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