Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Combination Therapy Gavin X. McLeod & Scott M. Hammer To cite this article: Gavin X. McLeod & Scott M. Hammer (1992) Combination Therapy, Hospital Practice, 27:sup2, 14-25, DOI: 10.1080/21548331.1992.11705596 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705596
Published online: 17 May 2016.
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Date: 05 June 2016, At: 00:51
Nucleoside Analogues:
Combination Therapy
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GAVIN X. McLEOD
and SCOTT M. HAMMER
Harvard University
Combination antiretroviral therapy is an important development in the management of HIV infection. AZT with ddC is the first such combination to be approved for clinical use. Several issues remain, however, including the precise clinical benefit and toxicity of combination therapy, its effect on drug resistance, and the development of ever more effective therapeutic strategies.
Antiretroviral therapy improves the quality oflife and survival of patients infected with the human immunodeficiency virus (HIV) type 1. Zidovudine (AZT, azidothymidine), the first antiretroviral nucleoside analogue approved by the Food and DrugAdministration, prolongs the lives of patients with acquired immunodeficiency syndrome, advanced AIDS-related complex (ARC), and those who have CD4 lymphocyte counts less than 350 cells/mm 3 .1. 2 This agent also delays the onset of AIDS in HIVinfected patients whose CD4 lymphocyte counts are below 500 cells/mm3 . 3 ·4 AZT has limitations, however, in that patients receiving therapy have inexorable disease progression, as manifested by the development of opportunistic infections, weight loss. malignancies, and/or neurologic abnor-
Or. Mcleod is Clinical and Research Fellow, Harvard Medical School and Division of Infectious Diseases, New England Deaconess Hospital, Boston. Dr. Hammer is Associate Professor of Medicine, Harvard Medical School, and Director, Research Virology Laboratory, New England Deaconess Hospital.
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mali ties. 5 The CD4 lymphocyte count, the surrogate marker most commonly followed in HIV infection, typically increases by 40 to 100 cells/mm3 within the frrst few months after AZT therapy is begun. 6 · 7 After four to six months of therapy, however, the CD4 count usually returns to pretherapy levels and continues to decline thereafter. In addition, as many as one third of patients with AIDS cannot tolerate AZT because of its toxicity. Thus, didanosine (ddl, dideoxyinosine) was approved in 1991 for patients with advanced HIV infection who are intolerant to or unresponsive to AZT. Clinical trials of ddl have demonstrated that the increase in CD4 lymphocyte counts is similar to that seen with AZT in terms of elevation and persistence. 8 ·IO A third nucleoside analogue, zalcitabine (ddC, dideoxycytidine), has been available through expanded-access programs and clinical trials as an alternative to or in combination \vith AZT. It was recently approved for the latter indication. Monotherapy with any of these three agents provides limited benefits; therefore, attention has
turned to combination therapy. Combination therapy is accepted practice in the treatment of cancer, tuberculosis, and certain bacterial infections such as enterococcal endocarditis. As in these diseases, combination therapy in HIV-infected patients may be advantageous for anumber of reasons. First, combination therapy may inhibit the virus more effectively by acting at more than one site or by acting additively or synergistically at a single site. Second, certain agents in the regimen may be more effective in particular tissues and cell populations. A combination of drugs that is active in lymphocytes and cells of monocyte/ macrophage lineage, as well as effective in crossing the blood-brain barrier, would appear to be the most efficacious for HIV infection. Third, combination therapy may allow reduced or alternating doses of each drug. thereby lessening the toxicity associated with the nucleoside analogues. Finally, recent reports of drug resistance lend support to the concept of combining therapies to delay or possibly prevent its development. Of the antiretroviral agents in clinical use or under investiga-
tion, combinations of the dideoxynucleosides are currently the regimens With the most immediate promise because of the degree of development of the individual agents and the accruing experimental data supporting their use. Since progression of HIV infection is only delayed by monotherapy, combining two or more drugs may prove beneficial in further sloWing the disease and in prolonging life.
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In Vitro Studies A number of in vitro studies have provided evidence that multiple drug therapy is superior to monotherapy. As AZT has been the mainstay of antiretroviral therapy, most studies have compared AZT alone With AZT plus one or more other agents. When two drugs are combined in vitro, the resulting effect on HIV replication may be additive (or indifferent), synergistic, or antagonistic. In vitro analysis is important because antagonistic effects may yield undesirable clinical results. For example, the combination of AZT and ribavirin is antagonistic because
Figure 1. Schematic depicts the chemical structures (A) of the nucleoside analogues (deoxynucleoside triphosphates) and their mechanism of inhibition of the physiologic deoxynucleoside triphosphates (B-D). These agents block human immunodeficiency virus replication by competitively inhibiting the deoxynucleoside triphosphates and terminating the HIV proviral DNA chain when incorporated by HIV reverse transcriptase. Azidothymidine triphosphate (AZT-TP) competes with deoxythymidine triphosphate (dTTP), dideoxycytidine triphosphate (ddC-TP) competes with deoxycytidine triphosphate (dCTP), and dideoxyinosine (ddl, not shown) is converted to dideoxyadenosine triphosphate (ddA-TP), which competes with deoxyadenosine triphosphate (dATP).
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the phosphorylation of AZT is inhibited. AZT and the other dideoxynucleosides inhibit the reverse transcriptase of HIV by directly competing with the incorporation of the respective normal nucleoside triphosphates into the growing viral DNA, thus terminating the proviral DNA chain. Each of the three dideoxynucleosides under discussion compete with a different nucleoside triphosphate: AZT with deoxythymidine triphosphate, ddl with deoxyadenosine triphosphate, and ddC with deoxycytidine triphosphate (see Figure 1 ). Combining dideoxynucleosides produces competitive inhibition of more than one nucleoside triphosphate, which results in additive or synergistic inhibition of the reverse transcriptase. In vitro studies have demonstrated that this antiretroviral effect occurs with a combination of dideoxynucleosides in simultaneous and alternating regimens. Using a transformed T-cellline (MT4). peripheral blood lymphocytes, and macrophages, R. E. Dornsife and colleagues showed that the simultaneous combination of AZT and ddl synergistically inhibited HIVm 8 in all cell types. 11 In addition, these investigators demonstrated that ddl did not enhance AZT's toxicity against normal human bone marrow progenitor cells. In studies by V. A. Johnson and co-workers, 12 combined AZT and ddl was synergistic even against AZT-resistant isolates, which suggests that when patients develop resistance to AZT, a combination regimen that includes AZT may still be beneficial in inhibiting Hiv. The continued benefit of AZT is thought to be related to the heterotypic HIV species in infected patients. HIV has a high rate of mutation, and 16
a number of subspecies of a particular viral strain can exist in a patient at one time. With exposure to AZT or other drugs, some of these species develop one or more mutations that may mediate resistance. However, other species that remain susceptible to AZT theoretically may still be present. The combination of AZT and ddC has also been shown to be effective. M. Baba and colleagues used the MT4 cell line to demonstrate an additive-to-synergistic effect by monitoring cytopathic activity. 13 And, using the transformed T-cell line CEM, S. A. Spector and co-workers found that inhibition of HIV replication was more prolonged with the alternating regimen of AZT and ddC compared with continual exposure to AZT. 14 The inhibition was measured by both HIV p24 antigen in the culture supernatant and unintegrated proviral DNA in CEM cells. J. J. Eron and colleagues have also recently demonstrated that combining AZT and ddC can synergistically inhibit both an AZT-sensitive and an AZT-resistant isolate. 15 In vitro, AZT in combination with a number of other compounds has been found to provide an additive or synergistic effect. These compounds include acyclovir, recombinant soluble CD4, dextran sulfate, recombinant a-interferon, and non-nucleoside reverse transcriptase inhibitors such as foscarnet, nevirapine, and pyridine derivatives. However, as noted above, caution is needed when using combination therapies, because ofthe antagonism between certain compounds. Antagonism has been reported not only with AZT and ribavirin, but also with ddC and ribavirin and with dextran sulfate and recombinant soluble CD4. 16
Resistance Combination therapy may delay or prevent the development of HIV drug resistance. During the six years that dideoxynucleoside agents have been used therapeutically, multiple reports of in vitro resistance to AZT. ddl, and ddC have appeared. B. A. Larder and co-workers 17 first reported the development of resistance to AZT in 1989. Using an in vitro assay system of HeLa CD4 cells, these investigators found a more than 100-fold decrease in AZT susceptibilities between certain pre- and posttherapy isolates. In a subsequent analysis of these and other isolates, development of AZT resistance has been correlated most often with five mutations in the reverse transcriptase. 18 · 19 These mutations occur at amino acid residues 41 (Met-> Leu), 67 (Asp-> Asn), 70 (Lys -> Arg), 215 (Thr -> Tyr or Phe). and 219 (Lys -> Gln), in an area of the reverse transcriptase that is responsible for nucleoside triphosphate binding (see Figure 2). In experiments employing site-directed mutagenesis of molecular clones, the degree of resistance has been shown to correlate with the number of mutations present. P. Kellam and associates have shown that the mutations occur in an ordered fashion, with those at 41, 70, and 215 being the most critical. 19 Resistance to AZT has been reported to occur more frequently in patients with AIDS or severe ARC, with partial or complete resistance common after six months of therapy. 20 Patients who are asymptomatic and have CD4 counts greater than 200 cells/mm3 appear to develop AZT resistance less frequently and to a lesser degree than patients with AIDS or advanced ARC.
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Resistance to ddl has now been reported by several groups, 21 -23 but it is much less pronounced than that reported with AZT. Depending on the assay system used, the decrease in susceptibility ranges from two- to 30-fold. Resistance to ddl has been associated with a single mutation at amino acid residue 7 4 (Leu - > Val) in the viral reverse transcriptase. Interestingly, the use of site-directed mutagenesis in molecular clones has revealed that this mutation confers not only decreased susceptibility to both ddi and ddC but increased susceptibility to AZT when one of the mutations associated with AZT resistance (amino acid residue 215) is present. Most recently, ddC resistance also has been reported to be associated with a mutation at amino acid residue 69 (Thr -> Asp). This mutation was shown to be associated with a fivefold decrease in ddC susceptibility in experiments using site-directed mutagenesis of a molecular clone and a plaque reduction sensitivity assay. 24 The clinical significance of resistance to the nucleoside analogues is still being investigated, but two reports have linked resistance to a poor clinical outcome. The Multicentre Canadian AZT Trial25 reported that patients with CD4 counts above 270 cells/mm3 had a greater likelihood of progression to AIDS if their isolates were AZT resistant. A recently published report by G. Tudor-Williams and colleagues26 analyzed results obtained in 23 children who had been receiving AZT monotherapy for nine to 39 months. In vitro resistance testing was performed on isolates from 19 subjects. Children who had deteriorated clinically or died had higher median 50% inhibitory concentrations (IC 50 ) than those
who remained stable (3.5 vs 0.57 ,uM). Eight of the 10 children whose isolates had an IC 50 greater than 2.0 ,uM deteriorated, whereas all nine children who remained stable had IC50 values below 2.0 ,uM. Both of these studies correlated viral resistance with disease progression, but neither proved that development of resistance is the primary factor that leads to a worse outcome. The increasing viral load associated with ad-
vanced HIV infection may increase the likelihood of drug-resistant mutations emerging in patients receiving therapy. The AIDS Clinical Trials Group (ACTG) recently released a preliminary analysis of ACTG 1168/117, a phase II/III trial designed to compare the efficacy and toxicityofmonotherapywith AZT or ddl in patients who had tolerated more than 16 weeks of AZT. Patients were entered into the study if they had AIDS or
Figure 2. Various mutations in human immunodeficiency virus reverse transcriptase are responsible for resistance to the nucleoside analogues. AZT(zidovudine) resistance is associated with the presence of one or more of five mutations (41, 67, 70,215, and 219) with 41, 70, and 215 being most important. Resistance to ddl (didanosine) is associated with a mutation at amino acid residue 74 in patients with the AZT-resistance mutation at position 215. Resistance to ddC (zalcitabine) is associated with mutations at position 69 or 74.
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ARC and CD4 counts less than 300 cells/mm 3 or if they were asymptomatic and had CD4 counts less than 200 cells/mm3 . The patients were then randomized to one of three treatment arms: AZT (600 mgtday), ddl (500 mgtday). or ddl (750 mgt day). Patients randomized to ddl at 500 mgtday had a statistically significant delay in the time to a new AIDS-defining event compared with the AZT group (oneyear rates: 28% vs 40%). No statistically significant difference in disease progression was noted between the group receiving ddl at 750 mgtday and that receiving AZT, but both ddl groups had a slight increase in CD4 cells (median, 10 cells/mm 3 ) compared with the AZT group. This preliminary report suggests that in patients with more advanced HIV infection, a change to monotherapy with ddl is beneficial after four months of AZT. Full analysis ofthese data and their implications is pending, but it is possible that AZT resistance may help explain these fmdings.
Toxicities Combination therapy may result in less overall drug toxicity in HlV-infected patients. The toxicities ofthe dideoxynucleoside agents are substantial. The primary toxicities of AZT (anemia, neutropenia, and myopathy) do not overlap with those of ddl and ddC (pancreatitis and peripheral sensory neuropathy). Because the toxicities of ddl and ddC are similar, combining these agents appears to have limited value. Consequently, most clinical trials involve the combination of AZT and ddl or AZT and ddC. Combination therapy can be given in alternating or concurrent regimens. As many of the side effects of the dideoxynucleo18
sides are dependent on dose and duration of therapy, alternating regimens could reduce toxicity while allowing full dosages of each drug to be given in alternating periods of one to six weeks. The peripheral neuropathy associated with ddC usually appears only after six weeks of therapy, thus accounting for the upper limit of cycling therapy. Concurrent therapy might provide more total antiretroviral treatment over time than alternating regimens, but toxicity might be greater; this issue will be resolved only through controlled clinical trials. In the five years since AZT was approved for clinical use, it has been determined that in both asymptomatic persons and patients with AIDS, a lower dose (500 to 600 mgtday), with reduced toxicity, is as effective as the higher dosage ( 1,200 to 1,500 mgtday) initially employed. It is to be hoped that the combination oflower-dose AZT and ddl or ddC at reduced dosages will improve clinical efficacy while reducing side effects.
Clinical Trials Published information on combination dideoxynucleoside therapy in the treatment of HIV infection is currently limited to phase 1/11 studies, although phase 11/111 studies are under way. The initial report of alternating AZT and ddC therapy by R. Yarchoan and co-workers 27 included six patients who were given 200 mg of AZT every four hours ( 1,200 mgtday) for one week, alternating with 0.03 mglkg of ddC every four hours (0.18 mgtkgtday) for a week. The patients, all of whom had AIDS or ARC, were (with one exception) maintained on this regimen for nine or more weeks.
One AIDS patient was taken off the regimen in the second week because of neutropenia and disseminated Mycobacterium avium-intracellulare infection. The other five received at least nine weeks of therapy; one patient stopped at nine weeks because of ddC-associated arthralgias during the sixth and eighth weeks. The four remaining patients received up to 28 weeks of therapy, and only one experienced peripheral sensory neuropathy (he had received ddC in a previous phase I trial). None of these five patients developed hematologic toxicity. The mean increase in CD4 counts was 48 cells/mm3 at nip.e weeks. Three patients who had serum HIV p24 antigenemia at study entry had decreases in this quantitative viral measurement, with two becoming antigen negative. This small trial of alternating AZT and ddC therapy was the first to point to the potential benefits of combination regimens. 1\vo ACTG studies have investigated weekly and monthly alternating regimens of AZT and ddC. In ACTG 04 7 and ACTG 050, 2 8· 29 the protocols were identical except that the first study had an AZT mono therapy arm, and patients enrolled in the second study had had hematologic toxicity with AZT and had lower CD4 counts at entry. The study dosages of AZT (1,200 mg.'day) and ddC (0.06 and 0.18 mgtkgtday) were two to six times higher than those currently recommended. Less toxicity was seen with the alternating regimens than occurs with continuous monotherapy using either drug. Patients had increased CD4 cell counts and decreased HlV p24 antigenemia while on the alternating regimen. An important phase 1/11 study, ACTG 106, reported recently by T.-C. Meng and colleagues, 30
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evaluated the safety and efficacy of concurrentAZT and ddC therapy in 56 patients with advanced HIV infection. All patients had been diagnosed with AIDS or advanced ARC and had CD4 counts ofless than 200 cells/mm3 • Patients were excluded from this study for severe anemia (hemoglobin < 10 gm/dl}, neutropenia (neutrophil count < 1,200/mm3 }, thrombocytopenia (platelet count< 100,000/mm3 }, renal insufficiency (creatinine clearance > 1.24 ml/sec), hepatitis (serum transaminases >3x upper limit of normal), history of previous peripheral neuropathy, pregnancy, or symptomatic visceral or rapidly progressing Kaposi's sarcoma. All study patients received aerosolized pentamidine (300 mg every four weeks) to prevent Pneumocystis cartnii pneumonia. The study-openlabel and dose-ranging-had six treatment arms: 1) AZT (300 mglday) and ddC (0.015
rnglkglday}; 2) AZT (600 rnglday) and ddC (0.015 mg/kgl day); 3) AZT ( 150 mglday) and ddC (0.015 mg/kglday); 4) AZT (300 mglday) and ddC (0.03 rnglkglday); 5)AZT (600 rnglday) and ddC (0.03 mg/kglday); and 6) AZT alone ( 150 mglday). At least eight patients were assigned to each regimen. Median follow-up was 40 weeks, and 48 patients completing at least 10 weeks of therapy. The pharmacokinetics of both drugs were not altered in eight patients studied. Concurrent therapy was well tolerated, and toxicity was limited. There were no significant differences among the six regimens with regard to drug toxicity. Ten patients (18%) developed hematologic toxicity, two of whom had to stop therapy. 1\vo patients developed severe paresthesias consistent with ddC neuropathy, which also required removal from the study. Most important, this study
Figure 3. Shown here are the effects of different dosing
regimens of combined therapy with AZr (zidowdine) and ddC (zalcitabine) in ACTG 106, an open-label phase 1/11 study of 56 patients with advanced HIV infection (CD4 lymphocyte counts less than 200 cells/mm:l). CD4 counts
demonstrated improved antiretroviral activity among patients treated with combination therapy as documented by improvements in weight, CD4lymphocyte counts, and HIV p24 antigenemia. Patients on each regimen had increased CD4 counts (see Figure 3). There were no statistical differences among the regimens, although the increase in CD4 counts with AZT monotherapy (regimen 6) was the smallest and the rate of decline was greatest. When a positive CD4 count response was defined as an increase of 50 cells/mm3 for two consecutive months, 25 of the 36 (69%) patients receiving AZT at a dosage of 300 or 600 mglday in combination with ddC responded. The patients who received the highest dosages of AZT (600 mglday) and ddC (0.03 mg/kgl day) had the greatest proportion of responders (seven of eight patients, 88%). This regimen also produced statistically significant
increased In all patients, but combination therapy at any dose was clearly superior to AZr monotherapy (left). Similarly, the percentages of patients who sustained CD4 counts higher than baseline were greater with combination therapy (right). (Adapted from Meng T-C30)
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decreases in serum HIV p24 antigen levels when compared with the other five regimens. Serum HIV p24 antigen levels decreased in all regimens except for regimen 6 (AZT alone). The increase in CD4 cells associated with combination therapy was superior and was sustained for a longer period than in previous controlled trials of AZT as monotherapy. Such comparisons must, of course, be made cautiously. Furthermore, the control arm of AZT monotheraPY in Meng's study used a lower dosage of AZT ( 150 mgtday) than in previous phase II/III studies and, interestingly, was found to be substandard. However, this phase I/11 study did provide important information showing that combination therapy with AZT and ddC was well tolerated and that toxicities were not more apparent than with either drug alone. Improvements in body weight, CD4 counts, and HIV p24 antigenemia seen with the higher-dosage regimens in ACTG 106 were among the data that led the FDA Antiviral Advisory Committee to recommend approval of ddC for use in combination with AZT. Other information that led to ddC's approval included an interim analysis of an ongoing randomized, double-blind phase II/III study sponsored by Burroughs Wellcome Co. (BW #34,225-02). This study includes patients with HIV infection who have had four weeks or less of prior therapy with AZT and CD4 counts of 300 cells/mm 3 or less. At the time of the interim analysis, 45 patients had received concurrent therapy with ddC (2.25 mg/day) and AZT (600 mg/day), and 47 had received AZT monotherapy (600 mg/day). Combination treatment produced a greater and more sus20
tained increase in CD4 counts than did AZT monotherapy. The mean peak increase in CD4 counts at eight weeks was 94 cells/mm 3 in the combination therapy group compared with an increase of 53 cells/mm 3 at 12 weeks in the AZT monotherapy group (see Figure 4). In addition, the mean CD4 count remained higher than baseline throughout the initial24-week period among patients receiving combination therapy. In contrast, the cell count approached baseline at 24 weeks among those receiving AZT monotherapy. The efficacy of combination therapy with AZT and ddC in patients who have received prior AZT therapy is still uncertain and may be revealed in ongoing studies such as ACTG 155. This phase II/III trial includes symptomatic patients with CD4 counts less than 300 cells/mm3 and asymptomatic persons with CD4 counts less than 200 cells/mm 3 . All 1,001 patients who entered this trial had at least. six months of prior AZT therapy. The study is comparing AZT monotherapy (600 mg/day), ddC monotherapy (2.25 mgtday), and combined AZT (600 mgtday) and ddC (2.25 mgtday). A phase I trial of combined AZT and ddi 31 was presented at the Seventh International Conference on AIDS in 1991. This study by A. C. Collier and coworkers was similar to the sixregimen study of AZT and ddC by Meng and co-workers. The study arms were 1) AZT ( 150 mg/day) and ddl (90 mg/day); 2) AZT (300 mg/day) and ddi (334 mg/day); 3) AZT (600 mg/day) and ddi (334 mg/day); 4) AZT (300 mg/day) and ddl (500 mg/day); 5) AZT (600 mg/day) and ddi (500 mg/day); and 6) AZT alone (600 mg/day). Fifty-five patients with CD4 counts less than 400 cells/mm3
and fewer than 120 days of prior AZT therapy were enrolled, and 37 patients completed at least 24 weeks of therapy. Seven patients withdrew voluntarily because of mild side effects, including headache, nausea, and disorientation, and nine patients required dose modifications. Toxicities included five cases of mild peripheral neuropathy, one of anemia, and two of transient liver function abnormalities. The pharmacokinetics of either drug were not altered by combination therapy. Although only preliminary data are available, all six regimens produced increases in CD4 counts within the first 12 weeks of treatment. Only the regimens containing AZT at a dose of 600 mg/day were associated with CD4 increases between 12 and 24 weeks. Thus, this initial phase I trial of AZT and ddi appears promising, but the results of ongoing studies are necessary to compare this regimen with AZTandddC.
Ongoing Studies In addition to ACTG 155 and the Burroughs Wellcome study, other studies comparing combination therapy with AZT and either ddi or ddC are currently under way. ACTG 143 is a phase I/II open-label study that has enrolled 126 asymptomatic HIV-infected patients. Subjects have been stratified according to prior AZT use and then enrolled in one of four treatment arms: AZT ( 150 mg/day) and ddi ( 134 mg/day); AZT (300 mg/day) and ddi (334 mg/day); AZT (600 mg/day) and ddi (500 mg/day); or ddi monotherapy (500 mg/day). ACTG 175 is a phase II/III, randomized, double-blind trial that includes patients with early HIV infection and CD4 counts between 200 and 500 cells/mm3 . The study has four
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arms: AZT monotherapy (600 mgtday); ddi monotherapy (400 mgtday); AZT (600 mgtday) plus ddi (400 mgtday); and AZT (600 mgtday) plus ddC (2.25 mgtday). This multicenter study has a target enrollment of 2,100 patients. The European Delta trial is a phase II/III, randomized, doubleblind study of 2,500 patients with CD4 counts between 50 and 350 cells/mm 3. The trial has three arms: AZT monotherapy (600 mgtday); AZT (600 mgtday) plus ddi (400 mgtday); and AZT (600 mgtday) plus ddC (2.25 mgtday). The Community Program Clinical Research Association (CPCRA) trial 007 is also a threearm study (AZT alone, AZT plus ddi, and AZT plus ddC) with a projected enrollment of 1,200 patients with CD4 counts less than 200 cells/mm3. When the results of these trials become available, the efficacy of combination therapy will be more fully appreciated, making possible more definitive recommendations regarding anti-HIV therapy at both early and advanced stages of infection.
and a-interferon include a reduction in HIV p24 antigen levels and a possible reduction in recoverable HIV from peripheral blood culture. However, this combination induces lymphopenia, and none of the five studies reported to date has detected an increase in CD4 lymphocytes. In addition, it does not appear to have an effect on survival. perhaps because of the small number of patients and the limited follow-up. Combination AZT and acyclovir has been investigated in five separate studies, with no definitive evidence that thecombinationismoreeffective than AZT alone. 37·41 The results of ACTG 063, which also explores this combination, are pending.
CombiningAZT and cytokines to reduce hematologic toxicities is also beneficial. Granulocytemacrophage colony-stimulating factor (GM-CSF). granulocyte colony-stimulating factor (GCSF), and recombinant erythropoietin all successfully reduce the hematologic toxicity (either neutropenia or anemia) associated with AZT. 42·44 Recombinant human erythropoietin significantly decreased transfusion requirements in AIDS patients whose endogenous erythropoietin levels were less than 500 IU/ml at the time they began receiving AZT. Both GM-CSF and G-CSF reduce the incidence of neutropenia caused by AZT, but G-CSF appears to be better tolerated.
Non-nucleoside Agents In addition to intensive study of dideoxynucleoside combinations, investigators are looking at combinations of a dideoxynucleoside and a drug from another class. AZT and a-interferon, for example, have been administered concomitantly, especially in patients with Kaposi's sarcoma. 32·36 Although this combination may result in significant hematologic toxicity, improvement in Kaposi's lesions were evident in 45% of patients whoreceived a-interferon at dosages lower than those needed to obtain a similar response when the agent is used alone. The antiretroviral effects of combined AZT
Figure 4. Shown here are some of the data that led the FDA to approve ddC (zalcitabine) for use in combination with AZT (zidovudine). Study 1 (Burroughs Wellcome trial 34,225-02) is a randomized, double-blind trial of 92 HIV.infected patients with baseline CD4 lymphocyte counts of 300 cells/mm3 or less. A mean peak increase of 94 cells/mm 3 was seen at week 8 with combined therapy (45 patients) and of 53 cells/mm3 at week 12 with AZT monotherapy (47 patients). In ACTG 106 (Study 2) combined therapy in 36 patients with baseline CD4 counts of less than 200 cells/mm 3 was associated with a mean peak increase of 97 cells/mm 3 at week 4. Results from ACTG 114 (Study 3), involving 262 patients who received AZT monotherapy, are shown for comparison purposes.
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Figure 5. Guidelines for Antiretroviral Therapy in Patients with Advanced HIV Infection HIV Seropositive CD4 Count 200-300 cells/mm3
J..
t
'¥
AZT (600 mglday) + ddC (2.25 mglday)
AZT (500-600 mglday) (see Figure 6)
..v Follow up monthly
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~
w
~~
Stability or Improvement
Intolerance or Toxicity
Clinical Deterioration or Steady Decline in CD4 Count
-.v
-.v
-.v
CD4 count every 3 months
Stop implicated drug Resume at lower dose when symptom/toxicity resolves
ddl* or ALI+ + ddl* or experimental therapy, such as non-nucleoside agents, tat inhibitors, protease inhibitors
-.v Recurrent Intolerance or Toxicity
-.v Depending on Toxicity: AZT (500-600 mglday) or ddl* or Azrt + ddl* or experimental therapy or add G-CSF or GM-CSF or erythropoietin
• > 75 kg=600 mglday; 50-74 kg=400 mglday; 35-49 kg=250 mglday
t 600 mglday G-CSF=granulocyte colony-stimulating factor GM-CSF=granulocyte-macrophage colony-stimulating factor NOTE: AZT +ddl is still considered experimental therapy.
Recommendations for Antiretroviral Therapy Six years ago, the only therapeutic option for patients with HN infection was AZT; today, the choices facing the primary care physician are complex. AZT clearly has benefit for the primary treatment of patients, but over time, the loss of efficacy and de22
velopment of toxicity limit its usefulness. The recent approval of ddl and ddC presents options that can be considered at various disease stages. The therapeutic options available to the individual patient can be evaluated best within the context of the present and past CD4 lymphocyte counts and clinical parameters, prior antiretroviral
therapy, and previous toxicity from that therapy. Candidates for antiretroviral therapy may be assigned to two groups: patients with CD4 counts less than 200 cells/mm3 (i.e., advanced infection), and patients with CD4 counts between 200 and 500 cells/mm3 (i.e., early infection). Antiretroviral therapy currently is not considered necessary in patients whose CD4 counts are greater than 500 cells/mm3 , although studies are exploring its possible benefit at this stage of disease. Patients who present with CD4 counts less than 200 cells/mm3 should be started on antiretroviral therapy immediately after routine physical and laboratory examinations reveal no contraindications such as severe anemia or current infection (see Figure 5). The therapy of choice is AZT monotherapy (500 to 600 mgtday) or combination therapy with AZT (600 mgtday) and ddC (2.25 mgtday). The FDA Antiviral Advisory Committee that recommended approval of ddC for use as combination therapy with AZT included in its criteria patients with CD4 counts less than 300 cells/mm 3 and significant clinical or immunologic decline. However, the strongest data on combination therapy come from ACTG 106, which included only patients with CD4 counts less than 200 cells/mm3 . Thus, the available data support combination therapy in patients with asymptomatic or symptomatic HIV infection and CD4 counts less than 200 cells/mm3 • For patients with counts between 200 and 300 cells/mm3 , the degree of symptomatic disease can be used to determine whether initial therapy with combined AZT and ddC might be preferable to AZT alone. Patients should be monitored once a month for taxi-
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city and intolerance to the drugs. If toxicity develops, the clinician should stop the implicated drug and resume therapy at a lower dose once the side effect resolves. If recurrent toxicity develops, alternatives include monotherapy with AZT or ddl, or the yet unproven combination of AZTandddl. At present, treatment guidelines are less clear-cut for patients whose CD4 counts are between 200 and 500 cells/mm3 (see Figure 6). In this group, the risk of toxicity from early combination therapy could outweigh its benefits. The Veterans Affairs Cooperative Study 298 45 revealed no survival benefit for early symptomatic patients treated with high-dose AZT monotherapy. However, the recent observational study by the Multicenter AIDS Cohort Study Group 2 noted a survival benefit with AZT in patients with CD4
counts less than 350 cells/mm3 . Patients whose CD4 counts are between 200 and 500 cells/mm3 have the option of enteringACTG 175 (see page 20) ifitis available in their community. In the event that the ACTG trial is not available and the patient has notreceived prior antiretroviral therapy, the appropriate choice of initial therapy would be AZT at 500 to 600 mg/day as currently recommended by the National Institute of Allergy and Infectious Diseases State-of-the-Art panel. 46 Response to AZT should be ascertained with a CD4 count every three to six months. If the patient remains asymptomatic and the CD4 count falls below 200 cells/mm3 or if the patient becomes symptomatic and the CD4 count falls below 300 cells/mm3 , three options appear reasonable: Continue AZT and add ddC at a dosage of 1.125 or 2.25 mg/day; change to ddl
monotherapy; or change to a concurrent or alternating regimen of AZT and ddl. Because ddl is not licensed for combination therapy, a regimen consisting of AZT and ddC is considered preferable at present. Furthermore, some third-party payers will not reimburse for the simultaneous administration of AZT and ddl until phase 11/111 trials clearly favor this combination regimen. Regardless of the CD4 lymphocyte count, the choice of initial regimen must always be based on the presence or history of hematologic abnormalities, pancreatitis, or peripheral neuropathy. Patients with severe neutropenia and/or anemia may benefit from monotherapy with ddl or a regimen of AZT combined with the appropriate cytokine (i.e., GM-CSF, G-CSF, or erythropoietin). Patients with a history of pancreatitis or known
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alcohol abuse should avoid ddl and possibly ddC, although the incidence of pancreatitis appears to be less with ddC. The duration of therapy should also enter into the physician's therapeutic decision making. Patients who are deteriorating clinically (e.g., severe weight loss, recurrent opportunistic infections) and have received monotherapy for more than six months should be considered clinically refractory. Changing to another agent or changing to a combination regimen, either concomitant or alternating, should be considered seriously. Clinicians also face a dilemma when a patient develops hematologic toxicity while receivingAZT ther-
apy: The AZT dose can be reduced, a cytokine can be added, or therapy can be changed to ddl. Because the minimal effective dosage of AZT appears to be greater than 150 mglday, reducing the dose of this agent to below 300 mg.'day must be considered only if other options are limited.
Conclusions The treatment of patients infected with HIV continues to evolve as new therapeutic options become available. FDA approval of combination therapy with AZT and ddC in patients with more advanced HIV infection heralds a new overall approach to antiretroviral therapy.
The experience being gained with combination dideoxynucleoside therapy in ongoing clinical trials will provide invaluable information concerning its clinical efficacy and impact on antiviral resistance. As we move into the next decade of the AIDS pandemic, advances in drug development, such as tat and protease inhibition, have created the hope that a major advance beyond dideoxynucleosides is at hand. It is likely, however, that for the foreseeable future, all promising new agents will be studied in combination with first-generation dideoxynucleoside agents to build on the advances in clinical management documented to date. D
References 1. Fischl MA et al: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. N Eng! J Med 317:185, 1987 2. Graham NMH et al: The effects on survival of early treatment of human Immunodeficiency virus infection. N Eng! J Med 326: 1037, 1992 3. Fischl MA et al: The safety and efficacy of zidovudlne (AZT) in the treatment of subjects with mildly symptomatic HIV infection: A double-blind, placebo-controlled trial. Ann Intern Med 112:727, 1990 4. Volberding PA et a!: Zidovudine in asymptomatic human immunodeficiency virus infection. N Eng! J Med322:941, 1990 5. Groopman JE: Zidovudine intolerance. Rev Infect Dis 12(Suppl5): 500, 1990 6. Fischl MA et al: Prolonged zidovudlne therapy in patients with AIDS and advanced AIDS-related complex. JAMA 262: 2405, 1989 7. Dournon E et al: Effect of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet II: 1297, 1988 8. LambertJS eta!: 2',3'-Dideoxytnosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: A phase I trial. N EnglJMed322:1333, 1990 9. Cooley TP eta!: Once-daily administration of 2' ,3'dideoxyinosine (ddi) in patients with the acquired Immunodeficiency syndrome or AIDS-related complex. Ibid, p 1340 10. Connolly KJ et al: Phase I study of2',3'-dideoxyinoslne (ddl) administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic
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intolerance to zidovudlne. Am J Med 91 : 4 71, 1991 11. Dornsife RE eta!: Anti-human Immunodeficiency virus synergism by zidovudine (3'-azldothymldine) and didanoslne (dideoxylnoslne) contrasts with their additive inhibition of normal human progenitor cells. Antimlcrob Agents Chemother 35: 322, 1991 12. Johnson VA et al: 1\vo-drug combinations of zidovudine, didanosine, and recombinant Interferon-a A inhibit replication of zldovudlne-reslstant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis 164:646, 1991 13. Baba Metal: Ribavirln antagonizes inhibitory effects of pyrimidine 2' ,3'-dideoxynucleosides but enhances inhibitory effects of purine 2' ,3'-dideoxynucleosldes on replication of human immunodeficiency virus in vitro. AntimlcrobAgents Chemother 31:1613, 1987 14. Spector SA et al: Human immunodeficiency virus inhibition Is prolonged by 3'-azido-3'-deoxythymidine alternating with 2',3'-dideoxycylidine compared with 3'-azido-3'-deoxythymldlne alone. Antimlcrob Agents Chemother 33: 920, 1989 15. Eron JJ et al: Synergistic inhibition of replication of HIV-1, including a zidovudlne-resistant Isolate, by the combination of zidovudlne and 2',3'-dideoxycylldine in vitro. Antimlcrob Agents Chemother 36: 1559, 1992 16. Vogt MW et al: Ribavlrln antagonizes the effect of azidothymidine on HIV replication. Science 235: 1376, 1987 17. Larder BA. Darby G, Richman DD: HIVwith reduced sensitivity to zidovudine (AZT) Isolated during prolonged therapy. Science 243: 1731, 1989
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18. Rooke eta!: Isolation of drug-resistant isolates of HIV-1 from patients on long-term zidovudine therapy. AIDS 3:411, 1989 19. Kellam Petal: Fifth mutation in human immunodeficiencyvirus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Nat! Acad Sci USA 89: 1934, 1992 20. Richman DD et al: Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. J Acquir Immune DeficSyndr3:743, 1990 21. StClair Met a!: Resistance to ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 253: 1557, 1991 22. Bach MC et al: Long-term follow-up of patients with HIV isolates resistant to zidovudine (AZT) treated with dideoxyinosine (ddl). Abstr TU.B.91, p 80. Seventh International Conference on AIDS, Florence, Italy, June 16-21, 1991 23. McLeod GX eta!: Didanosine and zidovudine resistance patterns in clinical isolates of human immunodeficiency virus type 1 as determined by a replication endpoint concentration assay. Antimicrob Agents Chemother 36:920, 1992 24. Fitzgibbon JE et al: Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother 36:153, 1992 25. Singer J et al: Clinical significance of in-vitro HIV resistance to zidovudine in early HIV-infected individuals after four years of therapy. Abstr W.B.2414, p 285. Seventh International Conference on AIDS, Florence, Italy, June 16-21, 1991 26. Tudor-Williams Get a!: HIV-1 sensitivity to zidovudine and clinical outcome in children. Lancet 339:15, 1992 27. Yarchoan Ret a!: Initial clinical experience with dideoxynucleosides as single agents and in combination therapy. Ann NY Acad Sci 616:328, 1990 28. Skowron G, Merigan TC: Alternating and Intermittent regimens of zidovudine (3'-azido-3'-deoxythymidine) and dideoxycytidine (2',3'-dideoxycytidine) in the treatment of patients with acquired Immunodeficiency syndrome (AIDS) and AIDS-related complex. Am J Med 88: 20S, 1990 29. Bozette Setal: ACTG 50: Alternating and Intermittent ddC and AZT in the treatment of persons with advanced HIV infection and hematologic Intolerance to AZT. Abstr S.B.425, p 192. Sixth International Conference on AIDS, San Francisco, June 20-23, 1990 30. MengT-C etal: Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. Ann Intern Med 116:13, 1992 31. Collier AC: Effect of combination therapy with zidovudine and didanosine (ddl) on surrogate markers. Oral Presentation. Seventh International Conference on AIDS, Florence, Italy, June 16-21. 1991 32. Krown Set a!: Interferon-awith zidovudine: Safety, tolerance, and clinical and virological effects in patients with Kaposi sarcoma associated with the ac-
quired immunodeficiency syndrome (AIDS). Ann InternMed 112:812, 1990 33. Hartshorn KL et al: Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant aA-interferon. Antimlcrob Agents Chemother 31 : 168, 1987 34. Berglund 0 et al: Combined treatment of symptomatic human immunodeficiency virus type 1 Infection with native interferon-alpha and zldovudine. J Infect Dis 163:710, 1991 35. Or holm Met a!: Suppression ofp24 antigen in sera from HIV-infected individuals with low-dose a-interferon and zidovudine: A pilot study. AIDS 3:97, 1989 36. Kovacs JA eta!: Combined zidovudine and interferon-a therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 111:280, 1989 37. Cooper DA eta!: The efficacy safety of zidovudine with or without acyclovir in the treatment of patients with AIDS-related complex. AIDS 5: 933, 1991 38. Fiddian AP et al: Preliminary report of a multicentre study of zidovudine plus or minus acyclovir in patients with acquired immunodeficiency syndrome or ARC.JinfectDis 18:79,1989 39. Hollander H et al: Phase I study oflow-dose zidovudine and acyclovir in asymptomatic human immunodHiclency virus seropositive Individuals. Am J Med 87: 628, 1989 40. Surbone A et al: Treatment of the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex with a regimen of 3'-azido-2',3'-dideoxythymidine (azidothymidine or zidovudine) and acyclovir. Ann Intern Med 108: 534, 1988 41. Collier AC et al: A pilot study of low-dose zidovudine in human immunodeficiency virus infection. N Eng! J Med 323:1015, 1990 42. Pluda JM et al: Subcutaneous recombinant granulocyte-macrophage colony stimulating factor used as a single agent and in an alternating regimen with azidothymidine In leukopenic patients with severe human immunodeficiency virus Infection. Blood 76:463,1990 43. Van der Wouw PA et al: Effects of recombinant human granulocyte colony-stimulating factor on leucopenia in zidovudine-treated patients with AIDS and AIDSrelated complex, a phase 1/11 study. Br J Haematol 78:319, 1991 44. Groopman JE eta!: Effect of recombinant human granulocyte-macrophage colony stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Eng! J Med 31 7: 593, 1987 45. Hamilton JD eta!: A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection: Results of the Veterans Affairs Cooperative Study. N Eng! J Med 326:437, 1992 46. State-of-the-Art Conference on Azidothymidine Therapy for Early HIV Infection. Am J Med 89: 335, 1990
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ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Combination Therapy Gavin X. McLeod & Scott M. Hammer To cite this article: Gavin X. McLeod & Scott M. Hammer (1992) Combination Therapy, Hospital Practice, 27:sup2, 14-25, DOI: 10.1080/21548331.1992.11705596 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705596
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Date: 05 June 2016, At: 00:51
Nucleoside Analogues:
Combination Therapy
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GAVIN X. McLEOD
and SCOTT M. HAMMER
Harvard University
Combination antiretroviral therapy is an important development in the management of HIV infection. AZT with ddC is the first such combination to be approved for clinical use. Several issues remain, however, including the precise clinical benefit and toxicity of combination therapy, its effect on drug resistance, and the development of ever more effective therapeutic strategies.
Antiretroviral therapy improves the quality oflife and survival of patients infected with the human immunodeficiency virus (HIV) type 1. Zidovudine (AZT, azidothymidine), the first antiretroviral nucleoside analogue approved by the Food and DrugAdministration, prolongs the lives of patients with acquired immunodeficiency syndrome, advanced AIDS-related complex (ARC), and those who have CD4 lymphocyte counts less than 350 cells/mm 3 .1. 2 This agent also delays the onset of AIDS in HIVinfected patients whose CD4 lymphocyte counts are below 500 cells/mm3 . 3 ·4 AZT has limitations, however, in that patients receiving therapy have inexorable disease progression, as manifested by the development of opportunistic infections, weight loss. malignancies, and/or neurologic abnor-
Or. Mcleod is Clinical and Research Fellow, Harvard Medical School and Division of Infectious Diseases, New England Deaconess Hospital, Boston. Dr. Hammer is Associate Professor of Medicine, Harvard Medical School, and Director, Research Virology Laboratory, New England Deaconess Hospital.
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mali ties. 5 The CD4 lymphocyte count, the surrogate marker most commonly followed in HIV infection, typically increases by 40 to 100 cells/mm3 within the frrst few months after AZT therapy is begun. 6 · 7 After four to six months of therapy, however, the CD4 count usually returns to pretherapy levels and continues to decline thereafter. In addition, as many as one third of patients with AIDS cannot tolerate AZT because of its toxicity. Thus, didanosine (ddl, dideoxyinosine) was approved in 1991 for patients with advanced HIV infection who are intolerant to or unresponsive to AZT. Clinical trials of ddl have demonstrated that the increase in CD4 lymphocyte counts is similar to that seen with AZT in terms of elevation and persistence. 8 ·IO A third nucleoside analogue, zalcitabine (ddC, dideoxycytidine), has been available through expanded-access programs and clinical trials as an alternative to or in combination \vith AZT. It was recently approved for the latter indication. Monotherapy with any of these three agents provides limited benefits; therefore, attention has
turned to combination therapy. Combination therapy is accepted practice in the treatment of cancer, tuberculosis, and certain bacterial infections such as enterococcal endocarditis. As in these diseases, combination therapy in HIV-infected patients may be advantageous for anumber of reasons. First, combination therapy may inhibit the virus more effectively by acting at more than one site or by acting additively or synergistically at a single site. Second, certain agents in the regimen may be more effective in particular tissues and cell populations. A combination of drugs that is active in lymphocytes and cells of monocyte/ macrophage lineage, as well as effective in crossing the blood-brain barrier, would appear to be the most efficacious for HIV infection. Third, combination therapy may allow reduced or alternating doses of each drug. thereby lessening the toxicity associated with the nucleoside analogues. Finally, recent reports of drug resistance lend support to the concept of combining therapies to delay or possibly prevent its development. Of the antiretroviral agents in clinical use or under investiga-
tion, combinations of the dideoxynucleosides are currently the regimens With the most immediate promise because of the degree of development of the individual agents and the accruing experimental data supporting their use. Since progression of HIV infection is only delayed by monotherapy, combining two or more drugs may prove beneficial in further sloWing the disease and in prolonging life.
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In Vitro Studies A number of in vitro studies have provided evidence that multiple drug therapy is superior to monotherapy. As AZT has been the mainstay of antiretroviral therapy, most studies have compared AZT alone With AZT plus one or more other agents. When two drugs are combined in vitro, the resulting effect on HIV replication may be additive (or indifferent), synergistic, or antagonistic. In vitro analysis is important because antagonistic effects may yield undesirable clinical results. For example, the combination of AZT and ribavirin is antagonistic because
Figure 1. Schematic depicts the chemical structures (A) of the nucleoside analogues (deoxynucleoside triphosphates) and their mechanism of inhibition of the physiologic deoxynucleoside triphosphates (B-D). These agents block human immunodeficiency virus replication by competitively inhibiting the deoxynucleoside triphosphates and terminating the HIV proviral DNA chain when incorporated by HIV reverse transcriptase. Azidothymidine triphosphate (AZT-TP) competes with deoxythymidine triphosphate (dTTP), dideoxycytidine triphosphate (ddC-TP) competes with deoxycytidine triphosphate (dCTP), and dideoxyinosine (ddl, not shown) is converted to dideoxyadenosine triphosphate (ddA-TP), which competes with deoxyadenosine triphosphate (dATP).
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the phosphorylation of AZT is inhibited. AZT and the other dideoxynucleosides inhibit the reverse transcriptase of HIV by directly competing with the incorporation of the respective normal nucleoside triphosphates into the growing viral DNA, thus terminating the proviral DNA chain. Each of the three dideoxynucleosides under discussion compete with a different nucleoside triphosphate: AZT with deoxythymidine triphosphate, ddl with deoxyadenosine triphosphate, and ddC with deoxycytidine triphosphate (see Figure 1 ). Combining dideoxynucleosides produces competitive inhibition of more than one nucleoside triphosphate, which results in additive or synergistic inhibition of the reverse transcriptase. In vitro studies have demonstrated that this antiretroviral effect occurs with a combination of dideoxynucleosides in simultaneous and alternating regimens. Using a transformed T-cellline (MT4). peripheral blood lymphocytes, and macrophages, R. E. Dornsife and colleagues showed that the simultaneous combination of AZT and ddl synergistically inhibited HIVm 8 in all cell types. 11 In addition, these investigators demonstrated that ddl did not enhance AZT's toxicity against normal human bone marrow progenitor cells. In studies by V. A. Johnson and co-workers, 12 combined AZT and ddl was synergistic even against AZT-resistant isolates, which suggests that when patients develop resistance to AZT, a combination regimen that includes AZT may still be beneficial in inhibiting Hiv. The continued benefit of AZT is thought to be related to the heterotypic HIV species in infected patients. HIV has a high rate of mutation, and 16
a number of subspecies of a particular viral strain can exist in a patient at one time. With exposure to AZT or other drugs, some of these species develop one or more mutations that may mediate resistance. However, other species that remain susceptible to AZT theoretically may still be present. The combination of AZT and ddC has also been shown to be effective. M. Baba and colleagues used the MT4 cell line to demonstrate an additive-to-synergistic effect by monitoring cytopathic activity. 13 And, using the transformed T-cell line CEM, S. A. Spector and co-workers found that inhibition of HIV replication was more prolonged with the alternating regimen of AZT and ddC compared with continual exposure to AZT. 14 The inhibition was measured by both HIV p24 antigen in the culture supernatant and unintegrated proviral DNA in CEM cells. J. J. Eron and colleagues have also recently demonstrated that combining AZT and ddC can synergistically inhibit both an AZT-sensitive and an AZT-resistant isolate. 15 In vitro, AZT in combination with a number of other compounds has been found to provide an additive or synergistic effect. These compounds include acyclovir, recombinant soluble CD4, dextran sulfate, recombinant a-interferon, and non-nucleoside reverse transcriptase inhibitors such as foscarnet, nevirapine, and pyridine derivatives. However, as noted above, caution is needed when using combination therapies, because ofthe antagonism between certain compounds. Antagonism has been reported not only with AZT and ribavirin, but also with ddC and ribavirin and with dextran sulfate and recombinant soluble CD4. 16
Resistance Combination therapy may delay or prevent the development of HIV drug resistance. During the six years that dideoxynucleoside agents have been used therapeutically, multiple reports of in vitro resistance to AZT. ddl, and ddC have appeared. B. A. Larder and co-workers 17 first reported the development of resistance to AZT in 1989. Using an in vitro assay system of HeLa CD4 cells, these investigators found a more than 100-fold decrease in AZT susceptibilities between certain pre- and posttherapy isolates. In a subsequent analysis of these and other isolates, development of AZT resistance has been correlated most often with five mutations in the reverse transcriptase. 18 · 19 These mutations occur at amino acid residues 41 (Met-> Leu), 67 (Asp-> Asn), 70 (Lys -> Arg), 215 (Thr -> Tyr or Phe). and 219 (Lys -> Gln), in an area of the reverse transcriptase that is responsible for nucleoside triphosphate binding (see Figure 2). In experiments employing site-directed mutagenesis of molecular clones, the degree of resistance has been shown to correlate with the number of mutations present. P. Kellam and associates have shown that the mutations occur in an ordered fashion, with those at 41, 70, and 215 being the most critical. 19 Resistance to AZT has been reported to occur more frequently in patients with AIDS or severe ARC, with partial or complete resistance common after six months of therapy. 20 Patients who are asymptomatic and have CD4 counts greater than 200 cells/mm3 appear to develop AZT resistance less frequently and to a lesser degree than patients with AIDS or advanced ARC.
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Resistance to ddl has now been reported by several groups, 21 -23 but it is much less pronounced than that reported with AZT. Depending on the assay system used, the decrease in susceptibility ranges from two- to 30-fold. Resistance to ddl has been associated with a single mutation at amino acid residue 7 4 (Leu - > Val) in the viral reverse transcriptase. Interestingly, the use of site-directed mutagenesis in molecular clones has revealed that this mutation confers not only decreased susceptibility to both ddi and ddC but increased susceptibility to AZT when one of the mutations associated with AZT resistance (amino acid residue 215) is present. Most recently, ddC resistance also has been reported to be associated with a mutation at amino acid residue 69 (Thr -> Asp). This mutation was shown to be associated with a fivefold decrease in ddC susceptibility in experiments using site-directed mutagenesis of a molecular clone and a plaque reduction sensitivity assay. 24 The clinical significance of resistance to the nucleoside analogues is still being investigated, but two reports have linked resistance to a poor clinical outcome. The Multicentre Canadian AZT Trial25 reported that patients with CD4 counts above 270 cells/mm3 had a greater likelihood of progression to AIDS if their isolates were AZT resistant. A recently published report by G. Tudor-Williams and colleagues26 analyzed results obtained in 23 children who had been receiving AZT monotherapy for nine to 39 months. In vitro resistance testing was performed on isolates from 19 subjects. Children who had deteriorated clinically or died had higher median 50% inhibitory concentrations (IC 50 ) than those
who remained stable (3.5 vs 0.57 ,uM). Eight of the 10 children whose isolates had an IC 50 greater than 2.0 ,uM deteriorated, whereas all nine children who remained stable had IC50 values below 2.0 ,uM. Both of these studies correlated viral resistance with disease progression, but neither proved that development of resistance is the primary factor that leads to a worse outcome. The increasing viral load associated with ad-
vanced HIV infection may increase the likelihood of drug-resistant mutations emerging in patients receiving therapy. The AIDS Clinical Trials Group (ACTG) recently released a preliminary analysis of ACTG 1168/117, a phase II/III trial designed to compare the efficacy and toxicityofmonotherapywith AZT or ddl in patients who had tolerated more than 16 weeks of AZT. Patients were entered into the study if they had AIDS or
Figure 2. Various mutations in human immunodeficiency virus reverse transcriptase are responsible for resistance to the nucleoside analogues. AZT(zidovudine) resistance is associated with the presence of one or more of five mutations (41, 67, 70,215, and 219) with 41, 70, and 215 being most important. Resistance to ddl (didanosine) is associated with a mutation at amino acid residue 74 in patients with the AZT-resistance mutation at position 215. Resistance to ddC (zalcitabine) is associated with mutations at position 69 or 74.
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ARC and CD4 counts less than 300 cells/mm 3 or if they were asymptomatic and had CD4 counts less than 200 cells/mm3 . The patients were then randomized to one of three treatment arms: AZT (600 mgtday), ddl (500 mgtday). or ddl (750 mgt day). Patients randomized to ddl at 500 mgtday had a statistically significant delay in the time to a new AIDS-defining event compared with the AZT group (oneyear rates: 28% vs 40%). No statistically significant difference in disease progression was noted between the group receiving ddl at 750 mgtday and that receiving AZT, but both ddl groups had a slight increase in CD4 cells (median, 10 cells/mm 3 ) compared with the AZT group. This preliminary report suggests that in patients with more advanced HIV infection, a change to monotherapy with ddl is beneficial after four months of AZT. Full analysis ofthese data and their implications is pending, but it is possible that AZT resistance may help explain these fmdings.
Toxicities Combination therapy may result in less overall drug toxicity in HlV-infected patients. The toxicities ofthe dideoxynucleoside agents are substantial. The primary toxicities of AZT (anemia, neutropenia, and myopathy) do not overlap with those of ddl and ddC (pancreatitis and peripheral sensory neuropathy). Because the toxicities of ddl and ddC are similar, combining these agents appears to have limited value. Consequently, most clinical trials involve the combination of AZT and ddl or AZT and ddC. Combination therapy can be given in alternating or concurrent regimens. As many of the side effects of the dideoxynucleo18
sides are dependent on dose and duration of therapy, alternating regimens could reduce toxicity while allowing full dosages of each drug to be given in alternating periods of one to six weeks. The peripheral neuropathy associated with ddC usually appears only after six weeks of therapy, thus accounting for the upper limit of cycling therapy. Concurrent therapy might provide more total antiretroviral treatment over time than alternating regimens, but toxicity might be greater; this issue will be resolved only through controlled clinical trials. In the five years since AZT was approved for clinical use, it has been determined that in both asymptomatic persons and patients with AIDS, a lower dose (500 to 600 mgtday), with reduced toxicity, is as effective as the higher dosage ( 1,200 to 1,500 mgtday) initially employed. It is to be hoped that the combination oflower-dose AZT and ddl or ddC at reduced dosages will improve clinical efficacy while reducing side effects.
Clinical Trials Published information on combination dideoxynucleoside therapy in the treatment of HIV infection is currently limited to phase 1/11 studies, although phase 11/111 studies are under way. The initial report of alternating AZT and ddC therapy by R. Yarchoan and co-workers 27 included six patients who were given 200 mg of AZT every four hours ( 1,200 mgtday) for one week, alternating with 0.03 mglkg of ddC every four hours (0.18 mgtkgtday) for a week. The patients, all of whom had AIDS or ARC, were (with one exception) maintained on this regimen for nine or more weeks.
One AIDS patient was taken off the regimen in the second week because of neutropenia and disseminated Mycobacterium avium-intracellulare infection. The other five received at least nine weeks of therapy; one patient stopped at nine weeks because of ddC-associated arthralgias during the sixth and eighth weeks. The four remaining patients received up to 28 weeks of therapy, and only one experienced peripheral sensory neuropathy (he had received ddC in a previous phase I trial). None of these five patients developed hematologic toxicity. The mean increase in CD4 counts was 48 cells/mm3 at nip.e weeks. Three patients who had serum HIV p24 antigenemia at study entry had decreases in this quantitative viral measurement, with two becoming antigen negative. This small trial of alternating AZT and ddC therapy was the first to point to the potential benefits of combination regimens. 1\vo ACTG studies have investigated weekly and monthly alternating regimens of AZT and ddC. In ACTG 04 7 and ACTG 050, 2 8· 29 the protocols were identical except that the first study had an AZT mono therapy arm, and patients enrolled in the second study had had hematologic toxicity with AZT and had lower CD4 counts at entry. The study dosages of AZT (1,200 mg.'day) and ddC (0.06 and 0.18 mgtkgtday) were two to six times higher than those currently recommended. Less toxicity was seen with the alternating regimens than occurs with continuous monotherapy using either drug. Patients had increased CD4 cell counts and decreased HlV p24 antigenemia while on the alternating regimen. An important phase 1/11 study, ACTG 106, reported recently by T.-C. Meng and colleagues, 30
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evaluated the safety and efficacy of concurrentAZT and ddC therapy in 56 patients with advanced HIV infection. All patients had been diagnosed with AIDS or advanced ARC and had CD4 counts ofless than 200 cells/mm3 • Patients were excluded from this study for severe anemia (hemoglobin < 10 gm/dl}, neutropenia (neutrophil count < 1,200/mm3 }, thrombocytopenia (platelet count< 100,000/mm3 }, renal insufficiency (creatinine clearance > 1.24 ml/sec), hepatitis (serum transaminases >3x upper limit of normal), history of previous peripheral neuropathy, pregnancy, or symptomatic visceral or rapidly progressing Kaposi's sarcoma. All study patients received aerosolized pentamidine (300 mg every four weeks) to prevent Pneumocystis cartnii pneumonia. The study-openlabel and dose-ranging-had six treatment arms: 1) AZT (300 mglday) and ddC (0.015
rnglkglday}; 2) AZT (600 rnglday) and ddC (0.015 mg/kgl day); 3) AZT ( 150 mglday) and ddC (0.015 mg/kglday); 4) AZT (300 mglday) and ddC (0.03 rnglkglday); 5)AZT (600 rnglday) and ddC (0.03 mg/kglday); and 6) AZT alone ( 150 mglday). At least eight patients were assigned to each regimen. Median follow-up was 40 weeks, and 48 patients completing at least 10 weeks of therapy. The pharmacokinetics of both drugs were not altered in eight patients studied. Concurrent therapy was well tolerated, and toxicity was limited. There were no significant differences among the six regimens with regard to drug toxicity. Ten patients (18%) developed hematologic toxicity, two of whom had to stop therapy. 1\vo patients developed severe paresthesias consistent with ddC neuropathy, which also required removal from the study. Most important, this study
Figure 3. Shown here are the effects of different dosing
regimens of combined therapy with AZr (zidowdine) and ddC (zalcitabine) in ACTG 106, an open-label phase 1/11 study of 56 patients with advanced HIV infection (CD4 lymphocyte counts less than 200 cells/mm:l). CD4 counts
demonstrated improved antiretroviral activity among patients treated with combination therapy as documented by improvements in weight, CD4lymphocyte counts, and HIV p24 antigenemia. Patients on each regimen had increased CD4 counts (see Figure 3). There were no statistical differences among the regimens, although the increase in CD4 counts with AZT monotherapy (regimen 6) was the smallest and the rate of decline was greatest. When a positive CD4 count response was defined as an increase of 50 cells/mm3 for two consecutive months, 25 of the 36 (69%) patients receiving AZT at a dosage of 300 or 600 mglday in combination with ddC responded. The patients who received the highest dosages of AZT (600 mglday) and ddC (0.03 mg/kgl day) had the greatest proportion of responders (seven of eight patients, 88%). This regimen also produced statistically significant
increased In all patients, but combination therapy at any dose was clearly superior to AZr monotherapy (left). Similarly, the percentages of patients who sustained CD4 counts higher than baseline were greater with combination therapy (right). (Adapted from Meng T-C30)
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decreases in serum HIV p24 antigen levels when compared with the other five regimens. Serum HIV p24 antigen levels decreased in all regimens except for regimen 6 (AZT alone). The increase in CD4 cells associated with combination therapy was superior and was sustained for a longer period than in previous controlled trials of AZT as monotherapy. Such comparisons must, of course, be made cautiously. Furthermore, the control arm of AZT monotheraPY in Meng's study used a lower dosage of AZT ( 150 mgtday) than in previous phase II/III studies and, interestingly, was found to be substandard. However, this phase I/11 study did provide important information showing that combination therapy with AZT and ddC was well tolerated and that toxicities were not more apparent than with either drug alone. Improvements in body weight, CD4 counts, and HIV p24 antigenemia seen with the higher-dosage regimens in ACTG 106 were among the data that led the FDA Antiviral Advisory Committee to recommend approval of ddC for use in combination with AZT. Other information that led to ddC's approval included an interim analysis of an ongoing randomized, double-blind phase II/III study sponsored by Burroughs Wellcome Co. (BW #34,225-02). This study includes patients with HIV infection who have had four weeks or less of prior therapy with AZT and CD4 counts of 300 cells/mm 3 or less. At the time of the interim analysis, 45 patients had received concurrent therapy with ddC (2.25 mg/day) and AZT (600 mg/day), and 47 had received AZT monotherapy (600 mg/day). Combination treatment produced a greater and more sus20
tained increase in CD4 counts than did AZT monotherapy. The mean peak increase in CD4 counts at eight weeks was 94 cells/mm 3 in the combination therapy group compared with an increase of 53 cells/mm 3 at 12 weeks in the AZT monotherapy group (see Figure 4). In addition, the mean CD4 count remained higher than baseline throughout the initial24-week period among patients receiving combination therapy. In contrast, the cell count approached baseline at 24 weeks among those receiving AZT monotherapy. The efficacy of combination therapy with AZT and ddC in patients who have received prior AZT therapy is still uncertain and may be revealed in ongoing studies such as ACTG 155. This phase II/III trial includes symptomatic patients with CD4 counts less than 300 cells/mm3 and asymptomatic persons with CD4 counts less than 200 cells/mm 3 . All 1,001 patients who entered this trial had at least. six months of prior AZT therapy. The study is comparing AZT monotherapy (600 mg/day), ddC monotherapy (2.25 mgtday), and combined AZT (600 mgtday) and ddC (2.25 mgtday). A phase I trial of combined AZT and ddi 31 was presented at the Seventh International Conference on AIDS in 1991. This study by A. C. Collier and coworkers was similar to the sixregimen study of AZT and ddC by Meng and co-workers. The study arms were 1) AZT ( 150 mg/day) and ddl (90 mg/day); 2) AZT (300 mg/day) and ddi (334 mg/day); 3) AZT (600 mg/day) and ddi (334 mg/day); 4) AZT (300 mg/day) and ddl (500 mg/day); 5) AZT (600 mg/day) and ddi (500 mg/day); and 6) AZT alone (600 mg/day). Fifty-five patients with CD4 counts less than 400 cells/mm3
and fewer than 120 days of prior AZT therapy were enrolled, and 37 patients completed at least 24 weeks of therapy. Seven patients withdrew voluntarily because of mild side effects, including headache, nausea, and disorientation, and nine patients required dose modifications. Toxicities included five cases of mild peripheral neuropathy, one of anemia, and two of transient liver function abnormalities. The pharmacokinetics of either drug were not altered by combination therapy. Although only preliminary data are available, all six regimens produced increases in CD4 counts within the first 12 weeks of treatment. Only the regimens containing AZT at a dose of 600 mg/day were associated with CD4 increases between 12 and 24 weeks. Thus, this initial phase I trial of AZT and ddi appears promising, but the results of ongoing studies are necessary to compare this regimen with AZTandddC.
Ongoing Studies In addition to ACTG 155 and the Burroughs Wellcome study, other studies comparing combination therapy with AZT and either ddi or ddC are currently under way. ACTG 143 is a phase I/II open-label study that has enrolled 126 asymptomatic HIV-infected patients. Subjects have been stratified according to prior AZT use and then enrolled in one of four treatment arms: AZT ( 150 mg/day) and ddi ( 134 mg/day); AZT (300 mg/day) and ddi (334 mg/day); AZT (600 mg/day) and ddi (500 mg/day); or ddi monotherapy (500 mg/day). ACTG 175 is a phase II/III, randomized, double-blind trial that includes patients with early HIV infection and CD4 counts between 200 and 500 cells/mm3 . The study has four
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arms: AZT monotherapy (600 mgtday); ddi monotherapy (400 mgtday); AZT (600 mgtday) plus ddi (400 mgtday); and AZT (600 mgtday) plus ddC (2.25 mgtday). This multicenter study has a target enrollment of 2,100 patients. The European Delta trial is a phase II/III, randomized, doubleblind study of 2,500 patients with CD4 counts between 50 and 350 cells/mm 3. The trial has three arms: AZT monotherapy (600 mgtday); AZT (600 mgtday) plus ddi (400 mgtday); and AZT (600 mgtday) plus ddC (2.25 mgtday). The Community Program Clinical Research Association (CPCRA) trial 007 is also a threearm study (AZT alone, AZT plus ddi, and AZT plus ddC) with a projected enrollment of 1,200 patients with CD4 counts less than 200 cells/mm3. When the results of these trials become available, the efficacy of combination therapy will be more fully appreciated, making possible more definitive recommendations regarding anti-HIV therapy at both early and advanced stages of infection.
and a-interferon include a reduction in HIV p24 antigen levels and a possible reduction in recoverable HIV from peripheral blood culture. However, this combination induces lymphopenia, and none of the five studies reported to date has detected an increase in CD4 lymphocytes. In addition, it does not appear to have an effect on survival. perhaps because of the small number of patients and the limited follow-up. Combination AZT and acyclovir has been investigated in five separate studies, with no definitive evidence that thecombinationismoreeffective than AZT alone. 37·41 The results of ACTG 063, which also explores this combination, are pending.
CombiningAZT and cytokines to reduce hematologic toxicities is also beneficial. Granulocytemacrophage colony-stimulating factor (GM-CSF). granulocyte colony-stimulating factor (GCSF), and recombinant erythropoietin all successfully reduce the hematologic toxicity (either neutropenia or anemia) associated with AZT. 42·44 Recombinant human erythropoietin significantly decreased transfusion requirements in AIDS patients whose endogenous erythropoietin levels were less than 500 IU/ml at the time they began receiving AZT. Both GM-CSF and G-CSF reduce the incidence of neutropenia caused by AZT, but G-CSF appears to be better tolerated.
Non-nucleoside Agents In addition to intensive study of dideoxynucleoside combinations, investigators are looking at combinations of a dideoxynucleoside and a drug from another class. AZT and a-interferon, for example, have been administered concomitantly, especially in patients with Kaposi's sarcoma. 32·36 Although this combination may result in significant hematologic toxicity, improvement in Kaposi's lesions were evident in 45% of patients whoreceived a-interferon at dosages lower than those needed to obtain a similar response when the agent is used alone. The antiretroviral effects of combined AZT
Figure 4. Shown here are some of the data that led the FDA to approve ddC (zalcitabine) for use in combination with AZT (zidovudine). Study 1 (Burroughs Wellcome trial 34,225-02) is a randomized, double-blind trial of 92 HIV.infected patients with baseline CD4 lymphocyte counts of 300 cells/mm3 or less. A mean peak increase of 94 cells/mm 3 was seen at week 8 with combined therapy (45 patients) and of 53 cells/mm3 at week 12 with AZT monotherapy (47 patients). In ACTG 106 (Study 2) combined therapy in 36 patients with baseline CD4 counts of less than 200 cells/mm 3 was associated with a mean peak increase of 97 cells/mm 3 at week 4. Results from ACTG 114 (Study 3), involving 262 patients who received AZT monotherapy, are shown for comparison purposes.
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Figure 5. Guidelines for Antiretroviral Therapy in Patients with Advanced HIV Infection HIV Seropositive CD4 Count 200-300 cells/mm3
J..
t
'¥
AZT (600 mglday) + ddC (2.25 mglday)
AZT (500-600 mglday) (see Figure 6)
..v Follow up monthly
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~
w
~~
Stability or Improvement
Intolerance or Toxicity
Clinical Deterioration or Steady Decline in CD4 Count
-.v
-.v
-.v
CD4 count every 3 months
Stop implicated drug Resume at lower dose when symptom/toxicity resolves
ddl* or ALI+ + ddl* or experimental therapy, such as non-nucleoside agents, tat inhibitors, protease inhibitors
-.v Recurrent Intolerance or Toxicity
-.v Depending on Toxicity: AZT (500-600 mglday) or ddl* or Azrt + ddl* or experimental therapy or add G-CSF or GM-CSF or erythropoietin
• > 75 kg=600 mglday; 50-74 kg=400 mglday; 35-49 kg=250 mglday
t 600 mglday G-CSF=granulocyte colony-stimulating factor GM-CSF=granulocyte-macrophage colony-stimulating factor NOTE: AZT +ddl is still considered experimental therapy.
Recommendations for Antiretroviral Therapy Six years ago, the only therapeutic option for patients with HN infection was AZT; today, the choices facing the primary care physician are complex. AZT clearly has benefit for the primary treatment of patients, but over time, the loss of efficacy and de22
velopment of toxicity limit its usefulness. The recent approval of ddl and ddC presents options that can be considered at various disease stages. The therapeutic options available to the individual patient can be evaluated best within the context of the present and past CD4 lymphocyte counts and clinical parameters, prior antiretroviral
therapy, and previous toxicity from that therapy. Candidates for antiretroviral therapy may be assigned to two groups: patients with CD4 counts less than 200 cells/mm3 (i.e., advanced infection), and patients with CD4 counts between 200 and 500 cells/mm3 (i.e., early infection). Antiretroviral therapy currently is not considered necessary in patients whose CD4 counts are greater than 500 cells/mm3 , although studies are exploring its possible benefit at this stage of disease. Patients who present with CD4 counts less than 200 cells/mm3 should be started on antiretroviral therapy immediately after routine physical and laboratory examinations reveal no contraindications such as severe anemia or current infection (see Figure 5). The therapy of choice is AZT monotherapy (500 to 600 mgtday) or combination therapy with AZT (600 mgtday) and ddC (2.25 mgtday). The FDA Antiviral Advisory Committee that recommended approval of ddC for use as combination therapy with AZT included in its criteria patients with CD4 counts less than 300 cells/mm 3 and significant clinical or immunologic decline. However, the strongest data on combination therapy come from ACTG 106, which included only patients with CD4 counts less than 200 cells/mm3 . Thus, the available data support combination therapy in patients with asymptomatic or symptomatic HIV infection and CD4 counts less than 200 cells/mm3 • For patients with counts between 200 and 300 cells/mm3 , the degree of symptomatic disease can be used to determine whether initial therapy with combined AZT and ddC might be preferable to AZT alone. Patients should be monitored once a month for taxi-
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city and intolerance to the drugs. If toxicity develops, the clinician should stop the implicated drug and resume therapy at a lower dose once the side effect resolves. If recurrent toxicity develops, alternatives include monotherapy with AZT or ddl, or the yet unproven combination of AZTandddl. At present, treatment guidelines are less clear-cut for patients whose CD4 counts are between 200 and 500 cells/mm3 (see Figure 6). In this group, the risk of toxicity from early combination therapy could outweigh its benefits. The Veterans Affairs Cooperative Study 298 45 revealed no survival benefit for early symptomatic patients treated with high-dose AZT monotherapy. However, the recent observational study by the Multicenter AIDS Cohort Study Group 2 noted a survival benefit with AZT in patients with CD4
counts less than 350 cells/mm3 . Patients whose CD4 counts are between 200 and 500 cells/mm3 have the option of enteringACTG 175 (see page 20) ifitis available in their community. In the event that the ACTG trial is not available and the patient has notreceived prior antiretroviral therapy, the appropriate choice of initial therapy would be AZT at 500 to 600 mg/day as currently recommended by the National Institute of Allergy and Infectious Diseases State-of-the-Art panel. 46 Response to AZT should be ascertained with a CD4 count every three to six months. If the patient remains asymptomatic and the CD4 count falls below 200 cells/mm3 or if the patient becomes symptomatic and the CD4 count falls below 300 cells/mm3 , three options appear reasonable: Continue AZT and add ddC at a dosage of 1.125 or 2.25 mg/day; change to ddl
monotherapy; or change to a concurrent or alternating regimen of AZT and ddl. Because ddl is not licensed for combination therapy, a regimen consisting of AZT and ddC is considered preferable at present. Furthermore, some third-party payers will not reimburse for the simultaneous administration of AZT and ddl until phase 11/111 trials clearly favor this combination regimen. Regardless of the CD4 lymphocyte count, the choice of initial regimen must always be based on the presence or history of hematologic abnormalities, pancreatitis, or peripheral neuropathy. Patients with severe neutropenia and/or anemia may benefit from monotherapy with ddl or a regimen of AZT combined with the appropriate cytokine (i.e., GM-CSF, G-CSF, or erythropoietin). Patients with a history of pancreatitis or known
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alcohol abuse should avoid ddl and possibly ddC, although the incidence of pancreatitis appears to be less with ddC. The duration of therapy should also enter into the physician's therapeutic decision making. Patients who are deteriorating clinically (e.g., severe weight loss, recurrent opportunistic infections) and have received monotherapy for more than six months should be considered clinically refractory. Changing to another agent or changing to a combination regimen, either concomitant or alternating, should be considered seriously. Clinicians also face a dilemma when a patient develops hematologic toxicity while receivingAZT ther-
apy: The AZT dose can be reduced, a cytokine can be added, or therapy can be changed to ddl. Because the minimal effective dosage of AZT appears to be greater than 150 mglday, reducing the dose of this agent to below 300 mg.'day must be considered only if other options are limited.
Conclusions The treatment of patients infected with HIV continues to evolve as new therapeutic options become available. FDA approval of combination therapy with AZT and ddC in patients with more advanced HIV infection heralds a new overall approach to antiretroviral therapy.
The experience being gained with combination dideoxynucleoside therapy in ongoing clinical trials will provide invaluable information concerning its clinical efficacy and impact on antiviral resistance. As we move into the next decade of the AIDS pandemic, advances in drug development, such as tat and protease inhibition, have created the hope that a major advance beyond dideoxynucleosides is at hand. It is likely, however, that for the foreseeable future, all promising new agents will be studied in combination with first-generation dideoxynucleoside agents to build on the advances in clinical management documented to date. D
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