WORLD AIDS DAY: Time to Help Victims of HIV Drug Studies and Resistance

We have repeatedly heard the following statements about multi-drug resistant HIV (MDR-HIV) patients in a host of meetings on treatment access and HIV research: “These patients no longer exist – they’re either dead or have responded to the latest ARVs”; “Only patients who do not adhere to their HIV regimens have MDR-HIV”; and “Our clinic cannot provide expanded access programs (EAPs) due to cost and staff restraints.” However, after surveying physicians around the country, we have found that although these patients are in a minority, they do exist and are anxiously waiting for access to viable regimens that could save their lives.

No one can deny that many patients can now suppress their HIV with effective regimens that cause fewer side effects. However, a vulnerable and often forgotten minority of people are still struggling with MDR-HIV while they anxiously await for access to life-saving regimens that would finally control their virus replication. Although some of these patients may have developed resistant HIV due to lack of adherence or other issues, many of them have been strictly following their doctor’s orders for years.

They’re often veterans of drug development research who have accumulated HIV resistance as they repeatedly joined antiretroviral (ARV) studies or traditional EAPs of a single new drug out of desperation to control their HIV viral load. As they signed up for studies that helped companies get their drugs approved by the FDA, many of these patients were exposed to suboptimal HIV regimens (namely, functional monotherapy or the addition of a single new active ARV to a failing HIV regimen). It is time to create a new paradigm to break the vicious cycle of single drug access that has failed these patients.

More: http://www.poz.com/pdfs/gmhc_treatmentissues_2012_12.pdf

Ten News Items That Have Made Me Happy During the Past Month

These past several weeks have been great on many fronts. While taking a shower this morning, I counted a few of the great pieces of news that have come our way amidst all the negative news that the media dwells on to increase ratings. 

http://www.thebody.com/content/67329/ten-news-items-that-have-made-me-happy-during-the.html

Diabetic Retinopathy in HIV Subjects Treated With EGRIFTA®

This is a study required by the FDA to determine if Egrifta use in HIV+ people with diabetes can increase the risks of diabetic retinopathy.


http://clinicaltrials.gov/ct2/show/NCT01591902

Diabetic retinopathy  is a complication of diabetes that affects the eyes. It's caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina).

At first, diabetic retinopathy may cause no symptoms or only mild vision problems. Eventually, however, diabetic retinopathy can result in blindness.

Diabetic retinopathy can develop in anyone who has type 1 diabetes or type 2 diabetes. The longer someone has diabetes, and the less controlled your blood sugar is, the more likely you are to develop diabetic retinopathy.

To protect their vision, patients with diabetes should take prevention seriously. Patients should carefully controlling their blood sugar level and scheduling yearly eye exams.

Previous studies have show that the use of growth hormone contributes to the development of diabetic retinopathy in humans. (http://care.diabetesjournals.org/content/17/6/531 )

Egrifta is a growth hormone releasing hormone, hence the concern from the FDA.

EGRIFTA® is an FDA-approved treatment for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy.


More information on Egrifta on Egrifta.com

New treatments for HIV associated lipodystrophy beyond Egrifta

Question from a person living with HIV:
May 2, 2012

I body build and work out, eat right, etc. The lipodystrophy I accumulated during my early use of Crixivan and others doesn't really go away that much. It's frustrating, depressing.

I do also appear to have some features of "muscle belly" where there is a space between my lower abs (possibly caused by strain). I've read about adbominoplasty.

Apart from egrifta, which my ID doc does not recommend, what other options are there now or on the horizon?

I want to get a CT scan of my gut to see just how pervasive it is. But to my knowledge, it's not just easy to go in to the organ area and remove the omentum, etc. That's all very risky.

Over the years I've gotten very depressed about it, even to the verge of eating disorders. I have 2 closets full of nice shirts that I can't/wont wear, as my gut protrudes. I'm otherwise very in shape and muscular.

What can I do? Is there any hope for this problem...

Answer from Nelson: New treatments for lipodystrophy beyond Egrifta

What to do if you think you have recently been exposed to HIV

This would definitely be the HIV medication combo that I would take if I was HIV negative and wanted to treat a potential HIV exposure (condom breakage, needle stick, etc). Prior studies were done using Truvada alone (two drugs combined in one pill), but adding raltegravir to Truvada makes a lot of sense. Raltegravir (brand name Isentress) is the HIV medication that lowers HIV viral load the fastest, which is something you need if you have been exposed in the last few hours. It also happens to be a very well tolerated medication.

Note: If you get exposed to HIV, you need to treat quickly (within 72 hours), and then stay on treatment for 4-8 weeks

But a one month supply of Isentress plus Truvada would cost more than $1000. Some people call local HIV doctors or health clinics to find out who has extra medications, or just pay for the medications themselves since insurance companies do not pay for post exposure prophyplaxis treatment. And that is where the dilemma lies..

Here is a small study using the Isentress+ Truvada combo for post exposure prophylaxis :
http://www.aidsmap.com/page/2227321/

Note: If the person that may have exposed you to HIV is on treatment and has undetectable viral load in their blood, the chances of infection are minimized.  So if you can ask that person about their lab numbers, that would provide additional information for your doctor to make a decision.

For HIV doctors around the United States: Directory of HIV Physicians

PoWeR asks for your support and end of year tax deductible donation

Program for Wellness Restoration (PoWeR,  http://powerusa.org/  ) is going through a tough financial time now that most industry educational grants have been eliminated.  We ask you to think about us when conmsidering organizations to make tax deductible donations before the end of the year.

In 2011, PoWeR has been able to accomplish the following with a very small budget :

- Provided 26 lectures on health to HIV positive people around the United States

- Published 78 blog articles  (http://survivinghiv.blogspot.com/ )

- Coordinated an upcoming expanded access program using two investigational drugs for people with HIV who have run out of treatment options. (http://bit.ly/tWkdk4  and http://bit.ly/s98yHL )

- Moderated http://health.groups.yahoo.com/group/PozHealth/ , a 9 year old listeserve with close to 4000 members from all over the world

- Produced a video to raise awareness on the challenges surrounding finding a practical cure for HIV (http://www.youtube.com/watch?v=Sj-dFQ6Yi7k )

- Provided technical advise to 4 other non profits ( Red Hispana, The Houston Buyers Club, The Positive Project, and Live Consortium)

- Answer questions  weekly at thebody.com ( http://bit.ly/twag7J )

- Created a petition to improve Medicare coverage of facial wasting therapies (http://bit.ly/rR2G0N )

- Created a resource list : http://powerusa.org/resources.html

If you or someone you know has been helped by our work and want to see us continue it, please do not hesitate to make a contribution by using this link:http://powerusa.org/donate.html or by sending a check to:

Program for Wellness Restoration

P.O. Box 667223

Houston, TX  77266

Thank you in advance for ensuring that our mission continues in 2012.

In health,

Nelson Vergel

Founding Director

Today is World's AIDS Day- Read the Staggering Numbers!

The Forgotten Minority: HIV+ Patients With No Available HIV treatment Options

Most successful HIV medication combinations require 3 medications that are fully active, but a small portion of long term survivors with long treatment history and accumulated HIV resistance mutations do not have the luxury of constructing a viable regimen to save their lives.

Several potent antiretrovirals (ARVs) in the past 4 years have enabled many patients with multidrug resistance (MDR) to suppress their HIV viral load.

Due to several factors, there is still a relatively small number of patients that have developed resistance or toxicity to the new ARV’s

To protect them from functional monotherapy, these patients are not allowed in pre- approval studies.

Some HIV ARV’s in phase II studies may potentially help those patients, but combining them after their respective approvals may take at least 3 or 4 years.

Some of these patients may be at risk of clinical decline and death if no viable regimen is available for them before 2012

We do not know how many of these patients there are in the U.S.

I performed a physician survey with the help of some researchers and activists to find out how many patients may be present in the U.S. with HIV multidrug resistance in deep salvage (one or zero active medications to treat their HIV).

These figures summarize our findings (click on figures to enlarge):

These are the HIV medications in current development. The ones with an asterisk are the ones that may work for patients with no options left.

The closest ones to approval are Taimed's ibalizumab ( an IV once every two weeks) which may be two years away from approval, and GSK's integrase inhibitor GSK572 (2-3 years) . Avexa recently stopped the development of   Apricitabine and Myriad may follow suit with their maturation inhibitor. A combination of at least two compounds will probably not be feasible until 2013.  Efforts towards creating an expanded access program using multiple investigational agents is currently under way but it may not be a possibility until 2011.  All companies and the FDA are welcoming the concept in its early stages.  I will provide an update during the last quarter of 2010.

I wish we could help patients who need help now.

Nelson Vergel

Update on Medicare's Decision to Help People with HIV-associated Facial Lipoatrophy

I sent this email to Medicare:

Sent: Wednesday, March 31, 2010 10:53 AM
To: Baldwin, JoAnna F. (CMS/OCSQ)
Subject: From the feedback tool - 100331-000018


Regarding:Decision Memo for Dermal injections for the treatment of facial lipodystrophy syndrome (FLS) (CAG-00412N)

I have the following questions:


1- Do patients have to remain depressed to get yearly touch ups ?
2- Are Sculptra and Radiesse (the two FDA approved options) to be included in Medicare part D formularies?
3- How much will doctors get paid for every session?
4- Will there be a maximum number of sessions per year allowed?

Thank you

Nelson Vergel
Founder
FacialWasting.org

******

This the reply from the JoAnna Baldwin from CMS. As you can tell, there is still a lot of work they need to do in establishing rates, etc. I will keep following up for updates.
nelson

(Background for this email for those who have not read Medicare's decision: http://www.hivandhepatitis.com/recent/2010/0326_2010_a.html )

Dear Mr. Vergel,

I hope to be able to help with some of your questions. Please see the below responses and please let me know if you have additional questions.

1- Do patients have to remain depressed to get yearly touch ups ?
I do not know exactly how local Medicare contractors will implement the policy so there is always potential for variation in implementation when the national coverage policy is not explicit. I would venture to say that some documentation would continue to exist in the patient’s medical record that depression is a continued concern and that these conversations be had between the patient and their treating physician. But again, the policy is not explicit in this regard.
2- Are Sculptra and Radiesse (the two FDA approved options) to be included in Medicare part D formularies?
I do not believe these products fall under Part D Medicare coverage. For example, if the injections are delivered in a physician’s office, then the physician would purchase the fillers and then bill Medicare for the fillers and for administering the injections. Part B co-pays and deductibles would apply to this service just as it would be applied to any other Medicare covered service.
3- How much will doctors get paid for every session?
The payment amounts are in the process of being established. Medicare participating providers would accept the payment amount as the full payment but again, co-pays for each office visit would still apply just as any other Medicare Part B service.
4- Will there be a maximum number of sessions per year allowed?
The national coverage policy does not limit the number of sessions per year.

Doctors and Patients Tell Medicare to Approve Facial Reconstruction

To see all comments provided by doctors and patients to Medicare to covince them to pay for facial wasting reconstruction, cut and paste this link to your browser:

http://www.cms.hhs.gov/mcd/ncpc_viewpubliccomments.asp?id=20&expand=Y

I surely hope that Medicare approves Sculptra, Radiesse and Silikon 1000 reimbursement to help those on disability and to set a precedent for insurance companies to follow. It has been six years and most people who need facial reconstruction cannot afford it even if helped through patient assistance programs.  The average reconstruction costs around $5000

Nelson

See more on facialwasting.org

Dealing with Fatigue- From TheBody.com

Response from Mr. Vergel I feel your pain :) I have dealt with this problem for years. I have good days and not so good days. Let me tell you what I have tried after reading research studies: Exercise- Exercise improves fatigue. I know...how do you exercise if you are tired? When I am exhausted I skip the gym, but if I have a little energy left I do a very light work out using weight settings that are half or less of my usual. I feel much better sometimes just showing up at the gym! Good sleep- I find that I need 8 hours. If I do not get them, I pay the price. I was concerned about sleep apnea since I wake up at least 2-3 times a night. My doctor prescribed a sleep study. You sleep in a clinic (with nice rooms that look like a hotel) and they hook you up to wires to measure your breathing, your brain waves, and your oxygen levels. I was diagnosed with mild sleep apnea and now have to go get a CPAP machine fitted soon. Google "CPAP sleep apnea" for more info. Do not eat dinner late. If you are not sleeping well because you feel like you need to pee frequently, have your doctor check your prostate to make sure it is not enlarged. Also, get a prostatic specific antigen (PSA) done just to make sure you do not have prostate cancer or prostatitis (infection). Sleep apnea can also give you the false impression that you need to pee, by the way. Provigil - This drug really helps me to feel awake when I have to work or travel. A study done in HIV found it to be effective to improve energy and depression. I start with 200 mg once a day in the morning. Most people use it twice a day but be careful not to take it too late or your sleep will be affected. It can make some people feel too "speedy" but I think this can be managed with a lower dose, even if you have to cut the pill in half. Also, we have some concerns of drug-drug interactions since it is metabolized by the same path as protease inhibitors, but no pharmaceutical company has agreed to do an interaction study of this popular drug. One of the best things of this drug is that it is not an amphetamine and your doctor can call it in without "triplicate" prescription requirements usually needed for drugs like Ritalin or Adderrall, two other really popular drugs used for HIV related fatigue. Wellbutrin- This antidepressant has stimulating effects on many. It does not seem to affect sexual function as much as most antidepressants. Coffee- My best friend. But you can crash after an hour or two, so be careful. Eating small balanced meals and avoiding sugars- This can keep your blood sugar more constant through the day. A peanut butter sandwich (or better yet, an almond butter one) on multigrain bread, or low fat cheese with apples can provide a good snack before the gym. Creatine- This supplement may help many. It increases strength in exercise and lean body mass. There is study that showed that our brains may have lower creatine levels than normal which could be associated with our fatigue. We need more data. Some people have gut problems or increases in creatinine that bothers doctors, so keep an eye on that. Carnitine + Coenzyme Q-10- These two supplements together have anecdotally helped some people with fatigue. I swear by a combo of 300 mg of Coenzyme Q-10 and 2000 mg of L-carnitine a day. Besides, the combo may have heart protective properties. Reduce your blood pressure with diet, exercise or medications. High blood pressure can make you feel winded. But nany blood pressure medications can also make you feel tired. So talk to your doctor. Hormones- Have your doctor check your thyroid, testosterone, DHEA and morning cortisone. You can supplement any of them that is found to be low. Hemoglobin- This is an automatic test that you get done with your blood work, so it is usually easily detected. Low hemoglobin can be caused by anemia, which can make you really tired. B-12 vitamin deficiency- Have your doctor check your blood levels of this vitamin. I inject one cc a week and I notice improvements in energy and appetite. We need more data on B-12 injections and HIV. It seems that oral forms do not get absorbed as well. Drug side effects- Sustiva made me extremely tired (it is also part of Atripla). Diovan for blood pressure had the same effect on me. This is one of the most challenging things to diagnose since most of us are taking so many pills. High HIV viral load- Has been associated with fatigue in some studies, so keep it undetectable if you can. Dehydration- Most of us do not drink enough water and are walking around tired due to dehydration. Drink 6-8 glasses of water a day if you can. Avoid fruit juices since most are loaded with sugar. Your heart-If all of the above does not work, talk to your doctor about a full cardiovascular work up with a stress test, EKG, and other tests that measure how your heart is working. People with heart problems experience a lot of fatigue. I am sure I am forgetting something..but these are the most important things that I have had to check in my life with fatigue. I hope this helps. Let me know if you find something that works! Nelson

Update on Body Shape Changes and HIV

This Month in HIV: 2009 Update on Body Shape Changes and HIV
A Conversation With Dr. Donald Kotler and Patient Activist Nelson Vergel

April 2009




From TheBody.com


Body shape changes are some of the most frustrating complications of HIV and HIV medications. Whether it's the loss of cheeks or the sudden swollen midsection, people with HIV have been mostly dealing silently with these issues since there are few treatments available. In This Month in HIV, HIV activist and long-time survivor Nelson Vergel leads a discussion with Donald Kotler, M.D., who is an expert on metabolic complications and HIV. They will fill us in on some of the latest updates on this issue.

Nelson Vergel: Hi, Bonnie. Thanks for having me here. And thanks to Dr. Kotler for joining us.

Dr. Kotler, I'd like to start with some basic questions, if you don't mind, to cover the basics about body changes and HIV.

In your opinion, how widespread are body changes in the HIV-positive population? Is there any way that somebody who was recently diagnosed with HIV can know how probable it is that he or she will experience body changes?

Dr. Donald Kotler: That's two questions.

The first one: How frequent are the body shape changes?

The answer is that it depends which shape you're talking about. Some people gain body fat, and others lose body fat. Of the people who gain body fat, for example in the belly, or behind the neck, it's about one-third of patients who have that kind of problem.

In terms of losing body fat and getting really skinny legs, or the skinny face that people notice that's so stigmatizing, in the old days it was almost everybody, and currently it's not many people.

With the change in the antivirals, specifically the stopping of the use of stavudine [d4T, Zerit] and limiting the use of zidovudine [AZT, Retrovir; this drug is also included in Combivir and Trizivir], many fewer people get really thin from lipodystrophy.

Now, the second question: Is there any way that somebody recently diagnosed can avoid these issues?

I gave part of the answer. You can avoid the loss of fat by the choice of medications. Very few people in the United States are taking the medications that will cause body fat loss.

A way of preventing body fat gain was shown about a year and a half ago at the international meeting in Sydney, Australia. Limiting the amount of weight that's gained as people start antivirals will limit the amount of fat that ends up in the belly.1

Nelson Vergel: How do we actually limit the amount of weight that people gain when they start HIV medications?

Dr. Donald Kotler: That's a good question. In the study, which was from Brazil, they use what's called the NCEP [National Cholesterol Education Program] diet. [NCEP was launched in November 1985 by the National Institutes of Health to help reduce illness and death from coronary heart disease in the United States.] It's a healthy diet for somebody with heart disease; it asks people to moderate carbohydrates, decrease fat and consume more fiber. So you tend not to eat things that are so rich and so dense in calories.

It's a standard type of diet for people with heart disease. At least in the study that was presented, people who started their first regimen, plus the diet, gained much less weight -- their cholesterol didn't go up nearly as much and their belly didn't get nearly as big as people who were allowed to eat whatever they wanted.

Nelson Vergel: Dr. Kotler, another issue is the actual word that we use for these changes. People have been using the word "lipodystrophy" for a long time. Is that still a correct word for what's happening in HIV?

Dr. Donald Kotler: Not really, though when you say it, everybody knows what you're talking about. So you could probably get away with it. But lipodystrophy, the classic lipodystrophy, really referred to genetic problems. It was something that people were born with that, as they developed, would show the wasting, would show the thinning of the skin in their face and arms and legs, etc.

The term lipodystrophy with respect to people who are HIV infected is used to mean anything -- fat loss or fat gain, which are not necessarily related, diabetes or high cholesterol, which, once again, may or may not be related to any of the other problems.

We would probably be better off if we were to call fat gain "lipohypertrophy," fat loss "lipoatrophy," and then talk about problems with sugar and fat separately, rather than try to make them all into the one thing.

Nelson Vergel: It is not one thing; they are different syndromes that may happen together or separately.

Dr. Donald Kotler: Right.

Nelson Vergel: You're saying that lipoatrophy -- which is fat loss under the skin in the extremities (e.g., legs), body and face -- is actually not occurring as much in the United States, because we're not using AZT or d4T. But how about fat gain? Is fat gain occurring as much as we used to see it in the '90s, for instance?

Dr. Donald Kotler: Fat gain is, I believe, as common now as it's ever been. I don't think that that's really changed. About one-third of the patients complain of fat gain.

Bonnie Goldman: Are most of the complaints about belly fat? Or are people still seeing fat gain in their neck? Is there one that's more likely?

Dr. Donald Kotler: Belly fat is much more likely. Belly fat is, like I said, a problem in about a third of the patients. Of the people who gain fat behind the neck, probably somewhere between 5 and 10 percent will have a big growth.

Interestingly enough, there are some obese people, who are not HIV infected and not otherwise ill, who actually have small humps. The humps are called buffalo humps, but in HIV, they seem to grow much, much larger.

Nelson Vergel: Dr. Kotler, how does somebody know if they're gaining more weight than normal because they're eating more, or whether it's something related to HIV, or HIV medications?

Some people complain about increased appetite once they start HIV medications. Is the fat gain related to their caloric intake (i.e., how much food people are actually taking in)? Or is there something else -- maybe the fact that their immune system may be getting better?

Dr. Donald Kotler: You know how much weight you can lose when you're sick and then, after you're done being sick, how much weight you can gain, and how fast you can gain weight just when you become healthy?

It turns out that when people start their antivirals, especially when the T cells are down around 200, they are sick. They may not know it. They may not realize it. But they're sick.

If you think about it, antivirals are not appetite stimulants. They're not anabolic agents. So how come people are gaining so much weight? I think the answer to that is that they were sick and had lost weight; so people were thinner than they would normally be and when they take antivirals, it brings them back to a normal weight -- "normal" in the United States is at risk of obesity.

Nelson Vergel: So it is actually better for somebody to start treatment when they're healthier, if they want to avoid any body changes? Is that it?

Dr. Donald Kotler: The literature would say yes. People have looked from the very start as to what makes people lose weight, what makes people gain weight. It turns out that it's a lot of things. Things related to the patient -- for example, family history.

Before you got HIV, if you were 280 pounds, you're probably a lot more likely, when all is said and done, to complain of a big belly than to complain of skinny legs. Whereas if you started out 5'10", 130 pounds, you are probably much more likely to complain that your face looks bad or the veins in your legs are really prominent, than complain of having a big belly.

If everybody in your family is obese, you're probably more likely to have problems on therapy by being obese rather than being skinny.

Nelson Vergel: Have you seen any differences whatsoever with respect to what people start with? Different types of HIV treatments? Are there any data out there that show whether people who start, for instance, on Atripla [efavirenz/tenofovir/FTC] versus Kaletra [lopinavir/ritonavir] or Truvada [tenofovir/FTC] have any differences in body changes?

Dr. Donald Kotler: There are not a lot of data on that, I must say. I don't know that I answered the last question well enough. But, there are many factors that will affect what happens to the patient. These factors can be related to the virus, they can be related to the HIV medication or they can be related to the patient himself, or herself.

For example, family history is related to the patient. Taking a drug like d4T is related to, obviously, the drug. Many people have several of these predisposing factors.

Nelson Vergel: Lipodystrophy (or what we used to call lipodystrophy and are now calling metabolic disorders) also includes increases in triglycerides and cholesterol, especially the bad cholesterol, and decreases in HDL [high-density lipoprotein], the good cholesterol.

Are people with increases in cholesterol and triglycerides more prone to having belly fat increases? Have you seen anything on that subject?

Dr. Donald Kotler: In general, people with a lot of belly fat tend to have increased levels of cholesterol. But there are some medications that, even if given to people who are very thin, will cause cholesterol levels to go up. And there are certain genetic tendencies in people that may make their cholesterol go up high, often when they take antivirals, whether or not they are obese. So you don't have everything or nothing. You can have a big belly and high cholesterol, but you don't necessarily have to have a big belly to have high cholesterol.

Bonnie Goldman: Dr. Kotler, can you specify which medications you are referring to in terms of raising the cholesterol, or raising the fats in the blood?

Dr. Donald Kotler: The one that does it more than any other is ritonavir [Norvir]. It turns out that it depends on how much you take. If you take, for example, the drug Reyataz [atazanavir], you only take one Norvir. If you're taking Kaletra, on the other hand, you take two Norvir. If you take the drug tipranavir [Aptivus], I believe you end up taking four Norvir in a day -- because that's what you need in order to get good drug levels to keep the virus under control. But it turns out that the more Norvir you take, the higher the fat levels are in the blood.

Bonnie Goldman: In Kaletra, you're taking the Norvir within the one pill that you're taking.

Dr. Donald Kotler: Right. You don't take a Norvir tablet. It's inside the Kaletra tablet.

Bonnie Goldman: Many people aren't aware that when they're taking Kaletra, they're also taking Norvir.

Nelson Vergel: Dr. Kotler, another assumption people make -- and I think even some clinicians out there -- is that if you treat high cholesterol with a cholesterol-lowering drug, or anything else that treats it, you will tend to decrease belly fat. Is that a right assumption? Are there any data to substantiate that?

Dr. Donald Kotler: No. It's the other way around. If you have a big belly and high cholesterol, and you make the belly small, the cholesterol will go down.

But if you have a big belly and high cholesterol, and you take a drug to lower the cholesterol, it may not do anything to your belly.

Nelson Vergel: Are there any treatments right now for the belly fat gain?

Dr. Donald Kotler: No. There are no treatments that are approved by the FDA [U.S. Food and Drug Administration]. Obviously, losing weight does something, although many people will say it doesn't do nearly as much as they want it to. You try to lose weight to lose your belly, but then you lose your butt, or your face looks worse and your belly doesn't change all that much.

Nelson Vergel: How about exercise?

Dr. Donald Kotler: Some people do that. Exercise will do it. The exercise that tends to do it is more resistance training exercise (i.e., lifting) than aerobics, surprisingly enough.

Nelson Vergel: Some people are actually afraid of aerobics because of fat loss.

Dr. Donald Kotler: Exactly. There are other people who have shown that some of the antidiabetic medicines, such as Glucophage [metformin], have been shown to decrease belly size.

There were several studies that looked at the drug growth hormone. Growth hormone did significantly lower belly size, but the FDA didn't approve it, likely because they were not happy with the side effect profile. They thought it was too toxic a drug.

Now, a month and a half ago, there was a meeting in London, the 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. At that meeting, two other treatments were talked about. One was a drug called IGF-1 [insulin-like growth factor 1], or IGF-1 combined to a binding protein.

It's what growth hormone causes to happen. But here, rather than using growth hormone, they use the IGF-1. And rather than this worsening toxicity, worsening blood sugar, it actually made it better. It also caused an anabolic effect: lean mass went up and the amount of fat in the trunk went down. But it didn't really lower it as much as had been seen before with growth hormone. But it was a little, tiny study, just to show that it could work.

In addition, there's a drug called tesamorelin, which [acts as a] growth hormone-releasing factor. So when you give tesamorelin, you get a growth hormone-like effect and that also causes belly fat to go down. It doesn't cause glucose to get worse, like growth hormone does.

At this same meeting in London, Julian Falutz from Montréal looked at the two studies of this drug, tesamorelin, to see if it mattered what kind of antivirals are used.2 Does it matter if someone is taking protease inhibitors or the non-nucleosides? Does it matter whether someone is taking Kaletra or Sustiva [efavirenz, Stocrin]? It turns out that it doesn't matter. The drug tesamorelin will cause body fat to decrease. It will cause belly fat to decrease, no matter what your drug is.

Nelson Vergel: That drug is not approved yet?

Dr. Donald Kotler: The drug is not approved yet. But there have been several studies that have shown its benefit -- three, actually. I believe the FDA is looking at it now or, if not now, very, very soon. [Click here for more on tesamorelin.]

Nelson Vergel: If you were an HIV-positive patient, right now, in 2009, and you had problems with belly fat, what would you do? Just diet and exercise? Is that all we have?

Dr. Donald Kotler: Right now diet and exercise are the best hope. I would not treat with an antidiabetic medicine in the absence of diabetes.

Nelson Vergel: So you're not sure whether, for instance, Glucophage, which is an antidiabetic drug, would do anything for somebody who is experiencing belly fat gain.

Dr. Donald Kotler: Let's say you have to wear a size 40 pants, or keep your pants so low that your belly hangs over in a not very nice looking way, and you start taking Glucophage. Your waist will probably go from 40 to 39. You wouldn't go down to a 33, or a 32, or even a 34. The effect of Glucophage is really tiny.

When it was used at high doses, the effect of growth hormone was more like two or three inches. You'd go down to a 37 or a 36 waist. But it was real toxic and caused a lot of problems. Drugs like tesamorelin cause your waistline to decrease only an inch or so.

Nelson Vergel: The unfortunate thing, in my point of view, is that we haven't really seen combinations of therapy. For instance, researchers have not looked at exercise plus either the growth hormone-releasing factor or Glucophage. As an activist, I think I'm also a little frustrated that there are no real guidelines on the nutritional aspects of this problem. Like you said, nutrition and dieting. Where do we send people when they want information about what to eat? Do you recommend just a Mediterranean diet? Anything specific?

Dr. Donald Kotler: A Mediterranean diet would work well. People tend to do better with low-carbohydrate diets, as opposed to low-fat diets whether they are HIV positive or HIV negative. For people who don't know what a Mediterranean diet is, it is olive oil, nuts, very low in highly saturated fats, more fish and less meat. [Click here for more details on what a Mediterranean diet is.] But there has been very little data published on it, in terms of its effects in HIV.

Nelson Vergel: That brings me to the next question. If you had all the money in the world, what would be your main research project, when it comes to the area of body shape disorders in HIV?

I'm interested in your view since you both see patients and do research -- which is a good thing since many researchers don't actually see patients.

Dr. Donald Kotler: That's an easy question. If I had all the money in the world, I would study everything. But if I could only do one thing, what would I do? It would be a comprehensive program in which I wouldn't be looking for one treatment, but rather, I would use the combination.

It would be diet and it would be exercise and it would be medication. Our laboratory presented a study at the lipodystrophy meeting in London, in which we compared diet and exercise to diet and exercise plus the drug rosiglitazone [Avandia], or simply rosiglitazone alone. Rosiglitazone is an insulin-sensitizing agent; it's an antidiabetic agent.

The question we asked is: If we treat an HIV-positive person with big-belly lipodystrophy and an HIV-negative person who has a big-belly metabolic syndrome the same, would they respond the same?

If I got somebody who has HIV to lose 15 pounds and get into good shape, would his or her insulin resistance change the same as someone who is HIV negative?

Although we didn't have enough people in the study to be able to be absolutely confident of the results, it seemed that the two groups responded pretty much the same.

The average weight loss we got was about 15 pounds. The changes in an HIV-positive and in an HIV-negative person were really pretty much the same not only in the belly, but also in things like cholesterol and the special types of good cholesterol and bad cholesterol.

It looked like HIV didn't really influence it very much. So in the absence of any other information, I would treat an HIV-positive person the same as I would treat an HIV-negative person with metabolic syndrome. The best treatment is to treat it all -- not looking for one magic pill, but instead getting people to eat less, getting people to eat smarter and getting people to exercise more. If there is high cholesterol, bring it down. If the triglycerides and other types of fat are high, bring them down.

If the usual medicines don't work, well, then you try other things, like fish oil (omega-3 fatty acid) or niacin. There are a number of these new medicines that have been tried in HIV. They seem to work about as well in HIV as in non-HIV; it's not so different.

So I think that the optimal way to do it is a whole integrated program.

Bonnie Goldman: But don't you think that many patients around the country don't have a physician that they could turn to who may have this kind of very understanding point of view?

Dr. Donald Kotler: Maybe not a lot of private doctors, but there are a lot of clinics that are putting together metabolic clinics that are putting together expertise to look at having a cardiologist or an endocrinologist treating diabetes go into the HIV clinics to treat people.

You're right. It's not really fully integrated. But I think that would be the best.

Nelson Vergel: As an activist, I think the community also has to take an active role in advocating for things like this. In Houston, Texas, we have a non-profit where we provide exercise and dieticians looking at people's diets and trainers. Yet in the past five years, we haven't been able to duplicate these kinds of programs anywhere else because of money. Money and funding are really tight lately, especially in HIV. People sometimes don't even have the money to get the treatments, the HIV medications, which are basic. So it's a battle.

My next question -- which is really relating to this -- is: How do we get insurance companies or Medicare/Medicaid -- other systems that pay for medication -- how do we get them to accept that body changes in HIV are not a cosmetic issue, per se. It's something that not only affects people's self-esteem, anxiety and depression, and quality of life, but it may actually be something that also affects their survival, eventually.

That's where we have the most challenge right now. How do we shift from perceiving this as a cosmetic issue -- shifting third-party payers, insurance companies, to see it as a clinical problem?

Dr. Donald Kotler: It's not really a medical question. It's a question for activists. I think that the answer is activism. My suggestion would be to push it as a comprehensive care program, rather than a reimbursement for drug X. Because in fact some of the treatments are so costly that I don't know that I would be happy paying for the treatment in somebody who is not watching their diet or someone who would not consider doing exercise. Or even -- which is what's happened before and which is what I think limited it before -- you don't necessarily even look at the results of what you're doing; that it's really considered more of an entitlement to get the prescription, as opposed to having somebody measure you, work out your risk, give you some treatment and follow up. If you're not responding the way you should, look to find out why. Sometimes the medicine is not even being taken.

I think it's important to accept the fact that there's not a magic bullet, but there are a lot of things that you can do to help yourself. I think that the activists should really push on that.

Nelson Vergel: That's my main goal. I just wanted to summarize it, because some people may be so concerned about this discussion, and they're considering going on HIV medications for the first time.

The fact is that we're not experiencing as many problems metabolically right now, compared to 10 years ago. Is that a fair statement, in your point of view? Should people be really concerned before they start treatment?

Dr. Donald Kotler: The one thing that doesn't seem to have changed is that if people gain weight, they may get a big belly.

On the other hand, the diabetes that used to be seen, especially with Crixivan [indinavir], we don't see much of that anymore. There may be more diabetes that comes with Zerit or AZT, but for people taking the newer medicines, we don't tend to see that nearly as much.

The lipoatrophy -- the skinny face, the skinny butt and the really skinny legs -- if we see somebody now who has that, it's somebody who has been treated with HIV medications for a long time, and has had that for years.

With the new HIV medicines, it doesn't tend to happen that much anymore. The high triglycerides and high cholesterol: We still see some of it, although much of it occurs in people who are genetically predisposed to it.

The new medicines, like the integrase inhibitor Isentress [raltegravir, MK-0518], the CCR5 antagonist Selzentry [maraviroc, Celsentri] or the entry inhibitor Fuzeon [enfuvirtide, T-20], don't seem to cause any of these problems.

I think that people now are a lot less likely to develop these changes than they were in the past. It may be that if people are really careful about trying to prevent weight gain and eating very healthily at the time they start their antivirals, they may be much less likely to get it. On the other hand, if somebody weighed 280 before any of this happened and you make them healthy again, they are, as likely as not, going to go back to a weight of 280.

Nelson Vergel: Are some of these changes related to aging, or are they really accelerated aging by HIV and HIV medications?

Doctors are also saying to patients, "Well, don't complain. You really are healthy. It's just that you are getting older, too."

Dr. Donald Kotler: They are steady changes. But if you look at HIV-negative people, even though the changes are pretty continuous, when do people start really seeing the belly fat? And when do men start losing their butt, even if they're not HIV infected? It seems to be somewhere between ages 45 to 50. At that point, jeans fit differently. They are no longer tight in the thighs and loose in the waist; it's the other way around.

Nelson Vergel: There are also some hormonal changes, too, right?

Dr. Donald Kotler: Right. People's own growth hormones go down. People's own testosterone levels go down.

Nelson Vergel: Even thyroid. We're seeing some reports on thyroid dysfunction in some patients, too, right?

Dr. Donald Kotler: That's kind of an immune reconstitution problem, though. You'll get laboratory abnormalities. It really causes your thyroid to get so bad that you need hormone replacement.

Nelson Vergel: So it is good for patients who are experiencing some of these changes to at least get some of their hormones checked and talk to their doctors about it, right?

Dr. Donald Kotler: Absolutely. Women tend to have more problems with thyroid than men, so it's especially important in a woman, because she might develop a thyroid problem totally independent of HIV. Not everything that happens to people who are HIV positive is really HIV related.

Nelson Vergel: Dr. Kotler, one last question from my side. We're seeing some reports on decreases in bone density. Is that something that you see in your practice? I'm not even talking about research. I'm talking about your practice. You see a lot of patients in New York. You've been around since the '80s. I think you're probably one of the leaders in metabolic disorders.

In your practice, are you starting to see any bone-related fractures or any bone-related problems?

Dr. Donald Kotler: Yes, I've been seeing this for a long time. In fact, the bones that I've seen break most commonly, being in the middle of a city, are bones in the feet in people who run on treadmills. I don't see a whole lot of broken hips, broken ribs or crushed vertebrae. But I've seen people break bones in their feet, simply by the pounding.

At the meeting in London, there were a couple of interesting talks about bone. It's known that thin bones, brittle bones, are very common. Whereas most people blame antivirals, you can also see it in HIV-positive people who are untreated. So HIV-positive, treatment-naive people also may have thinned, decalcified bones. If that's the case, well, then it can't just be due to drugs!

There are two possibilities. Actually, the one possibility that many researchers are leaning towards is that when you're sick, you have inflammation. Inflammation tends to cause bone to break down.

Just like somebody who has chronic bronchitis from cigarette smoking and on that basis gets brittle bones, somebody can have a chronic infection with HIV and get brittle bones. It was felt that it was just the inflammation.

However, a group from Ireland exposed growing bone cells to HIV in serum -- either a low viral load or a high viral load or a negative viral load -- and showed that, when you exposed the cells to HIV, the bone cells tended to turn into fat cells. Bone cells and fat cells are related. So there may be something about HIV itself that tends to shut off the calcium being laid down in the bone. That was brand new information that hadn't been seen before.

There was another study, though, and this was really very hard to understand. It was related to the SMART study. You remember the SMART study?3 In that study, patients either stayed on therapy or, when their T cells went up, they stopped therapy, and then when their T cells went down, they started treatment again. It was a big study of a couple thousand people. [Click here to read more about the SMART study and treatment interruptions.]

Two hundred seventy-five of the people in the study actually had bone density studies done, either when they were on continuous therapy, or starting and stopping.

In fact, in that study, the people who stayed on therapy tended to have more bone problems than those who started and stopped. The author said that is not a reason to start and stop. So don't take that as a reason. But the people who were on therapy and didn't stop were more likely to have fractures and, when they were followed over, I believe, two years, they were more likely to lose calcium in their bones than the people who did start and stop.

That was a surprise finding, as almost everything out of the SMART study is. Nobody's really sure what to make of it, other than, as we move forward, we probably should be concentrating on bone density and making sure that we don't allow our patients to get to the point where they are likely to have fractures.

Nelson Vergel: That's definitely a problem I'm seeing. Very few doctors are prescribing bone scans, DXA [dual energy X-ray absorptiometry] scans, before therapy or once every few years to follow up on patients even if they don't think it's a problem; it's just that it's really not part of standard of care. That's another activist issue.

Dr. Donald Kotler: The activist issue is reimbursement.

Nelson Vergel: Those who stayed on continuous therapy in the SMART study also had fewer problems with heart attacks and cardiovascular disease, right?

Dr. Donald Kotler: Right ... as well as other endpoints. The people who started and stopped are more likely to have problems with liver disease and are more likely to have problems with tumors. Starting and stopping has turned out not to be healthy.

Nelson Vergel: Any other questions, Bonnie? I think Dr. Kotler has been extremely helpful in clarifying some of the questions the community has.

Bonnie Goldman: If you have bone density issues, is it related to fat accumulation or fat wasting? Or are they all kind of the same phenomena?

Dr. Donald Kotler: Sort of, because they tend to be found in the same people. But no, I don't know how they are necessarily related in terms of the cause.

Bonnie Goldman: It sounds like there are hints of a lack of calcium in patients. Would this mean that it's a good idea to take calcium supplements to prevent bone density loss?

Dr. Donald Kotler: I don't know. I don't know if taking calcium supplements prevents it. That's the problem.

Nelson Vergel: Or exercise.

Dr. Donald Kotler: You should avoid vitamin deficiency. You should avoid eating too little calcium. That's mainly a problem in people who have trouble with milk and dairy. If you're lactose intolerant, you tend to eat less calcium than if you are not lactose intolerant.

Somebody who is at risk for bone loss should make sure they are taking enough calcium in their diet, should make sure there's at least enough vitamin D in their diet. I don't know, though, that just by taking an extra two vitamins everything will be cool. I just don't know that. I think that you would be better off having your bone density checked.

Certainly, if your bone density is low and you take the regular bone density medicines, like the kind that you see on TV, they do work.

I'm not sure how well vitamin D and calcium work. But the kinds of drugs, what are called bisphosphonates, that you either take every day, every week or every month, they do cause bone density to rise.

Bonnie Goldman: Do you see a lot of people having metabolic complication myths? They think it's due to all the protease inhibitors, or they think it's due to all antiretrovirals. Are there myths that we need broken?

Dr. Donald Kotler: I don't know. Patients tend, if they believe the doctor, to believe what the doctor tells them. So if there's a myth, it's probably the myth of the doctor. This whole idea that protease inhibitors caused everything didn't come from the patients. It came from the doctors. We had it wrong. We tend to have it wrong a lot, unfortunately.

Bonnie Goldman: I think that's one of the reasons that these kinds of complications -- bone, metabolic complications and body shape changes -- are so difficult. Because it's an ongoing understanding. And we don't know that much about this.

Dr. Donald Kotler: There's another part of it, though. It's that we're looking so hard at T cells, or viral load, that we just tend to forget about the rest. We're working so hard to make sure that people don't get cytomegalovirus (CMV), or toxoplasmosis, and die. When they get better and they're not going to die of the AIDS things, we can either say that's fine or ask what else would it be. As HIV docs we're not built to be worried about people's prostates or breast self-exams. We were aiming towards fighting pneumocystis pneumonia [PCP], CMV and all the rest. So we have had to retrain ourselves to be primary care physicians, to look at things that would happen to somebody who doesn't have a killer disease.

What happens to people without a killer disease? You either get cancer or heart disease. Or you develop Alzheimer's disease, or bad kidney disease, or all the other stuff. We're just coming around as doctors to realize that. Patients also have to come around.

Probably the best example of where patients and doctors have been caught short has to do with cigarette smoking. I knew it. If I had a patient who was dying of AIDS in 1985, I didn't bother much about them smoking cigarettes. What for? Now, it turns out that lung cancer is really common in HIV, and has nothing to do with HIV, it seems, and has everything to do with cigarette smoking.

So only lately have doctors like myself said, "Look, you're not going to die of AIDS. Why would you go through all that and then allow yourself to die of lung cancer? How could you be so crazy?" We're just getting around to that now.

Bonnie Goldman: You need to have a historic point of view to understand this whole issue, and how we came to the point where we're now dealing with this.

Dr. Donald Kotler: There's nobody to blame, because it's success. But if we want real success, it's not only not allowing somebody to die of AIDS, it's not allowing anybody to die before their time of anything. Drug overdose, as well.

Bonnie Goldman: And also dealing with quality-of-life issues -- you may live a long life, but you might have this belly that embarrasses you.

Nelson Vergel: Or facial wasting, or fatigue, or many other issues. One more question that I just thought of related to this talk about HIV doctors training themselves to be primary care physicians and treating people that are aging with HIV and who are showing up with some of these metabolic problems: Are there any Web sites, any groups, where guidelines are posted for doctors when it comes to metabolic disorders? One place, one document? Anything that doctors who are starting to treat HIV nowadays can go to to train themselves?

Dr. Donald Kotler: If you google "HIV metabolic guidelines," there have been several from the International Association of Physicians in AIDS Care, and from the International AIDS Society-USA. I believe that the Europeans also have one. There are some guidelines that are written. The early guidelines were not great. They would say, "In the absence of information, you probably should treat diabetes in HIV like you treat diabetes in non-HIV." For high cholesterol, or high triglycerides, as well, you should consider the medications. After that, you should treat just like you would treat anybody else.

I think the major point is that you don't ignore something that's bad. In the past, we ignored cigarette smoking, because we were worried that people were going to die of CMV.

Now we shouldn't ignore cigarette smoking. We shouldn't ignore high cholesterol, and we shouldn't ignore diabetes. We shouldn't ignore excess weight gain. We shouldn't ignore any of it.

Bonnie Goldman: So, success has allowed us to focus on these other details.

Dr. Donald Kotler: Yes, and those who are successful have more work to do.

Nelson Vergel: I also remind patients that HIV medications may have some side effects, but the worst side effect is leaving HIV untreated. I always say that, because sometimes we lose perspective and forget that these medications have kept a lot of us alive for 20-plus years. Sometimes the new guys and girls that are coming through with treatment are so afraid. I remind them that leaving HIV untreated can cause more problems than any side effects they may have in the future that can be treated by a good doctor.

Dr. Donald Kotler: I was in clinic today and saw a 24-year-old girl with a CD4 of 5, who had herpes around the rectum and around the vagina, who was being treated for MAC [Mycobacterium avium complex] infection in the liver, who has a huge liver, and who also probably has CMV. She had lost 70 pounds. She doesn't leave the house. She feels miserable. There's no reason for it.

Nelson Vergel: She got to a good doctor, though.

Dr. Donald Kotler: She's at a good clinic.

Nelson Vergel: A good clinic, that's lifesaving. Anything else, Bonnie? Dr. Kotler has been great.

Bonnie Goldman: I think this is really great, and hopefully it explains some of the phenomena that people have been experiencing. Maybe it will motivate a lot of people to go on a diet, do some exercise and take charge of their health in that way, while waiting for other treatments or other understanding of metabolic complications.

Nelson Vergel: Hopefully, we'll bother Dr. Kotler in the future to give us more details about any progress in this field, too. So, thank you.

Bonnie Goldman: Thank you so much for taking the time to talk with us. Thank you, Nelson, for joining us and for leading the conversation. I really appreciate that.

Nelson Vergel: Thanks a lot for having us! We'll talk to each other soon, I hope.

We want to know what you think of this podcast! Click here to take our quick survey!




References
Lazzaretti R, Pinto-Ribeiro J, Kummer R, Polanczyk C, Sprinz E. Dietary intervention when starting HAART prevents the increase in lipids independently of drug regimen: a randomized trial. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEAB303.
Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. December 6, 2007;357(23):2359-2370.
Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.
For more information on facial wasting, check out our lipoatrophy resource center.

Click here to read Mark King's latest blog about treatment for facial wasting.




You can find this article online by typing this address into your Web browser:
http://www.thebody.com/content/art51106.html

General Disclaimer: The Body is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, consult your health care provider.

Medicare seeks comments from community and clinicians about facial lipoatrophy reimbursement needs

For everyone who has complained about the lack of insurance
reimbursement for facial lipoatrophy treatment, or about the lack of
good permanent fillers approved for facial lipoatrophy, now is your
chance to do something. Please follow the link below
to submit a comment in response to Mediare's request for comments on
Reconstructive Treatment for Facial Lipodystrophy Syndrome. Even if
you have private insurance, private insurers are likely to follow the
lead of Medicare, the country's largest health program. Manufacturers
of facial fillers are more likely to seek FDA approval if there is a
potential for insurance reimbursement for their products. This is
probably the best opportunity we've ever had to do something about
insurance reimbursement for facial wasting procedures. With a new,
more enlightened administration in the White House, I think there's a
good chance that Medicare will change its policies in response to
reasonable arguments that treatment for facial wasting is
reconstructive (like reconstruction of a breast after breast cancer or
like surgery to eliminate disfiguring burn scars).

Powerful personal anecdotes about how facial wasting has affected you
are likely to be persuasive, particularly if you can talk about how it
has caused social isolation or impaired your ability to work. Pictures
will speak louder than words; if you have pictures of your face
before and after treatment for facial wasting, posting them with your
comments could help the cause enormousely. There is an email link on
the form for attachments.

If you choose to write personal anecdotes or submit pictures, the
government will redact (delete) anything you write about your personal
experience with facial lipoatrophy from the comments posted on the
website, and will not post personal photos (before you can comment,
you are required to read a statement from the government stating that
statements about personal health conditions will not be posted on the
website). But presumably, these comments (and photos) will still reach
the intended decision makers in the government in their unredacted
form. I personally chose to begin with a paragraph that stated my
opinion about the proposed change to policy and then discussed my
experience from working with people with HIV. Presumably, these
comments will be posted on the website. Then I went on to describe my
personal experience with facial lipoatrophy, providing a couple of
anecdotes that I thought demonstrated the effect it has had on me. I
presume these comments will not be posted, although I don't really
mind if they are.
Please click on the orange "comment" button to explain to Medicare why you think facial lipoatrophy is a medication-induced side effect that needs to be treated and covered. If you can add your own personal experience as a patient or as a clinician, even better!

We do not have much time. The deadline is Feb 16

http://www.cms.hhs.gov/mcd/ncpc_view_document.asp?id=20


For more information about facial reconstruction products in HIV, please visit facialwasting.org

Comparative Analysis of HIV+ and HIV- Interaction with Testosterone on Bone Mineral Density

Thanks to Jules Levin for providing this paper

Comparative Analysis of HIV+ and HIV- Interaction with Testosterone on Bone Mineral Density



Reported by Jules Levin

ICAAC/IDSA Oct 28 2008 Wash DC



R.RAGHUNATHAN 1,2,J.SINACORE 2,K.RYCHLIK 2, J.FARANO 1,C.PACHUCKI 1,2,and N.AZAD 1,2

1 Edward Hines VA Hospital

Hines, VA 60141

2 Loyola University Health System,Maywood, IL 60153



AUTHOR CONCLUSIONS



In age-matched HIV-infected men, a lower free testosterone corresponds significantly to a lower T-score at the lumbar spine.



A normal free testosterone level was protective of bone mineral density in HIV-infected patients compared to the control population.



Among HIV-uninfected men, an increase in free testosterone level does not correspond to an increase in T-scores.


Further studies evaluating the interaction of low free testosterone and HIV infection need to be conducted to better understand the bone-related effects.


Background: Given an increasingly younger HIV population with osteopenia/osteoporosis a retrospective controlled study was conducted to investigate the effects of testosterone on bone mineral density (BMD) in HIV infected and HIV non-infected populations.



Methods: A chart review was done on a group of 80 male HIV patients and 154 male control patients. The following variables were obtained from the HIV group: age, race, employment status, smoking, body mass index (BMI), duration of HIV, CD4 levels, viral load, type of antiretroviral use, co-morbidities, use of prednisone, heroin, alcohol, methadone use, ever use of androgen, bisphosphanate use, calcium use, alpha reductase inhibitor use, phosphodiesterase inhibitor use, lipids, and biochemical markers. The same variables were obtained from the control group except those pertaining to HIV and employment status. T-scores were used in both HIV and control groups to evaluate BMD.



Results: A univariate analysis of variance was used controlling for the following factors: age, race, BMI, prednisone, heroin, alcohol, smoking, methadone, androgen use, alpha reductase inhibitor use, phosphodiesterase inhibitor use, bisphosphanate use, and calcium use.







Conclusions: A normal testosterone level was protective of bone mineral density in HIV-infected patients compared to the control population. At the L-spine, HIV patients with low testosterone had a lower bone mineral density (p < 0.05). Treatment of osteopenia/osteoporosis with testosterone in HIV patients needs further evaluation.



BACKGROUND



Prevalence of osteoporosis in HIV-uninfected hypogonadal men is reported to be 12.3% vs. 6.0% in men with normal testosterone levels1.



Among patients enrolled in the Study to Understand the Natural History of HIV and AIDS (SUN), 52% had osteopenia and 10% had osteoporosis. Among these patients 78% were men, 25% were black, and 80% of patients received antiretrovirals (ART)2.



Up to 70% of treatment-naive HIV-infected men are reported to have low free testosterone3.



Whether an isolated HIV-related hypogonadism interaction plays a role in developing osteopenia/osteoporosis is unknown.



It remains unclear how HIV itself or other known attributable factors (such as age, sex, race, duration of HIV, ART, hypogonadism, etc.) lead to the development of osteopenia/osteoporosis.



There is a renewed interest in the pathogenesis, diagnosis, and management of osteoporosis in this population.



HYPOTHESIS

We hypothesize that patients with HIV with low free testosterone levels have lower T-scores.


METHODS/STATISTICAL ANALYSIS


A retrospective chart review was performed on two groups: 80 HIV-infected men and 154 HIVuninfected men (see Table 1 for epidemiologic characteristics in each population).


HIV-specific information was obtained in those men who were HIV-infected with low and normal testosterone (see Table 2).



An analysis of covariance was done controlling for the following factors: age, race, BMI, smoking, and use of prednisone, heroin, cocaine, alcohol, methadone, androgen, alpha reductase inhibitor, phosphodiesterase inhibitor, bisphosphanate, and calcium (see Figs 1 – 3, Table 4).



The serum free testosterone (FT) levels were measured by Quest diagnostics (using dialysis method Wood Dale II). The normal FT ranges 35 – 210 pg/mL (see Fig 4 for free vs. total testosterone correlations in HIV-infected and HIV-uninfected patients).




REFERENCES

1. Fink H.A., Ewing S.K., Orwoll E.S., et al. Association of Testosterone and Estradiol Deficiency with Osteoporosis and Rapid Bone Loss in Older Men. The Journal of Clinical Endocrinology and Metabolism 2006; 91(10): 3908 – 3915.

2. Calza L., Tampellini L., Chiodo F., et al. Bone Mass Loss in Patients with

HIV Type 1 Infection. Infectious Diseases in Clinical Practice 2007; 15(3):

160 – 166.

3.Wunder D.M., Bersinger N.A., Furrer H., et al. Hypogonadism in HIV 1-infected men is common and does not resolve during antiretroviral therapy. Antiviral Therapy 2007; 12:261 – 265.

Tenofovir Dosing for patients with kidney dysfunction

I have seen some confusion about Tenofovir (Viread, which is in Truvada and Atripla) dosing in those with kidney problems in my pozhealth at yahoogroups.com list, so I am posting this information.

So far, most of the problems with tenofovir and kidney function have been reported in treatment experienced patients on boosted protease inhibitors, african americans, people with diabetes, or those using other medications that may affect the kidneys. Naive patients on Atripla seem to be doing just fine.

By the way, for those of you who have not calculated your creatinine clearance, ask your doctor if that value is included in your lab report. If not , ask him or her to include it. You can also calculate it here:

http://cpsc.acponline.org/enhancements/212creatinineCalc.html


From
http://www.medscape.com/druginfo/monograph?cid=med&drugid=22106&drugname=Viread+Oral&monotype=monograph&secid=3


Special Populations
Dosage of tenofovir should be adjusted in adults with creatinine clearances less than 50 mL/minute. The manufacturer and some experts recommend that adults with creatinine clearances of 30 to 49 mL/minute should receive 300 mg of tenofovir once every 48 hours and those with clearances of 10 to 29 mL/minute should receive 300 mg twice weekly. Adults undergoing hemodialysis should receive 300 mg of tenofovir once every 7 days (based on 3 hemodialysis sessions per week, each lasting approximately 4 hours) or 300 mg after a total of approximately 12 hours of dialysis; the dose should be administered following completion of a dialysis session. Because safety and efficacy of these dosages have not been evaluated in clinical studies, clinical response to treatment and renal function should be closely monitored. The manufacturer states that dosage recommendations cannot be made for adults with creatinine clearances less than 10 mL/minute who are not undergoing hemodialysis since the pharmacokinetics of the drug have not been studied in such patients.
The usual dosage of the fixed-combination preparation containing emtricitabine and tenofovir disoproxil fumarate (Truvada®) can be used in adults with creatinine clearances of 50 mL/minute or greater. The manufacturer of the fixed-combination preparation recommends a dosage of one tablet (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) every 48 hours in adults with creatinine clearances of 30–49 mL/minute; response to therapy and renal function should be monitored in these patients since this dosing recommendation has not been evaluated in clinical studies. The fixed-combination preparation should not be used in adults with creatinine clearances less than 30 mL/minute, including those undergoing dialysis.

The usual dosage of the fixed-combination preparation containing tenofovir disoproxil fumarate, emtricitabine, and efavirenz (Atripla®) can be used in adults with creatinine clearances of 50 mL/minute or greater. The fixed-combination preparation should not be used in adults with creatinine clearances less than 50 mL/minute.

Dosage adjustment is not necessary in patients with hepatic impairment

The Coming Crisis in HIV Drug Development

Excellent article by Paul Dalton

Project Inform
The Coming Crisis in HIV Drug Development
By Paul Dalton

June 16, 2008

The last few years have seen tremendous progress in treating people with advanced and drug-resistant HIV. Four powerful drugs became available that either overcame drug resistance (Prezista [darunavir, TMC-114], Intelence [etravirine, TMC-125]) or were from entirely new classes [Selzentry (maraviroc), Isentress (raltegravir)].

This marked an important and unique moment in HIV drug development. Never before have so many new and effective drugs come out so close together. People with extensive experience taking HIV drugs have been able to put together powerful regimens with two or more fully active agents -- often for the first time.

Project Inform took pains to highlight both the tremendous promise of these new drugs as well as the importance of using them correctly -- emphasizing that this moment, or anything resembling it, is unlikely to recur. Our message was clear: 'Seize this opportunity, use the new drugs carefully, and don't waste this once-in-a-lifetime chance'.

As good as some of these newer drugs have looked in studies, there are emerging signs of trouble in the real world. Dr. Steven Deeks, a prominent HIV physician and researcher says, "Although the current generation of drugs are generally doing great, many patients are not responding in a durable manner. We are now following about 25 individuals who have failed all six drug classes. The key now is to design regimens to maintain immunologic and clinical stability while we wait for more drugs. I am concerned, however, as it will likely be a few years before we have another shot at getting the virus under control. We desperately need a second generation integrase inhibitor that works against viruses resistant to raltegravir."

Dr. Deeks' experience is far from typical. He follows many of the most treatment experienced people in the San Francisco Bay Area, many of whom have been on therapy since 1987. Although not typical, his experiences have been reported elsewhere, if in smaller numbers.

This suggests a burgeoning problem of people beginning to run out of treatment options, as has happened a couple of times during the epidemic. Project Inform is concerned that the most vulnerable people living with HIV will be left with few or no viable treatment options, possibly for many years.

One of the unintended effects of the recent successes in drug development is that fewer people are available for studies of experimental drugs aimed at treatment experienced folks. We saw this coming and have been counseling drug companies and the Food and Drug Administration (FDA) that the era of 'TORO-like' studies was coming to a close. These studies give volunteers optimized background therapy (the best combination of HIV drugs chosen with resistance test results) with either the experimental drug or a placebo. The design allows regulators, scientists and activists to clearly see the benefit of the new drug. (Some call these studies 'TORO-like' after those that led to the approval of Fuzeon [enfuvirtide, T20]).

This contrasts with how studies of first line treatment are done. When studying HIV drugs as first line, the basic model is head-to-head non-inferiority studies, which are designed to tease out the relative contribution of the entire regimens rather than the individual drugs. (Non-inferiority means that one drug or regimen is equivalent or 'close enough' to another.)

The FDA has allowed non-inferiority studies for drugs being studied as first line, but has insisted on placebo controlled superiority studies for treatment experienced studies. This made a good deal of sense when there were many people signing up for these studies. The situation is now quite different.

While there aren't enough people signing up for these kinds of studies, there's still a sizeable need for studying new HIV drugs. This, combined with the thin drug pipeline and the current difficulty recruiting for studies, may add up to real trouble down the line.

In meetings with many drug companies Project Inform has warned of this impending problem and recommended that they adopt new ways of studying their drugs. The reaction has been mixed. While some companies have been quite open to new ideas, it's fair to say that most would prefer to stick with models that have proven successful.

We have struggled to argue -- to the companies and the FDA -- that ways of studying and developing drugs are both necessary and possible. Gilead Sciences is one of the first to grapple with this. When it came time to do large, pivotal studies of their experimental integrase inhibitor, elvitegravir, there simply were not enough people in the US to enroll a typical study for treatment experienced people. Project Inform had warned Gilead, and others, of this eventuality and argued for studies that would more closely resemble the head-to-head, non-inferiority studies used for studying first-line drugs.

Over time Gilead came to agree that this was the way forward and submitted such a plan to the FDA. The FDA eventually allowed Gilead to move forward with this study design for elvitegravir. This is a great victory for people living with HIV. There is a great need for new treatments to be developed and for the FDA and companies to think and act creatively to ensure this happens.




An Overview of the Current State of HIV Drug Development
The Industry
As a whole, pharma has done a tremendous job developing HIV drugs. However, many visible signs are showing their fading commitment to HIV. Fewer new companies are getting into HIV, and some well established ones are either cutting back or eliminating their drug development plans. The marketplace for HIV drugs is both crowded and competitive. The scientific hurdles for developing new HIV drugs have also grown more difficult, making it a less attractive market for companies.

The FDA
The FDA is responsible for ensuring that drugs are safe and effective before they become available outside clinical studies. Recent media stories that focused on drug safety, particularly on Vioxx and Heparin, have created a somewhat fearful climate inside the FDA where new ideas are met skeptically. Their recent decision to green light elvitegravir's development shows that at least its antiviral division is open to creative drug development plans.

The Current Pipeline
All in all, the pipeline is both thin and unimpressive. There are a few 'me too' drugs (slight changes in existing drugs) which are helpful but not game changing. A few novel compounds may prove promising down the line, but they're struggling right now, due to either study results or in one case the company being bought by a company that doesn't want to work in HIV.

As for those drugs in human studies, the closest to approval is rilpivarine (TMC-278), an NNRTI for first line treatment being studied against Sustiva. Vicriviroc, Schering's CCR5 drug, continues to flounder but is still viable. Bevirimat, a maturation inhibitor from Panacos, has been hamstrung by formulation problems. Other drugs we are following are Pharmasset's racivir, and Avexa's apricitabine.

The Bottom Line
The past two years have been a boon to people with extensive treatment experience. Four successful new drugs, including two new classes, have meant most people can put together powerful, effective and tolerable regimens, even if they've never been able to get to undectable before. However, this period is now over, and we're experiencing a major downturn in the number of promising drugs in the pipeline.

This reinforces the importance of using the current crop of new drugs correctly. Your best chance at getting to and staying undetectable is to start a regimen with at least two and hopefully three fully active drugs. If you're able to do this and get your HIV level to undetectable, good adherence is the best way of keeping it there.

This also points to the need for treatment activists, like Project Inform, to continue to work with the companies, scientists and regulators to ensure that new drugs are developed.
Lastly, this situation points toward the need for a cure. It is only going to become more difficult to keep the companies, their researchers and the general public interested in HIV drugs. There's a growing sense that HIV is not that much of a problem anymore, at least not in wealthy countries.

The only real solution is a cure. While some may discount its possibility, we do not. Many promising approaches are under study, as well as a resurgence in community activism aimed at cure research. A conscientious program mounted by academia, industry, government and community is necessary to reach this goal.