Review question/objective

What is the best available evidence on the epidemiological association between gender and survival among HIV patients on antiretroviral therapy?

Background

The human immunodeficiency virus (HIV) continues to be a major global public health issue, having claimed more than 39 million lives. At the end of 2013, approximately 35.0 (33.1-37.2) million people are living with HIV globally, with 2.1 (1.9-2.4) million people becoming newly infected in 2013 alone.1

The World Health Organization (WHO) reported that 61% (57%-66%) of all persons eligible for HIV treatment in low- and middle-income countries had obtained antiretroviral therapy (ART) in 2012.1 In Africa, 63% (59%-66%) of people eligible for treatment were able to access ART in 2012.1 Similarly, 75% (66%-85%) in the Regions of America, 15% (11%-20%) in the Eastern Mediterranean Region, 38% (33%-43%) in the European Region, 50% (43%-65%) in the South-East Asia Region and 53% (35%-91%) in the Western Pacific Region were accessing such treatment.1

It has been documented that the widespread use of combination ART has improved the lives of people living with HIV through reducing morbidity and mortality.2 Different results have emerged from various studies regarding the effect of gender on mortality among HIV patients on ART.2 Historically, women have been poorly represented in HIV clinical trials even though almost half of the global HIV-infected population is female. Poor representation of women in clinical trials has led to the delay in accurate studies examining gender-specific differences in access to care, treatment outcomes and adherence in developing countries, gender-specific differences are more evident in developed countries, but no clear etiology for these differences has been identified.2-4 Generally speaking, studies from Europe and North America have shown a higher risk of death among women on ART than among men; in contrast, studies done in sub-Sahara African region have revealed that men on ART experience higher mortality rates than women.2,5 However, a study done in Ethiopia presents a different story in that females experience higher mortality rates than males.6

There is growing body of evidence on gender and ART in developing countries, much of which documents the same association repeatedly:7 disproportionately fewer men than women access ART3, and there is higher mortality among men than women on ART.3,8 Such studies typically on the possible mechanisms underlying the observed associations. Presumed mechanisms include: poor health-seeking behaviors among men leading to greater advancement of the disease at the time of ART initiation, differential rates of loss to follow-up leading to higher mortality, behavioral factors such as poor adherence, and/or biologic factors such as gender differences in immunologic responses to ART.2,9

Among patients who do start ART, late presentation has been cited as one of the main reasons for increased male mortality in ART programs.8,10 In sub-Saharan Africa, men appear to initiate ART late and at a more advanced stage of the disease than women4, and markers of advanced HIV disease at the time of ART initiation strongly predict early mortality on ART.9

Biologic differences between men and women have been suggested as shaping immunologic responses to ART and mortality risk. A study conducted in South Africa found that women had higher CD4+ cell counts at ART initiation than men, and slightly better absolute CD4+ cell increases on treatment.2,9

Still there are other studies which show that there is no association between gender and mortality.11-13

Therefore, in view of these conflicting findings, this review will provide the best available evidence for the specified topic so that it can be utilized in evidence based decision making in the care of patients on ART.

Inclusion criteria

Types of participants

Subjects above 15 years of age regardless of ethnicity, country of residence, duration on ART and with other baseline clinical characteristics will be included.

Phenomena of interest

The focus of interest of this review is the epidemiological association between gender as exposure (potential risk factor) and mortality as an outcome.

Types of outcomes

The outcome of interest in this review will be the survival status (i.e. whether subjects are alive or dead) of subjects.

Types of studies

Observational studies (cohort studies case-control studies and cross sectional) will be considered for inclusion.

Search strategy

A three-stage comprehensive search strategy will be used to identify all relevant published and grey literature. First, an initial search of databases Pub Med and CINAHL will be made to identify relevant keywords and search terms. This will be followed by a thorough second search using all identified keywords and index terms across major databases. Finally, the reference lists or bibliographies of all identified reports and articles will be checked manually for articles of interest.

Available electronic journal articles will be searched through HINARI, Popline, and MedNar databases. The JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Library, government websites and specific journals will also be explored to identify reviews that may act as sources of primary studies. In addition manual searches will be done for different books related to our topic as a source of potentially relevant research studies.

The following search strategy will be modified for the various databases and search engines.

Initial keywords/search terms:

["Gender" OR "Sex" AND "People on ART" OR "HIV patients", OR "Gender AND HIV Patients" OR "People on ART" OR "People living with HIV/ AIDS on ART", OR "effect of Gender" OR "effect of sex" OR "effect of gender on HIV"] and [survival OR "mortality"]

Databases to be searched:

PubMed, CINAHL, PopLine, LILACS, MedNar and Embase

Only English language studies fulfilling the inclusion criteria for this review mentioned above will be considered for inclusion. Research conducted following the start of ART until December, 2014 will be searched and considered.

In this systematic review survival status will be measured as whether the patient is alive or dead, excluding those subjects who are lost to follow-up, have been transferred out, have missed appointments and are unascertained, that is, whether they have died or not.

Assessment of methodological quality

All papers selected for inclusion in the review will be subjected to a rigorous, independent appraisal by three individuals. Regardless of their score, relevant papers will be included and their individual limitations and risk of bias and how that may impact on the results of this review will be discussed.

Standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instruments (JBI-MAStARI) (Appendix I) will be used. Any disagreements that arise among the reviewers will be resolved through discussions, or with a forth reviewer.

Data extraction

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II).

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as relative risk for cohort studies, and odds ratio for case control studies (for categorical data), weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. A random effects model will be used and heterogeneity will be assessed statistically using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Conflicts of interest

The authors declare that there is no conflict of interest.

References