JAIDS Journal of Acquired Immune Deficiency Syndromes:
Infectious Disease Comorbidities Adversely Affecting Substance Users With HIV: Hepatitis C and Tuberculosis
Friedland, Gerald MD
From the AIDS Program, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT.
Supported by grant R01DA025932-01, from the National Institute on Drug Abuse, National institutes of Health.
Correspondence to: Gerald Friedland, MD, AIDS Program, 135 College St, New Haven CT 06437 (e-mail: firstname.lastname@example.org).
The linkage between drug use, particularly injection drug use, and HIV/AIDS, hepatitis C (HCV), and tuberculosis (TB) has been recognized since the beginning of the HIV pandemic. These comorbid conditions affect drug users worldwide and act synergistically, with resultant adverse biologic, epidemiologic, and clinical consequences. Prevention, care, and treatment of TB and HCV can be successful, and both diseases can be cured. Special clinical challenges among drug users, however, can result in increased morbidity, mortality, and decreased therapeutic success. Among these are limited disease screening, inadequate and insensitive diagnostics, difficult treatment regimens with varying toxicities, and complicated pharmacokinetic and pharmacodynamic drug interactions. These may result in delayed diagnosis, deferred treatment initiation, and low completion rates, with the potential for generation and transmission of drug resistant organisms. Strategies to address these challenges include outreach programs to engage substance abusers in nonmedical settings, such as prisons and the streets, active screening programs for HIV, HCV, and TB, increased and broadened clinician expertise, knowledge and avoidance of drug interactions, attention to infection control, use of isoniazid preventive therapy, and creative strategies to insure medication adherence. All of these require structural changes directed at comprehensive prevention and treatment programs and increased collaboration and integration of needed services for substance abusers.
Substance abusers were at an increased risk of mortality and morbidity before the HIV epidemic.1 HIV/AIDS, however, has increased rates and severity of a wide array of comorbid conditions among drug users, including psychiatric, neurologic, hepatic, renal and pulmonary, and infectious diseases. This article focuses on hepatitis C virus (HCV) and tuberculosis (TB), as these coinfections are responsible for most of the morbidity and mortality among HIV-infected drug users worldwide. HCV is a particular concern in the United States and in industrialized countries of Western Europe, although rates of TB in these countries have fallen sharply. In Eastern Europe and in many of the most populous countries of Asia, HCV is widespread. In these countries, injection drug use (IDU) is an increasingly significant contributor to the spread of HCV, TB, and HIV/AIDS.
HEPATITIS C VIRUS
Epidemiology and Transmission
An estimated 130-180 million people are infected with HCV worldwide. HCV infection is the most common blood-borne infection in the United States, with an estimated 3.2-4.1 million chronically infected persons nationwide.2-4 Approximately 20%-30% of people living with HIV/AIDS and 60%-90% of IDU are coinfected with HCV in the United States.5,6 High rates of HCV coinfection have been reported in China7 and in other Asian countries and in countries of the former Soviet Union.8 IDU is the predominant mode of HCV transmission and accounts for more than 60% of new cases in Western countries.2 HCV titers in blood are significantly higher than those of HIV, and as a consequence HCV is transmitted more easily than HIV through the sharing of drug using paraphernalia. Acquisition of HCV is common among new and younger IDU, with incidence rates ranging from 10 to 40 per 100 person-years.9 Although far less common sexual transmission of HCV has recently been reported among gay men, and often in the context of non-IDU.
HCV is a major cause of morbidity and mortality among IDU, and is adversely affected by HIV at various points in its natural history. First, spontaneous recovery from HCV infection occurs in 15%-35% of those who are monoinfected, but only 5%-10% of those coinfected with HIV.10 Second, the long-term consequences of HCV infection, including cirrhosis, hepatic failure, and hepatic carcinoma are increased with HIV infection. HCV has become the principal cause of death from liver disease in the United States,11 and after HIV/AIDS, the second leading cause of death among those with HIV infection.12 HIV is associated with more rapid progression of cirrhosis and end-stage liver disease (ESLD).13,14 Coinfected persons have a 6-fold relative risk of ESLD and a 2-fold relative risk of cirrhosis compared with HCV infection alone, leading to a 15%-25% prevalence of cirrhosis within 10-15 years of infection.15 Factors contributing to accelerated fibrosis progression include low CD4 counts, detectable HIV-1 RNA levels, use of hepatotoxic medications, and frequent alcohol use.16 Compared with other people living with HIV/AIDS, IDU are more likely to present with advanced disease, poorly controlled HIV, alcohol use, and accelerated progression to ESLD. Although HIV accelerates HCV disease progression, it remains unclear if HCV accelerates the progression of HIV disease. This may result from a diminished ability to tolerate antiretroviral therapy (ART) among HIV-infected persons with chronic hepatic disease.14 Compared with monoinfected patients, increased risk of hepatocellular carcinoma has been found among those who are coinfected with HIV and HCV.11 The mean age for development of hepatocellular carcinoma in HCV monoinfected individuals is 69 years compared with a mean age of 42 years among persons coinfected with HIV.17
Diagnosis and Treatment
Because the prevalence of HCV is so high among IDU, all HIV-infected and noninfected IDU should be screened for HCV using a third-generation enzyme-linked immunoblot assay.2 Similarly, because persons with HCV have shared risk factors with HIV, HCV-infected patients should be tested for HIV. For patients who have HCV antibodies, testing should be done for HCV RNA because detection of viremia connotes active HCV disease. Staging of HCV infection usually requires liver biopsy to determine the degree of HCV-related fibrosis before offering treatment. Coinfected patients should be tested for antibodies to hepatitis B and A, and if found to be negative should be advised to receive immunization.
As opposed to HIV, HCV can be cured. Current therapeutic options for successfully treating HCV, however, remain limited and challenging, particularly in those coinfected with HIV and among IDU. The standard treatment for patients with genotype 1 (the most common circulating type in the United States) is the combination of pegylated interferon, given weekly, and weight-based daily ribavirin, given for a total of 48 weeks.2,17 Sustained virologic response (SVR), defined as negative serum HCV RNA 6 months after completion of therapy, is achieved in approximately 50% in monoinfected patients with genotypes 1 and 4 and in approximately 70% among patients with genotypes 2 and 3 (more commonly found in Europe and parts of Asia). For patients coinfected with HIV, SVR is approximately 41% among all patients, but only 29% in those with genotype 1, including IDU.17,18 In substance abusers and coinfected patients, SVR rates are lower, and side effects and dropout rates are higher. Side effects include anemia from ribavirin, granulocytopenia, fatigue, depression, and other neuropsychiatric effects from interferon. In addition, use of ART for HIV coinfection has been shown to increase risks of drug-related hepatoxicity.17
The timing of HCV treatment is important for HIV coinfected patients. Although there is often an urgency to begin HCV treatment, many experts recommend stabilization of HIV disease with ART, despite potential toxicities, before embarking on a course of HCV treatment.2,17,18 Because HIV infection accelerates the progression of HCV-related liver disease, treatment of chronic HCV infection is generally recommended for coinfected patients, including IDU. Despite this, there is limited access and uptake of HCV treatment by IDU and most remain untreated. This may be related in part to inadequate systems for surveillance of HCV in the community and clinical care setting, particularly among IDU.11,20 Even among those in care with known HCV infection, treatment is the exception. In a recent study, only 6% of HCV-infected IDU in care received treatment.20 Clinicians were found to be reluctant to offer treatment, citing lack of expertise, poor treatment adherence, perceptions that HCV infection will remain asymptomatic, concerns about the complexity and toxicity of treatment, and pessimism about HCV treatment tolerability and the likelihood of successful outcomes for IDU.19 Nevertheless, there is a growing body of literature demonstrating that treatment success is possible among coinfected IDU, particularly in the context of drug treatment21-23 and in carefully managed HCV and HIV treatment programs among incarcerated populations.24
Treatment for coinfected IDU carries risks that need to be balanced with potential benefits. Withholding a life-saving therapy for a specific population, such as IDU, is unethical.25 Recent treatment recommendations have been developed that take into account the importance of individualization and the need to address substance use and psychiatric comorbidities in HCV, before and during treatment.2
New antiviral therapy for HCV is urgently needed. A pipeline of new anti-HCV drugs is now in various stages of development, including HCV-specific protease and polymerase inhibitors, some of which are in advanced-stage to late-stage clinical trials. These will likely help to improve the outcomes of HCV treatment in the future, although because of risks for rapid selection of resistant mutants, such therapies will likely require coadministration with currently available therapies, that is, interferon and ribavirin. Further, most agents have been or are being studied in monoinfected patients. Little information is available regarding the therapeutic response or toxicities among coinfected persons and IDU.
Clearly, prevention of HCV is a priority in light of the limited treatment options for HCV disease among IDU, with and without HIV. The Institute of Medicine recommends that government agencies expand programs to reduce the risk of HCV infection among IDU by providing comprehensive HCV prevention programs (Table 1).11 These should include access to sterile needle and syringes and drug-preparation equipment and increased testing to detect HCV infection. In addition to supportive treatment environments and increased provider expertise, a comprehensive and holistic clinical approach is needed, one that attends to factors that contribute to progression of HCV disease and which are amenable to intervention, including ART, avoidance of hepatotoxic agents (which does include some ART medications), and the avoidance of alcohol.
Epidemiology and Transmission
Mycobacterium tuberculosis infection is present in an estimated one-third of the world's population or roughly 2 billion people. In the past year, there were an estimated 8-9 million new cases of TB, leading to 2-3 million deaths.26 TB and HIV have been tightly linked since the early years of the HIV/AIDS epidemic.27 Worldwide, TB is second only to HIV/AIDS in causing death from a communicable disease,28 and among those with HIV infection, TB is the most common opportunistic infection and major cause of morbidity and mortality.29 IDU in developed countries have rates of latent TB infection (LTBI) approaching 30%, and are 2-6 times more likely to contract TB compared with nonusers. One third of IDUs with TB are estimated to be HIV infected.30,31 Patients with TB and HIV infection are 5 times more likely to die during anti-TB treatment compared with patients who are HIV negative.30 TB incidence has fallen or stabilized among IDU in many industrialized countries but not in Eastern Europe and countries of the former Soviet Union.29
There are 2 major reasons why HIV-infected IDU have an increased risk of TB. First, HIV-induced immunosuppression results in high rates of LTBI reactivation among co-infected IDU. This is estimated to occur at an annual rate of 8%,32 similar to the lifelong risk in HIV-negative populations. Second, TB transmission occurs in settings that are crowded and poorly ventilated, such as those that are often populated by IDU (eg, prisons, drug treatment programs, homeless shelters, and soup kitchens).33,34 IDU may also be more contagious because of advanced TB, unattended disease, and higher rates of treatment failure.31
Diagnosis and Treatment
Diagnosis and treatment of TB in IDU in the context of HIV infection present numerous health and medical challenges. HIV reduces the sensitivity of TB diagnostic tests, including the tuberculin skin test and interferon-gamma release assays. In late stages of HIV, pulmonary disease presents in atypical fashion and the sputum smear, the most common diagnostic tool worldwide, becomes increasingly insensitive. In addition, extrapulmonary TB, notoriously difficult to diagnose, increases to close to 50% of cases. TB laboratory diagnostic tests are outmoded and cumbersome, and their availability is limited worldwide, which adversely affects vulnerable populations such as IDU. Even when available, current TB culture and drug-sensitivity testing can take weeks to months. Thus, TB diagnosis among IDU with and without HIV infection is often not confirmed or is delayed, leading to high rates of morbidity and mortality and ongoing transmission in congregate and public settings.33
When properly implemented, TB treatment can be highly successful, with cure rates of greater than 95%. The standard TB regimen worldwide includes a 2-month intensive phase of 4 drugs, designated as the “first-line” drugs, isoniazid (INH), rifampin or rifampicin, ethambutol, and pyrazinamide. This is followed by a continuation phase of INH and rifampicin only daily for 4 months, administered most effectively by directly observed therapy. Reasons for lower rates of treatment success among IDU include TB program deficiencies, poor patient medication adherence, increased toxicity, and high rates of patient attrition.
Emergence of TB drug resistance is particularly notable in countries with large populations of IDU.35 Multidrug-resistant TB (MDR TB), defined as resistance to at least the first-line drugs INH and rifampin, and extensively drug resistant TB, (XDR-TB), defined as MDR TB plus, resistance to the “second line” fluoroquinalones and injectible agents, are becoming increasingly common and recognized globally. WHO estimated in 2007 that there were more than 500,000 incident cases of multidrug-resistant and 1 million prevalent cases and 40,000 incident cases of XDR-TB.35 China, India, and the Russian Federation are countries where IDU contributes significantly to high HIV and TB rates and together accounted for an estimated 62% of the global burden of TB drug resistance.35 Drug resistant TB is a product of treatment failure and transmission of resistant organisms to susceptible hosts in congregate settings, such as hospitals, drug abuse treatment programs, and prisons. Hence, it would be expected that drug users would be disproportionately represented among patients with drug-resistant TB; these patients are at increased risk of treatment failure and mortality when they are also HIV infected.36 Available drugs and regimens are less potent, more complex, more toxic, and more expensive; and they require administration for longer periods of time, such as 4 or 5 drug combinations over a period of 18-24 months. A recent report on XDR-TB in HIV-infected patients in South Africa37 has renewed global awareness of drug-resistant TB and the threat it poses to individual patients and to public health, further challenging the success of TB, HIV/AIDS, and substance abuse treatment programs.38
Treatment of drug susceptible and drug-resistant TB among IDU, particularly in the context of HIV, can be complicated by additive toxicities, the immune reconstitution syndrome, and drug interactions. Highly prevalent hepatic, renal, neurological, psychiatric, gastrointestinal, and hematologic comorbidities among IDU1 can increase the risks for drug toxicities (Table 2). Immune reconstitution syndrome occurs in all populations with TB and HIV coinfection as a result of immune restoration after ART administration, which uncovers unsuspected TB or the worsening of already diagnosed TB. These complexities have resulted in concerns regarding the treatment of TB and HIV simultaneously, however, observational and demonstration studies39,40 and a recently completed randomized controlled trial41 make clear that concomitant treatment of HIV and TB is feasible, safe, and life saving and is associated with reductions in mortality of 55% among coinfected patients.
The provision of care and treatment of drug users with TB is complicated by well-known and problematic pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions among TB drugs, ART, and therapies for substance abuse (Table 3). Drugs used for the treatment of each of these diseases share metabolic pathways (ie, cytochrome P450, isoenzymes 3A4, and 2D6, and UGT1A1 enzymes) which can result in drug interactions that diminish the effectiveness of one, both, or all 3 therapies, producing opiate withdrawal or excess, or in different levels of anti-infective agents, with corresponding decreases in their therapeutic effects or increases in their side effects and toxicities.42-47
Rifampin, an important component of standard TB regimens, is a powerful inducer of hepatic enzymes46,48 and results in interactions with both substance abuse and HIV therapies. The PK and PD interaction between rifampin and methadone has been known for more than 40 years. In 1976, Kreek et al49 showed that 70% of patients receiving methadone and being treated for TB developed symptoms and signs of opiate withdrawal, whereas those patients receiving nonrifampin TB regimens had no withdrawal symptoms. Methadone plasma levels were 33%-68% lower during rifampin treatment. This interaction complicates the treatment of TB among opiate-addicted patients. Opiate withdrawal is often either not suspected by clinicians or discounted. This important drug interaction can be avoided by the substitution of rifabutin for rifampin because the former is less capable of inducing hepatic enzymes.46 Unfortunately, rifabutin is expensive and only available in developed countries, meaning that IDU in other parts of the world are usually unable to receive one of the better treatments for opiate addiction and TB. Rifampin also reduces levels of ART, including the nonnucleoside reverse transcriptase inhibitors, efavirenz and nevirapine,46 although the former has been found to remain effective in this context.50 Rifampin dramatically lowers levels of all protease inhibitors, further limiting treatment options for IDU patients who are TB and HIV coinfected. Opiate substitution therapies have minimal PK and PD effects on TB or antiretroviral therapies. Methadone levels, however, are markedly reduced by efavirenz and nevirapine, which may lead to moderate to severe opiate withdrawal; methadone levels may also, but to a lesser extent, be reduced by protease inhibitors.44 The integrase inhibitor raltegravir does not affect methadone levels. Buprenorphine, another opiate substitution therapy, has not been studied as thoroughly as methadone. Research suggests that PK interactions may occur between buprenorphine and ART, but that they are less frequent and less severe than they are with methadone.43
Structural and behavioral impediments can confound treatment success. Substance abuse treatment is often prerequisite for successful HIV and TB treatment, but lack of access to effective drug treatment is also common where these comorbid conditions occur. Resultant poor adherence to therapy, decreased retention in care, and poor continuity of care are also frequent, which increases risk for TB and HIV drug resistance.
The World Health Organization has elaborated a new strategy for control of TB in IDU and other populations.51 It includes the “3 Is”: intensive case finding using community-based screening for early identification of HIV and TB, infection control to reduce transmission of TB in community and health care settings, and INH preventive therapy to reduce reactivation of LTBI.
IDU are often wary of traditional medical settings, preferring to use emergency rooms intermittently and only when sick. Stigma, fear, and multiple comorbidities may contribute to this reluctance, resulting in delayed entry into care and treatment. Intensified TB case-finding among IDU in nonmedical settings, such as prisons, homeless shelters, and drug treatment programs, may help to address this issue.51 Screening for HCV, TB, and HIV and interventions to prevent disease and provide early treatment could have an impact on the community spread of these infections and their ensuing morbidity and mortality. For TB, air-borne infection control is a well-recognized way to prevent the spread of infection, yet it is poorly implemented.33 Enhanced airborne infection control in congregate settings can reduce the likelihood of drug-susceptible and drug-resistant TB transmission to IDU. Three major areas of infection control, administrative, environmental, and personal protective measures offer practical and feasible strategies to reduce the nosocomial and community-based transmission spread of TB.33,34 Preventive treatment for LTBI has been promoted as a method of reducing the incidence of active TB among HIV-infected patients in whom active disease has been ruled out, but only INH has been shown in randomized controlled trials to be efficacious and safe for this purpose. However, administration is prolonged (6 months to 1 year), with a risk of hepatitis and poor adherence. The greatest benefits have been achieved among adults who were tuberculin skin test positive, with a 62%-70% reduction in the development of active TB and a 20%-25% reduction in mortality. Despite this recommendation, worldwide estimates suggest that only 0.08% of patients with HIV who have been screened have received INH preventive therapy.51 Demonstrated success with drug users has been noted but it requires ongoing substance abuse therapy to achieve completion. Drug treatment programs have been shown to be effective as sites for delivering INH preventive therapy as a preventive measure. Use and adherence on ART has also been shown to reduce the risk of acquisition of TB in areas of high MTB prevalence.
Comorbidities contribute to the substantial global burden of disease experienced by drug users with HIV, and HCV and TB are the most important of these. Effective strategies for screening, prevention, and treatment exist, and both HCV and TB can be prevented and cured, but there are often social, economic, and political barriers that limit the accessibility of these services to drug users, thereby adversely impacting public health (Table 1 and 2). A comprehensive approach that includes drug abuse treatment and HIV testing, treatment, and care holds the greatest promise for screening, treating, and curing drug users with HCV and TB infections because this would ultimately reduce the spread of HIV, HCV, and TB to the population.52,53
The author is grateful for the assistance of Drs Monica Mercon and Robert Douglas Bruce in preparation of this article.
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HIV HCV; substance abuse; TB
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