Quadruple Diagnosis: Substance Use Disorder, Comorbid Psychopathology, Human Immunodeficiency Virus Infection, and Hepatitis C Virus Infection





Introduction


Comorbid substance use disorders (SUDs) and other psychiatric disorders (dual diagnosis) in individuals who are infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are common. Prevalence rates of such dual diagnoses vary significantly across reported studies, ranging from 10% to 50% or more, depending on the sample assessed. In a large cross-sectional study, up to half of the clients in an HIV-dedicated clinic carried a diagnosis of at least one psychiatric disorder, and nearly 40% also had psychoactive SUDs (other than marijuana)—with up to 12% of the latter having severe use disorder (formerly “dependence”) over the prior 12 months. In a review of the area, the prevalence of co-occurring substance use and mental health disorders ranged from a low of 10%—similar to the aforementioned study—to a high of 28% among persons living with HIV, and the concern for this triply diagnosed group continues to grow. A focus has grown on another triply diagnosed group—those diagnosed with an SUD, other psychiatric disorder, and HCV infection. One study of this group ( n = 293) coming for an initial hepatology clinic visit showed that 93% had a current psychiatric disorder or a history of at least one psychiatric disorder, and 73% had more than two disorders, with depressive disorder being the most common (81%), followed by posttraumatic stress disorder (PTSD) (62%), SUD (58%), bipolar affective disorder (20%), and other psychotic disorders (17%). Of note, SUDs are specifically associated with increased sensation seeking and impulsivity, both of which are related to high-risk behavior for HIV and HCV infection in this population. That is, unsafe sexual practices and needle sharing are greatly increased in this group. Vice versa, individuals with other psychiatric disorders may eventually develop SUDs, varying according to the specific type of disorder. SUDs contribute to psychological distress and the emergence of new psychiatric disorders, many times induced by the substance itself. Both SUDs and other psychiatric disorders manifest with impaired insight and judgment. The related ongoing change in mental status, in turn, contributes to the aforementioned HIV and HCV high-risk behaviors, including severe substance use urges, sharing of substances to facilitate immediate use, and use by injection with sharing of needles and injection paraphernalia to maximize the impact on sensation of such use. Similarly, in this setting as well, high urges to engage in sexual activity occur, sexual risk-taking discussion and precautions are neglected in favor of immediate sexual gratification, and unprotected sexual intercourse occurs (including very high-risk associated behaviors, such as trading sex for money). Given the high comorbidity between the dually diagnosed (SUDs and other psychiatric disorders), HIV infection, and HCV infection, the focus of this chapter is to examine recent data regarding the interactions between this specific form of dual psychiatric comorbidity with HIV and HCV infection, as well as other associated comorbidities, that is, HIV-associated neurocognitive disorder (HAND), morbidity, and mortality.


Nearly 37 million people are living with HIV around the world. In the United States, 1.2 million people are living with HIV, of whom 13% are unaware of their diagnosis. Regarding HCV infection, there are an estimated 3.5 million HCV-infected persons in the United States, 2.7 million in the general noninstitutionalized population, plus an additional 800,000 incarcerated, institutionalized, or homeless ; about half of all infected people are unaware that they are infected. Among patients with chronic HCV infection, approximately one-third progress to cirrhosis, at a median time of less than 20 years. The rate of progression increases with older age, alcohol use disorder, male sex, and HIV co-infection. About 25% of people living with HIV in the United States also have HCV infection, approximately 300,000 people. A meta-analysis found that HCV/HIV co-infected patients had a threefold greater risk of progression to cirrhosis or decompensated liver disease than HCV mono-infected patients. The risk of progression is even greater in HCV/HIV co-infected patients, with low CD4+ T lymphocyte count (i.e., CD4 cell count). Although effective antiretroviral therapy (ART) appears to slow the rate of HCV disease progression in HCV/HIV co-infected patients, the rate continues to exceed that in HCV mono-infected. Whether HCV infection accelerates HIV progression remains unclear, although some antiretroviral medications (ARVs) are associated with higher rates of hepatotoxicity in patients with chronic HCV infection.


For more than a decade, the mainstay of HCV treatment had been a combination regimen of pegylated interferon and ribavirin, but this regimen was associated with a poor rate of sustained virologic response (SVR) to HCV, especially in co-infected patients. Rapid advances in HCV drug development since 2011 led to the use of new classes of direct-acting antivirals (DAAs) that target the HCV replication cycle. Recently approved DAAs are used without interferon and with or without ribavirin and have higher SVR rates, reduced pill burden, less frequent dosing, fewer side effects, and shorter durations of therapy than the earlier approved regimens, yielding a new dawn for the medical treatment of the HIV/HCV co-infected patient. These gains have yet to be applied to the care of co-infected patients with SUDs and other psychopathology.




Scope of the Problem


High rates of HIV infection have been documented in individuals with dual diagnosis. In one study of persons living with HIV with comorbid SUDs and other psychiatric disorders ( n = 1,848), HIV prevalence was 4.7% versus only 2.4% in participants diagnosed with a SUD without another psychiatric disorder comorbidity. A cross-sectional survey of 3806 adults living with HIV infection across four major metropolitan areas in the United States showed that nearly 75% of respondents reported occasional use of psychoactive substances, 40% reported frequent use of various psychoactive substances, and only 28% declared abstinence from all psychoactive substances. In the group reporting frequent use of psychoactive substances, more were likely to be identified as heterosexual, had public health insurance, and endorsed increased symptoms of major depressive disorder (MDD) —illustrating the impact of triple diagnosis of SUDs, other psychiatric disorders, and HIV infection. In the quadruply diagnosed with HIV and HCV co-infection, it has been reported that nearly one-third have a concomitant mental disorder—predominantly depressive—whereas approximately one-fifth have active SUDs.




Substance Use Disorders (SUDs)


Intravenous substance use has long been associated with an increased prevalence of a comorbid psychiatric diagnosis— especially dysthymic disorder and MDD . Depressive spectrum disorders in intravenous substance-using individuals have been repeatedly linked to increased likelihood of sharing needles, syringes, and other paraphernalia, which further increases the risk of HIV and HCV transmission. Stein and colleagues examined the association of depressive disorder severity (i.e., MDD, dysthymic disorder, and substance-induced mood disorder lasting at least 3 months) with substance injection risk behaviors among injecting substance users. After controlling for multiple confounding variables, including age, race, gender, number of days on which injection drugs were used, and the average number of injections per injection-day, a diagnosis of a depressive disorder was still significantly associated with injection substance use behaviors.


Similarly, other data illustrate that individuals with depressive spectrum disorders are more likely to engage in unprotected sexual activity with intravenous substance-using individuals—heightening an already substantial risk of HIV and HCV transmission. This same population also demonstrates increased rates of sexual abuse, which predicts depressive features, increased suicidality, and increased nonadherence to antiretroviral therapy for HIV and direct-acting antiviral (DAA) therapy for HCV, making the risk of progression and viral resistance to HIV and HCV greater in these groups. Deleterious outcomes in HIV-infected intravenous substance users have been related to a variety of factors, including increased rates of HCV co-infection, decreased access to and engagement in care, diminished adherence to effective ART regimens, MDD and other depressive disorders, psychosocial stressors, and HIV-associated AIDS and non-AIDS (HANA) morbidity and mortality.


Among individuals who inject substances, studies have shown that up to one-third are at risk for severe MDD, with women experiencing greater severity. Correlates of depressed mood and general distress in both men and women include perceived functional limitations, greater negative feelings regarding condom use, higher life stressor burden and impact, lower social support availability and satisfaction, higher passive, maladaptive coping strategy use, and a lower sense of empowerment with higher external locus of control. Similarly, a history of physical abuse and minority ethnicity also appear to be significant predictors of MDD among intravenous drug users of both genders who are living with HIV. Methamphetamine-dependent men who have sex with men also demonstrate high lifetime rates of psychiatric disorders including major depression and anxiety disorders. Generalized anxiety disorder, specific phobia, bipolar disorder, and major depressive disorder have all been linked to higher rates of sexually transmitted infections, including gonorrhea and HIV. Crystal methamphetamine use has evolved to be a major risk factor for the development of MDD and other psychiatric disorders as well as increased transmission rates of HIV infection. Naturalistic interview studies have demonstrated the wide prevalence of a cycle of severe depressed and anxious mood level in the context of methamphetamine use as well as persistent anhedonia. Almost all respondents in such studies have reported that methamphetamine was severely damaging to social relationships, resulting in increased self-isolation. In addition, methamphetamine use has been tied closely to random sexual encounters and increased numbers of sexual partners, with a decreased likelihood of condom use. A better understanding of these patterns and risks is essential in developing effective prevention strategies. Alcohol use alone has been linked to multiple risk factors associated with HIV including sexually transmitted disease histories, condom nonuse, multiple sex partners, and lower HIV-related knowledge. These risks appear to increase substantially with increasing amounts of alcohol use, and individuals demonstrating abstinence from alcohol appear to have the lowest risk profile. The impact of alcohol upon these risk factors remains present even in the absence of other drug abuse.




Psychiatric Disorders Other Than SUDs


Common mental disorders among individuals with HIV and substance abuse include adjustment disorders, sleep disorders, depressive disorders, mania, dementia, delirium, psychosis, and personality disorders. A careful psychiatric assessment is necessary to engage in differential diagnostic considerations and differential therapeutics. There are three categories of mental disorders of concern in substance users living with HIV: substance-induced mental disorders, HIV-related mental disorders, and medication-related mental disorders.




Psychiatric Disorders in Human Immunodeficiency Virus Infection


Depressive Spectrum Disorders


Depression is a highly general term that specifies neither level of decreased mood nor the presence of a syndromal disorder including decreased mood. Syndromal depression is a collection of symptoms that—when taken in different combinations—characterize one of the depressive spectrum disorders, including MDD, dysthymia, adjustment disorder with depressed mood, substance-induced depressive disorder, and depression due to a general medical condition. Thus the etiology and pathophysiology of the various sub-types constituting the more properly described group of depressive spectrum disorders are quite varied. MDD, specifically, is the most common mood disorder in the general population, with a 12-month prevalence of 4.7% in men and 8.5% in women. MDD, also, is the most common mood disorder in people living with HIV infection, occurring at rates two to three times higher than that in the general population. Commensurate with the prevalence of MDD in the general population, the MDD rate in women living with HIV is higher than that of men. A study by Bhatia and Munjal examining the prevalence of depressive disorder in people living with HIV/AIDS undergoing ART demonstrated a 63% prevalence in females, thereby exceeding the 58.1% prevalence shown in males. Furthermore, MDD severity is associated with an increased frequency of intravenous substance use and associated high-risk behaviors, placing such individuals at greater risk for both HIV and HCV infection.


Despite the high rates of comorbidity between mood and SUDs, the origins of this association are not well understood. Self-medication, genetic predisposition, and psychosocial factors all may be involved. Further complicating this picture, epidemiological studies note that prevalence rates differ between individuals with primary MDD and a comorbid SUD versus the prevalence of a primary SUD with comorbid MDD. A study of individuals with primary MDD demonstrated a relatively low 8.5% prevalence rate for a comorbid SUD. In contrast, a study of individuals with a primary SUD and comorbid MDD showed a considerably higher 20% prevalence of MDD. The high prevalence of MDD in the population living with HIV speaks to the impact of inflammation in both disorders. Manifested by a potent inflammatory response, the acute stage of HIV infection involves a substantial elevation of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and IL-6. Of note, this potent inflammatory cytokine response has also been identified in HCV infection. As an etiological component of depressive disorders, this acute increase in pro-inflammatory cytokines induces sickness behavior—a behavioral complex of responses. Acting on the hypothalamus, the cytokine response induces changes in homeostatic set points resulting in fatigue and hypersomnolence, loss of appetite and subsequent weight loss, anhedonia, malaise, and neurocognitive symptoms. As depicted, the similarities between sickness behavior and MDD are striking; in turn, the associated, potent inflammatory response and accompanying pro-inflammatory cytokine elevations may in fact contribute to the etiology of MDD symptoms in persons living with HIV. Additional neurocognitive manifestations of the highly detrimental synergistic impact of HIV and MDD may include decreased attention and vigilance, cognitive slowing, and impaired working and episodic memory. Such neurocognitive deficits may reflect the propensity for MDD to be associated with increased cerebrospinal fluid (CSF) HIV load.


By means of the cytokine inducer, lipopolysaccharide (LPS), animal models of MDD also depict the impact of inflammation on behavior. Although acute inflammation is essential for pathogen removal and tissue repair, the impact of unchecked chronic inflammation may be significantly destructive. As might be expected, high life-stressor burden is a significant risk factor for the development of MDD, and— of relevance here—life stressors have been shown to activate the production of pro-inflammatory cytokines due, in part, to associated cortisol secretion. In turn, it has been suggested that chronic exposure to pro-inflammatory cytokines may contribute to glucocorticoid resistance by means of a decrease in glucocorticoid receptor alpha (the active form of the receptor) and an increase in glucocorticoid receptor beta (a relatively inert form). Such glucocorticoid resistance manifests as a decrease in the sensitivity of immune cells to glucocorticoid hormones that normally terminate the inflammatory response. In addition to neuroendocrine function, both neurotransmitter metabolism and neuronal plasticity are affected by the impact of cytokines on pathophysiologic processes. Through the stimulation of multiple signaling pathways, cytokines can activate indoleamine 2,3 dioxygenase (IDO). This stimulation of IDO results in the breakdown of tryptophan (TRP), serotonin’s primary amino acid precursor, into kynurenine (KYN), which converted to quinolinic acid (QUIN) in microglia, promotes glutamate release via the activation of N -methyl- d -aspartate (NMDA) receptors, an important factor in excitotoxicity.


Although depressive disorders may decline in patients not infected by HIV with advancing age, this does not appear true of persons living with HIV, who are at continued risk for depressive disorders well into older age. In addition, depressive disorders have been closely linked to apathy in patients living with HIV, and this apathy may reflect HIV infection of the brain. Both apathy and depressed mood are linked to suboptimal adherence to effective ART. Similarly, fatigue has also been linked to depressed mood and a diagnosis of MDD, with an increase in the release of pro-inflammatory cytokines, for example, TNF-α, and subsequent long-term neuroinflammation inducing fatigue in persons living with HIV. Furthermore, a recent study by Barroso et al. reported that HIV-related fatigue remains the most frequent complaint of patients living with HIV, and fatigue is known to be caused by pro-inflammatory cytokine release (particularly TNF-α) associated with the long-term inflammation seen in treated persons living with HIV. Depressive disorder severity has also been linked to a greater frequency of intravenous substance use and its associated high-risk behaviors.


Women appear to be a special at-risk group with regard to depressive disorders and intravenous substance use. Depressive disorder prevalence rates and severity are elevated among women who are both infected with HIV and intravenous substance users. Women also frequently report a history of childhood and adult trauma and poorer quality of life scores in the context of HIV infection, despite showing some protection against neurocognitive decline with respect to their male counterparts. Substance use, violence, and depressive disorders have been deemed a tripartite HIV risk among African American women, which remains an underexplored area of research. Women with a history of sexually transmitted infections (STIs) have been noted to be more likely to experience violence and depressive disorders, both individually and jointly. This described tripartite risk group is also reflective of those women having two or more sexual partners in the last 30 days as well as those having an early onset of alcohol use disorder. Similarly, ARV adherence has been noted to be low in substance-using women as compared with men; however, mental health care has been shown to be significantly associated with improved adherence in this patient subgroup as opposed to their male counterparts —again highlighting the need for effective psychiatric services in this at-risk group.


HIV-Associated Mania and Bipolar Affective Disorder in HIV Infection


HIV-induced mania may occur in up to 8% of late-stage patients. The impulsivity and hypersexuality associated with mania exacerbates an already increased risk for HIV and HCV infections. In addition, the considerably inflated risk of SUDs in mania further magnifies both impulsivity and high-risk behaviors. In addition to HIV infection itself, one of its complications, cryptococcal meningitis, may also present as mania in full-blown AIDS. The “great masquerader,” syphilis, may also present with mania. It has been suggested that the CSF of patients living with HIV being evaluated for HAND should be screened using both the venereal disease research laboratory (VDRL) and the fluorescent treponemal antibody (FTA) absorption test, since patients with a history of syphilis may lose serum reactivity in the setting of HIV infection (even when otherwise asymptomatic). Moreover, neurosyphilis itself may be asymptomatic in about 10% of cases. Corticosteroid treatment commonly used with acute presentations of Pneumocystis carinii pneumonia (PCP; later documented to be due to Pneumocystis jirovecii and now less common in the high-resource countries) in persons living with HIV carries a known risk for mania. Iatrogenic mania also remains a risk with zidovudine (ZDV) therapy, although ZDV (formerly azidothymidine [AZT]) is rarely used today. HIV-induced mania more frequently presents with neurocognitive impairment (NCI) in persons living with HIV and has been associated with a better response to the use of valproic acid over lithium.


Preexisting bipolar disorder in the context of HIV infection is especially problematic in that it involves cycling between depressive and manic episodes, with the complications related to decreased and increased goal-directed behavior in each phase, respectively. The manic phase of bipolar disorder increases the likelihood of psychoactive substance use and is related to increased impulsivity and sexual risk-taking behavior. One study examining the link between mania and HIV infection demonstrated that a significant majority of study participants had been sexually active in the past 6 months (75%). They disclosed engaging in high-risk sexual behaviors such as unprotected intercourse (69%), having multiple partners (39%), sex with prostitutes (24%, men only), and sex trading (10%). Severity of bipolar illness was also associated with HIV risk profile.


Psychosis and Thought Disorders


Up to 30%–50% of patients living with serious mental illness (SMI) have SUDs. Earlier studies by one prominent group in New York City suggested that the prevalence rate of HIV infection among persons living with SMI was variable, depending upon relevant factors in the population living with SMI, including homelessness, treatment setting and status, specific psychotic diagnosis, dual diagnosis with substance use disorders, and sampling method (open vs. anonymous). Additional foci of import directly related to persons living with SMI are cognitive impairment and psychotic symptoms that impede the planned use of risk precautions for sexual activity and injection substance use—and present special difficulties to control in this population. Another issue of import not addressed by the paper is the percentage of patients with co-infections—dual and triple, as mentioned earlier. HCV co-infection occurs in up to 25% of patients living with HIV in the United States. Worldwide, 10% of patients are co-infected with HIV and HBV, with an up to 20% HIV-HBV co-infection rate in Southeast Asia. The exact number of patients co-infected with HCV and HBV is unknown; in patients with chronic HBV infection, estimates of the rates of HCV co-infection vary from 9% to 30%. Finally, triple infection has been reported worldwide at a rate from 1%-7% ; hence, an attempt to dissect out the population living with SMI by these specific co-infection rates would be of interest. In addition to the cognitive impairment associated with chronic HIV infection, acute infection may also present with psychosis. New onset of psychosis can also emerge in chronically persons living with HIV, with methamphetamine use, in particular, being a significant risk factor. It cannot be concluded that only the typical risk factors apply to this patient population when the factors that would be specific to patients living with SMI contributing to their risk have not been taken into account (e.g., cognitive impairment and psychotic symptom severity). Frequently, patients living with SMI are managed while experiencing chronic cognitive impairment that might impede their adherence to antipsychotic medication therapy, which can result in ongoing psychotic symptoms that can prevent them from accessing and implementing precautions for preventing these infections. Future research should aim at assessing the contributions of these factors to additional risk for these infections in SMI patients. Health providers should discuss sexual health and risk for blood-borne viral infection with SMI patients and offer HIV testing to all patients 13 to 64 years of age at least once in their lifetimes and should offer HCV testing to all adults born from 1945 through 1965 once (without prior ascertainment of HCV risk factors) in the United States. HBV screening should be offered under specific circumstances, as recommended by the Centers for Disease Control and Prevention (CDC). Ongoing risk should result in more frequent testing per CDC recommendations for these infections. Worldwide screening recommendations for these infections may be accessed through the World Health Organization.




Psychosocial Issues in Persons Living With HIV


Childhood sexual experiences have been linked as a strong predictor to psychological distress as well as risk of substance abuse and HIV transmission risk. Among men who have sex with men (MSMs), those with a history of childhood sexual abuse were more likely to engage in high-risk sexual behaviors including unprotected receptive anal intercourse, trading sex for money or drugs, reporting HIV seropositive status, and experiencing nonsexual relationship violence. In addition, when confronting this group of at-risk individuals, it is useful to distinguish between forced childhood sexual abuse and consensual childhood sexual experiences. Individuals who experienced forced sexual contact have the highest risk of these three factors as compared with the consensual group who demonstrated only increased rates of substance abuse and HIV transmission risk compared with a no-exposure group. Thus, an assessment of these groups should include a discussion of patterns of risk exposure and childhood sexual exposure to better tailor interventions to the specific individual.


The role of past trauma in placing individuals at risk of HIV has also been found in large populations of women living with HIV. Hutton identified that among women prisoners, HIV risk behaviors in the 5 years preceding incarcerations included unprotected sex (56%), injection substance use (42%), sexual intercourse with a partner who injected drugs (42%), prostitution (30%), needle sharing (30%), receptive anal sex (19%), and having more than 100 sex partners (7%). After adjusting for age, education, race, HIV serostatus, and addictive disorders, posttraumatic stress disorder was associated with the practice of receptive anal sex and prostitution and appeared to contribute to these high-risk activities.


In addition, Myers identified an association between greater frequency of severe SUDs and increasing rates of HIV infection, depressive disorders, and higher chronic disease burden among women. Similarly, severe alcohol use disorder and trauma have been associated with increased depression and social instability in this group as well. It is important to note that both childhood trauma and depression severity appear to exacerbate ineffective and avoidant coping strategies, which may predispose this group to additional burdens of depression and disease throughout life. Likewise, among nonadherent women who are prescribed effective ART, the use of cocaine and heroin and a history of SUDs decreased the likelihood of acceptable adherence to effective ART. These items taken alone or together illustrate not only the need for substance abuse programs but also the important role of sexual abuse prevention efforts and abuse treatment strategies in at-risk groups.


Other data support a high prevalence of depression and substance use disorder among persons living with HIV enrolled in methadone maintenance treatment programs or needle exchange. Depression is extremely common in these programs, and one study has estimated rates as high as 54%. Women, persons with a comorbid alcohol abuse diagnosis, and those with diminished social support were more likely to be depressed, even after controlling for age, race, education, and HIV status. Those enrolled in methadone programs showed significantly less depression than similar participants in a needle exchange program.


Three predictors have been conceptualized as an stressor-support-coping model as follows. Life stressors (especially when unpredictable, uncontrollable, and chronic) are associated with greater distress. Social support (especially if available, satisfactory, and sufficient to the situation) may have both direct and indirect effects on reducing distress, the latter by buffering the negative impact of life stressors. Passive, maladaptive coping styles such as denial, or mental or behavioral disengagement (e.g., drinking alcohol or using substances to manage a stressor) may be expected to increase distress, as has been shown in persons living with HIV. In contrast, active coping strategies (e.g., taking action or reduce stressor impact, or creating a plan to cope with a stressor; positive reinterpretation and finding meaning in a stressor) may be expected to decrease distress.




Hepatitis C Virus (HCV) Infection


Another complicating factor that commonly exists in dually diagnosed individuals with HIV disease is the concurrent diagnosis of HCV infection, yielding the quadruply diagnosed. Large observational retrospective cohort studies in high-risk populations have demonstrated that approximately 25% of persons living with HIV are co-infected with HCV; the co-infected group is characterized by being older minority men more likely to acquire HIV through intravenous substance use. In addition, individuals co-infected with HIV and HCV are more likely to have a diagnosis of a depressive disorder, alcohol or substance use disorder, and a history of “hard-drug” use compared to the HIV monoinfected. Co-infected individuals are also less likely to have received effective ART during the previous year.


In one study of 293 patients being seen for an initial hepatology visit, 93% had a current or past history of at least one psychiatric disorder, and 73% carried at least two psychiatric disorder diagnoses. The most common disorders included depressive disorders (81%), posttraumatic stress disorder (62%), any substance use disorder (58%), bipolar affective disorder (20%), and other psychotic disorders (17%); in addition, 61 patients (21%) had AUDIT-C alcohol screening test scores indicating current, heavy alcohol use.


Neurocognitive Impairment Related to Substance Use Disorder, Other Psychiatric Disorder, HIV Infection, and HCV infection


Previous alcohol use disorder has been demonstrated to be linked with additive levels of cognitive dysfunction in populations living with HIV. Significant and synergistic interactions in the realm of reaction time (representing the domain of information processing speed) have been noted in populations living with HIV with a history of alcohol use disorder. There may also be neurocognitive complications of SUDs, including effects from both recreational and prescribed use of psychoactive substances as well psychoneurotoxicity of antiretroviral medications and cancer chemotherapy. Substance-induced NCI is of greatest concern regarding psychostimulant use, particularly cocaine and methamphetamine, but also is related to opioid use. Opioid use disorder is associated with NCI spanning multiple domains that may negatively affect daily psychosocial function and response to SUD treatment.


Of psychiatric disorders other than SUDs, MDD is the most common in the setting of current SUDs, HIV infection, and HCV infection. It is defined, in part, by neurocognitive symptoms—that is, by impaired memory and concentration. A systematic review and meta-analysis of cognitive function assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) battery in patients with MDD revealed significant, moderate neurocognitive deficits in executive function, memory, and attention in patients with MDD relative to controls (effect size d = −0.34 to −0.65). Significant, moderate deficits in executive function and attention ( d = −0.52 to −0.61) and nonsignificant, milder deficits in memory ( d = −0.22 to −0.54) were found to persist in remitted patients, suggesting that mild cognitive impairment (MCI) may occur separately from the episodes of MDD themselves.


One of the common complications of HIV infection is NCI. Numerous studies indicate the percentage of individuals living with HIV and having any NCI during the course of their infection to be 39%–54% overall, despite greater access to effective ART, with much fewer in recent studies meeting the criteria for HIV-associated dementia (HAD). Given these prevalence rates, clinicians working with patients living with HIV must screen for signs indicating the presence of NCI regardless of the lack of any associated symptoms; in turn, with a positive screen, a referral for a formal neuropsychological evaluation to fully delineate the etiology of the NCI is indicated. An assessment for associated deficits in functional status—as indicated by a decline in activities of daily living—is also warranted, as is the development of a treatment plan geared toward improving cognition and daily life function. HIV infects the brain during the initial stage of infection as part of the natural course of the infectious process and may eventually cause HIV-associated neurocognitive disorder (or HAND). HAND represents a spectrum proceeding from asymptomatic neurocognitive impairment (ANI) to mild neurocognitive disorder (MND) on to HIV-associated dementia (or HAD). Today, data show that ANI is the most common HAND condition; however, as the mildest one of the spectrum, there is frequent lack of its recognition. Likewise, MND may frequently be overlooked by the primary care provider who is not actively screening for NCI. As a whole, HAND is currently very common but less severe than it had been prior to the era of effective ART. Thus, it could be characterized as an “invisible epidemic.” The criteria defining these disorders were reviewed at the Frascati Conference, where HAD was defined by standardized testing as two standard deviations (SDs) or greater below demographically corrected means on at least two neurocognitive domains. Furthermore, in HAD, NCI must be associated with at least moderate interference with activities of daily living/functional status. For MND, the cognitive impairment must be documented by a milder decrement in standardized test performance of at least 1.0 SD below demographically corrected means on at least two domains and not meet the criteria for dementia (2 SDs or greater below demographically corrected means). This impairment must, in turn, be associated with at least mild decrements in functional status. Like MND, the newly coined condition of ANI is documented by NCI on standardized test performance of 1.0 SD below demographically corrected means on at least two domains and not meeting the HAD criteria; however, in contrast to MND, the NCI associated with ANI does not interfere with functional status. Hence, the designation of ANI is more fittingly described as a condition rather than a disorder or disease. For all of these conditions, there should be no evidence of another preexisting cause, including systemic and CNS opportunistic infections and tumors, non–HIV-associated neurological disease, metabolic causes, CNS toxicities due to prescribed medications, and potentially confounding psychiatric disorders (e.g., major depressive disorder and alcohol or SUDs). Screening tests useful for NCI in the general population, such as the Mini-Mental State Examination (MMSE) and (to a lesser extent) the Montreal Cognitive Assessment, do not perform particularly well among patients living with HIV. Disease-specific tests such as the HIV dementia scale (HDS), the Modified HIV Dementia Scale (m-HDS), and the International HIV Dementia Scale (IHDS), may be used but have recognized limitations as well. Thus, there is no single best screening test for HAND. Moreover, there are no US Food and Drug Administration (FDA)–approved specific treatments for HAND. Clinically, the first line generally used is the CNS-penetrating ARVs and the second line is the psychostimulants. Similarly, for HCV-associated NCI, the first-line treatment considered is the DAAs (or direct-acting antivirals).


Individuals with HIV and HCV co-infection may incur more substantial NCI than that occurring with either infection alone. Both HIV and HCV infections can deleteriously impact CNS processes. More specifically, and like HIV infection, HCV infection has been linked to increased depressive disorder rates and impairment in health-related quality of life—independent of the severity of associated liver disease and the related metabolic effects. Regarding HCV infection, the direct and detrimental CNS impact of HCV infection on the domains of attention, concentration, and information processing has been well documented ; notably, all of these deficits are consistent with the deleterious effects, too, of HIV infection. Extensive evidence attests to the impact of inflammation on the pathophysiology of all three disorders.


The impact of MDD itself on neurocognitive performance in populations living with HIV should not be overlooked. Published studies are scarce as of yet, but do support the link of MDD with NCI in HIV infection. Neurocognitive performance across multiple domains appears impaired on the latter group—including attention, neurocognitive flexibility, and motor speed. These results illustrate the potentially synergistic combinations of neurocognitive effects that triply diagnosed individuals may experience, which are further exacerbated in the quadruply diagnosed (with HCV infection as well). Along with the need for an exquisitely high level of clinical suspicion for neurocognitive disorders in this group of patients, it is especially important to recognize their associated deleterious impact on medication adherence—not only to ART for HIV treatment but also to the DAAs used in HCV treatment, and, in turn, on mortality. Even when suppression of plasma HIV load is attained long-term and sustained virologic response (SVR) is achieved with HCV treatment, the negative impact of the associated inflammatory processes may nevertheless make themselves known clinically. Thus addressing both HIV- and HCV-induced neurocognitive deficits will likely continue to be of high importance in the dually diagnosed psychiatric patient population.

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Jan 19, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Quadruple Diagnosis: Substance Use Disorder, Comorbid Psychopathology, Human Immunodeficiency Virus Infection, and Hepatitis C Virus Infection
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