Letter To the Editor
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 39(1) 1 May 2005
Zaccarelli, Mauro MD; Zinzi, Daniela MD; Trotta, Maria Paola MD; Liuzzi, Giuseppina MD; Sette, Pietro MD; Marconi, Patrizia MD; Acinapura, Rosa MD; Antinori, Andrea MD
III Divisione, Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Instituto Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Supported by grants of Ricerca Corrente e Finalizzata degli IRCCS, Ministero della Salute, and by the Programma Nazionale di Ricerca sull'AIDS, Istituto Superiore di Sanità, Italy.
To the Editor:
Atazanavir (ATV) is a recently licensed protease inhibitor (PI) showing a favorable lipid profile as compared with other drugs of the same class.1
In Italy, the drug has only been approved for use in PI-pretreated patients and with ritonavir boosting (ATV/r). Up to now, it has been available through an Early Access Program (EAP).
To evaluate the efficacy of switching to ATV/r from a previous antiretroviral (ARV) regimen, we performed an analysis of a group of patients enrolled in the EAP at our center.
Among an overall total of 149 patients treated with the ATV/r-containing regimen, we selected 102 patients who were switched to ATV/r plus a combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in the context of a simplification strategy: (1) as intolerant to the previous regimen (n = 76, 74.5%), (2) as reporting or being at risk for low adherence because of the pill burden or dosing frequency (n = 18, 17.7%), and (3) in case of treatment failure but related to discontinuation because of side effects or suboptimal adherence (n = 8, 7.8%).
All patients underwent a blood test, including a CD4+ cell count and HIV-1 RNA and metabolic assessment at baseline, every month during the first 3 months, and, subsequently, every 3 months. The patients were prospectively evaluated up to virologic failure, considered as 2 consecutive HIV RNA levels of >500 copies/mL or interruption of ATV/r for any cause. Survival analysis using the Kaplan-Meier method and Cox proportional hazard model was performed to assess the probability of and factors associated with failure and/or interruption.
The characteristics of patients were as follows: 63.7% were male, mean age was 42 years, intravenous drug use was reported in 37.3%; median CD4+ count at ATV/r initiation was 396 cells/μL; proportion of HIV RNA levels <500 copies/mL was 66.5%; median overall duration of pre-ATV/r therapy was 60 months; and median numbers of ARV drugs and treatment regimens used before ATV/r were 6 and 3, respectively. Twenty-nine patients (28.4%) experienced at least 1 pre-ATV/r virologic failure.
Switching to ATV/r, most patients simplified their combination regimen: 97 (95.1%) reduced their pill burden, and 66 (64.7%) reduced their daily dose, with 62 switching to a once-daily regimen.
Evidence of lipodystrophy (lipoatrophy and/or fat accumulation) was present in 78 patients (76.5%); lipodystrophy was diagnosed if reported by the patient and confirmed by medical examination.
Over a median follow-up of 6 months (range: 1-13 months, interquartile range: 3-9 months), 13 treatment failures were observed, of which 5 were virologic failures and 8 were ATV/r interruptions. Reasons for interruption were as follows: elevation in bilirubin level (2 patients), elevation in transaminase level (2 patients), skin rash (2 patients), stroke not related to ATV/r treatment (1 patient), and patient decision (1 patient). Treatment failure was less frequently observed in patients with lipodystrophy than among other patients (6 of 78 patients [7.7%] vs. 7 of 24 patients [29.2%]; P < 0.01).
The proportion of patients with <500 copies/mL of HIV RNA increased during follow-up from 66.5% at enrollment to approximately 90% from the second month up to 1 year.
A progressive decrease in cholesterol and triglycerides levels was observed through the course of follow-up, particularly from the sixth month of ATV/r therapy. No significant reversion of lipodystrophy was observed.
Kaplan-Meier survival analysis showed a probability of treatment failure of 10.0% at 3 months; 14.7% at 6 months, and 17.9% at 9 and 12 months. On multivariate analysis (Table 1), including factors significant in the univariate model, patients with diagnosed lipodystrophy at the time they switched to ATV/r had a significantly lower risk of failure. In contrast, having experienced at least 1 pre-ATV/r virologic failure was significantly associated with a higher risk of failure. A lower CD4+ cell count and higher HIV RNA level were not found to be significantly associated with ATV/r failure.
Table 1. Factors Related to Treatment Failure in Patients Taking ATV-Containing Regimens on Multivariate Analysis (Cox model)
Two observations were made from our experience with PI-pretreated patients switched to the ATV/r-containing combination regimen.
First, ATV/r showed effectiveness in rescuing patients who, even in course of effective treatments, showed adherence or toxicity problems and need of simplified therapy.
In our nonrandom sample, the proportions of treatment failure were comparable to those reported in other observational or randomized studies2-4 evaluating different simplification strategies.
Second, the evidence of a lower proportion of failure found in patients with lipodystrophy might be related to better adherence.
Indeed, before starting ATV/r, patients were informed by the physician responsible for their care that the drugs do not cause lipid elevation and may also improve lipodystrophy over time.1,5
It has already been demonstrated that the relation between lipodystrophy and adherence is a dynamic process. Better adherence is associated with an increased risk of developing lipodystrophy; however, in contrast, the patient's perception of lipodystrophy can lead to decreased adherence in long-lasting ARV treatments.6,7
Thus, in patients who experienced lipodystrophy syndrome, switching to ATV/r, with its low metabolic interference and easy dosing regimen, may offer a good chance for preserving long-term adherence.
REFERENCES
1. Wood R, Phanuphak P, Cahn P, et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr. 2004;36:684-692.
2. Martínez E, Arnaiz J, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med. 2003;349:1036-1046.
3. Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. Clin Infect Dis. 2002;34:504-510.
4. Maggiolo F, Ripamonti D, Ravasio L, et al. Outcome of 2 simplification strategies for the treatment of human immunodeficiency virus type 1 infection. Clin Infect Dis. 2003;37:41-49.
5. Haerter G, Manfras BJ, Mueller M, et al. Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir. AIDS. 2004;18:952-995.
6. Ammassari A, Antinori A, Cozzi-Lepri A, et al. Relationship between HAART adherence and adipose tissue alterations. J Acquir Immune Defic Syndr. 2002;31(Suppl 3):S140-S144.
7. Duran S, Saves M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS. 2001;15:2441-2444.
