ETHICAL CONSIDERATION IN INTERNATIONAL HIV VACCINE TRIALS

An Ethical analysis of HIV vaccine trials

IMPORTANT TERMINOLOGIES

For the sake of clear and sound understanding of our discussion..

 AIDS (acquired immunodeficiency syndrome) is a disease caused by a virus called HIV (Human Immunodeficiency Virus). VACCINE A biological preparation that typically contains substances with antigenic properties that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent induces an immune response to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.

 VACCINE EFFICACY The effectiveness of a vaccine, or how well it works. Can be defined as the reduction in the incidence of a disease among people who have received a vaccine compared to the incidence in unvaccinated people."Efficacy" is used in clinical trial settings, whereas "effectiveness" is used in real world (not carefully controlled) settings. PLACEBO IMMUNOGENICITY INCIDENCE

 RISK BEHAVIOUR CANDIDATE VACCINE An experimental vacccine used in a trial VIRAL LOAD A measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid. For example, it can be given in RNA copies per milliliter of blood plasma.

THE URGENCY TO DEVELOP SAFE, EFFECTIVE & GLOBALLY ACCESSIBLE HIV VACCINE

What makes HIV vaccine so imperative ?

1. The HIV pandemic

Global prevalence of disease and death related to HIV is increasing at alarming rate HIV is the most important infectious disease AIDS is now the major cause of death in Africa, and 4th worldwide More than 16,000 HIV infections occur everyday Two thirds of all adults and children with HIV/AIDS live in sub-Saharan Africa, where the epidemic has drastically reduced life expectancy

 The International AIDS Vaccine Initiative (IAVI) projects that a vaccine with just 50% efficacy administered to 30% of the population of developing countries between 2015 and 2030 would prevent approximately a quarter of the infections that would otherwise occur. Without a vaccine, the number of new infections per year could increase from 6 million to 10 million by 2030. Given these discouraging statistics and projections, the development of a safe and effective HIV vaccine remains a critical but elusive goal.

2. The inaccessibility to the most effective treatment

Antiretroviral Medication Complicated to administer Standard antiretroviral therapy (ART) consists of the combination of at least three antiretroviral (ARV) drugs to maximally suppress the HIV virus and stop the progression of HIV disease. Require close monitoring Cause adverse side effects diarrhoea, nausea, vomitting, rash, lipodystrophy (weight loss, lipid abnormalities, (abacavir in RV) increased risk of heart attack Extremely costly

3. Burden of disease is greatest in poorest countries

More than 95% of all HIV infections occur in developing countries Of the 33.3 million people living with HIV/AIDS across the world, 22.5 million are in Africa. Africa is home to two out of every 3 people living with HIV/AIDS South Africa also has one of the highest numbers of children under 15 living with HIV/AIDS in the world; estimates range from 180,000 to 280,000. South Africa has been hardest hit by the AIDS pandemic. One in five adults is HIV positive.

PHASES OF TESTING AND CLINICAL TRIALS

Pre-clinical Phase I Phase II Phase III

 Pre-Clinical Trials Animal trials are also known as pre-clinical trials. These often include mice, rabbits and rhesus macaques. But no matter how much we learn and study in animal models, only people become infected with HUMAN immunodeficiency virus. Since no animals have the same immune systems as humans, the only way to prove a vaccine's effectiveness is to test in people, so ultimately we have to move forward into human trials. Very few vaccines reach this point.

 Phase I Trials
Phase I trials are generally small (less number of healthy, uninfected participants at low risk of HIV infection than 100 participants) and designed to see if the vaccine is safe. Phase I trials usually last 12-18 months.

 Phase II Trials The goals of Phase II trials are usually to learn more about vaccine safety and to see if the vaccine generates an immune response. Phase II trials, which involve hundreds of participants, occur only after the experimental vaccine is shown to be safe in a smaller Phase I trial. Questions about the right dose and the scheduling of injections can usually be further sorted out here. Phase II trials can last 2 or more years.

 Phase III Trials After a successful Phase II trial, a Phase III trial involves several thousand high-risk volunteers to further assess if the vaccine works in preventing HIV infection. Phase III trials can last 3-5 years.

ETHICAL CONSIDERATIONS IN HIV PREVENTIVE VACCINE RESEARCH

Suggested guidance.

1. HIV vaccines development

Sufficient capacity and incentives should be developed to foster the early and ethical development of effective vaccines.

2. Vaccine availability
Any HIV preventive vaccine demonstrated to be safe and effective, as well as other knowledge and benefits resulting from HIV vaccine research, should be made available as soon aspossible to all participants in the trials on which it was tested, as well as to other populations at high risk of HIV infection. Plans should be developed at the initial stages of HIV vaccine development to ensure such availability.

3. Capacity building
Strategies should be implemented to build capacity in host countries and communities so that they can practice meaningful selfdetermination in vaccine development, can ensure the scientific and ethical conduct of vaccine development, and can function as equal partners with sponsors and others in a collaborative process.

4. Research protocols and study populations

In order to conduct HIV vaccine research in an ethically acceptable manner, the research protocol should be scientifically appropriate, and the desired outcome of the proposed research should potentially benefit the population from which research participants are drawn.

5. Community participation
To ensure the ethical and scientific quality of proposed research, its relevance to the affected community, and its acceptance by the affected community representatives should be involved in an early and sustained manner in the design, development, implementations, and distribution of results of HIV vaccine research

6. Scientific and ethical review

HIV preventive vaccine trials should only be carried out in countries and communities that have the capacity to conduct appropriate independent and competent scientific and ethical review.

7. Vulnerable populations
Where relevant, the research protocol should describe the social contexts of a proposed research population that create conditions for possible exploitation or increased vulnerability among potential research participants, as well as the steps that will be taken to overcome the and protect the dignity, safety , and welfare of the participants.

8. Clinical trial phases

As phases |, ||, ||| in the clinical development of a preventive vaccine all have their own particular scientific requirements and specific ethical challenges, the choice of study populations for each trial phase should be justified in advance in scientific and ethical terms in all cases. Early phase clinical trials should take place in sponsor (developed) countries, unless there are specific scientific and public health

9. Potential harms
The nature, magnitude and probability of all potential harms resulting from participation in an HIV preventive vaccine trial should be specified in the research protocol as fully as can be reasonably done, including provision for the highest level of care to participants who experience adverse reactions to the vaccine, compensation for injury related to the research, and referral to psychosocial and legal support.

10.Benefits
The research protocol should outline the benefits that persons participating in HIV preventive vaccine trials should experience as a result of their participation.

11. Control group

As long as there is no known effective HIV preventive vaccine a placebo control arm should be considered ethically acceptable in a phase ||| HIV preventive vaccine trial. Placebo-controlled vaccine trials are ethically acceptable as long as there is no known effective HIV preventive vaccine

12. Informed consent

Independent and informed consent based on complete, accurate, and appropriately conveyed and understood information should be obtained from each individual while being screened for eligibility for participation in an HIV preventive vaccine trial, and before he/she is actually enrolled in the trial.

13. Informed consent special measures

Special measures should be taken to protect persons who are, or may be, limited in their ability to provide informed consent due to their social or legal status.

14. Risk-reduction interventions

Appropriate risk-reduction counseling and access to prevention methods should be provided to all vaccine trial participants, with new methods being added as they are discovered and validated.

15. Monitoring informed consent and interventions

A plan for monitoring the initial and continuing adequacy of the informed consent process and risk-reduction interventions, including counseling and access to prevention methods, should be agreed upon before the trial commences

16. Care and treatment

Care and treatment for HIV/AIDS and its associated complications should be provided to participants in HIV preventive vaccine trials, with the ideal being to provide the best proven therapy, and the minimum to provide the highest level of care attainable in the host country.

17. Women
As women, including those who are potentially pregnant, pregnant, or breastfeeding, should be recipients of future HIV preventive vaccines, women should be included in clinical trials in order to verify safety, immunogenicity, and efficacy from their standpoint.

18. Children
As children should be recipients of future HIV preventive vaccines, children should be included in clinical trials in order to verify safety, immunogenicity, and efficacy from their standpoint.

DIFFICULTIES IN DEVELOPING EFFECTIVE HIV VACCINE

Challenges faced by researchers

1. HIV is a retrovirus its genetic information is contained in RNA instead of DNA. Currently, no vaccines against human retroviruses exist, so researchers lack prior models from which to work

2. Antiretroviral drugs, the most effective treatment strategy currently available, decrease a patient's viral load and delay the development of AIDS, but they do not eliminate HIV from the body. As a result, scientists have no examples of successful immune responses to guide them in vaccine development.

3. lack of suitable animal models on which to test vaccines before initiating trials with humans. Experiments currently involve chimpanzees infected with HIV and monkeys infected with Simian Immunodeficiency Virus (SIV), a related virus. However, vaccine candidates have invoked different responses in each animal model.

4. HIV's genetic variability and geographical distribution. There are nine subtypes, of the virus. Viruses from different subtypes can recombine to create new hybrid viruses, known as circulating recombinant forms (CRFs), which also infect humans. Subtypes and CRFs have different geographical distributions. For example, subtype B is most prevalent in the Americas, whereas subtypes C and E are the major causes of HIV/AIDS in Africa and

5. Need to be conducted in populations with high incidence of HIV infections, namely developing countries - to produce valid and timely results

ETHICAL ANALYSIS
1. 2. 3. 4. 5. Type of vaccine used Standard of Care Social Consequences Conflicting interests Enrolling vulnerable participants

1. TYPE OF VACCINE USED

An ethical analysis

TYPE OF VACCINE USED

most scientists believe that two classical approaches to developing viral vaccines, using whole inactivated or live-attenuated (weakened) viruses, cannot be employed for safety and ethical reasons. - During the mid- to late 1990s, controversy arose over attempts to introduce a live-attenuated HIV vaccine, thought to be particularly dangerous due to its potential to mutate and cause AIDS or other diseases. - Experiments with primates showed that some macaques who were given the candidate vaccine eventually developed an AIDS-like syndrome. This work also suggested that the strains used in the vaccines could be deadly to individuals with immature immune systems.

 In trials of other vaccines, however, liveattenuated vaccines against other infections have provided better protection of those immunized because they can stimulate a more substantial and broad-based immune response for example in H1N1, rubella, TB However, it can be argued from an ethical standpoint that it would be permissible to use a live-attenuated HIV vaccine with the potential to save millions of lives worldwide, even if a comparatively small number of people were at risk of infection from the vaccine itself

2. STANDARD OF CARE

An ethical analysis

STANDARD OF CARE
Inability of Worldwide, scientists, ethicists, research sponsors, and governments to reach consensus on accepted standard of care for trial participants who contract HIV during the course of a clinical trial an inevitable occurrence among the high-risk populations in which most HIV vaccine research is conducted. Factors such as time, duration, and severity of the disease are considered when researchers explore the provision of medical care during a clinical trial. The situation is complicated further when the disease is a chronic rather than acute condition as in HIV and when the trials are held in resource-constrained environments, as is the case of clinical trials held in developing countries

PRO
it is morally unacceptable to allow patients to receive less-than-optimal treatment, particularly when such treatments are known to be safe and effective. Rich countries sponsoring research in poorer countries have greater access to resources and are therefore ethically obligated to contribute to sustainable improvements in the overall health of developing nations, not simply tending to individual outcomes of research subjects.

 Generally, all parties believe that some medical care beyond the specific requirements of the research protocol should be provided to clinical trial participants. The majority opinion is that because communities and individuals participating in trials "are contributing to knowledge that is a global public good, [they] should benefit in return. The issue is what level of care should be provided, by whom, and for how long.

AGAINST
1. One option is the provision of the best treatment currently in existence worldwide - namely lifelong use of antiretroviral drugs (ARVs) As of 2006, the current cost of highly active antiretroviral treatment (HAART), the standard drug regimen for those infected with HIV, was estimated to be $730 per patientyear Clinical trials conducted in America or Europe would require that infected participants receive the best available care, a lifetime regimen of anti-retroviral drugs, but for similar trials held in developing countries, the prospect of such care is dim at present. Market prices for these drugs are often many times higher, particularly in the United States

2. Treatment of HIV/AIDS is much more than purchasing and supplying medications Frequent follow-up and monitoring of patients are required due to the high prevalence of side effects from HAART and the inevitable development of drug resistance. Developing countries and even clinical trial sites often lack the infrastructure to carry out this type of surveillance on a sustainable basis. Once the trial ends and researchers return to their home countries, ongoing treatment in the host countries would have to be continued by another entity, the identity of which is unclear.

3. One consequence of ensuring lifetime ARV therapy to infected trial participants is a sharp decrease in the scientific community (researchers)'s ability to conduct future HIV vaccine clinical trials. Funding and infrastructure are insufficient for full provision of such care. manufacturers' and other trial sponsors' incentives to conduct essential research in developing countries would quickly erode. High costs are likely to deter sponsors, researchers, and local health authorities from initiating innovative and more ambitious projects.

4. equity issues arises from provision of treatment Community and familial relations could become strained if research volunteers receive better medical care than their neighbors or relatives. the promise of superior medical care could become an undue incentive to participate in clinical trials. well-resourced, research-sponsored care in an otherwise impoverished healthcare facility is an example of global health inequities.

3. SOCIAL CONSEQUENCES OF HIV INFECTION

An ethical analysis

Social effects of HIV vaccine

Some vaccine candidates may cause you to appear HIV positive Volunteers participating in HIV vaccine trials may be falsely identified as HIV-positive simply through 1. their association with trial 2. by developing falsely positive HIV antibody test Volunteers will be counseled to only get HIV testing at the trial site because the site will

 Some people have experienced discrimination when they told others that they were participating in clinical research for an HIV vaccine. No medical side effects or problems are associated with appearing HIV infected on certain tests. However, others may treat volunteers unfairly if the experimental vaccine causes them to appear HIV positive. Participants will not be able to donate blood and they may also have difficulties with: getting insurance, hospitalization, traveling to

4. CONFLICTING INTERESTS

An ethical analysis

Conflicts of Interest
health care providers gain prestige, grants, and promotions through their research and publication of their work. Accordingly, they have a personal interest in recruiting and maintaining participants in their studies. However, some conflicting interests, particularly financial ones, create ethical problems because they may influence the numerous decisions researchers make over the course of a study. For example, such interests may lead researchers to overestimate the benefits of a study, underestimate the risks, fail to objectively review existing evidence, and, if necessary, halt an on-going study.

5. ENROLLING VULNERABLE PARTICIPANTS

An ethical analysis

VULNERABLE PARTICIPANTS

Adolescents participating age from 12 to 18 Women

1. Informed consent consent comes from parents. Most parents wont let their child to participate in vaccine trials. 2. Protected from harm no actual guarantee that these people will be protected from harm. 3. Right to withdraw participating in vaccine trials means that the participant will have to live with the consequences or side effects for the rest of their life. Theres no right to withdraw. 4. Privacy HIV AIDS is a stigmatized disease related to sex, blood and death. Those who participated would have to live with the assumption from the community; e.g: homosexual, commercial sex, etc. 5. Discrimination, violence, and social rejection are often experienced by adolescents and women when their HIV status to be exposed to partners and family members.

Study case : Participation of Adolescents in HIV vaccine trials in South Africa

OBSTACLES TO PARENTALCONSENT

Obstacles to Parental Consent

Child-headed households - orphans, children without resident adult guardians Many of adolescents attending the prenatal and family planning clinics dont live with parents

CONCLUSION
CLOSING: Volunteers in clinical trials cannot get HIV infection or AIDS by receiving an experimental vaccine. An experimental vaccine must successfully complete at least three stages of testing in people before it can be licensed. Human clinical trials are regulated by strict ethical and scientific controls, and occur at specialized research centers around the world.