Antiviral Potency of HAART Regimens and Clinical Success Are Not Strictly Coupled in Real Life Conditions: Evidence from the MASTER-1 Study Giampiero Carosi, MD,1 Francesco Castelli, MD,1 Fredy Suter, MD,2 Franco Maggiolo, MD,2 Anna Maria Orani, MD,3 Angelo Pan, MD,4 Massimo Andreoni, MD,5 Gian Marco Vigevani, MD,6 Renato Maserati, MD,7 Francesco Mazzotta,8 Carmine Tinelli,9 and the MASTER Study Group* 1
Institute of Infectious and Tropical Diseases, University of Brescia; 2Division of Infectious Diseases, Spedali Riuniti General Hospital, Bergamo; 3Division of Infectious Diseases, Lecco General Hospital; 4Division of Infectious Diseases, Istituti Ospitalieri, Cremona; 5Division of Infectious Diseases, Ospedale degli Infermi, Biella; 6Division of Infectious Diseases, S. Anna General Hospital, Como; 7Infectious Diseases Department, University of Pavia; 8 Division of Infectious Diseases, Ospedale S. M. Annunziata, Firenze; 9Biometrics Unit, Policlinico San Matteo, Pavia, Italy Purpose: To compare in a real clinical setting the largely unknown midterm clinical effectiveness of two protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimens with different potency and tolerability profiles in naïve patients. Method: This study was a multicenter, open-label, randomized trial in naïve patients with less than 400 CD4+ cell count/µL, regardless of viral load. Treatment arms were hard gel capsule saquinavir (HGCSQV)-based HAART (Arm A), with an expected more favorable tolerability profile, and indinavir (IDV)-based HAART (Arm B), with more potent virologic activity. While viroimmunological surrogate markers and World Health Organization (WHO) grade III toxicity (secondary endpoints) were regularly monitored, primary endpoints of the study were clinical and defined as any AIDS-defining event, AIDS-related death, WHO grade IV toxicity, drop outs, and protocol violations. Results: 262 consecutive patients were enrolled in the study from March 1, 1997 to December 31, 1997, in 24 different Italian clinical centers (132, Arm A; 130, Arm B). After 24 months of follow-up, patients who were enrolled in Arm B showed a significantly higher rate of virological success (75% had viremia below 500 copies/mL, CI = 12.9%, in the on-treatment analysis) and immunological gain (mean CD4+ cell count increase of 274 CD4+ cells/µL, SD = 234) when compared to patients enrolled in arm A (57%, CI = 15.5% and 223 CD4+ cells/µL, SD = 192; p = .0353 and .026, respectively). Despite the significant difference observed in surrogate markers, the number of total primary endpoints did not differ in the two groups (55 out of 132 in Arm A vs. 58 out of 130 personyears in Arm B; p = .86). Conclusion: Our results suggest that, after 24 months of follow-up in a real clinical setting, a PI-based HAART induces significant clinical benefits in naïve patients even in the absence of a complete suppression of viral replication. However, the long-term clinical impact of the possible accumulation of viral mutations in the presence of low-grade viral replication remains to be elucidated. Key words: clinical endpoints, HAART, real clinical setting
*Members of the MASTER-1 Study Group include: G. Carosi,1,3 F. Castelli,2,3,4 L.Tomasoni, A. Patroni (Brescia-1), F. Suter,3 F. Maggiolo, 3,4 M. Migliorino (Busto Arsizio), A.M. Orani,3 G. Castaldo, M. Nigro (Lecco), G. Carnevale,3 A. Pan3,4 (Cremona), M. Andreoni,3 A. Lingua (Biella), G.M.Vigevani,3, R. Visonà (Como), R. Ciammarughi, L.T. Martelli (Rimini), G. Pastore,3 N. Ladisa (Bari), L. Minoli,3 R. Maserati,3,4 C. Tinelli,4,6 L. Scudeller4,6 (Pavia), G.P. Cadeo,3 G. Paraninfo,5 D. Vangi, (Brescia-2), G. Riccio, V. Bartolacci (Pietra Ligure), M. Toti,3 C. Nencioni (Grosseto), A. Chirianni, V. Montesarchio (Napoli), A. Poggio, V. Mondino (Verbania), F. Mazzotta,3 M. Di Pietro, S. Lo Caputo3,4 (Firenze-1), S. Ranieri, G. Ballardini (Ravenna), S. Pauluzzi, G. Stagni (Perugia), A. Colomba (Palermo), G. Legnani (Bologna), D. Torre (Varese), G. Pagano (Genova), A. Scalzini (Mantova), F. Leoncini (Firenze-2), F.
Ghinelli (Ferrara), M. Moroni, (Milano), P. Cadrobbi (Padova), A. Borri (Mestre), F. De Lalla (Vicenza). The MASTER Project: 1 Scientific Director, 2Scientific Secretariat, 3Members of the Project Board, 4Members of the Writing Committee, 5Health Informatician Consultant, 6Statisticians. For correspondence and reprints contact: Prof. Giampiero Carosi, Institute of Infectious and Tropical Diseases, University of Brescia, Piazzale Spedali Civili, 1, 25123 Brescia, Italy. Email:
[email protected].
HIV Clinical Trials 2001;2(5):399–407 © 2001 Thomas Land Publishers, Inc.
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HIV CLINICAL TRIALS •
he availability of highly active antiretroviral therapy (HAART) since 1996 has dramatically changed the clinical impact of the HIV epidemic, at least in the developed world where HIV infection has acquired the feature of a chronic manageable illness that requires life-long treatment.1 Since the prognostic role of viral load as predictor of clinical progression has been demonstrated,2 viro-immunologic surrogate markers have become the gold standard for evaluating the effectiveness of antiretroviral regimens. This has prompted the registration of new therapies before their long-term clinical efficacy and safety are known. In addition, discordant viro-immunologic responses are often observed in clinical practice,3 and the relationship between virologic response to therapy and long-term clinical benefit has not been studied prospectively. Moreover, virological potency of complex threeor four-drug antiretroviral regimens is often offset by deterioration in the quality of life and is burdened by adverse events, which can lead to low adherence to prescribed treatment and the possible emergence of viral resistance. It has been suggested that hard gel capsule saquinavir (HGCSQV)-based regimens, which are more tolerated and have a nonoverlapping resistance profile, could also be clinically beneficial in the long term by preserving the option of switching to other PIbased regimens, if failure were to occur.4 Recently, a retrospective, nonrandomized study by Grabar and co-workers5 has suggested that the clinical outcome of HAART-treated individuals was largely unrelated to the virological potency of the regimen used. However, follow-up was too short to draw definitive conclusions, and longitudinal studies addressing this issue are lacking. In summary, despite unprecedented success, HAART still raises many questions. In particular, what is the midterm clinical effectiveness of protease inhibitor (PI)-based HAART regimens with different potency and tolerability profiles in the clinical practice, outside of closely monitored clinical trials? What is the value of viro-immunologic surrogate markers as predictors of midterm clinical effectiveness? To address these issues by means of specific studies, the MASTER Project (MAnagement Standardizzato di TERapia antiretrovirale [Standardized Management of Antiretroviral Therapy])
T
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was designed in early 1997 as a nonsponsored, multicenter, randomized, open-label, field conditions clinical trial to evaluate the midterm clinical benefit of the more potent (indinavir-based) versus the better tolerated (HGC-SQV-based) PI-based approach in antiretroviral-naïve and antiretroviral-experienced HIV-infected patients. Our preliminary results have also supported the idea that virological potency is not the main determinant of clinical efficacy of PI-based HAART.6,7 This article reports the final results on the naïve component of the study. MATERIALS AND METHOD Patients Consecutive antiretroviral-naïve patients (less than 4 months of previous nucleoside reverse transcriptase inhibitor [NRTI] therapy) were enrolled in 24 clinical centers in Italy from March 1 to December 31, 1997, after written informed consent was obtained. Entry criterion was CD4+ cell count below 400/µL, regardless of HIV viral load. Approval was obtained by the Italian Ministry of Health and by Ethical Committees of each participating center. Treatment Patients were randomized to receive either of the following treatments: Arm A =
AZT (or d4T) + ddX (ddI or ddC) + HGC-SQV
Arm B =
AZT (or d4T) + 3TC + IDV
Standard dosages were used: zidovudine (AZT, 250 mg bid), stavudine (d4T, 30 or 40 mg bid), didanosine (ddI, 200 mg bid), zalcitabine (ddC, 0.75 mg tid); lamivudine (3TC, 150 mg bid), HGC-SQV (600 mg tid); indinavir (IDV, 800 mg tid). Patients were regularly assessed (clinical outcome, CD4+ cell count, HIV RNA, toxicity) at 4-month intervals. Endpoints Primary endpoints of the study were defined as follows: 1. AIDS-related deaths; 2. AIDS-defining events; 3. WHO grade IV adverse events; 4. drop-outs and loss to follow-up (failure to report for more than 8 months); and
BENEFITS OF HAART IN CLINICAL PRACTICE
5. protocol violations. Viro-immunological failure was defined, starting from month 8 on, as (a) inadequate (< 1 log) HIV RNA decrease, (b) viral load higher than 30,000 copies/mL, and (c) increase of HIV RNA (> 1 log) compared to nadir or (d) decrease (>25%) of CD4+ cell count compared to baseline. All laboratory tests were performed at each individual center. When bDNA test was used, results were normalized to RT-PCR at the coordinating center using the conversion scale provided by the Panel on Clinical Practices for the Treatment of HIV Infection.8 When confirmed viro-immunological failure or WHO grade III toxicity (secondary endpoints) occurred after rechallenge, patients in Arm A were shifted to Arm B and patients in Arm B were shifted to four-drug therapy including 2 NRTI + 2 PI (SQV 400 mg bid + ritonavir [RTV] 400 mg bid). The rate of patients in whom viral replication was not detected (HIV RNA
