Identifying and Managing Infectious Disease Syndemics in Patients with HIV

Abstract

Purpose of review

We will present recent papers focusing on HIV synergistic interactions with other infectious disease syndemics (other STIs, tuberculosis, and hepatitis, as well as recent advances in the study of social and behavioral determinants that facilitate this clustering of infectious disease.

Recent findings

Significant advances in understanding the behavioral and structural determinants of HIV and other infectious disease synergisms have been made in the past years. Intervention strategies based on these new models have also been developed. It is now well understood that treating infectious disease syndemics will require a multidisciplinary and multipronged approach.

Summary

HIV is synergistic with multiple other infectious diseases because the risk behaviors that lead to HIV acquisition HIV may be similar to the other infections. The influence of HIV on the other infection may be due to immunosuppression associated with disease progression resulting in increased susceptibility (e.g. HIV and TB), especially when patients are not virologically suppressed using antiretroviral therapy (ART). In reverse, another infectious disease may, when not treated, influence HIV disease progression. Social/structural determinants like homelessness, mass incarceration, and structural discrimination precipitate psychiatric comorbidity, substance use, and risky sex behavior which lead to the spread and co-occurrence of infectious disease.

Introduction

Specific infectious diseases are central to HIV-related syndemics, particularly: tuberculosis, sexually transmitted infections (STI), viral hepatitis (HCV/HBV), as well as other infectious diseases in local contexts (e.g. schistosomiasis in endemic areas). They combine with the biological and psychosocial interactions that cluster within these comorbid conditions and are abetted by structural and social factors. Consequently, inter-related synergies may reinforce the expression of each condition. In this paper, we discuss the biological, social/structural and behavioral synergism related to HIV and other infectious diseases, and how they affect the expression of HIV disease outcomes.

Biological Synergism

Biological differences play a major role in facilitating HIV transmission, and differences between individuals may make them more or less susceptible to HIV. For example, male circumcision reduces HIV transmission by at least 60% because the foreskin contains a much larger concentration of cells that can acquire HIV than the rest of the penis (1). In women, pro-inflammatory cytokines and chemokines in genital secretions due to multiple factors, ranging from the use of some douching products to sexually transmitted infections, can increase risk for acquiring HIV (2).

HIV is synergistic with multiple other infectious diseases because the risk behaviors that lead to HIV acquisition HIV may be similar to the other infections, e.g. sex for STI and injection drug use and viral hepatitis, or synergistic infections may be geographically co-located, e.g. TB and HIV. In many cases, the influence of HIV on the other infection may be due to immunosuppression associated with disease progression resulting in increased susceptibility (e.g. HIV and TB), especially when patients are not virologically suppressed using antiretroviral therapy (ART). In reverse, another infectious disease may, when not treated, influence HIV disease progression (e.g. increased risk of neurosyphilis on people with HIV). Table 1 shows synergistic relationships between HIV and other infectious diseases.

Table 1.

Description of biological synergisms with HIV infections and potential interventions

Comorbid Infectious Disease	Impact of Comorbid Infectious Disease on HIV	Impact of one or both comorbid infectious diseases	Potential Interventions
Tuberculosis	None	Increased likelihood of reactivation of latent TB infection Decreasing CD4 in HIV patients linked to increased risk of TB acquisition in non-infected persons Decreasing CD4 in HIV patients is associated with more atypical disease presentation, including extrapulmonary TB HIV does not impact TB treatment	Integrated care services for HIV and TB Treatment of latent TB infection HIV test and treat strategies that focus on same-day ART treatment strategies (120)
Syphilis	Syphilis increases risk of HIV acquisition (121) Syphilis may increase the progression of HIV disease(13, 14), although data are inconclusive (15, 16, 122).	Decreasing CD4 in HIV patients linked to accelerated progression to neurosyphilis and atypical presentations (123, 124) High rates of syphilis acquisition in a subset of MSM with viral suppression with increased levels of condomless sex	Routine screening for syphilis in PWH Integration of STI and HIV services
Other STIs	Ulcerative and inflammatory STIs increase risk of HIV acquisition (125). STI can increase HIV replication through cytokine activation and upregulate genital tract HIV RNA,	HIV increases infection risk (126, 127) for men and women (128), and accelerates STI disease progression (129). STI increases HIV infectiousness in treatment naïve or non-adherent patients	Integrated services for HIV and STI Syndromic STI treatment
HCV	None	HIV changes rate of fibrosis from HCV (130)	Integrated HIV/HCV services HCV treatment with direct-acting antiviral replication treatment as prevention micro-elimination strategies (41, 42) Harm reduction services in PWID to prevent re-infection

Sexually Transmitted Infections

From 2012 to 2016, the global incidence of curable STIs (chlamydia, gonorrhoea, non-gonococcal urethritis, trichomoniasis and syphilis) increased from 357 to 376 million incident cases among people aged 15 and 49 years (3). In the presence of STIs, the inflammatory response by the host can also increase production of inflammatory cytokines and recruit immune cells to the genital tract (4–8), which in turn increases the risk for HIV acquisition and transmission. Ulcerative STIs like herpes simplex virus (HSV) and syphilis not only create a pro-inflammatory response that facilitates HIV transmission, but they also erode the epithelial barrier to transmission.

HIV co-infection affects syphilis and HSV presentation and expression as the HIV-associated immunosuppression increases in direct proportion to lower CD4 lymphocyte counts. Synergy between HIV and syphilis has long been understood (9). Not only is syphilis incidence in PWH is several-fold greater than in the general population, but the presentation of syphilis may be more severe or atypical, particularly in more immunosuppressed PWH who are more likely to develop multiple, deeper or larger chancres(10, 11). Moreover, syphilis progresses to tertiary syphilis 3.5 times more quickly in PWH than those without HIV (11), especially in more immunosuppressed PWH (12). Despite early research to the contrary (13, 14), recent data does not show that syphilis increases HIV progression(15, 16).

HIV and genital HSV have a bidirectional effect on each other. Reactivation of genital HSV increases HIV viral replication, risk of HIV transmission, and disease progression. Co-infection with HSV in PWH results in increased HSV viral shedding, risk of HSV transmission, and frequency and severity of HSV symptoms (17). Patients who are co-infected with HIV and genital HSV may benefit from treatment with antiviral medications for HSV, including chronic viral suppression (18).

Inflammatory bacterial STIs that cause urethritis (e.g., gonorrhea, chlamydia, ureaplasma, etc) have been associated with increased risk for HIV (19, 20), especially among amphetamine users (21).

In many settings, testing is limited and expensive, so syndromic treatment is common. Syndromic treatment misses a substantial number of people with STIs, and managing STIs can be optimized through the use of low-cost point-of-care testing (POCT) of STIs (22). Additionally, integrating HIV and STI services can address this biological synergism. Service integration for women with HIV has been shown to increase Pap smear screening, even when sexual health screening and education did not (23). Integrating such services for MSM with HIV appear to be feasible and acceptable (24). Integrating these services has also been shown to increase provision of pre-exposure prophylaxis for MSM without HIV (25). Integrated HIV and STI service delivery models make empiric sense, but need more evaluation in clinical trials and implementation studies. For MSM experiencing high levels of stigma, and where such sexual health services are not available, home testing for HIV and STIs could emerge as an effective strategy to address this synergism (26).

Tuberculosis

HIV increases risk of TB infection and disease progression and TB slows CD4 recovery and increases HIV progression and death among PWH. Treatment of both HIV with ART and latent TB infection (LTBI) with preventive therapy mitigate the impact of coinfection. More advanced HIV results in increased rate of reactivation of LTBI with increased likelihood of atypical and extrapulmonary TB, which may be challenging to diagnose. Moreover, tuberculosis increases HIV replication (27), resulting in increased HIV progression and death, while HIV accelerates TB disease progression, and impacts TB diagnosis and management(28). Of the 10 million people diagnosed with TB in 2018, 860,000 (8.6%) were among PWH. Mortality among those co-infected with HIV/TB was high (29.2%) and accounted for 33% of the 770,000 deaths among PWH (29), including the majority (69%) of HIV/TB patients on ART in South Africa (30).

Integrated HIV/TB programs, especially in high prevalence settings, are both feasible and improve health outcomes for both conditions. Key elements for such services include universal testing and treatment of HIV irrespective of CD4, screening and treatment for both TB and LTBI among all PWH, and patient-centred support and monitoring to ensure adherence and treatment retention (31). Among PWID, integrating services for addiction, HIV and TB demonstrate improved addiction treatment, HIV and TB outcomes in a study of PWH in Ukraine (32). Despite the benefits observed in this strategy, most LMICs fail to deploy this strategy.

HCV

HCV is the most prevalent chronic viral infection and prevalence is highest among PWID. Among PWID, HCV prevalence ranges from 52%−90% and is 9%−40% among PWH, depending on region. While HCV does not appear to alter HIV progression, the immunosuppressive nature of HIV, especially in those with decreasing CD4 counts, results in accelerated liver fibrosis and increased morbidity and death in HIV/HCV coinfected patients. Though the mechanism of HIV and its related influence on accelerated fibrosis is not known (33), early treatment of HCV in HIV/HCV patients is associated with halting or improving fibrosis progression (34). Initiating ART in HIV/HCV and restoring CD4 counts can reduce the rate of fibrosis in HIV/HCV patients. While university test and treat strategies have generally been successful in generalized epidemics, ART coverage levels in PWID with HIV remain low, related to patient-level factors like avoiding healthcare due to stigma or fear of discrimination (35), or HIV healthcare providers witholding ART from PWID until they are abstinent from drugs (36, 37).

Micro-elimination strategies of HCV in HIV/HCV co-infected patients (38), potentially using an integrated HIV/HCV service delivery model(39), can reduce the negative consequences of HIV/HCV. One such model initiated HCV treatment in over two-thirds of patients, but cured only about half of the HCV infections in PWH (40). The relatively low micro-elimination outcome in this setting was likely due to the lack of integration with addiction treatment services including opioid agonist therapies (OAT), challenges in engaging PWID who mistrust the healthcare system. Harm reduction services should be incorporated within these settings not only to reduce transmission to injecting partners, but also to reduce the risk of reinfection. Mathematical models suggest that a combination of OAT and syringe services programs (SSP) are optimally integrated in any HCV treatment as prevention efforts (41, 42).

Social and Structural Synergism

We define social and structural synergism as the relationship between social determinants of health and the ways in which modify disease risk, clinical presentation, or epidemiology. Social and structural factors interact with behavioral determinants of health in complex and multifaceted ways, explained in a simplified taxonomy below.

Incarceration

Over 10.3 million people are incarcerated with 2.2 million in the US (43), with both sexual and injection-related transmission occurring (44). Within prison drug injection is variable, but in Kyrgyzstan(45), Indonesia (46) and Ukraine (47), where HIV transmission is increasing, within prison injection is high. This behavior also increases transmission of viral hepatitis, and after release from prison, injection-related drug risk is several-fold higher due to disruption of injection networks and social instability (48). Crowding additionally contributes to elevated TB risk, which for PWH, they are at especially higher risk for tuberculosis outbreaks (49, 50).

Interventions that are likely to reduce the negative consequences of incarceration on HIV, viral hepatitis and TB include decriminalization of drug use (51), and for those remaining, scale-up of medications for opioid use disorder (MOUD) in prisons. Because the post-release period is risky (52) for those with or without HIV, it is crucial to markedly reduce the negative consequences of incarceration both through decriminalization of drug use, but also by releasing people in prison with substance use disorders and non-violent offenses. Two recent systematic reviews also support to use of MOUD initiated within prison and continuity post-release as being effective. Another strategy to reduce blood-borne virus transmission within prison include syringe services programs (SSP) (53, 54). Naloxone for overdose prevention for prisoners transitioning to the community is highly acceptable (55) and effective programs are now underway (56).

Homelessness and housing

Homelessness is associated with a 46-fold increased risk of TB, and a four-fold increased risk of HCV (57). STI infections among homeless youth are markedly higher than among the general population (58). Transitions through housing are especially problematic for people leaving jails (59) and for anyone evicted from stable housing, there are increased chlamydia and gonorrhea infections (60). Access to medical care, linkage to ART, and medication adherence has been shown to be a persistent problem for people unstably housed (61), and when housing is prioritized for PWH, their HIV treatment outcomes improve (62). In addition, homelessness interacts with many other social and biological synergisms of HIV.

Many formerly incarcerated individuals become homeless post-release, leading to an interactive “revolving door” effect(63). Homeless populations have a 10-fold increased risk of tuberculosis acquisition when compared to the general population (64). Tuberculosis outbreaks in the United States also frequently originate in homeless shelters (65).

Persons experiencing homelessness have high levels of substance use disorders, mental illness and HIV risk (66). Among youth, many are part of the LGBTQ+ community and when homeless, they experience elevated levels of drug use and injection initiation (67), reinforced by high rates of depressive disorders (68). The syndemic effects of housing instability and policy, incarceration, sexually transmitted infections, and HIV is currently being investigated by the Justice, Housing, and Health Study (JustHouHS) (69), which will publish their research on the topic in the coming years.

Like for other social factors, addressing housing instability will require an integrated approach. Rent supplements coupled with mental health support are an effective way to improve housing stability for homeless adults with mental illnesses (70). Case management was consistently associated with improved mental health and substance use disorder outcomes when compared with treatment as usual. When case management coupled is with “assertive community treatment” (essentially an improved and well staffed case management team), rates of homelessness and mental health outcomes are further improved (71). Housing first (72)and respite care (73) interventions are also effective.

Stigma, Minority Stress, and Intra-minority Stress

Gay and bisexual men experience high rates of depression (), anxiety, substance use disorders, and other psychiatric comorbidities (75) that put them at increased risk of HIV, STI, and HCV acquisition.

Minority stress theory posits that gay and bisexual men’s frequent interactions with heterosexism are a source of chronic stress, and lead to adverse mental health outcomes (76). Minority stress has been shown to be associated with HIV and STi risk behavior, adverse mental health outcomes, and substance use (77). While most research examining the association between minority stress and infectious disease has been conducted in western countries, recent scholarship has started to observe similar associations worldwide (78), implying that homophobia and infectious disease are strongly linked regardless of cultural context. Sexual minority stress is linked to a host of biological outcomes, including overall physical health, immune response, and outcomes specific to HIV, cardiovascular, hormonal, and metabolic health, and cancer (79).

To address minority stress, Burton and colleagues (80)have introduced the ESTEEM intervention, which is a tailored cognitive behavioral therapy model specifically designed to reduce and mitigate the effects of minority stress. Online interventions are effective in low-resource settings (81). Oldenburg and colleagues (82) have found that stigmatizing state-level policies were strongly associated with minority stress among gay and bisexual state residents, implying that passing LGBT-favorable legislation may be an effective way to impact the syndemic problem of minority stress, infectious disease, and psychiatric comorbidity.

A recent paper by Pachankis and colleagues (83) introduces a new theory of intraminority stress among gay and bisexual men. The theory proposes that a portion of the excessive burden of mental health disorders among sexual minority men can be explained by status-based pressures from within their communities to maintain markers of social status, namely: masculine norms, attractiveness, and wealth. Empirically testing this theory, the team found that intraminority stress theory was a better explanatory model for mental health outcomes than minority stress theory. Another recent paper by Burton and colleagues found that the same intraminority stressors were associated with lower aversion to to HIV and STI risk behavior, like condomless sex (84). Intraminority stress is also likely associated with increased substance and therefore HCV transmission, although this has yet to be investigated. As of yet, no tailored intervention for intraminority stress exists.

Transgender women also have a heightened burden of HIV infections. Although data are scarce and are not representative, meta-analysis estimates a 19.1% pooled HIV prevalence for transgender women worldwide. Evidence also suggests that transgender women have elevated rates of hepatitis C viral infections, with a recent cross-sectional study in San Francisco showing an anti-HCV seroprevalence nine times higher among transgender women than the general population(85), suggesting that harm reduction measures should be tailored to transgender populations.

Much of the theory linking minority stress to HIV/STI risk behavior is applicable to transgender individuals (86, 87); however, transgender people also face distinct challenges that put them at increased risk of infectious disease. Transgender people face high rates of identity based violence worldwide (88, 89) and are incarcerated at higher rates than the general population. In the United States, transgender women are incarcerated at twice the rate of the general population, and Black transgender women have a tenfold increased risk of incarceration (90). Homelessness and incarceration may lead to heightened rates of tuberculosis among transgender people (91), though robust prevalence data are lacking.

As African Americans made up 13% of the US population in 2018, but 42% of all HIV diagnoses (92), the role of race and structural racism in regards to infectious disease cannot be overstated. Black MSM do not have higher rates of risky sex behavior than their white counterparts (93), and evidence supporting explanatory models Black MSM elevated HIV incidence is inconclusive (94). Explanatory models for the high HIV incidence include lower access to healthcare services, increased rates of incarceration and stigma (94), and selective sexual partnering leading to higher likelihood of intercourse with an HIV-positive partner (95–98). The role of structural racism in understanding the HIV and infectious disease syndemics among African Americans in the United States and ethnic minorities around the world is a topic that deserves further study to ascertain causal mechanisms.

Intersectional stressors impact the mental health of individuals holding multiple marginalized identities (99) (e.g., Black MSM). Tailored interventions for such intersectional stressors are currently in development (100).

Behavioral Synergism

We define behavioral synergism as the relationship between non-biological, individual-level determinants of health, the pathways between them and infectious disease transmission, and their impact on the clinical expression and treatment of infectious disease. We include both psychological synergisms (e.g., psychiatric comorbidities) and synergisms relating to interactions with the environment and others (e.g., substance use) in this category.

Substance Use and Psychiatric Comorbidities

The prevalence and morbidity of depression among gay and bisexual men in the United States and elsewhere has reached epidemic proportions (74), both exceeding that of HIV/AIDS. Depression is known to influence HIV and STI sexual risk behavior among sexual minority men (101–104), as well as interfere with medication adherence (105). The prevalence of other stress-sensitive psychiatric conditions like anxiety is also very high among gay and bisexual men (75). These psychiatric comorbidities are associated with increased drug use (106) and sexual risk behavior (107).

Sexualized Drug Use (“Chemsex”)

Sexualized drug use, especially of stimulants, has evolved as a major driver of HIV transmission, especially among MSM. While general prevalence data is lacking, meta-analysis (108) of studies recruiting MSM from sexual health clinics and dating and sex apps had chemsex prevalences of 0–14% (109, 110). Stimulants are associated with elevated risk for depressive symptoms and suicidal ideation along with elevated condomless sex, resulting in increased HIV and STI transmission (111–113). Those involved in chemsex are less likely to seek medical care when they need it (114), often resulting in suicide, suggesting that low sexual health clinics must be more facile with dealing with stimulant use, which is challenging to treat. For individuals with stimulant disorders, an effective intervention is wide-scale pre-exposure prophylaxis (PrEP) (115).

Injection drug use

There are an estimated 15.6 million people who inject drugs (PWID) worldwide. Of the 15.6 million PWID worldwide, 17.8% are PLHIV, 9.1% are HBV-positive, and 52.3% are HCV-positive (116). One in three PWID meet the DSM-V definition for depressive disorder diagnoses, and one in four PWID has attempted suicide (117).

The gold standard for the treatment of opioid use disorder is MOUD (118). Models of MOUD delivery that combine HIV and HCV treatment, pre-exposure prophylaxis for HIV, and behavioral health services for HIV are needed to target the syndemic of OUD, HIV, and HCV (119). While some research on these integrated services exist, the relative effectiveness of different levels of integration is unknown.

Conclusion: Overlapping Biological, Behavioral and Social and Structural Synergies

In this review, we synthesize synergistic components of syndemic systems into biological, social/structural, and behavioral categories. Though this makes for convenient categorization, all elements’ syndemics are thoroughly intertwined and often mutually reinforce one another. In Figures 1 and 2 we represent the ways in which different levels of synergies impact infectious disease syndemics for PWID and MSM, respectively.

Figure 1.

Diagram of infectious disease syndemic pathways for PWID

(Original) This figure illustrates the ways in which different levels of synergies impact infectious disease syndemics for PWID. Arrows within the model indicate the direction of the synergistic effects. Larger arrows represent interactions that have been qualitatively deemed more significant for their respective populations.

Figure 2.

Diagram of infectious disease syndemic pathways for MSM

(Original) This figure illustrates the ways in which different levels of synergies impact infectious disease syndemics for MSM. Arrows within the model indicate the direction of the synergistic effects. Larger arrows represent interactions that have been qualitatively deemed more significant for their respective populations.

Important features contribute differently to specific populations; for example, depression reduces adherence to ART. While PWID and MSM experience epidemic rates of depressive disorders that often exceed 50%, this is a cross-cutting synergy for most key populations. Incarceration and drug use are similarly bidirectional. PWID, relative to MSM, experience much more profound levels of incarceration (lifetime 50% to 90%), which in turn results in higher-risk drug injection within prison and increased HIV and HCV transmission. Crowding increases the risk of TB exposure, which can result in increased HIV transmission and expression of HIV-related disease. Notably, there is substantial socio-demographic variation within both the PWID and MSM populations; some elements of the syndemic models in figures 1 and 2 will be more appropriate to some subsegments of these populations than others.

Table 2.

Social and structural synergisms

Social/Structural Factor	Impact on ID	Impact on other synergistic factors	Potential Interventions
Incarceration	Increases crowding leading to risk of TB transmission Increases HIV, STI, HBV, and HCV risk behavior	Increases injection drug use Increases depression	In-prison MOUD with post-release continuity(52, 131) In-prison NSP (54) Decriminalizing drug use to reduce incarceration levels
Homelessness and housing	Crowding in shelters increases risk of TB transmission	Increases psychiatric comorbidities and substance use disorders	Non-abstinence-contingent housing Housing vouchers Reducing incarceration will (132)
Minority stigma and Intraminority Stress	Leads to increased HIV, STI, HBV, and HCV risk behavior	Increases psychiatric comorbidities and substance use disorders	Psychotherapy tailored to sexual minority populations, such as the ESTEEM model (80) Changing stigmatizing laws and policies relating to gay and bisexual men (82)

Table 3.

Behavioral synergisms

Behavioral Factor	Impact on ID	Impact on other synergistic factors	Potential Interventions
Substance use	Injection drug use is a pathway of HIV and HCV transmission Increases STI and HBV risk behavior. Interferes with medication adherence	Increases psychiatric comorbidity Associated with increased experiences of violence	Community needle and syringe programs MOUD SBIRT screening Contingency management Relapse prevention, Cognitive behavior therapy
Psychiatric comorbidity	Increases HIV, HCV, HBV, and STI risk behavior Interferes with ART and other medication adherence	Increases substance use	Depression screening among gay and bisexual men Tailored cognitive behavioral therapy like ESTEEM for gay/bi men
Violence	Increases HIV, HCV, HBV, and STI risk behavior	Increases psychiatric comorbidity and substance use Intimate partner violence increases risk of homelessness	CBT-based interventions that tailored to victims of violence(133, 134) Web-based and remote interventions for victims of IPV(135) Economic strengthening interventions for victims combined with and gender transformative interventions for perpetrators(136) Housing interventions for victims of IPV(137)

Key points.

• HIV interacts with other infectious diseases often in bi-direction, synergistic ways

• Clustering of behavioral precursors to infectious disease explain why we observe high rates of infectious co-occurrence in certain populations

• Structural factors like minority stress, homelessness, and incarceration heavily exacerbate behavioral precursors to infectious disease