Prevalence of resistance mutations in a cohort of treatmentnave people with chronic HIV infection in

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WePeB5707
Prevalence of resistance mutations in a cohort of
treatment-naïve people with chronic HIV infection
in the U.S. CPCRA 058 R M Novak1, L Chen2, R D
MacArthur3, J Baxter4, K Huppler-Hullsiek2, G
Peng2, Y Xiang2, C Henley5, B Schmetter6, J Uy1,
M van den Berg-Wolf7, M Kozal8 and the CPCRA 058
Study Team for the Terry Beirn Community Programs
for Clinical Research on AIDS (CPCRA) 1University
of Illinois, Chicago, IL, United States
2University of Minnesota, Minneapolis, MN 3Wayne
State University, Detroit, MI 4University of
Medicine and Dentistry of New Jersey, Camden, NJ
5Southern New Jersey Clinical Trials, Belmar, NJ
6Social and Scientific Systems, Silver Springs,
MD 7Temple University, Philadelphia, PA 8Yale
University, New Haven, CT Contact e-mail
rmnovak_at_uic.edu
Table 1. Baseline Characteristics
Abstract Background The prevalence of
antiretroviral-resistant viral isolates from
recently infected persons is established, but it
is less clear if resistance mutations persist in
a chronically infected treatment-naïve
population. We report the prevalence of
persisting resistance mutations, and factors
associated with resistance for a subset of
patients in the CPCRA 058 FIRST trial. Methods
CPCRA 058 is an ongoing, prospective,
multicenter, randomized comparison (N1397) of 3
treatment strategies for treatment-naïve
patients. A subset of 491 baseline plasma samples
was randomly selected for genotype resistance
testing, stratified by year of enrollment (1999,
2000, 2001), geographic location (east, midwest,
west), and CD4 cell count (lt200, 2-350, gt350).
Resistance is defined using the IAS USA 2003
definition with additions at codons 215 and 69 in
the pol gene. Logistic regression models were
used to determine factors associated with
resistance. Results The cohort was 52 African
American, 16 Hispanic, and 29 white 19
female 31 with prior AIDS diagnosis. The mean
CD4 cell count was 269 cells/mm3. The estimated
prevalence of mutations to any drug class for the
cohort was 10.8 7.8 to NRTI, 3.0 to NNRTI and
0.7 to PIs, 0.7 to more than two classes. In a
multivariate model adjusting for age, gender,
race, injection drug use, CD4 count, HIV RNA,
geographic location, and year of enrollment,
whites were more likely to have resistance than
African Americans (odds ratio (OR) 2.1, 95
confidence interval (CI) 1.1 to 4.1, P0.03),
and there was a 40 increase per year in
prevalence of mutations (OR 1.4, CI 1.0 to
2.1, P0.05). Conclusions The prevalence of
resistance in this naïve cohort is 10.8, despite
low average CD4 cell count. These results provide
further evidence of the persistence of
antiretroviral drug resistance mutations, which
may have implications regarding baseline
genotyping of chronically infected patients.
IAS mutation tables and footnotes (2003).
NRTI mutations include 41L, 44D, 62V, 65R, 67N,
69A/D/N/S, 69insertion, 70R, 74V, 75I, 77L, 115F,
116Y, 118I, 151M, 184I/V, 210W, 215C/D/E/F/I/S/Y
and 219E/Q. NNRTI mutations include 100I, 103N,
106A/M, 108I 181C/I, 188C/H/L, 190A/S, 225H, 230L
and 236L. PI mutations include 30N, 46I/L, 48V,
50V, 82A/F/S/T, 84V and 90M. P-values are
for comparisons between the group with mutations
and the group without mutations. Percent
is of men only

• Results
• Patient Characteristics
• Among the 504 patients selected, 13 had used
  NRTI(s) and were excluded from the analysis. The
  characteristics of the remaining 491 patients are
  described in Table 1.In general, the
  characteristics of the patients with mutations
  were not significantly different from those
  without mutations. However, of those with and
  without mutations, the proportions who were
  non-Hispanic whites were 42 and 28,
  respectively (p0.02).
• Prevalence of Antiretroviral Resistance Mutations
• 11.6 (57/491) of the patients sampled had at
  least one resistance mutation, resulting in an
  estimated prevalence for the cohort of 10.8 (95
  CI 9.5 to 12.1).
• By drug class, the estimated prevalence for
  resistance mutations
• NRTIs7.8
• NNRTIs 3.0
• PIs 0.7
• 0.7 were resistant to more than one class.
• The estimated prevalence to any drug class
  increased from 7.8 in 1999 to 14.7 in 2001
  (p0.08, univariate analyses, Figure 1).
• There was no significant trend in the estimated
  prevalence of mutations by the other two
  stratification factors (CD4 cell count and
  geographic location, data not shown).
• Specific Antiretroviral Resistance Mutations
• The frequency of specific mutations observed is
  detailed in Table 2.
• No 184V mutations were observed, but 17 patients
  had a 118I mutation, which has also been
  associated with lamivudine resistance.
• Mutations at the 215 position of reverse
  transcriptase were also frequently seen (14
  samples), which have been associated with
  thymidine analog resistance, or reversion from
  215Y
• Variants in the 69 position were common, seen in
  12 samples.
• Other thymidine analogue mutations (TAM) observed
  were 41L, 44D, 70R, 210W, and 219Q.
• The K65R and I74V mutations were not observed.

Introduction Since the introduction of
antiretroviral therapy for persons with HIV
infection, mortality and morbidity related to HIV
disease have decreased. However, one of the
undesired consequences of therapy has been the
selection of viral variants with mutations that
lead to decreased drug susceptibility. New
infection with a viral strain already resistant
to antiretroviral drugs has a negative impact on
initial treatment response and shortens the time
to first virologic failure. The transmission of
HIV bearing antiretroviral resistance mutations
during acute HIV infection has been well
documented. Little is known about how long
resistance mutations acquired during primary
infection persist in the plasma of patients with
established infection who have not yet been
exposed to antiretroviral drugs. Thus, a critical
question in the HIV field is whether genotypic
resistance testing (GART) is indicated for these
chronically infected, antiretroviral-naive
patients preparing to initiate therapy. The
Terry Beirn Community Program for Clinical
Research on AIDS (CPCRA), a multicenter network,
began a treatment strategy trial for HIV-infected
persons naïve to treatment in 1999. The FIRST
trial (CPCRA 058) enrolled a cohort of 1397
demographically diverse treatment-naïve subjects
from 25 U.S cities. A substudy was designed to
determine the prevalence of primary drug
resistance in this large, demographically diverse
cohort of chronically infected patients.
Table 2. Number of Patients with Specific
Mutations by Drug Class

Methods Study Design The CPCRA FIRST study is an
ongoing, prospective, randomized trial that
compares three treatment strategies for the
initial treatment of antiretroviral naïve
patients with HIV infection 1) protease
inhibitor (PI) nucleoside reverse transcriptase
inhibitors (NRTI) 2) non-nucleoside reverse
transcriptase inhibitor (NNRTI) NRTI or 3) PI
NNRTINRTI. The FIRST study reached its target
enrollment and closed to accrual on January 11,
2002 with 1397 patients enrolled. The FIRST study
and all substudies have been approved by the
institutional review boards at the institutions
where the study is conducted, and written
informed consent has been obtained from all study
participants. Study Population HIV infected
persons were at least 13 years of age. Patients
were excluded from the FIRST study for the
following reasons pregnancy or breastfeeding,
any conditions that precluded successful
participation in the study, any previous PI or
NNRTI use, a cumulative total of greater than 4
weeks of NRTI use, or greater than 1 week of 3TC
use. For the resistance substudy, those with any
prior NRTI use were excluded. Data
Collection Prior to randomization, a baseline
evaluation was performed which included a CD4
cell count, HIV RNA level and other laboratory
measures. GARTs on stored specimens were
performed at a CPCRA-designated central
laboratory, with plasma derived viral RNA using
the TRUGENE HIV-1 Genotyping Kit and OpenGene DNA
Sequencing System. Statistical
Methods Resistance was defined as the presence of
at least one mutation in the IAS USA 2003
definition. Additional NRTI mutations that may
represent back revertants from earlier mutations
at 215 C/D/E/S and 69 A/N/S in the pol gene were
also included. Only mutations considered as
primary for the protease gene were included.
These include mutations at positions 30, 46, 48,
50, 82, 84 and 90. For the baseline resistance
analysis reported here, 504 baseline samples were
randomly selected from the entire FIRST cohort,
stratified by year of enrollment (1999, 2000,
2001), geographic location (East, Midwest, West),
and CD4 cell count (lt200, 200-350, gt350). In
order to establish a sample that represents
completely treatment-naïve individuals, patients
with any antiretroviral use were excluded. The
percent of patients with mutations from the
sample was calculated. The prevalence of
mutations for the cohort and corresponding 95
confidence interval (CI) were estimated from the
sample, using techniques for stratified random
samples. Simple and multivariate logistic
regression models were used to determine the
factors associated with resistance. The
following factors were included in the multiple
logistic regression models age, gender,
ethnicity, injection drug use (IDU), CD4 cell
count, viral load, year of enrollment and
geographic distribution.

Only mutations observed are shown in the table.

• Factors Associated with Resistance Mutations
• In univariate analyses there was a trend for
  increasing prevalence of mutations over time.
• In a multivariate model adjusting for age,
  gender, race (non-Hispanic white versus Hispanic,
  non-Hispanic white versus African American), IDU,
  CD4 cell count, and HIV RNA level, there was a
  40 increase per year in prevalence of mutations
  by later year of Non-Hispanic whites were more
  likely to enrollment (adjusted OR 1.4, 95 CI
  1.0 to 2.1, p0.05).
• have resistance compared to African Americans
  (16.7 versus 9.1, adjusted odds ratio (OR)
  2.1, 95 CI 1.1 to 4.1, p0.03).
• The percent of Hispanics with mutations was lower
  compared to that for non-Hispanic whites, but the
  difference was not significant (11.6 versus
  16.7, OR 0.6, 95 CI 0.3 to 1.5, p0.28).
• The prevalence of resistance mutations did not
  differ by age, gender, CD4 cell count, HIV RNA
  level, IDU, or geographic distribution

• Conclusions
• The prevalence of primary HIV antiretroviral
  resistance in a chronically infected,
  geographically, racially and sexually diverse
  group of patients with moderately advanced HIV
  disease exceeds 10, and appears to be increasing
  over time.
• Many resistant viral variants apparently do not
  drift back to wild type, but rather, persist well
  beyond the period of acute infection in the
  absence of drug selection pressure.
• Most mutations associated with a decline in
  replication capacity (e.g. M184V) were not found
• The most prevalent mutations were in the NRTI
  class, the drugs that have been available the
  longest time.
• These data support routine genotypic resistance
  testing in all treatment naïve patients prior to
  initiating antiretroviral therapy.