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Published in the Bulletin of Experimental Treatments for AIDS June 1997 issue, by the San Francisco AIDS Foundation.

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Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents

[Editor's Note, March 26, 2001 -- Revised guidelines are available at www.hivatis.org.]

The following draft guidelines were released June 19, 1997 by the U.S. Department of Health and Human Services (DHHS). BETA is reprinting the guidelines in full with the exception of the tables and figures. The "principles" referred to throughout the guidelines may be found in a companion document, "The Report of the NIH Panel to Define Principles of Therapy of HIV Infection." The complete documents, including tables, may be obtained from the HIV/AIDS Treatment Information Service (in Adobe Acrobat format) or from Healthcare Communications Group (in HTML format). Hardcopies may be obtained by calling the National AIDS Clearinghouse at 1-800-458-5231. There is a 30-day public-comment period during which comments may be sent to: The HIV/AIDS Treatment Information Service, P.O. Box 6303, Rockville, MD 20849-6303.

Links from this web page to tables II.-XVI. and figure 1 in the guidelines text are from Healthcare Communications Group.

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 consisted 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 (convener).

Members of the Panel who participated in the development of this document included: 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), Spencer Cox (Treatment Action Group, New York, NY), Martin Delaney (Project Inform, San Francisco, CA), Helene D. Gayle (Centers for Disease Control and Prevention), Fred Gordin, (Veterans Administration Medical Center, Washington, DC), Wayne Greaves (Howard University, Washington, DC), Mark Harrington (Treatment Action Group, New York, NY), John J. Henning (American Medical Association, Chicago, IL), Martin S. Hirsch (Massachusetts General Hospital, Boston, MA), Richard Marlink (Harvard AIDS Institute, Cambridge, MA), Henry Masur (National Institutes of Health), Celia Maxwell (AIDS Education and Training Center, Washington, DC), John W. Mellors (University of Pittsburgh, Pittsburgh, PA), David B. Nash (Thomas Jefferson University, Philadelphia, 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), Paul Volberding (University of California, San Francisco, CA), Gabriell Torres (St. Vincent's Hospital, New York, NY); participants from the Department of Health and Human Services: Barbara A. Brady (Office of HIV/AIDS Policy), Elaine M. Daniels (Office of HIV/AIDS Policy), David Feigel (Food and Drug Administration), Mark Feinberg (National Institutes of Health), Jonathan Kaplan (Centers for Disease Control and Prevention), Abe Macher (Health Resources and Services Administration), Lynne Mofenson (National Institutes of Health), Joseph O'Neill (Health Resources and Services Administration), Samuel Shekar (Health Care Financing Administration), Richard Riseberg (Office of the Secretary), Sharilyn K. Stanley (National Institutes of Health); Lucille C. Perez (Substance Abuse and Mental Health Services Administration.) The Panel would like to extend special appreciation to Charles Carpenter (Brown University School of Medicine, Providence, R.I) for his advice in the development of this document, and Gerry Bally (Health Canada) and Anita Rachlis (Sunnyside Health Science Center, Toronto, Canada) for their participation.


Introduction

The document contains recommendations for the clinical use of antiretroviral agents in the treatment of HIV-infected adults and adolescents. Guidance for the use of antiretroviral treatment in pediatric cases is not contained in this document, but will be addressed by the Panel in a future session. The guidelines are intended for use by physicians and other health care providers in the use of antiretroviral therapy in 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. While the guidelines represent the current state of knowledge regarding the use of antiretroviral agents, this is a rapidly evolving field and the document will be updated periodically to reflect changes based on scientific discoveries and advances in medical treatments for HIV infection. The recommendations are presented in the context of and with reference to the Principles of Therapy contained in the accompanying document. Together the documents should provide the pathogenesis-based rationale for therapeutic strategies as well as practical guidelines for implementing these strategies. These recommendations are not intended to substitute for the judgment of a physician who is 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, below), similar to the rating schemes used in previous guidelines on the prophylaxis of opportunistic infections (OI) 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. Thus, recommendations based on data from clinical 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. 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; and considerations for antiretroviral therapy in the pregnant woman.

TABLE I: RATING SCHEME FOR CLINICAL PRACTICE RECOMMENDATIONS

Strength of Recommendation

A: Strong, should always be offered
B: Moderate, should usually be offered
C: Optional
D: Should generally be offered
E: Should never be offered

Quality of Evidence for Recommendation

I: At least one randomized trial with clinical endpoints
II: Clinical trials with laboratory endpoints
III: Expert opinion


Use of Testing for Plasma HIV RNA Levels and CD4 T Cell Count in Guiding Decisions for Therapy

Decisions regarding initiation or changes in antiretroviral therapy should be guided by monitoring the laboratory parameters of plasma HIV RNA (viral load) and CD4 T-cell count, as well as the clinical condition of the patient. As discussed in Principle 2, results of the two laboratory tests gives the physician important information about the virologic and immunologic status of the patient and the risk of disease progression to AIDS. It should be noted that HIV viral load testing has been approved by the FDA only for the RT-PCR assay (Hoffman-La Roche) and only for determining disease prognosis. However, it is the consensus of the Panel that viral load testing is the essential parameter in decisions to initiate or change antiretroviral therapies. Measurement of plasma HIV RNA levels (viral load), using quantitative methods, should be performed at the time of diagnosis and every 3-4 months thereafter in the untreated patient (AIII) (See Table II). CD4 T-cell counts should be measured at the time of diagnosis and generally every 3-6 months thereafter (AIII). These intervals between tests are merely recommendations and flexibility should be exercised according to the circumstances of the individual case. Plasma HIV RNA levels should also be measured immediately prior to and again at 4 weeks after initiation of antiretroviral therapy (AIII). This time point allows the clinician to evaluate the initial effectiveness of therapy, since in most patients adherence to a regimen of potent antiretroviral agents should result in a large decrease (greater than 10-fold or 1 log) in viral load by 4 weeks. The absence of a response of this magnitude should prompt the physician to reassess patient adherence, rule out malabsorption, consider repeat RNA testing to document lack of response, and consider a change in drug regimen. HIV RNA testing should be repeated every 3-4 months to evaluate the continuing effectiveness of therapy (AII). With optimal therapy viral levels in plasma at 6 months should be undetectable, that is, below the limits of detection of the currently available assays (2). As more sensitive assays are developed, these levels of detection will undoubtedly be lower; however, the significance of suppression even beyond the current levels of detection, given the variability of test results at the lower limits of detectability, is unknown. If HIV RNA remains detectable in plasma after 6 months of therapy, the plasma HIV RNA test should be repeated to confirm the result and a change in therapy should be considered, according to the guidelines in the section "Considerations for changing a failing regimen" (BIII).

When making decisions regarding the initiation of therapy, the CD4 T-lymphocyte count and plasma HIV RNA measurement should be performed on two occasions to insure accuracy of measurement (BIII). 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 log10 increase or decrease. A significant decrease in CD4 T-lymphocyte count is a drop of greater than 30% from baseline for absolute cell numbers and a drop of greater than 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 samples 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). For further discussion of this area refer to "Considerations for changing a failing regimen"; in many such cases, expert consultation should be considered.


Established Infection

Patients with established HIV infection are discussed in two arbitrarily defined clinical categories: 1) asymptomatic infection or 2) symptomatic disease (wasting, thrush, unexplained fever) including AIDS, defined according to the 1993 CDC classification system. All patients in the second category should be offered antiretroviral therapy. Considerations for initiating antiretroviral therapy in the first category of patients are complex and are discussed separately below. Before initiating therapy in any patient, however, the following evaluation should be performed:

  • Complete history and physical (AII)
  • Complete blood count, chemistry profile (AII)
  • CD4 T-lymphocyte count (AI)
  • Plasma HIV RNA measurement (AI).

Additional evaluation should include routine tests pertinent to the prevention of opportunistic infections, if not already performed (VDRL, tuberculin skin test toxoplasma, hepatitis B, and CMV serologies and gynecologic exam with Pap smear), and other tests as clinically indicated (e.g. chest X-ray, HCV serology, ophthalmologic exam) (AII).

Considerations for Initiating Therapy in the Patient with Asymptomatic HIV Infection

It has been demonstrated that antiretroviral therapy provides clinical benefit in HIV-infected individuals with advanced HIV disease and immunosuppression (6-10). Although there is theoretical benefit to treatment for patients with CD4 T-cells greater than 500 cells/mm3 (see Principle 3), no long term clinical benefit of treatment has yet been demonstrated. A major dilemma confronting patients and practitioners is that the antiretroviral regimens currently available that have the greatest potency in terms of viral suppression and CD4 T-cell preservation are medically complex, are associated with a number of specific side effects and drug interactions, and pose a substantial challenge for adherence. Thus, decisions regarding treatment of asymptomatic, chronically-infected individuals must balance a number of competing factors that influence risk and benefit.

Table III 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, and decreasing drug toxicity by treating the healthier patient. Factors weighing against early treatment in the asymptomatic stable patient include the potential adverse effects of the drugs on quality of life, 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 risk of dissemination 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 in 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 characteristic 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 to 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

Once the patient and physician have decided to initiate antiretroviral therapy treatment should be aggressive, with the goal of maximal suppression of plasma viral load to undetectable levels. 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/mm3 or greater than 10,000 (bDNA) or 20,000 (RT-PCR) copies of HIV RNA/ml of plasma should be offered therapy (AII). However, 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 and RT-PCR shown in Figure 1 and Table IV (second and third lines or columns) have been corrected from the original Multicenter AIDS Cohort Study (MACS) data (first line or column) to be consistent with HIV-1 RNA values obtained in current clinical practice (11). Because the MACS values were obtained from plasma samples collected in heparin and stored for up to 10 years, they are lower than plasma HIV RNA determinations obtained using either bDNA or RT-PCR assays on freshly drawn plasma samples. Comparison of RT-PCR and bDNA results using the manufacturer's controls indicate that the HIV-1 RNA values obtained by RT-PCR are approximately two times higher than those obtained by bDNA (11). Thus, the MACS values must be multiplied by 2 to approximate current bDNA values and by approximately 4 to be consistent with current RT-PCR values. Table IV and figure 1 contain these corrected values.

In current practice there are two general approaches to initiating therapy in the asymptomatic patient: a 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 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 treatment before the development of significant immunosuppression and one should treat to achieve undetectable viremia; thus, almost all patients with less than 500 CD4 T-cells/mm3 would be started on therapy as would patients with higher CD4 T-cell numbers who have detectable plasma viral load. The more conservative approach to the initiation of therapy in the asymptomatic individual would delay treatment of the patient with less than 500 CD4 T-cells/mm3 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 greater than 500/mm3 would also be observed, except those at substantial risk of rapid disease progression because of a high viral load. For example, a patient with 25,000 copies of HIV RNA/ml of plasma, measured by RT-PCR, and a CD4 T-cell count of 410/mm3 has a 5.9% chance of progressing to an AIDS-defining complication of HIV infection in 3 years (Table IV). The aggressive physician would strongly recommend treatment for this patient to suppress the ongoing viral replication that is readily detectable; the more conservative physician should offer therapy, but the patient may elect to delay initiation of treatment because of the balance of considerations as discussed above. On the other hand, the patient with 120,000 (RT-PCR) or 65,000 (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/mm3) and should clearly be strongly encouraged to initiate antiretroviral therapy.

When initiating therapy in the patient naive to antiretroviral therapy, one should begin with a regimen that is expected to reduce viral replication to undetectable levels (AIII). Based on the weight of experience, the preferred regimen to accomplish this is 2 nucleoside analogues (NRTI) and one potent protease inhibitor (Table VI). Alternative regimens have been employed; these include substituting nevirapine for the protease inhibitor or, as a third choice, regimens consisting of 2 NRTI alone. These alternative regimens do not achieve the goal of suppressing viremia to below detectable levels as consistently as does combination treatment with 2 NRTI and a protease inhibitor 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 nevirapine in the drug-naive patient; further studies are pending. Although 3TC is a potent NRTI when used in combination with another NRTI, in situations in which suppression of virus replication is not complete, resistance to 3TC develops rapidly (12,13). 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 non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine and delavirdine, should also be used in this manner. Except when there are no other options, or in pregnancy as noted below, use of antiretroviral agents as monotherapy is contraindicated (EII).

Detailed information comparing the different nucleoside RT inhibitors, the non-nucleoside RT inhibitors, the protease inhibitors, and drug interactions between the protease inhibitors and other agents can be found in Tables VII, VIII, IX, X, XI, and XII. Particular attention should be paid to Tables IX, X, XI and XII regarding drug interactions between the protease inhibitors and other agents, as these are extensive and often require dose modification 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

All patients diagnosed with advanced HIV disease, which is defined as any condition meeting the 1993 CDC definition of AIDS should be treated with antiretroviral agents regardless of plasma viral levels (AI). All patients with symptomatic HIV infection without AIDS, defined as the presence of thrush or unexplained fever, should also be treated.

Special Considerations in the Patient with Advanced Stage Disease

Some patients present with opportunistic infections, wasting, dementia or malignancy and are first diagnosed with HIV infection at this advanced stage of disease. All patients with advanced HIV disease should be treated with antiretroviral therapy. When the patient is acutely ill with an OI or other complication of HIV infection, the clinician should consider clinical issues such as drug toxicity, ability to adhere to treatment regimens, drug interactions, and laboratory abnormalities when determining the timing of initiation of antiretroviral therapy. Once therapy is initiated, a maximally suppressive regimen, such as 2 NRTI and a protease inhibitor, should be used, as indicated in Table VI. Advanced stage patients being maintained on an antiretroviral regimen should not have the therapy discontinued during an acute opportunistic infection or malignancy, unless there are concerns regarding drug toxicity, intolerance, or drug interactions.

Patients who have progressed to AIDS are often treated with complicated combinations of drugs and the potential for multiple drug interactions must be appreciated. 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, VIII, IX, X, XI, and XII. 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 with all of the protease inhibitors, one might consider using rifabutin at a reduced dose, as indicated in Tables Tables VIII, IX, X and XI; this topic is discussed in greater detail elsewhere (14). Other factors complicating advanced disease are 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 AZT and the neuropathic effects of ddC, d4T and ddI 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 NNRTI whose metabolism involves the hepatic cytochrome p450 enzymatic pathway. At times, this can be exploited to improve the pharmacokinetic profile of selected agents such as saquinavir (by dosing with ritonavir); however, these interactions can also result in life threatening drug toxicity, as indicated in Tables X, XI and XII. 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 be 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.


Interruption of Antiretroviral Therapy

There are multiple reasons for temporary discontinuation of antiretroviral therapy, including intolerable side effects, drug interactions, first trimester of pregnancy, and unavailability of drug. There are no studies and no reliable estimate of the number of days, weeks or months that constitute a clinically important interruption of one or more components of a therapeutic regimen that would increase the likelihood of drug resistance. If there is a need to discontinue any antiretroviral medication for an extended time, clinicians and patients should be advised of the theoretical advantage of stopping all antiretroviral agents simultaneously, rather than continuing one or two agents, to minimize the emergence of resistant viral strains (see Principle 6).


Considerations for Changing a Failing Regimen

As with the initiation of antiretroviral therapy, the decision to change regimens should be approached with careful consideration of several complex factors. These factors include: recent clinical history and physical examination; plasma HIV RNA levels measured on two separate occasions; absolute CD4 T-lymphocyte count and changes in these counts; remaining treatment options in terms of potency, potential resistance patterns from prior antiretroviral therapies and potential for compliance/tolerance; assessment of adherence to medications; and preparation of the patient for the implications of the new regimen which include side effects, drug interactions, dietary requirements and possible need to alter concomitant medications (see Principles 6 and 7). In this regard, it is important to carefully assess patient compliance prior to changing antiretroviral therapy, as rising HIV RNA levels may be due to poor compliance or inadequate patient education about the therapeutic agents.

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, at least two and preferably three new drugs must be used; 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. 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.

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 plasma viral load or evidence of clinical progression; 2) individuals who have been on potent combination therapy including a protease inhibitor and whose viremia was initially suppressed but has again become detectable or who show clinical progression; 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 naive. If most or all available NRTI have been exhausted, therapy with two new protease inhibitors or with a new protease inhibitor and a new NNRTI should be considered.

Criteria for Changing Therapy

The goal of antiretroviral therapy, to improve the length and quality of the patient's life, is likely best accomplished by maximal suppression of viral replication to below detectable levels sufficiently early to preserve immune function. However, this is not always achievable with a given therapeutic regimen and frequently regimens must be modified. In general, the plasma HIV RNA level is the most important parameter to evaluate response to therapy, and increases in levels of viremia that are significant, confirmed and not attributable to intercurrent infection or vaccination indicate failure of the drug regimen regardless of stability of CD4 T-cell counts. Clinical features and sequential changes in CD4 T-cell count may complement the viral load test in evaluating a response to treatment. Specific criteria that should prompt consideration for changing therapy include:

  • Less than a 10-fold (1.0 log) reduction in plasma HIV RNA by 4 weeks following initiation of therapy;
  • Failure to suppress plasma HIV RNA to undetectable levels within 4-6 months of initiating therapy. In this regard, the degree of initial decrease in plasma HIV RNA should be considered. For instance, a patient with 106 viral copies/mL prior to therapy who stabilizes after 6 months of therapy at an HIV RNA level that is detectable but greater than 10,000 copies/mL may not warrant an immediate change in therapy.
  • Repeated detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance. The degree of plasma HIV RNA increase should also be con-sidered; the physician may consider short-term further observation in a patient whose plasma HIV RNA increases from undetectable to detectable (e.g.,5000 copies/mL) at 4 months. In this situation the patient should be followed very closely.
  • Any reproducible significant increase, defined as 3-fold or greater, from the nadir of plasma HIV RNA not attributable to intercurrent infection, vaccination, or test methodology;
  • Persistently declining CD4 T-cell numbers, as measured on at least two separate occasions (see Principle 2 for significant decline); and
  • Clinical deterioration. In this regard, a new AIDS-defining diagnosis that was acquired after the time treatment was initiated suggests clinical deterioration but may or may not suggest failure of antiretroviral therapy. If the antiretroviral effect of therapy was poor (e.g. greater than10-fold reduction in viral RNA), then a judgment of therapeutic failure could be made. However, if the antiretroviral effect was good but the patient was already severely immunocompromised, the appearance of a new opportunistic disease may not necessarily reflect a failure of antiretroviral therapy, but rather a persistence of severe immunocompromise that did not improve despite adequate suppression of virus replication. Similarly, an accelerated decline in CD4 T-cell counts suggests progressive immune deficiency providing there are sufficient measurements to assure quality control of CD4 T-cell measurements.

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 compliance 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

At present there are very few clinical data to support specific strategies for changing therapy; however, a number of theoretical considerations should guide decisions. Table XIII summarizes some of the most important guidelines to follow when changing a patient's antiretroviral therapy (see also above and Principle 7). Table XIV outlines some of the treatment options available when a decision has been made to change the antiretroviral regimen. 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 naive. This typically would include the use of 2 new nucleoside analogue agents and one new protease inhibitor or NNRTI agent, although a regimen such as two new protease inhibitors and another agent might also be used. In some individuals, this option is 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

It has been estimated that at least 50% and as many as 90% of patients acutely infected with HIV will experience at least some symptoms of the acute retroviral syndrome (Table XV) and can thus be identified as candidates for early therapy (15-17). However, acute HIV infection is often not recognized in the primary care setting because of the similarity of the symptom complex with those of the "flu" or other common illnesses. Additionally, acute primary infection may occur without symptoms. Physicians should maintain a high level of suspicion for HIV infection in all patients presenting with a compatible clinical syndrome (Table XV) and should obtain appropriate laboratory confirmation. Information regarding treatment of acute HIV infection from clinical trials is very limited. There is evidence for a short term effect of therapy on viral load and CD4 T-cell counts (18), but there are as yet no outcome data demonstrating a clinical benefit of antiretroviral treatment of primary HIV infection. Clinical trials completed to date have also been limited by small sample sizes, short duration of follow up and often by the use of treatment regimens that have suboptimal antiviral activity by current standards. Nevertheless, these studies generally support antiretroviral treatment of acute HIV infection. Ongoing clinical trials are addressing the question of the long term clinical benefit of more potent treatment regimens.

The theoretical rationale for early intervention as provided in Principle 10, is fourfold:

  • to suppress the initial burst of viral replication and decrease the magnitude of virus dissemination throughout the body;
  • to potentially decrease the severity of acute disease;
  • to potentially alter the initial viral "set point," discussed in Principle 2, which may ultimately affect the rate of disease progression;
  • and to possibly reduce the rate of viral mutation due to the suppression of viral replication.

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 expert 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; the potential need for continuing therapy indefinitely; and the possibility of blunting the evolution of an appropriate immune response. 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

Many experts would recommend antiretroviral therapy for all patients who demonstrate laboratory evidence of acute HIV infection (AII). Such evidence includes detectable HIV RNA in plasma using sensitive PCR or bDNA assays together with a negative or indeterminate HIV antibody test. While measurement of plasma HIV RNA is the preferable method of diagnosis, a test for p24 antigen may be useful when RNA testing is not readily available. It should be noted, however, that a negative p24 antigen test does not rule out acute infection. When suspicion for acute infection is high, such as in a patient with a report of recent risk behavior in association with symptoms and signs listed in Table XV, a test for HIV RNA should be performed (BII). As noted earlier, individuals may or may not have symptoms of the acute retroviral syndrome. Viremia occurs acutely after infection prior to the detection of a specific immune response; an indeterminate antibody test may occur when an individual is in the process of seroconversion.

Apart from patients with acute primary HIV infection, many experts would also consider therapy for patients in whom 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 this phase is based on the likelihood that virus replication in lymphoid tissue is still not maximally contained by the immune system during the first 6 months following infection. 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 docu-mented should be made using the "Asymptomatic Chronic Infection" algorithm mentioned previously (CIII). Except in the setting of post-exposure prophylaxis with antiretroviral agents (19), 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

Once the physician and patient have made the decision to use antiretroviral therapy for primary HIV infection, treatment should be implemented with the goal of suppressing plasma HIV RNA levels to below detectable levels (AIII). The weight of current experience suggests that the therapeutic regimen for acute HIV infection should include a combination of two nucleoside reverse transcriptase inhibitors and one potent protease inhibitor (AII). Although most experience to date with protease inhibitors in the setting of acute HIV infection has been with ritonavir, indinavir or nelfinavir (2,20-22), there are insufficient data to make firm conclusions regarding specific drug recommendations. Potential combinations of agents available are much the same as those used in established infection, listed in Table VI. It is recognized that these aggressive regimens may be associated with several disadvantages, including drug toxicity, large pill burden, cost of drugs, and the possibility of developing drug resistance that may limit future options; the latter is likely if virus replication is not adequately suppressed or if the patient has been infected with a viral strain that is already resistant to one or more agents. The patient should be carefully counseled regarding these potential limitations and individual decisions made only after weighing the risks and sequelae of therapy against the theoretical benefit of treatment (see above).

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

Testing for plasma HIV RNA levels and CD4 T-cell count and toxicity monitoring should be performed as described above in "Use of Testing for Plasma HIV RNA levels" i.e., on initiation of therapy, after 4 weeks, and every 3-4 months thereafter (AII). Some experts feel that testing for plasma HIV RNA levels at 4 weeks is not helpful in evaluating the effect of therapy for acute infection as viral loads may be decreasing from peak viremia levels even in the absence of therapy.

Duration of Therapy for Primary HIV Infection

Once therapy is initiated many experts would continue to treat the patient with antiretroviral agents indefinitely because viremia has been documented to reappear or increase after discontinuation of therapy (CII). However, some experts would treat for one year and then re-evaluate the patient with CD4 T-cell determinations and quantitative HIV RNA measurements. 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 Pregnant Woman

Guidelines for optimal antiretroviral therapy and for initiation of therapy in pregnant HIV-infected women should generally be the same as those delineated for non-pregnant adults (see Principle 8). Thus, the woman's clinical, virologic and immunologic status should be of primary importance in guiding treatment decisions. However, because the first trimester of pregnancy is the period of maximal organogenesis and risk for teratogenicity, consideration should be given to delaying initiation of antiretroviral therapy until after 14 weeks gestational age (BIII). For women already receiving therapy when they become pregnant, concern for potential teratogenicity may lead some women to consider stopping therapy until 14 weeks gestation. In both instances this decision should be carefully considered and discussed between the clinician and woman, and involves considerations related to the gestational age of the pregnancy, the woman's virologic, immunologic and clinical status, and what is known and not known about the potential effects of the antiretroviral drugs on the fetus. There are currently no data to address whether transient discontinuation of therapy in this manner would be harmful for the woman. However, a rebound in viral levels would be anticipated during the period of discontinuation and this rebound could be associated with increased risk of early in utero HIV transmission or could potentiate disease progression in the woman (23). Although the effects of protease inhibitors on the developing fetus during the first trimester are uncertain, many experts recommend continuation of a maximally suppressive regimen even during the first trimester when possible. 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 are used 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 AZT. 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 XVI. It is important to recognize that the predictive 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 (24).

Of the currently approved nucleoside analogue antiretroviral agents, the pharmacokinetics of only AZT and 3TC have been evaluated in infected pregnant women to date (25,26). Both appear to be well tolerated at the usual adult doses and cross the placenta, achieving concentrations in cord blood similar to that observed in maternal blood at delivery. All the nucleosides except ddI have preclinical animal studies that indicate potential fetal risk and have been classified as FDA pregnancy category C (defined in Table XVI); ddI has been classified as category B. In primate studies, all the nucleoside analogues appear to cross the placenta, but ddI and ddC appear to have significantly less placental transfer (fetal to maternal drug ratios of 0.3 to 0.5) than do AZT, d4T and 3TC (fetal to maternal drug ratios > 0.7)(27).

Of the non-nucleodie reverse transcriptase inhibitors, only nevirapine has been evaluated in pregnant women. The drug was well-tolerated after a single dose given to pregnant infected women in labor, and crossed the placenta and achieved neonatal concentrations equivalent to that in the mother. Data in multiple dosing during pregnancy are not yet available; studies on use of other non-nucleoside reverse transcriptase inhibitors in pregnancy have not been conducted.

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 and ritonavir both have significant placental passage (appearing in higher concentrations in the fetus than in the mother); however, in rabbits, indinavir shows little placental passage. 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.

To date, the only drug that has been shown to reduce the risk of perinatal HIV transmission is AZT 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 (28). This regimen was shown to reduce the risk of perinatal transmission by approximately 70-80%. There are insufficient data available at present to justify the substitution of any antiretroviral agent other than AZT for the purpose of reducing perinatal HIV transmission. Further research should address this question. For the time being, if combination antiretroviral therapy is administered to the pregnant woman, AZT should be included as a component of therapy and the intrapartum and neonatal AZT components of the regimen should be administered for the purpose of reducing the risk of perinatal transmission. For women in whom initiation of antiretroviral therapy for maternal health indications would be considered optional (e.g. CD4 count greater than 500/mm3 and plasma HIV RNA less than 10,000-20,000 RNA copies/mL) and who want to restrict their exposure to antiretroviral agents during pregnancy but still wish to reduce the risk of transmitting HIV to their infant, time-limited use of AZT as prophylactic monotherapy during the second and third trimesters of pregnancy is an appropriate option. In such circumstances, development of resistance is reduced by the limited viral replication existing in the patient and the time-limited exposure to the antiretroviral agent.

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 AZT-treated women this relationship is markedly attenuated (29). AZT is effective in reducing transmission regardless of maternal HIV RNA level. Therefore, the use of the full AZT regimen, 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 AZT, ddI, ddC, d4T, 3TC, saquinavir or indinavir alone or in combination with each other or with any other antiretroviral drug to the Antiretroviral Pregnancy Registry. This registry is a collaborative project jointly managed by Glaxo Wellcome, Hoffmann-LaRoche Inc., Bristol-Myers Squibb Co., and Merck & Co. Inc., with an advisory committee of practitioners and CDC and NIH staff; it is anticipated that additional antiretroviral drugs will be added to the registry in the future. The registry does not use patient names, and birth outcome follow-up is not obtained by registry staff from the reporting physician. The registry is an epidemiologic project to collect observational, non-experimental data on antiretroviral exposure during pregnancy for the purpose of assessing the safety of the use of these drugs in pregnancy on birth outcome. Registry data will be used to supplement animal toxicity studies and assist clinicians in weighing the potential risks and benefits of treatment for individual patients.

Referrals can be directed to Antiretroviral Pregnancy Registry, Post Office Box 13398, Research Triangle Park, NC 27709-3398; telephone (919)-483-9437 (can be called collect) or (800) 722-9292, ext. 39437; fax 919-315-8981.


Conclusion

The panel has attempted to use the advances in our understanding of the pathogenesis of HIV in the infected person and translate scientific principles and data obtained from clinical experience into recommendations that can be used by the clinician and patient to make therapeutic decisions. The recommendations are offered in the context of an ongoing dialogue between the patient and the clinician after having defined specific therapeutic goals with an acknowledgment of uncertainties. It is necessary for the patient to be entered into a continuum of medical care and services with the availability of expert referral and consultation. In order to achieve the maximal flexibility in tailoring therapy to each patient over the duration of his or her infection, drug formularies should allow for all FDA-approved NRTI, NNRTI, and PI as treatment options. The Panel remains committed to revising recommendations as new data become available.

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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33. Schapiro J, Winters M, Stewart F, et al: The effect of high-dose saquinavir on viral load and CD4 T-cell counts in HIV-infected patients. Ann Intern Med. 1996;124:1039-1050.

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Figures and tables from Healthcare Communications Group

Figure 1;

Table I; Table II; Table III; Table IV; Table V; Table VI; Table VII; Table VIII; Table IX; Table X, Table XI; Table XII; Table XIII; Table XIV; Table XV; Table XVI.

Page last updated 19 August 1997


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