At the Chicago Retrovirus Conference, data from several studies of efavirenz were reported: 60 weeks IDV+EFZ; 24 weeks EFZ+AZT/3TC; EFZ resistance; EFZ CSF concentration in monkeys; potentially key interaction data for NFV+EFV and EFV+141W94.

EFV is metabolized through the same process as other NNRTIs and protease inhibitors--through the P450 liver enzyme system. Part of the p450 system is the CYP3A4. EFV possesses enzyme inducing activity on CYP3A4. Enzyme inducing activity leads to an increase in metabolism. Increasing metabolism results in less drug remaining in your blood; therefore, you may have to raise the dose of the accompanying drug.

For example, EFV reduces IDV blood levels by 35%, so when EFV is used in combination with IDV the normal IDV dose of 800 mg every 8 hrs is increased to 1000 mg every 8 hrs.

In a EFZ+141W94 PK study presented at Chicago meeting, researchers looked at 6 HIV infected individuals (CD4 5-311 cells; bDNA 590-370,100 HIV copies/ml) received 141W94 1200 mg bid for 1 week in combination with 2 or 3 NRTIs (4 individuals received 1592U89). Following collection of samples on day 7, EFV 600 mg once daily was added for 1 week. After which samples were collected again.

The mean 141W94 AUC was decreased 36%, the mean Cmax was decreased 39%, and the mean Cmin was decreased 43%, after the addition of EFV. There was wide variability among 141W94 PK measures in this small subset of patients (CV%=71). For an explanation of Cmin and Cmax see the NATAP pharmacokinetics report.

The investigators said that the clinical effects of the decreased 141 drug levels is unknown although the 141 Cmin achieved with EFV is similar to concentrations shown to be effective using 900 mg bid 141 with NRTIs. The AUC, Cmin, and Cmax values for EFV in combination with 141 were slightly higher than those observed in another study of healthy volunteers after 7 days of EFV 600 mg qd. It remains to be seen if these higher values for EFV are due to differences in intersubject metabolism or whether there is a PK interaction with 141.

The Tmax represents the amount of time it takes to reach the Cmax which is the peak drug level. See PK Primer on web site (LINK-UP) for explanation of PK terminology. As you can see in the following table the 141W94 AUC, Cmax and Cmin are reduced when EFV is added. And, there is a good deal of variability. The number after the ( is the standard deviation and represents the observed variability.

During week 1, individuals received 141W94; during week 2 they received 141W94+EFV. CL/F (L/h) is the amount of clearance of drug as measured by liter per hour. You will note that as AUC declines the rate of clearance increases.

PK Interaction Between EFV and NFV in Healthy Volunteers

WD Fiske and others from DuPont Merck reported the data from this study and concluded that when taken in combination, both drugs should be taken at their regular doses. Dose modification is not necessary.

Investigators reported that coadministration of EFV 600 mg qd with NFV 750 mg tid in this study resulted in an increase of 20%, a statistically significant difference, in NFV AUC compared to NFV taken alone. The NFV Cmax was also increased by about 20%, also a statistically significant difference . The abstract did not specifically report the Cmin change but based upon visual observation of a PK line graph in the abstract the Cmin was higher at hour 8, and it was reported to me that the NFV Cmin increased by 22% in this study. The authors reported there is no significant difference between the effect on EFV drug levels when coadministered with NFV compared to levels of EFV taken alone.

After taking NFV, a hydroxylated metabolite of nelfinavir called AG-1402 or M-8 forms. Two entities are present- NFV and AG-1402. The abstract said that AG-1402 has comparable in vitro antiviral activity to NFV, and that EFV reduced AG-1402 AUC by 37% (statistically significant difference) as compared to NFV taken alone. It was reported to me that:

• EFV effect on NFV may or may not be clinically relevant

• It is not known to what degree M-8 contributes to the overall NFV in vivo antiviral response, if at all.

• There is 3 to 4 times more NFV present than AG-1402, so after factoring in the changes in blood levels for NFV and M-8, the sum of NFV + M-8 in circulation when coadministered with EFV is slightly higher than without EFV. Therefore, the overall clinical response shouldn’t be effected.

 

J Kahn and others reported a 60 week update (of cohort 4) for the drug combination of IDV+EFZ. 101 protease and NNRTI naive individuals were initially randomized to EFZ 200 mg once a day (qd) + IDV 800 mg tid (every 8 hours) or IDV alone. At 12 weeks those taking IDV alone added EFZ+d4T. After about 36 weeks doses of EFZ were increased to 600 mg once a day. In our January ‘98 newsletter, NATAP Reports, the 48 week data was reported with a discussion of dosing, pediatrics plans, and rash. The results observed at week 48 are sustained at week 60. DuPont Merck, the developer of Efavirenz, expects to submit their application (NDA-New Drug Application) to the FDA for accelerated approval in June ‘98. In an early 14 day monotherapy study where the dose was 200 mg the peak reduction in viral load was 1.7 log when using the Roche Amplicor 400 copy test.

In this table you will see reference to viral load of "<1 copy/ml" using the standard Roche Amplicor (<400 copies/ml) test. This was explained in our January ‘98 issue. The explanation is more extensive in the EFV report in the New Drug Section (LINK-UP). If a person’s Amplicor test result was "<1 copy/ml", that means the lab could not detect virus. It does NOT mean virus is not present, just that it wasn’t detectable. The Amplicor test is not as sensitive as the Roche Ultrasensitive test, so study investigators reported that at week 24,71% of participants with "<1 copy/ml" had Ultrasenstive results <40 copies/ml. And also at week 24, 87% of individuals with Ultrasenstive <40 copies/ml had "<1 copy/ml" by standard Amplicor test.

In other words, some individuals with <1 copy/ml had >40 copies/ml. And some individuals with >40 copies/ml had <1 copy/ml. It reflects, among other things, variability in testing results. It’s a little complicated but I hope this explanation is clear enough.

59 patients were initially randomized to EFV+IDV but 54 actually initiated treatment with EFV+IDV. 42 were initially randomized to the IDV arm and 42 actually initiated treatment in that arm. Leading up to week 60, investigators reported the % <400 copies/ml was 74% at week 12, 87% at week 16, and 94% at week 24; and, the % "<1 copy/ml" was 64% at week 12, 71% at week 16, 88% at week 24.

Premature Discontinuations (24 weeks)

One patient was discontinued from EFV due to rash

129 patients’ data from several similar cohorts ( a cohort is a group of study participants) were examined to conduct this analysis. Two factors were found to be significant predictors of treatment success or failure. The first predictor is baseline HIV RNA. Failure is defined as a rebound to above 400 copies/ml after having achieved consecutive readings below 400 copies/ml. Investigators found that for every 1 log increase in baseline viral load there was a 4.3 fold increased risk for treatment failure (rebound to >400 copies/ml). For example, 10,000 copies/ml to 100,000 copies/ml is a 1 log difference.

The second significant predictor in this study was whether or not a person lowered viral load to "<1 copy/ml". Investigators found that if viral load, in this study, was suppressed to between 1 and 400 copies/ml there was a 7.59 greater chance of rebounding to >400 copies/ml than if your viral load was "<1 copy/ml". Therefore, suggesting that lowering viral load to <400 copies/ml may not be as durable as lowering viral load to "1 copy/ml" or <40 copies/ml. In other words, the investigators concluded more durability may be expected from lowering your viral load to a low level. Other studies have also suggested that lowering viral load to <40 copies/ml will create more durability. Many leading authorities and treating physicians have accepted the idea that lowering viral load to <50 copies/ml will be more durable, but we don’t yet have much substantive long term data supporting this thinking.

Additionally, in certain circumstances it is difficult to know exactly what to do with this information. For example, if a person reduces their viral load to 300 copies/ml with a 3 drug regimen consisting of a protease inhibitor plus 2 NRTIs, should they change the regimen or add another drug to further reduce viral load to <50 copies/ml (lower limit of detection using the Ultrasenstive test)? That would be an individual decision, although the Abbott study #462 (ritonavir+saquinavir) suggested that a well timed treatment intensification was successful in lowering viral load to undetectable for those who had not yet reached undetectable with ritonavir+saquinavir alone. For more details on the 462 study see the current Double Protease Report on the NATAP web site(LINK-UP).

Preliminary week 24 results were reported on this non-protease inhibitor regimen.137 treatment naive individuals were randomized to receive AZT/3TC (twice daily) plus one of three doses of efavirenz (200 mg qd, 400 mg qd or 600 mg qd--qd means once a day), or the placebo group who received AZT/3TC alone. At week 16, individuals randomized to AZT+3TC alone added IDV+EFV. 24 weeks is too short a period of time to conclude that EFV+AZT/3TC is an equal substitute for a 3-drug potent protease containing regimen. Data from protease containing 3 drug regimens have shown suppression of viral load out to 1-2 years. But, this study is being closely followed to observe the durability of the data.

Patient demographics at enrollment were: 26/104 (25%) white, 66/104 (63%) African-American,12% other ethnicity, 87/104 (84%) male, 17/104 (16%) female.

Premature Discontinuations (24 weeks)

Changes in CD4 and Viral Load from Baseline

At week 16, several therapy changes were implemented for study participants when it was determined that all the efavirenz dose arms were statistically significant superior to the AZT/3TC arm:

• EFV+IDV was added to AZT+3TC

• The EFV 200mg and 400mg qd doses increased to 600mg qd and if person was not undetectable (400 copies/ml), IDV+d4T (d4T was substituted for AZT) was added

• Those who started treatment with EFV 600mg qd+AZT/3TC added IDV+d4T (d4T was substituted for AZT) if their viral load was not undetectable.

The tables below contains changes at both weeks 16 and 24.

CD4 increases are approximations based upon visual observations of line graph charts. The number of evaluable patients (n) at week 16 ranged from 27 to 30 for all 4 arms. At week 24, the n ranged from 20 to 24 individuals for all 4 arms. Again, at week 16, therapy changes were made for all arms. Individuals in all 4 arms received EFV 600 mg once daily after 16 weeks. So, it’s possible the sudden increases in the 200 and 400 mg arms were due to the improvements in the regimen at week 16. The therapy changes are described in the paragraph above.

The test with a lower limit of detection of 400 copies/ml was used. The peak reduction in viral load for the AZT/3TC group was 1.7 log at week 2. Remember that at week 16 participants made therapy changes. Although maybe not statistically significant, the mean viral load reeducation of the AZT/3TC arm was about 1.9 log at week 20 and decreased to 1.65 at week 24. There were 27-31 evaluable patients at week 16, and 21-24 at week 24. The viral load reductions in the table are approximations based on visual observation of a line graph. Again, at week 16 treatment regimens were improved.

For the individuals initially receiving AZT/3TC alone for 16 weeks, about 45% were <400 copies/ml at week 16; after adding EFV+IDV 65% were <400 copies/ml. This is significantly inferior to the 3 EFV treatment arms.

At week 24:

• 100% in the 600mg qd dose were <400 copies/ml

• 91% in the 400mg qd dose arm were <400 copies/ml

• 96% in the 200mg qd arm were <400 copies/ml.

DuPont Merck officials have said they believe the 600 mg qd dose has better antiviral activity and will create more durable viral load suppression than the other doses. As well, they believe the 600mg qd dose may be more effective suppressing resistant virus in the peripheral blood and CNS. How well the 600mg qd dose regimen can consistently suppress resistant virus remains to be confirmed with data. The K103N mutation is key to EFV resistance. Its presence can create 19 fold resistance to EFV (see Resistance Section below). At week 16, there were 27-31 evaluable patients, and at week 24, there were 21-24 evaluable patients in each of the 4 study arms.

* Patient reported multiple reasons for discontinuation.

NATAP reported 16 week Adverse Events data in a previous report following Hamburg. The same 16 week data was reported in Chicago. Rather than duplicating the effort, you can view the full Adverse Event Report in the other NATAP report on this web site (LINK UP). The main increase in incidence of a side effect between the dose groups occurs in the 600mg qd dose compared to the other two dose regimens with regards to dizziness. At the 600mg dose there is a higher reported incidence of dizziness (44%) as opposed to 29% in the 400mg arm and 19% in the 200mg arm. Company officials say generally that this side effect lasts for only several hours and seems to disappear within a couple of weeks. If this side effect continues to be a concern, it is recommended that you can consider several options--take the 600 mg dose before bedtime, take 300 mg twice per day, or if that’s not tolerable you can lower the dose to 400 mg once daily and you can take it at bedtime. As stated earlier company officials have said they think the 600mg dose has more antiviral activity.

Rash has been seen when treated with EFV but the company says that in most cases it resolves without requiring a change in EFV treatment.

Investigators in the animal CSF study found that EFV penetrates into the CSF of these monkeys. NATAP’s previous efavirenz report which appeared in the January newsletter, NATAP Reports, and on the web site contains data on EFV CSF penetration in 3 humans. The 200 mg dose was used and the CSF/Plasma ratios of EFV drug levels were 1.19%, 1.04% and 0.65% for the 3 persons. See the report for more information. At the Chicago conference, data was reported from this monkey study whose purpose was to determine the CSF concentrations and long term safety of chronic administration of EFV after 57 weeks of oral dosing in cynomolgus monkeys; and, to determine if there is if the CSF drug level is dose dependent. Three groups of monkeys received 15, 45, or 75 mg/kg of EFV for 1 week and then twice daily (8 hours apart) for 56 weeks. After 57 weeks plasma and CSF samples were obtained 3 hours after dosing and 16 hours or later after dosing. If you want to skip to the conclusions and avoid the data see the table below.

Here are a few considerations in interpreting and understanding and the measuring of CSF drug levels. The amount of time after dosing when you take a sample from the CSF can be important in assessing drug levels. Drug levels should be higher when sampling is close after the dosing. As time passes, the drug levels or concentration in the CSF usually decrease as you get closer to the next dose. Or, if the CSF drug level remain the same, the CSF/plasma ratio can increase because the plasma drug level declined as it nears the end of the dosing period.

It appears as though some antiretroviral drugs for treating HIV are less effective in suppressing virus in the CSF then in plasma. As well, it appears as if some drugs penetrate the CSF more effectively than others. Many drugs do not penetrate the CSF at levels which would adequately inhibit HIV. It may be important to keep a certain minimum level of drug concentration in the CSF, as it is necessary in the plasma, throughout the entire dosing period in order to maintain adequate viral suppression. If a treatment does not reach the CSF or brain at adequate levels to suppress HIV, continuing replication and consequent resistance may develop as it would in the blood. It appears crucial that research continue to identify drugs that penetrate the CSF well and to better understand their effect in the CSF as well as in the brain.

The brain may be a privileged or sanctuary site for HIV. Virus replication in the brain may have different characteristics than replication in the peripheral blood or in lymph tissue. Although researchers can measure drug concentrations in the CSF, they are unable to effectively directly assess the effect of therapy in the brain. Research in these areas is getting increasing attention, but currently many questions remained unanswered.

NATAP held a full day community conference on January 17, 1998 at NYU Medical Center where a key speaker was Dr Justin McArthur. He is a leading authority on HIV and the brain. He discussed what we know and what we don’t know about HIV and the brain, and HIV treatment and their effect on the brain. A summary of his talk is available on this web site (LINK UP).

The investigators in this CSF monkey study concluded that EFV in cynomolgus monkeys at clinically relevant plasma levels, penetrates the CSF achieving drug concentrations that may suppress HIV replication. CSF levels appear to approximate the unbound plasma (blood) concentrations of EFV. EFV is highly protein bound (99.46-99.76%) in the blood. Only the non-protein bound drug in plasma is available for inhibition of viral replication. There is no protein in the CSF so a 1% drug concentration in the CSF may be equal in effectiveness to the actual non-protein bound drug level in plasma.

The lower limits of quantification were 3.96 nM for the CSF test and 0.317 uM for the plasma test. The authors stated that plasma concentrations in the 30 and 90 mg/kg/day dose groups were similar to peak (13uM) and trough (5 uM) values observed in humans taking 600 mg once per day. The mean CSF drug level is higher at all 3 dosing levels at the 4 hour sampling time than at the (16 hour sampling time point. As well, the same can be said for the EFV levels in the plasma. Over time the levels go down, but the CSF/plasma ratios are higher at the (16 hour time point than the 4 hour time point.

Mean ( standard deviation. The standard deviation is the amount of variability that can occur from the mean. For example, 34.2 is the mean CSF drug level at 3 hours after dosing 15/mg/kg. This group received 15 mg/kg twice daily.

* The other 3 monkeys in this group had undetectable CSF levels (<4.0 uM)