Update On ART-2010
Update On ART-2010
Update On ART-2010
The faculty reported the following financial relationships or relationships to products or devices they or
their spouse/life partner have with commercial interests related to the content of this CME activity.
Andrew R. Zolopa, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb,
Gilead Sciences, Pfizer, and Tibotec and contracted research funding from Gilead Sciences, Merck, and
VIRxSYS .
Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from Avexa, Bristol-Myers
Squibb, Chimerix, GlaxoSmithKline, Inhibitex, Merck, Myriad, Pfizer, Tibotec, Tobira, and Virco
Laboratories; has received contracted research funding from GlaxoSmithKline, Merck, and TaiMed; and
has served on speaker bureaus for Bristol-Myers Squibb, Roche, and Virco Laboratories.
Anna Poppa has disclosed that she has served as a consultant for Pfizer and ViiV.
The planners and managers reported the following financial relationships or relationships to products or
devices they or their spouse/life partner have with commercial interests related to the content of this CME
activity:
The following planners and managers, Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia
Kimball, RN, BSN; Samantha Mattiucci, PharmD; Jan Schultz, RN, MSN, CCMEP; Patricia Staples,
MSN, NP-C, CCRN and Gordon West, PhD, CCMEP, hereby state that they or their spouse/life partner
do not have any financial relationships or relationships to products or devices with any commercial
interest related to the content of this activity of any amount during the past 12 months.
The opinions expressed in the educational activity are those of the faculty and do not necessarily
represent the views of the Annenberg Center, Clinical Care Options, and activity supporters. Please refer
to the official prescribing information for each product for discussion of approved indications,
contraindications, and warnings.
DISCLAIMER
Participants have an implied responsibility to use the newly acquired information to enhance patient
outcomes and their own professional development. The information presented in this activity is not meant
to serve as a guideline for patient management. Any procedures, medications, or other courses of
diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without
evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any
applicable manufacturer’s product information, and comparison with recommendations of other
authorities.
TARGET AUDIENCE
This activity is designed as a state-of-the-art curriculum for frontline physicians, registered nurses, and
other healthcare professionals involved in the management of HIV-infected patients.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Summarize the recommendations of the 2009 DHHS guidelines for timing of initial antiretroviral
therapy
Discuss data underlying the recommendations of preferred first-line regimens listed in the 2009
DHHS guidelines
Recount how choices are made between the different first-line antiretroviral regimen options
Relate long-term data from the MOTIVATE, BENCHMRK, and DUET trials
Describe new data on investigational agents including vicriviroc, soltegravir, cobicistat, and
TBR-652
Nurses will provide appropriate counsel for their patients about starting and adhering to
antiretroviral therapy
DISCLAIMER
The materials published on the Clinical Care Options Web site reflect the views of the reviewers or
authors of the CCO material, not those of Clinical Care Options, LLC, the CME provider, or the
companies providing educational grants. The materials may discuss uses and dosages for therapeutic
products that have not been approved by the United States Food and Drug Administration. A qualified
health care professional should be consulted before using any therapeutic product discussed. Readers
should verify all information and data before treating patients or using any therapies described in these
materials.
Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 3
Update on Antiretroviral Therapy
CONTENTS
When to Start Antiretroviral Therapy: Impact of ART on Sexual Transmission of HIV ................. 7
Posttest ....................................................................................................................................... 25
References.................................................................................................................................. 26
Consider the following patient case vignette and determine how you would manage this patient.
EM is a newly diagnosed 44-year-old black male with HIV-1 infection. He has been
referred to your practice for evaluation and possible treatment. He has no history of OI
and is not coinfected with hepatitis B (HBV) or C viruses. He has attended several follow-
up visits and is engaged in his own care. His HIV-1 RNA is 28,250 copies/mL and CD4+
cell count is 645 cells/mm³.
Guidelines on the timing of HIV therapy initiation from the DHHS, published in December 2009,
are summarized in Table 1.[1] The panel members were in agreement on the need for therapy in
patients with CD4+ cell counts < 350 cells/mm3; this recommendation was unchanged from the
previous version of the guidelines, published in 2008. However, a paradigm change occurred for
patients with higher CD4+ cell counts: For those with CD4+ cell counts 350-500 cells/mm3, the
panel now recommended therapy (but noted that although 55% were strongly in favor, 45%
were only moderately in favor of this recommendation). For those with CD4+ cell counts > 500
cells/mm3, the panel was divided: One half recommended therapy and the other half considered
that antiretroviral therapy was optional in this patient group.
Perhaps the most dramatic data supporting earlier use of antiretroviral therapy are those
from the NA-ACCORD cohort (Figure 1).[2] NA-ACCORD analyzed 17,517 asymptomatic HIV-
infected therapy-naive patients from 22 study groups in the United States and Canada, who
received medical care during 1996-2005. The study concluded that patients who started therapy
Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 5
at CD4+ cell counts < 500 cells/mm3 compared with those who started with counts above this
threshold were 1.94 times more likely to die during follow-up—a compelling observation.
Death from any cause was the only endpoint in this analysis. Female sex and older age were
significant risk factors for death among those that deferred therapy vs those who started
with CD4+ cell counts > 500 cells/mm3.
The findings of the ART-CC study are shown in Table 2.[3] This was a large European
collaborative study of antiretroviral-naive patients from 15 HIV cohorts. To address lead-time
bias, the ART-CC investigators input data from other studies, such as the MACS and the
CASCADE cohorts. This study had 2 endpoints: AIDS and death.
The ART-CC found that starting therapy at CD4+ cell counts in the 350-400 cells/mm3 range
resulted in favorable outcomes. Clearly, the greatest benefit was seen among patients who
began treatment at the lowest CD4+ count levels.
Therefore, these 2 studies produced similar findings in patients with lower CD4+ cell counts but
observed different outcomes in patients with less advanced disease. There is some evidence
that death rates in the general population differ between Europeans and Americans. The rate of
death per 100 patient-years of follow-up in European studies is in the order of 1.0[3] whereas in
US studies, it is closer to 1.5[2] to as high as 3.8.[4] The reasons for this difference are likely to be
complex, but it may also be that deaths are documented more rigorously in the United States
because of the US Centers for Disease Control and Prevention’s National Death Index database.
The SMART study was not designed to explore the question of when to start; primarily SMART
was a study of treatment interruption.[5] However, when considering the endpoints of
development of OIs and death, OIs alone, serious non-AIDS events, or a composite of the
Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 6
3 endpoints, a subanalysis of therapy-naive patients and patients who were off therapy at the
start of the study also indicated that better results were obtained when patients initiated therapy
at CD4+ cell counts > 350 cells/mm3 (Figure 2). Collectively, these data clearly support the
initiation of antiretroviral therapy at CD4+ cell counts > 350 cells/mm3. At CD4+ cell counts
> 500 cells/mm3, the weight of evidence is not quite as compelling, and additional data
addressing this question are expected in due course.
Other studies have also provided data showing that initiating antiretroviral therapy later appears
to be associated with several non-AIDS events. Ellis and colleagues[6] documented that a low
CD4+ cell count nadir was associated with a greater risk for neurocognitive disorders. Likewise,
a low CD4+ cell count nadir has been linked to arterial stiffness[7] and an increased risk of
fractures.[8] These studies provide further support for earlier therapy, although these apparent
benefits must be balanced against cost, tolerability, toxicity, and adherence requirements.
Data also indicate that for patients with an acute OI, starting antiretroviral therapy close to the
time of OI diagnosis improves outcome.[9,10] In the ACTG 5164 study reported by Zolopa and
colleagues,[10] patients were stabilized on OI therapy and began antiretroviral therapy within 2
weeks. Antiretroviral therapy need not be started immediately, therefore, but it should not be
delayed by months either.
A larger study, which was conducted in Rwanda and Zambia, included almost 3000 discordant
Collectively, these studies suggest that initiation of antiretroviral therapy by the infected partner
within a discordant couple confers a degree of protection against HIV transmission to the
uninfected partner.
Community viral load levels (ie, the average level of viremia among all infected patients in a
specific community) have been noted to decline with widespread use of effective antiretroviral
therapy. Data from San Francisco, California, were reported at 2010 Conference on
Retroviruses and Opportunistic Infections showing that between 2004-2008, decreased
community viral load was significantly associated with reduced numbers of new HIV cases
(P = .005).[15] There are also data from a cohort of injection drug users in Vancouver, Canada,
that show a link between longitudinal measures of community viral load and HIV incidence.[16]
There is a need to be cautious in interpreting “ecologic” studies such as these, as the
identification of a populationwide correlation does not prove causation. Certainly, however,
these data suggest that there is a link between antiretroviral therapy use and HIV incidence at
the population level. Indeed, health officials in San Francisco have now recommended that all
who are diagnosed HIV positive should receive antiretroviral therapy.[17].
Unlike other infectious diseases, in HIV, the burden is on the need to justify early treatment;
this is partly related to the toxicity of the early antiretroviral agents. However, the pendulum
may swing back in the future so that the emphasis is on identifying patients who should not be
treated. These include patients who are not willing or able to adhere to therapy (although in
patients with lower CD4+ cell counts, therapy should still be started). Whether treatment should
be recommended in long-term nonprogressors and elite controllers is unclear. Data from
University of California, San Francisco suggest that at least some elite controllers—meaning
patients who have undetectable HIV-1 RNA despite not receiving antiretroviral therapy—do
have a decline in their CD4+ cell count that is related to immune activation.[21] This suggests
that there may be a role for therapy in some of those patients.
All of these regimens have been shown in recent clinical trials to be highly effective with
between 78% and 86% of patients achieving HIV-1 RNA < 50 copies/mL at Week 48 (by intent-
to-treat analysis).[18-20] These regimens are also highly tolerable and allow for tailoring of choices
to suit the patient, as shown in the next series of patient cases. The data supporting designation
of these regimens as preferred will be reviewed later in this module.
“Acceptable” regimens constitute a third category of first-line therapies (Table 5). Here,
“acceptable” is intended to be understood as less satisfactory than preferred or alternative
regimens. Efavirenz with didanosine and lamivudine or emtricitabine can be an effective
regimen for some patients, but its tolerability is less well established than that of other options;
this combination has never been studied in large randomized clinical trials. Unboosted
atazanavir with either abacavir or zidovudine plus lamivudine could be considered in certain
situations, such as the patient who cannot tolerate ritonavir or other first-line alternatives.
The panel also identified a series of regimens that may be acceptable for therapy-naive patients
but for which additional data are needed (Table 6). This grouping includes maraviroc with
zidovudine/lamivudine, which was evaluated in the MERIT study; this category also includes
raltegravir, darunavir/ritonavir, and saquinavir/ritonavir when these agents are combined with
either abacavir/lamivudine or zidovudine/lamivudine (ie, NRTI backbones with which these
agents have not been studied in large clinical trials).
Table 6. DHHS Guidelines: First-line Regimens That May Be Acceptable but More Data
Are Needed[1]
Finally, the panel listed a number of regimens that should only be used with caution because
they have safety, resistance, or efficacy concerns, despite demonstrating virologic efficacy in
some studies (Table 7). This category includes nevirapine-based therapy, regardless of NRTI
backbone. It remains to be seen whether data from the ARTEN and ACTG 5208/OCTANE 2
trials lead to a reassessment of nevirapine in future guidelines. ARTEN was a randomized study
of nevirapine vs atazanavir/ritonavir, each combined with tenofovir/emtricitabine, in treatment-
naive men and women with CD4+ cell counts < 400 and < 250 cells/mm3, respectively.[24] The
efficacy of the nevirapine regimen was noninferior to that of atazanavir/ritonavir at 48 weeks of
follow-up. ACTG 5208 was a randomized trial conducted in 10 African countries.[25] Women with
no previous exposure to antiretroviral therapy (including single-dose nevirapine for prevention of
mother-to-child HIV transmission) and CD4+ cell counts < 200 cells/mm3 received either
nevirapine or lopinavir/ritonavir, each combined with tenofovir/emtricitabine. Time to virologic
failure or death was similar between treatment arms. In both ARTEN and ACTG 5208, rates of
discontinuation were higher in the nevirapine-treated arms.
In addition, the panel advises that regimens involving unboosted fosamprenavir should be used
with caution.
NRTI allocation was blinded, whereas efavirenz or atazanavir/ritonavir were given unblinded.
The study includes more than 1800 patients, which provides an opportunity to conduct factorial
analyses, although the investigators have not yet reported those data.
At baseline, the median HIV-1 RNA was 4.7 log10 copies/mL and the median CD4+ cell count
was 230 cells/mm3. At the time of entry into the study, 17% of the patients had a history of
AIDS, and 45% were analyzed by genotypic resistance testing at screening. HLA-B*5701
testing was not a requirement of entry, but patients known to have tested positive for this allele
were excluded.
Data from an unplanned interim analysis of this study requested by the data and safety
monitoring board, focusing on the NRTI comparison only, were published in 2009.[27] The final
analysis focused on the comparisons between atazanavir/ritonavir and efavirenz among the
overall populations and on the NRTI comparisons in the subpopulation with HIV-1 RNA
< 100,000 copies/mL.
In this final analysis, time to virologic failure was similar between atazanavir/ritonavir and
efavirenz, regardless of whether these agents were combined with abacavir/lamivudine or with
tenofovir/emtricitabine. The proportion of patients without virologic failure at Week 96 was also
similar between atazanavir/ritonavir and efavirenz, regardless of NRTI allocation (Figure 3).
In each case, these comparisons met criteria for noninferiority.
Regarding safety and tolerability, at Week 48, there were significantly greater increases in
total cholesterol with efavirenz than with atazanavir/ritonavir, combined with either NRTI pair.
Similarly, increases in low density lipoprotein cholesterol were significantly higher in the
efavirenz arms than in the atazanavir/ritonavir arms. Among patients who received atazanavir/
ritonavir with tenofovir/emtricitabine there was almost no change in low density lipoprotein
cholesterol. High density lipoprotein cholesterol increases were significantly higher with
efavirenz in both NRTI arms. By comparison, there were no significant differences between
efavirenz and atazanavir/ritonavir regarding their impact on triglycerides, although the greatest
rise in this marker was seen when atazanavir/ritonavir was given with abacavir/lamivudine.
There were no significant differences in total cholesterol–to–high density lipoprotein cholesterol
ratio between any of the arms. Finally, cholesterol increases were greater with use of
abacavir/lamivudine than tenofovir/emtricitabine.
The pattern can be compared with that seen in ACTG 5142, which evaluated lopinavir/ritonavir
vs efavirenz as first-line therapy.[29] In ACTG 5142, virologic failure was less frequent with use of
efavirenz than with lopinavir/ritonavir, but among patients with virologic failure, treatment with
the boosted PI was less likely to result in the emergence of resistance.
In summary, the final data from ACTG 5202 suggest that the virologic efficacy of first-line
atazanavir/ritonavir-based therapy is comparable to that of efavirenz-based therapy. In terms
of lipid impact and resistance at failure, atazanavir/ritonavir appears to be better than efavirenz.
However, efavirenz/tenofovir/emtricitabine retains the convenience of the only one-pill
once-daily regimen.
At Week 96, 14% of raltegravir patients had experienced virologic failure vs 16% of efavirenz-
treated patients. Resistance to raltegravir was documented in 4 patients (of 281 who were
randomized to the raltegravir arm) and resistance to efavirenz in 5 patients (of 282 randomized
to this drug). Both efavirenz and raltegravir are examples of antiretrovirals with a low genetic
barrier to resistance, meaning that significant resistance results from a single-point mutation.
These observations suggest that if patients begin therapy with 3 active, well-tolerated drugs, the
risk of resistance at virologic failure is small. Where resistance to these regimens does occur,
there is a significant chance that this will involve resistance to the anchor agent.
On the other hand, sustained periods of nonadherence, whether driven by the patient or by
erratic drug supply, are likely to be associated with a significant risk of failure and drug
resistance among those receiving efavirenz-based therapy. Other drawbacks include risk of
central nervous system adverse effects and risk for teratogenicity, which discourages use of
efavirenz in women who may become pregnant. There is increasing evidence that efavirenz
may be less lipid-friendly than some of the other contemporary regimens. In addition, data
suggesting that efavirenz may be associated with lower vitamin D levels have been reported.[32]
Finally, a link between efavirenz and lipoatrophy has been reported, at least in some studies.[33]
Choosing Raltegravir
Although the available data on raltegravir suggest this drug is well tolerated, long-term data
are lacking. The efficacy of raltegravir was shown to be noninferior to that of efavirenz in the
STARTMRK trials, with less impact on lipids.[30] Further, use of raltegravir-based therapy
results in faster virologic suppression than an efavirenz-based regimen, although the clinical
significance of this, if any, is not clear. Raltegravir does not appear to be teratogenic based on
current data and so may be a suitable option for women of child-bearing potential. In addition,
few drug-drug interactions have been noted with raltegravir.
Raltegravir is dosed twice daily; for some patients, this may be a disadvantage. As described
above, there is also the risk of resistance to raltegravir if the patient experiences virologic
failure, although second-generation integrase inhibitors are not currently available and so
integrase inhibitor sequencing is not a consideration at this time. Many clinicians have used
The drawbacks of boosted PI–based therapy include ritonavir-related adverse effects, which
can occur even at the low doses given for pharmacologic enhancement. Typically, these
agents are less convenient than other options; although once-daily boosted PI therapy is
possible, a complete single-pill regimen is not yet available in this class. In addition, boosted
PIs may increase lipids (although the data from ACTG 5202 suggest this relationship is not
straightforward), and some have been associated with lipohypertrophy. An interaction between
certain PIs and tenofovir that appears to result in reduced renal function has also been
reported[35] and is discussed further below.
Data on the safety and efficacy of atazanavir/ritonavir in first-line therapy have been reported
from the CASTLE study. CASTLE was a randomized comparison of atazanavir/ritonavir and
lopinavir/ritonavir in therapy-naive patients, each combined with tenofovir/emtricitabine.[19]
Similar to the pattern observed in ARTEMIS, the efficacy of the atazanavir/ritonavir regimen
was noninferior to lopinavir/ritonavir at Week 48 but reached statistical superiority at Week 96
(Figure 6).[37] Increases in CD4+ cell count were similar between arms at Week 96 (+268
cells/mm³ with atazanavir/ritonavir vs +290 cells/mm³ with lopinavir/ritonavir), as were resistance
Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 15
outcomes in patients with virologic failure. Atazanavir/ritonavir was better tolerated, with
reduced risk of gastrointestinal adverse effects and less impact on lipids than lopinavir/ritonavir.
Turning to alternative boosted PIs, once-daily dosing of lopinavir/ritonavir has been shown to
provide comparable efficacy to twice-daily dosing (Figure 7).[38] In study M05-730, therapy-naive
patients were randomized to receive lopinavir/ritonavir dosed 400/100 mg twice daily or 800/200
mg once daily, each combined with tenofovir/emtricitabine. For the first 8 weeks of the study,
the treatment arms were divided between tablet and capsule formulations of the boosted PI.
After 8 weeks, all patients received the tablet formulation. At Week 48, the antiviral response in
the once-daily arm was noninferior to twice-daily dosing, and CD4+ cell count responses were
comparable. Rates of discontinuation and adverse events, including diarrhea, were similar
between arms. In comparison to this trial, in both the ARTEMIS and CASTLE studies, a
substantial proportion of patients who were allocated lopinavir/ritonavir received the capsule
formulation.
These recent data indicate that effective virologic suppression occurs with the 2 preferred
boosted PIs atazanavir/ritonavir and darunavir/ritonavir and the alternative boosted PI
lopinavir/ritonavir. As such, choice of therapy may be influenced by the safety profile of the
drugs.
Several studies have indicated that PIs as a class are associated with increased risk of
myocardial infarction (MI). Data from the D:A:D study on the relationship between cumulative
exposure to individual PIs and MI risk are shown in Figure 9.[39,40] This data set was responsible
for identifying the apparent link between abacavir and MI, which has since been widely debated.
Cumulative lopinavir/ritonavir exposure was also associated with increased MI risk in this study,
as was cumulative exposure to indinavir. By contrast, there was no relationship between MI risk
and either nelfinavir or saquinavir use, regardless of whether saquinavir was given boosted or
unboosted. The study was not adequately powered to assess the relationship between MI risk
and exposure to antiretrovirals that have entered into clinical use more recently, in particular,
atazanavir and darunavir/ritonavir. Data on these agents is awaited with interest.
A report from the French Hospital Database on antiretroviral exposure and MI risk showed
similar data to the D:A:D cohort, with an odds ratio for MI of 1.4 per additional year of lopinavir/
ritonavir, 1.5 for fosamprenavir/ritonavir, and nonsignificant odds ratios for nelfinavir, saquinavir,
and indinavir.[41] Therefore, there may be differences between PIs regarding MI risk, but it is
difficult to establish this clearly using data from retrospective studies.
Atazanavir/ritonavir offers the lowest pill burden of available boosted PIs, lowest risk of
gastrointestinal intolerance, and relatively low risk of metabolic toxicities. The most significant
drawback of atazanavir/ritonavir therapy is the interaction with acid-reducing agents, especially
proton pump inhibitors. In addition, jaundice and scleral icterus can be problematic for some
patients.
Darunavir/ritonavir is generally well tolerated and presents a low risk of metabolic abnormalities.
There is, however, a risk of rash associated with use of this drug. Darunavir/ritonavir has
demonstrated at least comparable efficacy and better tolerability to lopinavir/ritonavir in first-line
therapy; however, there are no data comparing its efficacy and safety to that of efavirenz.
Lopinavir/ritonavir is the only boosted PI that is coformulated, and although now designated an
alternative option for first-line therapy, it remains the preferred PI for use in pregnant woman.
The tablet formulation does not require refrigeration. The major disadvantage of lopinavir/
ritonavir is that daily dosing requires 200 mg of ritonavir, which is twice that required for either
atazanavir or darunavir. Metabolic toxicity and gastrointestinal adverse effects are increased
relative to other PIs, and comparative studies have found virologic efficacy to be less robust
than that of atazanavir/ritonavir and darunavir/ritonavir.
Data from an unplanned interim analysis of this study requested by the data and safety
monitoring board, focusing on the NRTI comparison only, were published in 2009.[27] This
analysis found that among patients who had HIV-1 RNA > 100,000 copies/mL at screening, time
to virologic failure was shorter in those who received abacavir/lamivudine vs those who received
tenofovir/emtricitabine (HR: 2.33; 96% CI: 1.46-3.72). This observation could not be explained
by differences in treatment discontinuation because of suspected abacavir hypersensitivity
reaction, as similar results were seen across different categories of virologic failure: whether
early or later, with or without previous virologic suppression. In a post hoc analysis, there was
no significant difference between the NRTI groups in risk of rebound among subjects whose
HIV-1 RNA was < 50 copies/mL on 2 viral load tests. This provides reassurance that patients
who began abacavir/lamivudine with a high HIV-1 RNA some time ago and have achieved and
maintained undetectable HIV-1 RNA may have passed the point of greatest risk of virologic
failure.
Final results from this study, including follow-up to 96 weeks, were reported at the 2010
Conference on Retroviruses and Opportunistic Infections.[26] There were several interesting
findings relating to the performance of the NRTI backbones. Among patients with high baseline
HIV-1 RNA, the shorter time to virologic failure observed in the abacavir/lamivudine arm was
independent of the third drug used. The HR of failure in the higher HIV-1 RNA group for
abacavir/lamivudine vs tenofovir/emtricitabine was 2.22 (95% CI: 1.19-4.14) in the efavirenz arm
and 2.46 (95% CI: 1.20-5.05) in the atazanavir/ritonavir arm.
Virologic response rates in patients with baseline HIV-1 RNA < 100,000 copies/mL were
comparable at Week 96 (Figure 10). Time to virologic failure was similar for either NRTI
backbone, regardless of the third drug: With atazanavir/ritonavir, HR of failure for abacavir/
lamivudine vs tenofovir/emtricitabine was 1.26 (95% CI: 0.76-2.05) compared with 1.23 (95%
CI: 0.77-1.96) for efavirenz.
Regarding toxicity, the ACTG 5202 investigators found no difference between the NRTI arms
in the frequency of a number of prespecified events, namely MIs and other vascular events,
non-AIDS malignancies, substantial renal dysfunction, or fractures. As has been widely
reported, the D:A:D study investigators reported an association between current use of abacavir
and MI, as well as a trend toward as association of cumulative use of abacavir and increased MI
risk (Figure 11).[39,40] Data from Bedimo and colleagues[43] from the Veterans Administration
cohort suggest that this may be partly because of channeling bias in that patients who have
CKD are more likely to receive abacavir/lamivudine and CKD is itself associated with
cardiovascular events. (Although the D:A:D investigators tried to adjust for this possibility, they
did not have renal disease data on all patients.) The unadjusted Veterans Administration data
set showed a marginally nonsignificant association between cumulative abacavir use and acute
MI, and after adjustment to account for traditional cardiovascular risk factors and estimated
glomerular filtration rate (by MDRD calculation), the association was further attenuated.
Figure 11. D:A:D: recent and/or cumulative NRTI exposure and risk of MI.[39,40]
As described previously, investigators from the EuroSIDA study presented data at the 2010
Conference on Retroviruses and Opportunistic Infections showing that cumulative exposure to
tenofovir (and to certain PIs) was associated with increased risk of CKD and that this risk
remained elevated 1 year after stopping tenofovir (Figure 8).[35] However, the potential for
antiretroviral therapy to result in renal dysfunction is easier for clinicians to manage because
patients can be monitored regularly for early signs of kidney disease. By contrast, there is no
reliable surrogate marker to predict MI.
There is evidence that tenofovir has a greater impact on bone density than abacavir. In the
ASSERT study, 385 therapy-naive patients were randomized to receive efavirenz with either
tenofovir/emtricitabine or abacavir/lamivudine.[44] At Week 48 of therapy, patients receiving
tenofovir experienced significantly greater reductions in hip and lumbar bone density relative to
baseline compared with patients receiving abacavir. ACTG 5202 observed a similar pattern at
96 weeks of follow-up.[26]
NRTI-Sparing Regimens
When selecting first-line therapy for a patient with kidney disease and cardiovascular disease
and/or a high HIV-1 RNA, an NRTI-sparing strategy may be considered. The combination of
lopinavir/ritonavir with efavirenz was studied in treatment-naive patients in ACTG 5142 and
resulted in similar virologic efficacy as efavirenz plus NRTIs, but with greater risk of cholesterol
elevations and more antiretroviral drug resistance at failure.[29,33]
Atazanavir/ritonavir plus efavirenz has been evaluated in a single randomized trial, BMS-121,
although the comparator arms constituted different dosing regimens of this combination rather
than either drug combined with NRTIs.[45] The combination proved potent through 48 weeks of
treatment but was associated with significant increases in triglycerides and cholesterol.
The combination of darunavir/ritonavir and efavirenz has not been studied but may merit
evaluation. Studies investigating use of raltegravir with a boosted PI and with unboosted
atazanavir are ongoing. The prospect of combining raltegravir with an NNRTI appears less
attractive because of the low barrier to resistance of both components. Finally, maraviroc plus a
boosted PI is under investigation, as is vicriviroc plus a boosted PI.
The preferred drugs for use with tenofovir/emtricitabine are efavirenz, atazanavir/ritonavir,
darunavir/ritonavir, or raltegravir. All of these options offer high levels of efficacy and are well
tolerated by most patients, although their individual characteristics will govern their suitability
for each patient. In patients for whom none of these preferred options is appropriate, a range
of alternative regimens have been designated.
Regardless of which regimen is selected for therapy initiation, long-term toxicity, persistent
immune activation and inflammation, and comorbid diseases associated with aging remain
substantial concerns for the HIV field.
It is anticipated that first-line therapy options will expand in the future to include the NNRTI
rilpivirine (TMC278). Data on once-daily dosing of raltegravir plus NRTIs is expected in 2011.
In addition, preliminary data on cobicistat (GS9350), a pharmacologic enhancer, have been
presented and is discussed briefly later in this module. Additional data on NRTI-sparing
regimens may also be forthcoming.
The large phase III studies DUET, BENCHMRK, and MOTIVATE have now reported longer-
term data, demonstrating the durability of regimens containing etravirine, raltegravir, and
maraviroc, respectively, in treatment-experienced patients with highly drug–resistant virus. The
DUET studies compared etravirine with placebo, each combined with darunavir/ritonavir and
investigator-selected NRTIs with or without enfuvirtide. Superior virologic suppression was
maintained at Week 96 in the etravirine arm vs placebo: HIV-1 RNA < 50 copies/mL was
observed in 57% of etravirine recipients vs 36% of those on placebo (P < .0001).[46]
The BENCHMRK studies compared raltegravir with placebo in patients receiving an optimized
background regimen (OBR). Data through 156 weeks of follow-up were reported at the 2010
Conference on Retroviruses and Opportunistic Infections, showing persistent superior activity of
raltegravir vs placebo: HIV-1 RNA < 50 copies/mL was observed in 47% of raltegravir recipients
vs 18% of those on placebo (P < .001).[47]
The MOTIVATE studies compared maraviroc with placebo, each combined with OBR. Superior
virologic suppression was maintained at Week 96 in the maraviroc arms vs placebo: HIV-1 RNA
< 50 copies/mL was observed in 41% of those on twice-daily maraviroc vs only 7% of those on
placebo.[48]
Once-daily administration of currently used agents have also been explored in recently reported
trials. The use of once-daily darunavir/ritonavir in treatment-experienced patients was explored
in the ODIN study, in which pretreated patients with no darunavir resistance mutations were
Soltegravir
Soltegravir (previously known as S/GSK1349572) is a new integrase inhibitor that has
demonstrated potency in a 10-day monotherapy study.[53] Peak HIV-1 RNA reduction in the
50-mg dosing arm reached -2.5 log10 copies/mL in this study. In vitro data suggest that this
agent will remain active against some raltegravir-resistant variants,[54] and once-daily dosing
is anticipated.[55]
TBR-652
TBR-652 is a novel oral CCR5 inhibitor that appears to support once-daily dosing. Short-term
monotherapy with TBR-652 demonstrated potent antiviral activity in CCR5 antagonist-naive,
HIV-infected individuals with CCR5-tropic virus only.[56] Median maximal HIV-1 RNA reduction
from baseline was -1.8 log10 copies/mL with the 75-mg dose. Of interest, TBR-652 is also a
potent antagonist of CCR2, a chemokine receptor associated with several inflammation-related
diseases.
Long-term data in advanced patients demonstrate the durable efficacy of regimens containing
raltegravir, maraviroc, or etravirine. Despite these apparent riches, there remains a need for
antiretroviral agents to be used with care to secure optimal outcomes for the coming years, as
the drug development pipeline contains few new agents that use novel mechanisms or are
active against viruses that are resistant to current agents.
POSTTEST
Click on the appropriate response below.
3. Which of the following statements best describes the final results of ACTG 5202 at
Week 96 of follow-up?
4. Is the following statement TRUE or FALSE? According to the ODIN study, once-daily
darunavir/ritonavir was inferior to twice-daily darunavir/ritonavir in treatment-
experienced patient with no darunavir resistance mutations
A. True
B. False
A. Cobicistat
B. S/GSK1349572
C. TBR-652
1. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. Available at:
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed April 23, 2010.
2. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy
for HIV on survival. N Engl J Med. 2009;360:1815-1826.
3. Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free
HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352-
1363.
4. Lemly DC, Shepherd BE, Hulgan T, et al. Race and sex differences in antiretroviral therapy use
and mortality among HIV-infected persons in care. J Infect Dis. 2009;199:991-998.
5. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, Emery S, Neuhaus
JA, et al. 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;197:1133-1144.
6. Ellis R, Heaton R, Letendre S, et al. Higher CD4 nadir is associated with reduced rates of HIV-
associated neurocognitive disorders in the CHARTER study: potential implications for early
treatment initiation. Program and abstracts of the 17th Conference on Retroviruses and
Opportunistic Infections; February 16-19, 2010; San Francisco, California. Abstract 429.
8. Dao C, Young B, Buchacz K, Baker R, Brooks J, HIV Outpatient Study Investigators. Higher and
increasing rates of fracture among HIV-infected persons in the HIV Outpatient Study compared to
the general US population, 1994 to 2008. Program and abstracts of the 17th Conference on
Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, California.
Abstract 128.
9. Miró J, Manzardo C, Mussini C, et al. Survival outcomes and effect of early vs deferred cART
among HIV-1-infected patients diagnosed at the time of an AIDS-defining event in Europe and
Canada: a collaborative cohort analysis (1997 to 2004). Program and abstracts of the 17th
Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco,
California. Abstract 529.
10. Zolopa AR, Andersen J, Komarow L, et al. Early antiretroviral therapy reduces AIDS
progression/death in individuals with acute opportunistic infections: a multicenter randomized
strategy trial. PLoS ONE. 2009;4:(5)e5575.
11. HTPN 052. Preventing sexual transmission of HIV with anti-HIV drugs. Available at:
http://clinicaltrials.gov/ct2/show/NCT00074581?term=hptn+052&rank=1. Accessed May 19, 2010.
12. Reynolds S, Makumbi F, Kagaayi J, et al. ART reduced the rate of sexual transmission of HIV
among HIV-discordant couples in rural Rakai, Uganda. Program and abstracts of the 16th
Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal,
Canada. Abstract 52a.
13. Sullivan P, Kayitenkore K, Chomba E, et al. Reduction of HIV transmission risk and high risk sex
while prescribed ART: results from discordant couples in Rwanda and Zambia. Program and
abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11,
2009; Montréal, Canada. Abstract 52bLB.
14. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of
antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;[Epud ahead of print].
16. Wood E, Kerr T, Marshall BD, et al. Longitudinal community plasma HIV-1 RNA concentrations
and incidence of HIV-1 among injecting drug users: prospective cohort study. BMJ.
2009;338:b1649.
17. New York Times. City endorses new policy for treatment of HIV. Available at:
http://www.nytimes.com/2010/04/04/us/04sftreatment.html. Accessed April 23, 2010.
18. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus
lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22:1389-
1397.
20. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus
efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a
multicentre, double-blind randomised controlled trial. Lancet. 2009;374:796-806.
21. Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell
count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of
therapy. J Infect Dis. 2008;197:126-133.
22. Hammer S, Eron JJ, Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection:
2008 recommendations of the International AIDS Society USA Panel. JAMA. 2008;300:555-570.
23. European AIDS Clinical Society. Guidelines for the clinical management and treatment of HIV-
Infected adults in Europe. Available at: http://www.eacs.eu/guide/index.htm. Accessed June 7,
2010.
25. McIntyre J, Hughes M, Mellors J, et al. Efficacy of ART with NVP+TDF/FTC vs LPV/r+TDF/FTC
among antiretroviral-naive women in Africa: OCTANE Trial 2/ACTG A5208. Program and
abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19,
2010; San Francisco, California. Abstract 153LB.
26. Daar E, Tierney C, Fischl M, et al. ACTG 5202: final results of ABC/3TC or TDF/FTC with either
EFV or ATV/r in treatment-naive HIV-infected patients. Program and abstracts of the 17th
Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco,
California. Abstract 59LB.
27. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial
HIV-1 therapy. N Engl J Med. 2009;361:2230-2240.
28. Eron J Jr, Yeni P, Gathe J Jr, et al. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-
ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over
48 weeks: a randomised non-inferiority trial. Lancet. 2006;368:476-482.
29. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1
infection. N Engl J Med. 2008;358:2095-2106.
Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 27
30. Lennox J, DeJesus E, Lazzarin A, et al. Raltegravir demonstrates durable efficacy through 96
weeks (wk): results from STARTMRK, a phase III study of raltegravir (RAL)-based vs efavirenz
(EFV)-based therapy in treatment-naive HIV+ patients (pts). Program and abstracts of the 49th
Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2009;
San Francisco, California. Abstract H-924b.
31. Cohen CJ, Colson AE, Sheble-Hall AG, McLaughlin KA, Morse GD. Pilot study of a novel short-
cycle antiretroviral treatment interruption strategy: 48-week results of the five-days-on, two-days-
off (FOTO) study. HIV Clin Trials. 2007;8:19-23.
32. Welz T, Childs K, Ibrahim F, Poulton M, Post F. Efavirenz use is associated with severe vitamin D
deficiency in a large, ethnically diverse urban UK cohort. Program and abstracts of the 5th
International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-
22, 2009; Cape Town, South Africa. Abstract TUPEB186.
33. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of
nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment.
AIDS. 2009;23:1109-1118.
34. Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of Raltegravir
combined with optimized background therapy in treatment-experienced patients with drug-
resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect
Dis. 2010;50:605-612.
35. Kirk O, Mocroft A, Reiss P, et al. Chronic kidney disease and exposure to ART in a large cohort
with long-term follow-up: the EuroSIDA study. Program and abstracts of the 17th Conference on
Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, California.
Abstract 107LB.
36. Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in
treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS. 2009;23:1679-1688.
38. Gathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is
noninferior to twice-daily dosing and results in similar safety and tolerability in antiretroviral-naive
subjects through 48 weeks. J Acquir Immune Defic Syndr. 2009;50:474-481.
39. Lundgren J, Reiss P, Worm S, et al. Risk of myocardial infarction with exposure to specific ARV
from the PI, NNRTI, and NRTI drug classes: the D:A:D study. Program and abstracts of the 16th
Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal,
Canada. Abstract 44LB.
40. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection
exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data
collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201:318-330.
41. Lang S, Mary-Krause M, Cotte L, et al. Impact of specific NRTI and PI exposure on the risk of
myocardial infarction: a case-control study nested within FHDH ANRS CO4. Program and
abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11,
2009; Montréal, Canada. Abstract 43LB.
42. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs.
zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354:251-260
44. Stellbrink HJ, Moyle G, Orkin C, et al. Assessment of safety and efficacy of abacavir/lamivudine
and tenofovir/emtricitabine in treatment-naive HIV-1 infected subjects. ASSERT: 48-week result.
Program and abstracts of the 12th European AIDS Conference; November 11-14, 2009; Cologne,
Germany. Abstract PS 10/1.
45. Ward D, Bush L, Thiry A, et al. Atazanavir/ritonavir (ATV/r) and efavirenz (EFV) NRTI-sparing
regimens in treatment-naive adults: BMS-121 Study. Program and abstracts of the 46th
Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006;
San Francisco, California. Abstract H-1057.
46. Mills A, Cahn P, Molina J-M, Nijs S, Vingerhoets J, Witek J. Etravirine (ETR; TMC125)
demonstrates durable efficacy in treatment-experienced patients in the DUET trials: pooled 96-
week results. Program and abstracts of the 5th International AIDS Society Conference on HIV
Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract
MOPEB036.
47. Eron J, Cooper D, Steigbigel R, et al. Sustained antiretroviral effect of raltegravir at week 156 in
the BENCHMRK studies and exploratory analysis of late outcomes based on early virologic
responses. Program and abstracts of the 17th Conference on Retroviruses and Opportunistic
Infections; February 16-19, 2010; San Francisco, California. Abstract 515.
48. Hardy WD, Gulick R, Mayer HB, et al. Efficacy and safety of maraviroc in treatment-experienced
(TE) patients infected with R5 HIV-1: 96-week combined analysis of the MOTIVATE 1 and 2
studies. Program and abstracts of the 9th International Congress on Drug Therapy in HIV
Infection; November 9-13, 2008; Glasgow, UK. Abstract O425.
49. Cahn P, Fourie J, Grinsztejn B, et al. Efficacy and safety at 48 weeks of once-daily vs twice-daily
DRV/r in treatment-experienced HIV-1+ patients with no DRV resistance associated mutations:
the ODIN Trial. Program and abstracts of the 17th Conference on Retroviruses and Opportunistic
Infections; February 16-19, 2010; San Francisco, California. Abstract 57.
50. Zajdenverg R, Podsadecki TJ, Badal-Faesen S, et al. Similar safety and efficacy of once- and
twice-daily lopinavir/ritonavir tablets in treatment-experienced HIV-1-infected subjects at 48
weeks. J Acquir Immune Defic Syndr. 2010;[Epub ahead of print].
53. Lalezari J, Sloan L, DeJesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation
integrase inhibitor (INI), in INI-naive HIV-1-infected patients. Program and abstracts of the 5th
International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-
22, 2009; Cape Town, South Africa. Abstract TUAB105.
56. Palleja S, Cohen C, Gathe J, et al. Safety and efficacy of TBR 652, a CCR5 antagonist, in HIV-1-
infected, ART-experienced, CCR5 antagonist-naive patients. Program and abstracts of the 17th
Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco,
California. Abstract 53.