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A STATE-OF-THE-ART conference was convened recently by the National Institute of Allergy and Infectious Diseases to evaluate current information on the use of nucleoside analogue reverse transcriptase inhibitors for the treatment of human immunodeficiency virus (HIV) infection. Data generated from controlled clinical trials of zidovudine (Retrovir, Burroughs Wellcome Co, Research Triangle Park, NC), didanosine (Videx, Bristol-Myers Squibb Co, Wallingford, Conn), and zalcitabine (HIVID, Hoffman-LaRoche, Nutley, NJ) conducted in the United States and abroad were reviewed by an expert panel, which then formulated recommendations to guide clinicians and HIV-infected persons in the use of these agents.
Recommendations are supported by data from randomized, double-blind clinical trials, where possible, and derived from consensus interpretation of the weight of scientific evidence where such trials were not available. The recommendations represent the independent views of the panel and are not a policy statement of the National Institute of Allergy and Infectious Diseases or the federal government. The panel recognizes these guidelines will require modification in the future as new information becomes available. The panel was not charged with making recommendations for antiretroviral treatment of primary HIV infection, prophylaxis for occupational HIV exposure, or antiretroviral dosing for HIV dementia.
Infection with HIV usually progresses from initial seroconversion to apparent clinical latency, followed by progressive immunodeficiency, opportunistic infections, malignancies, and death. Although an average period of 10 years exists from seroconversion to advanced symptomatic disease, the rate of progression varies widely. Some HIV-infected individuals have remained healthy for more than 15 years following seroconversion. Lower numbers of CD4 sup + peripheral blood lymphocytes have generally been found to indicate the advancement of HIV disease. Following the primary HIV infection syndrome, CD4 sup + cell counts typically decline from normal values as HIV disease progresses. In the current recommendations, CD4 sup + cell count ranges were used to illustrate characteristic scenarios as a guide for clinical decision making.
The CD4 sup + cell counts vary from day to day and laboratory to laboratory, and similar levels do not necessarily reflect the same disease status in all patients. For example, very low CD4 sup + cell counts (less than 0.05x10 sup 9/L (50/microliters)) usually indicate advanced disease; however, some patients with these levels remain asymptomatic for extended periods of time while others succumb rapidly. The panel acknowledged that in addition to the rate of CD4 sup + decline, the onset of HIV-related symptoms (weight loss, fever, night sweats, diarrhea, candidiasis, and oral hairy leukoplakia) may have important prognostic implications; thus, the presence or absence of HIV-related symptoms has also been included in the clinical scenarios.
While knowledge of the clinical use of zidovudine has increased during the last several years, the panel was concerned overall by the drug's limited effectiveness and durability of response. The availability of other agents and data from additional studies have, in some instances, served to complicate the making of recommendations. Although the panel viewed each of the current nucleoside therapies as having a role in the treatment of HIV, the weaknesses of these agents underscored the importance of comprehensive primary care for HIV-infected persons and of patient involvement in the choice of treatment strategies.
Patients and physicians must be aware of the benefits, toxic effects, limitations, and knowledge gaps of the antiretroviral drugs when making treatment decisions. Physicians are obliged to educate patients about clinically sound treatment options and their impact on quality of life. These recommendations provide a basis for such discussions and support the use of scientifically valid treatment strategies appropriate to individual patient needs, priorities, and circumstances of daily life. Accordingly, the current recommendations are less prescriptive than those from a previous state-of-the-art conference held in 1990 (1).
The recommendations, summarized in the Table 1, are presented with relevant data and clinical interpretations, as follows:
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Recommendation
As first-line therapy, the panel recommends zidovudine, 600 mg daily in three divided doses.
Rationale
Two controlled clinical trials have compared zidovudine with didanosine and zidovudine with zalcitabine as initial therapy for HIV infection.
1. AIDS (acquired immunodeficiency syndrome) Clinical Trials Group (ACTG) study 116A compared didanosine (500 mg/d and 750 mg/d) with zidovudine (600 mg/d) to determine if didanosine was equivalent to zidovudine as a first-line therapy. Patients had advanced HIV disease and were either zidovudine naive or had 16 weeks or less of prior zidovudine treatment without intolerance. No difference in progression to AIDS or death was seen among the three regimens, although the overall survival trend favored zidovudine over didanosine of 500 mg per day (relative risk (RR), 1.4; 95% confidence interval, 0.99 to 1.97) (R. Dolin et al, unpublished data, 1993, and written communication, A. Cross et al, Bristol-Myers Squibb Co, 1992).
2. ACTG 114 compared zalcitabine (2.25 mg/d) with zidovudine (1200 mg/d for 28 days, then 600 mg/d) in patients with CD4 sup + cell counts of 0.20x10 sup 9/L or less. The study was designed to determine whether zalcitabine was equivalent in efficacy to zidovudine in individuals with 3 months or less of prior zidovudine treatment. Zidovudine was found to be superior to zalcitabine in terms of prolonging survival (P=.008) and in delaying time to progression (P=.03) (2).
The panel recommends using zidovudine 600 mg per day in three divided doses (ie, 200 mg three times a day) on the basis of clinical experience, which suggests that patient compliance may be enhanced by using this dosing interval without obvious changes in safety or efficacy.
When should therapy with nucleoside reverse transcriptase inhibitors be initiated?
Clinical Scenario 1
The first scenario describes asymptomatic patients with CD4 sup + cell counts greater than 0.50x10 sup 9/L and no prior antiretroviral treatment.
Recommendation.--Continue observation, with clinical and immunologic monitoring (CD4 sup + enumeration) every 6 months. Initiation of antiretroviral therapy is not recommended.
Exceptions to this recommendation might include individuals with laboratory changes that suggest disease progression, such as rapidly declining CD4 sup + cell counts, in whom initiation of antiretroviral therapy with zidovudine should be considered.
Rationale.--Three large clinical trials have studied, or are continuing to investigate, the use of zidovudine in the asymptomatic patient population with CD4 sup + cell counts greater than 0.50x10 sup 9/L:
1. Concorde I (3) was a European trial of immediate zidovudine vs deferred zidovudine (500 mg twice daily) in asymptomatic patients (Medical Research Council/Association Nationale de Recherche du SIDA, unpublished data, 1993). No difference in survival or progression to advanced disease was seen after a mean study period of 3 years in the subset of 710 patients with entry CD4 sup + cell counts greater than 0.50x10 sup 9/L.
2. European-Australian Collaborative Group protocol 020 was a placebo-controlled trial of zidovudine (500 mg twice daily) in 993 asymptomatic patients with CD4 sup + cell counts greater than 0.40x10 sup 9/L. No difference in progression to AIDS and severe AIDS-related complex (ARC) was observed during a median study period of 94 weeks, although zidovudine significantly delayed progression to a combined end point of AIDS/severe ARC/Centers for Disease Control and Prevention (CDC) group IV-C2 disease (CDC group IV-C2 disease included oral candidiasis, oral hairy leukoplakia, and herpes zoster) or to CD4 sup + cell counts less than 0.35x10 sup 9/L compared with placebo (4).
3. ACTG 019 is a study of two dosages of zidovudine (500 mg/d and 1500 mg/d) vs placebo (5). The portion of the study that enrolled patients with CD4 sup + cell counts greater than 0.50x10 sup 9/L is ongoing and expected to close for final analysis this month.
Clinical Scenario 2
The second scenario describes asymptomatic patients with CD4 sup + cell counts between 0.20 and 0.50x10 sup 9/L and no prior antiretroviral treatment.
Recommendation.--Two options are supported by the results of clinical trials in this population. These are (1) initiation of antiretroviral therapy with zidovudine or (2) continued observation with clinical and immunologic monitoring for disease progression, without initiation of antiretroviral therapy.
If initiation of zidovudine is chosen, the recommended dosage is 600 mg daily in three divided doses.
If continued monitoring without antiretroviral treatment is chosen, the subsequent development of HIV-related symptoms or laboratory evidence of disease progression, such as rapid decline in CD4 sup + cell counts, would then support the initiation of zidovudine 600 mg daily in three divided doses.
Rationale.--The following trials assessed the efficacy and safety of zidovudine in asymptomatic patients over prolonged study periods and showed that zidovudine is well tolerated in this population.
1. In ACTG 019, zidovudine was superior to placebo in delaying progression to AIDS and advanced ARC after a mean study period of 55 weeks in asymptomatic patients with starting CD4 sup + cell counts less than 0.50x10 sup 9/L. The study compared two dosages of zidovudine (500 mg/d and 1500 mg/d) with placebo. Hematologic toxicity and nausea were more frequently associated with zidovudine, although the lower dosage of zidovudine was well tolerated. Long-term follow-up revealed continued benefit in the CD4 sup + cell strata 0.30 to 0.50x10 sup 9/L in terms of delaying progression, but no differences were seen in overall survival during a 4-year period (P. A. Volberding et al, unpublished data, 1993) (5).
2. The Concorde I (3) trial showed no difference in progression of disease or survival during a 3-year study period in the subgroup of 912 patients with starting CD4 sup + cell counts less than 0.50x10 sup 9/L (Medical Research Council/Association Nationale de Recherche du SIDA, unpublished data, 1993). The rate of progression to severe ARC and AIDS was slower during the initial 55 weeks of study in the immediate zidovudine treatment group, which was consistent with the results of ACTG 019.
3. Burroughs Wellcome study 017, a European-Australian trial of zidovudine in asymptomatic patients with CD4 sup + cell counts between 0.20 and 0.40x10 sup 9/L, did not reveal a difference between zidovudine and placebo in delaying progression to AIDS and severe ARC after a 2-year period. In the first year, however, the rate of progression to AIDS or severe ARC was higher in the placebo than in the zidovudine recipient group, which is consistent with the benefits noted in Concorde I and ACTG 019 in this patient group during a similar time period (6).
Other large ongoing clinical trials (7,8) are comparing zidovudine, zalcitabine, and didanosine in monotherapy and combination regimens in asymptomatic patients.
In summary, several but not all studies have shown that zidovudine therapy provides some benefit of limited duration in asymptomatic patients. The benefits must be weighed against the drug's toxicity profile as well as the transient nature of its efficacy as a single-agent therapy. The duration of benefit from zidovudine in asymptomatic patients with CD4 sup + cell counts between 0.20 and 0.50x10 sup 9/L appears to be from 12 to 24 months.
Clinical Scenario 3
The third scenario describes symptomatic (other than initial seroconversion disease) patients with CD4 sup + cell counts between 0.20 and 0.50x10 sup 9/L and no prior antiretroviral treatment.
Recommendation.--Initiate antiretroviral therapy with zidovudine 600 mg daily in three divided doses.
Rationale.--Two clinical trials demonstrated a benefit of zidovudine in terms of delaying disease progression in this patient group. A third study supports the use of 600 mg per day as the recommended dosage.
1. ACTG 016 examined zidovudine (1200 mg/d in divided doses) vs placebo in symptomatic patients with CD4 sup + cell counts between 0.20 and 0.50x10 sup 9/L. Zidovudine significantly delayed progression to advanced ARC or AIDS compared with placebo during a median study period of 11 months. Hematologic toxicity occurred in less than 10% of those assigned to zidovudine. A definitive assessment of zidovudine's effect on survival was not possible in this study (M. A. Fischl et al, unpublished data, 1993) (9).
2. The Veterans Affairs Cooperative Study Group (10) protocol 298 evaluated immediate zidovudine vs deferred zidovudine (1500 mg/d) in symptomatic patients with CD4 sup + cell counts between 0.20 and 0.50x10 sup 9/L. In the deferred group, zidovudine was initiated when CD4 sup + cell counts decreased to less than 0.20x10 sup 9/L or AIDS developed. Immediate therapy significantly delayed disease progression compared with deferred therapy but did not lengthen survival after an average study period of more than 2 years. Early zidovudine therapy was associated with more side effects, which were reversible with dose reduction or interruption of therapy.
3. Based on data from patients who had recovered from a single episode of Pneumocystis carinii pneumonia, ACTG 002 demonstrated that a reduced dosage of zidovudine was not significantly different from the originally approved dosage of 1500 mg per day with respect to delaying time to new opportunistic infections. The lower dosage (1200 mg/d for 4 weeks, followed by 600 mg/d in divided doses) was found to be at least as effective as the higher dosage but also resulted in better survival and less toxicity (11). The panel felt comfortable with extrapolation of these findings to the symptomatic population with CD4 sup + cell counts between 0.20 and 0.50x 10 sup 9/L.
In addition, information on zidovudine toxicity from studies involving asymptomatic patients with CD4 sup + cell counts between 0.20 and 0.50x10 sup 9/L and similar dosages of zidovudine may also be extended to this population (Medical Research Council/Association Nationale de Recherche du SIDA, unpublished data, 1993, and P. A. Volberding et al, unpublished data, 1993) (3,5).
Clinical Scenario 4
The fourth scenario describes asymptomatic patients with CD4 sup + cell counts less than 0.20x10 sup 9/L and no prior antiretroviral treatment.
Recommendation.--Initiate antiretroviral therapy with zidovudine 600 mg daily in three divided doses.
Rationale.--Very few data bear directly on this clinical scenario.
1. Since asymptomatic patients with CD4 sup + cell counts less than 0.20x10 sup 9/L have a high risk of AIDS-defining illness and mortality, the panel felt such patients would likely benefit from zidovudine in similar fashion to patients with symptomatic disease in this CD4 sup + cell range (see "Clinical Scenario 5").
2. The recommendation that zidovudine be the drug of choice for this scenario is also based on extrapolation from the ACTG 116A and ACTG 114 trials, in which the majority of patients were symptomatic and had CD4 sup + cell counts less than 0.30x10 sup 9/L (R. Dolin et al, unpublished data, 1993) (2). Such extrapolation to this scenario was felt to be reasonable by the panel.
3. The panel noted that some physicians and patients might choose to initiate treatment with combination regimens, such as zidovudine and zalcitabine. The relative merits of combination therapy as initial therapy in asymptomatic patients with CD4 sup + cell counts less than 0.20x10 sup 9/L are currently unknown, but several large comparative trials are in progress.
4. While not the subject of this conference, consideration should be given to the initiation of prophylaxis against P carinii pneumonia in patients with CD4 sup + cell counts less than 0.20x10 sup 9/L (12).
Clinical Scenario 5
The fifth scenario describes symptomatic HIV-infected individuals with CD4 sup + cell counts less than 0.20x10 sup 9/L and no prior antiretroviral treatment.
Recommendation.--Initiate antiretroviral therapy with zidovudine 600 mg daily in three divided doses.
Rationale.--Data exist that show that zidovudine is useful in this patient group.
1. Burroughs Wellcome trial 02 compared zidovudine with placebo in patients with a previous diagnosis of P carinii pneumonia or other signs or symptoms of HIV disease. Patients randomized to receive 1500 mg per day of zidovudine had a significant decrease in mortality and reduction in the incidence of opportunistic infections compared with patients who received placebo. However, these findings were based on the blinded phase of the trial, which was terminated early because of the significant differences noted after approximately 4 months of observation (13,14).
2. Dosing of zidovudine has been better elucidated, although not thoroughly. The recommended dosage, 600 mg per day, is supported by the following studies: (1) ACTG 002 is summarized herein (refer to "Clinical Scenario 3"); and (2) a randomized study conducted by the Nordic Medical Research Council's HIV Therapy Group (15) compared zidovudine at 400 mg, 800 mg, and 1200 mg of total daily doses in individuals with AIDS or HIV-related symptoms and low CD4 sup + cell counts. Significant differences were not observed among the groups in terms of survival or time to disease progression.
The role of combination nucleoside therapy in this patient population remains to be assessed fully, although initiation of combination therapy might be contemplated by some physicians. Several panel members noted they would consider combination therapy for symptomatic patients with no prior antiretroviral treatment who present with severe immunodeficiency (eg, CD4 sup + cell counts less than 0.05x10 sup 9/L). Several small trials have evaluated zidovudine and didanosine combination regimens in therapy-naive patients (16-19). Other pilot studies have compared alternating and concomitant zidovudine and zalcitabine regimens with monotherapy in similar patients (20,21). The small numbers of subjects in these trials, patient variability, and variable dosages of the regimens tested complicate interpretation. Generally, trends were noted toward higher CD4 sup + cell counts sustained for a longer period ! of time in the combination as compared with monotherapy or alternating therapy arms. Furthermore, some of the trials demonstrated trends toward greater virological suppression with combination therapy. The clinical relevance of these preliminary findings is unclear and requires further exploration.
MODIFICATION OF THERAPY IN THE ABSENCE OF INTOLERANCE OR CLINICAL FAILURE
In patients tolerating an initial antiretroviral therapy, should the therapy be modified? If so, to what should the regimen be changed and under what circumstances?
Clinical Scenario 6
The sixth scenario describes patients tolerating zidovudine who are clinically stable (eg, CD4 sup + cell counts greater than 0.30x10 sup 9/L with no recent trend toward decline in CD4 sup + cell count).
Recommendation.--Continue zidovudine therapy.
Rationale.--No data exist that directly apply to this scenario. The clinical judgment of the panel was against recommending a change in therapy.
Clinical Scenario 7
The seventh scenario describes patients tolerating zidovudine who are clinically stable but who have evidence of further immunodeficiency (eg, CD4 sup + cell counts less than 0.30x10 sup 9/L).
Recommendation.--Two options can be supported by the results of clinical trials in this population. Panel members would recommend either switching to didanosine or continuing zidovudine.
Rationale.--Four clinical trials provide information relevant to this recommendation. Preliminary laboratory studies addressing issues of viral resistance, HIV phenotype, and different nucleoside activity in resting or replicating cells may also be relevant to treatment decisions (22).
1. Patients in ACTG 116A with 8 to 16 weeks prior zidovudine treatment who were randomized to receive didanosine showed lower rates of AIDS-defining illness than patients continued on zidovudine. However, these results pertain to a small subgroup of the study, and caution in interpreting such limited observations is warranted (R. Dolin et al, unpublished data, 1993).
2. ACTG 116B/117 was designed to determine whether didanosine was superior to zidovudine in patients with advanced HIV disease who had tolerated zidovudine for at least 16 weeks. Two dosages of didanosine (500 mg/d and 750 mg/d) were compared with continued treatment with zidovudine at 600 mg per day in patients with a median of 13.5 months of prior zidovudine treatment. Analysis showed significantly fewer new AIDS-defining events and deaths among the group receiving 500 mg per day of didanosine compared with the zidovudine group. The superiority of didanosine at 500 mg per day relative to zidovudine was independent of time on prior zidovudine treatment. No differences in survival were observed among the treatment groups (23).
3. ACTG 155 compared continued zidovudine treatment with switching to zalcitabine or to zidovudine-zalcitabine combination therapy in patients with advanced HIV disease who had tolerated at least 6 months of prior zidovudine therapy (M. Fischl et al, unpublished data, 1993). Overall analysis revealed no differences in survival or in progression to AIDS and death among the treatment groups.
Further analysis of ACTG 155 by entry CD4 sup + cell subgroups suggested a possible advantage of the zidovudine-zalcitabine combination in patients with entry CD4 sup + cell counts greater than 0.15x10 sup 9/L (M. Fischl et al, unpublished data, 1993). However, this subgroup was small (including only 15% of the progression events/deaths and 8% of the deaths in the trial), and again, caution in interpretation of these observations is warranted.
4. ACTG 119 was a small, open-label study in patients with AIDS or advanced ARC who had tolerated zidovudine for at least 48 weeks. Fifty-nine patients received zidovudine (500 to 1200 mg/d), whereas 52 received zalcitabine (2.25 mg/d). No differences were found in time to death/AIDS-defining events or in overall survival (24).
These trials provide some insight into the issue of whether to switch from zidovudine when clinically stable patients tolerating zidovudine have CD4 sup + cell counts less than 0.30x10 sup 9/L. However, patients in these studies may have had circumstances that motivated them to volunteer for randomized trials that included the possibility of being switched from continued zidovudine therapy. Thus, the study results might not truly represent the experience of a broader group of zidovudine-tolerant patients with stable disease, for whom continued zidovudine therapy might be preferred.
Panel members in favor of switching to didanosine after prolonged zidovudine treatment based their recommendation primarily on data from ACTG 116B/117. However, considerable uncertainty about the optimal interval to switch was acknowledged, since the optimal period could be as short as 2 months to well over 1 year. Those panel members in favor of continuing zidovudine treatment expressed concern whether the results from ACTG 116B/117 would translate into a clinically meaningful benefit in view of the potential for didanosine-related toxicity in patients who were currently stable.
The option of initiating combination therapy by adding didanosine or zalcita- bine to zidovudine was also considered. Few panel members recommended this option because of the current paucity of clinical efficacy and safety data.
MODIFICATION OF THERAPYIN RESPONSE TO THERAPEUTICFAILURE OR INTOLERANCE
Only limited data address whether didanosine or zalcitabine is superior as an alternative monotherapy in patients failing or intolerant to zidovudine. Protocol CPCRA (Community Programs for Clinical Research on AIDS) 002, as cited in "Clinical Scenario 8," found comparable efficacy of didanosine and zalcitabine in terms of progression of disease and a marginally significant survival benefit in favor of zalcitabine over didanosine (25,26). The majority of the panel members' recommendations regarding the choice of an alternative monotherapy were in favor of didanosine over zalcitabine, based on the greater extent of clinical familiarity.
Where combination therapy was considered to be an option, the panel could not recommend one combination over another based on current data. Patient preferences and the need to avoid serious dose-limiting toxic effects were seen as important considerations. Specific recommendations regarding modification of existing treatment regimens or initiation of alternative drugs clearly depend on the stage of HIV illness.
What are the optimal therapeutic interventions for patients who experience disease progression (therapeutic failure) on initial therapy?
Therapeutic failure in a patient with HIV disease receiving antiretroviral therapy includes clinical deterioration or other laboratory-based evidence of disease progression. Clinical deterioration would be suggested by new HIV-related events, including but not limited to progressive unexplained constitutional symptoms, such as fever, weight loss, or night sweats, or the appearance of new opportunistic infections or malignancy.
Laboratory parameters suggestive of progression would include rapidly declining CD4 sup + cell counts (or percentages) or increasing serum concentrations of HIV p24 antigen, beta sub 2 -microglobulin, or neopterin. More sophisticated assays, such as those that detect the emergence of zidovudine-resistant virus, increased quantitative viral load in serum or tissue, or certain phenotypic changes associated with more rapid progression (eg, change from non-syncytia-inducing strains to syncytia-inducing strains of HIV) may become useful in the future for detecting disease progression.
Clinical Scenario 8
The eighth scenario describes symptomatic patients with CD4 sup + cell counts between 0.05 and 0.50x10 sup 9/L who experience therapeutic failure on zidovudine therapy.
Recommendation.--Initiate alternative antiretroviral therapy.
Rationale.--The study conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA 002) compared didanosine and zalcitabine in advanced patients who failed or became intolerant to zidovudine. Overall, the study demonstrated comparable efficacy of didanosine and zalcitabine in terms of progression of disease. A survival benefit in favor of zalcitabine over didanosine was also observed (RR, 0.76; P=.07; adjusted RR, 0.62; P=.002) (25,26). However, the majority of the panel would support switching to didanosine based on clinical experience and extrapolation from ACTG 116B/117, which demonstrated delayed progression of disease in patients treated with didanosine compared with continued zidovudine, and from Bristol-Myers Squibb study 454-010, which showed delayed progression but not increased survival from switching from zidovudine to didanosine therapy (23,27).
The following studies provide information on didanosine dosing:
1. ACTG 118 (28), a didanosine dose comparison trial in patients intolerant to zidovudine, showed that 500 mg per day of didanosine in sachet form was similar in efficacy and toxicity to 200 mg per day. The highest dosage used in this trial, 750 mg per day, was associated with greater toxicity than either of the two smaller didanosine dosages.
2. The European Alpha Trial (29), which demonstrated that 200 mg per day of didanosine in sachet form had an equal effect on disease progression but less toxicity than 750 mg per day.
3. Extrapolation from ACTG 116B/117 indicated 750 mg per day of didanosine was less efficacious and more toxic than 500 mg per day (23).
Since ACTG 118 and the Alpha Trial entailed only dose comparisons of didanosine, the efficacy of didanosine relative to no antiretroviral treatment in these study populations could not be determined. An overview of the risks and benefits of various didanosine regimens tends to favor the currently approved dosage of 400 mg per day in tablet form (equivalent to 500 mg/d in the sachet formulation).
Tablets should be administered in divided doses given twice daily, with the dosage adjusted for weight (200 mg twice a day if patient weight is 60 kg or more; 125 mg twice a day if patient weight is less than 60 kg). The panel did not recommend use of lower didanosine doses based on the available data and clinical experience.
Clinical judgment might dictate use of combination therapy in some situations. Definitive data, however, are sorely lacking. To date, one large controlled study, ACTG 155, has evaluated the efficacy of combination therapy. The study showed no overall benefit from combination therapy compared with continued zidovudine therapy or switching to zalcitabine monotherapy in relatively advanced patients on zidovudine who were not experiencing clinical failure or intolerance at the time of study entry (M. Fischl et al, unpublished data, 1993). Other studies to investigate the utility of combination therapy in this and other patient populations are in progress.
Clinical Scenario 9
The ninth scenario describes individuals with CD4 sup + cell counts less than 0.05x10 sup 9/L who experience therapeutic failure on zidovudine therapy.
Recommendation.--Initiate alternative antiretroviral therapy, ie, didanosine or zalcitabine.
Rationale.--The panel recommends switching to monotherapy with didanosine or zalcitabine, over initiation of combination therapy, because of the increased incidence of serious toxicity in patients with advanced disease assigned to combination therapy in ACTG 155 and the lack of benefit of combination therapy as compared with monotherapy observed in patients with low CD4 sup + cell counts (M. Fischl et al, unpublished data, 1993).
If zalcitabine is chosen as monotherapy, the recommended dosage is 0.75 mg three times a day (which was tested in large comparative clinical trials) (M. Fischl et al, unpublished data, 1993) (24-26). For the recommended didanosine dose, see "Clinical Scenario 8."
What are the optimal interventions for patients who are intolerant to initial therapy?
Intolerance is a relative term, with clinical and laboratory manifestations, as well as subjective considerations. The frequency of untoward reactions to zidovudine is influenced by the stage of HIV disease. Late-stage patients are more likely to manifest serious or dose-limiting toxic effects than those with less-advanced HIV disease.
The primary side effects of zidovudine include clinical symptoms, such as headaches and nausea, other less-frequent conditions, such as myopathy, and hematologic disorders, such as anemia and neutropenia. Hemoglobin level persistently less than 80 to 90 g/L despite treatment with erythropoietin or frequent transfusions or neutropenia with an absolute neutrophil count persistently less than 0.50x10 sup 9/L will usually result in discontinuation of zidovudine (30). Although zidovudine-associated anemia and neutropenia may be treatable with growth factors or transfusions, current practice recommends switching to alternative regimens. Supporting data are inadequate to recommend dosages of zidovudine less than 500 mg per day.
For patients in whom zalcitabine or didanosine has been instituted as initial therapy, the major dose-limiting toxic effects include peripheral neuropathy and pancreatitis; the latter occurs less frequently as a complication of zalcitabine. Aphthous ulcers, another potential side effect of zalcitabine, can usually be treated symptomatically.
Importantly, patients' sense of well- being and satisfaction with the treatment must be taken into consideration when contemplating a change in therapy. Subjective perceptions of drug failure or intolerance may influence consistency of medication taking and are an important factor in deciding whether or not to modify an existing regimen.
Clinical Scenario 10
The 10th scenario describes asymptomatic patients with CD4 sup + cell counts greater than 0.50x10 sup 9/L who are intolerant to initial therapy with zidovudine.
Recommendation.--Discontinue antiretroviral therapy. Continue observation and clinical and laboratory monitoring every 6 months.
Rationale.--No data address this issue directly; this recommendation is based on data previously cited from the Concorde I trial and from the European-Australian Collaborative Group protocol 020, which failed to show conclusive evidence of a long-term beneficial effect of zidovudine therapy in HIV-infected patients with CD4 sup + cell counts greater than 0.50x10 sup 9/L (Medical Research Council/Association Nationale de Recherche du SIDA, unpublished data, 1993) (3,4).
Clinical Scenario 11
The 11th scenario describes stable, asymptomatic individuals with CD4 sup + cell counts between 0.05 and 0.50x10 sup 9/L who are intolerant to initial therapy with zidovudine.
Recommendation.--Initiate alternative monotherapy.
Rationale.--Refer to "Clinical Scenario 9."
This recommendation is also based on the following considerations:
1. Although ACTG 118 did not address whether didanosine is beneficial compared with no therapy, the panel felt that didanosine would likely benefit patients intolerant of zidovudine through extrapolation from ACTG 116B/117 (23,28).
2. The findings of CPCRA 002, as summarized in "Clinical Scenario 8." (25,26)
Clinical Scenario 12
The 12th scenario describes individuals with CD4 sup + cell counts less than 0.05x10 sup 9/L who are intolerant to initial therapy with zidovudine.
Recommendation.--Initiate alternative antiretroviral therapy, ie, didanosine or zalcitabine. The option of discontinuing all nucleoside therapy could be considered in this population (refer to "Clinical Scenario 9").
Rationale.--Available data do not adequately address this question. Importantly, the incidence of serious dose-limiting toxicity from nucleoside therapies is high in patients with more-advanced HIV disease. In these patients, quality of life could increase with discontinuation of nucleoside therapy; however, HIV titers might also escalate. Close monitoring of clinical status remains important in this group of patients regardless of the therapeutic option chosen.
COMMENT
Several critical issues for further consideration were identified by the panel. These included the application of CD4 sup + cell counts in clinical practice, issues in clinical trials design and statistical inference, discontinuation of nucleoside therapy in patients with very advanced illness, and clinical implications of HIV resistance to nucleoside therapy.
Role of Monitoring CD4 sup + Cell Counts in Clinical Practice
The CD4 sup + cell ranges chosen to illustrate the clinical scenarios are a means of identifying general clinical situations faced by HIV-infected patients and their clinicians. Although the trials reviewed were not designed to assess the prognostic role of CD4 sup + cell counts in selecting therapeutic options, the panel recommends serial monitoring of CD4 sup + cell counts, in conjunction with assessment of other clinical and laboratory evidence, as a measure of the degree of immune system deterioration and associated risk of opportunistic disease. Serial CD4 sup + cell counts provide the clinician with information on the rate as well as the magnitude of immunologic decline in HIV-infected individuals. Overall trends in CD4 sup + cell levels, more than single measurements, are viewed by the panel as an important factor in the therapeutic decision-making process in HIV infection.
Clinical Trials Design andStatistical Inference
The panel noted that most of the studies were designed to answer questions about comparative clinical safety and efficacy in certain specific clinical scenarios and that, for other clinical scenarios, study data were not available to answer questions about optimal treatment strategies. The panel thus had to extrapolate from the available data and to apply clinical judgment in reaching its recommendations. The panel would also have preferred further clinical follow-up and survival data from some of the studies reviewed.
Furthermore, the trials tended to enroll relatively uniform study groups, which was felt by some panel members to limit the generalizability of findings to other segments of the HIV-infected population. HIV-infected women, injection drug users, and racial and ethnic minorities were underrepresented in several studies. Panel members commented on the need for further data on drug safety, efficacy, and pharmacokinetics in these specific patient groups.
In making its recommendations, the panel focused chiefly on conclusions drawn from primary study analyses. In the course of deliberation, the relative meaning and limitations of subset analyses were explored. Subset analyses were seen as sometimes helpful for clarifying the overall data and as a means of identifying areas for further investigation. Inferences gleaned from such analyses, however, were viewed with particular caution due to their unreliable nature and were thought not to take precedence over those inferences supported by the primary analysis.
In extrapolating findings from research trials to clinical practice, the panel noted that no "average" patient exists. Experience clearly indicates that individual patients respond differently to nucleoside therapy. This document has attempted to identify common clinical scenarios and present the relevant data and interpretation of those data by this panel. We acknowledge that existing data are inadequate to allow further individualization of treatment at this time. In addition, clinicians and patients have no consistent prognostic factor on which to rely for decision making. Factors that may increase our ability to predict clinical outcomes in the future include several virological measures, such as HIV phenotype for syncytial induction and HIV nucleoside resistance mutation assays.
In some situations, the panel's sense of the weight of scientific evidence was not strong enough to translate into firm recommendations for clinical practice. Such situations emphasize the need for confirmatory trials that answer important questions about clinical effectiveness and the risk-benefit profiles of the nucleoside therapies. The long-term benefits of the available agents are clearly limited. Thus, the risks of toxic effects, quality-of-life considerations, and patients' evaluations of such issues must be weighed in decisions about the use of nucleoside therapy.
Discontinuation of Therapyin Advanced HIV Infection
The decision to stop antiretroviral therapy in advanced HIV disease is difficult because no study findings directly pertain. Some studies indicate viral load increases in a matter of days after discontinuation of nucleoside therapy, whereas others show a greatly increased risk of serious toxicity from antiretroviral therapy in patients with advanced HIV disease. In this situation, patients and clinicians must weigh the possible risks and benefits to maximize patient use of all indicated medications, including appropriate prophylaxis for opportunistic infections.
Clinical Significanceof HIV Resistance
The mechanism of HIV resistance to nucleoside therapies and the relation of such to clinical outcome remains to be fully elucidated. In ACTG 116B/117, zidovudine resistance was one of several factors that predicted failure of therapy (31). If the principal cause of nucleoside therapy failure is related to resistance, better correlation between clinical progression and resistance will need to be demonstrated in further studies. Early data using two drugs in vitro do not indicate whether combination will substantially slow or prevent the development of HIV resistance to nucleoside therapy. It is increasingly clear that direct measurements of viral activity and load will be necessary to assess the microbiological effects of anti-HIV therapies. The Panel recognizes that other antiretroviral therapies are now undergoing evaluation in preclinical and clinical trials and may eventually show therapeutic profiles superior to zidovudine, didanosine, or zalcitabine.
CONCLUSIONS
Treatment of HIV infection and disease requires all the skills of the primary care physician. Available antiretroviral nucleoside therapies have a role in the treatment of HIV infection, but the benefits of such treatment are unfortunately limited. Early intervention for HIV disease does not necessarily imply early drug treatment, and physicians need to integrate up-to-date scientific knowledge with other relevant needs to improve patient care. Management of overall health status, counseling to reduce risk behaviors, provision of psychosocial support, assessment of quality-of-life issues, and prevention of opportunistic infections all are in the domain of the clinician-patient relationship. The primary care provider has a responsibility to assess available support systems, to assure appropriate integration into the health care system, and to provide early diagnosis, immunizations, opportunistic infection prophylaxis, and treatment. The HIV epidemic reminds practitioners that t!
he finest expression of medicine lies in the optimal blend of science and the art of patient care.
This article was sponsored by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Public Health Service.
Members of the State-of-the-Art Panel include the following: Merle A. Sande, MD, University of California, San Francisco; Charles C. J. Carpenter, MD, Brown University, Providence, RI; C. Glenn Cobbs, MD, Veterans Affairs Medical Center, Birmingham, Ala; Robert W. Coombs, MD, PhD, Thomas R. Fleming, PhD, and King K. Holmes, MD, PhD, University of Washington, Seattle; Rebecca Denison, Women Organized to Respond to Life-Threatening Diseases, Oakland, Calif;; Mitchell H. Gail, MD, PhD, National Cancer Institute, Rockville, Md; Wayne Lamar Greaves, MD, Howard University, Washington, DC; Martin S. Hirsch, MD, Harvard University, Boston, Mass; Roberta Luskin-Hawk, MD, Saint Joseph Hospital & Health Care Center, Chicago, Ill; Donna Mildvan, MD, Beth Israel Medical Center, New York, NY; Charles A. Nelson, ACTG Community Constituency Group, Atlanta, Ga; John P. Phair, MD, Northwestern University, Chicago, Ill; Jay P. Sanford, MD, University of Texas, Dallas; Robert Schooley, MD, Un! iversity of Colorado, Denver; R. Gabriel Torres, MD, New York (NY) Medical College; and Robert Vazquez, Minority Task Force on AIDS, New York, NY. Members of the Division of AIDS, National Institute of Allergy and Infectious Diseases Planning Committee include the following: Lawrence Deyton, MSPH, MD, Community Clinical Research Branch; John Jermano, RN, MPH, Juanita Koziol, RN, MS, CS, and Carla Pettinelli, MD, PhD, Medical Branch; and Debbie Katz, RN, MS, Office of the Director.
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