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Report from the 9th Intenational Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Sydney, Australia. July 19-21, 2007
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Michael Dube
Indiana University School of Medicine
Indianapolis IN, USA
Overall there continues to be a progressive evolution of our understanding of the causes of lipodystrophy, dyslipidemia, cardiovascular disease, and other adverse effects of ART. While certainly there have been no major breakthroughs in management, the availability of agents with lesser effects on these parameters and a few therapeutic interventions have begun to be applied. Webcasts of the oral presentations at Lipo are now available freely online at :
http://www.intmedpress.com/lipodystrophy/default.cfm?itemtypeid=15&title=Webcasts.
Can nevirapine be safely substituted for other agents in those with high CD4 cell counts and virologic suppression?
This question was addressed by the observational Dutch cohort study ATHENA, presented by Ferdinand Wit. The concern of course is when nevirapine is started in ART-naive patients with high CD4 cell counts (>250 females, >400 males) there is excessive hepatotoxicity which can be severe. But does this carry over to individuals who are already virologically suppressed, and are switched to nevirapine? One published study from the EuroSida cohort (Antiviral Therapy 12:335, 2007) showed that switching to nevirapine with high CD4 cell counts was significantly safer in ART-experienced patients than in ART-naives. This was particularly true during the first 3 months of therapy. Similarly, the presentation from ATHENA reached similar conclusions. Those with low CD4 cell counts when ART was initiated, but who had high CD4 counts at the time of switching, tolerated the switch to nevirapine as well as ART-naive subjects with low CD4 counts whose initial therapy included nevirapine.
These observational data provide some additional comfort to those patients with virologic suppression and now have high CD4 counts who are considering a switch to nevirapine. It is possible though, that some of the hypersensitivity reactions seen in the ART-naive patients are due to newly started medications other than nevirapine, so that these reactions may be relatively over-reported and attributed to nevirapine. Said otherwise, ART-experienced patients who switch may actually have higher rates of nevirapine reactions - but since they may only be starting one new drug, this is not confounded by their other medications and only "true" nevirapine reactions get counted. A switch to nevirapine should still be always considered potentially risky and be monitored closely, until a randomized controlled trial more definitively establishes the safety of this sort of switch approach.
Do children with perinatally acquired HIV infection have problems with metabolism and body shape?
Kathy Mulligan of UCSF presented data on behalf of a large Pediatric ACTG cohort (127 boys, 113 girls) with prolonged antiretroviral exposures who were compared to HIV-uninfected control children. The kids receiving PI tended to have slightly more advanced HIV disease and longer durations of therapy than those on non-PI regimens. Total fat and limb fat were lower in both PI and no-PI groups but even though BMI was less in the HIV-infected subjects in general, trunk fat was not different in the PI-treated individuals - suggesting that perhaps PIs led to greater trunk fat accumulation in these kids. Lean body mass was similar to controls in both groups, which meant that the difference in BMI between HIV-infected kids and controls was primarily due to loss of (or conversely, failure to gain) body fat. Other than triglycerides being slightly higher in the non-PI subjects, compared to controls lipid values were quite similar. But the PI-treated kids had much greater elevations in triglycerides, but unlike the no-PI kids, the PI group also had significantly higher total cholesterol, LDL cholesterol, and non-HDL cholesterol levels and lower HDL cholesterol levels. There was evidence for increased insulin resistance in both of the HIV+ groups.
While these data are not as valuable as those from a randomized trial, they do suggest that attention needs to be paid to managing cardiovascular risk factors in children with HIV and perhaps greatest emphasis should be for those with more advanced HIV disease and those receiving PI therapy. It is not clear however, that PI use should be avoided in these children. Kathy Mulligan emphasized these were preliminary results and they continue to review the data for subsequent reporting.
Does tipranavir/ritonavir have different effects on body shape and glucose/lipid metabolism, as compared to lopinavir/ritonavir?
Andrew Carr from the host city of Sydney, Australia and the University of New South Wales presented metabolic and body composition results of a Boehringer Ingelheim-sponsored study that compared TPV/r to LPV/r over a short term of 48 weeks in initially ART-naive subjects. All received the thymidine analog-free nuke regimen of tenofovir-3TC with either either a higher ritonavir-boosted TPV regimen (500 mg TPV/200 mg RTV BID) or a lower ritonavir boosted TPV regimen (500 mg TPV/100 mg RTV BID), or Kaletra. Limb fat increased similarly in all 3 groups at week 48, but 48 weeks may not be sufficient time to see a decrease - even with thymidine analog-containing regimens, and there was no week 24 data so it is possible that limb fat had peaked earlier and was on its way down by week 48. However, based in the 96 week results of ACTG 5142 reported earlier this year at CROI (Haubrich, CROI 2007), it is unlikely that the Kaletra group was on its way down in this study so it is probably safe to say that, at least with these nukes, that limb fat will be maintained over time with tipranavir too in naive subjects. There was a modest decrease in visceral fat in all 3 groups. Impaired glucose tolerance and insulin resistance did not occur with any of the PIs compared to baseline. Increases in cholesterol were more marked with both TPV regimens than with Kaletra.
These data suggest that the body fat effects of these 2 PIs, TPV/RTV and Kaletra, are comparable. Further data are needed that compare these agents over greater periods of time are needed, but these short-term data found no major differences. Because insulin resistance was not seen, this suggests that either these PIs do not directly induce insulin resistance in HIV-infected patients on combination ART, or perhaps that (because thymidine analogs were not used in any subjects) co-administration of a thymidine analog may be necessary for these particular PI to induce insulin resistance and limb fat loss.
The growth hormone releasing factor analog tesamorelin (TH9507) reduces visceral fat, but what else does it do?
This GHRF analog has already been reported to significantly improve visceral fat accumulation by an average of 20% as compared to placebo in HIV-infected subjects with increased waist circumference and waist-to-hip ratio (CROI 2007). Importantly, this occurs without a significant decrease in subcutaneous fat. Steve Grinspoon from Harvard expanded on his CROI report on this growth hormone releasing factor (GHRF) analog, which recently received the name tesamorelin, from the Canadian biotech company Theratec. GHRF is made by the hypothalamus gland and stimulates the pituitary gland to produce growth hormone. But growth hormone therapy is associated with many side effects, including diabetes/impaired glucose tolerance/insulin resistance as well as various aches and pains like carpal tunnel syndrome and joint aches. None of these problems have been a major issue with tesamorelin, which is actually safe to give to patients with mild, diet-controlled diabetes. Because of a feedback mechanism, when a GHRF-like substance is administered, growth hormone levels from the pituitary increase but presumably do not reach excessive, or supraphysiologic, levels (as may happen when growth hormone itself is given) due to this feedback loop. Insulin-like growth factor-1 (IGF-1) increases when you give either GHRF or growth hormone, and it is the IGF-1 that appears to mediate the improvement in muscle mass and the reduction in belly fat seen with either tesamorelin or growth hormone. Levels of IGF-1 increased with tesamorelin by ~80% over placebo and the greater the increase in IGF-1, the greater the reduction in belly fat. The people who benefited the most from tesamorelin were those that had the most visceral fat to begin with. In a related poster presentation, there appeared to be some subjective and quality-of-life benefit to tesamorelin over placebo. Unfortunately this agent is occasionally associated with hypersensitivity reactions (~2%) which while none have been life-threatening, these may limit its long-term use.
So, it appears that tesamorelin is effective at reducing belly fat (particularly in those with a lot of it by CT) and this is associated with a variety of improvements in markers of cardiovascular risk, without the adverse glucose effects and with few of the adverse musculoskeletal effects of growth hormone. Its place in therapy remains to be clarified, and a lot will depend on how costly it will be. Alternatives for abdominal obesity in HIV-infected patients include metformin for those with impaired glucose tolerance, growth hormone for those without IGT, and of course diet and exercise should have a primary role here. If reduction of CV risk is the primary goal, interventions for smoking cessation and dyslipidemia may be more cost-effective than tesamorelin. Of course, there remains the consideration that increased belly fat, whilst it does occur in patients with HIV, appears to be less prevalent in men with HIV than in the general population. Even if increased belly fat is more common among HIV-infected women, it is likely that the effect of GH and GHRF analogs is somewhat attenuated in women. Further, we currently lack any long-term data with tesamorelin, so the durability of the response to it and the need for maintenance therapy, for how long, with what dose, also remain open questions. Finally, if this agent will be costly, more data will be needed to be able to target those individuals most likely to benefit from its use.
Does diabetes have the same impact on cardiovascular risk in HIV-infected patients as it does in the general population?
The multicenter, multi-continent DAD study has contributed greatly to our increased understanding of risk factors for development of cardiovascular disease in HIV-infected individuals. Signe Worm from Copenhagen presented an analysis of just how much does a diagnosis of diabetes contribute to the risk of myocardial infarction. The current NCEP guidelines consider a diagnosis of diabetes to be a "coronary heart disease (CHD) risk equivalent", meaning that if you have diabetes you should be considered to be at the same risk for heart attack as someone already diagnosed with CHD, and thus lipid problems should be managed just as aggressively in diabetics. There are older data from the general population to justify this approach, but some more recent studies have not confirmed that the magnitude of risk from diabetes alone is as great - thus this question of diabetes being a CHD risk equivalent is somewhat controversial in the general population as well.
Published guidelines for managing lipid disorders in HIV-infected patients on ART have stated that the NCEP guidelines should be followed just as they are in the general population. However, it has not been documented in HIV-infected patients that a diagnosis of diabetes carries the same CHD risk as it does in the general population. It is possible, because insulin resistance/impaired glucose tolerance may be present for decades before a diagnosis of diabetes is made in the general population, that there is cumulative risk incurred over a prolonged period even before overt diabetes is diagnosed. With HIV infection, if insulin resistance/impaired glucose tolerance is caused by antiretroviral therapy and is present only for a much shorter period of time before over diabetes is diagnosed, or if diagnosis of diabetes is made much sooner because of increased health care visits and routine blood glucose monitoring, or is diagnosed at a much younger age, it is possible that a current diagnosis of diabetes may have a much lesser impact on CHD risk.
The DAD data confirm that diabetes increases CHD risk, but a diagnosis of diabetes mellitus without known pre-existing CHD provided only about 1/3 of the CHD event risk that a prior CHD diagnosis gave. This would suggest that perhaps, a diabetes diagnosis in an HIV-infected individual should not necessarily lead to lipid management that is as aggressive as in an HIV-infected individual with pre-existing CHD but no diabetes. Alternatively, it could be argued that because HIV infection itself increases CHD risk, and because diabetes is discovered sooner, this early diabetes diagnosis would provide an excellent opportunity for preventative early lipid intervention in HIV-infected diabetics well before there is longer-term vascular damage from years of insulin resistance and impaired glucose tolerance. Importantly, the DAD results do not address the central question of, will the risks from following current NCEP guidelines for diabetics outweigh the benefits in those with HIV? For now, it seems reasonable to continue to follow the NCEP guidelines until there are more data including external validation of the DAD results on other prospective cohorts.
Can nucleoside RT inhibitors directly cause insulin resistance?
Current dogma has early insulin resistance from ART blamed on protease inhibitors, and late insulin resistance attributed to lipoatrophy induced by nucleoside drugs. But studies in healthy subjects have suggested that at least some NRTIs may cause early insulin resistance as well. The central finding presented by van Vonderan from Amsterdam was that peripheral tissue insulin resistance (as measured by the gold standard hyperinsulinemic clamp procedure) occurred only occurred in subjects (all male) who initiated zidovudine-lamivudine plus Kaletra and not in those who received nevirapine plus Kaletra. This ZDV-3TC associated insulin resistance was present at 3 months, a time point where limb fat was actually increased from baseline. At 24 months limb fat was down in the ZDV-3TC group, but this insulin resistance occurred well before limb fat had decreased, suggesting a more direct effect of the NRTI therapy. This data suggests that we need to pay attention to insulin resistance in future clinical studies that compare nucleoside backbones, not just PI vs no PI. And whilst it is tempting to speculate that, among the nucleoside RT inhibitors, only the thymidine analogs should adversely affect insulin resistance, it would be wise to actually obtain the data rather than assume - and be certain that the other NRTIs are in fact not involved in these effects.
Do dyslipidemia, insulin resistance, and body shape changes differ according to race/ethnicity?
Data presented by Carl Grunfeld of UCSF from the CPCRA FIRST study extend existing data on the effects of race/ethnicity on metabolic and body composition variables in subjects initiating ART. This was a large (400 subjects) multi-ethnic (61% African-American, 28% white, 11% Latino) cohort that is noteworthy because it examined changes over time in these parameters. Only 22% of subjects were women however, including only 8 Latinas and 3 whites, which severely limits the study's ability to address any race-gender interaction.
It is well-established that lipid levels in the general population differ across racial ethnic groups, and similar findings have been published in HIV-infected subjects on ART from cross-sectional studies (PLoS Medicine 2006). Latinos tended to have the most adverse changes in lipid levels, while African-Americans had the least - in spite of the fact that African-Americans were more likely to receive a ritonavir-boosted PI. Fasting glucose levels and insulin resistance by HOMA-IR worsened in African-Americans and particularly among Latinos, but not in whites, which is consistent with the observation in the general population that non-white race increases the risk of diabetes mellitus.
At baseline, there was more waist subcutaneous area (representing primarily fat) in Latinos, whilst there was evidence for more non-subcutaneous area (representing primarily muscle) among African-Americans. There were no differences over time in thigh SQ area (ie fat) or thigh non-SQ area (ie muscle) between groups, but arm SQ area decreased more in Latinos - consistent with a greater tendency to develop lipoatrophy over time. Waist SQ area also decreased among Latinos but increased slightly in whites and African-Americans, also consistent with a greater tendency to experience SQ fat loss.
So what are the clinical implications of these data? Perhaps we can worry less about our African-American patients when it comes to lipid changes on ART, but lipid levels should still be obtained in all patients on ART regardless. Perhaps we should worry more about our African-American and Latino patients with regards to developing diabetes mellitus, but we should already be doing that based on long-known data in the general population. Finally, perhaps we should worry more about lipoatrophy in Latinos, but vigilance for this side effect should be in place regardless of race/ethnicity. There is probably insufficient reason to prefer one class of antiretrovirals, or certain antiretrovirals within a class, for any particular racial/ethnic group based on these results.
Is lipoatrophy associated with vascular dysfunction?
It is well-known that the presence of lipoatrophy is associated with a variety of adverse cardiovascular risk factors such as dyslipidemia and insulin resistance, but as yet there has been no good evidence that cardiovascular event rates are higher or vascular dysfunction is greater among those with lipoatrophy or lipohypertrophy. The group from Indiana University presented data on a large cross-sectional study of vascular endothelial function measured by brachial artery reactivity by ultrasound that included detailed body composition analysis by DEXA and CT methods in 96 subjects in clinical HIV care. Half were ART-naive, and among the treated subjects 53% were on PI. Interestingly, vascular endothelial function tended to be worse among those subjects on ART with the lowest levels of limb fat compared to those with higher levels - suggesting a mechanism that somehow lipoatrophy (perhaps mediated by metabolic dysfunction) could lead to more cardiovascular disease. There was no relationship between visceral fat and endothelial function, and PI use also did not appear to be related to worse endothelial function by brachial artery reactivity testing.
Although PI use has generally been considered to be associated with endothelial dysfunction, early studies included many subjects on indinavir, which to date is the only PI conclusively shown to directly induce endothelial dysfunction. Another presentation at this meeting in ART-naive subjects reported that with initiation of ART, endothelial dysfunction improved even if subjects received the PI lopinavir-ritonavir. So, it is possible with currently-used PIs, that endothelial dysfunction is not a directly drug-induced problem. Regardless, endothelial dysfunction does occur and presumably will contribute to increased cardiovascular events. The mechanism by which lower limb fat is associated with endothelial dysfunction clearly deserves further study, and perhaps we should be particularly vigilant about managing cardiovascular risk in our patients with lipoatrophy.
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