Antiretroviral Treatment for Adult HIV Infection in 2002
Updated Recommendations of the
International AIDS Society-USA Panel
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
Progress in antiretroviral therapy has resulted
in achievements as well as new challenges.1 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 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 emerging1, 5 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.
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 recommendations1 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.
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 The number of
memory CD4 cells increases early after effective treatment, as a result of
redistribution from lymphoid tissues to the circulation.7 Naive CD4 cells, which
are essential for responses to new antigenic challenges, are restored gradually
with ongoing effective suppression of viral replication.8 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 Because
currently available antiretroviral regimens will not eradicate HIV,9, 10 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
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, 13 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
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 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 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, 15, 22-25 Finally, the
genetic complexity of HIV in persons increases with time, and this may
facilitate escape from host immune defenses.26 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 have not been able to
define a CD4 stratum above 200 cells/µL at which patients benefit from
initiation of therapy.12, 13 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 low28 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 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).5, 30, 31 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 patients with CD4
cell counts at any level who have a viral load above 50 000 to
100 000 copies/mL31 should be closely
monitored, because the CD4 cell count decreases more rapidly in untreated
persons with higher viral loads.28, 31 Initiation of therapy
may be considered in individuals with a viral load above 50 000 to
100 000 copies/mL,31 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, 33 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
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),34-84 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 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
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 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
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 Low-dose ritonavir
can pharmacologically enhance (or boost) saquinavir, indinavir, amprenavir, or
lopinavir (the latter available only in a coformulated capsule).90 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
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 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 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 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 an observation
similar to what has been reported with indinavir and amprenavir.96-98
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
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 used100; 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
Combining amprenavir with ritonavir increases
trough levels of amprenavir102 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, 104
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 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 Nevirapine has been
associated with severe rashes more often than has efavirenz.107, 108 Use of
corticosteroids has not had a beneficial effect.109 Hepatotoxicity,
including elevation of transaminases, jaundice, and rare cases of severe
clinical hepatitis, occurs with nevirapine more often than with efavirenz.107, 108 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
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 Efavirenz is
commonly prescribed because of its once-daily dosing and safety profile.108 Because of
teratogenicity in animals,108 efavirenz should be
avoided in women who are (or intend to become) pregnant. Hyperexcitability,
vivid dreams, nightmares, and hallucinations are associated with efavirenz.108 Mood disturbances
and personality changes may be persistent in some patients.108
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, 113 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, 113 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, 115 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, 117 In most such
patients,117 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.
Structured, supervised, or strategic treatment
interruptions (STIs) have been considered in very different situations:
following early therapy of acute HIV syndrome,118 following
suppressive antiretroviral therapy of established infection,119-121 and for
facilitating salvage after therapy has failed.122 The rationales for
interruption of therapy in these 3 settings are different, and the subject has
been extensively reviewed elsewhere.123, 124 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.
Adherence: Assessment and
Reinforcement
Incomplete adherence to one or more prescribed medications is a key cause of
virological failure of antiretroviral regimens.125 A recent study found
a doubling of the viral load for every 10% decrement from complete adherence.126 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, 128 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 Most remain
largely empiric and not evidence-based.129 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
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, 134 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
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 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 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, 137 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 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 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 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
Drug Resistance Testing
Guidelines for use of drug resistance testing in clinical practice have been
published.144-146
Randomized, prospective trials have demonstrated variable results with respect
to short-term virological benefit of genotype or phenotype testing.147-153 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 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 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
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 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 Thus, decisions
about adjusting doses of antiretroviral drugs based on level determinations
need to be individualized until more data are available.
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 Serum lipid
abnormalities improve with these changes but improvements in body composition
abnormalities have not been consistently documented in studies reported to
date.53 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, 157-159 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, 161 A lower, but
definite, rate of treatment failure in successive years has been reported with
nearly all regimens.14, 111 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 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 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 Addition of abacavir
or tenofovir disoproxil fumarate may also be of use in this setting.163
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, 152 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, 164 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 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 Examples of
possible alternative regimens (based on predicted resistance patterns) in the
setting of first regimen failure are given in Table 3.165
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 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, 167 The lamivudine-associated
M184V mutation enhances tenofovir's activity in vitro.167 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 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, 170 Among
treatment-naive patients treated with tenofovir monotherapy for 21 days, a 1.5
log10 reduction in HIV RNA was observed.171 The drug is
generally well tolerated.169, 170 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 Some virus with
multidrug-resistance mutations has reduced replicative capacity, or fitness,
relative to wild-type virus.122, 173, 174 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, 175 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, 176 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, 178 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
The concept of manipulating the immune response
for host benefit has received increased emphasis. Approaches include attempts
to augment (eg, interleukin 2180-184) or dampen (eg,
cyclosporin A, corticosteroids, hydroxyurea, and mycophenolic acid185, 186) the immune response
generally, and attempts designed to stimulate (treatment interruption and
"therapeutic" vaccination187-189) 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
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]).
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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