Cossarini, Francesca MD; Salpietro, Stefania MSc; Galli, Laura MSc; Gianotti, Nicola MD; Nozza, Silvia MD; Spagnuolo, Vincenzo MD; Hasson, Hamid MD; Bossolasco, Simona MD; Lazzarin, Adriano MD; Tambussi, Giuseppe MD; Castagna, Antonella MD
Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
The authors have no funding or conflicts of interest to disclose.
To the Editors:
Treatment simplification strategies in the setting of viral suppression during highly active antiretroviral therapy (HAART) are increasingly investigated in HIV-infected patients in response to the need to reduce toxicities, side effects, pill burden, and costs while perhaps improving adherence and maintaining efficacy. In this perspective, monotherapy with a ritonavir-boosted protease inhibitor (PI) is an appealing treatment simplification strategy in that PIs have a high potency, high genetic barrier, a low pill burden, are well tolerated, and do not show toxicities that are characteristics of nucleoside reverse transcriptase inhibitors.1–4
Noninferiority trials have demonstrated the feasibility of this strategy for lopinavir/r5 and darunavir/r.6,7 Atazanavir (ATV) has not been studied as extensively as other PIs for monotherapy treatment: previous studies including a limited number of patients showed conflicting results, with a percentage in virologic failure (VF) during simplification as high as 30% in one study.8–10 ATV, however, seems worth studying for a simplification strategy given its proven tolerability and once-daily dosing.
We describe here viroimmunologic response to a treatment simplification strategy with ATV monotherapy [atazanavir/ritonavir (ATV/r) 300/100 mg once daily or ATV 400 mg once daily] in patients with virologic suppression.
We retrospectively analyzed HIV-infected individuals currently followed at our clinic who switched from an HAART regimen to either an ATV/r or an ATV monotherapy while virologically suppressed (HIV RNA < 50 copies/mL) for at least the previous 6 months and with available immune and virologic records over at least 1 month after treatment simplification. Monotherapy was censored at last available visit or at the date of discontinuation (drug switches or interruption). The aim of the study was to evaluate the cumulative proportion of VF, defined as the first of 2 consecutive HIV RNA >50 copies per milliliter, and the immunologic variation, defined as CD4+ and CD8+ change, during ATV monotherapy. Results are expressed as median (interquartile range) or n (%).
Forty-three subjects were included: 30 (70%) men and 13 (30%) women with a median age of 45.2 (39.3–53.7) years. Patients' demographic characteristics are shown in Table 1. Before antiretroviral treatment initiation, CD4+ cell count and HIV RNA were 312 (251–510) cells per microliter and 118,769 (36,000–290,000) copies per milliliter.
Before switching to monotherapy, patients had been taking the last HAART for a median of 2.1 (1.3–5.4) years. Twenty-four patients (56%) were on a PI regimen [17 on ATV (40%)] before monotherapy.
ATV/r or ATV was prescribed in 30 (70%) and 13 (30%) patients, respectively. Patients switched to monotherapy mainly due to toxicity [31 (72%)] or reduction of pill burden [8 (19%)] (Table 1). After a median of 10.0 (5.4–23.4) months of follow-up, 3 subjects (7%) experienced VF: 2 patients were taking ATV 400 mg once daily and 1 patient was taking ATV/r 300/100 mg once daily. Overall CD4+ change during monotherapy was −9 (−79/+75) cells per microliter (P = 0.654); CD4+% change was 1 (−2.7/+3.9; P = 0.347), CD8+ change was −111 (−289/+19) cells per microliter (P = 0.003), and CD8% change was −5 (−7.1/−1; P < 0.0001).
ATV monotherapy was well tolerated, and no serious adverse events were recorded. No clinically significant modifications in renal function, fasting glucose, or lipid profile were observed (Table 2).
Total bilirubin increased significantly during ATV monotherapy (P = 0.0001), and aspartate aminotransferase decreased both during HAART (P = 0.001) and during monotherapy (P = 0.007; Table 2). Only the increase in total bilirubin was higher during monotherapy compared with HAART period, and changes of other safety parameters were not different between HAART and monotherapy periods.
In this single-center, retrospective, observational study, we found a very low proportion of VF on ATV monotherapy, comparable to or lower than what was reported by previous studies.8–10 Our results were very similar to those reported by Swindells et al and Vernazza et al over a similar follow-up period, whereas Karlstrom et al found a much greater proportion of VF: 30% (5 of 15 patients). These differences may be related in the different study designs and definition of VF. We studied patients who might have experienced VF before ATV monotherapy and used an HIV RNA threshold of 50 copies per milliliter. Swindells et al used a threshold of 400 copies per milliliter, Vernazza et al used a multiple endpoint of 2 consecutive measurements above 400 copies per milliliter or 3 above 200 copies per milliliter or 4 above 100 copies per milliliter, and both studied patients without history of VF. Both studies included patients without previous VFs. In this perspective, we observed a lower proportion of VF than what we might have expected based on those previous results.
Conversely, Karlstrom et al studied patients who did not experience previous failures to PIs but might have had other treatment failures and defined VF using an HIV RNA threshold of 20 copies per milliliter. In this perspective, we might have missed some VFs that were to be expected; nonetheless, an HIV RNA threshold of 50 copies per milliliter is the most widely used to define VF.
During ATV monotherapy, we also observed stable CD4+ counts and a reduction in CD8+ counts, which might argue in favor of a reduction in the magnitude of immune activation, although we did not have a direct measure of either activated T-cell subsets or inflammation markers. Bilirubin increased significantly, as expected during ATV treatment, especially considering that the majority of patients were not on ATV in their previous HAART regimen. We observed a reduction of aspartate aminotransferase both during last HAART regimen and during monotherapy, in line with the liver tolerability profile of ATV.11
Some limitations for the present study need to be highlighted. It is a single-center, retrospective, single-arm study with a limited sample size. To our knowledge, however, all studies published so far also have a relatively small sample size and there are no randomized studies comparing ATV monotherapy with an ATV-based HAART. The retrospective nature of this study might certainly have biased the study; nonetheless, our results may support a potential role for ATV in PI monotherapy simplification strategies and encourage further studies on this topic.
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