Etravirine: A Novel Nonnucleoside Reverse Transcriptase Inhibitor
Etravirine: A Novel Nonnucleoside Reverse Transcriptase Inhibitor
Purpose: The pharmacology, efficacy, and safety of etravirine and its clinical utility with respect to the available alternative human immunodeficiency virus (HIV) treatment options are reviewed.
Summary: While single mutations confer resistance to earlier nonnucleoside reverse transcriptase inhibitors (NNRTIs), etravirine exhibited an increased barrier to resistance by requiring multiple mutations for resistance to occur in preclinical studies. Randomized controlled trials have demonstrated the efficacy of etravirine in achieving HIV RNA viral loads of < 50 copies/mL and a significant increase in baseline CD4+ lymphocyte count in treatment-experienced patients. There has been a trend toward increased rates of death, progression to acquired immunodeficiency syndrome, and opportunistic infections in patients using placebo during Phase III trials. Baseline patient characteristics that correlate with changes in etravirine efficacy are reported. Mild-to-moderate rash and nausea are the most common adverse effects of etravirine. If rash is suspected, etravirine should be discontinued and rechallenge should be avoided due to the risk of severe and possibly fatal skin reactions. Unlike some antiretrovirals, increased risks of hepatic, lipid, or neuropsychiatric abnormalities are not correlated with its use. Several drug interactions are expected with etravirine use, and some may require dosage adjustment or substitution of concurrent drugs. No dosage adjustments are recommended for patients with mild-to-moderate hepatic or renal impairment.
Conclusion: Etravirine, a second-generation NNRTI, is efficacious in achieving viral suppression and improving the immune function in treatment-experienced HIV-infected patients.
According to the World Health Organization, approximately 5,700 people worldwide die from acquired immunodeficiency syndrome (AIDS) and 6,800 individuals become infected with human immunodeficiency virus (HIV) every day. While approximately 30 million people worldwide are infected with HIV, the rate of AIDS-related deaths has been declining in several countries over the past two years due to the broader availability of antiretrovirals. According to the Centers for Disease Control and Prevention (CDC), approximately 56,300 individuals in the United States are newly infected with HIV every year.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) comprise approximately 10% of the HIV drug market worldwide, and efavirenz leads this class with $680 million annual sales in the United States. Most guidelines recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) and either an NNRTI or protease inhibitor (PI) for first-line therapy for HIV infection (Table 1). A comparison of currently available NNRTIs is presented in Table 2. Efavirenz, the preferred first-generation NNRTI, exhibits superior virological response in treatment-naive patients, compared with lopinavir-ritonavir, nelfinavir, and other PIs. Efavirenz has a long half-life, allowing for once-daily administration, which is a unique feature compared with all other NNRTIs and most PIs. Furthermore, the use of NNRTIs to complement the NRTI backbone will preserve the option to use PIs if treatment failure occurs.
NNRTIs are associated with a low genetic barrier to resistance, meaning that the presence of one mutation may confer resistance to all first-generation NNRTIs, whereas multiple mutations must be present before resistance to PIs is observed. Other disadvantages of NNRTIs include the prevalence of intraclass cross-resistance and an increased frequency of NNRTI-resistant viral strains in treatment-naive patients. Consequently, the development of second-generation NNRTIs has focused on optimizing the resistance profile of first-generation NNRTIs. The numerous drug interactions with cytochrome P-450 (CYP) isoenzyme inducers and inhibitors, as well as the possibility of liver toxicity, especially in patients with hepatitis or elevated baseline liver function test values, have been limitations for both NNRTIs and PIs. In addition, the potential teratogenic and neuropsychiatric properties associated with efavirenz, as well as the increased frequency of skin rash with all NNRTIs, should be considered before use. Shortcomings of the currently available antiretrovirals, including the novel classes, sparked interest in the old targets to improve known classes such as NNRTIs.
Etravirine, the first second- generation NNRTI approved for marketing by the Food and Drug Administration (FDA), is also approved for use in Canada, Europe, and elsewhere. It is indicated for use in combination with other anti-retrovirals for treatment-experienced adults with multiclass-resistant HIV-1 strains. This article examines the safety and efficacy of etravirine.
Abstract and Introduction
Abstract
Purpose: The pharmacology, efficacy, and safety of etravirine and its clinical utility with respect to the available alternative human immunodeficiency virus (HIV) treatment options are reviewed.
Summary: While single mutations confer resistance to earlier nonnucleoside reverse transcriptase inhibitors (NNRTIs), etravirine exhibited an increased barrier to resistance by requiring multiple mutations for resistance to occur in preclinical studies. Randomized controlled trials have demonstrated the efficacy of etravirine in achieving HIV RNA viral loads of < 50 copies/mL and a significant increase in baseline CD4+ lymphocyte count in treatment-experienced patients. There has been a trend toward increased rates of death, progression to acquired immunodeficiency syndrome, and opportunistic infections in patients using placebo during Phase III trials. Baseline patient characteristics that correlate with changes in etravirine efficacy are reported. Mild-to-moderate rash and nausea are the most common adverse effects of etravirine. If rash is suspected, etravirine should be discontinued and rechallenge should be avoided due to the risk of severe and possibly fatal skin reactions. Unlike some antiretrovirals, increased risks of hepatic, lipid, or neuropsychiatric abnormalities are not correlated with its use. Several drug interactions are expected with etravirine use, and some may require dosage adjustment or substitution of concurrent drugs. No dosage adjustments are recommended for patients with mild-to-moderate hepatic or renal impairment.
Conclusion: Etravirine, a second-generation NNRTI, is efficacious in achieving viral suppression and improving the immune function in treatment-experienced HIV-infected patients.
Introduction
According to the World Health Organization, approximately 5,700 people worldwide die from acquired immunodeficiency syndrome (AIDS) and 6,800 individuals become infected with human immunodeficiency virus (HIV) every day. While approximately 30 million people worldwide are infected with HIV, the rate of AIDS-related deaths has been declining in several countries over the past two years due to the broader availability of antiretrovirals. According to the Centers for Disease Control and Prevention (CDC), approximately 56,300 individuals in the United States are newly infected with HIV every year.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) comprise approximately 10% of the HIV drug market worldwide, and efavirenz leads this class with $680 million annual sales in the United States. Most guidelines recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) and either an NNRTI or protease inhibitor (PI) for first-line therapy for HIV infection (Table 1). A comparison of currently available NNRTIs is presented in Table 2. Efavirenz, the preferred first-generation NNRTI, exhibits superior virological response in treatment-naive patients, compared with lopinavir-ritonavir, nelfinavir, and other PIs. Efavirenz has a long half-life, allowing for once-daily administration, which is a unique feature compared with all other NNRTIs and most PIs. Furthermore, the use of NNRTIs to complement the NRTI backbone will preserve the option to use PIs if treatment failure occurs.
NNRTIs are associated with a low genetic barrier to resistance, meaning that the presence of one mutation may confer resistance to all first-generation NNRTIs, whereas multiple mutations must be present before resistance to PIs is observed. Other disadvantages of NNRTIs include the prevalence of intraclass cross-resistance and an increased frequency of NNRTI-resistant viral strains in treatment-naive patients. Consequently, the development of second-generation NNRTIs has focused on optimizing the resistance profile of first-generation NNRTIs. The numerous drug interactions with cytochrome P-450 (CYP) isoenzyme inducers and inhibitors, as well as the possibility of liver toxicity, especially in patients with hepatitis or elevated baseline liver function test values, have been limitations for both NNRTIs and PIs. In addition, the potential teratogenic and neuropsychiatric properties associated with efavirenz, as well as the increased frequency of skin rash with all NNRTIs, should be considered before use. Shortcomings of the currently available antiretrovirals, including the novel classes, sparked interest in the old targets to improve known classes such as NNRTIs.
Etravirine, the first second- generation NNRTI approved for marketing by the Food and Drug Administration (FDA), is also approved for use in Canada, Europe, and elsewhere. It is indicated for use in combination with other anti-retrovirals for treatment-experienced adults with multiclass-resistant HIV-1 strains. This article examines the safety and efficacy of etravirine.