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STEP's Review of the 6th Conference on Retroviruses and Opportunistic Infections (CROI)

Light at the End of the Tunnel?

Winter, 1999

Overview

More than 3,500 people gathered in Chicago from January 31 through February 4, 1999, for the 6th Conference on Retroviruses and Opportunistic Infections (CROI). This conference began in 1994 as a small meeting for basic scientists studying the HIV virus and clinicians treating people with HIV. It is now one of the most important annual HIV gatherings, attracting virologists, immunologists, HIV community treatment activists, community press, and clinicians treating people with HIV.

The general media gave the greatest coverage to the presentation that convincingly demonstrated that HIV originated in monkeys and has been transferred to humans at least three times. However, the most clinically relevant and important presentations at the 6th CROI were those that hinted that HIV might be controlled with a combination of highly active antiretroviral therapy (HAART) and stimulation of the immune response to fight HIV. There is very real hope that someday, after suppression of viral replication and boosting of the immune system's response to HIV, patients will be able to stop HAART. Eradication might not be necessary-only containment of the virus, as occurs with herpes, cytomegalovirus (CMV), and several other viral infections.

Information about a number of intriguing issues was also presented at the 6th CROI:

  • Drug-resistant new HIV infections are becoming more common, and are now seen in 10 to 15 percent of all new infections.

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  • Many people on regimens containing two nucleoside reverse transcriptase inhibitors (NRTIs) and a PI find that when resistance occurs have resistance only to the NRTI and not the PI.

  • There appears to be a decreased risk of transmitting HIV while on HAART if HIV RNA numbers are low.

  • There is continued excellent data on the use of efavirenz as an alternative to a PI regimen with up to 48 weeks of followup.

  • Studies are showing impressive immune reconstitution, including new CD4 and CD8 cells capable of responding to new infections, even in people who begin HAART with very low numbers of CD4 cells.

  • There is good recovery of pathogen-specific immunity to pneumocystis pneumonia (PCP), cytomegalovirus (CMV), and mycobacterium avium complex (MAC) in most people on HAART. It appears safe to stop PCP preventatives on HAART after 3 to 6 months if the CD4 count stays above 200 and the viral load (HIV RNA) is low.

  • Lipodystrophy studies on men and women show these fat deposits to be a very significant problem for most people on PI therapy. The first few trials of switching to a non-PI drug to treat lipodystrophy were presented, as well as a few other novel approaches to treating lipodystrophy with other drugs.

  • New approaches to improving HIV-specific immunity and/or eradicating the residual population of HIV-infected cells after HAART include immune stimulants such as interleukin 2, and the isolation of HIV-specific immune cells (cytotoxic lymphocytes, or CD8 cells) expansion in the lab with re-infusion of many of these cells.


Stopping Your HAART?

Perhaps the most sobering statement of the entire conference was that of British physician Dr. Brian Gazzard, who said, "The patients who have done best are those who have lived long enough to realize that my previous advice was incorrect." (He was referring to a time prior to the availability of protease inhibitors, when he had recommended use of sequential NRTI monotherapy, followed by the addition of 3TC.)

Dr. John Mellors corroborated this when he that one of the basic assumptions about HAART therapy is now proven wrong; that all drugs need to be changed out at the time of treatment failure. New studies are showing that when people fail a combination of two NRTIs and a PI they often show no resistance to the PI at the time of failure.

[Note: Perspective editors wonder why the viral load can be increasing if the person is still taking a drug that should be preventing viral replication. Clearly, there is clinical failure, even if the resistance tests don't show resistance to the PI. So if the PI is not working, why continue it?]

There remain many unanswered questions about when to start therapy, what drugs to use, when to switch, and what drugs to switch to. Also, there still are very few options available for people with viral resistance to the current FDA-approved antiretroviral drugs. Metabolic complications of protease inhibitors are a major problem for the majority of people receiving them, and the role of resistance testing remains unclear.


Second-Generation Drugs Fight Resistant Virus

There are now 13 FDA-approved drugs to treat HIV and 2 more drugs-adefovir and amprenavir-are in expanded access. Amprenavir is a protease inhibitor (PI) that may have some activity against HIV strains that are resistant to the four currently available PIs. Clinical trials of the protease inhibitor ABT-378 are ongoing in untreated ("naïve") people, but the hope for ABT-378 is that it will control HIV replication in people who are resistant to the other PIs. No data is yet available on the use of ABT-378 in people who have failed a PI, although a clinical trial is under way.

Agouron presented very preliminary information on two new drugs, AG 1776, which is a second-generation PI, and AG 1549, which is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). These drugs are called second-generation because they appear to be active in vitro (in a test tube) against HIV that has become resistant to the current drugs in those classes. However, no data was presented on the pharmacologic properties of these drugs, for example, whether they are absorbed orally, how long they last in the system, and their potential toxicity. Before human trials can begin, much more animal research needs to be conducted on these two drugs. (Agouron did state that it expects to begin human trials of AG 1776 in 1999.)

DuPont presented pre-clinical data on two new NNRTI drugs that have good absorption and a long half-life in the body, DPC 961 and DPC 963, which may be effective against NNRTI-resistant viruses. However, the safety and effectiveness of these drugs has not been studied in human trials yet. Since most people who fail an NNRTI regimen will be resistant to the other 2 NNRTIs currently available, there is an urgent need for non-cross-resistant NNRTIs.


Trials & Errors: Studies look at which combinations are better

For many, the scare of fat redistribution that seems linked to PIs has people looking for good drug alternatives that don't include a PI. The most significant naïve therapy trial presented shows that a regimen that includes three NNRTIs work as well or better than the classic cocktails with a PI. The update on the trial conducted by DuPont, compared three treatment groups:

  • Efavirenz (Sustiva), zidovudine, and 3TC (one NNRTI and two NRTIs)

  • Efavirenz and indinavir (Crixivan) (one NNRTI and a PI)

  • Indinavir, zidovudine, and 3TC (two NRTIs and a PI)

After 48 weeks of follow-up, efavirenz plus the two NRTIs is at least as effective as the indinavir plus two NRTIs regimen. Based on an intent to treat analysis (including all patients who began on the trial) after 48 weeks, 71 percent of people receiving efavirenz/zidovudine/3TC had viral loads of less than 400 copies/ml, compared to only 48 percent for people assigned to indinavir/zidovudine/3TC.

When evaluated based on people actually on treatment, after 48 weeks, 98 percent of people on the efavirenz regimen had viral load levels below 400, compared to 86 percent for the indinavir-containing regimen. (There was a much higher dropout rate in the indinavir arm, compared to the efavirenz arm, explaining the very different results in the two analyses.)

After 48 weeks, viral load levels were below 50 in 71 percent of people assigned to the three-drug efavirenz arm, compared to only 47 percent for the three-drug indinavir arm. When viral loads were examined at 48 weeks, below 90 percent in the efavirenz arm were below 50 copies, compared to 80 percent with a below 50 viral load in the indinavir arm. There has been concern that an NNRTI regimen may not be as good as a PI-containing regimen, but the DuPont 006 trial shows that even in people with viral loads above 100,000, the NNRTI regimen performed as well, or better, than the PI-containing regimen.

The most common toxicity resulting from efavirenz was central nervous system complaints, noted in 55 percent of people. Those who were instructed about these problems before beginning therapy seemed to have less trouble. The most common complaints were vivid dreams, feeling confused, or even depressed. These symptoms were usually mild and resolved after 3 weeks in almost everyone.

CNA 3003. This study can be summed up by saying that the three drug combination in the study is better than the two drug combo, but still not good enough. The follow-up data presented by Margaret Fischl on this trial compared two drug combinations:

  • AZT and 3TC (two NRTIs)

  • AZT, 3TC, and abacavir (three NRTIs)

Abacavir is also called Ziagen, and is the most recently FDA-approved NRTI antiretroviral agent. The study was modified last year when it was observed that the triple-drug regimen was much better than the two-drug regimen. After 48 weeks of therapy with the triple NRTI combination, the number of people with viral loads less than 400 was 60 percent. However, in people who had viral load levels above 100,000 at the beginning of treatment, only 33 percent of people had a viral load less than 400 after 48 weeks. So, while this triple NRTI regimen may be effective in controlling HIV replication in people with low viral load levels, it is not potent enough to control HIV replication over the long term in people with higher viral loads. This combination had very low toxicity and has the advantage of saving two major classes of drugs -- the NNRTIs and the PIs -- for later use.

CNA 3005. Preliminary data was also presented by Schlomo Staszewski on a trial of two drug combinations in people with no prior therapy:

  • Abacavir, zidovudine, and 3TC

  • Indinavir, zidovudine, and 3TC

The follow-up is only 24 weeks. In both groups, 65 percent of people had achieved a viral load of less than 400, based on all people who began the trial. For people who were still on the therapy, the numbers increased to 85 percent. Longer follow-up from this trial will be available later this year.

Other Trials. There are several similar treatment strategy trials ongoing at the AIDS Clinical Trials Group (ACTG), and in the next year or so it is hoped there will be more long-term data comparing similar types of regimens as first-line selections.

However, it will still be difficult to know whether it is better to begin a regimen based on three NRTIs, or one that includes an NNRTI, a PI, or even two PIs in addition to two NRTIs. It may well be that one size does not fit all.

Also, the efficacy of the second-line regimen must be known, as you need to know which sequence of regimens provides the best control of HIV over the course of many years. It could be that A is better than B, as a first-line regimen, but the sequence B before A is better, overall, than A before B.


It's the Immune System, Stupid

Last year's conference was highlighted by Bruce Walker's presentation demonstrating that treatment with HAART very early after infection (within 90 days) resulted in the preservation of a strong immunologic response to HIV. The 6th CROI emphasized many researchers' growing realization: The key to controlling HIV infection is the immune system, not more and more antiretroviral drugs. In other words, it's the immune system, stupid! Franco Lori presented the most provocative and fascinating information of the week, reporting on attempts to use strategic intermittent interruptions in HAART ("drug holidays") to boost immune response to HIV. The goal is to improve response to HIV to a level sufficient to control HIV replication, so that antiretroviral therapy is no longer necessary. The basis for attempting this approach is the case of a person known as the "Berlin patient," who was treated shortly after HIV infection with ddI, d4T, and hydroxyurea (HU). Although the patient had stopped his therapy for a short period of time, and then eventually stopped all therapy after 6 months, there has been control of HIV for 21/2 years.

The following three factors, identified by Dr. Lori, may have been important in this patient achieving good virologic control after HAART:

  • The treatment was begun shortly after infection

  • The regimen contained HU

  • There was an interruption in HAART treatment

[Note: Perspective editors would add a fourth factor, that this patient had an excellent response to HAART, with very low HIV viral levels in the blood while on HAART.]

In order to study these factors further, Dr. Lori infected three monkeys with simian immunodeficiency virus, and then replicated the treatment regimen of the "Berlin patient," with the similar result that the monkeys were able to control their virologic infection when antiretroviral therapy was discontinued.

It is very important to emphasize that this was only one person, and treatment was started soon after HIV infection. Subsequently, Dr. Lori has treated three people with intentional interruptions in therapy, with treatment begun soon after HIV infection. While HIV became measurable in the blood, it took longer to come back after each break in therapy. The trial is still ongoing to see if eventually HAART can be stopped altogether.

Last year, Bruce Walker demonstrated that if HAART is begun within 3 months of HIV infection, a vigorous immune response to HIV can be preserved. He has attempted to stop therapy in people who were treated soon after HIV infection and who have had long-term suppression of HIV. However, this has resulted in the return of measurable HIV in the blood within a few weeks, and he has not attempted intermittent breaks in therapy, such as Dr. Lori is doing. It must be emphasized that most people who stop HAART have very rapid increases in HIV levels in the blood, whether therapy was begun soon after HIV infection or during the chronic infection stage. Also, there is a risk that intermittent therapy will lead to resistance, and permanent loss of control of viral replication. These are very preliminary reports demonstrating the increasing focus (finally) on augmenting the body's immune response to control HIV replication.

The rationale behind the research into intentional intermittent interruptions in HAART is based on the observations of Bruce Walker, and others, about long-term non-progressors (people infected with HIV for more than 10 years who retain normal immune system function on no therapy). Non-progressors show a strong immunologic response to HIV in both CD4 helper cell responses and CD8 cytotoxic lymphocyte (CTL) response, which may be the reason they can control HIV infection. Bruce Walker has shown that when people are treated soon after HIV infection, these immunologic responses to HIV are preserved, but in spite of that, when treatment is stopped, HIV usually begins to replicate and appear in the blood.

The idea is that short interruptions in treatment allow the immune system to be re-exposed to small amounts of HIV and mount an immunologic response, strengthening the ability of the body to eventually control HIV replication without HAART. This is essentially a type of auto-vaccination, and a rather novel approach to the treatment of any disease.

The argument for planned interruptions in the treatment of people who are treated during the chronic phase of HIV infection is even stronger, because specific immunologic responses to HIV are not observed even after 1 to 2 years of HAART in these people. Other approaches being investigated include the administration of interleukin-2, which is an indirect stimulant of CD4 activity, administration of OKT3, an antibody that can stimulate CD4 cells into dividing, and the administration of HIV vaccines such as Remune. The rationale underlying attempts to stimulate resting, latently HIV-infected, CD4 cells into dividing is as follows. These cells would then begin producing HIV, which would kill them, and with effective HAART, the HIV produced would be prevented from infecting other cells.


T-20: A new class of drugs

Trimeris Corp. has one of the more interesting new drugs to treat HIV, T-20, which interferes with the process of HIV binding to the CD4 (T-helper) cells. There are currently no other drugs that attack HIV at this point in its replication making this a whole new class of anti-HIV drugs called fusion inhibitors. In vitro studies showed that this drug had very potent effects on HIV. Now, a human study is showing similar good results.

HIV-positive people who had been heavily pre-treated received this drug twice a day by injection under the skin. Although the study reported very significant reductions in HIV levels in the blood, this benefit lasted only a week or so. This could mean that resistance developed rapidly, or more likely, that the body developed antibodies that eliminated this small protein. Future studies will have to be conducted to examine the drugs ability to suppress HIV over longer periods of time and its toxicity and long-term tolerability. Nonetheless, this is an exciting trial because it proves that compounds that interfere with the process of HIV binding to CD4 cells can result in significant reductions in HIV levels in people who have been treated with most every antiretroviral drug available.

As the first drug in this new class T-20 is something to keep your eye on. The biggest problem is the shots required to administer the drug. Researchers are working on a small pager-sized pump that would administer the drug slowly and constantly. If this drug continues to show promise it could be a much needed new option for those failing other drug classes.


Unsolved Mystery of Fat Redistribution

Over the last few years, people have been seeing strange unexplained side effects in PWAs that involve the unsightly and sometimes dangerous redistribution of fat. Recently at the 12th World AIDS Conference, for the first time, this phenomenon was really examined and taken seriously. Several of the leading researchers in the field of lipodistrophy spoke to a packed house about the serious and baffling problem of fat redistribution. There was not a lot of new or breakthrough information on the subject. But, there was clarification on the extent of these problems, what issues need to be addressed to better understand lipodystrophy, and what research needs to be conducted to fully understand this problem.

It was only a few years ago in 1997 that the first official report broke that something was happening to people with HIV/AIDS that involved lipids and insulin. The FDA reported on a small number of HIV-positive people that were developing diabetes and had high insulin levels. Then, came the news that people on PIs were experiencing heart attacks from abnormally high level of fat in the blood. Next, the news broke that physical changes were occurring in those on PI's. These changes included buffalo hump, large fat deposits on the back of the neck. Truncal obesity or abdominal girth (this was referred to as Crixa-belly or Protease Paunch) is also a problem. This is the increase of fatty deposits around the gut, and is often associated with feeling bloated and heartburn. Another problem seen in women is painful enlargement of the breasts. The loss of fat and tissue from the arms, legs, face and butt areas called lipodystrophy, or fat redistribution syndrome.

The cause of this fat redistribution is something that has stumped even the best researchers. PIs seem to be a part of the problem, but what they are doing to the body to cause this problem is unknown. However, some research indicates that PIs are not the culprit at all. One study looked at a group of pre-PI patients and found that lipodystrophy was seen in them in similar numbers to those we see today in people on PIs. Another study showed similar results when looking at incidence of buffalo hump in patients who were taking a PI and patients who were not taking a PI. Of the eight patients in the study, four people who developed buffalo hump were on a PI and the other four were not. However, most studies do show that the majority of people with this syndrome are receiving a PI containing therapy.

This symposium also examined just how wide spread these side effects are. The numbers of people reportedly experiencing these problems runs from 78% to 2%. Best guesses put the real number somewhere in the higher ranges, but more specific research needs to be done for more exact numbers. One problem is how health care providers and researchers measure these things. There is no standard tests or set criteria that doctors are using to measure and detect these problems. This is clearly another issue that needs addressed.

So, what can be done? Unfortunately, this conference provided little new information or research on how to treat these problems. The researchers did review some of the most common interventions that include:

  1. Growth Hormone.
  2. One study showed that people on growth hormone had significant decrease in body weight, decreased body fat by about 9%, and had lowered cholesterol and triglyceride levels.

  3. Troglitazone or Metformin shots.
  4. These are drugs that increase insulin sensitivity. People believe that lipodytrophy may be caused by insulin resistence in the periphial tissues.

  5. Diet and Exercise.
  6. In the western world drugs are studied and natural remedies such as these basic items are often overlooked. However, a recent study did look at the effect of diet and exercise on patients experiencing fat redistribution and found that diet changes and aerobic exercise did have an impact on lowering fat levels.

  7. Testosterone Therapy and other Anabolic Steroids.
  8. Seems to work well for truncal obesity and getting rid of the intra-abdominal fat layer, the fat that lies around the internal organs.

  9. Liposuction.
  10. Researchers at the conference say that this is only a temporary fix as their patients who have had this done have just put the fat back on after several months.

  11. Facial Implants.
  12. A purely cosmetic therapy.

Research presented at the conference focused on two of the most common methods of treatment. One is to change to a regimen that does not contain a PI. The other is to add a drug to treat the complication.

The first approach was reported by Ruiz and colleagues from Germany and Spain. They switched from a PI to a non- nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine (Viramune). People who had been on PIs for at least 9 months and who had viral loads below 400 copies/ml and CD4 cell counts above 100 were randomly selected to continue the PI or to switch to nevirapine. (All people who switched to nevirapine were given an antihistamine and none of them developed a rash from the nevirapine.)

After 12 weeks, the viral load remained low and the cholesterol and triglycerides had decreased in the nevirapine group, but measurable changes in body fat were not seen. This was a very preliminary report and it will take more time to see whether switching to nevirapine (or another NNRTI) will control HIV replication as well as the PI and whether the fat accumulations will go away.

Andrew Carr's group from Australia had a poster presentation that reported on a small group of people with FRS who had also switched to nevirapine, but 20 percent of his patients had increases in viral load when switched to the NNRTI.

Three posters reported on different drugs used to treat people with FRS, but since no one really knows what causes this complication (which is seen both with and without PIs, but clearly more frequently with PIs), it is difficult to devise a treatment strategy.

A study by Torres treated 8 people with growth hormone (which is extremely expensive) and noted a decrease in "buffalo humps" and abdominal girth (waist size), but no lowering of cholesterol and triglycerides, or improvements in fat deposits on arms or legs.

Another group administered the drug troglitazone, which sensitizes tissues to insulin. One theory about FRS is that it is caused by a loss of sensitivity of tissues to insulin, so that while insulin levels are not decreased, the body acts like there is less insulin available.

A third study used metformin, another insulin-sensitizing drug.

These latter two studies showed some improvements in metabolic parameters associated with FRS with the administration of insulin-sensitizing drugs, but these studies have very short-term follow-up and not all metabolic measurements nor body abnormalities improved. Realistically, until the actual mechanisms by which PIs cause the metabolic changes seen, therapy will be difficult.


A Tale of Two Trials of HAART Interruption

In one trial, Anthony Fauci and colleagues at the National Institutes for Health (NIH) identified three people who have received HAART and interleukin-2 for several years and who had no evidence of residual HIV-infected cells in their lymph nodes. However, they had just stopped HAART in these people, a couple of weeks before the Conference, to see if the virus would stay undetectable. It is possible that there is residual HIV in other areas of the body.

In another trial, interleukin-2 and the antibody OKT3 were used to purge the resting HIV-infected CD4 cells. However, even though they were able to show that they induced some of the resting CD4 cells to begin dividing and producing HIV, they could not demonstrate a decrease in the number of resting HIV-infected CD4 cells after the treatment.

It cannot be emphasized too much that these studies are very preliminary attempts to improve the body's immune response to HIV, whether by the use interruption of HAART as a form of auto-vaccination, the use of HIV vaccines, or other immune stimulants such as interleukin-2. No one knows if these approaches will work and what are the risks associated with them will be. Interleukin-2 has major toxicity in all people who receive it. Interruptions in HAART results in very rapid HIV replication in almost all people, and presents the risk of developing drug resistance, and the loss of benefits already achieved in the slow rebuilding of the immune system.

Very good data was presented by several groups showing that in almost all people on HAART, even when HAART is begun when the CD4 cell count is very low, there is a continued progressive improvement in the immune system. Recovery is seen in the numbers of memory cells (lymphocytes already programmed to defend the body against a specific infectious agent that the body has been exposed to in the past), as well as recovery of naïve cells (the very important lymphocytes that are able to mount an immune attack against infectious agents to which the body has not been exposed to in the past.)

Consequently, most people are recovering their immunity to fight off infections such as pneumocystis pneumonia (PCP), mycobacterium avium complex (MAC), cryptococcus, cytomegalovirus (CMV), and even Kaposi's sarcoma.

The recovery of immune response can be so strong that a new syndrome has been described, called immune stimulation syndrome. People who have had tuberculosis or MAC sometimes develop high fevers and inflammation or swelling in areas of prior infection, due to a strong immunologic response to residual infection. At first, it was thought that there was reactivated disease at these sites, but now this is recognized as a strong immune response to the bacteria, which resolves in a short period of time.





  
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This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.
 

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