Update from the 8th Retrovirus Conference
IntroductionThe 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.
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.
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.
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.
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.
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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