HIV in SA: Five graphs that tell the story

By Marcus Low

The recently published outputs of the Thembisa mathematical model of HIV in South Africa paint a remarkable picture of the history of HIV in this country. For the period from 1990 to 2015, we’ve plotted five graphs below using the estimates published on the Thembisa website. For all the graphs, a solid line indicates data which have been ‘matched’ against available survey data, while a dashed line represents data that are more uncertain as they are the Thembisa model’s projections or ‘best guesses’ based on previous trends in the data.

1. Life expectancy

graph1_lifeexpectancy_4

This graph shows life expectancy at birth in South Africa. It shows a dramatic drop to 53.6 as the HIV epidemic grew to its peak in 2005. The impressive increases since then has been attributed to the wide rollout of ARVs by the state (see next graph). This graph also makes it clear that, impressive as these increases are, they are mostly just a recovery to pre-HIV levels. Life expectancy in 1995 was 62; 20 years later in 2015 it was estimated to again be 62.

2. Antiretroviral treatment (ART)

graph3_art_4

This graph shows the total number of people in South Africa receiving antiretroviral treatment. Comparing this to the previous graph, notice how dramatically life expectancy increased as antiretrovirals (ARVs) became more widely used from the mid-2000s.

3. Number of new infections and HIV deaths

graph2_hivinfections_hivdeaths_4

The blue line on this graph shows the number of new HIV infections in South Africa by year. The good news is that the rate of new infections is decreasing from its peak of around 570 000 per year at the turn of the century. The red line represents HIV deaths per year and shows that yearly deaths peaked in 2005 at around 280 000 and then started declining (note the similar time that ARVs became more widely used in the previous graph). Notice how the red line is lower than the blue line – in other words, more people are becoming newly infected with HIV than people are dying of HIV. The result of this, as we will see in the next graph, is that the number of people living with HIV in South Africa is increasing. (Not shown on the graph: by 2015 a total of around 3.5 million people have died of HIV-related causes in South Africa.)

4. Number of people living with HIV

graph4_numberlivingwithhiv_4

This graph shows the number of people living with HIV in South Africa. That this number is continuing to increase is both a bad and a good thing. As we can see from the previous graph, this effect is driven by the still high rate of new HIV infections (bad) and by the fact that people living with HIV are living longer and no longer dying at the same rates as before (good).

5. HIV prevalence

graph5_hivprevalence_4

This graph shows HIV prevalence in South Africa. It is worth including here since HIV prevalence figures are often quoted in the media. Prevalence in this case is an indication of the percentage of the population who are living with HIV in a particular year. Prevalence is driven by the same forces driving the total number of people living with HIV (shown in the previous graph). The one key difference is that it also factors in that the total population of South Africa is growing. If you extend the model’s predictions into the future, HIV prevalence is expected to peak in 2016 and 2017 at 12.8% and then starts coming down slowly – but the total number of people living with HIV is only predicted to reach a peak of around 7.9 million during 2030.

Spotlight’s top 8 highlights of AIDS 2016

By Marcus Louw

As the dust settles in Durban and the circus moves on, we reflect on a few of the bigger moments of AIDS 2016. Below are some of the highlights we think may turn out to be significant.

 

  1. Ban Ki-Moon in town to talk medicines

For a few hours on Monday 18 July United Nations Secretary-General Ban Ki-Moon was in Durban. He was there to talk about HIV, but also to talk about access to medicines. Late in 2015 he had appointed a High Level Panel (HLP) to consider problems with access to medicines and the lack of innovation in important disease areas. That he chose to travel to Durban on the eve of receiving the HLP’s report on these issues is significant.

On Monday morning Anele Yawa, General Secretary of the Treatment Action Campaign, presented a memorandum to Ban Ki-Moon urging him to take steps to “never again let people die because they cannot access medicines”. If part of Ban Ki-Moon’s mission in Durban was to take the temperature ahead of receiving the HLP report, he would have found it to be scorching hot. Whether that has any influence on what happens with the HLP report and to what extent the report and its recommendations lives or dies within the United Nations remains to be seen.

  1. Close to 10 000 people in ‘Treatment for All!’ march

In the moment last week most reminiscent of 2000, close to 10 000 people led by the Treatment

Close to 10 000 people led by the Treatment Action Campaign marched to the Durban Convention Centre
Close to 10 000 people led by the Treatment Action Campaign marched to the Durban Convention Centre

Action Campaign marched to the Durban Convention Centre on Monday to hand memorandums to various high-ranking persons in the AIDS world including UNAIDS chief Michel Sidibe, Pepfar head Deborah Birx and deputy president Cyril Ramaphosa. The march was convened under the banner of “treatment for all now!”. Activists emphasised that 20 million people living with HIV need treatment, but do not have access to it. The march showed that large numbers of people can still be mobilised to demand that leaders do better in the AIDS response. (You can read the march memo here)

 

  1. UNAIDS U-turn on “end of AIDS” language

One of the big stories of AIDS 2016 is the shift away from “end of AIDS” rhetoric from UNAIDS. In a move welcomed by activists, UNAIDS Executive Director Michel Sidibe said that we are not currently heading toward an end to AIDS and TB. Along with a number of other speakers at the conference he highlighted the reduced funding available for the AIDS response and the fact that the rate of new HIV infections is not coming down. But, whether the change of course from UNAIDS together with the show of power on the streets of Durban will be enough to push the global AIDS response back on track is unclear.

 

  1. Disappointing results from TasP trial

There was great hope that the TasP (Treatment as Prevention) trial would show that providing more people with treatment earlier will reduce the rate of new infections in a community. Unfortunately, this important trial failed to show a significant reduction in new infections in communities with early treatment. The problem appears to be to get enough people tested and then to get those people to initiate treatment. In better news, new findings from the Partners trial confirmed that people who are stable on treatment with undetectable viral loads do not transmit HIV to their sexual partners. The sobering message from TasP then is that we’ll need to do a lot more to actually get people tested and on treatment, but Partners confirms that getting it right will have a huge impact on new infections.

 

  1. A potential turning point for community healthcare workers

In another notable statement from UNAIDS, Sidibe said that the world needs to train a million more community healthcare workers (CHWs). He said that South Africa should have 200 000. This is significant since the line from the Minister of Health in South Africa has until now been that 40 000 CHWs are enough for South Africa. It is now up to activists around the world to use Sidibe’s comments to push for the training and employment of many more CHWs.

 

  1. Questions about young women and girls

Much lofty rhetoric at this year’s conference focused on the extremely high infection rates in young women and girls. Much of the rhetoric was of course not from young people. When young people did speak out – interrupting South African Minister of Health Dr Aaron Motsoaledi – it was to say they want access to condoms and sanitary towels in schools.

 

  1. Speech of the conference delivered by Justice Edwin Cameron

On Tuesday morning Justice Edwin Cameron delivered the prestigious Jonathan Mann lecture. Apart from being humorous and moving, the speech had a remarkable moral force and clarity. One of the disappointments of AIDS 2016 was that more people did not name and shame countries for discriminatory laws that undermine both the rights of human beings and the AIDS response.

 

  1. Civil society march against crackdown by Indian government

On the morning of 21 July activists marched from the conference to the Indian Consulate in Durban. The activists were protesting the Indian government’s crackdown on civil society groups such as the Lawyers Collective and India’s yielding to pressure from the United States on intellectual property. The activists say that India’s status as the pharmacy of the developing world is under threat and with it the global supply of quality generic AIDS medicines.  The memorandum was endorsed by current, future and past leaders of the International AIDS Society.

 

  1. New evidence supports new models of care

One of the key themes of the 2016 conference was that we need to change the way healthcare systems deliver services to people living with HIV if we want to provide all people living with HIV with treatment. The evidence is in. It is now up to healthcare systems to start implementing more task-shifting, adherence clubs, and care models requiring fewer clinic visits.  There is also new evidence suggesting that offering people treatment on the same day as testing HIV positive leads to more people starting treatment. Not surprisingly, a community healthcare worker-based programme  helped to improve TB detection rates in a study in Malawi.

While it is hard to change the inertia of old ways of delivering care, we now seem to have reached a critical mass of evidence on what we need to do to make healthcare systems much more effective and efficient. Integrating these new ways of doing things must be a top priority for health departments in high HIV and TB burden countries.

In a show of solidarity with breast cancer patients across the world, activists covered the Roche stand at the conference with hundreds of bras
In a show of solidarity with breast cancer patients across the world, activists covered the Roche stand at the conference with hundreds of bras

 

  1. Breast cancer protest at an AIDS conference

In a show of solidarity with breast cancer patients across the world, activists covered the Roche

stand at the conference with hundreds of bras. The activists were protesting the high prices that Roche is charging for the breast cancer drug trastuzumab in South Africa and other countries.  In South Africa a course of the drug costs a half a million Rand. One of the protestors was a breast cancer patient from South Africa who has not been able to access trastuzumab. Her cancer has recently spread – something taking trastuzumab could potentially have prevented.

 

 

 

Won the battle, lost the war

By Marcus Low & Lotti Rutter

In the early days of the AIDS epidemic, the high price of antiretroviral medicines meant many lives were unnecessarily lost. While the global AIDS movement managed to force lower prices for key ARVs, the wider battle has not yet been won. Today, many people with hepatitis C, various cancers, drug-resistant tuberculosis and other conditions still cannot get the medicines they need to survive. This article explains the how inequality extends to drug development.

There are two broad problems with the way society currently pays for medicines.

The first, the innovation problem, is that we are not investing enough money and energy into finding treatments for diseases mostly affecting poor people. This is why most of our tuberculosis (TB) treatments today are more than fifty years old and not very good.

The second, the price problem, is that many of the medicines that are developed are sold at such high prices that people cannot afford them. This is why many people with hepatitis C cannot afford the highly effective new hepatitis C cures on the market. For these people the new cures might as well not exist.

The innovation problem

Last year, tuberculosis killed more people than any other infectious disease on the planet, including HIV. At 1.5 million deaths, it far outstripped headline-making outbreaks like Ebola (11,315 deaths in 21 months). Yet, in 2014 humanity invested less than US$700 million in TB research – only about a third of the two billion a year that the World Health Organisation estimates is required to bring an end to TB. Of this US$700 million, less than US$100 million was invested by the pharmaceutical industry. In fact, a number of large pharmaceutical companies have stopped doing TB research altogether.

The first part of this problem is simple. Since most people needing TB treatment are poor, pharmaceutical companies see little potential profit in developing new TB treatments. Companies choose rather to invest in researching medicines that will sell in rich countries – medicines for diabetes, heart disease, or erectile dysfunction.

The second part of the problem is more puzzling: given that industry does not invest, one would expect governments to step in to fill the gap. However, with the exception of the United States, governments do not. While the BRICS countries (Brazil, Russia, India, China and South Africa) have over 40% of the global TB burden, they contribute less than 4% of global investment in TB research.

The price problem

When the patent system does deliver important new medicines, as it sometimes does, those medicines are often priced out of reach for many of the people who need it. So, for example, the breakthrough hepatitis C drug sofosbuvir is priced at US$84 000 for an 84-day course. Similarly, high prices mean that women in South Africa who need the breast cancer drug trastuzumab often can’t afford its R500 000 price tag.

Companies argue that they have to ask these high prices to recoup their investment in developing the drugs and to fund their investment in developing new medicines. In recent years this argument has begun to wear very thin.

Companies argue that they have to ask these high prices to recoup their investment in developing the drugs and to fund their investment in developing new medicines
Companies argue that they have to ask these high prices to recoup their investment in developing the drugs and to fund their investment in developing new medicines

A United States senate investigation in 2014 found that the pricing of sofosbuvir had nothing to do with how much it costs to develop the drug. Rather than basing prices on the investments made into a drug, companies are typically setting prices at levels that maximise profits – even if that means many people can’t access the drug in question.

At a more fundamental level, high prices charged by pharmaceutical companies have brought into question the basic social contract between the public and the pharmaceutical industry.

The thinking is that the people, through our governments, grant patent monopolies to companies in return for investment in new medicines. However, enforcement of this social contract is very one-sided. While companies almost always get and maintain their patent monopolies, there is no enforcement of the expectation on companies to invest in research. Typically, companies invest only between 8 and 18% of revenue in research and development (R&D), while they typically spend double on marketing and advertising. In addition, the way in which companies spend their R&D funds is completely non-transparent.

All the available evidence suggests that we are not getting much bang for our buck in the current system where there is no obligation on industry to reciprocate high prices with high investment in R&D.

We have other options

Various solutions to these problems have been under discussion at the World Health Organisation (WHO) over the last decade – with very little progress to show for it. In addition, in 2015 the Secretary General of the United Nations, Ban Ki-moon, convened a High Level Panel to look at exactly these problems. Even if the HLP comes up with strong recommendations, it will be up to governments to make those recommendations a reality.

Some possible solutions include:

An R&D agreement or treaty

Given that industry is failing to invest in diseases that have an impact on poor people, governments have a responsibility to step in and fill that investment gap. One solution is an R&D treaty or agreement. Countries would all contribute to a central fund. Money in this fund would then be used to fund research in neglected areas like TB. This is a simple and workable solution. The only thing that is lacking is political will. Even if rich countries like the United States and Germany oppose such a treaty or agreement, there is nothing preventing other countries from going ahead without them.

Delinkage

When governments invest in research, they often do so in a way that allows companies to patent the products of that research. In this way, governments end up paying twice – once through research grants and again when paying high prices for patented medicines. If governments invest in a delinked way, they will not allow this double-payment to happen. In such a case, governments will fund research through grants and prizes and then ensure that all the research is paid for up front and that the research cost is “delinked” from the sale price of the eventual product. The so-called 3P Project (see our previous issue) is an example of a delinked model.

Bring balance to the system

International law allows for steps to be taken to balance the worst excesses or exploitation of patent monopolies. These balancing measures are commonly referred to as TRIPS flexibilities (Trade-Related Aspects of Intellectual Property Rights) and they include allowances for: compulsory licenses (overriding patents); only granting patents for truly innovative products and not for reformulations or new uses of old drugs; and for the public to file oppositions to the granting of specific patents.

The problem is that due to trade pressure from the United States Trade Representative, many countries have not written these TRIPS flexibilities into their national law – and if they have, they are often afraid to use them.

Doing away with pharmaceutical patents altogether

One of the remarkable things about the history of patents and medicines is that there is no evidence that providing increased patent protection around the world has led to greater medical advances. In fact, in the golden age of medical discovery from the 1940s to 1970s, much of the world did not offer any patent protection on medicines. There was also no increase in innovation following the TRIPS agreement in 1995, which compelled all World Trade Organisation member countries to provide for at least 20 years of patent protection.

It would of course not make sense to simply remove the patent system and not replace it with anything else. The world, after all, is in desperate need of new medicines. Governments would have to redirect the money they would have spent on purchasing patented medicines to providing research grants and sponsoring prize funds for the development of new medicines. All indications are that such a transition would in fact see R&D spending increase dramatically – given how little industry currently spends on R&D as a percentage of revenue.

Lotti Rutter is a Senior Researcher for Treatment Action Campaign

Marcus Low is an editor of Spotlight

 

QUOTES:

You are aware of the exploding prevalence of cancer around the world and in our own country. We have just moved in a circle. Just as the price of ARVs were unaffordable then, cancer drugs are devilishly unaffordable today. If no drastic action is taken today, we are going to be counting body bags like we are at war.”

Dr Aaron Motsoaledi, Health Minister of South Africa, 2016 budget vote speech.
“Rationing is the ultimate consequence of high drug prices. Unsurprisingly, this is unpopular and is causing a backlash. In a number of US states, politicians are seeking to pass legislation forcing drug companies to disclose more information about the cost of producing their high-priced remedies. There is even talk of capping prices. The industry argues that such caps would drive capital out of the industry, cutting innovation and ultimately harming patients. But that is a hard argument to sustain when companies such as Gilead and Vertex are earning gross margins of 90 per cent and share prices are sky high. Pharmaceutical innovation has been one of the great successes of the past century, improving the lives of people immeasurably round the globe. But if the current dispensation is to continue, the industry must learn to price with greater restraint.”

Financial Times, August 16, 2016.

 

The patent system is expensive. A decade-old study reckons that in 2005, without the temporary monopoly patents bestow, America might have saved three-quarters of its $210-billion bill for prescription drugs. The expense would be worth it if patents brought innovation and prosperity. They don’t.”

The Economist, August 8, 2015.

 

The future of antiretroviral treatment

By Polly Clayden & Simon Collins

We are in a very exciting time for HIV treatment (ART) for three reasons.

  1. South Africa, the country with the biggest HIV treatment programme, has agreed to make ART available to everyone who is living with HIV.
  2. An important new HIV drug – called dolutegravir – is expected to be available soon in low-income countries at a low price.
  3. Other developments may lead to treatment with only one or two drugs – instead of three, and two-monthly injections – instead of pills.

 

Over 17 million people with HIV are receiving ART worldwide. This is less than half of the over 36 million people living with HIV.

In 2015, the Strategic Timing of AntiRetroviral Treatment (START) and TEMPRANO studies showed the benefit of ART at all CD4 counts – even when higher than 500. This led the World Health Organisation (WHO) to recommend that everyone with HIV should start treatment. South Africa has also recently adopted this “treat all” strategy, doubling the number of HIV-positive people eligible for treatment.

The WHO also decided to recommend one main first-line combination for everyone in low- and middle-income countries (LMIC) including South Africa. This is a single pill with efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and either emtricitabine (FTC), or lamivudine (3TC). This simplified first-line ART in low-and middle-income countries including South Africa.

This is a very good combination. It is good at reducing even high viral load and it has been used by millions of people for over ten years.

However, a newer combination might have fewer side effects and therefore might be better. It will also reduce viral load quicker and have less risk or drug resistance. This will use dolutegravir instead of efavirenz and a new version of TDF called TAF.

Will everyone switch to the new combination straight away?

Even though studies have already proven the advantages of the newer drugs, there are still some gaps in the studies. The needs of HIV-positive people are different in LMIC. This is because there are larger populations of women of childbearing age, children, and people with TB and other co-infections.

Data from using these newer drugs universally on these groups of people are not yet available. The studies that approved dolutegravir and TAF were run in high-income countries. Information about the dose and compatibility with other antiretrovirals were mostly gained from studies in men – and not from studies in women in countries like South Africa.

What are the new drugs and what studies are still needed?

Dolutegravir

The integrase inhibitor dolutegravir (DTG) has many properties that make it an important potential drug for use in LMIC:

It only needs a 50mg once-daily dose. This means pills can be much smaller and cheaper to produce.

It has a very high barrier to drug resistance.

It is good at reducing viral load quickly and keeping it undetectable.

It has few side effects.

It has the potential to be low-cost.

It is easy to co-formulate with other HIV drugs in a single pill.

DTG was superior to EFV in the so-called SINGLE () trial in people receiving first-line treatment. Other DTG studies have shown it to be superior – or non-inferior – to other commonly used antiretrovirals in high-income countries both in first- and second-line treatment. But DTG studies have not yet included significant numbers of people who would be treated in LMIC.

The main studies for DTG had approximately 80% men and few non-white participants. They enrolled very few people co-infected with other diseases (a few with hepatitis B and none with TB or malaria). People with drug resistance were not included (especially with resistance to NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors).

Information about treating HIV/TB coinfection with a DTG-based regimen is limited.

A Phase I study in HIV-negative people showed that the TB drug rifampicin lowers drug levels of DTG. This study suggested a higher DTG dose will overcome the interaction – ie. taking 50 mg twice a day rather than once a day. Another study will give results on this strategy later in 2016. Other studies are looking at drug levels in people with TB, they could show that the current 50mg once-daily dose might be okay, despite the lower levels.

Information about DTG in pregnant women is also limited – although this is always the case with every new HIV drug. Early results suggest DTG drug levels in pregnancy are similar to those in non-pregnant adults but that they are lower compared with postpartum.

A small number of women became pregnant in the DTG studies and early-use programme, and numbers of use during pregnancy will increase in high-income countries. So far only 10 first trimester and 18 second/third trimester exposures have been reported to the Antiretroviral Pregnancy Registry (APR) of 31 July 2015. From these data there were none and one congenital defect respectively.

Several studies are planned or ongoing to look at DTG use in pregnancy.

Tenofovir alafenamide (TAF)

TAF is a new version of tenofovir and has the potential to replace TDF.

It only uses a low dose (25mg as opposed to TDF at 300mg once-daily doses).

It has lower risk of bone and kidney side effects.

The lower dose should make it less expensive than TDF.

TDF is currently the major driver of cost in LMIC generic first-line combinations. The Clinton Health Access Initiative (CHAI) estimates that TAF could lower the cost of first-line ART by as much as 50%. In South Africa this would allow a US$160 million reduction on the annual cost of ART by 2018.

As with DTG, there is currently less information about TAF with TB treatment and during pregnancy. Very few studies have used TAF in combination with DTG.

There are no data yet on interactions between TAF and rifampicin, but a significant interaction is predicted. This comes from modelling drug interactions between TAF and carbamazepine.

A drug-drug interaction study in HIV-negative participants to look at the interaction between TAF and rifampicin is being planned, followed by a study in people with TB.

Other pending studies will look at using TAF during pregnancy, including one looking at DTG and TAF together in an ART regimen in pregnant women.

How studies in South Africa will help global treatment

One very important study will start this year in South Africa. This will provide important new results for both dolutegravir and TAF.

The study – called ADVANCE will include approximately 1050 HIV positive people to compare three combinations for first-line treatment.

  1. DTG/TAF plus FTC
  2. DTG/TDF plus FTC
  3. EFV/TDF plus FTC

 

The results will be used to decide whether DTG/TAF/FTC (or 3TC) becomes the preferred first-line in WHO guidelines.

The main results will be the proportion of people with undetectable viral load after 48 weeks, though the study will run for two years.

There will also be sub-studies that will help to address the potential issues with TB coinfection and with pregnancy.

These three study groups will clarify when dolutegravir and TAF are best used – including with each other.

The DTG/TDF/FTC arm is included in the case drug interactions between TAF and rifampicin result in different side effects or in cases there are difference in pregnant women. Having data to support DTG use with TDF will still be able to show benefits over current standard of care.

The efavirenz group is the current standard of care in first-line in all LMIC. FTC and 3TC are interchangeable in almost all guidelines. Because this combination has been so widely used, the WHO needs a large new study to prove whether newer drugs are better before guidelines can be changed.

If successful, at least one generic manufacturer has already agreed to produce the new DTG/TAF/FTC FDC at a lower price than EFV/TDF/FTC.

Other future ARVs and strategies

Several other exciting advances might offer new options for treatment.

The first of these is the potential for ART to be given by long-acting (LA) injections rather than daily pills.

This research has always created a lot of interest and two drugs in late stage development show this can work. The two drugs are a new integrase inhibitor called cabotegravir LA and NNRT called rilpivirine LA. Both drugs have produced good results as oral drugs. Both are combined into the same dual injection, which only needs to be given every two months.

There are a few important cautions to be aware of.

The first is that the injection needs quite a large volume. Currently each treatment needs several injections into the buttocks. Even though most people reported discomfort from the injection, overall people in studies were happy with results compared to taking pills.

Secondly, these drug stay in the body for a long time. This makes it important to start with oral medication in case someone has serious side effects.

Thirdly, we need to understand how to safely stop long-acting drugs in order to minimise the chance of drug resistance. This will be especially important if there are problems with drug supply.

The following three drugs are also worth watching out for:

A new entry inhibitor (called fostemsavir).

A drug from a new class – a maturation inhibitor – currently called BMS-955176.

Very early results from a compound called EFdA. This drug might be available from a slow release deport that only needs to be replaced once a year.

Finally, tentative results from several small studies suggest that the properties of dolutegravir might enable this drug to be used in a unique way.

Early results reported that some people might be able to reduce their combination to a two-drug combination of dolutegravir plus 3TC. Even more surprising was that most people kept their viral load undetectable for up to six months after switching to dolutegravir as a single drug.

Together with the discussions earlier in this article on the cost of ART and the importance of wider access to ART, if larger studies show this reduced drug strategy to be safe, this will have global implications for how ART is used.

This could result in better treatment, using fewer drugs and which is therefore also less expensive. But this definitely needs further research before anyone tries this outside of a study.

Polly Clayden is the Co-founder of i-Base and an advocate, activist and journalist.

Simon Collins is a Treatment Advocate and co-founder of HIV i-Base.

 

A cure for HIV: Are we getting any closer?

By – Dr Thomas A. Rasmussen & Professor Sharon R. Lewin

Antiretroviral therapy (ART) has revolutionised the lives of people living with HIV and in many countries, life expectancy for someone living with HIV is now almost the same as someone not living with HIV. But ART is not a cure.

When ART is stopped, the virus rebounds within a few weeks in almost all infected individuals, even after many years of suppressive therapy. Understanding where and how HIV persists on ART and using these insights to develop therapies, which will ultimately enable us to cure HIV infection, or allow people living with HIV to safely stop ART with the virus staying under control, remain key goals in HIV research.

Over the past decade, there has been a substantial increase in our understanding of where and how HIV persists when someone is on ART. It is now clear that integration of the HIV genome into long-lived resting cells is a major barrier to a cure. This state is called HIV latency. But virus can also persist on ART in other forms. In both monkey models of HIV and in HIV-infected individuals on ART, virus has been found in T follicular helper cells, which are found in a specialised compartment in the lymphoid tissue. These cells are found in a part of the lymph node where penetration of immune fighting cells, or cytotoxic T-cells is limited. In some tissues, penetration of ART may not be optimal, which could also contribute to persistence. Finally, there is also some evidence that, in at least some individuals and in some sites, the virus may still be replicating at very low levels.

To date, there has been just one case of a cure for HIV, which occurred in the context of haematopoietic stem cell transplantation (HSCT) for leukaemia with HIV-resistant donor cells. HSCT is clearly not a feasible curative strategy for HIV, but we have learnt here that complete eradication of HIV is theoretically possible. Similar approaches have been tried, but no others have yet been successful and all six individuals receiving a similar transplant died of infection or cancer relapse within 12 months of transplantation.

Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte. This image has been coloured to highlight important features.
Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte. This image has been coloured to highlight important features.

Other case reports have confirmed that HSCT, even from a regular stem cell donor, can drastically reduce the frequency of infected cells, but when ART was subsequently discontinued, virus still rebounded off ART, although it took months and not weeks to rebound. These cases demonstrate that although reducing the frequency of latently infected cells might delay time to viral rebound, there is a need for continued effective immune surveillance against HIV to keep whatever remains in check.

Using gene therapy to either make a cell resistant to HIV or to literally remove HIV from the cell is now being actively investigated. The initial target of gene therapy was CCR5 – the same gene that is missing in some rare individuals that are naturally resistant to HIV. Clinical trials of gene therapy to eliminate CCR5 and make cells resistant to HIV was safe, but there remains much work to be done to increase the numbers of gene-modified cells. Other work, which still is at the stage of test-tube experiments, uses gene scissors to target the virus itself. This approach might be trickier than targeting CCR5 as the virus can rapidly mutate and change its genetic code so that the gene scissors no longer work.

By starting ART very early – within days to weeks of infection – it is possible to substantially reduce the number of latently infected cells, and this also helps preserve immune function. Although not an option for the majority of HIV-infected individuals who are diagnosed too late, early diagnosis and treatment could be an effective strategy to maintain immune control for some patients. Several years ago, French investigators described that post-treatment control was possible in up to 15% of individuals treated within months of infection. These data remain a little controversial as in other cohorts, post-treatment control is far less common. We still don’t fully understand what factors are important for post treatment control, but it seems that the nature of the immune is critically important. Interestingly, post-treatment control may differ in different ethnic groups. A recent report from Africa suggested that post-treatment control could occur at far higher frequencies in African populations than in Caucasians.

Early treatment of HIV-infected children at birth may also present an opportunity to induce post- treatment control. In the highly publicised case of the Mississippi child, ART was started 30 hours after birth and following cessation of ART at age 18 months, this child had a period of 2 years of post-treatment control. Early treatment of infants may potentially shift virus from hiding in long-lived to short-lived T-cells. Therefore, understanding the differences in where virus persists in children and in adults could provide important insights into novel strategies to find a cure for HIV. We will hear a lot about these approaches in Durban.

The reality is that most people globally are diagnosed with HIV years and not days after infection. The main strategies being tested to achieve remission is to reduce the amount of persistent virus and also boost the immune response to allow for long term control.

Activating the expression of HIV proteins in latently infected cells by drugs called latency-reversing agents could drive elimination of virus-expressing cells through immune- or virus-mediated cell death. This approach is usually referred to as “shock and kill”. A substantial body of research has helped identify latency-reversing agents including histone deacetylase inhibitors and disulfiram, which have now been tested in experimental clinical trials. These studies demonstrated that although HIV expression can be induced in patients on suppressive ART, this did not reduce the frequency of infected cells. In other words, shock but no kill.

On-going studies are looking at ways to augment the killing of these cells by boosting the immune system, for example through vaccines or medications that trigger suicide of the infected cells. Cure research is likely to benefit from the very significant investment in vaccines that have been developed to protect people from getting infected, some of these vaccines could work in cure too – for example vaccines that potently stimulate cells that are programmed to kill infected cells or alternatively highly effective antibodies, called broadly neutralising antibodies, that can also trigger killing of an infected cell. These vaccines are now being investigated in the setting of clinical trials in infected individuals on ART.

There have been some spectacular recent advances in the treatment of some cancers using drugs that boost the immune response – called immune checkpoint blockers.

These drugs reinvigorate exhausted T-cells so they can move in to action – against cancer cells and in the same way, against HIV-infected cells. These drugs, one that blocks CTLA4 and another that blocks PD1 are now in clinical trial in HIV-infected patients being treated for different cancers. Another way to boost the immune system is to trigger a very primitive immune response designed to respond to infections. These drugs are called toll-like receptor (TLR) agonists. In monkeys, TLR-7 agonists, currently being developed by Gilead, stimulate latently infected cells and an effective immune response leading to a modest reduction in infected cells. Clinical trials are now underway in HIV-infected individuals on ART.

 

Now, four years after the launch of the 2012 International AIDS Society (IAS) Global Scientific Strategy Towards and HIV Cure, we have had some successes and failures. We now have a clearer idea of where virus persists on ART, but still much to learn about different T-cell subsets and what happens inside tissue. We need better ways to measure total virus, especially virus that can rebound. Some advances in X-Ray imaging might help here, which could give a total snap shot of where the virus is sitting in the body. We also now know that activating latent virus is not enough to kill the cells. Other interventions are needed. A successful strategy will likely need two components – reducing the amount of virus that persists on ART and improving long-term immune surveillance to target any residual virus. We need far more work to be done on HIV cure in low income settings to better understand the effects of different HIV strains, the effects of co-infection and the impact of host genetics. Lessons from other fields, particularly oncology, transplantation and fundamental immunology, are all relevant to inform the next advances we need in cure research. Finally, we have to ensure that any intervention leading to a cure must be cost effective and widely available.

The implementation of combination ART in the mid-1990s is still regarded one of the most remarkable achievements in modern medicine. Life-long ART remains the single best option for any person infected with HIV. Finding a cure for HIV remains a major scientific challenge but many believe it to be within the realms of possibility and it will hopefully play an important role in seeing an end to HIV.

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*DR Thomas A. Rasmussen is a Clinical Research Fellow at the Doherty Institute

*Professor Sharon R Lewin is the Director of the Doherty Institute for Infection and Immunity and Professor at the University of Melboune

Is HIV elimination a pipe dream?

 by Dr Leigh Johnson –

 

A number of UNAIDS publications have promoted the idea that it is possible to “end the AIDS epidemic by 2030”. There are several encouraging signs to suggest that this may be true. It is now well-established that patients who are on antiretroviral treatment (ART) and with suppressed viral loads are virtually non-infectious.With the recent revisions to WHO treatment guidelines, which now recommend ART for all HIV-positive individuals regardless of CD4 count or clinical stage, it is theoretically possible that a high proportion of HIV-positive individuals will be treated. This could drive down HIV transmission rates to very low levels. UNAIDS has stated that critical to HIV elimination will be the achievement of the ‘90-90-90’ targets: by 2020, 90% of the HIV-positive population needs to be diagnosed, 90% of diagnosed individuals need to be on ART, and 90% of patients on ART need to be virologically suppressed.

But how likely is HIV elimination? Central to answering this question are mathematical models, which attempt to predict the future based on observed historical trends in HIV prevalence, and based on assumptions about the effect of different HIV prevention and treatment strategies on HIV transmission. This article briefly reviews some of the recent modelling studies that have attempted to answer this question, and discusses some of the limitations and uncertainties associated with modelling.

The first point to note is that the term ‘HIV elimination’ is a misnomer. Most frequently, modelling studies refer to ‘virtual elimination’, which is conventionally defined as an adult HIV incidence rate of less than 0.1% per annum. But even if HIV incidence among 15-49 year olds were constant at 0.1% per annum, the long-term HIV prevalence in 15-49 year olds would not drop below 1.7% (assuming a relatively high ART coverage and a near-normal life expectancy on ART). This is still an appreciable HIV prevalence, even by the standards of many countries in West Africa.

Even if we accept this definition of HIV elimination, mathematical models are not conclusive about whether universal ART eligibility and high rates of HIV testing and ART uptake (so-called ‘test and treat’ strategies) would lead to elimination. In a systematic comparison of several different models that were applied to South Africa, Eaton et al found that out of nine models, six suggested that ‘test and treat’ strategies would not be sufficient to achieve virtual elimination by 2050. Notably, the models were generally quite optimistic about the extent to which ART would reduce HIV infectiousness (in all cases by 90% or more), though a subsequent systematic review of observational data estimated an average reduction of only 64%. It was also subsequently found that almost all the models had under-estimated the HIV prevalence that was measured in a South African household survey, conducted after the initial model projections were published. Although this points to the fallibility of mathematical modelling, it is perhaps more important to note that the models generally did not show that HIV elimination was a likely outcome, despite erring on the side of optimism.

A question that naturally follows is whether a ‘test and treat’ strategy might achieve HIV elimination when combined with other HIV prevention strategies. In a recent study, we attempted to address this question for South Africa by projecting future HIV incidence trends using a wide range of different intervention scenarios. This study predicted that – given the current uncertainty around HIV prevention and treatment programmes in South Africa – the virtual elimination target of 0.1% would be reached by 2035 in only 2% of scenarios (Figure 1). The model also predicted that although South Africa would probably reach the first 90% target by 2020, the second and third 90% targets were quite unlikely: in only 0.4% of scenarios were all three targets met.

Figure 1: HIV incidence trends in South African adults aged 15-49
Figure 1: HIV incidence trends in South African adults aged 15-49

Solid lines represent mean of model estimates. Dashed lines represent 95% confidence intervals (taking into account uncertainty regarding future epidemiological parameters). Shaded grey area represents virtual elimination threshold. Source: Johnson et al

This study also assessed which epidemiological parameters it would be most important to focus on in order to reduce HIV incidence. The most important parameter was the rate of virological suppression in ART patients: for every 10% increase in the fraction of ART patients who are virologically suppressed, it was predicted that there would be a 14% reduction in the average annual number of new HIV infections. This implies that increasing rates of virological suppression in South African ART patients from the current level of around 77% to the 90% target would achieve an 18% reduction in HIV incidence. Other parameters that were significant included the rate of condom use in non-cohabiting relationships, the introduction of intensified risk-reduction counselling for HIV-positive adults, and the uptake of medical male circumcision. Interestingly, the timing of the change to universal ART eligibility was only the 5th-most important parameter. This suggests that the recent change to universal ART eligibility is not by itself likely to have as dramatic an impact on HIV incidence as many other interventions.

The case of South Africa stands in stark contrast to the case of Denmark, the subject of another recent modelling study. In this study, it was estimated that in 2009 the HIV incidence among Danish men who have sex with men (MSM) was 0.14% per annum, very close to the virtual elimination threshold of 0.1%. Although the fraction of HIV-positive adults in Denmark who were diagnosed was very similar to that estimated in South Africa (around 80% in 2013), the fraction of diagnosed individuals on ART was 92%, and the fraction of ART patients who were virologically suppressed was 98% – both well ahead of South Africa (Figure 2).

Figure 2: Treatment cascades in Denmark and South Africa in 2013
Figure 2: Treatment cascades in Denmark and South Africa in 2013

As the authors of this study note, Denmark is exceptional. In many other high income countries, there has been a resurgence in HIV incidence among MSM, despite increasing levels of ART coverage. This resurgence is often attributed to risk compensation and ‘disinhibition’, i.e. increased levels of sexual risk behaviour due to reduced fear of HIV in the era of highly effective therapy – and perhaps also reduced public messaging around safe sex as the HIV response has become increasingly medicalised.

Taken together, these results suggest that treatment alone is not going to end the HIV epidemic, although it might be possible in concentrated epidemic settings with exceptionally high levels of virological suppression. It will be important not to neglect the ‘traditional’ HIV prevention strategies in the pursuit of the 90-90-90 targets, and the allure of new prevention approaches should not detract from the need to sustain and improve existing programmes. But even with co-ordinated strengthening of existing programmes and introduction of new prevention approaches (such as universal ART eligibility and pre-exposure prophylaxis), it is unlikely that virtual elimination will be achieved in hyper-endemic settings such as South Africa within the next 20 years. Even if ‘elimination’ is achieved, there would need to be continued high levels of HIV testing and HIV prevention messaging over the longer term if a resurgence in HIV were to be avoided. Achieving true elimination will require fundamentally new technologies such as HIV vaccines. Until we have these in place, HIV elimination needs to be seen as an aspirational ideal rather than a practical target.

DR Leigh Johnson is a Researcher at the Department of Public Health & Family Medicine for the University of Cape Town.