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AIDS:
Research Letter

The ADAM study continued: maintenance therapy after 50 weeks of induction therapy

Reijers, Monique H. E.a; Weverling, Gerrit Janab; Jurriaans, Suzannec; Roos, Marijke T. L.d; Wit, Ferdinand W. N. M.a; Weigel, Hugo M.e; Kate, Reinier W. Tenf; Mulder, Jan Willemg; Richter, Clemensh; Hofstede, Hadewich J. M. Teri; Sprenger, Hermanj; Hoetelmans, Richard M. W.k; Schuitemaker, Hanneked; Lange, Joep M. A.a

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aNational AIDS Therapy Evaluation Centre, Department of Internal Medicine, bDepartment of Clinical Epidemiology and Biostatistics, and cDepartment of Human Retrovirology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; dDepartment of Clinical Viro-Immunology, CLB, Sanquin Blood Supply Foundation, Amsterdam, the Netherlands; eDepartment of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands; fDepartment of Internal Medicine, Kennemer Gasthuis, Haarlem, the Netherlands; gDepartment of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands; hDepartment of Internal Medicine, Academic Hospital Rijnstaete, Arnhem, the Netherlands; iDepartment of Internal Medicine, Academic Hospital Nijmegen, Nijmegen, the Netherlands; jDepartment of Internal Medicine, Academic Hospital Groningen, Groningen, the Netherlands; kDepartment of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.

Sponsorship: This study was supported financially by Roche and Bristol–Myers Squibb.

Received: 26 July 2000;

revised: 26 September 2000; accepted: 10 October 2000.

Induction–maintenance regimens in antiretroviral therapy might improve patient compliance by facilitating drug intake, reducing the pill burden and reducing the toxicity of antiretroviral drug regimens [1]. The induction–maintenance strategy has been investigated in three studies: the AIDS Clinical Trials Group (ACTG) 343, the Trilège, and the Amsterdam Duration of Antiretroviral Medication (ADAM) study. The three studies used different periods of induction therapy, patient populations, and antiretroviral agents. Nevertheless, each trial indicated that maintenance therapy with one or two antiretroviral drugs could not sustain the suppression of viral replication in a significant proportion of patients [2–4]. The duration of induction therapy varied from 3 to 6 months in the three studies. Perhaps this was too short to make maintenance therapy possible. At the time of the design of the ADAM study, it was speculated that with the duration of therapy, the amount of HIV-1 RNA in cellular and anatomical reservoirs would decrease further [5], reducing the risk of viral escape [6,7].

The design of the ADAM study provided the opportunity to investigate whether the duration of induction therapy was of significance for the results of maintenance therapy. All patients started the induction phase with a quadruple drug regimen consisting of stavudine (d4T, 40 mg twice a day), lamivudine (3TC, 150 mg twice a day), saquinavir hard-gelatin capsules (SQV-HGC, 600 mg three times a day) and nelfinavir (NFV, 750 mg three times a day). When saquinavir soft-gelatin capsules (SQV-SGC) became available (1 November 1997), all patients using SQV-HGC switched to SQV-SGC (800 mg three times a day). Patients were switched to SQV-SGC (1200 mg twice a day) and NFV (1250 mg twice a day) on 1 September 1998, in order to facilitate drug intake [8]. The baseline characteristics of the 65 patients enrolled have been reported elsewhere [9]. The randomization to maintenance therapy after 26 weeks of induction therapy was discontinued prematurely, because inferior suppression of viral replication was found in patients randomly assigned to maintenance therapy compared with patients randomly assigned to prolonged induction therapy [4]. Albeit with a smaller number of patients than initially targeted, the trial was continued to investigate whether the prolongation of induction therapy to 50 weeks could contribute to the results of maintenance therapy. Only patients with a plasma HIV-1-RNA concentration below the lower limit of quantification (LLQ) of an ultrasensitive assay at both weeks 48 and 49 were allowed to be randomly assigned at week 50 to continued quadruple drug therapy or to one of the following maintenance regimens: d4T plus NFV or SQV plus NFV. At week 50, 17 out of 65 patients were randomly selected. The reasons for not randomly selecting at week 50 were: lost to follow-up (three), previous randomization to maintenance therapy at week 26 (16), treatment failure (two), toxicity (10) [9], a plasma HIV-1-RNA concentration above the LLQ at weeks 48 and 49 (nine), or at the request of the patient (eight). One of the seven patients randomly assigned to continued quadruple therapy decided to take a ‘drug holiday', and another patient experienced lipodystrophy, leading to a switch of therapy. Ten patients were randomly assigned to maintenance therapy with either d4T plus NFV (six) or SQV plus NFV (four). One patient in each maintenance arm refused maintenance therapy.

At week 60, one out of five patients in the continued quadruple drug therapy arm had a plasma HIV-1-RNA concentration above the LLQ compared with three out of eight patients on maintenance therapy. At week 96, after a total follow-up of 46 weeks, treatment failure had occurred in one out of five patients (20%) using quadruple drug therapy, and in five out of eight patients (63%) using maintenance therapy (Fisher exact:P = 0.16). Subsequently, we compared patients randomly assigned to maintenance therapy at week 26 (n = 16) and week 50 (n = 10, Table 1). Patients were comparable for their baseline characteristics and change in CD4 and CD8 T cell counts at the time of randomization. The time to a plasma HIV-1-RNA concentration greater than 50 copies/ml of the ultrasensitive assay or greater than 400 copies/ml during maintenance therapy was comparable among patients who used induction therapy for 26 or for 50 weeks (Table 1).

Table 1
Table 1
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In conclusion, prolonging the induction therapy from 26 to 50 weeks does not seem to contribute to the virological success of the maintenance regimens.

As already stated, this study is limited by the small number of patients because of the premature discontinuation of enrolment. It is therefore unfortunate that a considerable number of patients refused study medication for personal reasons, both before (eight) and after (two) randomization. The results of the quality-of-life study indicated that the knowledge of an incomplete suppression of the viral load was of significance to the quality of life of the patients randomly assigned to maintenance therapy after 26 weeks of induction therapy [10]. It is therefore likely that the negative results of the interim analysis, which were communicated to the patients participating in the study, had influenced patients to abandon randomization at week 50.

Several studies have indicated that even after long-term suppression of viral replication to less than 50 copies/ml, low level replication remains present [11]. In addition, in the ACTG 343 and Trilège studies, failure during maintenance therapy appeared to be highly attributable to insufficient potency of the maintenance regimens [12,13]. It is therefore not surprising that even after 50 weeks of induction therapy, viral replication could again increase during maintenance therapy. Moreover, Fleury et al. [14] recently showed that the pool of proliferating CD4 T cells was found to be enlarged for at least 48 weeks after the start of antiretroviral treatment, suggesting that randomization after 50 weeks of induction therapy might still be accompanied by increased target cell availability [2].

In conclusion, patients randomly assigned to maintenance therapy after 50 weeks of induction therapy seem to have a rebound to a detectable HIV-1-RNA concentration in plasma more often than patients randomly assigned to continued quadruple drug therapy. The time to viral rebound is comparable for patients randomly assigned to maintenance therapy at weeks 26 and 50. Apparently, a longer period of induction therapy does not postpone viral rebound during maintenance therapy.

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Acknowledgements

The authors would like to thank Roche for supplying study medication and financial support, and Bristol–Myers Squibb for financial support. Furthermore all persons in the ADAM Study Team are acknowledged. Most of all, the patients in this study are thanked for their participation.

Monique H. E. Reijersa

Gerrit Jan Weverlingab

Suzanne Jurriaansc

Marijke T. L. Roosd

Ferdinand W. N. M. Wita

Hugo M. Weigele

Reinier W. Ten Katef

Jan Willem Mulderg

Clemens Richterh

Hadewich J. M. Ter Hofstedei

Herman Sprengerj

Richard M. W. Hoetelmansk

Hanneke Schuitemakerd

Joep M. A. Langea

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References

1. Cooper DA. Therapeutic strategies for HIV infection – time to think hard. N Engl J Med 1998, 339: 1319 –1321.

2. Havlir DV, Marschner IC, Hirsch MS. et al. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med 1998, 339: 1261 –1268.

3. Pialoux G, Raffi F, Brun-Vézinet F. et al. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine and indinavir in previously untreated HIV-1-infected patients. N Engl J Med 1998, 339: 1269 –1276.

4. Reijers MHE, Weverling GJ, Jurriaans S. et al. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet 1998, 352: 185 –190.

5. Perelson AS, Essunger P, Cao Y. et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature 1997, 387: 188 –191.

6. Cavert W, Notermans DW, Staskus K. et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 1997, 276: 960 –964.

7. Notermans DW, Jurriaans S, de Wolf F. et al. Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. AIDS 1998, 12: 167 –173.

8. Petersen A, Johnson M, Nelson M. Long-term comparison of BID and TID dosing of nelfinavir (NFV) in combination with stavudine (d4T) and lamivudine (3TC) in HIV patients. 12th World AIDS Conference. Geneva, Switzerland, 28 June–3 July 1998 [Abstract 12224].

9. Reijers MHE, Weigel HM, Hart AAM. et al. Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study. AIDS 2000, 14: 59 –68.

10. Nieuwkerk P, Reijers MHE, Weigel HM, Lange JMA, Sprangers MAG. Quality of life in maintenance- vs prolonged induction therapy for HIV. JAMA 2000, 284: 178 –179.

11. Zhang L, Ramratnam B, Tenner-Racz K. et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999, 340: 1605 –1613.

12. Descamps D, Flandre P, Calvez V. et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction–maintenance therapy. JAMA 2000, 283: 205 –211.

13. Havlir DV, Hellmann NS, Petropoulos CJ. et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA 2000, 283: 229 –234.

14. Fleury S, Rizzardi GP, Chapuis A. et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc Natl Acad Sci USA 2000, 97: 5393 –5398.

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© 2001 Lippincott Williams & Wilkins, Inc.

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