Antiretroviral Therapy in Injection Drug Users With HIV Disease: Using Drug Interactions to Design More Effective Treatment

Elinore F. McCance-Katz, MD, PhD
Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, New York, New York

There are between 800,000 and 1 million heroin users in the US, most of them injection drug users (IDUs). Dr. McCance-Katz outlined three treatment options for heroin addiction:

1. Detoxification (which fails in more than 90%)
2. Naltrexone (opiate antagonist) maintenance
3. Opiate agonist maintenance
• Methadone
• 1-acetyl-methadol (LAAM)
• Buprenorphine (not currently available in the US)

Only about 185,000 US heroin users are enrolled in a maintenance program.

IDUs account for 31% of prevalent HIV infections in the US. In northeastern urban areas they account for more than 50%. The treatment of choice for most of these people is long-term maintenance therapy.

For IDUs, consistent adherence with antiretroviral therapy is not possible without treatment for substance abuse. Opiate maintenance therapy stabilizes a chaotic lifestyle and provides a platform for other interventions, such as modified directly observed antiretroviral therapy. But Dr. McCance-Katz noted that cotreatment of HIV and substance abuse is complicated by interactions between many antiretrovirals and the drugs used for opiate maintenance. Opioids, protease inhibitors (PIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are all metabolized via isoforms of the cytochrome P450 (CYP) system. These interactions have several possible consequences in people on opiate maintenance therapy:

• Nonadherence with antiretrovirals
• Emergence of resistance to antiretrovirals
• Lack of efficacy of antiretroviral and opiate maintenance therapy
• Drug toxicity

AZT and NNRTI interactions with opioids

Most antiretroviral-opioid interaction studies reported to date involve methadone. Several years ago Dr. McCance-Katz showed increased AZT concentrations in people on methadone maintenance, because methadone inhibits the metabolism and renal clearance of AZT [1]. These findings raised concerns about AZT toxicity in people taking methadone.

To determine whether the AZT-methadone interaction extends to other opioids, Dr. McCance-Katz gave AZT to HIV-negative adults taking LAAM, buprenorphine, or naltrexone, and to HIV-negative controls not on opiate maintenance therapy [2]. Among people taking naltrexone, AZT levels were similar to those in controls. Burprenorphine and LAAM significantly decreased concentrations of AZT.

Further work by Dr. McCance-Katz showed that efavirenz given by directly observed therapy significantly lowered methadone's area under the concentration-time curve (AUC) by about 50%. Study participants experienced substantial opioid withdrawal symptoms.

Delavirdine, an inhibitor of the CYP3A4 isoform, modestly elevated methadone's AUC, without clinical consequences. Delavirdine significantly raised concentrations of LAAM and nor-LAAM, the major metabolite of LAAM. But delavirdine significantly lowered levels of dinor-LAAM, the second major LAAM metabolite. Dr. McCance-Katz concluded that delavirdine could be used by patients on opioid maintenance therapy without dose adjustment.

PI interactions with opioids

Methadone levels were significantly lower when coadministered with nelfinavir, [3] a finding confirming the work of others. Even so, Dr. McCance-Katz said, the methadone dose rarely needs to be adjusted when given with nelfinavir. Nelfinavir had little effect on LAAM concentrations. Nor-LAAM levels were higher when coadministered with nelfinavir, but dinor-LAAM levels were lower.

Methadone and LAAM had little effect on nelfinavir concentrations. LAAM increased levels of M8, nelfinavir's major metabolite, but that increase is not clinically meaningful.

In another study methadone levels fell 30% to 40% when given with lopinavir/ritonavir (Kaletra) and resulted in a significant increase in opioid withdrawal symptoms.

Clinical implications and conclusions

Dr. McCance-Katz concluded that differences between In-vitro and In-vivo findings on antiretroviral-opioid interactions underscore the need to conduct pharmacokinetic studies in humans when possible. Findings of such studies can help select an appropriate opioid and appropriate antiretrovirals, she added, stressing that treatment must be individualized based on clinical needs of the patient.

References

1. McCance-Katz EF, Rainey PM, Jatlow P, Friedland G. Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262). JAIDS 1998;18:435-443.



2. McCance-Katz EF, Rainey PM, Friedland G, et al. Effect of opioid dependence pharmacotherapies on zidovudine disposition. Am J Addict 2001;10:296-307.



3. McCance-Katz EF, Farber S,
Selwyn PA, O'Connor A. Decrease in methadone levels with nelfinavir mesylate. Am J Psychiatry 2000;157:481.


4. McCance-Katz EF, Gourevich MN, Arnsten J, Sarlo J, Rainey P, Jatlow P: Modified Directly Observed Therapy (MDOT) For Injection Drug Users with HIV Disease. Am J Addiction, in press.