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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e318157b0da
Letters to the Editor

Plasma Levels, Safety, and 60-Week Efficacy of a Once-Daily Double-Boosted Protease Inhibitor Regimen of Atazanavir, Saquinavir, and Ritonavir

Manosuthi, Weerawat MD*; Sungkanuparph, Somnuek MD†; Ruxrungtham, Kiat MD‡; Prasithsirikul, Wisit MD*; Athichathanabadi, Chatiya BSc*; Tantisiriwat, Woraphot MD§; Bowonwatanuwong, Chureeratana MD∥; Chumpathat, Nopphanath Med*; Chaovavanich, Achara MD*

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*Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand; †Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; ‡The HIV Netherlands-Australia-Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; §Department of Preventive Medicine, Faculty of Medicine, Srinakharinwirot University, Nakornnayok, Thailand; ∥Department of Medicine, Chonburi Hospital, Ministry of Public Health, Chon Buri, Thailand

To the Editor:

The administration of low-dose ritonavir as a pharmacokinetic enhancer of other protease inhibitors (PIs) provides many benefits and improves the management of HIV infection. PI-based regimens that contain RTV may increase drug bioavailability, possibly delaying or preventing the emergence of PI-resistant variants in HIV-infected patients.1,2 One potential role of double-boosted PI regimens is treatment for patients whose reverse transcriptase inhibitor options are limited due to drug resistance, but who still retain PI options. The goal of salvage therapy among these patients is still to achieve and maintain an undetectable plasma HIV-1 RNA level.

The addition of low-dose ritonavir results in increased plasma levels of both atazanavir (ATV) and saquinavir (SQV). ATV also significantly increases the SQV level.3-5 In addition, both PI drugs had nonoverlapping resistance profiles.6 However, there is scant data on the pharmacokinetics, efficacy, and metabolic effects of this regimen so far. We therefore conducted a prospective study to assess the steady-state minimum plasma concentrations (Cmin), safety, tolerability, and efficacy of a once-daily double-boosted PI regimen of ATV and SQV soft gel capsule (SQV-SGC) with low-dose ritonavir (r) for salvage therapy.

The study design was a prospective cohort study involving 24 HIV-infected patients in the Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand. Inclusion criteria for HIV-infected patients were: (1) older than 18 years, (2) previously treated with and failed all currently available nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, and (3) willing to participate and sign the informed consent. Exclusion criteria were: (1) baseline creatinine >1.5 mg/dL, (2) baseline aspartate aminotransferase (AST) >2 times upper normal value, and (3) previously received PI drugs. A once-daily dose of ATV/SQV-SGC/r at 300/1600/100 mg was given. All subjects were followed until 60 weeks. CD4 counts, plasma HIV-1 RNA, liver enzymes, and lipid profiles were assessed every 12 weeks. Additionally, liver enzymes were assessed at 8 weeks.

At 6 and 12 weeks, blood samples for ATV and SQV levels were obtained 24 hours after administration to analyze levels using a high-performance liquid chromatography assay. The assay was developed at the Department of Clinical Pharmacology at the University Medical Centre Nijmegen, the Netherlands. The sample peak heights were processed using ChromQuest software version 1.0 (Thermo Fisher Scientific, Waltham, MA).

Paired t test were used to compare serum lipid levels before and after 60 weeks of treatment. P value <0.05 was considered statistically significant. All analyses were performed using SPSS version 11.5 (SPSS, Chicago, IL). The institutional ethics committees of Bamrasnaradura Infectious Diseases Institute approved the study.

There were 24 patients, with 14 (58%) of them male. Mean plus or minus standard deviation (mean ± SD) baseline CD4 cell counts were 179 ± 132 cells/mm3; median (interquartile range [IQR]) log plasma HIV-1 RNA was 4.6 (4.0 to 5.0). Median (IQR) duration of prior antiretroviral therapy was 30 (20 to 41) months. Twenty-two (92%) patients had TAMs + M184V resistance mutations and 2 (8%) patients had TAMs + Q151M. All had NNRTI resistance. Distributions of Cmin are shown in Figure 1. Median (minimum-maximum) ATV Cmin was 720 (60-2540) ng/mL, and SQV Cmin was 300 (20-3540) ng/mL. Of 24 patients, 23 (95.8%) patients achieved adequate ATV Cmin and SQV Cmin. At week 8, no patients had grade 3 to 4 transaminase elevations. There was an increment of mean total bilirubin and indirect bilirubin at 8 weeks from baseline (0.6 vs. 2.0 mg/dL and 0.5 vs. 1.7 mg/dL; P < 0.001). No patients discontinued ATV/SQV-SGC/r due to adverse reactions.

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At baseline, 7 (29%), 11 (46%), 6 (25%), 3 (13%), and 5 (21%) patients had total cholesterol >200 mg/dL, low-density lipoprotein (LDL) cholesterol >130 mg/dL, LDL cholesterol >160 mg/dL, triglycerides >400 mg/dL and high-density lipoprotein (HDL) cholesterol <35 mg/dL, respectively. At 60 weeks, there were 12 (50%), 15 (63%), 9 (38%), 2 (8%), and 3 (13%) patients within the corresponding parameters. Mean LDL cholesterol at 60 weeks rose from baseline value (to 143.0 mg/dL from 122.3 mg/dL; P = 0.008). Five (21%) patients needed to commence taking or increase the dosage of antilipid agents.

After 60 weeks, 18 (75%) patients and 14 (58%) patients achieved undetectable HIV-1 RNA at <400 and <50 copies/mL, respectively. No major PI-associated mutation was detected after HIV-1 RNA >1000 copies/mL. At 12, 24, 36, 48, and 60 weeks, mean CD4 counts were 265, 298, 342, 353, and 389 cells/mm3, respectively.

Once-daily administration of ATV 300 mg and SQV-SGC 1600 mg boosted with 100 mg of ritonavir provided adequate trough plasma ATV and SQV levels. The recent Department of Health and Human Services (DHHS) guideline suggested minimum target trough concentration for ATV and SQV at >150 and >100 ng/mL, respectively.7 In our study, median ATV Cmin was 720 ng/mL. This was comparable to the previous study.3,4 However, SQV Cmin was 300 ng/mL, which was greater than the previous study.4 This may be explained by the difference of SQV formulation. Only 1 patient could not achieve adequate ATV and SQV levels. Boffito4 demonstrated that addition of ATV to SQV/r resulted in an increase in SQV levels. Conversely, ATV levels were not significantly changed by the addition of SQV. There was a wide range of ATV and SQV Cmins in the present study. Genetic polymorphism may play a role. The 3435C→T polymorphism at the multidrug resistance gene 1 (MDR1) may explain this variation.8 Plasma levels of ATV were significantly higher in HIV-infected patients with genotype CC than in those with CT or TT.8

As expected, hyperbilirubinemia was observed due to inhibition of uridine diphosphate glucuronosyltransferase 1A1 from ATV.9 Although this is a common event, fewer than 2% of patients discontinue ATV.10 No patients in our study needed to discontinue treatment due to serious adverse reactions. All PIs except ATV can cause dyslipidemia.7 In the present study, a regimen of ATV/SQV-SGC/r resulted in increased lipid levels after 60 weeks when compared to baseline, resulting in a rise in the proportion of patients who needed to commence lipid-lowering agents. The administration of low-dose ritonavir can also cause lipid elevation,11 so ritonavir was also responsible for these changes.

ATV/SQV-SGC/r has shown acceptable efficacy as salvage therapy. Nevertheless, the efficacy was relatively lower than previous reports conducted in ART-naive patients.12 The number of patients was relatively low in the present study, and the study design was not comparative. However, these results provide some evidence that supports the administration of this regimen.

In conclusion, the combination of a once-daily double-boosted PI regimen of ATV/SQV/r 300/1600/100 mg provided high plasma concentrations of both PIs. This double-boosted PI combination is effective as salvage regimen among HIV-infected patients who had no NRTI or NNRTI options. In addition, this regimen is safe and well tolerated. However, long-term metabolic complications, particularly dyslipidemia, is common and should be closely monitored. The results should be confirmed with further, larger scale comparative studies.

Weerawat Manosuthi, MD*

Somnuek Sungkanuparph, MD†

Kiat Ruxrungtham, MD‡

Wisit Prasithsirikul, MD*

Chatiya Athichathanabadi, BSc*

Woraphot Tantisiriwat, MD§

Chureeratana Bowonwatanuwong, MD∥

Nopphanath Chumpathat, Med*

Achara Chaovavanich, MD*

*Bamrasnaradura Infectious Diseases Institute Ministry of Public Health Nonthaburi, Thailand

†Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok, Thailand

‡The HIV Netherlands-Australia-Thailand (HIV-NAT) Research Collaboration Thai Red Cross AIDS Research Centre Bangkok, Thailand

§Department of Preventive Medicine Faculty of Medicine Srinakharinwirot University Nakornnayok, Thailand

∥Department of Medicine Chonburi Hospital Ministry of Public Health Chon Buri, Thailand

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ACKNOWLEDGMENTS

The authors acknowledge the Bamarasnaradura Infectious Diseases Institute for their grants.

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REFERENCES

1. Eron JJ Jr. HIV-1 protease inhibitors. Clin Infect Dis. 2000;30(Suppl 2):S160-S170.

2. Murphy RL, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS. 2001;15:F1-F9.

3. von Hentig N, Muller A, Rottmann C, et al. Pharmacokinetics of saquinavir, atazanavir, and ritonavir in a twice-daily boosted double-protease inhibitor regimen. Antimicrob Agents Chemother. 2007;51:1431-1439.

4. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen. AIDS. 2004;18:1291-1297.

5. Boffito M, Maitland D, Dickinson L, et al. Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses. AIDS Res Hum Retroviruses. 2006;22:749-756.

6. Colonno RJ, Thiry A, Limoli K, et al. Activities of atazanavir (BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother. 2003;47:1324-1333.

7. AIDSinfo. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://AIDSinfo.nih.gov. Accessed January 20, 2007. Rockville, MD: U.S. Department of Health and Human Services; 2006.

8. Rodriguez Novoa S, Barreiro P, Rendon A, et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C→T polymorphism at the multidrug resistance gene 1. Clin Infect Dis. 2006;42:291-295.

9. Fuster D, Clotet B. Review of atazanavir: a novel HIV protease inhibitor. Expert Opin Pharmacother. 2005;6:1565-1572.

10. Busti AJ, Hall RG, Margolis DM. Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004;24:1732-1747.

11. Shafran SD, Mashinter LD, Roberts SE. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med. 2005;6:421-425.

12. Malan M, Krantz E, David M, et al. Efficacy and safety of atazanavir-based therapy in antiretroviral naive HIV-1 infected subjects, both with and without ritonavir: 48-week results from AI424-089 [abstract]. Presented at: Conference on Retroviruses and Opportunistic Infections; 2006; Denver.

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