Achieving an end to the AIDS epidemic: Laying the ground work

TREATMENT AS PREVENTION A LARGE randomised study of treatment as prevention has closed more than three years early after interim analysis of the data showed that antiretroviral treatment reduced the risk of HIV transmission from treated partner to uninfected partner by 96%.

The magnitude of the reduction in risk is almost the same as that observed in multiple cohort studies in sub-Saharan Africa, and is the strongest effect seen in any trial that has used an antiretroviral-based prevention method.

HPTN 052 (67) is a large, international study which randomized 1736 male-female couples in which one partner was HIV-positive either to begin antiretroviral therapy immediately, or to wait until treatment was clinically indicated (at a CD4 count of 250 cells/mm3).

The study began enrolling participants in 2005 in Botswana, Brazil, India, Kenya, Malawi, South Africa and Zimbabwe, and recruited couples in which the HIV-positive partner had a CD4 cell count between 350 and 550 cells/mm3. The median CD4 count at the time of joining the study was 436 cells/mm3.

This level is higher than the threshold at which World Health Organization guidelines currently recommend starting treatment. The study was due to run until 2015. The study was halted after an interim review by the Data and Safety Monitoring Board, which found that 39 infections had occurred.

Twenty-eight could be genetically linked to the HIV-positive partner, and of these 27 occurred in couples where the HIV-positive partner did not begin antiretroviral therapy immediately.

This translates into a 96% reduction in the risk of transmission. This result washighly statistically significant (P<0.0001). “This breakthrough is a serious game changer and will drive the prevention revolution forward.

It makes HIV treatment a new priority prevention option,” said Michel Sidibé, Executive Director of the Joint United Nations Programme on HIV/AIDS (UNAIDS).

“Now we need to make sure that couples have the option to choose Treatment for Prevention and have access to it.” “People living with HIV can now, with dignity and confidence, take additional steps to protect their loved ones from HIV,” said Mr Sidibé.

“The recent results from the iPrEx trial showed that PrEP is effective in gay men and transgender women, while the CAPRISA 004 microbicide trial showed that 1% tenofovir gel is effective at reducing HIV risk for women.”

“Together, these results allow us to imagine a world in which men and women seek HIV testing with the knowledge and confidence that they will receive a range of highly effective options for staying healthy and protecting themselves and their partners—whatever the test result,” Warren added.

“The results of the study require us to rethink how we structure the delivery and funding of HIV services overall“. Mathematical modeling by WHO has stimulated great interest in the potential of ART to substantially reduce population HIV-1 incidence when administered through near-universal annual HIV-1 testing, linkage to care, and uptake of ART, regardless of CD4 count (together called the ‘Test and Treat’ or ‘Test and Linkage to Care’ concept).

Most individuals are infected for several years before CD4 decline or clinical disease necessitates ART, and although WHO HIV-1 treatment guidelines now recommend ART initiation at CD4 counts <500 cells/µL, <350 remains the standard in many countries, and the average CD4 at ART initiation is <200 in many settings, often due to late testing or fears about ART.

While ART adherence has been excellent in Africa, this success has been exclusively in individuals with advanced disease whose families are dedicated to provide tangible support to overcome severe structural and economic barriers to adherence because of the dramatic functional improvement they witness with ART.

It is unclear whether asymptomatic individuals and their families will share the same commitment to adherence when ART is given to asymptomatic individuals.

HIV TREATMENT – NEW DRUG CLASS HIV treatment combines drugs from different classes that interfere with different steps of the viral lifecycle but no existing drugs target the very first step – the initial attachment of the virus to a vulnerable host cell.

The recent Conference of Retroviral and Opportunistic Infections held in Boston USA March 2014 heard that combination therapy using a novel HIV attachment inhibitor demonstrated good safety and effectiveness, offering the promise of a new antiretroviral class that may be particularly beneficial for people with extensive resistance to current drugs.

A multi-national trial evaluating the safety and efficacy of the attachment inhibitor currently known as BMS-663068 involved 253 treatment-experienced people.

Participants had a mean CD4 cell count of around 230 cells/mm3 and many had experienced treatment failure with first- or second line HIV treatment. About half the participants had HIV with at least one major resistance mutation, but to be included in the study they had to have HIV that was still sensitive to raltegravir (Isentress), tenofovir (Viread, also in some co-formulations) and atazanavir (Reyataz).

Participants were randomised to five groups, four groups taking different doses of the trial drug and one control group taking atazanavir boosted with ritonavir.

All groups also took raltegravir and tenofovir at week 24, all dosing groups had similar results: 80% of people taking 400mg twice daily, 69% taking 800mg twice daily, 77% taking 600mg once daily and 72% taking 1200mg twice daily had a viral load below 50 copies/ml, compared with 75% in the atazanavir control arm. BMS-663068 was generally well tolerated at all doses and there were no signals of safety issues.

Injectable pre-exposure prophylaxis (PrEP) could be possible, new research involving monkeys suggests. Two separate studies showed that injecting the investigational integrase inhibitor GSK744LA provided long-lasting protection against HIV. In one study, a single dose was protective for an average of eight weeks.

Results of a second study showed that none of the monkeys given the drug became infected when exposed to SHIV (a virus that mimics the course of HIV infection in monkeys), and drug levels remained at potentially protective levels up to five weeks after the last injection.

On the basis of these results, investigators suggested that monthly injections with the product could be enough to protect against infection with HIV.

The first human studies assessing the efficacy of injected GSK744LA as PrEP for humans will start this year. WHAT WILL IT TAKE TO GET TO THE END OF AIDS? Achieving the goal of the end of AIDS will require the transformation of the HIV epidemic into low level endemic in most regions of the world over the next 10-15 years.

To achieve the end of AIDS we need to build on successes, learn from failures and implement to scale all the strategic and core interventions that over the last decade science has taught us.

These include: Know your epidemic – have detailed understanding of local epidemiology The HIV epidemic varies considerably between regions and even within countries.

A good example of how HIV prevalence varies between states and between Local Governments in Nigeria is illustrated in figure 3. A detailed understanding of the local epidemiology will enable each country to develop appropriate interventions that respond specifically to their communities’ needs.

The strong geographical variation in HIV prevalence within countries should be strategically used for commitment of resources for focused programmes in high prevalence zones.

“Knowing your epidemic” is essential for all countries, even those with stable and declining epidemics to identify “hotspots” Scale up of HIV prevention Several effective HIV prevention options including combination prevention are already available for reducing new HIV infections but are not being implemented at the necessary scale and magnitude to those who need it most.

Figure 8 provides from modelling of the potential impact of tackling individual HIV prevention options to scale in Nigeria. The gaps in current prevention options include: •HIV counselling and testing – It is estimated that in most middle and low income countries including Nigeria, more than 40% of individuals who are HIV positive may not be aware of their status thereby posing great dangers to transmitting the virus within their sexual contacts.

This is more so in vulnerable and marginalized groups like sex workers and MSM, who have high HIV prevalence. Innovative means of how to reach these group and others reluctant to test must be devised given the importance of HIV testing as a gateway to both prevention and treatment. •MTCT (breastfeeding transmission and reaching those mothers who do not attend antenatal care).

The number of pregnant women living with HIV who received antiretroviral in 2012 (900,000 worldwide) increased, with coverage rising from 57% in 2011 to 63% in 2012.

In Nigeria, only 58% of women attend ANC for the first time and retention in care and delivery in facilities has been a great challenge with only about 40% of women going on to deliver in health facilities.

The majority of women opt to deliver with Traditional Birth Attendants (TBAs), in churches and mosques and at home. Strategies must be developed to mobilize women to attend ANC and access PMTCT services or get them tested in the community and link them with ANC services at secondary or primary health clinics located within their communities. •Circumcision – providing circumcision scale up and creating demand.

Male circumcision has become a simple procedure that can be carried out in field settings. WHO and UNAIDS have developed guidelines that will assist in reducing the risk of acquiring HIV in adult males. The procedure takes 20 to 30 minutes.

In view of the slow pace in the scale up of the procedure, considerable shifts in culture and social norms are needed to increase the demand for adult male circumcision significantly. •Injecting drug use and the need to overcome stigma and discrimination among this group.

Also it will be very necessary to map out the location and size of the group and as part of the prevention package to this key population, the provision of methadone and clean needles.

•Need to implement new technologies like Pre-Exposure Prophylaxis (PrEP) and Treatment as Prevention (TasP, Test and Treat) in a targeted manner as part of a comprehensive HIV prevention approach (condoms, needle exchange, risk reduction etc.).

Nigeria is currently being supported through a grant from the Bill and Melinda Gates Foundation to the National Agency for the Control of AIDS (NACA) to implement a Demonstration study on PrEP among sero-discordant couples in four states – Plateau, Benue, Anambra and Abia states. •Importance of focusing resources that target key populations that have not been able to achieve low incidence, for example adolescents and young girls in particular.

In this regard, through the leadership of NACA and UNICEF, Nigeria has developed a strategic framework for engaging adolescents and young girls. Implementation of this strategy in this key population will not only reduce new infections but also create a pool of young people who will lead the fight among young people in the country.

•Targeting young people, including comprehensive sexual and reproductive health education in schools before they become sexually active. In this regard, it will be essential that the Federal Ministry of Education take the lead in scaling up the Family Life and HIV Education (FLHE) in schools and using the already existing platform of the National Youth Service Corp (NYSC) HIV and AIDS program to expand the peer education and reproductive health education to secondary schools in all states of the country.

Scale up of HIV treatment New WHO ART guidelines, released in June 2013, recommend earlier initiation of ART and use of simplified, more durable regimens.

For many people living with HIV, treatment is now medically indicated immediately upon HIV diagnosis, regardless of CD4 count. The new guidelines, which aim to maximize the therapeutic and preventive benefits of ART, increased the estimated number of people eligible for ART from roughly 15 million to 26 million.

We have eight months to reach the global target of 15 million people on antiretroviral therapy by 2015. By the end of 2012 almost 10 million people were benefiting from these lifesaving drugs in middle and low income countries.

In Nigeria, over 650,000 PLWHV are accessing ART in more than 500 centres. There are plans in the PCRP to expand the coverage of antiretroviral treatment to 1.2 million adults and children by 2017 through the establishment of additional 2000 treatment sites. This will amount to significant progress not only seen in Nigeria but in many low and middle income countries.

This has led in a growing number of countries to the laying the foundation and the groundwork for ending the AIDS epidemic by scaling up HIV treatment combined with other essential prevention and control activities.

However, millions still are in need of treatment. A recent review of prevention interventions observed that among biomedical interventions tools evaluated, effective antiretroviral treatment provides the greatest prevention effect, as it provides a dual effect of saving the lives of people living with HIV and sharply interrupting the transmission of HIV within the community.

One key issue has remained the issue of maintaining people on ART and ensuring that they have adequate adherence to the drugs in order to achieve virologic suppression and durability.

AIDS treatment is not a cure and for an effective viral suppression, individuals receiving treatment must have an adherence of 95% or risk the development of resistance to the drugs.

The use of treatment support partners within the family and community has been found helpful in promoting adherence amongst patients. Patients who fail the first line drugs are switched to second line drugs, which are often more complex and more toxic than first line drugs.

In addition, second and third line drugs are much more costly and hence all efforts must be made to ensure adherence to the first line regimen and prevent loss to follow up.

Various strategies have been used to assist with adherence; ranging from the use of alarms, to treatment support, electronic reminders to the use of cell phones. Many programs also have active mechanisms of tracking patients especially when they are lost to follow up.

This has helped with adherence to drugs, retention on drugs and prevented loss to follow up. Key enablers that will allow us to implement a more effective AIDS response at scale Community demand and accountability structures Mobilizing and engaging the community to ensure the uptake of comprehensive HIV services is a key component of laying the groundwork for ending the AIDS epidemic.

Advocacy is not as strong as it was in the beginning of the epidemic and therefore will need to be strengthened at all levels. We need to change this and in particular we need young people to inspire a new wave of activism and leadership in the AIDS response.

Engagement of civil society to assist governments in achieving their goals and adding depth to services, and reaching key populations is critical to reducing the number of new infections in the community.

The importance of embracing NGOs and CBOs that are doing the work on the ground to help key populations cannot be overemphasized. New partnerships and alliances including private sector and religious groups must be forged to provide a robust intervention. Shared responsibility and global solidarity must form the basis of partnership at all levels.

There is a dire need for developing countries to increase domestic investment in the AIDS response while, at the same time, there is a need for substantial and sustained international investment to tread the path to the End of AIDS There is a very important need to take AIDS out of isolation and link it to other health issues including co-infections (Tuberculosis, Hepatitis, Malaria, MNCH, Family Planning), co-morbidities (Heart disease, Liver disease, Hypertension and diabetes) and structural issues including stigma and discrimination, gender issues, poverty.

HIV needs to be integrated with other health issues. e.g. TB, sexual and reproductive health services, maternal and child health, non-communicable diseases such as cardiovascular disease etc.

•By addressing the HIV issue we also have an opportunity to impact on other health issues and contribute to a healthy population
•Providing HIV treatment has led to innovations like task-shifting, rapid HIV tests, etc. Many lessons for health system strengthening that would benefit all health care Health system strengthening
•Need to change concept of health system – expanding the “human family”
•AIDS has had huge impacts on so many health issues (other STIs, maternal and child mortality, TB) and non-health related issues (economy: marked reduction of destruction of the work force, the main reason for the massive support and worldwide solidarity, decrease gender and all forms of discrimination).

AIDS has created new opportunities for tackling other major world problems Sustained political will and incentives for political leadership – Political leaders need to keep up the momentum and fight complacency. Deal with underlying social drivers Stigma and discrimination
•HIV is not just a biomedical problem but a hugely behavioural and structural issue.

Even if we did have a preventative vaccine or a functional cure, we will still have stigma. Stigma against people living with HIV and those at higher risk of infection remains a significant barrier in successfully controlling the AIDS epidemic.

Where stigma and the fear of discriminatory treatment remain widespread, many people are deterred from seeking essential HIV services. Surveys under the People Living with HIV Stigma Index demonstrate that stigmatizing attitudes and discriminatory practices toward people living with HIV remain common in many countries.

Nearly 4 in 10 countries lack laws prohibiting HIV-related discrimination; 60 countries criminalize HIV transmission, exposure or non-disclosure; more than 40% of countries criminalize same-sex sexual relations; and punitive approaches to sex work and drug use exist in nearly all countries.

•HIV-related stigma and discrimination is a human rights violation that undermines prevention efforts by making people afraid to find out whether or not they are infected, to seek out information about how to reduce their risk of exposure to HIV, and to change their behaviour to more safe behaviour

•It is necessary to address such discrimination and stigma in order to achieve public health goals and overcome the epidemic

•Although progress on eliminating stigma and discrimination is difficult to quantify, several projects, programmes and activities throughout the world have successfully challenged stigma and discrimination.

In Nigeria the fight against stigma is led by the Network of People living with HIV in Nigeria (NEPWHAN) and was recently given a boost by passage of the antistigma bill by the National Assembly.

Legal barriers to the HIV response •Same sex relationships, sex work and sex outside of marriage are criminalised in many countries. Nigeria and Uganda recently passed laws against same sex relationships.

These laws further entrench HIV-related stigma and human rights violations

•The criminalisation of HIV transmission by those HIV positive people who have unprotected sex is impacting on people wanting to know their HIV status
•Travel restrictions based on HIV status is a human rights violation
•Drug policies hinder access to HIV prevention
•Decriminalisation of sex work and drug use can have an impact on the epidemic. Gender inequality and gender-based violence
•Gender equality and empowerment of women and girls is essential for reducing HIV incidence. Gender Based Violence (GBV) increases the risk of HIV infection.

A recent studies from South Africa in young women observed that women who had experienced violence from intimate partners had 50% more risk of acquiring HIV compared to women who had experienced no violence.

Women from Key Populations (women who inject drugs, female sex workers and transgender) are particularly at risk of experiencing violence. Studies from different countries including Nigeria have observed the high prevalence of rape, physical violence and other forms of abuse among sex workers.Women in conflict situations face increased vulnerability from rape, sexual abuse and other forms of violence.

Poverty Despite unprecedented progress in the past decade, in the global response to HIV, economic inequity, social marginalization and other structural factors have continued to fuel the HIV epidemic. The epidemic continues to undermine efforts to reduce poverty and marginalization.

HIV deepens poverty, exacerbates social and economic inequalities, diminishes opportunities for economic and social advancement and causes prolonged human hardship. Ending the AIDS epidemic and extreme poverty is within our power says Michele Sidibe, the Executive Director of UNAIDS.