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. (See Guidelines)
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). (See Guidelines)
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). (See Guidelines)
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). (See Guidelines)
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. (See Guidelines.)
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. (See Guidelines)
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. (see Guidelines)
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. (See Guidelines)
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). (See Principle 7 for additional considerations)
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). (See Guidelines)
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.
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