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Entry Inhibitors: The Bouncers at the Door

Winter 2002/2003

There is good news on the horizon for people whose HIV is resistant to many currently approved antiretrovirals -- the development of a new class of anti-HIV drugs called entry inhibitors. Entry inhibitors have shown promising results for people with few treatment options. The first of these drugs, T-20, may work when other drugs no longer do and is likely to be approved for use as early as March of this year.

Entry inhibitors work at HIV's first point of contact with a T-cell. They keep HIV from entering the T-cell by interfering with one of the steps involved in the entry process. Theoretically, at least, a drug could target any one of the proteins on the outside surface of HIV (gp120 or gp41, for example) or one of the receptors on the outside surface of the T-cell (CD4, CXCR4 or CCR5). To date, the most promising entry inhibitors work by targeting HIV's gp120 or gp41 proteins, or the T-cell's CCR5 receptor. These drugs work somewhat like nightclub bouncers, checking HIV's ID as the virus tries to enter the T-cell and not letting it inside. If the drug is effective, HIV is unable to use the T-cell to make copies of itself.


T-20 (enfuvirtide), also called Fuzeon, is the entry inhibitor furthest along in clinical trials. This drug, developed by Roche and Trimeris, is specifically called a fusion inhibitor. It sticks to HIV's gp41 protein, which HIV uses to bind to the T-cell. With its gp41 occupied by the drug, HIV is unable to fuse with the T-cell and send its genes inside.

T-20 is a molecule, like insulin, that can only be taken as an injection. It needs to be available to the body immediately and isn't stable as a pill. It comes in powdered form. In order to prepare an injection, a tube of sterile water is added to the powder and the solution is mixed. The solution is self-injected subcutaneously (under the skin) twice a day. The solution can foam while it's being injected and therefore needs to be injected carefully. The drug's greatest value will be to people whose HIV is resistant to many current anti-HIV medications.

Results from two critical Phase III studies presented at the 2002 International AIDS Conference in Barcelona in July show that T-20 has comparable strength to current antiretrovirals. The two studies, called TORO (T-20 vs. Optimized Regimen Only), are similar in design. Each study is following about 500 HIV-positive individuals for one year to compare the effects of T-20 plus other antiretrovirals to an antiretroviral combination without T-20 (the control group). The participants had previously used an average of twelve anti-HIV medications, and 80-90% had five or more primary mutations to all current classes of antiretrovirals. Not surprisingly, the trial participants had high viral loads and low CD4 counts. Based on the results of resistance testing, each individual was assigned a combination of three or more current or experimental anti-HIV medications. Two-thirds of the participants also used T-20. While the trials have not been completed, preliminary six-month results were presented at the conference and provide the most data on T-20 to date.

TORO-1 enrolled 491 people in the U.S., Canada, Mexico and Brazil. The average viral load was 158,489 copies/mL, and the average CD4 count was 80. After six months, the viral loads of those in the T-20 group dropped by 98%. The viral loads of those not on T-20 dropped by 82%. 20% of individuals on T-20 had undetectable viral loads (less than 50 copies/mL), compared to 7% in the control group. In addition, there was an average increase in CD4 count of 76 in the T-20 group, compared to 32 in the control group. There was no significant difference in study withdrawal rates between the T-20 and non-T-20 groups. 98% of people using T-20 experienced injection-site reactions (pain, swelling and/or redness around the injection area) and most reported these reactions to be hard to tolerate. While very few stopped using T-20 due to the reactions, the difficulty of using this drug should not be underestimated. Other side effects experienced by those on T-20 included fatigue, insomnia, and peripheral neuropathy.

TORO-2 enrolled 504 individuals in Europe and Australia. After six months, the individuals in the T-20 group found their viral loads to drop by 96%, as compared to the control group whose viral loads dropped by 78%. Of the individuals on T-20, 12% reached undetectable viral loads (less than 50 copies/mL) compared to 5% in the control group. CD4 counts increased by an average of 65 in the T-20 group, versus 38 in the control group. More individuals who were on T-20 withdrew from the study (17%) compared to the control group (5%), which is significantly different from TORO-1. Similar to TORO-1, 98% of individuals on T-20 had injection-site reactions, but only 3% withdrew due to these reactions. Less than 10% of those on T-20 experienced headaches, fever, and fatigue.

Overall, the results of these studies are promising. This drug seems to benefit the very people most in need of new options, people who have gone through most of the available drugs and developed resistance to them. While having to inject the drug twice a day poses a significant disadvantage, this did not seem to stop people from using T-20 (see Personal Perspective on page 16). The data provided from the TORO studies suggest that the drug is tolerable through six months. Completion of these studies will provide more information on T-20, and other T-20 clinical trials are ongoing. One positive early finding is that T-20 does not share mutations with current antiviral drugs, although mutations to T-20 have been identified and can develop.


Another fusion inhibitor being studied is T-1249. T-1249 also binds to HIV's gp41 protein, but it binds to a different part of the protein than T-20 does. If T-20 is the bouncer at the left side of the door, T-1249 stands at the right side of the same door. Both keep HIV from entering the T-cell. Like T-20, T-1249 is being developed by Roche and Trimeris, would be available only as a subcutaneous injection, and will be of greatest use to individuals with highly-resistant HIV. The information about T-1249 is still very preliminary. If T-1249 is approved, it will be available no sooner than 2007.

Data from several Phase I/II trials of T-1249 have been presented at recent conferences. At the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy last September, a Phase I/II study was presented that looked at the drug's safety, antiviral activity, and how the drug works in the blood. This study enrolled 115 HIV-positive individuals who had never used an entry inhibitor before (i.e. T-20) but had been on HIV treatment for several years. Participants stopped antiretroviral therapy two weeks before beginning the study, then took T-1249 alone, with no other antiretrovirals, for two weeks. At the start of the study, most individuals had a viral load of around 204,000 copies/mL. Most people had a CD4 count of 64. The study looked at various doses of T-1249, from 6.25 mg/day to 200 mg/day. The drug is currently made in quantities no larger than 50 mg, so the 200 mg dose required four injections a day. All but two of the participants completed the study. Decreases in viral load were observed - the higher the dose, the greater the decrease. The greatest drop was seen in those who took the highest dose; those on the 200 mg/day dose found their viral loads to drop by 99%. The maximum increase in CD4 count was 70 at the 150 mg/day dose. Fewer individuals (57%) experienced injection-site reactions than in the T-20 studies. The reactions were more common with higher doses. Other side effects included headache, fever, candidiasis (thrush), and diarrhea. Another study of T-1249 showed similar results.

T-1249 could be particularly useful for people with multi-drug resistant virus. In test tube studies, it doesn't seem to cause the same mutations as other current antiretrovirals -- or as T-20. This suggests that T-1249 could work when other medications, including T-20, do not. There is an on-going study looking at T-1249 in individuals for whom T-20 didn't work. Studies have also indicated that there may be a synergy between T-20 and T-1249. In other words, when used together, there seems to be an even greater antiviral effect than when either drug is used separately. If these results hold true in larger trials, this could be very good news for people with HIV. Further studies are being done to evaluate how T-1249 works in larger numbers of people.


SCH-C is an entry inhibitor that targets a different part of the entry process than T-20 and T-1249. This compound binds to the CCR5 receptor on the T-cell. Normally, HIV's gp120 protein binds to CCR5. With SCH-C there, gp120 is unable to attach to CCR5 and enter the T-cell. SCH-C is specifically called an attachment inhibitor and is being developed by Schering-Plough. Unlike other entry inhibitors, SCH-C can be taken as a pill. In test tube studies, it has shown activity against virus from a number of different HIV patients. This drug has a long way to go before possible approval.

In a Phase I/II study, twelve HIV-positive individuals with CD4 counts above 250 took SCH-C by itself every twelve hours for ten days with no other antivirals. Viral load was measured every six hours for the first three days, then every 24 hours for the remaining seven days. Participants also had phenotype testing performed before and after the study to check for new HIV mutations that might have developed. At the end of the study, ten of the twelve individuals had their viral loads drop by 68%; four of the twelve individuals had viral loads that dropped by 90%. Very few side effects were reported, the most common being headaches and unpleasant taste. However, several early studies of SCH-C have shown potential cardiac toxicity (premature heartbeats) in some patients, which may be associated with the drug. Careful monitoring is necessary in all ongoing trials. If SCH-C proves to be effective at lowering viral load and increasing CD4 counts in larger studies, its few side effects and potential availability in pill form are real advantages.

PRO 542

PRO 542, from Progenics, works somewhat like a decoy. It mimics the CD4 receptor found on the surface of T-cells. PRO 542 occupies HIV's gp120 protein, which would normally bind to the CD4 receptor. HIV is fooled into thinking that PRO 542 is the T-cell. As a result, it can't free itself to bind to a T-cell. Like most other entry inhibitors, PRO 542 has a difficult route of administration -- it is currently being tested as an intravenous infusion.

In a Phase I/II clinical trial, 22 HIV-positive adults who had been on treatment before were given a single intravenous infusion of PRO 542. They had viral loads greater than 3,000 copies/mL and CD4 counts greater than 50 when they started the study. The infusions were given at doses of 0.2-10 mg/kg based on individual body weight. No other antiretrovirals were given. PRO 542 was well tolerated and did not show toxicity at any of the doses tested. Participants' viral loads decreased to levels that were significantly lower. Most people's viral loads stayed at the same levels for up to one month after the study.

In another study, 18 HIV-positive children took various doses (0.2-10 mg/kg) of PRO 542 between one and four times a week for one month. After two weeks on the drug, some children had viral loads that dropped by 80%, and stayed at those lower levels for up to two weeks after they stopped the drug. Others' viral loads went down after the first infusion, but then continued to rise even while on drug. The greatest drop in viral load was seen in the children who received the highest dose, 10 mg/kg four times a week.

Preliminary results from a current Phase II study show that when people who had been on HIV treatment before took a single 25 mg/kg intravenous dose of PRO 542, their viral loads decreased by 60-80%. While PRO 542 would not be the first HIV-associated treatment administered intravenously, this certainly isn't ideal. Progenics is exploring the possibility of administering PRO 542 as a subcutaneous injection.

In summary, entry inhibitors create an important advance in HIV treatment, particularly for people with few other treatment options. Although most agents in this new class of drugs will be harder to take than previous antiretrovirals, the approval of T-20 is long awaited and will fill a great need. While the drug has been shown to work well, it can't do its job alone. To get the most benefit, people will most likely need to use T-20 with at least one other drug to which their virus isn't resistant. A greater number of treatment options, such as T-1249, SCH-C, and PRO 542, are essential for the growing number of people facing multiple drug resistance.

Donna M. Kaminski is ACRIA's Associate Director of Treatment Education.

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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
See Also
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