mantel‐Haenszel methods (Higgins 2008). Where possible, risk differences and number needed to treat to benefit (NNTB) will be calculated.
Unit of analysis issues
If studies reported outcomes using different measurement scales, the standardised mean difference will be estimated.
Dealing with missing data
The review authors will request further information from the primary investigators where required.
Assessment of heterogeneity
We will describe any heterogeneity between the study results and test this to see if it reached statistical significance using the Chi2 test. We will use the I2 statistic as a measure of heterogeneity and consider this to be significant when the P value is less than 0.10 (Higgins 2008).
Assessment of reporting biases
If combining the data and meta‐analysis is possible, we will assess publication bias using a funnel plot. We will try to identify and report on any selective reporting in the included trials.
Data synthesis
For the dichotomous outcome variables of each individual study, relative and absolute risk reductions will be calculated using a modified intention‐to‐treat (ITT) analysis. This analysis assumes that participants not available for outcome assessment have not improved (and probably represents a conservative estimate of effect). An initial qualitative comparison of all the individually analysed studies examine whether pooling of results (meta‐analysis) is reasonable. This will take into account differences in study populations, inclusion / exclusion criteria, interventions, outcome assessment, and estimated effect size.
The results from studies that met the inclusion criteria and reported any of the outcomes of interest will be included in the subsequent meta‐analyses. The summary weighted RR and 95% confidence interval (CI) (fixed‐effect model) will be calculated (Cochrane statistical package, Review Manager 5). For cross‐over studies, mean treatment differences will be calculated from raw data, extracted or imputed and entered as fixed‐effect generic inverse variance (GIV) outcome, to provide summary weighted differences and 95% CIs. In cross‐over trials, only data from the first arm will be included in a meta analysis if data is combined with parallel studies (Elbourne 2002). NNTB will be calculated from the pooled OR and its 95% CI applied to a specified baseline risk using an online calculator (Cates 2003).
Subgroup analysis and investigation of heterogeneity
An a priori sub‐group analyses are planned for:
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children versus adults (≥18 years);
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underlying condition: solid‐organ transplant, HIV/AIDS, use of antilymphocyte antibody or others;
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duration of prophylaxis;
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type of antiviral agent used; and
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use as primary prophylaxis versus secondary prophylaxis (following previous episode of VZV reactivation disease).
Sensitivity analysis
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Study quality.
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Study size.
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Variation in the inclusion criteria.
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Differences in the medications used in the intervention and comparison groups.
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Differences in outcome measures.
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Analysis using random‐effects model.
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Analysis by treatment received.
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Analysis by ITT.
