Efavirenz (EFV) + AZT/3TC (study 006)-48 Weeks Data for this PI Sparing Regimen

Efavirenz (EFV) + AZT/3TC (study 006)-48 Weeks Data for this PI Sparing Regimen

At the World AIDS Conference in Geneva during the Summer of '98, 24 weeks data on efavirenz+AZT/3TC was reported. At ICAAC in September '98, 36 weeks data was reported. At the recent Human Retrovirus Conference in Feb '99, K Tashima reported 48 week data for the use of this PI sparing regimen of efavirenz in combination with AZT+3TC from study 006. In this study, the EFV+AZT/3TC regimen was compared to indinavir+AZT+3TC and efavirenz+indinavir. When EFV and IDV are taken together, DuPont increases the dose of IDV to 1000 mg every 8 hours rather than 800 mg every 8 hours because EFV reduces the blood levels of IDV by about 30%.

Efavirenz is a potent NNRTI with a long half life of 40-55 hours which allows once daily dosing. It can be taken with or without food, but very high-fat meals can raise the blood levels of efavirenz. Efavirenz drug levels in blood is high above the IC90 of wild-type trough. This means that at the end of a dosing period (24 hours for EFV) the level of efavirenz in blood is well above that needed to suppress HIV replication. This could account for its potency. Preliminary studies show EFV penetrates the CSF. Tashima said pregnancy should be avoided while taking EFV. EFV can cause CNS side effects in the first few weeks after starting the drug. For most people, these side effects are reportedly transient as they lift within 2-4 weeks. Not everyone experiences these side effects. Their incidence in this study are described below. The CNS-related side effects can include dizziness, disorientation, insomnia, vivid dreams, and impaired concentration. DuPont recommends that taking EFV at bedtime may make the side effects easier to tolerate. If bedtime dosing is not helpful enough, you can consider splitting the dose. Normally, the dosing for EFV is 3 200 mg pills once daily. But, one can split the dose by taking 400 mg at bedtime and 200 mg upon waking.

Study 006 is an open-label randomized trial comparing safety and antiviral activity of efavrienz containing arms to indinavir+AZT+3TC. Participants were blinded to viral load until week 24 and were naïve to 3TC, NNRTIs and PIs. Week 48 data is being presented for the first 450 (about 150 per arm) of 1200 patients enrolled in the study. As a result of this study, efavirenz was included along with protease inhibitors as options for initial therapy for treatment naïve individuals in the Public Health Service Treatment Guidelines revised in December 1998.

The mean baseline CD4 count and viral load were about the same for the 3 treatment groups: 345 CD4s and about 58,800 copies/ml.

Discontinuations. At week48, 25% of individuals in the EFV+AZT+3TC discontinued. In the indinavir+AZT+3TC group 42% discontinued, and in the EFV+IDV arm 35% discontinued. Tashima reported that few discontinuations in the IDV+AZT+3TC arm were due to treatment failure (1%) and most of the discontinuations were reported to be due to adverse events mostly gastrointestinal related. Because the study was open-label observers have commented that the higher discontinuation rates in the IDV arms may have occurred after study participants realized they were randomized to indinavir rather than efavirenz. Following is a table of the reported reasons and percentages for discontinuations.

EFV+AZT+3TC
EFV+IDV
IDV+AZT+3TC

Continuing on Study
75%
65%
58%

Discontinuations
25%
35%
42%

Reasons for Discontinuation

..........Adverse Experience
  6%
6%
  19%

..........Treatment Failure
2%
  2%
1%

..........Randomized bot not dosed
4%
5%
4%

..........Lost to Follow-up
10%
11%
10%

..........Other
  4%
11%
8%

VIRAL LOAD SUPPRESSION

Methods of Analysis. Tashima reported the data in two ways: Observed Data or On Treatment analysis and by Intent-To-Treat analysis. Tashima said the On treatment analysis includes only the results of patients on study at each time point and can be considered to represent the potency of the treatment regimen. The Intent-To-Treat analysis known as noncompleter=failure analyzes missing data points as failures. This includes patients who were randomized but not dosed, patients who discontinued for side effects or virological failure, patients who were lost to follow-up, or those who discontinued for other reasons. Patients who had missing data who were undetectable on either side of a time point were consured or not included in this analysis.

The On Treatment analysis is a less stringent analysis because it includes only study participants who remain on study drugs. Anyone who discontinues study drugs is excluded from the On Treatment Analysis. The percent of people undetectable will be higher using this analysis because people who are considered virological failures (viral load above detection) may withdraw from the study. The Intent-To-Treat analysis is more stringent because it includes virological failures and others who discontinue study drugs. The percent undetectable will always be lower when using this analysis.

Table 1. Week 48 Intent-To-Treat Analysis for Individuals Receiving EFV+AZT+3TC:

Percent <400 copies/ml (n=142) 71%

Percent <50 copies/ml (n=144) 65%

Percent <400 copies/ml baseline VL <100,000 copies/ml 72%

Percent <400 copies/ml baseline VL >100,000 copies/ml 70%

Percent <50 copies/ml baseline VL <100,000 copies/ml 64%

Percent <50 copies/ml baseline VL >100,000 copies/ml (n=44) 66%

**Table 1. Week 48 Intent-To-Treat Analysis for Individuals Receiving EFV+AZT+3TC:**
Percent <400 copies/ml (n=142)	71%
Percent <50 copies/ml (n=144)	65%
Percent <400 copies/ml baseline VL <100,000 copies/ml	72%
Percent <400 copies/ml baseline VL >100,000 copies/ml	70%
Percent <50 copies/ml baseline VL <100,000 copies/ml	64%
Percent <50 copies/ml baseline VL >100,000 copies/ml (n=44)	66%

As you can see in Table 1, the percent below 400 and 50 copies/ml were about the same whether a person's viral load was above or below 100,000 copies/ml before starting study drugs.

Table 2. Week 48 On-Treatment Analysis for Individuals Receiving EFV+AZT+3TC:

Percent <400 copies/ml (n=93) 98%

Percent <50 copies/ml (n=103) 90%

Percent <400 copies/ml baseline VL <100,000 copies/ml 97%

Percent <400 copies/ml baseline VL >100,000 copies/ml 100%

Percent <50 copies/ml baseline VL <100,000 copies/ml 87%

Percent <50 copies/ml baseline VL >100,000 copies/ml (n=30) 97%

**Table 2. Week 48 On-Treatment Analysis for Individuals Receiving EFV+AZT+3TC:**
Percent <400 copies/ml (n=93)	98%
Percent <50 copies/ml (n=103)	90%
Percent <400 copies/ml baseline VL <100,000 copies/ml	97%
Percent <400 copies/ml baseline VL >100,000 copies/ml	100%
Percent <50 copies/ml baseline VL <100,000 copies/ml	87%
Percent <50 copies/ml baseline VL >100,000 copies/ml (n=30)	97%

It is not a mis-print. The percent <50 copies/ml was higher for those with baseline VL >100,000 copies/ml than for those with <100,000 copies/ml (97% vs 87%).

Table 3. Week 48 On-Treatment Analysis by Baseline Viral Load

Baseline Viral Load Percent <50 copies/ml Using Ultra-sensitive Test

<50,000 copies/ml (n=45)
87%

50,000-100,000 copies/ml (n=26)
89%

100,000-300,000 copies/ml (n=17)
94%

>300,000 copies/ml (n=13)
100%

**Table 3. Week 48 On-Treatment Analysis by Baseline Viral Load**
Baseline Viral Load	Percent <50 copies/ml Using Ultra-sensitive Test
<50,000 copies/ml (n=45)	87%
50,000-100,000 copies/ml (n=26)	89%
100,000-300,000 copies/ml (n=17)	94%
>300,000 copies/ml (n=13)	100%

The mean CD4 increase from baseline to week 48 was about 200 for those taking EFV+AZT+3TC.

Table 4. New Onset Adverse Experiences >Grade 2 Possibly or Probably Treatment Related Occurring with Frequency >5% at Week 48

EFV+AZT+3TC
IDV+EFV
IDV+AZT+3TC

Total No. of Patients
154
148
148

Rash, maculopapular
10%
15%
5%

Fatigue
7%
7%
9%

Headache
7%
6%
5%

Dizziness
9%
5%
1%

Insomnia
5%
5%
1%

Nausea
11%
5%
22%

Diarrhea
3%
4%
6%

Dyspepsia
1%
3%
5%

Vomiting
6%
3%
14%

Pain
1%
1%
10%

Concentration impaired
8%
1%
1%

Bilirubinemia elevated
0%
0%
7%

**Table 4. New Onset Adverse Experiences** >**Grade 2 Possibly or Probably Treatment Related Occurring with Frequency** >**5% at Week 48**
	EFV+AZT+3TC	IDV+EFV	IDV+AZT+3TC
Total No. of Patients	154	148	148
Rash, maculopapular	10%	15%	5%
Fatigue	7%	7%	9%
Headache	7%	6%	5%
Dizziness	9%	5%	1%
Insomnia	5%	5%	1%
Nausea	11%	5%	22%
Diarrhea	3%	4%	6%
Dyspepsia	1%	3%	5%
Vomiting	6%	3%	14%
Pain	1%	1%	10%
Concentration impaired	8%	1%	1%
Bilirubinemia elevated	0%	0%	7%

Discontinuations Due to Adverse Events

There were 10/154 discontinuations due to adverse events reported in the EFV+AZT/3TC arm: 3 due to CNS symptoms, 2 GI, 1 rash, and 4 other (anemia, fatigue, neutropenia, tachycardia/anemia). All the discontinuations due to rash, GI and CNS were Grade 1/2 and they began during the first 12 weeks of study. There were 28/148 discontinuations in the IDV+AZT+3TC arm: 16 due to GI symptoms, 4 kidney stones, 2 anemia, 6 other (sarcoma 2, hematemesis, depersonalization).

Table 5. Summary of New-Onset Rashes

EFV+AZT+3TC
EFV+IDV
IDV+AZT+3TC

N=154
N=148
N=148

No. of Patients
44 (29%)
50 (34%)
24 (16%)

Maximum severity

.....Grade 1
19
16
14

.....Grade 2
25
32
10

.....Grade 3
0
2
0

.....Grade 4
0
0
0

Median Duration
13 days
14 days
42 days

Discontinuation of EFV
1 (1%)
3 (2%)
Not available

**Table 5. Summary of New-Onset Rashes**
	EFV+AZT+3TC	EFV+IDV	IDV+AZT+3TC
	N=154	N=148	N=148
No. of Patients	44 (29%)	50 (34%)	24 (16%)
Maximum severity
.....Grade 1	19	16	14
.....Grade 2	25	32	10
.....Grade 3	0	2	0
.....Grade 4	0	0	0
Median Duration	13 days	14 days	42 days
Discontinuation of EFV	1 (1%)	3 (2%)	Not available

Table 6. Summary of Nervous System Symptoms

EFV+AZT+3TC
EFV+IDV
IDV+AZT+3TC

No of Patients
85 (55%)
73 (49%)
35 (24%)

Maximum severity

  .....Mild (Grade 1)
47
53
22

  .....Moderate (Grade 2)
32
18
13

  .....Severe (Grade 3)
6
2
0

  .....Maximal (Grade 4)
0
0
0

Median Duration
19 days
22 days
20 days

EFV Discontinuations
3 (2%)
2 (2%)
na

**Table 6. Summary of Nervous System Symptoms**
	EFV+AZT+3TC	EFV+IDV	IDV+AZT+3TC
No of Patients	85 (55%)	73 (49%)	35 (24%)
Maximum severity
.....Mild (Grade 1)	47	53	22
.....Moderate (Grade 2)	32	18	13
.....Severe (Grade 3)	6	2	0
.....Maximal (Grade 4)	0	0	0
Median Duration	19 days	22 days	20 days
EFV Discontinuations	3 (2%)	2 (2%)	na

Based on the data in Table 6 the CNS related EFV side effects are of mild to moderate in severity although 55% of participants experience these side effects. I think patients should receive adequate warning from their doctors of what side effects might occur prior to starting EFV. Individuals should be prepared to reduce activities during the first few weeks after starting EFV if side effects emerge. Activities such as driving might have to be eliminated while experiencing side effects.