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Safety profile and tolerability of amprenavir in the treatment of adult and pediatric patients with HIV infection
CLINICAL THERAPEUTICSWOL.
22, NO. 12,200O
Safety Profile and Tolerability of Amprenavir in the Treatment of Adult and Pediatric Patients with HIV Infection Louise Pedneault, MD,l Cindy Brothers, MSPH,’ Grace Pagano, MS,’ Paulina Tymkewycz, PhD,2 Jane Yeo, PhD,2 Judith Millard, PhD,l and Anny Fetter, M@ ‘Glaxo Wellcome HIV and Opportunistic Infections Clinical Development, Research Triangle Park, North Carolina, and ‘Glaxo Wellcome HIV and Opportunistic Infections Clinical Development, Greenford, Middlesex, United Kingdom
ABSTRACT Backgrotlnd: Amprenavir (APV) is a new HIV-l protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV-l infection. Objective: The aim of this study was to assess the safety profile and tolerability of APV. Methods: A review of data from 358 adults enrolled in 2 phase III, randomized, 48week, controlled studies and from 268 children enrolled in 1 phase II and 1 phase III study was conducted. The adult data were collected between February 25, 1997, and April 1, 1999. Data were collected in children from September 10, 1997, to January 15, 1999; these data were collected before completion of either study. Adults and children who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, APV was used in combination with 2 nucleoside reverse transcriptase inhibitors. Results: The most common drug-related adverse events in patients receiving APV were gastrointestinal events and oral/perioral paresthesia. The majority of adverse events were mild or moderate in intensity, early in onset, and transient. Nausea (27/358 patients, 8%), vomiting (15/358,4%), rash (1 l/358, 3%), and diarrhea/loose stools (9/358, 3%) were the most common adverse events associated with treatment discontinuation. Severe laboratory abnormalities possibly related to APV were rare. In children, the nature and frequency of adverse events were similar to those in adults. Metabolic complications were infrequent in APV studies to date; symptoms related to fat redistribution were reported in ~3% of patients treated with APV. Lipid or glucose laboratory abnormalities were reported with similar frequency in the APV and control groups in both studies in adults. Conclusions: In the clinical trials reviewed, APV was generally well tolerated when administered with other antiretroviral agents in adult and pediatric patients with HIV infection. Accepted
for publication
November 21, 2000.
Printed in the USA. Reproduction
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in whole or part is not permitted.
0149.2918/00/$19,00
L. PEDNEAULT ET AL
Key words: amprenavir, safety, tolerability, HIV, protease inhibitor. (C&z Thel: 2000;22: 1378-1394)
efficacy of APV in combination with various nucleoside reverse transcriptase inhibitors (NRTIs) was assessed.
INTRODUCTION
PATIENTS
Treatment with HIV- 1 protease inhibitors (PIs) is generally associated with gastrointestinal adverse events, such as nausea, vomiting, and diarrhea.’ In addition, PI-containing therapy is associated with abnormal fat redistribution, characterized by peripheral fat loss and central fat accumulation. Other adverse effects include metabolic effects such as elevated serum triglycerides and cholesterol, insulin resistance, and type 2 diabetes mellitus. Amprenavir* (APV) is a new HIV-1 PI that is administered twice daily. In combination with other antiretroviral agents, APV is highly effective, reducing plasma HIV- 1 RNA levels and increasing CD4+ cell counts.2-8 In combination with abacavir, APV restores CD4+ and CD8+ cell counts in both plasma and lymphoid tissue in patients with early HIV infection not treated previously with antiretroviral agents.3 Clinical data continue to evolve, but the distinct resistance profile of APV has been well defined both in vitro and in clinical isolates. The 15OV mutation appears to be unique to APV and shows only limited cross-resistance to the PI ritonavir.“12 In this article, we review the safety profile and tolerability of APV based on data collected from 2 phase III, randomized, controlled studies conducted in adults, and from 1 phase II study and 1 phase III study in children. Patients who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, the *Trademark: AgeneraseTM (Glaxo Wellcome Research Triangle Park, North Carolina).
Inc,
AND METHODS
Patient Populations The adult population consisted of patients enrolled in 2 international phase III clinical studies, PRO3001 and PRO3006. PRO3001 was a randomized, doubleblind, placebo-controlled study evaluating the efficacy and safety of APV 1200 mg BID in combination with lamivudine (3TC) 150 mg BID and zidovudine (ZDV) 300 mg BID (APV/3TC/ZDV) versus APV placebo in combination with 3TC 150 mg BID and ZDV 300 mg BID (3TC/ZDV) in patients previously untreated with antiretroviral agents.2,‘3*14 The study was conducted between February 25, 1997, and October 14, 1998. Patients had to have CD4+ cell counts 9200 cells/mm3 and plasma HIV-I RNA ~10,000 copies/ml to be included in the study. PRO3006 was an open-label, randomized study in patients previously treated with NRTIs but naive to PI therapy. The study compared the efficacy and safety of APV versus the PI indinavir (IDV), in combination with unspecified NRTIs. Patients with plasma HIV-l RNA a400 copies/ml were randomized to receive APV 1200 mg BID plus NRTIs (APV/NRTI) or IDV 800 mg TID plus NRTIs (IDV/NRTI).i4 PRO3006 was conducted between September 15, 1997, and April 1, 1999. In both studies, antiretroviral therapy could be modified if patients met a protocol-defined switch criterion (ie, intolerance, plasma HIV- 1 RNA >400 copies/ml, or disease progression). The safety data presented here only include
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CLINICAL
the clinical adverse events and laboratory abnormalities reported while patients were receiving randomized therapy. The pediatric populations studied were patients enrolled in studies PRO3004 and PRO2004; these studies are still ongoing and preliminary data collected before study completion are presented here. Study PRO3004, an international phase III triaLs enrolled patients aged 2 to 19 years who had or had not been treated previously with PIs. The data reported here were collected from September 10, 1997, to January 15, 1999. All patients received APV in combination with 2 NRTIs. APV was administered at a dose of 1200 mg BID (50-mg or 150-mg capsules) in patients 213 years of age who weighed 250 kg, or at a dose of 20 mg/kg BID in patients ~13 years of age and in patients 213 years of age who weighed ~50 kg. Patients unable to swallow the capsules received APV oral solution (15 mg/mL) at a dose of 22.5 mg/kg (1.5 mL/kg) BID. The second pediatric study, PR02004,7 is a phase II study that enrolled children aged 4 to 18 years who had or had not been treated previously with PIs. These data were collected from March 11, 1998, to January 15, 1999. Patients were randomized to receive APV oral solution 20 mg/kg BID or 15 mg/kg TID in combination with other antiretroviral agents. The dose of APV could be adjusted according to plasma drug concentrations obtained at steady state. Patients could switch to APV capsules (20 mg/kg BID or 15 mgkg TID) if they had difficulty taking the required volume of oral solution.
Safety Assessments Laboratory safety assessments were performed at regular intervals as part of the
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THERAPEUTICS’
clinical trials and included complete and differential blood counts and blood chemistry. Blood samples were not routinely collected under fasting conditions. In studies PRO3001 and PRO3006, patients were assessed at weeks 1, 2, and 4 and every 4 weeks thereafter. In studies PRO2004 and PRO3004, patients were assessed at weeks 2,4, and every 4 weeks until week 16, and every 8 weeks thereafter. Information on fat redistribution was reported by the investigators on an ongoing basis, However, because the studies were initiated before the first cases of fat redistribution were published, the case-report forms were not designed to collect specific information on this adverse event. The data reported in this analysis are a combination of information provided by investigators on standard adverse-event case-report forms and a review of adverse-event listings to identify clinical symptoms and signs potentially related to fat redistribution. Whenever necessaty, queries for further clarification were sent to investigators who had spontaneously reported clinical signs or symptoms consistent with fat redistribution.
Definition
of Terms
A clinical adverse event was defined as any untoward medical occurrence in a clinical investigation patient. The clinical adverse event did not necessarily have a causal relationship with study medication or medications. A drug-related adverse event was an adverse event that the investigator considered at least possibly related to APV or any other antiretroviral agent in the treatment regimen. For the open-label study PRO3006, adverse events were considered drug related if related to APV or IDV, but not if related to the NRTIs. A treatmentemergent adverse event was an adverse
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ET AL.
event that occurred while the patient was on treatment, that is, after administration of the first dose of study medication until discontinuation. Adverse events were graded for severity on a scale of 1 to 4. Grade 1 adverse events were those that required no therapy, but were monitored. Grade 2 adverse events were those that might have required minimal intervention and monitoring. If an adverse event required medical care and possibly hospitalization, it was classified as grade 3; if it required immediate assessment, active medical intervention, and hospitalization, it was classified as grade 4. A severe adverse event or laboratory abnormality was an event that fulfilled the protocol definition of grade 3 or 4 toxicity. Grades 1 and 2 were considered mild and moderate, respectively.
Statistical Analysis The safety populations for all the studies comprised patients who had been exposed to 21 dose of APV, thus, even patients who had taken only 1 dose of APV were included in the analysis. Adverse events were summarized using descriptive statistics. The Fisher exact test was used to compare treatment groups in all studies. In some cases, laboratory abnormalities were reported as clinical adverse events. However, for the analysis of laboratory measurements, only laboratory data were used.
RESULTS
Adult Studies Baseline Characteristics Baseline characteristics of patients enrolled in the 2 studies in adults are summarized in Table I. Within each study, the de-
mographic and baseline characteristics were well matched across treatment groups. Exposure to Study Medications A total of 232 HIV-infected adults were enrolled in study PRO3001, and 222 were exposed to 2 1 dose of APV (n = 113) or placebo (n = 109). The median duration of exposure to the randomized treatments of APVl3TCiZDV and 3TC/ZDV was 36 weeks (range
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Table I. Baseline patient and disease characteristics in the amprenavir (APV) studies in adults. PRO300 1 (treatment-naive) Characteristic Age, Y Median Range Sex, no. (%) Female Male Disease category, no. (%)* Asymptomatic or lymphadenopathy Symptomatic, not AIDS AIDS Plasma HIV-l RNA, log,, copies/mL Median Range CD4+ count, cells/mm3 Median Range
PRO3006 (NRTI-experienced)
APVi3TClZDV (Ii= 113)
3TClZDV (n = 109)
APV/NRTI (n = 245)
IDV/NRTI (n = 241)
35 21-62
3.5 17-62
38 22-7 1
36 21-67
13 (12) 100 (88)
11 (10) 98 (90)
46 (19) 199 (81)
52 (22) 189 (78)
87 (77) 21 (19) 5 (4)
87 (80) 22 (20) 0 (0)
157 (64) 66 (27) 21 (9)
152 (63) 63 (26) 26 (11)
4.6 3.6-6.1
4.7 3.1-6.3
3.9 2.6-6.1
4.0 2.6-7.0
448 216-1800
409 139-984
396 1O-969
414 9-1706
3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir. *Data for disease category were missing for 1 patient in the APV/NRTI group of PRO3006.
grade 22 that were considered by the investigator to be treatment related are summarized in Table II. Drug-related nausea, rash, vomiting, and mood disorders of at least moderate intensity were reported more often in the APVl3TClZDV group than in the 3TC/ZDV group. The incidence of all other drug-related adverse events was comparable in the 2 groups. In study PRO3006, conducted in patients who had been treated previously with NRTIs, the proportion of patients who experienced 2 1 adverse event, regardless of causality or toxicity grade, was similar in both treatment groups (97% for APV/NRTI vs 95% for IDV/NRTI). Diarrhea/loose stools and oral/perioral paresthesia were reported by significantly more patients in the APV/NRTI group than in
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the IDV/NRTI group (P < 0.001). Renal disorders (flank pain, urinary calculi, and urinary tract hemorrhage) and signs of chronic hypervitaminosis A (retinoidrelated toxicities, dry skin, xerostomia, and hair loss/alopecia) were reported in significantly more patients in the IDV/NRTI group than in the APV/NRTI group (P < O.OOl).‘” Other adverse events, reported irrespective of relationship to treatment, that were significantly more common in the IDV/NRTI group were oral/perioral lesions, taste disorders, abnormal bilirubin levels, and regurgitation and reflux (all P < 0.05). Rash of any grade was reported in 20% of the APV/NRTI group compared with 15% of the IDV/NRTI group; this difference was not statistically significant. Most patients-167 of 245 (68%) in the
CLINICAL THERAPEUTICS’
Table III. Time to onset and median treated with amprenavir. Adverse Event
duration
Median Duration (days)
3 6 7 11 20 25 32 35
60 64 22 10 29 32 4 16
often suc-
APV treatment, without interruption, through mild or moderate rash; if treatment was interrupted, reintroduction of APV did not result in recurrence of the rash. Severe cases of rash, including Stevens-Johnson syndrome, occurred in - 1% of patients. Among patients who had not been treated previously with antiretroviral agents in study PRO3001, no symptoms or signs consistent with a diagnosis of fat redistribution were reported in either treatment group during the randomized phase of the study. One patient randomized to 3TUZDV who switched after -41 weeks to quadruple therapy with APV/3TC/ZDV plus abacavir developed dorsocervical fat accumulation (“buffalo hump”) 20 weeks after this change. In contrast, more events related to fat redistribution were reported in study PRO3006, in patients who had been treated with NRTIs. Although the duration of exposure to each PI during the randomized phase was similar, the incidence of such events, summarized in Table IV, was significantly higher in the IDV/NRTI group than in the APV/NRTI group (29/24 1 [12%] vs 9/245 [4%]; P < 0.001). No deaths were reported during the randomized phases of the 2 adult studies. cessfully
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continued
adverse events for all adults
Median Time to Onset (days)
Oral/perioral paresthesia Flatulence Nausea Rash Diarrhea/loose stools Fatigue Vomiting Headache uation of APV. Study participants
of common
Laboratory Abnormalities The proportion of patients with any reported treatment-emergent laboratory abnormality in the APV/3TC/ZDV and APVINRTI groups of each study (86% and 87%, respectively) was similar to that reported in the 3TUZDV control group in PRO3001 (88%), and slightly lower than that in the IDV/NRTI group of PRO3006 (95%), which may be explained by elevated bilirubin and liver aminotransferase levels in patients treated with indinavir. Overall, few severe (grade 3 or 4) treatment-emergent laboratory abnormalities were reported in patients receiving APV (Table V). Median values for triglyceride, glucose, and cholesterol levels in all adult study treatment groups showed no clinically significant changes over 64 weeks, although slight initial increases in median cholesterol levels were observed with all 3 PI-containing regimens (Figures 1 through 3).t6 Adverse Events Leading to Treatment Discontinuation A similar proportion (19%-20%) of patients discontinued randomized therapy due to adverse events in all 3 PI-treated groups of PRO3001 and PRO3006, compared with
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ET AL.
4% in the 3TC/ZDV group of PRO3001 (Table VI). Overall, the most frequent reasons for discontinuing APV were gastrointestinal complaints and rash. DiscontinuaTable
IV. Summary randomized
of adverse phase
events
tion of any study medication
due to nausea in the APV treatment groups was more frequent among patients who had not been treated previously with antiretroviral agents
related
to fat redistribution
reported
No. (%) of patients with fat redistribution Lipodystrophy Unspecified Central Facial Dorsocervical fat pad Fat accumulation, central Morphological changes Central Peripheral Facial Fat wasting/loss of fat, peripheral
IDV/NRTI
(n = 245)
(n = 241)
9 (4)*
29 (12)+
symptoms
inhibitor; IDV = indinavir.
Table V. Most frequent grade 3 or 4 laboratory studies in adults.*
abnormalities
in the amprenavir
PRO300 1
Increased amylase Increased glucose Increased triglycerides
APVl3TCiZDV (n= 111)
(APV)
PRO3006
(treatment-naive)
Decreased neutrophils Increased ALT and/or AST Increased bilirubin
the
APVINRTI
APV = amprenavir; NRTI = nucleoside reverse transcriptase *P < 0.001 versus IDV/NRTI. ‘One patient in the IDV/NRTI group reported 2 symptoms.
Abnormality
during
of study PRO3006.
3TClZDV (n = 108)
(NRTI-experienced) APV/NRTI (n = 237)
IDV/NRTI (n = 239) 4 (2) 22 (9) 36 (15)
6 (5) 6 (5)
7 (6) 3 (3)
5 (2) 16 (7)
1 (
1 (
9 (4)
0 (0)
1 (cl)
2 (
5 (2) 9 (4) 14 (6)
3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir; ALT = alanine aminotransferase; AST = aspartate aminotransferase. *Reported by 72% of patients with postbaseline data in any group. Values are reported as no. (%) of patients experiencing the adverse event.
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CLINICAL THERAPEUTKY -+ -m+ -
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56 60 64
Time (wk)
Figure 1. Median plasma triglyceride concentrations in the amprenavir (APV) studies in adults. 3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir.
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20
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32
36
40
44
48
52
56
60
64
Time (wk)
Figure
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2. Median plasma glucose concentrations in the amprenavir studies (APV) in adults. 3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir.
L. PEDNEAULT ET AL.
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60
64
Time (wk) Figure 3. Median plasma cholesterol concentrations in the amprenavir studies (APV) in adults. 3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir.
Table VI. Most frequent adverse events resulting amprenavir (APV) studies in adults.*
in discontinuation
PRO300 1 (treatment-naive)
Total Nausea Vomiting Diarrhea/loose stools Abdominal pain Abdominal discomfort Rash Urinary calculi Renal symptoms Increased serum aminotransferase Abnormal fat distribution
levels
of study drug in the
PRO3006 (NRTI-experienced)
APVl3TClZDV (n= 113)
3TClZDV (n = 109)
APV/NRTI (n = 245)
IDVRVRTI
21 (19) 13 (12)
4 (4) 1 (
48 (20)
45 (19) 7 (3) 5 (2) 0 (0) 2 (
6 3 2 2 3 0 0 0 0
(5) (3) (2) (2) (3) (0) (0) (0) (0)
14 (6) 9 (4) 6 (2) 3 (1) 1 (
(n = 241)
3TC = lamivudine;
ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir. *Reported by 2 1%of patients in any group. Values are reported as no. (%) of patients experiencing the adverse event.
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compared with those who had been treated withNRTIs(13/113 [12%] vs 14/245 [6%], respectively). Almost all adverse events that led to discontinuation of APV were mild to moderate, but were considered by the investigator to be drug related.
Pediatric Studies Baseline Characteristics In both pediatric studies, PI-experienced patients had more advanced HIV disease than PI-naive children, as indicated by their disease classification, plasma HIV- 1 RNA levels, and CD4+ cell counts at entry (Table VII). Most of the PI-naive patients and all but I of the PI-experienced
children had been exposed previously to NRTIs. Of the PI-experienced patients enrolled in PRO3004 and PR02004, 55% (66/120) and 53% (g/15), respectively, had received r2 PIs before receiving APV. Exposure to Study Medications A total of 228 patients (109 PI-naive and 119 PI-experienced) enrolled in study PRO3004 were exposed to ~1 dose of APV, either as an oral solution or as capsules. At the time of data cutoff for this review, the median duration of APV exposure was 15 weeks (range O-34 weeks); 49 patients had received APV for >24 weeks. In study PR02004, 40 children (25 PI-naive and 15 PI-experienced) had
Table VII. Baseline patient and disease characteristics
in the pediatric studies of amprenavir.
PRO3004
PRO2004
PI-experienced (n = 119)
PI-naive (n = 25)
PI-experienced (n = 15)
7 2-18
8 2-19
6 3-12
8 4-11
Female Male Disease classification for patients aged
60 (55) 49 (45)
54 (45) 65 (55)
10 (40) 15 (60)
7 (47) 8 (53)
Nonsymptomatic Mildly symptomatic Moderately symptomatic Severely symptomatic Plasma HIV- 1 RNA, log,,, copies/ml Median Range CD4+ count, cells/mm”
6 (6) 36 (33) 37 (34) 16 (15)
4 (3) 16 (13) 36 (30) 44 (37)
6 (24) 10 (40) 9 (36)* -
1 (7) 5 (33) 9 (60)* _
4.3 2.84.1
5.0 2.6-6.8
4.5 2Xb6.3
5.4 4.3-6.9
408 9-3003
451 27-256
239 9-1412
PI-naive
Characteristic
(n = 109)
Age, Y Median Range Sex, no. (%)
Median Range PI = protease inhibitor. *Combined total for moderate plus severe.
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587 32-l 898
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received APV for a median duration of 16 weeks (range l-43 weeks) at the time of data cutoffi 17 patients had been treated with APV for ~24 weeks. Clinical Adverse Events All patients in studies PRO2004 and PRO3004 experienced 21 adverse event, regardless of causality or toxicity grade. Most patients experienced adverse events that were mild or moderate (1801228 [79%] in PRO3004 and 35/40 [88%] in PRO2004). The most common clinical adverse events, irrespective of relationship to treatment, were gastrointestinal or respiratory symptoms, and rash. The frequency and nature of clinical adverse events were generally similar among PI-naive and PI-experienced patients. In both studies, 5% of subjects (11 in PRO3004 and 2 in PRO2004) discontinued study treatment due to adverse events, most often gastrointestinal symptoms or rash. The oral solution of APV contains a high concentration of the excipient propylene glycol to increase APV solubility. Propylene glycol-associated adverse reac-
Table VIII. Most frequent drug-related of amprenavir.*
tions include seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, and hemolysis. I7 The adverse events reported in the 2 pediatric studies were therefore reviewed to determine whether they could have been related to propylene glycol; no such evidence was found. A higher proportion of adverse events was considered to be drug related in study PRO2004 (60%) than in study PRO3004 (29%) (Table VIII). However, the type of drug-related clinical adverse events reported in all children enrolled in both studies was similar. No major difference was observed between the PI-naive and PIexperienced subgroups. Similarly, the adverse-event profile did not differ between patients treated with 20 mg/kg BID or 15 mg/kg TID in study PRO2004 (data not shown). As in adults, most of the drugrelated events were gastrointestinal symptoms or rash. A detailed review of adverse-event listings failed to reveal any potential symptoms of fat redistribution in either pediatric study. One non-drugrelated death was reported in study PR03004. It occurred after 19 weeks of
adverse events of grade ~2 in the pediatric studies
PRO3004
Any drug-related adverse event Vomiting Nausea Diarrhea/loose stools Abdominal pain Rash
PRO2004
PI-naive (n = 109)
PI-experienced (n= 119)
Total (n = 228)
Total (n = 40)
36 (33) 18 (17) 11 (10) 12(11)
31 (26) 13 (11)
67 (29) 31 (14)
24 (60)
6 (6) 3 (3)
5 4 3 8
(4) (3) (3) (7)
16 (7) 16 (7) 9 (4) 11 (5)
3 (8) 0 (0) 16 (40) 3 (8) 8 (20)
PI = protease inhibitor. *Reported by 25% of patients in any group. Values are reported as no. (%) of patients experiencing the adverse event.
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treatment and was related to Pneumocystis . .. carmu pneumonia. Laboratory Abnormalities Overall, few severe (grade 3 or 4) treatment-emergent laboratory abnormalities were reported in children receiving APV. The most common severe laboratory abnormality was hyperamylasemia (2%) in PRO3004 and thrombocytopenia (5%) in PRO2004.
DISCUSSION APV was generally safe and well tolerated in clinical trials when administered in combination with other antiretroviral agents to 358 adult and 268 pediatric patients. APV has a safety profile comparable to that of other PIs; most adverse events are mild to moderate and involve the gastrointestinal system.‘*-*’ Current evidence suggests that APV and IDV may have somewhat distinct safety profiles (as described in results from PRO3006), although discontinuation rates due to adverse events were similar in the 2 groups. The most frequently reported adverse events, regardless of causality, in adults who received APV were gastrointestinal symptoms and rash. These events were generally reported more often in treatment-naive patients (PRO3001) than in previously treated patients (PRO3006). This suggests that some of the adverse events reported in PRO3001 may have been related to initiation of antiretroviral therapy, including NRTI therapy. Also, as APV (and IDV) are taken as part of multidmg regimens, other agents in the regimen, either individually or in combination, could have contributed to any of the adverse events reported. In the treatment-naive population, nausea, rash, and oral/perioral paresthesia were reported in significantly more
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patients in the APV/3TC/ZDV group than in the 3TC/ZDV group (P < 0.001). Among patients previously exposed to NRTIs, diarrhea/loose stools and oral/perioral paresthesia were reported in significantly more patients in the APV/NRTI group (P < 0.001) than in the IDV/NRTI group. Renal disorders (flank pain, urinary calculi, and urinary tract hemorrhage) and signs of chronic hypervitaminosis A (retinoid-related toxicities, dry skin, xerostomia, hair loss/alopecia) were reported in significantly more patients in the IDV/NRTI group than in the APV/NRTI group (P < 0.001). Most of the clinical adverse events commonly reported with APV were mild or moderate, early in onset, and transient. Nausea, vomiting, diarrhea/loose stools, and rash were the most common adverse events leading to APV discontinuation. Almost all events that led to discontinuation of study medication were drug related, and the majority were either mild or moderate. Long-term follow-up of adult patients receiving APV did not reveal any new safety concerns. The proportion of patients with any reported treatment-emergent laboratory abnormality in the APV/3TC/ZDV and APV/NRTI groups was similar to that reported in the 3TCYZDV group of PRO3001 and lower than that reported in the IDV/NRTI group of PR03006. The latter difference was mainly due to a higher rate of elevated bilirubin and liver aminotransferase levels in patients treated with IDV. Overall, few grade 3 or grade 4 treatment-emergent laboratory abnormalities were reported in patients receiving APV. Severe laboratory abnormalities occurred with similar frequencies in the APVi3TClZDV and 3TC/ZDV groups in PR03001, but were reported more frequently in the IDV/NRTI group
L. PEDNEAULT ET AL.
than in the APVINRTI group in study PRO3006. Despite the fact that blood samples were not routinely collected under fasting conditions, rates of severe treatment-emergent elevations in plasma triglyceride, cholesterol, and glucose levels were low with APV. The median values for plasma triglyceride and glucose levels remained stable over time in all treatment groups of PRO3001 and PRO3006, whereas slight increases in median cholesterol levels were observed in all 3 groups treated with PIcontaining regimens. At the time these trials started, the casereport forms did not contain specific sections or describe specific tests to collect data on fat redistribution. Therefore, the fat redistribution data presented in this review were reported on routine adverseevent forms. Also, the duration of exposure to APV (and IDV in PR03006) ranged from 15 weeks in PRO3004 to 56 weeks in PR03006. Thus, for some patients, potential fat redistribution symptoms may not have developed by the time data were collected for this analysis. Few cases of fat redistribution were reported with APV in either adult study; in study PRO3006, the incidence of adverse events related to fat redistribution was significantly higher in the IDV group (12% vs 4% in the APV/NRTI group; P < 0.001). Overall, the PRO3006 data in this review indicate that APV has a favorable safety profile, distinct from that of IDV. There is also some in vitro evidence suggesting that the effects of PIs on fat metabolism are not class specific. In vitro, nelfinavir, ritonavir, and saquinavir directly inhibit fat-cell differentiation (adipogenesis) and stimulate fat turnover (lipolysis), whereas IDV inhibits adipogenesis via retinoic acid signaling. APV ap-
peared to have little effect on adipogenesis or lipolysis in vitro.** The higher rate of adverse events consistent with chronic hypervitaminosis A observed with IDV in PRO3006 supports the in vitro findings of Lenhard et a1,23 who reported that IDV appears to stimulate the activity of the vitamin A metabolite retinoic acid in cell cult1 re. Nail defects, hyperbilirubinemia, alopecia, and renal complications have previously been described in association with IDV.24-26 Although the in vitro data may suggest that some IDV-associated adverse events occur due to alterations in retinoic acid signaling, other factors may influence the development of adverse events in humans, such as pharmacokinetic parameters, active metabolites, diet, and genetic predisposition. For these reasons, caution is required when relating in vitro findings to clinical adverse events in trials with IDV. The results of the 2 pediatric studies indicate that the safety and tolerability profile of APV in children is comparable to that seen in adults. The most common drugrelated clinical adverse events (grade 22) in children receiving APV were, as for adults, gastrointestinal symptoms and rash. The frequency and nature of these events were comparable in PI-naive and PI-experienced patients. Most clinical adverse events and laboratory abnormalities were mild to moderate, and only 5% of children discontinued APV due to an adverse event.
CONCLUSIONS The adverse-event data collected from 4 clinical trials indicate that APV was generally safe and well tolerated when administered with various NRTIs in adult and pediatric patients with a range of treatment experience and HIV disease sever-
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CLINICAL THERAPEUTICS’
ity. The APV safety and tolerability profile reported in children was similar to that described in adults. Most adverse events associated with APV therapy were gastrointestinal symptoms and rash. They were generally mild or moderate, early in onset. and transient.
ACKNOWLEDGMENTS Funding for the studies described in this review was provided by Glaxo Wellcome Research and Development. We thank the investigators and patients who took part in the studies described in this review. We also thank Pantaleo Nacci for statistical assistance and Justin Cook and Jeanne Wilson for writing and editing assistance.
Address correspondence to: Anny Fetter, MD, Glaxo Wellcome HIV and Opportunistic Infections Clinical Development, Glaxo Wellcome Research and Development, Greenford Road, Greenford, Middlesex UB6 OHE, UK.
REFERENCES I. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000;356: 1423-1430. 2. Goodgame JC, Pottage JC Jr, Jablonowski H, et al. Amprenavir in combination with lamivudine and zidovudine versus lamivudine and zidovudine alone in HIV- 1-infected antiretroviral-naive adults. Antiviral T/zm 2000;5:2 15-225. 3. Rizzardi G, Bart P Chapuis A, et al. Immunologic and virologic responses after long-term HAART in HIV- I -infected therapy naive adults at early stage of chronic infection. In: Program and abstracts of the Seventh Conference on
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Retroviruses and Opportunistic Infections; January 3@-February 2, 2000; San Francisco. Calif. Abstract 336. 4. Mellors J, Lederman M, Haas D, et al. Durable activity of ziagen (abacavir, ABC) combined with protease inhibitors (PI) in therapy naive adults. In: Program and abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago, Ill. Abstract 625. 5. Eron J, Haubrich R, Richman D, et al. Safety and efficacy of amprenavir in combination with other protease inhibitors. AIDS. 1998;12(Suppl 4):S38. Abstract. 6. Masur H, Falloon J, Thomas D, et al, for the CNA2007 study team. Durability of abacavir/amprenavir/efavirenz combination salvage therapy-preliminary 48week response (CNA2007). In: Program and abstracts of the Seventh European Conference on Clinical Aspects and Treatment of HIV Infection; October 23327, 1999; Lisbon, Portugal. Abstract 206. 7. Blanche S, Fetter A, Cox H, et al. A phase II study of amprenavir (APV, 14lW94, Agenerase’“) in antiretroviral-experienced children with HIV-infection; In: Program and abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, Calif. Abstract 695. 8. Church J, Rathore M, Rubio T, et al. Phase III study of amprenavir (APV, AgeneraseTM) in protease-inhibitor (PI) naive and experienced (EXP) HIV-infected children and adolescents. In: Program and abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections; January 30-February 2,200O; San Francisco, Calif. Abstract 693.
L. PEDNEAULT ET AL.
9. Partaledis JA, Yamaguchi K, Tisdale M, et al. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-l) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-l aspartyl protease. / virol. 1995;69:5228-5235.
10. Snowden W, Shortino D, Klein A. Development of amprenavir resistance in NRTI-experienced patients: Alternative mechanisms and correlation with baseline resistance to concomitant NRTIs. In: Program and abstracts of the Fourth International Workshop on HIV Drug Resistance and Treatment Strategies; June 12-l 6,200O; Sitges, Spain. Abstract 108.
11. Tisdale M, Myers RE, Maschera B, et al. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother. 1995;39: 1704-1710.
12. Myers R, Snowden W, Randall S, Tisdale M. Unique resistance profile of the protease inhibitor APV (14lW94) observed in vitro and in the clinic. Ad~i~d 7’her: 1998;3(Suppl 1):59-60.
13. Pedneault L, Fetter A, Hanson C, et al. Amprenavir (14lW94, APV): Review of overall safety profile. In: Program and abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago, Ill. Abstract 386.
14. Fetter A, Nacci P, Yeo J, et al. Tolerability profile of amprenavir (APV, 141W94) in combination with various NRTIs. In: Pro-
gram and abstracts of the Seventh European Conference on Clinical Aspects and Treatment of HIV Infection. October 23-27, 1999; Lisbon, Portugal. Abstract 8 13. 15. Fetter A, Nacci P, Lenhard J, et al. Fat distribution and retinoid-like symptoms are infrequent in NRTI-experienced subjects treated with amprenavir. In: Program and abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, Calif. Abstract 18. 16. Pedneault L, Hanson C, Nacci P, et al. Amprenavir: A new protease inhibitor with a favourable metabolic profile. In: Program of the First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, June 26-28, 1999; San Diego, Calif. Abstract 34. 17. Glover ML, Reed MD. Propylene glycol: The safe diluent that continues to cause harm. Pharmacotherapy. 1996; 16:690-693. 18. Viracept@ (nelfinavir) [package insert]. La Jolla, Calif: Agouron Pharmaceuticals, Inc; 2000. 19. Crixivan@ (indinavir) [package insert]. Whitehouse Station, NJ: Merck Research Laboratories Inc; 2000. 20. Norvir@ (ritonavir) [package insert]. Abbott Park, Ill: Abbott Laboratories, Inc; 2000. 21. Fortovase@ (saquinavir) [package insert]. Basel, Switzerland: Hoffmann-La Roche Laboratories; 2000. 22. Lenhard JM, Furtine ES, Jain RG, et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res. 2000;47: 121-129.
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23. Lenhard JM, Weiel JE, Paulik MA, Furhne ES. Stimulation of vitamin A, acid signaling by the HIV protease inhibitor indinavir. Biochem Pharmacol. 2000;59: 1063-l 068.
25. KakudaTN, Struble KA, Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency virus infection. Am J Health-Syst Pharm. 1998;55:233-254.
24. Bouscarat F, Bouchard C, Bouhour D. Paronychia and pyogenic granuloma of the great toes in patients treated with indinavir. N Engl d Med. 1998;338: 1776-l 777.
26. Bouscarat F, Prevot MH, Matheron S. Alopecia associated with indinavir therapy. N Engl J Med. 1999;34 I:6 18. Letter.
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22, NO. 12,200O
Safety Profile and Tolerability of Amprenavir in the Treatment of Adult and Pediatric Patients with HIV Infection Louise Pedneault, MD,l Cindy Brothers, MSPH,’ Grace Pagano, MS,’ Paulina Tymkewycz, PhD,2 Jane Yeo, PhD,2 Judith Millard, PhD,l and Anny Fetter, M@ ‘Glaxo Wellcome HIV and Opportunistic Infections Clinical Development, Research Triangle Park, North Carolina, and ‘Glaxo Wellcome HIV and Opportunistic Infections Clinical Development, Greenford, Middlesex, United Kingdom
ABSTRACT Backgrotlnd: Amprenavir (APV) is a new HIV-l protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV-l infection. Objective: The aim of this study was to assess the safety profile and tolerability of APV. Methods: A review of data from 358 adults enrolled in 2 phase III, randomized, 48week, controlled studies and from 268 children enrolled in 1 phase II and 1 phase III study was conducted. The adult data were collected between February 25, 1997, and April 1, 1999. Data were collected in children from September 10, 1997, to January 15, 1999; these data were collected before completion of either study. Adults and children who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, APV was used in combination with 2 nucleoside reverse transcriptase inhibitors. Results: The most common drug-related adverse events in patients receiving APV were gastrointestinal events and oral/perioral paresthesia. The majority of adverse events were mild or moderate in intensity, early in onset, and transient. Nausea (27/358 patients, 8%), vomiting (15/358,4%), rash (1 l/358, 3%), and diarrhea/loose stools (9/358, 3%) were the most common adverse events associated with treatment discontinuation. Severe laboratory abnormalities possibly related to APV were rare. In children, the nature and frequency of adverse events were similar to those in adults. Metabolic complications were infrequent in APV studies to date; symptoms related to fat redistribution were reported in ~3% of patients treated with APV. Lipid or glucose laboratory abnormalities were reported with similar frequency in the APV and control groups in both studies in adults. Conclusions: In the clinical trials reviewed, APV was generally well tolerated when administered with other antiretroviral agents in adult and pediatric patients with HIV infection. Accepted
for publication
November 21, 2000.
Printed in the USA. Reproduction
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in whole or part is not permitted.
0149.2918/00/$19,00
L. PEDNEAULT ET AL
Key words: amprenavir, safety, tolerability, HIV, protease inhibitor. (C&z Thel: 2000;22: 1378-1394)
efficacy of APV in combination with various nucleoside reverse transcriptase inhibitors (NRTIs) was assessed.
INTRODUCTION
PATIENTS
Treatment with HIV- 1 protease inhibitors (PIs) is generally associated with gastrointestinal adverse events, such as nausea, vomiting, and diarrhea.’ In addition, PI-containing therapy is associated with abnormal fat redistribution, characterized by peripheral fat loss and central fat accumulation. Other adverse effects include metabolic effects such as elevated serum triglycerides and cholesterol, insulin resistance, and type 2 diabetes mellitus. Amprenavir* (APV) is a new HIV-1 PI that is administered twice daily. In combination with other antiretroviral agents, APV is highly effective, reducing plasma HIV- 1 RNA levels and increasing CD4+ cell counts.2-8 In combination with abacavir, APV restores CD4+ and CD8+ cell counts in both plasma and lymphoid tissue in patients with early HIV infection not treated previously with antiretroviral agents.3 Clinical data continue to evolve, but the distinct resistance profile of APV has been well defined both in vitro and in clinical isolates. The 15OV mutation appears to be unique to APV and shows only limited cross-resistance to the PI ritonavir.“12 In this article, we review the safety profile and tolerability of APV based on data collected from 2 phase III, randomized, controlled studies conducted in adults, and from 1 phase II study and 1 phase III study in children. Patients who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, the *Trademark: AgeneraseTM (Glaxo Wellcome Research Triangle Park, North Carolina).
Inc,
AND METHODS
Patient Populations The adult population consisted of patients enrolled in 2 international phase III clinical studies, PRO3001 and PRO3006. PRO3001 was a randomized, doubleblind, placebo-controlled study evaluating the efficacy and safety of APV 1200 mg BID in combination with lamivudine (3TC) 150 mg BID and zidovudine (ZDV) 300 mg BID (APV/3TC/ZDV) versus APV placebo in combination with 3TC 150 mg BID and ZDV 300 mg BID (3TC/ZDV) in patients previously untreated with antiretroviral agents.2,‘3*14 The study was conducted between February 25, 1997, and October 14, 1998. Patients had to have CD4+ cell counts 9200 cells/mm3 and plasma HIV-I RNA ~10,000 copies/ml to be included in the study. PRO3006 was an open-label, randomized study in patients previously treated with NRTIs but naive to PI therapy. The study compared the efficacy and safety of APV versus the PI indinavir (IDV), in combination with unspecified NRTIs. Patients with plasma HIV-l RNA a400 copies/ml were randomized to receive APV 1200 mg BID plus NRTIs (APV/NRTI) or IDV 800 mg TID plus NRTIs (IDV/NRTI).i4 PRO3006 was conducted between September 15, 1997, and April 1, 1999. In both studies, antiretroviral therapy could be modified if patients met a protocol-defined switch criterion (ie, intolerance, plasma HIV- 1 RNA >400 copies/ml, or disease progression). The safety data presented here only include
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CLINICAL
the clinical adverse events and laboratory abnormalities reported while patients were receiving randomized therapy. The pediatric populations studied were patients enrolled in studies PRO3004 and PRO2004; these studies are still ongoing and preliminary data collected before study completion are presented here. Study PRO3004, an international phase III triaLs enrolled patients aged 2 to 19 years who had or had not been treated previously with PIs. The data reported here were collected from September 10, 1997, to January 15, 1999. All patients received APV in combination with 2 NRTIs. APV was administered at a dose of 1200 mg BID (50-mg or 150-mg capsules) in patients 213 years of age who weighed 250 kg, or at a dose of 20 mg/kg BID in patients ~13 years of age and in patients 213 years of age who weighed ~50 kg. Patients unable to swallow the capsules received APV oral solution (15 mg/mL) at a dose of 22.5 mg/kg (1.5 mL/kg) BID. The second pediatric study, PR02004,7 is a phase II study that enrolled children aged 4 to 18 years who had or had not been treated previously with PIs. These data were collected from March 11, 1998, to January 15, 1999. Patients were randomized to receive APV oral solution 20 mg/kg BID or 15 mg/kg TID in combination with other antiretroviral agents. The dose of APV could be adjusted according to plasma drug concentrations obtained at steady state. Patients could switch to APV capsules (20 mg/kg BID or 15 mgkg TID) if they had difficulty taking the required volume of oral solution.
Safety Assessments Laboratory safety assessments were performed at regular intervals as part of the
1380
THERAPEUTICS’
clinical trials and included complete and differential blood counts and blood chemistry. Blood samples were not routinely collected under fasting conditions. In studies PRO3001 and PRO3006, patients were assessed at weeks 1, 2, and 4 and every 4 weeks thereafter. In studies PRO2004 and PRO3004, patients were assessed at weeks 2,4, and every 4 weeks until week 16, and every 8 weeks thereafter. Information on fat redistribution was reported by the investigators on an ongoing basis, However, because the studies were initiated before the first cases of fat redistribution were published, the case-report forms were not designed to collect specific information on this adverse event. The data reported in this analysis are a combination of information provided by investigators on standard adverse-event case-report forms and a review of adverse-event listings to identify clinical symptoms and signs potentially related to fat redistribution. Whenever necessaty, queries for further clarification were sent to investigators who had spontaneously reported clinical signs or symptoms consistent with fat redistribution.
Definition
of Terms
A clinical adverse event was defined as any untoward medical occurrence in a clinical investigation patient. The clinical adverse event did not necessarily have a causal relationship with study medication or medications. A drug-related adverse event was an adverse event that the investigator considered at least possibly related to APV or any other antiretroviral agent in the treatment regimen. For the open-label study PRO3006, adverse events were considered drug related if related to APV or IDV, but not if related to the NRTIs. A treatmentemergent adverse event was an adverse
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ET AL.
event that occurred while the patient was on treatment, that is, after administration of the first dose of study medication until discontinuation. Adverse events were graded for severity on a scale of 1 to 4. Grade 1 adverse events were those that required no therapy, but were monitored. Grade 2 adverse events were those that might have required minimal intervention and monitoring. If an adverse event required medical care and possibly hospitalization, it was classified as grade 3; if it required immediate assessment, active medical intervention, and hospitalization, it was classified as grade 4. A severe adverse event or laboratory abnormality was an event that fulfilled the protocol definition of grade 3 or 4 toxicity. Grades 1 and 2 were considered mild and moderate, respectively.
Statistical Analysis The safety populations for all the studies comprised patients who had been exposed to 21 dose of APV, thus, even patients who had taken only 1 dose of APV were included in the analysis. Adverse events were summarized using descriptive statistics. The Fisher exact test was used to compare treatment groups in all studies. In some cases, laboratory abnormalities were reported as clinical adverse events. However, for the analysis of laboratory measurements, only laboratory data were used.
RESULTS
Adult Studies Baseline Characteristics Baseline characteristics of patients enrolled in the 2 studies in adults are summarized in Table I. Within each study, the de-
mographic and baseline characteristics were well matched across treatment groups. Exposure to Study Medications A total of 232 HIV-infected adults were enrolled in study PRO3001, and 222 were exposed to 2 1 dose of APV (n = 113) or placebo (n = 109). The median duration of exposure to the randomized treatments of APVl3TCiZDV and 3TC/ZDV was 36 weeks (range
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Table I. Baseline patient and disease characteristics in the amprenavir (APV) studies in adults. PRO300 1 (treatment-naive) Characteristic Age, Y Median Range Sex, no. (%) Female Male Disease category, no. (%)* Asymptomatic or lymphadenopathy Symptomatic, not AIDS AIDS Plasma HIV-l RNA, log,, copies/mL Median Range CD4+ count, cells/mm3 Median Range
PRO3006 (NRTI-experienced)
APVi3TClZDV (Ii= 113)
3TClZDV (n = 109)
APV/NRTI (n = 245)
IDV/NRTI (n = 241)
35 21-62
3.5 17-62
38 22-7 1
36 21-67
13 (12) 100 (88)
11 (10) 98 (90)
46 (19) 199 (81)
52 (22) 189 (78)
87 (77) 21 (19) 5 (4)
87 (80) 22 (20) 0 (0)
157 (64) 66 (27) 21 (9)
152 (63) 63 (26) 26 (11)
4.6 3.6-6.1
4.7 3.1-6.3
3.9 2.6-6.1
4.0 2.6-7.0
448 216-1800
409 139-984
396 1O-969
414 9-1706
3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir. *Data for disease category were missing for 1 patient in the APV/NRTI group of PRO3006.
grade 22 that were considered by the investigator to be treatment related are summarized in Table II. Drug-related nausea, rash, vomiting, and mood disorders of at least moderate intensity were reported more often in the APVl3TClZDV group than in the 3TC/ZDV group. The incidence of all other drug-related adverse events was comparable in the 2 groups. In study PRO3006, conducted in patients who had been treated previously with NRTIs, the proportion of patients who experienced 2 1 adverse event, regardless of causality or toxicity grade, was similar in both treatment groups (97% for APV/NRTI vs 95% for IDV/NRTI). Diarrhea/loose stools and oral/perioral paresthesia were reported by significantly more patients in the APV/NRTI group than in
1382
the IDV/NRTI group (P < 0.001). Renal disorders (flank pain, urinary calculi, and urinary tract hemorrhage) and signs of chronic hypervitaminosis A (retinoidrelated toxicities, dry skin, xerostomia, and hair loss/alopecia) were reported in significantly more patients in the IDV/NRTI group than in the APV/NRTI group (P < O.OOl).‘” Other adverse events, reported irrespective of relationship to treatment, that were significantly more common in the IDV/NRTI group were oral/perioral lesions, taste disorders, abnormal bilirubin levels, and regurgitation and reflux (all P < 0.05). Rash of any grade was reported in 20% of the APV/NRTI group compared with 15% of the IDV/NRTI group; this difference was not statistically significant. Most patients-167 of 245 (68%) in the
CLINICAL THERAPEUTICS’
Table III. Time to onset and median treated with amprenavir. Adverse Event
duration
Median Duration (days)
3 6 7 11 20 25 32 35
60 64 22 10 29 32 4 16
often suc-
APV treatment, without interruption, through mild or moderate rash; if treatment was interrupted, reintroduction of APV did not result in recurrence of the rash. Severe cases of rash, including Stevens-Johnson syndrome, occurred in - 1% of patients. Among patients who had not been treated previously with antiretroviral agents in study PRO3001, no symptoms or signs consistent with a diagnosis of fat redistribution were reported in either treatment group during the randomized phase of the study. One patient randomized to 3TUZDV who switched after -41 weeks to quadruple therapy with APV/3TC/ZDV plus abacavir developed dorsocervical fat accumulation (“buffalo hump”) 20 weeks after this change. In contrast, more events related to fat redistribution were reported in study PRO3006, in patients who had been treated with NRTIs. Although the duration of exposure to each PI during the randomized phase was similar, the incidence of such events, summarized in Table IV, was significantly higher in the IDV/NRTI group than in the APV/NRTI group (29/24 1 [12%] vs 9/245 [4%]; P < 0.001). No deaths were reported during the randomized phases of the 2 adult studies. cessfully
1384
continued
adverse events for all adults
Median Time to Onset (days)
Oral/perioral paresthesia Flatulence Nausea Rash Diarrhea/loose stools Fatigue Vomiting Headache uation of APV. Study participants
of common
Laboratory Abnormalities The proportion of patients with any reported treatment-emergent laboratory abnormality in the APV/3TC/ZDV and APVINRTI groups of each study (86% and 87%, respectively) was similar to that reported in the 3TUZDV control group in PRO3001 (88%), and slightly lower than that in the IDV/NRTI group of PRO3006 (95%), which may be explained by elevated bilirubin and liver aminotransferase levels in patients treated with indinavir. Overall, few severe (grade 3 or 4) treatment-emergent laboratory abnormalities were reported in patients receiving APV (Table V). Median values for triglyceride, glucose, and cholesterol levels in all adult study treatment groups showed no clinically significant changes over 64 weeks, although slight initial increases in median cholesterol levels were observed with all 3 PI-containing regimens (Figures 1 through 3).t6 Adverse Events Leading to Treatment Discontinuation A similar proportion (19%-20%) of patients discontinued randomized therapy due to adverse events in all 3 PI-treated groups of PRO3001 and PRO3006, compared with
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ET AL.
4% in the 3TC/ZDV group of PRO3001 (Table VI). Overall, the most frequent reasons for discontinuing APV were gastrointestinal complaints and rash. DiscontinuaTable
IV. Summary randomized
of adverse phase
events
tion of any study medication
due to nausea in the APV treatment groups was more frequent among patients who had not been treated previously with antiretroviral agents
related
to fat redistribution
reported
No. (%) of patients with fat redistribution Lipodystrophy Unspecified Central Facial Dorsocervical fat pad Fat accumulation, central Morphological changes Central Peripheral Facial Fat wasting/loss of fat, peripheral
IDV/NRTI
(n = 245)
(n = 241)
9 (4)*
29 (12)+
symptoms
inhibitor; IDV = indinavir.
Table V. Most frequent grade 3 or 4 laboratory studies in adults.*
abnormalities
in the amprenavir
PRO300 1
Increased amylase Increased glucose Increased triglycerides
APVl3TCiZDV (n= 111)
(APV)
PRO3006
(treatment-naive)
Decreased neutrophils Increased ALT and/or AST Increased bilirubin
the
APVINRTI
APV = amprenavir; NRTI = nucleoside reverse transcriptase *P < 0.001 versus IDV/NRTI. ‘One patient in the IDV/NRTI group reported 2 symptoms.
Abnormality
during
of study PRO3006.
3TClZDV (n = 108)
(NRTI-experienced) APV/NRTI (n = 237)
IDV/NRTI (n = 239) 4 (2) 22 (9) 36 (15)
6 (5) 6 (5)
7 (6) 3 (3)
5 (2) 16 (7)
1 (
1 (
9 (4)
0 (0)
1 (cl)
2 (
5 (2) 9 (4) 14 (6)
3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir; ALT = alanine aminotransferase; AST = aspartate aminotransferase. *Reported by 72% of patients with postbaseline data in any group. Values are reported as no. (%) of patients experiencing the adverse event.
1385
CLINICAL THERAPEUTKY -+ -m+ -
APVI~TCIZDV 3TClzDV APVINRTI IDV/NRTI
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12
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20
24
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,
28 32
,
,
,
(
36 40 44 48 52
,
,
56 60 64
Time (wk)
Figure 1. Median plasma triglyceride concentrations in the amprenavir (APV) studies in adults. 3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir.
110 100 5 ‘S i? F $ 5^ o+
90 80 70 60 + APVl3TCRDV -+- ~TCIZDV -A- APVlNRTl -x- IDWNRTI
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
Time (wk)
Figure
1386
2. Median plasma glucose concentrations in the amprenavir studies (APV) in adults. 3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir.
L. PEDNEAULT ET AL.
240 5 ‘Z 2
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200 160-
0 y 140za z ‘0 1205 5 looa, ’0
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I
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I
16
20
24
28
32
36
40
44
48
52
56
60
64
Time (wk) Figure 3. Median plasma cholesterol concentrations in the amprenavir studies (APV) in adults. 3TC = lamivudine; ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir.
Table VI. Most frequent adverse events resulting amprenavir (APV) studies in adults.*
in discontinuation
PRO300 1 (treatment-naive)
Total Nausea Vomiting Diarrhea/loose stools Abdominal pain Abdominal discomfort Rash Urinary calculi Renal symptoms Increased serum aminotransferase Abnormal fat distribution
levels
of study drug in the
PRO3006 (NRTI-experienced)
APVl3TClZDV (n= 113)
3TClZDV (n = 109)
APV/NRTI (n = 245)
IDVRVRTI
21 (19) 13 (12)
4 (4) 1 (
48 (20)
45 (19) 7 (3) 5 (2) 0 (0) 2 (
6 3 2 2 3 0 0 0 0
(5) (3) (2) (2) (3) (0) (0) (0) (0)
14 (6) 9 (4) 6 (2) 3 (1) 1 (
(n = 241)
3TC = lamivudine;
ZDV = zidovudine; NRTI = nucleoside reverse transcriptase inhibitor; IDV = indinavir. *Reported by 2 1%of patients in any group. Values are reported as no. (%) of patients experiencing the adverse event.
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CLINICAL THERAPEUTICS@
compared with those who had been treated withNRTIs(13/113 [12%] vs 14/245 [6%], respectively). Almost all adverse events that led to discontinuation of APV were mild to moderate, but were considered by the investigator to be drug related.
Pediatric Studies Baseline Characteristics In both pediatric studies, PI-experienced patients had more advanced HIV disease than PI-naive children, as indicated by their disease classification, plasma HIV- 1 RNA levels, and CD4+ cell counts at entry (Table VII). Most of the PI-naive patients and all but I of the PI-experienced
children had been exposed previously to NRTIs. Of the PI-experienced patients enrolled in PRO3004 and PR02004, 55% (66/120) and 53% (g/15), respectively, had received r2 PIs before receiving APV. Exposure to Study Medications A total of 228 patients (109 PI-naive and 119 PI-experienced) enrolled in study PRO3004 were exposed to ~1 dose of APV, either as an oral solution or as capsules. At the time of data cutoff for this review, the median duration of APV exposure was 15 weeks (range O-34 weeks); 49 patients had received APV for >24 weeks. In study PR02004, 40 children (25 PI-naive and 15 PI-experienced) had
Table VII. Baseline patient and disease characteristics
in the pediatric studies of amprenavir.
PRO3004
PRO2004
PI-experienced (n = 119)
PI-naive (n = 25)
PI-experienced (n = 15)
7 2-18
8 2-19
6 3-12
8 4-11
Female Male Disease classification for patients aged
60 (55) 49 (45)
54 (45) 65 (55)
10 (40) 15 (60)
7 (47) 8 (53)
Nonsymptomatic Mildly symptomatic Moderately symptomatic Severely symptomatic Plasma HIV- 1 RNA, log,,, copies/ml Median Range CD4+ count, cells/mm”
6 (6) 36 (33) 37 (34) 16 (15)
4 (3) 16 (13) 36 (30) 44 (37)
6 (24) 10 (40) 9 (36)* -
1 (7) 5 (33) 9 (60)* _
4.3 2.84.1
5.0 2.6-6.8
4.5 2Xb6.3
5.4 4.3-6.9
408 9-3003
451 27-256
239 9-1412
PI-naive
Characteristic
(n = 109)
Age, Y Median Range Sex, no. (%)
Median Range PI = protease inhibitor. *Combined total for moderate plus severe.
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587 32-l 898
L. PEDNEAULT ET AL.
received APV for a median duration of 16 weeks (range l-43 weeks) at the time of data cutoffi 17 patients had been treated with APV for ~24 weeks. Clinical Adverse Events All patients in studies PRO2004 and PRO3004 experienced 21 adverse event, regardless of causality or toxicity grade. Most patients experienced adverse events that were mild or moderate (1801228 [79%] in PRO3004 and 35/40 [88%] in PRO2004). The most common clinical adverse events, irrespective of relationship to treatment, were gastrointestinal or respiratory symptoms, and rash. The frequency and nature of clinical adverse events were generally similar among PI-naive and PI-experienced patients. In both studies, 5% of subjects (11 in PRO3004 and 2 in PRO2004) discontinued study treatment due to adverse events, most often gastrointestinal symptoms or rash. The oral solution of APV contains a high concentration of the excipient propylene glycol to increase APV solubility. Propylene glycol-associated adverse reac-
Table VIII. Most frequent drug-related of amprenavir.*
tions include seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, and hemolysis. I7 The adverse events reported in the 2 pediatric studies were therefore reviewed to determine whether they could have been related to propylene glycol; no such evidence was found. A higher proportion of adverse events was considered to be drug related in study PRO2004 (60%) than in study PRO3004 (29%) (Table VIII). However, the type of drug-related clinical adverse events reported in all children enrolled in both studies was similar. No major difference was observed between the PI-naive and PIexperienced subgroups. Similarly, the adverse-event profile did not differ between patients treated with 20 mg/kg BID or 15 mg/kg TID in study PRO2004 (data not shown). As in adults, most of the drugrelated events were gastrointestinal symptoms or rash. A detailed review of adverse-event listings failed to reveal any potential symptoms of fat redistribution in either pediatric study. One non-drugrelated death was reported in study PR03004. It occurred after 19 weeks of
adverse events of grade ~2 in the pediatric studies
PRO3004
Any drug-related adverse event Vomiting Nausea Diarrhea/loose stools Abdominal pain Rash
PRO2004
PI-naive (n = 109)
PI-experienced (n= 119)
Total (n = 228)
Total (n = 40)
36 (33) 18 (17) 11 (10) 12(11)
31 (26) 13 (11)
67 (29) 31 (14)
24 (60)
6 (6) 3 (3)
5 4 3 8
(4) (3) (3) (7)
16 (7) 16 (7) 9 (4) 11 (5)
3 (8) 0 (0) 16 (40) 3 (8) 8 (20)
PI = protease inhibitor. *Reported by 25% of patients in any group. Values are reported as no. (%) of patients experiencing the adverse event.
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treatment and was related to Pneumocystis . .. carmu pneumonia. Laboratory Abnormalities Overall, few severe (grade 3 or 4) treatment-emergent laboratory abnormalities were reported in children receiving APV. The most common severe laboratory abnormality was hyperamylasemia (2%) in PRO3004 and thrombocytopenia (5%) in PRO2004.
DISCUSSION APV was generally safe and well tolerated in clinical trials when administered in combination with other antiretroviral agents to 358 adult and 268 pediatric patients. APV has a safety profile comparable to that of other PIs; most adverse events are mild to moderate and involve the gastrointestinal system.‘*-*’ Current evidence suggests that APV and IDV may have somewhat distinct safety profiles (as described in results from PRO3006), although discontinuation rates due to adverse events were similar in the 2 groups. The most frequently reported adverse events, regardless of causality, in adults who received APV were gastrointestinal symptoms and rash. These events were generally reported more often in treatment-naive patients (PRO3001) than in previously treated patients (PRO3006). This suggests that some of the adverse events reported in PRO3001 may have been related to initiation of antiretroviral therapy, including NRTI therapy. Also, as APV (and IDV) are taken as part of multidmg regimens, other agents in the regimen, either individually or in combination, could have contributed to any of the adverse events reported. In the treatment-naive population, nausea, rash, and oral/perioral paresthesia were reported in significantly more
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patients in the APV/3TC/ZDV group than in the 3TC/ZDV group (P < 0.001). Among patients previously exposed to NRTIs, diarrhea/loose stools and oral/perioral paresthesia were reported in significantly more patients in the APV/NRTI group (P < 0.001) than in the IDV/NRTI group. Renal disorders (flank pain, urinary calculi, and urinary tract hemorrhage) and signs of chronic hypervitaminosis A (retinoid-related toxicities, dry skin, xerostomia, hair loss/alopecia) were reported in significantly more patients in the IDV/NRTI group than in the APV/NRTI group (P < 0.001). Most of the clinical adverse events commonly reported with APV were mild or moderate, early in onset, and transient. Nausea, vomiting, diarrhea/loose stools, and rash were the most common adverse events leading to APV discontinuation. Almost all events that led to discontinuation of study medication were drug related, and the majority were either mild or moderate. Long-term follow-up of adult patients receiving APV did not reveal any new safety concerns. The proportion of patients with any reported treatment-emergent laboratory abnormality in the APV/3TC/ZDV and APV/NRTI groups was similar to that reported in the 3TCYZDV group of PRO3001 and lower than that reported in the IDV/NRTI group of PR03006. The latter difference was mainly due to a higher rate of elevated bilirubin and liver aminotransferase levels in patients treated with IDV. Overall, few grade 3 or grade 4 treatment-emergent laboratory abnormalities were reported in patients receiving APV. Severe laboratory abnormalities occurred with similar frequencies in the APVi3TClZDV and 3TC/ZDV groups in PR03001, but were reported more frequently in the IDV/NRTI group
L. PEDNEAULT ET AL.
than in the APVINRTI group in study PRO3006. Despite the fact that blood samples were not routinely collected under fasting conditions, rates of severe treatment-emergent elevations in plasma triglyceride, cholesterol, and glucose levels were low with APV. The median values for plasma triglyceride and glucose levels remained stable over time in all treatment groups of PRO3001 and PRO3006, whereas slight increases in median cholesterol levels were observed in all 3 groups treated with PIcontaining regimens. At the time these trials started, the casereport forms did not contain specific sections or describe specific tests to collect data on fat redistribution. Therefore, the fat redistribution data presented in this review were reported on routine adverseevent forms. Also, the duration of exposure to APV (and IDV in PR03006) ranged from 15 weeks in PRO3004 to 56 weeks in PR03006. Thus, for some patients, potential fat redistribution symptoms may not have developed by the time data were collected for this analysis. Few cases of fat redistribution were reported with APV in either adult study; in study PRO3006, the incidence of adverse events related to fat redistribution was significantly higher in the IDV group (12% vs 4% in the APV/NRTI group; P < 0.001). Overall, the PRO3006 data in this review indicate that APV has a favorable safety profile, distinct from that of IDV. There is also some in vitro evidence suggesting that the effects of PIs on fat metabolism are not class specific. In vitro, nelfinavir, ritonavir, and saquinavir directly inhibit fat-cell differentiation (adipogenesis) and stimulate fat turnover (lipolysis), whereas IDV inhibits adipogenesis via retinoic acid signaling. APV ap-
peared to have little effect on adipogenesis or lipolysis in vitro.** The higher rate of adverse events consistent with chronic hypervitaminosis A observed with IDV in PRO3006 supports the in vitro findings of Lenhard et a1,23 who reported that IDV appears to stimulate the activity of the vitamin A metabolite retinoic acid in cell cult1 re. Nail defects, hyperbilirubinemia, alopecia, and renal complications have previously been described in association with IDV.24-26 Although the in vitro data may suggest that some IDV-associated adverse events occur due to alterations in retinoic acid signaling, other factors may influence the development of adverse events in humans, such as pharmacokinetic parameters, active metabolites, diet, and genetic predisposition. For these reasons, caution is required when relating in vitro findings to clinical adverse events in trials with IDV. The results of the 2 pediatric studies indicate that the safety and tolerability profile of APV in children is comparable to that seen in adults. The most common drugrelated clinical adverse events (grade 22) in children receiving APV were, as for adults, gastrointestinal symptoms and rash. The frequency and nature of these events were comparable in PI-naive and PI-experienced patients. Most clinical adverse events and laboratory abnormalities were mild to moderate, and only 5% of children discontinued APV due to an adverse event.
CONCLUSIONS The adverse-event data collected from 4 clinical trials indicate that APV was generally safe and well tolerated when administered with various NRTIs in adult and pediatric patients with a range of treatment experience and HIV disease sever-
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ity. The APV safety and tolerability profile reported in children was similar to that described in adults. Most adverse events associated with APV therapy were gastrointestinal symptoms and rash. They were generally mild or moderate, early in onset. and transient.
ACKNOWLEDGMENTS Funding for the studies described in this review was provided by Glaxo Wellcome Research and Development. We thank the investigators and patients who took part in the studies described in this review. We also thank Pantaleo Nacci for statistical assistance and Justin Cook and Jeanne Wilson for writing and editing assistance.
Address correspondence to: Anny Fetter, MD, Glaxo Wellcome HIV and Opportunistic Infections Clinical Development, Glaxo Wellcome Research and Development, Greenford Road, Greenford, Middlesex UB6 OHE, UK.
REFERENCES I. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000;356: 1423-1430. 2. Goodgame JC, Pottage JC Jr, Jablonowski H, et al. Amprenavir in combination with lamivudine and zidovudine versus lamivudine and zidovudine alone in HIV- 1-infected antiretroviral-naive adults. Antiviral T/zm 2000;5:2 15-225. 3. Rizzardi G, Bart P Chapuis A, et al. Immunologic and virologic responses after long-term HAART in HIV- I -infected therapy naive adults at early stage of chronic infection. In: Program and abstracts of the Seventh Conference on
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Retroviruses and Opportunistic Infections; January 3@-February 2, 2000; San Francisco. Calif. Abstract 336. 4. Mellors J, Lederman M, Haas D, et al. Durable activity of ziagen (abacavir, ABC) combined with protease inhibitors (PI) in therapy naive adults. In: Program and abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago, Ill. Abstract 625. 5. Eron J, Haubrich R, Richman D, et al. Safety and efficacy of amprenavir in combination with other protease inhibitors. AIDS. 1998;12(Suppl 4):S38. Abstract. 6. Masur H, Falloon J, Thomas D, et al, for the CNA2007 study team. Durability of abacavir/amprenavir/efavirenz combination salvage therapy-preliminary 48week response (CNA2007). In: Program and abstracts of the Seventh European Conference on Clinical Aspects and Treatment of HIV Infection; October 23327, 1999; Lisbon, Portugal. Abstract 206. 7. Blanche S, Fetter A, Cox H, et al. A phase II study of amprenavir (APV, 14lW94, Agenerase’“) in antiretroviral-experienced children with HIV-infection; In: Program and abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, Calif. Abstract 695. 8. Church J, Rathore M, Rubio T, et al. Phase III study of amprenavir (APV, AgeneraseTM) in protease-inhibitor (PI) naive and experienced (EXP) HIV-infected children and adolescents. In: Program and abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections; January 30-February 2,200O; San Francisco, Calif. Abstract 693.
L. PEDNEAULT ET AL.
9. Partaledis JA, Yamaguchi K, Tisdale M, et al. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-l) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-l aspartyl protease. / virol. 1995;69:5228-5235.
10. Snowden W, Shortino D, Klein A. Development of amprenavir resistance in NRTI-experienced patients: Alternative mechanisms and correlation with baseline resistance to concomitant NRTIs. In: Program and abstracts of the Fourth International Workshop on HIV Drug Resistance and Treatment Strategies; June 12-l 6,200O; Sitges, Spain. Abstract 108.
11. Tisdale M, Myers RE, Maschera B, et al. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother. 1995;39: 1704-1710.
12. Myers R, Snowden W, Randall S, Tisdale M. Unique resistance profile of the protease inhibitor APV (14lW94) observed in vitro and in the clinic. Ad~i~d 7’her: 1998;3(Suppl 1):59-60.
13. Pedneault L, Fetter A, Hanson C, et al. Amprenavir (14lW94, APV): Review of overall safety profile. In: Program and abstracts of the Sixth Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago, Ill. Abstract 386.
14. Fetter A, Nacci P, Yeo J, et al. Tolerability profile of amprenavir (APV, 141W94) in combination with various NRTIs. In: Pro-
gram and abstracts of the Seventh European Conference on Clinical Aspects and Treatment of HIV Infection. October 23-27, 1999; Lisbon, Portugal. Abstract 8 13. 15. Fetter A, Nacci P, Lenhard J, et al. Fat distribution and retinoid-like symptoms are infrequent in NRTI-experienced subjects treated with amprenavir. In: Program and abstracts of the Seventh Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, Calif. Abstract 18. 16. Pedneault L, Hanson C, Nacci P, et al. Amprenavir: A new protease inhibitor with a favourable metabolic profile. In: Program of the First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, June 26-28, 1999; San Diego, Calif. Abstract 34. 17. Glover ML, Reed MD. Propylene glycol: The safe diluent that continues to cause harm. Pharmacotherapy. 1996; 16:690-693. 18. Viracept@ (nelfinavir) [package insert]. La Jolla, Calif: Agouron Pharmaceuticals, Inc; 2000. 19. Crixivan@ (indinavir) [package insert]. Whitehouse Station, NJ: Merck Research Laboratories Inc; 2000. 20. Norvir@ (ritonavir) [package insert]. Abbott Park, Ill: Abbott Laboratories, Inc; 2000. 21. Fortovase@ (saquinavir) [package insert]. Basel, Switzerland: Hoffmann-La Roche Laboratories; 2000. 22. Lenhard JM, Furtine ES, Jain RG, et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res. 2000;47: 121-129.
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23. Lenhard JM, Weiel JE, Paulik MA, Furhne ES. Stimulation of vitamin A, acid signaling by the HIV protease inhibitor indinavir. Biochem Pharmacol. 2000;59: 1063-l 068.
25. KakudaTN, Struble KA, Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency virus infection. Am J Health-Syst Pharm. 1998;55:233-254.
24. Bouscarat F, Bouchard C, Bouhour D. Paronychia and pyogenic granuloma of the great toes in patients treated with indinavir. N Engl d Med. 1998;338: 1776-l 777.
26. Bouscarat F, Prevot MH, Matheron S. Alopecia associated with indinavir therapy. N Engl J Med. 1999;34 I:6 18. Letter.
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