Efavirenz/lamivudine/tenofovir disoproxil Disease Interactions

Severe acute exacerbations of HBV have been reported in HIV-1/HBV-coinfected patients who have discontinued products containing emtricitabine, lamivudine, and/or tenofovir disoproxil fumarate (DF) and may occur with discontinuation of tenofovir alafenamide-containing products. It is recommended that all patients with HIV-1 infection be tested for the presence of HBV before or when initiating products containing emtricitabine, lamivudine, tenofovir DF, or tenofovir alafenamide. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HIV-1/HBV-coinfected patients who discontinue products (including fixed-dose combination products) that contain emtricitabine, lamivudine, tenofovir DF, or tenofovir alafenamide. If appropriate, initiation or resumption of antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Hepatotoxicity including lactic acidosis, severe hepatomegaly with steatosis, fulminant hepatitis, and hepatic failure has been associated with the use of some nucleoside reverse transcriptase inhibitors (NRTIs) alone or in combination with other antiretroviral agents. Therapy with NRTIs should be administered cautiously in patients with preexisting liver disease, a history of alcohol abuse, or hepatitis. Therapy should be suspended if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. The use of abacavir is contraindicated in patients with moderate to severe liver dysfunction as its safety and efficacy have not been established in these patients.

The nucleoside reverse transcriptase inhibitors, didanosine, stavudine, and lamivudine, may cause pancreatitis. The incidence is generally low but is up to 7% with didanosine, and up to 18% in pediatric patients given lamivudine. Patients with a history of or known risk factors for pancreatitis (such as alcohol abuse or hypertriglyceridemia) should be monitored closely during therapy with these agents. Therapy should be discontinued at the first signs/symptoms suggestive of pancreatitis (e.g., nausea, vomiting, abdominal pain, hyperamylasemia with dysglycemia, rising triglycerides, decreasing serum calcium), and preferably permanently discontinued if clinical pancreatitis develops.

Efavirenz is not recommended for patients with moderate or severe liver dysfunction; insufficient data are available to determine whether dose adjustment is needed. Patients with mild liver dysfunction may receive efavirenz without dose adjustment. Due to extensive CYP450-mediated metabolism and limited clinical experience in patients with liver dysfunction, therapy with efavirenz should be administered cautiously in patients with mild liver dysfunction; careful monitoring is recommended for these patients. In addition, postmarketing cases of hepatitis (including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death) have occurred during therapy with efavirenz; reports have included patients with underlying liver disease (including coinfection with hepatitis B or C). Monitoring of liver enzymes before and during therapy is recommended for all patients.

During clinical trials, efavirenz was associated with an increase in the occurrence of serious psychiatric events, including severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, and manic reactions. Other factors associated with an increased occurrence of these psychiatric symptoms were history of injectable drug use, psychiatric history, or use of psychiatric medications at study entry; similar associations were observed in the efavirenz and control groups. Therapy with efavirenz should be administered cautiously in patients with current/history of psychiatric illness, emotional instability, or substance abuse. Patients with serious psychiatric adverse reactions should receive prompt medical evaluation to assess the possibility that symptoms are related to efavirenz use, and if so, to determine whether the risks of continued therapy outweigh the benefits.

QTc prolongation has been observed with the use of efavirenz. Alternatives to efavirenz should be considered when administered to patients at higher risk of torsade de pointes or when coadministered with a medication with known risk of torsade de pointes.

Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution should be taken with any patient with history of seizures. Anticonvulsant medications primarily metabolized by the liver (e.g., phenytoin, phenobarbital) may require periodic monitoring of plasma levels.

The apparent oral clearance of nucleoside reverse transcriptase inhibitors is decreased in patients with renal dysfunction. Dosage adjustments are recommended for lamivudine and stavudine in patients with CrCl less than 50 mL/min; zidovudine dosage should be reduced in patients with CrCl less than 15 mL/min. Fixed-dose combination products containing lamivudine are not recommended for patients with CrCl less than 30 or 50 mL/min; the manufacturer product information should be consulted.

In clinical trials, tenofovir disoproxil fumarate (DF) was associated with slightly greater reductions in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk have not been established. Calcium and vitamin D supplementation may be beneficial; however, the effect of such supplementation was not studied. Assessment of BMD should be considered for patients with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected, appropriate consultation should be obtained.

Tenofovir alafenamide (as a single ingredient product) is not recommended in patients with decompensated liver dysfunction (Child-Pugh B or C); safety and efficacy have not been established in these patients. No dose adjustment of tenofovir alafenamide is required in patients with mild liver dysfunction (Child-Pugh A).
-Combination products containing tenofovir alafenamide have not been studied in patients with severe liver dysfunction; some of these products are not recommended for use in such patients. No dose adjustment of tenofovir alafenamide-containing products is required in patients with mild or moderate liver dysfunction (Child-Pugh A or B).

The pharmacokinetics of tenofovir after a single 300 mg dose of tenofovir disoproxil fumarate (DF) have been studied in non-HIV infected subjects with moderate to severe liver dysfunction. There were no significant changes in tenofovir pharmacokinetics in subjects with liver dysfunction compared to those with normal liver function. No adjustment in tenofovir DF dosing is required in patients with liver dysfunction.

Tenofovir is primarily eliminated by the kidneys via glomerular filtration and active tubular secretion. Serum creatinine, estimated CrCl, urine glucose, and urine protein should be assessed in all patients before/when starting tenofovir (alafenamide or disoproxil fumarate [DF]) and during therapy when clinically appropriate. Serum phosphorus should also be assessed in patients with chronic kidney disease.

Postmarketing cases of renal impairment (including acute renal failure, proximal renal tubulopathy, and Fanconi syndrome) have been reported with tenofovir alafenamide-containing products; most cases had potential confounders that may have contributed to the reported renal events and may have predisposed patients to tenofovir-related side effects. Tenofovir alafenamide should be discontinued in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Renal impairment (including acute renal failure and Fanconi syndrome) has been reported with tenofovir DF. Close monitoring of renal function and dosing interval adjustment are recommended for all patients with CrCl less than 50 mL/min. Creatinine clearance should be calculated in all patients before starting tenofovir treatment and during treatment when clinically appropriate. Routine monitoring of serum creatinine and phosphorus is recommended for patients at risk of or with a history of renal dysfunction. Safety and efficacy have not been evaluated in patients with renal dysfunction using dose adjustments; therefore, the benefit of tenofovir DF treatment should be weighed against the risk of renal toxicity. Renal function should be evaluated in patients at risk of renal dysfunction who have persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness (may be indicators of proximal renal tubulopathy).