Skip Navigation LinksSkip Navigation Links
Centers for Disease Control and Prevention
Safer Healthier People
Blue White
Blue White
bottom curve
CDC Home Search Health Topics A-Z spacer spacer
spacer
Blue curve MMWR spacer
spacer
spacer

Report of the NIH Panel to Define Principles of Therapy of HIV Infection

Preface

The past 2 years have witnessed remarkable advances in the development of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection, as well as measurement of HIV plasma RNA (viral load) to guide the use of antiretroviral drugs. The use of ART, in conjunction with the prevention of specific HIV- related opportunistic infections (OIs), has been associated with dramatic decreases in the incidence of OIs, hospitalizations, and deaths among HIV- infected persons.

Advances in this field have been so rapid, however, that keeping up with them has posed a formidable challenge to health- care providers and to patients, as well as to institutions charged with the responsibility of paying for these therapies. Thus, the Office of AIDS Research, the National Institutes of Health, and the Department of Health and Human Services, in collaboration with the Henry J. Kaiser Foundation, have assumed a leadership role in formulating the scientific principles (NIH Panel) and developing the guidelines (DHHS/ Kaiser Panel) for the use of antiretroviral drugs that are presented in this report. CDC staff participated in these efforts, and CDC and MMWR are pleased to be able to provide this information as a service to its readers.

This report is targeted primarily to providers who care for HIV-infected persons, but it also is intended for patients, payors, pharmacists, and public health officials. The report comprises two articles. The first article, Report of the NIH Panel To Define Principles of Therapy of HIV Infection, provides the basis for the use of antiretroviral drugs, and the second article, Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, provides specific recommendations regarding when to start, how to monitor, and when to change therapy, as well as specific combinations of drugs that should be considered. Both articles provide cross-references to each other so readers can locate related information. Tables and figures are included in the Appendices section that follows each article. Although the principles are unlikely to change in the near future, the guidelines will change substantially as new information and new drugs become available.

Copies of this document and all updates are available from the CDC National AIDS Clearinghouse (1-800-458-5231) and are posted on the Clearinghouse World-Wide Web site (http://www.cdcnac.org). In addition, copies and updates also are available from the HIV/AIDS Treatment Information Service (1-800-448-0440; Fax 301-519-6616; TTY 1-800-243-7012) and on the ATIS World-Wide Web site (http://www.hivatis.org). Readers should consult these web sites regularly for updates in the guidelines.

Report of the NIH Panel To Define Principles of Therapy of HIV Infection

Panel Members

Charles Carpenter, M.D. Julia Hidalgo, S.C.D. Chair Center for AIDS Services Planning Brown University and Development The Miriam Hospital Baltimore, MD Providence, RI

Harold Jaffe, M.D. Mark Feinberg, M.D., Ph.D. Centers for Disease Control Executive Secretary and Prevention National Institutes of Health Atlanta, GA Bethesda, MD

Dan Landers, M.D. Wade Aubry, M.D. Magee Women's Hospital Blue Cross/ Blue Shield Association Pittsburgh, PA San Francisco, CA

Henry Masur, M.D. Dawn Averitt National Institutes of Health Women's Information Service Bethesda, MD

and Exchange (WISE) Atlanta, GA Philip Pizzo, M.D.

Children's Hospital/Harvard Medical John Coffin, Ph.D. School Tufts University School of Medicine Boston, MA Boston, MA

Douglas Richman, M.D. David Cooper, M.D. University of California, San Diego National Center for HIV Epidemiology La Jolla, CA

and Clinical Research Sydney, NSW, Australia Michael Saag, M.D.

University of Alabama, Birmingham Stephen Follansbee, M.D. Birmingham, AL Davies Medical Center San Francisco, CA Robert Schooley, M.D.

University of Colorado Health Peggy Hamburg, M.D. Sciences Center New York City Department of Health Denver, CO New York, NY

Valerie Stone, M.D., M.P.H. Mark Harrington Brown University School of Medicine Treatment Action Group Pawtucket, RI New York, NY

Bruce Walker, M.D. Melanie Thompson, M.D. Harvard Medical School AIDS Research Consortium of Atlanta Boston, MA Atlanta, GA

Patrick Yeni, M.D. Didier Trono, M.D. X. Bichat Medical School The Salk Institute for Biological Paris, France

Studies La Jolla, CA

Stefano Vella, M.D. Instituto Superiore di Sanita Laboratory of Virology Rome, Italy The material in this report was prepared for publication by:

Mark B. Feinberg, M.D., Ph.D. Office of AIDS Research National Institutes of Health

in collaboration with

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

and

Division of HIV/AIDS Prevention Surveillance, and Epidemiology National Center for HIV, STD, and TB Prevention


Report of the NIH Panel To Define Principles of Therapy of HIV Infection *

Summary

Recent research advances have afforded substantially improved understanding of the biology of human immunodeficiency virus (HIV) infection and the pathogenesis of the acquired immunodeficiency syndrome (AIDS). With the advent of sensitive tools for monitoring HIV replication in infected persons, the risk of disease progression and death can be assessed accurately and the efficacy of anti-HIV therapies can be determined directly. Furthermore, when used appropriately, combinations of newly available, potent antiviral therapies can effect prolonged suppression of detectable levels of HIV replication and circumvent the inherent tendency of HIV to generate drug-resistant viral variants. However, as antiretroviral therapy for HIV infection has become increasingly effective, it has also become increasingly complex. Familiarity with recent research advances is needed to ensure that newly available therapies are used in ways that most effectively improve the health and prolong the lives of HIV-infected persons. To enable practitioners and HIV-infected persons to best use rapidly accumulating new information about HIV disease pathogenesis and treatment, the Office of AIDS Research of the National Institutes of Health sponsored the NIH Panel to Define Principles of Therapy of HIV Infection. This Panel was asked to define essential scientific principles that should be used to guide the most effective use of antiretroviral therapies and viral load testing in clinical practice. Based on detailed consideration of the most current data, the Panel delineated eleven principles that address issues of fundamental importance for the treatment of HIV infection. These principles provide the scientific basis for the specific treatment recommendations made by the Panel on Clinical Practices for the Treatment of HIV Infection sponsored by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The reports of both of these panels are provided in this publication. Together, they summarize new dta and provide both the scientific basis and specific guidelines for the treatment of HIV-infected persons. This information will be of interest to health-care providers, HIV-infected persons, HIV/AIDS educators, public health educators, public health authorities, and all organizations that fund medical care of HIV-infected persons.


INTRODUCTION

The past 2 years have brought major advances in both basic and clinical research on acquired immunodeficiency syndrome (AIDS). The availability of more numerous and more potent drugs to inhibit human immunodeficiency virus (HIV) replication has made it possible to design therapeutic strategies involving combinations of antiretroviral drugs that accomplish prolonged and near complete suppression of detectable HIV replication in many HIV-infected persons. In addition, more sensitive and reliable measurements of plasma viral load have been demonstrated to be powerful predictors of a person's risk for progression to AIDS and time to death. They have also been demonstrated to reliably assess the antiviral activity of therapeutic agents.

It is now critical that these scientific advances be translated into information that practitioners and their patients can utilize in making decisions about using the new therapies and monitoring tools to achieve the greatest, most durable clinical benefits. Such information will allow physicians to tailor more effective treatments for their patients and to more closely monitor patients' responses to specific antiretroviral regimens.

A two-track process was initiated to address this pressing need. The Office of AIDS Research of the National Institutes of Health (NIH) sponsored the NIH Panel To Define Principles of Therapy of HIV Infection. This Panel was asked to delineate the scientific principles, based on its understanding of the biology and pathogenesis of HIV infection and disease, that should be used to guide the most effective use of antiretroviral therapy and viral load testing in clinical practice.

The Department of Health and Human Services (HHS) and the Henry J. Kaiser Family Foundation sponsored the Panel on Clinical Practices for the Treatment of HIV Infection. The HHS Panel was charged with developing recommendations, based on the scientific principles, for the clinical use of antiretroviral drugs and laboratory monitoring methods in the treatment of HIV-infected persons. Both documents -- the Report of the NIH Panel To Define Principles of Therapy for HIV Infection, developed by the NIH Panel, and the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, developed by the HHS Panel -- are provided in this report.

Together, these two documents summarize new data and provide both the scientific basis and specific guidelines for the treatment of HIV-infected persons. The goal of this report is to assist clinicians and patients in making informed decisions about treatment options so that a) effective antiretroviral therapy is introduced before extensive immune system damage has occurred; b) viral load monitoring is used as an essential tool in determining an HIV-infected person's risk for disease progression and response to antiretroviral therapy; c) combinations of antiretroviral drugs are used to suppress HIV replication to below the limits of detection of sensitive viral load assays; and d) patient adherence to the complicated regimens of combination antiretroviral therapy that are currently required to achieve durable suppression of HIV replication is encouraged by patient-provider relationships that provide education and support concerning the goals, strategies, and requirements of antiretroviral therapy.

The NIH Panel included clinicians, basic and clinical researchers, public health officials, and community representatives. As part of its effort to accumulate the most current data, the Panel held a 2-day public meeting to hear presentations by clinicians and scientists in the areas of HIV pathogenesis and treatment, specifically addressing the following topics: the relationship between virus replication and disease progression; the relative ability of available strategies of antiviral therapy to minimize HIV replication for prolonged periods of time; the relationship between the emergence of drug resistance and treatment failures; the relative ability of available strategies of antiviral therapy to delay or prevent the emergence of drug-resistant HIV variants; and the relationship between drug-induced changes in virus load and improved clinical outcomes and prolonged survival.

Summary of the Principles of Therapy of HIV Infection

  1. Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual.

  2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4+ T cell destruction, whereas CD4+ T cell counts indicate the extent of HIV-induced immune damage already suffered. Regular, periodic measurement of plasma HIV RNA levels and CD4+ T cell counts is necessary to determine the risk for disease progression in an HIV-infected person and to determine when to initiate or modify antiretroviral treatment regimens.

  3. As rates of disease progression differ among HIV-infected persons, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4+ T cell counts.

  4. The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy.

  5. The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents with which the patient has been treated previously.

  6. Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum schedules and dosages.

  7. The available effective antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases future therapeutic constraints.

  8. Women should receive optimal antiretroviral therapy regardless of pregnancy status.

  9. The same principles of antiretroviral therapy apply to HIV-infected children, adolescents, and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations.

  10. Persons identified during acute primary HIV infection should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays.

  11. HIV-infected persons, even those whose viral loads are below detectable limits, should be considered infectious. Therefore, they should be counseled to avoid sexual and drug-use behaviors that are associated with either transmission or acquisition of HIV and other infectious pathogens.

    These topics and other data assessed by the Panel in formulating the

scientific principles were derived from three primary sources: recent basic insights into the life cycle of HIV, studies of the extent and consequences of HIV replication in infected persons, and clinical trials of anti-HIV drugs.

In certain instances, the Panel based the principles and associated corollaries on clinical studies conducted in relatively small numbers of patients for fairly short periods of time. After carefully evaluating data from these studies, the Panel concluded that the results of several important contemporary studies have been consistent in their validation of recent models of HIV pathogenesis.

The Panel believes that new antiretroviral drugs and treatment strategies, if used correctly, can substantially benefit HIV-infected persons. However, as the understanding of HIV disease has improved and the number of available beneficial therapies has increased, clinical care of HIV-infected patients has become much more complex. Therapeutic success increasingly depends on a thorough understanding of the pathogenesis of HIV disease and on familiarity with when and how to use the more numerous and more effective drugs available to treat HIV infection. The Panel is concerned that even these new potent antiretroviral therapies will be of little clinical utility for treated patients unless they are used correctly and that, used incorrectly, they may even compromise the potential to obtain long-term benefit from other antiretroviral therapies in the future.

The principles and conclusions discussed in this report have been developed and made available now so that practitioners and patients can make treatment decisions based on the most current research results. Undoubtedly, insights into the pathogenesis of HIV disease will continue to accumulate rapidly, providing new targets for the development of additional antiretroviral drugs and even more effective treatment strategies. Thus, the Panel expects that these principles will require modification and elaboration as new information is acquired.


SCIENTIFIC PRINCIPLES


Principle 1. Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual.

Active replication of HIV is the cause of progressive immune system damage in infected persons (1-10). In the absence of effective inhibition of HIV replication by antiretroviral therapy, nearly all infected persons will suffer progressive deterioration of immune function resulting in their susceptibility to opportunistic infections (OIs), malignancies, neurologic diseases, and wasting, ultimately leading to death (11,12).

For adults who live in developed countries, the average time of progression to AIDS after initial infection is approximately 10-11 years in the absence of antiretroviral therapy or with older regimens of nucleoside analog (e.g., zidovudine {ZDV}) monotherapy (11). Some persons develop AIDS within 5 years of infection (20%), whereas others (less than 5%) have sustained long-term (greater than 10 years) asymptomatic HIV infection without decline of CD4+ T cell counts to less than 500cells/mm3. Only approximately 2% or less of HIV-infected persons seem to be able to contain HIV replication to extremely low levels and maintain stable CD4+ T cell counts within the normal range for lengthy periods (greater than 12 years), and many of these persons display laboratory evidence of immune system damage (12). Thus, HIV infection is unusual among human virus infections in causing disease in such a large proportion of infected persons.

Although a very small number of HIV-infected persons do not demonstrate progressive HIV disease in the absence of antiretroviral therapy, there is no definitive way to prospectively identify these persons. Therefore, all persons who have HIV infection must be considered at risk for progressive disease. The goals of treatment for HIV infection should be to maintain immune function in as near a normal state as possible, prevent disease progression, prolong survival, and preserve quality of life by effectively suppressing HIV replication. For these goals to be accomplished, therapy should be initiated, whenever possible, before extensive immune system damage has occurred.


Principle 2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4+ T cell destruction, whereas CD4+ T cell counts indicate the extent of HIV-induced immune damage already suffered. Regular, periodic measurement of plasma HIV RNA levels and CD4+ T cell counts is necessary to determine the risk for disease progression in an HIV-infected person and to determine when to initiate or modify antiretroviral treatment regimens.

The rate of progression of HIV disease is predicted by the magnitude of active HIV replication (reflected by so-called viral load) taking place in an infected person (5-10,13-18). Measurement of viral load through the use of quantitative plasma HIV RNA assays permits assessment of the relative risk for disease progression and time to death (5-10,13-18). Plasma HIV RNA measurements also permit assessment of the efficacy of antiretroviral therapies in individual patients (1,2,13,19-25). It is expert opinion that these measurements are necessary components of treatment strategies designed to use antiretroviral drugs most effectively. The extent of immune system damage that has already occurred in an HIV-infected person is indicated by the CD4+ T cell count (11,26-29), which permits assessment of the risk for developing specific OIs and other sequelae of HIV infection. When used in concert with viral load determinations, assessment of CD4+ T cell number enhances the accuracy with which the risk for disease progression and death can be predicted (27). Issues specific for the laboratory assessment of plasma HIV RNA and CD4+ T cell levels in HIV-infected infants and young children are discussed in Principle 9 (14-18,25,30). Important specific considerations regarding laboratory evaluations and HIV-infected persons include the following:

  1. In the newly diagnosed patient, baseline plasma HIV RNA levels should be checked in a clinically stable state. Plasma HIV RNA levels obtained within the first 6 months of initial HIV infection do not accurately predict a person's risk for disease progression (31). In contrast, plasma HIV RNA levels stabilize (reach a "set-point") after approximately 6-9 months of initial HIV infection and are then predictive of risk for disease progression (5-10). Following their stabilization, plasma HIV RNA levels may remain fairly stable for months to years in many HIV-infected persons (7,10). However, immunizations and intercurrent infections can lead to transient elevations of plasma HIV RNA levels (32-34). As a result, values obtained within approximately 4 weeks of such episodes may not accurately reflect a person's actual baseline plasma HIV RNA level. For an accurate baseline, two specimens obtained within 1-2 weeks of each other, processed according to optimal, validated procedures, and analyzed by the same quantitative method are recommended. The use of two baseline measurements serves to reduce the variance in the plasma HIV RNA assays that results from technical and biologic factors (19,22,35,36).

  2. Studies of populations of HIV-infected persons indicate that plasma HIV RNA levels gradually increase with time after infection (10). A steeper rate of increase is associated with an increased risk of disease progression. Within individual patients, the actual rate of change of plasma HIV RNA levels is unpredictable but can increase abruptly. Therefore, periodic monitoring of plasma HIV RNA levels is necessary to accurately gauge risk of disease progression. (See Guidelines.)

  3. Studies of the kinetics of HIV replication in infected persons indicate that levels of plasma HIV RNA should measurably decline within days of initiation of effective combination antiretroviral therapy (1,2,20,21,37). In patients in whom cessation of detectable new rounds of HIV infection of CD4+ T cells occurs, plasma HIV RNA levels should fall to approximately 1% of their initial levels within 2 weeks after initiation of therapy, reaching a nadir (ideally below the limit of detection of sensitive plasma HIV RNA assays) within approximately 8 weeks. Persons who have very high initial plasma HIV RNA levels may take longer to reach a nadir of plasma RNA levels following initiation of effective antiretroviral therapy (up to approximately 16 weeks). (See Guidelines.)

  4. Plasma HIV RNA assays provide the best measure of the activity of antiretroviral therapy of HIV-infected persons. Rebound of plasma HIV RNA levels following their suppression by antiretroviral therapy may indicate the outgrowth of drug-resistant HIV variants in a patient adherent to the regimen (see Principle 7 for additional considerations). Should the desired level of suppression of HIV replication be accomplished in treated patients by 16 weeks after initiation or alteration of an antiretroviral regimen, plasma HIV RNA levels should be checked periodically to document the continued activity of the chosen antiretroviral regimen.

  5. HIV RNA levels can vary by approximately threefold (0.5 log10) in either direction, upon repeated measurements (obtained withing days or weeks of each other) in clinically stable, HIV-infected persons (19,22,35,36). Changes greater than 0.5 log10 usually cannot be explained by inherent biological or assay variability and likely reflect a biologically and clinically relevant change in the level of plasma HIV RNA. It is important to note that the variability of the current plasma HIV RNA assays is greater toward their lower limits of sensitivity. Thus, differences between repeated measures of greater than 0.5 log10 may be seen at very low plasma HIV RNA values and may not reflect a substantive biological or clinical change.

  6. CD4+ T cell counts should be obtained for all patients who have newly diagnosed HIV infection (28,29) (See Guidelines).

  7. CD4+ T cell counts are subject to substantial variability due to both biological and laboratory methodologies (26) and can vary up to 30% on repeated measures in the absence of a change in clinical status. Thus, it is important to monitor trends over time rather than base treatment decisions on one specific determination.

  8. In patients who are not receiving antiretroviral therapy, CD4+ T cell counts should be checked regularly to monitor patients for evidence of disease progression. (See Guidelines.)

  9. In patients receiving antiretroviral therapy, CD4+ T cell counts should be checked regularly to document continuing immunologic benefit and to assess the current degree of immunodeficiency (28,29). (See Guidelines.)

  10. It is not yet known whether a given CD4+ T cell level achieved in response to antiretroviral therapy provides an equivalent assessment of the degree of immune system function or has the same predictive value for risk for OIs as do CD4+ T cell levels obtained in the absence of therapy. The potentially incomplete recovery of T cell function and the diversity of antigen recognition, despite CD4+ T cell increases induced by antiretroviral therapy, have raised concerns that patients may remain susceptible to OIs at higher CD4+ T cell levels. Until more data concerning this issue are available, the Panel concurs with recent U.S. Public Health Service/Infectious Diseases Society of America recommendations that prophylactic medications be continued when CD4+ T cell counts increase above recommended threshold levels as a result of initiation of effective antiretroviral therapies (i.e., that the provision of prophylaxis be based on the lowest reliably determined CD4+ T cell count) (28).

  11. Measurements of p24 antigen, neopterin, and beta-2 microglobulin levels have often been used to assess risk for disease progression. However, these measurements are less reliable than plasma HIV RNA assays and do not add clinically useful prognostic information to that obtained from HIV RNA and CD4+ T cell levels. As such, these laboratory tests need not be included as part of the routine care of HIV-infected patients.


Principle 3. As rates of disease progression differ among HIV-infected persons, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4+ T cell counts.

Decisions regarding when to initiate antiretroviral therapy in an HIV-infected person should be based on the risk for disease progression and degree of immunodeficiency. Initiation of antiretroviral therapy before the onset of immunologic and virologic evidence of disease progression is expected to have the greatest and most durable beneficial impact on preserving the health of HIV-infected persons. When specific viral load or CD4+ T cell levels at which therapy should be initiated are considered, it is important to recognize that the risk for disease progression is a continuous rather than discrete function (5,6,10,27). There is no known absolute threshold of HIV replication below which disease progression will not eventually occur. At present, recommendations for initiation of therapy must be based on the fact that the types and numbers of available antiretroviral drugs are limited. When more numerous, more effective, better tolerated, and more conveniently dosed drugs become available, it is likely that indications for initiation of therapy will change accordingly. Specific considerations regarding treatment include the following:

  1. Decisions made by health-care practitioners and HIV-infected patients regarding initiation of antiretroviral therapy should be guided by the patient's plasma HIV RNA level and CD4+ T cell count. (See Guidelines.)

  2. Data are not yet available that define the degree of therapeutic benefit in persons who have relatively high CD4+ T cell counts and relatively low plasma HIV RNA levels (e.g., CD4+ T cell count greater than 500/mm3 and plasma HIV RNA less than 10,000 copies/mL). However, emerging insights into the pathogenesis of HIV disease predict that antiretroviral therapy should be of benefit to such patients. For persons at low risk for disease progression, decisions concerning when to initiate antiretroviral therapy must also include consideration of the potential inconvenience and toxicities of the available antiretroviral drugs. Should the decision be made to defer therapy, regular monitoring of HIV RNA levels and CD4+ T cell counts should be performed as recommended (See Guidelines).

  3. Persons who have levels of HIV RNA persistently below the level of detection of currently available HIV RNA assays and who have stable, high CD4+ T cell counts in the absence of therapy are at low risk for disease progression in the near future. The potential for benefit of treatment for these persons is not known. Should the decision be made to defer therapy, regular monitoring of HIV RNA levels and CD4+ T cell counts should be performed as recommended (see Guidelines).

  4. Patients who have late-stage disease (as indicated by clinical evidence of advanced immunodeficiency or low CD4+ T cell counts, e.g., less than 50 cells/mm3) have benefited from appropriate antiretroviral therapy as evidenced by decreased risks for further disease progression or death (23,28). In such patients, antiretroviral therapy can be of benefit even when CD4+ T cell increases are not seen. Therefore, discontinuation of antiretroviral therapy in this setting should be considered only if available antiretroviral therapies do not suppress HIV replication to a measurable degree, if drug toxicities outweigh the anticipated clinical benefit, or if survival and quality of life are not expected to be improved by antiretroviral therapy (e.g., terminally ill persons).


Principle 4. The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy.

Studies of the biology and pathogenesis of HIV infection have provided the basis for using antiretroviral drugs in ways that yield the most profound and durable suppression of HIV replication. The inherent ability of HIV to develop drug resistance represents the major obstacle to the long-term efficacy of antiretroviral therapy (21). However, recent clinical evidence indicates that the development of drug resistance can be delayed, and perhaps even prevented, by the rational use of combinations of drugs that include newly available, potent agents to suppress HIV replication to levels that cannot be detected by sensitive assays of plasma HIV RNA (23,38-40). Cessation of detectable HIV replication decreases the opportunity for accumulation of mutations that may give rise to drug-resistant viral variants. Furthermore, the extent and duration of inhibition of HIV replication by antiretroviral therapy predicts the magnitude of clinical benefit derived from treatment (9,13,23-25).

The potential toxicities of therapy, as well as the patient's quality of life and ability to adhere to a complex antiretroviral drug regimen, should be balanced with the anticipated clinical benefit of maximal suppression of HIV replication and the anticipated risks of less complete suppression. Specific considerations regarding treatment include the following:

  1. Once a decision has been made to initiate antiretroviral therapy, the ideal goal of therapy should be suppression of the level of active HIV replication, as assessed by sensitive measures of plasma HIV RNA, to undetectable levels.

  2. If suppression of HIV replication to undetectable levels cannot be achieved, the goal of therapy should be to suppress virus replication as much as possible for as long as possible. Less complete suppression of HIV replication is expected to yield less profound and less durable immunologic and clinical benefits. Higher residual levels of HIV replication during therapy predispose the patient to more rapid development of antiretroviral drug resistance and associated waning of clinical benefit. In the absence of effective suppression of detectable HIV replication, it is currently impossible to identify a precise target level for suppression of HIV replication that will yield predictable clinical benefits. However, recent data indicate that suppression of HIV RNA levels to less than 5,000 copies/mL is likely to yield more greater and more durable clinical benefit than less complete suppression (24).

  3. The HIV RNA assays currently available have similar levels of sensitivity (19,41-46; Table_1). More sensitive versions of each of these assays are currently in development and will likely be commercially available in the future. Once these assays are available, the goal of antiretroviral therapy should be suppression of HIV RNA levels to below detection of these more sensitive assays. Less profound suppression of HIV replication is associated with a greater likelihood of development of drug resistance (23,40).

  4. Although suppression of HIV load to levels below the detection limits of sensitive plasma HIV RNA assays indicates profound inhibition of new cycles of virus replication, it does not mean that the infection has been eradicated or that virus replication has been stopped completely (37,47-50). HIV replication may be continuing in various tissues (e.g., the lymphatic tissues and the central nervous system) although it can no longer be detected by plasma HIV RNA assays. Strategies for potential eradication are being pursued in experimental studies, but the likelihood of their success is uncertain (37,51). Recent studies indicate that infectious HIV can still be isolated from CD4+ T cells obtained from infected persons whose plasma HIV RNA levels have been suppressed below detection for prolonged periods (up to 30 months) (49,50). Long-term persistence of HIV infection in such persons who have undetectable levels of plasma HIV RNA appears to be due to the existence of long-lived reservoirs of latently infected CD4+ cells, rather than drug failure (49,50). Continued monitoring of HIV RNA levels is necessary in patients who have achieved antiretroviral drug-induced suppression of HIV RNA to undetectable levels, as this effect may be transient. (See Guidelines.)


Principle 5. The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents with which the patient has been previously treated.

Several issues should be considered regarding the combination of antiretroviral drugs to be used in the treatment of an HIV-infected patient. The efficacy of a given regimen of combination antiretroviral therapy is not simply a function of the number of drugs used. The most effective antiretroviral drugs possess high potency, favorable pharmacologic properties, and require that HIV acquire multiple mutations in the relevant HIV target gene before high-level drug resistance is realized. In addition, drug-resistant HIV variants selected for by treatment with certain antiretroviral drugs may display diminished ability to replicate (decreased "fitness") in infected persons (21). Drugs used in combination should show evidence of additivity or synergy of antiretroviral activity, should lack antagonistic pharmacokinetic or antiretroviral properties, and should possess nonoverlapping toxicities. Ideally, the chosen drugs will display molecular interactions that increase the potency of antiretroviral therapy or delay the emergence of antiretroviral drug resistance. If multiple options are available for combination therapy, specific antiretroviral drugs should be employed so that future therapeutic options are preserved if the initial choice of therapy fails to achieve its desired result. Whenever possible, therapy should be initiated or modified with a rational combination of antiretroviral drugs, a predefined target for the degree of suppression of HIV replication desired, and a predefined alternative antiretroviral regimen to be used should the target goal not be reached. Specific considerations regarding treatment include the following:

  1. The combination of antiretroviral drugs used when therapy is either initiated or changed needs to be carefully chosen because it will influence subsequent options for effective antiretroviral therapy if the chosen drug regimen fails to accomplish satisfactory suppression of HIV replication.

  2. The best opportunity to accomplish maximal suppression of virus replication, minimize the risk of outgrowth of drug-resistant HIV variants, and maximize protection from continuing immune system damage is to use combinations of effective antiretroviral drugs in persons who have no prior history of anti-HIV therapy.

  3. No single antiretroviral drug that is currently available, even the more potent protease inhibitors (PIs), can ensure sufficient and durable suppression of HIV replication when used as a single agent ("monotherapy"). Furthermore, the use of potent antiretroviral drugs as single agents presents a great risk for the development of drug resistance and the potential development of cross-resistance to related drugs. Thus, antiretroviral monotherapy is no longer a recommended option for treatment of HIV-infected persons (see Guidelines). One exception is the use of zidovudine (ZDV) according to the AIDS Clinical Trials Group (ACTG) 076 regimen. This regimen is specifically for the purpose of reducing the risk for perinatal HIV transmission in pregnant women who have high CD4+ T cell counts and low plasma HIV RNA levels and who have not yet decided to initiate antiretroviral therapy based on their own health indications (52-54). This time-limited use of zidovudine by a pregnant woman to prevent perinatal HIV transmission has important benefits to infants and is not likely to substantially compromise her future ability to benefit from combination antiretroviral therapy.

  4. Antiretroviral drugs (e.g., lamivudine {3TC}) or the non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., nevirapine and delavirdine), that are potent, but to which HIV readily develops high-level resistance, should not be used in regimens that are expected to yield incomplete suppression of detectable HIV replication.

  5. At present, durable suppression of detectable levels of HIV replication is best accomplished with the use of two nucleoside analog reverse transcriptase (RT) inhibitors combined with a potent PI. In patients who have not been treated with antiretroviral therapy, suppression of detectable HIV replication has also been reported with the use of two nucleoside analog RT inhibitors combined with a NNRTI (e.g., zidovudine, didanosine, and nevirapine {40}). However, the role of this approach as initial antiretroviral therapy needs to be better defined before it can be recommended as a "first-line" treatment strategy. Furthermore, this approach is considerably less effective in persons who have been previously treated with nucleoside analog RT inhibitors (55-57). In the subset of previously treated patients who respond initially to such regimens, suppression of HIV replication is often transient and the associated clinical benefit is limited.

  6. The use of fewer than three antiretroviral drugs in combination may be considered as an option by HIV-infected persons and their physicians. In making this decision, it is important to recognize that no combination of two currently available nucleoside analog RT inhibitors has been demonstrated to consistently provide sufficient and durable suppression of HIV replication. Although the initial decline in HIV RNA levels following treatment with two RT inhibitors may be encouraging, the durability of the response beyond 24-48 weeks in controlled studies has been disappointing (40,56-60). Furthermore, the selection of drug-resistant HIV variants by antiretroviral regimens that fail to suppress HIV replication durably may compromise the range of future treatment options. Even in antiretroviral-drug-naive patients, the use of NNTRIs is not routinely recommended in combination with one nucleoside analog RT inhibitor, as the risk for selection of NNRTI-resistant HIV variants is high in regimens that fail to achieve suppression of detectable HIV replication (1,61). Certain combinations of two protease inhibitors (without added RT inhibitors) have been reported to provide suppression of detectable HIV replication in pilot studies (62,63); however, given the limited experience available with this approach, it should not be considered as a first-line regimen at the present time. (See Guidelines.)

  7. When a change in therapy is considered in a previously treated patient, a review of the person's prior history of anti-HIV therapy is essential. Drugs chosen as the components of a new antiretroviral regimen should not be cross-resistant to previously used antiretroviral drugs (or share similar patterns of mutations associated with antiretroviral drug resistance). (See Principle 7 for additional considerations.)

  8. When changing a failing regimen, it is important to change more than one component of the regimen. The addition of single antiretroviral agents, even very potent ones, is likely to lead to the development of viral resistance to the new agent. (See Guidelines.)


Principle 6. Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum schedules and dosages.

The use of combinations of potent antiretroviral drugs to exert constant, maximal suppression of HIV replication provides the best approach to circumvent the inherent tendency of HIV to generate drug-resistant variants. Specific considerations regarding treatment include the following:

  1. Combination therapy should be initiated with all drugs started simultaneously (ideally within 1 or 2 days of each other); antiretroviral therapies should not be added sequentially. Staged introduction of individual antiretroviral drugs increases the likelihood that incomplete suppression of HIV replication will be achieved, thereby permitting the progressive accumulation of mutations that confer resistance to multiple antiretroviral agents. Rather than strive to increase patient acceptance of therapy through the sequential addition of antiretroviral drugs, the Panel believes it is better to counsel and educate patients extensively before the initiation of antiretroviral therapy, even if it means a limited delay in initiating treatment.

  2. Whenever possible, combination antiretroviral therapy should be maintained at recommended drug doses. At any time after initiation of therapy, underdosing with any one agent in a combination, or the administration of fewer than all drugs of a combination at any one time, should be avoided. Antiretroviral drug resistance is less likely to occur if all antiretroviral therapy is temporarily stopped than if the dosage of one or more components is reduced or if one component of an effective suppressive regimen is withheld. Should antiretroviral drug resistance develop as a result of underdosing or irregular dosing of antiretroviral drugs, subsequent readministration of recommended doses of drugs on a regular schedule is unlikely to accomplish effective suppression of HIV replication.

  3. Patient adherence to an antiretroviral regimen is critical to the success of therapy. If antiretroviral drugs are used in inadequate doses or are used only intermittently, the risk for developing drug-resistant HIV variants is greatly increased. Effective adherence to complicated medical regimens requires extensive patient education about the goals and rationale for therapy before it is initiated, as well as an ongoing, active collaboration between practitioner and patient when therapy has been started. Counseling should include careful review of the drug-dosing intervals, the possibility of co-administration of several medications at the same time, and the relationship of drug dosing to meals and snacks.

  4. Available effective regimens of combination antiretroviral therapy require that patients take multiple medications at specific times of the day. Persons who have unstable living situations or limited social support mechanisms may have difficulty adhering to the recommended antiretroviral therapy regimens and may need special support from health-care workers to do so effectively. If circumstances impede adherence to the most effective antiretroviral regimens now available, therapy is unlikely to be of long-term benefit to the patient and the risk of selection of drug-resistant HIV variants is increased. Therefore, it is important to ensure that adequate social support is available for patients who are offered combination antiretroviral therapy. Health-care providers should work with HIV-infected patients to assess if they are ready and able to commit to a regimen of antiviral therapy. Health-care providers should make such assessment on an individual basis and not consider that any specific group of persons are unable to adhere.


Principle 7. The available effective drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases future therapeutic constraints.

Decisions to alter therapy will rely heavily on consideration of clinical issues and on the number of available alternative antiretroviral agents. Every decision made to alter therapy may limit future treatment options. Thus, available agents should not be abandoned prematurely. It is not known definitively whether the pathogenic consequences of a measurable level of HIV replication while on therapy are equivalent to those of an equivalent level in an untreated person; however, preliminary data suggest that this is the case. Thus, the level at which HIV replication continues while on an antiretroviral drug regimen that has failed to suppress plasma HIV RNA to below detectable levels should be considered as an indication of the urgency with which an alteration in therapy should be pursued. Specific considerations regarding treatment include the following:

  1. Increasing levels of plasma HIV RNA in a person receiving antiretroviral therapy can be caused by several factors. Identification of the responsible factor, wherever possible, is an important goal. Evidence of increased levels of HIV replication may signal the emergence of drug-resistant HIV variants, incomplete adherence to the antiretroviral therapy, decreased absorption of antiretroviral drugs, altered drug metabolism due to physiologic changes or drug-drug interactions, or intercurrent infection.

  2. Before the decision is made to alter antiretroviral therapy because of an increase in plasma HIV RNA, it is important to repeat the plasma HIV RNA measurements to avoid unnecessary changes based on misleading or spurious plasma HIV RNA values (e.g., the presence of intercurrent infection or imperfect adherence to therapy).

  3. Antiretroviral therapy should be changed when plasma HIV RNA again becomes detectable (repeatedly and in the absence of events such as imperfect adherence to the regimen, immunizations, or intercurrent infections that may lead to transient elevations of plasma HIV RNA levels) and continues to rise in a patient in whom it had been previously suppressed to undetectable levels. In a person whose plasma HIV RNA levels had been previously incompletely suppressed, progressively increasing plasma HIV RNA levels should prompt consideration of a change in antiretroviral therapy. (See Guidelines.)

  4. Evidence of antiretroviral drug toxicity or intolerance is also an important reason to consider changes in drug therapy. In certain instances, these manifestations may be transient, and therapy may be safely continued with attention to patient counseling and continuing evaluation. When it is necessary to change therapy for reasons of toxicity or intolerance, alternative antiretroviral drugs should be chosen based on their anticipated efficacy and lack of similar toxicities. In this situation, substitution of one drug (ideally of the same class and possessing equal or greater antiretroviral activity) for another, while continuing the other components of the regimen, is reasonable.


Principle 8. Women should receive optimal antiretroviral therapy regardless of pregnancy status.

The use of antiretroviral treatment in HIV-infected pregnant women raises important, unique concerns (64). HIV counseling and the offer of HIV testing to pregnant women have been universally recommended in the United States and are now mandatory in some states. A greater awareness of issues surrounding HIV infection in pregnant women has resulted in an increased number of women whose initial diagnosis of HIV infection is made during pregnancy. In this circumstance, or when women already aware of their HIV infection become pregnant, treatment decisions should be based on the current and future health of the mother, as well as on preventing perinatal transmission and ensuring the health of the fetus and neonate. Care of the HIV-infected pregnant woman should involve a collaboration between the HIV specialist caring for the woman when she is not pregnant, her obstetrician, and the woman herself. Treatment recommendations for HIV-infected pregnant women are based on the belief that therapies of known benefit to women should not be withheld during pregnancy unless there are known adverse effects on the mother, fetus, or infant that outweigh the potential benefit to the woman (64). There are two separate but interconnected issues regarding antiretroviral treatment during pregnancy: a) use of antiretroviral therapy for maternal health indications and b) use of antiretroviral drugs for reducing the risk of perinatal HIV transmission. Although zidovudine monotherapy substantially reduces the risk of perinatal HIV transmission, appropriate combinations of antiretroviral drugs should be administered if indicated on the basis of the mother's health. In general, pregnancy should not compromise optimal HIV therapy for the mother. Specific considerations regarding treatment of pregnant women include the following:

  1. Recommendations regarding the choice of antiretroviral agents in pregnant women are subject to unique considerations, including potential changes in dose requirements due to physiologic changes associated with pregnancy and potential effects of the drug on the fetus and neonate (e.g., placental passage of drug and preclinical data indicating potential for teratogenicity, mutagenicity, or carcinogenicity). (See Guidelines.)

  2. No long-term safety studies are available regarding the use of any antiretroviral agents during pregnancy. Because the first trimester of pregnancy (i.e., weeks 1-14) is the most vulnerable time with respect to teratogenicity (particularly the first 8 weeks), it may be advisable to delay, when feasible, the initiation of antiretroviral therapy until 14 weeks' gestational age. However, if clinical, virologic, or immunologic parameters are such that therapy would be recommended for nonpregnant persons, many experts would recommend initiating therapy, regardless of gestational age.

  3. Women who are already receiving antiretroviral therapy at the time that pregnancy is diagnosed should continue their therapy. Alternatively, if pregnancy is anticipated or discovered early in the first trimester (before 8 weeks), concern for potential teratogenicity may lead some women to consider stopping antiretroviral therapy until 14 weeks' gestation. Although the effects of all antiretroviral drugs on the developing fetus during the first trimester are uncertain, most experts recommend continuation of a maximally suppressive regimen even during the first trimester. Currently, insufficient data exist to support or refute concerns about potential teratogenicity. If antiretroviral therapy is discontinued for any reason during the first trimester, all agents should be discontinued simultaneously. Once they are reinstituted, they should be reintroduced simultaneously.

  4. Treatment of a pregnant woman with an antiretroviral regimen that does not suppress HIV replication to below detectable levels is likely to result in the development of antiretroviral drug-resistant HIV variants and limit her ability to respond favorably to effective combination therapy regimens in the future. The emergence of drug-resistant HIV variants during incomplete suppression of HIV replication in a pregnant woman may limit the ability of those same antiretroviral drugs to effectively decrease the risk of perinatal transmission if provided intrapartum and/or to the neonate.

  5. Transmission of HIV from mother to infant can occur at all levels of maternal viral loads, although higher viral loads tend to be associated with an increased risk of transmission (53,65). Zidovudine therapy is effective at reducing the risk for perinatal HIV transmission regardless of maternal viral load (53,54). Therefore, use of the recommended regimen of zidovudine alone or in combination with other antiretroviral drugs should be discussed with and offered to all HIV-infected pregnant women, regardless of their plasma HIV RNA level (54).


Principle 9. The same principles of antiretroviral therapy apply to HIV-infected children, adolescents, and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations.

Most of the data that support the principles of antiretroviral therapy outlined in this document have been generated in studies of HIV-infected adults. Adolescents infected with HIV sexually or through drug use appear to follow a clinical course similar to adults, and recommendations for antiretroviral therapy for these persons are the same as for adults (see Guidelines). However, although fewer data are available concerning treatment of HIV infection in younger persons, it is unlikely that the fundamental principles of HIV disease differ for HIV-infected children. Furthermore, the data that are available from studies of HIV-infected infants and children indicate that the same fundamental virologic principles apply, and optimal treatment approaches are also likely to be similar (14-18,25). Therefore, HIV-infected children, as previously described for HIV-infected adults, should be treated with effective combinations of antiretroviral drugs with the intent of accomplishing durable suppression of detectable levels of HIV replication.

Unfortunately, not all of the antiretroviral drugs that have demonstrated efficacy in combination therapy regimens in adults are available in formulations (e.g., palatable liquid formulations) for infants and young children (particularly for those aged less than 2 years). In addition, pharmacokinetic and pharmacodynamic studies of some antiretroviral agents have yet to be completed in children. Thus, effective antiretroviral therapies should be studied in children and age-specific pharmacologic properties of these therapies should be defined. Antiretroviral drugs selected to treat HIV-infected children should be used only if their pharmacologic properties have been defined in the relevant age group of the patient. Use of antiretroviral drugs before these properties have been defined may result in undesirable toxicities without virologic or clinical benefit.

Identification of HIV-infected infants soon after delivery or during the first few weeks following their birth provides opportunities for treatment of primary HIV infection and, perhaps, for facilitating the most effective treatment responses (16-18,66). Thus, identification of HIV-infected women through voluntary testing, provision of antiretroviral therapy to the mother and infant to decrease the risk of maternal-infant transmission, and careful screening of infants born to HIV-infected mothers for evidence of HIV infection will provide an effective strategy to ameliorate the risk and consequences of perinatal HIV infection.

The specific HIV RNA and CD4+ T cell criteria used for making decisions about when to initiate therapy in infected adults do not apply directly to newborns, infants, and young children (14-18). As with adults, higher levels of plasma HIV RNA are associated with a greater risk of disease progression and death in infants and young children (14-18). However, absolute levels of plasma HIV RNA observed during the first years of life in HIV-infected children are frequently higher than those found in adults infected for similar lengths of time, and establishment of a post-primary-infection set-point takes substantially longer in infected children (15-18). The increased susceptibility of children to OIs, particularly Pneumocystis carinii pneumonia (PCP), at higher CD4+ T cell counts than HIV-infected adults (30) further indicates that the CD4+ T cell criteria suggested as guides for initiation of antiretroviral therapy in HIV-infected adults are not appropriate to guide therapeutic decisions for infected children. In all, the need for and potential benefits of early institution of effective antiretroviral therapy are likely to be even greater in children than adults, suggesting that most, if not all, HIV-infected children should be treated with effective combination antiretroviral therapies.


Principle 10. Persons identified during acute primary HIV infection should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays.

Studies of HIV pathogenesis provide theoretical support for the benefits of antiretroviral therapy for persons diagnosed with primary HIV infection, and data that are accumulating from small-scale clinical studies are consistent with these predictions (49,66-73). Results from studies suggest that antiretroviral therapy during primary infection may preserve immune system function by blunting the high level of HIV replication and immune system damage occurring during this period and potentially reducing set-point levels of HIV replication, thereby favorably altering the subsequent clinical course of the infection; however, this outcome has yet to be formally demonstrated (51,73). It has been further suggested that the best opportunity to eradicate HIV infection might be provided by the initiation of potent combination antiretroviral therapy during primary infection (51).

The Panel believes that, although the long-term benefits of effective combination antiretroviral therapy of primary infection are not known, it is a critical topic of investigation. Therefore, enrollment of newly diagnosed patients in clinical trials should be encouraged to help in defining the optimal approach to treatment of primary infection. When this is neither feasible nor desired, the Panel believes that combination antiretroviral therapy with the goal of suppression of HIV replication to undetectable levels should be pursued. The Panel believes that suppressive antiretroviral therapy for acute primary HIV infection should be continued indefinitely until clinical trials provide data to establish the appropriate duration of therapy.


Principle 11. HIV-infected persons, even those whose viral loads are below detectable limits. Therefore, they should be considered infectious. Therefore, they should be counseled to avoid sexual and drug-use behaviors that are associated with either transmission or acquisition of HIV and other infectious pathogens.

No data are available concerning the ability of HIV-infected persons who have antiretroviral therapy-induced suppression of HIV replication to undetectable levels (assessed by plasma HIV RNA assays) to transmit the infection to others. Similarly, their ability to acquire a multiply resistant HIV variant from another person remains a possibility. HIV-infected persons who are receiving antiretroviral therapy continue to be able to transmit serious infectious diseases to others (e.g., hepatitis B and C and sexually transmitted infections, such as herpes simplex virus, human papillomavirus syphilis, gonorrhea, chancroid, and chlamydia) and are themselves at risk for infection with these pathogens, as well as others that carry serious consequences for immunosuppressed persons, including cytomegalovirus and human herpes virus 8 (also known as KSHV). Therefore, all HIV-infected persons, including those receiving effective antiretroviral therapies, should be counseled to avoid behaviors associated with the transmission of HIV and other infectious agents. Continued reinforcement that all HIV-infected persons adhere to safe-sex practices is important. If an HIV-infected injecting-drug user is unable or unwilling to refrain from using injection drugs, that person should be counseled to avoid sharing injection equipment with others and to use sterile, disposable needles and syringes for each injection.


SCIENTIFIC BACKGROUND

HIV Infection Leads to Progressive Immune System Damage in Nearly All Infected Persons

Early efforts to synthesize a coherent model of the pathogenic consequences of HIV infection were based on the presumption that few cells in infected persons harbor or produce HIV and that virus replication is restricted during the period of clinical latency. However, early virus detection methods were insensitive, and newer, more sensitive tests have demonstrated that virus replication is active throughout the course of the infection and proceeds at levels far higher than previously imagined. HIV replication has been directly linked to the process of T cell destruction and depletion. In addition, ongoing HIV replication in the face of an active but incompletely effective host antiviral immune response is probably responsible for the secondary manifestations of HIV disease, including wasting and dementia.

Beginning with the first cycles of virus replication within the newly infected host, HIV infection results in the progressive destruction of the population of CD4+ T cells that serve essential roles in the generation and maintenance of host immune responses (1-10). The target cell preference for HIV infection and depletion is determined by the identity of the cell surface molecule, CD4, that is recognized by the HIV envelope (Env) glycoprotein as the virus binds to and enters host cells to initiate the virus replication cycle (74). Additional cell surface molecules that normally function as receptors for chemokines have recently been identified as essential co-receptors required for the process of HIV entry into target cells (75). Macrophages and their counterparts within the central nervous system, the microglial cells, also express cell surface CD4 and provide targets for HIV infection. As macrophages are more resistant to the cytopathic consequences of HIV infection than are CD4+ T cells and are widely distributed throughout the body, they may play critical roles in persistence of HIV infection by providing reservoirs of chronically infected cells.

Although most of the immunologic and virologic assessments of HIV-infected persons have focused on studies of peripheral blood lymphocytes, these cells represent only approximately 2% of the total lymphocyte population in the body. The importance of the lymphoid organs, which contain the majority of CD4+ T cells, has been highlighted by the finding that the concentrations of virus and percentages of HIV-infected CD4+ T cells are substantially higher in lymph nodes (where immune responses are generated and where activated and proliferating CD4+ T cells that are highly susceptible to HIV infection are prevalent) than in peripheral blood (3,4,48). Thus, although the depletion of CD4+ T cells after HIV infection is most readily revealed by sampling peripheral blood, damage to the immune system is exacted in lymphoid organs throughout the body (3,4). For as yet unidentified reasons, gradual destruction of normal lymph node architecture occurs with time, which probably compromises the ability of an HIV-infected person to generate effective immune responses and replace CD4+ T cells already lost to HIV infection through the expansion of mature T cell populations in peripheral lymphoid tissues. The thymus is also an early target of HIV infection and damage, thereby limiting the continuation of effective T cell production even in younger persons in whom thymic production of CD4+ T cells is active (76,77). Thus, in both adults and children, HIV infection compromises both of the potential sources of T cell production, so the rate of T cell replenishment cannot continue indefinitely to match cell loss. Consequently, total CD4+ T cell numbers may decline inexorably in HIV-infected persons.

After initial infection, the pace at which immunodeficiency develops and the attendant susceptibility to OIs which arise are associated with the rate of decline of CD4+ T cell counts (11,26,27). The rate at which CD4+ T cell counts decline differs considerably from person to person and is not constant throughout all stages of the infection. Acceleration in the rate of decline of CD4+ T cells heralds the progression of disease. The virologic and immunologic events that occur around this time are poorly understood, but increasing rates of HIV replication, the emergence of viruses demonstrating increased cytopathic effects for CD4+ T cells, and declining host cell-mediated anti-HIV immune responses are often seen (12,78). For as yet unknown reasons, host compensatory responses that preserve the homeostasis of total T cell levels (CD4+ plus CD8+ T cells) appear to break down in HIV-infected persons approximately 1-2 years before the development of AIDS, resulting in net loss of total T cells in the peripheral blood, and signaling immune system collapse (79).

Although the progression of HIV disease is most readily gauged by declining CD4+ T cell numbers, evidence indicates that the sequential loss of specific types of immune responses also occurs (80-82). Memory CD4+ T cells are known to be preferential targets for HIV infection, and early loss of CD4+ memory T cell responses is observed in HIV-infected persons, even before there are substantial decreases in total CD4+ T cell numbers (80,81). With time, gradual attrition of antigen-specific CD4+ T cell-dependent immune recognition may limit the repertoire of immune responses that can be mounted effectively and so predispose the host to infection with opportunistic pathogens (82).

HIV Replication Rates in Infected Persons Can Be Accurately Gauged By Measurement of Plasma HIV Concentrations

Until recently, methods for monitoring HIV replication (commonly referred to as viral load) in infected persons were either hampered by poor sensitivity and reproducibility or were so technically laborious that they could not be adapted for routine clinical practice. However, new techniques for sensitive detection and accurate quantification of HIV RNA levels in the plasma of infected persons provide extremely useful measures of active virus replication (1,2,19,20,37,41-43). HIV RNA in plasma is contained within circulating virus particles or virions, with each virion containing two copies of HIV genomic RNA. Plasma HIV RNA concentrations can be quantified by either target amplification methods (e.g., quantitative RT polymerase chain reaction {RT-PCR}, Amplicor HIV Monitor (TM) assay, Roche Molecular Systems; or nucleic acid sequence-based amplification, {NASBA (R)}, NucliSens (TM) HIV-1 QT assay, Organon Teknika) or signal amplification methods (e.g., branched DNA {bDNA}, Quantiplex (TM) HIV RNA bDNA assay, Chiron Diagnostics) (42,43). The bDNA signal amplification method (41) amplifies the signal obtained from a captured HIV RNA target by using sequential oligonucleotide hybridization steps, whereas the RT-PCR and NASBA (R) assays use enzymatic methods to amplify the target HIV RNA into measurable amounts of nucleic acid product (41-43). Target HIV RNA sequences are quantitated by comparison with internal or external reference standards, depending upon the assay used. Versions of both types of assays are now commercially available, and the Amplicor assay was recently approved by the Food and Drug Administration for assessment for risk of disease progression and monitoring of antiretroviral therapy in HIV-infected persons. Target amplification assays are more sensitive (400 copies HIV RNA/mL plasma) than the first generation bDNA assay (10,000 copies HIV plasma), but the sensitivity of the bDNA assay has recently been improved (500 copies HIV RNA/mL plasma). More sensitive versions of each of these assays are currently in development (detection limits 20-100 copies/mL) and will likely be commercially available in the future.

All of the commercially available assays can accurately quantitate plasma HIV RNA levels across a wide range of concentrations (so-called dynamic range). Although the results of the three assays (i.e., the RT-PCR, NASBA (R), and bDNA) are strongly correlated, the absolute values of HIV RNA measured in the same plasma sample using two different assays can differ by twofold or more (44-46). Until a common standard is available that can be used to normalize values obtained with different assay methods, it is advisable to choose one assay method consistently when HIV RNA levels in infected persons are monitored for use as a guide in making therapeutic decisions.

The performance characteristics and recommended collection methods for the individual HIV RNA assays are provided (Table_1). For reliable results, it is essential that the recommended procedures be followed for collection and processing of blood to prepare plasma for HIV RNA measurements. Different plasma HIV RNA assays require different plasma volumes (an important consideration in infants and in young children). These assays are best performed on plasma specimens prepared from blood obtained in collection tubes containing specific anticoagulants (e.g., ethylenediaminetetraacetic acid {EDTA} or acid-citrate-dextran {ACD}) (Table_1) (44-46).

Quantitative measurement of plasma HIV RNA levels can be expressed in two ways: a) the number of copies/mL of HIV RNA and b) the logarithm (to the base 10) of the number of copies/mL of HIV RNA. In clinically stable, HIV-infected adults, results obtained by using commercially available plasma HIV RNA assays can vary by approximately threefold (0.5 log10) in either direction on repeated measurements obtained within the same day or on different days (35,36). Factors influencing the variation seen in plasma HIV RNA assays include biological fluctuations and those introduced by the performance characteristics of the particular assay (35,36,44-46). Variability of current plasma HIV RNA assays is greater toward their lower limits of detection and consequently changes greater than 0.5 log10 HIV RNA copies can be seen near the assay detection limits without changes in clinical status (35). Differences greater than 0.5 log10 copies on repeated measures of plasma HIV RNA likely reflect biologically and clinically relevant changes. Increased variance toward the limit of assay detection presents an important consideration as the recommended target of suppression of HIV replication by antiretroviral therapy is now defined as being HIV RNA levels below the detection limit of plasma HIV RNA assays. Immune system activation (by immunizations or intercurrent infections) can lead to increased numbers of activated CD4+ T cells, and thereby result in increased levels of HIV replication (reflected by significant elevations of plasma HIV RNA levels from their baseline values) that may persist for as long as the inciting stimulus remains (32-34). Therefore, measurements obtained surrounding these events may not reflect a patient's actual steady-state level of plasma HIV RNA. Unlike CD4+ T cell count determinations, plasma HIV RNA levels do not exhibit diurnal variation (26,36). Within the large dynamic range of plasma HIV RNA levels that can be measured (varying over several log10 copies), the observed level of assay variance is low (Table_1). Measurement of two samples at baseline in clinically stable patients has been recommended as a way of reducing the impact of the variability of plasma HIV RNA assays (19), and recent data support this approach (22).

The level of viremia, as measured by the amount of HIV RNA in the plasma, accurately reflects the extent of virus replication in an infected person (1,2,20,37). Although the lymphoid tissues (e.g., lymph nodes and other compartments of the reticuloendothelial system) provide the major sites of active virus production in HIV-infected persons, virus produced in these tissues is released into the peripheral circulation where it can be readily sampled (3,4,48). Thus, plasma HIV RNA concentrations reflect the level of active virus replication throughout the body, although it is not known whether specific compartments (e.g., the central nervous system {CNS}) represent sites of infection that are not in direct communication with the peripheral pool of virus.

The Magnitude of HIV Replication in Infected Persons Determines Their Rate of Disease Progression

Plasma HIV RNA can be detected in virtually all HIV-infected persons although its concentration can vary widely depending on the stage of the infection (Figure_1) and on incompletely understood aspects of the host-virus interactions. During primary infection in adults when there are numerous target cells susceptible to HIV infection without a countervailing host immune response, concentrations of plasma HIV RNA can exceed 107 copies/mL (83). HIV disseminates widely throughout the body during this period, and many newly infected persons display symptoms of an acute viral illness, including fever, fatigue, pharyngitis, rash, myalgias, and headache (84-86). Coincident with the emergence of antiviral immune responses, concentrations of plasma HIV RNA decline precipitously (by 2 to 3 log10 copies or more). After a period of fluctuation, often lasting 6 months or more, plasma HIV RNA levels usually stabilize around a so-called set-point (5,6,10,27,31,86). The determinants of this set-point are incompletely understood but probably include the number of susceptible CD4+ T cells and macrophages available for infection, the degree of immune activation, and the tropism and replicative vigor (fitness) of the prevailing HIV strain at various times following the initial infection, as well as the effectiveness of the host anti-HIV immune response. In contrast to adults, HIV-infected infants often have very high levels of plasma HIV RNA that decline slowly with time and do not reach set-point levels until more than a year after infection (14-18).

Different infected persons display different steady-state levels of HIV replication. When populations of HIV-infected adults are studied in a cross-sectional manner, an inverse correlation between plasma HIV RNA levels and CD4+ T cell counts is seen (87,88). However, at any given CD4+ T cell count, plasma HIV RNA concentrations show wide interindividual variation (87,88). In established HIV infection, persistent concentrations of plasma HIV RNA range from less than 200 copies/mL in extraordinary persons who have apparently nonprogressive HIV infection to greater than 106 copies/mL in persons who are in the advanced stages of immunodeficiency or are at risk for very rapid disease progression. In most HIV-infected and untreated adults, set-point plasma HIV RNA levels range between 103 and 105 copies/mL. Persons who have higher steady-state set-point levels of plasma HIV RNA generally lose CD4+ T cells more quickly, progress to AIDS more rapidly, and die sooner than those with lower HIV RNA set-point levels (5-7,10,27) (Figure_2, Figure_3, Figure_4). Once established, set-point HIV RNA levels can remain fairly constant for months to years. However, studies of populations of HIV-infected persons suggest a gradual trend toward increasing HIV RNA concentrations with time after infection (10). Within individual HIV-infected persons, rates of increase of plasma HIV RNA levels can change gradually, abruptly, or hardly at all (10). Progressively increasing plasma HIV RNA concentrations can signal the development of advancing immunodeficiency, regardless of the initial set-point value (10,75).

Plasma HIV RNA levels provide more powerful predictors of risk of progression to AIDS and death than do CD4+ T cell levels; however, the combined measurement of the two values provides an even more accurate method to assess the prognosis of HIV-infected persons (27). The relationship between baseline HIV RNA levels measured in a large cohort of HIV-infected adults and their subsequent rate of CD4+ T cell decline is shown (Figure_3) (27). Progressive loss of CD4+ T cells is observed in all strata of baseline plasma HIV RNA concentrations, but substantially more rapid rates of decline are seen in persons who have higher baseline levels of plasma HIV RNA (Figure_3) (27). Likewise, a clear gradient in risk for disease progression and death is seen with increasing baseline plasma HIV RNA levels (5,6,10,27) (Figure_2 and Figure_4).

HIV Replicates Actively at All Stages of the Infection

The steady-state level of HIV RNA in the plasma is a function of the rates of production and clearance (i.e., the turnover) of the virus in circulation (1,2,20,21,37). Effective antiretroviral therapy perturbs this steady state and allows an assessment of the kinetic events that underlie it. Thus, virus clearance, the magnitude of virus production, and the longevity of virus-producing cells can all be measured. Recent studies in which measurements of virus and infected-cell turnover were analyzed in this way in persons who had moderate to advanced HIV disease have demonstrated that a very dynamic process of virus production and clearance underlies the seemingly static steady-state level of HIV virions in the plasma (1,2,20,21,37).

Within 2 weeks of initiation of potent antiretroviral therapy, plasma HIV RNA levels usually fall to approximately 1% of their initial values (20,37) (Figure_5). The slope of this initial decline reflects the clearance of virus from the circulation and the longevity of recently infected CD4+ T cells and is remarkably constant among different persons (1,2,20,37). The half-life of virions in circulation is exceedingly short -- less than 6 hours. Thus, on average, half of the population of plasma virions turns over every 6 hours or less. Given such a rapid rate of virus clearance, it is estimated that 109 to 1010 (or more) virions must be produced each day to maintain the steady-state plasma HIV RNA levels typically found in persons who have moderate to advanced HIV disease (20). When new rounds of virus replication are blocked by potent antiretroviral drugs, virus production from the majority of infected cells (approximately 99%) continues for only a short period, averaging approximately 2 days (1,2,20,37). HIV-infected CD4+ T cells are lost, presumably as the result of direct cytopathic effects of virus infection, with an average half-life of an infected cell being approximately 1.25 days (20). The estimated generation time of HIV (the time from release of a virion until it infects another cell and results in the release of a new generation of virions) is approximately 2.5 days, which implies that the virus is replicating at a rate of approximately 140 or more cycles per year in an infected person (20,21). Thus, at the median period between initial infection and the diagnosis of AIDS, each virus genome present in an HIV-infected person is removed by more than a thousand generations from the virus that initiated the infection.

After the initial rapid decline in plasma HIV RNA levels following initiation of potent antiretroviral therapy, a slower decay of the remaining 1% of initial plasma HIV RNA levels is observed (37) (Figure_5). The length of this second phase of virus decay differs among different persons, lasting approximately 8-28 days. Most of the residual viremia is thought to arise from infected macrophages that are lost over an average half-life of about 2 weeks, whereas the remainder is produced following activation of latently infected CD4+ T cells that decay with an average half-life of about 8 days. Within 8 weeks of initiation of potent antiretroviral therapy (in previously untreated patients), plasma HIV RNA levels commonly fall below the level of detection of even the most sensitive plasma HIV RNA assays available (sensitivity of 25 copies HIV RNA/mL), indicating that new rounds of HIV infection are profoundly suppressed (Figure_5) (37). Fortunately, this level of suppression of HIV replication appears to have been maintained for more than 16 months in most patients who adhere to effective combination antiretroviral drug regimens (39). However, even this marked pharmacologic interference of HIV replication has not yet been reported to eradicate an established infection. Those rare persons who have been studied after having stopped effective combination antiretroviral therapy following months with undetectable levels of plasma HIV RNA have all shown rapid rebounds in HIV replication. Furthermore, infectious HIV can still be isolated from CD4+ T cells obtained from antiretroviral treated persons whose plasma HIV RNA levels have been suppressed to undetectable levels (less than 50 copies/mL) for 2 years or more (49,50). Viruses recovered from these persons were demonstrated to be sensitive to the antiretroviral drugs used, indicating that a reservoir of latently infected resting CD4+ T cells exists that can maintain HIV infection for prolonged periods even when new cycles of virus replication are blocked. It is not known whether additional reservoirs of residual HIV infection exist in infected persons that can permit persistence of HIV infection despite profound inhibition of virus replication by effective combination antiretroviral therapies (37,47,48). HIV infection within the CNS represents an additional potential sanctuary for virus persistence, as many of the antiretroviral drugs now available do not efficiently cross the blood-brain barrier.

Active HIV Replication Continuously Generates Viral Variants That are Resistant to Antiretroviral Drugs

HIV replication depends on a virally encoded enzyme, RT (an RNA-dependent DNA polymerase) that copies the single-stranded viral RNA genome into a double-stranded DNA in an essential step in the virus life cycle (21). Unlike cellular DNA polymerases used to copy host cell chromosomal DNA during the course of cell replication, RT lacks a 3' exonuclease activity that serves a "proofreading" function to repair errors made during transcription of the HIV genome. As a result, the HIV RT is an "error-prone" enzyme, making frequent errors while copying the RNA into DNA and giving rise to numerous mutations in the progeny virus genomes produced from infected cells. Estimates of the mutation rate of HIV RT predict that an average of one mutation is introduced in every one to three HIV genomes copied (21,89). Additional variation is introduced into the replicating population of HIV variants as a result of genetic recombination that occurs during the process of reverse transcription via template-switching between the two HIV RNA molecules that are included in each virus particle (21,90). Many mutations introduced into the HIV genome during the process of reverse transcription will compromise or abolish the infectivity of the virus; however, other mutations are compatible with virus infectivity. In HIV-infected persons, the actual frequency with which different genetic variants of HIV are seen is a function of their replicative vigor (fitness) and the nature of the selective pressures that may be acting on the existing swarm of genetic variants present (21). Important selective pressures that may exist in HIV-infected persons include their anti-HIV immune responses, the availability of host cells that are susceptible to virus infection in different tissues, and the use of antiretroviral drug treatments.

The rate of appearance of genetic variants of HIV within infected persons is a function of the number of cycles of virus replication that occurs during a person's infection (20,21). That numerous rounds of HIV replication are occurring daily in infected persons provides the opportunity to generate large numbers of variant viruses, including those that display diminished sensitivity to antiretroviral drugs. A mutation is probably introduced into every position of the HIV genome many times each day within an infected person, and the resulting HIV variants may accumulate within the resident virus population with successive cycles of virus replication (21). As a result of the great genetic diversity of the resident population of HIV, viruses harboring mutations that confer resistance to a given antiretroviral drug, and perhaps multiple antiretroviral drugs, are likely to be present in HIV-infected persons before antiretroviral therapy is initiated (21). Indeed, mutations that confer resistance to nucleoside analog RT inhibitors, NNRTIs, and PIs have been identified in HIV-infected persons who have never been treated with antiretroviral drugs (61,91,92). Once drug therapy is initiated, the pre-existing population of drug-resistant viruses can rapidly predominate. For drugs such as 3TC and nevirapine (and other NNRTIs), a single nucleotide change in the HIV RT gene can confer 100- to 1,000-fold reductions in drug susceptibility (1,61,93-95). Although these agents may be potent inhibitors of HIV replication, the antiretroviral activity of these drugs when used alone is largely reversed within 4 weeks of initiation of therapy due to the rapid outgrowth of drug-resistant variants (1,61,93-95). The rapidity with which drug-resistant variants emerge in this setting is consistent with the existence of drug-resistant subpopulations of HIV within infected patients before to the initiation of treatment (21,61). Because treatment with many of the available antiretroviral drugs selects for HIV variants that harbor the same or related mutations, specific treatments can select for the outgrowth of HIV variants that are resistant to drugs with which the patient has not been treated (referred to as cross-resistance) (96,97).

Drug-resistant viruses that emerge during drug therapy are predicted to replicate less well (are less fit) than their wild-type counterparts and are expected to attain lower steady-state levels of viral load than are present before the initiation of therapy (21). Evidence for such decreased fitness of drug-resistant viruses has been gleaned from studies of protease-inhibitor-treated or 3TC-treated patients, but this effect has not been apparent in NNRTI-treated patients (e.g., nevirapine or delavirdine) (1,61). Depending on its relative fitness, the drug-resistant variant can persist at appreciable levels even after the antiretroviral therapy that selected for its outgrowth is withdrawn. HIV variants resistant to nevirapine can persist for more than a year after withdrawal of nevirapine treatment (61). Zidovudine-resistant HIV variants and variants resistant to both zidovudine and nevirapine have also been shown to persist in infected persons and to replicate well enough to be transmitted from one person to another (98). Because HIV variants that are resistant to PIs often appear to be less fit than drug-sensitive viruses, their prevalence in patients who develop PI resistance may decline after withdrawal of the drug. However, although such variants may decline after drug withdrawal, they also may persist in patients at higher levels than their original levels and can be rapidly selected for should the same antiretroviral agent (or a PI demonstrating cross-resistance) be used again (97).

The definition of mutations associated with resistance to specific antiretroviral drugs and the advent of genetic methods to detect drug-resistant variants in treated patients have raised the possibility of screening HIV-infected patients for the presence of HIV variants as a tool to guide therapeutic decisions (92,99). However, this approach must be considered experimental and may prove very difficult to implement because of the complex patterns of mutations that increase resistance to some antiretroviral agents. Furthermore, the prevalence of clinically important populations of drug-resistant variants in many HIV-infected persons is likely to be below the level of detection of the available assays, thus potentially creating falsely optimistic predictions of drug efficacy (21,61).

Combination Antiretroviral Therapy That Suppresses HIV Replication to Undetectable Levels Can Delay or Prevent the Emergence of Drug-Resistant Viral Variants

Current strategies for antiretroviral therapy are much more effective than those previously available, and the efficacy of these approaches confirms predictions emerging from fundamental studies of the biology of HIV infection. Several important principles have emerged from these studies that can be used to guide the application of antiretroviral therapies in clinical practice:

  • The likelihood that HIV variants that are resistant to individual drugs (and possibly combinations of drugs) are already present in untreated patients must be appreciated.

  • The likelihood that drug-resistant variants are already present in an HIV-infected person decreases as the number of noncross-resistant antiretroviral drugs used in combination is increased.

  • The prevalence in untreated patients of HIV variants already resistant to antiretroviral agents that require multiple mutations in the virus target gene to confer high-level drug resistance is also expected to be lower as the number of required mutations increases. For example, high-level resistance to PIs (e.g., ritonavir and indinavir) requires the presence of multiple mutations in the HIV protease gene; some of these mutations affect the actual antiviral action of the drug, whereas others represent compensatory mutations that act to increase the fitness of the drug-resistant HIV variants (96,97,100). The prevalence of HIV variants that already harbor all of the mutations required for high-level resistance to these drugs is expected to be low in untreated patients.

  • Antiretroviral drugs that select for partially disabled (less fit) viruses may benefit the host by decreasing the amount of virus replication (and consequent damage) that occurs even after drug-resistant mutants have overgrown drug-sensitive viruses.

  • Incomplete suppression of HIV replication (as indicated by the continued presence of detectable levels of plasma HIV RNA) will afford the opportunity for continued accumulation of mutations that confer high-level drug resistance, and thereby facilitate the eventual outgrowth of the resistant virus population during continued therapy (23,39). The more effectively new cycles of HIV infection are suppressed, the fewer opportunities are provided for the accumulation of new mutations that permit the emergence of drug-resistant variants (97,100). Thus, initiation and maintenance of therapy with optimal doses of combinations of potent antiretroviral drugs with the intent of suppressing HIV replication to levels below the detection limit of sensitive plasma HIV RNA assays provide the most promising strategy to forestall (or prevent) the emergence of drug-resistant viruses and achieve maximum protection from HIV-induced immune system damage.

Antiretroviral Therapy-Induced Inhibition of HIV Replication Predicts Clinical Benefit

As active HIV replication is directly linked to the progressive depletion of CD4+ T cell populations, reduction in levels of virus replication by antiretroviral drug therapy is predicted to correlate with the clinical benefits observed in treated patients. Data from an increasing number of clinical trials of antiretroviral agents provide strong support for this prediction and indicate that greater clinical benefit is obtained from more profound suppression of HIV replication (9,13,23,38-40,56). For example, virologic analyses from ACTG 175 (a study of zidovudine or didanosine monotherapy compared with combination therapy with zidovudine plus either didanosine or zalcitabine) indicate that a reduction in plasma HIV RNA levels to 1.0 log below baseline at 56 weeks after initiation of therapy was associated with a 90% reduction in risk of progression of clinical disease (13). In a pooled analysis of seven different ACTG studies, durable suppression of plasma HIV RNA levels to less than 5,000 copies of HIV RNA/mL between 1 and 2 years after initiation of treatment was associated with an average increase in CD4+ T cell levels of approximately 90 cells/mm3 (24). Patients whose plasma HIV RNA levels failed to be stably suppressed to less than 5,000 copies/mL showed progressive decline in CD4+ T cell counts during the same period (24).

Decreases in plasma HIV RNA levels induced by antiretroviral therapy provide better indicators of clinical benefit than CD4+ T cell responses (9,13,24). Furthermore, in patients who have advanced HIV disease, clinical benefit correlates with treatment-induced decreases in plasma HIV RNA levels, even when CD4+ T cell increases are not seen. The failure to observe CD4+ T cell increases in some treated patients despite suppression of HIV replication may reflect irreversible damage to the regenerative capacity of the immune system in the later stages of HIV disease.

The most extensive data on the relationship between the magnitude of suppression of HIV replication induced by antiretroviral therapy and the degree of improved clinical outcome were generated during studies of nucleoside analog RT inhibitors used alone or in combination (9,13,24). These treatments yield less profound and less durable suppression of HIV replication than currently available combination therapy regimens that include potent PIs (and that are able to suppress HIV replication to levels below the detection limits of plasma HIV RNA assays) (23,37,39). Thus, it is likely that the relationship between suppression of HIV replication and clinical benefit will become even more apparent as experience with potent combination therapies accumulates.

Repair of immune system function may be incomplete following effective inhibition of continuing HIV replication and damage by antiretroviral drug therapy.

As discussed in the preceding principles, disease progression in HIV-infected patients results from active virus replication that inflicts chronic damage upon the function of the immune system and its structural elements, the lymphoid tissues. Because of the clonal nature of the antigen-specific immune response, in the absence of generation of immunocompetent CD4+ T cells from immature progenitor cells, it is likely that T cell responses may not be regained once lost, even if new rounds of HIV infection can be stopped by effective antiretroviral therapy (80,82,101). Similarly, it is not known if the damaged architecture of the lymphoid organs seen in persons with moderate to advanced HIV disease can be repaired following antiretroviral drug therapy. Should the residual proliferative potential of CD4+ and CD8+ T cells decline with increased duration of HIV infection and the magnitude of the cumulative loss and regeneration of lymphocyte populations, late introduction of antiretroviral therapy may have limited ability to reconstitute levels of functional lymphocytes. Thus, it is believed that the initiation of antiretroviral therapy before extensive immune system damage has occurred will be more effective in preserving and improving the ability of the HIV-infected person to mount protective immune responses.

Few reliable methods are now available to assess the integrity of immune responses in humans. However, the application of specific methods to the study of immune responses in HIV-infected patients before and after initiation of antiretroviral therapy indicates that immunologic recovery is incomplete even when HIV replication falls to undetectable levels. CD4+ T cell levels do not return to the normal range in most antiretroviral drug-treated patients, and the extent of CD4+ T cell increase is typically more limited when therapy is started in the later stages of HIV disease (82). Recent evidence indicates that the repertoire of antigen-specific CD4+ T cells becomes progressively constricted with declining T cell numbers (82). In persons who have evidence of a restricted T cell repertoire, antiretroviral therapy can increase total CD4+ T cell numbers but fails to increase the diversity of antigen recognition ability (82). It is not yet known if expansion of a constricted CD4+ T cell repertoire of antigen recognition might be seen with longer-term follow-up of such persons.

Reports of OIs occurring in antiretroviral-treated patients at substantially higher CD4+ T cell counts than those typically associated with susceptibility to the specific opportunistic infections raise the concern that restoration of protective immune responses may be incomplete, even when effective suppression of continuing HIV replication is achieved (102). However, other reports describe instances in which the clinical symptoms or signs of preexisting OIs were ameliorated (103-105), or in which new inflammatory responses to preexisting, but subclinical, OIs became manifest following initiation of effective combination antiretroviral therapy (106,107). These observations indicate that some improvement in immune function may be possible, even in patients who have advanced HIV disease, if sufficient numbers of pathogen-specific CD4+ T cells are still present when effective antiretroviral therapy is begun. The extent to which antiretroviral therapy can restore immune function when initiated in persons at varying stages of HIV disease is currently unknown but represents an essential question for future research.

References

  1. Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995;373:117-22.

  2. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995;373:123-6.

  3. Embretson J, Zupancic M, Ribas J, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993;362:359-62.

  4. Pantaleo G, Graziosi C, Demarest J, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993;362:355-8.

  5. Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 1995; 122:573-9.

  6. O'Brien TR, Blattner WA, Waters D, et al. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA 1996;276:105-10.

  7. Jurriaans S, van Gemen B, Weverling GJ, et al. The natural history of HIV-1 infection: virus load and virus phenotype independent determinants of clinical course? Virology 1994;204:223-33.

  8. Saksela K, Stevens CE, Rubenstein P, Taylor PE, Baltimore D. HIV-1 messenger RNA in peripheral blood mononucler cells as an early marker of risk for progression to AIDS. Ann Intern Med 1995;123:641-8.

  9. O'Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996;334:426-31.

  10. O'Brien TR, Rosenberg PS, Yellin F, Goedert JJ. Longitudinal HIV-1 RNA levels in a cohort of homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998 (in press).

  11. Enger C, Graham N, Peng Y, et al. Survival from early, intermediate, and late stages of HIV infection. JAMA 1996;275:1329-34.

  12. Haynes BF, Panteleo G, Fauci AS. Toward an understanding of the correlates of protective immunity to HIV infection. Science 1996;271: 324-8.

  13. Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. New Eng J Med 1996;335:1091-8.

  14. Dickover RE, Dillon M, Gillette SG, et al. Rapid increases in load of human immunodeficiency virus correlate with early disease progression and loss of CD4 cells in vertically infected infants. J Infect Dis 1994;170:1279-84.

  15. McIntosh K, Shevitz A, Zaknun D, et al. Age- and time-related changes in extracellular viral load in children vertically infected by human immunodeficiency virus. Pediatr Infect Dis J 1996;15:1087-91.

  16. Mofenson LM, Korelitz J, Meyer WA, et al. The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. J Infect Dis 1997;175:1029-38.

  17. Dickover RE, Dillon M, Leung K-M, et al. Early prognostic indicators in primary perinatal HIV-1 infection: importance of viral RNA and the timing of transmission on long term outcome. J Infect Dis 1998 (in press).

  18. Shearer WT, Quinn TC, LaRussa P, et al. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. New Engl J Med 1997;336:1337-42.

  19. Saag MS, Holodniy M, Kuritzkes DR, et al. HIV viral load markers in clinical practice. Nat Med 1996;2:625-9.

  20. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996;271:1582-6.

  21. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995;267:483-9.

  22. Raboud JM, Montaner JSG, Rae S, Conway B, Singer J, Schechter MT. Issues in the design of trials of therapies for subjects with human immunodeficiency virus infection that use plasma RNA level as an outcome. J Infect Dis 1997;175:576-82.

  23. Kempf D, Molla A, Sun E, Danner S, Boucher C, Leonard J. The duration of viral suppression is predicted by viral load during protease inhibitor therapy {Abstract 603}. In: Programs and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington DC, January 22-26, 1997.

  24. DeGruttola V, for the ACTG Cross Protocol Study Group. Prognostic value of CD4 counts and plasma HIV RNA: an ACTG cross protocol analysis. In: Proceedings of the Public Meeting of the NIH Panel To Define Principles of Therapy of HIV Infection, November 13-14, 1996. Washington, DC: Office of AIDS Research, NIH.

  25. Palumbo PE, Raskino C, Fiscus S, et al. Correlation of HIV plasma RNA levels with clinical outcome in a large pediatric trial (ACTG 152) {Abstract LB14}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington DC, January 22-26, 1997.

  26. Stein DS, Korvick JA, Vermund SH. CD4+ lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease: a review. J Infect Dis 1992;165:352-63.

  27. Mellors, JW, Muĺoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946-54.

  28. USPHS/IDSA Prevention of Opportunistic Infections Working Group: 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR 1997;46 (No. RR-12).

  29. El-Sadr W, Oleske JM, Agins BD, et al. Evaluation and management of early HIV infection. Clinical practice guideline no. 7. AHCPR publication no. 94-0572. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, January 1994.

  30. CDC. 1995 Revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR 1995;44(No. RR-4).

  31. Schacker T, Hughes J, Shea T, Corey L. Viral load in acute and very early HIV infection does not correlate with disease progression {Abstract 475}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington DC, January 22-26, 1997.

  32. Staprans SI, Hamilton BL, Follansbee SE, et al. Activation of virus replication after vaccination of HIV-1 infected individuals. J Exp Med 1995;182:1727-37.

  33. Stanley SK, Ostrowski MA, Justement JS, et al. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 1996;334: 1222-30.

  34. Brichacek B, Swindells S, Janoff EN, Pirrucello S, Stevenson M. Increased plasma human immunodeficiency virus type 1 burden following antigenic challenge with pneumococcal vaccine. J Infect Dis 1996;174: 1191-9.

  35. Raboud JM, Montaner JSG, Conway B, et al. Variation in plasma RNA levels, CD4 cell counts, and p24 antigen levels in clinically stable men with human immunodeficiency virus infection. J Infect Dis 1996;174: 191-4.

  36. Deeks SG, Coleman RL, White R, et al. Variance of plasma human immunodeficiency virus type 1 RNA levels measured by branched DNA within and between days. J Infect Dis 1997;176:514-7.

  37. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387:188-91.

  38. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337:725-33.

  39. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337: 734-9.

  40. Montaner J, Wainberg M, INCAS study results. In: Proceedings of the Public Meeting of the NIH Panel To Define Principles of Therapy of HIV Infection, Nov. 13-14, 1996. Washington, DC: Office of AIDS Research, NIH.

  41. Pachl C, Todd JA, Kern DG, et al. Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:446-54.

  42. Mulder J, McKinney N, Christopherson C, Sninsky J, Greenfield L, Kwok S. Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol 1994;32:292-300.

  43. Vandamme AM, Van Dooren S, Kok W, et al. Detection of HIV-1 RNA in plasma and serum samples using the NASBA amplification system compared to RNA-PCR. J Virol Methods 1995;52:121-32.

  44. Yen-Lieberman B, Brambilla D, Jackson B, et al. Evaluation of a quality assurance program for quantitation of human immunodeficiency virus type 1 RNA in plasma by the AIDS Clinical Trials Group Virology Laboratories. J Clin Microbiol 1996;34:2695-701.

  45. Schuurman R, Descamps D, Jan Weverling G, et al. Multicenter comparison of three commercial methods for quantification of human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 1996;34: 3016-22.

  46. Revets H, Marissens D, de Wit S, et al. Comparative evaluation of NASBA HIV-1 RNA QT, AMPLICOR-HIV monitor, and QUANTIPLEX HIV RNA assay, three methods for quantification of human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 1996;34:1058-64.

  47. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387:183-8.

  48. Cavert W, Notermans DW, Staskus K, et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 1997;276:960-4.

  49. Wong JK, Hezareh M, Gđnthard HF, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997;278:1291-4.

  50. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997;278:1295-8.

  51. Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995;333:450-1.

  52. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-80.

  53. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. New Engl J Med 1996;335:1621-9.

  54. CDC. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47(RR-2).

  55. D'Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med 1996;124:1019-30.

  56. CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus lovirride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trail. Lancet 1997;349:1413-21.

  57. Staszewski S, Loveday C, Picazo JJ, et al. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. JAMA 1996;276:111-7.

  58. Katlama C, Ingrand D, Loveday C, et al. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. JAMA 1996;276:118-25.

  59. Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. New Engl J Med 1995;333:1662-9.

  60. Van Leeuwen R, Katlama C, Kitchen V, et al. Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase I/II study. J Infect Dis 1995;171:1166-71.

  61. Havlir DV, Eastman S, Gamst A, Richman DD. Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients. J Virol 1996;70:7894-9.

  62. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors: a review for clinicians. JAMA 1997;277:145-53.

  63. McDonald CK, Kuritzkes DR. Human immunodeficiency virus type 1 protease inhibitors. Arch Intern Med 1997;157:951-9.

  64. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478-89.

  65. Cao Y, Krogstad P, Korber BT, et al. Maternal HIV-1 viral load and vertical transmission of infection: the Ariel Project for the prevention of HIV transmission from mother to infant. Nat Med 1997;3: 549-52.

  66. Luzuriaga K, Bryson Y, Krogstad P, et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. New Engl J Med 1997;336: 1343-9.

  67. Kinloch-De Loes S, Hirschel BJ, Hoen B, et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 1995;333:408-13.

  68. Lafeuillade A, Poggi C, Tamalet C, Profizi N, Tourres C, Costes O. Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis 1997;175:1051-5.

  69. Hoen B, Harzic M, Fleury H, et al. ANRS053 trial of zidovudine (ZDV), lamivudine (3TC), and ritonavir combination in patients with symptomatic primary HIV-1 infection: preliminary results {Abstract 232}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC, Jan. 22-26, 1997.

  70. Tamalet C, Martin IP, Lafeuillade A. Viral load and genotypic resistance pattern in HIV-1 infected patients treated by a triple combination therapy including nucleoside and protease inhibitors (NIS and PIS) initiated at primary infection (PHI) {Abstract 592}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC, January 22-26, 1997.

  71. Perrin L, Markowitz M, Calandra G, Chung M, and the MRL Acute HIV Infection Study Group. An open treatment study of acute HIV infection with zidovudine, lamivudine and indinavir sulfate {Abstract 238}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC, January 22-26, 1997.

  72. Markowitz M, Cao Y, Vesanan M, et at. Recent HIV infection treated with AZT, 3TC, and a potent protease inhibitor {Abstract LB8}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC, January 22-26, 1997.

  73. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1 specific CD4+ T cell responses associated with control of viremia. Science 1997;278:1447-50.

  74. Weiss RA. HIV receptors and the pathogenesis of AIDS. Science 1996;272: 1885-6.

  75. Moore, JP, Trkola A, Dragic T. Co-receptors for HIV-1 entry. Curr Opin Immunol 1997;9:551-62.

  76. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995;332:143-9.

  77. Darby SC, Weart DW, Giangrande PLF, Spooner RJD, Rizza CR. Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. Lancet 1996;347:1573-9.

  78. Koot M, B van't Wout AB, Kootstra NA, EY de Goede R, Tersmette M, Schuitemaker H. Relation between changes in cellular load, evaluation of viral phenotype, and the clonal composition of virus populations in the course of human immunodeficiency virus type infection. J Infect Dis 1996;173:349-54.

  79. Margolick JB, Muĺoz A, Donnenberg AD, et al. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. Nat Med 1995;7:674-80.

  80. Shearer G, Clerici M. Early T-helper cell defects in HIV infection. AIDS 1991;5:245-53.

  81. Schnittman SM, Lane HC, Greenhouse J, Justement JS, Baseler M, Fauci AS. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci USA 1990;87:6058-62.

  82. Connors M, Kovacs JA, Krevat S, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997;3:533-40.

  83. Piatak M Jr, Yang LC, Luk KC, et al. Viral dynamics in primary HIV-1 infection (letter). Lancet 1993:341:1099.

  84. Tindall B, Cooper DA. Primary HIV infection: host responses and intervention strategies. AIDS 1991;5:1-14.

  85. Kinloch-de Loes S, de Saussure P, Saurat JH, Stalder H, Hirschel B, Perrin LH. Symptomatic primary infection due to human immunodeficiency virus type 1: review of 31 cases. Clin Infect Dis 1993;17:59-65.

  86. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996; 125:257-64.

  87. Piatak M, Saag MS, Yang LC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993;259:1749-54.

  88. Cao Y, Ho DD, Todd J, Kokka R, et al. Clinical evaluation of branched DNA signal amplification for quantifying HIV type 1 in human plasma. AIDS Res Hum Retroviruses 1995;11:353-61.

  89. Mansky LM, Temin HM. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 1995;69:5087-94.

  90. Moutouh L, Corbeil J, Richman DD. Recombination leads to the rapid emergence of HIV-1 dually resistant mutants under selective drug pressure. Proc Natl Acad Sci USA 1996;93:6106-11.

  91. de Jong MD, Veenstra J, Stilianakis NI, et al. Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine. Proc Natl Acad Sci USA 1996;93:5501-6.

  92. Kozal MJ, Shah N, Shen N, et al. Extensive polymorphisms observed in HIV-1 clade B protease gene using high-density oligonucleotide arrays. Nat Med 1996;2:753-9.

  93. Schuurman R, Nijhuis M, van Leeuwen R, et al. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). J Infect Dis 1995;171:1411-9.

  94. Pluda JM, Cooley TP, Montaner JSG, et al. A phase I/II Study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced human immunodeficiency virus infection. J Infect Dis 1995;171:1438-47.

  95. Richman DD, Havlir D, Corbeil J, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994;68:1660-6.

  96. Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995;374:569-71.

  97. Condra JH, Holder DJ, Schleif WA, et al. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J Virol 1996;70:8270-6.

  98. Imrie A, Beveridge A, Genn W, et al. Transmission of human immunodeficiency type 1 resistant to nevirapine and zidovudine. J Infect Dis 1997;175:1502-6.

  99. Holodiny M, Mole L, Margolis D, et al. Determination of human immunodeficiency virus RNA in plasma and cellular viral DNA genotypic zidovudine resistance and viral load during zidovudine-didanosine combination therapy. J Virol 1995;69:3510-6.

  100. Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of mutations in HIV protease confers resistance in ritonavir. Nature Med 1996;2: 760-6.

  101. Kelleher AD, Carr A, Zaunders J, Cooper DA. Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. J Infect Dis 1996;173:321-9.

  102. Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349:1443-5.

  103. Whitcup SM, Fortin E, Nussenblatt RB, et al. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis (letter). JAMA 1997;277:1519-20.

  104. Hicks CB, Myers SA, Giner J. Resolution of intractable molluscum contagiosum in a human immunodeficiency virus-infected patient after institution of antiretroviral therapy with ritonavir. Clin Infect Dis 1997;24:1023-5.

  105. Benhamou Y, Bochet MV, Carriere J, et al. Effects of triple antiretroviral therapies including a HIV protease inhibitor on chronic intestinal cryptosporidiosis and microsporidiosis in HIV-infected patients {Abstract 357}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC, January 22-26, 1997.

  106. Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor {Letter}. Lancet 1997;349:995-6.

  107. Phillips P, Zala C, Rouleau D, Montaner JSG. Mycobacterial lymphadenitis: can highly active antiretroviral therapy (HAART) unmask subclinical infection? {Abstract 351}. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections. Washington, DC, January 22-26, 1997.

* Information included in these principles 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.

Appendices

Table_1 TABLE. Characteristics of plasma HIV RNA assays

Figure_1 FIGURE 1. Generalized time course of HIV infection and

disease

Figure_2 FIGURE 2. AIDS-free survival by baseline plasma HIV RNA and

CD4+ T cell levels

Figure_3 FIGURE 3. Association between rates of decline of CD4+ T cell

counts and baseline plasma HIV RNA level

Figure_4 FIGURE 4. Probability of AIDS by baseline HIV RNA level and

CD4+ T cell count

Figure_5 FIGURE 5. Rate of decline of plasma HIV RNA concentration

after initiation of potent combination antiretroviral therapy


Table_1
Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.

TABLE. Characteristics of plasma HIV RNA assays *
==================================================================================================
                                        Observed intra-assay
                 Linear dynamic         (copies/ mL) standard          Preferred
Assay         range + (copies/ mL)    deviation range (log10) &      anticoagulant
-----------------------------------------------------------------------------------
                         2   5.2
RT-PCR @           4 x 10 -10                <0.15- 0.33              ACD/EDTA **

                      2          6
bDNA ++         5 x 10 -1. 6 x 10             0.08- 0.2                 EDTA **

                       2       7
NASBA r &&       4 x 10 -4 x 10               0.13- 0.23            ACD/EDTA/HEP **
-----------------------------------------------------------------------------------
 * More sensitive versions of each of these assays (detection limits 20-100 HIV RNA copies/ mL)
   are currently in development and will likely be commercially available in the future.
 + Higher values can be measured with dilution of the specimen into the linear dynamic range
   for each assay.
 & Ranges are representative of those obtained in comparative analyses of plasma HIV RNA
   assays (44-46). Plasma HIV RNA assays tend to be more variable at or near the limit of
   quantitation. Thus, the significance of changes in HIV RNA levels at the lowest levels of
   quantitation for a given assay should be evaluated in light of this increased variability.
 @ Amplicor HIV Monitor (TM) assay (Roche Molecular Systems, Alameda, CA).
** ACD = acid citrate dextran (citrate; yellow-top tube); EDTA = ethylenediaminetetraacetic acid
   (purple-top tube); HEP = heparin (green-top tube).
++ Quantiplex (TM) HIV RNA bDNA assay (Chiron Diagnostics, Emeryville, CA).
&& NucliSens (TM) HIV-1 QT assay (Organon Teknika, Boxtel, The Netherlands).
==================================================================================================

Return to top.

Figure_1

Figure_1
Return to top.

Figure_2

Figure_2
Return to top.

Figure_3

Figure_3
Return to top.

Figure_4

Figure_4
Return to top.

Figure_5

Figure_5
Return to top.

Disclaimer   All MMWR HTML versions of articles are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the electronic PDF version and/or the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

**Questions or messages regarding errors in formatting should be addressed to mmwrq@cdc.gov.

Page converted: 10/05/98

HOME  |  ABOUT MMWR  |  MMWR SEARCH  |  DOWNLOADS  |  RSSCONTACT
POLICY  |  DISCLAIMER  |  ACCESSIBILITY

Safer, Healthier People

Morbidity and Mortality Weekly Report
Centers for Disease Control and Prevention
1600 Clifton Rd, MailStop E-90, Atlanta, GA 30333, U.S.A

USA.GovDHHS

Department of Health
and Human Services

This page last reviewed 5/2/01