42nd Annual ICAAC Meeting, San Diego, CA, September 2002
The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) convened in San Diego with almost 10,000 infectious disease specialists from around the world in attendance. A major focus of this conference was bioterrorism and biodefense. This meeting covers all types of infectious diseases, so HIV is only a small part of the agenda. This report will focus on the HIV-related major developments reported at the meeting with a comment on biodefense and vaccine development for sexually transmitted diseases (STD). Dr. David Ho, also presented his findings, which were widely publicized a week before ICAAC, about the discovery of proteins that can inhibit HIV replication.
www.medscape.com/viewarticle/442254). The site is free but you must register to use it.)
T-1249, also an entry inhibitor, is a slightly different protein than T-20 and needs to be injected only once a day, compared to twice a day for T-20. People who develop resistance to T-20 appear to still respond to T-1249. The results of the Phase I dose escalation study for T-1249 were reported at ICAAC. Doses up to 200 mg were studied and the higher the dose, the more HIV suppression was observed. The only significant adverse effect is the development of tender nodules at the injection site, which is also observed with T-20. In its current formulation, T-1249 contains 50mg/ml. So, a 200mg dose means that patients must receive four separate 1 ml injections to administer each dose. So, while doses above 200 mg were not evaluated in this study, their current formulation would limit the feasibility of using a higher dose.
While the outcome of the two regimens appears similar, there was some concern expressed about the relatively low number of people who have viral loads under 50 after 48 weeks of treatment in the Sustiva group. This is lower than observed in other trials. This may be due to the international nature of this trial (which makes comparisons to other trials difficult), the ethnic composition of this trial, possible differences in drug metabolism, adherence problems (which were not studied in depth in this trial), and/or the different viral load tests that were used during the course of this trial. The major side effect of atazanavir is an elevation in bilirubin, which does not appear to have any clinical significance. The atazanavir group had no elevations of cholesterol or triglyceride, which were observed in the Sustiva group. As reported in the last issue of the STEP Perspective, atazanavir resistance occurs through a unique mutation, which may actually result in increased sensitivity of other protease inhibitors. Based on this report and the potential unique resistance pattern, the dose is two pills once a day. Because it causes no elevations in cholesterol or triglycerides, atazanavir will be a very attractive first-line protease inhibitor. FDA approval is expected in the first half of 2003.
More progress relating to once-daily regimens was reported at ICAAC. One study compared once-daily Epivir, as a single 300 mg dose, to twice-daily Epivir, as two 150 mg doses, in 554 previously untreated people. All people in this trial also received Retrovir (AZT) and Sustiva. After 48 weeks of treatment, the number of people with HIV-1 RNA levels below 50 copies/mL (by intention-to-treat analysis) were 59 percent and 61 percent for the once-daily and twice-daily Epivir arms, respectively. There was no difference in the two arms even when people with high viral loads at baseline were evaluated. At the end of June 2002, the FDA approved a change in the labeling for Epivir to allow for once-daily dosing, "The recommended oral dose of Epivir for adults is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily, in combination with other antiretroviral agents." This change has not been well publicized by the manufacturer, GlaxoSmithKline.
Another once-daily drug, emtricitabine, continues in development. It is similar to Epivir (3TC) and has the same resistance pathway. A study compared emtricitabine to Zerit (d4T), both administered with Videx EC and Sustiva. After 24 weeks, both groups had a similar number of people with viral loads below 50 copies/mL -- 81 percent for emtricitabine, and 70 percent for Zerit (not a statistically significant difference). Since Epivir is approved for once-daily administration, it is not clear what advantage the use of emtricitabine offers. STEP would welcome a head-head comparison of these drugs, as it would with Sustiva and Viramune.
The infected partner was treated for 8 months. All the couples also received counseling about how to prevent HSV-2 transmission by use of condoms and abstinence during symptomatic herpes episodes. Symptomatic, laboratory-confirmed genital herpes occurred in 17 (2.3 percent) of the partners of placebo recipients and 4 (0.5 percent) of those whose partners were given valacyclovir, a statistically significant difference. There were additional cases documented only by blood test, the infection rates were 3.8 percent among the partners of placebo recipients and 1.9 percent in the partners in the valacyclovir group. Similar results were noted whether the infected partner was the man or the woman.
Questions remain about the use of higher doses of valacyclovir. In his review of this study for the Medscape Web site, Dr. H. Hunter Handsfield, from the University of Washington, writes:
"Despite these uncertainties, in my opinion there is no point in delaying the use of valacyclovir 500 mg once daily to help prevent transmission of genital herpes. Certainly, herpes-discordant monogamous couples, the population directly represented in the study, should be informed of this option (after confirmation of discordance using a type-specific serologic test) and offered treatment. Selected non-monogamous persons also should be offered therapy. Indeed, because most monogamous persons do not contribute importantly to sustained transmission of STDs, any population-based public health benefit in curtailing the HSV-2 epidemic likely will require treatment of infected persons outside monogamous relationships. For the moment, such treatment probably should be restricted to motivated patients who have been carefully counseled about all prevention strategies. Patients must be told that the risk of transmission is reduced but not eliminated; that they must take the medication correctly and consistently; that they still have the ethical responsibility to inform prospective partners that they have genital herpes; and still should use condoms and be alert to symptoms of recurrent herpes and avoid sex when they are present."
A couple of ICAAC sessions reported on progress, or lack thereof, on vaccines for STDs. Progress on development of vaccines for gonorrhea, chlamydia, and genital herpes remains slow. However, progress on a vaccine for human papillomavirus (HPV) is very encouraging. Most people acquire HPV infection in early adolescence. Therefore for people already infected with HIV and HPV, which increases the risk for cervical and anal cancer, a vaccine would be of interest if it could be used to treat HPV after infection has already occurred. However, research into this approach is probably a year or two away.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.