Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection
van der Valk, M.a; Gisolf, E. H.a; Reiss, P.a,b; Wit, F. W. N. M.a; Japour, A.d; Weverling, G. J.a,c; Danner, S. A.*; on behalf of the Prometheus study group
From the aInternational Antiviral Therapy Evaluation Center (IATEC) and the bDivision of Infectious Diseases, Tropical Medicine and AIDS, Department of Internal Medicine, Academic Medical Center, Amsterdam, the cDepartment of Clinical Epidemiology and Biostatistics, Academical Medical Center, Amsterdam, the Netherlands and dABBOTT Laboratories, Abbott Park, Illinois, USA. *See Appendix for study members.
Requests for reprints to Dr M. van der Valk, International Antiviral Therapy Evaluation Center, Academic Medical Center T0-119, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
Date of receipt: 6 October 2000;
revised: 1 February 2001; accepted: 14 February 2001.
Sponsorship: The Prometheus study was supported by ABBOTT Laboratories and Hoffmann-La Roche and the study extension was supported by ABBOTT Laboratories.
Background: Changes in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase inhibitors (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution of the two drug classes is unclear as they are usually administered concomitantly.
Method: The occurrence of lipodystrophy, as reported by physicians using no standardized criteria, was followed in patients randomly assigned to treatment with either a PI alone or a PI combined with an NRTI. The patients were part of a multicenter, open-label, randomized comparison of ritonavir (RTV)/saquinavir (SQV) with or without the addition of stavudine (d4T) in HIV-1-infected patients without prior PI and d4T experience (the Prometheus study).
Results: Lipodystrophy was reported in 29 of 175 (17%) patients during 96 weeks of follow up. Overall, it was reported significantly more frequently in patients who were randomized to RTV/SQV/d4T (22/88; 25%), than in patients randomized to RTV/SQV alone (7/87; 8%) (P = 0.003). When the analysis was limited to patients without any prior antiretroviral experience, lipodystrophy likewise was significantly more frequent in patients randomized to RTV/SQV/d4T (12/50; 24%) than in those randomized to RTV/SQV (2/44; 5%) (P = 0.008).
Conclusion: This randomized clinical trial, in spite of not having been blinded, supports a contributory role of NRTI in the development of antiretroviral therapy-associated lipodystrophy. The low incidence of lipodystrophy in patients with no or limited NRTI exposure supports further evaluation of NRTI-sparing regimens as alternatives to current antiretroviral regimens.
The use of protease inhibitor (PI)-containing combination antiretroviral therapy has recently been associated with increasing reports of a lipodystrophy syndrome, which involves central fat accumulation and peripheral fat wasting [1–3]. These changes in body fat distribution and the frequently accompanying metabolic disturbances such as hyperlipidemia have generally been attributed to the use of a PI, given the temporal relationship between the widespread introduction of PI and initial reports of the syndrome. It is important to realise, however, that patients who develop lipodystrophy syndrome while taking PI, almost always are concomitantly receiving treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) and frequently will also have had extensive prior NRTI exposure. Several observations suggest that NRTI may independently contribute to the development of this syndrome. First, several observational cohort studies have shown duration of exposure to NRTI to be an independent risk factor in the development of the syndrome during the use of PI-containing therapy [4–6]. Second, the lipodystrophy syndrome is increasingly being reported in patients who have never been exposed to PI drugs [7–9].
Results from randomized clinical trials that may clarify the relative contribution of PI and NRTI in the development of the lipodystrophy syndrome are not yet available. The long-term follow up of patients enrolled in the Prometheus study provided a unique opportunity to address this issue as patients in this trial, half of whom had never received prior antiretroviral treatment, were randomly assigned to treatment with either PI ritonavir (RTV) plus saquinavir hard gel capsules (SQV) alone, or RTV/SQV plus the NRTI stavudine (d4T).
The Prometheus study was a multicenter, open-label, randomized controlled trial, the main results of which have recently been reported . Patients were eligible for the study if they had documented HIV-1 infection, were 18 years of age or older and had not used PI and/or d4T prior to study entry. Participants were randomly assigned to either RTV 400 mg twice daily plus SQV 400 mg twice daily or RTV 400 mg twice daily plus SQV 400 mg twice daily plus d4T 40 mg twice daily (30 mg twice daily if body weight < 60 kg). Before randomization, patients were stratified according to their antiretroviral treatment history, baseline serum HIV-1 RNA, and baseline CD4 T cell count. Patients could intensify treatment after 12 weeks of follow up by adding wherever possible two new NRTI or non-nucleoside reverse transcriptase inhibitors to their regimen. During each scheduled visit, blood total cholesterol and triglyceride levels were obtained. Fasting was not mandated for blood draws. Standardized follow up and data collection was continued in all instances, including in patients who prematurely discontinued study medication. After the original 48 weeks of follow up, the protocol was extended to continue standardized data collection every 12 weeks up to week 96. Enrolment began in January 1997 and the last patient completed 96 weeks of follow up in December 1999. During the study, lipodystrophy was reported prospectively by the treating physician. Lipodystrophy was considered to be present when the physician judged the patient's body appearance to be compatible with that diagnosis.
During the initial 48 weeks of follow up (i.e. before general awareness of the syndrome in the HIV physician and patient community), lipodystrophy would only have been prospectively reported as a study-associated adverse event. When follow up was extended for a second year, the lipodystrophy syndrome had meanwhile become widely recognized and lipodystrophy was now pre-printed on the study data collection forms requesting the physicians purposely to indicate its presence or absence at every follow-up visit. All study physicians were made actively aware of this change in data collection for lipodystrophy during study site visits. In addition, following the first analysis of prospectively collected information in May/June 2000, physicians were asked to review retrospectively the clinical records of every patient that they had reported to have developed lipodystrophy. They were requested to complete a questionnaire that queried whether the lipodystrophy reported had been composed of solely lipoatrophy of the face, arms, legs, or buttock, or solely fat accumulation in the abdomen, breasts or elsewhere, or both.
The protocol and all amendments were approved by the institutional review boards of all participating institutions. All patients gave written informed consent.
For the primary analysis, patients were analysed according to their randomly assigned treatment regimen. In addition, analyses of subgroups were performed according to whether patients had been antiretroviral naive or had experience of a reverse transcriptase inhibitor drug at study entry. Furthermore, to study the relative risk of concurrent exposure to NRTI and PI versus sequential exposure to NRTI and PI, the occurrence of lipodystrophy in antiretroviral-naive patients randomized to RTV/SQV/d4T was compared with that in NRTI-experienced patients randomized to RTV/SQV alone. Time to onset of lipodystrophy was reported as median and interquartile ranges (IQR) . Kaplan–Meier curves, which were based on the prospectively reported presence of lipodystrophy, were generated to indicate the time to onset of lipodystrophy, stratified by treatment regimen. Patients who were not reported to have developed lipodystrophy were censored at their last follow-up visit. P values were calculated using the log rank test.
For the analysis of blood lipid concentrations, determinations of triglycerides and cholesterol were only considered for the period in which patients were taking randomized treatment, which could include treatment intensification as described above. In order to correct for intraindividual variation in lipid concentrations (given the uncertainty as to whether bloods had been drawn fasting or not), the median of the triglyceride and cholesterol levels obtained between weeks 3 and 48 were calculated for each patient. The difference was then calculated between the value obtained at baseline and this median, as a measure of the absolute change in triglycerides and cholesterol following the initiation of treatment.
Baseline serum HIV-1 RNA levels and CD4 cell counts, as well as the changes in these markers during treatment, are reported as median and IQR and compared between the treatment groups as randomized, using the Wilcoxon's two-sample test. This analysis was limited to the initial 48 weeks of treatment as HIV-1 RNA determinations were performed in a single central laboratory using a single assay (Amplicor; Roche Diagnostics, Branchburg, New Jersey, USA) only during this period, but not thereafter.
Potential risk factors for development of lipodystrophy were explored by univariate Cox proportional hazard analysis. Patients who were not reported to have developed lipodystrophy were censored at their last follow-up visit. Parameters considered as potential predictors of lipodystrophy were treatment arm, age, gender, prior treatment with NRTI, total duration of NRTI exposure, baseline cholesterol and triglyceride levels, and increases in cholesterol and triglyceride concentrations during treatment. Variables with a P values < 0.15 in the univariate analysis were entered in a multivariate model. All calculated P values were two-tailed and considered statistically significant if < 0.05.
Data were analysed using the SAS software package (version 6.12, SAS Institute, Cary, North Carolina, USA).
Patient disposition, baseline characteristics and treatment intensification regimen
Of the total 208 patients randomized into the Prometheus study, six patients who never started randomized treatment (one in the RTV/SQV arm, five in the RTV/SQV/d4T arm) were excluded (Fig. 1). Another 27 patients with incomplete data through 96 weeks of follow up were likewise excluded from the current analysis, in the majority of cases because they had become lost to follow up or had withdrawn consent for further data collection during the initial 48 week study period or the subsequent long-term follow up. These latter patients were comparable at baseline to the remaining 175/202 (87%) patients included in the current analysis, with respect to treatment randomization, stage of HIV infection and prior treatment with NRTI. At baseline, patients in the two treatment arms were comparable with respect to demographic characteristics, serum HIV-1 RNA level and CD4 cell count (Table 1). Baseline HIV-1 RNA was significantly higher in patients who were antiretroviral naive compared with those with prior antiretroviral experience [median HIV-1 RNA 4.6 log10 copies/ml (IQR, 4.2–5.1) versus 4.2 log10 copies/ml (IQR, 3.5–4.7) (P = 0.0001, Wilcoxon two-sample test)]. Baseline CD4 cell counts were 255 × 106 cells/l (IQR, 90–445) and 243 × 106 cells/l (IQR, 133–328) in the naive and experienced patients, respectively (P = 0.29).
Of the antiretroviral experienced patients, all had been exposed to zidovudine (median exposure 94 weeks), 56% to zalcitabine (57 weeks), 41% to lamivudine (30 weeks), 26% to didanosine (23 weeks), 9% to nevirapine (34 weeks), and 7% to loviride (104 weeks).
In the RTV/SQV arm (n = 87) 24% of patients remained on randomized treatment throughout 96 weeks; 46% intensified treatment after a median of 25 weeks (IQR, 22–49), and 30% prematurely discontinued study medication at some point during the 96 weeks of follow up. In the RTV/SQV/d4T arm (n = 88), 60% remained on randomized treatment, 7% intensified treatment after a median of 41 weeks (IQR, 22–49), and 33% prematurely discontinued study medication (Fig. 1). Intensification for all patients in the RTV/SQV/d4T arm was with lamivudine. In patients randomized to RTV/SQV alone, intensification included d4T in 36/40 patients (90%). Of the four remaining patients, three intensified treatment with zidovudine and lamivudine, and one with lamivudine alone.
HIV-1 RNA and CD4 cell responses during treatment
Following treatment, no significant differences were observed in the degree of virus suppression and immune recovery that was achieved. HIV-1 RNA levels declined 1.9 log10 copies/ml (IQR, 1.4–2.4) between week 0 and week 48 in the RTV/SQV arm (with 85% reaching serum HIV-1 RNA < 400 copies/ml at week 48) and 2.1 log10 copies/ml (IQR, 1.6–2.4) in the RTV/SQV/d4T arm (91% < 400 copies/ml) (P = 0.21). Median increases in CD4 cell counts between week 0 and week 48 were 160 × 106 cells/l (IQR, 80–280) and 180 × 106 cells/l (IQR, 120–290) for the RTV/SQV and RTV/SQV/d4T arms, respectively (P = 0.60).
Occurrence of lipodystrophy
Lipodystrophy was reported in 29/175 (17%) patients during the 96 weeks of follow up. It was more frequent in patients who were randomly assigned to treatment with RTV/SQV/d4T (22/88; 25%) than in patients assigned to treatment with RTV/SQV alone (7/87; 8%) (P = 0.003, χ2 test). Likewise, when limiting the analysis to patients who were antiretroviral naive at enrolment, patients randomized to RTV/SQV/d4T (12/50; 24%) were significantly more likely to develop lipodystrophy than patients randomized to RTV/SQV alone (2/44; 5%) (P = 0.008, χ2 test). Lipodystrophy was reported in 1/14 (7%) antiretroviral-naive patients who continued treatment with nothing but RTV/SQV for the entire period of follow up.
In the antiretroviral-experienced patients randomized to RTV/SQV alone, the duration of NRTI exposure before study entry (median 98 weeks; IQR, 53–214) was very similar to that of antiretroviral-naive patients randomized to RTV/SQV/d4T and thus exposed to NRTI for the first time during the study (follow up 96 weeks). The first group can be considered to have had sequential exposure to NRTI and PI, whereas the second group had concurrent exposure to NRTI and PI. Lipodystrophy was reported in 5/43 (12%) and 12/50 (24%) of these two particular groups of patients, respectively (relative risk 2.06; 95% confidence interval (CI) 0.79–5.39).
Time to lipodystrophy
Lipodystrophy was reported after a median of 68 weeks (range, 49–96). There was a significant difference in the occurrence of lipodystrophy over time between patients randomized to RTV/SQV alone and those randomized to RTV/SQV/d4T (P = 0.003, log rank test) (Fig. 2a). The same difference was observed when the analysis was restricted to antiretroviral-naive patients (P = 0.009, log rank test) (Fig. 2b).
Patients who intensified RTV/SQV therapy with d4T were followed for a median of 63 weeks (range, 11–86) after the addition of d4T. Lipodystrophy occurred in 4/36 (11%) patients from this group a median of 42 weeks after the addition of d4T (range, 28–81).
Risk factors for the development of lipodystrophy
In the multivariate Cox proportional hazard analysis, randomization to RTV/SQV/d4T was found to be the strongest independent risk factor for the development of lipodystrophy [hazard ratio (HR) 3.83; 95% CI, 1.61–9.14) (Table 2). Both baseline median cholesterol levels and median increases in these levels during treatment were higher in patients with lipodystrophy than in patients without lipodystrophy [baseline 4.9 mmol/l (IQR, 4.2–5.3) versus 4.3 mmol/l (IQR, 3.9–5.0) and increase 2.2 mmol/l (IQR, 1.3–2.9) versus 1.3 mmol/l (IQR, 0.8–2.0), respectively). Higher baseline cholesterol and higher increases in cholesterol levels during treatment were both independently associated with the development of lipodystrophy (HR, 1.57; 95% CI, 1.03–2.40 and HR, 1.64; 95% CI, 1.12–2.40, respectively). The following factors were not significantly associated with the development of lipodystrophy in the multivariate analysis: having received antiretroviral therapy before enrolment, duration of prior treatment, use of a particular NRTI before study entry, gender, age, baseline CD4 cell count, serum HIV-1 RNA, triglyceride level and increase in triglyceride level during treatment,.
In the antiretroviral-naive patients, randomization to RTV/SQV/d4T (HR, 6.65; 95% CI, 1.47–30.1) and the increase in cholesterol during treatment (HR, 2.47; 95% CI, 1.25–4.88) were independently associated with the occurrence of lipodystrophy. When limiting the analysis to antiretroviral-experienced patients, no significant risk factors were identified.
In those with lipodystrophy, fat accumulation as the sole characteristic was reported retrospectively by physicians to have been present more frequently in patients randomized to the PI-only arm, while isolated peripheral lipoatrophy was more commonly reported in those randomized to d4T/RTV/SQV [fat accumulation only in 2/7 (29%) versus 2/22 (9%) patients, and isolated lipoatrophy in 1/7 (14%) versus 7/22 (32%) patients, in the RTV/SQV and d4T/RTV/SQV arms, respectively]. Neither of these differences reached statistical significance (P = 0.24 and P = 0.63 by Fisher's exact two-sided t-test, respectively). The concomitant presence of fat accumulation and peripheral lipoatrophy was reported at a very similar frequency in both arms (57% in the PI-only arm and 59% in the d4T arm, respectively) (Table 3).
The widespread prolonged use of potent combination antiretroviral therapy in patients with HIV-1 infection has become associated with an increasing number of reports concerning body fat redistribution and metabolic abnormalities, commonly referred to as lipodystrophy syndrome. It has been suggested from several observational studies that both PI and NRTI may contribute to the development of this syndrome [4–6]. Definitive evidence for the contribution of each of these drug classes, however, has been difficult to obtain, as PI are rarely prescribed without concomitant prescription of NRTI. To our knowledge, ours is the first report concerning the occurrence of lipodystrophy in patients who were randomly allocated to treatment with just PI, or with PI plus one NRTI.
Patients randomized to RTV/SQV/d4T were significantly more likely to develop lipodystrophy than those randomized to RTV/SQV alone. This difference was also observed in the subgroup of patients who were antiretroviral naive prior to the study, as well as in the subset of these who remained on their randomized treatment throughout the complete 96 weeks of follow up. Reporting of lipodystrophy during the first year was solely on the basis of its recognition as a potential study-associated adverse event, and this may have resulted in an underestimation of the syndrome's prevalence. In view of the randomized nature of the study however, this should have affected both arms to a similar extent and should not have significantly biased either treatment arm for the difference in prevalence that we observed. Only a single patient who had never been exposed to NRTI developed lipodystrophy, which was limited to fat accumulation, while using RTV/SQV alone. These results strongly support the suggestion that NRTI contribute to the development of antiretroviral therapy-associated lipodystrophy, as has recently been hypothesized [11,12]. The first reports concerning a possible association between lipodystrophy and NRTI use were publicly presented in June 1999. All of the patients in our analysis were reported as having lipodystrophy before this date. Therefore, even though our study was not blinded, it is highly unlikely that the findings would have been biased by physicians being more likely to report lipodystrophy in the d4T-containing arm of the study.
One could expect that patients who are simultaneously exposed to both drug classes may be at highest risk. Our observation that antiretroviral-naive patients who were allocated to RTV/SQV plus d4T were more likely to develop lipodystrophy than NRTI-experienced patients who were allocated to PI alone, and so discontinued prior use of NRTI, supports such a view, although the difference did not reach statistical significance, possibly because of the limited numbers of participants in each of these two subgroups. Although the pathogenesis of the lipodystrophy syndrome remains unclear, it seems plausible that the concurrent presence of both PI- and NRTI-mediated biological mechanisms offers a greater likelihood for the syndrome to develop. It has been suggested that PI may adversely interact with different host cell proteins involved in lipid metabolism because of a partial amino acid sequence homology between such proteins and the HIV-1 protease . Drug-induced mitochondrial dysfunction in adipocytes has been suggested as a potential mechanism for the induction of lipodystrophy by NRTI [11,12]. NRTI may differ in the degree to which they inhibit mitochondrial function and their effect may be dependent on cell type, as has been observed in vitro[14,15]. In a number of observational studies, the current use of d4T rather than zidovudine was found to be associated with a greater risk of developing lipodystrophy, particularly peripheral lipoatrophy [5,16]. Our group recently reported that the concurrent use of RTV or indinavir results in significantly higher plasma exposure to d4T . If this also resulted in higher intracellular d4T trisphosphate levels in target adipose tissue, and mitochondrial toxicity is indeed involved in the pathogenesis of the lipodystrophy syndrome, the concurrent exposure of our patients to both RTV and d4T may have been particularly harmful.
In contrast to reports from a number of observational studies, we did not find the duration of prior NRTI exposure, age or gender to be additional independent risk factors for the development of lipodystrophy [5,6,18,19]. This may possibly be explained by a much shorter median time of 2 years prior NRTI exposure in our study population, compared with the much longer exposure reported in the observational studies [4,5]. Only 27 patients included in our study were women, which may have been insufficient to demonstrate a gender difference.
Higher baseline total cholesterol levels as well as higher increases in total cholesterol levels during treatment were associated with a somewhat higher likelihood of developing lipodystrophy, particularly in the subset of patients without prior antiretroviral experience. Such weak associations between metabolic and body appearance changes are consistent with findings in other studies [1,20]. Others have speculated that the changes in body composition and metabolic parameters may not be directly induced by the drugs but may be secondary to suppression of HIV infection and the return of host immunity towards normal . In our study, no major differences were observed in the degree of HIV suppression achieved or the level of immune recovery, as measured by changes in CD4 lymphocyte numbers, between patients assigned to differing treatment arms. Although this does not necessarily refute the importance of indirect therapy-related mechanisms, it does suggest that NRTI directly contribute to the pathogenesis of the lipodystrophy syndrome.
An important limitation of our study is the subjective method by which lipodystrophy was diagnosed and prospectively reported by the treating physicians. In addition, whether lipoatrophy, fat accumulation or both were present was sought retrospectively. In the absence of a consensus case definition of antiretroviral therapy-associated lipodystrophy, it is reassuring that other studies have found good agreement between lipodystrophy as assessed by physicians on the one hand and by the use of objective measurements such as dual energy X-ray absorptiometry and abdominal computed tomography, on the other hand .
In conclusion, the results from this randomized study strongly support the concept that NRTI contribute to the development of antiretroviral therapy-associated lipodystrophy syndrome. The low incidence of lipodystrophy in patients with no or limited NRTI exposure, at least over a period of 2 years, warrants the further evaluation of NRTI-sparing regimens as potentially less toxic alternatives to current standard potent combination antiretroviral regimens.
The authors want to thank the participants in this study, the ATHENA project team and E. van der Ven for data collection.
Note: Marc van der Valk was primarily responsible for writing the paper. Elisabeth Gisolf performed most of the analyses. Peter Reiss contributed to the study design and supervised the writing and presentation of the results. Ferdinand Wit analysed the results of the serum lipid determinations. Anthony Japour critically appraised the design of the study and presentation of the results. Gerrit Jan Weverling supervised the design and execution of all analyses. Sven Danner initiated the Prometheus study, contributed to the study design and supervised the writing and presentation of the results.
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The Prometheus Study Group. NATEC, Amsterdam: E. H. Gisolf, P. Reiss, G. J. Weverling, M. Duurvoort, E. Krijger, E. Brouwer, G. R. Visser, A. Klotz, C. Benschop, F. Wulfert; Academic Medical Center, Amsterdam: S. A. Danner (principal investigator), F. de Wolf, S. Jurriaans, P. Portegies; Institute for Tropical Medicine, Antwerp: R. Colebunders, J. Pelgrom, H. Wijnants, A. de Roo, K. Keersmaekers, M. Vandenbruanen, D. van den Branden, T. James; University Hospital Gent: F. van Wanzeele, B. van der Gucht; University Hospital Rotterdam: M. E. van der Ende, J. Nouwen, R. Deenenkamp, D. van der Meyden; University Hospital Nijmegen: P. P. Koopmans, K. Brinkman, H. ter Hofstede, B. Zomer; Ziekenhuis Walcheren, Vlissingen: W. L. Blok, C. Ruissen; University Hospital Groningen: H. Sprenger, G. Law, P. van der Meulen; OLVG locatie Prinsengracht, Amsterdam: C. ten Veen; St Elisabeth Ziekenhuis, Tilburg: J. R. Juttmann, C. van der Heul, R. Santegoets, B. van der Ven; Kennemer Gasthuis, Haarlem: R. W. ten Kate, M. Schoemaker; Ziekenhuis Leyenburg, Den Haag: R. H. Kauffmann, J. M. Henrichs, A. Maat, E. Prins; Medisch Spectrum Twente Enschede: C. H. H. ten Napel, K. Pogany, T. Duyts; Vrije Universiteit Brussel: P. Simons, P. Lacor, A. de Waele; University Hospital Leuven: E. van Wijngaarden, M. Lejeune; Department of Medical Psychology of the University of Amsterdam: P. Nieuwkerk, M. Sprangers; Virtual Central Laboratory, Zeist: R. Scholte, J. Dijkman. Cited Here...
protease inhibitors; combined therapy; lipodystrophy; reverse transcriptase inhibitors; HIV
© 2001 Lippincott Williams & Wilkins, Inc.
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