EDITORIALS

Combination Therapy for HIV Infection: Getting Closer

r ersons infected with the human immunodeficiency virus (HIV), their health care providers, and clinical investigators have recently expressed considerable interest in the possibility that combination therapy with antiretroviral agents might prove more beneficial than treatment with these agents used alone. The intensity of this interest has been heightened by the fact that zidovudine, which, until recently, was the only drug licensed for the treatment of HIV infection, has proved unsuccessful in completely suppressing virus replication (1) and in controlling disease progression over extended periods (2). In addition, virus isolates with diminished in-vitro sensitivity to zidovudine have emerged (3, 4) after treatment with this drug. Given the complexity of the HIV life-cycle and the ability of the virus to mutate (5), few believe that monotherapy, particularly with the nucleoside analogues, will suffice for the effective pharmacologic suppression of this virus. Therefore, keen attention will be focused on the results reported by Meng and colleagues in this issue of Annals (6). Because of the extraordinary interest in new information concerning any aspect of HIV infection, particularly treatment, publication of the results of phase I studies has become the rule rather than the exception. The paper by Meng and associates, which reports the results of such a phase I/II study, will certainly generate excitement because it provides encouraging, albeit preliminary, information on a subject pivotal to the way we will ultimately treat HIV-infected persons', that is, using combination chemotherapy. Before commenting on the "suggestions" and "trends" in the study, I emphasize that this is a pilot study that reports data collected from an extremely small sample (an average of eight patients per arm in a six-armed study). Although the authors provide complex statistical analyses of the observed differences among treatment groups, the information presented is nonetheless too preliminary to yield either firm conclusions regarding toxicity or recommendations for treatment with any of the combination regimens studied. Having clearly established this point, there are certain interesting and potentially important observations that emerge from the study and that must be confirmed. The combination of zidovudine and dideoxycytidine (ddC) appears to be well tolerated, and the toxicity of the combination seems no more severe than that reported with either drug alone. Next, the magnitude and duration of the elevations in CD4+ T-lymphocyte counts were both approximately twice those reported previously for either drug alone, and these elevations were seen in a larger percentage of patients following the combination regimen. Further evidence that ddC enhanced the response to zidovudine was provided by

the observation that regimen 3 (ddC, 0.005 mg/kg body weight every 8 hours plus zidovudine, 150 mg/d) was superior to regimen 6 (zidovudine, 150 mg/d). A caveat exists here, however, because 150 mg/d of zidovudine appears to be a suboptimal dose. In a previous editorial (7) concerning phase I trials of dideoxyinosine (ddl) (8, 9), I lamented the lack of an established minimal effective dose for zidovudine, despite the drug's long-time use. Although this information remains elusive, the study by Meng and associates may have inadvertently provided useful data in this regard. It was clear that zidovudine given at a dose of 150 mg/d was not as effective as 600 mg/d when each was given in combination with a comparable dose of ddC; yet 600 mg/d of zidovudine appeared no more toxic than 150 mg/d even when given in combination with ddC. As the authors point out, this observation suggests that clinicians should not use this lower dose of zidovudine either alone or in combination with other agents, except in cases of zidovudine-related toxicity. Unfortunately, the use of this suboptimal dose of zidovudine as the "zidovudine alone" regimen (to which combination therapy was compared) lessened the strength of the conclusion that combination therapy was superior to monotherapy. The apparent increased benefit observed with the combination regimens may be related to the demonstrable additive or synergistic activity of the two drugs in vitro (10, 11). Also, the emergence of resistance may have been diminished by the combination regimens. A recent report indicated that virus isolated from HIVinfected patients who had been treated with zidovudine for 12 months and who were subsequently switched to ddl showed an increased resistance to ddl after 12 months of ddl, whereas sensitivity to zidovudine increased (12). This observation suggests that alternation of a combination of agents with similar mechanisms of action (such as the nucleoside analogues) may be as effective as simultaneous combination therapy. One potential problem with combination regimens, such as those described by Meng and colleagues, is the emergence of resistance to both drugs. As the authors point out, combination regimens should include in their design the use of drugs with different mechanisms of action, as has been pursued in previous phase I trials (13-15). On 9 October 1991, the Food and Drug Administration approved didanosine for use in persons who had experienced treatment failure or who could not tolerate zidovudine therapy. The approval was based on the improvement in a surrogate marker (CD4+ T-lymphocyte count). The study by Meng and coworkers bases its claim of greater benefit of combination therapy over

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monotherapy on the decrease in p24 antigenemia and the increase in CD4+ T-lymphocyte counts. Clearly, the role of surrogate markers assumes increased importance in the decision-making process concerning the efficacy of drugs used to treat HIV infection. In both cases, however, the ultimate proof of efficacy must be determined by clinical end points. To this end, information gathered from the present clinical trial was used to design a larger and, it is hoped, definitive phase II/III trial, the AIDS Clinical Trials Group (ACTG) Study 155, comparing the combination of zidovudine (200 mg) plus ddC (0.01 mg/kg) every 8 hours compared with monotherapy with either drug alone. Finally, many patients have been treated for varying periods of time with zidovudine and either have become refractory to the beneficial effects of the drug or have developed a prohibitive toxicity. This problem has presented a substantial dilemma for both patients and physicians in seeking alternative treatments. Given the recent licensure of didanosine, patients and physicians may be tempted to extrapolate from the results of this preliminary study a rationale for combination therapy with zidovudine plus didanosine or for zidovudine plus any of a number of unapproved drugs available through buyers' clubs. The present trial is a pilot study and awaits confirmation. Currently, and until additional drugs for the treatment of HIV infection are approved for use, a reasonable course of therapy for HIV-infected persons unresponsive or intolerant to therapy with zidovudine is monotherapy with didanosine.

Anthony S. Fauci, MD National Institutes of Health Bethesda, MD 20892 Requests for Reprints: Anthony S. Fauci, MD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 31, Room 7A03, Bethesda, MD 20892. Medicine.

1992;116:85-86.

References 1. Ho DD, Moudgil T, Alam M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med. 1989;321:1621-5. 2. Fischl MA, Richman DD, Causey DM, Grieco MH, Bryson Y, Mildvan D, et al. Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. AZT Collaborative Working Group. JAMA. 1989;262:2405-10. 3. Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989; 243:1731-4. 4. Richman DD, Grimes JM, Lagakos SW. Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. J Acquir Immun Defic Syndr. 1990,3:7436. 5. Fauci AS. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988;239:617-22. 6. Meng TC, Fischl MA, Boota AM, Spector SA, Bennett D, Bassiakos Y, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced HIV disease. A phase I/II study. Ann Intern Med. 1991;116:13-20. 7. Fauci AS. ddl—a good start, but still phase I. N Engl J Med. 1990;322:1386-8. 8. Lambert JS, Seidlin M, Reichman RC, Plank CS, Laverty M, Morse GD, et al. 2',3'-dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med. 1990;322:1333-40. 9. Cooley TP, Kunches LM, Saunders CA, Saunders CA, Ritter JK, Perkins CJ, et al. Once daily administration of 2',3'-dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a phase I trial. N Engl J Med. 1990;322:1340-5. 10. Tornevik Y, Eriksson S. 2',3'-Dideoxycytidine toxicity in cultured human CEM T lymphoblasts: effects of combination with 3'-azido-3'deoxythymidine and thymidine. Mol Pharmacol. 1990;38:23743. 11. Eron JJ, Hirsch MS, Merrill DP, Chou TC, Johnson VA. Synergistic inhibition of HIV-1 by the combination of zidovudine (AZT) and 2',3'-dideoxycytidine (ddC) in vitro. [Abstract]. Seventh International Conference on AIDS, Florence, Italy, 16-21 June 1991. 12. St. Clair MH, Martin JL, Tudor-Williams G, Bach MC, Vavro CL, King DM, et al. Resistance to ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 ;253: 1557-9. 13. Kovacs J A, Deyton L, Davey R, Falloon J, Zunich K, Lee D, et al. Combined zidovudine and interferon-a therapy in patients with Kaposi sarcoma and acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1989;111:280-7. 14. Krown SE, Gold JW, Neidzwiecki D, Bundow D, Flomenberg N, Gansbacher B, et al. Interferon-alpha with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1990;112:812-21. 15. Fischl MA, Uttamchandani RB, Resnick L, Agarwal R, Fletcher MA, Patrone-Reese J, et al. A phase I study of recombinant human interferon-alpha 2a or human lymphoblastoid interferon alpha nl and concomitant zidovudine in patients with AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr. 1991;4:1-10.

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1 January 1992 • Annals of Internal Medicine • Volume 116 • Number 1

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Combination therapy for HIV infection: getting closer.

EDITORIALS Combination Therapy for HIV Infection: Getting Closer r ersons infected with the human immunodeficiency virus (HIV), their health care pr...
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