The 9th Conference on Retroviruses and Opportunistic Infections (CROI)

A Plethora of Small Steps

George M. Carter

Note: There have been several reviews of this conference by many excellent publications. Many of the abstracts and presentations may also be reviewed on the internet at http://www.retroconference.org. See the list of other organizations at the end of this article.

Introduction
Basic Science/Pathogenesis
T cell turnover--Background
So What's the Controversy?
Why is it Important to Understand This Controversy? Therapeutic Implications
Treatment - Nutrition
Treatment - New Drugs
Treatment - Old Drugs/Toxicities
Structured Treatment Interruptions (STIs)
HIV/AIDS in the Developing World
Addendum 1: Some Links
Addendum 2: Some Abbreviations Used Herein
Addendum 3: References/Further Reading

Introduction

The 9th CROI did not have any stunning breakthroughs that will wow the world. But there appeared to be a great number of small, incremental steps that collectively were intriguing and encouraging. Even the more dire data on antiretroviral (ARV) toxicities held, at least for this author, some hope that the incidence, while alarming, could be worse. And that it may be possible to manage these negative side effects. (ARV refers to the drugs used to treat HIV, like AZT, protease inhibitors, and so forth).

If you have web access, you can review abstracts and even some of the presentations at http://www.retroconference.org. Clearly, there is an enormous amount of information. I hope that this report will help to add to some areas that others may not have covered and another perspective to consider where there is overlap. Some of the excellent reporting being done is provided by AEGIS, AIDS Treatment News, GMHC's Treatment Issues, NATAP, and various listserves and newsgroups such as sci.med.aids, SAATHII, AIDS-India, critpath's AIDSact, and lipidlist among others. See the URL list at the end.

I'd like to thank IFARA Director, Fred Schaich for giving me the opportunity to interview a number of researchers for their Northwest US cable program. (IFARA stands for the International Foundation for Alternative Research on AIDS.) The interviews were quite illuminating for me and I found each of the individuals very forthcoming. These included Bill Powderly, Mark Hellerstein, Jon Kaiser, Bernard Hirschel and Kees Brinkman. Each also appeared to be open to novel therapeutic implications of some of their work, including the need for appropriate clinical evaluation of non-patentable interventions such as micronutrients and, possibly, some botanical interventions. This was a welcome surprise!

Basic Science/Pathogenesis

T cell turnover--Background

Recommendation: Check out some the articles for AIDS Community Research Initiative of America (ACRIA) found on the web at http://www.acria.org/treatment/treatment_edu_winterupdate2001_2002.html. There are several articles, notably some by Richard Jefferys, that are quite excellent reviews. Also, for those wanting a more technical discussion, there is an excellent review in Haase, Ann Rev Immunol. 1999;97:625. (Appendix 3 lists other references.)

First, it is important to clarify some terms. The cells that make up our organs and tissues are basically little bags of fat that are studded with molecules like CD4 that perform various functions. The widely-used term "T cells" refer specifically to a type of T cell that bears a marker called CD4. CD4+ T cells are the cells that often decline over time with HIV infection, greatly increasing the risk of developing a potentially lethal opportunistic infection as they drop below 200.

(Note: The "+" sign stands for "positive" and indicates, here, that the cell displays or expresses this molecule. Similar to someone being HIV+ (or "HIV-positive") meaning that there is HIV infection. If it does not express a protein, it may be written CD4- and then sometimes they can be stung together, so a cell could be CD4+CD8- meaning it only expresses CD4. A more refined analysis might show weak expression of one and stronger expression of another, denoted as bright. Thus, a cell could be CD4dimCD8bright.)

The other type of T cell carries a CD8 marker (CD8+ cells). Both types (or subsets) are called T cells because they're the immune system cells that get their "degree" by transiting through the thymus, a gland located in the mid-upper portion of the torso.

Like all cells, they start their journey as stem cells (or, if you like the magic phrase, hematopoietic progenitor cells). Generally arising in the bone marrow, the local soup of growth factors and cytokines that these cells are exposed to will influence the journey, telling them which way to go. Some stem cells will be guided through changes to become T cells and these will migrate to the thymus gland. As they make their passage through the thymus, they express both CD4 and CD8 (becoming CD4+CD8+ cells). Eventually, they are selected to become either CD4+ or CD8+ (the other receptor is downregulated) and they graduate as naïve cells. These cells are ready to wreak havoc on any new infection that might come along and cause the body problems. They leave the thymus and enter the peripheral circulation, or home in to lymphoid tissues such as is found in the spleen, gut (Peyer's patches of the Gut Associated Lymphoid Tissue or GALT) or in lymph nodes. In fact, the majority of the T cells in your body are located here; only a very few wind up cruising the blood highways, the veins and arteries.

These naïve T cells may then encounter an "antigen" presented by specialized cells such as B cells, macrophages ("big eaters") or a type of macrophage called the dendritic cell. Once the naïve cell is activated, it will become what is known as an effector cell. Many of these are shorter-lived and have a faster turnover rate. In the cases where the offending organism is dealt with effectively, some of these cells stick around to become longer-lived memory cells that turnover more slowly. These soldiers are on alert in case the enemy makes an unwelcome return.

Each soldier is a replica--or clone--of the original. And each clone is specific for one particular bit of a pathogen (or infecting agent). One type of cell called an antigen-presenting cell (APC) may prompt a T cell into activity by presenting a small piece of one protein from HIV to that T cell. Thus, you may develop a line of CD8+ HIV-specific T cells. One problem is that if that bit changes on HIV, the CD8+ cell will be running around looking to battle something that it can no longer see well.

Cells are identified further by using other receptors. For example, naïve cells may express CD45RA, CD62L. Memory cells, by contrast, would be missing one or both of these. Another way to look at cells is whether they are just hanging out (resting) or activated. Activated cells are identified as expressing CD38+, HLA-DR+ and sometimes CD25+, CD95+ or CD69+. Quiescent cells lack these (which you might see denoted CD38-DR-). Cells that are actively proliferating may be identified as Ki67+.

Next we jump into the pool. Just how many T cells are there in a body? According to Mike McCune, we don't really know. With some cell types, like red blood cells, we have a better idea. But T cells are more elusive, often hanging out in lymph tissues that are harder to access. Add to this that the numbers vary over time with age. And of course, the numbers will tend to increase during the response to an infection and subside afterward.

Frank Miedema (pronounced "mee'-de-ma") and his group, however, place a guestimate range of the total number. This is based in part on the ranges of the normal number of CD4+ cells found in adult blood (from around 600 to 1200) and CD8+ (500-800). That's in a small sample of blood (a volume of a microliter). In the whole body, they suggest a whopping average of 250,000,000,000 (250 billion or 2.5 x 1011). They also note an estimate of approximately 100,000,000 (100 million or 108) new T cells graduating and emigrating from the thymus per day or a fraction of 1% of the total (0.04%). In the Haase article noted above, they estimate that >109 naïve cells are produced in an infant, declining to an output of about 6-7 x 107 per day in adults.

Variables are used to describe the numbers of T cells found in the body. Their rate of turnover (p - "proliferation"), where they were coming from (s - "source") and where they were going to (d- "decay"). The steady rain of new cells that come into the system is the source of new, naïve T cells. Generally, these come from the thymus, but the spleen and bone marrow may produce some T cells, albeit at a lower rate. This is seen in mice and it is controversial whether it happens in humans; if it does, it contributes only a small amount to the pool.

Proliferation ("p") refers to cells dividing to make more of themselves in response to a stimulus (usually the presence of an antigen). The naïve or the memory cells are activated. These new cells aren't the ones coming from the thymus, but those that are produced when T cells divide and make copies of themselves (mitosis). Once they've done their job, a lot of the cells are programmed to commit suicide, a process known as apoptosis or programmed cell death. Such cell death is common, however evidence from disparate sources suggests it occurs at a significantly higher rate in HIV+ people.

The problem has partly been that when you look at the blood, you may get a false idea. For example, when people start antiretrovirals, there is often a substantial increase in T cells. Where did these come from? New cells being produced? Not at first. Cells dividing/proliferating? This is a logical speculation, but it turns out that a lot of the cells were still around--they had just been tied up doing their work in the lymphatic tissues. With the decline in viral load, they were free to circulate in the blood--this is called redistribution. This is the first phase of the recovery and is characterized also by a slow decrease in activated cells (fewer CD38+HLA-DR+ cells). A second, slower phase is characterized by a gradual increase in naïve T cells.

So like any pool, there's a certain amount to keep it full--the source (s) and proliferation (p). However, there are a couple of leaks in the pool. T cells have a life span and some die by apoptosis. Some live fast and loose, with a short life. Others may live for years. With HIV, obviously, CD4+ T cells are slowly being eroded away over the years of infection. This is represented by the letter "d" for decay. They use the word decay because it may mean d for destruction or it might mean that the cell simply is not picked up by the tools used to evaluate it (which means "decay" in that the label used to identify the cell is lost by one means or another).

In essence, this is where the "tap and drain" model comes into play. The tap being the "faucet" of the thymus producing new T cells. The drain is the loss of those cells by various mechanisms.

So What's the Controversy?

Essentially, it boils down to "what kills the T cells?"

But it may also be viewed as: what causes them to be hyperactive? That is:

1. Is it a consequence of homeostasis? That means, that the body is essentially producing more T cells to make up for losses, usually meaning from the thymus as opposed to new T cells coming from their proliferation. There is only so much room in the body. The ecology of their "biodiversity" must be kept in balance (or homeostasis).

2. Is this T cell hyperactivation a consequence of antigenic stimulation? In other words, is the presence of HIV and/or other infections causing the immune system to be overly revved up?

The answer is essentially, yes to both questions. Part of the issue is which contributes the most? The better this is understood, the more effective treatment strategies may be.

While the numbers of CD4+ T cells are declining, both when scientists look in the blood and in lymph tissues like lymph nodes, is it HIV that kills them directly? That is: HIV infects the cell, makes copies which then bud out and the cell ultimately expires. Clearly, the answer is partly yes. Some cells do die this way. Indeed, at the 2001 8th CROI, one study suggested that HIV kills cells directly by causing apoptosis through a pathway of damage to the mitochondria (#158). At this conference, the question was not addressed with the same fervor as in prior years, perhaps due to the more widespread recognition that it is not just HIV causing CD4+ cells to disappear over time.

And as Haase points out in his review article, most of the dying T cells are indeed uninfected "bystander" cells. He further points out that only 1 in 100 (written 1:100) to possibly as few as 1:400 cells carry HIV that is producing new virus (that is, they detect HIV RNA in the cell; the cells harbors a transcriptionally active genome). Other cells may have HIV-DNA, indicating they are infected, but don't show signs of producing new virus. It is estimated that about 5 x 106 cells, which may sound like a lot but is much less than the actively infected cells, have replication-competent virus but remain transcriptionally silent--that is, they're not making any HIV offspring.

Part of the current controversy arose as a result of older models that postulated that HIV was causing a massive turnover of CD4+ cells, resulting in waves of cells dying due to HIV. However, more recent studies have shown that the turnover rate in both CD4+ and CD8+ cells is considerably less than such a model might predict. Consensus appears to be developing that the overall turnover rate is only 2-3 times higher than uninfected controls rather than the predicted 6-10 times in previous days. So what drives the loss of CD4+ cells?

Methodology:

Different methods have been used to try to answer these questions. Part of the aim of these methods is to establish how T cells behave in the body. Most of the laboratory techniques brought to bear provide a snapshot of a person's T cells as they behaved in test tubes at the time blood was drawn. One method identifies actively dividing cells as measured by the expression of Ki67+ cells at different time points. Other blood tests can evaluate the numbers of naïve, memory/effector, activated and quiescent cells. Biopsies of tissues, often a lymph node, can give an analysis of what is going on in other compartments. Other tissues that have been investigated include vaginal washings, rectal mucosa, central nervous system fluid (from spinal taps) and other less frequently accessible tissues.

Some tests developed in the 1930s are being resurrected to evaluate how T cells live and die in people, using deuterated glucose or deuterated water. "Deuterated" means that an extra neutron (found in the nucleus of atoms) has been added, which makes the molecule into a "heavier" but stable isotope. This allows the molecule to be distinguished when it is taken up by cells. Deuterated water, for example, is known as D2O instead of H2O. The "D" (sometimes written 2H) reflects the additional neutron. These molecules can then be followed by an instrument known as a mass spectrometer.

It wasn't until the use of deuterated water or glucose (sugar) that researchers were able to directly evaluate what is going on with T cells in living humans. Deuterated glucose is somewhat limited in that it must be infused by IV and thus often is only used over a few days. While perhaps a little less specific, the deuterated water is taken orally and can be followed over a period of weeks. Other researchers used a chemical that has some potentially serious risks, bromodeoxyuridine (BrdU), to look at T cell turnover rates in 17 very brave individuals, giving infusions at different time points.

The Latest from the 9th CROI:

Mike McCune's group (#S12) examined differences in naïve, memory and effector (m/e) cells, their rate of turnover (p - "proliferation") and tried to establish where they were coming from (s - "source") and where they were going to (d- "decay"). They raised the question, why isn't the body replacing lost T cells? What they suggest is that HIV causes the immune system to respond in varying degrees in people. The more activated the cells are, the more HIV likes it. Part of the issue may revolve around whether cells are activated or not. Various markers on cells help to identify whether a cell is in a "resting" state or activated (see above). Several studies suggested that higher numbers of activated CD8 cells are more strongly associated with a more rapid rate of CD4 decline (see, e.g., #487).

Not everybody is alike: some folks have a higher level of activation (i.e., more CD38+DR+ cells), and this tends to correspond with how fast their disease is progressing. And this causes a pool of rapidly dividing effector cells to be persistently generated--and almost as quickly lost. Using ARV causes this rapid proliferation and loss of cells to diminish--there is less virus around, there is less need for an immune response. Essentially, there team interprets the data they've developed to suggest that overall, a lot of the loss of T cells derives from the exhaustion of the immune system. But people are different…

T cells are derived from stem cells that make there way to the thymus. As people age, however, the thymus involutes, or loses a certain amount of capacity to produce fresh new T cells. Are more T cells produced? Most of the data suggest that this is not happening (that is, that production of cells is not impaired).

But McCune et al., partially disagree with this. Indeed, they showed data indicating a greater thymic output among men with HIV than HIV-negative counterparts. This held true to a certain extent even after age 40, although with age, thymic weight and T cell production rapidly diminishes. But there are some individuals with more abundant thymus, and these individuals do appear to produce more new T cells. This is a logical finding, and correlates with findings in many studies that show that the older a person is when infected, the faster progression often is. By contrast, HIVnegative individuals had virtually no T cell production by the time they hit 40 years of age.

Using infusions of deuterated glucose over 7 days, Perelson's studies (#S9; see also #509) of uninfected versus HIV+ turnover rates found that there is a higher rate of activation of CD8 cells which declines with ARV. This was a study in 7 people with HIV who had not yet started ARV (treatment naïve), compared to 4 uninfected "controls." By contrast, there is only a trend in higher activation in CD4 cells that declines with ARV but a higher turnover (more cells are dying in the CD4 group, but not in the CD8+ group). They suggest that added T cell numbers from new production does not figure prominently in the equation. Destruction of cells is why they disappear, not because of a decrease in production.

Now a lot of this controversy is mired in mathematical models which may be limited in their relevance to humans. Some of the variables are not well defined. As noted above, d refers to decay of cells, but could reflect either cell death or simply a decay rate of the marker (e.g., BrdU). Observations are often conflicting. Another important variable in these equations is k, which is the fractional replacement rate of new T cells. But all of these equations may rely on variables that are only incompletely understood and/or may vary significantly between people of different ages. Let alone what these models may be crucially missing (e.g., the "resting" but infected cells that did in the overly enthusiastic model that predicted "eradication" a few years ago).

Kovacs et al. (#S10) aver that the most probable cause of T cell loss is from immune activation, inflammatory responses, with a relatively minor contribution from cytopathic effects. They have proposed, according to a mathematical model and derived from their observations in BrdU-labeling studies, that the decay rate doesn't change, but that HIV infection drives an increase in the numbers of faster turning over cells in both the CD4 and CD8 compartments. This subpopulation of rapidly proliferating cells diminishes with commencement of effective ARV that drives down viral load. But it doesn't affect the pool of more slowly turning over cells. They also feel that HIV does not adversely affect T cell production, per se.

This sounds a bit counterintuitive. The model describes events that seem to imply a larger pool of cells before ARV and a smaller one after. Doesn't this suggest that BOTH CD4 and CD8 counts should drop once people start ARV?

Sometimes this does happen--higher CD8 counts may drop. But CD4 counts rise! Well, we know that part of that increase is due to redistribution. Partly, their model suggest activation-induced proliferation that drives numbers of cells up overall, but only briefly as these cells quickly die. ARV driving down the HIV may allow some of those cells that were in the rapidly proliferating pool to survive--but not continue to actively proliferate. Bear in mind that these evaluations occur over a period of a few weeks, while the loss of CD4 cells over time is gradual. Another limitation: this was only 17 patients, of which only 6 were followed for 2-6 months after starting ARV.

As an aside, the researchers noted that their results paralleled the data produced by studies of Ki67+ cells. This suggests to this author that the use of a safer technology such as Ki67+ analysis obviates the need for further experimentation with the potentially carcinogenic BrdU infusions.

In a press release put out by the NIH, researchers claimed that some experiments had "put the controversy to rest" and that we now know the mechanisms of T cell death. Fauci, Perelson and Ho claim that the primary cause is an increased rate of CD4 cell death, caused principally by HIV cytopathicity (HIV directly kills the cells). But at the 9th CROI, Frank Miedema, underscoring that the controversy persists, turned to Dr. Ho and noted, "David, not in your wildest dreams, I would say."

Telomeres are the tips of DNA, a bit of which is clipped each time a cell divides. A cell can divide only so many times before the telomeres are used up and that's it for that cell. One would expect that repeated rounds of telomere shortening would result in a loss of a subset of cells, particularly if the models that show a high turnover rate are accurate.

However, telomere shortening, according to Miedema (#S11), happens in CD8s, not CD4s. That means there is a higher turnover rate among CD8+ cells. This exhausts the system. But, while one sees telomere shortening in the CD8 population, it is NOT seen among CD4 cells; so something else must be happening. In agreement with the Kovacs group, this suggests a higher rate of turnover among CD8 cells than in CD4 cells. Yet, there are data that Ki67+ higher than HIV negative in all subsets, naïve, memory, CD4 and CD8. Which suggests that indeed, there is an overall higher number of proliferating cells in all of these subpopulations.

Is this driven by mechanisms endeavoring to maintain homeostasis (where the thymic output of T cells increases) or immune activation? In Miedema's group, looking at the numbers of TRECs (excision circles of DNA suggestive of newly minted T cells arriving from the thymus), they don't see signs that there is an increased homeostatic responsiveness. They feel the preponderance of T cell loss is driven by immune activation.

Yet what they also found was that with lower CD4 counts, there was a higher proportion of naïve cells. This would suggest a homeostatic model--but this increase in naïve numbers may be a misleading signal. With ARV, the VL is reduced, but also the number of rapidly dividing cells is dropping. This argues against homeostatic response and is seen in both CD4 and CD8 subsets.

It appears from these data that effector T cells are the ones that are being eliminated. Memory cells, in any event, are preferentially productively infected. Naïve cells usually aren't, although Miedema's group identified a subset of X4-SI HI viruses that are found in delta-32 but infected individuals that preferentially replicate, albeit more modestly, in these naïve T cells. Again, it may be that the rapidly proliferating pool is made up of effector cells, possibly being driven to extinction too rapidly for detection. It is apparently not easy to distinguish between memory and effector cells in the lab, so they are often lumped together. Perhaps a subset of longer-lived CD4+ memory cells survive the first round of initial infection, lasting for years even, with minimal replication and thus conserving their telomeres. Or perhaps telomere shortening would be seen in HIV-specific CD4 T cells?

Hellerstein and his group also see a biphasic response and also feel that new production isn't really occurring to any great extent. Again, they saw a rapidly proliferating pool of cells and a slower proliferating group. Once ARV was commenced, the more rapidly dividing pool diminished. They look at the effector cells as the short-lived cells, the memory as longer-lived. Their experiments showed no particular effect is seen in naïve cells. They state that the primary defect is the inability of the body to produce long-lived memory cells and to keep such cells quiescent over time (#102).

The problem is that none of these results yet gives us a definitive understanding of why CD4 counts decline. The controversy--or some crucial aspects of it--do indeed persist.

But there are tantalizing clues that are suggesting that the direct effects of HIV may be more on suppressing bone marrow function (from whence derive the stem cells needed to make all the body's cells). Indeed, if one expands the scope of investigation beyond T cell population dynamics, there are lots of other data that show the role for other mechanisms. Oxidative stress, inflammation, damage to healthy cells and tissues all point to the need to consider interventions that may help slow progression and even help to not only attenuate the effects of antiretroviral toxicities, but actually enhance anti-HIV activity through calming excessive immune system activity while preserving T cell integrity.

Consider further what this means to immune responsiveness in adults. Lange et al. (#504-M) looked at how 29 HIV+ people (divided in 2 groups, one with a median CD4 of 40, the other with a median CD4 of 405) responded to various vaccines like tetanus, diphtheria and keyhole limpet hemocyanin compared to HIV-negative controls. Compared to controls, the HIV+ had diminished responsiveness. More profoundly immune suppressed people exhibited only a slightly worsened responsiveness than those with higher T cell counts.

As an interesting aside, the phenomenon of "immune restoration disease" may be instructive: people with T cell counts approaching zero begin to have massive T cell increases after they start ARV (especially among kids). Unfortunately, latent diseases that weren't getting much immune system attention may become a problem. Renewed immune activity may result in a flare up of symptoms. One physician at a dinner at the conference discussed the case of a boy who had developed a MAC infection at the age of 5 (around 1994). Some years later (around 1997), he started on ARV. What made this case particularly unusual was the development of symptoms three years after ARV (and an increase in T cells). These included night sweats, hepatosplenomegaly, increased protein in the urine. Eventually, they did biopsies of the liver and kidneys and discovered a lot of dead MAC bacteria that were apparently inducing a vigorous response. High-dose corticosteroid therapy helped the young man to recover.

And there's more to it than HIV infecting T cells. Commonly, monocytes are also infected. Other cell types that can be infected, with pathological consequences, include astrocytes, B-cells, a rather rare of CD4dimCD8bright cells (basically, a subset of activated CD8 cells that weakly express CD4; see #271). Indeed, at the Monday morning plenary session (#L2), researchers distinguished between two varieties of dendritic cells, myeloid-derived and plasmacytoid cells (PDC). Their experiments underscored that these cells, also found at sites where HIV infection might occur such as in the anal tract and vagina, were more readily infected by HIV. While these various cell types may not produce a lot of virus. But they do appear to be involved in screwing up the immune system's proper functioning in myriad ways.

Why is it Important to Understand This Controversy? Therapeutic Implications

One of the reasons is to understand what kills T cells. If there is more than one mechanism at work, we may have other options for intervening. One thought is to try intensification, using drugs like hydroxyurea or Prostratin (see below) to start to eliminate reservoirs in other cell types and in resting cells. This is being studied and complemented with IL-2 to bring the overall count up, including of naïve T cell subsets.

Kovacs et al., suggest that one of the mechanisms that is a more likely explanation is cytokine-mediated (e.g., TNF) and inflammatory responses causing the depletion in T cells. Hellerstein's group concurs with this.

The therapeutic implication thus might be means to interfere with this excessive response on the part of the body. For example, the use of carnitine to help normalize excessive levels of TNF as shown by DeSimone et al. some years ago. Selenium may also help to reduce excessive TNF. The use of antioxidants that restore glutathione (such as alpha lipoic acid and NAC) may also be useful to address the effects of oxidative stress. Only future clinical studies of such non-patented interventions will be able to tell us.

This may also have an effect on vaccine design. Stimulating the wrong type of immunity or overstimulating certain subsets may possibly hasten disease progression. This remains theoretical.

Treatment - Nutrition

The CROI is not exactly known as the "complementary medicine" conference…not even close. But there were two abstracts that actually looked at vitamins. A comment is in order before discussing them. Given that the treatment of lactic acidosis and certain heritable mitochondrial diseases is B vitamins (notably riboflavin and thiamine), carnitine and coenzyme Q10; given that nucleoside analog-related neuropathy may be amenable to treatment by acetylcarnitine; given the copious data showing the influence of nutritional status on HIV disease, it is perhaps a criminally stupid oversight that more research into this area is not provided. If this conference was just about pathogenesis and not treatment, leaving out such information might be acceptable. But given that drugs to treat HIV are central to many symposia, posters and plenaries, it is absurd not to include research that addresses means to attenuate their toxicities. Not to mention that the use of many such interventions is predicted by the various data on the pathogenesis of HIV disease and how it leads to AIDS (e.g., issues relating to oxidative stress, inflammatory responses, elevated inflammatory cytokines, activation-induced cell death (AICD) and so forth). This is merely a reflection of the bigoted "culture" of some "scientists" who are simply failing to be objective--or remain steadfastly ignorant to the data that do exist on the wide range of non-patented interventions.

On to the studies!

In #283, immunological activity was assessed among 70 acutely ill, hospitalized children in Malawi. 30% were severely vitamin A deficient; 34% moderately deficient and 36% had normal levels. The authors suggest that low vitamin A status may in some ways be immunologically "protective." That is, some of the kids with a severely depleted level of vitamin A also had lower levels of certain inflammatory cytokines such as IL-10 and higher levels of natural killer cells. Of course, this is somewhat relative, as the study notes, since these 70 children in Malawi were all acutely ill. To a certain extent, this conforms with data showing little benefit of supplemental vitamin A in terms of reducing mother-to-child transmission and in some other parameters. However, the notion that a significant number of nutrient-depleted children should remain with a severely impaired vitamin A status seems a bit ludicrous. And by contrast, studies using a multivitamin, which probably would make more sense rather than overdosing on a single nutrient, suggest a variety of benefits from slowed progression, to reduced numbers of pre-term children and so forth. This is a relatively inexpensive intervention. Unfortunately, the BBC reported in March that the people of Malawi are suffering from a serious epidemic of starvation. Clearly, food and clean water are the priority in many places. Still, the data are intriguing and bear following up.

The second study (#703) was a small, open label study involving 16 people. The study was based on the finding that there appears to be a relationship between elevated cholesterol and central adiposity (the big belly). So the group tried niacin, long known as a treatment for elevated cholesterol, at a median dosage of 3,000 mg/day. (This is a dose you definitely want to talk to your physician about before just doing it; can have some nasty side effects.) After six months of treatment, 81% of the participants saw a decrease in the central adiposity, and the average amount of the decrease was approximately 27%. This is an encouraging sign and suggests the need for more studies.

Treatment - New Drugs

Several new drugs to treat HIV are further along in their clinical evaluation. Some hold great promise. Others will at least provide some options or may have advantages such as once-per-day dosing. Nearly all claim to be less toxic, although it's a bit early in the game to believe these claims in their entirety.

Please click on this sentence for a table of antiretroviral drugs, which will be updated periodically. This report utilizes the generic name, even though the brand name may be more easily recognized among users in the US and Europe. The exception is the use of the shortened chemical name for some of the nucleoside analogs (a/k/a "nukes;" such as referring to AZT instead of zidovudine or the brand name, Retrovir). This is because the generic or chemical name is the one that counts--and may be of more relevance to international readers. Drugs in italics have not yet been approved by the FDA.

New Nukes (NRTIs)

Tenofovir (Viread) is a variant on a nucleoside analog reverse trancriptase inhibitor (NRTI) theme but this one is a nucleotide analog. This is a somewhat more active form and basically skips a couple steps the body has to do to get nukes to be active. It was recently approved by the FDA. Tenofovir in some ways is the "sister of 3TC" with a similar activity (not very strong) and toxicity (fairly mild). Tenofovir resulted in a 0.57 log drop at 48 weeks when used against a "stable background" of antiretroviral therapy (#413). This is barely beyond the range of PCR test variability, but probably will be more effective in combination. It appears to be active against viruses that are resistant to 3TC. There were several abstracts that also discussed a variety of issues, including the potential for the drug to cause mitochondrial toxicity (similar to 3TC; #708) and some 48-week data (#413-416). There may be some liver problems, so monitor closely! (Indeed, in March 2002, the FDA slapped the manufacturers for their egregious overselling of the drug.) So while not spectacular, it does appear to be a needed addition to the array of drugs to mix and match, especially given that it is a once-daily formulation.

DAPD (amdoxovir) was evaluated in vitro in #393 for its efficacy against strains resistant to other NRTIs. They looked at it also in combination with T20. DAPD worked modestly well against some resistant strains and seemed to have good activity when combined with T20. #464 noted that the drug, when it converts to the DXG form, works well against AZT and 3TC resistant viruses. Unfortunately, that was the extent of the data on this not-so-new drug. Earlier data from a short (2-week) dose-ranging study had shown that it can cause severe elevations in creatine phosphokinase (CPK), indicating damage to muscles (grade 4). Other negative effects included some increases in triglycerides and blood glucose, amylase as well as some nausea, vomiting, loss of appetite, stomach-intestine (abdominal) pain, headache, congestion, and wheezing; however, these were not in excess of grade 2, meaning they were relatively mild.

New Non-Nukes (NNRTIs)

TMC125 appears at first blush to have substantial antiviral activity--at least over a week (see #s 4 and 5). In 16 heavily pre-treated individuals, there was a 0.9 log drop after seven days, despite having previously failed nevirapine or efavirenz. This was essentially a monotherapy study since they retained the nukes they'd been using prior to the development of resistance to the NNRTI and they simply switched to TMC125 (an arguably unethical means of studying these drugs). In a monotherapy study in 15 ART-naïve for a week (900 mg bid), a 1.9 log drop and a 199 CD4 T-cell count increase was seen. Whether such responses are sustained is not yet known. However, their comparison with a 5-drug regimen (#5) was somewhat confusing. They apparently compared data from a different study, in a different population and ran the data through a computer program. This hardly seems to be valid and actually appears to reduce the credibility of these initially intriguing results. Despite these serious concerns over both the design (monotherapy, which risks for the patients involved, the development of resistance at least to this drug and possibly to the class of drugs) and peculiar and inappropriate interpretations, this appears to be a promising agent. Longer studies will tell what the toxicities, resistance patterns and antiviral benefits are in a more "real-world" context--at least in the world where access to such medications exists.

The dryly named 086 is "son of Sustiva" (efavirenz). At the ATAC conference with Bristol Myers Squibb, they tried to make it sound like the neurological side effects will be less, the data they presented suggested it was quite similar, which is not too surprising given the somewhat similar chemical structure. It may have some benefit against resistant strains. Data at the ATAC (see http://www.atac-usa.org/BMS.html) conference seemed to suggest that the optimal dosing is 50 mg/day, although the company seems to be pushing for 100 mg/day. The efficacy seemed to be about the same, according to the data they presented, and the toxicities less. Time will tell.

New Protease Inhibitors

Atazanavir (TAZ) is a new, once daily protease inhibitor; on the plus side, it does not appear to interfere with GLUT4 (which suggests it will not cause insulin resistance; or if it does, by a different mechanism). A big advantage is that it is a once/day dose (400 mg). Study #42 also showed that, used with saquinavir, there was no effect on fasting LDL or triglycerides after 48 weeks compared to the substantial increases in people using saquinavir/ritonavir. Still, this may not be long enough. Effects on viral load and CD4 count were similar (although the rit/saq arm saw a 149 T-cell increase over the 109 seen with TAZ). There are other side effects, including jaundice and hyperbilirubinemia.

Tipranavir (TPV) is taken with a small dose of ritonavir to boost its plasma level. (I can't help but think there must be better/safer/less costly ways to accomplish this. Grapefruit extract maybe? Milk thistle?) As with other PIs, the adverse events were mostly GI related--diarrhea, nausea. See #434.

Data at the CROI suggest that it may still work when a person's HIV is resistant to other protease inhibitors. However, the more drugs in the class one may have resistance to reduces the antiviral activity. In other words, people that were resistant to only one PI saw an average of 2.43 log drop in viral load after 80 weeks. But people with more mutations (greater than 5) had reductions of only 1.32 to 1.5, which, while not as strong, is still helpful for those whose options have been restricted by the development of resistance (see #560). This was a fairly small study, but the drug clearly represents another option. As with other drugs in this class, though, resistance can develop to tipranavir as well. To what extent this affects clinical benefit is not clear. We can hope that the more varieties of drugs that HIV must evade will weaken it so that even though the viral load isn't suppressed fully in rescue therapy, the immune system will be able to control it a bit better and/or it may cause less mayhem.

Entry inhibitors: Some go after the receptors.

In order for HIV to infect a cell, it has to attach to it. It has long been known that one of the proteins that stud its outer coat, gp120, likes to link up with the CD4 receptor. In the past few years, it was discovered that this protein opens up like some ghastly flower, allowing another HIV protein, gp41, to penetrate the infecting cell's membrane. It does this in part by grabbing hold of another receptor that is sometimes found nearby the CD4.

The second receptor (or "co-receptor") can come in different forms. Research at the moment suggests that receptors known as CCR5 or CXCR4 are the ones HIV most commonly uses. So the thought, therapeutically, was how to block that interaction and prevent the cell from being infected?

There are, broadly speaking, two ways to skin this pharmaceutical representative. One is to make a molecule to attach to the receptor itself. But because they are different, this will have to be done one receptor at a time. The first targets are CCR5 and CXCR4, respectively abbreviated to R5 and X4. (Other receptors that HIV may use to infect cells include Bob, BONZO, DC-SIGN and galactosyl ceramide--there are undoubtedly others.)

These receptors are used by the body to interact with other chemicals known as chemokines. Some of the chemokines include MIP-1alpha, MIP-1beta and RANTES. Some people actually are born without a functional CCR5 receptor, leading some hopeful researchers to postulate that its function in humans is of minimal value. This is ONLY theoretical. People with this variation actually carry the gene to express R5, but it is missing 32 amino acids, and thus they are sometimes referred to as delta-32 ("delta" being the Greek letter "d" and standing for deleted). (There are other polymorphisms, or variations on the genetic theme, but this is the primary one.)

The other implication of these so-called delta-32 homozygous recessive people (all of which means they don't display CCR5 receptor) is that they may not be as infected as easily. However, while it confers some protection, it is by far complete. Several individuals who have been identified without CCR5 have been infected by the X4-using HIV. These individuals see a much faster decline in T cells. Whether they progress more rapidly to AIDS has yet to be determined although some early evidence suggests that they may not. [Note: This I frankly don't understand; I can only presume they mean that after infection, CD4 count plummets steeply, but levels off before it drops below 200; thereafter, the time to AIDS is no longer. I have not seen data to confirm or refute this notion.]

One drug in this class is AMD3100, which failed to show any antiviral benefit and the study was stopped (see #391). We did learn something (aside from the fact that this drug doesn't work). One of the big advantages, it was thought, to this class of drugs was that HIV would not be able to develop resistance. That is, receptors that these drugs target won't mutate. Unfortunately, for this drug and others here, the big problem is that HIV does find a way around this class of drugs too (for AMD3100, resistance data are found in abstract 395).

SCH-C and SCH-D were also discussed. Resistance data are found in abstracts 396, 397 and 398, underscoring that one central hope for this approach has been dashed, at least for these drugs. The very first abstract (#1) dealt with SCH-C and showed that a 10 day dose of 25 mg every 12 hours resulted in some modest antiviral activity of a little over a half a log, with 4 of 12 people seeing a greater than one log drop. Viral loads were measured for an additional 6 days after treatment was stopped and rebound of virus was fairly rapid. A potentially serious problem was the prolongation of Q-T time, which may indicate a serious heart toxicity. The only abstract on SCH-D was 396, and merely showed that in the test tube, HIV can eventually evade the drug's effects after repeated passages.

TAK779 was not reported on at the conference, except for the in vitro data from session 19, where they found antiviral synergy when this drug or AMD3100 was used with T20 or T1249.

Entry inhibitors: Others go after HIV.

The other, arguably more successful, approach is to attack the HIV gp120 or gp41 where it binds to the co-receptor. This may be somewhat problematic because it may mean that the chemical will have to interact only after the unfolding of the gp120. That unfolding usually appears to happen just as HIV is on approach to a T-cell landing, readying for receptor docking. Encouragingly, some little pockets have been observed in these various conformations that may be exposed and thus can be filled by a novel chemical designed to fit in it--and make it hard for the HIV protein to do its job.

This is the idea behind both T-20 and T1249 which target HIV's gp41. T1249, the next generation after T20, was discussed in #82. Here they note that there are certain helical regions on gp41 to which both drugs bind. These regions are known as HR1 and HR2. The drugs are mimics (sequentially homologous) to HR2 and thus bind to HR1. The problem that this abstract reflects is that resistance may develop and they are trying to understand specifically how. Another effort was described in #392, where there was a suggestion that novel mechanisms that render HIV gp41 less sensitive to either drug were naturally occurring. These mechanisms have yet to be clearly defined. Another test tube study suggested that the drugs might have synergistic activity when used with DAPD (#393). Other formulations were studied in #417, including carbonate (CO3) and "TRIS" versions. The TRIS version caused significantly more adverse events and did not appear to be very effective. By contrast, the carbonate form appeared to be fairly effective after 48 weeks of study in an intent-to-treat analysis, although there were not many patients. A lower dose may be as effective. Side effects included diarrhea, nausea, lymphadenopathy, and nasopharyngitis. The study discussed in abstract #418 looked at various dosages of T20. All doses tended to improve outcomes when added to a regimen of ARV; 75 mg bid (twice a day) looked to be the best with an overall greater T cell increase than the 50 mg or 100 mg arms. It was not clear if this was a statistically significant difference.

The Progenics drug PRO542 targets gp120. From a recent press release: "In clinical studies, PRO 542 was well tolerated and produced statistically significant (p=0.007) acute reductions in viral load across all seven patients who received a single 25 mg/kg intravenous infusion of the drug. These findings extend previous studies of four intravenous doses ranging to 10 mg/kg. In addition, an analysis of data from 22 adults treated with single-dose PRO 542 in a Phase I/II study identified a subgroup of patients who were the most highly responsive to therapy. These patients were failing conventional therapies and had evidence of advanced disease as measured by low numbers of CD4 T cells (<200 cells/mm3) and/or high viral loads (>100,000 copies/mL) before treatment with PRO 542. CD4 T cells are key components of the immune system and the major targets of HIV infection. The viral load reductions in these patients ranged from 0.4 to 0.8 log(10) copies/mL, were dose-dependent, and were sustained for two to four weeks" (see http://ww2.aegis.org/news/pr/2002/PR020334.html). Thus, this may be a useful rescue therapy for those with diminishing options.

Prostratin is a drug derived from a plant found in the island nation of Samoa known as Homolanthus nutans. This drug is licensed to the AIDS Research Alliance of America (ARA), which plans to give 20% of any profits generated from the development of the drug to the Samoan government; other profits will be funneled into AIDS research. One of the characteristics that makes this a potentially interesting treatment is that, like hydroxyurea, it may help to flush out the virus hidden in resting cells. Some in vitro data presented in #406 showed that the drug had an effect on inducing expression of HIV in a line of monocytes, but without causing a generation of inflammatory cytokines. It also tended to downregulate the DC-SIGN receptor on immature dendritic cells; this activity may help to protect some of these cells from infection. As an aside, the main chemical is a phorbol ester, which is a chemical derivative of a family of chemicals found in croton oil (Croton tiglium). Croton is used as a "drastic" purgative for constipation in Indian traditional medicine. One might anticipate, then, diarrhea as a possible side effect! However, Prostratin is not considered to be a carcinogen, unlike its cousins. In fact, to the contrary, lab studies suggest that it may inhibit some tumors. So it is early to make comparisons. Clinical studies are anticipated.

Treatment - Old Drugs/Toxicities

The bad news in #36 was that over 30 months, over one-fourth of the people had a very serious, grade IV toxicity. The NIH reviewed CPCRA trials that included a total of 3,050 patients and evaluated their outcomes between late 1996 to the end of 2001. After 30-months, the rates for various problems arising were 10% for death, 13.5% for progression to AIDS and 27% of grade IV events. Grade IV events are extremely serious and potentially lethal. There were 663 grade IV events, broken down as liver-related (6.1%), neutropenia (3.9%), pancreatitis (2.2%), anemia (2.1%), psychiatric (2.1%), heart-related (1.6%), cardiovascular (1.6%), kidney-related (1.5%), thrombocytopenia (loss of platelets) (1.2%) and hemorrhage (0.9%). An event like this developing was associated with a risk 6-times higher of dying, which was similar to the risk of dying if one progressed to AIDS. The most deadly events included cardiovascular events (9x higher risk of death), kidney disease (6x higher) and liver disease associated (4-fold greater risk). People co-infected with hepatitis B or C had 4 times greater risk of liver problems compared to those who had only HIV.

For women using ARV, #722 reviewed the records of 825 participants in the HERS cohort (a group in the HIV Epidemiology Research Study). They found that having under 200 T cells resulted in a not surprisingly greater risk of hospitalization due to side effects. Other significant problems for women include kidney trouble and hypertension (high blood pressure). This suggests that it is important to keep a sharp eye on serum creatinine, urinary protein levels and blood pressure. (It may also suggest some routine consumption of delicious cranberry juice!)

Mitochondrial toxicity still figures prominently as a potential problem. In the SWATCH study that looked at different regimens among treatment naïve patients, they found that people using AZT+3TC+nelfinavir had half as many mitochondria after 48 weeks of treatment. Even more profound depletion was seen (to 18% of pre-treatment levels) in those taking ddI+d4T+efavirenz. Would a combination of a potent multi, B complex, CoQ10 (150-200 mg) and carnitine (1-3 grams) have prevented or attenuated this loss of the cell's powerhouses?

Another study of women over 40 indicated that protease inhibitor use was associated with declines in bone mineral density (#717). As noted in #718, various tests may help to identify such problems besides scanning technologies like DEXA. These include osteocalcin, urine pyridinolines, deoxypyridinolines, and bone-specific alkaline phosphatase. Others (#715) noted that osteocalcin was significantly lower in HIV+ treated patients versus untreated but that overall, the incidence of osteopenia (bone loss) or osteoporosis was higher than in HIV-negative individuals, underscoring a potential role for HIV in the loss of bone mineral density. Protease inhibitors may be acting as an accelerant to an underlying problem. This was also seen in #712.

A clue to how this might come about was presented in #714. Elevations in a cytokine called TRANCE were noted in 9 of 12 HIV+ people. TRANCE is secreted in a T-cell-dependent way from cells called osteoclasts, bone cells most involved in resorption of tissue (and thus its maintenance). This was also correlated with increased levels of another cytokine, TNF, which they note some have seen to be increased in treated patients. TNF and TRANCE acted together synergistically to cause bone demineralization and osteoclastogenesis. This underscores further the potential for interventions such as carnitine and selenium that may have a benefit in normalizing excessive levels of TNF.

Antiretrovirals don't seem to cause other populations any greater or lesser harm. In #724, liver toxicities among 692 patients were evaluated. As found elsewhere, the risk was higher if individuals were coinfected with chronic hepatitis B or C infections. In addition, there was a higher risk of hepatotoxicity among those using the NNRTIs (and nevirapine is available as a generic in Thailand, so it is probably the most commonly used one--and the most hepatotoxic).

Preventing and managing these types of negative effects is crucial. This is one of the many reasons that FIAR was formed! Numerous interventions that may help are off-patent drugs or dietary supplements. Clinical studies are desperately needed. There are numerous possibilities to protect kidney, liver, heart and nerve structure and function. Please also see the Preventing and Managing Toxicities and HIV Symptoms from DAAIR (http://www.daair.org) and click on Countering Toxicities.

Structured Treatment Interruptions (STIs)

They may work--if done correctly. There were several studies reviewed and some serious caveats were raised. While evidence so far doesn't suggest that people's immune systems respond in any effective way to control HIV, there do appear to be many people who could benefit from an interruption in therapy. Maybe not to reintroduce HIV to the immune system's attention, but at the very least to help people to recover from the cumulative toxic effects of the therapy.

One large review of a European cohort (#48) in people who stopped therapy found that it was dangerous to do if you had a lower T cell count (below 200). This was just an observation of many people, not a structured series of interruptions. This seems fairly logical. Yet, the harshness of the regimens and their toxicities will undoubtedly drive people off the drugs. Indeed, for those with higher counts, little adverse effect was noted in terms of clinical events. This suggests people with higher T cell counts may consider carefully monitored structured treatment interruptions.

Perhaps what is needed are means, perhaps very low-dose, subcutaneous IL-2, to help bring people over a certain threshold (above 200 T cells at least) before they attempt to go off drugs. Such very low doses of IL-2 are not being investigated. Some interesting data were presented suggesting that intermittent use of IL-2 may extend the "half-life" of T-cells quite significantly (#103, 104, 514), but these were at the higher, debilitating 5-day cycles of infusion.

Possible criteria for a successful STI include having a CD4 count greater than 200 and an undetectable viral load at the time of cessation and then close monitoring. If the count falls below say 150-200, re-start therapy. There are some immunological problems that could pose a challenge to some people. We've all known people who develop certain OIs even with a higher T cell count; there may be a reason for this. If your lowest-ever (or nadir) T cell count dropped below 50 at some point, there is a chance that some of the repertoire of T cells may be diminished. Thus, the old memory cells that looked out for an opportunistic infection like Pneumocystis carinii (PCP) may not be there or as effective. Such cases are rare and ARV does not seem to prevent them in any event. If you do have a reasonably high CD4 count and want to stop treatment, discuss the idea with your physician. Then monitor your bloodwork FREQUENTLY and assess the rate of CD4 decline. Pick a number you feel comfortable with (200?) for going back on treatment. If you T cell count is lower, but you are undetectable with viral load, see about trying a very low dose of IL-2 daily to bring the count up to a safer range. This is an experimental treatment, however, and you may find it difficult to get hold of.

HIV/AIDS in the Developing World

While the CROI may be a bit dismal at evaluating non-patented interventions, they have improved enormously with addressing the myriad challenges facing the developing world. The symposium entitled The Promise and Challenge of Antiretroviral Therapy in Developing Countries, highlighted the drastic change in attitudes and interest among US clinicians and researchers on the need for ARV access worldwide. The session was well-attended, and discussions of challenges to treatment implementation were made in the spirit of addressing these persistent problems rather than as excuses to continue to deny access to treatment. The presentations were excellent. Please feel free to view them at the CROI website (http://www.retroconference.org).

The Realities of Antiretroviral Therapy in Uganda was presented by Elly Katabira of Makerere Univ., Kampala, Uganda. I unfortunately missed this presentation.

Prevention of Mother-to-Child Transmission: Implementation, Programs, and Treatment of Mothers and Children was provided by Catherine Wilfert of Duke Univ. Med. Ctr. and Elizabeth Glaser Pediatric AIDS Fndn., Chapel Hill, NC. She delineated a number of different programs that they are involved with in 11 nations, including Thailand, South Africa, Dem. Rep. of the Congo, Zambia, Zimbabwe, Kenya, Malawi, Rwanda, and Tanzania. Perhaps the most important thing she said was that they were dedicated to implementing programs and ideas that the local community wished. Too often, aid is predicated on fulfilling the needs of the giver and not the community. Primarily, their efforts focus on voluntary testing, counseling, prevention of mother-to-child transmission and helping to identify populations in need of treatment. These are the stepping stones that are important to assure adequate access to care and the appropriate infrastructure.

Laboratory Monitoring of Antiretroviral Therapy in Developing Countries was presented by John Nkengasong, CDC Projet Retro-CI, Abidjan, Cote D'Ivoire. This session (#27) delineated some of the lower cost technologies for monitoring CD4 count and viral load. For example, dissociated p24 antigen may be a much less expensive means of determining viral load. While p24 testing has been available for some time, its relevance to disease progression was limited, partly because the protein would often become bound to antibody and subsequently be missed from detection. Boiling the plasma allows the p24 to dissociate from the antibody and Dr. Nkengasong noted that studies showed a good parallel with PCR results overall. Similarly, technologies like Dynabead may be employed at far less expense to evaluate CD4 counts.

Potential Antiretroviral Drug Resistance in Developing Countries: The Thailand Experience by Praphan Phanuphak of HIV-NAT, Thai Red Cross AIDS Res. Ctr. and Chulalongkorn Univ., Bangkok, Thailand. Some data were provided which appeared to suggest the transmission of drug-resistant strains. This is in populations who have not yet had any ARV treatment. He candidly discussed the need for access to generically-priced medication, and indicated that the health care system in Thailand was about to include HIV/AIDS in its 40 baht program (equivalent to about $1). In March, 2002, this was instituted, providing the lowest yet annual cost for AIDS treatment. However, a greater variety of drugs will be needed to address the enormous need in Thailand as well as even poorer nations in the region.

Addendum 1: Some Links

A few places to go for some of the more comprehensive reports on the Conference include:

AIDS Treatment News:
http://www.aidsnews.org, 1800-TREAT-12
GMHC Treatment Issues:
http://www.gmhc.org
For an excellent and extensive report, NATAP:
www.natap.org, 888-26-NATAP; http://www.natap.org/2002/9retro/ndx9retro.htm
AIDS Treatment Data Network: http://www.atdn.net,
On the web for the best database on the planet for AIDS: AEGIS:
http://www.aegis.org/

Addendum 2: Some Abbreviations Used Herein

3TC - lamivudine/Epivir - another nuke (see AZT)
AIDS - the Acquired Immune Deficiency Syndrome
ARV - Antiretroviral Therapy - the drugs used to treat HIV/AIDS.
AZT - azidothymidine/zidovudine/Retrovir - the first drug approved to treat HIV disease; a "nuke"
BrdU - bromodeoxyuridine, a drug used to label cells
CD4 - a marker on T cells that helps to identify them
CDC - Centers for Disease Control and Prevention
CMV - cytomegalovirus - a herpes virus that can cause gut or eye disease
CPCRA - Community Program for Clinical Research on AIDS
CROI - Conference on Retroviruses and Opportunistic Infections
d4T - stavudine/Zerit - another nuke
ddC - zalcitabine/Hivid - another nuke
ddI - didanosine/Videx - another nuke
DEXA - dual X-ray absorptiometry, a scanning technology used to evaluate bones and fat
FDA - Food and Drug Administration (referring to the one in the United States)
GALT - Gut Associated Lymphoid Tissue
GMHC - Gay Men's Health Crisis, the oldest and largest HIV/AIDS service center in America
HIV - Human Immunodeficiency Virus - the bug that causes AIDS.
IL-2 - Interleukin 2 a "cytokine" produced by the body; also used to increase T cell counts
IV - intravenous; injecting a drug into the veins
NAC - N-acetylcysteine, an amino acid; amino acids are the building blocks of proteins.
NIH - National Institutes of Health
OI - opportunistic infection - the diseases that most often happen when T cells get very low
STI - structured treatment interruption
TNF - Tumor Necrosis Factor, a cytokine
TREC - T-cell Receptor Excision Circle - a small piece of DNA found in new T cells leaving the thymus
VL - viral load

Addendum 3: References/Further Reading

These references were consulted in addition to the abstracts, notes from the sessions and other information obtained from the 9th CROI.

Cohen Stuart, JWT, et al. The dominant source of CD4+ and CD8+ T-cell activation in HIV infection is antigenic stimulation. J AIDS, 2000;25:203-211.
Deeks, SG, et al. CD4+ T cell kinetics and activation in human immunodeficiency virus-infected patients who remain viremic despite long-term treatment with protease inhibitor-based therapy. J Inf Dis, 2002;185:315-323.
Fleury, S, et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. 9thCROI#344, expanded at
http://www.pubmedcentral.nih.gov/articlerener.fcgi?tool=pubmed&pubmedid=10805798.
Haase, AT. Population biology of HIV-1 infection: Viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Ann Rev Immunol. 1999;97:625.
Hazenberg, MD, et al. T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nature, 2000 Oct;1(4):285-289.
Jefferys, R. Immune restoration: Repairing the damage. ACRIA Update, Winter 2001/02;11(1).
Kovacs, JA, et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med. 2001 Dec 17;194(12):1731-1741.
McCune, JMM, et al. Factors influencing T-cell turnover in HIV-1-seropositive patients. J Clin Inv. 2000;105:R1-R8.
Michael NL, Moore JP. HIV-1 entry inhibitors: Evading the issue. Nature Medicine, 1999;5(7):740-742.

George M. Carter is the director of a new, not-for-profit organization that is dedicated to the clinical evaluation of dietary supplements used in HIV, hepatitis C and hepatitis B. index.html.

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