Reports for NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment

July 7-11, 2001 Buenos Aires, Argentina

3 Year Durability of Efavirenz in the 006 Study

At the IAS Conference in Buenos Aires, Karen Tashima (Miriam Hospital, Providence, RI) reported data at 96 and 144 weeks on efavirenz (EFV) from the first big study of efavirenz (study 006) conducted by DuPont. This was a large multicenter, open-label, randomized trial comparing EFV+AZT/3TC to indinavir (IDV 800mg every 8 hrs)+AZT/3TC and also to EFV/IDV (IDV 1000mg every 8 hrs). The original cohort enrolled 450 patients but at week 96 patients were asked to re-enroll in the study and a number of them discontinued, so week 96 data on the original cohort may better reflect response to therapy while week 144 may reflect better the discontinuations. In order to collect better data on duration of treatment effect DuPont started an extended cohort several months after the initial cohort enrolled. The total of both cohorts is 1266 patients.

The purpose of this analysis is to report on the durability of response to EFV+AZT/3TC.

There are two noteworthy summary points from this study worth mentioning upfront: (1) some patients can still be experiencing nervous system symptoms after 2 years on EFV therapy. (2) Patients with >100,000 copies/ml of viral load appear to respond as well to therapy (with 3 years follow-up so far) as patients with <100,000 copies/ml of viral load before starting therapy.

Baseline viral load was 4.7 log (50,000 copies/ml) cd4 was 340

Time To Treatment Failure (TTF) is defined as 0 days for patients who were never dosed or who never had viral load <50 copies (complete failures). TTF is the time from start of treatment until a viral load rebound above 50 copies/ml, an AIDS-defining event, or discontinuing from the study for any reason for patients who had achieved viral load <50 copies/ml.

Duration of Response is the time from start of viral suppression <50 copies/ml to the time of TTF. This was reported in one of two ways: all reasons for failure (discontinued from the study for any reason or virologic failure >50 copies on 2 consecutive occasions; and virologic failure only

RESULTS:

• The percent of patients with viral load <50 copies/ml in the extended cohort at 96 weeks (ITT: non-completer=F) is 59% (n=407) in the EFV+AZT/3TC group compared to 42% in the EFV/IDV group and 35% in the IDV/AZT/3TC group.

  We all know the difficulties of remaining on an IDV three times per day regimen over the long term considering the adherence difficulties and the side effects, toxicities, and dietary & hydration requirements. IDV is often chosen as a comparison regimen in studies because it is difficult to stay on although it is potent.

• TTF in extended cohort at 144 weeks: 52% (n=422) receiving EFV/AZT/3TC at week 144 had <50 copies/ml. This compared to 35% for EFV/IDV and 30% for IDV/AZT/3TC arms.
  
  
• Duration of response All Reasons for Failure (including stopping therapy due to side effects, toxicities, viral load rebound) for the extended cohort: 65% for EFV/AZT/3TC vs 52% for EFV/IDV and 48% for IDV/AZT/3TC.
  
  
• Duration of Response – Only Virologic Failures (extended cohort): 80% of patients taking EFV/AZT/3TC at week 132 still had <50 copies/ml (having two consecutive viral loads >50 copies was considered failure), compared to about 70% for both other arms
  
  
• Duration of Response – All Reasons for Failure (extended cohort) >100,000 copies/ml: 60% at week 132 in EFV/AZT/3Tc arm still had <50 copies/ml. This compares to about 40% for both other arms
  
  
• Duration of Response – Only Virologic Failures (extended cohort) >100,000 copies/ml: 75% at week 132 still had <50 copies/ml in the EFV/AZT/3TC arm.
  
  
• Cd4 increases at week 144 were about 300 in the EFV and IDV arms and about 200 in the EFV/IDV arm

SAFETY:

Treatment related, new adverse events that were reported between weeks 72-144

Selected adverse events on interest:

• 31% in the EFV arm vs 37% in the EFV/IDV arm vs 41% in the IDV/AZT/3TC arm reported adverse events.
  
  
• elevated cholesterol: 3% in EFV arm; 5% in EFV/IDV and 2% in IDV arm
  
  
• -elevated triglycerides: 2-3% in all arms
  
  
• insomnia: 3% in both EFV arms and 0% in IDV arm
  
  
• depression: 2% in EFV arms and 1% in IDV arm
  
  
• fatigue: 2% in EFV arms and 0% in IDV arm
  
  
• lipodystrophy: interestingly only 1-2% incidence of this was reported across all 3 arms. This could reflect that these were events reported during weeks 72-144 not during first 72 weeks. But still, this low figure appears odd
  
  
• alopecia (hair loss on scalp): 2% in IDV arm but 0% in both EFV and IDV/EFV arm
  
  
• Flank pain: 4% in IDV arm; 2% in EFV/IDV arm; 0% in EFV arm
  
  
• renal calculus: 5% in IDV arm; 1% IDV/EFV arm; 0% EFV
  
  
• Renal pain: 3% in IDV arm; 2% IDV/EFV; 0% EFV

Number of patients with nervous system symptoms: after 1-2 years on EFV a small percent of patients (5% in this study) may still be experiencing nervous system symptoms

In the first month after starting treatment about 45% of patients reported nervous system symptoms in the EFV/AZT/3TC arm. This compares to about 10% in the IDV arm and about 38% in the EFV/IDV arm. 4 patients in the EFV arm discontinued due to these symptoms within the first 28 days, which is a rate just under 10% (4/45) for those who experienced such symptoms, or 1% for the total number of patients received the regimen (4/412). After about 1 year of treatment in study, 5-10% on EFV arm were experiencing nervous system symptoms and the total number of patients reported to have 6 discontinued from the EFV arm due to these symptoms was 6. In clinical practice you might expect these numbers to be higher. Interestingly, after almost two years (645 days) still about 5% of patients receiving EFV/AZT/3TC were reported to be experiencing nervous system symptoms. Again, this percent would be expected to be higher in clinical practice.

Discontinuations between weeks 72-144 for EFV/AZT/3TC:

• The study authors reported 2% of patients discontinued due to adverse events
• 2% for virologic failure
• 8% for administrative reasons or withdrew consent

These types of numbers are much lower under study conditions. In real clinical practice these numbers will be much greater for various reasons including adherence and willingness to tolerate regimentation and side effects tends to be more of a problem outside of closely monitored study conditions.