Current Interventions for People Living with HIV Who Use Alcohol: Why Gender Matters

Purpose of Review Alcohol is the most misused substance in the world. For people living with HIV (PLWH), alcohol misuse may impact ART adherence and viral suppression. This review of the most recently published alcohol intervention studies with PLWH examines how these studies considered gender in the samples, design, and analyses. Recent Findings Three searches were conducted initially, and 13 intervention studies fit our criteria with alcohol outcomes. In general, most studies did not consider gender and had used small samples, and few demonstrated significant efficacy/effectiveness outcomes. Five studies considered gender in their samples or analyses and/or were woman-focused with larger samples and demonstrated significant outcomes. Summary It is essential for women who misuse alcohol to not only be well represented in alcohol and HIV research but also for studies to consider the barriers to reaching them and their contextual demands and/or co-occurring issues that may affect participation and outcomes in intervention research. Supplementary Information The online version contains supplementary material available at 10.1007/s11904-021-00558-x.


Introduction
Although the world had strived for the 90-90-90 treatment target by the end of 2020, we are not yet there, and the global push for the 95-95-95 treatment target may be temporarily out of reach given that the COVID-19 pandemic has impeded the world's economies [1] and HIV treatment and prevention [2][3][4]. Additionally, alcohol, the most widely misused substance in the world [5], may be a key barrier to reaching this goal [6,7], especially when coupled with challenges related to the COVID-19 pandemic [2][3][4].
Specifically, alcohol misuse may impact engagement and retention of people living with HIV (PLWH) in the HIV treatment cascade, which is critical to ending the HIV epidemic [8,9]. Estimates suggest that 35 to 40% of PLWH may misuse alcohol [10]. Furthermore, myriad challenges often intersect with alcohol misuse that affects the health and well-being of PLWH [10]. If untreated, alcohol use disorder (AUD) can contribute to reduced adherence to antiretroviral therapy (ART), retention in HIV care [11,12], and virologic response to ART, increasing the risk of forward transmission. AUD also ultimately increases mortality among PLWH [13]. Daily alcohol misuse is associated with reduced survival of 6 years among PLWH [13]. Consequently, the intersecting epidemics of alcohol misuse and HIV should be addressed together to help PLWH reach viral suppression and reduce transmission [14]. However, it may not be as simple as this.
Research is growing to address the intersection of alcohol misuse among PLWH [15]. The field has rapidly advanced This article is part of the Topical Collection on Behavioral-Bio-Medical Interface and developed behavioral [15][16][17], pharmacological [18,19], and biobehavioral interventions [20,21] to reduce alcohol misuse among PLWH, with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) leading this effort [14]. Intervention approaches also have sought to reach key populations, including sexual minorities [22][23][24]. Intervention research, although nascent, also has extended its focus to cisgender women [25][26][27] and transgender women [25] living with HIV to address alcohol misuse.
However, this was not always the case, and the contemporary definition of gender is not binary (male-female), although most studies write in this fashion. For many years, women were excluded from or minimally involved in research [28]. For example, as recently as the 1980s, women were excluded from trials of HIV drugs [28]. Not until 1993 was the inclusion of women in National Institutes of Health research written into law [28,29]. Importantly, alcohol misuse among women has recently gained greater recognition [30][31][32][33]. Including women in HIV and alcohol intervention research is critical because women's physiological response to HIV and alcohol is different than men's response; consequently, intervention effects may differ [34,35]. NIAAA has highlighted the biological differences experienced by women when they drink and is in the process of reevaluating the recommended alcohol threshold for women [36].
This exclusionary trend also applies to pregnant populations, one of the most vulnerable populations to HIV, that historically have been excluded from alcohol research or addressed in research as a special population [37][38][39]. The need for more HIV and alcohol misuse research with this population is evident given the implication of prenatal drinking in fetal alcohol spectrum disorders (FASD) and other associated syndemic issues related to gender-based violence and ART adherence [40][41][42][43][44][45][46][47]. NIAAA has been supporting FASD research for almost 50 years [48] among First Americans and in South Africa where heavy drinking is prominent [49][50][51][52]. Nonetheless, more research is needed.
The impact of alcohol misuse and HIV has greater adverse consequences for women compared with men [6,34]. Hazardous alcohol use among women living with HIV (WLWH) is associated with HIV risk behaviors [53] and adverse health and HIV treatment outcomes [54], especially in economically underserved communities where heavy drinking may persist [54,55]. Moderate drinking has been found to be associated with increased vaginal shredding among WLWH on ART [56]. Increased alcohol intake has been found to be associated with lower ART adherence [7]. Given the associations among alcohol misuse, vaginal shedding, and ART adherence for WLWH, moderate to severe alcohol use may increase risk of forward HIV transmission [56][57][58][59]. These findings illustrate the need for intervention trials to not only include women but also include them in sufficient numbers and to incorporate a gender lens for intervention approaches and analyses.
Given the importance of understanding what has worked in the most recent intervention research literature with PLWH who misuse alcohol, this review also highlights intervention studies focused on alcohol outcomes. However, essential to this review was our search with a gender lens in seeking sample proportions and analyses. Consequently, the core of this review is a search for gender interventions and why gender matters. Understanding the multidimensional issues that WLWH face and alcohol misuse is complex.

Methods
To ensure our review reached saturation of the available literature, multiple literature searches were conducted between December 2020 and February 2021 utilizing PubMed, Embase, and Web of Science scientific databases, as well as confirmatory checks in the NIH RePORTER and ClinicalTrials.gov. We included publications that met the following criteria: (1) published between 2018 and early February 2021; (2) reported or proposed alcohol outcomes for a randomized trial; (3) equal to or greater than 50% of the sample comprised PLWH; (4) the sample included cisgender or transgender women; and (5) written in English. We then reviewed the publications to determine whether there was an adequate sample size for a rigorous intervention trial [59,60] and gender was accounted for in the study design (including intervention) and/or analysis (e.g., stratified analyses, gender as a moderator). Protocols were only included in this review if the proposed procedures considered women in the approach, intervention, design or outcomes, or if the intervention was developed for and about women and addressed alcohol as one of the proposed outcomes.
We conducted the search for publications in three phases. The initial search was conducted with a specific focus on seeking publications evaluating alcohol interventions for WLWH, including pregnant women; the second search expanded the criteria to alcohol interventions with PLWH; and the third search expanded the criteria to include a wide range of alcohol, drinking, and HIV-related terms to ensure that all appropriate publications were identified (see Appendix 1 for the entire search term list and criteria for each search).
After identifying published articles based on the search terms, research staff downloaded the results into an EndNote database and used a priori criteria to narrow the search using a categorical folder system. Although we made the search as comprehensive as possible, we did not search conference abstracts, theses, or dissertations; nor did we contact authors of unpublished articles. Our team reviewed the abstracts generated by the search. If the abstract indicated that the article might meet the specified criteria, it was reviewed in its entirety to ensure the inclusion criteria were met. Promising articles were then separated and presented to all of the present authors for their final review and approval for inclusion in this review.
As shown in Fig. 1, the combined searches returned 8076 results. Of these, 7302 were excluded because they did not meet the eligibility criteria. A majority of the articles excluded during the abstract review did not focus on PLWH, were HIV prevention studies (and thus did not include a large percentage of PLWH), were cross-sectional, reported secondary data analysis from a prior trial, or did not report or propose alcohol outcomes. As a result of these searches, 13 intervention articles (8 nongender and 5 gender-focused) and 3 protocols were included.

Non-gender Studies
Eight of the identified studies evaluated the efficacy or effectiveness of interventions to reduce alcohol use among PLWH but did not use a gender lens in the design or analyses [21,[61][62][63][64][65][66][67]. The sample sizes of these studies ranged from 93 to 614, with 75% reporting sample sizes of fewer than 250. Of the 1897 participants across these 8 studies, only 7.9% were female or gender non-conforming, with 62.5% of the studies reporting more than 95% male participants. All the interventions evaluated incorporated motivational interviewing. Two interventions included cognitive behavioral therapy (CBT) components [63,67] and 3 interventions included medication-assisted treatment for alcohol use [21,61,62]. All interventions were delivered individually, with one intervention reporting additional optional group intervention components [63].
All studies used self-report alcohol assessments, such as the Alcohol Use Disorders Identification Test (AUDIT) or the Alcohol Smoking and Substance Involvement Screening Test (ASSIST). Six studies used the Timeline Followback (TLFB) to assess outcomes such as days of drinking, drinks per drinking day, and number of heavy drinking days in the past month [21,[61][62][63][64]66]. Other self-report measures to assess alcohol-related outcomes included AUDIT and ASSIST. Also, 3 of the non-gender studies used phosphatidylethanol (PEth) biomarkers to assess alcohol abstinence [21,61,62]. Some studies included in this review also measured viral load using HIV RNA and the cut-off for viral suppression ranged from <20 to <50 copies/ml. Although most studies reported that participants reported reduced alcohol use at follow-up, only 3 studies demonstrated statistically significant intervention effects [63,64,67]. Go and colleagues conducted a trial comparing a culturally adapted motivational enhancement therapy and a brief alcohol intervention to standard of care among 440 PLWH in Thai Nguyen, Vietnam [63]. The findings from this study indicated that both intervention arms reported significantly greater abstinence and reductions in alcohol use and greater viral suppression at follow-up compared with participants in the standard of care arm. Madhombiro and colleagues demonstrated the efficacy of a combined motivational interviewing and CBT intervention to reduce AUDIT scores among 234 PLWH in Zimbabwe [67]. Lastly, Naar and colleagues reported the effectiveness of Health Choices, a motivational interviewing-based intervention, among 183 youth living with HIV that was implemented in and tested intervention delivery (home as compared with clinic settings) [64]. This study demonstrated that youth who received the intervention in a clinic setting were significantly more likely to maintain reductions in self-reported alcohol use and viral suppression (Table 1).

Gender Studies
Five of the identified studies evaluated the efficacy or effectiveness of interventions to reduce alcohol use among PLWH and used a gender lens in the design and/or analyses [26,27,[68][69][70]. The sample sizes in this group of studies ranged from 194 to 641. Three of the 5 studies comprised all women, with 1 study sample reporting 46% women and 1 study sample reporting 51.5% women [26,27,69]. A variety of intervention approaches were represented, including pharmacotherapy for  AUD, the information-motivation-behavior-skills framework, CBT, and feminist-based social cognitive theory. All studies used self-report measures to assess alcohol use outcomes. The TLFB was the assessment used most. PEth was only used in 1 study as a measure of alcohol use. Additionally, all studies assessed some proportion of viral load among participants, with viral suppression cut-offs at <200 copies/ml in 2 studies and 1360 copies/ml in 1 study. All studies reported significant intervention effects for alcohol use outcomes. Cook and colleagues conducted a trial testing the efficacy and safety of oral naltrexone among 194 primarily African American WLWH and found that participants in the naltrexone intervention arm were significantly more likely to report lower levels of unhealthy drinking at short-term followup but not at the follow-up endpoint compared with participants in the placebo arm. HIV viral suppression was also significantly better for women who reduced drinking as compared with women who continued unhealthy alcohol use at 4 months [26]. Huis and colleagues investigated the effects of an information-motivation-behavior-skills intervention with personalized feedback and a brief counseling session compared with a health education leaflet on alcohol use among 560 PLWH in South Africa [68]. This study found that participants in the intervention and counseling arms had significantly greater reductions in AUDIT scores from baseline to follow-up compared with participants in the control arm. Additionally, when comparing men and women, men had a greater percentage reduction in AUDIT scores compared with women. Papas and colleagues tested the efficacy of a cognitive-behavioral therapy (CBT) intervention to reduce alcohol use among 614 outpatients living with HIV with hazardous drinking enrolled at an HIV clinic in Eldoret, Kenya. They found significantly lower percentages of drinking days and drinks per drinking day in the CBT arm than the healthy life-styles educational intervention (HL) arm overall and at all study phases. Furthermore, adherence and competence scores in both the CBT and HL conditions did not differ significantly by gender [70].
Wechsberg and colleagues conducted a community-based cluster randomized trial evaluating the efficacy of a womanfocused HIV and substance use intervention to reduce substance use, including alcohol, and other risk behavior among 641 women who engaged in substance use [27]. Of the 641 women in the study, 317 were living with HIV and reported    Chi-square tests of independence using dried blood spot samples indicated there was no difference in the proportion of participants who had nondetectable viral loads at 6-month follow-up (n=118; p=0.83). However, there was a significant difference at 12-month follow-up (n=172; p=0.01).
Approximately 53% of participants in the Women's Health CoOp Plus arm (n=50) had nondetectable viral loads compared with 47% of participants in the HIV counseling and testing arm (n=45) at 12-month follow-up. The results from a sensitivity analyses among 317 participants who were living with HIV and reported engaging in alcohol use revealed that the intervention also was efficacious among this subsample and significantly reduced the number of drinks per drinking day and number of days of alcohol use in the past month. Lastly, Wechsberg and colleagues [69] conducted an implementation science hybrid modified stepped-wedge design implementing the Women's Health CoOp (WHC) intervention in matched health departments and substance abuse treatment clinics with 480 WLWH over four cycles in Cape Town, South Africa. Compared with cycle 1, women in cycle 4 were significantly less likely to report AUD risk at 6-month follow-up. Additionally, compared with women in cycle 1, women in cycle 4 were significantly more likely to report taking ART at follow-up with over 90% adherence at 6month follow-up. The likelihood of taking ART increased as women were enrolled in the later cycles and the risk of AUD decreased. The WHC intervention increased ART adherence and reduced alcohol use overall (Table 2).

Protocols for Ongoing Gender-Focused Studies
We also identified 3 protocols of ongoing studies currently considering gender in their evaluation of interventions that seek to reduce alcohol use among PLWH [71][72][73]. The 3 protocol papers reviewed include motivational interviewing, computer-based interventions, and the woman-focused intervention approaches. The planned sample sizes for these studies range from 60 to 200.
Two studies did not explicitly state a sample size goal for the recruitment of women, and participants are eligible regardless of gender. One study will recruit women exclusively. Two studies will use self-report alcohol measures (ASSIST or AUDIT) and 1 of these studies also will use urinalysis to assess alcohol outcomes. One study will exclusively use PEth and ethyl glucuronide (EtG) biomarker testing to assess alcohol outcomes. Two studies also will assess HIV outcomes using viral load, CD4+ cell count, and ART adherence measures (Table 3).

Discussion
So why is gender important in research? Women are the face of HIV globally because of gender norms and inequities [74]. Women face multiple contextual and structural barriers that may interfere with their ability to seek treatment for alcohol misuse and HIV care [55,75,76], let alone participate in research. Additionally, comprehensive gender-focused approaches are rare [77] and far too often childcare needs disproportionately hinder access to healthcare while also facing financial strain in less equitable employment as compared with men [76,78].
Additionally, women who misuse alcohol may experience multiple challenges, including stigma [75]. Staff may have negative attitudes and lack person-centered care toward women who use alcohol and who are seeking treatment [75]. More recently, the ability to validate ART adherence and demonstrate reductions in viral load transmission has become a major component of intervention outcomes, and therefore the need to address alcohol as an interfering factor to ART adherence is critical [79][80][81]. However, the cost for conducting large trials may be a constraint.
For decades, studies focused on women who were pregnant and used alcohol and consequent fetal alcohol effects. In fact, these women have not been treated as a whole person, for example, by taking into account the fact that they often face violence from partners, especially during pregnancy [43,82]. However, a recent study reviewing HIV medication adherence among women who are pregnant and living with HIV in sub-Saharan Africa brought attention to the importance of supporting not only the woman but also her partner and the family in addressing fear, stigma, and discrimination around HIV [39], as ART initiation and adherence can be compromised by lack of support from partners and friends and their alcohol use [42].
A majority of the interventions were conducted domestically within the USA; however, interventions conducted internationally were culturally adapted to suit the environment and population [63,67,69,70]. Regardless of location, most of the interventions contained a brief interview component. Studies conducted globally were more likely to identify significant reductions in alcohol consumption. Furthermore, the internationally focused studies were more likely to report higher levels of viral suppression and ART adherence, although few of the studies examined overall reported positive HIV outcomes. It is difficult to attribute these outcomes purely to whether a study was conducted internationally or domestically as many of the international studies had larger sample sizes-as they were conducted in areas with high HIV prevalence-thus they may have been more likely to report robust and significant outcomes. Lastly, the internationally focused interventions were also more likely to have a gender component or be genderfocused as compared with those conducted domestically.
It is a concern why some NIH-and NIAAA-supported studies have had such small participation of women relative to men. As gender intervention researchers, we believe there is much to do in addressing alcohol use, ART adherence, and other associated behavioral and psychological issues, including stigma and discrimination, other drug use, and genderbased violence. To better understand this, we reviewed numerous studies that address these intersectional issues and found that either they were HIV prevention studies, were not rigorous intervention studies, or did not have alcohol as an outcome variable. We acknowledge the importance of how motivational interviewing and a personalized approach can work to meet an individual where they are for engagement, but several of these approaches lacked gender sensitivity. Developing personalized action plans and empowering a woman to take action have been essential elements of the Women's Health CoOp, a woman-focused intervention for over 25 years for reducing alcohol and other drug misuse and more recently increasing ART adherence [27,69,83,84].
Nonetheless, how women are reached, whether an effort is made to oversample for adequate analyses, and sensitive consideration of their contextual needs and comorbid symptoms are essential to shaping a more just scientific response to the call for "why gender matters" More studies are needed with sexual minorities of women because they have higher rates of alcohol use, violence directed at them, HIV, and suicide [85][86][87]. Understanding the spectrum of gender is evolving as the world becomes more conscious and accepting.
The landscape of gender-focused interventions and applied research with women who misuse alcohol and other drugs, especially those living with HIV, requires not only sensitivity but also culturally congruent applications with the voice and involvement of the participants. As applied scientists over several decades, we have moved from the behavioral to biobehavioral, with treatment combinations and mixed methods to understand and conduct research that is meaningful and more impactful with many of the participants at the table, including peer advisory and community collaborative boards. However, there remains much to learn about what works best with each population.

Conclusion
In summary, alcohol misuse continues and FASD still is a public health issue [88][89][90]. Much can be done globally in intervention research with WLWH who misuse alcohol. Yet, intervention research cannot be everything to all. We also need to listen to women's stories, consider gendered measures and stratified approaches, empower women be more educated about their HIV status, reduce barriers to ART and alcohol treatment, measure efficacy and effectiveness to know what will work, and identify mediators and moderators that affect change to ultimately understand what can be sustained in the real world [91]. Gender matters and women matter because they are mothers of the next generation. Author Contribution (in No Particular Order) WMW provided the overall scientific direction for the review, significantly contributed to the writing, and finalized the manuscript. FAB substantially contributed to the writing of the manuscript. CPB significantly contributed to the writing of the methods and one subanalysis of a study in the article. YW conducted the search for interventions focused on pregnant women living with HIV and substantially contributed to the development of all components of the manuscript. BNH conducted the search for interventions focused on women living with HIV and contributed to the writing of the methods. IvdD conducted the search for interventions focused on women living with HIV and contributed to the development of the methods. All authors read and approved the final manuscript.
Funding Support for this review was provided by the RTI Global Gender Center and National Institute on Alcohol Abuse and Alcoholism grant R01AA022882.
Availability of Data and Material The search terms used for this review are available in the supplementary material of this article.
Code Availability Not applicable.

Declarations
Ethics Approval Not applicable.

Consent to Participate Not applicable.
Consent for Publication Not applicable.

Conflict of Interest The authors declare no competing interests.
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