The St Stephen's Centre, The Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Received 5 January 2005; returned 29 March 2005; revised 2 April 2005; accepted 19 April 2005
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Abstract |
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Methods: Individuals were identified who had failed previous HAART and who were then prescribed trizivir and tenofovir. Viral load and genotypic information were obtained to assess virological response.
Results: One hundred and twenty-two individuals were identified from a database containing 5883 patients. In a last observation carried forward intention to treat analysis, 34% of individuals achieved an undetectable viral load of <50 copies/mL at 1 year. Of those who were able to remain on treatment for 1 year, 65% achieved undetectability. We observed no effect regarding previous regimens on viral outcome. Accumulation of TAMs (thymidine analogue mutations) was associated with a decrease in the number of patients achieving an undetectable viral load (with <2 TAMs present 38% of patients developed undetectable viral loads, 1;2 TAMs 17% undetectable; P = 0.03). Using the mean cell volume as a measure of compliance, those with higher values were more likely to achieve a viral load <50 copies/mL (P = 0.04). A beneficial effect on cholesterol was noted regardless of virological outcome.
Conclusions: In compliant heavily pre-treated individuals with less than 2 TAMs, salvage therapy with trizivir and tenofovir is associated with suppression of viraemia and an improved lipid profile.
Keywords: HAART , HIV/AIDS , thymidine analogue mutations , cholesterol
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Introduction |
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The combination of trizivir (zidovudine/lamivudine/abacavir) (one tablet twice daily) and tenofovir (one tablet once daily) potentially offers an attractive and simple salvage regimen.7 Tenofovir disoproxil fumarate [R-9-(2-phosphonyl-methoxypropyl) adenine; tenofovir DF], the first nucleotide analogue reverse transcriptase inhibitor to be approved by the FDA, has been well tolerated and demonstrated efficacy in large clinical trials of naive and experienced patients, without evidence of long-term toxicity, including the mitochondrial toxicity that has been associated with some nucleoside analogue reverse transcriptase inhibitors.1116 Whilst trizivir, a triple nucleoside-based regimen, is a useful therapy with a favourable lipid profile, one large study demonstrated that it did not suppress viraemia as well as a non-nucleoside reverse transcriptase inhibitor based regimen.17
We therefore studied the efficacy and safety of the tenofovir and trizivir combination in patients requiring salvage therapy. Such a combination spares the use of protease inhibitors and subsequent side effects, including an adverse effect on lipid profile, which in turn may cause premature cardiovascular disease.1820 We therefore studied this profile and also investigated the use of resistance tests to establish patients who were more or less likely to respond to this regimen.
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Methods |
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The Chelsea and Westminster HIV cohort is one of the largest in Europe. HIV-positive patients are seen at regular intervals for clinical assessment, trial follow-up, and immunological and virological assessments. We have routinely prescribed HAART since 1 January 1996, the date at which HAART became routinely available at our institution in accordance with published guidelines.21 We undertook a systematic search of our database in order to identify those individuals who had received and failed at least one prior antiretroviral regimen and then received trizivir and tenofovir. Antiretroviral histories were collated from the clinical database and patient notes, as well as any available resistance mutation information. Genotypic tests (Virco NV, Mechelen, Belgium), CD4 results (TetraOne antibodies on an Epics XL-MCL facscaliber, Beckman Coulter, High Wycombe, UK) and plasma viral load (Quantiplex HIV RNA 3.0, Chiron, Halstead, UK) were recorded from the database.
Statistics
Statistical analyses were performed in SAS version 8.0 using parametric tests. Where appropriate, data were log10 transformed to stabilize the variance. MIXED procedure in SAS was used to calculate the difference in averages (DAVG), which represents the time weighted difference in viral load and CD4 count from baseline to each time point. On treatment and a last observation carried forward intention to treat analysis (ITT) was performed, firstly where the last observation (<50 copies/mL) was carried forward if data were unavailable at the time point and secondly, where any patient whose data were unavailable for any reason was assumed to have failed at the time of analysis. Fold changes from baseline were further calculated for viral load and CD4 count for each study time points and these have been presented as percentage change from baseline. Log rank 2 tests were used for comparisons and all P values presented are two-sided.
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Results |
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The mean CD4 increase on treatment was 131 cells/mm3, 66% of patients (on treatment) achieved a one log drop in viral load and 65% had an undetectable viral load (<50 copies/mL) at 1 year (Figure 1). Figure 1 demonstrates similar proportions of patients with undetectable viraemia on treatment at 6 months and at 1 year.
The accumulation of TAMs was associated with a decrease in the number of patients achieving an undetectable viral load. Patients with fewer than 2 TAMs had significantly better virological outcomes compared with those with two or more TAMs (Table 2). Out of 15 patients with virological failure, 12 individuals had resistance tests available at baseline. One patient had 5 TAMs plus M184V, 2 had 3 TAMs plus M184V, 3 had 2 TAMs (2 plus M184V) and 2 had 1 TAM (1 plus M184V). At failure, only two patients had more TAMs than at baseline and none had acquired the M184V mutation. Only three patients had the K65R mutation conferring resistance to tenofovir.22 Of these, two experienced virological failure (one by 6 months and one by 1 year). However, the patient who failed at 1 year had 4 TAMs and the patient who failed at 6 months had 2 TAMs, thus the effect of K65R remains unclear.
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In this analysis, we also investigated the effect on lipid profile (cholesterol), in those individuals who did and did not achieve an undetectable viral load. Figure 2, a DAVG analysis with 95% confidence intervals, demonstrates a statistically significant beneficial effect on cholesterol levels after 6 months of therapy that is maintained at 1 year, regardless of whether undetectability was achieved (P < 0.05). At 6 months, this was most evident in those who subsequently achieved undetectability although by 9 months to 1 year, all patients had significantly lower cholesterol levels than at the start of therapy.
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Discussion |
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We noted significant benefits on cholesterol levels that were maintained from 6 months to 1 year, regardless of outcome. In a large prospective randomized study comparing the safety and efficacy of tenofovir with stavudine (both in combination with lamivudine and efavirenz), a more favourable change in cholesterol was found in the tenofovir group at week 144, and these patients also had less lipodystrophy.26 Switching from stavudine to tenofovir is also associated with reversal of dyslipidaemia.27 Trizivir has also been extensively studied in this setting and in a number of comparative studies, median decreases in cholesterol were greater in those patients who received trizivir.2830 It is therefore not necessarily surprising that a trizivir and tenofovir combination was successful at reducing cholesterol although this is an important benefit of this regimen.
Lack of adherence to HAART is a significant reason for treatment failure. Trizivir and tenofovir has a lower pill burden in terms of both number of tablets and frequency of administration (and food restrictions)7 and we also found that those individuals with increased adherence, as measured by a higher MCV,23,24 were significantly more likely to have virological suppression at any of the time points measured.
In conclusion, the combination of trizivir and tenofovir was well tolerated and associated with a decreased cholesterol. Virological suppression could be achieved in those individuals with a previous history of exposure to components of this regimen and adherence to this protease inhibitor sparing regimen was associated with achieving undetectability. The measurement of TAMs can be used to guide treatment strategies in patients requiring salvage therapy.
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References |
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2. Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Ann Rev Immunol 2003; 21: 265304.[CrossRef][ISI][Medline]
3. Douek DC, Brenchley JM, Betts MR et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002; 417: 958.[CrossRef][ISI][Medline]
4.
Hammer SM. Increasing choices for HIV therapy. N Engl J Med 2002; 346: 20223.
5.
Stebbing J, Gazzard B, Douek DC. Where does HIV live? N Engl J Med 2004; 350: 187280.
6. Stebbing J, Gazzard B. Clinical utility of resistance testing. J HIV Therapy 2002; 7: 7580.
7. Anon. Pill burden key to doing well. AIDS Patient Care STDS 2000; 14: 2812.[CrossRef]
8.
Gallant JE. Strategies for long-term success in the treatment of HIV infection. J Am Med Assoc 2000; 283: 132934.
9. Fumaz CR, Tuldra A, Ferrer MJ et al. Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquir Immune Defic Syndr 2002; 29: 24453.[ISI][Medline]
10. Williams I, Asboe D, Babiker A et al. (2004). A virological benefit from an induction/maintenance strategy compared with a standard 3-drug regimen in antiretroviral naive patients: the FORTE trial. In: 11th CROI, San Francisco, CA, 2004. Abstract 564.
11. Fung HB, Stone EA, Piacenti FJ. Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. Clin Therap 2002; 24: 151548.[CrossRef][ISI][Medline]
12. Louie M, Hogan C, Hurley A et al. Determining the antiviral activity of tenofovir disoproxil fumarate in treatment-naive chronically HIV-1-infected individuals. Aids 2003; 17: 11516.[CrossRef][ISI][Medline]
13. Walker UA. Update on mitochondrial toxicity: where are we now? J HIV Therapy 2003; 8: 325.
14. Nelson M, Portsmouth S, Stebbing J et al. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS 2003; 17: F7F10.[CrossRef][ISI][Medline]
15.
Orkin C, Stebbing J, Nelson M et al. A randomized study comparing a three- and four-drug HAART regimen in first-line therapy (QUAD study). J Antimicrob Chemother 2005; 55: 24651.
16. Jones R, Stebbing J, Nelson M et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study. J Acquir Immune Defic Syndr 2004; 37: 148995.[Medline]
17.
Gulick RM, Ribaudo HJ, Shikuma CM et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004; 350: 185061.
18.
Sklar P, Masur H. HIV infection and cardiovascular diseaseis there really a link? N Engl J Med 2003; 349: 20657.
19.
Friis-Moller N, Sabin CA, Weber R et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349: 19932003.
20.
Bozzette SA, Ake CF, Tam HK et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003; 348: 70210.
21.
Yeni PG, Hammer SM, Carpenter CC et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS SocietyUSA Panel. J Am Med Assoc 2002; 288: 22235.
22. Winston A, Stebbing J. The K65R mutation in HIV-1 reverse transcriptase. J HIV Therapy 2004; 9: 257.
23. Steele RH, Keogh GL, Quin J et al. Mean cell volume (MCV) changes in HIV-positive patients taking nucleoside reverse transcriptase inhibitors (NRTIs): a surrogate marker for adherence. Int J STD AIDS 2002; 13: 74854.[CrossRef][ISI][Medline]
24. Romanelli F, Empey K, Pomeroy C. Macrocytosis as an indicator of medication (zidovudine) adherence in patients with HIV infection. AIDS Patient Care STDS 2002; 16: 40511.[CrossRef][ISI][Medline]
25. Descamps D, Flandre P, Joly V et al. Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir. J Acquir Immune Defic Syndr 2002; 31: 46471.[Medline]
26.
Gallant JE, Staszewski S, Pozniak AL et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. J Am Med Assoc 2004; 292: 191201.
27. Domingo P, Labarga P, Palacios R et al. Improvement of dyslipidemia in patients switching from stavudine to tenofovir: preliminary results. Aids 2004; 18: 14758.[CrossRef][ISI][Medline]
28. Katlama C, Gazzard B, Mallolas J et al. Comparison of metabolic abnormalities 48 weeks after switching from highly active antiretroviral therapy containing a non-nucleoside reverse transcriptase inhibitor to Trizivir versus continued highly active antiretroviral therapy. AIDS 2003; 17: 18556.[CrossRef][ISI][Medline]
29. Katlama C, Fenske S, Gazzard B et al. TRIZAL study: switching from successful HAART to Trizivir (abacavirlamivudinezidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Med 2003; 4: 7986.[CrossRef][Medline]
30. Lafeuillade A, Clumeck N, Mallolas J et al. Comparison of metabolic abnormalities and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART: the Trizal study. HIV Clin Trials 2003; 4: 3743.[ISI][Medline]
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