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3rd International Workshop on Clinical Pharmacology of HIV Therapy



The HIV-Infected Substance Abuse Patient as a Research Subject

Gerald H. Friedland, MD
Yale University School of Medicine, New Haven, Connecticut

Baseline demographic features, including geography, can sharply separate HIV-infected injection drug users (IDUs) from the population of HIV-infected gay men. Dr. Gerald Friedland illustrated that point by showing two maps of AIDS incidence in New York City in the 1980s with zip codes of highest proportions of new AIDS cases. One showed incident cases of AIDS in IDUs, the other in gay men. Except for one or two neighborhoods, there was no overlap. This underlies the great differences in race, sex, socioeconomic status among these two populations of people with HIV disease in the United States.

The estimated number of IDUs with AIDS rose from about 50,000 in 1991 to about 110,000 in 2000. Dr. Friedland expects that increase to continue. HIV affects IDUs beyond the US as well. IDU is the major risk for HIV infection in parts of Latin America, Europe and Asia, and high percentages of IDUs in these areas have HIV infection. IVDU and HIV infection as a consequence has now appeared in parts of southern Africa.

Under-representation of IDUs in clinical trials

Despite representing a high proportion of infected people on every continent, IDUs have not been proportionately represented in clinical trials. As a result, Dr. Friedland noted, problems unique to drug use and antiretroviral therapy have not been well studied. The same is largely true for diseases specific to substance abusers.

Dr. Friedland traced the low rate of IDU participation in clinical trials to four factors.

  • Structural, demographic, or attitudinal concerns
  • Behavioral issues
  • Sexual or reproductive issues (a reasonable proportion of IDUs are women, who were excluded from many early trials)
  • Medical exclusion criteria

The rationale for excluding IDUs from trials has evolved over the past two decades, Dr. Friedland noted. At first a history of substance abuse was enough to keep an HIV-infected person out of a trial. Eventually that proscription changed to "active substance abuse," usually as judged by the investigator. Most recently, exclusion from trials has rested on the investigator's anticipation of a person's poor compliance with the study protocol.

Dr. Friedland listed the percentage of IDUs enrolled in a few North American and European trials, as well as in studies conducted by two US research groups, the AIDS Clinical Trials Group (ACTG) and the Community Programs for Clinical Research on AIDS (CPCRA).

Percentage of IDUs enrolled in specific trials and in studies of two trials groups

Network or trial Percentage of IDUs enrolled
ACTG 13.2
CPCRA 23.3
Delta (Europe) 12 (n = 3207)
Caesar (Canada, Australia, Europe, South Africa) 13 (n = 1840)
DuPont 006 (US, Canada, Germany, Puerto Rico) 12 (n = 1266)

Those percentages do not match the proportion HIV-infected people in the US who acquired their infection by injection drug useľabout 30%. Despite the low percentage of IDUs in the Delta study, Dr. Friedland noted, IDUs make up about 20% to 30% of more recent European trial populations, proportions reflecting the high percentage of HIV-infected IDUs in southern Europe.

Burden of comorbidities among IDUs

Dr. Friedland outlined the health status and comorbidities of IDUs:

  • The population is heterogeneous, but most IDUs have a low socioeconomic status.
  • Overall age-specific morbidity and mortality among IDUs is 10 to 20 times higher than among non-IDUs.
  • IDUs have an increased rate of a wide array of diseases, including:
    • Trauma
    • Neurologic disorders
    • Hepatic, renal, and pulmonary diseases
    • Psychiatric problems
    • Drug-related complications
    • Infectious diseases

In one survey of 375 IDUs, 24% had been diagnosed at least once with skin abscesses, 23% with pneumonia, and 10% with endocarditis.

Approximately 20% to 50% of people with HIV/AIDS have severe mental illness, five times the rate in the general population. The prevalence of mental illness is even higher among substance abusers with HIV infection. From 20% to 40% of HIV-infected substance abusers suffer from major depression.

A survey of a cohort of 4042 HIV-infected people selected to represent the entire US HIV population documented high rates of substance abuse [1]. About 45% of the cohort had a history of drug abuse; over 30% had used marijuana; over 20% had injected drugs; and about 10% had abused sedatives, cocaine, or alcohol. More than 35% had at least one mental disorder, and over 25% had depression or received mental health care. Approximately 10% had a history of generalized anxiety disorder or panic disorder.

The IDU-HIV-HCV triad

In many IDU populations, substance abuse, HIV infection, and hepatitis C virus (HCV) infection constitute a challenging triad, with these characteristics:

  • The prevalence of HCV infection ranges from 50% to 80% among IDUs.
  • Hepatic disease has become the major cause of morbidity and mortality among HIV-infected IDUs.
  • HCV accelerates the natural history of HIV infection.
  • HIV accelerates the natural history of HCV infection.
  • Treatment of HIV infection complicates treatment for hepatitis, and vice versa.

Treatment of both HIV infection and HCV infection improved dramatically with the introduction of potent antiretroviral combinations and interferon plus ribavirin. But research has yet to yield much information on coinfection with these two viruses, partly because hepatitis often excludes HIV-infected people from antiretroviral trials. At the same time, active drug use excludes people from HCV therapy trials. Dr. Friedland called for more research of coinfected individuals.

Pain management remains a problem in people with AIDS and can be a particular problem for IDUs. One study of nearly 600 people with AIDS and 600 with cancer determined that 16% of the AIDS patients had adequate pain control compared with 58% of the cancer patients [2]. Poor pain management breeds distrust in patients and inclines them to avoid clinical trials.

Treatment adherence among IDUs

Injection drug use can negatively influence adherence with treatment. In Vancouver injection drug use decreased adherence by 58%, and poor adherence correlated with increased mortality [3]. Another study isolated two independent predictors of antiretroviral treatment acceptance, trust in physicians and trust in medications. In this study a survey of 200 IDUs recorded the following findings:

  • 77% believe antiretrovirals to be harmful when taken with heroin or cocaine.
  • 67% will not take antiretrovirals if planning to get high on drugs.
  • 61% believe antiretrovirals are harmful when taken with methadone.
  • 60% have seen people suffer side effects and die after starting antiretrovirals.
  • 59% have seen people suffer side effects and die after stopping street drugs.

Other work has confirmed the intuitive assumption that the tolerability of antiretrovirals directly affects the success of these regimens [4]. And unfortunately many clinical problems among substance abusers overlap antiretroviral side effects:

Overlap between substance abuse problems and antiretroviral toxicities

Clinical problem/toxicity Antiretroviral involved
Psychiatric Efavirenz, AZT
Gastrointestinal Protease inhibitors, AZT
Hepatic Protease inhibitors and NNRTIs
Neurologic ddI, d4T
Renal Indinavir
Hematologic AZT

Design issues and recommendations

Dr. Friedland outlined nine design and methodologic issues that must be considered when planning drug interaction research addressing the needs of HIV-infected substance abusers:

  • In-vitro versus In-vivo studies
  • Within-subject versus between-subject studies
  • Opiate-dependent versus non-opiate-dependent trial participants
  • Single-dose versus steady-state pharmacokinetic studies
  • Restriction of other medications (including smoking and coffee)
  • Inpatient versus outpatient studies
  • Urine drug screening
  • Payment and coercion
  • Intravenous access

Dr. Friedland closed with the following recommendations:

  1. More studies of HIV therapeutics are needed in drug users, and the array of abused substances studied should be broadened to include both prescribed and illicit substances of abuse.


  2. When incorporating substance abusers into clinical trials, sufficient numbers should be obtained to enable stratification by substance abuse status.


  3. The overall clinical care of drug users should be improved with integration of medical, psychiatric, and substance abuse services. This in turn, will bring more drug users into HIV drug interaction and therapeutic trials.


  4. Side effect and toxicity profiles of HIV therapies in drug users should be better defined.


  5. The cadre of interested and expert researchers who bridge both substance abuse and HIV therapeutic areas should be increased.

References

  1. Turner BJ, Fleishman JA, Wenger N, et al. Effects of drug abuse and mental disorders on use and type of antiretroviral therapy in HIV-infected persons. J Gen Intern Med 2001;16:625-633.


  2. Rosenfeld B, Breitbart W, McDonald MV, et al. Pain in ambulatory AIDS patients. II: Impact of pain on psychological functioning and quality of life. Pain 1996;68:323-328.


  3. Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr 2001;28:47-58.


  4. Girard PM, Guiguet M, Bollens D, et al. Long-term outcome and treatment modifications in a prospective cohort of human immunodeficiency virus type 1-infected patients on triple-drug antiretroviral regimens. Clin Infect Dis 2000;31:987-994.

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