Website Launched For 2010 National Latino AIDS Awareness Day – A new website has been launched for the 2010 National Latino AIDS Awareness Day (NLAAD). The website contains information on community events, HIV testing, and care for Latino/Hispanic-Americans. Resources are available in both Spanish and English. NLAAD will occur this year on October 15. For more information, please see the NLAAD website.

Black AIDS Institute And Merck Create New Black HIV/AIDS Advocacy Network – The Black AIDS Institute and the pharmaceutical company Merck have announced the establishment of the Black Treatment Advocates Network (BTAN). The goals of BTAN include improving HIV care and treatment for the African-American community, strengthening leadership and advocacy, and educating African-American communities about HIV and AIDS. The Network will sponsor regional training for advocates and will have an educational website. BTAN’s first action will be to set up pilot advocacy communities in Jackson, MS; Philadelphia; and Houston. For more information, please see the Black AIDS Institute and Merck websites.

Survey Finds Gaps In Communication Between HIV/AIDS Patients And Doctors – An AIDS Treatment for Life International Survey of over 2,000 HIV-positive patients worldwide found that although two-thirds of people with HIV also have other conditions, such as heart disease or diabetes, communication with their doctors about these conditions is limited. Only half of the patients surveyed had discussed past medical conditions with their doctor; a quarter of patients had never told their doctors about drug side effects they were experiencing. The International Association of Physicians in AIDS Care (IAPAC), which conducted the study, urged doctors to more thoroughly discuss their patients’ other health concerns at medical visits. For more information, please see the IAPAC (pdf) press release.

Clinical Trial Tests Efficacy Of Probiotics On Immune Function In HIV-Positive Adults – A new clinical trial at the AIDS Healthcare Foundation is testing whether a strain of the probiotic bacteria Bacillus coagulans can help increase CD4 (white blood cell) counts in people with HIV. The three month study is based on results in Africa showing that probiotic yogurt increased CD4 counts; however, it is not known if the results will also hold for Americans, who have better access to a nutritious diet. Researchers hope the probiotics will work indirectly to boost the immune system by reducing leakage of harmful bacteria from the intestines. For more information, please visit the Sustenex website.

Two of the studies focused on rates of cancers, particularly non-AIDS-defining cancers, in people with HIV and AIDS.

AIDS-defining cancers are cancers that are common in people with advanced HIV infections as a result of their weakened immune systems. Although they can appear in people who are HIV-negative, the development of these cancers in a person with HIV is closely tied to the health of the immune system. As a result, a person with HIV who has an AIDS-defining cancer is usually classified as having AIDS.

In contrast, developing a non-AIDS-defining cancer does not lead to a diagnosis of AIDS. Non-AIDS-defining cancers are in some cases more common in people with HIV than in the general population, but can occur even in people who carefully control their HIV infection.

Antiretroviral therapy has significantly improved the health and survival of people living with HIV. As a result, the rates of AIDS-defining cancers such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma have decreased.

However, longer lifespans increase the risk for non-AIDS-defining cancers. As people with HIV survive longer with antiretroviral therapy, non-AIDS-defining cancers, which develop over a long time period, become more common.

In general, studies presented at AIDS 2010 found that the rate of non-AIDS-defining cancers among people with HIV and AIDS has increased rapidly, with HIV-positive individuals generally being diagnosed with such cancers at an earlier age than HIV-negative adults.

Two additional studies showed that Selzentry (maraviroc) is not associated with a higher risk of cancer and that switching to Isentress (raltegravir) during chemotherapy may allow cancer patients to safely receive full-dose chemotherapy.

Non-AIDS-Defining Cancers Are Increasing In People With AIDS

A study from the National Cancer Institute and the Centers for Disease Control (CDC) presented an estimation of the number of cancers over time in the U.S. AIDS population.

According to the study authors’ estimations, the number of AIDS-defining cancers decreased and the number of non-AIDS-defining cancers increased significantly among people with AIDS. Researchers attributed these changes to the growth and aging of the AIDS population and increased rates of certain cancers.

The researcher analyzed data from the CDC and cancer registries across the United States, and found that the share of adults aged 50 years or older increased from 8 percent of the population with AIDS in 1991 to 29 percent in 2005.

During the same period, AIDS-defining cancers, mainly Kaposi’s sarcoma and non-Hodgkin’s lymphoma, decreased 75 percent from 7,284 cases in 1993 to 1,736 cases in 2005.

In contrast, non-AIDS-defining cancers increased nearly six-fold from 416 cases in 1991 to 2,437 cases in 2005. Anal cancer and prostate cancer had the largest increases, with 20-fold and 12-fold increases in the number of cases, respectively.

Rates of lung cancer and Hodgkin’s lymphoma remained fairly stable.

The researchers also estimated that 4,388 cases of cancer occurred between 2004 and 2007 among people from 34 states who were HIV-positive but did not have AIDS. This included 892 cases of lung cancer, 381 cases of anal cancer, and 327 cases of Hodgkin’s lymphoma.

However, the researchers did not indicate if these numbers were increasing or decreasing over time.

The researchers emphasized that “cancer prevention and treatment in HIV-positive persons is increasingly important.”

People With HIV Get Non-AIDS-Defining Cancers Earlier And More Often

Another study examined the rate of cancer and age at cancer diagnosis in patients at an HIV clinic in Atlanta. Researchers found that many non-AIDS-defining cancers occurred at higher rates and at an earlier age in people with HIV compared to the general Atlanta population.

From 2000 to 2007, 512 clinic patients were diagnosed with cancer. Of these, 62.5 percent had AIDS-defining cancers and 37.5 percent had non-AIDS-defining cancers.

On average, the age of HIV-positive patients at cancer diagnosis was 42 years old. Except for Hodgkin’s lymphoma, all non-AIDS-defining cancers occurred earlier in the HIV-positive clinic population than in the general population.

Breast cancer occurred in the HIV-positive population an average of 7 years earlier than in the general Atlanta population. Liver cancer was diagnosed an average of 16 years earlier.

Additionally, cancer rates in people with HIV were much higher compared to the general Atlanta area population, except for prostate cancer and breast cancer. Lung cancer occurred 4.5 times more often than expected, after taking into account age, race, and gender; Hodgkin’s lymphoma occurred 20 times more often than expected, and anal/rectal cancer occurred 68 times more often.

The researchers reported that the clinic patients in general had fairly advanced HIV infections. Of those diagnosed with non-AIDS-defining cancers, average CD4 (white blood cell) counts were 263 cells per microliter for men and 344 cells per mcroliter for women.

Only 17 percent of the men and 11 percent of the women had undetectable viral loads (amount of virus in the blood) at the time of their cancer diagnosis.

The researchers did not determine whether the low CD4 counts and high viral loads played a role in the rate of cancer occurrence.

The scientists concluded that people with HIV should consider cancer screening earlier than the general population.

Selzentry Does Not Increase Cancer Risk

A study sponsored by Pfizer, the maker of Selzentry, reported the rate of cancer development for treatment-naïve and treatment-experienced clinical trial participants taking Selzentry. Results showed that participants in the Phase 2b/3 trials were not more likely to get cancer from taking Selzentry.

Selzentry belongs to a relatively new class of antiretrovirals called entry inhibitors. Entry inhibitors work by preventing HIV from entering and infecting human cells.

Although approved for use in treatment-experienced patients in 2007 by the U.S. Food and Drug Administration, there were concerns that Selzentry might cause cancer because of the unique way it works, which is different from other antiretroviral drugs.

To see if people taking Selzentry are actually at higher risk of developing cancer, researchers analyzed tumors reported in studies involving both treatment-experienced and treatment-naïve HIV-positive trial participants. A total of 1,499 patients were given Selzentry, 361 patients received Sustiva (efavirenz), and 270 received a placebo.

Cancer rates were similar for patients given Selzentry to rates for patients given Sustiva or the placebo. Rates of AIDS-defining cancers ranged from 0.6 percent to 1.6 percent of participants taking Selzentry, versus 0 percent to 2.4 percent of participants taking Sustiva or a placebo.

Rates of non-AIDS-defining cancers ranged from 0.8 percent to 3.6 percent for participants taking Selzentry, versus 1.6 percent to 2.5 percent for participants taking Sustiva or a placebo.

In all cases, these differences were not large enough to be significant.

Researchers also found that older age was associated with higher overall risk of tumor development in both treatment-experienced and treatment-naïve patients.

Isentress-Based HAART Is Safe And Effective During Chemotherapy

A small study investigated the safety and efficacy of Isentress-based HAART in HIV-positive patients treated for lymphoma with chemotherapy. Results showed that Isentress is effective in patients receiving chemotherapy and patients can receive full-dose chemotherapy while on Isentress.

In the past, doctors have worried about drug interactions between antiretrovirals and chemotherapy drugs. As a result, HIV-positive cancer patients often temporarily stop antiretroviral treatment while undergoing chemotherapy or take a reduced dose of chemotherapy drugs.

However, both of these adjustments can affect a patient’s health, either by allowing HIV to multiply again or by limiting the effectiveness of the chemotherapy.

Since Isentress is an integrase inhibitor, a relatively new class of antiretroviral drugs that work differently than most antiretrovirals, researchers thought Isentress may be safe even during chemotherapy.

To test this hypothesis, researchers examined nine patients treated for lymphoma with Isentress-based HAART and chemotherapy at the Centre hospitalier de l’Université de Montréal between May 2008 and December 2009.

Of the nine patients studied, seven had non-Hodgkin’s lymphoma and two had Burkitt’s lymphoma. Four patients were treatment-naïve, four patients had already achieved viral suppression with another antiretroviral regimen, and one patient had started antiretroviral treatment but still had a detectable viral load.

During chemotherapy and treatment with Isentress, eight of the nine patients achieved or maintained undetectable viral loads. Three months after chemotherapy, seven of the nine patients had survived (78 percent); two died due to progression of their lymphoma.

None of the patients developed antiretroviral treatment-related side effects during the chemotherapy.

The researchers concluded that Isentress can be used safely and effectively with full-dose chemotherapy for treatment of lymphoma.

For more information, please see the AIDS 2010 conference website.

Previous guidelines advised patients to begin HAART after the onset of AIDS symptoms or when their CD4 (white blood cell) count dropped below 200 cells per microliter.

In 2009, however, the World Health Organization released new guidelines recommending that treatment start when CD4 counts drop to 350 cells per microliter. Proponents argued that this number better protects patients from long-term immune system damage.

Some doctors feel there might be benefits to initiating HAART even earlier, perhaps as soon as HIV is diagnosed. Others worry that this will maximize exposure to antiretroviral drug toxicity and side effects and argue treatment should be delayed until necessary for health reasons.

In the panel discussion, doctors and activists, including a speaker with HIV, debated the benefits and drawbacks to starting HAART early.

Arguments For Starting Early HAART: HIV Causes “Irreversible Damage”

The first speaker on the panel was Dr. Steven Deeks, professor of medicine at the University of California in San Francisco, who argued for starting HAART as soon as possible.

When diagnosed, he said, patients have two options. “Option one is to do nothing; but that is an active decision in which you are going to allow a virus, which is known to be pathogenic and cause some irreversible damage, to replicate at will. That could, perhaps, affect your long-term outcome and your quality of life.”

“Option two,” he said, “is to go on therapy immediately, and that also is associated with harm. Each of these drugs has toxicity; and so the question is, how do you manage it? How do you balance it?”

Dr. Deeks stated that in his opinion, it is much easier to predict and manage the consequences of drug toxicity than the results of viral progression due to a lack of treatment.

“I think most of the toxicity with the current generation of drugs can be managed,” Dr. Deeks said. “On the other hand, I think that the harm of ongoing virus replication, in terms of the irreversible damage it does to the immune system…on [the heart], [brain], bone and so forth, is far greater than any potential harm from the drugs.”

He added that since most patients will be taking antiretrovirals for several decades, a few extra years of treatment are not likely to have much additional effect on toxicity.

“At the end of the day, they are going to spend most of their life on therapy. Do we actually have less long-term toxicity by preserving those three or four years?”

However, Dr. Deeks conceded that the push to start HAART at CD4 counts higher than 350 cells per microliter was presently based on opinion, not research.

“There are lots of data that can inform what to do, but none of it is definitive. At the end of the day, you, as the patient, need to decide which of the two options you want to pursue. Both are associated with potential harm,” Dr. Deeks said.

AIDS Activist: Clinical Trials Are Needed On Benefits And Risks Of Early HAART

Another speaker in the session was Mark Harrington, executive director of Treatment Action Group, a non-profit organization focusing on AIDS research and policy. Harrington, who is HIV positive, was less convinced of the wisdom of starting treatment early.

Harrington delayed treatment for more than 10 years after his diagnosis. By that time, HAART had been developed and he was able to avoid some of the earlier, more toxic drug regimens.

He emphasized the need for clinical trial data before making any decisions on earlier HAART treatment. “There is a human right to informed consent based on the best available information,” he argued.

“There is a mandate on us to do the research to provide rigorous, controlled clinical trial evidence so that people with HIV…can make a truly informed decision and not one that is just based on even the most expert informed opinion,” he added.

Harrington also suggested that the first priority should be making sure everyone who meets the current guidelines is receiving antiretroviral therapy. He noted that, even in the United States, there are many patients well below the 350 CD4 cell count threshold that are unable to get access to HAART.

“In the U.S., we have huge disparities in our health systems. People with HIV are often from groups suffering from other socioeconomic problems…and are not in a position to get good health care in many parts of the country,” he said.

“We have Band-Aid solutions like the AIDS drug assistance programs in some states, but there is a waiting list of over 2,000 people with AIDS/HIV that need therapy right now,” he added.

Harrington also pointed out the need for more research into better, less toxic antiretrovirals that can be taken less often, and he stressed the need for research toward a cure for HIV.

“We need to accelerate research on curative therapy, both for people at early infection and later infection,” he said.

In the end, he argued, “People [should] get treatment based on what is best for them.”

U.S. Global AIDS Coordinator Emphasizes Personal Health Decisions Over Policy

The final speaker on the panel was Dr. Eric Goosby, the U.S. Global AIDS Coordinator, who emphasized the need to separate government policy decisions from personal health choices.

“There needs to be a real distinction between what a provider who is in front of a patient should be thinking about…versus a more public health thought process,” he said.

“The provider/patient interaction must retain the assumption that the physician or nurse practitioner or health officer in front of that patient is always, and every time, making decisions that they believe are in the best interest of the patient,” he added.

As a result, a patient’s personal treatment decisions should not necessarily be governed by official guidelines and policies, which are also affected by financial and social factors.

Dr. Goosby did not definitively state a position on early HAART treatment, but agreed with Harrington that more clinical trials are necessary.

“The science clearly shows that we should be trying to put patients on [HAART at CD4 counts of] 350. The science above that is less clear,” he said.

On the other hand, he stated, “The issue of unchecked viral replication with the persistent fueling of inflammation and acceleration of [blood vessel] damage, [heart disease] acceleration, etc., are all a real concern.”

START Trial Studies Benefits Of Starting HAART At CD4 Counts Of 500

A clinical trial testing the effects of starting HAART when a person’s CD4 count drops below 500 cells per microliter is currently underway.

The study – named Strategic Timing of Antiretroviral Treatment (START) – is carried out jointly by the University of Minnesota, the National Institutes of Health, various European HIV institutes, and several pharmaceutical companies.

The study is currently recruiting participants.

For more information on the panel discussion, please see the AIDS 2010 webpage on the Kaiser Family Foundation website. For more details on the START study, please visit the United States Clinical Trials registry.

The studies, which yielded mostly positive results, illustrate the growing variety of treatment and medication options for people with HIV.

The three studies involving new treatment regimens all use Isentress (raltegravir), an integrase inhibitor approved by the United States Food and Drug Administration in 2007.

Integrase inhibitors are a relatively new class of drugs. They work by blocking the protein the virus uses to insert its DNA into the DNA of a healthy cell, thus preventing HIV from replicating. Isentress is currently the only approved integrase inhibitor.

In one study, Isentress was evaluated in a simplified two-drug combination treatment with Kaletra (lopinavir/ritonavir), a protease inhibitor. Two other studies tested the efficacy of replacing protease inhibitors with Isentress.

Protease inhibitors often increase cholesterol levels, which increases a patient’s risk of developing heart disease. Researchers predicted that switching to Isentress would reduce the risk of heart disease.

In all three studies, the new regimens involving Isentress have so far successfully suppressed the virus, produced few side effects, and decreased cholesterol levels in people with HIV.

The other two studies tested new drugs in Phase 2 development. Both drugs have demonstrated short-term efficacy and safety. One of the drugs is a CCR5 antagonist, like Selzentry (maraviroc). The other is a new integrase inhibitor, like Isentress.

Study Of The Two-Drug Combination Of Kaletra And Isentress

A 96-week-long Phase 3 study is currently assessing the safety and efficacy of taking Kaletra with Isentress. The new combination is compared to Kaletra plus Truvada (emtricitabine/tenofovir), which contains two reverse transcriptase inhibitors.

The study participants are all treatment-naïve, meaning they have not taken antiretroviral medications before.

The 48-week study results revealed that the combination of Kaletra and Isentress suppressed the virus as effectively as Kaletra plus Truvada. The treatment was well tolerated, and the most common side effects were diarrhea and high cholesterol. High cholesterol has been associated with protease inhibitors like Kaletra.

Researchers concluded that the two-drug combination of Kaletra and Isentress is promising as an effective treatment for HIV.

The Kaletra/Isentress treatment combination is unusual because it consists of only two medications and does not involve reverse transcriptase inhibitors.

The current regimen for people with HIV who are beginning treatment consists of three ART drugs: two reverse transcriptase inhibitors (such as those contained in Truvada) and a third drug, usually a protease inhibitor (such as Kaletra).

However, reverse transcriptase inhibitors have been associated with lipodystrophy, a side effect in which fat gets redistributed abnormally on the body. Changes in fat distribution can lead to changes in body shape and can also cause cardiovascular disease. As a result, researchers have experimented with antiretroviral regimens, such as the Kaletra/Isentress combination, that do not contain reverse transcriptase inhibitors.

The trial is ongoing but is no longer recruiting participants.

Replacement Of Protease Inhibitors With Once Or Twice Daily Isentress

A Phase 4 study evaluated the switch from a protease inhibitor regimen to a once or twice daily dosage of Isentress, an integrase inhibitor. The trial followed 222 participants with HIV for 24 weeks.

Researchers hoped switching to Isentress would lower participants’ cholesterol levels. In addition, Isentress is currently given twice daily. If effective, a once daily dosage would decrease treatment burdens for patients.

Researchers measured the effectiveness of the once daily dosage and monitored the patients’ cholesterol levels after switching from the protease inhibitor regimen.

Replacing the protease inhibitor regimen with Isentress was effective in all patients except in those who had previously demonstrated resistance to reverse transcriptase inhibitors. The once daily dosage of Isentress performed slightly worse than twice daily dosing.

In addition, as predicted, the patients’ cholesterol levels were significantly lowered after the switch to Isentress.

The study, sponsored by Hospital Carlos III in Madrid, is ongoing and currently recruiting participants.

Replacement Of Protease Inhibitors With Isentress

A 48-week Phase 3 study has been completed that compared patients taking protease inhibitors to those who switched to Isentress, an integrase inhibitor. The participants in both groups of the study started with low viral loads (amount of HIV in the blood).

At 48 weeks, the two regimens were similarly effective at maintaining low viral loads. Additionally, switching to Isentress effectively lowered cholesterol levels in patients.

There was a slight increase in the number of patients experiencing side effects. Side effects that led to treatment discontinuation occurred in 4 percent of patients treated with the Isentress regimen versus 2 percent of those on the protease inhibitor regimen.

Study Of A New CCR5/CCR2 Antagonist, TBR-652

Tobira Therapeutics completed a Phase 2 study of a possible new treatment, TBR-652, a dual CCR5/CCR2 antagonist.

CCR5/CCR2 antagonists work by blocking the CCR5 and CCR2 proteins on the outside of immune cells. When these proteins are blocked, the drug prevents HIV from attaching to and infecting the cells. Selzentry is the only currently approved CCR5 antagonist.

The study tested the antiviral ability, safety, and tolerability of TBR-652 taken once daily for 10 days. This is the first study of TBR-652 that has tested the medication on people with HIV.

A previous Phase 1 trial showed that the drug was well tolerated in HIV-negative subjects. The 54 HIV-positive participants in the Phase 2 trial also tolerated the drug well; there were no serious side effects or deaths.

Additionally, when TBR-652 was taken as the sole antiretroviral medication, the researchers reported significant antiviral activity, as measured by viral load.

“Our unique, dual CCR5/CCR2 investigational drug may provide a new strategy that would complement the well-established benefits of currently available virus-suppressing treatments for HIV,” said David Martin, Senior Vice President of Drug Development and Regulatory Affairs for Tobira Therapeutics in a press release.

The drug will require further trials at longer durations to determine whether it is a viable treatment option.

Study Of A New Integrase Inhibitor, S/GSK1349572

Shionogi-GlaxoSmithKline Pharmaceuticals is testing a new integrase inhibitor, S/GSK1349572, in an ongoing 24-week Phase 2b study on patients who are resistant to the integrase inhibitor Isentress.

The results through Day 11 have revealed that most of the subjects have tolerated the new drug well. The most commonly observed side effects were diarrhea and insomnia.

The study continues to observe the efficacy of the new integrase inhibitor against a variety of HIV-variants resistant to Isentress.

The trial is currently recruiting participants.

For more information, please see the AIDS 2010 conference website.

However, the study authors caution that their results, which include only 48 weeks of trial data, are still preliminary. Longer follow-up periods will be necessary to ensure the regimen will be safe and effective long-term.

Currently, the standard treatment regimen for HIV includes at least three antiretroviral medications from two different drug classes, usually two nucleoside reverse transcriptase inhibitors (NRTIs), plus either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor (PI).

This combination therapy is generally successful in decreasing HIV replication, increasing healthy CD4 cell counts, and partially restoring the immune system.

However, there have been a number of short- and long-term harmful side effects reported in response to the current combination ART, especially with protease inhibitor-based therapy.

Some of the side effects include hyperlipidemia (elevation of lipids, such as cholesterol, in the blood), insulin resistance, lipodystrophy (abnormal fat redistribution), and an increased risk of heart problems.

As a result, researchers have explored simplified ART maintenance regimens that do not contain protease inhibitors as an alternative long-term drug option.

In this study, participants who had never received antiretroviral therapy were treated first with a standard dual NRTI/PI regimen, consisting of Combivir (zidovudine/lamivudine) plus Kaletra (lopinavir/ritonavir).

After achieving viral suppression (viral load, or amount of HIV virus in the blood, of less than 50 copies/milliliter), participants were randomly assigned to either continue the Combivir/Kaletra regimen, or switch to Trizivir.

Trizivir is a triple-NRTI regimen, and does not contain a protease inhibitor. Previous studies have shown Trizivir is associated with more favorable lipids and fewer drug interactions compared to regimens containing protease inhibitors.

The study showed that Trizivir was as good as Combivir/Kaletra at maintaining viral suppression halfway through the study, at 48 weeks. The trial will continue for an additional 48 weeks.

Additionally, researchers noted that the NRTI-only regimen, Trizivir, decreased participants’ pill burden from six or eight pills per day to two per day, which could improve adherence.

Adherence – taking medications as prescribed – is important to reduce HIV drug resistance and maintain virus suppression.

The researchers did note some limitations to the study, including a small sample size; only about 100 participants were analyzed. This was partly because the researchers were strict about allowing participants to continue, which could bias the study results toward a favorable outcome.

The study was also open-label, which means participants knew which medications they were taking.

Finally, the results only cover a fairly short duration, which means that it may be too early to predict the success of the treatment long-term.

Safety and effectiveness of the drug regimen will be studied after the full 96 weeks of the study are completed, which is expected to give more information on its long-term potential.

For more information, please see the study in AIDS Patient Care And STDs.

Therapeutic HIV vaccines work by enhancing the body’s natural immune response, helping to control HIV in people already infected with the virus.

This is in contrast to preventative vaccines, which are used in HIV-negative individuals to prevent infection.

Researchers hope therapeutic vaccines will decrease dependence on antiretroviral drugs, which must be taken for life and often have serious side effects.

“A vaccine that enhanced the body’s ability to control HIV and delayed or decreased the dependence on anti-HIV drugs would be a major breakthrough for HIV treatment,” said Dr. Melanie Thompson, a lead investigator of one of the HIV vaccine trials.

No therapeutic vaccines are currently approved by the United States Food and Drug Administration.

DNA Vaccines

DNA vaccines contain pieces of DNA into which copies of several viral genes have been inserted. When human cells take up the DNA, they produce proteins encoded in the viral genes.

Researchers hope that the body’s immune system will recognize these proteins as harmful foreign agents and mount a powerful protective response.

DNA vaccines are a relatively new idea, and their effectiveness has not been well studied yet, although preliminary clinical trials have usually found them to be safe.

A small Phase 1 clinical trial investigating a therapeutic HIV DNA vaccine from GeoVax Labs is currently recruiting participants (pdf).

To be eligible for the GeoVax study, participants must have begun antiretroviral treatment within six months of diagnosis with HIV/AIDS. Additionally, individuals who have been HIV-positive for up to six months, but are yet to begin treatment, may be eligible for enrollment in the study.

Participants will be monitored to determine the safety of the vaccine and strength of their immune response for up to 77 weeks. For this initial study, only 10 to 12 people will be enrolled in the trial.

So far, studies in HIV-positive primates treated with the vaccine soon after infection gave good results. Clinical trials will now see if these results extend to HIV-infected humans as well.

Another Phase 1 DNA vaccine trial is also currently recruiting participants in London.

This trial, run by the Imperial College London and the Medical Research Council, will test a new therapeutic DNA vaccine coupled with immune-based therapy, which includes hormones and proteins called cytokines.

Immune-based therapies could help patients’ immune systems fight viruses on their own. Hormones and cytokines help regulate the immune system and can be used to induce, or prevent, growth and activity of particular cells in the immune system.

The researchers are especially interested in “why some people with HIV progress more slowly to disease and have longer survival without highly active antiretroviral therapy (HAART) than others.”

Their goal is to see if the vaccine plus immune-based therapy can create long-term nonprogressors, who are able to control the HIV virus for long periods of time without antiretrovirals.

The trial began in September 2009 and will investigate the safety and efficacy of the vaccine plus immune-based therapy for 52 weeks in approximately 30 HIV-positive individuals.

Study participants must be aged 18 or over with viral loads of less than 50 copies/milliliter and more than 400 CD4 cells/microliter.

Dendritic Cell Vaccines

Another novel vaccine type that will be tested in several new clinical trials is a dendritic cell vaccine, which is prepared using the participant’s own cells. Dendritic cell vaccines are considered to be very promising, because they are somewhat customized to each person.

To make a dendritic cell vaccine, researchers collect blood from participants and isolate a certain type of immune cell called a dendritic cell.

After exposing the cells to HIV proteins to prompt an immune response, the cells are reinjected into the study participant in hopes that they will now be activated and fight against HIV.

A Phase 1/2 clinical trial run by the University of Pittsburgh and the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) is currently recruiting participants.

Eligible candidates must be at least 18 years of age with CD4 cell counts of at least 350 cells/microliter and HIV RNA levels between 5,000 and 100,000 copies/milliliter. Participants must also be antiretroviral therapy naïve.

Baylor Research Institute along with Baylor University and the ANRS are also organizing a Phase 1 clinical trial to assess the safety and efficacy of a dendritic cell vaccine in HIV patients on HAART.

The study, which began in November 2008, is currently recruiting participants and enrollment is estimated at 19 patients.

Participants must be 18 years or older and must have been on HAART for at least 12 months prior to enrollment. Additionally, participants must have CD4 cell counts of at least 500 cells/microliter and HIV RNA levels no greater than 50 copies/milliliter.

Protein Vaccines

Finally, there is a more traditional vaccine trial that is currently recruiting HIV-positive participants in Italy. Traditional HIV vaccines contain virus proteins that are injected into the participant in hopes of increasing immune response to the virus.

The Phase 2 trial in Italy will evaluate the safety and efficacy of an HIV Tat vaccine. Tat is an HIV protein released by infected cells that increases the rate of replication of the virus.

The study was initiated by the Instituto Superiore di Sanita in September 2008 and will enroll about 160 participants.

Participants must be between the ages of 18 and 55, must not possess anti-Tat antibodies, and must be on successful HAART with HIV viral concentrations of less than 50 copies/milliliter and at least 200 CD4 cells/microliter.

The trial will measure immune responses to the Tat protein in participants for 144 weeks, or about two and a half years.

For more information on therapeutic vaccine clinical trials, please see the United States Clinical Trial Registry.

However, the amounts were too low to actually show anti-HIV activity.

Scientists believe that stem cell-based gene therapy is a promising prospect to eventually replace highly active antiretroviral therapy (HAART) (see related AIDS Beacon news).

“We hope to provide patients with long term protection from immunodeficiency and free them from a life long dependence on antiviral drugs with this treatment,” said Dr. David DiGiusto, lead author of the study in email correspondence with The AIDS Beacon.

The advantage to gene therapy is that treatments would be one-time or periodic, rather than having to take a daily pill.

This study in particular focused on RNA-based gene therapy. RNA is genetic material that is similar to DNA. RNA can affect which proteins are produced by a cell, and could offer a way to prevent infected cells from making the proteins HIV needs to survive and replicate.

The current study was small, with only seven participants. All of the participants had HIV- and AIDS-related lymphoma and were scheduled to undergo blood stem cell transplants, a common treatment for lymphoma.

For the trial, the scientists slightly modified the transplant. After collecting blood stem cells from the participants, the cells were mixed with antiviral RNA pieces, which block HIV by preventing the virus from infecting new cells and keep it from replicating.

The patients then received a transplant of their genetically modified blood stem cells containing the antiviral RNA.

Unfortunately, the transplanted stem cells did not produce enough disease-resistant blood cells to effectively suppress HIV in the participants.

However, the modified cells survived and produced the antiviral RNA for up to two years, indicated the possibility for long-term therapy for HIV patients.

The authors also stated that the results of the transplant were encouraging because the procedure was accomplished safely with minimal side effects in the participants. There had been concern that the antiviral RNA would be toxic to the patients, or that they could develop cancer, which is sometimes associated with antiviral genetic material.

The researchers found the results a promising step toward gene therapy for HIV. Dr. John Rossi, an author on the paper, told The AIDS Beacon in email correspondence that they are in the process of designing a new, improved clinical trial.

“We are planning to modify the conditions for another stem cell trial to get better numbers of gene modified cells,” said Dr. Rossi.

Improving the transplant procedure could generate more HIV resistant stem cells, resulting in more effective disease treatment.

For more information, please see the study in Science Translational Medicine (abstract).

“Ultimately, immunotoxins will be of value in HIV treatment only if they can enable patients to stop HAART for prolonged periods, sufficient to provide a meaningful quality of life benefit,” wrote the authors.

Although still preliminary, the authors believe the idea is promising enough that it should be tested in clinical trials.

The major problem with highly active antiretroviral therapy (HAART) is that it does not completely eliminate the virus from the body.

Infected cells, called “reservoirs,” hold HIV in a dormant state. Although HAART prevents new cells from being infected, it cannot kill cells that are already infected by HIV.

As soon as HAART is stopped, the virus starts multiplying again and the infection spreads.

Over the past two decades, research groups at the National Institutes of Health have focused on developing treatments to kill the infected cells. These cells can be identified by the presence of a virus protein, called Env, on their surface.

Immunotoxins, which have been used successfully to treat a certain type of leukemia, can be designed to recognize Env and kill infected cells that display the protein.

Previous Phase 1 clinical trial results with immunotoxins in the pre-HAART era were disappointing; no antiviral or immune-enhancing effects were observed at the maximum tolerated dose, which was below the typical dose for cancer immunotoxins.

The dosage could not be increased at that time because of possible liver toxicity.

Since then, however, the authors have created a new immunotoxin that is more powerful and less toxic. So far it has only been studied in the lab.

The authors suggest that now, with the development of HAART, these Env-targeted immunotoxins may work significantly better than they did in the earlier clinical trials.

In laboratory tests in combination with HAART, the immunotoxins were able to keep HIV levels low even 30 days after HAART was stopped; without the immunotoxins, virus levels had already rebounded 30 days after HAART was stopped.

“These results highlight the particular value of combining HAART drugs, which potently block HIV replication, with Env-targeted toxins, which kill cells that are already infected,” wrote the authors.

If these results are verified in clinical trials, it could mean that people diagnosed with HIV would receive a combination of HAART and immunotoxins only temporarily, rather than having to take HAART their entire lives to ensure virus suppression.

As a result, the authors argue that “the time has come” for clinical trials to evaluate Env immunotoxins as complement therapy with HAART in treating and eradicating HIV.

Dr. Edward Berger, lead author on the paper, discussed plans for future trials with The AIDS Beacon.

“We hope to get 3B3-PE38 [a new immunotoxin] into Phase 1 clinical trials, and are in process with the FDA. It would be given only to infected people whose viral loads have been greatly suppressed by [antiretrovirals], and the [antiretrovirals] would continue during the short period (1-2 weeks) of immunotoxin treatment.”

Dr. Berger also thought the treatment could have some limited potential in post-exposure prophylaxis. Post-exposure prophylaxis is treatment given to someone who has been exposed to HIV, and can help prevent the infection from taking hold.

“Post-exposure prophylaxis is a realistic consideration, but only if administered on one or two occasions. The reason is that the PE38 [immunotoxin] portion of the [treatment] is of bacterial origin, and thus would be recognized as ‘foreign’ by the immune system, leading to production of antibodies that would neutralize the activity of the [immunotoxin]. Hence regular use for prevention would not be feasible.”

For more information, please see the study on the PLoS Pathogens website.

Patrick Burke, Vice President of Corporate and Business Development at Myriad Pharmaceuticals, stated in an interview with The AIDS Beacon that Myriad is currently looking for a partner to advance MPC-4326 and an additional novel HIV drug. This partner would then acquire rights to advance the drugs further.

Myriad’s Phase 2 clinical trial into the efficacy and safety of MPC-4326 was terminated June 10.

MPC-4326 is an investigational drug that is a viral maturation inhibitor. The first in a new class of drugs, MPC-4326 prevents the HIV virus from maturing correctly by blocking a necessary enzyme, leaving the virus harmless.

Preclinical studies indicated that the drug is effective against strains of the HIV virus that are resistant to approved antiretroviral drugs.

In early clinical trials MPC-4326 did not pose any safety risks and successfully decreased the amount of HIV virus in the blood of HIV-positive participants.

The company stated in its press release that the focus on anti-cancer drugs is an effort to “conserve its financial resources to extend [Myriad's] projected cash runway beyond 2013,” indicating that the move away from anti-HIV drugs is for financial reasons rather than problems with safety or efficacy.

As of June 14, information on MPC-4326 had been removed from Myriad’s website, although cached versions were still available.

Studies indicated a slow rate of development of viral resistance to MPC-4326, which suggests it could be especially useful in HIV treatment. As viral resistance to approved drugs becomes more common, Myriad hoped MPC-4326 would prove effective in combination with other antiretrovirals.

Trials also showed that MPC-4326 had fewer of the drug-drug interactions that are common amongst some of the currently available HIV therapies.

For more information, please see the press release on the Myriad Pharmaceuticals website. For information on the terminated clinical trial, please see the United States clinical trials registry.