I am reporting to you from a pre-ICAAC community meetingheld by Merck in Redondo Beach California. It's being held a week beforethe ICAAC meeting in San Diego. I will also try to report back highlightson a daily basis from the ICAAC meeting. Following ICAAC comprehensive reportswill be posted.
Merck is conducting a pharmacokinetics (PK) study of ritonavir+indinavirin healthy volunteers. PK is the effect of a drug upon a second drug interms of blood levels. In other words, ritonavir will increase the bloodlevels of indinavir. A PK study will measure and evaluate the exact effectso that appropriate dosing can be selected. They said their PK study willbe conducted while both drugs are at steady state in the blood. The following4 dose combinations will be explored in this pilot study-
PK is being performed with both high and low fat meals.The results will soon be analyzed and then Merck will move onto a clinicalstudy in HIV-infected.
Merck is researching a new protease inhibitor it is callinga 2nd generation PI. L-756-423 is in pre-clinical development, not a potentCYP3A4 inhibitor (not a potent inhibitor of the liver enzymes system thatprocess drugs as ae other PIs), has less renal secretion than IDV, has alonger half life than IDV, and phase II is planned for early 1999.
Lipodystrophy or Fat Redistribution
Don Kotler, MD, the Director of GI and Immunology at StLukes-Roosevelt, addressed the phenomena of lipodystrophy and elevated lipidsthat has been observed over the past approximate year. Immediately beloware bullet point summary conclusions Dr Kotler arrives at based on datafrom studies he discusses in the full text of the article following thebullet points and my commentary.
Commentary from Jules Levin-- it remains uncertainwhat the cause of this syndrome is. This syndrome has become a public healthconcern, because many individuals are stopping or refusing to begin therapyfor HIV due to a fear of the adverse effects of lipodystrophy. Kotler'sresearch and opinions based on that research need further exploration andconfirmation. As well, other potential explanations including that of Carrand Cooper need further exploration. Their data is preliminary. We needcontinuing research and dedication of funding to determine the cause ofthis syndrome. A number of studies have recently started or are in the planningstages. Although we are anxious for faster answers to the problem, we willhave to wait for these answers because research moves more slowly than welike. In the meantime it is important to continue unrelenting pressure onthe pharmaceutical industry, governmental agencies such as the NIH &the FDA, and the ACTG & academic researchers to produce answers forus. We have to lobby the NIH and the HHS and insist they immediately providea large pool of research grant money for independent research efforts. Theymust make a high priority of this issue and the availability of fundingfor research in this area. The NIH has disappointed me in their commitmentto this problem. They are supposed to represent our interests and take moreof a leadership role than they have in resolving this problem. However,our activist experience tells us that these govt agencies will respond toour pressure if we act. I encourage all of you to contact the NIH, the FDA,andHealth and Human Services to register your support for research leadingto a better understanding of this syndrome and for a treatment of it.
NIH OAR (Office of AIDS Research)- 301 496-5046
NIH Division of AIDS- William Duncan 301 496-8210
FDA Office For Special Health Issues-Richard Klein 301827-4460
HHS- Eric Goosby 202 690-5560
HHS- Donna Shalala, Secretary of HHS 202 690-7000, fax202 690-7203
Dr Kotler's Talk. The 3 main elements of the syndromeare a change in the shape of the body, a change in lipid levels, changesin glucose and insulin. The glucose and insulin changes in a minority ofcases leads to clinical diabetes and in a majority of cases leads to indicationsof resistance to insulin. The latter may only be a metabolic abnormalitywhich is not at all obvious unless you take specific measurements. Peoplewith insulin resistance can have a normal blood sugar, and not in any waybe considered a diabetic. Some researchers think the syndrome may be relatedto insulin resistance. The changes in the body are common and can be seenby everyone. Other charactertistics of this syndrome that have been reportedinclude: elevated triglycerides, low testosterone, hypertension, myocardialinfarction or premature cardiovascular disease. We are talking about morethan cosmetic concerns-- potentially serious health outcomes.
The changes in altered "body habitus" are seenin both men and women. The most obvious is an increase in abdominal girth.This is not very hard to detect. Patients will tell you their waist sizeis increasing, their dress size is changing, the way their pants fit isdifferent. The increase in abdominal girth is not just related to increasedfat in the belly. It's related to a specific increase in fat deep insidethe belly. Doctors have described observing thinning of the extremities,prominence of veins, and increased wrinkling in the face. Women seem tohave a similar phenomena. In a study presented from Brown University, agroup of about 120 women taking combination therapies were interviewed,and about 20 women described symptoms that were consistent with the lipodystrophysyndrome. Virtualy everyone of the women complained of an increased abdominalgirth size, and a minority complained of thinning of skin of the face andthe extremities. The most common consistent and specific finding is increasedabdominal girth.
We have seen similar alterations in body fat distributionin the past in people with HIV even before they received any treatment forHIV.
Dr Kotler went on to show CT scans of both normal individualsand those with changes as described above. Fat deep within the belly iscalled visceral fat, and it's an accumulation of this type of fat that ischaracteristic of lipodystrophy. Visceral fat increases while fat underthe skin decreases. A CT scan showed a person with visceral obesity whoseamount of fat under the skin was thin. This is very rarely seen in a healthyadult, but if it is seen in a healthy adult it is seen as part of what'scalled Syndrome X. Syndrome X is well known to be associated with elevatedtriglycerides, elevated cholesterol, insulin resistance or diabetes, occasionallya buffalo hump, hypertension, and a very high risk for myocardial infarction(heart disease). He showed an MRI of a person with lipodystrophy in whichthe amount of fat under the skin is barely seen, but the intra-abdominalarea aside from the intestine is solidly encased in fat. This situationcan be quantified by CT scan or MRI, or a surrogate discussed below.
Another related phenomena is the so-called buffalo hump.It has received attention out of proportion with its rate of occurrence.It's an increase of a specific depot of fat underneath the skin. It's seenin Cushing's disease. Buffalo humps typically are a sign of a long-termexcess of cortisol often caused by a tumor. There are other depots thathave a similar type of fat that respond differently than the rest of thefat under the skin. Some people can have this under their arms. One studyreported 8 individuals with buffalo hump, but 4 were taking Pis and 4 werenot. Of all the studies reported at the Retrovirus Meeting in February thiswas the only one suggesting maybe the problem was not related so speficallyto Pis themselves. They ruled out Cushing Syndrome but they did not cautionthat ruling out Cushing Syndrome does not rule out elevated cortisol levels.In fact, people who are being treated with cortisone such as after a kidneytransplant or a liver transplant, or being treated with steroids for asthmaor other inflammatory diseases may as well develop truncal obesity, highblood lipids, buffalo hump, and hypertension.
At last February's Retrovirus Conference and again in Geneva,an Australian research group reported their findings related to lipodystrophy.Drs Carr and Cooper have done a nice job of defining what they call peripherallipodystrophy. They use a technique called DXA to look at body composition,but this method may miss thinning of skin in the belly and an increase ofvisceral fat. They interviewed patients on combination therapy and reportedthat 64 to 75% of people taking PI therapy said their was a change in theshape of their body. The change in their body shape was associated withthinning of the extremities and specifically a loss of fat in the extremities,not necessarily a loss of muscle. They also reported that many of thesepatients had elevated gluocose, triglycerides, and cholesterol. They reportedinsulin levels were elevated for the amount of glucose that was in theirblood, which is significant for insulin resistance. But, only one of theirpatients had diabetes.
One of the patients was not on a PI, but the Australiangroup has a theory that suggests the cause of lipodystrophy is the PI. Theysay the HIV protease has similarities to some human enzymes, and those enzymesare related to fat metabolism. They hypothesize that there are sufficientcirculating levels of protease inhibitor to block those enzymes leadingto a delayed disappearance of fat leading to an increase in the fat contentin the blood which leads to lipodystrophy. There is another enzyme in whichthey say something occurs. Although what they are saying is not clear, theysuggest there is a metabolic block related to this enzyme in fat cells causedby the protease inhibitor which leads to death of fat cells. These are fatcells that are under the skin. If there are less fat cells under the skinto accept fat and an increased level of fat circulating in the blood, theonly other place for the fat to go would be deep into the viscera. Theyare therefore suggesting that the site of the abnormality is not the deepfat in the belly where you see the increase, but rather underneath the skinwhere you see a decrease.
Most of the large number of studies reported in Genevawere "me too" studies, and in essence just echoed the resultsof other studies. There was little new information. There does seem to bestrong evidence that Pis do produce elevated lipids. But there is no increasingevidence (beyond Carr & Cooper's original presentation at RetrovirusFeb '98) they cause the rest of the syndrome, other than the fact that wesee the syndrome now more than we've seen it before.
That is a review of some of the literature on this subject.The data in the literature is pretty minimal. What is it we don't know?First, we don't really have a definition for the syndrome. We don't knowif it's the elevated lipids, the body habitus changes, the insulin resistance,or if it's 2 or 3 of these, if it's all of these or if it's none of thesethat may be causing lipodystrophy. We don't know how specific it is forany of these changes. Kotler's own feeling is that it has nothing to dowith an absolute level of anything, but rather it has to do with a change.For example, elevated triglyceride levels are quite common. In studies Kotlerpublished with Dr Carl Grunfeld in 1989 and in 1991 elevated fasting triglycerideslevels were found in 50% of HIV+ people including patients with and withoutAIDS irrespective of whether they were taking any therapy at all. Now Isee people who have elements of the syndrome such as the increase in abdominalgirth, but not everybody has elevated triglycerides. But it appears mostpeople who go on therapy have a rise in triglycerides. If they start outwith normal triglycerides they become elevated, if they start out elevatedthey become even more elevated. On the other hand, if they start out verylow they may just rise to normal. But, in every case there is a rise.
Another example is the body habitus change. In someonewho starts out obese, they are more likely to develop a buffalo hump andto develop a huge belly, and not necessarily to develop the thinning ofthe face and the arms. On the other hand, patients who start out thin aremore likely to show the effects of the fat redistribution in the face, armsand legs and not necessarily show such a large belly. In either case, thereis still an alteration in the distribution between what's under the skinand what's deep, but there is not necessarily some number that providesa cutoff. In looking ahead for planning studies we have to look at changerather than looking at absolute numbers.
The same thing can be said about insulin and insulin resistance.Although only 2%-3% taking PIs develop diabetes, in a study reported fromGermany almost all patients put on PIs had a decrease in glucose tolerancebut none of them became diabetic. So, in order to try and come up with adefinition of the syndrome we are going to have to look at changes ratherthan absolute numbers. Since we don't know exactly what we're looking formaybe that's why some people say they see it at a rate of 70% and othersreport seeing it a rate of 2%, and everyone appears to agree it's probablyaround 20%.
We are uncertain if it's the same in men and women, blacksor caucasions, gay vs IV drug users. Whether or not genetics play a roleis also uncertain. For example, if a person's family has a history of heartdisease, we don't know if they are more likely or not to develop this syndrome.Most people (doctors, researchers) suspect there will be adverse outcomesand the adverse outcomes will be cardiovascular-heart disease and stroke.These often take a long time to develop. In the non-HIV syndromes that includetruncal obesity, events may not develop until there are 20-30 years of abnormalities.We've been looking at this HIV-related syndrome for 2 years. We don't knowbut we suspect there will be adverse events.
The pathogenesis of this syndrome is uncertain. The onestrong hypothesis is Carr & Cooper's, which talks about a specific PIeffect interacting with specific human proteins. But, there are some uncertaintiesrelated to that hypothesis. The major uncertainty is that there are peoplewho have many elements of the syndrome who aren't taking PIs including oneof the patients Carr and Cooper studied. The specificity for PIs is uncertain.Additionally, many experienced clinicians including myself have reportedseeing patients with elements of this syndrome before Pis were even availableor prior to taking any HIV treatment. Another uncertainty is the site ofabnormality. Is this a problem that's related to the visceral fat and asudden increase in ability to produce or trap fat in the viscera? Or, isthe problem the subcutaneous fat and a decreasing ability to trap fat whichis what the Australians think?
Is Lipodysrophy Associated With the Magnitude of ViralLoad Reduction Rather than Taking a PI, or Any Other ART? A major problem that none of the previous studies dealt with ishow do you separate a direct from an indirect effect of the PI? PIs aremore than a molecule in the body. Pis produce a clinical effect in the body.That effect includes a drop in viral burden, and a partial reconstitutionof immune function. How do you separate a direct effect from an indirecteffect? It's very important to separate a direct from an indirect effect.If there's a direct effect, it makes it more difficult to continue usingthe drug if you are experiencing the syndrome. If it's an indirect effect,maybe that indirect effect can be blocked or avoided and the drug can stillbe used. In the past this was very difficult to study, and in the studiesthat have been conducted the control group were people taking non-PI regimenswho were often not doing so well in supressing viral burden. So, they werenot on PIs and they did not have a strong antiviral effect or strong immunereconstitution. These studies did not therefore answer the question. Maybeit's the magnitude of the antiviral effect that is associated with the developmentof the syndrome. It's only now that we may be able begin to answer thisquestion with long-term focus because we have more potent non-PI regimens.We can look at changes in triglycerides levels or changes in body habitusfrom before to during therapy. The overriding problem is determining causeand effect.
It's pretty easy to do this (determine cause and effect)when dealing with a drug for tuberculosis, plague or cholera. It's a lotharder when you are trying to approach this in an epidemiological way. Thereare statistical criteria you can use that will allow you to make strongeror weaker statements. For example, lets look at temporality. If you believethat something is a cause and another thing is an effect, you better becertain that the cause was there before the effect. On the other hand Ihave two patients with lipodystrophy who had lipodydystrophy as far backas 1991. They had increase in abdominal fat and elevated triglycerides asfar back as 1991 while they started PI therapy in 1996. Their diagnosisof lipodystrophy was made more recently when everyone elses diagnosis wasmade. In those patients the effect preceded the cause, therefore it is hardto believe that the effect in these patients was caused by PIs.
However, in the opinion of this author (Jules Levin), thisdoes not exclude the possibility that the syndrome is associated with PItherapy. PI therapy may exacerbate the syndrome for some individuals ifit's not the direct cause.
As researchers start to look at cause and effect you willhave to look at the strength of the association. You'll have to look atspecificity and temporality.
At St Lukes-Roosevelt, we've been doing body compositionstudies in HIV since 1984. We've studied almost 1000 HIV+ people, and manypeople who we've used as matching controls. In one study we looked at howPIs may have a direct effect versus the indirect effect of plasma viralburden, and how they may promote the body composition changes of the syndrome.In the first study I'll discuss we used MRIs. At the time of data analysiswe have 26 HIV+ people of whom 12 had the obvious syndrome. We were ableto match 26 control people by age, height, sex, weight, race, etc. We didwhole body MRI studies; we looked at slices of many MRIs up and down thebody. In each MRI we looked at the amount of fat and lean tissue, the amountof visceral or underneath the skin, and then summed them to come up witha volume. It's a high-tech way to look at whole body fat.
The study had 15 men and 11 women. They found that theHIV+ men weighed less than the HIV- controls. They did not have wasting.The HIV+ men had more visceral fat, less subcutaneous fat, and less totalfat than the HIV- men. These differences were statistically significant.The changes in women were not so pronounced as with men. The HIV+ womenhad a little less subcutaneous fat, a little less total fat, and a littlemore visceral fat than the HIV- women. But, the differences in women didnot reach statistical significance as they did in the HIV+ men. HIV+ menwith truncal obesity weighed more than HIV+ men without truncal obesity.The difference in weight was all in body fat. And, the difference in bodyfat was all within the viscera. There was no difference in subcutaneousfat between those with truncal obesity and those who did not have truncalobesity. This suggests you have to look at the change in visceral fat todiagnose the body composition change. Looking at only the subcutaneous sectionmay not be enough. The HIV+ women had similar trends. HIV+ women with truncalobesity had more visceral fat than HIV+ women without truncal obesity. Thedifferences in subcutaneous and total fat were insignificant.
There are two additional points to be made from this study.People with an increase in visceral fat had a CD4 count of 400, while thosethat did not have an increase in visceral fat had a CD4 count of 80. Theviral load was lower in those individuals with visceral fat. It appearedthat the persons having the syndrome were better off immunologically andhad a lower viral burden than those who did not have the syndrome.
A second study was more epidemiological in nature. In thisstudy they wanted to look at the possibility that some of the patients theytreated in the past had the same body composition changes as patients beingtreated now. And, they wanted to look at the effects of antiretroviral therapyor plasma viral load on the distribution of body fat. 96 HIV+ people werestudied from the current era (since 1/1/96), and they were matched with96 HIV+ people seen before 1/1/96, and with 96 healthy controls (HIV-).Kotler said it was likely that very few of the individuals seen before 1/96were on any kind of effective antiviral therapy.
They did routine body composition studies and looked atskinfolds, but did not do MRIs. The visceral fat of the individuals seenin the current era was about the same as those seen before 1/96, and asthe HIV- individuals (control group). This applied to men and women. But,both of the HIV+ groups had less subcutaneous fat than the HIV- individuals.Individuals with HIV had less subcutaneous fat than HIV- persons regardlessof whether or not they used PIs or potent therapy. They performed a statisticalanalysis called a multiple regression analysis. Based on this analysis,the data showed that simply being HIV+ can cause reductions in subcutaneousfat for both men and women. The data suggests that PI therapy was not associatedwith loss of subcutaneous fat, because there was no difference in the amountof subcutaneous fat between those seen before 1/96 and after 1/96. But,the data suggests that the HIV disease process alone may be associatedwith the development of lipodysrophy or elements of lipodystrophy.
Then, they looked at the 96 patients they've seen since1/1/1996. Half were taking a PI regimen, 1/4 of them were taking antiviralswithout a PI, and the other 1/4 were not taking any antiretroviral therapyat all. Based upon their statistical analysis the researchers concludedthat--taking antivirals with or without PIs did not siginificantly contributeto visceral obesity. But, viral burden was associated with visceral fat,and it was an indirect effect. People with lower viral load were morelikely to have more visceral fat.
Dr Kotler thinks individuals with more advanced HIVand who respond better to therapy with good CD4 increases and potent viralload suppression are more likely to experience lipodystrophy. Familyhistory may play a role. For example, a family history of heart diseaseor diabetes may play a role. A person's genetic disposition towards hypertension,diabetes, or heart disease may be a contributing factor. The process ofHIV disease or the process of recovery from HIV, that being immune reconstitutionmay be contributing factors.
What studies need to be done?Several studies that will compare PI regimens to PI sparing regimens areplanned by CPCRA and ACTG. These studies will look at lipodystrophy, outcomes,and in some ways mechanisms. The second type of study that is necessaryto look at what does the syndrome have to do with HIV? If you can seethe syndrome after a kidney transplant or Syndrome X, how is it relatedto HIV? This will be a harder study to conduct.
Kotler is working with the CPCRA in planning their PI vsPI sparing study. It will look at epidemiology, demographics, natural history,and outcomes. Both the ACTG and CPCRA will be looking at metabolic consequences.We need studies looking at prevention and treatment. It will be up to independentinvestigators to look at methods of study of pathogenesis of the syndrome-thosebeing either directly related to protease or perhaps indirect; indirectbeing simply metabolic such as hypercortisolism and the possibility thatthe syndrome is a result of partial immune reconstitution leading to anautoimmune type disease. Kotler has researched elements of hypercortisolismand is currently looking at the autoimmune aspect. There are several otherinvestigators looking at similar questions. Kotler expressed hope that overthe next 1-2 years we'll have epidemiological data on a large number ofpatients and pathogenesis data coming out of smaller more focused studies.