Report of the NIH Panel to Define Principles of Therapy of HIV Infection
SCIENTIFIC
PRINCIPLES
Principle
1.
Ongoing HIV replication leads to immune system damage and progression to AIDS.
HIV infection is always harmful, and true long-term survival free of clinically
significant immune dysfunction is unusual.
Active
replication of HIV is the cause of progressive immune system damage in infected
persons (1-10). In the absence of effective inhibition of HIV replication by
antiretroviral therapy, nearly all infected persons will suffer progressive
deterioration of immune function resulting in their susceptibility to
opportunistic infections (OIs), malignancies, neurologic diseases, and wasting,
ultimately leading to death (11,12). For adults who live in developed countries,
the average time of progression to AIDS after initial infection is approximately
10-11 years in the absence of antiretroviral therapy or with older regimens of
nucleoside analog (e.g., zidovudine [ZDV]) monotherapy (11). Some persons
develop AIDS within 5 years of infection (20%), whereas others (<5%) have
sustained long-term (>10 years) asymptomatic HIV infection without decline of
CD4+T cell counts to <500 cells/mm 3 . Only approximately 2% or less of
HIV-infected persons seem to be able to contain HIV replication to extremely low
levels and maintain stable CD4+T cell counts within the normal range for lengthy
periods (>12 years), and many of these persons display laboratory evidence of
immune system damage (12). Thus, HIV infection is unusual among human virus
infections in causing disease in such a large proportion of infected persons.
Although
a very small number of HIV-infected persons do not demonstrate progressive HIV
disease in the absence of antiretroviral therapy, there is no definitive way to
prospectively identify these persons. Therefore, all persons who have HIV
infection must be considered at risk for progressive disease. The goals of
treatment for HIV infection should be to maintain immune function in as near a
normal state as possible, prevent disease progression, prolong survival, and
preserve quality of life by effectively suppressing HIV replication. For these
goals to be accomplished, therapy should be initiated, whenever possible, before
extensive immune system damage has occurred.
Principle
2.
Plasma HIV RNA levels indicate the magnitude of HIV replication and its
associated rate of CD4+T cell destruction, whereas CD4+T cell counts indicate
the extent of HIV-induced immune damage already suffered. Regular, periodic
measurement of plasma HIV RNA levels and CD4+T cell counts is necessary to
determine the risk for disease progression in an HIV-infected person and to
determine when to initiate or modify antiretroviral treatment regimens.
The
rate of progression of HIV disease is predicted by the magnitude of active HIV
replication (reflected by so-called viral load) taking place in an infected
person (5-10,13-18). Measurement of viral load through the use of quantitative
plasma HIV RNA assays permits assessment of the relative risk for disease
progression and time to death (5-10,13-18). Plasma HIV RNA measurements also
permit assessment of the efficacy of antiretroviral therapies in individual
patients (1,2,13,19-25). It is expert opinion that these measurements are
necessary components of treatment strategies designed to use antiretroviral
drugs most effectively. The extent of immune system damage that has already
occurred in an HIV-infected person is indicated by the CD4+T cell count
(11,26-29), which permits assessment of the risk for developing specific OIs and
other sequelae of HIV infection. When used in concert with viral load
determinations, assessment of CD4+T cell number enhances the accuracy with which
the risk for disease progression and death can be predicted (27). Issues
specific for the laboratory assessment of plasma HIV RNA and CD4+T cell levels
in HIV-infected infants and young children are discussed in Principle 9
(14-18,25,30). Important specific considerations regarding laboratory
evaluations and HIV-infected persons include the following:
1.
In the newly diagnosed patient, baseline plasma HIV RNA levels should be checked
in a clinically stable state. Plasma HIV RNA levels obtained within the first 6
months of initial HIV infection do not accurately predict a person's risk for
disease progression (31). In contrast, plasma HIV RNA levels stabilize (reach a
"set-point") after approximately 6-9 months of initial HIV infection
and are then predictive of risk for disease progression (5-10). Following their
stabilization, plasma HIV RNA levels may remain fairly stable for months to
years in many HIV-infected persons (7,10). However, immunizations and
intercurrent infections can lead to transient elevations of plasma HIV RNA
levels (32-34). As a result, values obtained within approximately 4 weeks of
such episodes may not accurately reflect a person's actual baseline plasma HIV
RNA level. For an accurate baseline, two specimens obtained within 1-2 weeks of
each other, processed according to optimal, validated procedures, and analyzed
by the same quantitative method are recommended. The use of two baseline
measurements serves to reduce the variance in the plasma HIV RNA assays that
results from technical and biologic factors (19,22,35,36).
2.
Studies of populations of HIV-infected persons indicate that plasma HIV RNA
levels gradually increase with time after infection (10). A steeper rate of
increase is associated with an increased risk of disease progression. Within
individual patients, the actual rate of change of plasma HIV RNA levels is
unpredictable but can increase abruptly. Therefore, periodic monitoring of
plasma HIV RNA levels is necessary to accurately gauge risk of disease
progression.
3.
Studies of the kinetics of HIV replication in infected persons indicate that
levels of plasma HIV RNA should measurably decline within days of initiation of
effective combination antiretroviral therapy (1,2,20,21,37). In patients in whom
cessation of detectable new rounds of HIV infection of CD4+T cells occurs,
plasma HIV RNA levels should fall to approximately 1% of their initial levels
within 2 weeks after initiation of therapy, reaching a nadir (ideally below the
limit of detection of sensitive plasma HIV RNA assays) within approximately 8
weeks. Persons who have very high initial plasma HIV RNA levels may take longer
to reach a nadir of plasma RNA levels following initiation of effective
antiretroviral therapy (up to approximately 16 weeks).
4.
Plasma HIV RNA assays provide the best measure of the activity of antiretroviral
therapy of HIV-infected persons. Rebound of plasma HIV RNA levels following
their suppression by antiretroviral therapy may indicate the outgrowth of
drug-resistant HIV variants in a patient adherent to the regimen (see Principle
7 for additional considerations). Should the desired level of suppression of HIV
replication be accomplished in treated patients by 16 weeks after initiation or
alteration of an antiretroviral regimen, plasma HIV RNA levels should be checked
periodically to document the continued activity of the chosen antiretroviral
regimen.
5.
HIV RNA levels can vary by approximately threefold (0.5 log10) in either
direction, upon repeated measurements (obtained withing days or weeks of each
other) in clinically stable, HIV-infected persons (19,22,35,36). Changes greater
than 0.5 log10 usually cannot be explained by inherent biological or assay
variability and likely reflect a biologically and clinically relevant change in
the level of plasma HIV RNA. It is important to note that the variability of the
current plasma HIV RNA assays is greater toward their lower limits of
sensitivity. Thus, differences between repeated measures of greater than 0.5
log10 may be seen at very low plasma HIV RNA values and may not reflect a
substantive biological or clinical change.
6.
CD4+T cell counts should be obtained for all patients who have newly diagnosed
HIV infection (28,29).
7.
CD4+T cell counts are subject to substantial variability due to both biological
and laboratory methodologies (26) and can vary up to 30% on repeated measures in
the absence of a change in clinical status. Thus, it is important to monitor
trends over time rather than base treatment decisions on one specific
determination. 8. In patients who are not receiving antiretroviral therapy,
CD4+T cell counts should be checked regularly to monitor patients for evidence
of disease progression. (See Guidelines.)
9.
In patients receiving antiretroviral therapy, CD4+T cell counts should be
checked regularly to document continuing immunologic benefit and to assess the
current degree of immunodeficiency (28,29).
10.
It is not yet known whether a given CD4+T cell level achieved in response to
antiretroviral therapy provides an equivalent assessment of the degree of immune
system function or has the same predictive value for risk for OIs as do CD4+T
cell levels obtained in the absence of therapy. The potentially incomplete
recovery of T cell function and the diversity of antigen recognition, despite
CD4+T cell increases induced by antiretroviral therapy, have raised concerns
that patients may remain susceptible to OIs at higher CD4+T cell levels. Until
more data concerning this issue are available, the Panel concurs with recent
U.S. Public Health Service/Infectious Diseases Society of America
recommendations that prophylactic medications be continued when CD4+T cell
counts increase above recommended threshold levels as a result of initiation of
effective antiretroviral therapies (i.e., that the provision of prophylaxis be
based on the lowest reliably determined CD4+T cell count) (28).
11.
Measurements of p24 antigen, neopterin, and b-2 microglobulin levels have often
been used to assess risk for disease progression. However, these measurements
are less reliable than plasma HIV RNA assays and do not add clinically useful
prognostic information to that obtained from HIV RNA and CD4+T cell levels. As
such, these laboratory tests need not be included as part of the routine care of
HIV-infected patients.
Principle
3.
As rates of disease progression differ among HIV-infected persons, treatment
decisions should be individualized by level of risk indicated by plasma HIV RNA
levels and CD4+T cell counts.
Decisions
regarding when to initiate antiretroviral therapy in an HIV-infected person
should be based on the risk for disease progression and degree of
immunodeficiency. Initiation of antiretroviral therapy before the onset of
immunologic and virologic evidence of disease progression is expected to have
the greatest and most durable beneficial impact on preserving the health of
HIV-infected persons. When specific viral load or CD4+T cell levels at which
therapy should be initiated are considered, it is important to recognize that
the risk for disease progression is a continuous rather than discrete function
(5,6,10,27). There is no known absolute threshold of HIV replication below which
disease progression will not eventually occur.
At
present, recommendations for initiation of therapy must be based on the fact
that the types and numbers of available antiretroviral drugs are limited. When
more numerous, more effective, better tolerated, and more conveniently dosed
drugs become available, it is likely that indications for initiation of therapy
will change accordingly. Specific considerations regarding treatment include the
following:
1.
Decisions made by healthcare practitioners and HIV-infected patients regarding
initiation of antiretroviral therapy should be guided by the patient's plasma
HIV RNA level and CD4+T cell count.
2.
Data are not yet available that define the degree of therapeutic benefit in
persons who have relatively high CD4+T cell counts and relatively low plasma HIV
RNA levels (e.g., CD4+T cell count >500/mm 3 and plasma HIV RNA <10,000
copies/ mL). However, emerging insights into the pathogenesis of HIV disease
predict that antiretroviral therapy should be of benefit to such patients. For
persons at low risk for disease progression, decisions concerning when to
initiate antiretroviral therapy must also include consideration of the potential
inconvenience and toxicities of the available antiretroviral drugs. Should the
decision be made to defer therapy, regular monitoring of HIV RNA levels and
CD4+T cell counts should be performed as recommended.
3.
Persons who have levels of HIV RNA persistently below the level of detection of
currently available HIV RNA assays and who have stable, high CD4+T cell counts
in the absence of therapy are at low risk for disease progression in the near
future. The potential for benefit of treatment for these persons is not known.
Should the decision be made to defer therapy, regular monitoring of HIV RNA
levels and CD4+T cell counts should be performed as recommended.
4.
Patients who have late-stage disease (as indicated by clinical evidence of
advanced immunodeficiency or low CD4+T cell counts, e.g., <50 cells/mm 3)
have benefited from appropriate antiretroviral therapy as evidenced by decreased
risks for further disease progression or death (23,28). In such patients,
antiretroviral therapy can be of benefit even when CD4+T cell increases are not
seen. Therefore, discontinuation of antiretroviral therapy in this setting
should be considered only if available antiretroviral therapies do not suppress
HIV replication to a measurable degree, if drug toxicities outweigh the
anticipated clinical benefit, or if survival and quality of life are not
expected to be improved by antiretroviral therapy (e.g., terminally ill
persons).
Principle
4.
The use of potent combination antiretroviral therapy to suppress HIV replication
to below the levels of detection of sensitive plasma HIV RNA assays limits the
potential for selection of antiretroviral-resistant HIV variants, the major
factor limiting the ability of antiretroviral drugs to inhibit virus replication
and delay disease progression. Therefore, maximum achievable suppression of HIV
replication should be the goal of therapy.
Studies
of the biology and pathogenesis of HIV infection have provided the basis for
using antiretroviral drugs in ways that yield the most profound and durable
suppression of HIV replication. The inherent ability of HIV to develop drug
resistance represents the major obstacle to the long-term efficacy of
antiretroviral therapy (21). However, recent clinical evidence indicates that
the development of drug resistance can be delayed, and perhaps even prevented,
by the rational use of combinations of drugs that include newly available,
potent agents to suppress HIV replication to levels that cannot be detected by
sensitive assays of plasma HIV RNA (23,38-40). Cessation of detectable HIV
replication decreases the opportunity for accumulation of mutations that may
give rise to drug-resistant viral variants. Furthermore, the extent and duration
of inhibition of HIV replication by antiretroviral therapy predicts the
magnitude of clinical benefit derived from treatment (9,13,23-25).
The
potential toxicities of therapy, as well as the patient's quality of life and
ability to adhere to a complex antiretroviral drug regimen, should be balanced
with the anticipated clinical benefit of maximal suppression of HIV replication
and the anticipated risks of less complete suppression. Specific considerations
regarding treatment include the following:
1.
Once a decision has been made to initiate antiretroviral therapy, the ideal goal
of therapy should be suppression of the level of active HIV replication, as
assessed by sensitive measures of plasma HIV RNA, to undetectable levels.
2.
If suppression of HIV replication to undetectable levels cannot be achieved, the
goal of therapy should be to suppress virus replication as much as possible for
as long as possible. Less complete suppression of HIV replication is expected to
yield less profound and less durable immunologic and clinical benefits. Higher
residual levels of HIV replication during therapy predispose the patient to more
rapid development of antiretroviral drug resistance and associated waning of
clinical benefit. In the absence of effective suppression of detectable HIV
replication, it is currently impossible to identify a precise target level for
suppression of HIV replication that will yield predictable clinical benefits.
However, recent data indicate that suppression of HIV RNA levels to <5,000
copies/mL is likely to yield more greater and more durable clinical benefit than
less complete suppression (24).
3.
The HIV RNA assays currently available have similar levels of sensitivity
(19,41-46; Table). More sensitive versions of each of these assays are currently
in development and will likely be commercially available in the future. Once
these assays are available, the goal of antiretroviral therapy should be
suppression of HIV RNA levels to below detection of these more sensitive assays.
Less profound suppression of HIV replication is associated with a greater
likelihood of development of drug resistance (23,40).
4.
Although suppression of HIV load to levels below the detection limits of
sensitive plasma HIV RNA assays indicates profound inhibition of new cycles of
virus replication, it does not mean that the infection has been eradicated or
that virus replication has been stopped completely (37,47-50). HIV replication
may be continuing in various tissues (e.g., the lymphatic tissues and the
central nervous system) although it can no longer be detected by plasma HIV RNA
assays. Strategies for potential eradication are being pursued in experimental
studies, but the likelihood of their success is uncertain (37,51). Recent
studies indicate that infectious HIV can still be isolated from CD4+T cells
obtained from infected persons whose plasma HIV RNA levels have been suppressed
below detection for prolonged periods (up to 30 months) (49,50). Long-term
persistence of HIV infection in such persons who have undetectable levels of
plasma HIV RNA appears to be due to the existence of long-lived reservoirs of
latently infected CD4+ cells, rather than drug failure (49,50). Continued
monitoring of HIV RNA levels is necessary in patients who have achieved
antiretroviral drug-induced suppression of HIV RNA to undetectable levels, as
this effect may be transient.
Principle
5.
The most effective means to accomplish durable suppression of HIV replication is
the simultaneous initiation of combinations of effective anti-HIV drugs with
which the patient has not been previously treated and that are not
cross-resistant with antiretroviral agents with which the patient has been
previously treated.
Several
issues should be considered regarding the combination of antiretroviral drugs to
be used in the treatment of an HIV-infected patient. The efficacy of a given
regimen of combination antiretroviral therapy is not simply a function of the
number of drugs used. The most effective antiretroviral drugs possess high
potency, favorable pharmacologic properties, and require that HIV acquire
multiple mutations in the relevant HIV target gene before high-level drug
resistance is realized.
In
addition, drug-resistant HIV variants selected for by treatment with certain
antiretroviral drugs may display diminished ability to replicate (decreased
"fitness") in infected persons (21). Drugs used in combination should
show evidence of additivity or synergy of antiretroviral activity, should lack
antagonistic pharmacokinetic or antiretroviral properties, and should possess
nonoverlapping toxicities. Ideally, the chosen drugs will display molecular
interactions that increase the potency of antiretroviral therapy or delay the
emergence of antiretroviral drug resistance. If multiple options are available
for combination therapy, specific antiretroviral drugs should be employed so
that future therapeutic options are preserved if the initial choice of therapy
fails to achieve its desired result. Whenever possible, therapy should be
initiated or modified with a rational combination of antiretroviral drugs, a
predefined target for the degree of suppression of HIV replication desired, and
a predefined alternative antiretroviral regimen to be used should the target
goal not be reached. Specific considerations regarding treatment include the
following:
1.
The combination of antiretroviral drugs used when therapy is either initiated or
changed needs to be carefully chosen because it will influence subsequent
options for effective antiretroviral therapy if the chosen drug regimen fails to
accomplish satisfactory suppression of HIV replication.
2.
The best opportunity to accomplish maximal suppression of virus replication,
minimize the risk of outgrowth of drug-resistant HIV variants, and maximize
protection from continuing immune system damage is to use combinations of
effective antiretroviral drugs in persons who have no prior history of anti-HIV
therapy.
3.
No single antiretroviral drug that is currently available, even the more potent
protease inhibitors (PIs), can ensure sufficient and durable suppression of HIV
replication when used as a single agent ("monotherapy"). Furthermore,
the use of potent antiretroviral drugs as single agents presents a great risk
for the development of drug resistance and the potential development of cross
resistance to related drugs. Thus, antiretroviral monotherapy is no longer a
recommended option for treatment of HIV-infected persons (see Guidelines). One
exception is the use of zidovudine (ZDV) according to the AIDS Clinical Trials
Group (ACTG) 076 regimen. This regimen is specifically for the purpose of
reducing the risk for perinatal HIV transmission in pregnant women who have high
CD4+T cell counts and low plasma HIV RNA levels and who have not yet decided to
initiate antiretroviral therapy based on their own health indications (52-54).
This time-limited use of zidovudine by a pregnant woman to prevent perinatal HIV
transmission has important benefits to infants and is not likely to
substantially compromise her future ability to benefit from combination
antiretroviral therapy.
4.
Antiretroviral drugs (e.g., lamivudine [3TC]) or the nonnucleoside reverse
transcriptase inhibitors (NNRTIs; e.g., nevirapine and delavirdine), that are
potent, but to which HIV readily develops high-level resistance, should not be
used in regimens that are expected to yield incomplete suppression of detectable
HIV replication.
5.
At present, durable suppression of detectable levels of HIV replication is best
accomplished with the use of two nucleoside analog reverse transcriptase (RT)
inhibitors combined with a potent PI. In patients who have not been treated with
antiretroviral therapy, suppression of detectable HIV replication has also been
reported with the use of two nucleoside analog RT inhibitors combined with a
NNRTI (e.g., zidovudine, didanosine, and nevirapine [40]). However, the role of
this approach as initial antiretroviral therapy needs to be better defined
before it can be recommended as a "first-line" treatment strategy.
Furthermore, this approach is considerably less effective in persons who have
been previously treated with nucleoside analog RT inhibitors (55-57). In the
subset of previously treated patients who respond initially to such regimens,
suppression of HIV replication is often transient and the associated clinical
benefit is limited.
6.
The use of fewer than three antiretroviral drugs in combination may be
considered as an option by HIV-infected persons and their physicians. In making
this decision, it is important to recognize that no combination of two currently
available nucleoside analog RT inhibitors has been demonstrated to consistently
provide sufficient and durable suppression of HIV replication. Although the
initial decline in HIV RNA levels following treatment with two RT inhibitors may
be encouraging, the durability of the response beyond 24-48 weeks in controlled
studies has been disappointing (40,56-60).
Furthermore,
the selection of drug-resistant HIV variants by antiretroviral regimens that
fail to suppress HIV replication durably may compromise the range of future
treatment options. Even in antiretroviral-drug-naive patients, the use of NNTRIs
is not routinely recommended in combination with one nucleoside analog RT
inhibitor, as the risk for selection of NNRTI-resistant HIV variants is high in
regimens that fail to achieve suppression of detectable HIV replication (1,61).
Certain combinations of two protease inhibitors (without added RT inhibitors)
have been reported to provide suppression of detectable HIV replication in pilot
studies (62,63); however, given the limited experience available with this
approach, it should not be considered as a first-line regimen at the present
time. 7. When a change in therapy is considered in a previously treated patient,
a review of the person's prior history of anti-HIV therapy is essential. Drugs
chosen as the components of a new antiretroviral regimen should not be
cross-resistant to previously used antiretroviral drugs (or share similar
patterns of mutations associated with antiretroviral drug resistance).
8.
When changing a failing regimen, it is important to change more than one
component of the regimen. The addition of single antiretroviral agents, even
very potent ones, is likely to lead to the development of viral resistance to
the new agent. (See Guidelines)
Principle
6.
Each of the antiretroviral drugs used in combination therapy regimens should
always be used according to optimum schedules and dosages. The use of
combinations of potent antiretroviral drugs to exert constant, maximal
suppression of HIV replication provides the best approach to circumvent the
inherent tendency of HIV to generate drug-resistant variants. Specific
considerations regarding treatment include the following:
1.
Combination therapy should be initiated with all drugs started simultaneously
(ideally within 1 or 2 days of each other); antiretroviral therapies should not
be added sequentially. Staged introduction of individual antiretroviral drugs
increases the likelihood that incomplete suppression of HIV replication will be
achieved, thereby permitting the progressive accumulation of mutations that
confer resistance to multiple antiretroviral agents. Rather than strive to
increase patient acceptance of therapy through the sequential addition of
antiretroviral drugs, the Panel believes it is better to counsel and educate
patients extensively before the initiation of antiretroviral therapy, even if it
means a limited delay in initiating treatment.
2.
Whenever possible, combination antiretroviral therapy should be maintained at
recommended drug doses. At any time after initiation of therapy, underdosing
with any one agent in a combination, or the administration of fewer than all
drugs of a combination at any one time, should be avoided. Antiretroviral drug
resistance is less likely to occur if all antiretroviral therapy is temporarily
stopped than if the dosage of one or more components is reduced or if one
component of an effective suppressive regimen is withheld. Should antiretroviral
drug resistance develop as a result of underdosing or irregular dosing of
antiretroviral drugs, subsequent readministration of recommended doses of drugs
on a regular schedule is unlikely to accomplish effective suppression of HIV
replication.
3.
Patient adherence to an antiretroviral regimen is critical to the success of
therapy. If antiretroviral drugs are used in inadequate doses or are used only
intermittently, the risk for developing drug-resistant HIV variants is greatly
increased. Effective adherence to complicated medical regimens requires
extensive patient education about the goals and rationale for therapy before it
is initiated, as well as an ongoing, active collaboration between practitioner
and patient when therapy has been started. Counseling should include careful
review of the drug-dosing intervals, the possibility of coadministration of
several medications at the same time, and the relationship of drug dosing to
meals and snacks.
4.
Available effective regimens of combination antiretroviral therapy require that
patients take multiple medications at specific times of the day. Persons who
have unstable living situations or limited social support mechanisms may have
difficulty adhering to the recommended antiretroviral therapy regimens and may
need special support from healthcare workers to do so effectively. If
circumstances impede adherence to the most effective antiretroviral regimens now
available, therapy is unlikely to be of long-term benefit to the patient and the
risk of selection of drug-resistant HIV variants is increased. Therefore, it is
important to ensure that adequate social support is available for patients who
are offered combination antiretroviral therapy. Healthcare providers should work
with HIV-infected patients to assess if they are ready and able to commit to a
regimen of antiviral therapy. Healthcare providers should make such assessment
on an individual basis and not consider that any specific group of persons are
unable to adhere.
Principle
7.
The available effective drugs are limited in number and mechanism of action, and
cross resistance between specific drugs has been documented. Therefore, any
change in antiretroviral therapy increases future therapeutic constraints.
Decisions to alter therapy will rely heavily on consideration of clinical issues
and on the number of available alternative antiretroviral agents. Every decision
made to alter therapy may limit future treatment options. Thus, available agents
should not be abandoned prematurely. It is not known definitively whether the
pathogenic consequences of a measurable level of HIV replication while on
therapy are equivalent to those of an equivalent level in an untreated person;
however, preliminary data suggest that this is the case. Thus, the level at
which HIV replication continues while on an antiretroviral drug regimen that has
failed to suppress plasma HIV RNA to below detectable levels should be
considered as an indication of the urgency with which an alteration in therapy
should be pursued. Specific considerations regarding treatment include the
following:
1.
Increasing levels of plasma HIV RNA in a person receiving antiretroviral therapy
can be caused by several factors. Identification of the responsible factor,
wherever possible, is an important goal. Evidence of increased levels of HIV
replication may signal the emergence of drug-resistant HIV variants, incomplete
adherence to the antiretroviral therapy, decreased absorption of antiretroviral
drugs, altered drug metabolism due to physiologic changes or drug-drug
interactions, or intercurrent infection.
2.
Before the decision is made to alter antiretroviral therapy because of an
increase in plasma HIV RNA, it is important to repeat the plasma HIV RNA
measurements to avoid unnecessary changes based on misleading or spurious plasma
HIV RNA values (e.g., the presence of intercurrent infection or imperfect
adherence to therapy).
3.
Antiretroviral therapy should be changed when plasma HIV RNA again becomes
detectable (repeatedly and in the absence of events such as imperfect adherence
to the regimen, immunizations, or intercurrent infections that may lead to
transient elevations of plasma HIV RNA levels) and continues to rise in a
patient in whom it had been previously suppressed to undetectable levels. In a
person whose plasma HIV RNA levels had been previously incompletely suppressed,
progressively increasing plasma HIV RNA levels should prompt consideration of a
change in antiretroviral therapy. (See Guidelines.)
4.
Evidence of antiretroviral drug toxicity or intolerance is also an important
reason to consider changes in drug therapy. In certain instances, these
manifestations may be transient, and therapy may be safely continued with
attention to patient counseling and continuing evaluation. When it is necessary
to change therapy for reasons of toxicity or intolerance, alternative
antiretroviral drugs should be chosen based on their anticipated efficacy and
lack of similar toxicities. In this situation, substitution of one drug (ideally
of the same class and possessing equal or greater antiretroviral activity) for
another, while continuing the other components of the regimen, is reasonable.
Principle
8.
Women should receive optimal antiretroviral therapy regardless of pregnancy
status.
The
use of antiretroviral treatment in HIV-infected pregnant women raises important,
unique concerns (64). HIV counseling and the offer of HIV testing to pregnant
women have been universally recommended in the United States and are now
mandatory in some states. A greater awareness of issues surrounding HIV
infection in pregnant women has resulted in an increased number of women whose
initial diagnosis of HIV infection is made during pregnancy. In this
circumstance, or when women already aware of their HIV infection become
pregnant, treatment decisions should be based on the current and future health
of the mother, as well as on preventing perinatal transmission and ensuring the
health of the fetus and neonate. Care of the HIV-infected pregnant woman should
involve a collaboration between the HIV specialist caring for the woman when she
is not pregnant, her obstetrician, and the woman herself. Treatment
recommendations for HIV-infected pregnant women are based on the belief that
therapies of known benefit to women should not be withheld during pregnancy
unless there are known adverse effects on the mother, fetus, or infant that
outweigh the potential benefit to the woman (64). There are two separate but
interconnected issues regarding antiretroviral treatment during pregnancy: a)
use of antiretroviral therapy for maternal health indications and b) use of
antiretroviral drugs for reducing the risk of perinatal HIV transmission.
Although zidovudine monotherapy substantially reduces the risk of perinatal HIV
transmission, appropriate combinations of antiretroviral drugs should be
administered if indicated on the basis of the mother's health. In general,
pregnancy should not compromise optimal HIV therapy for the mother. Specific
considerations regarding treatment of pregnant women include the following:
1.
Recommendations regarding the choice of antiretroviral agents in pregnant women
are subject to unique considerations, including potential changes in dose
requirements due to physiologic changes associated with pregnancy and potential
effects of the drug on the fetus and neonate (e.g., placental passage of drug
and preclinical data indicating potential for teratogenicity, mutagenicity, or
carcinogenicity).
2.
No long-term safety studies are available regarding the use of any
antiretroviral agents during pregnancy. Because the first trimester of pregnancy
(i.e., weeks 1-14) is the most vulnerable time with respect to teratogenicity
(particularly the first 8 weeks), it may be advisable to delay, when feasible,
the initiation of antiretroviral therapy until 14 weeks' gestational age.
However, if clinical, virologic, or immunologic parameters are such that therapy
would be recommended for nonpregnant persons, many experts would recommend
initiating therapy, regardless of gestational age.
3.
Women who are already receiving antiretroviral therapy at the time that
pregnancy is diagnosed should continue their therapy. Alternatively, if
pregnancy is anticipated or discovered early in the first trimester (before 8
weeks), concern for potential teratogenicity may lead some women to consider
stopping antiretroviral therapy until 14 weeks' gestation. Although the effects
of all antiretroviral drugs on the developing fetus during the first trimester
are uncertain, most experts recommend continuation of a maximally suppressive
regimen even during the first trimester. Currently, insufficient data exist to
support or refute concerns about potential teratogenicity. If antiretroviral
therapy is discontinued for any reason during the first trimester, all agents
should be discontinued simultaneously. Once they are reinstituted, they should
be reintroduced simultaneously.
4.
Treatment of a pregnant woman with an antiretroviral regimen that does not
suppress HIV replication to below detectable levels is likely to result in the
development of antiretroviral drug-resistant HIV variants and limit her ability
to respond favorably to effective combination therapy regimens in the future.
The emergence of drug-resistant HIV variants during incomplete suppression of
HIV replication in a pregnant woman may limit the ability of those same
antiretroviral drugs to effectively decrease the risk of perinatal transmission
if provided intrapartum and/or to the neonate.
5.
Transmission of HIV from mother to infant can occur at all levels of maternal
viral loads, although higher viral loads tend to be associated with an increased
risk of transmission (53,65). Zidovudine therapy is effective at reducing the
risk for perinatal HIV transmission regardless of maternal viral load (53,54).
Therefore, use of the recommended regimen of zidovudine alone or in combination
with other antiretroviral drugs should be discussed with and offered to all
HIV-infected pregnant women, regardless of their plasma HIV RNA level (54).
Principle
9.
The same principles of antiretroviral therapy apply to HIV-infected children,
adolescents, and adults, although the treatment of HIV-infected children
involves unique pharmacologic, virologic, and immunologic considerations. Most
of the data that support the principles of antiretroviral therapy outlined in
this document have been generated in studies of HIV-infected adults. Adolescents
infected with HIV sexually or through drug use appear to follow a clinical
course similar to adults, and recommendations for antiretroviral therapy for
these persons are the same as for adults (see Guidelines). However, although
fewer data are available concerning treatment of HIV infection in younger
persons, it is unlikely that the fundamental principles of HIV disease differ
for HIV-infected children. Furthermore, the data that are available from studies
of HIV-infected infants and children indicate that the same fundamental
virologic principles apply, and optimal treatment approaches are also likely to
be similar (14-18,25). Therefore, HIV-infected children, as previously described
for HIV-infected adults, should be treated with effective combinations of
antiretroviral drugs with the intent of accomplishing durable suppression of
detectable levels of HIV replication.
Unfortunately,
not all of the antiretroviral drugs that have demonstrated efficacy in
combination therapy regimens in adults are available in formulations (e.g.,
palatable liquid formulations) for infants and young children (particularly for
those aged <2 years). In addition, pharmacokinetic and pharmacodynamic
studies of some antiretroviral agents have yet to be completed in children.
Thus, effective antiretroviral therapies should be studied in children and
age-specific pharmacologic properties of these therapies should be defined.
Antiretroviral drugs selected to treat HIV-infected children should be used only
if their pharmacologic properties have been defined in the relevant age group of
the patient. Use of antiretroviral drugs before these properties have been
defined may result in undesirable toxicities without virologic or clinical
benefit.
Identification
of HIV-infected infants soon after delivery or during the first few weeks
following their birth provides opportunities for treatment of primary HIV
infection and, perhaps, for facilitating the most effective treatment responses
(16-18,66). Thus, identification of HIV-infected women through voluntary
testing, provision of antiretroviral therapy to the mother and infant to
decrease the risk of maternal-infant transmission, and careful screening of
infants born to HIV-infected mothers for evidence of HIV infection will provide
an effective strategy to ameliorate the risk and consequences of perinatal HIV
infection.
The
specific HIV RNA and CD4+T cell criteria used for making decisions about when to
initiate therapy in infected adults do not apply directly to newborns, infants,
and young children (14-18). As with adults, higher levels of plasma HIV RNA are
associated with a greater risk of disease progression and death in infants and
young children (14-18). However, absolute levels of plasma HIV RNA observed
during the first years of life in HIV-infected children are frequently higher
than those found in adults infected for similar lengths of time, and
establishment of a post-primary-infection set-point takes substantially longer
in infected children (15-18). The increased susceptibility of children to OIs,
particularly Pneumocystis carinii pneumonia (PCP), at higher CD4+T cell counts
than HIV-infected adults (30) further indicates that the CD4+T cell criteria
suggested as guides for initiation of antiretroviral therapy in HIV-infected
adults are not appropriate to guide therapeutic decisions for infected children.
In all, the need for and potential benefits of early institution of effective
antiretroviral therapy are likely to be even greater in children than adults,
suggesting that most, if not all, HIV-infected children should be treated with
effective combination antiretroviral therapies.
Principle
10.
Persons identified during acute primary HIV infection should be treated with
combination antiretroviral therapy to suppress virus replication to levels below
the limit of detection of sensitive plasma HIV RNA assays. Studies of HIV
pathogenesis provide theoretical support for the benefits of antiretroviral
therapy for persons diagnosed with primary HIV infection, and data that are
accumulating from small-scale clinical studies are consistent with these
predictions (49,66-73). Results from studies suggest that antiretroviral therapy
during primary infection may preserve immune system function by blunting the
high level of HIV replication and immune system damage occurring during this
period and potentially reducing set-point levels of HIV replication, thereby
favorably altering the subsequent clinical course of the infection; however,
this outcome has yet to be formally demonstrated (51,73). It has been further
suggested that the best opportunity to eradicate HIV infection might be provided
by the initiation of potent combination antiretroviral therapy during primary
infection (51).
The
Panel believes that, although the long-term benefits of effective combination
antiretroviral therapy of primary infection are not known, it is a critical
topic of investigation. Therefore, enrollment of newly diagnosed patients in
clinical trials should be encouraged to help in defining the optimal approach to
treatment of primary infection. When this is neither feasible nor desired, the
Panel believes that combination antiretroviral therapy with the goal of
suppression of HIV replication to undetectable levels should be pursued. The
Panel believes that suppressive antiretroviral therapy for acute primary HIV
infection should be continued indefinitely until clinical trials provide data to
establish the appropriate duration of therapy.
Principle
11.
HIV-infected persons, even those whose viral loads are below detectable limits.
Therefore, they should be considered infectious. Therefore, they should be
counseled to avoid sexual and drug-use behaviors that are associated with either
transmission or acquisition of HIV and other infectious pathogens. No data are
available concerning the ability of HIV-infected persons who have antiretroviral
therapy-induced suppression of HIV replication to undetectable levels (assessed
by plasma HIV RNA assays) to transmit the infection to others. Similarly, their
ability to acquire a multiply resistant HIV variant from another person remains
a possibility. HIV-infected persons who are receiving antiretroviral therapy
continue to be able to transmit serious infectious diseases to others (e.g.,
hepatitis B and C and sexually transmitted infections, such as herpes simplex
virus, human papillomavirus syphilis, gonorrhea, chancroid, and chlamydia) and
are themselves at risk for infection with these pathogens, as well as others
that carry serious consequences for immunosuppressed persons, including
cytomegalovirus and human herpes virus 8 (also known as KSHV). Therefore, all
HIV-infected persons, including those receiving effective antiretroviral
therapies, should be counseled to avoid behaviors associated with the
transmission of HIV and other infectious agents. Continued reinforcement that
all HIV-infected persons adhere to safe-sex practices is important. If an
HIV-infected injecting-drug user is unable or unwilling to refrain from using
injection drugs, that person should be counseled to avoid sharing injection
equipment with others and to use sterile, disposable needles and syringes for
each injection.