Epivir Drug Information
Generic name: LAMIVUDINE
Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC] Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC]
Uses of Epivir
- EPIVIR is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection. Limitations of Use:
- The dosage of this product is for HIV‑1 and not for HBV. EPIVIR is a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection. Limitations of Use: The dosage of this product is for HIV‑1 and not for HBV.
Dosage & Administration of Epivir
Recommended Dosage for Adult Patients
The recommended dosage of EPIVIR in HIV-1–infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. If lamivudine is administered to a patient infected with HIV‑1 and HBV, the dosage indicated for HIV‑1 therapy should be used as part of an appropriate combination regimen.
Recommended Dosage for Pediatric Patients
EPIVIR scored tablet is the preferred formulation for HIV-1–infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing EPIVIR scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow EPIVIR tablets, the oral solution formulation may be prescribed.
The recommended oral dosage of EPIVIR tablets for HIV-1–infected pediatric patients is presented in Table 1. Table 1. Dosing Recommendations for EPIVIR Scored (150-mg) Tablets in Pediatric Patients a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. b Patients may alternatively take one 300-mg tablet, which is not scored.
Oral Solution The recommended dosage of EPIVIR oral solution in HIV-1–infected pediatric patients aged 3 months and older is 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution.
Patients with Renal Impairment Dosing of EPIVIR is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2. Table 2.
Adjustment of Dosage of EPIVIR in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of EPIVIR in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.
| a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies ( 14.2 )]. b Patients may alternatively take one 300-mg tablet, which is not scored. | ||||
| Weight (kg) | Once-Daily Dosing Regimen a | Twice-Daily Dosing Regimen Using Scored 150-mg Tablet | ||
| AM Dose | PM Dose | Total Daily Dose | ||
| 14 to <20 | 1 tablet (150 mg) | ½ tablet (75 mg) | ½ tablet (75 mg) | 150 mg |
| ≥20 to <25 | 1½ tablets (225 mg) | ½ tablet (75 mg) | 1 tablet (150 mg) | 225 mg |
| ≥25 | 2 tablets (300 mg) b | 1 tablet (150 mg) | 1 tablet (150 mg) | 300 mg |
| Creatinine Clearance (mL/min) | Recommended Dosage of EPIVIR |
|---|---|
| ≥50 | 150 mg twice daily or 300 mg once daily |
| 30-49 | 150 mg once daily |
| 15-29 | 150 mg first dose, then 100 mg once daily |
| 5-14 | 150 mg first dose, then 50 mg once daily |
| <5 | 50 mg first dose, then 25 mg once daily |
Side Effects of Epivir
Clinical Trials Experience Clinical Trials Experience in Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety profile of EPIVIR in adults is primarily based on 3,568 HIV-1–infected subjects in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea, and cough.
Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007. EPIVIR 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar.
Selected laboratory abnormalities observed during therapy are summarized in Table 4. Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007) The frequencies of selected laboratory abnormalities reported in subjects receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.
Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300 Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside‑experienced pediatric subjects receiving EPIVIR alone or in combination with other antiretroviral agents. In an open‑label dose‑escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with EPIVIR.
Three of these subjects died of complications of pancreatitis. In a second open‑label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to EPIVIR plus RETROVIR.
Pancreatitis was observed in 1 subject in this trial who received open‑label EPIVIR in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy. Selected laboratory abnormalities experienced by therapy‑naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6. Table 6.
Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300 Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of EPIVIR was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing.
One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. Neonates: Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation. Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes).
Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1–infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of EPIVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.
Body as a Whole Redistribution/accumulation of body fat. Endocrine and Metabolic Hyperglycemia. General Weakness.
Hemic and Lymphatic Anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic Lactic acidosis and hepatic steatosis, posttreatment exacerbations of hepatitis B. Hypersensitivity Anaphylaxis, urticaria.
Musculoskeletal Muscle weakness, CPK elevation, rhabdomyolysis. Skin Alopecia, pruritus.
| a Either zidovudine monotherapy or zidovudine in combination with zalcitabine. | ||
| Adverse Reaction | EPIVIR 150 mg Twice Daily plus RETROVIR (n = 251) | RETROVIR a (n = 230) |
| Body as a Whole | ||
| Headache | 35% | 27% |
| Malaise & fatigue | 27% | 23% |
| Fever or chills | 10% | 12% |
| Digestive | ||
| Nausea | 33% | 29% |
| Diarrhea | 18% | 22% |
| Nausea & vomiting | 13% | 12% |
| Anorexia and/or decreased appetite | 10% | 7% |
| Abdominal pain | 9% | 11% |
| Abdominal cramps | 6% | 3% |
| Dyspepsia | 5% | 5% |
| Nervous System | ||
| Neuropathy | 12% | 10% |
| Insomnia & other sleep disorders | 11% | 7% |
| Dizziness | 10% | 4% |
| Depressive disorders | 9% | 4% |
| Respiratory | ||
| Nasal signs & symptoms | 20% | 11% |
| Cough | 18% | 13% |
| Skin | ||
| Skin rashes | 9% | 6% |
| Musculoskeletal | ||
| Musculoskeletal pain | 12% | 10% |
| Myalgia | 8% | 6% |
| Arthralgia | 5% | 5% |
| a The median duration on study was 12 months. b Either zidovudine monotherapy or zidovudine in combination with zalcitabine. c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. ULN = Upper limit of normal. ND = Not done. | ||||
| Test (Threshold Level) | 24-Week Surrogate Endpoint Trials a | Clinical Endpoint Trial a | ||
| EPIVIR plus RETROVIR | RETROVIR b | EPIVIR plus Current Therapy c | Placebo plus Current Therapy c | |
| Absolute neutrophil count (<750/mm 3 ) | 7.2% | 5.4% | 15% | 13% |
| Hemoglobin (<8.0 g/dL) | 2.9% | 1.8% | 2.2% | 3.4% |
| Platelets (<50,000/mm 3 ) | 0.4% | 1.3% | 2.8% | 3.8% |
| ALT (>5.0 x ULN) | 3.7% | 3.6% | 3.8% | 1.9% |
| AST (>5.0 x ULN) | 1.7% | 1.8% | 4.0% | 2.1% |
| Bilirubin (>2.5 x ULN) | 0.8% | 0.4% | ND | ND |
| Amylase (>2.0 x ULN) | 4.2% | 1.5% | 2.2% | 1.1% |
| a Includes pain, discharge, erythema, or swelling of an ear. | ||
| Adverse Reaction | EPIVIR plus RETROVIR (n = 236) | Didanosine (n = 235) |
| Body as a Whole | ||
| Fever | 25% | 32% |
| Digestive | ||
| Hepatomegaly | 11% | 11% |
| Nausea & vomiting | 8% | 7% |
| Diarrhea | 8% | 6% |
| Stomatitis | 6% | 12% |
| Splenomegaly | 5% | 8% |
| Respiratory | ||
| Cough | 15% | 18% |
| Abnormal breath sounds/wheezing | 7% | 9% |
| Ear, Nose, and Throat | ||
| Signs or symptoms of ears a | 7% | 6% |
| Nasal discharge or congestion | 8% | 11% |
| Other | ||
| Skin rashes | 12% | 14% |
| Lymphadenopathy | 9% | 11% |
| ULN = Upper limit of normal. | ||
| Test (Threshold Level) | EPIVIR plus RETROVIR | Didanosine |
| Absolute neutrophil count (<400/mm 3 ) | 8% | 3% |
| Hemoglobin (<7.0 g/dL) | 4% | 2% |
| Platelets (<50,000/mm 3 ) | 1% | 3% |
| ALT (>10 x ULN) | 1% | 3% |
| AST (>10 x ULN) | 2% | 4% |
| Lipase (>2.5 x ULN) | 3% | 3% |
| Total Amylase (>2.5 x ULN) | 3% | 3% |
Warnings & Cautions for Epivir
Patients with Hepatitis B Virus Co-Infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re‑emergence of HBV DNA. Although most events appear to have been self‑limited, fatalities have been reported in some cases.
Similar events have been reported from postmarketing experience after changes from lamivudine‑containing HIV‑1 treatment regimens to non‑lamivudine–containing regimens in patients infected with both HIV‑1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment.
Important Differences among Lamivudine ‑ Containing Products EPIVIR tablets and oral solution contain a higher dose of the same active ingredient (lamivudine) than EPIVIR‑HBV tablets and EPIVIR‑HBV oral solution. EPIVIR‑HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in EPIVIR‑HBV are not appropriate for patients co-infected with HIV‑1 and HBV.
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co‑infected with HIV‑1 and HBV. If treatment with EPIVIR‑HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV‑1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV‑1 treatment. If a decision is made to administer lamivudine to patients co‑infected with HIV‑1 and HBV, EPIVIR tablets, EPIVIR oral solution, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen.
Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1–infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.
Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including EPIVIR. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues.
Treatment with EPIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.
Pancreatitis
In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, EPIVIR should be used with caution. Treatment with EPIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received EPIVIR oral solution (at weight band-based doses approximating 8 mg per kg per day) concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets. EPIVIR scored tablet is the preferred formulation for HIV-1‑infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol.
Consider more frequent monitoring of HIV-1 viral load when treating with EPIVIR oral solution.
Drug Interactions with Epivir
Drugs Inhibiting Organic Cation Transporters Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine.
Pregnancy Safety for Epivir
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data).
The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR.
The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose ( see Data ).
Data Human Data: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was following first trimester exposure to lamivudine-containing regimens and following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa.
These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans.
Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 times higher than human exposure at the recommended daily dose.
Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.
Pediatric Use of Epivir
Pediatric Use The safety and effectiveness of EPIVIR in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older. EPIVIR scored tablet is the preferred formulation for HIV-1‑infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate because pediatric subjects who received EPIVIR oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets in the ARROW trial.
Contraindications for Epivir
EPIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.
Overdosage Information for Epivir
There is no known specific treatment for overdose with EPIVIR. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.
Clinical Studies of Epivir
Adult Subjects Clinical Endpoint Trial NUCB3007 (CAESAR) was a multicenter, double‑blind, placebo-controlled trial comparing continued current therapy (zidovudine alone or zidovudine with didanosine or zalcitabine ) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. The median duration on trial was 12 months. Results are summarized in Table 9.
Table 9. Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Trials Dual Nucleoside Analogue Trials: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination.
More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression. Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multicenter, double‑blind, controlled trial in which subjects were randomized 1:1 to receive EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10.
Figure 1. Virologic Response through Week 48, EPV20001 a,b (Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR. b Responders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit. Table 10.
A small, randomized, open‑label pilot trial, EPV40001, was conducted in Thailand. Figure 1. Virologic Response Through Week 48, EPV20001ab Intent-to-Treat
Pediatric Subjects Clinical Endpoint Trial ACTG300 was a multicenter, randomized, double‑blind trial that provided for comparison of EPIVIR plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1–infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median duration on trial was 10.1 months for the subjects receiving EPIVIR plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy.
Results are summarized in Table 11. Table 11. Number of Subjects (%) Reaching a Primary Clinical Once-Daily Dosing ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects.
HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing EPIVIR and abacavir, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of EPIVIR and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3.
Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort. The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.
Table 12. Virologic Outcome of Randomized Treatment at Week 96 a (ARROW Randomization 3) Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations of EPIVIR and abacavir (75% and 72% ) than in those who had received solution formulation(s) (with EPIVIR solution given at weight band-based doses approximating 8 mg per kg per day) at any time (52% and 54% ), respectively. These differences were observed in each different age group evaluated.
| a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States. | |||
| Endpoint | Current Therapy (n = 460) | EPIVIR plus Current Therapy (n = 896) | EPIVIR plus an NNRTI a plus Current Therapy (n = 460) |
| HIV-1 progression or death | 90 (19.6%) | 86 (9.6%) | 41 (8.9%) |
| Death | 27 (5.9%) | 23 (2.6%) | 14 (3.0%) |
| a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks. b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48. c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment. | ||
| Outcome | EPIVIR 300 mg Once Daily plus RETROVIR plus Efavirenz (n = 278) | EPIVIR 150 mg Twice Daily plus RETROVIR plus Efavirenz (n = 276) |
| Responder a | 67% | 65% |
| Virologic failure b | 8% | 8% |
| Discontinued due to clinical progression | <1% | 0% |
| Discontinued due to adverse events | 6% | 12% |
| Discontinued due to other reasons c | 18% | 14% |
| Endpoint | EPIVIR plus RETROVIR (n = 236) | Didanosine (n = 235) |
|---|---|---|
| HIV-1 disease progression or death (total) | 15 (6.4%) | 37 (15.7%) |
| Physical growth failure | 7 (3.0%) | 6 (2.6%) |
| Central nervous system deterioration | 4 (1.7%) | 12 (5.1%) |
| CDC Clinical Category C | 2 (0.8%) | 8 (3.4%) |
| Death | 2 (0.8%) | 11 (4.7%) |
| a Analyses were based on the last observed viral load data within the Week 96 window. b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96. c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. d Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing). | ||
| Outcome | EPIVIR plus Abacavir Twice-Daily Dosing (n = 333) | EPIVIR plus Abacavir Once-Daily Dosing (n = 336) |
| HIV-1 RNA <80 copies/mL b | 70% | 67% |
| HIV-1 RNA ≥80 copies/mL c | 28% | 31% |
| No virologic data | ||
| Discontinued due to adverse event or death | 1% | <1% |
| Discontinued study for other reasons d | 0% | <1% |
| Missing data during window but on study | 1% | 1% |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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