Intravenous drug use is a worldwide phenomenon, and it is a major risk factor for HIV infection in many parts of the world (sub-Saharan Africa being the most notable exception). Antiretroviral treatments and adequate clinical care have improved the quality of life for many HIV-infected people, but the morbidity and mortality rates of HIV-infected IV drug users are still ten to twenty times higher than those exhibited by members of other risk groups.

At the Community Forum on July 14, 1999, Dr. Gerald Friedland, Director of the Yale University AIDS Program, and Dr. Richard Gold of the St. Vincent's HIV Center discussed current issues in substance use and HIV therapy, presenting both the results of recent clinical trials and their own clinical observations.

Addressing Multiple Challenges

Dr. Friedland described the trio of problems faced simultaneously by many IV drug users: substance abuse, HIV infection, and psychiatric disorders. These three conditions are chronic and treatable, but because of complex care requirements, few IV drug users receive comprehensive treatment.

Antiretroviral treatment has been proven beneficial in the overall prognosis of HIV-infected individuals, but the benefits of treatment are not equally distributed among members of all risk groups, as members of some groups are less likely to access treatment. In a study conducted by S.A. Strathdee and colleagues, published in the Journal of the American Medical Association in 1998, it was determined that even in an environment in which antiretroviral therapies were offered free-of-charge, only 40% of the HIV-infected IV drug users studied had received antiretroviral medications. Furthermore, the majority (66%) of these patients received double combinations, even though triple combination therapy is known to be most effective in the treatment of HIV infection. The researchers found that among the HIV-infected IV drug users studied:

• Women were two times less likely to take antiretroviral medications than men.
• Patients enrolled in drug or alcohol treatment programs were three times more likely to take antiretroviral medications than those not enrolled in treatment programs.
• Patients with physicians who had the least experience treating people with HIV were five times less likely to take antiretroviral medications than patients with experienced physicians.

In order to successfully treat current and former IV drug users for HIV infection, care providers must be willing to go to patients, engaging them in treatment through non-traditional means. Dr. Friedland described the Community Health Care Van, a successful program reaching substance users in New Haven, CT. The van follows the city's needle exchange program van, and provides medical care, social work and substance abuse services, and HIV testing and counseling free-of-charge to community members.

Interactions between Methadone and Antiretroviral Medications

Substance abuse treatment can be pharmacologic, or it can involve self-help, support groups, acupuncture, or a combination of these methods. Methadone, the most commonly used and most effective pharmacologic treatment for opiate (heroine, morphine) addiction, has been in use since the 1960s. Methadone is an opiate agonist, which is a substance that binds to opiate receptors in the brain through chemical reactions. This process mimics the body's reaction to heroin without heroin's debilitating effects.

Participation in clinical trials by substance users and individuals on methadone maintenance therapy has historically been low, and little is known about the interactions between methadone and protease inhibitors (PIs - nelfinavir, saquinavir, fortovase, etc.) or methadone and non-nucleoside reverse transcriptase inhibitors (NNRTIs - efavirenz, nevirapine, and delavirdine). There is limited information regarding the interactions between methadone and the nucleoside reverse transcriptase inhibitors (NRTIs - AZT, 3TC, ddI, etc.), which is detailed below.

AZT and Methadone Interactions

The first study examining the interactions between methadone and AZT was published in the Journal of AIDS by E.L. Schwartz et al. in 1992. The results of this pharmacokinetic (drug interaction) study debunked the myth that "AZT eats methadone," that is, that AZT decreases methadone levels when the two medications are taken together. AZT has no effect on methadone levels, but methadone produces a 43% increase in the AUC (area under the curve - a measurement of drug levels in the body) of AZT when the two are used simultaneously. The results of the 1992 study were confirmed in a study by E.F. McCance-Katz et al., published in the Journal of AIDS in 1998. McCance-Katz's team recorded a 41% increase in the AUC of AZT when dosed with methadone, and stated that the study confirms that methadone-maintenance patients receiving standard ZDV [AZT] doses experience greater ZDV exposure . . . Increased toxicity surveillance and possibly reduction in ZDV dose are indicated when these two agents are given [together].

ddI, d4T, and Methadone Interactions

In pharmacokinetic studies of ddI, d4T, and methadone, methadone was shown to decrease the AUC of d4T by 18%, a clinically insignificant decrease. d4T did not alter methadone levels. When ddI and methadone were dosed together, the AUC of ddI dropped 60%, while the blood level of methadone was not affected. The decrease in ddI levels may have been attributable to the tablet formulation of ddI. Methadone slows gastrointestinal motility, and it is likely that the tablet stayed in the stomach for an extended period and was destroyed by stomach acid before the medication was released into the blood stream. Other formulations of ddI are under examination.

Protease Inhibitor and Methadone Interactions

Limited information is available regarding the interactions between both nevirapine and methadone and ritonavir and methadone. The FDA has 20 reports on file of nevirapine leading to opiate withdrawal. In an article published by F.L. Altice et al. in the journal AIDS in 1999, the authors described seven patients taking nevirapine and methadone together. Three of the seven patients experienced withdrawal symptoms, and a marked increase in methadone doses was required in order to maintain the therapeutic effect of the methadone.

In a study examining ritonavir and methadone, no interactions between the two substances were found. Data from this study may be flawed, however, as a methadone dose of 5 grams, about one tenth of the standard dose, was used in the study. More studies of specific interactions are necessary, as the nature of specific interactions cannot be anticipated or presumed.

Facilitating Treatment Success

Dr. Richard Gold spoke briefly about the issues of adherence and barriers to care for substance users. As an introduction, he made several comments about specific recreational drugs, and suggested Drugs in Partyland, a brochure produced by GMHC, as a resource for anecdotal evidence regarding drug interactions. A recent situation involved an individual who died after taking Norvir (ritonavir) and ecstasy. On autopsy, blood levels of ecstasy were discovered to be ten times higher than they would have been without Norvir present. Recreational drugs can also affect the virus directly. It has been shown that HIV replicates twenty times faster in the presence of cocaine than without it.

Adherence Issues

In his practice, Dr. Gold usually divides drug users into two categories, and has different treatment priorities for each group. For the "occasional dabbler," i.e., someone who uses recreational drugs infrequently, Dr. Gold focuses on harm reduction. For the "hard core" drug user, i.e., someone for whom drug use affects overall quality of life, Dr. Gold's first priority is for the patient to enter a drug treatment program. Dr. Gold views HIV infection as secondary to drug addiction, and believes that the treatment of HIV is feasible, especially with regards to adherence, only after substance abuse issues have been addressed.

Barriers to Care

Several elements are crucial in order to increase the level of adherence, and hence the level of care, for substance users:

• Education - Understanding why it is important to treat HIV infection and how different medications work in the body. Effective education can lead to better adherence.
• Managing Side Effects - Helping patients anticipate the side effects of antiretroviral medications and recognize them as such, not as withdrawal symptoms.
• Eliminating disabling co-factors - Addressing basic concerns such as housing and food.

Q&A

Q: Please comment on the use of marijuana for medical purposes.

A: The speakers referred to Donald Abrams, M.D., the Assistant Director of the UCSF AIDS Program at San Francisco General Hospital, and his position that the benefits and consequences of marijuana use must be weighed against each other. [Addition: Dr. Abrams and his co-authors stated in a 1997 Research and Literature Review that while care providers "have been impressed with positive effects in weight gain, mood and quality of life in their patients smoking marijuana, the potential detrimental effects of marijuana smoking in patients without HIV infection are numerous. Interestingly, most of the literature is at least twenty years old and often conflicting reports can be found, occasionally by the same author. With regard to patients with HIV infection, the impact of smoked marijuana on immune function, pulmonary function, gonadal function and neuropsychiatric status have not yet been described and would seem to be particularly critical safety parameters to examine."]

Q: Please comment on the interactions between alcohol and HIV medications.

A: Both alcohol and HIV medications are metabolized in the liver, and the liver may not be as efficient when processing both substances.

Q: Please discuss the interactions between methadone, antiretroviral medications, and anti-depressants.

A: A few noteworthy interactions: Wellbutrin (Zyban) should not be taken with protease inhibitors, as seizures may result. Barbiturates should not be taken with methadone. Always discuss all medications with your primary care provider to check for interactions.

Q: Is directly-observed therapy the best method for treating substance abusers / recovering addicts?

A: Many believe that this method is most effective for ensuring adherence. It can be useful during the initiation of antiretroviral therapy, to help "prime" an individual to take medication by introducing the new regimen in a controlled environment.