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Looking Ahead: NIAID’s Future HIV/AIDS Therapeutics Priorities

NIAID

Since the 1980s when the HIV/AIDS epidemic was first recognized, NIAID-supported clinical research has helped to save millions of lives and played a key role in defining the standard of care for treating HIV infection. This blog post describes what we are seeking for the next wave of HIV/AIDS therapeutic approaches. Specifically, we have identified the following three research priorities: 1) finding a cure for HIV-infected individuals; 2) developing therapeutic strategies for preventing and treating tuberculosis (TB) and hepatitis C in HIV-infected individuals and individuals at high risk for co- infection; and 3) addressing the long-term consequences of treatment of HIV infection.

A cure for HIV/AIDS would have a significant impact on the global burden of HIV/AIDS by reducing HIV prevalence and providing increased hope for controlling and ultimately ending the pandemic. Current antiretroviral therapy (ART) used to treat HIV infection suppresses the virus’ ability to replicate but does not eliminate the hiding spots in the body where the virus lays dormant (called “reservoirs”). We define a “cure” for HIV-infected people as permanent remission of disease in the absence of therapy. Currently, we are investigating two distinct approaches toward this type of cure: identifying each of the HIV reservoirs and finding ways to eliminate them; and maintaining and/or boosting the immune system, so that it can control HIV replication on its own when ART is discontinued. Evaluating both approaches will require innovative and rigorous clinical research. Additionally, specialized laboratories will be needed to measure a variety of parameters, such as reservoir size, the low levels of virus that continue to persist, and anti-HIV immunity. These clinical activities will need to be closely linked with existing efforts to discover and develop strategies for a cure.

Until there is a cure for HIV infection it is critical that we continue to develop strategies for preventing, diagnosing and treating infectious diseases commonly associated with HIV, such as TB, which is the leading cause of death in persons with HIV/AIDS. Our TB research agenda will include the development of new regimens for prevention and treatment. The goal is to have treatment regimens that are effective, well-tolerated and shorter in duration, that do not interfere with the effectiveness of ART, and that target drug-sensitive and resistant TB, including extensively drug resistant TB. Discovery and careful assessment of improved diagnostics, drug-sensitivity testing, and biomarkers for predicting disease progression and therapeutic responses are priorities since TB manifests itself in different ways in HIV/AIDS patients and is much more difficult to diagnose than in people without HIV infection.

Co-infection with HIV and hepatitis C virus is another area of major concern. Current therapies for hepatitis C are often poorly tolerated and are not effective against all subtypes of the virus. At least seven new treatments are in development for hepatitis C infection, and we hope that some of these will lead to safer and more effective regimens for people infected with both HIV and hepatitis C virus. In addition to new treatments, there is a great need for new hepatitis C diagnostic tools, including detection of proteins in blood that predict treatment success or failure.

To further our discussion on the future directions of therapeutics research, please consider the following:

  • Are the three priority areas that we have identified for HIV/AIDS therapeutics research the appropriate priorities?
  • What is the best way to link the discovery and clinical evaluation of possible cures for HIV/AIDS?
  • Are we defining an HIV/AIDS “cure” appropriately?
  • On what areas of TB and hepatitis C clinical research should NIAID focus? Are there other infectious agents that deserve priority efforts?
  • What are the most important non-infectious co-morbidities associated with HIV infection that NIAID should address in its research agenda?
  • Can earlier initiation of antiretroviral therapy for HIV infection prevent some of the premature aging and other co-morbidities associated with treated HIV disease, or are other targeted therapeutic approaches required?
  • What is the best approach for advancing HIV, TB, and hepatitis C biomarker research?

For both TB and hepatitis C, significant research efforts are supported by several public and private sector funders, including other divisions within NIAID. These areas of the therapeutics agenda need to be coordinated with existing research efforts to facilitate more efficient clinical research planning and highly productive collaborations.

Effective therapy for HIV infection has been available for about 15 years. During this time, antiretroviral drugs have become safer and easier to take. However, we still do not fully understand the consequences of long-term treatment of HIV infection, especially the mechanisms driving residual inflammation. A major concern is the increased rates of certain conditions experienced by HIV-infected individuals who have been infected for long periods of time, even those whose viral load has been adequately suppressed with ARV therapy. These include the onset of early aging characteristics, cardiovascular disease, insulin resistance, non-AIDS-associated cancers and kidney disease. Basic and clinical research are needed to define the underlying mechanisms of these conditions and develop therapeutic strategies to target these mechanisms. The key to developing novel therapeutic strategies will involve both the investigation of biomarkers and the evaluation of novel HIV therapies.

We welcome your thoughts and feedback on these issues. It has been interesting to see the responses to our two previous blog postings, and I hope you will continue to comment.

In the next blog posting, we will examine the direction of NIAID’s HIV vaccine clinical research priorities.

Comments

  1. Robert Reinhard says:

    Thank you for the post. I was very pleased to see recently that NIAID has issued its grant announcement RFA-AI-10-009, the
    Martin Delaney Collaboratory: Towards an HIV-1 Cure (U19) based on the proposal which was articulated in the journal Science last year. The RFA allots an initial set of funds totaling $8.5 million in FY 2011. The prospect of eradication from latent reservoirs has become much more promising and this line of inquiry should be sustained and funded continually in succeeding years at levels necessary to advance the agenda with the proper stimulus. The RFA’s requirements for private sector partnerships are also a welcome feature, and so incentives for private sector interest should be expanded.
    Because expert research has already taken place at several universities, funds for more merit based projects, in addition to the 1-2 collaborative grants of the RFA, should also be considered.
    As to the structure and governance of the collaboratory effort, it should include public/community representatives and meaningful community engagement in all aspects of design, application and translation for all proposals.
    Thank you and NIAID for issuing this important RFA. Over time, it is hoped, the collaboratory concept will grow and model itself on similar broad network activities such as CHAVI, CAVD and other initiatives that harness the talents of international researchers.

  2. Seyed Mohsen Khatami says:

    Dear Dr. Carl W.Diffenbach,
    Director of NIAID’s Division of AIDS
    Hello
    The only rational therapeutic strategy and priority right now is to find a “cure” for HIV-infected individuals.
    The rational therapeutic definition for a “cure” regarding HIV-infected people as permanent remission of disease is based on designing of a strategy by changing the pattern of infection in order to successfully elicit a sustained immune response against HIV and its strategy for replication.
    Every effort based on identification of “HIV reservoir” according the ambiguous definition presented by some researchers in recent time is an irrational therapeutic strategy and priority. The consequence of such research investment is wasting the materials and human resources.
    Recollect that the main reservoir for HIV is its intelligent strategy to integrate its genome in the chromosome of specific cells.
    In the end I must also emphasize our time tragic handicap to utilize the information and tool associating with mapping of human genome for addressing the therapeutic crises of HIV/AIDS, different forms of cancer and etc… in effective way.
    This emphasis is identifying our time enormous need and requirement for the change of technologic paradigm in the field of biomedical research and technology. Every investment in this regard can bear its fruits in near future.
    Best regards,
    Seyed Mohsen Khatami

  3. Edward Hook says:

    I was a bit suprised to see that there is no mention of STDs and STD prevention in your blog on Therapeutics for HIV Prevention. Given the crucial role that these infections play both as risk markers and as biological amplifiers of transmission, to not include them in these comments suggests that we may missing an important opportunity for addressing the epidemic as work towards a cure continues. Failure to focus both on uninfected persons with other STDs to identify those at risk and on STDs in persons with HIV as markers for continuuing transmission risk will only continue to fuel the epidemic. Ned Hook

  4. Marina Nunez,MD,PhD says:

    On what areas of hepatitis C clinical research should NIAID focus?
    -use of anti-HCV specific antivirals in HIV-infecetd patients
    -pathogenic mechanisms to explain an accelerated liver disease progression
    -Identification of patients with faster progression of disease through non-invasive markers.
    Other co-morbidities in need of study?: HIV-HBV co-infection
    General comment: we are in need of more open study networks to include centers which despite capability are not accepted to participate in the big cohort studies. Also, a network for HIV-HCV and another for HIV-HBV would be of great help in uniting research efforts.

  5. Jules Levin says:

    Currently it is estimated about 20-25% with HIV in the USA and Europe are ver 50 years old and it’s also estimated by 2015 50% of those with HIV will be over 50. Of great concern is patients who are over 60 who are often those with long-term HIV-infected, started ART & HAART with low CD4 nadirs, and have additional serious risk factors. The early emergence of comorbidities in HIV+ individuals has been reported for several years now along with great concerns that patients are experiencing accelerated aging due perhaps in part to HIV and premature onset of comorbidities. The NIH should convene a meeting to design the studies needed to address the research questions enumerated below. Research can take years to conduct & analyze, this would put aging patients at great risk because there are no interventions nor much understanding of the pathogenesis to address aging in HIV, so we are greatly concerned that the death rates may soon increase and morbidities and debilitations will become serious. Therefore, the NIH and DAIDS needs to declare the Aging/HIV problem the highest priority now for research and attention; declare this an emergency situation; conduct meetings, public hearings, and convene an ‘Aging Committee’ to strategize how to move ahead with timely research and actions and to over see the effort. The funding process to be redesigned to eliminate the standard review process for funding study requests; often the committees doing review now do not understand the problem. In addition, we need a dedicated set-aside for funding rather than the usual competitive grant submission process. We need a streamlined process for implementing studies & projects & for funding them, that could be non-competitive in the traditional sense. In addition, if increased comorbidities & mortalities emerge soon, the care infrastructure will be totally unprepared to address clinical care & the services patients & clinics may need. We need to convene a committee to discuss potential development facing the system & patients and how we can prepare for the potentially overwhelming need. For example, adequate access to specialists in bone, CVD, renal, diabetes, and neurology must be planned, an overhaul of the care system to accomodate these concerns is in order.

  6. I applaud NIAID for placing the cure for HIV/AIDS first on the list of top priorities on the research agenda. I hope that this position will insure the increase of funding for the most important field of research today – the study of HIV Controllers and Long-Term Nonprogressors – as institutions around the world are indeed confirming that these rare individuals represent a functional cure for HIV infection.
    I must remark, however, on the lack of reference to the development of a therapeutic vaccine for HIV as a strategic priority, and note that HIV is not mentioned at all in Item 2 of your list of research priorities. These important topics should be included in any dialogue pertaining to the next wave of therapeutic approaches for HIV.
    Thank you.

  7. David Nalos says:

    I applaud and congratulate NIAID for setting an agenda that places a cure for HIV at the forefront. With the basic science in rapid development, I believe that a concerted effort to expand current clinical trial sites into cure research would bring our efforts full circle and would be the most efficient way to conduct these trials. Current sites already have deep connections with their local communities, and these communities have a huge population of HIV-positive folks who are ready, willing, and excited to participate in clinical trials for an HIV cure. I would also recommend research into co-morbid mental health conditions as these occur at much higher rates in the HIV-positive population and require different standards of care. Thanks again for your continued commitment.

  8. Orlando Roman says:

    Assure all networks (especially the ACTG) supply NIA (“a lead in aging research”)with all CSF and neuro data. NIA and NINDS should specifically target mechanisms such as severe headaches, migraines, mononeuropathy, toxoplasmosis, minor neurocognitive disorder (MND), myopathy, strokes and tremors. NIA/OAR/ARAC should directly coordinate bio-marker improvements to ACTG/ALLRT’s NeuroScreen.
    Improvements to the areas of cardiovascular disease, insulin resistance, non-AIDS-associated cancers, kidney diseases, and characteristics of early aging are important. Also important is “… concern that HIV-infected individuals are 15–21 years older phenotypically than their chronological ages…”.
    Consequences of these co-morbidities and long-term treatment of HIV infection comparable to their incidence rates in the entire and minority populations will aid in development of the strategic research agenda and help in ‘rental capacity’. Disease incidence, prevalence, mortality, and burden of diseases and other adverse health conditions in relations to the entire/minority populations for age related diseases, cardiovascular health and diabetes should be supplied by the newly formed NIMHD and others.
    While protocols are still in development the Statistical Analysis Plans (SAPs) should be specific to increase #s of racial & ethnic groups,(and also HIV+ women). New statistical measures should account for equipoise by including genomic data (ie, IL-28 interferon response in HCV infected AAs), and ratios of screening to enrollment. The SAPs should reflex the studies drop-out/discontinuation and drug failures rates.
    The networks should create mono and HIV infected joint trials for conditions such as liver diseases, cardiovascular diseases, diabetes/metabolic conditions, non-AIDS malignancies, and psychiatric conditions.
    A suggested topic for next year’s SBIR awards are platform technologies grants for non-invasive biomarkers for different severities of liver diseases. A real effort is needed to increase the percentage of SBIR awarded especially in, “the In-Vitro Immunization System of Human T-Cell Immune Responses to HIV-1 Vaccine Antigens, but also in rare diseases and orphan products. NIAID and the future SBIR/STTR awardees should appoint community representatives as quickly as possible.
    Creation of null-responder adaptive trial designs using resistance and SNP data for newer DAAs are needed in HCV and HIV co-infected individuals. NIAID/OAR/ARAC should focus on creating Inter-IC trials with network cohorts such as ViraHep-C and DILI. Other deserving infectious agents are NIAID Category B agents such as viral encephalitis, hepatic encephalopathy and their connection to HAD. ViraHep-C is a NIDDK cohort with HCV mono-infected African Americans and Caucasians.
    The strategy should incorporate a definition of ‘cure’ for both therapeutic & preventative vaccines. In future in-human trials, appropriate use of in-vitro and non-human primate data should be in the protocols before beginning the trials. The definition should integrate what therapeutic and preventive vaccines will produce. And the research priorities for therapeutic and preventative trials should included correlates of protection. The new International Research in Infectious Diseases, including AIDS (IRIDA) and Infectious Disease Clinical Research Support Services (CRSS)(with the assistance of MHRP) should be tasked with the definition of ‘cure’.
    Why are results of RV144 now being duplicated in non-human primate after the in-human trial ended?
    What data exist data from CHAVI and NCI/SAIC-Frederick that can assist in the creation of correlates of protection?
    The Leadership RFA awardees should involve domestic and international community representatives who are knowledgeable in creatively usurping joint network resources. We can aid in the development of this comprehensive integrated health strategy.
    Thank you for your consideration.

  9. Igor Grant says:

    The future directions are very well reasoned, but seem to lack any mention of neurological complications of HIV, which persist despite modern ARV, and represent an important source of morbidity and reduced quality of life in many with HIV. It seems that if elimination of viral reservoirs is one of the objectives, then examination of the brain as one such reservoir is highly relevant. Furthermore, accumulating data [eg., the CHARTER Study] underscore the persistence of neurocognitive disorders despite modern combination ARV, indicating the importance that therapeutic networks like ACTG need to address this consistently in terms of central and peripheral nervous system function. Additionally, the effects of drugs of abuse in fostering viral persistence and modified response to ARV are areas of urgent need of study. In regard to early aging, there are likely to be significant interactive effects of age and HIV on neurological functioning, which may be of public health concern on a par with accelerated cardiovascular, metabolic, and other morbidities.

  10. Malek H. says:

    Creation of null-responder adaptive trial designs using resistance and SNP data for newer DAAs are needed in HCV and HIV co-infected individuals. NIAID/OAR/ARAC should focus on creating Inter-IC trials with network cohorts such as ViraHep-C and DILI. Other deserving infectious agents are NIAID Category B agents such as viral encephalitis, hepatic encephalopathy and their connection to HAD. ViraHep-C is a NIDDK cohort with HCV mono-infected African Americans and Caucasians.

  11. Coco Jervis says:

    Treatment Action Group outlines issues of concern and questions about network restructuring research priorities and network structure.
    Thank you for the opportunity to address emerging scientific opportunities and challenges which will necessitate changes in research priorities and network structures within the NIAID clinical trials networks for HIV/AIDS and other infectious diseases. The network restructuring process provides us with a critical window of opportunity to further the development of better network governance, a robust scientific agenda and greater efficiencies to advance the standard of care for those living with HIV, tuberculosis (TB), or hepatitis C virus (HCV) infection in the coming years.
    Treatment Action Group (www.treatmentactiongroup.org) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. We are science-based treatment activists working to expand and accelerate vital research and effective community engagement with research and policy institutions. TAG catalyzes open collective action by all affected communities, scientists, and policy makers to end AIDS.
    TAG has four projects focused on research and development activities that will be closely monitoring the future pluripotent trials networks. These four projects focus on issues of greatest concern to people living with HIV in the United States and around the world – 1) basic science, biomedical prevention, and vaccines; 2) antiretroviral drug discovery and development and the comorbidities associated with HIV infection; 3) TB/HIV coinfection; and 4) HIV/viral hepatitis coinfection with hepatitis B and C viruses (HBV, HCV). TAG also supports a policy program which includes advocacy for domestic and international treatment access, science-based treatment and prevention policies, universal access to care and treatment for people with HIV, and stronger global and domestic health systems.
    Below are the overarching recommendations that we’d like to make regarding the future of HIV therapeutics, HCV and TB/HIV clinical research agenda priorities during the next funding cycle:
    The HIV therapeutics agenda should address two overarching themes:
    Improving the safety and convenience of antiretroviral therapies used to suppress HIV: While treatment has made huge strides, many individuals around the world still receive suboptimal first-line therapy with stavudine (d4T) and nevirapine (NVP), which are no longer used in first-line HIV therapy in the developed world. There is an urgent need to define optimal first- and second-line ART regimens which are potent, safe, tolerable, inexpensive, and compatible with TB therapy. Long-acting weekly or monthly regimens should be developed if possible.
    Addressing consequences of HIV infection that viral suppression alone cannot: To a large extent, the DAIDS priorities outlined in this blog post reflect this theme.
    For cure research, the HIV reservoirs that are impervious to current antiretrovirals need to be eliminated or controlled. It is gratifying that curing HIV infection has emerged as a priority but it is important to acknowledge that therapeutic approaches aiming toward this goal are in their infancy. The types of trials that will be needed in the near term will likely be small, exploratory, and often intensive in terms of monitoring and sampling of participants. There will need to be a strong translational component to ensure results are fed back into basic science efforts to better understand HIV latency and reservoirs. To facilitate this type of research, a new therapeutic network will need to have accessible entry points for investigators with potentially promising approaches identified through R01 or other non-network mechanisms. Rather than have protocols be drafted in the absence of clear regulatory guidance, it will be important for DAIDS to facilitate discussions of regulatory and trial design issues upfront, particularly around issues with ethical and safety implications such as interruption of antiretroviral therapy. Community consultations will also be critical, and DAIDS should consider grants to support community awareness of cure-related research as is done with HIV vaccine research (the AIDS Policy Project has been doing sterling work in this regard). Issues of intellectual property should also be considered pro-actively to ensure they do not slow efforts to move promising candidates from the lab to the clinic. Cross-network collaboration should be promoted and facilitated where appropriate (e.g. researchers in both vaccine and therapeutic networks may be pursuing similar assays for evaluating the antiviral activity of HIV-specific immune responses).
    TB and hepatitis infections in people with HIV are exacerbated by immunological deficits that may not be fully addressed by HIV suppression on ART.
    The third priority, “the long-term consequences of treatment of HIV infection,” is not yet optimally defined and should be modified to encompass both the long-term consequences of treated HIV infection and the long-term consequences of HIV-induced immune dysregulation. The impact of the virus on the immune system leads to deficits in immune competence that persist after viral replication is suppressed by treatment. Examples include depletion of naïve T cells, skewing of the CD4:CD8 ratio, accumulation of anergic and/or senescent memory T cells and, as mentioned in this blog post, elevated levels of inflammation. These immunological changes closely parallel those observed in the HIV-uninfected elderly, strongly suggesting that there is an immunological contribution to the increased risk of co-morbidities reported in people with HIV compared to their age-matched HIV-negative counterparts.
    We believe the evidence supports prioritizing this issue, because it suggests that successfully addressing immune dysregulation could prevent or ameliorate multiple co-morbidities. In the context of a therapeutic network (or networks), this will require a greater emphasis on immunology than has historically been the case. There are likely to be parallels with cure-related research in that small translational studies will be needed to explore potential therapies, such as those that might increase thymic function, speed reconstitution of naïve T cells, decrease inflammation and/or decrease numbers of senescent T cells. If promising approaches can be identified, it will be important to have the capacity to evaluate their clinical impact in larger targeted trials (e.g. enrolling individuals who face the highest risk of clinical progression, such as those with poor CD4 recovery despite HIV suppression). Effective therapeutic candidates could conceivably shed light on the contribution (if any) of immune dysregulation to the pathogenesis of specific co-morbidities and might also be applicable to both people with HIV and the HIV-uninfected elderly. Although there is evidence to suggest that earlier initiation of ART may substantially limit HIV-induced immune dysregulation, many individuals will continue to be at risk due to late diagnosis.
    The range of co-morbidities for which individuals with HIV remain at risk will also require support of multi-disciplinary research within a new therapeutic network or networks. The current INSIGHT network has provided an exemplary model by involving collaborators such as Lewis Kuller and Russell Tracy with broad experience in relevant issues outside of the HIV field. Such multi-disciplinary collaborations should be explicitly encouraged and facilitated in the network restructuring.
    In seeking to better understand the clinical implications of aging with HIV, perinatally infected individuals represent a unique population that must be included in the new network(s).
    Hepatitis C Clinical Research
    HCV treatment is quickly approaching a turning point. Scientific progress—made possible through government grants—in our understanding of the genetic makeup and lifecycle of hepatitis C virus have led to a bonanza in drug development. Dozens of new antiviral agents are in clinical trials, and a host of backup compounds follow in preclinical development.
    It is time to scale up HCV clinical research. The opportunity to address key questions in the next five to seven years must not be squandered. Lessons from HIV research can be used as a blueprint for avoiding pitfalls and speeding development and implementation of optimal HCV treatment strategies.
    Crucial areas for scaling up HCV Clinical Research include:
    • Multi-experimental agent trials
    • Population-specific questions,
    • Development of treatment strategies and assessment of models to deliver HCV care and treatment —will remain unaddressed unless a public/private research partnership with the capacity to conduct trials is created.
    Treatment Strategy – Trials in HCV monoinfected and HIV/HCV coinfected populations:
    Although direct acting antivirals (DAAs) for hepatitis C offer the promise of a cure, they are usually not studied—or understudied—in hard-to-treat populations until after they have been approved. Some people have urgent need for new HCV treatment; they did not respond to, or could not tolerate standard of care and are unlikely to be included in registration trials. Thus, NIAID should conduct treatment strategy trials in the HCV monoinfected and HIV/HCV coinfected:
    • Persons with advanced liver disease
    • Treatment experienced people (null responders, non-responders, partial responders, people who experienced viral breakthrough and relapsers)
    • Transplant candidates and recipients
    • People with renal disease
    • African-Americans
    • Latinos and Latinas
    • Current and former drug users
    • People with psychiatric disorders
    • People over 65 years of age
    • Pediatric populations
    • People with other co-morbid conditions, among whom HCV is highly prevalent, such as members of the bleeding disorders community
    • People with recent exposure to HCV (post- exposure prophylaxis studies)
    Need for more operational and basic research for HCV
    Operational and basic research should be integrated into these studies. More information is needed on host and virus specific information, such as predictors of disease progression and response to antiviral treatment, situations in which interferon may still be necessary, and additional research into non-invasive means to assess liver disease.
    Optimal models for delivery of HCV care and treatment should be evaluated in the context of clinical trials, such as: how best to support adherence and successfully treat people with medical and psychiatric comorbidities? How can HCV treatment be delivered in resource-limited settings?
    Key recommendations for trial designs
    • We support the development of a trial design structure that allows for interdisciplinary collaboration (specialists in hepatology, gastroenterology, infectious disease, addiction medicine, psychiatry, pharmacology, immunology and virology).
    • A structure is needed that supports rapid protocol development through external, peer-based protocol review.
    • We recommend a structure that promotes cross-company collaboration on multi- experimental agent trials (in close collaboration with regulators).
    • Additionally, a structure that supports mentoring and training of new, young investigators, as investigators and clinicians is critically needed.
    • The trial design should advance the capacity to perform HCV, TB treatment trials internationally, particularly in resource-limited countries.
    • Additionally, there is a great need to promote capacity to perform trials in unique venues (i.e. methadone clinics, correctional facilities).
    TB/HIV Clinical Research
    The expansion of the DAIDS clinical trials networks to include tuberculosis (TB) mono- and co-infection studies offer the potential to significantly improve clinical trial capacity and strengthen infectious disease research. However, the process of restructuring the clinical trials networks needs to be done thoughtfully in order to maximize benefit to public health.
    The newly reconfigured pluripotent trials networks must reflect expertise of each of the diseases, at a minimum, at the following levels:
    NIAID must define a prioritized scientific agenda for tuberculosis clinical trials encompassing the most important questions for all forms of tuberculosis, including adult and pediatric, drug-sensitive and drug-resistant, pulmonary and extrapulmonary, and HIV positive and HIV negative disease. Leadership groups and sites which wish to conduct TB clinical trials must be responsive to the NIAID TB research agenda and must specify which TB research questions will be addressed in any successful network application which commits to addressing TB.
    The networks’ leadership cannot be limited to AIDS clinical trial experts who are interested in expanding their capacity to conduct TB studies. Experienced TB researchers and their institutions need to be a part of the leadership structure. This will ensure that the scientific agenda of the networks will address key scientific questions that will lead to significant improvements in preventing and curing TB.
    The networks’ decision-making bodies and advisory committees must be expanded to include experts, including community activists, from TB affected communities. The community advisory boards must include people who have gone through TB treatment and work in partnership with community based organizations to provide appropriate training and support to the advocates to ensure that they are literate in TB science, research, and policy to meaningfully participate in the network structures. The capacity of experienced HIV and other community representatives serving on the network should also be strengthened to enable them to better understand TB and other diseases of public health importance that the reconstituted network aims to address. This will allow the advisory bodies to keep a broader goal of the networks in mind and reduce the potential of pitting one disease research priority against another.
    Trial sites must have the experience and programmatic expertise in providing standard of care for TB. This will require that sites not only have access to eligible study volunteers, but also have skilled staff and the necessary infrastructure to provide optimal care. Baseline criteria for site eligibility must be established in consultation with public institutions and pharmaceutical companies that have experience in conducting TB clinical trials. These criteria should then be the basis for assessing a site’s capacity to conduct or rapidly scale up its capacity to conduct disease-specific studies. For instance, laboratories must be able to accurately diagnose TB and conduct the appropriate tests to monitor treatment outcomes that are required for drug registration trials.
    Currently, there are not enough GCP- and GLP-compliant clinical trial sites that are able to conduct late stage TB vaccine and treatment studies. To address this gap, during and after the site selection, and as new vaccines and drugs advance through the clinical pipeline, NIAID may have to develop a system for building the capacity of sites to conduct these studies.
    There needs to be clarity around the role of the Division of Microbiology and Infectious Diseases (DMID) in this pluripotent trials networks and the appropriate direction of any DMID assets or resources which are contributed to the DAIDS-supported network effort. A clear definition of the scope of each division’s work in TB research should be included in the comprehensive NIAID TB research agenda discussed above. The TB research agendas of DMID and DAIDS must be synergistic and there should be a clear mandate to each division of what types of research questions they can and should pursue. The pluripotent clinical trials group(s) may likely be better suited to evaluate TB treatment in people with HIV on antiretroviral therapy (ART) or TB vaccines in infants, children, or adults with HIV. While DMID could focus more of its funding on basic science research to better understand the spectrum of TB disease and the immune response which is the foundation for the development of new compounds and strategies to prevent and treat infection and disease.
    Regulatory science: What is the best approach for advancing TB biomarker research?
    The networks should play an important role in defining the regulatory pathway and validating the tools and surrogate biomarkers needed to speed up the time it takes to conduct drug and vaccine research. The lack of definitive surrogate markers to predict stable cure or correlates of immunity to demonstrate vaccine-induced protection delays research and complicates regulatory approval. Validated biomarkers that can measure drug activity in real time and definitively predict cure or failure without requiring long follow-up will improve the accuracy of trial results, and reduce the cost and time of TB clinical trials. The DAIDS clinical trials networks already have the infrastructure to support the banking of samples across studies and trial sites. There is no such coordinated biobanking system in TB research that can provide a well-characterized cohort for treatment and vaccine studies. The development of a biobank for TB research is essential to the identification and validation of surrogate markers for monitoring treatment outcomes and vaccine efficacy.
    Vaccines: What mechanisms would help ensure that the best ideas for vaccine clinical research are identified and implemented?
    HIV vaccine research has enjoyed a consistent flow of funds to conduct large-scale phase II and III studies of promising candidates. On the other end of the spectrum is TB vaccine research which despite having 10 candidates entering or in phase I and II clinical studies has little to no capacity or the resources to significantly scale up trial sites to conduct phase III studies. The expansion of the HIV Vaccines Trials Network (HVTN) to conduct TB vaccine trials increases the number of potential trial sites that are already GCP and GLP compliant and have experience running large-scale clinical studies. Therefore it may be necessary to encourage collaboration between and cross-training of HIV and TB vaccine research institutions and trial sites. Experienced HIV trials sites could help to strengthen the capacity of TB vaccine sites to conduct studies that are compliant with regulatory requirements. These sites, in turn, could provide technical assistance to HIV vaccine sites to better understand how to evaluate a TB vaccine. This would be a long-term commitment but would help to address some of the gaps in the TB vaccine infrastructure, and limit the chance of a promising vaccine candidate stagnating in the pipeline because of poor clinical research or lack of phase III trial capacity.
    Treatment: On what areas of TB clinical research should NIAID focus?
    With five new compounds in clinical studies and a number of ongoing trials evaluating new treatment strategies, there is the potential to significantly improve treatment for drug-resistant TB, and there is the promise of shortening the duration of drug-susceptible TB in the next two to four years. Even with the efforts of research consortia such as the CDC-funded TB Trials Consortium (TBTC), the TB Alliance, and pharmaceutical companies like J&J/Tibotec and Otsuka, there are still a number of important research questions that have yet to be answered adequately. Addressing these gaps could significantly accelerate the evaluation of TB treatment regimens and may best be answered by the expanded trials networks.
    Ongoing phase II clinical trials evaluating new drugs to treat drug-resistant TB are comparing optimized or standard background regimens of second-line drugs with placebo to the experimental drug plus the same regimens. Most of the drugs used in treating drug-resistant TB have never been licensed for treating TB disease, and their use is based on anecdotal and clinical evidence. As a result, it is unclear what the individual contribution of each of these drugs is to the success or failure of the regimens. This information is critical to determining the optimal combination of drugs to use as standard of care and the networks can play a lead role in documenting this information.
    There is a mountain of evidence supporting the use of isoniazid preventive therapy (IPT) in children and adults who are latently infected with drug-susceptible TB. However very little data exists on effective preventive treatment strategies for persons latently infected with drug-resistant TB. As new diagnostic technologies that are able to diagnose drug-resistant TB in a matter of hours are scaled up in TB control programs, the ability to identify contacts of persons infected with drug-resistant TB will rise as will the need to provide a proven treatment for preventing latent infection from progressing to active drug-resistant TB. If current phase IIb trials of TMC207 and OPC67683 prove these drugs to be effective in improving treatment outcomes for drug-resistant TB, it should follow that they be evaluated for latent DR-TB infection.
    As more drug candidates enter the pipeline, there is an opportunity to vastly improve the standard of care in TB drug treatment. With the establishment of the Critical Path to TB Regimens there is a push to evaluate new drugs concurrently in regimens rather than sequentially. However none of the product developers or TB research consortia has the capacity to evaluate regimens of multiple new compounds. The AIDS Clinical Trials Network, on the other hand, has been conducting such trials for years, and as a newly reconfigured network with TB expertise could initiate phase IIb studies of Tibotec’s TMC207 in combination with Otsuka’s OPC67683.
    Despite being at greater risk for disease progression and being misdiagnosed, infants and children, pregnant women, people with HIV, and drug users have been excluded from many TB clinical trials. As a result many of the new compounds will be approved without any information on how best to use them in pediatric TB, during pregnancy, in conjunction with ART and/or opiate substitution therapy (OST). A global research network with multiple sites in high burden settings could provide safety and PK data to guide the use of new compounds in these special populations.
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  12. Justin W. Millard says:

    As for a Therapeutic, Eradicative-Type “Cure”, what about pursuing the use of a Radio-Labeled, False Nucleoside, kinda like a natural substrate for the Reverse Transcriptase enzyme – the Nucleoside – allowing it to circulate in the body, with complete volume of distribution, until all the HIV-1 virions have taken up the chemical and then “Zap” the virus inside the patient with radiation just as oncology patients receive radiation treatment, focused or enhanced by the Yttrium Chloride as the Beta-emitting radiochemical. Load enough of these Radio-Labeled/False Nucleosides/tides, etc; into Empty HIV-1 Virus Shells (IE, Empty HIV-1 Virus Shells with NO HIV-1 Viral Contents – so as to act as a Perfect Transport Vehicle or Vector for the radiopharmaceutical) the empty HIV-1 virus shells act as a perfect transporter, because they already have the gp120 surface receptor molecule imbedded in the shell to specifically direct the loaded pharmaceutic to the right destination, the human CD4 molecular surface receptor. All the while not causing infection, because we will have engineered the Empty HIV-1 Virus Shells Plus Radiopharmaceuticals to be added that way. So the drug gets to its target, without causing too much collateral damage, and then You burn the virus out of the patient. Perhaps to check of the efficacy or thoroughness of the radiation treatment in an experiment might be to inject inside the Infectious HIV-1 Virus Sample To Be Given To The Test Subject, specifically, inject into each virus or chemical reconstitute into each Infectious Virion, a Gamma-Emitting Diagnostic Radio-Label, specifically Indium-111, or something that works, and perform a full body X-ray? or radiation detecting scan to see how much of the Indium-111 remains, within the natural half-life of Indium-111 to be obtain meaningful data, And see How Much Radiation or How Many Radiation Treatments are required to Burn the HIV-1 Virus To High Hell (Extinguish the Indium-111) From A Test Patient.

  13. raju kale says:

    please tell me whther complete cure for hiv ? when it come in force what time wil it take to get the result