Recommended Topic Related To:

Epivir

"On March 20, we recognize the impact of HIV/AIDS on American Indians, Alaska Natives and Native Hawaiians. This 7th national observance is our chance to raise awareness of the risks of HIV to Native people, to help communities understand what con"...

Epivir

CLINICAL PHARMACOLOGY

Mechanism of Action

Lamivudine is an antiviral agent [see CLINICAL PHARMACOLOGY].

Pharmacokinetics

Pharmacokinetics in Adults: The pharmacokinetic properties of lamivudine have been - studiedin-asymptomatic,-HIV-4-infected-adult patients after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.

The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected patients.

The steady-state pharmacokinetic properties of the EPIVIR (lamivudine) 300-mg tablet once daily for 7 days compared with the EPIVIR (lamivudine) 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR (lamivudine) 150 mg twice daily with respect to plasma AUC24,SS; however, CmaxSS was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,SS and Cmax24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration in HIV-1-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.

The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily.

Effects of Food on Oral Absorption: An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected patients on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states; therefore, EPIVIR (lamivudine) Tablets and Oral Solution may be administered with or without food.

Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.

Binding of lamivudine to human plasma proteins is low ( < 36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism: Metabolism of lamivudine is a minor routeofelirhination. Inman, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.

Elimination: The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). In 20 HIV-1-infected patients given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean + SD) of total clearance of lamivudine.

In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (ti/2) ranged from 5 to 7 hours. In HIV-1 -infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg.

Special Populations: Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7).

Table 7: Pharmacokinetic Parameters (Mean ± SD) After a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults With Varying Degrees of Renal Function

Parameter Creatinine Clearance Criterion
(Number of Subjects)
> 60 mL/min
(n = 6)
10-30 mL/min
(n = 4)
< 10 mL/min
(n = 6)
Creatinine clearance (mL/min) 111 ± 14 28 ±8 6±2
Cmax (mcg/mL) 2.6 ±0.5 3.6 ±0.8 5.8 ±1.2
AUC7infin;(mcg•hr/mL) 11.0 + 1.7 48.0 ±19 157 ±74
Cl/F (mL/min) 464 ± 76 114 ± 34 36 ± 11

Exposure (AUC∞), Cmax) and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see DOSAGE AND ADMINISTRATION].

Based on a study in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is "re"c"ommeiTdeli;'follo^n^corre^tioii of dose for creatinine clearahceTthat no additional dose modification be made after routine hemodialysis or peritoneal dialysis.

It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.

The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.

Hepatic Impairment: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Pediatric Patients: In Study NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric patie'nts !(age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the 9 infants and children (range: 5 months to 12 years of age) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults. The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.

Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 1.

Figure 1. Systemic Clearance (L/hr«kg) of Lamivudine in Relation to Age

Systemic Clearance (L/hr«kg) of Lamivudine in Relation to Age - illustration

After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric patients ranging from 4 months to 14 years of age, Cmax was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose.

Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 patients ranged from 5.6% to 30.9% (mean + SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.

Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients ( > 3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges > 3 months old [see ADVERSE REACTIONS].

Geriatric Patients: The pharmacokinetics of lamivudine after administration of EPIVIR (lamivudine) to patients over 65 years of age have not been studied [see Use in Specific Populations].

Gender: There are no significant gender differences in lamivudine pharmacokinetics. Race: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions: Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a study of 19 healthy male subjects [see WARNINGS and PRECAUTIONS].

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and PRECAUTIONS].

Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive patients in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once: a day for 5 days with concomitant administration of lamivudine 300 mg"with~the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUCoo, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine [see DRUG INTERACTIONS].

Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr) [see DRUG INTERACTIONS].

Microbiology

Mechanism of Action: Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ.

Antiviral Activity: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values (50% effective concentrations) were in the range of 0.003 to 15 µM (1 µM = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 µM (range: 0.200 to 2.007 uM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 µM (1.37 to 3.68 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003 to 0.120 uM in peripheral blood mononuclear cells. Ribavirin (50 µM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells. In HIV- 1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the full prescribing information for EPIVIR (lamivudine) -HBV for information regarding the inhibitory activity of lamivudine against HBV.

Resistance: Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (Ml 84V/I).

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients. Susceptibility of clinical isolates to lamivudine and'zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include: rtL80I and rtA181T. Similar FIBV mutants have been reported in HIV-1 -infected patients who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus [see WARNINGS and PRECAUTIONS].

Cross-Resistance: Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddl) and zalcitabine (ddC). In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase1 Inhibitors, including lamivudine, have emerged.

Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Patients With Viroloqic Failure: Study EPV20001: Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level ≥ 400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies/mL and 4.6 log10 copies/mL, respectively.

Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent amino acid substitutions associated with efavirenz resistance (LI001, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained a treatment-emergent lamivudine resistance-associated substitution (Ml841 or Ml 84V).

Genotypic analysis of on-therapy isolates from patients (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance substitutions, isolates from 7/22 contained treatment-emergent efavirenz resistance substitutions, and isolates from 5/22 contained treatment-emergent lamivudine resistance substitutions.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited a 25- to 295-fold decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed an 85- to 299-fold decrease in susceptibility to lamivudine.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 3/13 patients exhibited a 21- to 342-fold decrease in susceptibility to efavirenz, and isolates''from 4/13 patients exhibited a 29- to 159-fold decrease in susceptibility to lamivudine.

Study EPV40001: Fifty patients received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus lamivudine 300 mg once daily and 50 patients received zidovudine 300 mg plus abacavir 300 mg plus lamivudine 150 mg all twice daily. The median baseline plasma HIV-1 RNA levels for patients in the 2 groups were 4.79 logio copies/mL and 4.83 logiocopies/mL, respectively. Fourteen of 50 patients in the lamivudine once-daily treatment group and 9 of 50 patients in the lamivudine twice-daily group were identified as virologic failures.

Genotypic analysis of on-therapy HIV-1 isolates from patients (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 patients had an abacavir and/or lamivudine resistance-associated substitution Ml 84V alone. On-therapy isolates from patients (n = 6) receiving lamivudine twice daily showed that isolates from 2 patients had Ml 84V alone, and isolates from 2 patients harbored the M184Vsubstitution in combination with zidovudine resistance-associated amino acid substitutions.

Phenotypic analysis of on-therapy isolates from patients (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 patients exhibited a 32- to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 patients'were susceptible to zidovudine,

Phenotypic analysis of on-therapy isolates from patients (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 patient exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine.

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

Clinical Studies

The use of EPIVIR (lamivudine) is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

Adults

Clinical Endpoint Study: NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of EPIVIR (lamivudine) or EPIVIR (lamivudine) plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on study was 12 months. Results are summarized in Table 8.

Table 8: Number of Patients (%) With at Least One HIV-1 Disease Progression Event or Death.

Endpoint Current Therapy
(n = 460)
EPIVIR plus
Current Therapy
(n = 896)
EPIVIR plus an
NNRTI* 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%)
* An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Surrogate Endpoint Studies: Dual Nucleoside Analogue Studies: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These studies 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 Studies in Therapy-Naive Adults: EPV20001 was a multi-center, double-blind, controlled study in which patients were randomized 1:1 to receive EPIVIR (lamivudine) 300 mg once daily or EPIVIR (lamivudine) 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.

Figure 2. Virologic Response Through Week 48, EPVZQOOl'(lntent-to-Treat)

Virologic Response Through Week 48, EPVZQOOl'&dagger;(lntent-to-Treat) - illustration

* Roche AMPLICOR HIV-1 MONITOR.
Responders at each visit are patients who had achieved and maintained HIV-1 RNA < 400 copies/mL without discontinuation by that visit.

Tabic 9: Outcomes of Randomized Treatment Through 48 Weeks (Intent-to-Treat)

Outcome EPIVIR 300 mg
Once Daily
plus RETROVIR
plus Efavirenz
(n = 278)
EPIVIR 150 mg
Twice Daily
plus RETROVIR
plus Efavirenz
(n = 276)
Responder* 67% 65%
Virologic failure 8% 8%
Discontinued due to clinical progression < 1% 0%
Discontinued due to adverse events 6% 12%
Discontinued due to other reasons 18% 14%
* Achieved confirmed plasma HIV-1 RNA < 400 copies/mL and maintained through 48 weeks.
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.
Includes consent withdrawn, lost to followup, protocol violation, data outside the study-definedschedule, and randomized but never initiated treatment.

The proportions of patients with HIV-1 RNA < 50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving EPIVIR (lamivudine) 300 mg once daily and 63% for patients receiving EPIVIR (lamivudine) 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in patients receiving EPIVIR (lamivudine) 300 mg once daily and 146 cells/mm3 for patients receiving EPIVIR (lamivudine) 150 mg twice daily.

A small, randomized, open-label pilot study, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 logio copies/mL) were enrolled. Two of the treatment arms in this study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75%o (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group.

Pediatric Patients

Clinical Endpoint Study: ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR (lamivudine) plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range: 0 to 4,650 cells/mm3 for patients ≤ 5 years of age; mean: 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for patients > 5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 logiocopies/mL. The median duration on study was 10.1 months for the patients receiving EPIVIR (lamivudine) plus RETROVIR and 9.2 months for patients receiving didanosine monotherapy. Results are summarized in Table 10.

Table 10: Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

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%)

Last reviewed on RxList: 3/11/2011
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


WebMD Daily

Get breaking medical news.