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Report on the 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
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London UK 6-8 november 2008
Jacqueline Capeau MD
CDR Saint-Antoine, Inserm, UPMC-Paris6, Paris France
Jacqueline.capeau @inserm.fr
Even if the first editions of this annual workshop was mainly dedicated to HIV-related lipodystrophies, the field covered at present is much more wider. For its 10th birthday, this meeting covered a number of HIV-related complications, linked to the treatment but also to the ongoing infection, leading to comorbidities at the cardiovascular, renal, bone levels and to an increased prevalence of cancers. Mitochondrial toxicity induced by the drugs so as a chronic low grade inflammation induced by the drugs but also by the virus could play a leading role in the cardiovascular and bone diseases while cancers might be related to decreased immunity. Identification of biomarkers useful to identify these conditions are required. Moreover, since the patients are aging, it appears that most complications are increased in severity as compared to the non-infected population, suggesting a worsening of age-related comorbidities affecting the cardiovascular system, adipose tissue, bone, kidney, liver and brain in patients infected with HIV.
All the abstracts are published in a special issue of Antiviral Therapy 2008, 13, suppl 4. The indication close to the name of the first author refers to the page in this supplement.
Insulin resistance: effect of new ART
The group of G Moyle London UK (P Randell A18 and A29) presented 3 studies on the topic.
A study performed in 19 healthy volunteers searched for the effect of tenofovir (300 mg QD) versus placebo on muscle insulin sensitivity evaluated by an euglycemic hyperinsulinemic clamp and revealed that tenofovir did modify neither insulin sensitivity nor adipokine or endothelial markers level.
Similarly when comparing the effect of raltegravir (400mg BID) versus lopinavir boosted with ritonavir (400/100 mg BID) for 2 weeks, P Randell et al did not find any effect of raltegravir on muscle insulin sensitivity while LPV/r induced a 16% decrease, as previously reported.
In treatment-experienced patients on a double PI, the authors (A30) evaluated the effect of the switch towards boosted darunavir (600 mg BID) on insulin sensitivity. They did not observe a modification in insulin sensitivity and in the more insulin resistant patients, insulin sensitivity tended to improve.
Alterations in body fat distribution
Two groups studied human fat samples from visceral and subcutaneous area to try to understand the different phenotypes observed during lipodystrophy with loss of subcutaneous fat while the visceral depot is expanded.
In the group of F Villaroya and M Giralt (J Villaroya , Barcelona Spain, A3) working in collaboration with P Domingo, they could study 10 biopsies issued from subcutaneous fat from lipodystrophic patients and 7 biopsies issued from visceral fat (4 from the same patients). The expression of a number of genes was evaluated: mitochondrial dysfunction was present in both types of samples. A phenotype of poor differentiation was observed only in samples issued from the subcutaneous depot. Markers of inflammation and macrophages were observed in the two depots but were not equivalent. Therefore, in HIV-infected patients the profile of gene expression is different in the two fat depots.
C Vatier (in the group of J Capeau and B Antoine, Paris, A3), presented data obtained on healthy lean women and performed with fat samples issued from subcutaneous and visceral fat depot from the same subjects incubated ex vivo with different antiretroviral molecules. PIs (NFV, LPV, RTV) but not stavudine were able to induce an inflammatory profile with increased IL-6 production in subcutaneous fat samples but were devoid of an effect in visceral samples. This resulted in increased free fatty acid release from subcutaneous but not visceral fat. These results help to understand the opposite effect of some antiretroviral molecules on the two fat depots.
Several in vitro studies evaluated the effect of efavirenz on adipocyte differentiation and function and reported that efavirenz was highly deleterious in the setting. The group of F Villaroya (J Gallego-Escuredo A24) compared the effects of efavirenz and nevirapine on murine and human adipocyte differentiation and observed that efavirenz strongly inhibited differentiation and exhibited toxicity while nevirapine did not impair and even enhance differentiation.
E Hammond (A8 from the group of D Nolan Perth Australia) presented further data on sequential adipose tissue biopsies from patients under thymidine analogue NRTI before and after switch towards other NRTIs. Fat samples from patients under tNRTI exhibit an inflammatory phenotype with invading macrophages expressing a number of pro-inflammatory cytokines while the expression of adiponectin is decreased. When patients are switched from thymidine analogues, the level of mtDNA was partly restored but the inflammatory phenotype poorly reversed in patients with the more severe lipoatrophic phenotype. Evaluation of these markers in the serum was generally not correlated with their expression in fat tissue.
E Martinez (A9, Barcelona Spain) showed data on limb fat obtained comparing patients with intermittent relative to continuous thymidine sparing antiretroviral therapy in patients with lipoatrophy. 147 patients were randomized to continuous (n=44) viral-guided group (maintained at HIV-1 RNA<30 000 copies/ml, n=50) or immune-guided group (maintained at CD4>350/mm3, n=53). Compared to the continuous treatment group, patients with immune and viral-guided interruptions gained more limb fat (+700-900 g at 24 months). Bone mineral density in femur and lumbar spine remained stable or increased on the two interruption groups whereas it decreased in the continuous treatment group.
Metabolic alterations
M Boffito (A6, London UK) studied the effect of boosting dosages of ritonavir on metabolic parameters in healthy volunteers. She previously presented at the 2008 CROI meeting that RTV100 mg BID but not RTV 100 mg QD increased triglycerides concentrations after 2 weeks and that reduced HDL and CD36 expression in blood leucocytes were observed for both RTV doses. In 20 individuals randomized to RTV 100 then 200 for 2 weeks with a washout period of 2 weeks in between or the reverse scheme, they found that CD40 plasma levels were increased with the two doses while the inflammation marker us-CRP (C reactive protein) and the endothelial marker sICAM remained unmodified. RTV 200 but not 100 increased adipophilin gene expression, a marker of lipid-laden macrophages. Thus boosting doses of RTV can modify some parameters and the effect is generally related to the RTV dose.
Several studies evaluated the effect of switching NRTI to TDF/FTC.
The study of G Ionescu (A68, D Kotler group from New-York) evaluated the effects on fat, liver and muscles of substituting TDF for ZDV versus continuing ZDV in patients treated for an average of 5 years by a ZDV-containing regimen. Five controls and 7 switching patients completed the study. At week 24, whole body, lower limb and visceral fat increased in the switch group and decreased in the ZDV continuation group as expected. Hepatic fat content and lactate clearance by the liver tended to improve in the switch group. Skeletal and cardiac muscle mitochondrial function tended to improve while muscle insulin sensitivity remained unmodified.
In the TOTEM study presented by MA Valentin ( Group of C Katlama Paris, A44), dyslipidemic patients under NRTI were switched to TDF/FTC. Lipid levels, TG and LDL-c, decreased early at week 4 and remained lower at week 12. The proportion of patients with a LDL-c level higher than 4,1 mmol/l decreased from 48% at baseline to 26% at week 12. Therefore, switching the NRTI backbone to TDF/FTC was beneficial for the lipids in dyslipidemic patients.
The RECOMB study performed in Spain and presented by E Martinez (A35) evaluated the limb fat change 48 weeks after switching from ZDV/3TC to FTC/TDF (n=39) versus continuing on ZDV/3TC (n=41). Median change from basal level in total limb fat measured by DEXA-scan was +392 g in the FTC/TDF group vs -257 g in the ZDV/3TC group. The recovery in limb fat was observed in particular in patients with lower limb fat level (<7,2 kg), prolonged exposure to ZDV (more than 5 years) and BMI <25kg/m2. Therefore, switching from ZDV allowed a good recovery in limb fat even if lipoatrophy was severe and if exposure to ZDV was prolonged.
In the prospective, open-label, single arm SETTLE study presented by JC Gathe (Houston, A49), 24 HIV-infected suppressed patients were switched from ABC/3TC to TDF/FTC for 48 weeks. At week 4, total cholesterol and triglycerides were decreased but the effect was not maintained at week 48. However, the proportion of patients with total cholesterol over 240 mg/dl decreased from 43% at baseline to 33 % at week 48 and the proportion of patients with TG over 200 mg/dl decreased from 54% at baseline to 29% at week 48.
Metabolic results from the BICOMBO substudy BICOMBOmet (performed in Barcelona and directed by D Podzamczer) were presented by M Saumoy (A7). BICOMBOmet is a multicentre trail comparing TDF/FTC (n=55) versus ABC/3TC (n=48) in virologically suppressed patients. At week 48, a significant increased in total cholesterol, LDL-c and Apo B but also of HDL-c and Apo-A1 was observed in ABC/3TC compared to TDF/FTC. LDL to HDL and Apo A1 to Apo B ratios remained stable in both arms. An increase in small, dense LDL-c subfractions was observed in both arms but only ABC/3TC use was associated with an increase in the more atherogenic B phenotype and a decrease in LDL particles size. Therefore, ABC/3TC led to a more atherogenic profile. However, no change was observed in the estimated CV risk.
Cardiovascular alterations
To investigate whether increased CRP levels and HIV infection are independently associated with acute myocardial infarction (AMI), V Triant ( from the S Grinspoon group in Boston A5) performed a study in the a large US healthcare system in Boston. Among patients between 1997 and 2006 with a recent CRP determination and AMI (CRP determination between 3 years and 1 week prior to AMI), 487 were HIV-infected and 69870 were not. Multivariable logistic regression analysis was used to test the association of increased CRP and HIV with AMI after adjustment for demographic and other cardiovascular covariates: increased CRP (OR : 2.13) and HIV (OR: 1.93) were independently associated with AMI. HIV patients with increased CRP have a fourfold increased risk of AMI compared to those with neither risk factor. Measurement of CRP may be useful in the cardiovascular assessment and prediction of AMI in HIV-infected patients.
The involvement of the renin-angiotensin system (RAS) in the ART-induced adverse effects was evaluated in cultured adipocytes by F Boccara (from the group of M Caron and J Capeau in Paris A10). The association of ATV and LPV with boosting concentrations of RTV was able to up-regulate the RAS system on adipocytes and to induce an increased oxidative stress. Two angiotensin II type 1 receptors blockers (ARB), irbesartan and telmisartan used as antihypertensive drugs, were able to revert the effect of the boosted PI. Therefore, the adipocyte RAS system might be activated by some ART and ARBs could be beneficial in that setting.
Bone toxicity
A subgroup of the BICOMBO study evaluated bone toxicity, the BICOMBO body composition substudy, and was presented by A Curran (A35). The authors compared the long-term effect on body fat and bone mineral density after switching from NRTI to either TDF/FTC (n=25) or ABC/3TC (n=20). The two groups were similar at baseline with 5 kg limb fat. After 96 weeks, there was an absolute gain of limb fat in the two groups of about 300g in the TDF/FTC group and 750g in the ABC/3TC group. Total fat was decreased by 130g in the TDF/FTC group but increased by 1.8 kg in the ABC/3TC group. Bone mineral density was significantly increased in both groups. Patients on thymidine analogues at baseline experienced higher increments in limb fat than those not. Therefore, after 96 weeks of follow-up, switching from NRTI to either TDF/FTC or ABC/3TC similarly improved bone mass density, the gain in limb fat was not different in the two groups but the increase in total fat mass was more marked in the ABC/3TC combination.
DL Jacobson (A15) presented data from the multicentre PACTG1045 study on total body and spine bone mineral density across Tanner stages in 236 vertically HIV-infected compared to 143 uninfected children and youth (7-24 years). Among females, there was no significant differences between HIV- and HIV+ subjects for total body bone mineral density and bone mineral content at any Tanner stage. In contrast among males, HIV+ subjects presented lower BMD and BMC than HIV- at Tanner stages 3 to 5 while at stages 1-2 these parameters were not different. These data suggest that perinatally infected males might be at increased risk for bone mineral disease during adulthood.
B Grund (A14) presented data on the bone mineral density obtained in the body composition substudy of the SMART study (A Carr). Bone parameters were compared in 98 patients randomized to the viral suppression (VS) group and 116 in the drug conservation group (DC) and followed for a mean duration of 2.4 years. At baseline 73% of patients were on ART, 12% had osteoporosis, median T-scores were -0.5 (femur) -0.9 (spine by quantitative computed tomography qCT) and -0.7 (spine by DEXA). In the VS group participants received ART for 93% of the follow-up compared to 37% in the DC group. BMD declined by 0.9% per year (femur) 2.9% (spine qCT) and 0.4% (spine DEXA) in the VS group and significantly less in the DC group. The differences were significant at the two levels and with the two types of measurements. No consistent drug-specific association with BMD decline was found. In the parent study, with the entire cohort, the number of reported fractures as grade 4 adverse events was significantly higher in the VS group. Therefore, continuous ART is associated with progressive decline in BMD and possibly more fractures relative to intermittent CD4-guided ART.
Renal toxicity
SME Vrouenraets (from the P Reiss department in Amsterdam A16) compared glomerular filtration rate (GFR) measured directly or estimated by different methods in the PREPARE study including in 19 patients with suppressive ART under ZDV/3TC switched or not to TDF/FTC for 24 weeks. The mean measured GFR by using radioactive iothalamate decreased by 11 ml/min-1.73m2 in the TDF/FTC group as compared to a 7 ml/min-1.73 m2 increase in the ZDV/3TC group after 24 weeks. Among the estimated methods, a significantly greater reduction was observed in the TDF compared to the continued ZDV arm for all estimated GFR methods except the creatinine clearance and cystatin derived GFR. The mean (accuracy) and SD (precision) of the deviations from the measured GFR were reasonably good for the Cockroft-Gault and the creatinine clearance methods but MDRD with 4 or 6 parameters and cystatin C underestimated real GFR and performed poorly.
Therefore, mean GFR decreased by almost 10% at 6 months after switch to TDF and routine monitoring of renal function is warranted. In this small group, Cockroft calculation best reflected measured GFR than the other estimated measures.
Cancer
The distribution of AIDS and non-AIDS defining malignancies was studied in the French 2006 ONCOVIH study by E Lanoy (from the D Costagliola group in Paris A17). This was a national cross-sectional study with a prospective reporting of all new cases of malignancies diagnosed in HIV-infected patients in 2006 in over 300 care centers. Overall, 694 new malignancies were reported: the most common were non-Hodgkin lymphomas (21.5%) Kaposi's sarcoma (15.9%) anal cancers (8.2%) Hodgkin's lymphoma (7.6%) cutaneous non-melanoma ((6.8%) and hepatocarcinomas (5.6%). Almost two thirds were non-AIDS defining. However, both AIDS-defining and non AIDS-defining were diagnosed in patients with lower CD4 T-cells count than the whole French population of HIV-infected patients. This suggests that a better control of HIV and its associated immunodeficiency could prevent malignancies in HIV-infected patients.
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