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Managing Drug-Drug Interactions in HIV Disease

  • Authors: Authors: Charles Flexner, MD and Stephen C. Piscitelli, PharmD
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Target Audience and Goal Statement

"Managing Drug-Drug Interactions in HIV Disease" is intended for front line primary care physicians, physician specialists, pharmacists and advanced nurse clinicians and nurse practitioners who have an understanding of the clinical management of persons with HIV/AIDS.

The goal of this activity is to present a comprehensive review of the management of drug-drug interactions in patients with HIV disease.

On completion of this continuing medical education offering, participants will be able to:

  1. List the major mechanisms of drug interactions, and discuss which mechanisms have the greatest clinical impact.
  2. Identify the drugs that have the greatest propensity to cause drug interactions in HIV-infected patients
  3. Discuss the role of drug interactions and adherence in the management of HIV-infected patients.
  4. Describe the effect of food on the absorption of antiretroviral and HIV-related drugs.

Accreditation Statements

    For Physicians

  • Medical Education Collaborative, a nonprofit education organization, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    Medical Education Collaborative designates this educational activity for a maximum of 1 hour in Category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

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    For Nurses

  • This offering has been approved for 1.2 contact hours by the Arizona Nurses' Association, accredited as an approver of continuing education in nursing by the Western Regional Accrediting Committee of the American Nurse's Association, and hence meets the nursing continuing education requirements of most states. HLC, Inc. is approved as a provider of continuing education by the California Board of Registered Nursing (Provider No. 02464), and the Florida Board of Nursing (Provider No. 27I0364), and awards 1.2 contact hours of credit for this activity. Approval for credit is for registered nurses.

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    For Pharmacists

  • Medical Education Collaborative, Inc. has assigned 1 contact hour (0.10 CEUs) of continuing pharmaceutical education credit. ACPE provider number: 815-999-00-019-H02. Certificate is defined as a record of participation.

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For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

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Managing Drug-Drug Interactions in HIV Disease


What Drugs Are Most Likely To Be Involved In Drug Interactions?


1. P450 inhibitors

HIV Protease inhibitors
HIV Non-nucleoside reverse transcriptase inhibitors
Macrolide antibiotics
Azole antifungals
Non-nucleoside reverse transcriptase inhibitors

2. P450 inducers

Rifamycin antibiotics
HIV Protease inhibitors
HIV Non-nucleoside reverse transcriptase inhibitors
Anticonvulsants (that are P450 inducers)

3. Metabolized drugs with narrow therapeutic indices

Non-sedating antihistamines
Long-acting opiate analgesics
Promotility agents
Long-acting benzodiazepines
Ergotamines and dihydroergotamine
Illicit drugs
Coumarin anticoagulants
Oral contraceptives

4. Renally cleared drugs with narrow therapeutic indices

Ganciclovir (Cytovene®)
Foscarnet (Foscavir®)

5. Drugs with specific requirements for absorption

Ketoconazole (Nizoral®) and itraconazole (Sporanox®)
Didanosine (Videx®)
6. Special Case: Sildenafil (Viagra®)

Sildenafil is a CYP 450 substrate (mainly 3A4), and is a very weak P450 inhibitor (several isoforms). Its inhibition is likely to be clinically insignificant, because clinical drug concentrations are far below those required to inhibit microsomal enzymes in vitro.

However, sildenafil's concentrations are significantly increased with 3A4 inhibitors (AUC +182% with erythromycin, and +56% with cimetidine). Therefore, caution should be advised when administering sildenafil with protease inhibitors or NNRTIs. All protease inhibitors and delavirdine could decrease sildenafil clearance and increase sildenafil effects. Inducers (ritonavir, nelfinavir, and nevirapine) could increase sildenafil clearance and reduce sildenafil effects. However, no data exist on any of these interactions yet.

The package insert also warns against combining the drug with nitrates such as amyl nitrate (also known as "poppers") because of serious hypotension.

"Red Flag" List and Alternatives

The following information is presented in table format for ease of use. Alternative suggestions have been included whenever possible.

1. Cytochrome P-450 inhibitors:

Warning - Agents that impair drug metabolism of other drugs which share the same pathway increase concentrations of the co-administered drug.

HIV Protease inhibitors Ritonavir (Norvir®) strongest
Amprenavir (Agenerase®) intermed
Indinavir (Crixivan®) intermed
Nelfinavir (Viracept®)intermed
Saquinavir (Fortovase®/ Invirase®) - weakest
Saquinavir (Invirase®/Fortovase®) has less potential to cause drug interactions
Macrolides Erythromycin and clarithromycin (Biaxin®) are both inhibitors of CYP450, however, the inhibition may be greater with erythromycin Azithromycin (Zithromax®) is not metabolized by CYP450 and may be substituted if clinically warranted
Antifungals Listed by strength of inhibition:
Ketoconazole (Nizoral®) > Itraconazole (Sporanox®) > Fluconazole (Diflucan®)

Ketoconazole (Nizoral®) and Itraconazole (Sporanox®) are potent inhibitors of CYP450

Fluconazole (Diflucan®) is associated with less drug interactions when dosages of 200 mg or less are used. As dose is increased, there is a greater potential for drug interactions.
Topical antifungals such as clotrimazole (Mycelex®) troches and nystatin may be useful for prophylaxis of thrush or minor infections. For more severe fungal infections, amphotericin B (Fungizone®, Abelcet®, AmBisome®, Amphotec®) may be used
Non-nucleoside reverse transcriptase inhibitors Delavirdine (Rescriptor®) is a potent inhibitor of CYP450 potentially raising concentrations of other drugs

Efavirenz (Sustiva®) is a mixed inhibitor/inducer, depending on the concomitant drug

While it may be beneficial in some cases to use delavirdine to increase concentrations of other drugs (e.g. protease inhibitors), alternatives in this class would be nevirapine and efavirenz (Sustiva®) or perhaps nucleoside analogs (i.e., didanosine [Videx®], zidovudine [Retrovir®]) if clinically appropriate
H2 Antagonists Cimetidine (Tagamet®) is a CYP450 inhibitor with a high propensity for causing interactions Any other H2antagonist
i.e. Ranitidine (Zantac®)
or Famotidine (Pepcid®)

2. Cytochrome P-450 Inducers:

Rifabutin (Mycobutin®) and Rifampin (Rifadin®, Rimactane®)
Potent inducers of CYP450 and may decrease concentrations of drugs metabolized by these pathways For patients receiving protease inhibitors, rifampin should be avoided.
However, rifabutin (Mycobutin®) may be used with indinavir (Crixivan®), amprenavir (Agenerase®) and nelfinavir (Viracept®) at one-half the normal dose (150 mg/day).
For ritonavir (Norvir®), rifabutin (Mycobutin®) can be used on an every-other-day basis or 3 times weekly at one half the normal dose (150 mg q M-W-F).
In patients requiring MAC prophylaxis, azithromycin (Zithromax®) or clarithromycin
(Biaxin®) may be substituted for rifabutin
HIV Protease inhibitors:
Nelfinavir (Viracept®) and Ritonavir (Norvir®)
Moderate inducers of CYP450, potentially decreasing concentrations of other drugs which are metabolized In this class Alternatives would be:
amprenavir (Agenerase®)
indinavir (Crixivan®)
saquinavir (Fortovase®)
delavirdine (Rescriptor®)
or perhaps nucleoside analogs, i.e.
didanosin e (Videx®)
zidovudine (Retrovir®) could be used if clinically appropriate
Non-nucleoside reverse
transcriptase inhibitors:
Nevirapine (Viramune®) and Efavirenz (Sustiva®)
Moderate inducers of CYP450, potentially decreasing concentrations of other drugs Alternatives in this class would be delavirdine or perhaps nucleoside analogs i.e.
didanosine (Videx®)
zidovudine (Retrovir®)
if clinically appropriate


Major / moderate inducers of CYP450, potentially decreasing concentrations of other drugs. If clinically warranted, possible alternative anti-epileptics include:
valproic acid (Depakene®, Depakote®)
gabapentin (Neurontin®)
lamotrigine (Lamictal®)
topiramate (Topamax®)
tigabine (Investigational Tabitril®)

3. Metabolized drugs with narrow therapeutic indexes:

WARNING - All of these agents should be avoided, especially with potential P450 inhibitors, as they may produce serious or life-threatening side effects if their concentrations are increased or decreased.

Non-sedating antihistamines Terfenadine (Seldane®) Astemizole (Hismanal®)
*although removed from US market, patients may still have supplies
Newer non-sedating antihistamines such as fexofenadine (Allegra®) and loratadine (Claritin®) can be safely used with P450 inhibitors, as well as most over-the counter preparations
Antiarrythmics Flecainide (Tambocor®) Encainide (Enkaid®) Quinidine Antiarrhythmic therapy should be closely monitored and used with caution in patients receiving inhibitors of cytochrome P-450
Long-acting opiate analgesics Fentanyl (Sublimaze®, Duragesic®) Alternative analgesics include hydromorphone, codeine, and NSAIDs , particularly in patients receiving ritonavir (Norvir®)
Promotility agents Cisapride (Propulsid®) Metoclopramide (Reglan®)
Long-acting benzodiazepines Midazolam (Versed®) Triazolam (Halcion®)
Ergotamines and dihydroergotamine Cafergot® Hydergine®D.H.E. 45®
Illicit drugs Ecstacy/XTC/MDMA
Coumarin anticoagulants Warfarin (Coumadin®)
Oral contraceptives Oral contraceptives should not be given concurrently with P450 inducers, as this can decrease their concentrations and lead to unwanted pregnancy

4. Renally cleared drugs with narrow therapeutic indices:

Foscarnet (Foscavir®)
Ganciclovir (Cytovene®)
Adjust dose for renal function with these agents
Cidofovir (Vistide) may be used if clinically appropriate, but this agent can cause irreversible renal insufficiency

(Any drugs that are nephrotoxic may decrease aminoglycoside clearance and increase likelihood of aminoglycoside toxicity)

Other antibiotics covering gram – bacteria:
Aztreonam (Azactram®)
Broad Spectrum penicillins and cephalosporins

5. Drugs with specific requirements for absorption:

Ketoconazole (Nizoral®)
Itraconazole (Sporanox®)
Require an acidic gastric pH for optimal absorption - avoid in patients with achlorhydria or those receiving H2-antagonists, antacids, or proton pump inhibitors Fluconazole can be substituted if clinically appropriate. Topical antifungals such as clotrimazole (Mycelex®) troches and nystatin may be useful for prophylaxis of thrush or minor involvement. For more severe fungal infections, amphotericin B (Fungizone®, Abelcet®, AmBisome®, Amphotec®) may be used
Didanosine (Videx®) Must be taken on an empty stomach and separated from indinavir by one hour since the buffer component may impair indinavir (Crixivan®) absorption Administer didanosine (Videx®) once daily on empty stomach to lessen inconvenience associated with indinavir. Can use alternative nucleoside analogs if clinically appropriate
Fluoroquinolones Must be separated from di- and trivalent cations ( calcium products, antacids, iron preparations, DDI , etc) to avoid chelation and decreased therapeutic effect Separate quinolone from cations by 2-4 hours - administer quinolone first. Also, other antimicrobials with appropriate coverage (i.e. cephalosporins ) may be used if clinically appropriate