Nevirapine

Mechanism of Action

The primary mechanism by which non-nucleoside reverse transcriptase inhibitors such as nevirapine function is by binding to the reverse transcriptases, which are unique to HIV. The binding of the nevirapine causes the formation of a hydrophobic pocket near the active site of the reverse transcriptase. This new pocket causes an alteration in the three-dimensional configuration of the substrate-binding site, which ultimately leads to hindering HIV DNA synthesis. An important point to note is that while nevirapine is effective against HIV-1, it is not effective against HIV-2 since it is non-competitive as an inhibitor.[5]

Nevirapine undergoes extensive hepatic metabolism; it is a CYP2B6 and 3A substrate. It is excreted in the urine (approximately 80%) and the feces (approximately 10%) and has a half-life of 25 to 30 hours.

Administration

Adult patients: this medication is administered orally and has a variable dosage depending on the length of time of the drug's administration. During the initial 14 days of the administration, the dosage is 200 mg tablet once daily. For every day following the first 14 days, the dosage is 200 mg tablet twice daily. This medication is given in combination with other antiretroviral drugs.

Pediatric patients: this medication is administered orally in liquid form and has a variable dosage depending on how long the medication has been administered. During the initial 14 days of administering the drug, the dosage is 150 mg/m once daily. For every day following the first 14 days, the dosage is 150 mg/m twice daily.

There is no need for dose adjustment in renal impairment. In hemodialysis patients, no adjustment is necessary, but a 200 mg IR supplement should be administered following dialysis.[6] For patients with hepatic impairment, see the Contraindications section.

Adverse Effects

Among the most well-known side effects of taking this medication is the damage it can cause to the liver.[7]

Serious reactions also include Stevens-Johnson syndrome, anaphylaxis, toxic epidermal necrolysis, severe stomatitis, and autoimmune conditions.

Other common side effects/reactions include:

• Jaundice
• Rash
• Fever
• Nausea
• Fatigue
• Headache
• Abdominal pain
• Joint ache
• Edema
• Blisters
• Lipodystrophy

Contraindications

Decreased Liver Function, Hepatomegaly, and Cirrhosis

• Nevirapine is contraindicated in patients with Child-Pugh Class B or C liver impairment because of its potential hepatotoxic effects. If the liver is already damaged or has decreased function, administration of nevirapine could lead to liver failure.

Pregnancy

• In treatment-naive patients, nevirapine should be avoided during pregnancy, although there is no known risk of fetal harm based on human data and animal studies.
• For virologically suppressed, treatment-experienced patients, nevirapine therapy may continue during pregnancy if baseline CD4 counts are above 250.
• Pregnant patients should be enrolled in the Antiretroviral Pregnancy Registry.

Drug-Drug Interactions

• Nevirapine is contraindicated for concomitant administration with atazanavir.
• Many other agents that also affect or are metabolized by the hepatic CYP450 system will require caution or dose adjustments and, in some cases, changes in therapy.[8]

Monitoring

Routine examination of serum nevirapine levels in patients on this medication is crucial because different levels of nevirapine present indicate the medication’s effectiveness, or lack thereof, in suppressing the targeted viral infection. Previously conducted clinical research has found that a plasma trough concentration of nevirapine greater than 4000 ng/mL correlates highly with the medication’s ability to suppress the viral load of HIV such that it is undetectable. A plasma trough concentration of nevirapine less than 3000 ng/mL strongly correlates with the probability of virologic failure in patients receiving ART involving nevirapine.[9]

It is also critical to conduct routine checks of liver function in patients treated with nevirapine, as it is known to have potentially severe hepatotoxic side effects.[10] In adult patients, LFTs should be checked at baseline, then 2 to 8 weeks following treatment initiation or changes, then every 3 to 6 months. In pediatric patients, LFTs should be taken at baseline, then every two weeks for four weeks, then every three months

Beyond monitoring nevirapine singularly, it is essential to understand its pharmacokinetic interaction with enzymes and other drugs. Patients seeking treatment for HIV may present with a prior list of medications that they already take, and being aware of those medications’ potential interactions with nevirapine and the side effects of nevirapine can prevent unpredictable interactions. For example, nevirapine is a known inducer of cytochrome P450 enzymes, which means that this effect will impact any medication metabolized by this enzyme. Its dosing and administration will have to be adjusted accordingly for any given patient.

Another significant interaction is that of nevirapine and methadone.[11] Both nevirapine and methadone are metabolized by CYP2B6, which is a member of the human cytochrome P450 superfamily, but nevirapine is also an inducer of this enzyme. Due to nevirapine’s ability to upregulate CYP2B6’s metabolic function, methadone becomes metabolized significantly more quickly when administered simultaneously with nevirapine. This situation can pose a danger to the patient if the dosing of methadone is not adjusted accordingly, as someone utilizing it may metabolize it too quickly and then begin to exhibit withdrawal symptoms.[2][12]

Toxicity

When discussing the toxicity of this drug, it is often secondary to the hepatic damage caused by the drug. There is currently no known antidote for nevirapine overdose.

Another essential point to note regarding nevirapine toxicity is that of the currently known NNRTIs and protease inhibitors; it is the only one that has not shown any negative effect on lipids to date.[13]

Enhancing Healthcare Team Outcomes

Managing patients taking nevirapine requires several factors, one of which is cohesive interprofessional teamwork. For treatment to be conducted smoothly and for the patient to receive the most significant benefit possible from it, every member of the interprofessional healthcare team, including clinicians (MDs, DOs, NPs, and PAs), nursing staff, and pharmacists, must be well informed about the treatment regimen and must actively work to ensure all members of the team are on the same page.[14]  

Another critical component is the meticulous and regular follow-up with said patients. Because of this medication’s known potential for causing hepatotoxicity in those consuming it, patients’ liver functions must be monitored, especially in the beginning stages of treatment.[14] Again, interprofessional coordination and open communication are crucial elements of effective patient monitoring for therapeutic effectiveness and safety.

It is also important to note that the effectiveness of this medication relies heavily on patient compliance with taking the medication as prescribed. It is up to healthcare professionals to ensure patients are well informed about their responsibilities in ensuring they receive maximal improvement from the treatment. Healthcare professionals must further ensure that they view their patients as more than their illness and consider factors such as social support, finances, and mental health when monitoring patient adherence. If they note any signs of non-adherence (in patient interviews, failure to pick up prescriptions, etc.), they must immediately alert all interprofessional team members to implement interventions. All drugs require teamwork and open communication, but this is heightened for HIV therapy since non-adherence can invalidate entire classes of antiretroviral agents. Below are some examples of recommendations for methods to increase the success of HIV treatment in patients on antiviral therapy:

• Actively monitoring patient compliance with regular visits to see their healthcare professional.
  • Beyond initially presenting for medical care, it is essential to ensure a patient follows up with their healthcare provider to determine treatment efficacy.
• Patients should be asked for self-reported adherence regularly
  • Although patients overestimate their adherence, self-reporting has a high predictive value.
• When monitoring patient adherence, checking refill data from the patient’s respective pharmacy is recommended.
  • Observational studies involving medical records and claims data confirm the validity of pharmacy refill data used to measure patient adherence to antiretroviral therapy.  
• Altering patient regimens from being complex to simpler once-daily regimens is a recommendation.
  • Several studies have shown that switching patients to an easier regimen for taking medication improves their overall adherence.
• Using technological devices to set reminders for taking medication is a recommendation.
  • Studies have shown that setting routine alarms or reminders helps to increase adherence. Examples of some methods include receiving reminders via text message and receiving weekly check-ins from the clinic either via text message or phone call.
• Working to concurrently provide antiretroviral therapy with screening, managing, and treating various mental illnesses is recommended.
  • Randomized, controlled trials have shown that for patients with illnesses such as depression, providing them with cognitive-behavioral therapy and adherence counseling helps to improve their compliance with taking medication on time.[14]

With an interprofessional team approach that includes clinicians, specialists (particularly those infectious disease specialists who focus on HIV therapy), mid-level practitioners, nurses, and pharmacists, patient outcomes will be better, and adverse events will be minimized. [Level 5]