Metabolics/Inflammation and Such At IAC
David Alain Wohl, MD - The University of North Carolina
".....a chorus supporting more aggressive treatment of HIV to prevent complications [early ART]...." Low CD4 & detectable viral load not good: from Jules
low CD4 & detectable viral load are not good and associated with increased risk for non-AIDS events.... "HIV therapy started before profound CD4 depletion is protective against a host of non-AIDS conditions......cerebrovascular disease associated with having a most recent CD4 cell count below 200/mm3 and a viral load above 400 copies/mL....nadir CD4 cell count < 350/mm3 and last viral load were each associated with development of a non-AIDS event. [preliminary small study] Inflammatory markers including hsCRP and IL-6 plus D-dimer also tended to decline with aspirin...... SMART study found -dimer levels [inflammation marker] were predictive of poor outcomes....... elevated D-dimer was independently associated ....with higher HIV RNA level, being off ART at baseline.......higher CD4 counts and use of ART regimens containing both PI and NNRTI were protective."
Those looking for sessions on topics such as cardiovascular disease, metabolic disorders and inflammation at the International AIDS Conference (IAC) last month could be found wandering the halls of the Washington Convention Center. Some slipped into promisingly titled sessions only to find a panel telling those assembled what they already knew. Others navigated the escalators and hallways to find posters that were scattered across the convention center, as if part of some scavenger hunt for eggs of knowledge. Lastly, a few weary souls found themselves accidentally in presentations about the civil rights of PLWH in Nepal or rights abuses of sex workers in Cambodia and just stayed.
Overall, there was less coverage of issues metabolique at IAC 2012 than any major HIV conference since the approval of Crixivan. Perhaps it was the attention being paid at this IAC to cure and elimination of HIV, or a lack of much that is new in the complex world of complications of HIV and its therapies. To be fair, the International Workshop on Co-Morbidities and Adverse Drug Reactions in HIV was held the week before in the nation's capital and may have siphoned some of the latest and greatest regarding the conditions that persist among those who live, and will for decades to come, with HIV infection.
Some of what I was able to find of potential interest to the provider is described below, starting with various studies that give us a bit more information about the effects HIV therapies have on metabolic parameters, then moving on to problems that are unrelated to ART and may actually be prevented with HIV therapy, and lastly to risk factors for inflammation.
Big Bellies Abound
Almost all of my patients blame their big round bellies on their HIV medications. Never mind that Daddy and brother Ned have midsections that also generously spillover their belt buckles and that they consume a 3,000 calories of the best Southern cuisine has to offer (washed down with a bottle of Mountain Dew - 16 ounce bottle on sale for $0.69 at Winn Dixie) a day but only burn through 15 calories (twisting open the Mountain Dew bottle). Certainly, there are some people who develop a pathological build up of fat deep in their abdomens, but this seems to be the minority of patients on ART nowadays. Part of the problem in clinic is that faced with a plentiful paunch it is a challenge to differentiate visceral fat accumulation from the weight gain in fat that accompanies a return to feeling well. Typically, those who are simply victims of calorie poisoning gain fat all over while lipodystrophic look more like a lower case 'b' with legs.
Moyle and colleagues examined data from the CASTLE Trial (a comparison of atazanavir/ritonavir to lopinavir/ritonavir in treatment naïve patients also taking tenofovir/emtricitabine) to detect differences between the study arms in patterns of fat changes across CD4 and BMI ranges (1). They also looked at the incidence of what they call hypertriglyceridemic waist (HTW) phenotype, defined as elevated triglycerides (>177 mg/dL in men, >133 mg/dL in women) plus a high waist circumference (>90 cm in men, >85 cm in women). CT scans through the belly and whole body DEXA scans were used to measure regional fat. Of the 224 people included, 30% were women, 60% were non-white and median BMI was 24 kg/m2. Over 96 weeks, participants in both groups had an increase in waist to hip ratio and gained fat but the increase in fat was significantly greater for atazanavir (29%) versus lopinavir (15%). Subgroup analyses found that CD4 cell count and BMI drove these results. Only those with CD4 cell counts below 50/mm3 had significant changes in limb and subcutaneous fat and this was greater with atazanavir therapy. Visceral fat did not increase significantly in either study group when stratified by CD4. Likewise, those with a BMI <22 had significant gains in limb and subcutaneous fat (but not visceral fat) over 96 weeks on atazanavir, while there was no major change in any fat depot during therapy with lopinavir across BMI tertiles. Differences between treatment arms again showed greater gains in visceral and subcutaneous fat with atazanavir in those with lowest BMI. Despite these results, the incidence of HTW was greater in the lopinavir arm (18% versus 10%), a consequence of the greater increase in triglycerides on this regimen. While the authors concentrate on the HTW results and the potential for the combination of elevated waist circumference and hypertriglyceridemia, the study also demonstrates a) sicker people tend to gain more fat than those who start therapy earlier, b) the fat gained was mostly pinch-an-inch-fat and was generalized rather than sequestered to the midsection, and c) atazanavir/ritonavir clearly can lead to gains in fat, including visceral fat - here seen in those with low CD4 counts at baseline - above what is seen with lopinavir/ritonavir.
A separate study conducted at UNC examined the effects of a different regimen on body shape (2). Raltegravir combined with tenofovir/emtricitabine was administered to 30 African-American men and women initiating HIV therapy. In this study the mean BMI was high at 28. Again CT and DEXA were used to assess body shape changes over 2 years. Here, fat in all regions (visceral, limb, trunk) increased significantly over time. Lipid and insulin parameters did not significantly change; bone density fell slightly. The generalized fat gain seen also in this study further supports a 'return to health profile' rather than a dysmorphic preferential accumulation of belly fat after initiation of HIV therapy with this regimen in African-Americans.
In reconciling these results we can look to what is common among them. Foremost, fat gains appear to be proportional, with increases in fat in multiple depots. Lipoatrophy, fat loss, was not observed and truly does appear to be rare in the absence of thymidine analogues. CASTLE, like several older studies, suggests that those who start thin gain more fat than those who start heavier. This makes sense intuitively (as those who are sicker would be expected to experience a recovery that is accompanied by weight gain). In the UNC study, we found even those who were in no way underweight gained fat after starting HIV therapy. However, subgroups analyses such as those conducted in the CASTLE analysis were not done as the sample size was small and it is possible that those at the lower end of the BMI spectrum drove gains in fat. Overall, the work presented indicates that with ART comes fat and that this is probably mostly accounted for by a redirection of calories previously spent fighting a losing battle against a virus that replicates mercilessly.
Some of the most interesting presentations at the conference for the therapeutic-minded were the head-to-head, drug X-versus-drug Y variety. In addition to providing the HIV management equivalent of a boxing match, these trials let us see what regimens do to lipids, renal function, bone health and alike.
In the SPIRIT Study, patients stably suppressed on a ritonavir-boosted PI were randomized to maintain their therapy or switch to the fixed dose single tablet regimen of rilpvirine/tenofovir/emtricitabine (3). Simplification to the fixed dose was successful with rates of viral suppression that were high and just as good as with the continuation of the PI therapy. However, there were some impressive changes in lipids with the switch: at 24 weeks, there was a 16 mg/dL drop in LDL-cholesterol and a decline in triglycerides of 53 mg/dL among those who switched compared to little to no change for those maintained on PI therapy. The total cholesterol to HDL cholesterol ratio was significantly improved with simplification. Switching to is a common way rilpvirine/tenofovir/emtricitabine is being prescribed and these data support such a change from a PI when lipid lowering is desired.
In the GS-114 Study, atazanavir boosted with either ritonavir or cobicistat administered to treatment-naïve patients also assigned tenofovir/emtricitabine, provided a clean head-to-head of the metabolic effects of these two pharmacologic boosters (4). Lipid parameters rose in both study arms, tending to be less with cobicistat, but the differences did not achieve statistical significance. Similarly, there was some less GI toxicity with cobicistat, but this was modest. Overall, these data demonstrate that these boosters are more alike than not.
SPIRIT Study: Switching boosted PI to Rilpivirine In-combination with Truvada as a Single-Tablet Regimen Week 24 Results - (07/23/12)
Cobicistat versus Ritonavir as Pharmacoenhancers in Combination with Atazanavir Plus Tenofovir DF/Emtricitabine: Phase 3 Randomized, Double Blind, Active-Controlled Trial, Week 48 Results - (07/24/12)
The Other Side of the Coin: Does Early HIV Prevent Clinical Events?
While studying the adverse effects of ART is important and necessary, there continues to be evidence that HIV therapy started before profound CD4 depletion is protective against a host of non-AIDS conditions. At IAC, the best showing for the treat-'em-early crowd was the same study that showed us for sure that ART is prevention. The HIV Prevention Trials Network (HPTN) study 052 was in a sense a when-to-treat trial in that HIV-positive people with CD4 cell counts 350-550/mm3 (well above starting thresholds in the countries where the study was conducted) were randomized to start ART immediately or delay until CD4 hit 250/mm3 or less. A longer time to disease progression and significantly fewer HIV-related clinical events, driven by extra-pulmonary tuberculosis was seen in the early HIV therapy arm and included in the original New England Journal of Medicine publication. Longer-term data on these and other clinical outcomes were presented at IAC (5). During a median of 2 years of follow-up, 24% in the delay ART arm started HIV therapy at a CD4 cell count of about 230/mm3. No significant difference between early and later ART starters in the time to primary events (death, advanced AIDS, tuberculosis, severe bacterial infections or select serious non-AIDS events) was seen. However, there was a trend favoring early ART. Further, those older than 40 years of age had significant protection from these events with early ART in multivariable analyses. Early ART was significantly associated with fewer cases of tuberculosis but also other AIDS-associated events including HSV, zoster, persistent thrush and seborrhea. The median CD4 cell count at time of event was in the 500s, suggesting a protection of ART that extends to those with counts that are considered to be high but in actuality are sub-normal. These are useful data and point again to a benefit (and no harm) of early ART for individual health that augments its value as a method to prevent HIV transmission.
Effect of Early versus Delayed Initiation of Antiretroviral Therapy (ART) on Clinical Outcomes in the HPTN 052 Randomized Clinical Trial - (07/26/12)
That ART may have a role in preventing non-AIDS events, such as cardiovascular disease (CVD), and that the risk of such conditions is increased among those who do not benefit early from ART is suggested by other studies presented at IAC. In a study conducted at UNC, the incidence and determinants of cerebrovascular disease were examined in cohort of 2,583 patients with HIV infection (6). Of these 53 developed cerebrovascular events during the period of study, 1999-2010 - an incidence of 3.87 per 1,000 person-years. This was more than double the rate of cerebrovascular disease in the general NC population (1.72 per 1,000 person-years). Factors determined in multivariable analysis to be independently associated with these events included the traditional including age, hypertension, and dyslipidemia but also having a most recent CD4 cell count below 200/mm3 and a viral load above 400 copies/mL.
Incidence and clinical features of cerebrovascular events in HIV-infected adults in the Southeastern United States - (08/15/12)
Another study looked at AIDS and non-AIDS events in a cohort of 675 patients in Barcelona who had a CD4 cell count of at least 500/mm3 (7). Most (78%) were on ART, 80% were male and 28% were HCV co-infected. Median age was 43 years. Non-AIDS events were considered those that led to a first admission to the hospital due to non-AIDS defining malignancies, cardiovascular, neuropsychiatric, liver-related or end-stage renal disease. There were 85 such events, mostly malignancies and CVD. Age, nadir CD4 cell count < 350/mm3 and last viral load were each associated with development of a non-AIDS event. Even after initiation of ART, the crude incidence rate of non-AIDS events was 4-fold higher for those with a nadir CD4 cell count below 350/mm3.
In an investigation sure to make many patients happy, a CD4 cell count above 200/mm3 was again found to be protective against CVD, but so was alcohol consumption (8). The study done in (where else?) France looked at 1,154 patients started on PI-based regimens from 1997-1999 who were followed in an observational cohort for a median of 6 years. The incidence rate for major CVD events (mostly myocardial infarction and stroke) was 0.75 per 100 person-years. Factors independently associated with CVD events included being male, being older, smoking (big time), and CD4 <200/mm3. A protective factor was drinking up to 4 (3 for women) "alcohol units" per day. More alcohol intake was not associated with any benefit. In a subset of 675 patients with addition metabolic data available, these factors remained significant as was hypertriglyceridemia and family history of CVD. So, you wonder, what is an alcohol unit? The standard definition is 10 mL of pure alcohol, which is surprisingly little. For instance, a pint of beer can include 3 alcohol units and a glass of wine 2. So, don't over do it.
An Aspirin A Day May Keep the Platelet Aggregation Away
Once it became clear that markers of inflammation are higher in HIV-infected persons and could signal threats to long-term well being, different anti-inflammatories have been thrown at HIV-positive people. Interestingly, there are few data on one of the oldest and most commonly used anti-inflammatories, aspirin. In a teeny but kind of cool study from New York aspirin was administered at a dose of 81 mg for one week to 25 HIV-infected cases whose viral loads were stably suppressed on ART (median CD4+ cell count was 630/mm3) plus 44 uninfected controls (9). Significant decreases in platelet aggregation and activity as well as immune activation were seen in the HIV-positive folks, albeit generally not to levels seen in the uninfected controls. However, the effects of aspirin lingered even a week after cessation of the medication (aspirin's effects can continue during the entire three month life span of a platelet). At baseline, the HIV-positive cases were older than the controls, and had ten times the rate of current smoking, not surprising they also had higher levels of platelet aggregation and immune activation compared to controls. Inflammatory markers including hsCRP and IL-6 plus D-dimer also tended to decline with aspirin. This is an interesting study that certainly will be followed with larger and longer-term investigations. Before reaching for Herr Bayer's old time pain reliever, providers should weigh the risks and benefits of aspirin in their patients with HIV and follow general recommendations regarding its use to prevent CVD.
Low-Dose Aspirin for Activation: Increased platelet activity and immune activation in HIV-positive subjects on antiretroviral therapy is attenuated with low-dose aspirin- (08/06/12)
Another switch study looked at what happens to markers of inflammation, coagulation and endothelial function in a small cohort of patients treated with abacavir/lamivudine containing ART changed to tenofovir/emtricitabine (10). All participants had HIV RNA levels that were <50 copies/mL; 13 maintained their abacavir/lamivudine regimen and 14 switched to tenofovir/emtricitabine. At 6 months hsCRP appeared to have dipped in both arms, but more so in the group who changed to tenofovir/emtricitabine with a 44% difference between arms at that time point (hsCRP = 1.8 versus 1.3, p=0.04). There was no significant difference between the arms in any single other parameter examined. The abacavir hsCRP story is full of twists and turns leaving most dizzy from the data.
In the landmark SMART study that found that drug holidays were bad for the health of people living with HIV infection, a curious finding was that at baseline, D-dimer levels were predictive of poor outcomes. On-study changes in D-dimer were less impressive as a factor associated with badness, but the assay has nonetheless found a firm foothold as part of the metabolic panel used in clinical studies. In an analysis of baseline data from the SMART study as well as the ESPIRIT and SILCAT trials, factors associated with baseline elevation of D-dimer (> 0.377 ug/ml - the 4th quartile in the mixed cohort) were sought (11). The results showed that elevated D-dimer was independently associated with older age, black race, female sex, study of origin (ESPRIT and SILCAAT), higher HIV RNA level, being off ART at baseline, lower eGFR and increased levels of CRP and IL-6. In contrast, higher CD4 counts and use of ART regimens containing both PI and NNRTI were protective. Therefore, generally being in poorer health was associated with elevated D-dimer, which in some studies was itself associated with reduced mortality. Some may say, "Duh".
Factors associated with elevated D-dimer levels in HIV-infected individuals: 'viral replication associated with D-dimer' - (07/30/12)
Obesity and Inflammation
We started with studies that described an increase in generalized fat accumulation among those starting ART. As HIV is diagnosed earlier, before profound depletion of the CD4 cell count, many people are entering clinic with plenty of already accumulated fat. It is obvious that obesity is a health hazard for all, regardless of HIV status. The association between obesity and markers of inflammation and atherosclerosis were investigated in an analysis from the SUN Study, an observational cohort study that enrolls patients from clinics in Denver, Minneapolis, St. Louis and Providence (12). Patients included were those who were ART naïve with CD4 cell counts between 100 and 500 or ART experienced with a CD4 >100/mm3 (I am not sure why these were the inclusion criteria). A total of 494 patients were included. Median age was 41 years, 61% were white non-Hispanics (see list of SUN Study cities above), and 22% were women. At baseline, 41% were smokers; median weight was 175 pounds and 95% were on ART. Median CD4 was 474/mm3. An incredible 38% were obese and 23% overweight, leaving only 38% at normal weight (2% were underweight). Those who were obese were more likely to have elevated inflammatory markers including CRP and IL-6, D-dimer, and greater carotid intimal thickness. They also had lower vitamin D levels. The analysis was only univariate so it is unclear how this all shakes out when looking for independence of these associations. Interestingly, when re-assessed two years later, 10% of the cohort had moved into a higher BMI category (yikes!).
While there were fewer 'wow' studies in this area of research than seen, say at CROI 2012, many of the presentations at IAC did harmonize to an extent, presenting a chorus supporting more aggressive treatment of HIV to prevent complications. Besides ART there was little else collectively recommended by the IAC studies to guide those looking to age well with HIV. Cleaner ART will surely help. At CROI, there was an emphasis on addressing the traditional risks that limit human shelf life. Here we see the same and who can argue with smoking cessation, mindful weight management and attention to lipids? That there may be other, unique contributors to risk among people living with the virus is suggested by data tallying a continued low hum of immune activation, inflammation and microbial translocation that makes us all nervous. These are hot areas of research and as more is learned and interventions tested and developed we can expect to see more attention paid to complications at a future IAC.
Immune Activation, Inflammation and Complications of HIV 19th IAC 2012: Written by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine - (07/31/12)
Co-Morbidities Report from 14th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV and XIX International AIDS Conference -Written by Todd Brown, MD, PhD Associate Professor of Medicine and Epidemiology Johns Hopkins University - (08/17/12)
XIX International AIDS Conference
July 22-27, 2012 Washington, DC
14th International Workshop on
Adverse Drug Reactions in HIV
Washington DC, July 19-21 2012
1. Moyle G, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. MOPE081.
2. Wohl D, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEPE0103.
3. Palella F, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.
4. Gallant J, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0103.
5. Grinsztejn BE, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THLBB05.
6. Vinikoor M, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. PE092
7. Torres B, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THPE043
8. Protopopescu C, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THPE082
9. O'Brien M, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THAB0202.
10. Alozie O, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. THPE093.
11. Borges AH, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEPE094.
12. Conley L, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEPE096.