DRUG-DRUG INTERACTIONS WITH SPECIAL REFERENCE TO ARV & OI DRUGS

A drug interaction occurs when one drug is given with or shortly after another drug alters the effect of one drug or both drugs. Drug interactions pose one of the common problems as often patients take more than one drug at a given time. It is estimated that a hospitalized patient receives an average of 5 - 10 drugs. When several drugs are given together, interactions are bound to occur.  This module highlights

Session objectives

·         To discuss various types and mechanisms of drug-drug, drug–food and herbal drug   interactions with a special focus on  antiretroviral agents

·         To discuss risk factors for ARV drug interactions and drug –disease interactions and their impact on patient drug therapy

·         To discuss how harm from drug interactions can be minimized.

OBJECTIVES

By the end of the module, pharmacists will be able:

·         To describe different types and mechanism of drugs interactions

·         To understand the impact of drug interactions on patients

·         To identify risk factors and importance of drug interactions with ARV agents

·         To identify high risk patients and harmful interactions and minimize harm from drug interactions

Drug-drug interactions can be defined as the modulation of the pharmacologic activity of one drug (i.e., the object drug) by the prior or concomitant administration of another drug (i.e., the precipitant drug). In these reactions, the pharmacologic properties of the object drug and/or the precipitant drug can be either severely enhanced or diminished. The interaction can be potentiated, or synergistic, when the combined effect of the two drugs is greater than

the total effects of the drugs used separately. The interaction can be expressed as antagonized when the resulting effect is less than the combined effects of the two drugs when used separately or when the effect partially or completely nullifies the effect(s) of each drug. In some instances, predictable drug-drug interactions in· patients are beneficial, and clinicians allow them to occur because they result in lower doses of the drug(s) being administered while still achieving therapeutic serum drug levels.

Beneficial Effects

Combination therapy in some cases is based on drug interactions.  Probenecid is a drug that decreases excretion of penicillin. Both are given together/ so that the dose of penicillin can be reduced. Hydrochlorothiazide and spironolactone are combined together to maintain potassium levels within normal range. However, beneficial effects are very few, most are harmful.

Harmful Effects

These can be in terms of lack of efficacy or toxicity. Whenever the levels of drugs in the body are increased due to interactions, toxicity of that drug is enhanced. If levels are decreased viz., due to enhanced metabolism of the drug it may result into lack of response.

Thus drug-drug interactions carry potential risk both outside and inside the body. Not only do drug interactions present a danger to the patient, but they can also greatly increase healthcare costs. Patients on a combination of drugs require hospitalization or more laboratory tests to monitor resolution of these interactions. It is important that personnel responsible for drug dispensing and administration of drugs are aware of these interactions, especially clinically important interactions, and should educate and observe patients so that patients report immediately in the event of unexpected outcome. Whenever there is an unexpected response to a drug, consider "drug-drug Interaction" as one of the possibility for the unexpected response.

Drug interactions in patients on Antiretroviral therapy (ART)

Patients with HIV who are receiving antiretroviral (ARV) therapy are at high risk for drug–drug interactions, which can significantly impact patient care and represent a substantial opportunity cost for healthcare systems. Although studies are limited, clinically significant drug-drug interactions involving ARVs and co-administration of contraindicated drugs are common in developed countries. A substantial proportion of these have had an adverse impact on ARV exposure. Data from developing countries are sparse, though it is likely that clinically significant drug interactions are prevalent. Highly active antiretroviral therapy (HAART) involves a regimen of at least three agents. Polypharmacy is largely unavoidable for patients receiving ARVs, with life-long treatment and changes of drug combinations along the way almost a certainty. Drug interactions may arise due to the pharmacokinetics or pharmacodynamics of administered compounds.  Lowering of ARV or concomitant drug levels to below therapeutic ranges can lead to treatment failure, drug resistance and reducing the number of effective regimens available to treat the patient. Conversely, drug interactions may result in increased exposure to ARVs or co-administered drugs, precipitating drug toxicity or greater severity and incidence of adverse reactions.

Risk factors for HIV Drug interactions

New drugs

The introduction of new ARV agents increases the number of effective regimens available, but also the complexity of treatment. Assessment of the potential for drug interactions during the clinical phase of drug development, although comprehensively undertaken, is at best incomplete. Screening of a new molecular entity for potential as a substrate, inducer or inhibitor of Phase I and Phase II metabolic enzymes and influx/efflux drug transporters is limited by a lack of validated expression systems and standardized protocols, particularly for drug transporters. It cannot be assumed that drugs from the same class have broadly similar potential for interaction. In addition, there will always be surprises from unanticipated Drug interactions that emerge after licensing, and may lead to increased risk of toxicity or diminished therapeutic effect. There is a need for standard protocols for interaction screening of new drugs, as well as clinical vigilance as experience in their use develops.

Co-infection

In many developing countries, HIV/AIDS epidemiology may overlap with other infections such as tuberculosis (TB). TB infection risk is considerably higher in HIV-infected patients, irrespective of the setting. TB therapy, like HIV treatment, is complicated by drug resistance and requires multiple agents, which have varying potential to interact with ARVs. Difficulties in treating TB in HIV patients may arise due to interactions with rifampicin, a potent inducer of liver enzymes. Many ARVs contraindicate the use of rifampicin, while others may require dose modification. Not all dose adjustments are straight forward however; for example, when co-administered with rifampicin, there are wide inter-individual variations in plasma efavirenz concentrations.

Infection with hepatitis C virus (HCV) is a common cause of morbidity in HIV patients. Therapy for chronic HCV infection, which conventionally involves ribavirin and interferon, Emerging HCV therapies join ARVs in being among the most therapeutically risky drugs for Drug interactions, due to inhibition or induction of liver enzymes. Treatment of co-infection will become increasingly complex.

There are a number of well-recognized opportunistic infections associated with HIV infection, for which patients may require treatment or prophylaxis. Although HIV specialists may be experienced in the treatment of such conditions, the agents used often have complex interactions with ARVs. For example, the exposure of many azole antifungals is increased by PIs and decreased by NNRTIs, but some azoles such as fluconazole may also increase exposure of nevirapine and other ARVs.

Polypharmacy and an ageing population

The introduction of highly active antiretroviral therapy (HAART) in the mid-1990s has led to increased life expectancy for HIV patients there is an increasing number of patients over 50 years of age living with HIV, hence, HIV can be viewed as a chronic condition, which will eventually need to be managed alongside chronic conditions associated with ageing. As one would expect, the likelihood of being prescribed contraindicated medication alongside ARV regimens has been found to increase significantly in older patients.

As a result of disease state and metabolic side effects of ARV regimens, HIV patients often are at high risk for cardiovascular disease. The choice of lipid-lowering agents, antihypertensives and smoking cessation therapy need to be carefully considered in these patients, and the most appropriate agents may not always be those used as first line in hospital formularies.

Over the counter products cannot be disregarded; many patients have used herbal remedies or supplements which could have potentially compromised their HIV management as a result. It is likely that in practice the use of herbal remedies and supplements that have potential to be problematic in HIV care, such as St John’s wort, garlic and Echinacea. Herbal remedies used by patients are often under reported by patients or the information not routinely requested by healthcare professionals. Another factor that may be significant is the impact of recreational or illicit drug use on HIV management. Interaction studies are few and patients may not give accurate information about their use.

MECHANISM OF DRUG INTERACTIONS

Drug interactions are frequently characterized as pharmacokinetic or Pharmacodynamic in nature. These interactions frequently cause marked shifts in serum drug levels and alter clinical response. Pharmacokinetic interactions are not predictable as there may be individual variation. Pharmacodynamic interactions are related to the pharmacologic activity of the interacting drugs. These interactions are frequently associated with synergism, antagonism, or altered cellular transport, and they affect organ systems and/or receptor sites.

The causes and significance of drug interactions are multifaceted and include drug dose; serum drug level; route of administration; drug metabolism; duration of therapy; and patient factors, such as age, gender, weight, genetic predisposition, and other factors. All interactions are not clinically important, as slight change in drug concentration in the body may not produce significant alteration in drug response.

a)            Pharmacodynamic. Interactions generally take place between drugs acting on same type of receptors or physiological system viz., the effect of anti-histaminic like chlorpheniramine on CNS is increased by alcohol as both cause CNS depression. The effect of propranolol on heart is increased by verapamil. Both of them cause depressive action on heart. Such interactions are predictable and it is important to observe them when such drugs are administered together.

Additive toxicity

Use of alcohol may enhance liver toxicity of INH, paracetamol. All cephalosporines when given with amino glycosides (gentamicin, amikacin) increase renal toxicity. Close patient monitoring for renal toxicity is very important. It is recommended that renal function tests should be done frequently.

Concomitant administration of furosemide and lithium results into lithium toxicity. When

furosemide is given with gentamicin ototoxicity is potentiated.

Increased bone marrow toxicity of zidovudine and ganciclovir and peripheral neuropathy, pancreatitis and lactic acidosis with didanosine and Stavudine (DDI/D4T).  Alcohol, pentamidine, valproic acid cause additive pancreatoxicity with didanosine, stavudine, zalcitabine.  Abacavir is metabolized by alcohol dehydrogenate.  Therefore, alcohol can

increase Abacavir levels and toxicity.

Additive and synergistic effect

Additive and synergistic effect of combination antiretroviral therapy  (HAART) is greater than monotherapy, as seen with DDI/hydroxyurea, and ABC/mycophenolic acid. 

Antagonistic

Zidoivdine (AZT) and Stavudine (d4T) reduces antiviral effect.

Corticosteroid decrease the hypoglycemic response to glipizide, glimepride. Beta blockers mask the symptoms of hypoglycemia. Patient monitoring is very important for any hypoglycemic response. Furosemide a diuretic, interacts with many drugs, when given with NSAID, furosemide's clinical response is decreased.

b)            Pharmacokinetic Drug Interactions. Pharmacokinetic means absorption, distribution metabolism and excretion of drugs.

i.        Absorption. Most drugs in tablet, liquid or capsule form are absorbed from small intestines. Once absorbed, they circulate in blood stream and are available for action. The quantity of drug available is known as bioavailability. Drugs, food and drinks can alter the absorption of drugs. This is one important site of drug interaction. LPV/r is food-independent but LPV/r paediatric preparation must always be taken with food.  With food, didanosine absorption is decreased by upto 50%.

Antacids and laxatives reduce INH absorption from GIT, therefore, INH should be administered an hour before these drugs are given. Iron when taken with calcium or milk products chelates, therefore, not absorbed into the body. Iron supplements taken with antibiotics can reduce or stop the ability of the antibiotics to fight infection. (Iron and the antibiotic bind together in the stomach, instead of being absorbed into the bloodstream. Ampicillin should be taken empty stomach since its absorption decreases when taken with food. Ampicillin and Amoxicillin when taken with allopurinol increases the chances for skin rashes.

ii.     Distribution. The drug moves from blood stream into various fluids and tissues or drug may get bound to plasma proteins. This is another site for drug interactions. One drug may displace another drug from these sites.

iii. Metabolism. Most drugs are metabolized in the liver. The liver has many enzymes that metabolize the drugs and these enzymes can be induced or inhibited by drugs thus causing increase or decrease in metabolism of other drugs.   Interactions involving induction may be delayed since new enzymes must be synthesized. Rifampicin is a potent inducer of hepatic metabolism and significantly decreases the concentration of protease inhibitors (PIs)  such as ritonavir, lopinavir, nelfinavir, saquinavir, to subtherapeutic levels.  Rifampicin may also increase metabolism of anticonvulsants, theophylline, verapamil and due to enzyme induction in the liver responsible for their metabolism resulting into reduced action of these drugs and significantly reduces the concentration of PIs to sub-therapeutic levels.  Efavirenz has all three properties of acting as substrate, induction and inhibition of enzymes.

Box 9.1 Inhibitors and inducers of drug metabolism

Inhibitors of Drug Metabolism	Inducers of Drug Metabolism
·         Protease inhibitors ·         Delavirdine ·         Efavirenz ·         Fluconazole ·         Itraconazole ·         Ketoconazole ·         Voriconazole ·         Isoniazid ·         Ciprofloxacin ·         Erythromycin ·         Diltiazem ·         Verapamil ·         Amiodarone ·         Cimetidine ·         Omeprazole ·         Fluoxetine ·         Grapefruit juice	·         Nevirapine ·         Efavirenz ·         Ritonavir ·         Rifampin ·         Rifabutin ·         Phenobarbital ·         Carbamazepine ·         Phenytoin

ARVs are among the most therapeutically risky drugs for drug interactions, due to potent inhibition or induction of liver enzymes, such as the cytochrome P450 isoenzymes (CYP450), which metabolize a broad array of other medications. Each PI and non-nucleoside reverse transcriptase inhibitors (NNRTIs) has a different drug interaction profile, depending primarily on its potency as an inducer or inhibitor of CYP3A4 and/or other P450 enzymes

Ritonavir is the most potent CYP3A4 inhibitor and consequently has the most drug interactions and contraindications. NVP is a CYP3A4 inducer. EFZ is both an inducer and inhibitor of CYP3A4. Nelfinavir, ritonavir, and the NNRTIs can significantly decrease the estrogen levels in contraceptives. Women taking these drugs cannot rely on oral contraceptives and should use another or an additional method of contraception.

PIs and EFZ can raise the serum conc of cisapride and non-sedating antihistamines (astemizole, terfenadine), which can lead to cardiotoxicity. They can also increase the serum concentration of benzodiazapines resulting in prolonged sedation. Therefore, PIs and these other drugs should not be administered together.

iv.  Excretion. Drugs are excreted primarily by kidneys. One drug may decrease or increase the excretion of drugs.  Probenecid can increase levels of Zidovudine (ZDV or AZT). INH inhibits excretion of diazepam. Patient monitoring is important as diazepam response may be enhanced.

Thus, due to drug interaction at any of the above site the concentration of one drug in the body may either decrease or increase; if it is decreased, there is a lack of therapeutic response and if it is increased there may be toxicity.

Drug interactions involving protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are more likely to be attributable to hepatic metabolic pathways than drug-interactions involving nucleoside or nucleotide reverse transcriptase inhibitors, which in some cases can be due to competition for renal tubular secretion. Clinically significant Drug interactions are more likely with regimens containing PIs than those containing NNRTIs.

Drug Interactions outside the Body

Patients in intensive care units (lCU) often receive numerous medications by the parenteral route. Frequently two or more drugs are delivered simultaneously through the same line and the risk of physicochemical incompatibilities is thus important. Physical or visual incompatibilities present in the form of precipitation, effervescence, color change, and related visual changes. Interactions can occur during formulation and mixing of drugs and some examples are shown as below:

·            Thiopentone and suxamethonium react chemically, therefore, should not be withdrawn in the same syringe.

·            Ketamine is incompatible with barbiturate & diazepam, therefore, should not be withdrawn in the same syringe.

·            Protamine zinc insulin should not be combined with soluble insulin, if combined a precipitate will be formed.

·            Phenytoin precipitates in dextrose solutions e.g. D5W.

·            Valproate infusion should NOT be given with saline.

·            Amphotericin precipitates in saline and fat emulsion.

·            Gentamicin is physically/chemically incompatible with most beta-lactams resulting in loss of antibiotic effect.

·     Adsorption of tuberculin PPD to glass and plastic surfaces.

Drug interactions with ARVs and possible alternatives

Commonly interacting drugs with ARV drugs along with possible moderate or high level of clinical outcome of the interaction and suggested strategies for prevention, monitoring, and managing any potential interactions are shown in Annexure I.

Protease Inhibitors
Primary mode of elimination of PIs is hepatic and as a class often the genesis of many drug interactions, therefore, avoid using in combination with the following medicines:

·         Ergots, astemizole, cisapride, midazolam, triazolam, rifampin, rifabutin, simvastatin, lovastatin

·         Phenytoin, phenobarbital, carbamazepine (i PI levels, h CBZ levels)

·         St. John’s Wort, garlic.

·         Proton pump inhibitors and Irinotecan should not be used with atazanavir

Interactions with Ritonavir

Ritonavir is the most potent CYP3A4 inhibitor and consequently has the most drug interactions and contraindications, therefore, consult a reference in all situations.  It is a “Pharmacoenhancer”, hence always err on the side of conservatism.  Ritonavir can significantly increase corticosteroid concentrations.

Do not use ritonavir with	Possible Alternatives
Piroxicam	Aspirin
Amiodarone, flecainide, quinidine
Astemizole & Terfenadine	Loratidine, cetirizine, or fexofenadine
Cisapride
Alprazolam Chlorazepate Diazepam Midazolam Triazolam	Temazepam Lorazepam
Didanosines
Voriconazole
Fluticasone
Alfuzosin

Ritonavir when administered with fluticasone results in fluticasone induced Cushing’s Syndrome since fluticasone is a 3A4 substrate and ritonavir a 3A4 inhibitor

NNRTI

All NNRTIs are metabolized by the CYP3A4 enzyme (EFV also metabolized by 2B6). Delavirdine can inhibit CYP3A4 enzyme. Nevirapine can induce CYP3A4

Efavirenz can inhibit or induce CYP3A4 enzyme.

NRTI

Ganciclovir, flucytosine, pentamidine cause additive bone marrow suppression with Zidovudine. Zidovudine antagonisis stavudine (competition for intracellular activation). Didanosine inhibits absorption of other agents (fluoroquinolones, tetracyclines, dapsone, ketoconazole, indinavir, delavirdine) due to didanosine buffer.  Ribavirin significantly increases didanosine levels, therefore, do not use together.  Vincristine, cisplatin, isoniazid cause additive neurotoxicity, whereas, alcohol, pentamidine, valproic acid cause additive pancreatoxicity with didanosine, stavudine, zalcitabine. Ribavirin should NOT be used with didanosine. Abacavir is metabolized by alcohol dehydrogenase (alcohol can increase abacavir levels and toxicity).

Erectile Dysfunction Agents

Sildenafil, vardenafil, and tadalafil are all extensively metabolized by CYP3A4. When sildenafil was given concurrently with indinavir, saquinavir, or ritonavir, the AUC for sildenafil was increased by a factor of 2- to 11-fold. The AUCs of vardenafil and tadalafil were increased when given with ritonavir. Based on these data, the following is generally recommended when erectile dysfunction agents are combined with PIs:

Sildenafil – use reduced initial dose of 25 mg q48h and monitor for adverse effects. Tadalafil – use initial dose of 5 mg, and do not exceed a single dose of 10 mg in 72 hours. Vardenafil – use initial dose of 2.5 mg, and do not exceed a single 2.5-mg dose in 72 hours.

Ergot Alkaloids

Ergotamine derivatives are contraindicated with all PIs because of potential ergotism due to enhanced levels caused by CYP450 inhibition. Although the majority of case reports have described this event during therapy with ritonavir, other drugs associated with this interaction include indinavir and nelfinavir. Ergotamine derivatives should not be prescribed in patients receiving concurrent PI therapy. Alternative medications should be considered.

HMG-CoA Reductase Inhibitors

Dyslipidemia occurs in approximately 70% of patients taking PIs, often requiring the use of HMG Co-A reductase inhibitors for treatment. Studies have been conducted evaluating the potential interaction between PIs and the HMG-CoA reductase inhibitors, commonly referred to as “statins” (pravastatin, atorvastatin, lovastatin, rosuvastatin, and simvastatin). When these drugs were studied with concurrent ritonavir/saquinavir, the AUC of simvastatin increased by a factor of 32 and atorvastatin by a factor of 4.5, whereas the AUC for pravastatin was reduced by a factor of 0.5. Significant drug interactions have also been reported with lopinavir/ritonavir when given concurrently with simvastatin or atorvastatin. After co-administration, the AUC increased by 5.9-fold for atorvastatin, whereas the pravastatin levels increased 0.3-fold. Similar results have also been reported with co-administration of nelfinavir with atorvastatin or simvastatin. Lovastatin and simvastatin are contraindicated with all PIs and DLV. Pravastatin is the safest drug for treating hyperlipidemia during concurrent PI therapy. Atorvastatin can be used cautiously at lower doses (5-10 mg) with careful titration. Rosuvastatin can be used at lower doses (5mg) with careful titration.

Sedative/Hypnotics

Ritonavir has been shown to significantly impair the oral clearance of alprazolam and triazolam in healthy volunteers. This potential for increased benzodiazepine levels would lead to potentiation of the sedation and respiratory depression associated with these compounds. Although data describing this interaction are primarily based on ritonavir use, these drugs should not be administered with any of the PIs. Acceptable sedative/hypnotic drugs, including zolpidem, lorazepam, or temazepam, may be used. Midazolam, or triazolam should not be prescribed for patients receiving PIs. Lorazepam or oxazepam may be considered.

Psycotropic agents

Due to the complex nature of ritonavir metabolism, increased or decreased levels of psychotropic agents may occur. Monitor patients closely when changing psychotropic agents or adding ritonavir.

Monitor desipramine levels when used with ritonavir. Ritonavir may reduce olanzapine levels. When used with ritonavir, start with low dose of olanzapine, risperidone, aripiprazole, ziprasidone, quetiepine. Clozapine – relatively contraindicated due to allergic agranulocytosis risk. Avoid chlorpromazine, thioridazine, haloperidol  increased risk of EPS and tardive dyskinesia (irreversible) in HIV patients. Avoid pimozide

FOOD DRUG INTERACTIONS

Generally, administering oral medication along with food or at a meal time is a convenient manner of drug dosing. However, drug interactions can occur that modify the activity of the drug (decrease or increase drug effects) or impair the nutritional benefit of certain food. The most commonly observed type of drug-food interaction affects drug absorption.

Effect of Food on Drug Absorption: Food can decrease a drug's rate of absorption and/or decrease the extent of absorption of numerous drugs (Box 9.2). Examples of drugs whose absorption is decreased when taken with food include penicillin, tetracycline, erythromycin, levodopa, phenytoin, and digoxin. Drugs whose absorption increases when taken with food include spironolactone, griseofulvin, and itraconazole. With some drugs, this food-drug interaction may be utilized to achieve higher serum drug levels or to use lesser amounts of drug per dose. For example, administering the drug ketoconazole with acidic beverages (colas) leads to high and prolonged serum levels for ketoconazole. Generally, these interactions have an insidious onset and may not be clinically evident except for failure to achieve the therapeutic goals of therapy or loss of disease control. Continuous long-term monitoring of patients is needed when drugs and food must be taken together.

In addition to affecting absorption of drugs, food can interact with drugs in a variety of other ways.

Other Effects of Foods: Other examples of drug-food interactions are as follows:

1)   Vitamin K found in green leafy vegetables, tomatoes, coffee, beef liver, green tea, alfalfa tablets, etc. and some nonprescription vitamin-mineral products can antagonize the anticoagulant effect of warfarin, resulting in decreased anticoagulant activity and lowered prothrombin time (PT) laboratory blood tests;

2)   Vitamin B6 (pyridoxine) found in avocados, beans, peas, sweet potatoes, bacon, beef liver, pork, tuna, and some nonprescription vitamin-mineral products, increases the metabolism of levodopa, producing decreased blood levels of dopamine and antiparkinsonism effects;

3)   Calcium, magnesium and aluminum found in food supplements or antacid compounds bind (chelate) with tetracycline to form an insoluble complex resulting in significantly decreased absorption of tetracycline and decreased antibiotic effect; and 4) calcium in vitamin-mineral products and liquid enteral nutritional supplements interact with some fluoroquinolone antibiotics (ciprofloxacin, enoxacin, and others) and with phenytoin, reducing their bioavailability and resulting in decreased antibiotic activity and loss of seizure control, respectively.

Box 9.2. Effects of Food on Drugs

Drugs	Effect(s) of Food
Acetaminophen, aspirin, digoxin	Decreased/delayed drug absorption
ACE inhibitors (captopril and	Significant decrease in serum drug levels
moexipril)
Fluoroquinolones (ciprofloxacin,	Avoid taking with antacids (esp. magnesium and
levofloxacin, ofloxacin,	aluminum types) and iron products; significantly
trovafloxacin), Tetracycline	decreased drug absorption
Didanosine or ddl	Food in general and acidic foods juices
	significantly decrease drug absorption
Saquinavir, griseofulvin,	Food, especially high-fat meals, improves drug
itraconazole, lovastatin,	absorption; take with food, or within two hours of
spironolactone	a meal
Famotidine	Decreased/delayed drug absorption
Ketoconazole	Acidic foods/juices and sodas (e.g., cola)
	significantly increase drug absorption
Iron, levodopa, penicillins (most erythromycin), tetracycline,	High-carbohydrate meals decrease drug absorption
When the increased or decreased absorption effects of food are undesirable,
take drug on an empty stomach, either one hour before or two hours after meals.

Box 9.3. Food –drug interactions with ARV drugs.

Class	Food restrictions
Nucleoside Analog Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (ABC)	No
Didanosine (ddI)	On empty stomach
Emtricitabine (FTC)c	No
Lamivudine (3TC)	No
Stavudine (d4T)	No
Zidovudine (ZDV, AZT)	No
Tenofovir (TDF)	No
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz (EFV)	On empty stomach; avoid taking after high-fat meals because of increased peak concentration
Nevirapine (NVP)	No
Protease Inhibitors (PIs)
Fosamprenavir (fAPV)	No
Atazanavir (ATV)	Take with food
Indinavir (IDV)	No food if taken alone, can be taken with or without food if combined with RTV(r)
Lopinavir (LPV)	Take with food; new formulation can be taken with or without food
Nelfinavir (NFV)	Take with food
Ritonavir (RTV)	Take with food
Saquinavir (SQV)	Take with food
Tipranavir (TPV)	Take with food

HERBAL DRUGS INTERACTIONS

The use of herbal or natural products in the general population as well as by prescribers is growing significantly every year. These products are considered both safe and effective alternatives to traditional medicine and about 70% of patients may not be informing their physician or pharmacist of their herbal product use, therefore, the potential and incidence for adverse reactions and drug-drug interactions is unknown and not being monitored. Other reasons that make adverse reactions to these products likely include a lack of standardization of content of natural products, variations in the strength of the active ingredient, contamination by fungal organisms, and adulteration with other potentially harmful natural products. Potential adverse effects of herbs and drug-herb interactions of selected herbs are listed in Box 9.4.

Box 9.4. Drug Interactions of Selected Herbal or Food Products.

Drug	Herbal/Food	Drug Interactions Reported
Alprazolam	Kava	Synergistic CNS activity of alprazolam
Amantadine	Quinine	Elevated serum drug levels of amantadine
		and risk of toxicity (ataxia, mental confusion)
Amoxicillin and	Khat	Delayed or decreased absorption of
ampicillin		amoxicillin and ampicillin
Buspirone	Grapefruit (juice)	Increased serum drug levels of buspirone
Calcium channel Blockers (amlodipine, felodipine, nifedipine, nisoldipine)	Grapefruit (juice)	Increased serum drug levels: amlodipine 15%, felodipine >300%, nifedipine 35%, nisoldipine 400%
Carbamazepine	Grapefruit (juice)	Increased serum drug levels by about 40%
	Quinine	Elevated serum drug levels of carbamazepine by about 37%
Cyclosporine	Grapefruit (juice)	Increased serum drug levels and increased usual ADRs of cyclosporine
Digoxin	Quinine	Elevated serum digoxin levels by about 75%
	Licorice	Elevates serum digoxin levels 4-fold
	Hawthorn	Increased cardiac toxicity
	Ginseng (Siberian)	Elevates serum digoxin levels by about 75%
	St. John's wort	Decreases serum digoxin conc. by 25%
Estrogen	Grapefruit (juice)	Increased serum drug levels by 37%
	Herbal tea	Increased serum drug levels by 28%
Lithium	Herbs with diuretic properties(broom,buchu,dandelion, juniper)	Increased serum drug levels of lithium
Midazolam	Grapefruit juice	Increased serum drug levels of midazolam
Paroxetine and other SSRls	St. John's wort	Incoherent, confused, nausea, weakness, and fatigue; effects occurred 10 days after paroxetine was discontinued and first dose of St. John's wort was initiated
NNRTI’s-Nevirapine, Efavirenz, Delaviridine	St. John's wort	plasma concentrations of NNRTI’s may be reduced decreasing the clinical efficacy. Assess the patient’s response to NNRTI. Adjust the dose of NNRTI as needed.
Phenobarbital	Quinine	Elevated serum phenobarbital levels by about 35%
Quinidine	Grapefruit (Juice)	Reduced and delayed cardiac effects (QTc).
Spironolactone	Licorice	Mineralocorticoid of licorice blocked; hypokalemia and muscle weakness
Theophylline	St. John's wort	Increases serum theophylline concentration by about 50%
Triazolam	Grapefruit (Juice)	Increased serum drug levels of triazolam
Warfarin	Dashen	Increased anticoagulant activity or increased INR
	Ginkgo biloba, garlic, feverfew and cayenne	Platelet aggregation inhibitor effects and increased risk of bleeding/bruising
	Ginseng (Siberian)	Decreased anticoagulant activity or decreased INR
	Licorice	Increased anticoagulant activity or increased INR
	Alfalfa	Decreased anticoagulant activity or decreased INR
	Vitamin E (doses of 200 IU/day)	Increased anticoagulant activity and platelet aggregation inhibition, thus increased risk of bleeding
	Ginger	Increased anticoagulant activity, increased INR, prolonged bleeding
	Quinine	Increased anticoagulant activity or increased INR

Herbal therapy use has become more frequent in both the general population and the HIV-infected population.

In the setting of PI or NNRTI - based HAART, supplemental garlic and St. John’s Wort are contraindicated.  All herbal products should be used with caution until further data are available regarding their effects with concurrent HAART.

DRUG-DISEASE INTERACTIONS

Certain drugs have the capability to exacerbate acute and/or chronic disorders. Beta-adrenergic blocking agents can precipitate and exacerbate diseases such as asthma, chronic obstructive pulmonary disease, and peripheral vascular disease. These drugs can also blunt the typical signs and symptoms of a hypoglycemic reaction in diabetic patients and alter insulin utilization in the body. These drugs and calcium channel modulators, particularly verapamil, have negative inotropic and negative chronotropic effects on the heart and can exacerbate diseases such as congestive heart failure. Prednisone can aggravate congestive heart failure and cause fluid overload. Because a number of these interactions may have an insidious onset, continuous long ­term monitoring of patients may be needed.

The magnitude of the drug interactions problem increases significantly in certain patient populations and as the number of medications taken each day increases. Drug interactions that may be of minor clinical significance in patients with less severe forms of a disease can cause significant exacerbation of the clinical condition in patients with more severe forms of the disease.

Conditions that place patients at high risk for drug interactions              

High risk associated with the severity of disease state being treated

Asthma

Cardiac arrhythmia

Critical care/intensive care patients Diabetes

Epilepsy

Hepatic disease

Hypothyroid

Aplastic anemia

High risk associated with drug interaction potential of related therapy        -

Autoimmune disorders

Cardiovascular disease

Gastrointestinal disease

Infection

Psychiatric disorders

Respiratory disorders

Seizure disorders

Patient populations at high risk include the elderly, critical care patients, and patients undergoing complicated surgical procedures. The elderly population is at high risk because of the number of medications consumed, complicated drug regimens, and clinical states often presented. About 80% of elderly patients routinely take prescription and nonprescription medications concurrently. Some patients, may see multiple physicians for acute and chronic conditions, as well as obtain medication from more than one community pharmacy.

NRTI Doses with Renal Insufficiency

NRTI/NTRTIs are cleared through the kidneys, except for ABC, which undergoes hepatic metabolism.  Therefore, except for ABC, dose adjustment of NRTI/NtRTIs is necessary in patients with significant renal failure.

Antiretroviral therapy-associated hepatic toxicity

Antiretroviral therapy-associated hepatic toxicity is of increasing concern in the management of patients with HIV/AIDS. Liver toxicity has been reported in some HIV-infected patients being treated with drugs from all of these classes of ARV drugs: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although the majority of cases involve asymptomatic elevations of liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), severe, and, in a minority of cases, life threatening, liver disease has been reported in patients treated with ARV drugs. The exact causes of elevated plasma levels of AST and ALT are complex and, in many cases, obscure. The combination of viral hepatic disease, drugs that act adversely directly on the liver and drugs that act on other systems of the body which in turn, adversely affect the liver, can result in hepatic toxicity. Such toxicity may be inappropriately attributed solely to the direct effect of a drug. Knowledge of the possible causes of liver toxicity, drug-drug interactions and ways to avoid it, should reduce the risk of developing hepatotoxicity. These patients require frequent monitoring of the patient, both clinically and by utilizing liver function tests on a regular basis. If signs and symptoms of liver disease do develop, prompt and expert management is essential.

Do not co-administer ribavirin and didanosine, this combination is contraindicated since fatal hepatic failure and other ddI-related toxicities have been reported with co-administration.

Conclusion

In resource-poor settings, inflexibility of regimens may make management of drug interactions  more of a challenge. On a public health level, the scale-up and coverage of ARVs, antimalarials and anti-TB drugs may take precedence over the quality of prescribing in the first instance. However, as coverage increases, a programmatic approach could be taken on national or regional levels to improve vigilance for and recognition of important drug interactions. In areas where disease epidemiology overlaps, protocols for treatment of co-infection could be incorporated into existing ARV programmes, taking into account local drug availability.

Drug interactions are largely unavoidable in HIV management, and the problem is likely to worsen. They can significantly impact patient care and lead to morbidity if not appropriately managed. Searchable electronic databases of HIV drug interactions are available, which are a useful tool for HIV healthcare professionals and non-specialists for managing drug interactions involving ARVs.

If combination therapy of interacting drugs cannot be avoided, the patient should be advised of any potential adverse effects. Always monitor the patient for any changes in clinical response when starting, stopping, or changing the dose of interacting drugs. Also monitor for any signs/symptoms of known toxicities. Appropriate clinical intervention should be taken when necessary.

Key learning points

·         ARVs are among the most therapeutically risky drugs for drug interactions, and are largely unavoidable in HIV management. They can significantly impact patient care and lead to morbidity if not appropriately managed. Minimize harm from drug interactions by dose adjustment or using alternatives.

·         Identification of clinically significant drug interactions is fundamental to improving the quality of prescribing in HIV management.

·         Clinically significant Drug interactions are more likely with regimens containing PIs than those containing NNRTIs. Ritonavir is a “Pharmacoenhancer” and has the most drug interactions and contraindications, therefore, consult a reference in all situations and always err on the side of conservatism. 

·         In patients receiving following medicines review interactions from time to time:

      ° Anti--tubercular therapy (ATT), especially with PIs: adjust dose of PIs

      ° Oral contraceptives: use alternative contraception

      ° Ketoconazole: use for no more than 1-2 weeks

      ° Ergotamines: CONTRAINDICATED

      ° Seizure medications: monitor viral load and drug levels/clinical symptoms closely

•    Always monitor the patient for any changes in clinical response when starting, stopping, or changing the dose of interacting drugs for appropriate clinical intervention.

•   Whenever there is an unexpected response to a drug, consider "drug-drug Interaction" as one of the possibility for the unexpected response and  monitor for any signs/symptoms of known toxicities.

Annexure 1.  Commonly occurring moderate to severe ARV drug interactions of clinical significance.

Drug / Drug class	Interacting ART Drug / Drug class	Potential Effect		Management
Anti- Tuberculosis drugs
Rifampicin	Nevirapine (NVP)	The plasma concentrations of NVP may be reduced, decreasing the efficacy. Potential of additive hepatotoxicity exists.		Careful monitoring may be done to adjust the dose of NVP.
	Efavirenz (EFV)	The plasma concentrations of EFV may be reduced, decreasing the efficacy.		Careful monitoring may be done to adjust the dose of EFV.
	Lopinavir/ low dose Ritonavir (LPV/r)	The plasma concentrations of LPV/r may be reduced, decreasing the efficacy.		Careful monitoring the patient’s response to LPV/r during co-administration with Rifampicin. It may be necessary to increase the dose of Ritonavir. Co administration is however not recommended.
	Nelfinavir (NFV)	The plasma concentration of NFV is reduced, decreasing the efficacy.		Co administration is not recommended.
	Saquinavir (SQV)	Plasma SQV concentrations may be reduced. In addition SQV may elevate serum Rifampicin concentrations, increasing the risk of side effects. Hepatotoxicity has been reported.		Co administration is not recommended.
Rifabutin	Nevirapine (NVP)	The plasma concentrations of NVP may be reduced, decreasing the efficacy.		Careful monitoring may be done to adjust the dose of NVP.
	Efavirenz (EFV)	The plasma concentrations of EFV may be reduced, decreasing the efficacy.		Careful monitoring may be done to adjust the dose of EFV.
	Lopinavir/ low dose Ritonavir (LPV/r)	The plasma concentrations of LPV/r may be reduced, decreasing the efficacy. In addition Ritonavir may elevate serum rifabutin levels, increasing the risk of rifabutin hematologic toxicity.		Co administration of Rifabutin & Ritonavir is not recommended. I unavoidable decrease the dose of Rifabutin to 150 mg, daily.
	Nelfinavir (NFV)	The plasma concentration of NFV is reduced, decreasing the efficacy.		Reduce the dose of Rifabutin to 150 mg, daily.
	Saquinavir (SQV)	Plasma SQV concentrations may be reduced. In addition SQV may elevate serum Rifabutin concentrations, increasing the risk of side effects		Co administration is not recommended. Add Ritonavir to SQR if Co administration is unavoidable. Dose of Rifabutin, 150 mg once daily.
INH	Didanosine Stavudine	Risk of peripheral neuropathy may be increased during concurrent use of two or more agents that are associated with this adverse effect.		Patients should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Recommended dosages should generally not be exceeded.
	Indinavir (mild)	Indinavir has been shown to increase the plasma concentration of isoniazid (inhibition of INH metabolism).		Interaction is unlikely to be of clinical importance
	Atazanavir (moderate)	May increase the plasma concentrations of atazanavir (inhibition of  metabolism)		Pharmacologic response to atazanavir should be monitored whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy
Pyrazinamide	No interaction	-		-
Ethambutol	Didanosine Stavudine	Risk of peripheral neuropathy may be increased during concurrent use of two or more agents that are associated with this adverse effect.		Patients should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Recommended dosages should generally not be exceeded. Therapy to be reinstituted only after resolution of neuropathy symptoms.
Clarithromycin	Efavirenz (EFV)	Plasma concentrations of clarithromycin may be reduced.		Alternative therapy such as azithromycin be considered. No dosage adjustments are recommended
	Lopinavir/ low dose Ritonavir (LPV/r)	Plasma levels of clarithromycin may be elevated		No dose adjustment for clarithromycin is required in case of normal renal function. Clarithromycin dose should be reduced in patients with renal impairment.
	Saquinavir (SQV)	Plasma levels of both clarithromycin & SQV may be elevated		Monitor for adverse effects associated with both the drugs. Dose reductions of SQV may be required. Alternatively azithromycin may be considered.
Antifungal
Ketoconazole	Nevirapine (NVP)	Ketoconazole levels may significantly decrease if NVP is continued for more than 2 weeks. NVP plasma levels may increase but is not considered clinically significant.		Co administration is not recommended. If required ketoconazole should not be given for more than 1-2 weeks.
	Lopinavir/ low dose Ritonavir (LPV/r) Nelfinavir (NFV) Saquinavir (SQV)	Plasma levels of antiretroviral agent  may be elevated increasing the risk of toxicity		Monitor the patient for protease inhibitor toxicity. Consider reducing the LPV/r dose. Do not exceed 200 mg/ day of ketoconazole
Itraconazole	Lopinavir/ low dose Ritonavir (LPV/r)	Plasma levels of LPV/r may be elevated increasing the risk of toxicity		Monitor the patient for protease inhibitor toxicity. Consider reducing the LPV/r dose. Do not exceed 200 mg/ day of Itraconazole.
	Nelfinavir (NFV)	Potential for bidirectional interaction		Monitor the patient for toxicities.
	Saquinavir (SQV)	Bidirectional interaction observed. Plasma levels of SQV & itraconazole may be elevated.		No dose adjustment necessary if SQV is unboosted. May need to decrease itraconazole dose.
Oral contraceptives
(Ethinyl oestradiol)	Nevirapine (NVP)  Efavirenz (EFV) Lopinavir/ low dose Ritonavir (LPV/r) Nelfinavir (NFV)	The efficacy of oral contraceptives may be reduced leading to possible unintended pregnancy		Use alternative or additional methods for contraception.
Anticonvulsants
Carbamazepine / Phenytoin)	Nevirapine (NVP) Nelfinavir (NFV) Saquinavir (SQV)	Plasma concentrations of antiretroviral agent may be reduced		Serum drug concentrations of  antiretroviral agent should be monitored during co-administration with phenytoin / Carbamazepine and the antiretroviral regimen is adjusted as necessary.
	Lopinavir/ low dose Ritonavir (LPV/r)	Levels of both phenytoin & LPV/r may be reduced leading therapeutic failure of phenytoin &  risk of reduced viral susceptibility and resistance development with LPV/r.		Monitor serum phenytoin levels. Monitor patients for potentially reduced antiretroviral response.
Phenobarbitone	Efavirenz (EFV) Lopinavir/ low dose Ritonavir (LPV/r) Nelfinavir (NFV)	May reduce serum levels of antiretroviral drugs and thus their antiviral efficacy		Antiretroviral response should be monitored whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary.
Opioid substitution Treatment (OST)
Methadone	Nevirapine (NVP) Efavirenz (EFV) Lopinavir/ low dose Ritonavir (LPV/r) Nelfinavir (NFV)	Methadone levels may be reduced resulting in opiate withdrawal symptoms. Lopinavir alone with methadone may increase levels of methadone leading to methodone toxicity including QTc prolongation and ventricular arrhythmias.		Monitor patients for opiate withdrawal symptoms during cotherapy. Monitor for signs of methadone overdose if the NNRTI’s are discontinued. Adjust the methadone dose as needed.
Buprenorphine	Efavirenz (EFV)	plasma concentrations and efficacy of buprenorphine may be reduced. No opiate withdrawal reported.		Pharmacologic response to buprenorphine should be monitored & dose adjusted as needed.
Lipid Lowering agents
Simvastatin / Lovastatin	Efavirenz (EFV)	Plasma concentration of simvastatin may be reduced resulting in diminished hypolipidemic efficacy.		Adjust simvastatin dose according to lipid response. Simvastatin dose not to exceed the maximum recommended. Pravastatin may be less likely to interact
	Lopinavir/ low dose Ritonavir (LPV/r) Nelfinavir (NFV) Saquinavir (SQV)	Plasma concentrations of lipid lowering agent may be significantly elevated increasing the risk of side effects (e.g., myopathy, rhabdomyolysis, acute renal failure)		Simvastatin & lovastatin should not be co administered with LPV/r. Fluvastatin and pravastatin are probably safer alternatives, since they are not metabolized by CYP 3A4. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated.
Atorvastatin	Efavirenz (EFV)	Plasma concentration of atorvastatin may be reduced resulting in diminished hypolipidemic efficacy.		Adjust atorvastatin dose according to lipid response. Atorvastatin dose not to exceed the maximum recommended. Pravastatin may be less likely to interact
Cisapride	Efavirenz (EFV) Lopinavir/ low dose Ritonavir (LPV/r) Nelfinavir (NFV) Saquinavir (SQV) Amprenavir Atazanavir Indinavir	Increased cisapride plasma concentrations with cardiotoxicity including life threatening arrhythmias (e.g., Torsades de pointes) may occur		Co administration contraindicated
Non-sedating antihistaminics
Astezimole, terfenadine	Saquinavir (SQV)		Inhibition of the CYP450 3A4 enzyme and may interfere with the metabolism of astemizole and terfenadine. The accumulation of astemizole or terfenadine may prolong the QT interval and possibly may lead to the development of ventricular arrhythmias, including torsades de pointes; cardiac arrest; and sudden death.	Co administration contraindicated. Loratadine, cetirizine, or fexofenadine may be safer alternatives.
Corticosteroids
Fluticasone	LPV/r, Ritonavir		Due to inhibition of fluticasone metabolism via CYP450 3A4, coadministration may increase the systemic exposure of fluticasone  administered intranasally or by inhalation. Systemic corticosteroid effects such as adrenal suppression, Cushing's syndrome, osteoporosis, and exacerbation of diabetes mellitus have been reported	Co administration is not recommended. Alternatives to fluticasone should be considered, particularly for long-term use.
Benzodiazepines
Alprazolam, Midazolam, Diazepam, Nitrazepam	Ritonavir, LPV/r		Elevated plasma concentrations of benzodiazepines due to inhibition of CYP450 3A4 activity by ritonavir.	It may be appropriate to use lower benzodiazepine dosages or use agents that are not metabolized by the CYP450 3A4 pathway (e.g., lorazepam, oxazepam,temazepam).
Warfarin	Amprenavir (AMP) Delavirdine (DLV) Indinavir ( IDV) Nelfinavir (NFV) Saquinavir (SQV)		Plasma concentrations and/or pharmacologic effects of warfarin may be increased. The exact mechanism of interaction is unknown. In some cases ritonavir has been reported to increase plasma concentration of warfarin leading to bleeding episodes.	INR monitoring is recommended to monitor toxicity of WAR. The INR should be checked frequently and anticoagulant dosage adjusted accordingly.
	Ritonavir Efavirenz		Plasma concentrations and/or pharmacologic effects of warfarin may be decreased. The exact mechanism of interaction is unknown.	INR monitoring is recommended to monitor for efficacy of WAR. The INR should be checked frequently and anticoagulant dosage adjusted accordingly.

Selected Interactions between Antiretrovirals (ARVs)

Protease Inhibitors
Lopinavir/ritonavir (LPV/r)	Do not coadminister with Fosamprenavir (fAMP), Tipranavir (TPV)
Atazanavir (ATV)	Do not use with Indinavir (IDV) due to additive risk of indirect bilirubinaemia, in previously PI-experienced patients use RTV boosting. If given with ddI (enteric coated) should be given at different times
Nelfinavir (NFV)	If co-administered with LPV/r, decrease NFV to 100 mg bid
Ritonavir (RTV)	Used as a boosting agent for most of the PIs
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz (EFV)	Requires RTV boosting when used with SQV, ATV, fAMP, IDV
Nevirapine (NVP)	Do not co-administer with ATV. Requires boosting with RTV when used with IDV, SQV
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir (TDF)	ATV should be boosted with RTV when co-administered with TDF Caution when used in combination with ddI and NNRTIs in treatment-naive patients (potential virologic failure)
Didanosine (ddI)	Separate administration from other agents by 2 hours When co-administered with TDF increased ddI levels can cause CD4 lymphocyte suppression: decrease ddI dose to 250 mg. Increased incidence of lactic acidosis with d4T
Zidovudine (AZT)	Do not co-administer with d4T due to antagonistic effect
Lamivudine (3TC)	Do not co-administer with Emtricitabine (FTC)

Group exercises

Case 1:

Savita, a 25 year-old HIV+ woman on ART prescription which includes Zidovudine,  lamivudine and lopinavir/ritonavir (LPV/r) comes to your hospital pharmacy with prescriptions for her recently diagnosed tuberculosis. She is going to begin treatment with first line anti-tuberculosis drugs. She is given prescription for the treatment of tuberculosis which reads: Isoniazid 300mg OD, Rifampicin 600mg OD, Pyrazinamide 750 mg BD & Ethambutol 1000mg OD.

Is this an appropriate regimen for her?

Can you identify any possible drug interaction

Case 2:

Ram Manohar is 45 year-old HIV+ male presenting for routine follow-up.  He has been on Highly Active Anti-Retroviral Therapy (HAART) for two years. CD4 count: 480 cells/mm3 HIV RNA < 50 copies/mL.   His current HAART medication regimen is: Nevirapine 200 mg bid, Lamivudine 150mg bid, Zidovudine 300 mg bid.

He comes into the pharmacy after seeing a physician for his migraines headaches which have been a problem for years. He is been prescribed Ergotamine + caffeine.

Is this an appropriate regimen for him? Can you identify any possible drug interaction.

Case 3:

Tarachand is a 41 year-old male presents with symptoms of thrush, fever & continued weight loss with diarrhea & lymphadenopathy for over one month. He has a CD4 count of 180 cells/mm3 and a HIV viral load of 120000 copies/mL. He was diagnosed with AIDS and started on ARV medications as follows: Zidovudine 300 mg bid, Stavudine 40 mg bid, Nevirapine 200 mg once daily for the first 2 weeks, then increase to 200 mg bid and Fluconazole.

Is this an appropriate regimen for him? Can you identify any possible drug interactions.

Case 4:

Mr. Shivnaryana, a 50 year-old male who has been HIV+ for 5 years and is stable on ARV therapy, presents to the clinic to get medication to treat his thrush. Earlier he was treated with Ketoconazole 200mg, which seemed to help at first and then stopped working. His current ARV regimen is: Nevirapine 200 mg bid, Zidovudine 300 mg bid, Lamivudine 150 mg bid

Is Ketoconazole, an appropriate medication to use with his current ARV regimen?

What is an alternative antifungal agent for this patient?

Antiretroviral drug interaction resources for further reading:

1. David S. Tatro. Drug interaction facts 2007, the authority on drug interactions. 1st Ed. St. Louis. Missouri: Wolters Kluwer Health, Publishers; 2007.
2. Scott M. Hammer; Joseph J. Eron, Jr; Peter Reiss; et al. Antiretroviral Treatment of Adult HIV Infection: 2008. Recommendations of the International AIDS Society USA Panel. JAMA. 2008;300(5):555-570
3. Giuseppe Barbaro1, Andrea Scozzafava, Antonio Mastrolorenzo and Claudiu T. Supuran. Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their  pharmacological Interactions Useful for Improving Therapeutic Outcome. Current Pharmaceutical Design, 2005, 11, 1805-1843.
4. Aberg JA.Drug-drug interactions with newer antiretroviral agents.Top HIV Med. 2008 Dec;16:146-50.
5. www.hiv-druginteractions.org
6. http://nacoonline.org
7. http://www.healthline.com/druginteractions
8. www.hivpharmacology.com