Indications

Indinavir is an alpha-amino acid amide protease inhibitor used as a treatment therapy for Human immunodeficiency virus (HIV) infections, which can lead to acquired immunodeficiency syndrome (AIDS). The FDA approved indinavir in 1996 as it was among the first HIV protease inhibitors authorized in the United States.[1] Indinavir has decreased the likelihood of death due to AIDS progression.  It is no longer available in the United States or Europe as it has many adverse effects, and there are better drugs. The article remains for historical value.

According to guidelines from the U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents, the use of indinavir is no longer recommended. However, it is used off-label as a part of boosted regimen in combination(ritonavir+indinavir). Indinavir is commonly combined with HIV antiretroviral medications, such as the HIV protease inhibitor ritonavir. Indinavir is also subject to a high viral protease gene mutation rate. Therefore an Indinavir monotherapy regime is rarely used to prevent the likelihood of drug resistance.[2]

Recent studies have analyzed the effects of indinavir as an anti-cancer agent.[3] Human papillomavirus is induced by increased expression of eukaryotic translation initiation factor 4E (eIF4E), potentially leading to cervical cancer. Indinavir is an inhibitor of eIF4E. Therefore, recent research has examined its role as a possible cervical cancer treatment.[4] According to a recent preclinical study, ritonavir's boosted indinavir regimen decreased tumor hypoxia and improved the delivery of chemotherapeutic drugs. Tissue inhibitor of metalloproteinase-3 (TIMP-3) plays a vital role in carcinogenesis. The study observed that modulation of TIMP-3 by protease inhibitors boosted regimens block the cervical intraepithelial neoplasia(CIN) and carcinoma cervix progression. These observations may lead to new therapeutic indications of protease inhibitors to treat cervical carcinoma; however, substantial research is needed before clinical approval.[5]

Mechanism of Action

Indinavir acts through a competitive inhibition mechanism. The medication binds the active catalytic site of HIV protease, inhibiting the enzyme's ability to cleave polypeptides into active, infectious proteins. This inhibition, in turn, decreases the number of cleaved polypeptides in the blood, which therefore aids in reducing the amount of active HIV RNA in vivo.

Mechanism of Resistance: Viral resistance to indinavir is due to mutations that result in the expressing amino acid substitutions in the viral protease and flap mutations.[6] Additionally, Gag mutations are responsible for resistance to indinavir therapy.[7]

Pharmacokinetics

Absorption: Indinavir is rapidly absorbed in the fasting state, and food alters the bioavailability of indinavir. When indinavir is administered with a meal high in calories, fat, and protein, it substantially decreases absorption. However, administering indinavir with light meals does not alter trough concentration and absorption.Distribution: Plasma protein binding of indinavir is approximately 60%.Metabolism: CYP3A4 is the primary enzyme that metabolizes indinavir. Indinavir is metabolized to one glucuronide conjugate and six oxidative metabolites.Elimination: Less than 20% of indinavir is excreted unchanged in the urine. Indinavir has a half-life of 1.8 ± 0.4 hours.

Administration

Indinavir is administered orally in 100 mg, 200 mg, 333 mg, and 400 mg capsules. The most common indinavir dosage is 800 mg, which is taken as two 400 mg capsules every 8 hours. Recommendations are that patients do not take the medication with food, only water or other liquids (i.e., tea, juice, or coffee). Patients may choose to take indinavir either 1 hour before a meal or two hours after consuming a meal to maximize absorption. If taken with a large meal rich in protein and/or fat, it will diminish the drug's efficacy because of reduced absorption.[1] However, foods such as bread and milk may be consumed with indinavir as long as the portions remain small. If a patient misses a dose, the recommendation is that the patients take the next dose at the appropriate time interval. Therefore, one should not take multiple doses at the same time.

Dual Combination Therapy with Protease Inhibitors (PI)

The following are protease inhibitors used in combination with indinavir. Only one PI would typically be administered concurrently with indinavir. The most common regiment for dual therapy is as follows:

Indinavir (800 mg, orally, every 8 hours) + ritonavir (100 mg to 200 mg, orally twice daily). Note: take ritonavir with 48 oz of water.[8]

Combination Therapy with two Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Indinavir (800 mg, orally, every 8 hours) + zidovudine (200 mg, orally, every 8 hours) + lamivudine (150 mg, orally, twice a day) reduces HIV RNA levels below 500 copies per milliliter.[9]

Studies suggest that both treatment plans result in similar plasma HIV RNA and CD4+ levels.[10]

Optimal dosing remains undetermined for pediatric patients. However, indinavir was considered a category C medication under the prior FDA categorization for drugs in pregnancy.

Use in Specific Patient Populations

Patients with Hepatic impairment: If a patient is diagnosed with hepatic insufficiency before starting treatment, the prescriber should lower the indinavir dosage to 600 mg.

Patients with Renal Impairment: The pharmacokinetics of indinavir have not been evaluated in patients with renal insufficiency. Furthermore, patients should consume an average of 1.5 liters or approximately six glasses of 8 fluid ounces of liquid daily to ensure adequate hydration. Remaining hydrated will help prevent and severity both nephrolithiasis and/or urolithiasis. Additionally, if nephrolithiasis or urolithiasis occurs, the medication should be held for 24 to 72 hours or discontinued altogether.[11]

Pregnancy Considerations: Optimal dosing remains undetermined for pregnant patients. However, indinavir was considered a category C medication under the prior FDA categorization for drugs in pregnancy. According to the manufacturer's product labeling, there is a lack of adequate studies on pregnant patients. Given the inadequate information on the use of indinavir during pregnancy, its use is not recommended in HIV-infected pregnant patients. Clinicians should encourage patients exposed to indinavir during pregnancy to register in the antiretroviral pregnancy registry.[12]

Breastfeeding Considerations: Information regarding the evidence of indinavir use during breastfeeding is limited. Indinavir is not a recommended antiretroviral medication during breastfeeding.[13]

Adverse Effects

Most Common Adverse Reactions

• Nephrolithiasis/urolithiasis: This may occur with symptoms such as flank pain and hematuria or asymptomatic. Administration of antiretroviral therapy (ART) to patients increases the risk of renal insufficiency.[14] Indinavir is commonly known for causing lithiasis, specifically nephrolithiasis and ureterolithiasis.[1][15] This effect is because indinavir is only soluble in acidic conditions.[16] Additionally, asymptomatic crystalluria has a 66% incidence.[17] Hepatitis B and hepatitis C comorbidities, inadequate hydration, predisposing kidney conditions, and immune deficiencies increase the risk of nephrolithiasis and renal impairment.[1][17] Indinavir may also lead to pyelonephritis. Management of indinavir-associated nephrolithiasis is conservative. Recommendations are to temporarily discontinue the indinavir and maintain adequate hydration with pain management.
• Hyperglycemia, leading to insulin resistance
• Heart attack
• Diabetes leading to ketoacidosis
• Hemolytic anemia
• Lipodystrophy

Most Common Less Serve Side Effects

• Diarrhea
• Nausea
• Vomiting
• Fatigue

Rare Side Effect

Hydronephrosis

Hepatotoxicity: Likelihood score: C (a frequent cause of serum bilirubin elevations and probable cause of rare instances of clinically apparent liver injury). The pattern of serum enzyme elevations due to indinavir therapy can be cholestatic or hepatocellular, associated with indirect hyperbilirubinemia. Acute liver injury due to indinavir is generally self-limited, although rare cases of acute liver failure have been reported.[18]

Drug Interactions: Indinavir is an inhibitor of CYP3A4. Therefore, concurrent administration of indinavir and medications metabolized by CYP3A4 can increase plasma concentrations, increasing therapeutic and adverse effects. On the contrary, coadministration of indinavir and other medications that inhibit CYP3A4 may reduce indinavir clearance and result in increased plasma concentrations of indinavir. This interaction commonly occurs with herbal supplements such as St. John's wort (Hypericum perforatum) and primarily occurs due to the activation of pregnane-X-receptor (PXR).[19][20]

Contraindications

Indinavir metabolism occurs via hepatic cytochrome CYP450, specifically the subfamily CYP3A4; hence medications metabolized by CYP3A4 are contraindicated.[17]

• Alpha 1-adrenoreceptor antagonists
• Antiarrhythmics
• Ergot derivatives
• Sedatives and hypnotics
• Gastrointestinal motility agents
• Neuroleptics
• HMG-CoA reductase inhibitors
• PDE5 inhibitors
• Midazolam[21]

Additionally, patients taking phosphodiesterase inhibitors type 5 (PDE5) to treat erectile dysfunction such as sildenafil and tadalafil can cause unwanted side effects such as hypotension and prolonged erections. These side effects may become exacerbated when taken with indinavir. (according to product labeling)

Monitoring

Patients with a history of kidney stone formation or those at an increased risk of kidney stone development may still be treated with indinavir, although clinicians can consider other alternatives.[1] However, all patients should be closely monitored during the first six months of treatment. Renal function and urinary health require monitoring throughout treatment with indinavir.[17] The majority of stones produced by indinavir are considered radiolucent. Therefore, conventional methods such as CT scans and X-rays of the kidney, ureters, and bladder (KUB) cannot detect such stones. Therefore, monitoring should occur through a urine analysis capable of detecting crystalluria.[17][22] Clinicians should monitor HIV viral load and CD4 lymphocyte to select appropriate treatment regimens and opportunistic infection prophylaxis.[23]

Toxicity

A 2001 review of Indinavir overdoses (n=79) took into account all reports of indinavir overdose. It defined an acute overdose as a single dose of 2400 mg and a chronic overdose as recurring doses less than or equal to 2400 mg.[24] The study found that 66% of patients (52/79) experienced an adverse event. It is important to note that the most common reactions for chronic and acute overdoses were gastrointestinal (nausea, vomiting, abdominal pain) and renal-related (nephrolithiasis/flank pain/renal colic pain).

Common treatment methods for symptomatic Indinavir overdose include hydration (oral or intravenous), diuresis, and activated charcoal to decrease absorption. 87% of patients recovered based on follow-up information provided (n=45).[24] Additionally, an overdose report suggested that 50 mg of activated charcoal was given orally in combination with IV fluids, and the patient was asymptomatic within 4 hours of treatment.[25]

Enhancing Healthcare Team Outcomes

According to indinavir overdose data, it was determined that 70% (46/66) overdoses were accidental.[24] Therefore, all interprofessional healthcare team members must communicate clearly to ensure appropriate care coordination. 

To decrease the likelihood that a patient misinterprets dosing instructions or is unable to read or comprehend them, patients must receive adequate counsel from a pharmacist and/or clinician. Additionally, those responsible for the patient's care should adequately follow up with the patient to ensure that the patient is dosing indinavir correctly, as compliance is essential for effective treatment. Nurses with specialty training in HIV patient care can educate patients and their families about the importance of compliance and side effects. Since ineffective dosing and administration can lead to therapeutic failure, these collaborative strategies can significantly improve patient outcomes with indinavir therapy. A study concluded that an interprofessional approach using psychosocial training providers, such as social workers, health educators, and community outreach workers, in collaboration with primary care can enhance  HIV continuum services.[26][Level 5]