Human papillomavirus (HPV) vaccine for individuals with HIV infection

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

  • To determine the efficacy of HPV vaccination in HIV-infected individuals in preventing HPV infection.

  • To assess the potential adverse events of HPV vaccination in HIV-infected individuals.

Background

Description of the condition

Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, causing an estimated 6.2 million incident infections each year (Weinstock 2004). HPV is responsible for 5.2% of the world’s cancer burden (Parkin 2006). High-risk strains of HPV, including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66, are the primary cause of cervical cancer, with HPV 16 and 18 causing 70% of invasive squamous cervical cancer. High-risk HPV strains are also responsible for 85-90% of anal cancer, 40% of vulvar cancer, 40-70% of vaginal cancer, 40-50% of penile cancer, and 12-35% of oropharyngeal cancers (Parkin 2006, Grulich 2010). Non-oncogenic types of HPV, especially HPV 6 and 11, can cause genital warts and respiratory papillomatosis. 

Two vaccines to prevent HPV infection are currently available for use in women and men aged 9 to 26 years old: quadrivalent vaccine against HPV 6, 11, 16, 18 and bivalent vaccine against HPV 16, 18. The World Health Organization (WHO) recommends integrating HPV vaccination into national immunization policies where prevention of HPV-related disease is a public health priority, HPV vaccination is programmatically feasible and economically sustainable, and cost-effectiveness has been considered (WHO 2009). The European Medicines Agency, the United States Food and Drug Administration, and the Japanese Ministry of Health, Labour, and Welfare have approved both vaccines for use; however, HPV vaccines are not currently included in the WHO Model List of Essential Medicines.

For maximal effectiveness, the HPV vaccine should be administered to individuals prior to sexual debut, as most HPV infections are acquired within 3-4 years after onset of sexual activity (Patel 2008, Winer 2003, Collins 2002). The WHO recommends prioritization of HPV vaccination in 9-to-13 year old girls (WHO 2009). In the United States of America, the Advisory Committee on Immunization Practices (ACIP) recommends that the HPV vaccine be given to 11-to-12-year-old girls and boys, with catch-up vaccinations for teenagers and young adults through age 26 (Markowitz 2007, ACIP 2011).

HIV-infected populations are at increased risk for both HPV infection and HPV-related cancers. In sub-Saharan Africa, where the burden of HIV is greatest, 25% of women in the general population have cervical HPV infection (Clifford 2005); cervical cancer is the most common cancer in African women (Sitas 2006). Squamous intraepithelial lesions of the cervix are 4 times more prevalent in HIV-infected women, compared to HIV-uninfected women (Massad 2004). Men who have sex with men (MSM) have a 47.2% prevalence of anal HPV, compared with 12.2% in men who have sex with women (Nyitray 2011); HIV-infected MSM are twice as likely to develop anal cancer than HIV-uninfected MSM (Goedert 1998, Goedert 2000). In HIV-infected populations, the incidence of anal cancer is 42 times higher than in the general population (Sitas 2006).

The purpose of this study is to review systematically the efficacy and safety of HPV vaccines in individuals infected with HIV.

Description of the intervention

Two vaccines to prevent HPV infection are currently available for use in women and men aged 9 to 26 years old: quadrivalent vaccine against HPV 6, 11, 16, 18 and bivalent vaccine against HPV 16, 18. This systematic review compares HIV-infected individuals who received any HPV vaccination to HIV-infected individuals who have not received HPV vaccination or who received placebo.

Objectives

  • To determine the efficacy of HPV vaccination in HIV-infected individuals in preventing HPV infection.

  • To assess the potential adverse events of HPV vaccination in HIV-infected individuals.

Methods

Criteria for considering studies for this review

Types of studies

  • Randomised controlled trials (RCTs)

  • Non-randomised controlled trials

  • Observational studies (e.g. cohort studies), if there is a comparator

Types of participants

  • Individuals who are infected with HIV or have AIDS, regardless of age, sex, stage of illness, or treatment.

Types of interventions

  • Vaccination with any HPV vaccine including quadrivalent or bivalent, compared to placebo or to no intervention. HIV-infected individuals receiving HPV vaccination will be compared against HIV-infected individuals not receiving vaccination or receiving placebo. 

Types of outcome measures

Primary outcomes
  • HPV seroconversion, defined as serum antibodies against HPV 6, 11, 16, or 18

  • Cervical, vulvar, vaginal, penile, or anal infection with HIPV type 6, 11, 16, or 18

  • Cervical intraepithelial neoplasia (CIN) grades 2 or 3, vaginal intraepithelial neoplasia (VAIN) grades 2 or 3, vulvar intraepithelial neoplasia (VIN) grades 2 or 3, or anal intraepithelial neoplasia (AIN) grades 2 or 3

  • Number, incidence, frequency, and seriousness of adverse events

Secondary outcomes
  • Mortality from HPV-related malignancy or post vaccination

  • Permanent disability from vaccination

  • HIV viral load or shedding after vaccination

  • CD4 count after vaccination

  • Completion rate of 3 doses of HPV vaccine series

  • Acceptability

Search methods for identification of studies

See search methods used in reviews by the Cochrane Collaborative Review Group on HIV Infection and AIDS.

Electronic searches

We will formulate a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press and in progress). Full details of the Cochrane HIV/AIDS Review Group methods and the journals hand-searched are published in the section on Collaborative Review Groups in The Cochrane Library.

  Journal and trial databases

We will search the following electronic databases, in the period from 01 January 1991, the year the first HPV L1-VLP-based prophylactic vaccine patent application was filed, to the search date:

  • CENTRAL (Cochrane Central Register of Controlled Trials)

  • EMBASE

  • PsycINFO

  • PubMed

  • Web of Science / Web of Social Science

  • World Health Organization (WHO) Global Health Library, which includes references from AIM (AFRO), LILACS (AMRO/PAHO), IMEMR (EMRO), IMSEAR (SEARO), and WPRIM (WPRO).

Along with appropriate MeSH terms and relevant keywords, we will use the Cochrane Highly Sensitive Search Strategy for identifying reports of randomised controlled trials in MEDLINE, and the Cochrane HIV/AIDS Group's validated strategies for identifying references relevant to HIV infection and AIDS. The search strategy will be iterative, in that references of included studies will be searched for additional references. All languages will be included.

See Appendix 1 for our PubMed search strategy, which will be modified and adapted as needed for use in the other databases.

Conference databases

We will search conference abstract archives on the web sites of the Conference on Retroviruses and Opportunistic Infections (CROI), the International AIDS Conference (IAC), and the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS), for abstracts presented at all conferences through 2012.

Searching other resources

In addition to searching electronic databases, we will contact individual researchers, experts working in the field and authors of major trials to address whether any relevant manuscripts are in preparation or in press. The references of published articles found in the above databases will be searched for additional pertinent materials.

We will search WHO’s International Clinical Trials Registry Platform (ICTRP) to identify ongoing trials.

Data collection and analysis

The methodology for data collection and analysis will be based on the guidance of Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008). Two authors will independently examine abstracts of all studies identified by electronic or bibliographic scanning. Where necessary, we will obtain the full text to determine the eligibility of studies for inclusion.

Selection of studies

One author will perform a broad first cut of all downloaded material from the electronic searches to exclude citations that are plainly irrelevant. Two authors will read the titles, abstracts and descriptor terms of the remaining downloaded citations to identify potentially eligible reports. We will obtain full text articles for all citations identified as potentially eligible, and two authors will independently inspect these to establish the relevance of the article according to the pre-specified criteria. Where there is uncertainty as to the eligibility of the record, we will obtain and review the full article.

Two authors will independently apply the inclusion criteria, and any differences arising will be resolved by discussion with a neutral arbiter. We will review studies for relevance based on design, types of participants and outcome measures.

Data extraction and management

Two authors will independently extract data into a standardised, pre-piloted data extraction form. The following characteristics will be extracted from each included study:

  • Administrative details: trial identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year(s) in which study was conducted; details of other relevant papers cited;

  • Details of the study: study design; type, duration and completeness of follow up; location/orientation of study (e.g. higher-income vs. low or middle-income country; stage of HIV epidemic)

  • Details of participants: HIV-infected persons, including age, gender, ethnicity, baseline immune status (e.g. CD4 count, HIV viral load), antiretroviral therapy, reported sexual debut status

  • Details of intervention: HPV vaccine type (bivalent versus quadrivalent), vaccine dosage, comparator of no vaccination or placebo

  • Details of outcomes: Serum antibodies against HPV 6, 11, 16, or 18; cervical, vulvar, vaginal, penile, or anal infection with HPV type 6, 11, 16, or 18; CIN 2-3, VIN 2-3, VAIN 2-3, or AIN 2-3; number, incidence, frequency, seriousness of adverse events

  • Details necessary for risk of bias assessment

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the bias assessment tool described in the Cochrane Handbook (Higgins 2008). We will resolve any disagreement by discussion or by involving a neutral third party to adjudicate.

The Cochrane approach assesses risk of bias in individual studies across six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential biases.

Sequence generation (checking for selection bias)

  • Adequate: investigators described a random component in the sequence generation process, such as the use of random number table, coin tossing, card or envelope shuffling

  • Inadequate: investigators described a non-random component in the sequence generation process, such as the use of odd or even date of birth, algorithm based on the day or date of birth, hospital or clinic record number.

  • Unclear: insufficient information to permit judgment of the sequence generation process.

Allocation concealment (checking for selection bias)

  • Adequate: participants and the investigators enrolling participants cannot foresee assignment (e.g., central allocation; or sequentially numbered, opaque, sealed envelopes).

  • Inadequate: participants and investigators enrolling participants can foresee upcoming assignment (e.g., an open random allocation schedule, a list of random numbers), or envelopes were unsealed, non-opaque or not sequentially numbered.

  • Unclear: insufficient information to permit judgment of the allocation concealment or the method not described.

Blinding (checking for performance bias and detection bias)

  • Adequate: blinding of the participants, key study personnel and outcome assessor and unlikely that the blinding could have been broken. Not blinding in the situation where non-blinding is unlikely to introduce bias.

  • Inadequate: no blinding or incomplete blinding when the outcome is likely to be influenced by lack of blinding.

  • Unclear: insufficient information to permit judgment of adequacy or otherwise of the blinding.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

  • Adequate: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome or missing outcome data balanced in number across groups.

  • Inadequate: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.

  • Unclear: insufficient reporting of attrition or exclusions.

Selective reporting

  • Adequate: a protocol is available which clearly states the primary outcome is the same as in the final trial report.

  • Inadequate: the primary outcome differs between the protocol and final trial report.

  • Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

Other forms of bias

  • Adequate: there is no evidence of bias from other sources.

  • Inadequate: there is potential bias present from other sources (e.g., early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design).

  • Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias

For blinding and incomplete outcome data, multiple entries can be made if more than one outcome (or time points) is involved.  For non-randomised studies, we may add domains to assess bias, such as matching or adjustment for confounding variables.

We will assess the quality of evidence across the body of evidence using the GRADE approach (Guyatt 2008), which defines the quality of evidence for each outcome as “the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest” (Higgins 2008). The quality rating across studies has four levels: high, moderate, low or very low. Randomised trials are considered to be of high quality but can be downgraded for any of five reasons; similarly, observational studies are considered to be of low quality, but can be upgraded for any of three reasons. The five factors that decrease the quality of evidence are 1) limitations in study design; 2) indirectness of evidence; 3) unexplained heterogeneity or inconsistency of results; 4) imprecision of results and 5) high probability of publication bias.  The three factors that can increase the quality level of a body of evidence are 1) large magnitude of effect; 2) if all plausible confounding would reduce a demonstrated effect and 3) the presence of a dose-response gradient.

Observational studies will be assessed for risk of bias using the above criteria, as well as other measures including a 9-point rigor scale for assessing the quality of non-randomised studies (Kennedy 2010a, Kennedy 2010b). We will also consult the Cochrane Handbook's chapter on non-randomised studies (Higgins 2008). If necessary, we will contact the Cochrane Bias Methods Group for additional guidance.

Measures of treatment effect

Two authors will independently analyze the data. For randomised controlled trials, we will calculate the relative risk (RR) for dichotomous outcomes and the 95% confidence interval (CI). For continuous data we will calculate a weighted-mean difference.

We will use Review Manager 5 provided by the Cochrane Collaboration for statistical analysis and GRADEpro software (GRADEpro 2008) to produce GRADE Summary of Findings tables and GRADE evidence profiles. We will summarise dichotomous outcomes for effect in terms of risk ratio (RR), rate ratio and number needed to treat (NNT) with their 95% confidence intervals. We will perform tests for interaction to compare estimates within subgroups using methods described by Altman and colleagues (Altman 2003).

We will summarise rate data for individual studies in terms of rate ratios with their 95% confidence intervals. Standard errors for each estimate will be estimated using methods described by Rothman and colleagues (Rothman 1998).

We will calculate summary statistics using meta-analytic methods and present findings in GRADE Summary of Findings tables and GRADE Evidence Profiles for all outcomes of interest. 

Unit of analysis issues

The unit of analysis will be the individual study participant.

Dealing with missing data

We will contact study authors if it is necessary to obtain data missing from published reports.

Assessment of heterogeneity

We will use the I2 statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity (I2 greater than 50%), we will explore it by pre-specified subgroup analysis.

If heterogeneity persists, we will present results separately and report reasons for the observed heterogeneity.

Assessment of reporting biases

Where we suspect reporting bias we will attempt to contact study authors and ask them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.

We will assess the potential for publication bias for the studies using funnel plots. We will attempt to minimise the potential for publication bias by our comprehensive search strategy that includes evaluating published and unpublished literature.

Data synthesis

We will conduct meta-analysis, if appropriate, using Cochrane's Review Manager software (RevMan 2011) and present results using the Mantel-Haenzel rate ratio. We will use both fixed and random effects models and conduct sensitivity analysis to explore differences between the two models. If meta-analysis is not possible, a narrative synthesis of studies will be undertaken. Data will also be presented using the GRADEpro software (GRADEpro 2008). GRADE evidence profiles and summary of findings tables will be generated.

When interventions and study populations are sufficiently similar across the different studies, we will pool the data across studies and estimate summary effect sizes using both fixed- and random-effects models.  We intend to compare the estimates from fixed- and random-effects models in an attempt to explore the influence of small-study effects on results of a meta-analysis with intra-study heterogeneity. Specifically, we will estimate the log (risk ratio) for each included study and use the inverse variance method to calculate study weights. The inverse variance method assumes that the variance for each study is inversely proportional to its importance, therefore more weight is given to studies with less variance than studies with greater variance. If the estimates between the two modeling approaches are similar, then we can assume effects from small-studies only slightly affect the intervention's summary estimate. If estimates from random-effects are qualitatively substantially more beneficial than fixed-effects estimates, we will investigate whether the interventions were more effective in smaller studies than in larger studies. If upon reviewing the methodologies of the included studies we conclude that the larger studies were more rigorous, we may consider presenting only results from larger studies in a meta-analysis. As such, we intend to explore potential methodologic reasons for those differences in fixed- or random-effects estimates.

We will summarise the quality of evidence for the studies separately for each outcome for which data are available in GRADE Summary of Findings tables and GRADE evidence profiles (Guyatt 2008).

Subgroup analysis and investigation of heterogeneity

Heterogeneity will be explored by analyses per subgroup, which will be performed for populations or types of interventions that are dissimilar in a meaningful way. These analyses could include subgroup analyses based on the HIV risk group, perinatally-acquired vs sexually acquired, the study region, higher-income vs. low or middle-income country, characteristics of key populations, or other factors.

If possible, we will perform sub-group analysis by baseline immune status (e.g. CD4 count) of study participants and by gender. Heterogeneity will also be explored using further sub-group analyses by setting (middle- or low- versus high-income country) and by HPV vaccine type (quadrivalent versus bivalent). A test for interaction will be performed for each subgroup comparison.

If pooled results are heterogeneous for the selected studies, we will conduct sensitivity analyses to identify studies with outlying results for further examination.

Appendices

Appendix 1. PubMed Search Strategy (example)

Search #PubMed search strategy, which will be modified and adapted as needed for use in the other databases (01 Jan 1996-search date)
#1Search randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [MeSH] OR random allocation [MeSH] OR double-blind method [MeSH] OR single-blind method [MeSH] OR clinical trial [pt] OR clinical trials [MeSH] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [MeSH] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [MeSH] OR evaluation studies [MeSH] OR follow-up studies [MeSH] OR prospective studies [MeSH] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw] ) OR non-randomi*[tw] OR before after study[tw] OR time series[tw] OR case control[tw] OR prospective cohort[tw] OR retrospective cohort[tw] OR cross-section*[tw] OR prospective[tw] OR retrospective[tw] OR research design[mh:noexp] OR follow-up studies[MeSH] OR prospective studies[MeSH] OR control*[tw] OR prospectiv*[tw] OR volunteer*[tw] OR longitud*[tw] OR evaluat*[tiab] OR pre-post[tw] OR (pre-test[tw] AND post-test[tw]) NOT (animals [MeSH] NOT human [MeSH])
#2Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv-1*[tiab] OR hiv-2*[tiab] OR hiv1[tiab] OR hiv2[tiab] OR hiv infect*[tiab] OR human immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR human immuno-deficiency virus[tiab] OR human immune-deficiency virus[tiab] OR ((human immun*) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno-deficiency syndrome[tiab] OR acquired immune-deficiency syndrome[tiab] OR ((acquired immun*) AND (deficiency syndrome[tiab])) HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv-1*[tiab] OR hiv-2*[tiab] OR hiv1[tiab] OR hiv2[tiab] OR hiv infect*[tiab] OR human immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR human immuno-deficiency virus[tiab] OR human immune-deficiency virus[tiab] OR ((human immun*) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno-deficiency syndrome[tiab] OR acquired immune-deficiency syndrome[tiab] OR ((acquired immun*) AND (deficiency syndrome[tiab])) OR Sexually Transmitted Diseases[Mesh] OR sexually transmitted[tiab] OR Syphilis[Mesh] OR syphilis[tiab] OR Antiretroviral Therapy, Highly Active[Mesh]
#3Search Papillomavirus Vaccine[MeSH] OR human papillomavirus vaccin*[tiab] OR human papilloma virus vaccin*[tiab] OR HPV vaccin*[tiab] OR HPV L1 vaccin*[tiab] OR human papillomavirus L1 vaccin*[tiab] OR alphapapillomavirus vaccin*[tiab] OR Gardasil[tiab] OR Merck HPV vaccin*[tiab] OR “Merck HPV vaccin”*[tiab] OR Merck human papillomavirus vaccin*[tiab] OR “Merck human papillomavirus vaccin”*[tiab] OR Cervarix[tiab] OR GSK HPV vaccin*[tiab] OR “GSK HPV vaccin”*[tiab] OR GSK human papillomavirus vaccin*[tiab] OR “GSK human papillomavirus vaccin”*[tiab] OR GlaxoSmithKline HPV vaccin*[tiab] OR “GlaxoSmithKline HPV vaccin”*[tiab] OR GlaxoSmithKline human papillomavirus vaccin*[tiab] OR “GlaxoSmithKline human papillomavirus vaccin”*[tiab] OR quadrivalent HPV vaccin*[tiab] OR “quadrivalent HPV vaccin”*[tiab] OR QHPV[tiab] OR HPV4[tiab] OR bivalent HPV vaccin*[tiab] OR “bivalent HPV vaccin”*[tiab] OR BHPV[tiab] OR HPV2[tiab] OR human papillomavirus type 6 vaccin*[tiab] OR HPV type 6 vaccin*[tiab] OR HPV6 vaccin*[tiab] OR human papillomavirus type 11 vaccin*[tiab] OR HPV type 11 vaccin*[tiab] OR HPV11 vaccin*[tiab] OR human papillomavirus type 16 vaccin*[tiab] OR HPV type 16 vaccin*[tiab] OR HPV16 vaccin*[tiab] OR human papillomavirus type 18 vaccin*[tiab] OR HPV type 18 vaccin*[tiab] OR HPV18 vaccin*[tiab]
#4#2 or #3
#5#1 and #4

What's new

DateEventDescription
10 April 2013AmendedContact details updated.

Declarations of interest

None known.

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