Introduction

Despite an array of evidence-based interventions (EBIs) to prevent HIV [1], the HIV pandemic continues to affect 35 million people globally with 2.1 million new infections estimated annually [2]. HIV treatment as prevention (TasP) is proposed as a powerful strategy to reduce HIV transmission [3]. In July 2014, UNAIDS called for an ambitious new global target for 90 % of people living with HIV (PLH) to be diagnosed, 90 % of them to be prescribed with antiretroviral therapy (ART), and 90 % of them to achieve sustained virological suppression, worldwide [4]. Achieving this 90-90-90 target by 2020 will, by 2030, decrease the HIV/AIDS burden by 90 % from that in 2010 [5]. The HIV care continuum provides a framework for the quantification of attrition, as PLH move in a step-wise fashion from being diagnosed with HIV, to linkage and retention in HIV care, to initiating and adhering to ART, and finally, to achieving sustained virological suppression—ART’s ultimate goal [6].

Despite the documented health and survival benefits from universal ART, irrespective of CD4 count [7••], a number of challenges at each step in the HIV treatment cascade exist. Suboptimal engagement at each step in the HIV treatment cascade limits the effectiveness of HIV prevention efforts, with negative consequences for individuals and public health, including increasing HIV transmission to others. Identifying factors that negatively contribute to poor outcomes in specific populations or resource settings are crucial for care providers, interventionists, policy-makers, and funders.

Though numerous factors have been correlated with decrements in the HIV care continuum, alcohol use disorders (AUDs) contribute prominently by virtue of their sheer societal magnitude. Despite complications from alcohol consumption being a major preventable cause of death [8•], extraordinarily few individuals having a treatable AUD receive treatment [9]. HIV and AUDs are intricately intertwined and mutually reinforcing epidemics that contribute to poor outcomes. These outcomes are exacerbated further in PLH co-infected with HCV infection [10, 11]. AUDs among PLH are two to four times higher than those in the general population [12]. AUDs are associated with increased HIV risk-taking behaviors [13, 14], delays in HIV diagnosis [15], decreased receipt of ART [16], and decreased adherence to ART [16], which may then lead to development of drug resistance, cognitive decline [17, 18], and premature mortality. AUDs potentially negatively impact every stage of the HIV treatment cascade. Interventions aimed towards treating AUDs, therefore, have enormous potential to improve outcomes and increase the number of individuals engaged at each step of the care continuum.

In this paper, we extend a previous systematic review of the impact of AUDs on ART adherence, health-care utilization, and treatment outcomes [16] and we systematically reviewed the more recent literature (2010–2015) on the impact that AUDs have on each stage of the HIV treatment cascade, in the era of recommendations to treat PLH with ART earlier in the course of their disease.

Methods

Literature Search

Ovid (including Medline), Scopus (including Embase), and the Web of Science were queried for original human research published in English from January 2010 until May 2015. References from selected articles were also reviewed for relevant publications. The search strategy combined keywords from each of three conceptual categories: (1) alcohol use disorders (including “alcohol,” “alcoholism,” or “alcohol drinking”), (2) HIV/AIDS (such as “human immunodeficiency virus” or “HIV-1”), and (3) stage of HIV treatment cascade (including “diagnosis,” “linkage to care,” “retention in care,” “adherence,” or “transition to care”).

Study Selection

The search in the selected databases yielded a total of 658 articles (Ovid = 22, Scopus = 452, Web of Science = 184) of which 525 remained after eliminating duplicates. The following inclusion criteria were applied: (1) patients who drank alcohol at any level or met screening or diagnostic criteria for having an AUD, (2) patients with HIV/AIDS, and (3) reference to one or more components of the HIV treatment cascade including (a) testing and diagnosis, (b) linkage to and (c) retention in care, (d) prescription and initiation of ART, (e) ART adherence, and (f) attainment and maintenance of viral suppression. Reviews, non-peer-reviewed articles, basic or translational science papers, and qualitative research describing experiences rather than associations of AUDs and the HIV cascade were excluded. Papers in languages other than English and those with outcomes other than stages of the HIV treatment cascade such as drinking outcomes, sexual risk behaviors, cognitive outcomes, and HIV risk reduction or HIV prevention were also eliminated. A total of 53 articles were selected after application of inclusion and exclusion criteria. Figure 1 shows the Consolidated Standards of Reporting Trials (CONSORT) flow diagram for this systematic review.

Fig. 1
figure 1

Systematic review CONSORT diagram

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Data Extraction

Data from identified articles were extracted using a standardized extraction form and included the following: study authors, study site, year and duration of study, World Bank designation for income level of setting, World Health Organization designation of per capita alcohol consumption of the setting, study design, population characteristics, sample size, type of measurement used to measure alcohol use or screen for AUDs, and definition of AUD used. The component of the HIV cascade being evaluated was also noted, including measures of HIV testing, diagnosis, health-care utilization, antiretroviral prescription, ART adherence, and virologic suppression; some assessments targeted more than one step in the care continuum.

Results

Fifty-three studies fulfilled the inclusion criteria, and findings are presented in Table 1. Most studies examined the final stages of the HIV treatment cascade (Fig. 2), ART adherence, and viral suppression. Thirty-three studies focused on alcohol use and ART adherence [19–26, 27•, 28–49, 50•, 51], and 17 targeted viral suppression [21, 25, 33, 35, 50•, 51–53, 54•, 55–62]. Fewer studies, however, focused on the early stages of the cascade with only three examining the association on HIV diagnosis [63, 64, 65•], two on linkage to care [24, 66], four on retention in care [55, 66–68], and seven on ART initiation [24, 54•, 59, 60, 69–71].

Table 1 Influence of alcohol use or alcohol use disorders on each component of the HIV treatment cascade, 2010–2015
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Fig. 2
figure 2

Summary of publications focusing on the relationship of alcohol on the HIV continuum of care

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Most of the studies (77 %) found that alcohol use, though variably defined, negatively impacted one or more stages of the HIV care continuum, while eight studies found no association. Two studies, which addressed more than one step in the cascade, found a negative association between alcohol use and at least one stage of the cascade as well as no association between alcohol use and another stage of the cascade. Finally, one study found a positive association between alcohol use and a stage of the HIV cascade, namely ART adherence.

Thirty-one studies used cross-sectional study designs and 20 used longitudinal cohort designs. Additionally, there was broad representation of study sites, including from low-, middle-, and high-income settings, as designated by the World Bank, with most settings being from countries that consumed moderate to high (>9 L) levels of alcohol per capita annually. Alcohol consumption was inconsistently defined in multiple ways. Validated screening instruments for AUDs included WHO’s Alcohol Use Disorders Identification Test (AUDIT) [72], which is based on quantifying the number of standardized drinks, while others used the CAGE [73], which is based on symptom severity. Numerous studies, however, defined alcohol use or disorders without referring to standardized measures.

The average annual per capita consumption for each study setting is listed in Table 1 [74]. There is notable variation between countries, with Russia having the highest level, at 15.1 L/person, and Ethiopia, Benin, and Mali having the lowest alcohol consumption levels, at 4.2, 2.1, and 1.1, respectively. The majority of countries here, however, exhibit moderate levels of alcohol use, at 9–11 L/person, e.g., the USA with 9.2 and Uganda with 9.8. There is no association between income level or the annual per capita alcohol consumption and studies that did not find a negative association between alcohol use and a specific step in the HIV treatment cascade. For example, Switzerland is a high-income country with moderate per capita alcohol use (10.7 L), which is one of the studies that found no association between alcohol use and viral suppression. On the other hand, negative associations between alcohol use and specific steps in the HIV treatment cascade were seen in countries with a low level of per capita alcohol use, such as India (4.3 L), as well as those with a high level of per capita alcohol use, such as Russia (15.1 L).

Discussion

As expected based on previous reports [16], most studies reviewed here, but not all, found an association between alcohol consumption, variably and inconsistently defined, and negative consequences on various steps of the HIV treatment cascade. The overwhelming majority of studies focused specifically on how alcohol use affects ART adherence, the step that has previously been of particular interest to many researchers [16]. For most high-income settings, the largest level of attrition is earlier in the HIV treatment cascade, primarily in HIV diagnosis and linkage and retention in HIV care [75••, 76–79]. The mechanism that mediates the effect of alcohol on ART adherence is widely believed to involve cognition and decision-making: impairment after heavy drinking may lead to forgetfulness about taking one’s medications at the appropriate time. Seven studies reviewed here, however, did not find an association between alcohol use and reduced ART adherence [24, 26, 35, 38, 39, 45, 47]. This may be due to the way alcohol consumption and/or ART adherence was defined (self-report, pill count, pharmacy refills, etc.), both of which varied greatly between studies. Three of these studies did not use standardized screening measures for alcohol use [38, 39, 47], but the other four used either the AUDIT [72] or the AUDIT-C [80] or the Addiction Severity Index (ASI) cutoffs [81]. The reasons why these studies did not find an association between alcohol consumption and adherence, while all others did, may have to do with other confounding factors that could have impacted adherence like unstable housing [82] and food insecurity [83], or alternatively, it may be that only those with the highest severity of alcohol consumption (e.g., dependence rather than hazardous or harmful drinking) influenced ART adherence. One study found a positive association between alcohol use and CD4 counts, a measure indirectly related to ART adherence [51]. This unreplicated but provocative study from France showed that compared to no alcohol consumption, low alcohol consumption (<10 g/day) was associated with higher CD4 counts. This low level of alcohol consumption, however, is not associated with having an AUD and would therefore not be amenable to intervention. Lifestyle characteristics, including a culture of leisurely drinking and diet, may be mediating the positive effect of low/moderate alcohol consumption on HIV health outcomes. Moreover, it is important to note that while other studies were focused on problematic alcohol consumption, this was the only one focusing on low-level alcohol consumption.

Seventeen studies examined the impact of alcohol on viral suppression, the final and arguably most important stage of the HIV treatment cascade. Viral suppression has been shown to be of crucial importance for both the HIV-infected individual and the general population. HIV-infected people with early viral suppression are more likely to have direct positive HIV-related health outcomes [84, 85] but also do not contribute appreciably to onward HIV transmission to sexual partners [3]. Most (N = 14) of the 17 studies reviewed found a negative association between alcohol use and viral suppression, yet 3 did not [25, 35, 51]. All the studies used standardized measures of alcohol use, potentially leaving the reasons why no association was found having to do with the populations studied and/or the level of alcohol use severity, or other confounding factors noted previously for the adherence studies. The effect of alcohol use on viral suppression is likely mediated via ART adherence levels, although future studies are needed to address the possibility of a more direct link or, alternatively, the contribution of the types of ART prescribed, including those with longer half-lives that may be more forgiving to intermittent periods of non-adherence [86, 87]. Importantly, the definitions of alcohol consumption and alcohol use severity varied widely between studies and influenced the results of this review. For example, one study differentiated between regular alcohol use and daily alcohol use; it found daily alcohol consumption to be correlated with not achieving viral suppression, whereas regular use, defined by the authors as drinking “a few times a week,” was not [62]. Additionally, ART treatment-experienced patients compared to ART-naïve or newly diagnosed patients are less likely to achieve viral suppression, by virtue of either having baseline genotypic resistance mutations or having been non-adherent previously. Therefore, in studies that do not specify previous ART experience or baseline resistance mutations, the role of alcohol on viral suppression is not clear, making it important to clearly delineate these factors within studies. Last, it is well documented that physicians may defer or withhold ART for PLH with any underlying or perceived substance use disorder. Though most of the data confirming this finding is for people who inject drugs, stereotypes vary in terms of the ways that clinicians view alcohol and whether it is culturally normative for some settings.

A small number of studies focused on the earlier stages of the HIV treatment cascade, specifically those preceding ART adherence. Three studies examined the impact of alcohol use on HIV diagnosis, by primarily examining alcohol use and HIV testing behaviors [63, 64, 65•]. All three studies found that meeting screening criteria for having a treatable AUD was associated with lower levels of HIV testing or, importantly, with being HIV infected and unaware of their HIV-positive status. Two studies of PLH in jail, from the same study sample, did not find an association with having an AUD and being linked to HIV care [24, 66]. Though the sample was large, unique aspects of the sample (i.e., being comprised of jail detainees) who had multiple social, medical, and psychiatric comorbidities that may have interfered considerably with linkage to care or even the measure used for AUDs, previously used cutoffs for the alcohol subscale in the Addiction Severity Index may have influenced the lack of association. Four studies examined retention in care, including the two with jail detainees [24, 66]. Both studies that did not involve jail detainees found an association between alcohol use and poor retention in care [55, 67]. Finally, seven studies focused on ART prescription [24, 54•, 59, 60, 69–71] and most found a negative association between alcohol use and delays in being prescribed with ART, but two studies did not [24, 70]. Most of these studies, however, did not use standardized measures of alcohol use.

While most high-income countries, as classified by the World Bank, have concentrated HIV epidemics among key populations, like men who have sex with men, drug users, and others, many low- or middle-income countries (LMICs) experience generalized epidemics affecting the entire population [88]. Alcohol consumption is highly prevalent in all parts of the world [89], with the exception of a small number of countries where its use is banned or strongly discouraged due to religious restrictions. Importantly, most of the studies reported in this review are from countries with a moderate level of annual drinking per capita (9 to 11 L). With the exception of one study from Russia [68], almost none of the studies were from countries with the highest levels of consumption. In such settings, it will be crucial to not only examine the impact of AUDs on the HIV continuum of care but to also design targeted or structured interventions to reduce problematic alcohol use (e.g., higher taxation for alcohol, increased legal sanctions for intoxication, social marketing campaigns, etc.). When reviewing the presented studies from high-income and LMICs, nearly half (25 out of 53) was conducted in LMICs. Only 2 of 25 studies from LMICs [26, 47] did not find an association between alcohol use and various stages of the cascade. Though there are likely biological and/or sociocultural factors that underlie patterns and severity of alcohol consumption, the World Health Organization recommends standardizing levels of alcohol consumption, though recognizing that quantifying alcohol consumption levels may be challenging as drink sizes vary greatly [90]. Nonetheless, findings here suggest that LMICs face similar issues as high-income countries, where alcohol and HIV treatment are concerned. While there has been an abundance of data stemming from high-income countries, in the past, there were few studies from LMICs. With the majority of PLH now residing in LMICs, the number of studies from these settings included in this review confirms many findings gleaned from high-income settings. It should be noted that the HIV continuum of care has not been standardized globally and each one of its steps is often defined differently based on location [91]. For example, viral suppression has been variably defined at less than 50, 200, and 500 copies/mL thresholds. Thus, in order to better correlate the impact of alcohol and AUDs on the HIV care continuum, it is also crucial to standardize each step of the care cascade.

While countries develop their national guidelines and strategies to combat the HIV epidemic, it will be necessary to incorporate evidence-based interventions (EBIs) that target all types of substance use disorders, including alcohol and drugs, as well as to focus on every step in the continuum of care [92]. Despite CDC’s Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention, which is divided into primary HIV prevention, linkage and retention in care, and ART adherence, few EBIs specifically target problematic alcohol consumption. Absent from most care continuums are primary prevention programs that might include expanded coverage of pre-exposure prophylaxis [93] and increased types (e.g., point-of-care) and frequency of HIV testing [94] for people at risk of HIV infection. An emphasis for using these EBIs for individuals with AUDs is crucial to ensure that the interventions are used for the right target group. Once people are diagnosed with HIV, it is important that they become seamlessly linked to care and stay retained in care. Despite an array of EBIs currently available that targets various components of the HIV care continuum [92], the emergence of interventions that is effective at more than one step in the continuum is likely to have the most effectiveness and traction by public health administrators and policy experts. Moreover, such interventions must be tested and found to be effective in patients with AUDs. Most HIV prevention interventions have either not been tested or adapted to address problematic alcohol consumption. Indeed, detailed analysis of some EBIs shows that individuals with underlying substance use disorders do not fare as well as those without them when the intervention is provided. An important finding here is that, generally, alcohol consumption and/or AUDs negatively contribute to all components of the HIV treatment cascade. Importantly, interventions that directly address alcohol consumption may have a high likelihood of influencing the HIV care continuum for PLH and AUDs.

Evidence from the treatment of opioid use disorders convincingly suggests that addiction treatment is effective for both primary [95] and secondary [69, 96] HIV prevention. The data for treating alcohol use disorders, however, is still emerging. A systematic review of several types of psychosocial interventions (i.e., cognitive-behavioral coping skills, brief interventions, motivational interviewing, and hepatitis health promotion) found little support for their use in reducing alcohol consumption [97]. Though several pharmacological interventions (e.g., naltrexone, acamprosate) have reduced several outcomes associated with alcohol consumption (time to relapse, number of heavy or any drinking days, etc.) [10], the best evidence in comparative controlled trials, however, is the use of pharmacological therapies like naltrexone [98], either in the oral or extended-release injection formulation [99–101]. A systematic review and meta-analysis, however, showed no differences between most pharmacological agents in their ability to reduce relapse to any alcohol use but did find a reduction in days of heavy drinking for most approved (i.e., naltrexone and acamprosate) and some off-label medications [102]. The acceptability of pharmacological treatments for AUDs, however, will be crucial for their uptake [103]. The extent to which alcohol reduction, rather than complete elimination of use, will translate to improvements in each step of the HIV treatment cascade remains likely but unknown and needs empiric support from prospective controlled trials.

Conclusion

This systematic review examined the impact of alcohol use and AUDs on the HIV treatment cascade in recent years, as ART is being expanded to more patients. As guidelines emerge to include immediate ART for all patients irrespective of CD4 counts, factors that influence the HIV care continuum may differ, especially for the latter part of the cascade since ART is sometimes withheld from patients perceived to have problems with alcohol. It is, thus, crucial to holistically establish broad-based interventions that target problematic alcohol consumption so that they may exert their influence across the entire spectrum of the HIV care continuum. Moreover, findings here point to the need for standardization of measures, not only for each step of the treatment cascade but also for measures of alcohol consumption, with an eye towards AUDs that are amenable to treatment. From an international perspective, the use of the AUDIT is validated on every continent and is highly specific and sensitive for identifying AUDs, including levels of severity. The challenge with using the AUDIT, however, is that it relies on individuals to accurately quantify a standard drink, when drinks are context specific, have varying levels of alcohol content, and are not consistently quantified. EBIs that target alcohol use, as well as those targeting the individual stages of the continuum, are needed and should be adequately scaled for high-risk individuals and PLH globally, as part of a concerted effort to reduce both primary and secondary HIV transmission, to improve both individual and public health mandates, and to help eliminate HIV for future generations. Such EBIs may include the Holistic Health Recovery Program (HHRP) [104], which has previously been used to reduce HIV risk and promote ART adherence specifically for PLH with opioid use disorders. Recently, this EBI has been adapted for individuals with AUDs [105] and, if found to be effective, can be disseminated in a variety of settings, including in clinical care, addiction treatment, and community-based settings. Additionally, the CDC, WHO, and UNAIDS have called for integration of addiction treatment in HIV specialty and primary care settings [106, 107], including pharmacological interventions, and there is ongoing research to determine best practices. Such integration has not yet included alcohol treatment within clinical care settings. Ultimately, the best results for improving HIV treatment outcomes in PLH with AUDs will be to ensure high-quality integration of prevention and treatment services that use a wide range of options that are suitable to patients.