Wednesday, October 29, 2008

Biology of a Cure for HIV

When are they going to find a cure, doc?”

HIV is epidemic, infecting 2.5 million people a year, and 33 million people worldwide and has been responsible for more than 25 million deaths. During the early days of the epidemic, many people who were infected died within a matter of months. We have crossed significant hurdles since then. Therapy for HIV started with just one drug – zidovudine, or AZT – and has evolved into combination therapy with several potent drugs. Today standard treatment for HIV is called Highly Active Anti-Retroviral Therapy, or HAART. Patients who take HAART can mitigate most of the fatal complications of HIV infection, although many people still do not have access to these life-saving medications. Despite the success of HAART, recipients are committed to lifelong therapy which can be costly, toxic, and complicated. The risk for someone who stops HAART is that the disease can come back, putting the sufferer at constant risk of a poor outcome. Understandably, many HIV-infected persons wonder why there hasn’t been a cure. Some patients have even expressed concern that there are doctors, pharmaceutical companies, and even governments who are suppressing a cure. Before such human failures are blamed for HIV, we still have the difficult challenge of HIV itself.

Some of the reasons why HIV has proven so tenacious lie deep within the biology of the virus...

Taking a fast hold…

From the earliest time points after transmission, HIV quickly insinuates itself into an unsuspecting host patient, like a parasite. HIV is primarily acquired by blood and body fluid exchange through sexual transmission (heterosexual or homosexual) or via the bloodstream directly (in the case of an improperly screened blood supply or intravenous drug use). No matter how it is acquired, once introduced into the body swarms of HIV virus particles (called virions) quickly spread to the body’s lymph nodes – the transit locations for most immune cells. HIV then multiples vigorously and from the lymph nodes disseminates widely throughout the body. Since HIV infection is not localized to one discrete area of the body, therapy, in order to be effective, must penetrate all of the nooks and crannies in which HIV may be hiding. At the current time not all of the drug constituents of HAART pervade into the various HIV-hosting compartments in the body. An example of this is HIV and the brain. Although HIV infects the brain and can lead to significant dementia, some drugs penetrate the fluid around the brain very poorly. People who take those drugs have undetectable viral quantities in routine blood tests, but may still have detectable HIV in the brain fluid, making control of the virus more challenging.

Another reason why a cure is not forthcoming is because of the concerted attack HIV poses to our immune system. The hallmark of HIV infection is the rapid, progressive loss of important cells of the body’s immune organs, the infected person’s CD4 T cells, leading to the Acquired Immunodeficiency Syndrome or, the more familiar moniker, AIDS. The CD4 T cell is critical for guiding various aspects of the body’s immune responses towards the many microbes to which we are exposed, including HIV itself. Even antibiotics require our immune system to do the majority of the work in cleaning up infections. The loss of CD4 T cells not only makes us vulnerable to opportunistic infections but also limits our ability to eradicate HIV from our system, even with HAART. The remaining immune cells are stymied by the propensity of HIV to mutate rapidly, making it challenging for consistent patterns to be recognized by the host. (At the risk of oversimplification, the immune system works by recognizing constant and variable patterns on ‘foreign’ materials and microbes that don’t originate in the host and targeting these invaders and the cells that harbor them for destruction and elimination.)

“But doesn’t HIV therapy improve the CD4 T cell counts?”

It’s true that the CD4 T cells in the blood are replenished when patients consistently take HAART. But despite the best available therapy, HIV-infected persons retain residual defects in their immune system. For instance, the majority of CD4 T cells are, in fact, found in the intestinal wall, and these are not fully replenished by HAART. Though it is difficult to predict the significance of these residual intestinal immune defects, one can envision that HIV could take advantage of holes in the immune system in order to persist in the host.

The Persistence (Despite) Time

The reduction of circulating HIV virus, or viremia, by HAART is the best predictor of a patient’s long-term outcome. A relatively common scenario is to see a patient’s quantity of virus start at more than 750,000 copies per milliliter and then rapidly drop to undetectable levels with the initiation of HAART. However, studies have shown that stopping HAART is detrimental. No matter how long the patient has been taking HAART, an interruption in therapy results in the virus recovering its numbers. Where, then, does HIV hide when people are on HAART?

In addition to the widespread dissemination of HIV early on in the infection, some HIV virions also infect a smaller population of cells and that allow the virus to remain in a latent state, not multiplying the way other virions do. In this situation, the genetic material of HIV is integrated stably in between stretches of the patient’s own DNA. This population of integrated HIV virus resting within cells is called the latent reservoir. Although the virus in the latent reservoir doesn’t harm the body (as far as we know), it is sufficiently hidden from the immune system to resist eradication. In addition, currently available antiretroviral drugs are predominantly active against multiplying virus. Because this latent state of HIV is characterized by a general lack of multiplicationfar fewer multiplying virions, the virus is safe even when patients are on HAART.

“Most cells in the body must die at some point. Why not wait for these reservoir cells to die, then allow HAART to finish off the virus?

In fact, the latent reservoir itself is a long-lasting population of cells infected with HIV. The lifespan of the latent reservoir has been estimated in years to decades, and only very few are thought to die during a person’s life. It is hypothesized that it would take 40 years or more for HIV within this reservoir to be eradicated entirely with HAART – an impractical amount of time for a cure.

“So is there any hope for a cure?”

Although some scientists feel that HIV eradication is impossible, the past 20 years has seen an explosion in new therapies for HIV, and there are newer agents in the pipeline. Never in the history of medicine have such large strides been made against a disease in such a short period. We still have much to learn about the virus, but with knowledge will come further answers as to how to better treat HIV. As a hopeful example, there are a number of people who were found to be resistant to HIV infection altogether. Through careful genetic studies, it was learned that cells from these individuals lacked a molecule on their surface called CCR5. CCR5 is normally manipulated by HIV to gain entry into host cells. So, the people who were CCR5 deficient were actually protected from HIV. Scientists used this knowledge to design drugs that block CCR5, thereby helping to control the ability of HIV to infect new cells. This class of drugs, CCR5 inhibitors, has recently been approved for the treatment of difficult to control HIV.

In 2008 we have crossed many important milestones in HIV research and treatment, some of which have been explored here. But we have many more milestones to come. Further investigation will reveal new ways to control HIV, until one day a cure will finally be in our grasp.

Thursday, October 16, 2008

Surrogate endpoints in medical trials

What if I tell you that, in those who survive heart attacks, the presence of abnormal electrical conductions from the lower chambers of the heart (ventricular arrhythmias1) is a risk factor for sudden death? That the risk of dying is in fact two to threefold higher in those patients after heart attacks with ventricular arrhythmias and no or mild symptoms? You’d insist we find a way to reduce those ventricular arrhythmias. And if I tell you that we already have two drugs, anti-arrhythmics called encainide and flecainide, that are quite good at doing just that, suppressing those arrhythmias? Perfect, you’d say.

You’d prescribe the medications to your patients and be reassured shortly afterwards on observing a reduction in their ventricular arrhythmias. Admittedly, small studies have not yet shown an increase in survival, but you’d accept that as a limitation of small studies. The reduction in ventricular arrhythmias is real, and larger studies collaborating your view that the drugs thus must also improve survival seem inevitable.

Such was the scenario in late 1989, and for the reasons above doctors regularly gave the anti-arrhythmic drugs encainide and flecainide to patients with ventricular arrhythmias after heart attacks. Then, the preliminary results of the Cardiac Arrhythmia Suppression Trial (CAST) trial were published in the New England Journal of Medicine (NEJM), and the medical community was stunned.

(The vertical line (y-axis) represents survival, and the horizontal line (x-axis) the passage of time.)

N Engl J Med. 1989;321:406-412.

CAST trial

As you would expect, in viewing the graphs, the CAST trial as it was initially designed had to be stopped early.

In the trial, patients after heart attacks with ventricular arrhythmias and no or mild symptoms whose arrhythmias would suppress with encainide or flecainide were given either the anti-arrhythmic agents or a placebo (a sugar pill). They were then followed for an extended period of time. The purpose of the study was to finally answer whether the suppression of these ventricular arrhythmias would truly increase survival.

Although the CAST trial was groundbreaking in this regard - the first well-designed trial to study the question of whether antiarrhythmic drugs safely and effectively reduce the risk of sudden death - the outcome for many physicians seemed to be a foregone conclusion. At the time a few probably even flinched at the idea of giving some of the patients a placebo.

Instead, those patients given encainide and flecainide had about a three-fold increase in overall mortality. They clearly did worse no matter how you analyzed the data: deaths from arrhythmias, nonfatal cardiac arrests, deaths from non-arrhythmic cardiac causes, death from any cause, etc. As Dr. Jeremy Ruskin wrote in an editorial that accompanied the results of the CAST trial, the “results … astounded most observers and challenge[d] much of the conventional wisdom about antiarrhythmic drugs and some of the arrhythmias they have been used to treat.”

Where had doctors’ thinking gone wrong?

Doctors began to equate the indisputable clinical endpoint of survival with the surrogate endpoint, the presence or absence of ventricular arrhythmias. Rather than studying survival of patients as the endpoint in their trials, doctors used the surrogate endpoint, ventricular arrhythmias, and then began in their minds to blur the distinction between reductions in ventricular arrhythmias and survival.

Simply put, the lessons of the CAST trial are that studies are still essential to answering clinical questions, despite what the medical community may believe on faith or common sense may tell you, and you shouldn’t rely heavily on surrogate endpoints.

Next up, Zetia and Vytorin?

A similar scenario potentially exists today with the cholesterol medication Zetia or ezetimibe. Zetia was approved in 2002 by the FDA and is sold both alone and in combination with a statin (the current standard in cholesterol medications), as Vytorin. Zetia works via a novel mechanism and as a result allows for further reductions in cholesterol in patients already on statins. It also is available for people who don’t tolerate statins.

Historically, drugs that lower cholesterol have been proven to prevent heart attacks and save lives, but will that necessarily always be true? Zetia received its FDA approval in large part based on its ability to lower cholesterol, the surrogate endpoint, but does Zetia prevent heart attacks and saves lives? There is no data to prove that. Despite FDA approval of Zetia six years ago, that data is not expected for at least another few years when a large trial called the IMPROVE-IT trial (critics argue that Merck and Schering-Plough were slow to initiate such a trial) studying about 10,000 patients is finally expected to be completed. Until then what should doctors recommend to their patients?

Could we discover that lowering cholesterol is not a sufficient surrogate? That Zetia does not in fact prevent heart attacks or save lives? Could the medical community find itself again with its pants down as it did when the results of the CAST trial were revealed? Possibly. Estimated sales of Zetia and Vytorin in 2007 close to $5 billion suggest that the lessons of the CAST trial perhaps no longer ring loudly. Growing uncertainty, however, has led guidelines to recommend more and more that Zetia not be used as a first line agent in lowering cholesterol.

How much should we rely on surrogate endpoints?

Despite historical failures of surrogate endpoints, such as with the CAST trial, surrogate endpoints have an important use in medical research, particularly with clinical endpoints that are rare or do not occur for protracted periods of time. For example, approximately a quarter of patients with chronic hepatitis C go on to develop cirrhosis (the replacement of the liver by scar tissue), but the process occurs over several decades. Imagine evaluating medications for preventing cirrhosis in hepatitis C and waiting over thirty years to determine whether the drugs are effective. Instead, most trials today look for the eradication of the hepatitis C virus from patients, a surrogate endpoint which has been shown to be associated with the lack of progression to cirrhosis.

Satisfying public demand for new medications and public demand for shortened approval processes for drugs require the use of surrogate endpoints; however, with a shortened approval process, post-marketing surveillance for key clinical endpoints and adverse events become even more crucial.

Our better understanding of science and medicine at the molecular level continually generates surrogate endpoints, but these surrogate endpoints must be meticulously and vigilantly selected. In addition, the medical community must always underscore the distinction between clinical and surrogate endpoints. The lessons of the CAST trial should not be forgotten.


1The heart is made of four chambers, two small chambers on the top (atria) and two large chambers on the bottom (ventricles). The atria merely feed the ventricles extra blood at the end of the filling cycle, but the ventricles are the workhorses of the heart sending blood to the lungs and the rest of the body. The normal electrical conduction of the heart begins in a node of the atria and spreads to the rest of the heart in a systematic fashion. Ventricular arrhythmias are abnormal spontaneous electrical conductions originating from the ventricles (six or more per hour).

Tuesday, October 7, 2008

High blood pressure (hypertension), in short

Mr. Jones, a fifty-four year old man, had been into the office several times in the last year. He was reasonably thin, walked regularly, and felt great. Each time his blood pressure was slightly elevated, around 142/84. Each time I reminded him of the importance of blood pressure control.

He was already on blood pressure medications, but he was resistant to the idea of taking more medication. I knew though that, despite his protests, his diet (as he was a bachelor) was loaded with salt and that he could possibly control his blood pressure simply by lowering the salt in his diet. Each visit we discussed the sources of sodium in his diet, and I encouraged changes.

Otherwise, I told him, we needed to increase his blood pressure medications. A mild elevation in his blood pressure would unlikely kill him in the near future, but an increased risk of a stroke or a heart attack over time was real. Each time he reassured me that he would start watching the sodium in his diet and get his blood pressure under control.

In the end the decision on what to do was his, but short of twisting his arm I strongly pushed for changes. How important to him was the salt in his meals? While life is not only about quantity (years lived) but also the quality of those years, perhaps he was able and willing to make a few simple lifestyle changes. I couldn’t say that better blood pressure control would necessarily prevent a heart attack or stroke (we all have to die of something), but it would certainly lower his risk and potentially delay the possibility.

Several months later at his next appointment Mr. Jones, a statistician, returned with excitement. To my surprise and admittedly even to his own surprise, he finally decided to heed my advice.

Statistically significant

He started looking at the labels of foods, and he was amazed by how much sodium was in just about everything he ate. He then didn’t just reduce his sodium intake, but he decided to test the hypothesis and followed his blood pressure over several months with the same care and exactness with which he had done everything in his life. Once he had collected enough blood pressure readings, he performed a full statistical analysis and was surprised to discover, as he said, that not only was his doctor right but how much cutting down on sodium lowered his blood pressure.

Hypertension as a silent killer

While hypertension occurs in over half of people over sixty-five years of age, it is actually quite prevalent in the population as a whole. Population data from the United States around the year 2000 suggest that hypertension is present in about one third of people eighteen years and older.

What are the symptoms of high blood pressure? None. How do patients with high blood pressure feel? Great.

Because there are no symptoms, people often don’t know that they have hypertension, and once diagnosed the lack of symptoms and lack of immediate risks add to people’s poor compliance with treatment. The problem is that blood pressure elevations, even mild elevations, are associated with significant medical problems: heart disease (such as thickening of the heart, heart attacks, and heart failure), strokes, bleeding strokes, and kidney failure.

The risks of high blood pressure, including death, are correlated with the degree of elevation. The risk lies as a continuum on blood pressure readings. There is no magical blood pressure; the body doesn’t know numbers. The risks are also not immediate, except in special circumstances, but cumulative over time.

What is the number one risk of death to man or woman in the United States? Prostate cancer? Breast cancer? Colon cancer? By far, heart attacks and strokes.

“So my blood pressure is elevated. I’ve had high blood pressure all my life. That’s just the way my body is...”

That nothing has happened to you does not mean you are healthy and that something won’t happen. High blood pressure is a high-stakes numbers game. That you’ve walked into the middle of traffic without looking and weren’t killed doesn’t mean that it’s safe or that if you continue to do so that you won’t be hit and killed the next time you venture out.

Things worse than death…

In fact, getting killed instantly is not necessarily a bad way to pass, but as in motor vehicle accidents that’s not usually what happens with high blood pressure. Living with a disability the rest of your life (such as not being able to move the right side of your body and needing someone to feed you and wipe you, not being able to talk, or not being able to walk three feet without stopping due to shortness of breath) – feeling terrible and not being able to do the activities you want to do with your friends and family – that is the typical consequence and misery of poorly controlled hypertension.

Causes of blood pressure

There are numerous causes of hypertension. The most common by far, the one most people think about when hypertension is mentioned, is called essential or primary hypertension (high blood pressure not due to other identifiable causes), and is the focus of this entry. Other explanations for high blood pressure include white coat hypertension (being in the doctor’s office), medicines such as oral contraceptives, kidney diseases, sleep apnea, and thyroid and other endocrine abnormalities. Ruling out these secondary causes is part of a doctor’s initial evaluation of a patient’s hypertension.

Am I doomed?

Thankfully there are therapies to lower blood pressure, and plenty of studies show that lowering blood pressure significantly reduces risks. Clinical trials suggest mean reductions of a quarter to a third of strokes or heart attacks with control of blood pressure. The benefits are generally seen with long-term reductions in blood pressure; however, the elderly, given their overall greater risk, are more likely to benefit even from short term reductions in blood pressure.

Many medications are available to lower blood pressure (including various diuretics, ACE inhibitors, angiotensin receptor blockers - ARBs, calcium channel blockers and beta blockers), but lifestyle changes, such as Mr. Jones’ reduction in dietary sodium, can have significant effects on blood pressure. Lifestyle changes, in fact, are recommended as the first treatment option in people with mild hypertension. Only when a patient has failed lifestyle changes are medications recommended, according to national guidelines.

Despite doctors being well aware of these guidelines and the importance of lifestyle changes for their patients, doctors find themselves over time reaching more often and sooner for medications. Doctors, after seeing many failed attempts at lifestyle changes, may come to expect the next patient to fail as well. They may fear patients will not follow-up in a timely way and instead be left with poorly controlled blood pressure. Then, not only is the patient exposed to health risks, but the doctor fears his own malpractice risks. In addition, to counsel a patient on diet and exercise and changing habits is time consuming. In the age of insurance-imposed short visits, doctor usually don’t have the time to properly or effectively do so. Giving a pill is much easier. Patients faced with their own monetary and time constraints often cannot make the frequent visits to the doctor needed for this approach.

Lifestyle changes are not easy to make. Losing weight or getting used to lower levels of salt requires a focus and commitment. Patients are typically motivated to improve their health and make changes on first being diagnosed with high blood pressure, but the commitment tends to wane. Taking a pill is much easier.

Lifestyle changes, however, are key. Possible lifestyle changes include but are not limited to cutting down on dietary sodium, losing weight, aerobic exercise, avoiding excessive alcohol intake, and better handling stress. While each have an impact on blood pressure and your health, together they have a much greater impact.

Doctors treat high blood pressure because doctors can easily measure it and treat it. Taking a medicine to lower your blood pressure may be effective in lowering your blood pressure, but it does nothing for the other chemical changes occurring in your body that doctors do not routinely measure and that are detrimental to your health. Hypertension for many people is merely a sign of more significant underlying health issues developing from a poor diet, little exercise, and excess weight. The analogy frequently used is that of the tip of the iceberg with the remainder of the massive iceberg underwater and out of view.

Dietary sodium

Sodium clearly plays a role in high blood pressure as hypertension is mainly seen in societies in which people eat more than 2.3 g of sodium per day. The excess sodium intake over many years is thought to play a role. In societies in which people take in less than 1.2 g sodium per day, hypertension is actually rare.

Lowering dietary sodium intake lowers blood pressure. Some people are more sensitive to changes in dietary sodium intake, but on average the drop in blood pressure is about 5 points (mm Hg). The full effect is generally seen within a month, with other further benefits over the long term.

Where is the sodium in your diet? Everywhere. Any food you haven’t made yourself is loaded with salt. Virtually all prepared foods, frozen dinners, soups, restaurant meals, condiments, and sauces for instance are loaded with sodium. Even foods labeled “low sodium” have excessive amounts of sodium. Even food in the local hospital cafeteria has way too much sodium. (Beware: any food that is truly low in sodium is probably high in sugar or fat.) Food companies are in the business of selling food, and salt enhances flavor.

To all those that love salt in their meals and can’t imagine living without it, the taste of salt is a habit. The more salt you regularly have in your meals the more you’ll want and vice versa. You have to be willing to let your taste buds adjust over time.

Just a little overweight

Being overweight is thought to contribute to about a quarter to a third of cases of high blood pressure, and being overweight not only increases your risk of high blood pressure but also your risk of diabetes mellitus, high LDL cholesterol, low HDL cholesterol, and a thickened heart among other medical issues.

Not unexpectedly there are benefits to your blood pressure from losing weight. In those with high blood pressure, one study showed that a 10 percent reduction in weight resulted in a 4 point (mm Hg) drop in blood pressure. Other studies demonstrate 5-20 mm Hg drops in blood pressure for each 10 kg of weight loss. In overweight individuals a sustained loss of weight results in a lower risk of developing hypertension down the road.

Note that even by eating less you will be reducing your sodium content, but the benefits of weight loss are independent of the reduction in sodium intake.


Regular, continued aerobic exercise lowers blood pressure about 5 mm Hg, and certainly exercise has other benefits, including weight loss, a lower cholesterol, an increase in HDL (good cholesterol), and a decrease in overall mortality. (All the benefits of exercise, countless – a discussion for another entry.)


Although there appears to be a health benefit from small amounts of alcohol, alcohol consumption is another example of when more is not necessarily better. There is a clear association between excess alcohol intake and health risks including hypertension, independent of its extra calories and the associated extra weight. A maximum of one drink per day is recommended for women, two drinks per day for men.

Personality traits and stress

Stress and personality traits have been implicated in high blood pressure but a direct link is difficult to prove. There is a concern, however, that while their effects on blood pressure and the body in the short term may be reversible, that over time they may result in chronic, physiological changes.

And to those without high blood pressure, are there benefits from lifestyle changes?

In people with normal blood pressure, the decrease in blood pressure from lifestyle changes are small, but even small changes could over long periods possibly have benefits as well. To the degree that people are able and willing to make changes, there is no reason for them not to do so.


So while there is clearly more to be said about high blood pressure, hopefully this will induce people to have their blood pressure checked and managed – not only with medications but also with lifestyle changes. How to make change (changing habits) is also a discussion for another entry…

What other questions about high blood pressure do people have that perhaps their doctors haven’t discussed with them?