For decades, achieving an “undetectable” viral load has been considered the gold standard of HIV treatment. Yet a small number of people living with HIV continue to show detectable levels of viral RNA in their blood despite strict adherence to antiretroviral therapy (ART), no evidence of drug resistance, and no signs of treatment failure.

New research from Johns Hopkins University may provide an important explanation—and considerable reassurance.

In a study published in Nature Communications, investigators found that the vast majority of these persistent viral signals are not caused by active, infectious HIV. Instead, they originate from defective copies of the virus that are incapable of causing new infections.

The phenomenon, known as non-suppressible viremia (NSV), has long puzzled clinicians and patients alike. Individuals with NSV maintain detectable HIV RNA levels even while taking effective ART and without evidence that the virus is actively replicating.

Researchers analyzed samples from more than 50 individuals receiving long-term HIV treatment. Their findings revealed that approximately 95% of the detectable viral RNA originated from highly defective viral genomes carrying abnormalities in a region known as the 5′ leader, a critical genetic segment involved in viral replication and packaging. These defects render the virus incapable of producing infectious particles.

The discovery has significant implications for both clinical care and patient peace of mind.

Many people living with HIV are taught that any detectable viral load could indicate treatment failure or increased risk of transmission. According to the study’s authors, that assumption may not apply in many NSV cases.

The defective viral copies identified in the study can still produce fragments of viral RNA that appear on laboratory tests, but they lack the ability to establish new infections. This means that detectable HIV RNA does not always equate to infectious virus.

For patients who experience persistent low-level viral detection despite excellent adherence, these findings may help reduce anxiety surrounding laboratory results and lessen concerns about viral rebound.

The researchers also developed a laboratory assay called CLAWS (Capturing 5′ Leader Anomalies Without Sequencing). The test can rapidly distinguish intact HIV RNA from defective HIV RNA without requiring extensive genetic sequencing.

The investigators believe this technology could help clinicians determine whether detectable viral RNA represents a true clinical concern or simply reflects harmless defective viral remnants. Such distinctions could become increasingly important in HIV cure research and in monitoring participants enrolled in experimental treatment interruption studies.

Implications for HIV Cure Research

The study also contributes to a growing understanding of HIV persistence

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While ART effectively suppresses viral replication, HIV establishes long-lived reservoirs within infected immune cells. Most of these reservoirs contain defective proviruses that cannot generate infectious virus. The new findings suggest that these defective genomes may account for much of the residual viral material detected in blood during long-term therapy.

Researchers observed that defective viral RNA becomes increasingly dominant over time in individuals receiving long-term ART, further supporting the idea that residual detectable virus often reflects biological “noise” rather than active infection.

The findings do not change the importance of adherence to antiretroviral therapy, nor do they suggest that all detectable viral loads are benign. Genuine treatment failure, drug resistance, and viral rebound remain critical clinical concerns that require careful evaluation.

However, the study provides compelling evidence that many cases of persistent low-level viremia are driven by defective viral copies rather than infectious HIV. As diagnostic tools improve, clinicians may be better equipped to distinguish between harmless viral remnants and clinically significant viral activity.

For people living with HIV, that distinction could offer not only better medical guidance but also greater confidence in the effectiveness of modern treatment.

Global AIDS News Today will continue following developments in HIV reservoir research, cure strategies, and advances in viral load monitoring as they emerge.

There are about a dozen therapeutic vaccines for HIV in various stages of development. However, the puzzling fact is that there’s no measurable emphasis to support their development to get to market.

AIDS 2022 is taking place July 29^th to August 2^nd in Montreal after unprecedented efforts to establish universal COVID-19 therapeutic vaccination became the dominant paradigm for controlling our latest pandemic. Funding HIV vaccines — such as VaccC5, AELIX, IAVI G003, or any of the preclinical constructs in the literature — with same resources allocated for Operation Warp Speed could help bring the end to the AIDS crisis.

The different vaccine models have historically been studied for HIV prophylactic vaccines — given to uninfected, healthy people to prevent HIV infection — and therapeutic vaccines — intended for people already infected with HIV to boost their immune system to fight HIV infection.

HIV’s replication cycle, which causes its pathogenicity, has been studied for five decades. While the antibodies generated in response to the presence of HIV do not slow disease progression, therapeutic HIV vaccines produce HIV-specific cell-mediated immune responses that can control the virus after the interruption of antiretroviral treatment. They are being investigated as a treatment strategy approach designed to bring about a ‘functional cure’ to HIV – indefinite HIV suppression without antiretroviral treatment. Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults represent one of the most compelling promises of HIV therapeutic vaccine research.

A growing number of HIV therapeutic vaccines have been part of human studies to boost pre-existing immune responses by using multiple constructs — such as direct-DNA and viral vectors containing HIV protein expressing genes with and without adjuvants, DC-based vaccines, or a combination of these. Therapeutic vaccines for HIV infection should aim to elicit anti-viral CD8 T cells (CTLs), CD4 T cells, and neutralizing antibodies since these immune responses work in concert to control viral replication.

Unfortunately, approaches tested to date have used a piecemeal approach, often targeting only a few regions of HIV. They have not produced a significant salubrious result, primarily because they mitigate HIV’s primary strength of evading a CTL mediated response by interfering with immune signaling.

Live-attenuated vaccines administer a controllable dose of the live vaccine to build immunity against it. This approach has successfully controlled smallpox, polio, and measles. Whole-killed or attenuated virus vaccines are weakened or killed by using one or more of either heat or chemicals (e.g. glutaraldehyde and gamma radiation) to eliminate replication. A therapeutic vaccine that uses live attenuated HIV as opposed to vectors, VLPs, or only a few of the HIV proteins is likely to be successful in generating a kind of response that would counter HIV.

The question at AIDS 2022 is whether the leadership of the National Institute of Allergy and Infectious Disease (NIAID) and other globally recognized research institutions have given up on therapeutic vaccines for HIV. Do none of these demonstrate enough scientific utility to justify further dedication of resources by the AIDS clinical trials groups, the military HIV Research Program and the HIV Research Collaboratories, or is the status quo of the current paradigm of treatment considered adequate?

Inside the Pipeline-A Background on Recent HIV Therapeutic Vaccine Studies at AIDS 2022
Therapeutic vaccines demonstrate the ability to induce specific immune responses with better viral control, as well as a limited ability to contain viral replication once antiretroviral therapy is interrupted.

In March 2021, AELIX Therapeutics reported a single-center trial of a three-drug therapeutic vaccine (AELIX-002). The therapy was given to patients within six months of HIV acquisition who had been virologically suppressed for a year or more, designating those patients as having been treated with an early start. The efficacy of the AELIX-002 results was considered a step forward by the International AIDS Society (IAS), and considered “…an exciting step forward to HIV cure research” by IAS President Adeeba Kamarulzaman.

In May 2021, ImmunityBio set out to enroll 46 participants for a Phase I “HIV Cure Study” (A5386). With sponsorship from NIAID and the AIDS Clinical Trials Group (ACTG), this study is assessing the safety, level of acceptance, and efficacy of the Anktiva plus anti-HIV vaccine, featuring IL-15 superagonist N-803, in neutralizing antibodies. Thus far, the vaccine’s Anktiva molecule’s “kick and kill” approach induced viral transcription in CD4+T cells, while strongly activating CD8+ effector memory T cells and NK cells emitting them to viral reservoirs.

Immunity Bio’s Phase 2 study, reducing HIV persistence in lymph nodes by IL-15 receptor super-agonist (N-803) in acute HIV infection, is designed to test immunostimulatory effects of Anktiva administration in May of 2021. The study was conducted by the Walter Reed Army Institute of Research’s U.S. Military HIV Research Program (MHRP) at the Thai Red Cross AIDS Research Centre in Bangkok.

Bionor Holding, AS is currently in Phase II trials of its therapeutic vaccine Vacc-4x. It is a vaccine comprising of four synthetic proteins resembling HIV’s Gag proteins. This vaccine has shown encouraging results in Phase I and Phase II trials being conducted specifically to assist for structured therapeutic interruptions.

In March 2022, Moderna, with Excision BioTherpeutics, reached a breakthrough in HIV therapy, testing a second mRNA HIV therapeutic vaccine, MRNA-1574.The vaccine is designed to target HIV envelope trimers through mRNA rather than using broad antibodies. The trial took place collaboratively between Moderna and the National Institutes of Health (NIH), which at the time was in partnership with the Division of AIDS. The expected outcome, built on research by William Schief, Ph.D. at Scripps University is that B-cell response will evolve into more broad and efficient neutralizing antibodies over time.

In March 2018, NIAID, in collaboration with Auro Vaccines LLC, posted the combination antiretroviral therapy (cART) clinical trial. cART trial results indicated sustained reduction in viral replication, while also making it clear that cART cannot completely eradicate HIV in tissue compartments on its own. As a result, continued research is underway to develop strategies to eliminate persistent viral reservoirs, while boosting host immunity to control viral replication once cART is discontinued. With those additional elements, therapeutic HIV vaccines could augment immunologic control of HIV infection.

In May 2022, the clinical trial for the therapeutic HIV vaccine IAVI G003 took place, led by a collaboration known as the Accelerate the Development of Vaccines and New Technologies to Combat the AIDS Epidemic (ADVANCE) program comprised of IAVI-ADAVANCE Partner Clinical Research Center (CRC) Network and Moderna. This Phase 1 trial was executed in Rwanda and South Africa to evaluate the mRNA HIV vaccine antigen. The trial built on the progress from Phase I clinical trial in the U.S. of IAVI G001, which demonstrated that vaccination with the HIV immunogen eOD-GT86omer (recombinant protein) safely induced the targeted immune responses in 97% of healthy adults in the study. The process created an induction of broadly neutralizing antibodies (bnAbs), objectively the first-step of establishing an efficacious HIV vaccine.

Funding for this trial was provided through the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), United States Agency for International Development (USAID), with additional support provided by the Bill and Melinda Gates Foundation through grants to Moderna and the Collaboration for AIDS Vaccine Discovery (CAVD) Vaccine Immunology Statistical Center (VISC).

Counting the Dollars: NIH NIAID HVTN Funding and L’institute Pasteur’s Investment

In August 2021, the NIH announced it was being awarded $53 million annually from L’Institut Pasteur, over the next five years, to find a cure for HIV. This initiative expands a 2016 initiative, increasing funding by 75% and the number institutions supported from six to ten annually.

The Activists in the Corner: IAVI, AVAC, and TAG

Advocacy leaders like Seth Berkley, at IAVI; Mitch Warren, Executive Director at The AIDS Vaccine Advocacy Coalition; and Mark Harrington, of Treatment Action Group haven’t been at the forefront of therapeutic vaccine development, despite the potential of this research to radically change the course of the AIDS crisis. It would be a legitimate question to ask whether the powers that be will now emphasize therapeutic vaccines, considering the lack of results with prophylactic vaccines and ongoing issues related to neurological side effects and drug resistance that can occur with antiretroviral treatment. IAVI has developed partnerships in 25 countries with a staff of more than 200, yet AmFAR’s initiatives to advance the cure agenda has yet to focusing on HIV remission studies using therapeutic vaccines to facilitate strategic therapeutic interruptions. Both IAVI and AVAC played a critical role in forming The Global AIDS Vaccine Initiative, which brings together developing country and donor governments, the World Health Organization, UNICEF, the World Bank, the vaccine industry in both industrialized and developing countries, research and technical agencies, civil society organizations, the Bill and Melinda Gates Foundation, and other private philanthropists. (No specific data on HIV-specific research or outcomes.)

We’ve seen tens of billions generated by the development of the COVID-19 therapeutic vaccines rushed into commercial development and facilitated by public funds in response to the pandemic. Would a therapeutic vaccine for HIV be any less rewarding financially to investors, to the governments supporting the Global Fund, PEPFAR, and other international health commodity procurement programs? Science writer Jon Cohen’s book Shots in the Dark, The Wayward Search for an AIDS Vaccine, demonstrates how directed, organized, goal-oriented research barely exists for new paradigms in the HIV therapeutic vaccine arena.

Without a robust, bold effort to secure a new initiative in the AIDS Clinical Trials Groups and the HIV Vaccine Trials Network for therapeutic vaccines, the race for remission studies may slow to a crawl at AIDS 2022.

Special thanks and recognition to David Miller and Frank Maresca for their considerable contributions to this article.

This article originally appeared in healthhiv.org

The International AIDS Society (IAS) held the world’s largest scientific gathering on HIV science in Paris, France this year, a country where 37% of patients with AIDS have evidence of toxoplasmic encephalitis.

Toxo has been reported as the most common opportunistic infection in HIV/AIDS in developed countries and the most common cause of focal brain lesions, coma and death. It commonly causes encephalitis in HIV-postive patients and increases the risk of HIV Associated Neurological Disorders (HAND) by 60%.

HAND is becoming increasingly prevalent as Anti-Retroviral Therapy (ART) allows HIV patients to live longer lives. Several poster sessions at IAS 2017 discussed the issue of HAND.

Ei Kinai from the National Center for Global Health and Medicine in Tokyo, Japan presented on The Impact of Age and Time of Disease on HAND. The study concluded that, “Older patients are more likely to have neurocognitive decline at early stages of HIV infections.” It is also known that the prevalence of Toxo increases with age, an aspect that was not addressed in the study.

Galia Manuelle Aurora Santos from Lausanne University Hospital Center in Lausanne, Switzerland presented on the link between depressive symptoms and HAND. This study suggests that addressing depressive symptoms, especially in HIV positive-women, might potentially improve the neurocognitive outcome of HIV-positive patients. Toxo has been linked to depression in numerous studies.Vincent Senecal of the Centre de Recherche du CHU de Quebec, Centre de Recherche en Infectiologie, Quebec, Canada shed light on HAND pathogenesis by studying the interactions of HIV with the anti-inflammatory chemokine, fractalkine (FKN). The results indicated that HIV reduced FKN receptor expression in microglia/macrophages which could have important implications in chronic inflammation and immune activation for HAND. It has been found in separate studies that Toxo also down-regulates FKN after 24 hours of infection.

HAND continues to be a major concern in HIV patients and the connection between HAND and toxo is an understudied issue that may help to better understand and potentially treat HAND. New studies to determine if toxo has a causative effect contributing to neurocognitive decline in people living with HIV are essential.

Toxo infects approximately 1.1 million people each year in the United States. The global prevalence is estimated between 2 and 3 billion and there is no cure. Acute infection in the immune compromised is often deadly if not aggressively treated with Pyrimethamine (Daraprim). In 2014, the CDC designated Toxo a Neglected Parasitic Infection (NPI), targeting it for public health action based on the number of people infected and the severity of the disease. Less than a year later, Martin Shkreli, then CEO of Turing Pharmaceuticals, acquired the rights to Daraprim and raised the price of the now 64 year old drug 5000%, a notorious move that increased an annual prescription to $634,500 for patients weighing more than 60 kilograms (132 pounds).

Without an available cure and considering the unfavorable treatment options at hand, our only immediate hope to alleviate the burden of toxo is to prevent human exposure to the offending pathogen causing the initial disease.

Toxo can only complete its life cycle and produce infectious spores on cat feces. Most people and animals become infected by unknowingly ingesting or inhaling these spores which makes cleaning a cat’s litter box a high-risk activity, particularly to those who are immune- compromised. Simple precautions should be taken that can eliminate the risk of toxo infection.

Toxo is also transmitted by consuming the raw or rare meat of previously infected animals and is a leading cause of death from foodborne illness in the United States. The general public is warned of toxo risk by the mandated menu advisory, “Consuming raw or undercooked meats, poultry, seafood, shellfish, eggs or unpasteurized milk may increase your risk of foodborne illness,” But public awareness on how to prevent toxo infections is otherwise extremely limited.

With more than one third of the U.S population sharing their homes with pet cats, the responsibility to provide the warnings and resources necessary to protect the general public from the burdens of toxo and create a safer environment for both humans and cats, should be a high priority of our public health d healthcare systems.

viable solutions to reducing the risk of toxo are essential. One such alternative to using masks and gloves when changing kitty litter is a self-contained cat waste disposal system (created by Toxoplasmosis Solutions, an enterprise of BetterBox) which allows cat owners to safely contain and dispose of domestic cat waste without exposing themselves or their environment to toxo’s infectious spores. Additional tools that the public can utilize including public service announcements on how to properly handle and prepare raw meet, are needed.

Toxo’s life cycle is dependent on cat waste contaminating the environment of its future hosts. Considering that the majority of cats in the U.S. are domesticated and living in human homes, mechanically blocking the life cycle of this devastating disease by implementing responsible cat waste disposal procedures is an effective option.

Legislators in the U.S. need to be encouraged to develop a national toxoplasmosis bill supporting the additional research, education, prevention, and treatment efforts. The latest scientific findings regarding “latent” toxo along with the compelling epidemiology to inform legislators, public health officials, and health insurance providers that an investment towards designing public awareness has great potential to reduce healthcare costs and disease burden in the United States and globally.

This article originally appeared in panaware.wordpress.com

An HIV preventative vaccine is making its way through the clinical trial system with a new study beginning enrollment later this year. Mosaico is the latest in a string of primate and then human studies stretching over the past fifteen years, testing vaccine candidate Ad26.Mos4.HIV. The Phase III clinical trial will evaluate the Janssen Pharmaceutical vaccine in men who have sex with men (MSMs) and transgender women and men. Mosaico is a collaboration between Janssen, the NIH, the HVTN and the U.S. HIV Military Research Program (MHRP.)

“We’re very excited because it’s an exciting product that has been extensively tested in earlier-stage trials. People appear to not only develop a strong immune response but a lasting immune response, which is important in a vaccine,” stated Dr. Susan Buchbinder, MD, Protocol Chair of the Mosaico Trial and Director of Bridge HIV at the San Francisco Department of Public Health.

Mosaico (HPX3002/HVTN 706) will be enrolling 3,800 transgender individuals and men who have sex with men at fifty-five sites throughout the United States, Latin America, and Europe. In the U.S., twenty-two sites throughout sixteen cities will enroll HIV negative, at risk participants. Sites in Argentina, Brazil, Italy, Mexico, Peru, Poland and Spain will also participate in the study.

Mosaico is the largest clinical trial to date evaluating the promising “Mosaic’” vaccine candidate, that, if successful, will be able to be used globally against all strains of HIV. This is due to its genetic inserts, which contain various HIV strains. Producing an effective vaccine that would maintain protection against the numerous strains of HIV found around the world has been a major challenge in vaccine research and development. The establishment of one vaccine that can be used in every population and against all clades of HIV is essential to the eventual eradication of HIV.

According to Dr. Buchbinder, the vaccine used is “designed to be a global vaccine. It takes information from multiples clades around the world. If effective, we hope people could be protected against multiple strains of HIV so we don’t need to recreate a vaccine for each region of the world.”

Mosaico is a complementary study to Imbokodo, a separate clinical trial of a near identical vaccine which has already completed enrollment.

The one difference between the vaccines being studied is that, in the Mosaico trial, a mosaic insert is added to the third and fourth injections (four total injections) and for Imbokodo a Clade C insert is used. Clade B is included in this mosaic insert, and is the prominent clade of HIV seen in North America and Europe. Clade C is the most common strain in Southern Africa. As well as examining different regions, the two studies will examine the vaccine in different populations of people.

Studies have shown that men and women can elicit different immune responses to a vaccine. When asked if a vaccine might behave differently in transgender people on hormone therapy, Dr. Buchbinder stated that this is why they are testing it specifically in transgender men and women because they don’t know how the hormones some transgender people take will affect their immune response.

A 2019 systematic review and meta-analysis published in the American Journal of Public Health found that an estimated 14% of all transgender women are living with HIV and 44% of black/African American transgender women are currently living with HIV. The CDC recognizes transgender men and women as being at a high risk for HIV. Many transgender individuals experience stigma, social rejection, workplace discrimination, difficulty obtaining employment and social isolation. This can contribute to risky behaviors and prevent them from fully integrating into society, building healthy support systems and accessing HIV testing and medical care.

Imbokodo enrolled 2,600 sexually-active women ages eighteen through thirty-five from five African countries (South Africa, Malawi, Mozambique, Zambia, and Zimbabwe). These countries were chosen due to the extremely high risk of HIV in young women. In the regions being studied there are 3,500 new HIV infections per week in young girls and women. In South Africa, the hardest hit area of Southern Africa, although HIV rates are very high in men who have sex with men at 26.8% and a rate reported in transgender women to be double that of MSMs; young cisgender women are at an even higher risk. Young cisgender women between the ages of fifteen and twenty-four alone, make up 37% of new infections. The large Phase II clinical trial is expected to be completed in 2021.

Results from Mosaico are expected in 2023, with researchers hoping to achieve at least a 65% protective rate against HIV. Stay tuned….

Originally published in Destination: Cure, A&U Magazine — https://aumag.org/2019/10/21/mosaico-trial-testing-hiv-preventative-vaccine/

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Originally published on PanAware on Wordpress.com on November 1, 2019. By Jeannie Wraight.

In order to keep their virus suppressed, most people living with HIV must take antiretrovirals (ARVs) daily. If ARVs are stopped, an increase in viral load to detectable levels is usually seen after three to four weeks. However, a small group of HIV-positive people are able to discontinue therapy without viral rebound for an extended period of time. These people are referred to as post-treatment controllers.

At one time, HIV antiretroviral therapy consisted of many pills taken several times a day. Despite a massive reduction in the number of pills, current HIV regimens—even one-pill-a-day regimens—can be difficult to maintain on a daily basis due to side effects, co-morbidities, high cost, stigma and/or difficulty remembering to take one’s pill(s). Also for some, having to take ARVs every day is a constant reminder that they’re living with HIV and makes adherence more difficult.

Researchers are developing ARVs that can be taken less often then the daily medications that people living with HIV currently must contend with. Long-acting ARVs are in development and they may allow for weekly or even monthly injections in lieu of daily dosing.

In addition to long-acting ARVs, researchers are also looking at a small group of individuals with HIV who are able to maintain an undetectable viral load after discontinuing therapy. Post-treatment controllers may offer clues to develop strategies and new drugs that could help others to better control HIV and allow for less frequent use of ARVs.

Descriptions vary, but one definition of post-treatment controllers is those who are able to maintain viral loads of 400 or fewer copies per milliliter of blood for at least twenty-four weeks after stopping HIV therapy. An exact percentage of people who are able to control their virus is unknown, but researchers estimate the number to be between five and fifteen percent of people living with HIV. However, as most people on ARVs don’t interrupt their therapy, it is difficult to know exactly who or how many actually belong to this group.

Post-treatment controllers are different from “HIV controllers” who are able to maintain undetectable viral loads without ARVs. Less than one percent of people living with HIV are thought to be HIV controllers.

There are several well known cases of post-treatment control. Most notably, the VISCONTI cohort. VISCONTI stands for Viro-Immunologic Sustained Control After Treatment Interruption. The VISCONTI cohort was a group of fourteen Italian people living with HIV who began ARVs within ten weeks of HIV infection. They remained on ARVs for a minimum of three years and, after discontinuing treatment, were able to suppress HIV to undectable levels for an average of seven and a half years.

The “French teenager” is another well documented case. The girl was born with HIV and received prophylactic ARVs shortly after birth (though the exact time frame is unclear). She remained on treatment for six years. At the time of the most recent report in 2016, she had remained off therapy with an undectable viral load for twelve years.

Very early treatment after HIV infection as in the VISCONTI cohort and the French teenager is thought to possibly limit the establishment of viral reservoirs . However, a very small handful of cases differ greatly from the others in as they were positive for some time before initiating antiretroviral therapy.

In 2011 a (then) fifty-one year old Argentinian woman was reported to have discontinued ARVs in 2007 after eleven years of treatment. In addition to having started ART a substantial period of time after HIV infection, the Argentinian woman had been defined as having AIDS before she began taking ARVs. In fact, she was quite sick before initiating therapy, unlike nearly all other cases of post-treatment controllers who began ARVs very early on after their initial infection with HIV.

A study in 2018 described three individuals who were also considered “chronically infected” and were able to control their virus after stopping ARVs. It’s unclear whether the Argentinian woman is among the three people studied.

As it’s now standard of care to begin ART immediately following diagnosis and remain on treatment indefinitely, how would we be able to tell who is a post–treatment controller? One study published last year examined post-treatment controllers in hopes of determining characteristics that may help to identify who may belong to this group. They found that post-treatment controllers had smaller viral reservoirs and that reservoir size may be a useful biomarker in determining who may be a post-treatment controller.

More studies on post-treatment controllers could help to establish if a person needs to be on lifelong ARVs or if they belong to the small group of people living with HIV who are able to stop HIV treatment and remain undectable. Further studies could potentially also offer clues for the development of drugs and strategies to help others maintain temporary viral suppression after discontinuing ART.

Originally published in Destination: Cure, A&U Magazine — https://aumag.org/2019/07/31/post-treatment-controllers-hiv-treatment/

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Originally published on PanAware on Wordpress.com on August 22, 2019. By Jeannie Wraight.

As described previously in Destination: Cure, HIV hides in clusters of cells called viral reservoirs where they remain inactive indefinitely. As these cells are not producing HIV, they are not recognized as a threat by the immune system. HIV antiretrovirals (ARVs) are unable to penetrate these latently infected cells. Latent HIV has the potential to awaken and begin reproducing. If a person who is on ARVs and virally suppressed stops taking their ARVs or becomes drug-resistant, latently infected cells can awaken, resulting in viral rebound. It takes only one latently infected cell for this to occur.

Researchers have found latent HIV in several types of cells, including resting T cells, follicular dendritic cells, and macrophages. Macrophages are long-lived cells derived from monocytes that can reside in tissue in several places throughout the body, including the liver, lungs, brain and bone marrow. Macrophages engulf viruses, bacteria, fungi and dead cells in a process called phagocytosis.

BIT225 works by targeting the protein in HIV that is responsible for viral assembly, interfering with its ability to properly replicate. With HIV replication incompetent, the virus is unable to infect additional cells.

Researchers conducted a Phase II study at two sites in Thailand to discover if adding BIT225 to an ARV regimen produced additional virological and immunological benefit beyond that of ARVs alone.

BIT225-009 enrolled twenty-seven patients and analyzed whether BIT225, in addition to Atripla, showed a benefit over Atripla and placebo. All study participants were treatment naive. The study ran for twelve weeks and all participants remained on ARVs after the study concluded. Researchers focused on safety pharmacokinetics and the impact on virological and immunological markers.

A statistically significant benefit was seen in those on BIT225 and Atripla versus those on Atripla and placebo in CD8+ and activated CD4 T cell populations. This difference in these levels is evidence of the immune system recognizing and responding to the replication-incompetent virus as a foreign invader thus producing an immune response to eliminate the perceived threat.

According to the poster authors: “The commencement of a decline of activated CD4+ cell levels at week 6 suggests that virus from these reservoir cells is being eradicated, and cleared by week 12 when levels return to those seen in the ART + placebo group.”

Researchers looked at changes in the levels of Soluble CD163 (sCD163), a macrophage immune marker. High levels of sCD163 are seen prior to initiating ARVs, but decrease once viral suppression had occurred. However, this is not the case with all HIV-positive individuals. High levels of this immune marker in people living with HIV with well controlled viremia are linked to an increased risk of morbidity and mortality. Study participants taking BIT225 with Atripla experienced a greater decrease in sCD163 than those on Atripla and placebo. According to the poster authors, the ability of BIT225 to show a greater decrease of this immune marker in people living with HIV may show cause for use of BIT225 in high-risk patients.

The importance of this immune marker was further evidenced in a separate study (not involving BIT225) in people co-infected with HIV and HCV. In this study, sCD163 levels decreased when participants began ARVs, but did not normalize. In those co-infected with HIV and HCV, sCD163 was linked to the progression of fibrosis.

BIT225 was found to be safe with no serious adverse events (AEs). The most common minor AEs were dizziness at thirteen percent for those on BIT225 and Atripla versus eight percent for Atripla and placebo; headache at nine percent for BIT225 and Atripla versus two percent for Atripla and placebo; and nausea at six percent for BIT225 and Atripla versus six percent for Atripla and placebo.

The results of this study indicate that BIT225 may play a role as part of a potential cure regimen if its demonstrated ability to eradicate HIV from macrophages is further shown in additional studies. It also shows promise as an HIV therapeutic, particularly in high-risk individuals.

It’s important to realize that this therapy is not produced by Big Pharma. It is currently owned by a small Australasian Biotech company (Biotron) that, as with most biotechs, has limited funds for further studies. Advocacy is needed to ensure continued research of this drug with support by the NIH, AIDS Clinical Trials Group, and other funding mechanisms.

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Originally published on PanAware on Wordpress.com on April 9, 2019. By Jeannie Wraight.

To date there are over 100 documented cases of HIV remission and one occurrence of HIV eradication. Researchers are currently investigating numerous HIV cure and remission strategies including monoclonal antibodies; gene therapies; stem cell transplants (such as the procedure that cured Timothy Ray Brown); and post-treatment control and therapeutic vaccines/other immune-boosting agents that would allow the immune system to more effectively control HIV. Also being studied is a new approach currently known as ”block and lock” where researchers attempt to essentially ‘lock down” the HIV reservoir to prevent dormant HIV from becoming active.

The most widely recognized and studied approach is the kick and kill strategy, which aims to reactivate the latent HIV in viral reservoirs and then kill these infected cells with a combination of antiretrovirals and immune-boosting agents. Although a recent kick and kill study failed to achieve its goals, as reported in last month’s Destination: Cure column, several other kick and kill studies are planned with varying components.

When investigating these strategies, it’s essential to keep in mind that in addition to efficacy, an effective HIV cure strategy must be one that is not only safe and efficacious but also is affordable to the entirety of the world. As such, strategies such as stem cell transplants and costly gene therapies, if they were to work, would likely have a limited reach excluding much of the developing world, where the majority of people living with HIV reside. Although some strategies will only be applicable to certain people or populations, a viable overall cure must be accessible to everyone.

At AIDS 2018, a new class of drug called RNA helicase translation inhibitors was unveiled. Translation inhibitors (TI) are being researched and developed as an HIV therapeutic that could also be applicable in a kick and kill strategy. Numerous aspects of this class of drug, as well as the company that is developing TIs, check all the boxes of an intervention worthy of attention.

Unlike current antiretrovirals that work against HIV itself, TIs target a human host factor, DDX3. Although DDX3 is involved in several cellular functions of RNA metabolism, preclinical and mice assays have shown no toxicities related to inhibiting DDX3. Strong activity against HIV replication, including numerous drug- resistant strains, has been observed in preclinical research and drug resistance is expected to be minimal or unlikely. A DDX3 TI approach could also be used as salvage therapy to treat those with multi- drug resistant HIV, or in addition to ARVs, to limit the occurrence of drug resistance.

By inhibiting the DDX3-mediated viral protein translation apoptosis (cell death) can be induced. If this is shown in vivo in the presence of HIV, it could disrupt the establishment of viral reservoirs, thus making DDX3 translation inhibitors a good candidate to be studied as part of a cure strategy.

In addition, DDX3 is involved the replication of various viruses, tumor proliferation and the above-mentioned inflammation. Thus, as well as activity against HIV replication, it may also show benefit against several HIV-related comorbidities and co-infections such as hepatitis C, Kaposi sarcoma, and immunesuppressive-related tumors. TIs are expected to reduce the inflammatory state associated with HIV, directly acting on the production of inflammatory mediators as observed in cellular assays. HIV-related inflammation has been associated with numerous HIV co-morbidities that can greatly impair health, quality of life and survival.

“Translation inhibitors are promising compounds to treat HIV infections and in particular to attack resistance. If you target host factors crucial for the viral replication [such as DDX3] it makes it much more difficult for the virus to escape because the protein cannot mutate to escape the inhibition. A combination of both inhibitors against host factors as well as antiviral compounds will be one of the best combinations of drugs you can have,” stated Prof. Dr. T.B.H. Geijtenbeek, Head of the Department Experimental Immunology at the University Medical Center of Amsterdam.

The makers of translation inhibitors, First Health Pharmaceuticals BV, have therapeutics in development for numerous viral infectious diseases such as HIV, HCV, Zika, Ebola and Dengue fever, as well as anti-tumor agents for several forms of cancer. Typically, when I write about notable research, my focus is solely on the drug and the research that makes it credible. However, in the case of translation inhibitors, the company behind the drug and their mission play a vital role, in addition to the research, in why we should focus on TIs and what makes them viable as an HIV therapeutic/potential component of a kick and kill strategy that could be used across the globe.

First Health Pharmaceuticals BV has created a non-profit organization founded with the purpose of promoting life science R&D for the benefit of humanity in general. First Health Pharmaceuticals BV has pledged to donate a portion of the proceeds from their therapeutics and the largest part of its antivirus pipeline to its non-profit First Health United foundation, to provide their medications free or at cost to low-income countries, especially in the sub Saharan region. Thus, drugs created and approved for any of the indications targeted, including an HIV therapeutic or cure, will be made accessible to all who need them. It’s extremely heartwarming and rare to see a pharmaceutical company that values lives over profits. I will be closely following the development of this new class of drug and reporting my findings in future columns.

This article is reprinted with permission from A&U Magazine.

Originally published on PanAware on Wordpress.com on April 9, 2019. By Jeannie Wraight.

By Jeannie Wraight

A new study published in the Journal of Immunology suggests that co-infection with toxoplasmosis (toxo), a parasitic infection common in people with AIDS, may play an important role in strengthening HIV’s ability to overcome the immune system.

Until the introduction of ARVs, toxo encephalitis (TE) was a leading cause of death in people with AIDS. While instances of TE have diminished, toxo infection still has consequences that may have significant immunological consequences.

Toxoplasmosis made headlines in 2015 when Martin Shkreli, former CEO of Turing Pharmaceuticals, raised the price of its toxo drug Daraprim (pyrimethamine), by 5,456 percent (from $13.50 to $750), making it the second most expensive drug in the U.S. Not long after, Shkreli, dubbed “the most hated man in America,” received what some saw as his karmic fate in the form of a seven-year prison sentence for securities fraud. Public outrage highlighted the importance of Daraprim and toxo, a disease contracted by over 60 million Americans. Research suggests toxo may be connected to neurocognitive disorders, diabetes, and a myriad of other disease manifestations. Despite this and the CDC’s designation of toxo as a neglected parasitic infection targeted as a priority for public health action, toxo receives little attention or research funding.

In a recent study, researchers looked at the effect of toxoplasmosis on plasmacytoid dendritic cells (pDCs), which secrete interferon alpha (IFN-α), a substance involved in HIV suppression and immune modulation. During HIV infection, pDCs decrease in number and those that remain produce less IFN-α, which reduces the immune system’s ability to suppress HIV. Researchers found toxo inhibited IFN-α produced in response to HIV, preventing pDCs from functioning. pDC cells are a critical mediator of interleukin-10 (IL-10), which has been associated with more rapid disease progression in late stages of HIV infection. However, the role of IL-10 in HIV is controversial, possibly maintaining both protective and detrimental effects. Researchers also found that toxo decreased tumor necrosis factor-alpha (TNF-α) produced in response to HIV.

Decreasing TNF-α could be detrimental as an important function of TNF-α is to activate neutrophil cells, stimulating the response by neutrophils and macrophages that inhibit HIV infection.

According to researchers, “[o]ur findings [further] imply a convergent mechanism of inhibition of TLR [toll-like receptor] signaling by T. gondii (toxo) and IL-10 and suggest potential negative consequences of HIV/T. gondii coinfection.” TLR is involved in permitting HIV infection in latent mass cells, part of the HIV reservoir. The results of this NIH-supported research suggest that toxoplasmosis/HIV co-infection may have important implications for HIV cure research and further investigations to uncover the role of toxoplasmosis in HIV’s evasion of the immune system are needed.

Approximately 1.1 million people acquire toxo each year in the U.S. Although acute infection is treatable, there is no cure for toxoplasmosis. Under constant pressure from a competent immune system, the parasites persist within cysts where they slowly replicate in the body for the duration of their host’s life. This latent stage may be reactivated if the immune system becomes suppressed, causing potentially devastating effects to the brain, lungs, eyes, and other organs. People living with HIV or cancer, the elderly, transplant patients, and pregnant women are at high risk of reactivation. Mothers with active toxo can pass the infection to their unborn children, potentially causing birth defects and miscarriage.

Toxo can infect all mammals and birds, but it can only complete its life cycle in cats. Upon a cat’s primary infection, hundreds of millions of infectious spores, called oocysts, are distributed into the environment through the cat’s feces for a short time until the cat develops an immune response or receives appropriate treatment. Humans can develop toxo by inhaling or ingesting the microscopic oocysts or by consuming the undercooked meat of an infected animal. The CDC recommends the best approach to minimizing the risk of contracting toxo for people who are immune comprised is to avoid exposure to anything that may be contaminated by cat feces.

It can’t be stressed enough that this does not mean you need to or should get rid of your cat. Studies have shown that the bond between people and their pets can improve their quality of life by increasing fitness, lowering stress, and evoking a sense of happiness; however, improved methods for handling and disposing of cat feces are needed. The best approach to minimizing the risk of contracting toxoplasmosis, particularly for those who are immune-compromised, is by avoiding exposure to cat feces when possible and cooking meats to a minimum internal temperature of 165° F. A new self-contained, yet-unnamed litter box system, created by an inventor in Middlebury, Connecticut, Christopher Romano, will be available soon to protect against possible exposure to toxo through cat feces.

Prevention of toxo through stronger designation and promotion of federal guidelines, as well as studies to ascertain the consequences of toxo co-infection with HIV and other diseases, should be made a priority by the NIH and the CDC in order to prevent continued public health burden by this neglected parasitic infection.

This article is reprinted with permission from A&U Magazine.

Originally published on PanAware on Wordpress.com on September 3, 2018. By Jeannie Wraight.

In the early HAART days prior to 2005, as many as sixty percent of PLWHA in the developed world experienced diarrhea. Currently, in the developing world, it is estimated that close to 100 percent of PLWHA have experienced chronic diarrhea either from infectious or noninfectious causes.

Although AIDS-related diarrhea has decreased significantly with the global use of ART, the incidence of noninfectious diarrhea (NID) has increased. HIV enteropathy—or gastrointestinal damage related to HIV infection—as well as the use of ART are the main causes of NID in PLWHA. Over 750,000 newborns, infants and children die annually from potentially treatable HIV-associated infectious diarrhea.

New data from the ADVENT study, which analyzed Mytesi (formally known as crofelemer), shows a potential treatment that can significantly decrease incidents of noninfectious HIV-related diarrhea. Mytesi is an anti-secretory agent that is the only FDA-approved therapy in the U.S. for treatment of noninfectious diarrhea in PLWHA on ART. It is also currently available on formulary in Zimbabwe. Although the source of crofelemer, which is extracted and purified from a tree in the Amazon rainforest, is a timely and expensive process, its manufacture is currently working on processes that could make Mytesi more cost-effective for African countries where, many can argue, it is needed most.

Researchers for the ADVENT study evaluated Mytesi or placebo in 272 PLWHA for a four-week period, after which, all of the participants were offered the opportunity to take Mytesi for an additional twenty weeks. This study, which ultimately led to the FDA-approval of crofelemer, showed that significantly more PLWHA who received Mytesi achieved a clinical response verses those on placebo. Clinical response was defined as a reduction in watery stools from an average of twenty per week at study entry, to less than two watery stools per week during the four-week placebo-controlled phase.

However, the original analysis of the ADVENT study only included results from the four-week placebo controlled study and not the entire twenty to twenty-four weeks that participants took crofelemer. Since the results do not characterize the reduction in diarrhea among all of the participants in the study over the entire duration of the study, and as there is a substantial benefit from a fifty percent or greater reduction in watery stools, a supplemental analysis was performed to review the long-term efficacy of crofelemer. This analysis was presented at the 9th IAS Conference on HIV Science in Paris.

In this analysis of ADVENT, researchers reviewed the entirety of data in study participants. The endpoints analyzed included:

• average change in watery stools over four to twenty-four weeks in crofelemer-treated patients

• proportion of study participants with greater than a fifty percent, seventy-five percent, and 100 percent reduction in the number of watery stools

Participants in the study had NID for at least one month while taking a stable ART regimen and had CD4 cell counts over 100. Almost eighty percent had evaluable stool diary data and completed the placebo-free extension phase.

Of the participants, the average age was forty-five years, sixteen percent were female, and sixty percent were non-Caucasian (thirty-eight percent Blacks/African-Americans, twenty percent Hispanics/Latinos). On average, participants had had diarrhea for six years and reported an average of twenty watery stools per week. Additionally, fifty-nine percent had used at least one antidiarrheal medication.

The proportion of people with ≥50%, ≥75%, and 100% reduction in number of watery stools was forty-eight, thirty-five, and fifteen percent by week 4; seventy-two, sixty, and forty-one percent by week 12; and seventy-three, sixty-three, and fifty percent by week 20, respectively.

The proportion of people achieving clinically relevant reductions in watery stools at any time point was not significantly different whether analyzed by concomitant protease inhibitor use (sixty-six percent were taking protease inhibitors) or by diarrhea etiology (seventy-five percent attributed diarrhea to ART while twenty-five percent to HIV infection and/or other causes).

None of the participants on the study reported serious adverse events attributed to crofelemer. Mytesi has no clinically relevant drug-drug interactions, and does not affect CD4 counts or viral load.

In the supplemental analysis, the researchers concluded that Mytesi was associated with clinically relevant and sustained reductions in NID that were not apparent from the ADVENT trial primary responder analysis.

Mytesi represents a therapy which is direly needed throughout both the industrial world and developing nations to reduce HIV-related noninfectious diarrhea. A reduction in incidences of diarrhea has been found to have an important impact on a person’s quality of life, their physical health and the absorption of ARVs. With HIV ARVs, as well as HIV itself, known to cause diarrhea in a large number of PLWHA, Mytesi should be considered an obvious adjunct therapy for those prescribed ARVs throughout the world.

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Originally published on PanAware on Wordpress.com on June 14, 2018. By Gary Blick, MD, and Jeannie Wraight.

When first discussing the potential of writing a monthly column on HIV cure, my editor here at A&U Magazine asked a very valid question. He wanted to know if I thought I would be able to find enough material for a monthly column. At that time, nearly five years ago, information on cure-related issues was somewhat scarce. This was the main reason I wanted to write Destination: Cure—to be able to gather and report the bits of scattered news, research, and breakthroughs on what was becoming an emerging field of research.

Over the years I’ve had little trouble finding cure-related topics to focus on. In addition to scientific research, there were and still are many political, ethical, social, funding and policy issues that encompass “HIV cure.” Since beginning this column in 2013, I’ve attempted to focus on these issues as they continue to evolve.

A lot has changed since my first column. We’ve come a long way, particularly in HIV reservoir research, scientific collaboration, and heightened funding. However, we still have a vast road ahead of us with many unanswered questions and dilemmas.

For example, how do we know when we’ve found a cure or remission? Several researchers are working on biomarkers that can measure trace amounts of HIV in certain cells and reservoirs. Until these biomarkers are available, it would be difficult to declare a person cured or know if a therapy or cure strategy is successful.

Debate continues about how long a person must remain off ARVs until they are considered in remission. HIV remission is different from an eradication cure, where HIV is completely removed from the body. HIV remission is currently defined similarly to cancer remission in terms of a person being able to remain illness-free without the use of ongoing treatment. Some researchers suggest borrowing the timeframe instituted in cancer patients to define when HIV remission has been achieved. This is normally five years.

Perhaps one of the most important questions that continues to be asked by some is: Do we really still need a cure and is it ethical to continue to search for one? For many this is a no-brainer. However, there are those that argue about the necessity and fairness of spending money on an HIV cure. Some claim that since the approval of over thirty HIV antiretroviral medications have succeeded in turning HIV/AIDS from a deadly disease to a “manageable chronic illness,” that it’s time for HIV to take a backseat to other life- threatening illnesses.

There are over 7,000 “rare diseases” affecting people in the United States. According to a fact sheet from The National Organization for Rare Disorders (NORD), “There are more Americans who live with a rare disease than ALL of those who have either HIV, Heart Disease or Stroke.” Only five percent of rare diseases have FDA-approved treatments. It’s likely that a tiny fraction of the HIV research budget, since the discovery of HIV, could have either cured or found treatments for a number of these diseases.

This argument may be strengthened as U=U and PrEP allow HIV to become untransmittable and easier to protect against, respectively, particularly as ARVs become more available to a greater number of people in the developing world.

So then, is it fair or necessary that such a large amount of resources, including those from government, commercial, foundation and private sector finances, continue to be used for HIV cure and remission efforts?

On an ethical level, few of us are qualified to answer that. However, on a financial level, and in terms of human lives lost, the answer is unequivocally yes.

Despite a massive decrease of forty-eight percent in AIDS-related deaths since the global scale-up of ARVs, there were still 1.1 million deaths from HIV/AIDS-related causes in 2015. Despite over thirty years of research and many HIV therapies, millions of people will continue to die of AIDS and HIV- related illnesses.

The U.S. government currently invests approximately $26 billion domestically, and $6.6 billion globally, to the fight against HIV/AIDS. The need for funding both in the U.S. and abroad is likely to only grow greater with each year. A cure or remission for HIV is the only means of eventually eliminating this financial burden and freeing up funding for other diseases.

As such, the search must continue and questions regarding scientific, ethical, financial and logistic considerations of cure research will need to be fairly, intelligently and timely asked, confronted and resolved. Many questions remain, but as the puzzle slowly takes shape, we must maintain the momentum so many have come together to create.

Originally published on PanAware on Wordpress.com on May 8, 2018. By Jeannie Wraight.

By Jeannie Wraight

Research performed at Case Western found increased levels of HIV in the saliva and blood of people who had severe periodontitis (inflammation of the gums around the teeth). They discovered byproducts of bacteria, called metabolic small chain fatty acid (SCFA), that are associated with periodontitis, which can work together to awaken dormant HIV and cause it to reactivate, leading to an increase in residual HIV.

This research is described in the article “Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFb and multiple histone modifications,” published in January 2015 in the journal Virology.

The Case Western research reaffirmed earlier research conducted at the University of Kentucky that also demonstrated a strong correlation between oral bacteria and latent HIV activation in T cells. Both studies suggest a link between oral healthcare and increased HIV replication and support the importance of treating and preventing oral bacterial infections.

Additionally, oral bacteria were linked by the Case Western researchers to increased rates of Kaposi’s sarcoma-associated herpesvirus (KSHV), which is known to be associated with HIV.

The mouth is a breeding ground for bacteria. In total, approximately 700 strains of bacteria have been found to inhabit the oral cavity. Particular strains vary from person to person and depend on many factors including environment, health and the food a person eats.

Bacteria is not necessarily a bad thing. Most of the bacteria in the mouth are beneficial organisms that live in harmony with each other, maintaining a healthy microbiota (bacterial colony). It’s when “bad” strains of bacteria overtake the “good” that oral manifestations such as periodontitis, gingivitis, and infections can occur.

Periodontitis is often more severe, and can occur with an enhanced frequency, in HIV-positive individuals. It is initiated by bacterial strains that include Porphyromonas gingivalis. A higher level of these bacteria have been found in HIV-positive versus HIV-negative individuals.

Studies show that individuals living with HIV also have higher levels of a bacteria strain called Streptococcus mutans (S. mutans). S. mutans contributes to the formation of caries (the scientific term for cavities and tooth decay). Caries increase the severity of periodontitis.

A strong link has also been shown between the inflammation caused by periodontitis and oral bacterial infections and the development of cardiovascular disease. Bacteria can leak into the bloodstream and trigger inflammation. Inflammation leads to atherosclerosis (hardening of the arteries), which can cause a heart attack or stroke.

As our knowledge of the importance of microbiota in diseases such as HIV grows, additional research on the potential use of probiotics has begun to show the benefits of certain probiotics in restoring healthy microbiota. The utilization of probiotic mouthwash to restore and maintain a healthy microbiota balance in the oral cavity is growing in popularity. One such oral probiotic mouthwash, called BreathActiv, has been suggested specifically for HIV patients due to its inclusion of S. rattus JH145, which reduces S. mutans.

The importance of oral health care is often overlooked by both HIV patients and their physicians. The Case Western research suggests that more attention should be paid to maintaining a healthy balance of oral bacteria.

People living with HIV should discuss an oral health plan with their clinician as part of their holistic treatment of HIV. This may include regular visits to their dentists, early treatment of periodontitis, mouth infections and other oral manifestations common to HIV-positive patients, and the institution of prevention efforts that include daily brushing, flossing, and other methods to decrease harmful bacteria.

Further research into the extent oral bacteria have on inflammation and latent HIV activation and methods of stabilizing the oral microbiota is warranted.

By Jeannie Wraight

Originally published on PanAware on Wordpress.com on July 12, 2016. By Jeannie Wraight.

In February of 2014, The National Institutes of Health granted Montaner’s lab a four-year, $6.2 million grant to conduct a multi-site trial to investigate interferon. The study will be the largest clinical trial of a potential cure strategy to date, and continues earlier research of interferon that showed promising results.

Interferon is a protein naturally produced by cells when a microbe, such as a virus or bacteria, is detected. Interferon belongs to a group of proteins called cytokines. Cytokines are messenger proteins that help cells to communicate between each other. Interferon up=regulates defense host mechanisms designed to protect the cell from viral infection and activates immune cells, such as natural killer cells and macrophages. Early on in the HIV pandemic before antiretroviral use, pegylated interferon was investigated as a means of controlling the virus and delaying disease progression. Although there was some effect when used in patients who were antiretroviral-naive, interferon was not pursued as soon as ART was available. The idea of studying it again with ART is to see if interferon can eliminate HIV by activating anti-viral mechanisms newly recovered due to ART.

Montaner explained in a presentation at ID Week in San Diego, California, this past October 2015, that the production of interferon is an early immune response. It is triggered by the presence of microbes (in this case HIV) to produce a response that attempts to overpower the virus, creating pressure to prevent uninfected cells from becoming infected. Interferon-mediated cells interact with at least nine points during viral replication including reverse transcription, integration, packaging and budding of the virus from the cell, providing numerous targets to potentially reduce the amount of virus being produced. When a cell is infected with HIV, the virus produces its own countermeasures against interferon, but by boosting interferon and its ability to make more uninfected cells resistant to any incoming HIV, it may be possible to slow the production of HIV and reduce the number of infected cells.

In 2013 results were published from a study that Montaner conducted using pegylated interferon (PegIntron) to determine if individuals with suppressed viral loads could stop taking their antiretrovirals for a period of time with the help of weekly injections of interferon. The study, although small, produced very intriguing results.

Twenty virally suppressed study participants with high CD4 counts were given interferon in addition to their ARV regimens for five weeks, after which the ARVs were discontinued and participants continued weekly injections of interferon as a monotherapy. At week 12, almost half of the study participants maintained viral loads under 400 copies. Given the option to conclude the study or continue taking interferon while remaining off ARVs, nine individuals elected to stay on interferon for a full twenty-four weeks. Of the nine, seven maintained viral loads below 400 copies for the course of the study. Surprisingly, aside from viral load, when the amount of HIV inside cells was measured, it was lower than before they started interferon. This would indicate that the interferon decreased the size of viral reservoirs. Despite these results, some of the participants did not respond to interferon for reasons not yet known.

Three separate studies performed by researchers studying interferon in HIV/HCV co-infected individuals, also noted a decrease in HIV, adding further weight to Montaner’s study.

A second study was conducted by Montaner’s lab using interferon alpha IIb which was completed in August. This study enrolled twenty individuals, out of which seventeen completed the study. Much of the data has not yet been released but what we do know so far that a decrease in HIV RNA was seen in rectal tissue in about half of the participants. Interferon was said to be relatively well tolerated by study participants.

Montaner’s lab is currently enrolling the NIH-funded study mentioned at the beginning of this article. It is a Phase II clinical trial that will be conducted at three sites in Philadelphia. The study will measure the extent of decrease in integrated HIV proviral DNA in the blood and tissues with the use of pegylated interferon alpha-2b with or without a period of interferon monotherapy after an interruption of ART. This will determine if the size of viral reservoirs are decreased and if interferon should potentially be further studied as part of a combination cure strategy.

by Jeannie Wraight

For more information on the study and its sites, please log on to: www.clinicaltrials.gov/ct2/show/NCT02227277.

Originally published on PanAware on Wordpress.com on July 1, 2016. By Jeannie Wraight.

In the two years that followed HPTN 045 it’s become apparent that it is not as simple as an undetectable viral load equates to being non-infectious while a detectable viral load equals being infectious. Research subsequent to HPTN 045 has taught us several things: whereas an undetectable viral load DOES decrease the risk of transmitting HIV to negligible (near non-existent) levels, other factors then increase the risk back upward. We know that sexually transmitted diseases increase the risk but it is not clear by how much. We also know that anal sex increases the level of risk in comparison to vaginal sex. The risk of transmission is also greater when the positive person is the inserting partner.

Another important factor when weighing risk is that an undetectable viral load is a snap shot of how much virus was in the blood at the time the test was taken. Since this number can fluctuate, the amount may have increased or decreased since that time. It can be different from month to month, week to week, day to day and even hour to hour. So a person may have been undetectable at the time of their last test but may not be shortly after. Viral load measurements are taken from the blood (peripheral). Research has determined that peripheral viral load may differ from HIV viral load found in semen, vaginal or anal fluids. Thus, your viral load may be undetectable in your blood but may be higher in other body fluids that can effect transmission.

In summary, additional factors can play a role in the level of transmission in the presence of an undetectable viral load:

• Sexually transmitted diseases

• Fluctuations in viral load from time of testing to sexual exposure

• Differences in peripheral viral load from viral load in semen, vaginal or anal fluids

• Type of sex – anal versus vaginal

• Role or position as in being the inserting partner or the receiving partner.

Originally published on PanAware on Wordpress.com on January 21, 2014. By Jeannie Wraight.

Researchers are looking for new types of medications that will eliminate or partially eliminate the need for ongoing ARV treatment. However, research is being hindered and not by a lack of knowledge or ideas on how to slow the virus but by financial considerations. One such drug whose progress is being slowed is a therapeutic vaccine called GenePro (delta4SHIVku2).

As our understanding of the pathogenesis of HIV and the effects the virus has on the immune system has progressed through the years, so has and is the premise for the role of therapeutic vaccines.

A successful therapeutic vaccine is now thought to be one that produces a CD8+ memory cell response capable of killing infected cells and decreasing viral load to undetectable levels. Recent data aimed at eliciting a cure for HIV supports this hypothesis and the importance of CD8 cells, suggesting that a strong CD8 response is necessary in combination with awakening latent HIV in order to eliminate HIV reservoirs, highlighting the importance therapeutic vaccines may hold in maintaining viral clearance.

CD8 responses are believed to be lost in most HIV patients with the possible exception of elite responders. Elite responders (approximately 5% of people living with HIV) are able to maintain a suppressed viral load without the use of HIV antiretrovirals. Elite responders are able to maintain an undetectable viral load (below 50 copies/ml), sustain a CD4 count above 500 and do not experience symptoms related to HIV, for a period greater than 10 years, all in the absence of ARVs.

Research indicates that many elite controllers not only continue to possess CD8 cells after infection but that these cells have a superior capacity to proliferate. Although additional host restriction mechanisms appear to be necessary to elicit the viral control elite controllers possess, data indicates a strong CD8 response has been shown to be present in the majority of elite controllers and in many cases are a major factor in controlling viremia.

GenePro, made by a company named ImmunoGenetix, is a DNA based therapeutic vaccine, with a consistent lentiviral composition. This differentiates GenePro as it more closely mimics the virus, for appropriate immune responses. In mouse model and primates GenePro produced potent CD8 cells similar to those seen in elite controllers. These CD8 cells maintained HIV specific memory through out the life of the animals.

GenePro contains seven proteins which in vitro and animal studies show an ability to produce high levels of non-infectious proteins which elicits a much stronger immune response then other DNA vaccines that have been studied. GenePro stimulates a potent antibody response without the need for protein or viral vector boosts. GenePro doesn’t integrate into the genome host so there is no chance of mutations and it does not carry infectious virus. Electroporation is used to introduce it into the body, affording for superior infiltration into cells.

In a study of 19 macaques infected with SHIV, 12 primates where given injections of GenePro. The seven primates who did not receive GenePro developed progressive infection. The vaccinated macaques all achieved viral load decreases below the level of detection.

Cost is an important aspect of an effective therapeutic vaccine to ensure universal access. According to Dr. Mike McGrath MD. Ph.D, Professor of Laboratory Medicine, Medicine and Pathology at the University of California at San Francisco (UCSF) “Importantly, the cost of this approach is much less than one where the vaccine requires boosts with either recombinant viral proteins (expensive) or an infectious expression vector such as a pox virus or an adeno virus (more dangerous to health care and laboratory workers involved in utilizing these types of vector,etc).

Despite these positive results, funding for continued studies of GenePro has not surfaced, leaving the vaccine in the same position as many other potentially beneficial therapies not only in HIV but in all areas of medicine. Countless drugs have been delayed or lost due to difficulty finding the funds needed to continue into human clinical trials after successful animal studies. This conundrum has been dubbed ‘ The Valley of Death’ as scientists spend their time not producing data but in pursuit of money, often resulting in the loss of the drug.

In this case, the makers of GenePro were awarded $21 million dollars in NIH grants to develope and take the therapeutic vaccine to its present point. With invitro and animal study showing successful results, a strong CD8 response and viral load decrease to undetectable levels (the exact effect now thought to define a successful therapeutic vaccine) continued support from the NIH would be not only advantageous but is a practical utilization of scarce funds.

Without a system within the NIH that views potential research projects based on merit and results and which commits to assisting in taking a drug that shows extreme promise through development, countless drugs will continue to be lost. In the case of HIV, simple common sense dictates that funding a drug such as a therapeutic vaccine that shows potential in allowing for less use of ARV’s is not only an ethical and beneficial pursuit but is a common sense approach to tackling the growing cost of life long ARVs with a cost effective solution and is well worth the investment.

Originally published on PanAware on Wordpress.com on January 21, 2014. By Jeannie Wraight.

With the recent flurry of HIV “cure” reports, it’s becoming increasingly more difficult to sort out who’s actually been cured and what stories are media hype, wishful thinking, or premature reports of success.

Most people recognize headlines depicting cures in the form of herbal remedies or drugs yet to be tested in a single human being as either media hype or outright rubbish aimed at selling newspapers, stock or a product.

But what about the cases we hear announced at respected scientific conferences that sound completely realistic? How many of the cases of “functional cures” we’ve celebrated over the past three years are really actual cures?

Several of these cases come complete with a wake of conflicting reports and opinions creating confusion as to their merit.

In my black-and-white way of thinking it seems an obvious enough question to ask who, by scientific standards, is actually cured?

I posed this question to several HIV researchers and cure activists and recived many different answers. This is really not surprising as the in-depth parameters of exactly what defines a cure are not all that clearly outlined.

Currently there are two types of HIV cures. They’re defined by the International AIDS Society (IAS) as follows:

1. Sterilizing/eradication cure: Complete eradication of HIV-infected cells from the body.

2. Functional cure: Undetectable viremia without ART; no disease progression; no CD4 loss; lack of HIV transmission.

One aspect that creates confusion is there is no specifically defined time frame for when a person is deemed functionally cured. How long should an undetectable viral load and a normal CD4 count in the absence of ARVs be present before it’s considered a functional cure?

There’s also no clear identification of what significance circulating HIV fragments in the body retain. What does having a “very low level” of HIV fragments as found in Timothy Ray Brown (the Berlin Patient) and the Mississippi baby, who was treated early with ARVs, actually mean? What importance do they have? How can eradication be determined if single cell assays used to measure very low levels of virus can’t differentiate between HIV competent of replicating and HIV “debris.”

Shouldn’t the development and standardization of assays specifically designed to identify replication-competent HIV, as well as to detect HIV in certain difficult to reach places, be a main priority? These are issues that are being looked at but maybe we should hold back on the “c” word until they are better understood.

It’s also becoming more and more apparent that the current definition of a “cure” really could do with a broader sub-classification to include all the different types of “cures” based on how the cure was obtained, i.e., bone marrow transplant, early use of ARVs, or a new therapeutic agent.

As of right now, there is no one who has achieved a sterilizing cure — at least no one upon whom everyone can agree.

The terms “HIV remission” and “post-treatment controllers” are being used by some in the scientific arena. Hopefully they will be adopted by the media to further separate and define cases currently referred to as simply “functional cures.”

The courses each “cure” took to obtain this state are quite different. The types of ways each cure was reached further define the cures themselves and it may be helpful to break them down even more.

These are the main cases that some are calling cured of HIV, and, from my best understanding, this is how they are currently defined:

Stem-cell transplants:

• Timothy Ray Brown: Some believe Timothy to be a case of a sterilizing cure but other experts feel more comfortable calling this a functional cure.

• The Boston Patients: Some are calling this a functional cure while others believe it is too soon to tell.

Very early treatment with ARVs:

• The Mississippi baby: Conservatively called “HIV remission.”

• The VISCONTI Study (fourteen individuals): Being called “HIV remission.”

• A sixty-seven-year-old German man (treated within ten weeks of exposure to HIV and off ARVs for nine years): Many are calling this a functional cure.

It’s time for the formulation of more precise definitions of HIV “cures” to be devised and utilized not only within the HIV scientific community but also to curtail the media from inaccurate “cure” reports.

Hope is a beautiful thing. False hope can be dangerous and cruel to those hoping to be cured. Shouldn’t we more accurately define a “cure” before counting the cured?

This blog entry is dedicated to Eric Blue for his bravery and selfless contribution to cure research. The 12-year-old who lived with HIV and leukemia passed on July 5, 2013, three months after receiving an umbilical cord transplant which attempted to cure him of HIV and leukemia. You will be forever remembered little brother.

This article is reprinted with permission from A&U Magazine.

Originally published on PanAware on Wordpress.com on January 21, 2014. By Jeannie Wraight.

There may be several advantages to utilizing LAP ARVs. Advantages to long acting ARV’s being used as treatment include:

• Improved adherence

• Reduced drug interactions

• Reduced toxicities

• Possible lower costs

Used as PrEP, adherence would predictably increase with a weekly or monthly injection in compassion to daily oral administration. Cost may also be lowered significantly. LAP ARVs can be administered either orally, via subcutaneous injection or inter-muscular injections. Administration may take place once a week, every two weeks, once a month or even less frequent.

LAPARVs in development include:

• Ibalizuab (monoclonol antibody) as an entry inhibitor for drug resistant HIV. Research suggests Ibalizumab may be effective as a once a month long-acting ARV.

• Gsk1265744 also known as GSK 744 is an integrase inhibitor. Analysis of 8 studies involving 245 people who were studied using oral or injected GSK744 shows it is well tolerated with few lab abnormalities.

• TMC278 (Rilpivirine), an integrase inhibitor, showed full protective benefit in macaque as LAP PrEP following rectal exposure.

• TMC278 in combination with GK1265744 is being studied in a phase I clinical trial in HIV negative individuals. The two drugs will be given through various interventions (IM, subq and oral) in a randomized, open label study to investigate the safety, tolerability and pharmacokinetics of repeat dose administration of the two drugs over a period of four months.

Originally published on PanAware on Wordpress.com on January 21, 2014. By Jeannie Wraight.

HIV-associated enteropathy remains a substantial problem for both HIV patients on HAART and those who are not receiving treatment. It is estimated that about 15-30% of HIV+ people, even when on antiretroviral therapy, continue to live with this persistent and debilitating condition for which there is currently no effective marketed intervention. HIV-associated enteropathy, first described in 1984, is a change in intestinal structure and function in HIV-infected persons. There is a lack of research not only on potential treatments, but also on the role of this condition in HIV disease progression and its effects on HAART and treatment for co-infections.

Gut associated lymphoid tissue (GALT) harbors a majority of the body’s immune system and is an important mucosal target of HIV for acute, primary and chronic infection. The massive and rapid depletion of CD4+ T cells from GALT that occurs with HIV infection is predictably a cause of the progressive deterioration of intestinal immune and digestive functions, which is collectively termed “enteropathy.” After prolonged viral suppression by antiretroviral therapy, there may be partial restoration of the HIV-associated intestinal mucosal barrier defect despite persisting alterations of the mucosal immune system. Chronic diarrhea is the most common clinical manifestation of HIV-associated enteropathy, which is diagnosed via endoscopy and is also characterized by increased GI inflammation, increased intestinal permeability and results in malabsorption and subsequently malnutrition, significantly impacting clinical outcomes, as well as the quality of life, in people living with HIV. Immunologically, it is hypothesized that the loss of CD4+ T helper cell function in GALT contributes to HIV-associated enteropathy via the disruption of the homeostasis between adaptive and innate immune responses. It is now well-established that HIV infection transforms the intestinal mucosa from a balanced system to one of chronically activated inflammation leading to disruption of epithelial barrier integrity and microbial translocation with subsequent inflammation and co-infection.

HIV-associated enteropathy is under diagnosed and not given the attention that it previously received when it caused life-threatening conditions such as wasting syndrome. The incidence of this condition is still higher than expected even with the advent of and increased access to HAART. Rising costs of treating HIV patients who are living longer due to the initial success of HAART are now being driven by manifestations of consequences driven by chronic immune activation and subsequent inflammation and the long-term consequences of ARVs, such as lypodystrophy, which is suspected to contribute to cardiovascular disease. Studies on nutritional interventions in people living with HIV to address HIV-associated enteropathy, immune restoration, reductions in diarrhea, metabolic complications and patterns of drug resistance have shown that aggressively improving the quality of life in people living with HIV during the fourth decade of the epidemic improves clinical outcomes and reduces associated costs.

Data from a pilot study presented at both the XIX International AIDS Conference (AIDS 2012) and CROI 2013 illustrates how nutritional address of this condition can be achieved utilizing a specific protein source. Researchers led by Dr. David Asmuth studied the effects of EnteraGam™ (serum bovine-derived immunoglobulin/protein isolate or SBI) on gastrointestinal (GI) symptoms, mucosal immunity, bacterial translocation and the impact on imbalances in the gut microbiota. In an initial 8-week study of 8 patients with HIV-associated enteropathy and in a 48-week extension in 5 patients, EnteraGam was found to increase duodenal CD4+ cell density and CD4/CD8 ratios as well as improve nutrient absorption. A significant and dramatic decrease in diarrhea plus an improvement in stool frequency and consistency was maintained throughout the study and there were notable positive changes in gut microbiota.

Dr. David Asmuth, lead author of an article reported the results of an open-label pilot study of EnteraGam published in the May 22, 2013 issue of the journal AIDS, a leading HIV/AIDS peer-reviewed publication. In addition to effects on HIV-associated enteropathy, the corresponding reduction in intestinal inflammation and restoration of mucosal immunity further validate the continuing dialogue regarding the effects of HIV infection on the gut and the need to restore mucosal immune function to pre-infection levels.

A larger randomized, blinded study testing SBI as distinct nutrition for management of HIV-associated enteropathy is currently underway to confirm these results (www.clinicaltrials.gov, NCT01828593). This study on EnteraGam is the only clinical trial currently being performed nationwide on patients suffering with HIV-associated enteropathy.

EnteraGam™, a medical food, is being developed for the management of HIV-associated enteropathy in patients who have impaired capacity to absorb nutrients from food. Patients with HIV-associated enteropathy suffer from malnutrition due to this impaired absorption. These patients also face persistent bouts of chronic diarrhea, which predictably provokes the development of drug resistance.

The question of the impact of HIV-associated enteropathy on a case study presented at the 14th International Workshop on the Clinical Pharmacology of HIV Therapy in Amsterdam, the Netherlands in April of this year spurred discussion of the effect of this condition on the pharmacology of HIV and Hepatitis C treatments as it affects the level of medication and drug-interactions. HIV-associated enteropathy was also the topic of a presentation at the 30 Years of HIV Science: Imagine the Future meeting that took place at Institut Pasteur from May 21-23, 2013 in Paris, France. The historic meeting brought together 500 leading world-renowned scientists, clinicians and community activists in the very place where HIV was discovered, for which the conference organizer, Francoise Barre-Sinoussi, won the Nobel Prize in 2008. It was suggested that addressing HIV-associated enteropathy will reduce microbial translocation in the gut and thus the chronic inflammation that plagues HIV patients, even those chronically, successfully suppressed on HAART.

It is obvious from discussions at these recent meetings that despite the current issues of budgetary convolutions due to sequestration in the U.S. and austerity measures in Europe, public research dollars are going to be necessary for further studies on HIV-associated enteropathy. Some community leaders are hoping to provoke the development and circulation of concept sheets by leading Principal Investigators for the ACTG and other HIV research networks at the upcoming 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) taking place from June 30-July 3, 2013 in Kuala Lumpur. This will be the largest scientific meeting focused on HIV this year and represent our best chance of seeing HIV-associated enteropathy studies move forward.

A clinical investigation of EnteraGam™ as a nutritional therapy along with HAART on HIV-associated enteropathy by publicly facilitated HIV research networks could further validate the data presented at AIDS 2012 and CROI and reported in the May 22, 2013 issue of AIDS and translate to tens of millions of dollars saved in public health costs. Continuing to ignore HIV-associated enteropathy comes at too high a price both for patients and our global efforts to change the course of the epidemic.

It is hard to digest that persistent and debilitating HIV-associated enteropathy is still the state of affairs given the advancements made over the past 15 years in the treatment of HIV. HIV-associated enteropathy is affecting the pharmacology and efficacy of HAART, Hepatitis C treatment, psychotropic medications and impairs mucosal integrity in the gut, which studies indicate is a fundamental mechanism of the chronic inflammation in HIV infection and persists despite durable viral suppression in patients on HAAART.

These are hard times with dozens of agendas pushing equally important clinical priorities in public health systems and scientific investigation programs, while competing for dwindling funding dollars. We learned at the beginning of the AIDS crisis that innovative approaches often yield disproportionately beneficial results that translate to unexpected advances across the field of public health. HIV-associated enteropathy is but one example where advances can be made that will yield more sustainable patient outcomes for the long haul ahead, as the agenda for the XX International AIDS Conference is being set.

Originally published on PanAware on Wordpress.com on January 21, 2014. By Jeannie Wraight.

In comparison to Atripla, the first one-pill-once-a-day combination antiretroviral medication that has become the most widely used drug in people infected with HIV both in the U.S. and PEPFAR-partner countries, Stribild was found to be non-inferior (of the same or slightly better efficacy) to Atripla and have a “generally acceptable” safety profile.

Atripla is two NRTIs (tenofovir and emtricitabine, called Truvada) and an NNRTI (efavirenz). While it’s approval has been highly anticipated by both HIV clinicians and patients, there are several issues that need to be taken into consideration when hailing it as a significant advancement in the treatment of HIV and predicting the effect this new treatment will have on the HIV pandemic.

As we have seen success with current HAART, an increasing number of patients are on these drugs for longer periods of time and data is beginning to emerge on the consequences of chronic use of ARVs. The issues with treatment adherence, viral evolution and cross-resistance are resulting in rising drug resistance and data on the world’s most popular NRTI, tenofovir (part of the Truvada combination), has demonstrated nephrotoxicity. As Truvada and Atripla have been positioned at first line therapy, are the most popular ARVs in the world, Atripla and Stribild share an NRTI backbone and elvitegravir and raltegravir confer cross-resistance, patients who are resistant to Truvada and Atripla will also be resistant to Stribild. There are also concerns over the recent approval by the FDA of Truvada (tenofovir and emtricitabine) for pre-exposure prophylaxis (PrEP). HIV-negative people on Truvada PrEP who still become infected are at risk of developing resistance to tenofovir and/or emtricitabine, which would eliminate both Atripla and Stribild as treatment options from the initiation. Resistance mutations often have degrees of cross-resistance or class-wide resistance, so the development of a mutation in the virus of a person on one HAART regimen may also make other related drugs inactive, wiping out several treatment options in the process, even some that the person has never used.

Further significantly limiting the number of patients who are eligible for this drug, due to concerns about nephrotoxicity and renal excretion, the inability to safely use the drug to treat patients with creatinine clearances of less than 70mL/min and need to stop using it if creatinine clearance falls below 50 mL/min. Increased creatinine levels and kidney damage occurred, including cases of Fanconi syndrome and proximal tubular dysfunction, all in patients taking Stribild. In a study published in the April 2012 issue of AIDS, tenofovir was found to be associated with an increased risk of kidney damage and chronic kidney diseases that increases over time, which does not immediately appear reversible. There was a 34% increased risk of proteinuria/year and a 33% increase annually in chronic kidney disease risk, which was found to be independent of other potentially confounding factors including age, diabetes, high blood pressure, smoking, HCV co-infection and various HIV infection parameters. As the drug causes diarrhea (reported by 22% of study participants taking Stribild), there is an increased risk of dehydration, which will exacerbate renal function if the volume depletion is severe enough and compound the issue of renal toxicity.

The impairment in renal function is through to be associated with cobicistat. As a CTP3A4 and CYP2D6 inhibitor, there is significant potential for drug-drug interactions, enhancement of side effects, new side effects and alteration of effectiveness of other medications commonly prescribed to HIV patients in addition to HAART; the full range of interactions is unknown. Also of note, idiopathic protease gene mutations and protease inhibitor resistance developed in 9 and 3 participants taking Stribild.

NRTIs are a vital component of effective HAART regiments, often referred to as “the backbone”, and are included in all recommended regimens of expert bodies in the U.S. and Europe. Studies on HAART regimens that do not contain any NRTIs, “nuke sparing”, have shown they are not as durable or robust. This has been demonstrated with different drug classes, including integrase inhibitors and protease inhibitors, which are less prone to fail when constructed around a strong NRTI backbone. HAART regiments can be thought of as the defense in football. The role of NRTIs is that of the linebacker; no matter how good the rest of the defensive line is, the defense’s success is significantly determined by the It is important to note that the primary rationale behind nuke sparing is based on the long-term toxicities of some current popular NRTIs and the lack of effective NRTIs available for patients with drug resistant virus. Given these issues, there is a critical need to develop new, more active, less toxic NRTIs for drug resistant and treatment experienced HIV patients.

As mentioned above, a strong NRTI backbone is essential to an effective and durable HAART regimen. However, the extensive use of Truvada means that patients who fail these regimens often have drug resistance and drug mutations are archived latently in long-lived cells and can become activated years later or circulate at levels not easily detected with current technology. Subsequently, the number of effective, tolerable HAART regimens available to treatment experienced patients are often very limited; there may be more than 20 ARV drugs on the market but only 3 or 4 effective sequential regimens can be constructed. A new NRTI with the right characteristics would significantly improve treatment options for drug resistant patients: effective against common resistance mutations, not be subject to cross-resistance, not cause cross- or class-resistance, safe and well tolerated and able to be used with available HIV drugs in non-inferior HAART regimens.

The NRTI pipeline is disturbingly dry. BMS-986001 is a Phase II thymidine analogue, like AZT and d4T, being developed as an alternative to AZT for treatment naïve patients. GS-7340 is a Phase II tenofovir pro-drug, so it has cross-resistance with tenofovir and will have the same interactions. The most promising candidate, which also happens to be closest to the goal line, is apricitabine (ATC) in Phase III by Avexa.

ATC has been found to have no cross resistance with other NRTIs, no resistance development up to 144 weeks, be very well tolerated and be used in combination with all other available ARV drugs, with the exception of 3TC and FTC as no two cytidine analogues should be used together. ATC is active against the M184V and L74V mutations and TAMs and no resistance has developed in patients on treatment for up to at least 144 weeks. It has a safety profile at least as good as that of FTC and 3TC, and demonstrated no evidence of mitochondrial, bone marrow, pancreatic, hepatic and renal toxicities. The FDA has approved a registration study of 300 patients whose options for effective HAART treatment are limited by drug resistance and/or tolerability with the primary endpoint of a reduction in viral load at day 14 on functional ATC monotherapy. On day 14 the background regimen will be changed to two new active ARVs, all patients will continue on ATC and safety, durability and resistance evaluated.

Where are big pharma and the ACTG? Big pharma is licensing fewer, earlier stage ARV candidates and concentrating exclusively on once daily combination drugs for treatment naïve patients or PrEP and market share among well-suppressed treatment experienced patients. Drug resistant and treatment-experienced patients are a growing market segment. ATC is in late stage clinical development for treatment experienced patients, currently dosed twice daily and not easily incorporated into once daily combination drugs. While once daily combination medications are no doubt extremely successful in treatment naïve patients, they are much less so for treatment-experienced patients who require a more individual approach to construct an effective, tolerable and durable regimen. The current domination of once daily combination drugs for HIV does not benefit a significant and growing segment of the patient population. ATC is the most promising and advanced NRTI candidate and the completion of its clinical development should be prioritized for federally facilitation via an HIV clinical trials network.

Originally published on PanAware on Wordpress.com on January 15, 2014. By Jeannie Wraight.