The future of antiretroviral treatment

The future of  antiretroviral treatmentBy Polly Clayden & Simon Collins - We are in a very exciting time for HIV treatment (ART) for three reasons.

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?


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.