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State-of-the-Art Conference on azidothymidine therapy for early HIV infection
NIH STATE-OF-THE-ART CONFERENCE
State-of-the-Art Conference on Azidothymidine Therapy for Early HIV Infection Sponsored by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Public Health Service
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his State-of-the-Art Conference, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, was convened to evaluate available scientific information and to resolve safety and efficacy issues related to the use of zidovudine in the treatment of HIV-infected persons with few or no symptoms of disease. The resultant statement is intended to advance understanding of this issue and to be useful to health professionals and the public. The statement was prepared by a nonadvocacy, non-Federal panel of experts based on (1) presentations during a l-day public session by investigators working in areas relevant to the questions; (2) questions and statements from conference attendees, including those presented during an open discussion period that was part of the public session; (3) closed deliberations by the panel during the remainder of the first day and the entire second day. This statement is an independent report of the panel and is not a policy statement of NIAID or the Federal Government.
INTRODUCTION With the spread of the acquired immunodeficiency syndrome (AIDS) epidemic and the realization that between 800,000 and 1.5 million Americans are infected with the human immunodeficiency virus (HIV), physicians in every part of the United States are being called upon to provide primary care for persons with HIV infection. Since there is more information about the length of time a person can be infected with HIV before symptoms begin to occur, physicians are seeking guidelines for HIV antibody testing and counseling, patient monitoring, and treatment of persons presenting in the early stages of disease. Advances in AIDS research, especially the devel-
From the Division of AIDS. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Office of Communications, Building31. Room 7A32, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
opment of zidovudine (azidothymidine/AZT; Retrovir@) for the treatment of persons with advanced HIV disease, and demonstration of effective prophylaxis against Pneumocystis carinii pneumonia (PCP), have brought major changes in clinical practice. Currently, zidovudine is the only antiretroviral drug approved by the Food and Drug Administration. In August 1989, NIAID announced the results of two studies conducted by the AIDS Clinical Trials Group (ACTG), showing that zidovudine can delay disease progression with minimal side effects in HIV-infected persons with fewer than 0.50 X log CD4 (T4) cells/L, whether asymptomatic or mildly symptomatic. On March 2 of this year, the Food and Drug Administration approved expanded zidovudine label indications to include these groups. On March 3, NIAID convened the State-of-theArt Conference on AZT Therapy for Early HIV Infection. A panel of experts, including clinical investigators, community physicians, statisticians, and community representatives with a special interest in AIDS treatment issues, was charged with formulating recommendations for facilitating the transfer of results of the recently completed clinical trials into the practice of medicine to benefit the largest possible number of persons who are infected with HIV. The panel concluded that a large proportion of the asymptomatic and mildly symptomatic HIVinfected population are candidates for early therapy with zidovudine. This document presents the recommendations made at this conference. The panelists are fully cognizant that these recommendations are made at a time of rapid advances in our knowledge of many aspects of HIV disease and that new scientific developments may alter the state of the art at any time. Periodic state-of-the-art conferences to update recommendations for patient care will be convened as new data on therapies for HIV infection become available. Moreover, the panelists are fully aware that the recommendations to expand the use of zidovudine have major social and economic implications and will further intensify current problems in securing adequate health care, including diagnosis and treatment, for disadvantaged and underserved popula-
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tions. They strongly believe that optimal care of infected patients demands resolution of these problems. Finally, for early intervention to occur, HIVinfected persons must first identify themselves through HIV testing, preceded and followed by appropriate counseling. Barriers to identification, such as lack of access to health care, likelihood of discrimination in many areas, and fear of the loss of health insurance, must be overcome.
majority of these subjects tolerated lower doses of zidovudine without further serious hematologic toxicity. This clinical trial demonstrated that zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV infection and fewer than 0.500 X lo9 CD4 cells/L.
ACTGProtocol 019
This study was designed to evaluate the safety and efficacy of zidovudine therapy in asymptomatic persons with HIV infection, comparing higher and lower doses of zidovudine to placebo [2]. The higher To evaluate the efficacy and safety of zidovudine dose, 300 mg five times daily, was chosen to dupliearly in the treatment of HIV infection, a placebocate that used in the original phase II trial, and the controlled trial was conducted in 711 subjects with lower dose, 100 mg five times daily, was thought to mildly symptomatic disease [l]. Three hundred fifbe close to the minimum effective dose at the time ty-one subjects were assigned to placebo and 360 to the study was designed. Study participants were zidovudine at an oral dose of 200 mg every 4 hours. stratified by entry CD4 positive lymphocyte counts Subjects were arbitrarily stratified according to the into two substudies-one of individuals with more number of pretreatment CD4 lymphocytes; stra- than 0.500 X lo9 CD4 cells/L, the second with fewer tum I consisted of subjects with a pretreatment than 0.500 X lo9 CD4 cells/L. Stratification was CD4 lymphocyte count more than 0.200 X lo9 CD4 made at the level of 0.500 X lo9 CD4 cells/L in order cells/L but fewer than 0.500 X lo9 CD4 cells/L, and to compare responses with those obtained from the stratum II consisted of subjects with a pretreatparallel ACTG Protocol 016. Subjects were moniment CD4 cell count more than or equal to 0.500 X tored for clinical progression and toxicity with roulo9 CD4 cells/L but fewer than 0.800 X lo9 CD4 tine clinical visits and laboratory studies, including cells/L. Fifty-one subjects developed AIDS, ad- markers of antiviral and immunologic effects, such vanced AIDS-related complex (ARC), or died as as serial CD4 lymphocyte counts and HIV antigen their first critical event. Thirty-four placebo recipilevels. The study was designed to detect an effect of ents developed a first critical event (AIDS, ad- zidovudine using primary endpoints of progression vanced ARC, or death) compared with 15 zidovuto AIDS, advanced ARC, or death and secondary endpoints defined by immunologic and virologic dine recipients (p = 0.0017). Significant differences in the number of critical events occurred for sub- markers. A total of 1,338 evaluable subjects were randomjects in stratum I but not for subjects in stratum II. Thirty-four placebo recipients in stratum I devel- ized to the three treatment arms. Baseline laboratooped a first critical event as compared with 12 zido- ry characteristics were well balanced in the treatvudine recipients (p = 0.0005). Twenty-two sub- ment groups. The subjects enrolled were primarily jects developed AIDS (19 in the placebo group and white (Ql%), males (92%), and homosexual or bisexthree in the zidovudine group). Only two placebo ual (87%). Progression to AIDS was documented in 33 plarecipients and three zidovudine recipients in stratum II developed a critical event (p = 0.63). Sub- cebo recipients, in 11 recipients of 500 mg zidovujects receiving zidovudine in stratum I had in- dine, and in 14 recipients of 1,500 mg zidovudine, corresponding to event rates (cases per 100 patient creases in the number of CD4 cells as compared with those receiving placebo, in whom a decline in years of observation) of 6.6,2.3, and 3.1, respectivethe number of CD4 cells was noted. Levels of HIV ly. Similarly, rates of progression to AIDS or adantigen decreased significantly among antigenemic vanced ARC were 7.6, 3.6, and 4.3 in the three zidovudine recipients. In addition, zidovudine re- groups. The majority of study endpoints were due confirmed cases of AIDS, cipients were less likely to develop detectable anti- to histopathologically gen during the study. Symptomatic adverse reac- most of which were defined by PCP. The decrease tions were uncommon and included malaise, in progression rates in the zidovudine treatment fatigue, dyspepsia, nausea, vomiting, and bloating. groups was statistically significant, particularly in The most common serious adverse reactions were the 500-mg dosage group. anemia and neutropenia, which occurred in only 5% Zidovudine also demonstrated benefit on seconand 4%, respectively, of zidovudine recipients. The dary study endpoints. The decline in CD4-positive
MAJORCONTROLLEDCLINICALTRIALS THAT LED TO CURRENT RECOMMENDATIONS ACTGProtocol 016
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cells was significantly reduced with zidovudine treatment in both dosage groups. HIV antigen levels were also reduced. These laboratory effects persisted for at least 48 weeks after starting therapy. The toxicities in this study were similar to those seen in the treatment of more advanced HIV disease but were less frequent and less severe. Severe hematologic toxicities (anemia or neutropenia) were more common in the 1,500-mg dose group but not significantly more frequent in the 500-mg group than in the placebo group. Severe anemia was seen in 6.3% of the higher dose group, 1.1% in the lower dose group, and 0.2% in placebo recipients. Transfusion was required in nine subjects, all in the 1,500mg zidovudine group. Severe neutropenia occurred in 6.3%, 1.8%, and 1.6% of the higher dose, lower dose, and placebo groups, respectively. Transaminase levels were not increased in either zidovudine dose group. Nausea was the only major toxicity more common with 500 mg of zidovudine (3.3%) than with placebo (0.2%). Less severe toxicities occurred in both zidovudine dosage groups but did not generally interfere with continued drug administration. In summary, protocol 019 demonstrated that a total daily dosage of 500-mg zidovudine was effective for asymptomatic subjects with fewer than 0.500 X log CD4 cells/L in reducing progression to advanced disease. Furthermore, this dose of zidovudine was associated with very low rates of severe toxicity. ACTG Protocol 002 To evaluate the efficacy and safety of a lower dose of zidovudine in the treatment of advanced HIV disease, a randomized controlled trial was conducted in 524 subjects after a first episode of PCP [3]. Two hundred sixty-two subjects were assigned to zidovudine at an oral dose of 250 mg every 4 hours (standard treatment group) and 262 to zidovudine at an oral dose of 200 mg every 4 hours for 4 weeks followed by 100 mg every 4 hours (low-dose treatment group). Endpoints to determine the effectiveness of a lower dose of zidovudine included disease progression and changes in the number of CD4 lymphocytes and levels of detectable HIV antigen in serum. The median length of follow-up was 25.6 months. A statistically better survival was noted for the low-dose treatment group (p = 0.019, Wilcoxon test). Two hundred fifteen subjects (82%) in the standard treatment group and 214 (82%) in the lowdose treatment group developed another opportunistic infection (p = 0.91). No statistically significant difference between the two groups in the time to another opportunistic infection was noted (p = 0.56). The number of CD4 lymphocytes increased in
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both treatment groups. No differences between the two groups in the number of CD4 lymphocytes or levels of detectable antigens in serum were noted. One hundred one (39%) of subjects in the standard treatment group developed serious anemia, as compared with 77 (29%) in the low-dose treatment group, and 134 subjects (51%) in the standard treatment group developed serious neutropenia as compared with 96 (37%) in the low-dose treatment group. In conclusion, a lower daily dose of zidovudine was as effective, resulted in a better survival rate, and was considerably less toxic than the initial dose tested.
CARCINOGENICITYSTUDIES Vaginal squamous cell cancers have occurred in low frequencies after prolonged administration of high doses of zidovudine to mice and rats. The doses associated with these cancers were approximately 4 to 40 times greater than the dosage used in humans with HIV infection. The mechanisms that may be responsible for this carcinogenicity are unknown. No cancers have yet been associated with zidovudine use in humans.
ZIDOVUDINERESISTANCE/iv v/mu Isolates of HIV from individuals never treated with zidovudine are highly susceptible to zidovudine. Viral isolates from patients with AIDS or advanced ARC treated with zidovudine at 1,200 mg/ day for periods greater than 6 months commonly exhibit reduced susceptibility to zidovudine, and a wide range of concentrations are required to inhibit growth [4]. Progressive stepwise reductions in susceptibility to zidovudine appear to develop with time. Each stepwise reduction in susceptibility appears to be associated with the acquisition of an additional mutation in the reverse transcriptase gene of HIV. In vitro cross-resistance of zidovudine-resistant mutants can be demonstrated against other nucleoside analogues that, like zidovudine, possess a 3azido group; however, cross-resistance has not been demonstrated against other antiretroviral compounds, including 2’,3’dideoxycytidine (ddC) and 2’,3’dideoxyinosine (dd1). A clinical significance of the acquisition of drug resistance has not been demonstrated. However, isolates with high-level resistance readily replicate in cell cultures at zidovudine concentrations that are not attainable clinically. Definitive data regarding development of resistance in asymptomatic individuals treated with 500 mg of zidovudine per day are not available. Yet, preliminary data suggest that resistance can occur but at a relatively lower rate in such individuals.
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The overall significance of drug resistance to HIV will be better delineated as more information becomes available. At present, however, the risks of the emergence of resistant virus do not outweigh the documented benefits of zidovudine therapy at earlier stages of HIV infection.
RECOMMENDATIONS:HIV TESTING Early treatment with zidovudine and other drugs can only occur after HIV infection is identified. The demonstrated benefit of medical treatment early in HIV disease is an incentive to determine the HIV antibody status of individuals at risk. An essential part of identifying infection is performing an appropriate HIV risk assessment. Such an assessment is expected in the care of all patients by all physicians. Included in this assessment are a sexual, drug use, and transfusion history. The widespread application of this practice will reduce the frequency of initial identification of HIV infection after the development of AIDS, an occurrence that represents the loss of an opportunity to prevent or delay disease progression. Those individuals at highest risk have been documented clearly [5]. The primary care physician should appreciate the many impediments to a frank discussion with patients about HIV risk. In addition to fear of discrimination and loss of job and health insurance, these impediments include the patients’ fear of rejection by the physician; physician discomfort in dealing with discussions of sexuality and intravenous drug use; and the physician’s fear of acquiring HIV infection from patients. In some populations, lack of availability of follow-up care discourages both patients and physicians from addressing the issue of HIV testing. HIV testing must be confidential, with pre- and post-test counseling and with results (positive or negative) provided in person. No positive test results should be given to a patient until the screening test has been confirmed, most commonly by a Western blot. In screening tests confirmed by a Western blot, the incidence of false positives is extremely low. It is an individual’s right to decline testing. However, individuals at high risk who decline testing need to be educated that the more they know about their health status, the greater their ability to make informed decisions. Individuals at high risk who decline testing should be monitored at regular intervals, and testing should be encouraged repeatedly.
sons with HIV. Many studies have shown the value of following CD4 lymphocyte counts as markers of immune status. Therefore, physicians managing persons with HIV infection should be familiar with the use of this test. CD4 counts decline progressively during the course of HIV infection. However, there is significant variability in individual patients, and many other conditions, such as acute viral infections, can transiently cause large fluctuations in CD4 counts. CD4 lymphocyte counts should be measured in an experienced laboratory with quality assurance procedures in place. To follow CD4 measurements in an individual patient, physicians are advised to use the same laboratory and, optimally, to obtain specimens at the same time of day. At the time of diagnosis of HIV infection, a baseline CD4 lymphocyte count should be obtained. When major treatment decisions are to be made or when unexpected or discrepant results are obtained, a CD4 count should be repeated after at least 1 week. In general, follow-up CD4 counts should be performed every 6 months (Figure 1). More frequent CD4 counts, every 3 to 4 months, are indicated if CD4 counts are approaching the level at which other treatment decisions are to be made, for example, initiating zidovudine therapy at CD4 counts of fewer than 0.500 X log/L or PCP prophylaxis at fewer than 0.200 X log/ L (Figures 1 and 2). After CD4 counts fall to fewer than 0.200 X log/L, and the patient is receiving PCP prophylaxis and zidovudine, there is no definite clinical indication for repeat CD4 counts. Some patients may, however, find this information helpful for individual decision-making. Physicians and patients should be aware of the variability of CD4 counts in an individual, as well as the variability due to laboratory methodology. Variations in the CD4 counts of 20% are common and should not be overinterpreted.
INITIATION OF THERAPY
The availability of early treatment requires a means of monitoring the immunologic status of per-
Therapy with zidovudine is recommended for both symptomatic and asymptomatic HIV-infected individuals whose CD4 counts are fewer than 0.500 X log/L. This recommendation is based on the results of ACTG studies 016 and 019 (summarized earlier) that demonstrated unequivocal benefit from early initiation of zidovudine therapy in delaying progression to advanced disease. Recent virologic studies further support the concept of early initiation of therapy. Plasma viremia has been shown to exist in high titers in patients with more advanced disease [6,7]. Early therapy may diminish the level of free virus in plasma, thereby reducing viral load. The recommended dose of zidovudine is 500 mg/
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IMMUNOLOGICEVALUATIONAND MONITORINGOF IMMUNE STATUS
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Risk Assessment 1 HIV Antibody Screening (enzyme-linked immunosorbent assay, ELISA)
If Seropositive
If Seronegative Counsel to modify risk behavior
l
l
2nd ELISA If positive, Western blot to confirm infection
Immunologic Monitoring CD4 Test
I < 0.500 x 10’ cells/L
0.500 to 0.600 x 10’ cells/L
> 0.600 x 10’ cells/L Followup in 6 months with repeat CD4 test
Followup every 3 months with CD4 test
1. I
1
I If CD4 count goes below 0.500 x 1 09/L
If CD4 count approaches 0.500 x 1 09/L
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Repeat CD4 tests < 0.500 x 1Og/L one week apart
1 Recommend Zidovudine (see Figure 2)
Figure
1. General
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day (100 mg by mouth every 4 hours while awake). Previous studies had used higher doses of zidovudine, based primarily on pharmacokinetic projections of the dose most likely to be effective. ACTG studies 002 and 019 demonstrated that lower doses of zidovudine are at least as effective as higher doses and are associated with significantly fewer
in early
HIV disease.
side effects, especially when administered to asymptomatic patients. When making decisions regarding initiation of zidovudine therapy, several important caveats should be noted. First, documentation of a positive HIV antibody test should be obtained before initiation of zidovudine therapy. Second, the determina-
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Initiate Zidovudine (Following 2 CD4 counts c 0.500 x 1Og/L, 1 week apart)
Followup monthly for 3 months . CBC each month
Followup every 3 months ----------------------------------------------------------------------l
l
CBC every visit (every 3 months)
CD4 test every other visit (every 6 months)
If new symptoms or toxicity -__---___--_______________
If CD4 count < 0.300 x log/L and no new symptoms - - - - - - - - - - - - - -or - - -toxicity --- ---- --
or
Followup as clinically indicated
Repeat CD4 test every 3 months
If CD4 count < 0.200 x 1Og/L ____________________--------------l l
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Figure
2. General
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Initiate PCP prophylaxis Further CD4 testing not medically indicated CBC
= complete
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tion of CD4 counts is subject to considerable variation in the same patient. If the patient’s initial CD4 lymphocyte count is close to 0.500 X log/L (A 0.100 X log/L), the count should be repeated. Optimally, two consecutive CD4 counts below 0.500 X log/L should be obtained at least 1 week apart before initiation of therapy (Figure 1). Third, although certain laboratory studies, such as &-microglobulin, neopterin, and HIV antigen, have been shown to have some prognostic value in the progression of HIV disease, their utility in predicting individuals who are more likely to benefit from zidovudine therapy has not been established. Therefore, there is no laboratory marker other than the CD4 count that is necessary in deciding when to initiate zidovudine therapy. Finally, the decision to initiate antiretroviral therapy should be a joint decision between the patient and the physician. The decision to initiate therapy can be especially difficult for the patient, who is often confused by conflicting information in the lay literature. The physician can assist the patient in making the most appropriate decision by being open to questions and informing the patient of all possible options based on currently available information. In patients for whom benefit has not been documented, such as for individuals with more than 0.500 x log/L CD4 lymphocytes, potential emergence of drug resistance as well as cost, toxicity, and other factors should combine to encourage monitoring CD4 cell counts rather than initiating therapy. PATIENT MANAGEMENT Zidovudine therapy should be provided within the context of a comprehensive primary care plan for the patient with HIV infection. The complexity of the illness requires attention to overall patient care needs, including assessment of general health status; provision for psychosocial support; consideration of issues such as housing, income, and continuing access and reimbursement for health care; referral for drug abuse treatment; and evaluation of family and social support systems. Attention should be given to education about HIV infection, including symptoms of more severe disease, prognosis, transmission, and prevention counseling. Specific education about zidovudine, dosing schedule, side effects, drug interactions, and compliance should be provided. The institution of zidovudine treatment is a long-term commitment to continuing therapy and follow-up, and treatment should be offered within a system providing continuity of care wherever possible. This will often fall within the province of primary care practitioners.
Related primary care issues that should be addressed in evaluating patients with early HIV infection included screening for syphilis and other sexually transmitted diseases, purified protein derivative (PPD) screening for A4ycobacterium tuberculosis infection, and serology for toxoplasma if indicated. Isoniazid prophylaxis should be given to PPD-positive patients. Hepatitis B immunization for patients with negative serology may also be considered. Pneumococcal and influenza vaccination should be offered. For women, a gynecologic examination with particular attention to sexually transmitted disease screening and cytologic examination by Papanicolaou smear is indicated, and pregnancy counseling and prevention services should be discussed and offered. PCP prophylaxis should be initiated for patients with confirmed CD4 lymphocyte counts fewer than 0.200 X log/L. Frequency of Visits Follow-up contact should be scheduled 2 weeks after initiation of therapy to identify new symptoms and possible drug side effects, to assess and reinforce compliance, and to provide an opportunity for the patient to express concerns and review information previously discussed. Additional visits should be scheduled as needed until both patient and health care provider believe that the treatment plan is understood and is being properly implemented. For patients whose disease is clinically stable, follow-up visits may be scheduled at 3-month intervals (Figure 2). The development of significant adverse events or symptoms suggesting clinical deterioration should be an indication for an increased frequency of visits. Laboratory Monitoring At initiation of zidovudine therapy, baseline complete blood cell count, differential, and chemistries should be obtained. Women should have a serum pregnancy test if appropriate. Abnormal laboratory values discovered at baseline should be followed. Although severe hematologic toxicity is uncommon in patients with early HIV disease who are receiving recommended doses of zidovudine, periodic monitoring is indicated. Because the decline in hemoglobin, when it occurs, is usually manifest within 12 weeks after initiation of treatment, monitoring of complete blood cell counts may be done monthly for the first 3 months and then, if stable, every 3 months thereafter. Patients who begin treatment with low baseline values may require more frequent monitoring until stability is ensured.
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Thrombocytopenia is rarely seen as a result of zidovudine therapy. Because macrocytosis routinely occurs during therapy with zidovudine, lack of an increase in mean corpuscular volume to a level of at least 95 fL after 5 months on therapy may be an indicator of noncompliance. Given the low frequency of zidovudine-induced laboratory abnormalities in asymptomatic and mildly symptomatic populations, monitoring of other routine laboratory parameters should be performed only as clinically indicated. Management of Adverse Events Hemoglobin 80 g/L and granulocytopenia less than 0.750 X log/L are indications of more serious hematologic toxicity and require dose interruption with reinstitution of a lower dose or dose reduction alone. (In protocol 019, dose reduction was to 300 mg/day.) Red blood cell transfusion may be an option for some patients. The potential for development of serious myopathy or myositis after more than 1 year of therapy is of concern during long-term treatment in asymptomatic or mildly symptomatic populations. At routine visits, patients should be questioned for symptoms suggesting myopathy/myositis, including myalgias, loss of muscle mass, weight loss, and proximal muscle weakness. Muscle enzyme elevation may precede symptoms by weeks, and creatine phosphokinase evaluation at 3-month intervals may be helpful in patients receiving treatment for 1 year or more. Depending on the severity of symptoms, dose interruption or dose reduction should be considered. Gastrointestinal and constitutional symptoms occasionally occur shortly after the institution of zidovudine therapy in this population. Malaise, fatigue, nausea, vomiting, dyspepsia, and bloating may be sufficiently distressing to patients to require dose reduction. Interruption of dose followed by reinstitution of therapy at a lower dose with upward titration may be helpful in some patients. Drug Interactions Intermittent therapy with acetaminophen is not contraindicated and can be given to patients taking zidovudine. Likewise, toxicity has not been shown by acyclovir in combination with zidovudine. Concomitant therapy with other drugs having potential hematologic toxicity may require more frequent monitoring. Patients receiving drugs for treatment of opportunistic infections or malignancies clearly require more frequent monitoring for toxicity and may require dose interruption. Discontinuation of Zidovudine Therapy Recommendations as to when and if zidovudine 342
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therapy should be discontinued due to lack of efficacy cannot be made at this time.
DIRECTIONSFOR FUTURERESEARCH Before the results of ACTG studies 016 and 019 were available, use of zidovudine was licensed for HIV-infected persons with AIDS and advanced AIDS-related complex. Protocols 016 and 019 have demonstrated that earlier initiation of zidovudine significantly delays progression to these clinical events. Furthermore, the 500-mg daily dose of zidovudine was associated with minimal toxicity yet was at least as efficacious as the higher dosage. However, there remain a number of unanswered questions relevant to the optimal treatment of this patient population. (1) Because the participants in these trials were followed for a maximum of 2 years, the long-term effects of early intervention with zidovudine on delaying clinical progression and in prolonging survival are not yet known. Also, although considerable experience regarding the side effects of zidovudine has been accumulated, the potential for long-term adverse side effects from zidovudine is yet unknown. (2) These studies considered three daily dosages of zidovudine (500,1,200, and 1,500 mg), based on an every 4 hours dosing regimen. It is not known whether other daily dosages, dose schedules, or dosages based on body weight would result in greater therapeutic benefit or fewer adverse side effects. Similarly, these studies were not designed to determine whether the initiation of zidovudine therapy at other times in the disease process might be more efficacious. The demonstrated ability of zidovudine to delay the decline of CD4 lymphocytes and to affect viral activity, as measured by serum levels of HIV antigen, show that there may be benefits of even earlier initiation of zidovudine in this population. However, if the effects of zidovudine are transient, due to development of resistant virus, or other factors, it is possible that later initiation of the drug could be more efficacious. Current data from protocols 016 and 019 cannot resolve this issue. However, additional follow-up of these participants, as well as information from ongoing studies being conducted by the Veterans Administration and by a multinational European study group, could provide critical information about the relative efficacy of these treatment strategies. (3) It is possible that there are subgroups of patients for whom other treatment strategies using zidovudine are more efficacious than those recommended in this report. However, the identification of such subgroups was beyond the scope of these studies. Although there is no evidence to suggest that the beneficial effects of zidovudine are differ89
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ent in women, people of color, and intravenous drug users, these populations were not heavily represented in these studies. (4) Studies to date have determined neither the value of zidovudine in asymptomatic pediatric populations nor the risk of zidovudine in pregnant women. (5) Scientific data are limited on the efficacy of combination antiviral drug therapy or strategies that involve the use of alternating zidovudine with other drugs. Nor is it known whether or when zidovudine should be discontinued in favor of another treatment in the presence of new disease symptoms or changes in laboratory markers. (6) Finally, further research is needed on the use of CD4 lymphocyte counts and other immunologic markers for the initiation of therapy and the management of patients. Each of these markers can be subject to considerable variability within individual patients. Resolution of these questions will complement the tremendous advances in the treatment of HIVinfected persons that have been made in the past 3 years.
APPENDIX MEMBERS OF THE STATE-OF-THE ART PANEL: Charles C.J. Carpenter, M.D., Panel Chair, Professor of Medicine, Brown University, Providence, Rhode Island; Ron Brookmeyer, Ph.D., Associate Professor, Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland; Robert B. Couch, M.D., Professor and Chairman, Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas; Margaret A. Fischl, M.D., Professor of Medicine, Department of Medicine, Director, Comprehensive AIDS Program, University of Miami School of Medicine, Miami, Florida; Debra Fraser-Howze, Executive Director/CEO, Black Leadership Commission on AIDS, New York, New York; Gerald Friedland, M.D., Professor of Medicine and Epidemiology and Social Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Pamela G. Kidd, M.D., Assistant Professor, Director of Hematopathology, Department of Laboratory Medicine, University of Washington, Seattle, Washington; Stephen W. Lagakos, Ph.D., M.P.H., Professor, Harvard School of Public Health, Boston, Massachusetts; Chuck Mayer, Chairman, Medical Affairs Committee, National Association of People with AIDS and PACT for Life, Tucson, Arizona; June E. Osborn, M.D., Chairman, National Commission on AIDS, Dean, School of Public Health, University of Michigan, Ann Arbor, Michigan; Douglas D. Richman, M.D., Professor of Pathology and Medicine, University of California at San Diego, Staff Pathol-
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ogist and Chief, Virology Section, Veterans Administration of San Diego, San Diego, California; Michael S. Saag, M.D., Assistant Professor of Medicine, Director, University of Alabama at Birmingham, AIDS Outpatient Center, UAB Department of Medicine, Birmingham, Alabama; Merle A. Sande, M.D., Professor and Vice Chairman of Medicine, University of California at San Francisco, Chief, Medical Service, San Francisco General Hospital, San Francisco, California; Jay P. Sanford, M.D., President/Dean, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Renslow Sherer, M.D., Director, AIDS Prevention Services, Cook County Hospital, Chicago, Illinois; Neil R. Schram, M.D., Chair, AIDS Task Force, American Association of Physicians for Human Rights, Harbor City, California; Melanie A. Thompson, M.D., President, AIDS Research Consortium of Atlanta, Inc., Atlanta, Georgia; Paul A. Volberding, M.D., Associate Professor of Medicine, University of California at San Francisco, Chief, AIDS Program, San Francisco General Hospital, San Francisco, California; Sheldon M. Wolff, M.D., Endicott Professor and Chairman, Department of Medicine, Tufts University School of Medicine, Physician in Chief, New England Medical Center, Boston, Massachusetts. PRESENTERS: Margaret A. Fischl, M.D.: “NIAID AIDS Clinical Trials Group Protocol 016: The Safety and Efficacy of AZT in the Treatment of Patients With Early ARC” Paul A. Volberding, M.D., and Stephen W. Lagakos, Ph.D., M.P.H.: “NIAID AIDS Clinical Trials Group Protocol 019: The Safety and Efficacy of AZT for Asymptomatic HIV-Infected Individuals” Margaret A. Fischl, M.D.: “NIAID AIDS Clinical Trials Group Protocol 002: The Safety and Efficacy of AZT in the Treatment of Patients With Post First Episode PCP” John D. Hamilton, M.D.: “Veterans Administration Study # 298: AZT Treatment of AIDS and ARC, Part I: Treatment of Patients With ARC” Maxime Seligmann, M.D.: “Concorde I Study: AZT in Asymptomatic HIVInfected Individuals” Mitchell Gail, M.D., Ph.D.: “Recent Deficits in the Incidence of AIDS” Sandra N. Lehrman, M.D.: “AZT Carcinogenicity” Douglas D. Richman, M.D.: “AZT Resistance” MEMBERS OF THE PLANNING COMMITTEE: Charles C.J. Carpenter, M.D., Panel Chairperson, Professor of Medicine, Brown University, Providence, Rhode Island; Elaine Baldwin, M.Ed., Chief, Information Projects Section, Office of Communications, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Nancy Blustein, Special Assistant to the Associate Direc-
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tor for Treatment Research, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Daniel F. Hoth, M.D., Director, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Deborah G. Katz, R.N., MS., Chief, Regulatory Compliance Section, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Carla B. Pettinelli, M.D., Ph.D., Medical Officer, Treatment Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
ACKNOWLEDGMENT The panel and planning committee thanks Michele Dillon, Penelope Murphy, April Pace, Marie1 Smith, and Kathleen lsner of Prospect Associates, Rockville. Maryland, for their technical assistance and logistical support.
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REFERENCES 1. Fischl MA, Richman DD, Hansen N, eta/. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type I (HIV) infection: a double blind, placebo-controlled trial. Ann Intern Med 1990; 112: 727-37. 2. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CDCpositive cells per cubic millimeter. N Engl J Med 1990; 322: 941. 3. Fischl MA, Parker CB, Pettinelli C, eta/. The efficacy and safety of a lower daily dose of zidovudine in the treatment of patients with AIDS-associated pneumocystis carinii pneumonia. N Engl J Med 1990 (in press). 4. Larder BA. Darby G. Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731-4. 5. Centers for Disease Control. Public Health Service guidelines for counseling and antibody testing to prevent HIV infection and AIDS. MMWR 1987; 36: 50915. 6. Ho D. Moudgil T, Alam M. Quantitation of human immunodeficiency virus type I in the blood of infected persons. N Engl J Med 1989; 321: 1621-5. 7. Coombs R, Collier A, Allain JP. et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626-31.
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State-of-the-Art Conference on Azidothymidine Therapy for Early HIV Infection Sponsored by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Public Health Service
T
his State-of-the-Art Conference, which was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, was convened to evaluate available scientific information and to resolve safety and efficacy issues related to the use of zidovudine in the treatment of HIV-infected persons with few or no symptoms of disease. The resultant statement is intended to advance understanding of this issue and to be useful to health professionals and the public. The statement was prepared by a nonadvocacy, non-Federal panel of experts based on (1) presentations during a l-day public session by investigators working in areas relevant to the questions; (2) questions and statements from conference attendees, including those presented during an open discussion period that was part of the public session; (3) closed deliberations by the panel during the remainder of the first day and the entire second day. This statement is an independent report of the panel and is not a policy statement of NIAID or the Federal Government.
INTRODUCTION With the spread of the acquired immunodeficiency syndrome (AIDS) epidemic and the realization that between 800,000 and 1.5 million Americans are infected with the human immunodeficiency virus (HIV), physicians in every part of the United States are being called upon to provide primary care for persons with HIV infection. Since there is more information about the length of time a person can be infected with HIV before symptoms begin to occur, physicians are seeking guidelines for HIV antibody testing and counseling, patient monitoring, and treatment of persons presenting in the early stages of disease. Advances in AIDS research, especially the devel-
From the Division of AIDS. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Office of Communications, Building31. Room 7A32, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
opment of zidovudine (azidothymidine/AZT; Retrovir@) for the treatment of persons with advanced HIV disease, and demonstration of effective prophylaxis against Pneumocystis carinii pneumonia (PCP), have brought major changes in clinical practice. Currently, zidovudine is the only antiretroviral drug approved by the Food and Drug Administration. In August 1989, NIAID announced the results of two studies conducted by the AIDS Clinical Trials Group (ACTG), showing that zidovudine can delay disease progression with minimal side effects in HIV-infected persons with fewer than 0.50 X log CD4 (T4) cells/L, whether asymptomatic or mildly symptomatic. On March 2 of this year, the Food and Drug Administration approved expanded zidovudine label indications to include these groups. On March 3, NIAID convened the State-of-theArt Conference on AZT Therapy for Early HIV Infection. A panel of experts, including clinical investigators, community physicians, statisticians, and community representatives with a special interest in AIDS treatment issues, was charged with formulating recommendations for facilitating the transfer of results of the recently completed clinical trials into the practice of medicine to benefit the largest possible number of persons who are infected with HIV. The panel concluded that a large proportion of the asymptomatic and mildly symptomatic HIVinfected population are candidates for early therapy with zidovudine. This document presents the recommendations made at this conference. The panelists are fully cognizant that these recommendations are made at a time of rapid advances in our knowledge of many aspects of HIV disease and that new scientific developments may alter the state of the art at any time. Periodic state-of-the-art conferences to update recommendations for patient care will be convened as new data on therapies for HIV infection become available. Moreover, the panelists are fully aware that the recommendations to expand the use of zidovudine have major social and economic implications and will further intensify current problems in securing adequate health care, including diagnosis and treatment, for disadvantaged and underserved popula-
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tions. They strongly believe that optimal care of infected patients demands resolution of these problems. Finally, for early intervention to occur, HIVinfected persons must first identify themselves through HIV testing, preceded and followed by appropriate counseling. Barriers to identification, such as lack of access to health care, likelihood of discrimination in many areas, and fear of the loss of health insurance, must be overcome.
majority of these subjects tolerated lower doses of zidovudine without further serious hematologic toxicity. This clinical trial demonstrated that zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV infection and fewer than 0.500 X lo9 CD4 cells/L.
ACTGProtocol 019
This study was designed to evaluate the safety and efficacy of zidovudine therapy in asymptomatic persons with HIV infection, comparing higher and lower doses of zidovudine to placebo [2]. The higher To evaluate the efficacy and safety of zidovudine dose, 300 mg five times daily, was chosen to dupliearly in the treatment of HIV infection, a placebocate that used in the original phase II trial, and the controlled trial was conducted in 711 subjects with lower dose, 100 mg five times daily, was thought to mildly symptomatic disease [l]. Three hundred fifbe close to the minimum effective dose at the time ty-one subjects were assigned to placebo and 360 to the study was designed. Study participants were zidovudine at an oral dose of 200 mg every 4 hours. stratified by entry CD4 positive lymphocyte counts Subjects were arbitrarily stratified according to the into two substudies-one of individuals with more number of pretreatment CD4 lymphocytes; stra- than 0.500 X lo9 CD4 cells/L, the second with fewer tum I consisted of subjects with a pretreatment than 0.500 X lo9 CD4 cells/L. Stratification was CD4 lymphocyte count more than 0.200 X lo9 CD4 made at the level of 0.500 X lo9 CD4 cells/L in order cells/L but fewer than 0.500 X lo9 CD4 cells/L, and to compare responses with those obtained from the stratum II consisted of subjects with a pretreatparallel ACTG Protocol 016. Subjects were moniment CD4 cell count more than or equal to 0.500 X tored for clinical progression and toxicity with roulo9 CD4 cells/L but fewer than 0.800 X lo9 CD4 tine clinical visits and laboratory studies, including cells/L. Fifty-one subjects developed AIDS, ad- markers of antiviral and immunologic effects, such vanced AIDS-related complex (ARC), or died as as serial CD4 lymphocyte counts and HIV antigen their first critical event. Thirty-four placebo recipilevels. The study was designed to detect an effect of ents developed a first critical event (AIDS, ad- zidovudine using primary endpoints of progression vanced ARC, or death) compared with 15 zidovuto AIDS, advanced ARC, or death and secondary endpoints defined by immunologic and virologic dine recipients (p = 0.0017). Significant differences in the number of critical events occurred for sub- markers. A total of 1,338 evaluable subjects were randomjects in stratum I but not for subjects in stratum II. Thirty-four placebo recipients in stratum I devel- ized to the three treatment arms. Baseline laboratooped a first critical event as compared with 12 zido- ry characteristics were well balanced in the treatvudine recipients (p = 0.0005). Twenty-two sub- ment groups. The subjects enrolled were primarily jects developed AIDS (19 in the placebo group and white (Ql%), males (92%), and homosexual or bisexthree in the zidovudine group). Only two placebo ual (87%). Progression to AIDS was documented in 33 plarecipients and three zidovudine recipients in stratum II developed a critical event (p = 0.63). Sub- cebo recipients, in 11 recipients of 500 mg zidovujects receiving zidovudine in stratum I had in- dine, and in 14 recipients of 1,500 mg zidovudine, corresponding to event rates (cases per 100 patient creases in the number of CD4 cells as compared with those receiving placebo, in whom a decline in years of observation) of 6.6,2.3, and 3.1, respectivethe number of CD4 cells was noted. Levels of HIV ly. Similarly, rates of progression to AIDS or adantigen decreased significantly among antigenemic vanced ARC were 7.6, 3.6, and 4.3 in the three zidovudine recipients. In addition, zidovudine re- groups. The majority of study endpoints were due confirmed cases of AIDS, cipients were less likely to develop detectable anti- to histopathologically gen during the study. Symptomatic adverse reac- most of which were defined by PCP. The decrease tions were uncommon and included malaise, in progression rates in the zidovudine treatment fatigue, dyspepsia, nausea, vomiting, and bloating. groups was statistically significant, particularly in The most common serious adverse reactions were the 500-mg dosage group. anemia and neutropenia, which occurred in only 5% Zidovudine also demonstrated benefit on seconand 4%, respectively, of zidovudine recipients. The dary study endpoints. The decline in CD4-positive
MAJORCONTROLLEDCLINICALTRIALS THAT LED TO CURRENT RECOMMENDATIONS ACTGProtocol 016
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cells was significantly reduced with zidovudine treatment in both dosage groups. HIV antigen levels were also reduced. These laboratory effects persisted for at least 48 weeks after starting therapy. The toxicities in this study were similar to those seen in the treatment of more advanced HIV disease but were less frequent and less severe. Severe hematologic toxicities (anemia or neutropenia) were more common in the 1,500-mg dose group but not significantly more frequent in the 500-mg group than in the placebo group. Severe anemia was seen in 6.3% of the higher dose group, 1.1% in the lower dose group, and 0.2% in placebo recipients. Transfusion was required in nine subjects, all in the 1,500mg zidovudine group. Severe neutropenia occurred in 6.3%, 1.8%, and 1.6% of the higher dose, lower dose, and placebo groups, respectively. Transaminase levels were not increased in either zidovudine dose group. Nausea was the only major toxicity more common with 500 mg of zidovudine (3.3%) than with placebo (0.2%). Less severe toxicities occurred in both zidovudine dosage groups but did not generally interfere with continued drug administration. In summary, protocol 019 demonstrated that a total daily dosage of 500-mg zidovudine was effective for asymptomatic subjects with fewer than 0.500 X log CD4 cells/L in reducing progression to advanced disease. Furthermore, this dose of zidovudine was associated with very low rates of severe toxicity. ACTG Protocol 002 To evaluate the efficacy and safety of a lower dose of zidovudine in the treatment of advanced HIV disease, a randomized controlled trial was conducted in 524 subjects after a first episode of PCP [3]. Two hundred sixty-two subjects were assigned to zidovudine at an oral dose of 250 mg every 4 hours (standard treatment group) and 262 to zidovudine at an oral dose of 200 mg every 4 hours for 4 weeks followed by 100 mg every 4 hours (low-dose treatment group). Endpoints to determine the effectiveness of a lower dose of zidovudine included disease progression and changes in the number of CD4 lymphocytes and levels of detectable HIV antigen in serum. The median length of follow-up was 25.6 months. A statistically better survival was noted for the low-dose treatment group (p = 0.019, Wilcoxon test). Two hundred fifteen subjects (82%) in the standard treatment group and 214 (82%) in the lowdose treatment group developed another opportunistic infection (p = 0.91). No statistically significant difference between the two groups in the time to another opportunistic infection was noted (p = 0.56). The number of CD4 lymphocytes increased in
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both treatment groups. No differences between the two groups in the number of CD4 lymphocytes or levels of detectable antigens in serum were noted. One hundred one (39%) of subjects in the standard treatment group developed serious anemia, as compared with 77 (29%) in the low-dose treatment group, and 134 subjects (51%) in the standard treatment group developed serious neutropenia as compared with 96 (37%) in the low-dose treatment group. In conclusion, a lower daily dose of zidovudine was as effective, resulted in a better survival rate, and was considerably less toxic than the initial dose tested.
CARCINOGENICITYSTUDIES Vaginal squamous cell cancers have occurred in low frequencies after prolonged administration of high doses of zidovudine to mice and rats. The doses associated with these cancers were approximately 4 to 40 times greater than the dosage used in humans with HIV infection. The mechanisms that may be responsible for this carcinogenicity are unknown. No cancers have yet been associated with zidovudine use in humans.
ZIDOVUDINERESISTANCE/iv v/mu Isolates of HIV from individuals never treated with zidovudine are highly susceptible to zidovudine. Viral isolates from patients with AIDS or advanced ARC treated with zidovudine at 1,200 mg/ day for periods greater than 6 months commonly exhibit reduced susceptibility to zidovudine, and a wide range of concentrations are required to inhibit growth [4]. Progressive stepwise reductions in susceptibility to zidovudine appear to develop with time. Each stepwise reduction in susceptibility appears to be associated with the acquisition of an additional mutation in the reverse transcriptase gene of HIV. In vitro cross-resistance of zidovudine-resistant mutants can be demonstrated against other nucleoside analogues that, like zidovudine, possess a 3azido group; however, cross-resistance has not been demonstrated against other antiretroviral compounds, including 2’,3’dideoxycytidine (ddC) and 2’,3’dideoxyinosine (dd1). A clinical significance of the acquisition of drug resistance has not been demonstrated. However, isolates with high-level resistance readily replicate in cell cultures at zidovudine concentrations that are not attainable clinically. Definitive data regarding development of resistance in asymptomatic individuals treated with 500 mg of zidovudine per day are not available. Yet, preliminary data suggest that resistance can occur but at a relatively lower rate in such individuals.
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The overall significance of drug resistance to HIV will be better delineated as more information becomes available. At present, however, the risks of the emergence of resistant virus do not outweigh the documented benefits of zidovudine therapy at earlier stages of HIV infection.
RECOMMENDATIONS:HIV TESTING Early treatment with zidovudine and other drugs can only occur after HIV infection is identified. The demonstrated benefit of medical treatment early in HIV disease is an incentive to determine the HIV antibody status of individuals at risk. An essential part of identifying infection is performing an appropriate HIV risk assessment. Such an assessment is expected in the care of all patients by all physicians. Included in this assessment are a sexual, drug use, and transfusion history. The widespread application of this practice will reduce the frequency of initial identification of HIV infection after the development of AIDS, an occurrence that represents the loss of an opportunity to prevent or delay disease progression. Those individuals at highest risk have been documented clearly [5]. The primary care physician should appreciate the many impediments to a frank discussion with patients about HIV risk. In addition to fear of discrimination and loss of job and health insurance, these impediments include the patients’ fear of rejection by the physician; physician discomfort in dealing with discussions of sexuality and intravenous drug use; and the physician’s fear of acquiring HIV infection from patients. In some populations, lack of availability of follow-up care discourages both patients and physicians from addressing the issue of HIV testing. HIV testing must be confidential, with pre- and post-test counseling and with results (positive or negative) provided in person. No positive test results should be given to a patient until the screening test has been confirmed, most commonly by a Western blot. In screening tests confirmed by a Western blot, the incidence of false positives is extremely low. It is an individual’s right to decline testing. However, individuals at high risk who decline testing need to be educated that the more they know about their health status, the greater their ability to make informed decisions. Individuals at high risk who decline testing should be monitored at regular intervals, and testing should be encouraged repeatedly.
sons with HIV. Many studies have shown the value of following CD4 lymphocyte counts as markers of immune status. Therefore, physicians managing persons with HIV infection should be familiar with the use of this test. CD4 counts decline progressively during the course of HIV infection. However, there is significant variability in individual patients, and many other conditions, such as acute viral infections, can transiently cause large fluctuations in CD4 counts. CD4 lymphocyte counts should be measured in an experienced laboratory with quality assurance procedures in place. To follow CD4 measurements in an individual patient, physicians are advised to use the same laboratory and, optimally, to obtain specimens at the same time of day. At the time of diagnosis of HIV infection, a baseline CD4 lymphocyte count should be obtained. When major treatment decisions are to be made or when unexpected or discrepant results are obtained, a CD4 count should be repeated after at least 1 week. In general, follow-up CD4 counts should be performed every 6 months (Figure 1). More frequent CD4 counts, every 3 to 4 months, are indicated if CD4 counts are approaching the level at which other treatment decisions are to be made, for example, initiating zidovudine therapy at CD4 counts of fewer than 0.500 X log/L or PCP prophylaxis at fewer than 0.200 X log/ L (Figures 1 and 2). After CD4 counts fall to fewer than 0.200 X log/L, and the patient is receiving PCP prophylaxis and zidovudine, there is no definite clinical indication for repeat CD4 counts. Some patients may, however, find this information helpful for individual decision-making. Physicians and patients should be aware of the variability of CD4 counts in an individual, as well as the variability due to laboratory methodology. Variations in the CD4 counts of 20% are common and should not be overinterpreted.
INITIATION OF THERAPY
The availability of early treatment requires a means of monitoring the immunologic status of per-
Therapy with zidovudine is recommended for both symptomatic and asymptomatic HIV-infected individuals whose CD4 counts are fewer than 0.500 X log/L. This recommendation is based on the results of ACTG studies 016 and 019 (summarized earlier) that demonstrated unequivocal benefit from early initiation of zidovudine therapy in delaying progression to advanced disease. Recent virologic studies further support the concept of early initiation of therapy. Plasma viremia has been shown to exist in high titers in patients with more advanced disease [6,7]. Early therapy may diminish the level of free virus in plasma, thereby reducing viral load. The recommended dose of zidovudine is 500 mg/
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Risk Assessment 1 HIV Antibody Screening (enzyme-linked immunosorbent assay, ELISA)
If Seropositive
If Seronegative Counsel to modify risk behavior
l
l
2nd ELISA If positive, Western blot to confirm infection
Immunologic Monitoring CD4 Test
I < 0.500 x 10’ cells/L
0.500 to 0.600 x 10’ cells/L
> 0.600 x 10’ cells/L Followup in 6 months with repeat CD4 test
Followup every 3 months with CD4 test
1. I
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I If CD4 count goes below 0.500 x 1 09/L
If CD4 count approaches 0.500 x 1 09/L
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Repeat CD4 tests < 0.500 x 1Og/L one week apart
1 Recommend Zidovudine (see Figure 2)
Figure
1. General
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day (100 mg by mouth every 4 hours while awake). Previous studies had used higher doses of zidovudine, based primarily on pharmacokinetic projections of the dose most likely to be effective. ACTG studies 002 and 019 demonstrated that lower doses of zidovudine are at least as effective as higher doses and are associated with significantly fewer
in early
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side effects, especially when administered to asymptomatic patients. When making decisions regarding initiation of zidovudine therapy, several important caveats should be noted. First, documentation of a positive HIV antibody test should be obtained before initiation of zidovudine therapy. Second, the determina-
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Initiate Zidovudine (Following 2 CD4 counts c 0.500 x 1Og/L, 1 week apart)
Followup monthly for 3 months . CBC each month
Followup every 3 months ----------------------------------------------------------------------l
l
CBC every visit (every 3 months)
CD4 test every other visit (every 6 months)
If new symptoms or toxicity -__---___--_______________
If CD4 count < 0.300 x log/L and no new symptoms - - - - - - - - - - - - - -or - - -toxicity --- ---- --
or
Followup as clinically indicated
Repeat CD4 test every 3 months
If CD4 count < 0.200 x 1Og/L ____________________--------------l l
-.
Figure
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Initiate PCP prophylaxis Further CD4 testing not medically indicated CBC
= complete
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tion of CD4 counts is subject to considerable variation in the same patient. If the patient’s initial CD4 lymphocyte count is close to 0.500 X log/L (A 0.100 X log/L), the count should be repeated. Optimally, two consecutive CD4 counts below 0.500 X log/L should be obtained at least 1 week apart before initiation of therapy (Figure 1). Third, although certain laboratory studies, such as &-microglobulin, neopterin, and HIV antigen, have been shown to have some prognostic value in the progression of HIV disease, their utility in predicting individuals who are more likely to benefit from zidovudine therapy has not been established. Therefore, there is no laboratory marker other than the CD4 count that is necessary in deciding when to initiate zidovudine therapy. Finally, the decision to initiate antiretroviral therapy should be a joint decision between the patient and the physician. The decision to initiate therapy can be especially difficult for the patient, who is often confused by conflicting information in the lay literature. The physician can assist the patient in making the most appropriate decision by being open to questions and informing the patient of all possible options based on currently available information. In patients for whom benefit has not been documented, such as for individuals with more than 0.500 x log/L CD4 lymphocytes, potential emergence of drug resistance as well as cost, toxicity, and other factors should combine to encourage monitoring CD4 cell counts rather than initiating therapy. PATIENT MANAGEMENT Zidovudine therapy should be provided within the context of a comprehensive primary care plan for the patient with HIV infection. The complexity of the illness requires attention to overall patient care needs, including assessment of general health status; provision for psychosocial support; consideration of issues such as housing, income, and continuing access and reimbursement for health care; referral for drug abuse treatment; and evaluation of family and social support systems. Attention should be given to education about HIV infection, including symptoms of more severe disease, prognosis, transmission, and prevention counseling. Specific education about zidovudine, dosing schedule, side effects, drug interactions, and compliance should be provided. The institution of zidovudine treatment is a long-term commitment to continuing therapy and follow-up, and treatment should be offered within a system providing continuity of care wherever possible. This will often fall within the province of primary care practitioners.
Related primary care issues that should be addressed in evaluating patients with early HIV infection included screening for syphilis and other sexually transmitted diseases, purified protein derivative (PPD) screening for A4ycobacterium tuberculosis infection, and serology for toxoplasma if indicated. Isoniazid prophylaxis should be given to PPD-positive patients. Hepatitis B immunization for patients with negative serology may also be considered. Pneumococcal and influenza vaccination should be offered. For women, a gynecologic examination with particular attention to sexually transmitted disease screening and cytologic examination by Papanicolaou smear is indicated, and pregnancy counseling and prevention services should be discussed and offered. PCP prophylaxis should be initiated for patients with confirmed CD4 lymphocyte counts fewer than 0.200 X log/L. Frequency of Visits Follow-up contact should be scheduled 2 weeks after initiation of therapy to identify new symptoms and possible drug side effects, to assess and reinforce compliance, and to provide an opportunity for the patient to express concerns and review information previously discussed. Additional visits should be scheduled as needed until both patient and health care provider believe that the treatment plan is understood and is being properly implemented. For patients whose disease is clinically stable, follow-up visits may be scheduled at 3-month intervals (Figure 2). The development of significant adverse events or symptoms suggesting clinical deterioration should be an indication for an increased frequency of visits. Laboratory Monitoring At initiation of zidovudine therapy, baseline complete blood cell count, differential, and chemistries should be obtained. Women should have a serum pregnancy test if appropriate. Abnormal laboratory values discovered at baseline should be followed. Although severe hematologic toxicity is uncommon in patients with early HIV disease who are receiving recommended doses of zidovudine, periodic monitoring is indicated. Because the decline in hemoglobin, when it occurs, is usually manifest within 12 weeks after initiation of treatment, monitoring of complete blood cell counts may be done monthly for the first 3 months and then, if stable, every 3 months thereafter. Patients who begin treatment with low baseline values may require more frequent monitoring until stability is ensured.
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Thrombocytopenia is rarely seen as a result of zidovudine therapy. Because macrocytosis routinely occurs during therapy with zidovudine, lack of an increase in mean corpuscular volume to a level of at least 95 fL after 5 months on therapy may be an indicator of noncompliance. Given the low frequency of zidovudine-induced laboratory abnormalities in asymptomatic and mildly symptomatic populations, monitoring of other routine laboratory parameters should be performed only as clinically indicated. Management of Adverse Events Hemoglobin 80 g/L and granulocytopenia less than 0.750 X log/L are indications of more serious hematologic toxicity and require dose interruption with reinstitution of a lower dose or dose reduction alone. (In protocol 019, dose reduction was to 300 mg/day.) Red blood cell transfusion may be an option for some patients. The potential for development of serious myopathy or myositis after more than 1 year of therapy is of concern during long-term treatment in asymptomatic or mildly symptomatic populations. At routine visits, patients should be questioned for symptoms suggesting myopathy/myositis, including myalgias, loss of muscle mass, weight loss, and proximal muscle weakness. Muscle enzyme elevation may precede symptoms by weeks, and creatine phosphokinase evaluation at 3-month intervals may be helpful in patients receiving treatment for 1 year or more. Depending on the severity of symptoms, dose interruption or dose reduction should be considered. Gastrointestinal and constitutional symptoms occasionally occur shortly after the institution of zidovudine therapy in this population. Malaise, fatigue, nausea, vomiting, dyspepsia, and bloating may be sufficiently distressing to patients to require dose reduction. Interruption of dose followed by reinstitution of therapy at a lower dose with upward titration may be helpful in some patients. Drug Interactions Intermittent therapy with acetaminophen is not contraindicated and can be given to patients taking zidovudine. Likewise, toxicity has not been shown by acyclovir in combination with zidovudine. Concomitant therapy with other drugs having potential hematologic toxicity may require more frequent monitoring. Patients receiving drugs for treatment of opportunistic infections or malignancies clearly require more frequent monitoring for toxicity and may require dose interruption. Discontinuation of Zidovudine Therapy Recommendations as to when and if zidovudine 342
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therapy should be discontinued due to lack of efficacy cannot be made at this time.
DIRECTIONSFOR FUTURERESEARCH Before the results of ACTG studies 016 and 019 were available, use of zidovudine was licensed for HIV-infected persons with AIDS and advanced AIDS-related complex. Protocols 016 and 019 have demonstrated that earlier initiation of zidovudine significantly delays progression to these clinical events. Furthermore, the 500-mg daily dose of zidovudine was associated with minimal toxicity yet was at least as efficacious as the higher dosage. However, there remain a number of unanswered questions relevant to the optimal treatment of this patient population. (1) Because the participants in these trials were followed for a maximum of 2 years, the long-term effects of early intervention with zidovudine on delaying clinical progression and in prolonging survival are not yet known. Also, although considerable experience regarding the side effects of zidovudine has been accumulated, the potential for long-term adverse side effects from zidovudine is yet unknown. (2) These studies considered three daily dosages of zidovudine (500,1,200, and 1,500 mg), based on an every 4 hours dosing regimen. It is not known whether other daily dosages, dose schedules, or dosages based on body weight would result in greater therapeutic benefit or fewer adverse side effects. Similarly, these studies were not designed to determine whether the initiation of zidovudine therapy at other times in the disease process might be more efficacious. The demonstrated ability of zidovudine to delay the decline of CD4 lymphocytes and to affect viral activity, as measured by serum levels of HIV antigen, show that there may be benefits of even earlier initiation of zidovudine in this population. However, if the effects of zidovudine are transient, due to development of resistant virus, or other factors, it is possible that later initiation of the drug could be more efficacious. Current data from protocols 016 and 019 cannot resolve this issue. However, additional follow-up of these participants, as well as information from ongoing studies being conducted by the Veterans Administration and by a multinational European study group, could provide critical information about the relative efficacy of these treatment strategies. (3) It is possible that there are subgroups of patients for whom other treatment strategies using zidovudine are more efficacious than those recommended in this report. However, the identification of such subgroups was beyond the scope of these studies. Although there is no evidence to suggest that the beneficial effects of zidovudine are differ89
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ent in women, people of color, and intravenous drug users, these populations were not heavily represented in these studies. (4) Studies to date have determined neither the value of zidovudine in asymptomatic pediatric populations nor the risk of zidovudine in pregnant women. (5) Scientific data are limited on the efficacy of combination antiviral drug therapy or strategies that involve the use of alternating zidovudine with other drugs. Nor is it known whether or when zidovudine should be discontinued in favor of another treatment in the presence of new disease symptoms or changes in laboratory markers. (6) Finally, further research is needed on the use of CD4 lymphocyte counts and other immunologic markers for the initiation of therapy and the management of patients. Each of these markers can be subject to considerable variability within individual patients. Resolution of these questions will complement the tremendous advances in the treatment of HIVinfected persons that have been made in the past 3 years.
APPENDIX MEMBERS OF THE STATE-OF-THE ART PANEL: Charles C.J. Carpenter, M.D., Panel Chair, Professor of Medicine, Brown University, Providence, Rhode Island; Ron Brookmeyer, Ph.D., Associate Professor, Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland; Robert B. Couch, M.D., Professor and Chairman, Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas; Margaret A. Fischl, M.D., Professor of Medicine, Department of Medicine, Director, Comprehensive AIDS Program, University of Miami School of Medicine, Miami, Florida; Debra Fraser-Howze, Executive Director/CEO, Black Leadership Commission on AIDS, New York, New York; Gerald Friedland, M.D., Professor of Medicine and Epidemiology and Social Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Pamela G. Kidd, M.D., Assistant Professor, Director of Hematopathology, Department of Laboratory Medicine, University of Washington, Seattle, Washington; Stephen W. Lagakos, Ph.D., M.P.H., Professor, Harvard School of Public Health, Boston, Massachusetts; Chuck Mayer, Chairman, Medical Affairs Committee, National Association of People with AIDS and PACT for Life, Tucson, Arizona; June E. Osborn, M.D., Chairman, National Commission on AIDS, Dean, School of Public Health, University of Michigan, Ann Arbor, Michigan; Douglas D. Richman, M.D., Professor of Pathology and Medicine, University of California at San Diego, Staff Pathol-
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ogist and Chief, Virology Section, Veterans Administration of San Diego, San Diego, California; Michael S. Saag, M.D., Assistant Professor of Medicine, Director, University of Alabama at Birmingham, AIDS Outpatient Center, UAB Department of Medicine, Birmingham, Alabama; Merle A. Sande, M.D., Professor and Vice Chairman of Medicine, University of California at San Francisco, Chief, Medical Service, San Francisco General Hospital, San Francisco, California; Jay P. Sanford, M.D., President/Dean, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Renslow Sherer, M.D., Director, AIDS Prevention Services, Cook County Hospital, Chicago, Illinois; Neil R. Schram, M.D., Chair, AIDS Task Force, American Association of Physicians for Human Rights, Harbor City, California; Melanie A. Thompson, M.D., President, AIDS Research Consortium of Atlanta, Inc., Atlanta, Georgia; Paul A. Volberding, M.D., Associate Professor of Medicine, University of California at San Francisco, Chief, AIDS Program, San Francisco General Hospital, San Francisco, California; Sheldon M. Wolff, M.D., Endicott Professor and Chairman, Department of Medicine, Tufts University School of Medicine, Physician in Chief, New England Medical Center, Boston, Massachusetts. PRESENTERS: Margaret A. Fischl, M.D.: “NIAID AIDS Clinical Trials Group Protocol 016: The Safety and Efficacy of AZT in the Treatment of Patients With Early ARC” Paul A. Volberding, M.D., and Stephen W. Lagakos, Ph.D., M.P.H.: “NIAID AIDS Clinical Trials Group Protocol 019: The Safety and Efficacy of AZT for Asymptomatic HIV-Infected Individuals” Margaret A. Fischl, M.D.: “NIAID AIDS Clinical Trials Group Protocol 002: The Safety and Efficacy of AZT in the Treatment of Patients With Post First Episode PCP” John D. Hamilton, M.D.: “Veterans Administration Study # 298: AZT Treatment of AIDS and ARC, Part I: Treatment of Patients With ARC” Maxime Seligmann, M.D.: “Concorde I Study: AZT in Asymptomatic HIVInfected Individuals” Mitchell Gail, M.D., Ph.D.: “Recent Deficits in the Incidence of AIDS” Sandra N. Lehrman, M.D.: “AZT Carcinogenicity” Douglas D. Richman, M.D.: “AZT Resistance” MEMBERS OF THE PLANNING COMMITTEE: Charles C.J. Carpenter, M.D., Panel Chairperson, Professor of Medicine, Brown University, Providence, Rhode Island; Elaine Baldwin, M.Ed., Chief, Information Projects Section, Office of Communications, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Nancy Blustein, Special Assistant to the Associate Direc-
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tor for Treatment Research, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Daniel F. Hoth, M.D., Director, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Deborah G. Katz, R.N., MS., Chief, Regulatory Compliance Section, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Carla B. Pettinelli, M.D., Ph.D., Medical Officer, Treatment Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
ACKNOWLEDGMENT The panel and planning committee thanks Michele Dillon, Penelope Murphy, April Pace, Marie1 Smith, and Kathleen lsner of Prospect Associates, Rockville. Maryland, for their technical assistance and logistical support.
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REFERENCES 1. Fischl MA, Richman DD, Hansen N, eta/. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type I (HIV) infection: a double blind, placebo-controlled trial. Ann Intern Med 1990; 112: 727-37. 2. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CDCpositive cells per cubic millimeter. N Engl J Med 1990; 322: 941. 3. Fischl MA, Parker CB, Pettinelli C, eta/. The efficacy and safety of a lower daily dose of zidovudine in the treatment of patients with AIDS-associated pneumocystis carinii pneumonia. N Engl J Med 1990 (in press). 4. Larder BA. Darby G. Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731-4. 5. Centers for Disease Control. Public Health Service guidelines for counseling and antibody testing to prevent HIV infection and AIDS. MMWR 1987; 36: 50915. 6. Ho D. Moudgil T, Alam M. Quantitation of human immunodeficiency virus type I in the blood of infected persons. N Engl J Med 1989; 321: 1621-5. 7. Coombs R, Collier A, Allain JP. et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626-31.
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