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January 1998 Volume 1, Number 3-4, Section 5

NNRTI - Non-nucleoside Reverse Transcriptase Inhibitor Section
    Efavirenz (DMP-266) Interactions with nelfinavir.
    Delavirdine (Rescriptor) Interactions with Ritonavir and Nelfinavir
    Nevirapine (Viramune) Nevirapine+Indinavir Study
Efavirenz (DMP-266) (Sustiva-brandname). DMP-266 is a new NNRTI (non-nucleoside reverse transcriptase inhibitor). The efavirenz pivotal studies from which data is used by the FDA for consideration of approval are ongoing. An expanded access program started in October for individuals with <50 CD4. On December 16, DuPont Merck announced new expanded eligibility criteria: a person is eligible if at any time they have had a CD4 count <400, if they are failing or intolerant to their current treatment, and their physician is unable to assemble a treatment combination without Sustiva that is likely to produce a sustained reduction of virus in the blood.

In ongoing studies, efavirenz is being taken once a day at a dose of 600 mg with or without food. The long half-life of the drug (40-52 hrs) lends itself to once-daily dosing. The most common side effects are CNS symptoms and are associated with taking the 600 mg dose: lightheadedness or dizziness, and antihistamine-like effects have been seen when using the higher doses. Company officials say experience so far indicates these symptoms usually last several hours and seem to dissipate within a few weeks after starting medication. Company officials say these side effects can be addressed by adjusting the dosing regimen by taking the 600 mg dose before bedtime, by taking 300 mg twice daily, or if that’s not tolerable by lowering the dose to 400 mg once per day. But they believe the 600 mg dose may be more potent in the long term. Rash has also been seen when treated with efavirenz, but the company reports that in most cases it resolves without requiring any change in efavirenz treatment.

A pediatric study using nelfinavir+266 is just beginning using 50 and 75 mg capsules. Children who are capable of swallowing a capsule will be eligible. A liquid formulation is being developed.

Efavirenz should not be used as monotherapy, as resistance can develop rapidly. It should only be used as part of a combination therapy well designed to adequately suppress viral load.

The original dose used in earlier studies was 200 mg once a day. A key mutation in the development of resistance to efavirenz is K103N. DuPont Merck increased the dose to 600 mg daily hoping it will well suppress this mutation; and, it was also chosen to suppress other single mutations associated with NNRTI resistance. Company officials say the dose increase is likely to cause increased antiviral activity of DMP-266. In a 14- day monotherapy study where the 200 mg dose was compared to placebo the peak reduction in viral load was 1.7 log when using the Roche Amplicor 400 copy test.

CSF. In a small study of 3 individuals, investigators reported that efavirenz penetrated the CSF in all three. The 3 patients were receiving DMP-266 200 mg once a day in combination with indinavir in a study for 28 days when samples were taken. Plasma (blood) and CSF samples were both obtained at the same time point. See Table 10.

Table 10. Results - DMP - 266 CSF Drug Levels


Time Post




Dose (hr)

CSF (nM)

Plasma (nM)

















Indinavir+Efavirenz. Study participants were randomized to either indinavir monotherapy or indinavir+efavirenz. Baseline CD4 and viral load are in table 11. After it was determined that efavirenz decreased indinavir AUC (indinavir concentration in the blood over the 8-hour dosing period) by about 35%, study participants who were taking 800 mg indinavir with efavirenz increased their indinavir dose to 1000 mg every 8 hours by about 12 weeks into the study. Also, after 12 weeks individualsreceivingindinavir monotherapy were permitted to add d4T+efavirenz. If taking indinavir with efavirenz, DuPont Merck recommends 1000 mg indinavir every 8 hours. The dose of efavirenz used in this study was initially 200 mg once per day but was raised after a minimum of 36 weeks to 600 mg once a day. More detailed data on side effects are available on NATAP website.

**NOTE: Based on the following information study investigators believe that the more you lower your viral load the more durability you will obtain. Investigators used the Amplicor 400 copy test to see if there was any virus signal. They found that they were unable to detect virus signal from 80% of the individuals in the efavirenz+indinavir arm using the 400 copy test. This does NOT mean viral load was not present in the blood.

Study investigators said, the individuals in this study for whom they found no viral load signal were better able to remain below detection by the standard Amplicor test (<400 copies/ml). Their viral load reduction was more durable. For those for whom no signal was found about 90% had less than 400 copies/ml at 48 weeks. For those for whom a signal was detected, at week 48 about 60% of these individuals remained less than 400 copies/ml. From a mathematical model used to analyze the results, they concluded those who had no signal were 8 times more likely to remain less than 400 copies/ml at 48 weeks than those for whom they detected a signal but had less than 400 copies/ml. See Tables 11 and 12

Table 11. DMP-266+Indinavir




- N (# of individuals)






-HIV RNA, approx

123,000 copies/ml


-Prior Therapy



At Week 48    



-VL dec.,
400 copy test

-2.4 log

-1.9 log

-% <400 copies/ml



-No VL signal**



-CD4 inc.

+250 CD4

+150 CD4

Table 12. This is a Summary of Rashes

Toxicity Grade DMP-266+indinavir Indinavir
I 19/84 (22.6%) 11/42 (26.2)
II 9/84 (10.7%) 1/42 (2.4%)
III 0/84 1/42
total rashes 28/84 (33.3%) 13/42 (31%)

There has been 1 case of Stevens Johnson Syndrome (serious rash) out of 1300 individuals who’ve received efavirenz, which investigators think was due to another medication the person was taking.

Pharmacokinetics (PK) for efavirenz+nelfinavir. A PK interaction study has been conducted for efavirenz taken with nelfinavir in healthy volunteers. Investigators reported that with coadministrtion of both drugs (750 mg nelfinavir 3x/day and 400 mg efavirenz once-daily), and after steady state blood levels were reached for both drugs, nelfinavir AUC (overall blood levels over a fixed time period) increased 15% and the Cmax (peak blood level of drug) of nelfinavir was increased 30%. Investigators reported there was no significant effect on efavirenz AUC or Cmax by nelfinavir. Further studies are in progress to determine proper dosing, and explore safety and efficacy. These results are different than when combining efavirenz with indinavir. Indinavir blood levels are decreased 30-35%, and so DuPont Merck recommends the dose of indinavir should be increased to 1000 mg every 8 hrs.

Efavirenz+AZT/3TC. This study ex-plores the safety and efficacy of three different doses of DMP-266 + AZT/3TC vs AZT/3TC alone in treatment naive individuals who are asymptomatic or mildly symptomatic, a relatively healthy group. It also explores an unusual and potentially useful therapeutic approach of using efavirenz+2 nucleosides as a first line treatment (rather than a protease regimen), thereby strategically preserving the protease inhibitor option for a future time. The preliminary follow-up data extends only to 16 weeks but the study is ongoing and additional information will be reported. The four treatment arms are:

        • AZT/3TC
        • 200 mg efavirenz once-daily+AZT/3TC
        • 400 mg efavirenz once-daily +AZT/3TC
        • 600 mg efavirenz once-daily +AZT/3TC

See Table 13

Table 13. DMP-266+AZT/3TC


200mg 266

400mg 266

600mg 266











-VL approx

45,700 copies/ml




Early Discontinuation





-adverse event (a/e)










-withdrew consent





-lost to followup





Week 16        
-mean CD4 increase
approx, (n)

+115 CD4 (22)

+125 (21)

+125 (21)

+155 (17)

-mean VL decrease
(400 copy test), (n)

-1.4 log (26)

-2.1 log (28)

-2.1 log (24)

-1.9 log (25)

-% <400 copies/ml





Ultrasensitive test - <40 copies/ml

4 (15%)

23 (74%)

17 (63%)

16 (64%)

Delavirdine. In October Upjohn & Pharmacia called a small community meeting to report preliminary data from a new study of a triple regimen containing delavirdine and to discuss their development plans for their proteaseinhibitor (PNU140690). Thedelavirdinestudy comparedAZT+3TC+delavirdine, AZT+3TC, and delavirdine+AZT. The study has not yet been presented at an AIDS scientific meeting. Although the study participants were not AZT naive, they were required to have less than 6 months AZT experience. 80% had no prior AZT experience.

117 individuals were randomized to one of the 3 arms. The baseline CD4 counts and viral load were about 350 and 31,500 copies/ml. An interim analysis after 32 weeks of a 1 year study showed that those receiving delavirdine plus AZT/3TC had a CD4 increase of 96, a 2.0 log reduction in viral load when using a more sensitive test (40 copies/ml), a 1.5 log reduction when using the standard 400 copies/ml test, 50% were <40 copies/ml, and 63% were <400 copies/ml n=45).

By comparison, at week 32, those receiving AZT/3TC had a CD4 increase of 70 cells, a 1.3 log reduction from baseline, 31% were <400 copies/ml, and 12% were <40 copies/ml. Those receiving delavirdine+AZT had a 20 CD4 increase, 0.5 log reduction in viral load, 5% were <400 copies/ml, and 0% were <40 copies/ml.

Preliminary interaction when combining Nelfinavir with Delavirdine. It is uncertain which doses of the two drugs should be used when taken together. Studies are planned or already ongoing to explore the various dosing combination of the two drugs. ACTG 359 is for individuals who have failed indinavir; it started in November ‘97 and is exploring use of 3 and 4 drug regimens includingnelfinavir+saquinavir+delavirdine 600 mg bid; adefovir (new nucleotide) will also be used in this study. Initial interaction (PK) data should be available soon. As well, Upjohn has a study exploring different dose regimens for using nelfinavir with delavirdine. Two doses of delavirdine (400 or 600 mg tid) will be explored with nelfinavir 750 mg tid in combination with d4T and ddI. Experimenting using drugs before proper dosing is identified can result in either one of two potentially harmful outcomes. The blood concentration of a drug could be too low resulting in resistance developing; or, blood levels of a drug could be too high resulting in toxicities.

Upjohn conducted an initial study exploring interactions between delavirdine and nelfinavir in 24 healthy volunteers. Group A received nelfinavir 750 mg every 8 hrs for 1 week followed by concomitant treatment with nelfinavir 750 mg every 8 hrs plus delavirdine 400 mg every 8 hrs. Group B received delavirdine 400 mg every 8 hrs for 1 week followed by concomitant treatment with delavirdine 400 mg every 8 hrs plus nelfinavir 750 mg every 8 hrs. All doses were taken with food. See Tables 14 and 15.

Table 14. Mean Changes in Nelfinavir Pharmacokinetic (blood levels)
Values obtained from 12 individuals in group A


NLF alone


Mean Change

NLF AUC (ug h/mL, 0-8 hrs)



+113% ( 25%)

NLF Cmax (ug/mL)



+93% ( 24%)

NLF Cmin (ug/mL)



+146% ( 37%)

Table 15. Mean Changes in Delavirdine Pharmacokinetic Values

The following data was obtained from 7 individuals in group B


DLV alone


DLV AUC (uM h, 0-8)

210 ( 112)

122 ( 24)

DLV Cmax (uM)

32 ( 16)

21 ( 5)

DLV Cmin (uM)

21 ( 13)

10 ( 3)

Safety. 4/24 individuals discontinued the study due to neutropenia. Two subjects experienced serious (grade 3/4) neutropenia as a result of the combination. In each case, the neutropenia resolved after stopping both drugs. Investigators said except for the neutropenia the combination was well tolerated. If using these two drugs together, absolute neutrophil count should be frequently monitored.

As you can see the AUC of delavirdine was reduced by about 40% in this study; the Cmax was reduced by about 34%; and the important Cmin, also called the trough, was reduced by about 50%. Delavirdine and nelfinavir concentration data were available for 20 patients in a community practice setting where individuals received the two drugs at their normally recommended doses for over 1 month. Blood samples were obtained between 6 to 9 hrs after the doses of both drugs. The median Cmin or trough concentration of delavirdine was about 40% lower than when taking delavirdine in combination with nucleosides. The reduced Cmin or trough of delavirdine is the reason that a higher dose of delavirdine of 600 mg tid will be explored in the above mentioned clinical study where nelfinavir will be combined with delavirdine and d4T and ddI in 3 and 4 drug combinations. Trough levels will be evaluated. Again, it may be preferable to wait until proper dosing regimens have been identified before using these combinations.

Preliminary PK of Combining Ritonavir with Delavirdine. This was a small preliminary interaction study (n=12). 10/12 individuals had AIDS. The baseline CD4 counts were about 163 with a wide variability among the participants. 600 mg bid of ritonavir was administered for at least 14 days with nucleosides. Delavirdine 400 mg tid was added. Participants had prior ritonavir experience of 1 to 12 months. There was no group who started with delavirdine and then added ritonavir after steady state of delavirdine was reached. They used historical PK values of delavirdine, and PK values observed in a previous PK study using ritonavir at 300 mg bid. Based on these previous observations and other information, Upjohn does not expect ritonavir will have a significant effect on delavirdine blood levels.

ACTG 359 is just beginning. The regimens available in the study will include ritonavir+saquinavir+delavirdine; adefovir will also be used in the study. In this study delavirdine dosing will be 600 mg bid. Investigators will be analyzing interaction data in the initial stage of the study. It is expected that saquinavir should not effect delavirdine blood levels, but this study will explore 3 drugs used together all of which effect the CYP450 liver enzyme system.

In the interaction (PK) study, delavirdine increased overall ritonavir blood levels by 70%. See Table 16 for the effects on specific PK parameters.

Table 16. Delavirdine effect on ritonavir PK


RTV alone


Mean increase (range)

RTV AUC (ugxhrs/mL, 0-12)



inc. 60% (22-90%)

RTV Cmax (ug/mL)



inc. 66% (24-109)

RTV Cmin (ug/mL)



inc. 84% (41-127)

Safety. There was 1 grade 4 elevation of triglycerides; 1 grade 3 elevation of LFTs; 1 grade 1 rash; and 1 grade 2 thrombocytopenia. All of these side effects may have been experienced by one person.

Indinavir + Delavirdine. As explained in the July issue of NATAP Reports, delavirdine increases indinavir blood levels. Please refer to that article for detailed discussion. A trial will be conducted exploring two indinavir doses (400 mg tid or 600 mg tid) with 400 mg tid delavirdine. As well, a 2 times per day dose regimen study is planned: 800 or 1000 mg bid indinavir plus 600 mg bid delavirdine.

Neviraptine (Viramune). Nevirapine + Indinavir Study.  24 individuals enrolled in what was originally designed as an open label study to determine the effects of pharmacokinetics (PK) or blood levels of these two drugs when used together. Participants were protease inhibitor naive but were permitted to continue their background NRTI therapy. This report is of the long term extension of the study. 19 participants completed the PK part of the study. 17 enrolled and 12 remain in the extension. Reasons for dropout throughout the trial were: failure to return to clinic/lost to follow-up (6); adverse events - rash (2), kidney stones (1); viral load failure (2); consent withdrawal (1).

The median baseline CD4 was 434; the median baseline viral load was low at 3.5 log (about 3,100 copies/ml). 53% of the participants had prior nucleoside experience. One half were on NVP+IDV and half were on NVP+IDV+nucleosides. As reported by NATAP more extensively in our July issue of NATAP Reports, there was a statistically significant reduction in indinavir AUC (-28%), Cmin (-38%) and Cmax (-11%) when taken with nevirapine. There was no significant effect of indinavir on nevirapine blood levels. Despite the PK effect of indinavir on nevirapine, indinavir was given at its usual dose of 800 mg every 8 hrs in this study. Some doctors are using 1000 mg of indinavir every 8 hours. Alex Dusek, of Boehringer Ingelheim, reported in Hamburg that after 60 weeks 92% (n=12) were below 400 copies/ml, and their median CD4 increase was 250. The mean viral load reduction was 1.9 log at 32 weeks; and, 9/12 participants had >100 CD4 increases at week 32. All patients under 400 were also under 20 copies per ml. It is important to remember that the median baseline viral load was low at 3,100 copies/ml, making it easier to potently suppress viral load and to sustain it.

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