In a prospective, multicentre, switch study to identify the most frequently occurring nucleoside reverse transcriptase inhibitor (NRTI)-associated toxicities that cause NRTI withdrawal in virologically suppressed HIV-infected patients, among those who underwent stavudine substitution by tenofovir, 271 had hypertriglyceridemia and 193 had hypercholesterolemia. After 12 weeks of switching from stavudine to tenofovir, triglyceride and cholesterol levels showed significant decreases, which suggests that such a switch may reverse, at least partly, stavudine-associated dyslipidaemia.
Unfortunately highly active antiretroviral therapy (HAART) has been recognized to be increasingly associated with the emergence of morphological and metabolic disorders, mainly dyslipidemia, insulin resistance and fat redistribution syndromes, the so-called lipodystrophy syndrome . Hyperlipidemia and lipodystrophy may be present concomitantly, but this is not necessarily always the case .
Hyperlipidemia has emerged as an important complication of HAART [3,4]. The major concern is its potential for premature atherosclerosis and coronary artery disease, although this has not yet been conclusively established [5,6]. Statins are the mainstay of drug therapy for hyperlipidemia, but they worsen polypharmacy, have side-effects and drug–drug interactions, and many of them cannot be used with protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors .
A more attractive strategy to target this metabolic toxicity is to identify the drug presumed to be associated with hyperlipidemia and undertake a switch approach.
The increase in lipids has been associated more frequently with most PI and stavudine. In a recently presented study (GS903) , in which antiretroviral-naive patients were given lamivudine and efavirenz, the addition of tenofovir was compared with that of stavudine. The tenofovir arm showed a better total fasting lipid profile, with significantly lower increases in triglyceride levels, total and LDL-cholesterol, and a greater increase in HDL-cholesterol.
Currently, the substitution of a single antiretroviral agent is only considered advisable for toxicity reasons. In clinical trials, tenofovir has shown an optimal safety profile [9,10]. All available data so far suggest that tenofovir could be a valid alternative to be used when substituting stavudine as a result of toxicity in patients receiving HAART [11,12].
Between September 2002 and May 2003 we conducted a prospective, multicentre, switch study with the main objective of identifying the most frequently occurring nucleoside reverse transcriptase inhibitor (NRTI)- associated toxicities causing NRTI withdrawal in virologically suppressed HIV-infected patients (Recover Study). A nucleotide reverse transcriptase inhibitor was substituted for the offending drug in 1350 heavily pretreated patients (72% were at the third line of therapy or higher) and the side-effects are being prospectively followed over a 48-week period. No other drug substitution was allowed concomitantly with tenofovir.
The individuals enrolled are predominantly men (70%), half of them had been intravenous drugs users and the mean CD4 cell count at baseline was 529 cells/μl. Lipodystrophy and peripheral neuropathy have been the two major causes of NRTI substitution (50 and 13%, respectively). Stavudine was the most frequently switched drug (n = 844, 63%).
Among the patients substituting stavudine for tenofovir, 271 had hypertriglyceridemia and 193 had hypercholesterolemia. A third of these patients have reached 12 weeks of follow-up after tenofovir therapy was initiated. For all selected patients the overall median (interquartile range) of the previous treatment period with stavudine was 4 years (2–5 years).
The Student's t-test was used to detect between-group differences. Results show that triglyceride levels (n = 94) dropped from a mean of 458.11 mg/dl [95% confidence interval (CI) 396.73–519.58] at baseline to a mean of 278.50 mg/dl (95% CI 248.85–308.15) at 12 weeks (P < 0.001; see Fig. 1a). Twenty per cent of these patients returned to normal values. Cholesterol levels (n = 70) dropped from a mean of 265.73 mg/dl (95% CI 254.98–276.48) at baseline to a mean of 230.96 mg/dl (95% CI 220.26–241.66) at 12 weeks (P < 0.001; see Fig. 1b). No virological rebound has been seen after switching to tenofovir. No significant changes in CD4 cell counts were observed.
There is increasing experience with switching the PI component of a successful HAART regime with the objective of reducing toxicity, including hyperlipidemia . Most of these studies have substituted the PI with nevirapine, efavirenz or abacavir, and have shown that dyslipidemia is at least partly reversible.
However, the approach of withdrawing NRTI in order to reduce toxicities (mainly body-shape changes) has been investigated only more recently.
Although increases in LDL-cholesterol and triglyceride levels have most clearly been associated with PI, not all the remaining NRTI have the potential for the induction of lipid disturbances. In a recent prospective cohort study including PI-naive HIV-1-infected patients receiving two NRTI, hypercholesterolemia was associated with NRTI exposure, and hypertriglyceridemia was statistically linked specifically to stavudine . Hyperlipidemia is clearly linked to lipodystrophy and insulin resistance. In a recent trial, tenofovir showed a significantly better lipid profile than stavudine . Nonetheless, the strategy of improving the lipid profile in patients receiving stavudine by switching to tenofovir has been explored only in a small pilot study including 36 patients . The decrease in total cholesterol was statistically significant. There was a trend, although not statistically significant, towards a decrease in triglyceride levels. Of interest was the fact that the improvement in hypercholesterolemia was seen at every timepoint, including early controls at weeks 4 and 12.
In summary, our results confirm that dyslipidemia linked to stavudine can be partly or completely reversed after the substitution by tenofovir in highly experienced patients in the short term. Our data also suggest that the switch from stavudine to tenofovir is virologically safe, may avoid the need for lipid-lowering drugs, and may decrease the patient's risk of suffering cardiovascular events.
The Recover Study is currently ongoing in 120 Spanish centres and hopefully results at 48 weeks will confirm the data outlined in this preliminary communication.
The authors would like to thank Gilead Sciences, SL, for its continuous support in the development of the study.
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Appendix: the RECOVER study group
R. Rodríguez Perez, A. Ocampo, C. Miralles, J. Pedreira, E. Losada, R. Ojea, A. Asorey, A. Mariño, A. Prieto, Antonio Moreno, M.T. Vazquez, B. de la Fuente, F. Dronda, A. Antela, G. Esquinas, J. Sanz, Ana Moreno, J.L. Casado, C. Barros, T. Martín, J. Sanz, J. Elizaga, M. Rodríguez Zapata, R. Rubio, F. Pulido, M. Cordero, A. Chocarro, V. Roca, M.J. Tellez, P. Miralles, J. Berenguer, J. Cosín, B. Padilla, J.C. López, V. Estrada, R. Torres, F. Cuadra, C.R. Herranz, F. Marcos, S. Hernandez, A. Lorenzo, J.R. Barbera, L. Porras, F. Orihuela, F. Jiménez, J.M. Antúnez, M.A. Muniaín, M.J. Ríos, R. Creagh, J.M. Mesa, L. Orbea, A. Menchero, J. Hernández Quero, M. Delgado, M.C. Galvez, V. Gutiérrez-Rave, F. Rosa, F. García de la Llana, A. Vergara, A. Muñoz, J.A. Terrón, J.L. Gómez, M. Hayek, M.A. Cárdenas, J.M. Zarzalejo, J. Gómez Diaz, C. Fariñas, R. Teira, X. Camino, R. Silvariño, S. Echevarría, J. Baraiaetxaburburu, J. Uriz, P. Arazo, M. Egido, J.A. Amiguet, M. Aldamiz, M.A. del Pozo, J. Sanchez, M. Sala, A. Ortí, A. Delegido, M. Cervantes, V. Falco, P. Barrufet, L. Force, E. Ribera, I. García, C. Pigrau, I. Ocaña, C. Cortés, H. Knobel, S. Vega, J. Mascaró, L. Moner, F. Baguena, E. Pedrol, J. Blanch, J. Vilaró, A. Ochoa, D. Dalmau, L. Ferrer, M. Aranda, J. Carmena, R. Vicente, M.J. Galindo, E. Ortega, M. García, C. Minguez, J. Flores, M. Salavent, J. López Aldeguer, J.M. Cuadrado, E. González, C. Galera, R.M. Blazquez, P. Liaño, J.A. García, A. Cano, I. Vigueras, J. Colomina, P. Saiz de la Hoya, M. Riera, A. Salas, E. Rodríguez, J. Murillas, M. Leyes, R. Canet, P. Mallaina, M.L. Alvarez, P. Ferrer, R. Sánchez de la Rosa.