Treatment of HIV Infection
Nevirapine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients.
Because adults with high pretreatment CD4 T-cell counts are at increased risk for serious and life-threatening hepatotoxicity associated with nevirapine, the drug should not be initiated in women with pretreatment CD4 T-cell counts exceeding 250 cells/mm or in men with CD4 T-cell counts exceeding 400 cells/mm unless potential benefits outweigh risks.
(See Cautions: Hepatic Effects.)
Nevirapine generally has been used in HIV nonnucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimens that include nevirapine and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).
The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,
The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that nevirapine is not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents because it has been associated with serious and potentially fatal toxicity (e.g., hepatic events and severe rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis) and did not meet noninferiority criteria when compared to efavirenz in clinical trials.
Study BI 1046
Safety and efficacy of nevirapine (200 mg once daily for the initial 2 weeks, then 200 mg every 12 hours) have been evaluated in conjunction with zidovudine (200 mg 3 times daily) with or without didanosine (125 or 200 mg twice daily) for initial antiretroviral therapy in a randomized, double-blind study in treatment-naive (had not previously received antiretroviral therapy) adults (study BI 1046). Study BI 1046 included 151 adults (median age 36 years) with baseline CD4 T-cell counts of 200-600 cells/mm (mean 376 cells/mm) and mean baseline plasma HIV-1 RNA levels of 4.41 log10 copies/mL (25,704 copies/mL). Patients were randomized to receive a 3-drug regimen of zidovudine, didanosine, and nevirapine or a 2-drug regimen of zidovudine and didanosine or zidovudine and nevirapine.
The primary endpoint was the proportion of patients with plasma HIV-1 RNA levels less than 400 copies/mL and not previously failed at 48 weeks. At 48 weeks, the virologic response rate was 45% in those receiving the 3-drug regimen (zidovudine, didanosine, and nevirapine), 19% for those receiving zidovudine and didanosine, and 0% in those receiving nevirapine and zidovudine. The mean increase in CD4 T-cell count above baseline was 139 cells/mm in those receiving the 3-drug regimen compared with 87% in those receiving zidovudine and didanosine.
Safety and efficacy of nevirapine extended-release tablets were evaluated in a randomized, double-blind, double-dummy, phase 3 trial in antiretroviral-naive adults (85% male, 75% white, 20% black, 29% from North America) who received a regimen of nevirapine immediate-release tablets (200 mg once daily) for 14 days with 2 NRTIs (tenofovir and emtricitabine) and were then randomized to continue therapy with nevirapine immediate-release tablets (200 mg twice daily) or switch to nevirapine extended-release tablets (400 mg once daily) with the same background regimen of 2 NRTIs (study 1100.1486; VERxVE). At baseline, the mean plasma HIV RNA level was 4.7 log10 copies/mL and the mean CD4 T-cell count was 228 cells/mm; approximately 66% of patients had baseline plasma HIV RNA levels of 100,000 copies/mL or lower. At 96 weeks, 67% of those receiving immediate-release nevirapine and 69% of those receiving extended-release nevirapine had plasma HIV RNA levels less than 50 copies/mL and the mean change from baseline in CD4 T-cell count, adjusted for baseline HIV viral load stratum, was 222 or 244 cells/mm, respectively.
Study BI 1090
Nevirapine has been evaluated for use in conjunction with other antiretroviral agents in adults with advanced HIV-1 infection (study BI 1090). This study was a placebo-controlled, double-blind, randomized study that included 2,249 adults (median age 36.5 years, 79% male, 70% white, median baseline CD4 T-cell count 96 cells/mm, median baseline plasma HIV-1 RNA level 4.58 log10 copies/mL [38,291 copies/mL]; 89% had previously received antiretroviral therapy). Patients were randomized to receive nevirapine (200 mg once daily for 2 weeks, then 200 mg twice daily) and lamivudine (150 mg twice daily) with a background antiretroviral regimen or lamivudine with a background regimen; the background regimen was one NRTI (58%), 2 or more NRTIs (34%), or HIV protease inhibitors (PIs) and NRTIs (8%). Prior to study entry, 45% of patients had previously experienced an AIDS-defining clinical event.
At 48 weeks, 18% of those receiving a regimen that included nevirapine had plasma HIV-1 RNA levels less than 50 copies/mL compared with 2% of those not receiving the NNRTI. At 1 year, the change from baseline CD4 T-cell count for the overall trial population was 64 cells/mm in those receiving nevirapine compared with 22 cells/mm in those not receiving the drug. At 2 years, 16% of those receiving nevirapine had experienced events classified as US Centers for Disease Control (CDC) class C events compared to 21% of those in the control arm.
Safety and efficacy of switching from nevirapine immediate-release tablets to nevirapine extended-release tablets was evaluated in an ongoing open-label, phase 3 trial in antiretroviral-experienced adults with HIV-1 RNA levels less than 50 copies/mL (approximately 50% had been receiving immediate-release nevirapine for at least 3 years; approximately 50% were receiving a background regimen of tenofovir and emtricitabine and the remaining patients were receiving abacavir [or zidovudine]) and lamivudine. Patients were randomized (2:1 ratio) to switch to nevirapine extended-release tablets (400 mg once daily) or continue therapy with nevirapine immediate-release tablets (200 mg twice daily) with their current background regimen of 2 NRTIs (study 1100.1526; TRANxITION). At 48 weeks after randomization, 93% of those receiving extended-release tablets and 91% of those receiving immediate-release tablets continued to have plasma HIV-1 RNA levels less than 50 copies/mL.
Nevirapine is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in children 15 days of age or older (oral suspension or immediate-release tablets). Alternatively, nevirapine extended-release tablets may be used in pediatric patients 6 years of age or older.
For initial treatment in HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a ritonavir-boosted PI, NNRTI, or integrase strand transfer inhibitor (INSTI) in conjunction with 2 NRTIs (dual NRTIs).
The HHS panel states that nevirapine in conjunction with 2 NRTIs is an alternative (not a preferred) regimen for initial treatment in pediatric patients older than 14 days and less than 3 years of age. The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) in conjunction with 2 NRTIs is the preferred regimen for antiretroviral treatment in pediatric patients 14 days to less than 2 years of age and also a preferred regimen in those 2 years of age to less than 3 years of age.
Although nevirapine is only labeled by FDA for use in neonates 15 days of age or older, the HHS panel states that nevirapine and 2 NRTIs is the preferred regimen for initial antiretroviral treatment in neonates younger than 14 days of age if HIV infection has been confirmed and a decision is made to initiate treatment in this age group. However, consultation with an expert in pediatric HIV infection is recommended since clinical trial data are not available suggesting that initiation of antiretroviral treatment within the first 14 days of life improves outcome compared with initiation after 14 days of age. If a regimen of nevirapine and 2 NRTIs is initiated in a neonate younger than 14 days of age, the HHS panel states that a change to lopinavir/ritonavir and 2 NRTIs should be considered when the infant is 14 days of age with postmenstrual age at least 42 weeks (i.e., time elapsed since first day of the mother's last menstrual period to birth plus time elapsed after birth).
Nevirapine should not be used in postpubertal or adolescent girls with CD4 T-cell counts exceeding 250 cells/mm or adolescent boys with CD4 T-cell counts exceeding 400 cells/mm, unless benefits clearly outweigh risks.
(See Cautions: Hepatic Effects.)
For further information on treatment of HIV infection in pediatric patients,
Study BI 1100.1368
Safety and efficacy of nevirapine in HIV-infected pediatric patients have been evaluated in an open-label, randomized study in treatment-naive children 3 months to 16 years of age (49% male, 81% black, 19% white, median baseline plasma HIV-1 RNA level 5.45 log10 copies/mL, median baseline CD4 T-cell count 527 cells/mm, 4% previously received antiretroviral therapy). Children received nevirapine oral suspension (dose based on body surface area or body weight; maximum 400 mg daily) in conjunction with lamivudine and zidovudine. At 48 weeks, 47% of patients had plasma HIV-1 RNA levels less than 400 copies/mL.
Safety and efficacy of nevirapine also have been evaluated in an open-label, phase 1 or 2 study that included 8 HIV-infected children 2-16 months of age who were treatment-naive. These pediatric patients received a 3-drug regimen of oral zidovudine (180 mg/m given every 8 hours), oral didanosine (120 mg/m given every 12 hours), and nevirapine (120 mg/m given once daily for 28 days, then 200 mg/m given every 12 hours). Plasma HIV-1 RNA levels were reduced at least 96% (a decrease of 1.5 log10 copies/mL) in 7 of 8 patients within 2-4 weeks of initiating therapy and, at 6 months, were still below baseline levels in 5 of 6 infants whose treatment started when they were 4 months of age or younger; the regimen was well tolerated in all patients.
Nevirapine extended-release tablets were evaluated in an open-label, nonrandomized, crossover trial in 85 HIV-infected pediatric patients 3 to less than 18 years of age who had received at least 18 weeks of immediate-release nevirapine and had plasma HIV-1 RNA levels less than 50 copies/mL (55% female, 93% black, approximately 84% from Africa, median baseline CD4 T-cell count 925 cells/mm [range 207-2057 cells/mm]). Following a 10-day period of treatment with immediate-release nevirapine, patients were switched to extended-release nevirapine in conjunction with other antiretrovirals. After 10 days of treatment with the extended-release preparation, steady-state pharmacokinetics were determined and 40 of the initial study patients were enrolled in an optional extension phase of the trial to evaluate safety and antiretroviral activity of extended-release nevirapine. At 24 weeks, 39 of these patients continued to have plasma HIV-1 RNA levels less than 50 copies/mL and 1 patient had discontinued the drug because of an adverse reaction. When the 39 patients were stratified according to age, median CD4 T-cell counts in those 3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years of age were 1113, 853, and 682 cells/mm, respectively. These CD4 T-cell counts were similar to those observed at baseline.
Prevention of Perinatal HIV Transmission
Nevirapine is used in conjunction with other antiretroviral agents for prophylaxis or empiric HIV therapy in neonates for prevention of perinatal HIV transmission.
Although various nevirapine regimens have been used alone or in conjunction with other antiretrovirals for prevention of perinatal HIV transmission in limited-resource areas (e.g., sub-Saharan Africa), including single-dose intrapartum/neonatal nevirapine regimens (e.g., a single nevirapine dose given to the mother at the onset of labor and a single nevirapine dose given to the neonate within 72 hours after birth) and 6-week neonatal nevirapine regimens, single-dose nevirapine regimens (either alone or in conjunction with intrapartum/neonatal zidovudine regimens) are not recommended in the US. Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.
In the US, multiple-drug antiretroviral regimens are considered the standard of care for treatment of HIV-1 infection in pregnant women and for prevention of perinatal HIV transmission. The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that all pregnant HIV-infected women in the US should receive multiple-drug antiretroviral therapy, regardless of the woman's plasma HIV RNA level or CD4 T-cell count. In addition, to further decrease the risk of perinatal HIV transmission, the HHS panel states that pregnant HIV-infected women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or with unknown HIV RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor (or 3 hours before scheduled cesarean delivery) and continued until delivery (unless contraindicated) and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an antiretroviral regimen (either prophylaxis or empiric HIV therapy) initiated as soon as possible after birth (preferably within 6-12 hours) and continued for 4-6 weeks. HIV-exposed neonates at low risk of perinatal HIV acquisition (e.g., those born to an HIV-infected mother who received standard multiple-drug antiretroviral treatment during pregnancy with sustained viral suppression near the time of delivery and with no concerns related to maternal adherence to the treatment regimen) can receive a neonatal prophylaxis regimen that includes only zidovudine. However, a combination antiretroviral regimen that includes zidovudine and 1 or 2 additional antiretrovirals should be used in neonates at higher risk of HIV acquisition, including those born to HIV-infected women who did not receive antepartum or intrapartum antiretrovirals, received only intrapartum antiretrovirals, received antepartum and intrapartum antiretrovirals with suboptimal viral suppression near delivery (i.e., detectable plasma HIV RNA levels), or had primary or acute HIV infection during pregnancy or during breast-feeding. This strategy of combined antepartum, intrapartum, and neonatal antiretrovirals reduces perinatal HIV transmission by several mechanisms, including lowering maternal antepartum viral load and providing pre- and postexposure prophylaxis in the infant.
Antiretrovirals in HIV-exposed Neonates
The choice of a neonatal antiretroviral prophylaxis regimen or a neonatal empiric HIV therapy regimen should be based on an assessment of the likelihood of perinatal HIV transmission.
Although the HHS panel states that a 4-week zidovudine prophylaxis regimen can be used alone in HIV-exposed neonates at low risk, those at higher risk of HIV acquisition (e.g., those born to HIV-infected women who did not receive antepartum or intrapartum antiretrovirals, received only intrapartum antiretrovirals, or received antepartum and intrapartum antiretrovirals with suboptimal viral suppression near delivery) should receive a 2-drug prophylaxis regimen that includes a 6-week zidovudine prophylaxis regimen and a 3-dose nevirapine prophylaxis regimen. Alternatively, the HHS panel states that neonates at highest risk can receive empiric HIV therapy with a 3-drug regimen of zidovudine, lamivudine, and nevirapine. The 3-drug empiric HIV therapy regimen serves as antiretroviral prophylaxis to prevent acquisition of HIV and also serves as early treatment for neonates who are later confirmed to have acquired HIV. The optimal duration of empiric HIV therapy in neonates at highest risk of HIV acquisition is unknown. Many experts recommend that the 3-drug regimen be continued for 6 weeks; others discontinue nevirapine and/or lamivudine if results of the neonate's HIV nucleic acid amplification test (NAAT) are negative, but recommend continuing the zidovudine regimen for 6 weeks.
Because safety and dosage data are not available, the HHS panel states that use of antiretrovirals other than zidovudine, lamivudine, and nevirapine cannot be recommended for premature HIV-exposed neonates (gestational age less than 37 weeks).
For information on the risk of perinatal transmission of HIV and additional information regarding recommendations for use of antiretroviral agents for prevention of perinatal HIV transmission,
Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.