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Update from the 8th Retrovirus Conference

March/April 2001


The new Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents created a buzz among science investigators, AIDS treatment community advocates, and the press prior to the opening session of the 8th Conference on Retroviruses and Opportunistic Infections (CROI), held in Chicago in February. The new Guidelines recommend that HIV positive individuals and their physicians consider withholding antiretroviral therapy when a person's T-cell count is above 350 (previous Guidelines recommended therapy initiation when T-cell count fell below 500). The new Guidelines also suggest that treatment be considered when viral load exceeds 20,000 or 30,000 copies (previous recommendations were at 10,000 or 20,000 copies depending on which test was used).

"Although antiretroviral therapy has provided extraordinary benefits to many patients, we know that we cannot eradicate HIV infection with currently available medications," Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) and co-chair of the panel that created the guidelines, noted in a press statement. "We also recognize that serious toxicities are associated with the long-term use of antiretroviral drugs. The new treatment guidelines provide patients and their doctors with evidence-based recommendations for initiating antiretroviral therapy that take into account both the benefits and potential risks of currently available treatment regimens." The Guidelines were developed by the Panel on Clinical Practices for the Treatment of HIV Infection, a joint effort of the Department of Health and Human Services and the Henry J. Kaiser Family Foundation.

A rather larger body of AIDS treatment community advocates and activists met over two days to discuss long-term clinical efficacy and tolerability of anti-HIV therapy, the feasibility of conducting long-term antiretroviral therapy trials, and to establish a national coalition of HIV advocates. Reports from ongoing and proposed long-term effective research were submitted during day one. The overall goals of these studies are to evaluate strategies of drug-free periods compared to continued therapy; to evaluate treatment strategies that both improve quality of life and delay progression of disease; and to evaluate the effect of mega-antiretroviral therapy (five or more meds) compared to standard antiretroviral therapy (usually triple combinations).

The treatment community appears to be at a crossroads, as new (and sometimes conflicting) data indicates that the highly touted "hit hard, hit early" treatment strategy initiated in 1995-6 may not have been the best strategy for the majority of HIV positive individuals. (See "HIV Guidelines Now Say 'Hit Later'," in News Briefs.)

However, in an effort to work more effectively and efficiently, treatment community advocates from around the U.S agreed to establish an advocate coalition. The coalition will work toward improving relations and communications between community and pharmaceutical companies; establishing a national advocate training and mentoring network; and expanding international advocacy relationships with partners from Canada, Europe, Africa, and Latin America.

Given the news of the new Guidelines in treatment, it came as no surprise that the following questions dominated the four-and-a-half day conference. When to start antiretroviral therapy? When and how to change treatment regimens? What are the short-term and long-term effects of structured treatment interruptions (STI) or structured intermittent therapy (SIT)? Why are high-risk behaviors on the rise again? How are behaviors affecting HIV transmission rates? Who is at high risk for HIV infection, and why? What new drugs are on the horizon, and when will they be available? How are researchers and pharmaceuticals addressing concerns about toxicity and body-shape changes?

Robert Siliciano, M.D., Johns Hopkins University School of Medicine, presented data showing that while current highly active antiretroviral therapy (HAART) comes close to stopping the virus, viral reservoirs can exist and low levels of virus replication can take place in resting (dormant) T-cells of individuals who have responded well to HAART. Studies continue to determine whether a low viral load (as opposed to an undetectable viral load) results from or contributes to the emergence of drug resistance, in which case the drugs can no longer fight the virus.

Many labs reported from ongoing studies indicating that short-term treatment interruptions or long-term treatment interruptions may be the direction of anti-HIV therapy, as it is highly unlikely that HIV can be eradicated with current treatments. Because of the numerous short-term and long-term toxicities associated with HAART, a number of clinical trials are being pursued that may eventually reduce an individual's time of treatment (and influence the Guidelines). One option is a long-term structured treatment interruption, where HAART is stopped until the viral load or T-cells reach a pre-determined level. Once the pre-determined level is reached, HAART is re-started until viral load declines or T-cells increase; the cycle is then repeated. Several studies indicate that viral load and T-cells return to pre-interruption levels when HAART is resumed.

However, there are a number of factors to consider: length of time on HAART and level of adherence; risk of developing resistance or sensitivity to meds; and an increase in risk of virus transmission during an interruption. Moreover, what works for acutely (newly) infected individuals may not work for chronically infected individuals.

All of these interruptions are called "structured," meaning that individuals should never try this on their own. This type of treatment interruption is still in experimental stages, and should be closely monitored by a physician or in a clinical setting.

For Old-Timers

Dr. Stephen Deeks and colleagues of the University of California at San Francisco answered a question that's on the minds of many, many people living with HIV: What happens to all those folks who took AZT monotherapy back in the '80s and went on HAART in the '90s, but never got to "undetectable?" Is therapy doing them any good?

They found pretty good results in a group of these patients, who had an average of 124 T-cells when going on HAART. The risk of disease was only 41% after four years, despite having detectable HIV in their blood. Dr. Deeks said this is "dramatically" better than what you would expect after four years with no treatment.

Heart Attacks?

Dr. Deeks had earlier reported that his patients were doing better with therapy even if they weren't undetectable. Another doctor following up on a previous report was Dr. Keith Henry of the University of Minnesota. He earlier shook up the HIV world by reporting on two young men -- one only 29 -- who had heart attacks while on HAART. Now Dr. Henry and colleagues were back with a presentation on whether HAART increases the risk of cardiovascular disease.

They found changes associated with increased risk for coronary artery disease in a group of 100 people taking Crixivan combination therapy. The risk factors were increased levels of triglycerides and total cholesterol, decreased HDL (the "good" cholesterol), and increased insulin resistance (found in 56%). The doctors recommended medical intervention for these conditions. Not quite new information, but it's good to know people with HIV have a solid watchdog in Dr. Henry.

Aspirin for Peripheral Neuropathy

Another group looking for immediately practical information was the Community Research Initiative on AIDS (CRIA) in New York City. They gave 31 people an aspirin preparation to be placed directly on the skin where nerve damage was causing pain. Neuropathy is a common and often debilitating condition in HIV, resulting from either medications or from the virus itself. CRIA found significant improvement (25 to 30% better) with the use of topical aspirin in diethyl ether (ASA/DE). They used 375mg three times a day.

Viramune and Pregnancy

Viramune (nevirapine) is so effective at cutting transmission from a previously untreated mother to her newborn, using only two doses of the drug, that doctors looked at whether it can further cut transmission for women already on combination therapy. It can't. The international trial looked at 1,500 moms, 99% of them taking at least one HIV drug -- half of them were on triple combination therapy. Whether or not you added Viramune, the transmission rate was 1.5%.

Sustiva and TB

No, you don't get tuberculosis from taking Sustiva (efavirenz). But blood levels of the popular HIV drug go down when people take rifampin for their TB infection. Spanish researchers suggested that your Sustiva dose be upped to 800mg a day (four 200mg capsules instead of three).

In the Pipeline

Once-Daily Protease Inhibitor

48-week results from a Phase II study of Bristol-Meyer Squibb's new once-daily HIV protease inhibitor, BMS-232632, indicates that higher doses of the new PI compares favorably against three times-a-day Viracept (nelfinavir). The safety and antiretroviral activity of three doses of BMS-232632 (200, 400, and 500mg) was compared against Viracept at 750mg; both were tested in monotherapy for 2 weeks and then in combination with Videx (ddI) and Zerit (d4T) for the duration, in 265 HIV positive individuals (38% women; 43% non-white) taking antiviral meds for the first time, who had viral loads greater than or equal to 2,000 copies. The most common side effects were diarrhea and nausea. It is recommended that BMS-232632 be taken with a light meal. There were no significant elevations in cholesterol, LDL-cholesterol (the bad kind), or triglycerides (fat in the blood) observed. Phase III studies, also involving participants taking anti-HIV meds for the first time, have started.

Fusion Inhibitors

Exciting possibilities in antiretroviral therapy are the experimental fusion or early inhibitors. Taken as a self-administered injection, these drugs are formulated to block HIV before it enters the T-cell. This is accomplished by interfering with stages of attachment and fusion between HIV and the cell.

T-1249, what Dr. Roy Gullick of Cornell University in New York City called "the son of T-20" (both drugs are made by the same company), was studied in people for the first time. The very early study looked at different doses of the drug taken by itself either once or twice a day, for a total of two weeks. Higher doses were better at decreasing viral load, and the data supports once-daily dosing. Adverse side effects: hypersensitivity reaction (oral ulcers, bumpy rash, fever) and grade 4 (serious) neutropenia (lowering of white blood cells). The most common side effects reported were injection site irritation (usually mild), headache, dizziness, and diarrhea.

Chemokine Receptor Inhibitor

Researchers are developing a new class of drugs that stop the virus from entering, or fusing into, cells. The chemokine receptors CCR5 and CXCR4 are identified as co-receptors on the T-cells required for HIV to enter the cells. Initial data indicates that the compound SCH-C has excellent potency against a broad range of resistant virus; is compatible with existing anti-HIV meds; can reduce viral load (the amount of virus in the blood); and was well tolerated. A second-generation compound, SCH-D, with ten times more potency, is also being studied.

New Protease Inhibitor

A new type of protease inhibitor that works at lower concentrations and against resistant virus is in the works. One "femtomolar protease inhibitor" was reported on, TMC126. It has not yet been studied in people. Researchers are still looking at the chemical structure of these compounds and figuring out how they act in the test tube with multi-drug resistant virus. The researcher who made the oral presentation labeled TMC126 "a resistance-repellent PI" in his report. Cute, but don't hold your breath.

New Non-Nuke

Then there's TMC120 (made by the same company, as you can imagine from its name). This is a non-nucleoside (like Viramune and Sustiva) that is also supposed to work against drug-resistant HIV. At 50mg or 100mg twice a day in a small group of only 28 people, the drug showed significant viral load decreases after one week, with few side effects.

The Third World

Doctors and researchers are more and more thinking about what can be done to fight the HIV epidemic in developing countries, and the organizers of this year's Retrovirus conference addressed this issue. HIV advocate George M. Carter of DAAIR (Direct AIDS Alternative Information Resources), in New York City, reported on this as well. "They framed this very intensively scientific conference with an economist, Jeffrey Sachs at the opening, and a physician, Anne-Valerie Kaninda, from Doctors Without Borders [at the closing] to discuss the absolute necessity for generic-pricing for AIDS drugs. While I can certainly argue some of the points made by Sachs, I think it is vitally important to recognize what an enormous leap this is toward that goal of breaking down the price barrier. Even a few years ago, the notion that politics, science, and medicine were (sometimes hideously) intermeshed was an incomprehensible notion to many researchers and clinicians so enveloped by their own laser-like narrow beams of focus of their research."

Additional reports and late breaking news from the 8th Annual Retrovirus Conference will also be included in the May/June issue of Positively Aware.

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