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Highlights From the 10th Annual Retrovirus Conference

By Dan Dunable

April 2003

In February of 2003, over 3,900 of the world's leading medical researchers and clinicians met in Boston for what is considered by many to be the most important scientific conference on HIV/AIDS held each year. The 10th Annual Conference on Retroviruses and Opportunistic Infections, also known as the Retrovirus Conference, is "a scientifically focused meeting for the world's leading researchers working to understand, prevent, and treat HIV/AIDS and it's complications."

The conference is sponsored by the Foundation for Retrovirology and Human Health in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) and the Centers for Disease Control (CDC).

Most of the meeting, including abstracts, poster presentations and even many Webcasts of plenary sessions and symposiums are available online at the official conference Web site: www.retroconference.org/2003.

This year's conference began with a press conference featuring members of the Scientific Program Committee as well as William Jefferson Clinton, 42nd President of the United States, this year's keynote speaker.

David Ho, M.D., who chaired the press conference, was also the Chair of the Scientific Program Committee this year. He expressed excitement and optimism about the research being presented this year in the area of vaccines. The "shift from emphasis on [vaccines focused on] killer T cells to neutralizing antibodies" is very encouraging and may have a major impact on vaccine development.

Harold Jaffe, M.D., from the CDC, gave a brief update on epidemiology, reminding us of the continuing spread of HIV in the United States where approximately 50% of new infections are disproportionately in African Americans. He suggested that the increases in new infections here may be accounted for by "fading memories" of the initial devastation of the disease before HAART, as well as illicit drug use, optimism of current treatments available, and the use of the Internet (which is an avenue for easy, anonymous sex) -- particularly among gay men. Dr. Jaffe stated that approximately 25% of those here in the U.S. who are HIV positive are unaware of their infection, and that voluntary HIV testing should be a routine part of medical care with an increased emphasis on early detection.

Constance Benson, M.D., from the University of Colorado Health Science Center in Denver, highlighted several treatment issues that she felt were especially significant. One particularly disturbing study looked at nevirapine drug resistance showing up in HIV-infected women's breast milk given nevirapine to reduce the chances of passing on the virus to their newborn. Nevirapine has been shown to be extremely effective at reducing vertical transmission when given as a single dose to the mother at the onset of labor and again to the infant as prophylaxis. However, breast-feeding by the mother is another risk factor of transmission and, in this study, nevirapine-resistant virus was found in higher concentration in the breast milk than in the mother's plasma, indicating a possible risk of infecting the newborns during breast-feeding with a strain of the virus that is not only resistant to nevirapine, but likely resistant to the entire class of nonnucleosides, of which nevirapine belongs. Dr. Benson stressed that she would not, at this time, change any recommendations regarding the use of nevirapine for reducing vertical transmission since it is extremely effective and we don't yet know the clinical impact of the resistance found in this study. This subject needs to be studied much further before assumptions can be made.

Dr. Benson also stressed the importance of other studies being presented this week, including some which looked at the risk of heart disease in persons receiving HAART, as well as the impact of hepatitis viruses on HIV infection. She was particularly excited about one study, which showed that solid organ transplantation was as favorable for HIV-infected as for those who were not HIV positive.

Next was John Mellors, M.D., from the University of Pittsburgh School of Medicine. Dr. Mellors was optimistic about this year's conference, as he said that this is "an exciting and important year" in research with studies being presented showing many new drugs in the pipeline -- including new drug candidates that will block the entry of HIV into the cells, as well as the targeting of existing classes of drugs with new products designed to overcome resistance. Dr. Mellors also stressed that existing therapies are improving, especially regarding pill burden and frequency of dosing, and that this "ease of medication is contributing to the success [of antiretroviral therapy]." He was very excited about the ability of these therapies to work in resource-limited settings. Dr. Mellors cited abstracts presented during this year's conference that showed the effectiveness of once daily dosing in geographical areas many thought incapable of providing effective treatment. These studies demonstrate that the treatment of HIV is "shifting from logistics to an ethical issue." He said that it is now a "matter of generating resources so HAART can be given."

In a question and answer press conference with former president Clinton, many of the questions to President Clinton were regarding the current administration's increase of AIDS funding globally. Clinton felt that we are now at "an appropriate level of giving" as relating to our resources. He hopes that the U.S. will give money to countries that will partner with us to ensure that the money is used appropriately, and also stated that our increase in funding will hopefully motivate the Europeans to also increase their giving. He felt that the European countries should direct their efforts towards the former Soviet Union, which currently has the fastest growing rates of new infections.

President Clinton stated that the biggest problem globally was the lack of a comprehensive system in place that would provide a reproducible program with which countries that are failing in their efforts to control HIV infection could copy the efforts of those countries that are having success, such as Uganda. He also admitted that he was wrong when, while president, he opposed needle-exchange programs. In a comment related to both needle-exchange and education efforts regarding condom effectiveness, he stated that we should "let science, not politics, triumph over prevention."

President Clinton closed the press conference by stating that "this is [also] an American problem," referring to thoughts by some that the reasons for rising infection rates among certain populations here in the U.S. are beliefs that HIV is now a problem overseas, and not here at home anymore.

After the press conference, the Opening Session began with a discussion of the evolution of human retroviruses by John Coffin, followed by a very moving performance by an HIV-positive choir from Durban, South Africa called Sinikithemba and a keynote lecture by President Clinton.

The founder and director of Sinikithemba gave an impassioned speech about her life as an HIV-infected woman in South Africa. She only has access to antiretrovirals because of a pilot study being conducted in her country. She stressed that the beliefs held by many that people in resource-limited areas will not adhere to HAART are totally unfounded. She has been on HAART for over 6 months, has lived without electricity, running water and any money during portions of that time and yet she has NEVER missed a single dose of her medications. She moved the audience of scientists and researchers and received an extended standing ovation when she finished her talk.

President Clinton (who volunteered his time for this conference) next gave his keynote lecture. He covered many of the points he also discussed during the press conference, but this time to a crowd of close to 4,000 as opposed to the 100 or so reporters present at the press conference. His presence and determination seemed to move the audience, especially as he stated his appreciation for the work done by those attending. He acknowledged that many of us in the audience have been working in this field for many years. He said that we should all feel proud when the history books describe this pandemic, that we were part of the solution, and that many could be taking an easier road working elsewhere, and probably earning a better living.

President Clinton stressed the need to end this war on condoms and again apologized for his stance on needle exchange while he was in office. He stressed that we need to ensure that the current administration's increase in global AIDS funding does not come from monies taken away from other healthcare programs; that it needs to be new money and that more of it should go through the Global AIDS Fund.

The Opening Session closed with his plea for the scientists, researchers and community activists in the audience to not get discouraged, that if we "keep at it, we will prevail."

On Tuesday, February 11th, the actual scientific portion of the Retrovirus Conference began, with over 800 abstracts presented as either oral or poster sessions. The Oral Abstracts, which number close to 200, were abstracts submitted that the Scientific Program Committee viewed as important enough to have one of the investigators of the study give a live presentation, usually lasting 15 minutes, to the attendees at the conference. In addition 7 plenary lectures took place, as well as 10 roundtable symposia.

The Retrovirus Conference is an International Scientific Conference. Although the predominance of the abstracts submitted were from North America (approximately 68%), many were submitted from other parts of the world, most notably Europe, along with a small amount from Asia, Africa, Oceania and South America. The majority of the abstracts submitted originated from various Universities (approximately 55%), with the balance coming from governments, hospitals, industry, private practice and other groups.

Tuesday's first plenary lecture featured Ronald O. Valdiserri from the CDC in Atlanta, GA, discussing his abstract "Preventing New HIV Infections in the U.S.: What Can We Hope to Achieve?" (Abstract 4). The CDC estimates that between 850,000 and 950,000 persons in America are currently living with HIV or AIDS with approximately 280,000 of them are unaware that they are infected. The primary reason most people here are being tested and becoming aware of their HIV-positive status is because they become sick and receive an HIV antibody test as part of their medical treatment. Even though we are in the beginning of the third decade of this epidemic, many people in the U.S. are still not finding out about their HIV infection until they become sick. Less than 1 in 5 of the people newly diagnosed in the U.S. each year stated that they were tested because "it was recommended to them."

HIV incidence in the U.S. has been fairly stable for the last decade or so at approximately 40,000 new infections per year. However, recent trends in HIV diagnosis, sexual behavior among HIV-positive persons and recent syphilis outbreaks -- especially among men who have sex with men (MSM) -- indicate a need for better HIV testing and prevention services. It has been shown that awareness of their HIV status motivates many HIV-infected persons to practice safer sex behaviors and that there is a strong need to provide HIV testing and prevention services as a routine component of health care. Health care providers can play an important role in preventing the spread of HIV in the U.S.

There were numerous abstracts presented that detailed new agents being studied as possible antiretrovirals. One of these new drugs, TMC114 is a protease inhibitor (PI) currently in Phase I and Phase II trials to evaluate its safety as well as antiretroviral activity. Abstract 8 described the results of administering TMC114 with a low dose of ritonavir (TMC114/r) in a group of 50 PI-experienced patients. All 50 patients were currently failing a PI-containing regimen at study entry, and most of these patients (97%) responded to the drug. This study demonstrated that TMC114 is safe and well tolerated by patients, as well as effective in patients that have developed resistance to other PIs.

Another abstract presented also reflected the general feeling of optimism so present at this year's conference regarding the "bumper crop" of new candidates for antiretroviral therapy, as noted by David Mellors, M.D. Abstract 14lb, presented by Diego Miralles, described a new fusion inhibitor in clinical trials presently going by the name T-1249. Although this was a small study of only 50 patients, many of the scientists present at this conference considered the results especially important and encouraging. T-1249 was shown in this study to be effective at suppressing virus that had become resistant to another fusion inhibitor, T-20, which was FDA approved on March 13, 2003. The reason for the excitement was the realization that we already have in the pipeline, an antiretroviral that will work in those people who become resistant to a drug that was just approved.

Additionally, there were abstracts presented which detailed new drugs in existing classes of approved antiretrovirals; nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and the protease inhibitors (PI). There were also many new drugs being studied in classes yet to be approved, drugs which it is hoped will be effective at treating patients who have become resistant to currently approved antiretrovirals, and also which will hopefully be even more effective at achieving and sustaining virologic and immunologic responses. Some of these new drugs are in the classes of fusion inhibitors, integrase inhibitors, entry inhibitor co-receptors and maturation inhibitors.

As stated repeatedly during this year's conference, the abundance of new drugs being studied, both in existing classes and new classes, is exciting and cause for much optimism regarding the future of antiretroviral therapy.

One of the plenary lectures presented at this year's conference was entitled "Mechanisms of HIV Neuropathogenesis" (Abstract 58) and was presented by Donna Gabuzda, M.D., from the Dana-Farber Cancer Institute and Harvard School of Medicine here in Boston. In this lecture, Dr. Gabuzda described the impact of HIV on the central nervous system (CNS), primarily through the development of dementia and other neurologic disorders.

Although the incidence of HIV-associated dementia (HAD) has declined greatly since the emergence of HAART, HIV neurological diseases are now becoming more common once again as persons are living longer. A major reason for this is the difficulty of most of the currently approved drugs ability to cross into the CNS, which in turn allows the CNS to become a reservoir for long-term viral persistence. Neuro-invasion of HIV occurs by way of the trafficking of infected monocytes, particularly CD16+ monocytes, across the blood-brain barrier. HAD seems to occur in late stages of the disease likely due to factors such as the loss of immune control associated with disease progression, increased immune activation, increased trafficking of activated monocytes into the CNS and the late emergence of viral variants that impact CNS disease progression. Risk factors for HAD appear to be CD4 T-cell counts less than 200, high viral load, anemia and older age.

Dr. Gabuzda described the role of CD16+ monocytes on the progression of HAD and ascertained that increases of CD16+ monocytes increase the risk of HIV-associated dementia regardless of CD4 T-cell count. Understanding more about the role of these CD16+ monocytes and improving the ability of antiretroviral drugs to cross into the CNS will help prevent and treat HAD in the future.

Numerous oral abstracts were presented dealing with immune-based therapies and treatment strategies. Oral Abstract 62, presented by Y. Levy, the principal investigator of this study originating from France, described the impact of combining two therapeutic vaccines, the ALVAC-VIH 1433 and Lipo-6T, along with administration of interleukin-2 (IL-2) during structured treatment interruptions in chronically infected patients. 70 patients were enrolled in this study, all with CD4 >350 and HIV RNA viral loads <50 copies. They all had been treated for at least one year either with HAART alone or in combination with IL-2. The control group (n=37) stayed on HAART alone, while the treatment arm (n=33) received the two vaccines at weeks 0, 4, 8 and 12 followed by three cycles of IL-2 at weeks 16, 24 and 32. All patients in both arms with viral loads <50 at week 36 were proposed to stop HAART at week 40.

At week 40, 91% (63/69) of patients did stop HAART. At week 52, 5% (2/37) of the control arm (no vaccines or IL-2 during study) were still able to stay off HAART, while 24% (8/33) of those who received the vaccinations and IL-2 were able to continue without HAART. Re-initiation of HAART had been recommended if patients viral load rose to >50,000 at week 44, or >10,000 copies after week 48.

The study coordinators concluded that the vaccines were safe and well tolerated, and that the administration of the two vaccines along with IL-2 in this study resulted in a higher frequency of immunological response, a sustained immunological response, and also a sustained virologic response. There was a suggestion that the IL-2 was not needed for the immunological responses shown in this trial, although it may have been needed for the virological response.

Numerous abstracts were also presented which delved even more deeply into the subject of treatment interruptions, which seemed to dominate the number of abstracts involving treatment strategies. Abstract 64, by J. Ananworanich, was a particularly well presented study describing the results of a trial conducted by the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT 001.4). This trial compared two different treatment interruption strategies against a control arm receiving continuous HAART.

One treatment interruption strategy was based on CD4 counts. In this arm, treatment interruptions were begun if CD4 cells rose to >350 copies or above 30% of baseline. Treatment was re-initiated if CD4 T cells went below 350 copies or dropped to 30% below baseline. The other treatment strategy was a one-week on/one-week off HAART cycle approach. Again, the control arm did not receive any treatment interruptions; they remained continuously on HAART throughout the trial.

All three arms had similar clinical, adverse event and quality of life outcomes. The proportion of patients were also similar in all three arms with regards to achieving CD4 counts >350 at study end, although the CD4 guided arm did show the largest CD4 count decreases during the study. The week on/week off arm had the largest virologic failure rate with 30%, although each of the failures regained viral loads <50 copies and CD4 counts above 350 after resuming their antiretroviral regimen. There were no failures in either the continuous treatment arm or the CD4 guided treatment interruption arm.

The percentage of time on antiretroviral therapy for each arm was 100% for the continuous treatment arm, 33% for the CD4 guided arm, and 59% for the week on/week off arm. The study coordinators concluded that the CD4 guided treatment strategy was the best antiretroviral cost saving strategy and had similar virological outcomes to continuous treatment.

There were also presentations held concerning research on microbicides. Because of the likely inability to find a true vaccine against the acquisition of HIV in the near future, and the lack of options available to prevent HIV infection (abstinence and condoms don't provide enough options for everyone, and are not options for many, especially under-empowered women in many parts of the developing world), more and more research is being devoted to the subject of microbicides.

One abstract (Abstract 105), presented by Z. Ambrose of the National Cancer Institute, delivered unexpected, and disappointing, results. In initial clinical trials of a vaginal microbicide being tested in control animals (macaques), the potential microbicide BCD (2-hydroxypropyl-betacyclodextrin) was enormously successful in reducing SIV (the simian equivalent to HIV) transmission in the control animals. However, as presented in new data here at the Retrovirus Conference, a re-challenge of SIV to the control animals after vaginal administration of BCA did not provide protection of transmission of SIV. The reason why the potential microbicide failed to provide protection during the second challenge, even though it did during the initial challenge is not yet known. Further research is being conducted to examine this.

For additional information from the Retrovirus Conference, please visit the Treatment Resource Center at AIDS Survival Project in Atlanta, GA, or visit the official conference Web site at www.retroconference.org/2003.




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