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AIDS 2002 Barcelona and Seville: XIV International AIDS Conference and HIV Resistance Meeting

Fall 2002

Article: A STEP Conference Review

This year, the biannual International AIDS Conference (IAC) was held in Barcelona, Spain, preceded by the HIV Resistance meeting in Seville, Spain. While STEP did not attend these meetings, we have followed closely the reports from these meetings and present the highlights below. The focus and emphasis of this year's IAC was clearly on getting antiretroviral drug treatment to the vast majority of people living with HIV in the developing world. The United States has about 900,000 cases of HIV infection, while Southern Africa has over 28 million people living with HIV infection! About 5 million people have died of AIDS since the last IAC, two years ago in South Africa. In spite of all the talk about funding AIDS treatment programs, the funding for the UN's Global AIDS Fund remains very poor. Also, AIDS treatment activists were very vocal and visible, protesting high drug prices and a speech by U.S. Secretary of Health and Human Services Tommy Thompson.

International AIDS Conference Highlights

The highlights of the HIV treatments studies reported at the IAC are summarized below. These were follow-up reports on T-20, reports of early human trials of the new class of drugs called integrase inhibitors, the report of a large strategy trial conducted by the AIDS Clinical Trials Group (ACTG), and the report of the use of Viread (tenofovir) in previously untreated people.

T-20: An Entry Inhibitor

T-20 is known as an entry inhibitor, because it is a compound that interferes with the ability of HIV to enter into the T-cell. Trimeris, who owns T-20, has filed with the FDA for approval in the U.S., and approval is expected later this year. The drug is a small protein that is not absorbed in the stomach and must be given as an injection under the skin, twice a day. However, T-20 has been shown to cause impressive reductions in levels of the HIV virus in the blood (or viral load) when added to other drugs in people with multiple drug-resistant mutations.

Two presentations reported on results from ongoing T-20 trials, in which T-20 added to other HIV drugs is compared to a placebo injection. Both studies observed that the group that received T-20 had twice the viral load decrease compared to the placebo group. These results were maintained over 24 weeks, although it is known that resistance to T-20 does develop in some people. Almost all people had nodules develop at the injection sites that did not go away completely over time. This drug will be of help to people with HIV with multiple drug resistances.

Integrase Inhibitors Finally in Clinical Trials

Many compounds have been evaluated for their ability to inhibit integrase, the unique HIV enzyme that allows the virus to copy its genetic message into the body's cellular DNA. In the past, all of these compounds were too toxic to move into human trials, but reported at the IAC were two more integrase inhibitors that have passed all the animal toxicity testing and are moving into early clinical trials to determine safety and dosing. These are S-1360 and L-870,810. S-1360 was administered to 18 HIV-negative people for 14 days and no significant side effects were observed. L-870,810 was well absorbed in animal testing and had good levels in the blood. This compound will now move into human testing. Thus, the search for a new class of drugs to target another HIV enzyme may finally be producing some compounds.

A Large Strategy Trial in Previously Untreated People

The ACTG presented for the first time the results of a large, complicated study in treatment-naive (never treated before) people, Study 384. The study included two separate sets of comparisons in what is called a factorial design. The nucleoside reverse transcriptase inhibitor (NRTI) combination of AZT/3TC was compared to d4T/ddI. Also the initial use of a non-nucleoside reverse transcriptase inhibitor (NNRTI) (Sustiva) was compared to a protease inhibitor (PI) (Viracept), and also to a combination of the PI plus the NNRTI. In the PI and NNRTI groups, when virologic failure or toxicity developed, participants were switched to the alternate combination of NRTI and either the PI or NNRTI. There were two basic questions being asked in this study. First, how does the use of AZT/3TC compare to d4T/ddI? Second, how does the strategy of the use of a 4-drug combination compare to the use of two sequential 3-drug combinations? Since this is a complex study, the table below may be helpful in understanding the six possible treatment groups that the 980 people participating in this study were randomized to.

 NNRTI (Sustiva)PI (Viracept)NNRT/PI

When people in group A failed, they were switched to group D, when people in group B failed; they were switched to group C, and so forth. The groups E and F were considered treatment failures when they failed their first 4-drug regimen.

The most important result of this study is that the success rate of using two sequential 3-drug regimens was the same as using a 4-drug regimen. A secondary finding of the study was that the group that performed the best on their first regimen was group A, the group that received Sustiva/AZT/d4T.

A subsequent preliminary presentation was given a few weeks later at the summer Adult AIDS Clinical Trial Group (AACTG) meeting in Washington, D.C., reporting on the metabolic substudy of 384. The future results of the metabolic substudy may be of more interest than the primary study, as comparison can be made between an NNRTI versus a PI-containing regimen, and between AZT/3TC and d4T/ddI. The preliminary data presented in Washington showed that peripheral fat loss was greater in the d4T/ddI group. There was also greater toxicity associated with the d4T/ddI combination, particularly neuropathy. Future results will include measures of cholesterol, insulin resistance, and other metabolic comparisons from Study 384.

Viread (Tenofovir) in Previously Untreated People

Results of a trial comparing Viread/Sustiva/Epivir to Zerit/Sustiva/Epivir in 600 people were reported. Study 903 found that these two regimens were equally effective in viral load suppression and T-cell increases after 48 weeks of treatment. Between 81 and 82 percent of people achieved viral loads below 50 copies per mL of blood in both groups at 48 weeks. Viread was approved by the FDA to be used as part of a salvage regimen. The results of this trial also support consideration of the use of Viread in previously untreated people. Gilead will be asking the FDA to include this use in its product labeling. Viread is taken once a day, with food, and is well tolerated by most people. It does not appear to cause mitochondrial toxicity. (See the article on mitochondrial toxicity in this issue of the STEP Perspective.)

Article: A STEP Conference Review

Bare-Backing Superinfection Dangers

There was a great deal of press attention given to a report of what appears to be a very well documented case of infection with a second, stronger strain of HIV, in someone doing well and not on antiretroviral therapy. The person had been treated at the time of initial (primary) HIV infection and did well after a couple of treatment interruptions, maintaining a low viral load. However, the person had a sudden large increase in their viral load and very sophisticated testing demonstrated that the person was infected with a second strain of HIV, which the immune system was unable to contain. The fact that a person could be reinfected (so-called "superinfection") has been known for some time, but this was the first well documented superinfection. What is of greater significance, however, is that while the person had evidence of strong HIV-specific immune responses, these immune responses did not protect from a second HIV infection. This raises serious concerns about the ability of any HIV vaccine to protect someone from HIV infection. This case also reinforces the dangers of "bare-backing" amongst HIV-positive persons. It is possible to be reinfected -- with a more aggressive, or even drug-resistant, strain of HIV.

Changing HIV Treatment Guidelines: Is It Safe to Stop HAART?

A reassuring, but small, study reported on the outcome of stopping treatment in people who had started antiretroviral treatment under the old HIV treatment guidelines, for whom treatment would not be recommended under the new HIV treatment guidelines. Most major HIV treatment guidelines have changed from recommending treatment for people with less than 500 T-helper (CD4) cells, to recommending that people with between 200 and 350 T-helper cells consider therapy, and that people with fewer than 200 T-helper cells definitely begin HIV therapy.

A group from Argentina randomized 36 people who had pretreatment T-cell counts above 350 and a viral load less than 60,000 copies per mL to either continue or stop HIV therapy. The viral load in the group that stopped therapy returned to close to the pretreatment viral load, and the T-cell decreases were not very rapid, only about a 14-cell decrease. The average follow-up in this small study is less than 1 year. However, it should offer some reassurance to people who are considering stopping highly active antiretroviral therapy (HAART) because they started under the old guidelines, and would not be recommended to start HAART were they being evaluated to start HAART today. For many people who are tolerating their regimen well, continuing HAART is still also a very reasonable consideration.

PI Interactions

Another small study of concern and interest is yet another report of the complicated interactions of two protease inhibitors (PIs) that are commonly prescribed together. Kaletra and Agenerase may be a very useful combination in people with multiple PI-resistant mutations. However, there appears to be a complicated and not completely predictable interaction between the two drugs. There is a two-way interaction: Agenerase appears to decrease to blood levels of Kaletra, and Kaletra appears to decrease the blood levels of Agenerase. So, a higher dose of Kaletra (533 mg versus 400 mg) may be needed when these two drugs are combined. The dose of Agenerase studied varied from 600 mg to 900 mg twice a day. Also, NNRTIs are known to decrease Kaletra blood levels.

The major concern with the results of this and other studies of the interactions of Kaletra and Agenerase is that there is a great deal of variation in the blood levels from person to person. Therefore, this study, like others, concluded that it would be advisable to measure blood levels of the PIs when they are prescribed together. This is not currently routinely done in practice in the U.S.

Drug Holidays Before Starting a New Regimen

Dr. Katlama presented results from a trial in which 70 people were randomized to either start a new salvage regimen immediately or to take an 8-week "drug holiday" prior to starting the new HAART regimen. The group who had the 8-week drug holiday had twice as great a chance of achieving a viral load decrease of 1 log or more (a 10 times bigger decrease) after 24 weeks on the new regimen. Half (50 percent) of the group that had the 8-week drug holiday achieved at least a 1- log reduction in viral load, compared to only 24 percent for the group that did not have the drug holiday prior to starting their new treatment regimen.

All people were started on the same new regimen, which included 4 NRTIs, an NNRTI, hydroxyurea, and 3 PIs, also known as mega-HAART. Most people reportedly tolerated this very aggressive regimen. However, there is a risk of a significant decrease in T-cells during the drug holiday and more than 24 weeks of follow-up is needed to determine if this type of structured treatment interruption is of benefit. A similar study found no difference with this approach. There still needs to be a larger study, with longer follow-up, to resolve this issue.

HIV Resistance Meeting Highlights

Atazanavir Resistance Findings

The next PI to be approved will probably be atazanavir (ATV). It is a once-a-day drug that does not cause changes in cholesterol or triglycerides. Early trials in people with PI-resistant virus were not too encouraging; however, a report from the meeting in Seville found that the first mutation that develops to ATV does not appear to cause resistance to the other PIs. So this raises the possibility that ATV could be used first and then if resistance were to develop, HIV would still be sensitive to the other PIs. However, clinical trials will need to confirm if this is in fact what would happen in people.

A Toxic Second-Generation NRTI Resurrected?

An NRTI known as FTL was dropped from development in the early 1990s due to serious toxicity, including some deaths from hepatitis. Another company has purchased this drug and is trying to resume clinical trials. They reported at the resistance meeting that the mutation that develops to this drug does not cause cross-resistance to other NRTIs. While this is an encouraging finding, the serious toxicity of this drug observed in earlier trials needs to be addressed before further testing of this drug resumes.

Trimeris also reported was that the resistance that develops to T-20, the entry inhibitor, does not confer resistance to the next entry inhibitor in development called T-1249. Another encouraging report is that the transmission of drug-resistant HIV appears to have decreased slightly in the United States in the last 2 years. This is good news, since the rate of increase was significant for the prior few years. Most people still expect the next revision of the Public Health Service HIV Treatment Guidelines to recommend HIV resistance testing prior to beginning HIV treatment, even in people who have been infected for some time.

The above highlights from the HIV Resistance Meeting in Seville are based on a summary of the significant findings presented by Dr. John Mellors at this summer's ACTG meeting, with some editorial comments added by the author of this STEP Conference Review.

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