Long-Term Comparison of Nevirapine Versus Efavirenz When Combined with Other Antiretroviral Drugs in

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Long-Term Comparison of Nevirapine Versus
Efavirenz When Combined with Other Antiretroviral
Drugs in HIV-1 Positive Antiretroviral-Naïve
Persons- The NNRTI Substudy of the CPCRA 058
FIRST Study van den Berg-Wolf M1, Peng G2, Xiang
Y2, Huppler Hullsiek K2, Chen L2, MacArthur RD3,
Novak RM4, Kozal M5, Schmetter B6, Henely C7,
Dehlinger M8 1. Temple University, Philadelphia,
Pa, USA 2. University of Minnesota, Minneapolis,
Mn, USA, 3. Wayne State University, Detroit, Mi,
USA 4. University of Illinois, Chicago, Il, USA
5. Yale University School of Medicine, New
Haven, Ct, USA 6. Social and Scientific Systems,
Silver Springs, Md, USA 7. Meridian Health
System, Neptune, N J, USA 8. Division of AIDS,
NIAID, Bethesda, Md, USA
BACKGROUND
TABLE 3 Antiretroviral Drug Changes During
Follow-up
CPCRA 058 (FIRST) was a randomized open-label
trial comparing three initial antiretroviral
treatment strategies in 1,397 HIV-infected
antiretroviral-naïve persons. Treatment
strategies are defined by classes of drugs, not
specific antiretrovirals (ARVs). Enrollment was
from March 1999 to January 2002 at 17 clinical
units in the United States. Before randomization
in the main study, participants were given the
option of additional substudy randomizations or
pre-selecting the drugs within each strategy arm.
Participants consenting to the NNRTI substudy
were further randomized to efavirenz or
nevirapine (11 allocation), taken together with
other classes of drugs within the strategy (the
randomized cohort Figure 1). In addition, we
report on participants who were randomized to the
NNRTI containing arms of FIRST, but chose to
select the NNRTI used in combination with other
ARVs (the non-randomized cohort Figure 1).
Efavirenz (N111) Nevirapine (N117)
Overall() Overall() Overall()
Switched to alternate NNRTI 3.6 2.6
Discontinued assigned NNRTI 69.4 72.6
2-class strategy () 2-class strategy () 2-class strategy ()
Switched to alternate NNRTI 1.9 3.4
Discontinued assigned NNRTI 69.2 70.7
Initiated PI 28.8 44.8
Switched NRTI 76.9 74.1
3-class strategy () 3-class strategy () 3-class strategy ()
Switched to alternate NNRTI 5.1 1.7
Discontinued assigned NNRTI 69.5 74.6
Discontinued PI 62.7 61.0
Switched PI 11.9 25.4
Switched NRTI 74.6 84.7
Categories are not mutually exclusive. There were no significant differences between the groups. Categories are not mutually exclusive. There were no significant differences between the groups. Categories are not mutually exclusive. There were no significant differences between the groups.
METHODS

• Population participants naïve to active
  combination antiretroviral treatment.
• Primary Endpoint time to HIV-RNA gt 50 copies/mL
  (at or after month 8 visit) or death.
• Secondary Endpoints progression to AIDS or
  death, changes in CD4 cell count, percent of
  participants with HIV-RNA lt 50 copies/mL, HIV
  drug resistance seen at the first time HIV-RNA gt
  1000 copies/mL (at or after month 4 visit),
  safety and tolerability of the drugs, and grade 4
  adverse events.
• ARV therapy management participants enrolled
  into the FIRST study could change ARVs for any
  reason however, they were encouraged to stay
  within the assigned strategy if possible.
• Sample size 200 primary events were required for
  80 power to detect a hazard ratio of 0.67 at the
  0.05 level of significance (2-sided). When the
  FIRST study closed, 187 primary events had
  occurred within the NNRTI substudy.
• Statistical Methods (intent to treat)
• Time to event analyses Kaplan-Meier life table
  summaries and Coxs proportional hazards models.
  The models were stratified by randomized strategy
  in the main FIRST study (2-class strategy with no
  PI or 3-class strategy). Hazard ratios compare
  efavirenz to nevirapine. Rates are per 100
  person years of follow-up.
• Changes in CD4 cell count longitudinal
  regression models adjusted for baseline values.
• Proportion with HIV-RNA lt 50 copies/mL models
  for longitudinal binary data.
• Sensitivity Analyses
• For both the randomized cohort and the
  non-randomized cohort, analyses were repeated
  with models adjusting for baseline factors
  considered to be potential confounding variables
  (age, race, gender, prior AIDS, history of
  injection drug use, baseline CD4 cell count and
  HIV RNA level).
• Those models were repeated for the combined data
  set, including an indicator for randomization
  status and the interaction between randomization
  status and NNRTI drug.

TABLE 4 Event Rates
Efavirenz (N111) Efavirenz (N111) Nevirapine (N117) Nevirapine (N117) Hazard Ratio2 95 CI) P-value
No. Event Rate1 No. Event Rate1 Hazard Ratio2 95 CI) P-value
Primary endpoint3 89 41.2 98 42.8 0.92 (0.69-1.23) 0.59
Death 20 3.8 18 3.2 1.18 (0.62-2.23) 0.61
HIV RNA gt 50 copies/mL 82 42.0 94 45.9 0.89 (0.66-1.19) 0.42
AIDS or death 34 7.4 23 4.4 1.67 (0.98-2.83) 0.06
HIV RNA gt 1000 copies/mL 71 28.7 86 36.4 0.80 (0.58-1.10) 0.17
With resistance to NNRTI drugs 32 12.9 49 20.6 0.65 (0.41-1.01) 0.05
NRTI drugs 5 2.0 25 10.5 0.20 (0.08-0.52) lt0.01
Any ARV drugs 33 13.3 54 22.7 0.60 (0.39-0.93) 0.02
Grade 4 event 24 5.4 43 10.2 0.55 (0.33-0.9.) 0.02
Discontinue randomized drug due to toxicity 20 4.5 16 3.2 1.34 (0.70-2.59) 0.38
1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 1. Rates are per 100 person-years 2. Hazard ratios are for the comparison of efavirenz versus nevirapine3. Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit)
Figure 3Percent with HIV RNA lt 50 Copies/mL
RESULTS for Randomized Cohort

• The NNRTI substudy enrolled 228 participants 111
  to the efavirenz group and 117 to the nevirapine
  group (Figure 1). An additional 416 participants
  were prescribed efavirenz, and 261 were
  prescribed nevirapine.
• Median follow-up time was 65 months
  (inter-quartile range 5771 months).
• Among participants randomized to the 3-class
  strategy, nelfinavir was the most frequently
  prescribed PI. One person in the nevirapine group
  was prescribed efavirenz at study entry (Table
  2).
• About 75 discontinued the assigned NNRTI drug
  during follow-up (p0.68 for difference between
  the two groups Table 3).
• More participants in the nevirapine group either
  initiated a PI (among those in the 2-class
  strategy, p0.08) or switched PIs (among those in
  the 3-class strategy, p0.06) than the efavirenz
  group (Table 3).
• There was no significant difference between the
  groups for the primary endpoint (time to death or
  HIV RNA level gt 50 copies/mL) hazard ratio (HR)
  0.92, p0.59 Figure 2 and Table 4).
• The rate of AIDS or death was higher in the
  efavirenz group (HR 1.67, p0.06 Table 4)
  The rate of death only did not differ between the
  groups.
• The rate of grade 4 events was lower for the
  efavirenz group than for the nevirapine group
  (HR0.55, p0.02 Table 4). However, the percents
  with grade 4 elevated AST or ALT levels were
  similar (Table 5).
• The rate of discontinuation of randomized drugs
  due to toxicity was similar (HR1.34, p0.38,
  Table 4). The majority (86) of the toxicities
  were grade 1 to 3.
• The rates of virologic failure (HIV RNA gt 1000
  copies/mL) were similar (HR 0.80, p 0.17
  Table 4). However, the rate of virologic failure
  associated with any drug resistance was lower in
  the efavirenz group (HR 0.60, p0.02).

Figure 4Mean CD4 Cell Count Change from Baseline
TABLE 5 Hepatic Toxicity
Efavirenz (N111) Efavirenz (N111) Nevirapine (N117) Nevirapine (N117) P-value
No. Events No. Events P-value
gt10 ULN at least once during follow-up or grade 4 AE 7 6.3 10 8.5 0.52
gt 5 ULN at least once during follow-up 16 14.4 18 15.4 0.84
gt2.5 ULN at least once during follow-up 30 27.0 38 32.5 0.37
Upper limit of normal for AST or ALT, required at each follow-up visit Upper limit of normal for AST or ALT, required at each follow-up visit Upper limit of normal for AST or ALT, required at each follow-up visit Upper limit of normal for AST or ALT, required at each follow-up visit Upper limit of normal for AST or ALT, required at each follow-up visit Upper limit of normal for AST or ALT, required at each follow-up visit
TABLE 6 Comparison of Hazard Ratios1
ofRandomized and Non-randomized Cohorts in FIRST
Event Randomized to Substudy Randomized to Substudy Not Randomized to Substudy3 Combined Data3 Interaction P-value4
Event Unadjusted Adjusted3 Not Randomized to Substudy3 Combined Data3 Interaction P-value4
Primary2 0.92 (0.69-1.23) 0.95 (0.71-1.28) 0.79 (0.67-0.95) 0.79 (0.66-0.94) 0.30
AIDS or death 1.67 (0.98-2.83) 2.21 (1.27-3.84) 0.90 (0.64-1.26) 0.88 (0.63-1.23) 0.02
HIV RNA gt 1000 copies/mL with resistance 0.60 (0.39-0.93) 0.61 (0.39-0.95) 0.75 (0.55-1.02) 0.74 (0.54-1.01) 0.53
Grade 4 Event 0.55 (0.33-0.90) 0.51 (0.30-0.85) 0.89 (0.67-1.17) 0.88 (0.67-1.16) 0.08
1 Hazard ratios (95 CI) are for the comparison of efavirenz versus nevirapine 2 Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 3 Adjusted for age, gender, race, prior AIDS, history of injection drug use, baseline CD4 cell count and HIV RNA level 4 From an interaction test between study drug (efavirenz or nevirapine) and substudy randomization status 1 Hazard ratios (95 CI) are for the comparison of efavirenz versus nevirapine 2 Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 3 Adjusted for age, gender, race, prior AIDS, history of injection drug use, baseline CD4 cell count and HIV RNA level 4 From an interaction test between study drug (efavirenz or nevirapine) and substudy randomization status 1 Hazard ratios (95 CI) are for the comparison of efavirenz versus nevirapine 2 Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 3 Adjusted for age, gender, race, prior AIDS, history of injection drug use, baseline CD4 cell count and HIV RNA level 4 From an interaction test between study drug (efavirenz or nevirapine) and substudy randomization status 1 Hazard ratios (95 CI) are for the comparison of efavirenz versus nevirapine 2 Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 3 Adjusted for age, gender, race, prior AIDS, history of injection drug use, baseline CD4 cell count and HIV RNA level 4 From an interaction test between study drug (efavirenz or nevirapine) and substudy randomization status 1 Hazard ratios (95 CI) are for the comparison of efavirenz versus nevirapine 2 Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 3 Adjusted for age, gender, race, prior AIDS, history of injection drug use, baseline CD4 cell count and HIV RNA level 4 From an interaction test between study drug (efavirenz or nevirapine) and substudy randomization status 1 Hazard ratios (95 CI) are for the comparison of efavirenz versus nevirapine 2 Time to death or to HIV RNA level gt 50 copies/mL (at or after month 8 visit) 3 Adjusted for age, gender, race, prior AIDS, history of injection drug use, baseline CD4 cell count and HIV RNA level 4 From an interaction test between study drug (efavirenz or nevirapine) and substudy randomization status
TABLE 1 Baseline Characteristics
Efavirenz (N111) Nevirapine N117) Overall (N228)
Age (mean years) 38 36 37
Female () 23 22 23
Race/Ethnicity () Race/Ethnicity () Race/Ethnicity () Race/Ethnicity ()
Latino/Latina 16 18 17
African American 60 60 60
White/other 24 22 23
Prior AIDS event () 38 37 37
Hepatitis B () 5 5 5
Hepatitis C () 21 16 18
History of injection drug use () 15 18 17
2-class NNRTI Strategy () 47 50 48
CD4 cells (median cells/mm3) 181 196 186
HIV RNA (median log 10 copies/mL) 5.0 5.1 5.0
There were no significant differences between the two groups. There were no significant differences between the two groups. There were no significant differences between the two groups. There were no significant differences between the two groups.
RESULTS of Comparison of Randomized
andNon-randomized Cohorts in FIRST

• The hazard ratios for the primary endpoint (HIV
  RNA gt 50 copies/mL or death) favored the
  efavirenz group over the nevirapine group for
  both the randomized and non-randomized cohorts
  (pooled HR 0.79, 95 CI 0.66-0.94 Table 6).
• The hazard ratios for virologic failure
  associated with any drug resistance also favored
  the efavirenz group. (pooled HR 0.74, 95 CI
  0.54-1.01 Table 6).
• For AIDS or death events, there was a significant
  interaction between NNRTI drug and substudy
  randomization status (Table 6). In the
  randomized substudy there was a significantly
  increased risk of AIDS or death in the efavirenz
  group that was not present in the non-randomized
  cohort.
• In the combined cohort, there was no difference
  between the groups for the rate of grade 4 events
  (Table 6)
• All results were consistent with on-treatment
  analyses.

TABLE 2 Antiretroviral Drugs Prescribed at
Study Entry
Efavirenz (N111) Nevirapine (N117) Overall (N228)
PI() PI() PI() PI()
Nelfinavir 27 26 26
Indinavir 14 9 11
Ritonavir-boosted PI 14 15 14
No PI 46 50 48
NRTI () NRTI () NRTI () NRTI ()
Abacavir Lamivudine 27 30 29
Didanosine Stavudine 25 29 27
Zidovudine Lamivudine 22 16 19
Stavudine Lamivudine 11 12 11
Single NRTI 12 9 11
Other 3 4 3
One person randomized to the nevirapine group was prescribed efavirenz at study entry. One person randomized to the nevirapine group was prescribed efavirenz at study entry. One person randomized to the nevirapine group was prescribed efavirenz at study entry. One person randomized to the nevirapine group was prescribed efavirenz at study entry.
CONCLUSIONS

• In the NNRTI substudy, the efavirenz and
  nevirapine groups did not differ significantly
  for rate of HIV RNA gt 50 copies/mL or death
  however pooled results indicate that the
  nevirapine group has increased risk of the event.
  
• There was no differences found for CD4 cell
  increases over time in the two groups.
• Nevirapine was associated with more drug
  resistance at the time of virologic failure.
• The different results for AIDS or death events in
  the randomized and non-randomized cohorts suggest
  residual confounding in the non-randomized
  cohort.
• Larger, longer-term randomized trials are needed
  to assess the clinical outcome of AIDS or death
  with adequate power comparing efavirenz with
  nevirapine as initial antiretroviral treatment
  options.
• Joint analyses of randomized and non-randomized
  cohorts can potentially improve power for
  treatment comparisons and permit assessment of
  residual confounding for non-randomized analyses.

We would like to thank all the participants who
volunteered to be part of this study. Supported
by grants (5U01AI042170-10 and 5U01AI046362-03)
from the National Institute of Allergy and
Infectious Diseases, National Institutes of
Health, USA. Reprints mvan_at_temple.edu