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42nd Annual ICAAC Meeting, San Diego, CA, September 2002

Winter 2002/2003

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.


New Anti-HIV Proteins Identified

Dr. David Ho, published a report in Science Express, the online version of Science Magazine on September 26, 2002, that received extensive media coverage. For many years it has been known that a type of white blood cell, the CD8 lymphocyte, produces a factor that can inhibit HIV replication. This factor has been called the CD8 antiviral factor, or CAF. Dr. Jay Levy, has done a lot of research on this subject. Normally, CD8 cells kill infected cells by coming into direct contact with them. However, they also produce a factor, which is made up of small proteins, that can inhibit HIV replication in nearby cells. Many people have been trying to isolate this factor and now it seems that researchers in Dr. Ho's lab have identified these proteins. Using very elegant protein isolation and identification techniques, Dr. Ho studied the CD8 cells of three long-term nonprogressors (people infected with HIV for more than 10 years who still have normal immune systems without any treatment). The proteins that Dr. Ho's lab identified were initially discovered 20 years ago. They are a group of proteins called alpha-defensin 1, 2 and 3. They were known to kill bacteria by piercing the wall of the bacteria. By using purified alpha-defensin 1, 2, and 3, and antibodies to block them, Dr. Ho's group showed that they appear to be the long-sought-after CAF. This research raises many more questions, such as the potency of these proteins, their potential use clinically, and whether or not these proteins are the cause of some people being long-term nonprogressors. Another interesting fact is that some people naturally have low levels of alpha-defensin 3, so does this help in predicting progression of HIV infection. Other researchers expressed some skepticism prior to Dr. Ho's presentation whether these proteins were the CAF. However, the data presented strongly supported the conclusion that these three proteins are the CAF. (For more details of this presentation, see the review on Medscape (www.medscape.com/viewarticle/442254). The site is free but you must register to use it.)


Entry Inhibitors

The newest class of HIV drugs, the entry inhibitors, has been discussed in the last several issues of the STEP Perspective. Further analysis of the T-20 (Fuzeon®) trials and a report on T-1249 were presented. The T-20 analysis evaluated responses to T-20 in salvage trials where T-20 or placebo was added to a regimen of the best available drugs. This analysis showed that there was a consistent 10-fold decrease (1 log, or about 90 percent) attributable to the T-20 in all of the subgroups analyzed. These subgroups included gender, ethnicity, baseline viral load, T-cell counts, and number of resistant mutations. What still needs to be presented is the resistance data for T-20. Not everyone responded to T-20 and the company has yet to report which baseline mutations predicted no response to T-20. This is important data so that when T-20 is approved some time this year, a likely cost will be between $12,000 to $15,000 per year, people will know if they might benefit from T-20.

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.

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Once-Daily Drugs

A large international trial compared the newest once-a-day protease inhibitor, atazanavir, to Sustiva in people without any prior HIV therapy. All people also received Combivir (AZT and 3TC). There were over 800 people enrolled in this trial. The results of treatment were reported after 48 weeks. The table below shows the HIV levels after 48 weeks.

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.


Intent-to-Treat Analysis

AtazanavirEfavirenz
Number of discontinuations65 (16%)79 (20%)
HIV-1 RNA <400 copies/mL70% (283/404)64% (257/401)
HIV-1 RNA <50 copies/mL32% (129/404)37% (148/401)


Is It Safe to Stop ART if You Started Above Current Treatment Guideline Recommendations?

People who had begun antiretroviral therapy (ART) at higher T-cell counts then current treatment guidelines recommend therapy stopped ART in this study. A total of 49 people were followed in this Spanish observational study begun in 1999. They all had begun ART with T-cell counts between 350 and 500 and HIV RNA loads between 10,000 and 70,000. ART was restarted if the T-cell numbers dropped below 300 or HIV RNA rose to above 70,000 on two measurements. The average time off of treatment was 13.5 months, with a range from 4 months to greater than 3 years. Of concern was that 16 months after restarting ART, the T-cell counts were still lower than when ART was stopped. The rate of T-cell loss during the time off treatment was steady at about 25 cells over 4 months, on average. HIV RNA tended to rise to pre-treatment levels rapidly after stopping ART. In general, this study, and others, show that with close monitoring, it is pretty safe to stop ART if ART was started with higher T-cell counts than current guidelines recommend for starting ART.


HIV Subtypes Show Extensive Recombination

Thomas Quinn presented a lecture reviewing what is currently known about the various subtypes of HIV-1 around the world. There were initially about five major subtypes of HIV-1 identified. The subtypes are referred to by letters, A, B, C, etc. The predominant HIV-1 types differ geographically. Subtype B is the predominant type in North America and Europe, C and A in Southern Africa, and E in Southeast Asia. However, more recent data has now identified subtypes from A to L, with type I actually being a combination of parts of type A, G, H, and K. Cameroon is the country with the most diverse population of subtypes of HIV. There are some potentially clinically relevant concerns about the different subtypes of HIV. The most significant concern is that an effective HIV vaccine would have to work against many types of HIV, not just the main subtype present in one geographic area. Second, there is some data to suggest that it is easier to transmit subtype C. Third, so far it appears that the subtype present does not affect the response to ART. The implication of most concern, as noted by Dr. Quinn, is that the various recombinations mean that there is a lot of "superinfection", or infection with a second strain of HIV in someone already HIV-infected. This is because the only way for these recombinations to be occurring is for a person to have more than one subtype of HIV in their body.


Prevention and Vaccines for Sexually Transmitted Diseases

Dr. Larry Corey, M.D. of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, presented the first trial ever to show a decrease in transmission of a viral infection with the use of an antiviral medication. This study evaluated the use of an anti-herpes drug, valacyclovir, at 500 mg daily, to a placebo in the prevention of genital herpes. This was a large, multinational trial with 96 study centers. There were 1,494 monogamous, heterosexual couples in which one partner had documented infection with herpes simplex virus type 2 (HSV-2) and the other was HSV-2-seronegative.

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.





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

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