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Epivir

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Epivir




CLINICAL PHARMACOLOGY

Mechanism Of Action

Lamivudine is an antiviral agent [see Microbiology].

Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg.

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

The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss 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 subjects. Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg per 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 per 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 per 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 subjects 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 tablets and oral solution may be administered with or without food.

Distribution

The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L per 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 (less than 36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg per 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 route of elimination. In man, 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 per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.

In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per 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
AUC∞ (mcg•h/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 trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL per 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 recommended, following correction of dose for creatinine clearance, that 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 Trial NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric subjects (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 per kg per day. In the 9 infants and children (age range: 5 months to 12 years) receiving oral solution 4 mg per 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 subjects, as shown in Figure 1.

Figure 1: Systemic Clearance (L/h•kg) of Lamivudine in Relation to Age

Systemic Clearance (L/h•kg) of Lamivudine in Relation to Age -  Illustration

After oral administration of lamivudine 4 mg per kg twice daily to 11 pediatric subjects ranging in age from 4 months to 14 years, Cmax was 1.1 ± 0.6 mcg per 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 subjects receiving an 8-mg per kg per day dose and adults receiving a 4-mg per kg per day dose.

Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg per kg per day, CSF lamivudine concentrations in 8 subjects 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 per mL.

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

Geriatric Patients: The pharmacokinetics of lamivudine after administration of EPIVIR to subjects over 65 years 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 trial 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 subjects [see WARNINGS AND PRECAUTIONS].

Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject 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 AUC ∞, 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 subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h) [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 per 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 μM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 μM (range: 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 μM 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-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 (M184V/I).

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some subjects 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 HBV mutants have been reported in HIV-1-infected subjects 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 (ddI) and zalcitabine (ddC). In some subjects treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.

Genotypic and Phenotypic Analysis of On-therapy HIV-1 Isolates from Subjects with Virologic Failure

Trial EPV20001: Fifty-three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level greater than or equal to 400 copies per mL) by Week 48. Twenty-eight subjects 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 subjects in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies per mL and 4.6 log10 copies per mL, respectively.

Genotypic analysis of on-therapy isolates from 22 subjects identified as virologic failures in the lamivudine once-daily group showed that isolates from 0 of 22 subjects contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10 of 22 subjects contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8 of 22 subjects contained a treatment-emergent lamivudine resistance-associated substitution (M184I or M184V).

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

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

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

Trial EPV40001: Fifty subjects received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus lamivudine 300 mg once daily and 50 subjects received zidovudine 300 mg plus abacavir 300 mg plus lamivudine 150 mg all twice-daily. The median baseline plasma HIV-1 RNA levels for subjects in the 2 groups were 4.79 log10 copies per mL and 4.83 log10 copies per mL, respectively. Fourteen of 50 subjects in the lamivudine once-daily treatment group and 9 of 50 subjects in the lamivudine twice-daily group were identified as virologic failures.

Genotypic analysis of on-therapy HIV-1 isolates from subjects (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from subjects (n = 6) receiving lamivudine twice daily showed that isolates from 2 subjects had M184V alone, and isolates from 2 subjects harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.

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

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

Clinical Studies

The use of EPIVIR is based on the results of clinical trials in HIV-1-infected subjects 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.

Adult Subjects

Clinical Endpoint Trial

NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR 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 per mm³ (median = 122 cells per 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 trial was 12 months. Results are summarized in Table 8.

Table 8: Number of Subjects (%) 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 NNRTIa 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 An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Surrogate Endpoint 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 multi-center, 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. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm³ (median = 362 cells per mm³), and median baseline plasma HIV-1 RNA of 4.66 log10 copies per mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.

Figure 2: Virologic Response through Week 48, EPV20001ab (Intent-to-Treat)

Virologic Response through Week 48, EPV20001ab - Illustration

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 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)
Respondera 67% 65%
Virologic failureb 8% 8%
Discontinued due to clinical progression < 1% 0%
Discontinued due to adverse events 6% 12%
Discontinued due to other reasonsc 18% 14%
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.

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

A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm , median plasma HIV-1 RNA 4.8 log10 copies per mL) were enrolled. Two of the treatment arms in this trial 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 subjects with HIV-1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once-daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies per mL were 54% (29 of 54) in the once-daily lamivudine group and 67% (35 of 52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells per mm³ in the once-daily lamivudine group and 216 cells per mm³ in the all-twice-daily group.

Pediatric Subjects

Clinical Endpoint Trial

ACTG300 was a multi-center, 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 age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white. The mean baseline CD4+ cell count was 868 cells per mm³ (mean: 1,060 cells per mm³ and range: 0 to 4,650 cells per mm³ for subjects aged less than or equal to 5 years; mean: 419 cells per mm³ and range: 0 to 1,555 cells per mm³ for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL. 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 10.

Table 10: Number of Subjects (%) 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: 3/6/2015
This monograph has been modified to include the generic and brand name in many instances.

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