Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss

Marit G A van Vonderen, Michiel A van Agtmael, Elly A M Hassink, Ana Milinkovic, Kees Brinkman, Suzanne E Geerlings, Matti Ristola, Arne van Eeden, Sven A Danner, Peter Reiss, MEDICLAS study group, F Kroon, M Youle, R ten Kate, Marit G A van Vonderen, Michiel A van Agtmael, Elly A M Hassink, Ana Milinkovic, Kees Brinkman, Suzanne E Geerlings, Matti Ristola, Arne van Eeden, Sven A Danner, Peter Reiss, MEDICLAS study group, F Kroon, M Youle, R ten Kate

Abstract

Background: Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy.

Methodology/principal findings: Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups.

Conclusions/significance: Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available.

Trial registration: ClinicalTrials.gov NCT 00122226.

Trial registration: ClinicalTrials.gov NCT00122226.

Conflict of interest statement

Competing Interests: Marit van Vonderen reports having received reimbursement of travel costs for international conferences from Abbott, Boehringer Ingelheim and UCB Pharma. Peter Reiss reports having received research grants and/or honoraria for consultancy/advisory boards or speaking engagements from Gilead Sciences, Boehringer Ingelheim, Hoffman LaRoche, GlaxoSmithKline, Merck & Co, Bristol Myers Squibb, Tibotec and Theratechnologies. Sven Danner reports having received honoraria for the advisory board from GlaxoSmithKline. Michiel van Agtmael declares having received honoraria for giving lectures and participating in advisory boards/expert panels of Glaxo Smith Kline, Bristol Myers Squib, Boehringer Ingelheim and Merck and having received a research grant from Abbott. Kees Brinkman declares having received honoraria for giving lectures and participating in advisory boards/expert panels of Glaxo Smith Kline, MSD, Gilead, Roche, Pfizer and BMS. Matti Ristola reports having received research grants and/or honoraria for consultancy/advisory boards or speaking engagements from Abbott, Boehringer Ingelheim, Hoffman LaRoche, GlaxoSmithKline, Merck & Co, Bristol Myers Squibb, Tibotec, Swedish Orphan, Pfizer and Schering-Plough. Suzanne Geerlings reports having received honoraria for the advisory board from MSD. Elly Hassink, Ana Milinkovic and Arne van Eeden report no conflict of interest.

Figures

Figure 1. Patient disposition.
Figure 1. Patient disposition.
ZDV/3TC/LPV/r zidovudine/lamivudine/lopinavir/ritonavir. NVP/LPV/r nevirapine/lopinavir/ritonavir.
Figure 2. Body composition by Dexa and…
Figure 2. Body composition by Dexa and CT.
Shown are estimated means±standard error of the mean (mixed model repeated measures analysis with correction for differences in baseline values). ZDV/3TC/LPV/r zidovudine/lamivudine/lopinavir/ritonavir. NVP/LPV/r nevirapine/lopinavir/ritonavir. *p

Figure 3. Body composition by anthropometry.

Shown…

Figure 3. Body composition by anthropometry.

Shown are estimated means±standard error of the mean (mixed…

Figure 3. Body composition by anthropometry.
Shown are estimated means±standard error of the mean (mixed model repeated measures analysis with correction for differences in baseline values). ZDV/3TC/LPV/r zidovudine/lamivudine/lopinavir/ritonavir. NVP/LPV/r nevirapine/lopinavir/ritonavir. *p
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References
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Figure 3. Body composition by anthropometry.
Figure 3. Body composition by anthropometry.
Shown are estimated means±standard error of the mean (mixed model repeated measures analysis with correction for differences in baseline values). ZDV/3TC/LPV/r zidovudine/lamivudine/lopinavir/ritonavir. NVP/LPV/r nevirapine/lopinavir/ritonavir. *p

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