Integrated care of severe infectious diseases to people with substance use disorders; a systematic review

Comorbid Hepatitis C virus (HCV) and hepatitis B virus (HBV), human immunodeficiency virus (HIV), and Mycobacterium tuberculosis (TB) infections are common among people with substance use disorders (SUDs). Due to a low level of attention to personal health care needs, treatment of such severe infectious diseases may be difficult for people who inject drugs (PWID). Additionally, PWID have a sustained high risk of transmitting these severe infections [1‐3]. Globally, 1.7 million PWID were estimated to be HIV positive in 2016 [4]. Injection substance use is estimated to account for 1% of new HBV infections and 23% of new HCV infections, respectively [5]. A new global strategy to eliminate viral hepatitis that aims to reduce HCV incidence by 90% and mortality by 65% by 2030 was endorsed by the World Health Assembly in 2016 [5]. The World Health Organization (WHO) and the United Nations Sustainable Development Goals (SDGs) have also decided that the global strategies are to end the acquired immune deficiency syndrome (AIDS) epidemic by 2030 and the TB epidemic by 2035 [6‐8].To succeed with such ambitious goals, high availability of coordinated care between medical treatment and prevention, psychological care and social-related services for people with SUD is pivotal. A systematic search to identify efficacy of integrated care models on treatment outcomes of severe infectious diseases among people with SUD is required.

Integrated models may improve treatment completion and adherence among people who often are marginalized and hard to reach within current health services systems [2, 3, 9, 10]. Comparing the efficacy of these models is therefore of high importance. Different integrated treatment models may improve the access for completing treatment or achieving virus suppression over time but most studies are small and not sufficiently powered to quantify the effect size, and the patterns have been slightly mixed [11‐15].

Definitions of the concept of “integrated care” vary. In the hospital setting, WHO defined integrated care as: “an approach to strengthen people-centred health systems through the promotion of the comprehensive delivery of quality services across the life-course, designed according to the multidimensional needs of the population and the individual and delivered by a coordinated multidisciplinary team of providers working across settings and levels of care (…)” [16]. However, this definition is arguably too broad and unspecific, hence, for the purpose of this paper we have chosen to alter the definition of integrated care to “comprehensive set of patient-centered health services that involve the care of chronic infectious disease as a part of coordinated services for people with SUD.” Integrate care models and collaborative health services may improve health outcomes to medical care, as well as reduce the burden of disease among people with physical and mental disorders [17], prevent severe infectious diseases [18], improve engagement in TB services [19], and increase patients adherence and staff satisfaction [11]. Systematic reviews suggest that the composition of the integrated models must be described in more detail to identify effective integrated care models that can be implemented in various settings [11, 18‐20]. Previous systematic reviews have mostly identified descriptive reports or cohort studies, and only few randomized controlled trials (RCTs) [11, 17, 21]. Also, a number of these studies have methodological limitations such as short follow up period, loss-to-follow-up rate on more than 30%, unclear design and mixed outcome indicators [11, 20]. In light of the SDGs and the World Health Assembly global strategy for viral hepatitis, TB and AIDS epidemics, a systematic review is imperative to increase knowledge and understanding how to best reach universal coverage of these severe infectious diseases among people with SUD.

In this systematic review, we will examine the effect of integrated health care for people with SUD receiving treatment for HCV, HBV, HIV, and TB. Randomized controlled trials and cohort studies presenting quantitative comparative estimates will be compared to relevant outcomes for each infectious disease. We hypothesized that integrated care models might be useful to reach marginalized low adherent people with SUD, although a high risk of bias and loss-to-follow-up could underpowered the results. This systematic review will summarize the impact of integrated care models on the treatment of severe infectious diseases among people with SUD and will grade the evidence base on methodological quality.

Altogether, 1640 studies were identified in Embase and PubMed, and references to 1135 related reviews and RCTs were considered (Additional file 2). However, only three studies on HCV [13, 26, 27], five on HIV [14, 15, 28‐30], and two on TB [31, 32] fulfilled the inclusion criteria (Fig. 1). Nine integrated models in ten studies were identified, whereas two studies assessed a similar integrated model. We did not identify any relevant studies on hepatitis B. The CONSORT 2010 checklist or the NOS were employed for assessing the quality of the included studies (Additional files 4 and 5). All included studies assessed integrated models of care when participants underwent medical treatment for HIV, HCV or TB. Nine studies recruited patients from either a primary health care centers for people with SUD, OAT outpatient clinics or specialist outpatient clinics for HIV or HCV infected [13‐15, 26‐30, 32]. One study evaluated TB treatment among hospitalized patients [31]. Four studies also included people without SUD [26‐29]. Six out of ten studies were considered to have a loss-to-follow-up rate on more than 30% (Table 2) [13, 15, 26, 27, 29, 32].

Different integrated care models were identified. All studies assessed integrated care in multidisciplinary teams or collaborative care teams. Three studies evaluated various psychosocial interventions integrated with treatment of an infectious disease in an OAT program delivery by DOT [13, 31, 32]. Seven studies evaluated the efficacy of brief psychological interventions, regular telephone calls, or social and mental health services in collaboration with other health professionals [14, 15, 26, 28‐30, 33].

Nine integrated care models were identified, which were subsequently divided into two groups; (1) integrated care with OAT; and (2) integrated care without OAT.

We assessed the impact of integrated care models among patients with SUD and severe infectious diseases. Many relevant studies were excluded due to a low level of collaborative care involvement, or measurements of outcomes that were not relevant to our review. Overall, most of the included studies were considered to have a high risk of biases and both the results and methodology were heterogeneous. A recurrent finding was a high loss-to-follow-up rate, unclear description of the interventions, and underpowered studies. Moreover, differences in potential confounders between groups in cohort studies including age, proportion of homelessness, proportion of people who inject drugs, employment status, level of education, and severe psychiatric disorders to name but a few. Potential confounders may further bias the interpretation of the results.

The impact of integrated treatment among people with SUD on viral suppression, HCV SVR and TB treatment completion is uncertain according to our findings. In our review, a quantitative meta-analysis has not been performed due to limited comparable studies of high quality. Only two studies found an effect of integrated treatment. One of them found an effect of integrated OAT given to hospitalized TB-infected patients on treatment completion and medication adherence [31]. The second one found an effect on collaborative care when antivirals and OAT were given as DOT with or without psychosocial interventions [32]. Other OAT integrated models had uncertain effects. A meta-analysis published in 2016 suggested that OAT was associated with an increase in ART coverage and adherence to ART, and limited evidence for OAT decreasing mortality for PWID on ART [25]. A similar impact of OAT on adherence to hepatitis C and TB treatment has not been shown. However, Altice, FL, et al. (2011) evaluated in a multicenter study an integrated OAT model in a HIV clinical care settings, and found no association between integrated OAT and viral suppression [35]. An important limitation was the lack of a control group, which was the reason why we did not include it in our review.

The adherence to medical treatment in an integrated care model may be influenced by many other factors affecting the patient’s ability to follow up treatment as prescribed. Personal characteristics such as age, gender, mobility, lack of motivation, somatic and psychiatric comorbidities, and previous experiences, are some of the examples [36]. OAT as a part of an integrated care model may have an impact on patient’s ability and interest to follow up medical treatment. Comprehensively integrated care models, including OAT, may consist of different medical, psychological and social approaches influencing the effect on integrated care. The efficacy of these approaches is uncertain and must be explored more in detail in the future RCTs with sufficient power in order to study more precisely the effectiveness of integrated care and how it influences adherence and treatment completion.

Three studies that included psychological intervention by clinical psychologists or psychosocial intervention by nurses under clinical guidance of a clinical psychologist as a part of the integrated care were included in this literature review. The effects of psychological intervention on our outcomes are too weak to measure quantitatively. A previous systematic review has measured the effects of psychosocial interventions on people with SUD and severe mental illnesses quantitatively independently of infectious disease treatment [21]. Different psychosocial interventions were assessed, including MI, CBT, and skills training. Overall, the results were affected by low to very low rate of evidence and unclear risk of bias. Based on 32 RCTs, no compelling evidence to reduce substance use or improve mental state in patients with severe mental illnesses was found. However, a systematic review and meta-analysis on collaborative care models have shown to be useful to enhance mental and physical outcomes among patients with mental disorders [17]. Three studies included people with SUD, but no intervention was qualified to be included as collaborative care models. The main focus of the studies was integrating or coordinating primary care with an ongoing psychosocial oriented substance use treatment program. It is uncertain whether a psychological intervention that is used in the treatment of severe infectious diseases among patients with SUDs improves the viral suppression or treatment completion. Again, there is an urgent need for high-quality RCTs with a detailed description and definition of integrated treatment models effect on quantitatively outcomes measurements, and where the risk of bias is reduced.

Three of the included studies in this systematic review evaluated DOT as a tool to increase treatment completion [13, 31, 32]. Generally, DOT did not meet our definition of integrated care but was included as one of several approaches on three of the integrated care models. In two of the cases, it is uncertain how much the DOT element per se affected the results. In our review, two studies including DOT in an integrated setting showed a significant effect on TB treatment completion. DOT is a controversial method due to challenges with patient’s autonomy and could leave the patients as a passive recipient of therapy [37]. However, DOT is a part of the WHO strategy, “Directly Observed Therapy Short course,” whose proposing to increase the completion of the TB treatment, and reduce contamination [38]. DOT has been less commonly implemented in HIV, HBV, and HCV strategies due to lack of compelling evidence in support for this treatment. DOT has been evaluated in a systematic Cochrane review as a treatment modality to affect treatment completion on TB infected [12]. Interestingly, DOT was compared to self-administration of therapy and compared between PWIDs receiving TB prophylaxis as DOT to standard care. DOT compared to self-administration showed a similar pattern to completion of TB cure, but stratified analyses on people with SUD or marginalized people were not surveyed. Similarity, one study that was included in the Cochrane review compared DOT to standard care among PWIDs [39]. Three hundred PWID received TB prophylaxis delivered by DOT or no observation. Treatment completion was not significantly different between DOT compared to self-administration.

The etiological treatment for hepatitis C and HIV have improved significantly in the last decade. New DAAs against chronic hepatitis C are better tolerated and have a better efficacy than traditional interferon-based treatment, and could therefore markedly reduce the global chronic hepatitis C epidemic [5, 40]. A high cost has limited the distribution to not only low- and middle-income countries, but also high income countries such as Norway [5, 41]. From February 1, 2018, however, all chronic HCV patients in Norway have given an opportunity to receive treatment with DAAs regardless of genotype and liver fibrosis level. Among recent advances in ART against HIV are increased potency making single tablet treatment feasible, better tolerance, and improved viral suppression [42, 43]. In our review, DAAs were not tested systematically in a separate study, and stratified analysis based on this item is not surveyed. However, Norton et al. (2017) have evaluated new DAAs among people who actively use drugs and received OAT in an integrated model [44]. The results of this non-controlled study showed that substance use and OAT are independently associated to a high SVR rate (> 90, 95% CI: 42 - 99%) when DAAs are given in a coordinated service. Due to the small sample size and lack of control group, the results are uncertain and must be confirmed in high-quality studies. Further integrated care models and new antivirals may contribute to ensuring better availability and treatment completion.

The chief limitation of this review is the lack of relevant studies, which fulfilled our inclusion criteria. Thus, we were unable to conduct a meta-analysis. Heterogeneity of these studies and methodological shortcomings also made it more challenging to synthesize clear patterns of evidence. In an attempt to minimize methodological shortcomings, we opted a strict definition for inclusion. A wider definition of search strategy will include a wider range of approaches but also approaches where the health care is not substantially different from more traditional given health care. This could make it more difficult to assess meaningful effects from comparisons. Thus, trying to balance these aspects we have opted for slightly narrower definition of integrated care than Haldane et al. (2017) have used in a review focusing on HIV, substance use and service integration [11]. Nevertheless, integrated treatment, as well as substance use disorder, are frequently used terms that are used with a range of definitions. Several synonyms and terms applied in the literature, makes it challenging to create a search strategy that identify all terms and synonyms used without using extremely broad search strategies. The additional pragmatic search on references and cross-references of relevant reviews, and RCTs, including two more relevant studies, is a high proportion of studies compared to those identified in the main search. Still, we cannot rule out that some studies lack. Integrated treatment can be seen as a continuous scale from studies comparing models with limited differences from conventional strategies to the studies with pronounced differences. Choosing where to set the exact threshold of the “borderline” studies with limited differences can be difficult. However, the studies with limited differences between more conventional and integrated are unlikely to inform as much on the effects of integrated treatment as studies with more pronounced differences.

Furthermore, one could argue that RCTs and cohort studies measuring other outcomes than HIV viral suppression, HCV SVR and TB treatment completions should be included for a wider range of integrated models. On the other hand, subjective outcomes such as self-reported adherence to treatment approaches, change of substance use, and as well as self-reported change of risk behavior are substantiality uncertain outcomes, which are affected by weaknesses. These risks are potentially more pronounced among people who actively use drugs than others due to the drugs effect on cognitive functions [45]. Due to these argumentations, in this review we want to identify all high-quality studies with hard outcomes on at least one of the infectious diseases.

Finally, one could argue that studies assessing non-SUD patients groups could be included in the assessment, but that could further add to the heterogeneity, and it would be uncertain to what extent the findings could be generalized to people with SUD.

This systematic review identified various integrated care models to reach and treat a group of marginalized patients with substance use disorders and severe infectious diseases. Even most of the included studies had high risks of biases and presented uncertain results. Hospitalized patients, who received integrated treatment for opioid use disorder during TB treatment, seemed to improve medication adherence and treatment completion. Additionally, integrated psychosocial interventions and directly observed OAT together with ART have been shown to improve the HIV viral suppression. For chronic HCV infected, no studies yet have shown compelling evidence of its benefits.