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These Guidelines were developed by the Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation. Leadership of the Panel consists of Anthony S. Fauci, National Institutes of Health, Bethesda, MD (co-chair); John G. Bartlett, Johns Hopkins University, Baltimore, MD (co-chair); Eric P. Goosby, DHHS (convener); Mark D. Smith, California HealthCare Foundation, San Francisco, CA, formerly of the Henry J. Kaiser Foundation (convener.) Succeeded by Sophia W. Chang, Henry J. Kaiser Foundation. Current members of the Panel include: Jean Anderson (Johns Hopkins University, Baltimore, MD), Rodney Armstead (Watts Health Foundation, Inc., Inglewood, CA), A. Cornelius Baker (National Association of People with AIDS, Washington, DC), David Barr (Forum for Collaborative HIV Research, Washington, DC), Samuel A. Bozzette (SDVA Medical Center, San Diego, CA), Charles Carpenter (Brown U. School of Medicine, Providence, RI), Spencer Cox (Treatment Action Group, New York, NY), Elaine M. Daniels (Oxo-Chemie, Inc.), Martin Delaney (Project Inform, San Francisco, CA), Fred Gordin, (Veterans Administration Medical Center, Washington, DC), Wayne Greaves (SPRI, Edison, NJ), Mark Harrington (Treatment Action Group, New York, NY), Martin S. Hirsch (Massachusetts General Hospital, Boston, MA), John W. Mellors (University of Pittsburgh, Pittsburgh, PA), Sallie Perryman (New York State Department of Health, New York, NY), Robert T. Schooley (University of Colorado, Denver, CO), Renslow Sherer (Cook County HIV Primary Care Center, Chicago, IL), Stephen A. Spector (University of California San Diego, La Jolla, CA), Sharilyn K. Stanley (Texas Department Of Health), Gabriel Torres (Bentley-Salick Medical Practice, New York, NY), Paul Volberding (University of California, San Francisco, CA); participants from the Department of Health and Human Services: Oren Cohen (National Institutes of Health), T. Randolph Graydon (Health Care Financing Administration), Heidi Jolson (Food and Drug Administration), Jonathan Kaplan (Centers for Disease Control and Prevention), Abe Macher (Health Resources and Services Administration), Henry Masur (National Institutes of Health), Lynne Mofenson (National Institutes of Health), Jeffrey Murray (Food and Drug Administration), Joseph O'Neill (Health Resources and Services Administration), Alice Pau (National Institutes of Health), Lucille C. Perez (Substance Abuse and Mental Health Services Administration), Steve Piscitelli (National Institutes of Health), Richard Riseberg (Office of the Secretary), ), Jack Whitescarver (National Institutes of Health). Non-voting observers include: Gerry Bally (Health Canada), Jeffrey Jacobs (AIDS Action Council, Washington, DC), Richard Marlink (Harvard AIDS Institute, Cambridge, MA), Celia Maxwell (AIDS Education and Training Center, Washington, DC), Daniel Simpson (Indian Health Service). Summary This report recommends that care should be supervised by an expert, and makes recommendations for laboratory monitoring with particular emphasis on measurement of plasma levels of HIV RNA. The report also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special considerations are provided for adolescents and pregnant women. As with treatment of other chronic conditions, therapeutic decisions require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Like the treatment of most chronic diseases, antiretroviral regimens are complex, have major side effects, pose difficulty with compliance, and carry serious potential consequences with the risk of resistance from non-adherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is important for all medical conditions, but is considered especially critical for HIV infection and its treatment. With regard to specific recommendations, treatment should be offered to all patients with the acute HIV syndrome, those within six months of seroconversion, and all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy in asymptomatic patients depend on virologic and immunologic factors. In general, treatment should be offered to individuals with fewer than 500 CD4 + T cells/mm 3 or plasma HIV RNA levels exceeding 10,000 copies/ml (bDNA assay) or 20,000 copies/ml (RT-PCR assay). The strength of the recommendation to treat asymptomatic patients should be based on the patient's willingness to accept therapy, the probability of adherence with the prescribed regimen and the prognosis in terms of time to an AIDS-defining complication as predicted by plasma HIV RNA levels and CD4 + T cell counts, which independently help to predict prognosis. Once the decision has been made to initiate antiretroviral therapy, the goal is maximum viral suppression for as long as possible. Results of clinical trials to date indicate that this may currently be best achieved with a potent protease inhibitor (PI) or the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Another option is the combination of saquinavir plus ritonavir combined with one or two NRTIs. Other currently available regimens may be used in selected settings, but are considered by many to be less likely to produce maximum viral suppression. Results of therapy are evaluated primarily with plasma HIV RNA levels; these are expected to show a one log (10 fold) decrease at eight weeks and no detectable virus (<500 copies/ml) at 4-6 months after initiation of treatment. Failure of therapy (i.e., plasma HIV RNA levels exceeding 500 copies/ml) at 4-6 months may be ascribed to non-adherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, resistance, and other factors that are poorly understood. Patients whose therapy fails should change to at least two new agents that are not likely to show cross-resistance with drugs given previously; ideally, the regimen should be changed to a completely new regimen devoid of anticipated cross-resistance and with clinical trial data supporting a high probability of viral response. Rational changes in therapy may be especially difficult to achieve for patients for which the preferred regimen has failed, due to limitations in the available alternative antiretroviral regimens that have documented efficacy; these decisions are further confounded by problems with adherence, toxicity, and resistance. In some settings it may be preferable to participate in a clinical trial with or without access to new drugs or to use a regimen that may not achieve the optimal virologic goal. It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has a mechanism to update recommendations on a regular basis, and the most recent information is available on the HIV/AIDS Treatment Information Service website (http://www.hivatis.org). Guidelines for the Use of Antiretroviral Agents In HIV-Infected Adults and Adolescents These guidelines are intended for use by physicians and other health care providers who use antiretroviral therapy to treat HIV-infected adults and adolescents and serves as the companion document to the therapeutic principles formulated by the National Institutes of Health (NIH) Panel to Define Principles of Therapy of HIV Infection. The recommendations in this document are presented in the context of and with reference to the Principles of Therapy contained in the companion document. Together the documents should provide the pathogenesis-based rationale for therapeutic strategies as well as practical guidelines for implementing these strategies. While the guidelines represent the current state of knowledge regarding the use of antiretroviral agents, this is a rapidly evolving field of science, and the availability of new agents or new clinical data regarding the use of existing agents will result in changes in therapeutic options and preferences. Thus, in recognition of the need for frequent updates to this document, a subgroup of the Panel, the Antiretroviral Working Group, will meet monthly to review new data as it becomes available; recommendations for changes in this document will then be submitted to the Panel and incorporated as appropriate. Copies of this document and all updates are available from the HIV/AIDS Treatment Information Service-ATIS (1-; TTY 1-; Fax ) and on the ATIS Web site (http://www.hivatis.org). They are also available from the National Prevention Information Network (NPIN) Web site (http://www.cdcnpin.org). These recommendations are not intended to substitute for the judgment of a physician who is an expert in the care of HIV-infected individuals. It is important to note that the Panel felt that where possible the treatment of HIV-infected patients should be directed by a physician with extensive experience in the care of these patients. When this is not possible, it is important to have access to such expertise through consultations. Each recommendation is accompanied by a rating that includes a letter and a Roman numeral (Table I), similar to the rating schemes used in previous guidelines on the prophylaxis of opportunistic infections (Ols) issued by the U.S. Public Health Service and the Infectious Diseases Society of America (1). The letter indicates the strength of the recommendation, based on the opinion of the Panel, while the Roman numeral rating reflects the nature of the evidence for the recommendation (Table I). Thus, recommendations based on data from clinical2 trials with clinical endpoints are differentiated from those with laboratory endpoints such as CD4 + T lymphocyte count or plasma HIV RNA levels; where no clinical trial data are available, recommendations are based on the opinions of experts familiar with the relevant scientific literature. It should be noted that the majority of clinical trial data available to date regarding the use of antiretroviral agents have been obtained in trials enrolling predominantly young to middle-aged males. While current knowledge indicates that women may differ from men in the absorption, metabolism and clinical effects of certain pharmacologic agents, clinical experience and data available to date would suggest that there are no significant gender differences known that would modify these guidelines. However, theoretical concerns exist. The Panel urges continuation of the current efforts to enroll more women in antiretroviral clinical trials so that the data needed to re-evaluate this issue can be gathered expeditiously. This document addresses the following issues: the use of testing for plasma HIV RNA levels (viral load) and CD4 + T cell count; considerations for when to initiate therapy in established HIV infection; special considerations for therapy in patients with advanced stage disease; interruption of therapy; considerations for changing therapy and available therapeutic options; the treatment of acute HIV infection; considerations for antiretroviral therapy in adolescents; and considerations for antiretroviral therapy in the pregnant woman. Use of Testing for Plasma HIV RNA Levels and CD4 + T Cell Count in Guiding Decisions for Therapy When making decisions regarding the initiation of therapy, the CD4 + T lymphocyte count and plasma HIV RNA measurement should ideally be performed on two occasions to ensureaccuracy and consistency of measurement (Blll). However, in patients who present with advanced HIV disease, antiretroviral therapy should generally be initiated after the first viral load measurement is obtained in order to prevent a potentially deleterious delay in treatment. It is recognized that the requirement for two measurements of viral load may place a significant financial burden on patients or payers. Nonetheless, the Panel feels that two measurements of viral load will provide the clinician with the best information for subsequent follow-up of the patient. Consistent with Principle 2, plasma HIV RNA levels should not be measured during or within four weeks after successful treatment of any intercurrent infection, resolution of symptomatic illness, or immunization. Because there are differences among commercially available tests, confirmatory plasma HIV RNA levels should be measured by the same laboratory using the same technique in order to ensure consistent results. A minimally significant change in plasma viremia is considered to be a 3-fold or 0.5 log 10 increase or decrease. A significant decrease in CD4 + T lymphocyte count is a decrease of >30% from baseline for absolute cell numbers and a decrease of >3% from baseline in percentages of cells (3,4). Discordance between trends in CD4 + T cell numbers and plasma HIV RNA levels can occur and was found in 20% of patients in one cohort studied (5). Such discordance can complicate decisions regarding antiretroviral therapy and may be due to a number of factors that affect plasma HIV RNA testing (see Principle 2). In general, viral load and trends in viral load are felt to be more informative for guiding decisions regarding antiretroviral therapy than are CD4 + T cell counts; exceptions to this rule do occur, however. For further discussion refer to "Considerations for changing a failing regimen;" in many such cases, expert consultation should be considered. Established Infection
Additional evaluation should include routine tests pertinent to the prevention of Ols, if not already performed (VDRL, tuberculin skin test, toxoplasma lgG serology, and gynecologic exam with Pap smear), and other tests as clinically indicated (e.g., chest X-ray, hepatitis C virus (HCV) serology, ophthalmologic exam) (All). Hepatitis B virus (HBV) serology is indicated in a patient who is a candidate for the hepatitis B vaccine or has abnormal liver function tests (All), and CMV serology may be useful in certain individuals, as discussed in the "USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with the Human Immunodeficiency Virus" (1) (Blll). Considerations for Initiating Therapy in the Patient with Asymptomatic HIV Infection Table lll summarizes some of the factors that the physician and the asymptomatic patient must consider in deciding when to initiate therapy (see also Principle 3). Factors that would lead one to initiate early therapy include the real or potential goal of maximally suppressing viral replication; preserving immune function; prolonging health and life; decreasing the risk of drug resistance due to early suppression of viral replication with potent therapy; decreasing drug toxicity by treating the healthier patient; and possibly decreasing the risk of viral transmission. Factors weighing against early treatment in the asymptomatic stable patient include the potential adverse effects of the drugs on quality of life, including the inconvenience of most of the maximally suppressive regimens currently available; the potential risk of developing drug resistance despite early initiation of therapy; the potential for limiting future treatment options due to cycling of the patient through the available drugs during early disease; the potential risk of transmission of virus resistant to protease inhibitors and other agents; the unknown durability of effect of the currently available therapies; and the unknown long term toxicity of some drugs. Thus, the decision to begin therapy in the asymptomatic patient is complex and must be made in the setting of careful patient counseling and education. The factors that must be considered in this decision are: 1) the willingness of the individual to begin therapy; 2) the degree of existing immunodeficiency as determined by the CD4 + T cell count; 3) the risk of disease progression as determined by the level of plasma HIV RNA (Table IV and Figure 1; see also Principles document); 4) the potential benefits and risks of initiating therapy in5 asymptomatic individuals, as discussed above; and 5) the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. In this regard, no individual patient should automatically be excluded from consideration for antiretroviral therapy simply because he or she exhibits a behavior or other characteristics judged by some to lend itself to noncompliance. Rather, the likelihood of patient adherence to a complex drug regimen should be discussed and determined by the individual patient and physician before therapy is initiated. To achieve the level of adherence necessary for effective therapy, providers are encouraged to utilize strategies for assessing and assisting adherence that have been developed in the context of chronic treatment for other serious diseases; in this regard, intensive patient education regarding the critical need for adherence should be provided, specific goals of therapy should be established and mutually agreed upon and a long-term treatment plan should be developed with the patient. Intensive follow up should take place to assess adherence to treatment and to continue patient counseling for the prevention of sexual and drug injection-related transmission. Initiating Therapy in the Patient with Asymptomatic HIV Infection Tables V and VI summarize the recommendations regarding when to initiate therapy and what regimens to use. In general, any patient with less than 500 CD4 + T cells/mm 3 or greater than 10,000 (bDNA) or 20,000 (RT-PCR) copies of HIV RNA/ml of plasma should be offered therapy (All). This recommendation is based on the relationship between viral load, CD4+ T cell counts, and rates of HIV disease progression in men. Recent data suggest that viral load in women is approximately 50% lower compared with viral load in men for the same rate of CD4+ T cell decline and time to AIDS (12). These findings are limited to non-pregnant women who acquired HIV primarily by injection drug use, and have not been consistently observed (13). No changes in current guidelines for viral load threshold to offer treatment are recommended because these differences are within the error of the viral load assay and the applicability of these conclusions to other populations of women with HIV infection is unknown. The strength of the recommendation for therapy should be based on the readiness of the patient for treatment as well as a consideration of the prognosis for disease-free survival as determined by viral load, CD4 + T cell count (Table IV and Figure 1), and the slope of the CD4 + T cell count decline. Note that the values for bDNA shown in Figure 1 and Table IV (first line or column) are the uncorrected HIV RNA values obtained from the Multicenter AIDS Cohort Study (MACS). It had previously been thought that these values, obtained on stored heparinized plasma specimens, should be multiplied by a factor of two to adjust for an anticipated two-fold loss of RNA ascribed to the effects of heparin and delayed processing on the stability of RNA. However, more recent analysis suggests that the reduction ascribed to these factors is # 0.2 log, so that no significant correction factor is necessary (Mellors J, personal communication, October 1997). RT-PCR values are also shown in Table IV and Figure 1; comparison of the results obtained from the RT-PCR and bDNA assays using the manufacturer's controls consistently indicate that the HIV-1 RNA values obtained by RT-PCR are approximately two times higher than those obtained by the bDNA assay (14). Thus, the MACS values must be multiplied by approximately 2 to be consistent with current RT-PCR values. A third test for HIV RNA, the Nucleic-Acid Sequence Based Amplification (NASBA), is currently used in some clinical settings. However, formulas for converting values obtained from either bDNA or RT-PCR assays to NASBA-equivalent values cannot be derived from the limited data available at this time. This information will be added to the guidelines when it becomes available. In current practice there are two general approaches to initiating therapy in the asymptomatic patient: a therapeutically more aggressive approach that would treat most patients early in the course of HIV infection due to the recognition that HIV disease is virtually always progressive; and a more therapeutically cautious approach in which therapy may be delayed because the balance of the risk of clinically significant progression and other factors discussed above are felt to weigh in favor of observation and delayed therapy. The aggressive approach is heavily Based on the Principles of Therapy, particularly the Principle that one should begin treatment6 before the development of significant immunosuppression and one should treat to achieve undetectable viremia; thus, all patients with less than 500 CD4 + T cells/mm 3 would be started on therapy as would patients with higher CD4 + T cell numbers who have plasma viral load > 10,000 (bDNA) or 20,000 (RT-PCR)(Table V). The more conservative approach to the initiation of therapy in the asymptomatic individual would delay treatment of the patient with <500 CD4 + T cells/mm 3 and low levels of viremia who have a low risk of rapid disease progression, according to the data in Table IV; careful observation and monitoring would continue. Patients with CD4 + T cell counts > 500/mm 3 would also be observed, except those at substantial risk of rapid disease progression because of a high viral load. For example, the patient with 60,000 (RT-PCR) or 30,000 (bDNA) copies of HIV RNA/ml, regardless of CD4 + T cell count, has a high probability of progressing to an AIDS-defining complication of HIV disease within 3 years (32.6% if CD4 + T cells are greater than 500/mm 3 ) and should clearly be encouraged to initiate antiretroviral therapy. On the other hand, a patient with 18,000 copies of HIV RNA/ml of plasma, measured by RT-PCR, and a CD4 + T cell count of 410/mm 3 has a 5.9% chance of progressing to an AIDS-defining complication of HIV infection in 3 years (Table IV). The therapeutically aggressive physician would recommend treatment for this patient to suppress the ongoing viral replication that is readily detectable; the therapeutically more conservative physician would discuss the possibility of initiation of therapy, but recognize that a delay in therapy due to the balance of considerations discussed above is also reasonable. In either case, the patient should make the final decision regarding acceptance of therapy following discussion with the health care provider of specific issues relevant to his/her own clinical situation. When initiating therapy in the patient naïve to antiretroviral therapy, one should begin with a regimen that is expected to reduce viral replication to undetectable levels (Alll). Based on the weight of experience, the preferred regimen to accomplish this is 2 nucleoside analogues (NRTIs) and one potent protease inhibitor (Pl); however, recent data with the use of efavirenz (an NNRTI) in place of the PI may support such a substitution (Table VI). Alternative regimens have been employed; these include ritonavir and saquinavir (with one or two nucleoside analogues) or nevirapine as a substitute for the protease inhibitor. Ritonavir and saquinavir (hard gel capsule) dual PI therapy (without an NRTI) appears to be potent in suppressing viremia below detectable levels, and has convenient BID dosing; however, the safety of this combination has not been fully established according to FDA guidelines. In addition, this regimen has not been directly compared to the proven regimens of 2 NRTIs and a PI, and thus the Panel recommends that at least one additional NRTI be used when the physician elects to use 2 PIs as initial therapy. Substituting nevirapine for the PI, or Using 2 NRTIs alone does not achieve the goal of suppressing viremia to below detectable levels as consistently as does combination treatment with 2 NRTIs and a PI and should be used only if more potent treatment is not possible. It should be noted, however, that Some experts feel that there are currently insufficient data to choose between a three drug regimen containing a protease inhibitor and one containing efavirenz or nevirapine in the drug-naïve patient; further studies are pending. In one large trial, efavirenz, a newly approved NNRTI, was at least equivalent to the PI, indinavir (when either drug was combined with 2 NRTIs), in terms of suppression of HIV plasma viremia to <50 copies/ml over 48 weeks of follow-up. Likewise, other regimens using two PIs or a PI and a non-nucleoside reverse transcriptase inhibitor (NNRTI) as initial therapy are currently in clinical trails with data pending; in one, the combination of efavirenz with indinavir was as effective as when the PI was used with two NRTIs. Although no direct comparative trials exist that would allow a ranking of the relative efficacy of the NNRTIs, the demonstrated ability of efavirenz in combination with 2 NRTIs to suppress viral replication to a similar degree as a PI with 2 NRTIs support a preference for efavirenz over the other available NNRTIs at this time. The NRTI abacavir, in combinationwith ZDV and 3TC, appears to suppress plasma viral load to a similar degree whencompared with indinavir plus 2 NRTIs after 48 weeks of follow-up. This 3 NRTI regimen spares the initial use of PIs and NNRTIs; however, because the durability of viral load suppression with this regimen that includes drugs from a single drug class (i.e. NRTIs) is uncertain, and because abacavir is associated with a potentially life-threatening hypersensitivity syndrome, a PI-containing or efavirenz-containing regimen is preferred (Table VI). Insufficient clinical trial data are available to guide the optimal use of abacavir as a potent NRTI in combination with PIs and/or NNRTIs. Although 3TC is a potent NRTI when used in combination with another NRTI, in situations in which suppression of7 virus replication is not complete, resistance to 3TC develops rapidly (15, 16). Therefore, the optimal use for this agent is as part of a three or more drug combination that has a high chance of complete suppression of virus replication. Other agents in which a single genetic mutation can confer drug resistance, such as the NNRTIs efavirenz, nevirapine and delavirdine, should also be used in this manner. Use of antiretroviral agents as monotherapy is contraindicated (DI), except when there are no other options, or in pregnancy to reduce perinatal transmission as noted below. When initiating antiretroviral therapy, all drugs should be started simultaneously at full dose with the following three exceptions: dose escalation regimens are recommended for ritonavir, nevirapine, and in some cases, ritonavir plus saquinavir. The addition of hydroxyurea to certain antiretroviral regimens may enhance the activity of these agents; however, due to a number of toxicities and a relative lack of data from controlled clinical trials, a role for hydroxyurea in the treatment of HIV infection remains uncertain. Detailed information comparing the different nucleoside RT inhibitors , non-nucleoside RT inhibitors, the protease inhibitors, and drug interactions between the protease inhibitors and other agents can be found in Tables VII-XIII. In addition, because certain investigational new drugs are available to physicians for use in selected patients, Table XIV has been provided for the physician treating patients under investigational protocols. Particular attention should be paid to Tables IX-XII regarding drug interactions between the protease inhibitors and other agents, as these are extensive and often require dose modification or substitution of various drugs. Toxicity assessment is an ongoing process; assessment at least twice during the first month of therapy and every 3 months thereafter is a reasonable management approach. Initiating Therapy in Advanced HIV Disease Special Considerations in the Patient with Advanced Stage Disease Patients who have progressed to AIDS are often treated with complicated combinations of drugs and the potential for multiple drug interactions must be appreciated by clinician and patient. Thus, the choice of which antiretroviral agents to use must be made with consideration given to potential drug interactions and overlapping drug toxicities, as outlined in Tables VII-XIII. For instance, the use of rifampin to treat active tuberculosis is problematic in a patient receiving a protease inhibitor, which adversely affects the metabolism of rifampin but is frequently needed to effectively suppress viral replication in these advanced patients. Conversely, rifampin lowers the blood level of protease inhibitors, which may result in suboptimal antiretroviral therapy. While rifampin is contraindicated or not recommended for use with all of the protease inhibitors, one might consider using rifabutin at a reduced dose, as indicated in Tables VIII-XI; this topic is discussed in greater detail elsewhere (17). Other factors complicating advanced disease are8 wasting and anorexia, which may prevent patients from adhering to the dietary requirements for efficient absorption of certain protease inhibitors. Bone marrow suppression associated with ZDV and the neuropathic effects of ddC, d4T and ddl may combine with the direct effects of HIV to render the drugs intolerable. Hepatotoxicity associated with certain protease inhibitors may limit the use of these drugs, especially in patients with underlying liver dysfunction. The absorption and half life of certain drugs may be altered by antiretroviral agents, particularly the protease inhibitors and NNRTIs whose metabolism involves the hepatic cytochrome p450 (CYP450) enzymatic pathway. Some of these PIs and NNRTIs (ritonavir, indinavir, saquinavir, nelfinavir and delavirdine) inhibit the CYP450 pathway; others (nevirapine) induce CYP450 metabolism. CYP450 inhibitors have the potential to increase blood levels of drugs metabolized by this pathway. At times, adding a CYP450 inhibitor can improve the pharmacokinetic profile of selected agents (such as adding ritonavir therapy to the hard gel capsule formulation of saquinavir) as well as contribute an additive antiviral effect; however, these interactions can also result in life threatening drug toxicity, as indicated in Tables X-XIII. Thus, health care providers should inform their patients of the need to discuss any new drugs, including over the counter agents and alternative medications, that they may consider taking, and careful attention should be given to the relative risk versus benefits of specific combinations of agents. Initiation of potent antiretroviral therapy is often associated with some degree of recovery of immune function. In this setting, patients with advanced HIV disease and subclinical opportunistic infections such as MAI or CMV may develop a new immunologic response to the pathogen and thus new symptoms may develop in association with the heightened immunologic and/or inflammatory response. This should not be interpreted as a failure of antiretroviral therapy and these newly presenting opportunistic infections should be treated appropriately while maintaining the patient on the antiretroviral regimen. Viral load measurement is helpful in clarifying this association. Class Adverse Events Interruption of Antiretroviral Therapy Considerations for Changing a Failing Regimen It is important to distinguish between the need to change therapy due to drug failure versus drug toxicity. In the latter case, it is appropriate to substitute one or more alternative drugs of the same potency and from the same class of agents as the agent suspected to be causing the toxicity. In the case of drug failure where more than one drug had been used, a detailed history of current and past antiretroviral medications, as well as other HIV-related medications, should be obtained. Optimally and when possible, the regimen should be changed entirely to drugs that have not been taken previously. With triple combinations of drugs, as least two and preferably three new drugs should be selected that are not subject to anticipated cross-resistance to drugs given previously; this is based on the current understanding of strategies to prevent drug resistance (see Principles 4 and 5). Assays to determine genotypic resistance are commercially available; however, these have not undergone field testing to demonstrate clinical utility and are not FDA-approved. The Panel does not recommend these assays for routine use at the present time. Viral resistance to antiretroviral drugs is an important, but not the only, reason for treatment failure. Genetically distinct viral variants emerge in each HIV-infected individual over time after initial infection. Viruses with single drug resistant mutations exist even prior to therapy, but are selected for replication by antiviral regimens that are only partially suppressive. The more potent a regimen is in durably suppressing HIV replication, the less likely the emergence of resistant variants. Thus the goal of therapy should be to reduce plasma HIV RNA to below detectable limits using the most sensitive assay available (<50 copies/ml), thereby providing the strongest genetic barrier possible to the emergence of resistance. Genotypic assays are available for detecting specific HIV genetic variants (mutations). They are based on PCR technologies and can generally detect mutations in plasma samples with more than 1000 copies/ml of HIV RNA. Two methods of sequencing the amplified HIV-1 are available. One is based on copying amplified DNA templates and the other on hybridization of the amplified nucleic acid. Species constituting 20% or more of10 amplified product can usually be detected by current techniques. Expert clinical interpretation is necessary to put results in their proper perspective, including an appreciation of the patient's previous treatment history and available options for further treatment. A compilation of the most common HIV-1 mutations selected by the three classes of antiretroviral agents is available on the Internet at http://hiv-web.lanl.gov. Phenotypic assays measure the 50% or 90% inhibitory concentrations of a drug against the virus in vitro. Although standard phenotypic assays are cumbersome and time-consuming, more rapid assays based on recombinant DNA technology are under study. Phenotypic assays may also miss minor species of resistant viruses, and may miss early mutations that precede the appearance of detectable increases in inhibitory concentrations. HIV resistance assays may prove useful both in guiding initial therapy and in changing failing regimens. However, the value of any assay in such circumstances remains to be fully established, and each assay or assay service requires standardization and validation. Although viruses resistant to all classes of antiretroviral drugs have now been reported, transmission of such viruses remains uncommon. Epidemiologic surveys are needed to monitor the prevalence of resistant viruses in specific populations. Pretreatment screening for resistance may prove useful in certain populations, such as individuals with primary HIV syndromes, particularly if the regional prevalence is above 5-10%. Testing to determine if resistance is a contributing factor in drug failure and to guide subsequent treatment recommendations should be done while the patient is taking the drugs, since wild type virus is likely to replace resistant strains in the absence of antiretroviral drug pressure. The presence of viral resistance to a particular drug suggests that that drug, and drugs to which the virus is likely cross-resistant, are likely to be unsuccessful in suppressing viral replication. In contrast, the absence of resistance to a drug does not necessarily indicate that its use will be successful, particularly if that drug or drugs sharing cross-resistance have been used previously. In such situations, minority populations of resistant viruses may be present in reservoirs, and may emerge rapidly under selection pressure afforded by the drug in question. The usual rationale to change therapy is based on plasma HIV RNA levels and CD4+ T cell counts, and the most useful information to guide the choice of alternative regimens is a detailed drug treatment history. The safest approach remains to change all drugs in a failing regimen, regardless of the results of resistance testing. Three different populations of patients should be considered with regard to a change in therapy: 1) individuals who are receiving incompletely suppressive antiretroviral therapy, such as single or double nucleoside therapy, with detectable or undetectable plasma viral load (discussed further below); 2) individuals who have been on potent combination therapy including a protease inhibitor and whose viremia was initially suppressed to undetectable levels but has again become detectable; and 3) individuals who have been on potent combination therapy including a protease inhibitor and whose viremia was never suppressed to below detectable limits. While these groups of individuals should have treatment regimens changed in order to maximize the chances of durable, maximal viral RNA suppression, the first group may have more treatment options as they are protease inhibitor naíve. Criteria for Changing Therapy
A final consideration in the decision to change therapy is the recognition of the still limited choice of available agents and the knowledge that a decision to change may reduce future treatment options for the patient (see Principle 7). This may influence the physician to be somewhat more conservative when deciding to change therapy. Consideration of alternative options should include potency of the substituted regimen and probability of tolerance of or adherence to the alternative regimen. Clinical trials have shown that partial suppression of virus is superior to no suppression of virus. On the other hand, some physicians and patients may prefer to suspend treatment in order to preserve future options or because a sustained antiviral effect cannot be achieved. Referral to or consultation with an experienced HIV clinician is appropriate when one is considering a change in therapy. When possible, patients requiring a change in an antiretroviral regimen but without treatment options using currently approved drugs should be referred for consideration for inclusion in an appropriate clinical trial. Therapeutic Options When Changing Antiretroviral Therapy Table XV summarizes some of the most important guidelines to follow when changing a patient's antiretroviral therapy. Table XVI outlines some of the treatment options available when a decision has been made to change the antiretroviral regimen. As noted in the footnote to the table, there are extremely limited data to suggest that any of these alternative regimens will be effective, and careful monitoring and consultation with an expert in the care of such HIV-infected patients is desirable. As stated above, a change in regimen because of treatment failure should ideally involve complete replacement of the regimen with different drugs to which the patient is naíve and to which cross-resistance is not anticipated. This typically would include the use of 2 new NRTIs and one new PI or NNRTI, two PIs with one or two new NRTIs, or a PI combined with an NNRTI. Dose modifications may be required to account for drug interactions when using combinations of PIs or a PI and NNRTI (Table XII). In some individuals, these options are not possible because of prior antiretroviral use, toxicity or intolerance. In the clinically stable patient with detectable viremia for whom an optimal change in therapy is not possible, it may be prudent to delay changing therapy in anticipation of the availability of newer and more potent agents. It is recommended that the decision to change therapy and design a new regimen should be made with assistance from a clinician experienced in the treatment of HIV infected patients through consultation or referral. Acute HIV Infection The theoretical rationale for early intervention, as provided in Principle 10, is sixfold:
The physician and the patient should be fully aware that therapy of primary HIV infection is based on theoretical considerations, and the potential benefits, described above, should be weighed against the potential risks (see below). Most authorities endorse treatment of acute HIV infection based on the theoretical rationale, limited but supportive clinical trial data, and the experience of HIV clinicians. The risks of therapy for acute HIV infection include adverse effects on quality of life resulting from drug toxicities and dosing constraints; the potential, if therapy fails to effectively suppress viral replication, for the development of drug resistance which may limit future treatment options; and the potential need for continuing therapy indefinitely. These considerations are similar to those for initiating therapy in the asymptomatic patient and were discussed in greater detail in the section "Considerations in Initiating Therapy in the Asymptomatic HIV-infected Patient." Whom to Treat During Acute HIV Infection Apart from patients with acute primary HIV infection, many experts would also consider therapy for patients in who seroconversion has been documented to have occurred within the previous six months (CIII). Although the initial burst of viremia in infected adults has usually resolved by two months, treatment during the 2-6 month period after infection is based on the likelihood that virus replication in lymphoid tissue is still not maximally contained by the immune system during this time. Decisions regarding therapy for patients who test antibody positive and who believe the infection is recent but for whom the time of infection cannot be documented should be made using the "Asymptomatic Chronic Infection" algorithm mentioned previously (CIII). Except in the setting of post-exposure prophylaxis with antiretroviral agents (23), no patient should be treated for HIV infection until the infection is documented. In this regard, all patients presenting without a formal medical record of a positive HIV test, such as those who have tested positive by available home testing kits, should undergo ELISA and an established confirmatory test such as the Western Blot (AI) to document HIV infection. Treatment Regimen for Primary HIV Infection Since 1) the ultimate goal of therapy is suppression of viral replication to below the level of detection, and 2) the benefits of therapy are based primarily on theoretical considerations and 3) long term clinical outcome benefit has not been documented, any regimen that is not expected to maximally suppress viral replication is not considered appropriate for treating the acutely HIV-infected individual (EIII). Additional clinical studies are needed to delineate further the role of antiretroviral therapy in the primary infection period. Patient Follow-up Duration of Therapy for Primary HIV Infection The optimal duration and composition of therapy are unknown and ongoing clinical trials are expected to provide data relevant to these issues. The difficulties inherent in determining the optimal duration and composition of therapy initiated for acute infection should be considered when first counseling the patient regarding therapy. Considerations for Antiretroviral Therapy in the HIV-Infected Adolescent Puberty is a time of somatic growth and hormonally-mediated changes, with females developing more body fat and males more muscle mass. Although theoretically these physiologic changes could affect drug pharmacology, particularly in the case of drugs with a narrow therapeutic index that are used in combination with protein-bound medicines or hepatic enzyme inducers or inhibitors, no clinically significant impact of puberty has been noted to date with the use of NRTIs. Clinical experience with PIs and NNRTIs has been limited. Thus, it is currently recommended that medications used to treat HIV and opportunistic infections in adolescents should be dosed based on Tanner staging of puberty and not specific age. Adolescents in early puberty (Tanner I-II) should be dosed under pediatric guidelines, while those in late puberty (Tanner V) should be dosed by adult guidelines. Youth who are in the midst of their growth spurt (Tanner III females and Tanner IV males) should be closely monitored for medication efficacy and toxicity when choosing adult or pediatric dosing guidelines. Considerations for Antiretroviral Therapy in the HIV-Infected Pregnant Woman Women who are in the first trimester of pregnancy and who are not receiving antiretroviral therapy may wish to consider delaying initiation of therapy until after 10 to 12 weeks gestation, since this is the period of organogenesis when the embryo is most susceptible to potential teratogenic effects of drugs; the risks of antiretroviral therapy to the fetus during that period are unknown. However, this decision should be carefully considered and discussed between the health care provider and the patient and should include an assessment of the woman's health status and the potential benefits and risks of delaying initiation of therapy for several weeks. If clinical, virologic or immunologic parameters were such that therapy would be recommended for nonpregnant individuals, many of the Panel members would recommend initiating therapy regardless of gestational age. Nausea and vomiting in early pregnancy affecting the ability to adequately take and absorb oral medications may be a factor in the decision regarding treatment during the first trimester. Some women already receiving antiretroviral therapy may recognize their pregnancy early enough in gestation that concern for potential teratogenicity may lead them to consider temporarily stopping antiretroviral therapy until after the first trimester. There are insufficient data to support or refute teratogenic risk of antiretroviral drugs when administered during the first 10-12 weeks of gestation. However, a rebound in viral levels would be anticipated during the period of discontinuation and this rebound could theoretically be associated with increased risk of early in utero HIV transmission or could potentiate disease progression in the woman (27). 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. If antiretroviral therapy is discontinued during the first trimester for any reason, all agents should be stopped simultaneously to avoid development of resistance. Once the drugs are reinstituted, they should be introduced simultaneously for the same reason. The choice of which antiretroviral agents to use in pregnant women is subject to unique considerations (see Principle 8). There are currently minimal data available on the pharmacokinetics and safety of antiretroviral agents during pregnancy for drugs other than ZDV. In the absence of data, drug choice will need to be individualized based on discussion with the patient and available data from preclinical and clinical testing of the individual drugs. The FDA pregnancy classification for all currently approved antiretroviral agents and selected other information relevant to the use of antiretroviral drugs in pregnancy is shown in Table XVIII. It is important to recognize that the predicitive value of in vitro and animal screening tests for adverse effects in humans is unknown. Many drugs commonly used to treat HIV infection or its consequences may have positive findings on one or more of these screening tests. For example, acyclovir is positive on some in vitro assays for chromosomal breakage and carcinogenicity and is associated with some fetal abnormalities in rats; however, data on human experience from the Acyclovir in Pregnancy Registry indicate no increased risk of birth defects to date in infants with in utero exposure to acyclovir (28). Of the currently approved nucleoside analogue antiretroviral agents, the pharmacokinetics of only ZDV and 3TC have been evaluated in infected pregnant women to date (29, 30). Both appear to be well tolerated at the usual adult doses and cross the placenta, achieving concentrations in cord blood similar to those observed in maternal blood at delivery. All the nucleosides except ddl have preclinical animal studies that indicate potential fetal risk and have been classified as FDA pregnancy category C (defined in Table XVIII); ddl has been classified as category B. In primate studies, all the nucleoside analogues appear to cross the placenta, but ddl and ddC appear to have significantly less placental transfer (fetal to maternal drug rations of 0.3 to 0.5) than do ZDV, d4T and 3TC (fetal to maternal drug ratios>= greater than 0.7) (31). Of the non-nucleoside reverse transcriptase inhibitors, only nevirapine administered once at the onset of labor has been evaluated in pregnant women (32). The drug was well-tolerated after a single dose, and crossed the placenta and achieved neonatal blood concentrations equivalent to those in the mother. The elimination of nevirapine administered during labor in the pregnant women in this study was prolonged (mean half-life following a single dose, 66 hours) compared to non-pregnant individuals (mean half-life following a single dose, 45 hours). Data on multiple dosing during pregnancy are not yet available. Delavirdine has not been studied in Phase I pharmacokinetic and safety trials in pregnant women. In premarketing clinical studies, outcomes of 7 unplanned pregnancies were reported. Three of these were ectopic pregnancies, and three resulted in healthy live births. One infant was born prematurely with a small ventricular septal defect to a patient who received approximately 6 weeks of treatment with delavirdine and ZDV early in the course of pregnancy. Efavirenz (Sustiva) is a newly approved non-nucleoside reverse transcriptase inhibitor. In a developmental toxicity study, pregnant cynomolgus monkeys received efavirenz from gestational day 20 to 150 in a dose 30 mg/kg twice daily, which was expected to achieve plasma concentrations which approximate those in humans given 600 mg daily (33). Three of 20 fetuses had gross malformations: anencephaly and unilateral anophthalmia in one fetus; microphthalmia in another; and cleft palate in a third (Table XVII). No malformations were seen in the concurrent control group of animals. No data exist regarding the teratogenic potential of other NNRTIs in primates; the absence of these data should not be interpreted to mean that these other agents are safe to use in pregnancy. Although studies of combination therapy with protease inhibitors in pregnant infected women are in progress, there are currently no data available regarding drug dosage, safety and tolerance in pregnancy. In mice, indinavir has significant placental passage, but in rabbits, little placental passage was observed. Ritonavir has been shown to have some placental passage in rats. There are some special theoretical concerns regarding the use of indinavir late in pregnancy. Indinavir is associated with side effects (hyperbilirubinemia and renal stones) that theoretically could be problematic for the newborn if transplacental passage occurs and the drug is administered shortly before delivery. This is because the immaturity of the metabolic enzyme system of the neonatal liver would likely be associated with prolonged drug half-life leading to extended drug exposure in the newborn, which could lead to potential exacerbation of physiologic neonatal hyperbilirubinemia. Additionally, due to immature neonatal renal function and the inability of the neonate to voluntarily ensure adequate hydration, high drug concentrations and/or delayed elimination in the neonate could result in a higher risk for drug crystallization and renal stone development than observed in adults. These concerns are theoretical and such effects have not been reported; because the half-life of indinavir in adults is short, these concerns may only be relevant if drug is administered near the time of labor. Gestational diabetes is a pregnancy-related complication that can develop in some women; administration of any of the four currently available protease inhibitors has been associated with new onset diabetes mellitus, hyperglycemia or exacerbation of existing diabetes mellitus in HIV-infected patients (34). Pregnancy is itself a risk factor for hyperglycemia and it is unknown if the use of protease inhibitors will exacerbate this risk. Health care providers caring for infected pregnant women who are receiving protease inhibitor therapy should be aware of this possibility, and closely monitor glucose levels in their patients as well as instruct their patients in recognizing the early symptoms of hyperglycemia. To date, the only drug that has been shown to reduce the risk of perinatal HIV transmission is ZDV when administered according to the following regimen: orally administered antenatally after 14 weeks gestation and continued throughout pregnancy, intravenously administered during the intrapartum period, and to the newborn for the first 6 weeks of life (35). This chemoprophylactic regimen was shown to reduce the risk of perinatal transmission by 66% in a randomized, double blind clinical trial, pediatric ACTG 076 (36). There are insufficient data available at present to justify the substitution of any antiretroviral agent other than ZDV for the purpose of reducing perinatal HIV transmission; further research will address this question. For the time being, if combination antiretroviral drugs are administered to the pregnant woman for treatment of her HIV infection, ZDV should be included as a component of the antenatal therapeutic regimen whenever possible, and the intrapartum and neonatal ZDV components of the chemoprophylactic regimen should be administered for the purpose of reducing the risk of perinatal transmission. If a woman does not receive ZDV as a component of her antenatal antiretroviral regimen (e.g. because of prior history of non-life threatening ZDV-related severe toxicity or personal choice), intrapartum and newborn ZDV should continue to be recommended; when use of ZDV is contraindicated in the woman, the intrapartum component may be deleted but the newborn component is still recommended. ZDV and d4T should not be administered together due to potential pharmacologic antagonism. When d4T is a preferred nucleoside for treatment of a pregnant woman, it is recommended that antenatal ZDV not be added to the regimen; however, intrapartum and neonatal ZDV should still be given. The antenatal dosing regimen used in the perinatal transmission prophylaxis trial PACTG 076 was ZDV 100 mg administered five times daily, and was selected based on the standard ZDV dosage for adults at the time the study was designed in 1989 (see Table XIX). However, recent data have indicated that administration of ZDV three times daily will maintain intracellular ZDV triphosphate at levels comparable with those observed with more frequent dosing (37, 38). Comparable clinical response also has been observed in clinical trials among persons receiving ZDV twice daily (39-41). Thus, the current standard ZDV dosing regimen for adults is 200 mg three times daily, or 300 mg twice daily. A less frequent dosing regimen would be expected to enhance maternal adherence to the ZDV perinatal prophylaxis regimen, and therefore is an acceptable alternative antenatal dosing regimen for ZDV. In a recent short-course antenatal/ intrapartum ZDV perinatal transmission prophylaxis trial in Thailand, administration of ZDV 300 mg twice daily for 4 weeks antenatally and 300 mg every 3 hours orally during labor was shown to reduce perinatal transmission by approximately 50% compared to placebo (42). The lower efficacy of the short-course 2-part ZDV prophylaxis regimen studied in Thailand compared to the 3-part ZDV prophylaxis regimen used in PACTG 076 and recommended for use in the U.S. could result from the shorter antenatal duration of ZDV, oral rather than intravenous administration during labor, lack of treatment for the infant, or a combination of these factors. In the United States, identification of HIV-infected pregnant women before or as early as possible during the course of pregnancy and use of the full 3-part PACTG 076 ZDV regimen is recommended for prevention of perinatal HIV transmission. The time-limited use of ZDV alone during pregnancy for chemoprophylaxis of perinatal transmission is controversial. The potential benefits of standard combination antiretroviral regimens for treatment of HIV infection should be discussed with and offered to all pregnant HIV-infected women. Some women may wish to restrict exposure of their fetus to antiretroviral drugs during pregnancy but still wish to reduce the risk of transmitting HIV to their infant. For women in whom initiation of antiretroviral therapy for treatment of their HIV infection would be considered optional (e.g. CD4 + count >500/mm 3 and plasma HIV RNA less than 10,000-20,000 RNA copies/ml), time-limited use of ZDV during the second and third trimesters of pregnancy is less likely to induce the development of resistance due to the limited viral replication existing in the patient and the time-limited exposure to the antiretroviral drug. For example, the development of resistance was unusual among the healthy population of women who participated in Pediatric (P)-ACTG 076 (43). The use of ZDV chemoprophylaxis alone during pregnancy might be an appropriate option for these women. However, for women with more advanced disease and/or higher levels of HIV RNA, concerns about resistance are greater and they should be counseled that a combination antiretroviral regimen that includes ZDV for reducing transmission risk would be more optimal for their own health than use of ZDV chemoprophylaxis alone. Monitoring and use of HIV-1 RNA for therapeutic decision-making during pregnancy should be performed as recommended for non-pregnant individuals. Transmission of HIV from mother to infant can take place at all levels of maternal HIV-1 RNA. In untreated women, higher HIV-1 RNA levels correlate with increased transmission risk. However, in ZDV-treated women this relationship is markedly attenuated (34). ZDV is effective in reducing transmission regardless of maternal HIV RNA level. Therefore, the use of the full ZDV chemoprophylaxis regimen, including intravenous ZDV during delivery and the administration of ZDV to the infant for the first six weeks of life, alone or in combination with other antiretrovirals, should be discussed with and offered to all infected pregnant women regardless of their HIV-1 RNA level. Health care providers who are treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to antiretroviral drugs (either administered alone or in combinations) to the Antiretroviral Pregnancy Registry. The registry collects observational, nonexperimental data regarding antiretroviral exposure during pregnancy for the purpose of assessing potential teratogenicity. Registry data will be used to supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits of treatment for individual patients. The20 registry is a collaborative project with an advisory committee of obstetric and pediatric practitioners, staff from CDC and NIH, and staff from pharmaceutical manufacturers. The registry allows the anonymity of patients, and birth outcome follow-up is obtained by registry staff from the reporting physician. Referrals should be directed to 115 North Third Avenue, Suite 306, Wilmington, NC 28401; telephone or 1-; fax 1-. Conclusion The Panel remains committed to revising their recommendations as such new data become available. N *Information included in these guidelines may not represent FDA approval or approved labeling for the particular products or indications in question. Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval. |
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