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Rescue Therapy With Once-Daily Atazanavir-Based Regimens for Antiretroviral-Experienced HIV-Infected Patients
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[Letters to the Editor]
"....The major finding of this study is that even if management of HIV-infected patients who have experienced prior virologic failure is challenging and often not successful, nowadays, pretreated patients in need of rescue therapies can also benefit from simple regimens, at least in the short-term. In this cohort, all patients received a once-daily regimen with a low pill burden and the initial virologic decline was deeper than expected....Further studies are needed to confirm these observations, to define the best scenario for these once-daily combinations, and to optimize the most effective therapeutic measures in this population."
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 42(2) June 2006 pp 258-259
Dronda, Fernando; Antela, Antonio; Perez-Elias, Maria J.; Casado, Jose L.; Moreno, Ana; Moreno, Santiago
Servicio de Enfermedades Infecciosas, Hospital Ramon y Cajal, Madrid, Spain
To the Editors:
Antiretroviral treatment for patients who have failed previous regimens is frequently complex; includes a high number of drugs, doses, and pills, and is inconvenient for HIV-infected patients.1,2 Protease inhibitors (PIs) are frequently included in these regimens because the nonnucleosides are no longer useful because of development of high-level cross-resistance. The administration of most PIs requires multiple daily doses and a high number of pills, but development of once-daily PI-containing combinations has been achieved recently.3-5 Atazanavir (ATV) is a new, potent, safe, and well-tolerated azapeptide PI that can be dosed once daily and has shown a good efficacy, tolerability, and convenience profile in clinical trials of PI-experienced patients.6-8 However, there is little information about its efficacy in heavily antiretroviral-experienced HIV-infected patients. The administration of ATV, together with other drugs approved for once-daily dosing, can allow regimens to be fully administered once a day. We evaluated the efficacy and safety of ATV-based rescue regimens, in combination with drugs approved for once-daily administration, given in a clinical setting.
We describe a prospective cohort study of multiexperienced patients who initiated salvage therapy at a single center in Madrid, Spain. All antiretroviral-experienced HIV-seropositive patients (n = 56) who initiated a rescue highly active antiretroviral therapy with an ATV-based regimen between March 2003 and September 2004 were included in this analysis. ATV was administered through an early access program for the drug in Spain. Treatment-experienced patients with 2 consecutive viral load determinations above 1000 copies/mL were included. CD4 cell counts and HIV-1 RNA plasma levels, as well as blood and chemistry analyses, were determined at baseline and every 12 weeks thereafter. The primary end point was the virologic outcome, measured by variation in plasma HIV RNA levels and the proportion of patients with HIV RNA level <50 copies/ml, at month 12. Secondary objectives included immunologic response and safety. We adopted a 5% significance level for all tests. Analyses were performed using statistical software (version 11.0; SPSS, Chicago, IL).
Demographics and baseline characteristics are shown in Table 1. Median CD4 was 257, nadir CD4 was 160. 61% were HCV+ & 7% HBV+. Most patients were young men (71%), former injection drug users (65%), and severely pretreated. Patients were receiving their 10th line of antiretroviral therapy during a median of almost 4 years, and the median number of prior taken drugs was 9. Most patients (91%) had failed with at least one PI, and 69% had received 2 or more PIs. Patients had 5 median PI mutations; 17% had UPAMS; patients had 10 median NRTI mutations: 21% >5 NAMs; 21% M184V; 8% 'multiresistant'. 29% had NNRTI resistance. Other drugs included in the combination regimens were didanosine (ddI) + tenofovir disoproxil fumarate (TDF) (62.5%), lamivudine (3TC) + TDF (16%), ddI + 3TC (12.5%), ddI + 3TC + TDF (7%), and efavirenz + TDF (2%). Almost half of the patients (48%) were on "drug holidays" (ie, discontinuation of treatment because of lack of virologic response with prior regimens). Median HIV RNA and CD4 cell count (interquartile range, IQR) values at 6 and 12 months were 1.8 log10 (1.7-3.08) and 411 cells/mL (237-573), and 1.8 log10 (1.7-2.65) and 325 (184-541) cells/mL, respectively. Proportion of patients achieving HIV RNA <50 copies/mL at the same time points were 46% and 48%, respectively. After 12 months, data from 46 patients were available for analyses. From baseline to month 12, median CD4 cell count change was +68 cells/mL, and the median viral load decrease was 2.5 log10.
The major finding of this study is that even if management of HIV-infected patients who have experienced prior virologic failure is challenging and often not successful, nowadays, pretreated patients in need of rescue therapies can also benefit from simple regimens, at least in the short-term. In this cohort, all patients received a once-daily regimen with a low pill burden and the initial virologic decline was deeper than expected. At 12 months, almost half of our patients had a viral load <50 copies/mL, a percentage that is comparable with the results from a 48-week rescue trial in which 38% of patients reached <50 copies/mL when included on ATV/ritonavir (RTV) combination regimens.8 In this trial, antiretroviral-experienced patients who had had virologic failure on 2 or more highly active antiretroviral therapy regimens were randomized to receive ATV (boosted with RTV or in combination with saquinavir) or lopinavir/RTV.8 Median prior exposure to any PI, nonnucleoside reverse transcriptase inhibitor, and nucleoside reverse transcriptase inhibitor were 2.5, 1.5, and 5.1 years, respectively. A quarter of patients included in the ATV/RTV arm had 4 or more PI mutations.8
In our cohort, patients were receiving (median) their 10th line of antiretroviral therapy when they started the ATV-containing regimen, and the median number of mutations was high in both the retrotranscriptase (10, IQR: 5-15) and protease (5, IQR: 4-8) genes. Twenty-five percent of patients had key mutations in the protease gene. TDF was the most frequently used retrotranscriptase inhibitor because many patients were naive for this drug. DDI plus TDF combination, which was administered to almost two thirds of the patients, is no longer recommended because of a possible deleterious effect on CD4 reconstitution.9 Despite these facts, the virologic responses were good and a subsequent increase in the CD4 cell counts was observed.
Although this is an observational, clinical cohort study with a limited number of patients, and we cannot exclude the possibility that our results were distorted by residual confounding or unmeasured factors, it shows that antiretroviral-experienced HIV-infected patients may also benefit from simple regimens with low pill burden administered once daily, and can achieve a sustained immunovirologic response. Further studies are needed to confirm these observations, to define the best scenario for these once-daily combinations, and to optimize the most effective therapeutic measures in this population.
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