Update #1, Opening Day, Day 2, Sunday and Monday February 5 and 6 from the Retroviruses and Opportunistic Infections National Meeting
Dr. Eric Daar offers perspectives of interest on topics from the 13th Conference on Retroviruses and Opportunistic Infections (held in Denver, Colorado February 5-8, 2006)
- Culturing Hepatitis C Virus in vitro
- HIV Transmission
- Drug-Drug Interactions
- Screening for Sexually Transmitted Infections (STIs)
The Conference on Retroviruses and Opportunistic Infections has become one of the most important HIV/AIDS research meetings of the year. This year there were over 3,800 leading researchers and clinicians from around the world in attendance with nearly 1000 presentations summarizing new clinical and laboratory research, as well as discussing issues related to co-infections and co-morbidity. The meeting opened on the evening of February 5th with an opening plenary and keynote session.
The 11th Annual Bernard Fields memorial Lecture was given by Bette Korber from the Los Alamos National Laboratory. She described global HIV variation and its implications for vaccine development. Her presentation summarized data on the distribution of different HIV groups and clades, or subtypes from around the world. She also talked about her work in describing where HIV is likely to have emerged from, using molecular techniques to track when HIV likely jumped species from non human primates to humans. Her work took advantage of the oldest available strain from Africa, found from a frozen specimen in 1959, in order to trace the evolution back SIV in chimpanzees- suggesting that this virus entered humans in approximately 1930. She talked about how the extensive variability in HIV is an enormous obstacle to vaccine development and some of the strategies that are being looked at in order to overcome this problem.
The opening Keynote Lecture was provided by James Curran from Emory University. Dr. Curran had been at the CDC when the first cases of AIDS were described. His presentation was entitled, "25 Years of HIV Pandemic: Lessons Learned." He talked about the original reports of AIDS in 1981, the identification of the causative pathogen, HIV in Europe and in the United States, the development of the screening HIV antibody test, and many of the events related to this emerging epidemic that occurred during these early years. He talked about the many advances in both prevention and treatment and emphasized the importance of investigators continuing their hard work in order to overcome some of the remaining obstacles such as the development of an effective vaccine, and perhaps even HIV eradication.
Another Plenary lecture was presented on the first full day of the meeting by Dr. John Bartlett, from Johns Hopkins University entitled, "10 Years of Heart: Principles for the Future". Dr. Bartlett reminded the group that it has been 10 year since the first availability of potent antiretroviral therapy. He summarized how the rapid introduction of protease inhibitors into the standard of care resulted in marked reductions in AIDS-related mortality. He shared with the audience what he felt were some of the most important advances during the last 10 years, including several key events surrounding the Vancouver International AIDS Meeting in 1996 with the description of HIV dynamics showing that there are about 10 billion viral particles produced on a daily basis, the potency of triple drug therapy, and even discussion of potential eradication. He further talked about some of the unique treatment strategies that have more recently been considered, including strategies of using treatment interruption in different patient populations, a topic that was widely discussed during the ensuing days of this meeting. Like Dr. Curran, he emphasized the importance of continuing to work hard in order to advance the field and the importance of focusing efforts in the developing world.
Culturing Hepatitis C Virus in vitro
During the first full day of the meeting there was a Plenary Lecture by Dr. Wakita from the Tokyo Metropolitan Institute for Neurosciences in Japan describing lessons learned from in vitro cultivation of HCV. He reminded the audience that one of the obstacles to advancing our understanding of HCV pathogenesis as well as developing a vaccine and expanding treatment options has been the lack of an in vitro culture system or a small animal model for HCV. He described his work in developing an in vitro culture system using a strain of HCV from a patient who experienced fulminant infection. The virus was cloned, and a HCV replicon was created that replicated well in a cell line and was transmittable to chimpanzees (the only known animal model). Although there are clearly some limitations to the data, it does hold promise that the culture system will be available to allow us to grow the virus in vitro, and advance vaccine development and create a system for testing new treatment strategies.
There were several presentations in a symposium that summarized potential strategies for preventing transmission. Dr. Myron Cohen from the University of North Carolina, Chapel Hill, presented on the potential role antiretroviral therapy may have on preventing HIV transmission. He discussed animal data that has shown the potential efficacy of pre- and post-exposure prophylaxis . He talked about studies that are utilizing pre-exposure prophylaxis, as well as recent CDC guidelines for nonoccupational post exposure prophylaxis. He did emphasize the lack of efficacy data and concerns about toxicity and the possibility of selecting for resistance if transmission were to occur. Data was also presented regarding the relationship between antiretroviral therapy and viral load in blood and genital secretions. This discussion focused on how different drugs achieve different levels in the genital tract and how this might be important with regards to the impact antiretroviral therapy may have on HIV transmission.
In the same session there was a presentation given by Dr. Sharon Hillier from the University of Pittsburgh, School of Medicine, and the Magee Women's Hospital in Pennsylvania. She summarized issues unique to women, one of the fastest growing groups with HIV infection around the world. She talked about some of the cultural and social problems faced by women that limit their ability to protect themselves from HIV infection, as well as the importance of them being empowered by the availability of methods that do not rely on the use of the male condoms. This included discussion of the female condom and diaphragm, as well as the development of various agents that might alter vaginal pH in order to reduce infection, as well as the development of antiviral compounds, or so-called 'microbicides'. In fact, she noted that there has been a tremendous amount of interest and research in microbicides development over the last several years with 5 products in 6 large microbicide trials that are anticipated to report results as soon as 2007 or 2008.
There were several important presentations describing issues related to HIV transmission. Dr. Viani and colleagues studied recently infected adolescents in a multicenter adolescent trial network study called 'ATN 022'. These investigators used the detuned assay to identify adolescents that were recently infection, probably within the last 180 days. These individuals were from 15 different cities and were assessed for the presence of virus with any major drug resistant mutation. They showed that approximately 18 percent had evidence of resistance; the majority being resistant to NNRTIs. This is consistent with what has been seen in adult cohorts of recently infected individuals, and emphasizes the importance of looking for drug resistance prior to initiating antiretroviral therapy.
There were several important presentations at this meeting related to the pharmacokinetic interactions between drugs. One study assessed the interaction between lopinavir/ritonavir and tipranavir, two PIs that are often active in treatment-experienced subjects. They found that by increasing the dose of lopinavir/ritonavir to the equivalent to 4 capsules twice a day with an extra dose of ritonavir, or by giving extra doses of ritonavir with standard doses of lopinavir/ritonavir they were partly able to overcome some of the reduction in lopinavir levels seen when co-administered with tipranavir. Despite this, there was considerable variability in lopinavir levels and the authors recommended that if used together therapeutic drug monitoring should be considered.
Dr. Pham and colleagues at Johns Hopkins looked at the interaction between lopinavir/ritonavir and atazanavir. In this case they found with standard doses reasonably good levels of both drugs were maintained, although the clinical situation which these two drugs might be used in combination remains to be seen. Because there are many people who have extensive drug resistance and are looking at novel agents that they can use together, one study by Dr. Scholler from Tibotec, analyzed the drug-drug interaction between their new NNRTI TMC-125, with a recently approved PI called tipranavir that has been used for treatment-experienced patients. Unfortunately, they found that when these two drugs were used in combination there was a marked reduction in the TMC 125 levels, making this a nonviable option.
Finally, another pharmacokinetic study that may be relevant for the practitioner analyzed data from subjects taking both lopinavir/ritonavir and the lipid-lowering drug rosuvastatin. In this case lopinavir levels were unchanged but there was a 1.5 to 2-fold increase in rosuvastatin levels, the latter being based upon data from historical controls. Based upon these results the authors suggest that these drugs could be used together, although probably best to start with low dose rosuvastatin and titrate up based upon response to therapy.
There were several presentations looking at the potential utility of screening for STIs in asymptomatic individuals. The significance of this is that the presence of STIs is a marker for unsafe sexual activity and if active infection occurs or the STIs are transmitted it can be associated with morbidity as well as increased risk of HIV transmission. One study by Dr. Rieg and colleagues from Harbor-UCLA Medical Center screened 212 HIV-infected men who have sex with men followed in an urban clinic. Survey information was collected along with testing for syphilis as well as gonorrhea and chlamydia in urine as well as at the pharynx and the rectal sites. These investigators found that 13 percent of subjects tested positive for 35 STIs, with many identified at the rectal and pharyngeal mucosa, locations that are not routinely screened in clinical practice. Those with STIs were all treated and proven to be cured of this infection and then all enrolled subjects were tested again at 6 months. At the second visit many subjects from the cohort were found to be newly infected. The strongest predictor of being infected was having had at least two partners in the last six months. This kind of data will be important for ultimately defining the optimal strategies for screening at risk individuals for asymptomatic STIs.
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