AIDS CLINICAL CARE

From the publishers of Journal Watch and The New England Journal of Medicine June 2008 Vol. 20 No. 6

J O U R N A L WAT C H H I V
Does Viral-Load Testing
Reduce Drug Resistance in
Resource-Poor Settings?
Despite viral-load testing, high levels
of drug resistance at first virologic
failure were found in KwaZulu-Natal,
South Africa.
H igh levels of multiclass resistance
have been reported at first treat-
ment failure in resource-poor settings
that lack viral-load testing, and pro-
longed viremia before the recognition
of treatment failure has been thought
to be responsible.
Researchers studied the resistance pat-
terns of HIV in 115 patients in South
Africa who experienced virologic failure
while receiving their first potent anti-
retroviral therapy (ART) regimen. Pa-
tients were recruited from two regional
referral centers that, unlike most
resource-poor settings, had viral-load
testing available. More than 97% of the
patients were infected with clade C
virus. At the time of virologic failure, pa-
tients had been on ART (91% on NNRTI-
based regimens) for a median of 11
months, but the time on treatment while
viremic was not reported. Self-reported
adherence was high, with 83% of pa-
tients reporting >95% adherence.
Approximately 84% of patients had
virus with at least one mutation; 64% of
patients had dual-class resistance, and
3% had triple-class resistance. The most
common mutations were M184V (64%)
and K103N (51%). Thymidine analogue
mutations were found in viruses from
32% of patients. Although 20% of pa-
tients had received suboptimal NRTI
therapy prior to potent ART, mutation
rates were not different in this group.
Comment: Access to viral-load testing
did not prevent high-level multiclass re-
ence, recent opportunistic infection,
low CD4-cell count, and prior subopti-
mal ART did not predict drug resistance.
Based on previous comparisons of re-
sistance patterns in clade C and non-C
virus, the preponderance of clade C vi-
rus in this study did not seem to influ-
ence the high frequency of mutations;
however, studies in larger cohorts are
needed to better define the resistance
characteristics of clade C virus.
Physician training and practice were
not described and may have played a
role. The 2004 South African ART guide-
lines recommend viral-load testing every
6 months until the viral load exceeds
5000 copies/mL; at that point, testing
should be repeated at 3 months, and, if
the viral load remains >5000 copies/mL,
a regimen switch should be considered.
Whether study clinicians followed these
guidelines is unclear; if they did, the de-
lay before switching regimens may not
have been substantially shorter than de-
lays in cohorts without viral-load testing.
— Renslow Sherer, MD
TA B LE O F
J O U R N A L WAT C H H I V
Does Viral-Load Testing
Reduce Drug Resistance
in Resource-Poor Settings? ................. 45
Rapid ART Scale-Up
Needed in South Africa ...................... 45
Early Virologic Failure
with Tenofovir/FTC + Nevirapine
as Initial Therapy ................................46
Emergence of the K65R Mutation
with NNRTI-Based Regimens ............. 47
When to Initiate ART? ........................... 47
More Evidence That Transmitted
Resistance Does Matter — An
Analysis from ACTG 5095 ..................48
INICAL A I D S
CL
CA
AIDS
Dr. Sherer is the Director of the Inter-
national AIDS Training Center at the
University of Chicago.
Marconi VC et al. Prevalence of HIV-1
drug resistance after failure of a first
highly active antiretoviral therapy regimen
in KwaZulu Natal, South Africa. Clin
Infect Dis 2008 May 15; 46:1589.
Rapid ART Scale-Up
Needed in South Africa
A mathematical model suggests that rapid
scale-up is critical if universal access is to
be achieved during the next 5 years for all
people in need of treatment.
D uring the past 5 years, substantial
progress has been made in South
Africa to expand care and treatment for
HIV-infected individuals. However, only
about 30% of people with AIDS in South
Africa are currently receiving antiretro-
viral therapy (ART). How quickly would
CO N T EN T S
CD4-Cell Depletion in
an HIV-1 Elite Controller ....................48
Nevirapine Hypersensitivity ................. 49
Caution Urged When
Combining Lopinavir/Ritonavir
and Rosuvastatin ................................. 49
Effect of HSV Suppression
on HIV Incidence................................50
HIV Incidence Among Men with Early
Syphilis: A Tale of Three Cities ..........50
ANTIRETROVIRAL ROUNDS
Resistance: What You Don’t
Know — Can It Hurt You?.................. 51
W A T C H

Cefixime tablets (Suprax; 400 mg) are now available in the U.S. for the
RE

sistance in this cohort. The degree of
resistance seen is comparable to what
has been found in resource-poor set-
tings that lack viral-load testing.
What might explain these results?
In the multivariate analyses, poor adher-
first time since 2002. Cefixime is the only CDC-recommended oral
treatment for uncomplicated urogenital and rectal gonorrhea. The other
recommended option is an injection of ceftriaxone (Rocephin).
Centers for Disease Control and Prevention (CDC). Availability of cefixime 400 mg
tablets — United States, April 2008. MMWR Morb Mortal Wkly Rep 2008 Apr 25;
57:435.

AIDS Clinical Care is an editorially independent publication of the Massachusetts Medical Society. ©2008 Massachusetts Medical Society.
All rights reserved. Disclosure information about our authors can be found at http://aids-clinical-care.jwatch.org/misc/board_disclosures.dtl
Page 46
EDITOR-IN-CHIEF
Paul E. Sax, MD
Clinical Director, HIV Program and Division
of Infectious Diseases, Brigham and Women’s
Hospital; Associate Professor of Medicine,
Harvard Medical School, Boston
EXECUTIVE EDITOR
Catherine Tomeo Ryan, MPH
ASSOCIATE EDITORS
Salim S. Abdool Karim, MD, PhD
Pro Vice-Chancellor, University of KwaZulu-
Natal, Durban, South Africa; Professor of Clinical
Epidemiology, Columbia University; Adjunct
Professor of Medicine, Cornell University,
New York
Helmut Albrecht, MD
Professor of Medicine and Division Chief,
Division of Infectious Diseases, University of
South Carolina School of Medicine, Columbia
Sonia Nagy Chimienti, MD
Associate Clinical Professor of Medicine,
University of Massachusetts Medical School;
Attending Physician, Division of Infectious
Diseases and Immunology, UMass Memorial
Medical Center, Worcester
Carlos del Rio, MD
Professor of Medicine and Vice-Chair, Department
of Medicine, Emory University School of
Medicine; Chief of Medicine, Grady Memorial
Hospital, Atlanta; Director for Clinical Sciences
and International Research, Emory Center of
AIDS Research, Atlanta
Judith Feinberg, MD
Professor of Medicine,
University of Cincinnati College of Medicine
Gerald H. Friedland, MD
Consulting Editor
Professor of Medicine, Epidemiology and Public
Health, Yale University School of Medicine;
Director, AIDS Program, Yale-New Haven Hospital
Keith Henry, MD
Professor of Medicine,
University of Minnesota School of Medicine;
Director, HIV Clinical Research, Hennepin County
Medical Center, Minneapolis
Charles B. Hicks, MD
Associate Professor of Medicine,
Duke University Medical Center;
Associate Director, Duke University
AIDS Research and Treatment Center, Durham
Abigail Zuger, MD
Associate Clinical Professor of Medicine, Albert
Einstein College of Medicine; Attending Physician,
St. Luke’s-Roosevelt Hospital Center, New York
CONTRIBUTING EDITOR
Judith Currier, MD, MSc
Professor of Medicine and Associate Director,
Center for Clinical AIDS Research and Education,
UCLA Medical Center, Los Angeles
PAST EDITORS-IN-CHIEF
Deborah J. Cotton, MD, MPH
1989–2003
Gerald H. Friedland, MD
1989–1995
MASSACHUSETTS MEDICAL SOCIETY
Charleen M. Hamilton, Mary A. Nastuk,
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Christopher R. Lynch
Vice President for Publishing
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Editorial Operations and Development
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AIDS CLINICAL CARE
ART programs need to be scaled up there
in order for all ART-eligible patients to
have access to treatment by 2012?
Researchers developed a simulation
model to project the effects of five
potential scale-up scenarios in South
Africa: zero growth (no new treatment
slots are created), constant growth (a
fixed number of new treatment slots
is created each year), moderate growth
(an increasing number of new treatment
slots is created each year), rapid scale-
up (the number of new treatment slots
doubles each year), and full capacity
(enough slots are available each year
to treat all patients in need).
The projections show that, without
any additional ART scale-up, approxi-
mately 2.5 million HIV-infected adults
in South Africa will die between 2007
and 2012. If more-aggressive scale-
up strategies are implemented, fewer
people will die: 2.2 million under the
constant-growth scenario, 1.5 million
under the moderate-growth scenario,
and 1.2 million under rapid scale-up.
In all scenarios, increasing capacity for
CD4-cell–count monitoring and priori-
tizing delivery of ART to those with the
lowest CD4-cell counts would result
in significantly fewer deaths.
If rapid growth is implemented, by
2012, all South Africans who are clini-
cally eligible for ART (an estimated 2.5
million) will have access to it. In con-
trast, only 2.2 million people will have
access under the moderate-growth
scenario, 831,000 under the constant-
growth scenario, and 364,000 under
the zero-growth scenario.
Comment: This model illustrates the
benefits of scaling up ART access in
South Africa, which has the largest
number of HIV-infected people of any
country. Successful implementation
of ART scale-up will require sufficient
human resources, strong logistic sys-
tems, uninterrupted treatment supplies,
improved laboratory capacity for treat-
ment monitoring, and expanded edu-
cation to maintain high levels of treat-
ment adherence.
A major challenge will be the number
of patients already receiving ART who
will need to be switched to second-
and third-line regimens because of
treatment failure. Second-line drug
combinations are costly and require
additional effort to ensure adherence.
Patients who require regimen switches
are thus likely to place a large burden
Volume 20 Number 6
on health-service capacity, thereby con-
straining ongoing efforts to scale up
treatment for patients awaiting ART.
— Salim S. Abdool Karim, MD, PhD
Walensky RP et al. Scaling up antiretro-
viral therapy in South Africa: The impact
of speed on survival. J Infect Dis 2008
May 1; 197:1324.
Hirschhorn LR and Skolnik R. Making
universal access a reality — What more
do we need to know? J Infect Dis 2008
May 1; 197:1223.
Early Virologic Failure with
Tenofovir/FTC + Nevirapine
as Initial Therapy
Investigators stopped a clinical study
when three of seven patients receiving
tenofovir/FTC + nevirapine experienced
early virologic rebound; each had evi-
dence of multiclass viral resistance.
T
he combination of tenofovir, FTC
(or 3TC), and nevirapine is listed
in several guidelines as a preferred or
alternative regimen for initial HIV treat-
ment. However, this combination has
never been studied in a fully powered,
prospective clinical trial. Now, results
from small studies raise concerns about
its antiviral efficacy.
In this open-label clinical trial,
treatment-naive patients were random-
ized to receive once-daily tenofovir/
FTC plus either nevirapine (200 mg
twice daily) or ritonavir-boosted ata-
zanavir. The primary purpose of the
study was to evaluate changes in plas-
ma lipid levels. However, in April 2007,
investigators decided to conduct an
interim analysis of efficacy, after data
from the DAUFIN study showed early
virologic failures with once-daily teno-
fovir, 3TC, and nevirapine (ACC May
2007, p. 38, and Abstract 503, 14th
Retrovirus conference, 2007).
Seven patients were enrolled in each
arm at the time of the interim analysis.
Despite only 12 weeks of therapy, three
patients in the nevirapine arm experi-
enced virologic failure versus none in
the boosted-atazanavir arm. All three
patients had resistance mutations
detected at 12 weeks that were not pres-
ent at baseline — K65R, Y181C, and
G190A in patient 1; T69N, K101E, Y181C,
and M184V in patient 2; and K103N,
Y181C, and M184V in patient 3. The
June 2008
three patients had good self-reported
adherence and appropriate nevirapine
trough concentrations (>3 mg/dL);
before starting therapy, each had a
high viral load (>100,000 copies/mL)
and a low CD4 count (<200 cells/mm3).
Based on these findings, the trial was
stopped early.
Comment: Data on the combined use of
tenofovir, FTC (or 3TC), and nevirapine
are decidedly mixed, with worrisome
reports of early virologic failure coming
from at least two small prospective clini-
cal trials. These results have particularly
important implications in resource-
limited settings, where nevirapine use
is much more widespread and where
d4T toxicity has led some treatment
programs to substitute tenofovir for d4T.
A fully powered, industry-sponsored
trial is currently underway to evaluate
tenofovir/FTC plus either once- or
twice-daily nevirapine (with boosted
atazanavir used in the control arm).
Until results are available, clinicians
should refrain from using tenofovir/FTC
plus nevirapine as initial therapy.
— Paul E. Sax, MD
Lapadula G et al. Risk of early virological
failure of once-daily tenofovir-emtricitabine
plus twice-daily nevirapine in antiretroviral
therapy–naive HIV-infected patients. Clin
Infect Dis 2008 Apr 1; 46:1127.
Emergence of the
K65R Mutation with
NNRTI-Based Regimens
In the Swiss HIV Cohort Study, emergence
of the K65R mutation was significantly
associated with tenofovir-containing
regimens that were anchored by NNRTIs
rather than by PIs.
A ccording to the latest guidelines
from the U.S. Department of Health
and Human Services, tenofovir/FTC
plus efavirenz is one of the preferred
antiretroviral regimens for treatment-
naive patients. However, concerns have
been raised recently about the emer-
gence of the K65R mutation and sub-
sequent tenofovir resistance in patients
who receive this regimen.
In this retrospective analysis from the
Swiss HIV Cohort Study, investigators
reviewed data from all patients who had
genotypic resistance tests performed
aids-clinical-care.jwatch.org
while they were receiving tenofovir. The
K65R mutation was associated with con-
comitant ddI use, presumably because
both drugs select for this mutation. Fur-
thermore, some thymidine-analogue mu-
tations, such as D67N, K70R, T215F, and
K219E/Q, were not found in association
with the K65R change, which suggests
antagonism between these modifica-
tions. Interestingly, the K65R mutation
was strongly associated with NNRTI-
based regimens but did not arise in the
setting of PI-anchored treatments. One
possible mechanism underlying this
finding is a novel mutational pattern
that incorporates both tenofovir and
NNRTI resistance, thereby conferring
a fitness advantage with the associated
modifications.
Comment: The authors raise the issue
of whether we should exercise more
caution when prescribing tenofovir
with efavirenz for treatment-naive pa-
tients. However, data from large, ran-
domized, prospective trials do not indi-
cate a need for such caution. Compared
with AZT/3TC plus efavirenz, tenofovir/
FTC plus efavirenz has superior viro-
logic and immunologic efficacy, with
fewer adverse events (N Engl J Med
2006; 354:251). Furthermore, in combi-
nation regimens, efavirenz is superior
to most PIs, such as lopinavir/ritonavir
(Abstract THLB0204, XVI International
AIDS Conference, 2006), and is not in-
ferior to newer PIs, such as atazanavir
( J Acquir Immune Defic Syndr 2004;
36:1011). Although there are no pub-
lished results from trials comparing
efavirenz against PIs in combinations
containing tenofovir/FTC, data from
long-term follow-up of patients receiv-
ing tenofovir/FTC plus efavirenz are
reassuring ( J Acquir Immune Defic
Syndr 2008; 47:74). Because high-level
efavirenz resistance can arise as a result
of a single mutation, whereas PI resis-
tance requires multiple mutations, the
K65R mutation could very well arise
more often with NNRTI-anchored regi-
mens. In fact, in previous trials in
which PIs were compared with efavi-
renz, resistance mutations were more
common with the NNRTI (Abstract
THLB0204, XVI International AIDS
Con ference, 2006). Resistance, how-
ever, is not the only factor that influ-
ences clinical efficacy. Tenofovir/FTC
plus efavirenz is associated with a low
incidence of adverse events and a high
rate of adherence, which likely contrib-
Page 47
ute to its superior clinical efficacy, even
with the higher rate of drug resistance.
— Manish Sagar, MD
Dr. Sagar is an Assistant Professor of
Medicine at Harvard Medical School
in Boston.
von Wyl V et al. Factors associated with the
emergence of K65R in patients with HIV-1
infection treated with combination anti-
retroviral therapy containing tenofovir.
Clin Infect Dis 2008 Apr 15; 46:1299.
When to Initiate ART?
In the SMART study, initiating ART at
CD4 counts >350 cells/mm3 rather than
at <250 cells/mm3 was associated with
lower risks for opportunistic disease,
death, and other adverse outcomes.
C urrent guidelines recommend start-
ing antiretroviral therapy (ART) for
asymptomatic HIV-infected patients
only when the CD4 count is ≤350 cells/
mm3. However, no randomized trials
have been conducted during the era of
potent ART to readdress this issue.
In the SMART study (ACC Jan 2007,
p. 1, and N Engl J Med 2006; 355:2283),
5472 HIV-infected patients with CD4
counts >350 cells/mm3 were random-
ized to a viral-suppression group (VS;
immediate initiation or reinitiation of
ART; continuous ART thereafter) or to
a drug-conservation group (DC; therapy
started at CD4 counts <250 cells/mm3
and discontinued at counts >350 cells/
mm3). To assess the benefit of immedi-
ate versus deferred therapy, investiga-
tors recently analyzed the outcomes of
a subgroup of SMART participants who
had been ART-naive or had not received
ART for ≥6 months before randomiza-
tion. Of 477 such patients, 228 were in
the DC group and 249 were in the VS
group. Median CD4 counts at treatment
(re) initiation were 236 cells/mm3 and
>400 cells/mm3, respectively. Mean
follow-up duration was 18 months. All
analyses were intention-to-treat.
The composite endpoint — opportu-
nistic disease (OD) or all-cause death;
fatal or nonfatal OD; or serious non-
AIDS events (cardiovascular/hepatic/
renal disease or non–AIDS-defining
malignancy) or death from non-OD
causes — was significantly more com-
mon in the DC group than in the VS
Page 48
group (21 vs. 6; hazard ratio, 4.2;
P=0.002). The three individual adverse-
outcome measures were also significantly
more common with DC than with VS.
Comment: Existing HIV treatment
guidelines are conservative because of
drug-toxicity concerns and lower risk
for disease progression at higher CD4
counts (i.e., >350 cells/mm3). This re-
port suggests that adverse events, in-
cluding “non-AIDS” events, are more
common than previously thought at
high CD4-cell counts and that the risk
for such events can be reduced with
early ART. Given that this study was a
subgroup analysis from a larger trial,
and that only about half of the partici-
pants were truly ART-naive, these find-
ings require confirmation in a random-
ized, controlled trial that addresses the
risks and benefits of early ART initiation.
— Daniel J. Diekema, MD, MS
Dr. Diekema is an Associate Clinical
Professor in the Departments of
Internal Medicine and Pathology
at the University of Iowa Roy J. and
Lucille A. Carver College of Medicine.
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AIDS CLINICAL CARE
The Strategies for Management of Anti-
retroviral Therapy (SMART) Study Group.
Major clinical outcomes in antiretroviral
therapy (ART)–naive participants and in
those not receiving ART at baseline in the
SMART study. J Infect Dis 2008 Apr 15;
197:1133.
More Evidence That
Transmitted Resistance
Does Matter — An Analysis
from ACTG 5095
Having NNRTI resistance at baseline more
than doubles the risk for virologic failure
on initial efavirenz-based regimens.
T reatment guidelines from the U.S.
Department of Health and Human
Services now recommend HIV genotyp-
ic resistance testing prior to the initia-
tion of antiretroviral therapy (ACC Jan
2008, p. 7). Although these recommen-
dations seem sound and are based on
data demonstrating considerable levels
of transmitted resistance, little is known
about the influence of such resistance
on virologic suppression and treatment
outcomes. In this case-cohort analysis
from ACTG 5095, investigators per-
formed genotypic resistance testing on
baseline plasma samples and examined
the effect of transmitted NNRTI resis-
tance on treatment outcomes among
treatment-naive patients who were
randomized to efavirenz-containing
regimens.
Overall, 5% of patients had transmit-
ted NNRTI resistance, and the risk of
failure in this population was signifi-
cantly higher than in those without
baseline NNRTI resistance (hazard ra-
tio, 2.3; 95% confidence interval, 1.2–
4.5; P=0.02). These results persisted
after adjustment for race/ethnicity
and self-reported recent adherence,
factors that were associated with treat-
ment failure in previous analyses from
ACTG 5095 (ACC Oct 2006, p. 85, and
JAMA 2006; 296:769). Time to first
virologic failure was also significantly
shorter among those with baseline
NNRTI resistance than among those
without.
Notably, three subjects with baseline
NNRTI resistance did not experience vi-
rologic failure; all had received AZT/
3TC/abacavir plus efavirenz (rather
Volume 20 Number 6
than AZT/3TC plus efavirenz), which
suggests that the additional antiretro-
viral activity of the four-drug regimen
may have prevented the detected re-
sistance from manifesting as virologic
failure.
Comment: These data provide clinical
evidence that detecting transmitted
resistance in a pretreatment genotype
is important to patient management.
Whether currently available resistance
tests are optimal for this purpose is not
yet certain; such tests detect resistant
virus only when it makes up a meaning-
ful proportion of the circulating virus
(about 20%). Approaches that permit
more-sensitive detection of resistance
mutations are being evaluated as a way
to further improve treatment results.
For the present, standard baseline geno-
typic HIV resistance testing is a proven
approach to better treatment outcomes.
— Charles B. Hicks, MD
Kuritzkes DR et al. Preexisting resistance
to nonnucleoside reverse-transcriptase
inhibitors predicts virologic failure of an
efavirenz-based regimen in treatment-
naive HIV-1–infected subjects. J Infect
Dis 2008 Mar 15; 197:867.
CD4-Cell Depletion
in an HIV-1 Elite Controller
A case report of an HIV-1 elite controller
with progressive CD4-cell depletion
H IV-1 elite controllers have been
the focus of intense research.
These individuals have a unique ability
to spontaneously control virus repli-
cation in the absence of antiretroviral
drugs and are usually able to preserve
high CD4-cell counts for prolonged
periods of time.
In this report, researchers describe a
man coinfected with HIV and hepatitis
C virus (HCV) who has not received
antiretroviral therapy (ART) since 2000.
During the past 10 years, most of his
plasma viral load measurements have
been below the limit of detection for
standard ultrasensitive HIV RNA assays
(<50 copies/mL), but his CD4 count
has declined from >400 cells/mm3 to
<200 cells/mm3.
Amplification of HIV from culture su-
pernatant of CD4 lymphocytes revealed
a replication-competent clade B virus
June 2008
that did not harbor mutations in the nef
gene. In addition, markers of immune
activation (HLA-DR and CD38) on CD4
and CD8 cells were present at signifi-
cantly higher levels than those seen in
elite controllers with high CD4-cell
counts or in HIV-uninfected individu-
als. Immune activation in this patient
could not be explained by microbial
translocation, as levels of lipopolysac-
charide (LPS), LPS binding protein,
soluble CD14, and endotoxin-core anti-
body were all low. Researchers detected
high numbers of HIV-specific CD8-
lymphocyte responses targeting HIV
gag proteins.
Comment: The authors of this case
report suggest that, in the absence of
measurable plasma viral load, CD4-cell
decline is probably the result of im-
mune activation (ACC Apr 2008, p. 34,
and J Infect Dis 2008; 197:126), which
has been associated with disease pro-
gression. The mechanisms behind CD4-
lymphocyte loss and immune activation
in this case remain unknown. Possibili-
ties include other active chronic viral
infections and their consequences
(such as HCV infection and liver cirrho-
sis), ongoing HIV replication in seques-
tered sites, and chronic low-level plas-
ma viremia that is below the limit of
detection of currently available assays.
How combination ART might benefit
this patient is unclear; presumably, by
reducing antigen load that is not appar-
ent by our current plasma HIV RNA as-
says, one might alter immune system
homeostasis and halt CD4-cell loss.
Regardless of the mechanisms involved,
given the clinical consequences of low
CD4-cell counts, clinicians faced with
patients like this one should consider
the potential benefits of starting ART.
— Florencia Pereyra, MD
Dr. Pereyra is an Instructor of
Medicine at Harvard Medical School
and a junior faculty member at
the Partners AIDS Research Center,
Massachusetts General Hospital, and
Division of Infectious Diseases at
Brigham and Women’s Hospital
in Boston.
Andrade A et al. CD4+ T cell depletion in
an untreated HIV type 1–infected human
leukocyte antigen–B*5801–positive patient
with an undetectable viral load. Clin
Infect Dis 2008 Apr 15; 46:e78.
aids-clinical-care.jwatch.org
Nevirapine Hypersensitivity
A large cohort study in the Netherlands
helps identify which treatment-experienced
patients are most likely to develop nevira-
pine hypersensitivity reactions.
A pproximately 7% of patients who
commence nevirapine-containing
antiretroviral therapy (ART) experience
treatment-limiting rashes, hepatotoxicity,
or both. Such hypersensitivity reactions
(HSRs) tend to occur within the first
4 months of therapy and, in extremely
rare cases, can be life threatening. High
pretreatment CD4-cell counts are a
known risk factor for nevirapine HSR,
particularly among women. Conse-
quently, the nevirapine package insert
now contains a black box warning indi-
cating that the drug should be avoided
in women with CD4 counts >250 cells/
mm3 and in men with CD4 counts >400
cells/mm3. These recommendations,
however, are based mostly on data from
treatment-naive patients. Do they also
apply to treatment-experienced patients
following CD4-cell increases during
therapy?
To address this question, investiga-
tors evaluated data collected from all
22 hospitals and clinics in the Nether-
lands that provide ART. Between April
1998 and July 2006, 3752 patients (934
treatment naive; 2818 treatment experi-
enced) initiated nevirapine-containing
regimens. Hypersensitivity was defined
as rash or hepatotoxicity that occurred
within 18 weeks of starting therapy and
that led to nevirapine discontinuation.
A total of 231 patients (6.2%) dis-
continued nevirapine because of pre-
sumed HSRs (174 had rash, 49 had
hepatotoxicity, and 8 had both). In a
multivariate analysis, HSR rates were
higher in treatment-experienced pa-
tients who had low pre-ART and high
current CD4 counts (>250 cells/mm3
in women; >400 cells/mm3 in men)
than in treatment-naive patients who
had low CD4 counts. This elevated risk,
however, was essentially limited to pa-
tients who had detectable viral loads
when they started nevirapine therapy.
Other independent risk factors included
female sex and Asian ethnicity.
Comment: These data help define
which patients can likely be switched
safely to nevirapine-containing regi-
mens. One problem with the study is
the retrospective identification of
Page 49
HSRs, which could have led investiga-
tors to overestimate incidence, as not
every treatment-limiting rash is a true
HSR. Furthermore, the results should
be confirmed in more ethnically diverse
populations with different genetic back-
grounds.
Ultimately, we must identify the ge-
netic markers that predict nevirapine
HSR. Although abacavir hypersensitiv-
ity is essentially limited to hu man leuko-
cyte antigen (HLA) B*5701–positive
patients, finding a similarly clear asso-
ciation between certain HLA genotypes
and nevirapine HSR has proven more
difficult. A recent study confirmed that
rashes are significantly more common
in patients with HLA class II allele
DRB1*01, especially 0101 (AIDS 2008;
22:540); whether HSRs involving
hepatotoxicity and fever are also more
common in such patients is unclear.
Other studies have suggested that class I
major histocompatibility complex
alleles such as HLA-Cw8 and HLA-B14
could play a role.
— Helmut Albrecht, MD
Wit FWNM et al. Discontinuation of
nevirapine because of hypersensitivity
reactions in patients with prior treatment
experience, compared with treatment-
naive patients: The ATHENA Cohort Study.
Clin Infect Dis 2008 Mar 15; 46:933.
Caution Urged When
Combining Lopinavir/
Ritonavir and Rosuvastatin
In a pharmacokinetic study involving 20
healthy volunteers, coadministration of
lopinavir/r and rosuvastatin significantly
increased rosuvastatin levels yet attenu-
ated the LDL-lowering effect of the drug;
one study participant experienced a
grade 4 elevation in creatinine phospho-
kinase levels.
A mong HIV-infected patients receiv-
ing antiretroviral therapy (ART),
response to lipid-lowering treatment
is often suboptimal, in part because of
drug interactions and toxicity. When
coadministered with certain PIs, some
statins may have reduced effectiveness
(pravastatin) or variable effectiveness
(low-dose atorvastatin), and others may
be contraindicated because of the po-
tential for dangerously high levels in the
Page 50
blood (simvastatin and lovastatin). Re-
searchers hypothesized that rosuvastatin
(Crestor) might be a better option for
patients taking PIs because it undergoes
relatively little metabolism through the
pivotal cytochrome P450 3A4 pathway.
However, new data highlight worrisome
interactions between rosuvastatin and
lopinavir/ritonavir.
Healthy volunteers took 20 mg of
rosuvastatin alone for 7 days, then
lopinavir/r (400/100 mg twice daily)
alone for 10 days, and then the combi-
nation for 7 days. Intensive pharmaco-
kinetic monitoring was conducted,
with complete data available from
15 volunteers.
Plasma rosuvastatin levels increased
significantly when the drug was coad-
ministered with lopinavir/r (geometric
mean ratio, 2.1 for the area-under-the-
curve analysis and 4.7 for the maximum-
concentration analysis). However, total
median cholesterol decreased only 21%
with the combination of rosuvastatin
and lopinavir/r, compared to 27% with
rosuvastatin alone (P=0.03). Similarly,
LDL cholesterol decreased only 26%
with the combination, compared to 31%
with rosuvastatin alone (P=0.01). One
study participant experienced an asymp-
tomatic rise in creatinine phospho-
kinase levels to 17-fold above the
upper limit of normal.
Comment: The authors speculate that
the paradoxical reduction in the lipid-
lowering effects of rosuvastatin despite
increased levels of the drug in the pres-
ence of lopinavir/r may be due to inhi-
bition of a hepatic transporter, decreas-
ing the level of rosuvastatin at its site of
action within hepatocytes. Until more
safety, efficacy, and dosing data are avail-
able, clinicians should carefully monitor
patients who are receiving rosuvastatin
for treatment of PI-associated LDL
elevations. — Keith Henry, MD
Kiser JJ et al. Drug/drug interaction be-
tween lopinavir/ritonavir and rosuva-
statin in healthy volunteers. J Acquir
Immune Defic Syndr 2008 Apr 15;
47:570.
AIDS CLINICAL CARE
Effect of HSV Suppression
on HIV Incidence
Among “recreational-facility” workers
in Tanzania, acyclovir treatment did
not decrease the risk for acquiring
HIV infection.
F indings from a variety of investiga-
tions indicate that risk for acquiring
HIV is increased among individuals who
are infected with herpes simplex virus
type 2 (HSV-2). Might suppression of
HSV-2 infection reduce the risk for HIV
acquisition? To find out, researchers
conducted a double-blind study of acy-
clovir suppressive therapy among fe-
male recreational-facility workers in 19
communities in northwestern Tanzania.
The women, aged 16 to 35, were HIV-
seronegative and HSV-2–seropositive.
Participants were randomized to re-
ceive acyclovir (400 mg twice daily)
or placebo. Among the 821 women who
were enrolled, about 80% completed
follow-up (mean duration, >1.5 years for
each treatment group). Mobile clinics
were used for follow-up visits, which
occurred every 3 months.
Overall, evidence of genital HSV-2
infection was detected infrequently
at follow-up visits and was similar be-
tween the two study groups. Six epi-
sodes of genital ulceration or blisters
were seen in the placebo group versus
nine episodes in the acyclovir group.
Cervicovaginal lavage specimens, ob-
tained from 450 randomly selected
participants at 6, 12, and 24 months,
yielded HSV DNA in only 4.7% and
3.8% of samples, respectively. The
HIV seroconversion rate was 7% for
each group. Acyclovir treatment had
no effect on the incidence of HIV infec-
tion (rate ratio, 1.08; 95% confidence
interval, 0.64–1.83). No serious ad-
verse events were associated with
acyclovir use.
Comment: Despite a wealth of data sug-
gesting an association between HSV-2
infection and HIV acquisition risk, no
such association was demonstrated in
this group of women who were deemed
to be at moderately high risk for HIV
infection. Because of the relatively low
HIV seroconversion rate in the overall
cohort, the study could have been under-
powered to detect between-group differ-
ences. I am left wondering whether a
difference would have been seen be-
Volume 20 Number 6
tween the two treatment groups if the
prevalence of active HSV-2 infection
had been higher.
— Larry M. Baddour, MD
Dr. Baddour is a Professor of Medicine
in the Division of Infectious Diseases
at Mayo Clinic College of Medicine
in Rochester, Minnesota.
Watson-Jones D et al. Effect of herpes
simplex suppression on incidence of
HIV among women in Tanzania. N Engl
J Med 2008 Apr 10; 358:1560.
HIV Incidence Among Men
with Early Syphilis:
A Tale of Three Cities
Among men diagnosed with early syphi-
lis at STD clinics in Atlanta, Los Angeles,
and San Francisco, annual HIV incidence
was estimated to be 9.5% overall and
12.0% for MSM.
H aving syphilis increases the risk for
acquiring and transmitting HIV in-
fection. Syphilis outbreaks in several cit-
ies among men who have sex with men
(MSM) have raised concerns that HIV
infection rates in this population might
rise (MMWR Morb Mortal Wkly Rep
2003; 52:1229). To estimate the inci-
dence of HIV infection in men newly
diagnosed with early syphilis, investiga-
tors analyzed remnant serum specimens
and deidentified epidemiologic data that
were gathered at STD clinics in Atlanta,
Los Angeles, and San Francisco between
2004 and early 2006.
Specimens were available from 457
men with early syphilis (primary, sec-
ondary, or early latent disease); 80% of
these men were MSM. The prevalence of
Western blot–confirmed HIV infection
was 41% among all men with early syph-
ilis and 45% among the 357 with primary
or secondary syphilis. Prevalence was
47% among MSM overall, with the high-
est rates (70%) among those in Atlanta.
Judging by the results of sensitive/less-
sensitive HIV assays and the absence of
a contradictory history of HIV testing
and antiretroviral treatment, HIV infec-
tion in 11 men (including 10 MSM) was
probably recent. HIV RNA testing of EIA-
negative samples suggested that four
(continued on page 52)
June 2008
ANTIRETROVIRAL ROUNDS
Resistance: What You
Don’t Know — Can It
Hurt You?
A 50-year-old man with long-
standing HIV infection was ad-
mitted to the hospital with gallstone-
related pancreatitis. Despite extensive
prior treatment with multiple agents
in all three major drug classes, he had
maintained clinical stability on a regi-
men of tenofovir/FTC and ritonavir-
boosted fosamprenavir for the previous
3 years, with his CD4 count stable at
300 to 500 cells/mm3 and his viral load
measuring either <50 copies/mL or
50 to 500 copies/mL. At this level of
viremia, no resistance test had been
performed. In the days preceding his
admission and during much of his hos-
pital stay, however, the man was un-
able to take anything by mouth, includ-
ing his antiretrovirals. His viral load
rebounded to 15,000 copies/mL, and a
genotypic resistance test was ordered.
After recovery, the man resumed the
same antiretroviral regimen, and his
viral load quickly fell again to <50
copies/mL. The resistance test ordered
during admission demonstrated the
following mutations:
• NRTI: 20wt/R, 35I, 41wt/L, 67N,
74V, 115F, 181C, 184V, 214F, 215Y,
219R, 221Y
• NNRTI: 135T, 181C, 221Y
• PI: 10I, 13V, 20R, 35D, 36I, 37D,
48V, 54T, 63P, 71V, 73S, 82A,
89V, 90M, 93L
The interpretation of this genotype
was that the virus was resistant to all
NRTIs (partial resistance to tenofovir)
and NNRTIs (the report did not in-
clude etravirine) and had preserved
susceptibility only to the PIs darunavir
and tipranavir.
He is tolerating the current regimen
well, with no drug-related side effects.
Self-reported adherence to medica-
tions is excellent.
Would you change his regimen? If
so, to what?
aids-clinical-care.jwatch.org
RESPONSE 1 the difficulty in my clinic of accessing
J O S E P H C . G AT H E , J R ., M D,
FAC P, F I D S A
Based on the scenario presented, I
would not change this patient’s regi-
men. His viral load was <50 copies/mL
at the latest evaluation and was consis-
tently undetectable before his hospital-
ization. The problem comes in trying
to interpret the results of his genotypic
resistance test, especially given the epi-
sodes of low-level viremia. At face val-
ue, the data would suggest that his vi-
ral load fell from 15,000 copies/mL to
<50 copies/mL with only one partially
active agent (tenofovir). However, such
a decline is extremely unlikely, even
if one assumes some activity from
fosamprenavir.
One interpretation is that the geno-
typic test results are inaccurate. Ample
data suggest that quality-control issues
occur with genotypic and phenotypic
testing — and that individual test re-
sults should be placed in the context
of treatment history and clinical pre-
sentation. In my own practice, it is
not unusual to receive resistance test
reports that make no clinical sense.
An alternative interpretation is that
this genotypic test is accurate. Several
studies have shown that, even with
low-level viremia for as little as 6 to
12 months, patients can accumulate
additional mutations (including those
associated with drugs they have never
received) that would jeopardize their
future treatment options (Abstract 615,
13th Retrovirus Conference, 2006; Ab-
stract 874, 15th Retrovirus Conference,
2008; AIDS 2007; 21:721). Still, I
would not have expected this patient
to respond so well to a regimen to
which the virus has limited genotypic
susceptibility.
Although I would not change this
patient’s regimen now, I would remain
vigilant for further clinically significant
episodes of low-level viremia. Should
such episodes occur, I would consider
switching the patient to a regimen that
includes two new active agents. Possi-
bilities include the integrase inhibitor
raltegravir, the fusion inhibitor enfuvir-
tide, the PI darunavir, and the second-
generation NNRTI etravirine. I would
not suggest a CCR5 inhibitor because of
Page 51
tropism assays and because I doubt
this patient has CCR5-tropic virus,
given his triple-class resistance (Ab-
stracts 655 and 233, 13th Retrovirus
Conference, 2006).
In summary, clinicians should treat
the patient, not the chart or the lab re-
ports. Thus, I would keep this patient
on his current regimen and follow him
closely. Should low-level viremia recur,
I would consider switching him to an-
other regimen to prevent the develop-
ment of further resistance.
Dr. Gathe is in private practice in
Houston.
RESPONSE 2
RICHARD ELION, MD
Although this patient has maintained
long-term virologic suppression on his
current regimen, the viral genotype in-
dicates the presence of substantial re-
sistance, which presumably developed
during some period of nonadherence.
This resistance poses a serious threat
to his virologic suppression and, con-
sequently, to his long-term treatment
options. If he were to become viremic,
he would likely develop additional re-
sistance to PIs and lose susceptibility
to that drug class entirely. I would
therefore recommend changing his
regimen to one that positions him for
more-durable suppression over time.
This approach might seem counter-
intuitive because he is doing well now,
but not switching would be akin to
not wearing a seatbelt just because
one hasn’t hit any major bumps in
the road yet.
For this patient’s next regimen, I
would avoid nucleosides because of the
risk for future toxicity, coupled with
the diminished likelihood of effective-
ness and limited potency due to resis-
tance. Instead, I would recommend a
combination of raltegravir, etravirine,
and ritonavir-boosted darunavir, with
raltegravir being the key component.
This drug focuses on a new target; the
patient’s virus is not resistant to it; and
it is potent, tolerable, and administered
twice daily, placing it in harmony with
the other agents in the regimen. In the
Page 52
BENCHMRK trials, patients who re-
ceived two active agents in addition
to raltegravir had greater rates of viro-
logic suppression than did those who
received only one active agent beyond
raltegravir (Abstracts 105aLB and
105bLB, 14th Retrovirus Conference,
2007). Etravirine is a reasonable option
because the patient’s virus has only
one associated mutation (181C), and,
according to DUET data, at least three
such mutations are required to dimin-
ish response (Abstract 32, XVI Interna-
tional HIV Drug Resistance Workshop,
2007). Darunavir would also be expect-
ed to have excellent activity, given this
patient’s viral genotype and the results
of the POWER studies (Abstract 157,
13th Retrovirus Conference, 2006). If
the patient was tested for and found to
have CCR5-tropic virus (which seems
likely, given his high CD4-cell count
over time), maraviroc could be sub-
stituted for any of the drugs that I’ve
recommended.
In summary, one should not settle for
virologic suppression in a patient with
a known viral genotype that predicts
long-term problems. The availability of
active and tolerable regimens for this
patient argues for a proactive switch to
ensure long-term immunologic stability
and virologic suppression.
Dr. Elion is the Director of Clinical
Research at Whitman-Walker Clinic
in Washington, DC.
T E L L U S W H AT Y O U W O U L D D O
How would you manage this patient?
Send your thoughts to arcase@mms.org,
and we’ll publish a selection of re-
sponses in an upcoming issue.
AIDS CLINICAL CARE
JOURNAL WAT C H HIV
(continued from page 50)
men might have been undergoing HIV
seroconversion at the time of the initial
syphilis test; results for two additional
men were suggestive but could not be
confirmed.
Estimates of HIV incidence for men
with early syphilis were 9.5% per year
overall and 12.0% per year for MSM;
estimates for men with primary or
secondary syphilis were 9.5% per year
overall and 10.5% per year for MSM.
Stratified analyses revealed such inci-
dence to be highest in white men
(14.3% per year) and in men <30 years
old (14.1% per year).
Comment: The findings of this study
are not novel, in that previous epi-
demiologic data have suggested a
high level of concordance between
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Volume 20 Number 6
the prevalences of HIV and syphilis,
particularly in MSM. What is important
to note here is that acquisition of HIV
is not uncommon in the setting of
early syphilis, with annual rates rang-
ing from 9.5% to 14.3%. Healthcare
providers must continue to emphasize
the importance of safe sex in prevent-
ing transmission of all STDs, including
syphilis and HIV. In addition, providers
should test all patients with early syph-
ilis for HIV infection, as per CDC
guidelines.
— Sonia Nagy Chimienti, MD
Buchacz K et al. HIV incidence among
men diagnosed with early syphilis in
Atlanta, San Francisco, and Los Angeles,
2004 to 2005. J Acquir Immune Defic
Syndr 2008 Feb 1; 47:234.
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