Modernising ART

By Dr Michelle Moorhouse

South Africa, like many lower and middle-income countries, follows the World Health Organization (WHO) recommended public health approach, using standardised drug regimens to treat HIV. This along with task shifting from doctors to NIMART (Nurse initiation and management of antiretroviral therapy) trained nurses has enabled more than 3.9 million people living with HIV (PLWH) to access life-saving antiretroviral therapy (ART) since 2003. ART is undeniably one of the biggest successes of modern medicine, along with vaccines and antibiotics

While we have some pretty great treatments already, there is still room for

improvement. Current first-line ART is a big pill to swallow, it has some unpleasant side effects, resulting in poor adherence and virological failure, and resistance develops quite easily; it will not get any cheaper over time. From the more logistical aspect, the high dose of the drugs that make up first-line ART means they use more ingredients meaning they cost more, and is the reason the pill is so big, which in turn means the packaging is big, and takes up more space in the pharmacy. Clearly, we need treatments which are easier to take in terms of size and are cheaper. And if you compare first-line ART in lower middle income countries (LMIC), some of the drugs being used are no longer recommended in better resourced settings.

Current first line ART

So, let’s look a little more closely at our current first-line ART. According to our

ART is undeniably one of the biggest successes of modern medicine, along with vaccines and antibiotics

national guidelines, most people living with HIV (PLWH) will receive a combination of efavirenz (EFV), tenofovir (TDF) and emtricitabine (FTC) or lamivudine (3TC) as first-line ART. FTC/3TC, which are structurally almost identical, really contribute very little in the way of toxicity generally and are usually continued through subsequent lines of therapy so I am not going to say much more about them here, and going to confine my deliberations to EFV and TDF.

What is great about this combination is that millions of PLWH around the world have been treated with it for years so there is a wealth of experience with it – a bit like that comfortable T-shirt we like to sleep in, for us as prescribers, but perhaps not so much for PLWH. The regimen has proven virological efficacy, is generally well tolerated, is simple to take as it is dosed once daily and is co-formulated into a single tablet fixed-dose combination (FDC).

What are the problems with EFV? It comes with some unpleasant side effects (abnormal dreams, nightmares, hallucinations even and other neuropsychiatric type symptoms mainly; occasionally rash); has a very low resistance barrier; and requires a high dose. Its safety in pregnancy has been established despite a bumpy start in early development and it plays relatively well with most other drugs, including TB drugs (but not all, for example some contraceptives such as implantables). EFV is an example of one of the first-line drugs which has disappeared from first-line treatment in many wealthier countries.

Alternatives to EFV

So how do we improve on EFV? There are a number of alternatives to EFV to consider which are currently available in South Africa. Rilpivirine (RPV) is one option, from the same class of ARVs as EFV, and is dosed at 25 mg (compared to 600 mg of EFV which contributes significantly to the size of the FDC). RPV is much better tolerated than EFV and is incredibly cheap, which is always good news in a drug which could be potentially be used to treat millions of people. The downside is that it is not yet available in any FDCs in South Africa, can’t be used with rifampicin-based TB treatment or in anyone with a high viral load when starting treatment, and in the public sector we don’t do viral loads at treatment initiation, so it too has its warts. However, it is being studied in some interesting new combinations so let’s not completely set it aside just yet. Certainly as a switch option RPV is a very good choice in patients who don’t tolerate EFV, and there are studies which support this.

Dolutegravir (DTG) is another option already available in South Africa. Again, another low dose drug at 50 mg. In registrational first-line studies no one with virological failure developed any DTG resistance which means this drug is incredibly robust. DTG was also the first drug to ever beat EFV in a head-to-head study, where pretty much all others had previously tried and failed, and this was probably a lot to do with the fact that DTG is more tolerable than EFV. And as the saying goes, if it sounds too good to be true… In fact, there are emerging data suggesting there may be some side effects which include dizziness and anxiety. But this is coming mainly from European cohorts, which do not have the same genetic diversity of African populations. Currently a massive study called ADVANCE that compares DTG to EFV is underway in South Africa and includes screening for these types of symptoms. DTG is also available already co-formulated in SA with abacavir (ABC) and 3TC, but it is not practical to roll out this particular FDC programmatically as ABC is very expensive.

But as DTG requires only a 50 mg dose, if it were to be introduced into the public sector programme, produced by a generic manufacturer with South Africa’s buying power as the largest consumer of generic ART in the world, DTG would be an affordable option for first-line ART, and is currently an alternative option in the WHO guidelines. With regard to DTG and TB drugs there is an interaction, which can be overcome by adjusting the dosing of the DTG, but this might not be necessary – some studies are underway to look into this. One of the current challenges with DTG is at this stage we don’t know a lot about DTG in pregnant women. Botswana made the bold move of introducing DTG into their HIV treatment programme in June 2016, including for pregnant women and it is anticipated that they will present data on the first pregnancies at the IAS conference in Paris in July 2017 which will start to fill this gap. So, we have a very robust drug that is well tolerated and can be co-formulated into a small inexpensive pill – looks promising.

Then there are also other future third-drug options which are not available in South Africa (or indeed anywhere else) as yet. These include doravirine and bictegravir. Doravirine is from the same class of drugs as EFV and RPV. It is still in phase 3 of development (registrational studies) and whether or not it will ever hit our shores is unknown. Bictegravir, also in phase 3, is a drug which is very similar to DTG and is co-formulated with tenofovir alafenamide fumarate (TAF), which I will discuss a little more below, and FTC.

An alternative to TDF

So, moving on to TDF. The problems with TDF are in some ways similar to those with EFV. The high dose means a high active pharmaceutical ingredient requirement which drives the pill size and the cost. And it also has some toxicity associated with it. Currently, we do not have any alternatives available in South Africa  that are any better but there is one which should be available soon, namely TAF (tenofovir alafenamide fumarate). TAF, like the TDF in current first-line ART is a pro-drug of tenofovir. TAF is given at a much lower dose (approximately 10-fold lower) than TDF. TAF is associated with much less kidney and bone toxicity than TDF. The ADVANCE study will also compare TAF and TDF, as most studies of DTG used ABC as the backbone, and also would not have included many African participants. TAF has not been studied with TB drugs or in pregnant women as yet, but these studies are underway. Once we have a better understanding of this, on account of the better safety profile and the lower dose which will result in significant reductions in cost, TAF is set to be a favourable option to replace TDF.

And in fact, if DTG, FTC and TAF are co-formulated potentially we are looking at a future first-line regimen, to quote Prof Francois Venter, “smaller than an aspirin” which is incredibly potent, incredibly robust, incredibly well tolerated, all while being incredibly cheap – incredible isn’t it?

ART does not exist in a vacuum

All of this is very important, while we have such tough targets to chase – the famous 90-90-90. And to achieve that third 90 we need to modernise treatments so that PLWH can adhere to them. When there are so many other challenges to overcome within a healthcare system, optimising ART to be as simple, safe, efficacious and robust as possible facilitates safer task shifting to other cadres of staff which may help alleviate some of the human resource shortages faced within healthcare facilities.

But no matter how good the drugs are, ART does not exist in a vacuum, and ART alone will not achieve the three 90s. ART will not fix the healthcare system. ART will not address stigma. ART will not help us achieve that first 90 – 90% of PLWH knowing their status. ART will not find the missing in action to test them – the men, the key populations, the adolescents, girls and young women – and then link them to care to achieve the second 90. ART will not then retain them in care, and measure their viral load so we can see if we are reaching that third 90.

Massive investment in infrastructure and development of systems backed by political will is critical. Civil society must remain engaged and all of this must be backed by a National Strategic Plan (NSP) that is realistic, detailed, and embodies the principles of equity and access. There is a massive amount of work to be done to conquer HIV in South Africa, but optimised ART is certainly a great step in the right direction.

Dr Michelle Moorhouse – Wits Reproductive Health and HIV Institute and Southern African HIV Clinicians Society

How HIV shaped us

By Professor Glenda Gray & Professor James A. McIntyre

HIV changed the nature of health in South Africa as our new democracy emerged. Seemingly overnight, in front of our eyes, young people and children died in unprecedented numbers. HIV slashed life expectancy, wiped out a generation of economically active adults in their prime across sub-Saharan Africa, reversed gains in under-five mortality and created a cohort of AIDS orphans. It also revealed the inter-relatedness between social behaviour, stigmatisation, cultural mores, religious beliefs and human health. HIV changed our society at a time when South Africa needed no distraction as it battled to rebuild a nation post-apartheid.

From 1998 to 2003, civil society together with AIDS activists, doctors and scientists used scientific evidence, in the face of government AIDS denialism, to force the use of antiretrovirals for the prevention of mother to child transmission of HIV-1, and subsequently the roll out of antiretrovirals as life-saving treatment. Our work at the Perinatal HIV Research Unit (PHRU) in Soweto was at the centre of these controversies. We had established the PHRU when we commenced research into the prevention of mother to child transmission of HIV-1 (PMTCT). Initially, we evaluated interventions to minimise breast milk transmission of HIV-1, before embarking upon the PETRA study, one of the first antiretroviral perinatal transmission studies to be conducted after the famous USA ACTG 076 study, which demonstrated that AZT could reduce perinatal transmission significantly. Because of our involvement in the management and follow-up of HIV-1 infected pregnant women and their infants, we became one of the first public sector sites to conduct antiretroviral treatment trials in adults and children. This gave us the necessary comfort to propagate the use of antiretrovirals in Soweto. Soweto, thus became one of the first demonstration projects for both PMTCT and ARV treatment roll-out, funded by the French government’s Fonds de Solidarité Thérapeutique International (FSTI) in a direct grant to the PHRU.

This Demonstration of Antiretroviral Treatment (DART) was approved under strict conditions by the then Minister of Health, Dr Manto Tshabalala-Msimang. However, as the governmental denialism intensified, our efforts to secure additional funding from the Pangaea Global AIDS Foundation and Clinton Foundation were closed down. We received a phone call from the then AIDS Director at the National Department of Health (NDOH), instructing us to stop developing the proposal, and communication with the donors then stopped without explanation. A decade later, Pangaea acknowledged the South African government pressure to stop working with us.

Political interference at this time was rife and the use of antiretrovirals for PMTCT was seen as a subversive activity. The Castro Hlongwane, Caravans, Cats, Geese, Foot & Mouth and Statistics: HIV/AIDS and the Struggle for the Humanisation of the African document – partly penned by Thabo Mbeki and distributed to ANC branches throughout South Africa – attacked South Africa’s earliest and most prominent AIDS scientists, including Salim Abdool Karim and ourselves. Abdool Karim’s research was characterised as “anti-human” promoted by “corporate forces” and we were singled out, because of our work using antiretrovirals for preventing mother-to-child transmission of HIV, as “killers of Black Women”.

"Political interference at this time was rife and the use of antiretrovirals for PMTCT was seen as a subversive activity"
“Political interference at this time was rife and the use of antiretrovirals for PMTCT was seen as a subversive activity”

In 1999, results from a study in Uganda, showed that a single dose of nevirapine given to HIV-1 infected pregnant women in labour and a dose administered to their infants within 72 hours could reduce PMTCT. These results galvanised us to try and secure this nevirapine-based intervention for HIV-1 infected women in our clinic, and we relied on donations to keep a steady supply before nevirapine was officially available for PMTCT. We supplied nevirapine under tense conditions at the Chris Hani Baragwanath Hospital. One day, a doctor from a peripheral hospital phoned, asking us to supply nevirapine to a HIV-infected woman in labour. He sent an ambulance to the PHRU. We gave the driver the nevirapine tablet and syrup, only to be phoned by the hospital superintendent admonishing us, as he barred this pregnant woman from access to a drug proven to be efficacious, effectively allowing HIV exposure during birth without prophylaxis.

In 2003/2004, government policy changed under pressure mounting from civil society as well as political pressure within the political-government structures. In an era where the cost of drugs was declining, we were fortunate beneficiaries of USAID and Elizabeth Glaser Pediatric AIDS Foundation funding that enabled scaling up treatment in Soweto. In a space of six months, our team, lead by Dr Lerato Mohapi, put just under 1 000 people in treatment; and our PMTCT programme directed by Dr Avy Violari, expanded in Soweto, accelerating access by opening PMTCT programmes in every antenatal clinic.

Even though we were involved with rolling out care, and scaling up interventions for maximum impact, we knew we also had to focus on the clinical science, and designed a number of programmes, which were funded under the CIPRA-SA banner. Studies executed under this programme impacted on international guidelines that revolutionised treatment management for infants, as well as defining that antiretroviral treatment could be executed by nurses instead of doctors. The Children with HIV Early Antiretroviral (CHER) study, undertaken at the Chris Hani Baragwanath and Tygerberg Hospitals showed that early treatment in HIV-infected infants could significantly reduce deaths3. The CIPRA-SA study demonstrating that ARV care could be task-shifted to nurses allowed for the mass roll out of treatment in South Africa and beyond3. We continued with PMTCT research which continued to help elucidate and refine regimens to make them more potent, the requirement to eliminate paediatric HIV.

Knowing that the only effective way to control the HIV epidemic was through prevention, the PHRU expanded its focus beyond PMTCT and ARV treatment for adults and children.

At this time the South African AIDS Vaccine Initiative, was established, and Glenda Gray transitioned from treatment into prevention. Tasked with taking the South African developed HIV vaccine candidates into first-in-man studies10, both in South Africa and the US, Gray would embark on leading these studies as well as lead the first HIV vaccine efficacy study in South Africa. For the past decade, finding an effective vaccine has been the fixation of most of Gray’s clinical research.

James McIntyre, driven by the need to continue to fine-tune innovation to take interventions to scale, turned to implementation science which saw the wide-spread roll out of treatment and PMTCT programmes. Concerned by the huge burden of HIV amongst men who have sex with men (MSM) and the lack of appropriate treatment for MSM in the public sector, McIntyre pioneered the development of MSM services in South Africa, that have become a model for both prevention and treatment.

Now, just over a decade and a half after the International AIDS Conference in 2000, South Africa’s burden of disease estimates indicate a nine-year increase in the average life expectancy from an all-time low in 2005, where total life expectancy was under 55 years. Our under-five mortality has been slashed by half from 80/1 000 to 40/1 000. Similarly spectacular gains have been made in infant mortality rates: from 54/1 000 to just under 30/1 000. Maternal deaths have also declined from 190 to 155/100 000. Most of this is attributed to the scale up of antiretovirals in the public sector.

These spectacular gains made by South Africa are a tribute to the activists, health care workers and scientists, who, faced with a horrific epidemic, did the right thing, and “en masse” spoke truth to power, and were relentless in their pursuit of scientific evidence and ruthless in their implementation of that. To have been part of this crusade, and look back, and see how much progress has been made is gratifying. Now we have to ensure that the lessons garnered in our experience with the HIV epidemic, are recapitulated in the quadruple burden of disease and the interconnecting epidemics of: communicable and non-communicable diseases; maternal and child mortality; and injury and violence.  

 

Professor Glenda Gray is the President of the South African Medical Research Council, Research Professor of Paediatrics at the University of the Witwatersrand.

Professor James A. McIntyre is the Executive Director of the Anova Health Institute, International vice-chair of the International Maternal Paediatric and Adolescent AIDS Clinical Trials Network.

HIV and non-communicable diseases: a dangerous partnership

Dr Tolu Oni

WHAT: Evolution of the HIV epidemic

Over the years, HIV and the ensuing global epidemic has resulted in millions of deaths. With the advent of antiretroviral therapy, and the advocacy efforts of civil society, HIV-related mortality has significantly decreased, as has mother-to-child transmission.

Consequently, a worldwide epidemic, characterised by fear, illness and death, has been transformed – with HIV-infected patients now able to live longer in good health in settings where antiretroviral therapy (ART) is equitably accessible and initiated early.

The global burden of HIV continues to vary considerably, with a disproportionally high prevalence in sub-Saharan African countries and other low- and middle-income countries (LMIC).

In these settings, HIV-related deaths remain unacceptably high, with delays in diagnosis and access to treatment. However, in many LMIC, sustained and expanding provision of ART, at increasingly higher CD4 cut-off values, has resulted in increasing life expectancy and decreasing incidence of new infections.

There is therefore a need to move from a system designed as an emergency response to one of chronic disease management, with an accompanying shift from a predominant mortality focus to focusing on morbidity (living with HIV and other diseases) and the improvement of quality of life.

WHY: Changing patterns of disease in countries with significant HIV burden

This ongoing evolution of the HIV epidemic towards being considered a chronic disease is occurring against a background of population transition. Many low and middle-income countries are experiencing rapid, unplanned urbanisation, resulting in a significant proportion of urban dwellers living in informal settlements.

This changing environment is associated with changing behaviour with decreased physical activity, increased consumption of processed high salt/high sugar foods, increased rates of tobacco smoking and alcohol/substance abuse. This is resulting in an accompanying rise in non-communicable diseases (NCD) such as diabetes and heart disease, and NCD risk factors like obesity and high blood pressure.

Of note, this rise in NCDs is considerably higher in low and middle-income countries. A recent study showed that in South Africa, almost four out of every five people over the age of 50 years has high blood pressure. Another research study conducted in South Africa found that three to four out of every five women are overweight or obese. One research study in South Africa found that among HIV-infected patients attending a clinic for ART, one in five were also on treatment for another chronic disease, predominantly treatment for diabetes and/or high blood pressure.

Given that less than 50% of people with high blood pressure are aware of their diagnosis, this figure is likely to be a gross underestimate, and is on the rise as a greater number of HIV-infected individuals age. The increase in NCD and NCD risk factors is even more pronounced in socio-economically disadvantaged populations, the same populations with a high prevalence of HIV. This trend is set to continue across LMIC as countries continue to urbanise and undergo epidemiological transition.

But in addition to simply co-existing in the same populations, these diseases are also known to interact with some ART drugs known to increase the risk of insulin resistance associated with diabetes. In addition, some ART drugs are known to interact with drugs for the treatment of diabetes and high cholesterol. These data highlight the existing overlap between HIV/NCD co-morbidity, and the different pattern of multi-morbidity to that described in high-income countries emerging. This multi-morbidity – the presence of two or more chronic diseases (including HIV) – has been shown in South Africa, and results in greater difficulty of patients to self-manage.

Where there is a mismatch between the workload (including clinic visits, behaviour change, taking long term medication and so on) and the capacity to meet these demands, this may result in poor adherence and could undo the health outcomes and quality of life advances achieved through ART roll-out. Therefore a holistic, coordinated and coherent approach to integrated management is needed.

The roll-out of ART across high-burden settings was accompanied by a mobilisation of global funds to finance these efforts. In these countries, parallel health systems were set up to facilitate the diagnosis, initiation of treatment and monitoring of disease control. These programs have been largely effective at reaching a wide population and rolling out ART access. Many lessons have been learnt in the establishment of HIV programmes, including the importance of prevention, screening and early detection, early treatment and treatment monitoring. With a strong focus on viral-load suppression once ART is initiated, these programmes were designed with a strong focus on monitoring disease control, with systems in place to address sub-optimal disease control – and they have resulted in significant gains in HIV mortality.

The recognition of tuberculosis as an important co-morbidity led to integration service delivery, including screening and co-management, as well as integration of healthcare workers providing care for HIV and TB, resulting in improved HIV and TB outcomes in co-infected patients. These lessons are highly relevant for the control of NCDs and there is a need for a systems approach to integrating chronic infectious and non-communicable disease prevention, screening, diagnosis and management.

Successes notwithstanding, there are common challenges faced by both HIV and NCD programmes that could benefit from a combined effort.

Advocacy by civil society movements was key to achieving affordable equitable access to ART. There is a need for all role players including patient and civil society groups, non-governmental organisations, clinicians and researchers to combine forces and bolster advocacy efforts to address common HIV and NCD challenges including:

improving access to, and uptake of, services by hard to reach and vulnerable populations such as adolescents, migrants, and incarcerated persons.

the need to adopt a Health-in-All-Policies approach to address socio-environmental determinants of these diseases with a stronger focus on prevention

the need to address shared risk factors such as alcohol/substance use through intersectoral collaboration

access to newer medication and advocacy for development of better combinations of drugs

access to palliative care for these conditions

WHEN? Right now

A Global Health Film Festival held at the University of Cape Town in April 2016 screened “Fire in the Blood”, a documentary about access to ART.

The documentary could have been entitled: “When the world realised they should care about HIV”, as it showed effectively how slow the world was to mobilise to respond to the need for access for all and the consequences of the slow response. The last frame of the documentary had the statement: “Help prevent a sequel”.

We welcome the news of a change in treatment policy towards treating all who test positive as this will ensure HIV is a manageable chronic condition (in addition to contributing to prevention efforts). But without a concerted effort right now to address NCD in the general population, the sequel is already playing albeit in slow motion.

From a patient and health system perspective, this conversation must include HIV-infected persons and the HIV programmes in the health system. With the recent announcement of the test and treat policy, we can celebrate the remarkable journey to achieving ART access to all HIV-infected persons. But alongside these achievements must be a shift to improving morbidity, as well as mortality.

Addressing the NCD epidemic in this, and the general population is key to achieving this goal to prevent a reversal of the gains in mortality and morbidity achieved.  

 

DR Tolu Oni is a Senior Lecturer, School of Public Health and Family Medicine, University of Cape Town.