Antiretroviral Treatment for Adult HIV Infection in 2002

Updated Recommendations of the International AIDS Society-USA Panel

Author Information <http://jama.ama-assn.org/issues/v288n2/rfull/#aainfo>
Patrick G. Yeni, MD; Scott M. Hammer, MD; Charles C. J. Carpenter, MD; David
A. Cooper, MD, DSc; Margaret A. Fischl, MD; Jose M. Gatell, MD, PhD; Brian
G. Gazzard, MA, MD; Martin S. Hirsch, MD; Donna M. Jacobsen, BS; David A.
Katzenstein, MD; Julio S. G. Montaner, MD; Douglas D. Richman, MD; Michael
S. Saag, MD; Mauro Schechter, MD, PhD; Robert T. Schooley, MD; Melanie A.
Thompson, MD; Stefano Vella, MD; Paul A. Volberding, MD
Objective  New information warrants updated recommendations for the 4
central issues in antiretroviral therapy: when to start, what drugs to start
with, when to change, and what to change to. These updated recommendations
are intended to guide practicing physicians actively involved in human
immunodeficiency virus (HIV)– and acquired immunodeficiency syndrome
(AIDS)–related care.
Participants  In 1995, physicians with specific expertise in HIV-related
basic science and clinical research, antiretroviral therapy, and HIV patient
care were invited by the International AIDS Society-USA to serve on a
volunteer panel. In 1999, others were invited to broaden international
representation. The 17-member panel met regularly in closed meetings between
its last report in 2000 and April 2002 to review current data. The effort
was sponsored and funded by the International AIDS Society-USA, a
not-for-profit physician education organization.
Evidence and Consensus Process  The full panel was convened in late 2000 and
assigned 7 section committees. A section writer and 3 to 5 section committee
members (each panel member served on numerous sections) identified relevant
evidence and prepared draft recommendations. Basic science, clinical
research, and epidemiologic data from the published literature and abstracts
from recent (within 2 years) scientific conferences were considered by
strength of evidence. Extrapolations from basic science data and expert
opinion of the panel members were included as evidence. Draft sections were
combined and circulated to the entire panel and discussed in a series of
full-panel conference calls until consensus was reached. Final
recommendations represent full consensus agreement of the panel.
Conclusions  Because of increased awareness of the activity and toxicity of
current drugs, the threshold for initiation of therapy has shifted to a
later time in the course of HIV disease. However, the optimal time to
initiate therapy remains imprecisely defined. Availability of new drugs has
broadened options for therapy initiation and management of treatment
failure, which remains a difficult challenge.
JAMA. 2002;288:222-235
JST20002
Progress in antiretroviral therapy has resulted in achievements as well as
new challenges. 1 <http://jama.ama-assn.org/issues/v288n2/rfull/#r1>  The
partial restoration of CD4 and CD8 T cell number and function during
suppression of human immunodeficiency virus 1 (HIV-1) replication with
potent antiretroviral therapy has resulted in dramatic reductions in
morbidity, mortality, and health care utilization. 2-4
<http://jama.ama-assn.org/issues/v288n2/rfull/#r2>  However, the toxicity of
many current regimens, suboptimal activity and tolerability, and the
emergence of drug resistance all point to the need for treatment strategies
to address these challenges. These strategies include both new antiviral
drugs and approaches to enhance host cellular immune control of HIV
replication. This evolution in the field prompts the need for a reevaluation
of current treatment guidelines, particularly regarding when to initiate
therapy. The changing threshold for initiating therapy that has been
emerging 1 <http://jama.ama-assn.org/issues/v288n2/rfull/#r1> , 5
<http://jama.ama-assn.org/issues/v288n2/rfull/#r5>  is the result of
recognition of limitations of currently available agents and is not
necessarily a reflection of a major change in our understanding of disease
pathogenesis, nor an indication that more aggressive treatment approaches
should not be pursued. This is a constantly evolving field and HIV/AIDS
(acquired immunodeficiency syndrome) practitioners will need to keep pace
with current knowledge.



METHODS



The International AIDS Society-USA volunteer antiretroviral panel was
convened in 1995 to develop treatment recommendations. The panel's goal was
to develop current recommendations for use of antiretroviral therapy in the
developed world. The panel included physicians with expertise in
HIV-associated basic science, clinical research, and patient care. It was
expanded in 1999 to broaden its international representation.
The full panel convened in late 2000 to review new data affecting its
previous recommendations 1
<http://jama.ama-assn.org/issues/v288n2/rfull/#r1>  and assign committees
for 7 sections: rationale, when to initiate therapy, initial regimens,
treatment interruptions, monitoring therapy, changing therapy, and adjuvant
therapy. A section writer and 3 to 5 section contributors were appointed
(each panel member served on numerous sections) for each section. Each
section committee met to identify relevant data and prepare draft
recommendations for the sections, which were reviewed and discussed by the
full panel. Data from the published literature and abstracts from recent
scientific conferences were considered. Evidence strengths were considered
according to parameters such as type of study (eg, randomized prospective
trial, cohort data, case reports), number of subjects, duration of
follow-up, and publication source. For example, published prospective
studies with more than 20 patients and more than 48 weeks of follow-up were
given high priority. Evidence from abstracts from scientific meetings that
had not been published within 2 years of presentation were generally
excluded. Extrapolations from basic science data and expert opinion of panel
members were included as evidence. Draft sections with supporting data and
preliminary recommendations were combined and circulated to the entire panel
and discussed in a series of full-panel conference calls. The panel chair
and vice-chair obtained group consensus on recommendations and they or
section writers revised the report as necessary after each panel meeting or
conference call. Recommendations herein are made by full-panel consensus
agreement.



WHEN TO INITIATE ANTIRETROVIRAL THERAPY



Rationale for Treatment in Established HIV Infection

Highly active antiretroviral therapy (HAART) is usually effective in rapidly
reducing plasma HIV RNA levels (ie, viral load) in antiretroviral-naive
patients, accompanied by a gradual increase in CD4 cell counts, sometimes to
normal levels. 6 <http://jama.ama-assn.org/issues/v288n2/rfull/#r6>  The
number of memory CD4 cells increases early after effective treatment, as a
result of redistribution from lymphoid tissues to the circulation. 7
<http://jama.ama-assn.org/issues/v288n2/rfull/#r7>  Naive CD4 cells, which
are essential for responses to new antigenic challenges, are restored
gradually with ongoing effective suppression of viral replication. 8
<http://jama.ama-assn.org/issues/v288n2/rfull/#r8>  For many
antiretroviral-naive patients, CD4 cell counts increase to levels at which
the patients are no longer generally susceptible to serious opportunistic
infections. 3 <http://jama.ama-assn.org/issues/v288n2/rfull/#r3>  Because
currently available antiretroviral regimens will not eradicate HIV, 9
<http://jama.ama-assn.org/issues/v288n2/rfull/#r9> , 10
<http://jama.ama-assn.org/issues/v288n2/rfull/#r10>  the goal of therapy is
to durably inhibit viral replication so that the patient can attain and
maintain an effective immune response to most potential microbial pathogens.
11 <http://jama.ama-assn.org/issues/v288n2/rfull/#r11>
Considerations in Initiating Therapy in Asymptomatic Infection

Recent cohort data have provided support for the CD4 cell count being the
major determinant of initiating therapy. 12
<http://jama.ama-assn.org/issues/v288n2/rfull/#r12> , 13
<http://jama.ama-assn.org/issues/v288n2/rfull/#r13>  These studies have
shown an increased mortality when antiretroviral therapy is initiated in
patients with CD4 cell counts below 200/µL compared with initiation at
higher levels. It is clear, therefore, that antiretroviral therapy should
not be delayed until the patient is at high risk for serious opportunistic
diseases (ie, at a CD4 cell count 200/µL). 12-15
<http://jama.ama-assn.org/issues/v288n2/rfull/#r12>
The CD4 cell level above 200/µL at which to initiate therapy remains
unclear. Some serious illnesses, especially active tuberculosis and
bacteremic pneumonia, may occur when the CD4 cell count is above 200/µL.
16-20 <http://jama.ama-assn.org/issues/v288n2/rfull/#r16>  In addition, the
immune reconstitution syndrome and its associated morbidity may be observed
in some patients starting antiretroviral therapy at low CD4 cell counts. 21
<http://jama.ama-assn.org/issues/v288n2/rfull/#r21>  Furthermore, some
laboratory markers show lower rates of favorable responses when
antiretroviral therapy is delayed until the 200 cells/µL threshold is
reached. These include less rapid increase in CD4 cell count and potentially
decreased ability to reduce viral load to below the limit of detection. 12
<http://jama.ama-assn.org/issues/v288n2/rfull/#r12> , 15
<http://jama.ama-assn.org/issues/v288n2/rfull/#r15> , 22-25
<http://jama.ama-assn.org/issues/v288n2/rfull/#r22>  Finally, the genetic
complexity of HIV in persons increases with time, and this may facilitate
escape from host immune defenses. 26
<http://jama.ama-assn.org/issues/v288n2/rfull/#r26>  These considerations
support use of a CD4 cell count threshold higher than 200/µL. However, there
are no definitive data with clinical end points that define at which level
above 200 CD4 cells/µL antiretroviral therapy is best started. The available
data from cohort studies, with one exception, 27
<http://jama.ama-assn.org/issues/v288n2/rfull/#r27>  have not been able to
define a CD4 stratum above 200 cells/µL at which patients benefit from
initiation of therapy. 12
<http://jama.ama-assn.org/issues/v288n2/rfull/#r12> , 13
<http://jama.ama-assn.org/issues/v288n2/rfull/#r13>  Inherent biases that
occur with cohort studies, which are observational and not randomized, and
relatively limited follow-up in the studies reported to date (2 to 3 years),
mean that conclusions from the analyses must be interpreted with caution.
However, these are the best data available, there is general consistency
across most studies, and it is questionable whether a randomized trial to
study the issue of when to start therapy will ever be feasible.
In persons with CD4 cell counts above 350/µL, risk of 3-year clinical
progression is low 28 <http://jama.ama-assn.org/issues/v288n2/rfull/#r28>
and additional concerns about impact of antiretroviral regimens on quality
of life, risk of serious adverse drug effects, and limitations on future
treatment options generally outweigh the benefits of durable viral
suppression. However, it should be noted that roughly a third or more of
persons have no treatment-limiting adverse effects for at least 3 years
after initiation of treatment, leaving an option to physicians and patients
to initiate therapy at higher CD4 cell counts. 29
<http://jama.ama-assn.org/issues/v288n2/rfull/#r29>  For persons who have
already initiated therapy at higher CD4 cell count thresholds (eg, 400, 450,
or 500 cells/µL) and have had durable HIV RNA suppression and no adverse
effects over periods of months to years, it is not clear whether it is safe
to discontinue therapy. Physicians and patients must thoroughly weigh risks
and benefits of starting antiretroviral therapy for CD4 cell counts in the
200/µL to 350/µL range and above, and make individualized informed decisions
( Table 1
<http://jama.ama-assn.org/issues/v288n2/fig_tab/jst20002_t1.html> ). 5
<http://jama.ama-assn.org/issues/v288n2/rfull/#r5> , 30
<http://jama.ama-assn.org/issues/v288n2/rfull/#r30> , 31
<http://jama.ama-assn.org/issues/v288n2/rfull/#r31>  The strength of the
recommendation should depend on the immunologic status, as well as the
patient's understanding of and commitment to an often complex regimen.
Although available data supporting the use of a specific viral load
threshold as an independent indicator for initiating therapy are scarce, 31
<http://jama.ama-assn.org/issues/v288n2/rfull/#r31>  patients with CD4 cell
counts at any level who have a viral load above 50 000 to 100 000 copies/mL
31 <http://jama.ama-assn.org/issues/v288n2/rfull/#r31>  should be closely
monitored, because the CD4 cell count decreases more rapidly in untreated
persons with higher viral loads. 28
<http://jama.ama-assn.org/issues/v288n2/rfull/#r28> , 31
<http://jama.ama-assn.org/issues/v288n2/rfull/#r31>  Initiation of therapy
may be considered in individuals with a viral load above 50 000 to 100 000
copies/mL, 31 <http://jama.ama-assn.org/issues/v288n2/rfull/#r31>  or a
rapidly declining CD4 cell count even if it is above 350/µL. Some
observational studies indicate that viral load early in the course of HIV
disease is lower in women than in men, but there are no documented sex
differences in the relation of CD4 cell count to risk of opportunistic
infections. 32 <http://jama.ama-assn.org/issues/v288n2/rfull/#r32> , 33
<http://jama.ama-assn.org/issues/v288n2/rfull/#r33>  Thus, treatment
recommendations are the same for women as for men.
Therapy continues to be recommended in all patients with symptomatic
established HIV infection. Immediate treatment, but not prophylaxis, of a
serious opportunistic infection in patients with advanced HIV disease may
take precedence over starting antiretroviral therapy. If potential for
adverse drug-drug interactions exists (eg, protease inhibitors [PIs] and
rifampin in treatment of Mycobacterium tuberculosis infection), it is wise
to choose drugs with minimal or no interactions, or to delay antiretroviral
treatment for a few weeks, until drugs causing the interactions can be
discontinued. Clinicians should be aware of risk of immune reconstitution
illness associated with initial increase in CD4 cell counts in patients
starting antiretroviral therapy when there is a confirmed or suspected
opportunistic infection. 21
<http://jama.ama-assn.org/issues/v288n2/rfull/#r21>



ESTABLISHED INFECTION: INITIAL THERAPY



Choice of Initial Therapy

No drug combination can be defined as the optimal initial regimen in all
patients. Therapy should thus be individualized using a number of criteria,
including efficacy and durability of antiretroviral activity, tolerability
and adverse effects ( Table 2
<http://jama.ama-assn.org/issues/v288n2/fig_tab/jst20002_t2.html> ), 34-84
<http://jama.ama-assn.org/issues/v288n2/rfull/#r34>  convenience of the
regimen, drug-drug interactions, and potential salvageability of initial
regimen.
The differences in "clinical activity" that are observed in clinical trials
between regimens that contain 2 nucleoside reverse transcriptase inhibitors
(NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI)
or a single (or boosted) PI are often too small to differentiate relative
efficacy. The durability of the first regimen is primarily related to issues
of adherence, tolerability, and convenience, and baseline virological or
immunologic status. Drugs with long half-lives and those for which regular
timing of food or hydration is less crucial are likely to have an advantage.
Daily adverse effects, even if minor, may reduce adherence. Finally,
concerns for long-term toxic effects may be an important cause of patient
reluctance to take certain medications. Regimens that involve drugs taken
twice a day are likely to be associated with better adherence than those
involving drugs taken 3 or more times a day. 85
<http://jama.ama-assn.org/issues/v288n2/rfull/#r85>  Once-daily regimens may
further facilitate adherence and permit directly observed therapy in
individual circumstances.
Many patients will ultimately experience at least one treatment failure.
Because the initial regimen affects choices available for subsequent
regimens, consideration should be given to such issues as overlapping
toxicities (eg, with PIs in the case of lipid abnormalities or with some
NRTIs in the case of neuropathy) and intraclass cross-resistance (see "First
or Second Failure" section). There are currently no data on preferred
sequencing of NRTIs. Stavudine and didanosine in combination should be
avoided or used with caution in pregnant women because of increased risks of
lactic acidosis. 86 <http://jama.ama-assn.org/issues/v288n2/rfull/#r86>
There are generally 3 types of initial combination regimens that should be
considered: (1) a PI (with or without low-dose ritonavir) with 2 NRTIs; (2)
an NNRTI with 2 NRTIs; or (3) 3 NRTIs. Other regimen combinations include a
PI (with or without low-dose ritonavir) with an NNRTI plus 1 or 2 NRTIs,
which should be reserved for special circumstances; and a PI (with low-dose
ritonavir) with an NNRTI (see below).
Protease Inhibitor–Based Regimens
Data from randomized controlled trials with clinical outcomes attest to the
effectiveness of PIs in combination with NRTIs. 87
<http://jama.ama-assn.org/issues/v288n2/rfull/#r87>  However, some regimens
containing single PIs are often difficult to adhere to because of
3-times-a-day regimens or food constraints (eg, indinavir), or large pill
burdens (eg, nelfinavir and amprenavir). Nelfinavir can be taken twice a
day, but it is absorbed best when administered with a fatty meal. 88
<http://jama.ama-assn.org/issues/v288n2/rfull/#r88>
Data on benefits of PIs, in combination with low-dose ritonavir to provide a
pharmacokinetic boosting effect, are appearing in studies in treatment-naive
patients. 89 <http://jama.ama-assn.org/issues/v288n2/rfull/#r89>  Low-dose
ritonavir can pharmacologically enhance (or boost) saquinavir, indinavir,
amprenavir, or lopinavir (the latter available only in a coformulated
capsule). 90 <http://jama.ama-assn.org/issues/v288n2/rfull/#r90>  Ritonavir
inhibits enzymes of the cytochrome P450 system; it may act early on
absorption and first-pass metabolism, increasing peak plasma concentrations
with a co-administered PI (eg, with indinavir or amprenavir); or it may
inhibit subsequent metabolism and extend the half-life of the second PI with
an increase in trough level of drug (eg, with lopinavir or saquinavir). Such
considerations may be important for drugs for which toxicity is related to
peak concentrations and risks of virological failure to low trough levels.
Advantages of such regimens include once- or twice-daily dosing and
minimization of specific food requirements. Nelfinavir is not sufficiently
enhanced by low-dose ritonavir to justify this combination. 91
<http://jama.ama-assn.org/issues/v288n2/rfull/#r91>
There are no comparative studies to determine which boosted PI regimen has
the highest level of activity. Also, optimal dose of the PI or ritonavir in
such a combination is often not well defined. Higher doses of ritonavir (eg,
>100 mg twice a day) in the combination may result in a higher incidence of
gastrointestinal adverse effects and lipid abnormalities. 92
<http://jama.ama-assn.org/issues/v288n2/rfull/#r92>  Little is known about
optimal alternative regimens when initial boosted PIs fail.
Specific Ritonavir-Enhanced Protease Inhibitor–Containing Regimens
Lopinavir/ritonavir is an important new addition to the list of approved
agents. In one study (48-week analysis), lopinavir/ritonavir plus 2 NRTIs
were superior to nelfinavir plus 2 NRTIs in reducing viral load to below 50
copies/mL. 93 <http://jama.ama-assn.org/issues/v288n2/rfull/#r93>  Grade 3
or 4 elevations in triglyceride levels are significantly more common with
lopinavir/ritonavir than with nelfinavir, and high frequencies of grades 3
and 4 cholesterol and triglyceride abnormalities (up to 30%) have been seen
when lopinavir/ritonavir is combined with NRTIs and NNRTIs in salvage
regimens. 94 <http://jama.ama-assn.org/issues/v288n2/rfull/#r94>  There have
been few virological failures of lopinavir/ritonavir-containing regimens in
studies of treatment-naive patients. Thus, there are few data on the
patterns of resistance associated with this drug when used in an initial
regimen or to guide recommendations on the preferred alternative regimens
after lopinavir/ritonavir has failed. Early failures are associated
predominantly with the lamivudine-associated M184V mutation when this agent
is part of a lopinavir/ritonavir–containing regimen, 95
<http://jama.ama-assn.org/issues/v288n2/rfull/#r95>  an observation similar
to what has been reported with indinavir and amprenavir. 96-98
<http://jama.ama-assn.org/issues/v288n2/rfull/#r96>
Indinavir/ritonavir (800 mg/100 mg, respectively, twice a day) may be widely
used, but it is unclear whether this is the optimal dose combination, or if,
for example, 800 mg/200 mg or 400 mg/400 mg is preferable. Incidence of
renal adverse effects including stones, flank pain, and hematuria was higher
(up to 20% at 24 weeks) in patients who had been treated previously with
indinavir 800 mg 3 times a day and were then switched to
indinavir/ritonavir. 99 <http://jama.ama-assn.org/issues/v288n2/rfull/#r99>
Saquinavir 800 or 1000 mg plus ritonavir 100 mg twice a day may be often
used because of the adverse effects that are associated with a higher dose
of ritonavir (200 mg twice a day), but there is little published comparative
experience with this regimen. The pill burden is high if the soft gel
saquinavir formulation is used. Ritonavir/saquinavir 400 mg/400 mg, twice a
day, has also been used 100
<http://jama.ama-assn.org/issues/v288n2/rfull/#r100> ; in this regimen,
ritonavir provides antiretroviral activity as well as pharmacoenhancement.
Whether this increases the likelihood of reducing viral loads to below the
limit of detection remains unclear. The 24-week, intent-to-treat analysis of
a once-daily regimen containing saquinavir (1600 mg, soft gel formulation)
plus ritonavir (100 mg) showed that it was virologically inferior to an
efavirenz-containing regimen, but the saquinavir/ritonavir group had a
higher rate of gastrointestinal adverse effects. 101
<http://jama.ama-assn.org/issues/v288n2/rfull/#r101>
Combining amprenavir with ritonavir increases trough levels of amprenavir
102 <http://jama.ama-assn.org/issues/v288n2/rfull/#r102>  and reduces
amprenavir pill burden from 16 to 8 pills a day. Given the tolerance profile
and high pill burden of amprenavir, and effectiveness of
amprenavir-containing combinations after prior PI regimens have failed, use
of this combination may be preferred in the treatment-experienced setting.
Nonnucleoside Reverse Transcriptase Inhibitor–Based Regimens
A triple-drug regimen that includes an NNRTI and 2 NRTIs is one of the
preferred combinations for initial therapy of established infection, given
the effectiveness and the PI-sparing aspect. Three NNRTIs are currently
approved in the United States: nevirapine, delavirdine, and efavirenz. No
major trials have yet directly compared these drugs. Delavirdine is less
often used because of its high pill burden and 3-times-a-day dosing, but it
is the only currently available NNRTI that inhibits cytochrome P450,
allowing a reduction in the dose of associated PIs. 103
<http://jama.ama-assn.org/issues/v288n2/rfull/#r103> , 104
<http://jama.ama-assn.org/issues/v288n2/rfull/#r104>
Nevirapine has been studied in the ATLANTIC trial, which compared an
NNRTI-based regimen with a PI-based regimen and a triple NRTI-based regimen.
105 <http://jama.ama-assn.org/issues/v288n2/rfull/#r105>  Although not
powered to provide definitive conclusions, the results suggested that
activity of nevirapine in a multidrug regimen was similar to that of
indinavir. Comparability in viral suppression at 36 weeks between
nevirapine-containing and nelfinavir-containing regimens (each with 2 NRTIs)
has been reported. 106 <http://jama.ama-assn.org/issues/v288n2/rfull/#r106>
Nevirapine has been associated with severe rashes more often than has
efavirenz. 107 <http://jama.ama-assn.org/issues/v288n2/rfull/#r107> , 108
<http://jama.ama-assn.org/issues/v288n2/rfull/#r108>  Use of corticosteroids
has not had a beneficial effect. 109
<http://jama.ama-assn.org/issues/v288n2/rfull/#r109>  Hepatotoxicity,
including elevation of transaminases, jaundice, and rare cases of severe
clinical hepatitis, occurs with nevirapine more often than with efavirenz.
107 <http://jama.ama-assn.org/issues/v288n2/rfull/#r107> , 108
<http://jama.ama-assn.org/issues/v288n2/rfull/#r108>  Recently, nevirapine
has been shown to be associated with favorable changes in lipid profiles,
which include decreases in cholesterol and triglyceride levels and increases
in HDL levels in patients who discontinued PIs. 110
<http://jama.ama-assn.org/issues/v288n2/rfull/#r110>
In an open-label study, zidovudine/lamivudine/efavirenz produced a marker
response equivalent or superior to that seen with a similar NRTI backbone
given with indinavir for up to 96 weeks of follow-up. 111
<http://jama.ama-assn.org/issues/v288n2/rfull/#r111>  Efavirenz is commonly
prescribed because of its once-daily dosing and safety profile. 108
<http://jama.ama-assn.org/issues/v288n2/rfull/#r108>  Because of
teratogenicity in animals, 108
<http://jama.ama-assn.org/issues/v288n2/rfull/#r108>  efavirenz should be
avoided in women who are (or intend to become) pregnant. Hyperexcitability,
vivid dreams, nightmares, and hallucinations are associated with efavirenz.
108 <http://jama.ama-assn.org/issues/v288n2/rfull/#r108>  Mood disturbances
and personality changes may be persistent in some patients. 108
<http://jama.ama-assn.org/issues/v288n2/rfull/#r108>
Triple-NRTI Regimens
Triple-NRTI regimens have become a viable alternative as initial therapy.
The largest body of evidence at present is for regimens that contain
abacavir. An abacavir/zidovudine/lamivudine combination produced a decrease
in viral load (to <400 copies/mL) at 48 weeks equivalent to that produced by
zidovudine/lamivudine/indinavir in a placebo-controlled trial. 112
<http://jama.ama-assn.org/issues/v288n2/rfull/#r112> , 113
<http://jama.ama-assn.org/issues/v288n2/rfull/#r113>  However, more complete
viral suppression (assessed with an assay with a limit of detection of 50
copies/mL) was less likely with the 3-NRTI regimen in those patients with a
pretreatment viral load above 100 000 copies/mL. 112
<http://jama.ama-assn.org/issues/v288n2/rfull/#r112> , 113
<http://jama.ama-assn.org/issues/v288n2/rfull/#r113>  Thus, these regimens
are not routinely recommended as initial treatment for patients with high
viral loads (eg, >100 000 copies/mL) or with low CD4 cell counts until more
data are available. The twice-daily regimen, low pill burden, few daily
toxic effects, and lack of undesirable pharmacokinetic interactions are
potential advantages of zidovudine/lamivudine/abacavir regimens.
Availability of these 3 drugs in a fixed-dose combination is also likely to
facilitate adherence. Severe hypersensitivity reactions to abacavir occur in
about 3% of patients, 114
<http://jama.ama-assn.org/issues/v288n2/rfull/#r114> , 115
<http://jama.ama-assn.org/issues/v288n2/rfull/#r115>  and is an important
consideration.
A virus mutation at codon 184 substantially reduces sensitivity to
lamivudine and somewhat (2- to 4-fold) to abacavir. This mutation is often
detected during virological failure with abacavir-containing regimens. 116
<http://jama.ama-assn.org/issues/v288n2/rfull/#r116> , 117
<http://jama.ama-assn.org/issues/v288n2/rfull/#r117>  In most such patients,
117 <http://jama.ama-assn.org/issues/v288n2/rfull/#r117>  viral mutations
associated with resistance to zidovudine are not detected, and in theory
other NRTIs would be effective in subsequent regimens. However, continuing
treatment with this 3-drug combination, despite the presence of detectable
HIV, may be accompanied by development of other NRTI-associated mutations.
Protease Inhibitor/NNRTI–Based Regimens, With or Without NRTI
The combination of a PI with an NNRTI and an NRTI (ie, drugs from all 3
classes), is not routinely recommended because the risks of multiclass drug
resistance (thus limiting future treatment options) and toxicity may be
high. However, in the setting of a patient with advanced disease and a high
near-term mortality risk who has an opportunistic infection for which no
effective therapy exists (eg, cryptosporidiosis), a 3-class regimen may be
considered to assure a high degree of activity and to try to achieve rapid
immunologic restoration. Simplification of such a regimen can be considered
subsequently. The second setting in which to consider a 3-class regimen is
when the patient is infected with a drug-resistant strain whose in vitro
resistance testing profile suggests that such a regimen may be effective.
Protease inhibitor (enhanced with low-dose ritonavir) and NNRTI regimens
without an NRTI component may be of interest for certain settings; however,
insufficient data exist on when to recommend such NRTI-sparing regimens as
initial therapy.



TREATMENT INTERRUPTIONS



Structured, supervised, or strategic treatment interruptions (STIs) have
been considered in very different situations: following early therapy of
acute HIV syndrome, 118 <http://jama.ama-assn.org/issues/v288n2/rfull/#r118>
following suppressive antiretroviral therapy of established infection,
119-121 <http://jama.ama-assn.org/issues/v288n2/rfull/#r119>  and for
facilitating salvage after therapy has failed. 122
<http://jama.ama-assn.org/issues/v288n2/rfull/#r122>  The rationales for
interruption of therapy in these 3 settings are different, and the subject
has been extensively reviewed elsewhere. 123
<http://jama.ama-assn.org/issues/v288n2/rfull/#r123> , 124
<http://jama.ama-assn.org/issues/v288n2/rfull/#r124>  Given the paucity of
available controlled studies and the potential risks, STIs cannot be
recommended for current clinical practice, and should preferably be
attempted in the context of cohort studies or clinical trials.



MONITORING ANTIRETROVIRAL THERAPY



Adherence: Assessment and Reinforcement

Incomplete adherence to one or more prescribed medications is a key cause of
virological failure of antiretroviral regimens. 125
<http://jama.ama-assn.org/issues/v288n2/rfull/#r125>  A recent study found a
doubling of the viral load for every 10% decrement from complete adherence.
126 <http://jama.ama-assn.org/issues/v288n2/rfull/#r126>  In another study,
the viral load response was greater in inmates in a prison where treatment
was directly observed than in patients treated with comparable regimens in
an outpatient research clinic (85%-100% vs 50%-80%). 127
<http://jama.ama-assn.org/issues/v288n2/rfull/#r127> , 128
<http://jama.ama-assn.org/issues/v288n2/rfull/#r128>  Factors that limit
full adherence are complex and incompletely defined but may include high
pill number and large pill size, medication schedule and dietary
restrictions, toxic adverse effects, and ineffective education and support
of patients regarding adherence. Progress in developing new drug
formulations (eg, didanosine without the buffer) and fixed-dose combinations
(eg, lamivudine/zidovudine/abacavir, lamivudine/zidovudine, and
lopinavir/ritonavir) that can simplify regimens is encouraging.
Ways of improving adherence are being investigated. 129
<http://jama.ama-assn.org/issues/v288n2/rfull/#r129>  Most remain largely
empiric and not evidence-based. 129
<http://jama.ama-assn.org/issues/v288n2/rfull/#r129>  Effective
communication between patient and provider is essential both before and
after treatment has begun. Some health care centers may use nonphysicians
(pharmacists, nurses, peer educators, and others) to effectively assess and
support adherence, but the physician should also be actively involved. Once
treatment has begun, weekly contact may be appropriate until the patient has
established a consistent daily routine of medication use and has passed the
time that any short-term adverse effects would be expected. Reinforcing the
need for adherence at every health care provider contact is important.
CD4 Cell Counts and Viral Load

In the asymptomatic individual, antiretroviral activity is evaluated by
assessing changes in CD4 cell count and viral load. A decrease in viral load
(indicating a reduction in virus replication) and increase in CD4 cell count
(indicating an improvement in immune competence) in response to
antiretroviral drugs are both associated with clinical efficacy. 130-132
<http://jama.ama-assn.org/issues/v288n2/rfull/#r130>
The CD4 cell count typically increases by more than 50 cells/µL at 4 to 8
weeks after antiretroviral therapy has been started or changed, followed by
an additional increase of 50 to 100 cells/µL per year thereafter. 133
<http://jama.ama-assn.org/issues/v288n2/rfull/#r133> , 134
<http://jama.ama-assn.org/issues/v288n2/rfull/#r134>  Once CD4 cell counts
exceed 200/µL for 3 to 6 months, there are reduced risks of many
opportunistic infections and prophylaxis against certain pathogens can often
be stopped. 17 <http://jama.ama-assn.org/issues/v288n2/rfull/#r17>
Current HIV RNA tests have reliable detection limits of about 50 copies/mL,
and quantification using commercial tests is reliable at 200 copies/mL. 5
<http://jama.ama-assn.org/issues/v288n2/rfull/#r5>  With repeated
measurements, differences of 0.2 to 0.3 log10 (30% to 50%) are considered
significant evidence of a change in viral load. 135
<http://jama.ama-assn.org/issues/v288n2/rfull/#r135>  Virologically
effective therapy generally reduces viral load by more than 90% (ie, a
1-log10, or 10-fold, reduction) within 8 weeks of treatment. 136
<http://jama.ama-assn.org/issues/v288n2/rfull/#r136> , 137
<http://jama.ama-assn.org/issues/v288n2/rfull/#r137>  Failure to attain a
90% reduction by 4 weeks of therapy suggests poor adherence, viral
resistance, or inadequate drug exposure.
On initiation of therapy, sequential measurements of CD4 cell count and
viral load at 4, 8 to 12, and 16 to 24 weeks have been used to assess the
early response to antiretroviral therapy. 138-140
<http://jama.ama-assn.org/issues/v288n2/rfull/#r138>  A continued decline in
viral load at each measurement, together with an increase in CD4 cell count,
indicates a drug combination is appropriately active in vivo, and indirectly
indicates patient adherence and baseline viral susceptibility. In some
instances CD4 cell counts might not increase, or may decrease, with
successful suppression of viral replication (HIV RNA, <50 copies/mL). 141
<http://jama.ama-assn.org/issues/v288n2/rfull/#r141>  Reasons for this
phenomenon are not well understood. Drug-related toxic effects and ongoing
opportunistic disease should be investigated. Although no specific
intervention has been studied well enough to be recommended at this time, it
is important to monitor viral load and CD4 cell counts more frequently in
patients with such discordant responses.
Once virological suppression has been achieved (2 sequential measurements
below the limit of detection of the most sensitive assay available), viral
load and CD4 cell numbers are usually monitored every 8 to 12 weeks. 142
<http://jama.ama-assn.org/issues/v288n2/rfull/#r142>  More frequent
monitoring may be appropriate in case of intercurrent illness, change in
antiretroviral therapy, introduction of a new treatment that could interfere
pharmacologically with antiretroviral drugs, or if adherence to therapy
becomes questionable. Frequent monitoring may show, even in patients with
drug-sensitive virus who report optimal adherence, occasional small
increases in detectable plasma virus (blips) in the range of 50 to 400
copies/mL. There is no evidence to date that such isolated blips are
predictive of subsequent overt treatment failure. 143
<http://jama.ama-assn.org/issues/v288n2/rfull/#r143>
Drug Resistance Testing

Guidelines for use of drug resistance testing in clinical practice have been
published. 144-146 <http://jama.ama-assn.org/issues/v288n2/rfull/#r144>
Randomized, prospective trials have demonstrated variable results with
respect to short-term virological benefit of genotype or phenotype testing.
147-153 <http://jama.ama-assn.org/issues/v288n2/rfull/#r147>  Results of
studies showing no difference between study groups may have been affected by
the interpretation of the resistance information, particularly an
under-recognition of the degree of NRTI cross-resistance, and lack of
treatment options for patients in whom several regimens have failed. Despite
the limitations of these trial results, the clinical value of drug
resistance testing is recognized and it is now considered standard-of-care
in the management of treatment failure. 145
<http://jama.ama-assn.org/issues/v288n2/rfull/#r145>  Data are not yet
available on which method or type of resistance testing is superior in any
given clinical setting. Resistance testing information can provide guidance
when selecting which drugs to exclude or include in a new regimen. Testing
should be performed when the selective pressure of the failing regimen is
still present because resistance may not be detected following withdrawal of
the drugs. 122 <http://jama.ama-assn.org/issues/v288n2/rfull/#r122>
However, resistance mutations archived at the cell level may persist, with
potential to rapidly reemerge if the failing regimen is reintroduced. In
treatment-naive persons, drug resistance testing should be strongly
considered in those who may have been infected with a resistant viral
strain, particularly those with more recent infection, or when the initial
response is suboptimal in the face of excellent drug adherence. 154
<http://jama.ama-assn.org/issues/v288n2/rfull/#r154>
Drug Concentration Monitoring

Adjusting doses of a drug to maintain a desired plasma level is common with
some drugs and has been suggested for antiretroviral drugs. 155
<http://jama.ama-assn.org/issues/v288n2/rfull/#r155>  This may be more
practical with some classes of antiretroviral drugs than others. The NRTIs
are especially problematic, because they require intracellular activation
and because intracellular concentrations are more difficult to measure than
plasma levels. Additionally, drug concentration data are most meaningful in
the context of the phenotypic susceptibility of the patient's viral strain,
which can be determined only in the setting of detectable viral loads.
The drug trough concentration ideally should not fall below the level
necessary to control HIV replication, and the peak concentration should be
below the range at which toxic effects would be expected. Composite data on
the Cmin, Cmax, and area under the concentration curve (AUC) are generally
known and available in the prescribing information for most available drugs,
as is the drug concentration necessary in vitro to suppress the replication
of wild-type HIV. However, there is substantial interpatient and
intrapatient variability in pharmacokinetics, and suppression may be
impossible if resistance has emerged. Adding yet more complexity are the
different methods of determining suppression thresholds (eg, using IC90 or
IC50) and the effect of protein binding and how this is accounted for in the
data reported. Data on the effect of Cmax, AUC, or the shape of the
drug-decay curve on drug toxicity or effect may be even less firm.
If monitoring of drug levels is considered, practical issues must be
addressed, including adherence problems and assay availability, reliability,
and cost. Possible causes of variations in drug levels must be considered,
including drug-drug interactions with prescription, over-the-counter,
alternative, or recreational drugs, and malabsorption due to coincident
gastrointestinal disease or food effects. Finally, drug steady-state should
have been reached before concentrations are measured.
Drug-concentration monitoring may be of particular value in cases of
treatment failure (eg, initial or subsequent therapy), or when salvage
therapy with a ritonavir-enhanced PI–based regimen has been initiated,
especially if other drugs with known pharmacological interactions, such as
efavirenz, are also prescribed (drug resistance testing should also be
considered).
Drug concentration monitoring is commercially available in some areas.
However, it is difficult to make clear recommendations, because the
therapeutic range of plasma concentrations is not known for most drugs.
Moreover, few studies have demonstrated the clinical usefulness of
drug-concentration monitoring. 156
<http://jama.ama-assn.org/issues/v288n2/rfull/#r156>  Thus, decisions about
adjusting doses of antiretroviral drugs based on level determinations need
to be individualized until more data are available.



ESTABLISHED INFECTION: CHANGING THERAPY



Changing Drugs Because of Incomplete Adherence, Adverse Effects, or
Intolerance

In the absence of virological or immunologic failure, a regimen may pose
problems with adherence, intolerance, or cumulative (long-term) toxic
effects. As long as the antiviral activity of the overall regimen is
maintained, exchanging individual components of the regimen is acceptable.
Examples of such substitutions are a change of stavudine for zidovudine or
nevirapine for efavirenz, or substitution of low-dose ritonavir-boosted PIs
for single PI components of a regimen.
Substituting individual antiretroviral agents is frequently indicated
because of drug-specific toxic effects. In clinical settings in which the
offending agent cannot be easily determined, or in which there are
significant safety concerns, treatment should be completely interrupted so
that acute adverse effects can resolve while alternative regimens are
considered. Among patients with serum lipid abnormalities and lipodystrophy,
abacavir or nevirapine can be substituted for the PI component. 53
<http://jama.ama-assn.org/issues/v288n2/rfull/#r53>  Serum lipid
abnormalities improve with these changes but improvements in body
composition abnormalities have not been consistently documented in studies
reported to date. 53 <http://jama.ama-assn.org/issues/v288n2/rfull/#r53>
More studies and longer patient follow-up are needed. When a change in a
drug class is planned, it is preferable to do so in the setting of
successful virological suppression.
Changing Therapy Because of Treatment Failure

The definition of "treatment failure" (a term that subsumes virological,
immunologic, or clinical failure) depends on the clinical setting and
mirrors the objective of ongoing therapy at a given time in the patient's
treatment course. The duration of response is predicted by level of viral
suppression obtained while receiving therapy within 8 weeks. 138
<http://jama.ama-assn.org/issues/v288n2/rfull/#r138> , 157-159
<http://jama.ama-assn.org/issues/v288n2/rfull/#r157>  In the case of the
first or second regimen, when virus is wild type or harbors few resistance
mutations, maintaining an undetectable viral load is an achievable goal of
therapy; in this setting, treatment failure is best defined as inability to
achieve a viral load below assay detection limits (eg, <50 copies/mL) or as
any sustained return of the viral load to above the target value (eg, >400
copies/mL). With increasing rounds of treatment failure, the level and
spectrum of virus resistance may increase, and it may become more difficult
to construct an active combination. In patients for whom several regimens
have failed, the virus may become multiply resistant, with fewer than 3
active drugs being available, and the objective of achieving stable
undetectable viral load with conventional regimens may be unrealistic.
Problems with toxicity may further restrict the number of available drugs.
The goal of therapy in this setting is primarily to prevent clinical
progression, and failure can be defined as a deterioration of the CD4 cell
count or the occurrence of a serious opportunistic infection.
First or Second Failure
Treatment failure occurs within the first year of therapy in a substantial
proportion of treatment-naive patients. 160
<http://jama.ama-assn.org/issues/v288n2/rfull/#r160> , 161
<http://jama.ama-assn.org/issues/v288n2/rfull/#r161>  A lower, but definite,
rate of treatment failure in successive years has been reported with nearly
all regimens. 14 <http://jama.ama-assn.org/issues/v288n2/rfull/#r14> , 111
<http://jama.ama-assn.org/issues/v288n2/rfull/#r111>  Thus, failure should
be anticipated as part of the long-term strategy of antiretroviral
treatment. In the case of confirmed treatment failure, an intervention
should be considered promptly in order to minimize emergence of cumulative
drug resistance and cross-resistance that will limit availability of
alternative options. 162
<http://jama.ama-assn.org/issues/v288n2/rfull/#r162>  However, treatment
failure is not always associated with viral resistance, particularly during
initial viral rebound or if virus remains detectable at a low level after
several months of therapy. 96
<http://jama.ama-assn.org/issues/v288n2/rfull/#r96>  In such circumstances a
thorough assessment of adherence, dietary requirements, drug-drug
interactions, and bioavailability is the first step. In situations where
there is no evidence of resistance or adherence issues, adding a new drug or
drugs (ie, regimen intensification) may be considered. However, since
intensification may add to the complexity of the treatment regimen, such an
approach could aggravate problems with adherence. Some drugs, particularly
the NNRTIs and lamivudine, generally should not be used alone as
intensification agents because of risk of single-step, high-level
resistance. Intensifying with ritonavir as a pharmacological enhancer of
another PI may be effective in the short term in patients for whom a regimen
with a single PI is failing. 152
<http://jama.ama-assn.org/issues/v288n2/rfull/#r152>  Addition of abacavir
or tenofovir disoproxil fumarate may also be of use in this setting. 163
<http://jama.ama-assn.org/issues/v288n2/rfull/#r163>
When a decision is made to change therapy because of sustained virological
failure, the new regimen should be one with highest likely effectiveness, as
predicted by the patient's complete drug history and the resistance test
result, as well as highest likelihood of tolerability and adherence. New
regimens should contain at least 2, and if possible 3, drugs deemed to be
active. Virus that replicates during treatment failure may not be resistant
to all of the drugs in the failing regimen. 96
<http://jama.ama-assn.org/issues/v288n2/rfull/#r96> , 152
<http://jama.ama-assn.org/issues/v288n2/rfull/#r152>  However, latently
infected lymphocytes may harbor archived virus resistant to drugs used in
the past but not detected by routine resistance testing. Shared-resistance
mutations conferred by an individual drug may lead to cross-resistance among
drugs in the same class, complicating the choice of alternative regimens.
146 <http://jama.ama-assn.org/issues/v288n2/rfull/#r146> , 164
<http://jama.ama-assn.org/issues/v288n2/rfull/#r164>  With currently
approved NNRTIs, risk of complete NNRTI-class cross-resistance is high when
an NNRTI-containing regimen fails. With PIs, intraclass cross-resistance is
not so predictable. Depending on the pattern of resistance, an alternative
PI (or a combination of PIs) can often be selected. With NRTIs, extent of
class cross-resistance is greater than anticipated previously, and level of
resistance to some drugs (eg, stavudine) is more difficult to infer from
genotype or phenotype. 145
<http://jama.ama-assn.org/issues/v288n2/rfull/#r145>  In rare circumstances,
multidrug resistance to NRTIs may develop through a unique pathway of
resistance (eg, the Q151M complex or a 2–amino acid insertion at codon 69).
145 <http://jama.ama-assn.org/issues/v288n2/rfull/#r145>  Examples of
possible alternative regimens (based on predicted resistance patterns) in
the setting of first regimen failure are given in Table 3
<http://jama.ama-assn.org/issues/v288n2/fig_tab/jst20002_t3.html> . 165
<http://jama.ama-assn.org/issues/v288n2/rfull/#r165>
Tenofovir was recently approved for treatment of HIV infection. In its
active diphosphate form, the drug has a prolonged intracellular half-life,
which permits once-daily dosing. 166
<http://jama.ama-assn.org/issues/v288n2/rfull/#r166>  The drug is active
against isolates containing certain NRTI-associated resistance mutations,
including the Q151M complex, but has diminished activity against isolates
with the T69S insertion, the K65R mutation, and those with multiple
NRTI-associated mutations (NAMs), particularly M41L and L210W. 166
<http://jama.ama-assn.org/issues/v288n2/rfull/#r166> , 167
<http://jama.ama-assn.org/issues/v288n2/rfull/#r167>  The
lamivudine-associated M184V mutation enhances tenofovir's activity in vitro.
167 <http://jama.ama-assn.org/issues/v288n2/rfull/#r167>  The signature
mutation associated with this drug is K65R, but in clinical trials and
animal studies, this mutation arises infrequently and is not consistently
associated with loss of antiretroviral activity. 168
<http://jama.ama-assn.org/issues/v288n2/rfull/#r168>  In phase 3 trials in
antiretroviral-experienced patients with virological failure, tenofovir has
produced a consistent 0.6 log10 decrease from baseline in viral load and
modest rises in CD4 cell counts over 24 and 48 weeks or longer. 169
<http://jama.ama-assn.org/issues/v288n2/rfull/#r169> , 170
<http://jama.ama-assn.org/issues/v288n2/rfull/#r170>  Among treatment-naive
patients treated with tenofovir monotherapy for 21 days, a 1.5 log10
reduction in HIV RNA was observed. 171
<http://jama.ama-assn.org/issues/v288n2/rfull/#r171>  The drug is generally
well tolerated. 169 <http://jama.ama-assn.org/issues/v288n2/rfull/#r169> ,
170 <http://jama.ama-assn.org/issues/v288n2/rfull/#r170>  No serious renal
dysfunction or bone density alterations have been reported to date. The
available clinical trial results suggest a role for tenofovir in management
of treatment-experienced patients. Results from ongoing studies will help
define the role of tenofovir in management of drug-naive patients.
Multiple Failures
Treatment histories and results of resistance testing may indicate that 2 or
fewer active drugs are available for therapy in patients in whom numerous
regimens have failed.
Evidence of low rates of clinical progression in such patients, who continue
antiretroviral therapy despite viral replication and presence of resistance,
argues for continuing treatment in the face of virological failure. 172
<http://jama.ama-assn.org/issues/v288n2/rfull/#r172>  Some virus with
multidrug-resistance mutations has reduced replicative capacity, or fitness,
relative to wild-type virus. 122
<http://jama.ama-assn.org/issues/v288n2/rfull/#r122> , 173
<http://jama.ama-assn.org/issues/v288n2/rfull/#r173> , 174
<http://jama.ama-assn.org/issues/v288n2/rfull/#r174>  Stabilization of CD4
cell numbers and absence of clinical progression have been demonstrated when
viral load is sustained at a level 3-fold (0.5 log10) below the patient's
natural set point (pretreatment value). 172
<http://jama.ama-assn.org/issues/v288n2/rfull/#r172> , 175
<http://jama.ama-assn.org/issues/v288n2/rfull/#r175>  Conversely, when all
drugs in a regimen are stopped there may be an apparent reversion to
wild-type virus within 8 to 12 weeks, associated with a rapid increase in
viral load and marked decrease in CD4 cell count. 122
<http://jama.ama-assn.org/issues/v288n2/rfull/#r122> , 176
<http://jama.ama-assn.org/issues/v288n2/rfull/#r176>  Although there is a
risk of accumulating additional resistance mutations, continuing drug
regimens that maintain selective pressure on the virus is preferable to
discontinuing all antiretroviral therapy, especially in settings in which
the CD4 cell counts are maintained despite a rebound in viral replication.
In cases in which a change in the therapy cannot be delayed, adding 1 new
drug (eg, a drug available through expanded access) may not result in a
profound and durable effect, and the best therapy should be selected, based
on treatment history, tolerance, and resistance testing. The regimen may
include drugs recycled from previous, failed regimens. Multidrug rescue
therapy (6 or more drugs, also called "megaHAART") in this setting may
exhibit a substantial degree of antiretroviral activity. 177
<http://jama.ama-assn.org/issues/v288n2/rfull/#r177> , 178
<http://jama.ama-assn.org/issues/v288n2/rfull/#r178>  However, this approach
may lead to toxic effects and problems with adherence, adverse drug-drug
interactions, and increased cost. Moreover, the effect on CD4 cell count is
not entirely predictable. 179
<http://jama.ama-assn.org/issues/v288n2/rfull/#r179>



ADJUVANT THERAPY TO ANTIRETROVIRAL DRUGS



The concept of manipulating the immune response for host benefit has
received increased emphasis. Approaches include attempts to augment (eg,
interleukin 2 180-184 <http://jama.ama-assn.org/issues/v288n2/rfull/#r180> )
or dampen (eg, cyclosporin A, corticosteroids, hydroxyurea, and mycophenolic
acid 185 <http://jama.ama-assn.org/issues/v288n2/rfull/#r185> , 186
<http://jama.ama-assn.org/issues/v288n2/rfull/#r186> ) the immune response
generally, and attempts designed to stimulate (treatment interruption and
"therapeutic" vaccination 187-189
<http://jama.ama-assn.org/issues/v288n2/rfull/#r187> ) relevant HIV-specific
immune effector responses. At this point, however, insufficient clinical
data exist to recommend these approaches outside the setting of clinical
trials. In addition, in the case of hydroxyurea, significant toxicities have
emerged that have dampened enthusiasm for this agent. 190
<http://jama.ama-assn.org/issues/v288n2/rfull/#r190>



SUMMARY



The future of antiretroviral therapy rests with the development of new drugs
that will result in simpler, more effective, and less toxic regimens along
with development of an improved understanding of innate immune system
responses and novel approaches to exploit these responses. Several new
agents are currently in development, derived from current drug classes (eg,
the NRTIs amdoxovir and emtricitabine, the NNRTIs DPC-083 and TMC-125, and
the PIs atazanavir and tipranavir) and new drug classes, including entry
inhibitors (eg, enfuvirtide) and integrase inhibitors. Potential advantages
of these drugs include once-daily dosing, smaller pill size, lower incidence
of adverse effects, new viral targets, and activity against virus that is
resistant to other drugs in the respective classes. The benefits of current
and future agents will continue to be felt by HIV-infected persons in the
developed world. Extending these benefits to those living with HIV in the
developing world is a challenge that needs to be met.



Author/Article Information


Author Affiliations: Hôpital Bichat-Claude Bernard, X. Bichat Medical
School, Paris, France (Dr Yeni); Columbia University College of Physicians
and Surgeons, New York, NY (Dr Hammer); Brown University School of Medicine,
Providence, RI (Dr Carpenter); University of New South Wales, Sydney,
Australia (Dr Cooper); University of Miami School of Medicine, Miami, Fla
(Dr Fischl); Hospital Clinic, University of Barcelona, Barcelona, Spain (Dr
Gatell); Chelsea and Westminster Hospital, London, England (Dr Gazzard);
Harvard Medical School, Boston, Mass (Dr Hirsch); The International AIDS
Society-USA (Ms Jacobsen); Stanford University Medical Center, Stanford,
Calif (Dr Katzenstein); University of British Columbia, Canada (Dr
Montaner); University of California San Diego and San Diego VA Healthcare
System (Dr Richman); The University of Alabama at Birmingham (Dr Saag);
Universidade Federal do Rio de Janeiro, Brasil (Dr Schechter); University of
Colorado School of Medicine, Denver (Dr Schooley); AIDS Research Consortium
of Atlanta, Georgia (Dr Thompson); Istituto Superiore di Sanità, Rome, Italy
(Dr Vella); University of California San Francisco and San Francisco
Veterans Affairs Medical Center (Dr Volberding).

Corresponding Author: Patrick Yeni, MD, Hôpital Bichat-Claude Bernard,
Department of Infectious Diseases, 46 Rue Henri-Huchard, Paris, Cedex 18
France 75877 (e-mail: [log in to unmask]
<mailto:[log in to unmask]> ).
Reprints: Patrick Yeni, MD, International AIDS Society–USA, 1001 B O'Reilly
Ave, San Francisco, CA 94129.
Financial Disclosure: Dr Yeni: grant support/advisor/speakers bureau (ANRS
[French National Agency for AIDS Research], Boehringer Ingelheim,
Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Hoffmann-La Roche, Tibotec,
Triangle); Dr Hammer: site investigator/consultant/grants (Boehringer
Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH grants
AI46386, AI48013, AI42848, Roche-Trimeris, Shionogi, Shire BioChem,
Tibotec-Virco, Triangle); Dr Carpenter: principal investigator (National
Institutes of Health and Centers for Disease Control and Prevention grants);
Dr Cooper: grant support/honoraria/consultant (Abbott, Boehringer Ingelheim,
Bristol-Myers Squibb, Chiron, Commonwealth Department of Health and Ageing
[Canberra ACT Australia], Gilead, GlaxoSmithKline, Merck Sharp & Dohme, NIH,
Pfizer, Roche); Dr Fischl: grant support/advisor (Abbott, Agouron,
Bristol-Myers Squibb, DuPont, GlaxoSmithKline, Triangle, National Institutes
of Health); Dr Gatell: grant support/site investigator/advisor/speakers
bureau (Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, DuPont, Gilead
Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novirio, Pharmacia & Upjohn,
Roche, Schering-Plough, Vertex, Visible Genetics), and uncompensated expert
testimony for the European Union regarding merger of DuPont and
Bristol-Myers Squibb; Dr Gazzard: grant support/advisor (Abbott,
Bristol-Myers Squibb, DuPont, Gilead, Glaxo Wellcome, Pharmacia & Upjohn);
Dr Hirsch: grant support/consultant/lecture sponsorship (Bristol-Myers
Squibb, GlaxoSmithKline, Merck, NIH, Schering-Plough, Takeda, Trimeris); Dr
Katzenstein: stock/research funding/honoraria/advisor/assay kits or reagents
(Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck,
ViroLogic, Visible Genetics, Doris Duke Charitable Trust Distinguished
Clinical Scientist Award, and obtained patent US 5,968,730 "PCR Assays for
Monitoring Antiviral Therapy and Making Therapeutic Decisions in the
Treatment of AIDS" issued October 15, 1999); Dr Montaner: grant support/ad
hoc advisor/speaker at sponsored events (Abbott, Agouron, BioChem Pharma,
Boehringer Ingelheim, Bristol-Myers Squibb, DuPont, Gilead, Glaxo Wellcome,
Hoffmann-La Roche, Merck Frosst Laboratories, Pfizer, Pharmacia & Upjohn,
Province of British Columbia, Canadian Institute for Health Research, Shire,
and is a coapplicant on a patent for use of a PCR-based mitochondrial DNA
assay); Dr Richman: consultant (Abbott, Bristol-Myers Squibb, Chiron,
Department of Veterans Affairs, Gilead, GlaxoSmithKline, Merck, NIH,
Novirio, Pfizer, Roche, Takeda, Triangle, ViroLogic); Dr Saag:
consultant/speakers bureaus/grant support (Abbott, Agouron, Bristol-Myers
Squibb, DuPont, Gilead, GlaxoSmithKline, Hoffman-La Roche, Janssen, Ortho
Biotech, Pfizer, Pharmacia & Upjohn, Shire, Tibotec, Triangle, Trimeris,
ViroLogic); Dr Schechter: grant support/honoraria/consultant (Abbott, Brazil
National Research Council, Brazil Ministry of Health, Boehringer Ingelheim,
Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, NIAID, Roche, World
Health Organization); Dr Schooley: stock options/grant
support/honoraria/consultant/lecture sponsorship (Agouron, AnorMed,
Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Mojave, NIH, Pan
Pacific Pharmaceuticals, Roche, Tanox, Triangle Pharmaceuticals, Vertex
Pharmaceuticals, ViroLogic); Dr Thompson: grant
support/honoraria/consultant/lecture sponsorship/advisor (Abbott
Laboratories, Agouron, Agouron/Pfizer, Boehringer Ingelheim, Bristol-Myers
Squibb, Centers for Disease Control and Prevention Adult Spectrum of Disease
Study, Chiron, DuPont Pharmaceuticals, Gilead Sciences, GlaxoSmithKline,
Merck, NIAID Acute Infection and Early Disease Research Network, NIAID
Community Programs for Clinical Research on AIDS, Oxo-Chemie, Roche, Serono,
Triangle Pharmaceuticals, Trimeris, and ViroLogic); Dr Vella: lecture
sponsorship for satellite meetings or continuing medical education programs
(Abbott, Agouron, Boehringer Ingelheim, Bristol-Myers Squibb,
GlaxoSmithKline, Merck, Roche); and Dr Volberding: honoraria/consultant
(Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead,
GlaxoSmithKline, Merck, NIAID [Center for AIDS Research]).
Funding/Support: This work was sponsored by the International AIDS
Society-USA (IAS-USA) and funded through a reserve fund independent of
commercial companies, funded by private donations and interest income. Of
note, the panel members were not compensated for this activity. The IAS-USA
received grant support for continuing medical education programs and
production of Topics in HIV Medicine from Abbott Laboratories, Agouron
Pharmaceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, Department of
Health and Human Services/Health Resources and Services Administration
[subcontract], DuPont, Gilead Sciences, GlaxoSmithKline, Merck US Human
Health, Ortho Biotech, Roche Laboratories, Schering Corporation, Virco,
ViroLogic, and Visible Genetics, Inc, as well as substantial gifts in kind
from Microsoft Corporation, the Gill Foundation, and Philanthropy by Design.
However, these funding sources did not support the project represented
herein.
Acknowledgment: We thank Morris Schambelan, MD and Constance A. Benson, MD
(Chairs of the IAS-USA Complications of Antiretroviral Therapy Expert Panel)
for the review of the manuscript, and Michelle Tayag for administrative
support in preparing the manuscript.




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.