Update On ART-2010

ANNUAL UPDATE
Update on Antiretroviral Therapy
PROGRAM DIRECTOR STAFF

Andrew R. Zolopa, MD Elaine P. Seeskin
Associate Professor of Medicine Senior Managing Editor, HIV
Director, Stanford Positive Care Program Clinical Care Options, LLC
Principal Investigator, Stanford AIDS Clinical Trials Unit
Stanford University School of Medicine Edward King, MA
Stanford, California Vice President, Editorial
Clinical Care Options, LLC
FACULTY
Joseph J. Eron, Jr., MD Anna Poppa
Professor of Medicine Editorial Contributor
University of North Carolina School of Medicine
Director, AIDS Clinical Trials Unit
Associate Director, Clinical and Translational Research
Center
University of North Carolina
Chapel Hill, North Carolina
Jointly sponsored by Annenberg Center for Health

Sciences at Eisenhower and Clinical Care Options, LLC
This activity is supported by educational grants from:
Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 1

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Andrew R. Zolopa, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb,
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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
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This activity is designed as a state-of-the-art curriculum for frontline physicians, registered nurses, and
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GOAL
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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
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Update on Antiretroviral Therapy
CONTENTS
When to Start Antiretroviral Therapy: Cohort Data ....................................................................... 5
When to Start Antiretroviral Therapy: Impact of ART on Sexual Transmission of HIV ................. 7
When to Start Antiretroviral Therapy: The START Trial ............................................................... 8
When to Start Antiretroviral Therapy: Comorbidity ...................................................................... 8
When to Start Antiretroviral Therapy: Conclusions ...................................................................... 9
Choice of Initial Antiretroviral Therapy .......................................................................................... 9
New Data on Efavirenz vs Boosted PI and vs Raltegravir .......................................................... 12
Choosing Among Preferred First-line Agents ............................................................................. 14
Should TDF/FTC Always Be the Preferred NRTI Backbone? ..................................................... 18
What to Start: Conclusions ......................................................................................................... 22
Update on Treatment-Experienced Patients ............................................................................... 22
Update on Investigational Antiretroviral Agents in Treatment-Naïve and

Treatment-Experienced Patients ................................................................................................ 23
Summary: Antiretroviral Therapy in 2010 ................................................................................... 24
Posttest ....................................................................................................................................... 25
References.................................................................................................................................. 26

When to Start Antiretroviral Therapy: Cohort Data
The optimal time to begin antiretroviral therapy remains a critical question for the HIV field,
and consensus about the appropriate CD4+ cell count at which to start therapy has evolved
in response to emerging data. Experts agree that therapy is indicated at CD4+ cell counts
< 350 cell/mm3 to prevent progression of HIV disease and the risk of opportunistic infection (OI).
However, at CD4+ cell counts > 350 cells/mm³, there is more diversity of clinical opinion over
the extent to which benefits might outweigh risks of initiating therapy, although most experts and
the US Department of Health and Human Services (DHHS) guidelines would argue for therapy
when CD4 cell counts are between 350 and 500 cells/mm3.
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.
Table 1. DHHS Guidelines for Initiation of Antiretroviral Therapy[1]
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
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.
Figure 1. NA-ACCORD: survival benefit of earlier ART by baseline factor.[2]
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.
Table 2. ART-CC: Risk of AIDS or Death by Baseline CD4+ cell Count[3]
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
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.
Figure 2. SMART: risk of immediate vs deferred HAART.[5]
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.
When to Start Antiretroviral Therapy: Impact of ART on Sexual

Transmission of HIV
Data from observational studies strongly suggest that successful antiretroviral therapy
diminishes risk of HIV transmission; a large randomized study (HPTN 052) is designed to
explore this issue further during a 5-year period in sub-Saharan Africa and is now fully
accrued.[11]
A nonrandomized study conducted in Rakai, Uganda, included 205 discordant couples.[12]

In this study, the HIV-infected partner was started on antiretroviral therapy if needed for clinical
reasons relating to HIV infection. During a relatively brief follow-up period of 1.1-1.5 years,
there were 34 transmission events among the couples in which the HIV-infected partner was
untreated (a transmission risk of 8.6 per 100 patient-years of follow-up) and no transmission
events in the couples in which the infected partner had started antiretroviral therapy. We should
realize that there is the potential for bias in observational studies such as this and therefore a
need for caution in interpreting their findings. Specifically, people who accept and adhere to
antiretroviral therapy may also be more likely to follow recommendations about safer sex
practices.
A larger study, which was conducted in Rwanda and Zambia, included almost 3000 discordant

couples who were followed for a median of 512 days.[13] There were 175 documented
transmission events, 171 of which occurred from an infected participant who was not receiving
antiretroviral therapy. There were only 4 transmission events from patients who were on therapy
(3.4 vs 0.7 transmissions/100 person-years; a 5-fold reduction in risk). When those who became
infected from these 4 treated patients were analyzed, it was found that transmission occurred
early in the study period. However, HIV-1 RNA data from around the time of transmission are
incomplete, and so it is unclear if high viral titers despite therapy were a contributing factor.
More recently, Donnell and colleagues[14] presented findings from a randomized trial of acyclovir
conducted in southern and eastern Africa. The study included 3381 HIV-serodiscordant couples
in which the HIV-infected partner was coinfected with herpes simplex virus-2 and was not on
antiretroviral therapy at enrollment. Antiretroviral therapy was initiated in those with clinical
indications (n = 349). The first subanalysis, reported at the 2010 Conference on Retroviruses
and Opportunistic Infections, compared HIV-1 transmission rates among the subset of couples
whose HIV-infected partner initiated antiretroviral therapy vs couples not initiating antiretroviral
therapy. Each HIV transmission event was confirmed virologically. Of 103 confirmed
transmission events, 102 occurred in couples where the infected partner was not receiving
antiretroviral therapy. This equates to a 92% reduction in HIV-1 transmission risk in treated vs
untreated couples (P = .004).
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].
When to Start Antiretroviral Therapy: The START Trial

The START trial is focused on answering the question of when to start therapy in a rigorous
fashion. This international trial will randomize treatment-naive patients with CD4+ cell counts
> 500 cells/mm3 to immediate vs deferred (until CD4+ cell counts fall to < 350 cells/mm³)
antiretroviral therapy and has begun enrolling volunteers in a feasibility study. Study endpoints
include AIDS or death, diabetes, liver failure, renal failure, cancer, or cardiovascular disease.
This type of multiple endpoint will assess the patient’s overall risk of disease progression and/or
development of complications.
When to Start Antiretroviral Therapy: Comorbidity

The DHHS treatment guidelines note a number of scenarios in which antiretroviral therapy
should be considered regardless of CD4+ cell count (Table 1).[1] These include history of an
AIDS-defining illness, specified OIs, pregnancy, HIV-associated nephropathy, and HBV
coinfection (where HBV therapy is indicated). Other conditions that might indicate a need to
start therapy include rapid decline in CD4+ cell count and high HIV-1 RNA levels, although
these are not associated with the same importance. With the antiretroviral regimens currently
available for first-line therapy, all of which have been proven effective in patients with HIV-1
RNA > 100,000 copies/mL,[18-20] high HIV-1 RNA is perhaps the least significant of these factors.
Pregnancy, HIV-associated nephropathy, and HBV coinfection have become almost absolute
indications for beginning antiretroviral therapy regardless of CD4+ cell count.
Table 1. DHHS Guidelines for Initiation of Antiretroviral Therapy[DHHS 2009]
When to Start Antiretroviral Therapy: Conclusions

In conclusion, observational data and the SMART subanalysis[5] are concordant on the need to
start antiretroviral therapy at CD4+ cell counts > 350 cells/mm3. Delaying therapy until the CD4+
cell count drops to < 350 cells/mm3 is no longer supported by the DHHS guidelines. There is 1
large observational study that strongly supports treatment initiation at CD4+ cell counts > 500
cells/mm3,[2] but others are more equivocal.[3]
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.
Choice of Initial Antiretroviral Therapy

The December 2009 update of the DHHS guidelines included several changes to the
categorization of first-line antiretroviral therapy.[1] There are now 4 options listed as preferred
regimens (Table 3). All of these include tenofovir/emtricitabine combined with either efavirenz,
atazanavir/ritonavir, darunavir/ritonavir, or raltegravir.

Table 3. DHHS Guidelines: Preferred First-Line Regimens[1]
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.
December 2009 DHHS Guidelines: Alternative Regimens

Alternative first-line regimens are shown in Table 4. The word “alternative” should be interpreted
with caution; it is important to recognize that in many respects, these remain satisfactory
regimens whose efficacy is supported by clinical trial data. The requirements and tolerances
of individual patients vary, and one of these “alternative” regimens may actually be the best
option for some patients. Some of these agents (eg, lopinavir/ritonavir, abacavir/lamivudine,
fosamprenavir/ritonavir, and saquinavir/ritonavir) are indeed included as preferred agents in
other guidelines.[22,23] Saquinavir will become available as a generic formulation later in 2010,
and it will be interesting to see whether this development has any impact on its use.
Table 4. DHHS Guidelines: Alternative First-line Regimens[1]
“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.

Table 5. DHHS Guidelines: Acceptable First-line Regimens (Those That May Be Selected
for Some Patients but Are Less Satisfactory Than Preferred or Alternative Regimens)[1]
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.

Table 7. DHHS Guidelines: First-line Regimens That Should Be Used With Caution[1]
New Data on Efavirenz vs Boosted PI and vs Raltegravir

The data supporting the designation of preferred regimens were provided by the ACTG 5202,
CASTLE, ARTEMIS, and STARTMRK trials .
ACTG 5202: Final Data

The final results from ACTG 5202 were reported at the 2010 Conference on Retroviruses and
Opportunistic Infections.[26] ACTG 5202 is a randomized trial of first-line antiretroviral therapy
and is the largest and most comprehensive head-to-head comparison of efavirenz with a
boosted PI, each coupled with commonly used NRTI backbones. Participants were randomized
to 1 of 4 arms:
• Tenofovir/emtricitabine with atazanavir/ritonavir
• Tenofovir/emtricitabine with efavirenz
• Abacavir/lamivudine with atazanavir/ritonavir
• Abacavir/lamivudine with efavirenz
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.

Figure 3. ACTG 5202: efficacy of atazanavir/ritonavir vs efavirenz at Week 96.[26]
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.
Analysis of the emergence of resistance at failure identified a number of differences between

the NNRTI and boosted PI strategies. Among patients with virologic failure, the frequencies of
any major mutation and of any NRTI mutation were significantly lower with use of atazanavir/
ritonavir than with efavirenz, regardless of NRTI allocation. No major PI resistance mutations
were observed in patients failing atazanavir/ritonavir, which is consistent with previous data on
first-line boosted PI therapy.[18,19,28]
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.
STARTMRK: Efavirenz vs Raltegravir

The integrase inhibitor raltegravir has been compared head to head with efavirenz, both paired
with tenofovir/emtricitabine, in STARTMRK, a large randomized, placebo-controlled study of
therapy-naive patients.[20] Extended results through 96 weeks of follow-up were reported at the
2009 Interscience Conference on Antimicrobial Agents and Chemotherapy. [30] The proportion of
patients with HIV-1 RNA < 50 copies/mL at Weeks 48 and 96 was comparable between arms
(Figure 4). Raltegravir was noninferior to efavirenz at both time points. Increase in CD4+ cell
count at Week 48 was greater with raltegravir (189 vs 163 cells/mm³ with efavirenz, P = .0184),
but overall change at Week 96 was similar between arms (240 vs 225 cells/mm³, respectively).
In addition, significantly greater changes in lipid levelswere observed with efavirenz vs
raltegravir.
Figure 4. STARTMRK: efficacy of raltegravir vs efavirenz at Weeks 48 and 96.[20,30]
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.
Choosing Among Preferred First-line Agents

Choosing Efavirenz
Efavirenz has a long track record in first-line therapy compared with other “third-agent”
antiretrovirals, and its safety and efficacy are well established. It is conveniently administered
with tenofovir/emtricitabine as a single-pill once-daily regimen. The long half-life of efavirenz can
be forgiving of certain types of nonadherence: Patients who miss a dose intermittently or skip
doses on a weekend are unlikely to experience virologic rebound as a result.[31]
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

raltegravir in constructing regimens for highly treatment–experienced patients and its efficacy is
proven in that setting[34]; some clinicians may, therefore, choose to save raltegravir for later lines
of therapy.
Choosing Boosted PIs

Boosted PIs have been widely used as first-line agents for many years. As described above,
data from ACTG 5202 demonstrated that atazanavir/ritonavir is as effective as efavirenz in the
treatment-naive setting and is associated with less resistance at failure.[26] Boosted PIs typically
have a high genetic barrier to resistance and, therefore, may be more forgiving of suboptimal
adherence (within limits). Treatment with boosted PIs may be a better option than efavirenz for
women who wish to become pregnant.
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.
Which Boosted PI?

The ARTEMIS study was a randomized comparison of once-daily darunavir/ritonavir vs
lopinavir/ritonavir, each given with tenofovir/emtricitabine, in treatment-naive patients.[18,36] At
Week 48, virologic response rates were similar across treatment arms, and darunavir/ritonavir
met criteria for noninferiority to lopinavir/ritonavir by time to loss of virologic response (TLOVR)
analysis. By Week 96, however, efficacy in the darunavir/ritonavir arm was superior to that seen
with lopinavir/ritonavir (Figure 5). There were similar gains in CD4+ cell counts across treatment
groups at Week 96 (+171 cells/mm³ with darunavir/ritonavir vs +188 cells/mm³ with lopinavir/ ).
In summary, data from ARTEMIS indicate that first-line therapy with darunavir/ritonavir is at
least as effective as lopinavir/ritonavir, and offers advantages in terms of tolerability.
Figure 5. ARTEMIS: efficacy of darunavir/ritonavir vs lopinavir/ritonavir at Weeks 48 and

96.[18,36]
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
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.
Figure 6. CASTLE: efficacy of atazanavir/ritonavir vs lopinavir/ritonavir at Weeks 48 and

96.[19,37]
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.
Figure 7. M05-730: efficacy of once-daily vs twice-daily lopinavir/ritonavir at Week 48.[38]
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.

A recent analysis from the EuroSIDA study explored the relationship between cumulative
exposure to antiretroviral therapy and risk of chronic kidney disease (CKD).[35] The analysis
included 6843 HIV-infected patients with ≥ 3 serum creatinine measures and corresponding
body weight measures, providing 21,482 patient-years of follow-up. Cumulative exposure to
tenofovir, atazanavir, lopinavir/ritonavir, or indinavir was each associated with increased risk of
CKD. Risk of CKD in patients who discontinued tenofovir remained elevated for 1 year, whereas
the risk in patients stopping atazanavir or lopinavir/ritonavir returned to a level similar to that
seen in patients who were never exposed to these drugs. Figure 8 shows the adjusted
incidence rate ratio, or the risk of decreased renal function over time, for each agent. The
increased rate ratio was small, between 1.1 and 1.2 depending on the method of calculation.
Whereas a link between indinavir and decreased renal function could be anticipated, the
association with atazanavir was unexpected. The investigators tried to censor patients who
were also receiving tenofovir, although most people who received boosted atazanavir also
received tenofovir.
Figure 8. EuroSIDA: cumulative antiretroviral exposure and risk of CKD.[35]
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.

Figure 9. D:A:D: cumulative PI exposure and risk of MI.[39,40]
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.
To summarize, the boosted PI options of atazanavir/ritonavir and darunavir/ritonavir (each

with tenofovir/emtricitabine) are preferred first-line options according to the DHHS guidelines,
whereas lopinavir/ritonavir, fosamprenavir/ritonavir, and saquinavir/ritonavir are designated in
these guidelines as components of alternative regimens (in combination with specified NRTI
backbones).[1] At present, there are no data from a large, head-to-head comparison of
atazanavir/ritonavir and darunavir/ritonavir, although the ACTG is undertaking such a study.
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.
Should TDF/FTC Always Be the Preferred NRTI Backbone?

As described previously, the 2009 DHHS guidelines designated 4 preferred regimens, all of
which include tenofovir/emtricitabine as the NRTI backbone. However, the guidelines also make
clear that for some patients, one of the alternative regimens may be a better choice than a
preferred regimen. The next patient case vignette explores some of these issues.
The efficacy of tenofovir/emtricitabine was documented in the GS 934 study in which this
combination was proven superior to zidovudine/lamivudine at Week 48. Tolerability of
tenofovir/emtricitabine was also favorable compared with zidovudine/lamivudine.[42]
Tenofovir/emtricitabine was the NRTI backbone used in several recent large-scale studies
comparing third agents. Recent data exploring the efficacy and tolerability of this NRTI
backbone were obtained from ACTG 5202, described previously in this module. To recap,
ACTG 5202 was a large, randomized comparison of 4 antiretroviral regimens given to therapy-
naive patients: efavirenz with tenofovir/emtricitabine, efavirenz with abacavir/lamivudine, or
atazanavir/ritonavir with either NRTI backbone.[27] The study was designed to make pairwise
comparisons between efavirenz and atazanavir/ritonavir and between the 2 NRTI backbones.
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.
Figure 10. ACTG 5202: efficacy of abacavir/lamivudine vs tenofovir/emtricitabine in

patients with baseline HIV-1 RNA < 100,000 copies/mL at Week 96.[26]

In summary, in the final analysis of ACTG 5202, the inferior activity of abacavir/lamivudine in
patients with high baseline HIV-1 RNA was observed in both the efavirenz and
atazanavir/ritonavir arms. In addition, despite differences in tolerability, virologic efficacy was
similar between abacavir/lamivudine and tenofovir/emtricitabine in patients with lower HIV-1
RNA (< 100,000 copies/mL) at screening.
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.

Figure 8. EuroSIDA: cumulative antiretroviral exposure and risk of CKD.[35]
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]
In summary, the DHHS guidelines recommend tenofovir/emtricitabine in preference to

abacavir/lamivudine for first-line therapy.[1] However, for patients with kidney disease, or those
with a high risk for osteoporosis, who are HLA-B*5701-negative and have HIV-1 RNA < 100,000
copies/mL, abacavir/lamivudine remains an appropriate choice.
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.

What to Start: Conclusions
The December 2009 revision to the DHHS guidelines contained a number of changes relating to
preferred and alternative options for first-line antiretroviral therapy.[1] Tenofovir/emtricitabine is
the preferred NRTI backbone for patients without kidney disease. Recent data on the efficacy
and safety of abacavir warrant consideration, particularly the observation of comparable efficacy
of abacavir/lamivudine to tenofovir/emtricitabine in patients with lower HIV-1 RNA in ACTG
5202[26] and the Veterans Administration analysis questioning the association between abacavir
and MI risk.[43]
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.
Update on Treatment-Experienced Patients

The causes of antiretroviral treatment failure are well established. Nonadherence, inadequate
potency, suboptimal dosing, host genetics, poor absorption, pharmacokinetics, transmitted
resistance, and drug interactions can all contribute to insufficient drug levels in the patient. Viral
replication in the presence of drug leads to resistance, which in turn generates more resistance.
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

randomized to darunavir/ritonavir 800/100 mg once daily or 600/100 mg twice daily, each
combined with an OBR.[49] At 48 weeks, the efficacy of the once-daily regimen was noninferior
to the twice-daily regimen (Figure 12). Treatment was well tolerated in both arms, although lipid
abnormalities were significantly more frequent in the twice-daily arm.
Figure 12. ODIN: once-daily vs twice-daily darunavir/ritonavir in treatment-experienced

patients at Week 48.[49]
Likewise, study M06-802 compared once-daily and twice-daily lopinavir/ritonavir in combination

with investigator-selected NRTIs in patients who were treatment-experienced but lopinavir
naive.[50] At Week 48, the efficacy of once-daily therapy was noninferior to that seen in the twice-
daily arm in the overall study population (Figure 13). In the small group of patients who had ≥ 3
PI resistance mutations at baseline, virologic response rates were lower in the once-daily arm.
Figure 13. M06-802: once-daily vs twice-daily lopinavir/ritonavir in treatment-experienced

patients.[50]
Update on Investigational Antiretroviral Agents in Treatment-Naive

and Treatment-Experienced Patients
Vicriviroc
VICTOR-E3 and -E4 are phase III trials that evaluated the safety and efficacy of vicriviroc plus
an OBR containing a boosted PI vs OBR alone in treatment-experienced HIV-infected patients
with CCR5-tropic virus. A recent pooled analysis of these trials found that addition of vicriviroc
was not associated with improved virologic efficacy.[51] Vicriviroc demonstrated improved
efficacy only among a subset of patients with ≤ 2 active drugs in their OBR.

Cobicistat
Cobicistat (previously known as GS-9350) is a CYP3A inhibitor that lacks antiviral activity
against HIV-1 but boosts concentrations of coadministered drugs that are metabolized by
CYP3A, potentially providing alternative to ritonavir boosting. An investigational single-tablet
formulation containing tenofovir, emtricitabine, cobicistat, and an investigational integrase
inhibitor, elvitegravir, has been evaluated in a randomized phase II study comparing its safety
and efficacy with that of coformulated efavirenz/tenofovir/emtricitabine in 71 therapy-naive
patients.[52] In this small study, response rates across the treatment arms appeared similar at
Week 24: 90% vs 83% of patients in the elvitegravir- vs efavirenz-containing arms, respectively,
had HIV-1 RNA < 50 copies/mL at Week 24 in an intent-to-treat missing-equals-failure analysis.
In a second randomized phase II study, cobicistat-boosted atazanavir plus emtricitabine/

tenofovir was compared with ritonavir-boosted atazanavir plus emtricitabine/tenofovir in 79
treatment-naive patients.[52] Response rates appeared comparable at Week 24: 84% vs 86%
of cobicistat/atazanavir vs atazanavir/ritonavir patients, respectively, had HIV-1 RNA
< 50 copies/mL at Week 24 in an intent-to-treat missing-equals-failure analysis.
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.
Summary: Antiretroviral Therapy in 2010

Current guidelines now recommend initiation of antiretroviral therapy at higher CD4+ cell counts
than previously. There are now several effective regimens that are recommended for treatment
initiation, the efficacy of each having been evaluated in large, randomized clinical trials.
Although options for first-line therapy have expanded, decision making for each individual
patient has perhaps become more complicated.
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.

To receive free CME credit for this article,
Please complete the following posttest online at:
clinicaloptions.com/CCOHIV2010
POSTTEST
Click on the appropriate response below.
1. According to the US Department of Health and Human Services (DHHS) treatment

guidelines published in December 2009, which of the following is a criterion for
initiating antiretroviral therapy in an HIV-infected patient?
A. CD4+ cell count > 500 cells/mm3

B. Pregnancy
C. Hepatitis C
D. HIV-1 RNA > 100,000 copies/mL
2. Which of the following is a preferred regimen for first-line antiretroviral therapy

according to the December 2009 DHHS guidelines?
A. Atazanavir plus tenofovir/emtricitabine

B. Darunavir/ritonavir plus abacavir/lamivudine
C. Efavirenz/tenofovir/emtricitabine
D. Lopinavir/ritonavir plus tenofovir/emtricitabine
3. Which of the following statements best describes the final results of ACTG 5202 at
Week 96 of follow-up?
A. Virologic efficacy of efavirenz was comparable to atazanavir/ritonavir only among

patients receiving abacavir/lamivudine
B. Virologic efficacy of efavirenz was comparable to atazanavir/ritonavir only among
patients receiving tenofovir/emtricitabine
C. Virologic efficacy of efavirenz was comparable to atazanavir/ritonavir regardless of
NRTI backbone
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
5. Which of the following agents is under investigation as a pharmacologic booster of

antiretroviral therapies?
A. Cobicistat
B. S/GSK1349572
C. TBR-652

REFERENCES
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
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atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naive HIV-1
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among antiretroviral-naive women in Africa: OCTANE Trial 2/ACTG A5208. Program and
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
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infection. N Engl J Med. 2008;358:2095-2106.
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(EFV)-based therapy in treatment-naive HIV+ patients (pts). Program and abstracts of the 49th
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Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, California.
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ANNUAL UPDATE

Update on Antiretroviral Therapy

PROGRAM DIRECTOR STAFF

Jointly sponsored by Annenberg Center for Health

This activity is supported by educational grants from:

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 1

Elaine P. Seeskin has no significant financial relationships to disclose.

Edward King, MA, has no significant financial relationships to disclose.

DISCLOSURE OF UNLABELED USE

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 2

PHYSICIAN CONTINUING MEDICAL EDUCATION

NURSING CONTINUING EDUCATION

INSTRUCTIONS FOR CREDIT

When to Start Antiretroviral Therapy: Cohort Data ....................................................................... 5

When to Start Antiretroviral Therapy: The START Trial ............................................................... 8

When to Start Antiretroviral Therapy: Comorbidity ...................................................................... 8

When to Start Antiretroviral Therapy: Conclusions ...................................................................... 9

Choice of Initial Antiretroviral Therapy .......................................................................................... 9

New Data on Efavirenz vs Boosted PI and vs Raltegravir .......................................................... 12

Choosing Among Preferred First-line Agents ............................................................................. 14

Should TDF/FTC Always Be the Preferred NRTI Backbone? ..................................................... 18

What to Start: Conclusions ......................................................................................................... 22

Update on Treatment-Experienced Patients ............................................................................... 22

Update on Investigational Antiretroviral Agents in Treatment-Naïve and

Summary: Antiretroviral Therapy in 2010 ................................................................................... 24

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 4

Table 1. DHHS Guidelines for Initiation of Antiretroviral Therapy[1]

Figure 1. NA-ACCORD: survival benefit of earlier ART by baseline factor.[2]

Table 2. ART-CC: Risk of AIDS or Death by Baseline CD4+ cell Count[3]

Figure 2. SMART: risk of immediate vs deferred HAART.[5]

When to Start Antiretroviral Therapy: Impact of ART on Sexual

A nonrandomized study conducted in Rakai, Uganda, included 205 discordant couples.[12]

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 7

When to Start Antiretroviral Therapy: The START Trial

When to Start Antiretroviral Therapy: Comorbidity

Table 1. DHHS Guidelines for Initiation of Antiretroviral Therapy[DHHS 2009]

When to Start Antiretroviral Therapy: Conclusions

Choice of Initial Antiretroviral Therapy

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 9

December 2009 DHHS Guidelines: Alternative Regimens

Table 4. DHHS Guidelines: Alternative First-line Regimens[1]

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 10

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 11

New Data on Efavirenz vs Boosted PI and vs Raltegravir

ACTG 5202: Final Data

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 12

Analysis of the emergence of resistance at failure identified a number of differences between

STARTMRK: Efavirenz vs Raltegravir

Choosing Among Preferred First-line Agents

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 14

Choosing Boosted PIs

Which Boosted PI?

Figure 5. ARTEMIS: efficacy of darunavir/ritonavir vs lopinavir/ritonavir at Weeks 48 and

Figure 6. CASTLE: efficacy of atazanavir/ritonavir vs lopinavir/ritonavir at Weeks 48 and

Figure 7. M05-730: efficacy of once-daily vs twice-daily lopinavir/ritonavir at Week 48.[38]

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 16

Figure 8. EuroSIDA: cumulative antiretroviral exposure and risk of CKD.[35]

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 17

To summarize, the boosted PI options of atazanavir/ritonavir and darunavir/ritonavir (each

Should TDF/FTC Always Be the Preferred NRTI Backbone?

Figure 10. ACTG 5202: efficacy of abacavir/lamivudine vs tenofovir/emtricitabine in

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 19

Copyright © 2010 Clinical Care Options, LLC. All rights reserved. 20