Panacos Pharmaceuticals Presents Key Data on the Novel Mechanism of Action Of its Lead HIV Drug Candidate, PA-457

Tuesday February 11, 12:00 pm ET

GAITHERSBURG, Md., Feb. 11 /PRNewswire/ -- Panacos Pharmaceuticals, Inc. today presents important new data demonstrating how its drug candidate PA-457 attacks and disarms the Human Immunodeficiency Virus (HIV). At the "10th Conference on Retroviruses and Opportunistic Infections" in Boston, MA, the Company provides compelling evidence that PA-457 is the first in a new class of HIV therapeutics that act at the end of the virus life cycle. Furthermore, PA-457 is effective against strains of the virus that are resistant to currently available drugs.

In a collaborative study with researchers at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD), Panacos scientists demonstrated that PA-457 selectively blocks a key step in HIV maturation, a process that occurs as the virus buds from infected cells. Following PA-457 treatment, the released virus particles have a defective core structure and are non-infectious. These results show conclusively that PA-457 has a mechanism of action quite distinct from currently approved drugs.

Data are also presented demonstrating that PA-457 potently inhibits clinical isolates of HIV as well as virus strains resistant to currently available drugs. Furthermore, PA-457 is synergistic in action with approved HIV drugs, an important characteristic since the compound would likely be used in combination with drugs that act at other points in the virus life cycle. The compound can be administered orally and results of pre-clinical safety tests are promising. Panacos plans to file an IND by mid-2003 to initiate human clinical trials.

"There is an enormous demand for new HIV drugs that are effective against drug resistant strains of the virus," commented Dr. Carl Wild, Panacos' Chief Science Officer and speaker at the Retrovirus Conference. "Our strategy is to develop therapeutic compounds that inhibit the virus in different ways than approved drugs. PA-457 is an example of a compound that has a novel mechanism of action and therefore is active against HIV strains that are resistant to current reverse transcriptase and protease inhibitors. As such, this drug candidate offers a completely new approach for treating HIV/AIDS."

Panacos is also presenting data from its HIV fusion inhibitor program at the Conference. Fusion to the human cell, the first step in virus infection, represents an attractive target for HIV drug development. Panacos scientists have extensive experience in fusion inhibitor discovery, having previously played major roles in the discovery of protein and peptide-based HIV fusion inhibitors that provide proof of concept for this approach. At Panacos they have designed a proprietary technology to discover small molecule, orally available fusion blockers that are likely to have a competitive advantage in the antiviral market.

Mymetics' Potent In Vitro AIDS Therapy Research Results to Be Presented at 10th Conference on Retroviruses and Opportunistic Infections

Tuesday February 11, 1:30 pm ET

ANNAPOLIS, Md., Feb. 11 /PRNewswire-FirstCall/ -- Mymetics Corporation  today announced that the Company will present research findings on a new approach to treating HIV and other retroviral diseases at the 10th Conference on Retroviruses and Opportunistic Infections. Mymetics is testing a novel class of anti-retroviral agents designed to disrupt molecular mimicry, an inter-reaction between a retrovirus and host cells discovered by the Company which contributes to disease progression. The Retroviruses Conference will take place at Hynes Convention Center, Boston, MA from February 10-14, 2003.

At the Retroviruses meeting, the Company will present its data in a poster entitled, "Highly-Conserved HIV-gp41 Peptides based on Molecular Mimicry are Potent Inhibitors of HIV-1 Replication." The poster will describe preclinical research concerning novel, gp41-derived peptides that are designed to inhibit HIV without the detrimental impact of immunosuppression. The poster presentation will appear Tuesday, February 11, Session Time 1:30 - 3:30 pm. Mymetics' Founder and Chief Scientific Officer, Dr. P.F. Serres, a co-author on the poster will also be present.

Data presented at the Retroviruses Conference focus on the exceptionally potent blocking ability of several Mymetics peptides in vitro against a range of more than 10 clades or strains of HIV. In certain cases, the Mymetics peptides' in vitro activity matches or exceeds the entry inhibitor agents recently shown to reduce viral load in human clinical trials.

For five of the HIV strains tested, peptides based on IL-2-homologous regions of HIV-gp41 were 28-, 66-, 5-, 13-, and 37-times, respectively, more potent inhibitors of HIV replication than peptides derived from regions of HIV-gp41 that are not homologous to IL-2. The Company believes that these findings demonstrate the value of anti-retroviral drug discovery based on an understanding of molecular mimicry.

Mimicry appears to provoke the body's own immune system into attacking IL-2 and those cells that produce IL-2, which may explain why HIV infection leads to AIDS and ultimately the fatal breakdown of the body's immune system. When antibodies and killer T-cells mount an attack against gp41, they also attack the host cell that is the source of IL-2, compromising the body's ability to defend itself. (IL-2 stimulates the normal activity of immune cells, including those generated to fight retroviral infection.) In addition, by binding to the IL-2 receptor, gp41 may interfere with the normal activity of IL-2.

Based on these results, the Company expects to continue to advance both its therapeutic and vaccine programs, and targets animal model (in vivo) tests within the next six months. The Company also anticipates the initiation of clinical trials in 2004 based on the successful completion of the preclinical program.

Recent Preclinical Results and Presentations

Previously, at the recent Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), the Company presented data on two novel gp41-derived peptides, each of which demonstrated potent inhibition of HIV in vitro. In addition, Mymetics' research teams have confirmed antigenic cross-reactivity between gp41, an HIV surface protein, and IL-2, a critical cytokine that Mymetics dubs the "maestro" of the immune response. This demonstrated mimicry between gp41 and IL-2 allows gp41 to bind to the host cell's receptor for IL-2, which the Company believes is a critical step leading to immunosuppression.

Furthermore, in December 2002, Mymetics presented early, preclinical potency data at the International Feline Retrovirus Research Symposium concerning small, anti-retroviral peptides, including one that was only eight amino acids long but still demonstrated significant activity despite its small size. The Company believes that this is in part due to the ability of this very small protein to retain its unique helical configuration.

While anti-FIV compounds constitute an interesting secondary market, Mymetics plans to apply its findings from its FIV program to the human model (HIV), targeting shorter peptides that would, in theory, be significantly less complex to make than large compounds presently in late-stage development. Shorter compounds would be less expensive to manufacture, easier to deliver, and offer superior bio-availability. Reduced complexity would also translate into greater availability for patients, and reduced cost to the healthcare system.

Anti-Retroviral Programs

Based on the Company's approach to molecular mimicry, Mymetics' scientists are pursuing multiple programs in retroviral diseases:

HIV Therapeutics: Mymetics is in the preclinical phase, developing and testing peptides and other compounds that adhere to gp41 or the IL-2 receptor site without suppressing the immune system. The Company's focus leverages its fundamental insight into gp41/IL-2 mimicry.

HIV Vaccine: The Company's researchers are also seeking to create a modified form of gp41 that generates an immune response against the viral protein, but not against IL-2.

Therapeutics to treat additional retroviruses: Mymetics is studying other retroviruses, including FIV and HTLV, which also display a form of mimicry. Some of these viruses are associated with diseases including certain leukemias (oncoviruses) and multiple sclerosis.

About Mymetics

Mymetics is an international biotechnology company developing therapeutic products and vaccines against retroviruses. The Company's R&D pipeline focuses on programs in HIV infection, as well as additional retroviruses associated with diseases that include certain leukemias (oncoviruses) and multiple sclerosis. Mymetics' key discovery-a subtle mimicry between HIV and the host cells-forms the basis of the Company's platform technology and pipeline.

Resistance Data Presented Show Early Use of Atazanavir May Lead to Increased Viral Susceptibility to Other Protease Inhibitors

Tuesday February 11, 1:50 pm ET

Data Presented at Major Medical Meeting Also Show Improved Virologic Suppression and Lipid Profile for Atazanavir Patients Previously Treated with Nelfinavir

BOSTON, Feb. 11 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb Company presented resistance data today at a medical meeting in Boston from several Phase II and Phase III studies of atazanavir, an investigational protease inhibitor (PI) under development for the treatment of HIV/AIDS. The data suggest that the I50L is the signature amino acid change following atazanavir treatment that results in atazanavir specific resistance and increased susceptibility to all other PIs. In addition, the Company presented data suggesting that long-term therapy with atazanavir resulted in sustained virologic suppression and that patients switching to atazanavir from nelfinavir (another protease inhibitor) exhibited improved virologic suppression and a significant decrease in serum lipid levels.

Resistance Data

Data presented suggested that early use of atazanavir may lead to increased viral susceptibility to other marketed protease inhibitors and may help preserve other treatment options due to the unique I50L amino acid change that leads to atazanavir-specific resistance.

The retrospective study of more than 1,500 patients treated in two Phase II and three Phase III clinical trials showed that overall, the emergence of atazanavir resistance was infrequent. Of the 26 atazanavir resistant isolates recovered from patients susceptible to atazanavir (used as the sole PI) at the time of treatment initiation, all contained the unique I50L amino acid change.

"The distinct resistance profile of atazanavir may help preserve future treatment options with other marketed protease inhibitors," said Richard Colonno, Vice President, Infectious Diseases Drug Discovery, Bristol-Myers Squibb. "If approved, atazanavir could provide physicians with additional flexibility in treating their patients should resistance to atazanavir occur."

Studies on recombinant viruses also showed that the I50L substitution was indeed responsible for this unique resistance phenotype. In contrast, isolates resistant to atazanavir at study entry failed to induce an I50L change and, subsequently, displayed higher resistance levels to both atazanavir and other protease inhibitors.

Virologic Suppression and Lipid Data

Data from a long-term, open-label observational switch study showed that patients who switched from nelfinavir to atazanavir for 24 weeks of treatment experienced improved virologic suppression and a clinically significant reduction of total cholesterol (TC), LDL (bad cholesterol) and triglycerides (TG).

Three hundred sixty-nine patients completing a Phase II dosing trial (BMS AI424-008) were eligible for the open-label switch trial (BMS study AI424-044), which looked at the safety and efficacy of atazanavir. After 72 weeks, patients were eligible to switch from a nelfinavir-based regimen to one containing atazanavir (400 mg once-daily), ZERIT® (stavudine) (40 mg twice- daily) and 3TC (150 mg twice-daily). Sixty-three subjects were switched from nelfinavir to atazanavir, and patients who were previously on atazanavir in the Phase II study remained on treatment.

Twenty-four weeks following a switch from nelfinavir to atazanavir, 86 percent of the 63 subjects had HIV-RNA less than 400 copies/mL, compared to 71 percent prior to the switch at study entry (ITT analysis). In addition, 59 percent of patients in the nelfinavir/atazanavir switch arm had HIV-RNA less than 50 copies/mL, compared to 50 percent of patients at study entry (ITT analysis).

Patients in the nelfinavir/atazanavir switch arm also experienced significant decreases in total cholesterol, LDL-C and triglyceride levels toward pre-antiretroviral treatment levels. Patients switched from nelfinavir to atazanavir experienced median reductions in TC from 202 mg/dL to 169 mg/dL; reduction in fasting LDL from 132 mg/dL to 99 mg/dL and reduction in fasting TG from 127 mg/dL to 102 mg/dL.

Discontinuations due to adverse events were infrequent and comparable across cohorts. Asymptomatic elevation in indirect bilirubin (without hepatic transaminase elevation) was the most frequent laboratory abnormality.

On December 20, 2002, Bristol-Myers Squibb submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for atazanavir, an azapeptide viral protease inhibitor of HIV-1. It is the first NDA for a protease inhibitor to be submitted with pharmacokinetic data supporting the potential for once-daily administration. In May 2002, Bristol- Myers Squibb filed for the registration of atazanavir with the European Medicines Evaluation Agency.

In the United States, Bristol-Myers Squibb is currently enrolling patients in an Early Access Program (EAP) to provide atazanavir to eligible patients infected with HIV. An EAP provides medicines to patients in need of alternative therapy prior to the medicine's approval.

HIV-infected patients who have experienced treatment failure with other available antiretroviral agents and who require an alternative antiretroviral agent in order to construct a new treatment regimen may be eligible to participate in the EAP. Reasons for treatment failure include a sufficient degree of antiretroviral resistance, intolerance or adherence problems. Physicians must use atazanavir in combination with two or more new or recycled antiretroviral agents. In addition, patients must meet other protocol- specified eligibility criteria.

Ugandan AIDS Vaccine Trials Begin on Humans

By Paul Busharizi

KAMPALA (Reuters) - Ugandan researchers have begun injecting volunteers with one of the world's few prototype HIV/AIDS vaccines targeting the strain of the virus ravaging East Africa, the research team said Tuesday.

The trial will involve uninfected volunteers in Uganda considered to be at low risk of HIV infection, who will be given the vaccine to see whether it is safe and creates immunity.

"The trials will go on for about two years after which we hope we can move it to the next phase," principal researcher Pontiano Kaleebu told Reuters.

About half a million people have died in Uganda from the deadly disease and it is estimated that about 1.5 million are infected with HIV, the virus that causes AIDS.

The vaccine being tested does not contain HIV and cannot cause HIV infection, Kaleebu said.

Researchers say the vaccine is the only one being tested on humans that is tailored to the virus common in Uganda and other East African countries, HIV subtype A.

Most vaccines being tested on humans are for subtypes other than A, the researchers said. It is possible that different vaccines may have to be developed to treat different subtypes prevalent in various regions, they added.

Making a vaccine against HIV is difficult because the virus integrates itself into cells and attacks the very immune cells that are normally stimulated by a vaccine.

In the early 1980s Uganda was at the epicenter of the AIDS epidemic but some studies show it has turned the tide of the disease by running an aggressive education program that advocates abstinence and safe sex.

Researchers said the tests were intended to build on progress being made in Britain and Kenya where volunteers have already undergone testing for the vaccine.

The first trial, in which the vaccine will be tested on the 50 volunteers, will precede a larger second phase, also involving uninfected, low-risk candidates.

A third phase is planned to test the vaccine on an even larger scale on a high-risk population.

Through government partnerships with international pharmaceuticals firms, treatment costs have fallen drastically to about 80,000 shillings ($42) a month from more than a million shillings five years ago.

The government-run Uganda Virus Research Institute (UVRI) and the International AIDS Vaccine Initiative (IAVI), a non-profit organization, are conducting the trails jointly.

48-Week Resistance Data Comparing GW433908, Boosted and Unboosted, With Nelfinavir in Treatment-Naive HIV+ Patients

Tuesday February 11, 3:30 pm ET

AT A GLANCE

-- After 48 weeks, no mutations characteristic of amprenavir (APV) resistance were observed in patients taking the investigational protease inhibitor (PI) 908 boosted with ritonavir. -- Mutations selected by unboosted 908 were consistent with those selected by APV. -- Mutations observed with other PIs were not detected among patients taking boosted or unboosted 908.

BOSTON, Feb. 11 /PRNewswire/ -- Forty-eight-week data were presented here today from two Phase III studies (NEAT and SOLO) of treatment-naive patients with HIV infection, evaluating the resistance profile of the investigational protease inhibitor (PI) GW433908 (908) dosed twice a day (BID) or 908 boosted with the PI ritonavir (908/r) dosed once a day (QD) compared to the PI nelfinavir (NFV) BID. The medications in both studies were administered as part of combination therapy that also included 300 mg abacavir (ABC) BID and 150 mg lamivudine (3TC) BID. ABC and 3TC are nucleoside reverse transcriptase inhibitors (NRTIs).

908 is the calcium phosphate ester pro-drug of amprenavir (APV) and was co-discovered by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals.

In the SOLO study, no patients (0 percent) in the 908/r arm, out of 32 subjects experiencing virologic failure or with ongoing viral replication, had detectable primary or secondary PI mutations. In contrast, 27 of 54 patients (50 percent) in the NFV arm developed primary or secondary PI mutations. The clinical relevance of the resistance data is currently under evaluation.

In the NEAT study, 5 of 29 patients (17 percent) who experienced treatment failure in the unboosted 908 arm had mutations characteristic of APV resistance. NFV-selected mutations were observed in 7 of 26 patients (27 percent) who experienced virologic failure in the nelfinavir arm.

In the NEAT study, mutations selected by 908 were consistent with the spectrum of mutations selected by APV. Mutations detected in patients taking unboosted 908 included I54L/M, M46I and V32I+I47V. Mutations observed with other PIs (D30N, I54V, V82A/T/S, L90M) were not detected among patients taking unboosted 908.

In the SOLO study, there was a statistically significant difference between 908/r QD and NFV BID in the incidence of treatment emergent mutations selected by either the study PI (P<0.001) or the NRTIs ABC and 3TC (P<0.001). There were no primary nor secondary protease mutations in the 908/r QD arm, including those associated with the development of resistance to APV or ritonavir. Likewise, there was no development of reduced phenotypic susceptibility. Emergence of resistance in NFV-treated subjects was significantly greater with D30N and/or L90M detected in 21 of 54 patients (39 percent) who experienced virologic failure.

The incidence of resistance to 3TC was significantly lower (13 percent) in patients treated with 908/r who experienced treatment failure or had ongoing viral replication (4 of 32 subjects) than those treated with NFV (57 percent; 31 of 54). Resistance to ABC was rare (<1 percent) across both the NEAT and SOLO studies, affecting only 5 of 900 patients exposed to ABC. Two isolates with a K65R mutation and three isolates with the L74V substitution were observed.

Emergence and incidence of resistance was determined using genotypic and phenotypic analyses of viral protease, reverse transcriptase and gag cleavage sites at baseline and during therapy for patients who were experiencing virologic failure or who had ongoing viral replication.

"The potential development of virological resistance is an important consideration for patients receiving combination therapy," said Doug Manion, M.D., vice president of Clinical Development, GSK. "The absence of PI- resistance selection at 48 weeks by 908 boosted with ritonavir is encouraging."

These data add to 48-week safety and efficacy results of the NEAT trial and 24-week safety and efficacy data from the CONTEXT trial, also presented this week, and 48-week data from the SOLO trial, presented in November 2002 at the 6th International Congress on Drug Therapy in HIV Infection in Glasgow, United Kingdom.

Summary of Clinical Trials with 908

More than 1,200 people have participated in three Phase III trials to test the safety and efficacy of 908: NEAT, SOLO and CONTEXT. NEAT was a Phase III, randomized, open-label, parallel-group, 48-week study that compared 908 BID and nelfinavir BID, both in combination with ABC and 3TC in 249 antiretroviral therapy-naive patients. The primary endpoint was the proportion of subjects with vRNA <400 c/mL at 24 and 48 weeks. Forty-eight-week data from the NEAT study will also be presented this week.

The SOLO study was an open-label trial with 649 HIV+, treatment-naive patients. Participants were randomized to receive either 1400 mg of 908 plus 200 mg ritonavir (908/r) QD or 1250 mg of nelfinavir BID. All participants also received the two NRTIs ABC and 3TC. The trial, conducted at more than 100 research centers worldwide, was designed to assess the safety and efficacy of each regimen over a period of 48 weeks.

The CONTEXT study is an open-label trial in PI-experienced subjects with prior virologic failure assessing 908 dosed at 700 mg BID in combination with 100 mg ritonavir, or 908 at 1400 mg QD in combination with 200 mg ritonavir, compared to a third treatment arm of 400 mg lopinavir/100 mg ritonavir BID. Participants also receive two NRTIs. The trial is fully enrolled with more than 300 patients and is being conducted at more than 100 research centers worldwide. The study is assessing the safety and efficacy of each regimen at 24 and 48 weeks. Results at 24 weeks from the CONTEXT trial will also be presented here.

Once approved, GSK will market 908 and GSK and Vertex will co-promote it in the United States and key markets in Europe.

GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

Expanded Clinical Data on Ampligen(R) in HIV Disease to Be Presented at The 16th International Conference on Antiviral Research

Wednesday February 12, 8:50 am ET

Phase II B Study Evaluates Experimental Immunotherapy in 'Holiday' Period When Antiviral Cocktails are Discontinued

PHILADELPHIA, Feb. 12 /PRNewswire-FirstCall/ -- Hemispherx Biopharma Inc., a leading company in the experimental-stage development of immune based therapies primarily addressing the diseases of HIV/AIDS and Chronic Fatigue Syndrome, announced today that its clinical abstract entitled: "A Phase II B Prospective, Randomized, Control Study Evaluating Ampligen® During Structured Treatment Interruption (STI) of HAART in HIV Infection" has been selected for oral presentation at Session I of the 16th Annual International Conference on Antiviral Research on Monday, April 28, 2003 at 11:15 a.m.

The selection of the clinical results for oral presentation at the distinguished congress of international researchers followed a rigorous peer-review process by medical scientists, unaffiliated with Hemispherx, with expertise in human immunology and viral infections.

The upcoming presentation will expand upon ongoing clinical trials referenced earlier at international meetings in Prague, Barcelona and Naples (Florida) within the last eight months. The results, performed in collaboration with LabCorp of America, Inc, the owner of ultra sensitive HIV measurement technology, will emphasize changes in the blood's HIV concentration and the number and character of immune cells,

Currently, clinical research sites in the U.S., located in California, Connecticut, Florida (2 sites), New Jersey, New York, Pennsylvania and the District of Columbia (Washington, D.C.), are running two Phase IIb Clinical Trials testing the efficacy of Ampligen® as a viable combination therapy (Salvage) used in conjunction with approved antiviral regimens as well as a potential Strategic Treatment Intervention (STI), where patients' antiviral regimens are interrupted and Ampligen® is substituted to minimize the debilitating side effects inherent with antiviral therapy.

Sex Riskier When Internet Used to Find Partners

By M. Mary Pennell

BOSTON (Reuters Health) - Results of a survey of men who seek male sex partners on the Internet suggest that such men are likely to engage in high risk sexual behavior, usually preceded by recreational drug use or drinking.

Dr. Sabina Hirshfield, deputy director of research and evaluation at the Medical and Health Research Association of New York City, presented the findings here at the 10th Annual Conference on Retroviruses and Opportunistic Infections.

She said the 2,934 men were recruited through chat room banners posted on Gay.Com, a popular gay Web site, during June and July of 2002. The men completed a 60-item online questionnaire asking about sex, drug use and drinking patterns over the previous six months.

In an interview with Reuters Health, Hirshfield said the survey was anonymous so "there is no way to verify the information, but previous studies of computer-generated surveys suggest that people are more willing to honestly disclose risky sexual behaviors to a computer instead of a face-to-face or telephone interview."

Generally the men were, "young, white and well-educated," and all the men were over age 18, she said. Eighty percent reported sex only with men, 19% with men and women, and less than 1% only with women. Overall, 8% of the men were HIV infected.

Twenty-seven percent of the men reported having more than 100 lifetime sex partners and 6% of them said they had had more than 10 partners in the past 30 days.

About 84% met sex partners online and 64% of these men who found partners online said they often had unprotected anal sex, compared to 58% of men who said they did not meet sex partners on the Internet.

Eighty percent of HIV-infected men surveyed reported they had HIV-negative partners. Among those who met partners online, HIV-infected men were more likely than HIV-negative men to report having unprotected anal sex. Of the 10 men who were diagnosed with syphilis during the six-month period, nine said they met their sex partners on the Internet and four reported being HIV infected.

Overall, 43% reported engaging in some type of illicit drug use and 34% reported drinking until drunk one to three days per week.

The factors associated with unprotected sex were age younger than 30, no college education and the use of recreational drugs or excessive drinking before sex, Hirshfield said.

HIV Drugs May Cut Older Adults' Death Risk More

NEW YORK (Reuters Health) - The potent drug "cocktails" used to fight HIV may be particularly effective at prolonging older adults' lives, according to a new study.

Some past research has suggested that, compared with younger individuals, HIV-positive people older than 50 may have a blunted immune-system recovery when on highly active antiretroviral therapy (HAART).

But the new study suggests that when it comes to life and death, HAART actually benefits older patients more.

When researchers looked at nearly 800 HIV-positive adults who had or had not received HAART, they found that treatment cut the risk of death by 72% among those age 50 and beyond.

Treatment also slashed younger adults' death risk, but by a less-dramatic 58.5%.

Drs. John L. Perez and Richard D. Moore of Johns Hopkins University in Baltimore, Maryland, conducted the study. The findings appear in the January 15th issue of the journal Clinical Infectious Diseases.

Because HAART carries significant side effects, and because its ability to restore older people's immune systems has been questioned, it is important to see whether treatment does in fact prolong older patients' lives, according to the researchers.

Based on their findings, they conclude that HAART "substantially improves the survival rate for older individuals and supports the importance of treatment in this group."

The study included 253 patients aged 50 and older and 535 between the ages of 18 and 49 seen at the Johns Hopkins HIV Clinic between 1990 and 2001.

Overall, there were nearly twice as many deaths in the older group. But among patients who received HAART, 83% of older patients were alive three years after starting treatment, as were 89% of younger patients.

SOURCE: Clinical Infectious Diseases 2003;36:212-218.

Study: Experimental AIDS Vaccine Safe for Babies

By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - An experimental AIDS  vaccine seems to be safe for babies born to women infected with HIV, and early signs suggest it may help protect them from infection, U.S. researchers said on Wednesday.

The vaccine, made by Aventis Pasteur, is one of dozens being tested although few experts believe any of them could actually prevent HIV infection in a global population.

Instead, doctors are hoping to use different vaccines on different groups in the hope of preventing some infections.

One of these areas is in mother-to-child transmission of the AIDS virus. About a quarter of children born to HIV-infected mothers catch the virus, either during birth or through breast milk.

Giving the mother and baby drugs can reduce this risk, but a vaccine might be safer, more effective and perhaps cheaper.

A network of doctors across the United States, led by Dr. Elizabeth MacFarland of the University of Colorado Health Sciences Center, tested Aventis Pasteur's experimental ALVAC-HIV vCP205 -- which is a vaccine using canarypox, a distant relative of the virus used in the smallpox vaccine -- combined with several proteins from the AIDS virus.

The idea is to prime cells to recognize and destroy cells infected with HIV.

They tested 23 babies with four doses of the vaccine. All were born to HIV-infected mothers in the United States.

It was a phase I-II study designed to show that the vaccine was safe, not to prove it works, said Aventis Pasteur's Jim Tartaglia.

"It wasn't designed as an efficacy trial. You would have to do a whole new trial to show that," Tartaglia, head of research for the company, said in a telephone interview.

The study showed the vaccine was safe, with no serious side-effects in the babies, the researchers told the 10th annual Conference on Retroviruses and Opportunistic Infections in Boston, the major annual scientific meeting on AIDS.

Tartaglia said it often takes a long time, sometimes years, to determine whether a baby has contracted the AIDS virus. The babies were not tested to see if they contracted HIV but the vaccine did cause an immune response in the babies, which would suggest it may help to prevent HIV infection.

DISCUSSIONS IN AFRICA?

Tartaglia said Aventis Pasteur is now deciding what to do next. He said the company would discuss this with authorities in Africa -- the region hardest-hit by HIV -- and the National Institutes of Health in the United States.

A separate team of researchers tested a slightly different version of the vaccine in HIV-infected adults who had been keeping the virus controlled using drugs.

A strong cocktail of medicines known as highly active antiretroviral therapy or HAART can keep AIDS at bay and keep patients healthy, but they are expensive and have unpleasant side-effects.

And the virus can eventually mutate to resist the drugs, forcing doctors to re-formulate the cocktail.

Many researchers are testing the idea of a "drug holiday" to give patients a break and the give the body a chance to fight the virus on its own.

A team of French researchers told the conference they tested 48 patients on HAART with four doses of the vaccine. Four months after starting, they were taken off HAART.

Again, the study was meant to show the approach was safe and the researchers noted no severe reactions to the vaccine.

After 44 weeks, 21 percent of the patients still have the virus well under control and have not needed to re-start the drugs, they said.

Tartaglia stressed it is too soon to tell whether the vaccine can be used to relieve patients on HAART.

"Is it a six-month drug holiday? Is it a 12-month drug holiday? I think we are in the early stages of the field," he said.

Based in Lyon, France, Aventis Pasteur is owned by French drugmaker Aventis SA.

Vaccine Said Unlikely to Protect From AIDS

By DANIEL Q. HANEY, AP Medical Editor

BOSTON - The death of three monkeys that had gotten an AIDS vaccine in a Boston lab suggests that a closely watched strategy intended to blunt the deadly progression of HIV may not provide total protection from the disease.

For several years, researchers have concentrated on crafting vaccines that prompt the body to mount a vigorous challenge to HIV and hold the virus in check.

Much of the enthusiasm for this approach comes from experiments on monkeys, which appear to survive for years with these vaccines even after they receive high doses of the monkey form of HIV.

However, at a conference Wednesday, researchers from Beth Israel Deaconess Medical Center in Boston who helped develop the strategy reported that monkeys eventually appear to fall sick and die, even after showing promising resistance to the virus.

"This suggests that viral escape will prove to be a challenge," Dr. Daniel Barouch, one of the Boston researchers, said at the 10th Conference on Retroviruses in Boston.

In his experiment, three of four vaccinated monkeys got sick during three years of follow-up after their shots with an experimental vaccine created by Merck & Co.

Typically these new vaccines take a two-step approach. The first, called the prime, is HIV genes that are injected into muscle, where they are taken up by cells and result in production of viral proteins. The second is the boost, often a harmless hollowed-out virus that carries in more HIV genes.

Together, if all goes as planned, they induce the body to mount an attack by killer T cells that destroy HIV-infected cells. This may not prevent an infection, but it can minimize its consequences by keeping virus levels low.

Dr. David Ho, scientific director of the Aaron Diamond AIDS Research Center in New York City, said the monkey deaths are "enough to be worrisome."

In fact, Ho said the emphasis in the vaccine field seems to be shifting back toward an older strategy that many had dismissed as unworkable against HIV. Ordinarily, vaccines do their job by prompting the immune system to churn out antibodies that recognize an invading germ and kill it before it ever establishes an infection.

Even though the body readily makes antibodies against HIV, they cannot penetrate a thick coat of sugar that covers the virus' surface. However, new studies suggest it is possible to concoct antibodies that actually do kill HIV, and studies are under way to find ways to trigger their production.

Several vaccines based on the prime-boost approach are already in human testing, and the Boston monkey results do not mean they are doomed. The monkeys received only the prime, not the boost, stage of the strategy, and some experts said the experiment is not a fair test of the current generation of vaccines.

Among the furthest along are vaccines from Merck that have been given to about 600 human volunteers so far.

"You shouldn't read too much into it," Dr. Emilio Emini, head of Merck's AIDS vaccine program, said of the monkey results.

He said effective vaccines using this strategy will almost certainly be more sophisticated than the one used in Boston, since they will carry in more viral genes, giving the body more targets to mount a defense.

Dr. Norman Letvin, another of the Boston researchers, said scientists assumed from the start that the vaccine would not always stop the virus completely. Unvaccinated monkeys fared even worse, so "this tells us that a T cell vaccine has the ability to slow disease progression."

At Wednesday's meeting, Merck scientists presented data on another experimental vaccine that appeared to be still working well in monkeys 2 1/2 years following infection with an especially aggressive form of the virus.

"I am encouraged," said Merck's Dr. John Shiver. "There are very obvious things we can do to improve that vaccine."

Furthest along in testing is VaxGen's AIDSVax vaccine, a more traditional approach using the outer shell of the AIDS virus. It has already been given to 7,900 volunteers in America, Europe and Thailand. Results are expected within a month or two.

Drug-Resistant HIV Passed Through Breast Milk

By Deborah Mitchell

BOSTON (Reuters Health) - HIV-infected women given a single dose of the anti-AIDS drug nevirapine during labor to prevent them from transmitting the virus to their baby harbor HIV in their breast milk that is resistant to the drug, according to the results of a small clinical trial.

The most common mutation found in the new study is associated with resistance to all other drugs in nevirapine's class, a team of researchers from California and Africa report. This could mean that the women are at risk of transmitting drug-resistant disease to their infants through breast milk.

Dr. Constance A. Benson of the University of Colorado Health Science Center in Denver, who did not participate in the study, said the findings don't warrant a change in policy. In settings where health care resources are scarce, she explained, the benefits of giving laboring HIV-positive women nevirapine to prevent their baby from becoming infected probably still outweigh the risks.

Dr. John Mellors of the University of Pittsburgh, Pennsylvania agreed. "To change policy based on these data would be a very big mistake."

The concentration of drug-resistant virus in breast milk was significantly higher than levels detected in the blood, Dr. E. Lee of Stanford University in Palo Alto noted here at the 10th Conference on Retroviruses and Opportunistic Infections on Wednesday.

Lee and colleagues at Stanford and at the University of Zimbabwe, Harare, followed HIV-infected women in Chitungwiza, Zimbabwe, who participated in a study in which they received a single dose of nevirapine at the onset of labor.

The women were subsequently monitored for HIV levels in plasma, the cell-free portion of the blood, and breast milk at two, eight, 16 and 20 weeks after delivery. Complete information was available for plasma samples and breast milk samples for 33 and 20 women, respectively.

After eight weeks, mutations in breast milk associated with nevirapine resistance were detected in 13 of the 20 women (65%), while such mutations were found in plasma in eight of the 33 women (40%). Four infants had confirmed HIV infection.

The most common mutation the researchers found is known to confer resistance to other drugs in the same class of drugs as nevirapine, known as non-nucleoside reverse transcriptase inhibitors.

All of the women were infected with a type of HIV known as subtype C. Whether these findings can be generalized to other HIV subtypes must be confirmed.

Changes in Prevalence of Mutations Associated with HIV Treatment Failure; Resistance Data on Mutation Patterns Can Help Predict Future Treatment Options

Thursday February 13, 3:30 pm ET

AT A GLANCE

-- The prevalence of most key mutations associated with antiretroviral resistance have changed significantly from 1999-2002.

-- The largest increase was seen in the K65R and Y115F mutations, while thymidine analog mutations (TAMs) and most mutations associated with protease inhibitors have decreased steadily.

-- Resistance data from mutational patterns associated with specific drug combinations may be useful in predicting potential treatment failure or choosing future treatment options.

BOSTON, Feb. 13 /PRNewswire/ -- The results from a longitudinal study of the relative frequency of various types of HIV mutations associated with the use of antiretroviral therapy (ART) were presented today at a meeting of leading AIDS researchers. The study showed that the prevalence of most key mutations associated with antiretroviral resistance have changed significantly from 1999-2002.

Specifically, the results showed that the prevalence of thymidine analog mutations (TAMs) and other key mutations associated with HIV drug resistance has decreased significantly as reported in the LabCorp Database in recent years, while mutations such as K65R and Y115F are on the rise.

"Although further studies are needed to determine the reasons behind these findings, the increased use of three drug regimens, the introduction of new drugs and/or drug combinations and changes in the submission of patient samples for genotyping may all be factors affecting the changing patterns of HIV mutations in this large sample," said Doug Manion, M.D., vice president of Clinical Development, GSK.

The results come from a longitudinal study of the relative frequency of all primary mutations and many combinations of mutations associated with ART from January 1, 1999, through July 1, 2002. The study involved nearly 38,000 genotypic tests performed between 1999 and mid-2002 to identify mutations associated with HIV resistance to antiretroviral drugs, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

Trends in the use of specific antiretroviral therapies in the United States during the same time period also were presented by the researchers.

Study investigators noted that the databases used are not linked, and the results show independent trends, not a direct correlation between drug usage and mutation incidence. However, the data show that the changes in prescribing patterns of antiretroviral therapy and in the mutations associated with specific drugs or drug combinations follow expected parallel trends. Further studies are warranted to directly show the relationship between mutations, antiretroviral therapy choices and clinical practices.

The following trends were seen in mutations associated with resistance to the three classes of drugs included in the study:

    Wild-Type

    -- Wild-type samples increased from 29 percent to 37 percent.

    NRTIs

    -- The greatest proportional increases were for K65R (from 0.64 percent to

       1.69 percent) and for Y115F (0.59 percent to 1.42 percent).

    -- TAMS decreased steadily, including: T215Y (32 percent to 23 percent);

       D67N, K70R and 219E/Q (13 percent to 8 percent); and M41L, L210W and

       T215Y (17 percent to 11 percent).

    -- L74V also decreased (9.77 percent to 7.85 percent).

    -- No significant changes were seen in M184V (44 percent to 42 percent),

       T69SXX (0.81 percent to 0.73 percent) or Q151M (1.79 percent to 1.39

       percent).

    NNRTIs

    -- Y181C decreased from 19 percent to 12 percent.

    -- K103N was stable (29 percent to 30 percent).

    Protease Inhibitors

    -- All PI-associated mutations decreased with the exception of a small

       increase in I50V.

    -- The most pronounced decreases were seen for M461/L, V82A, 184V and

       L90M.

"Resistance to antiretroviral therapy is a major factor that limits the effectiveness of drug therapy. As specific drugs increase or decrease in usage, the prevalence of mutations associated with those drugs should also rise or fall, although many other factors may alter the rate of mutant selection," said Manion.

Resistance Data May Help Predict Best Options

In a related study, resistance data were used to evaluate the median phenotype for 30 mutational patterns associated with resistance to NRTIs. Although further study is needed to determine utility in clinical practice, study investigators believe the technique may be useful to minimize the potential for the rapid selection of mutations resistant to multiple NRTIs arising from specific drug combinations, and guide the selection of treatment options after virologic failure.

"For example, patterns involving 65R and/or 74V in conjunction with M184V are associated with resistance to multiple NRTIs, and require substantially fewer mutations than TAM patterns associated with resistance to multiple NRTIs. TAMs individually and in many combinations do not increase phenotypic resistance to the NRTIs as much as some individual NRTI-associated mutations," said Manion.

In the study, a major database was searched for paired genotypes and phenotypes, and 10,478 unique pairs were studied based on clinically determined phenotypic "breakpoints" associated with resistance to the various drugs in the NRTI class.