Benefits of dolutegravir treatment for all substantially outweigh the risks

Providing an antiretroviral regimen of dolutegravir, tenofovir and lamivudine to all adults living with HIV in sub-Saharan Africa, regardless of viral suppression or plans to have children, would prevent more ill health than policies which restricted use of the regimen in women of childbearing potential or people with suppressed viral load, a modelling study published in The Lancet HIV shows. Moreover, it would be cost saving.

Antiretroviral treatment based on the integrase inhibitor dolutegravir is recommended by the World Health Organization as the preferred option for first-line treatment of all adults in low- and middle-income countries. Dolutegravir is recommended because the drug has few side-effects, is highly potent and has a high barrier to the development of resistance mutations if viral load should rebound.

Another important reason for recommending dolutegravir is that the drug is available in a low-cost generic form in many lower-income countries as result of a licensing agreement between the Medicines Patent Pool and the drug’s developer ViiV Healthcare. The Medicines Patent Pool has licensed dolutegravir to several manufacturers of generic antiretroviral products for incorporation into fixed-dose combination tablets with tenofovir DF and lamivudine.

In September 2017 the Bill and Melinda Gates Foundation announced that it will guarantee minimum sales volumes to two Indian manufacturers, Aurobindo and Mylan Laboratories, for a combination of dolutegravir, tenofovir and lamivudine sold at a cost of $75 a year to ministries of health and public-sector purchasers. The combination is available at this price in 92 countries. Many countries in sub-Saharan Africa have been making plans to introduce dolutegravir and lamivudine as a universal first-line regimen, simplifying the delivery of treatment.

But despite the recommendations and the improved affordability of dolutegravir, there is still uncertainty over how best to make the drug available in some countries.

Potential barriers to universal use of dolutegravir in first-line treatment

Two concerns have arisen about the use of dolutegravir in first-line treatment. The first relates to the risk of neural tube defects in infants exposed to dolutegravir at conception or in early pregnancy. A study in Botswana detected a significantly higher rate of neural tube defects in infants of mothers who had been taking dolutegravir at the time of conception, compared to other antiretroviral therapy (ART) regimens. As the overall number was small, investigators said that they would continue to monitor this safety signal.

Since that safety signal was reported, the World Health Organization has advised that countries introducing dolutegravir-based ART should ensure that reliable and consistent contraception is available for all women of child-bearing potential, and where that is not possible, women should be offered an alternative efavirenz-based regimen. But some African countries have gone further, and decided that for the time being, women of childbearing age will start treatment with an efavirenz-based regimen, regardless of contraceptive availability.

The second concern is about switching to dolutegravir in the absence of viral load testing. The World Health Organization recommends that people already taking another first-line regimen can be switched to dolutegravir, tenofovir and lamivudine if they have a viral load below 1000 copies/ml. However, if the regimen is failing and the individual has a higher viral load, resistance to lamivudine and tenofovir is likely to be present, weakening the antiviral potency of dolutegravir-based regimen. If the new regimen fails to suppress viral load, and keep it suppressed because of resistance to tenofovir and lamivudine, the consequence could be the development of resistance to dolutegravir too. That would remove the option of using dolutegravir in second-line treatment and require the use of a more expensive protease inhibitor instead.

Modelling the options for dolutegravir introduction

To look at the potential trade-offs between introducing dolutegravir as a universal first-line regimen – or restricting its use to specific groups of people – an international group of researchers led by Professor Andrew Phillips at University College London, used an existing model (HIV Synthesis Model).

The model evaluated the population-level risks and benefits of five strategies:

• Tenofovir, lamivudine and efavirenz for all
• Tenofovir, lamivudine and dolutegravir for all
• Tenofovir, lamivudine and dolutegravir, excluding women intending to have children
• Tenofovir, lamivudine and dolutegravir, excluding people switching from a first-line regimen with viral loads above 1000 copies/ml 
• Tenofovir, lamivudine and dolutegravir, excluding women intending to have children and people switching from a first-line regimen with viral loads above 1000 copies/ml.

The model assumed that only 16% of women aged 15-55 years would intend to have no children, that dolutegravir is 1.5 times more potent than efavirenz and that resistance to dolutegravir developed at a rate 13 times lower than for efavirenz. Neurological toxicity on dolutegravir would occur at half the rate of people taking efavirenz.

Key findings

If people with viral loads above 1000 copies/ml on an existing first-line regimen and women intending to have children were excluded from dolutegravir treatment, only 43% of adults living with HIV would receive dolutegravir over a 20-year period. If only women intending to have children were excluded from dolutegravir treatment, 54% would receive the drug.

Over 20 years, the most restrictive dolutegravir prescribing guidelines would result in 4% fewer people having a viral load below 1000 copies/ml than with a universal dolutegravir policy, but the death rate in people on ART would be almost twice as high (1.25 deaths per 100 person-years vs 0.72 per 100 person-years).

Looking at adverse birth outcomes, the modelling found that neural tube defects would occur in 0.6% of births under a policy of universal dolutegravir prescribing, compared to 0.03% of births if women intending to have children were excluded from receiving dolutegravir. But because of the greater potency of dolutegravir and better viral suppression, the rate of mother-to-child transmission would be lower under a universal dolutegravir policy than if all restrictions applied (2.8% versus 3.9%).

Looking at the development of dolutegravir resistance – the rationale for the policy of restricting first-line switches to those with a viral load below 1000 copies/ml – the modelling showed that 6.7% of people over a 20-year period would have dolutegravir resistance (transmitted or acquired) under a universal policy. In comparison, 4.4% would have resistance under the policy of restricting first-line switches.

The universal dolutegravir regimen averted the largest number of disability-adjusted life years (DALYs) per year (58,200), compared to 22,300 for the most restrictive policy. DALYs measure the amount of life lost in a population as a result of premature death or disability.

For a country of 10 million people, all the dolutegravir regimens would save between $5 million and $10 million a year, with the greatest saving associated with the universal dolutegravir regimen.

The universal dolutegravir policy showed an incremental cost-effectiveness ratio of $44 compared to tenofovir, lamivudine and dolutegravir when restricted to people with viral load below 1000 copies/ml. All other policies showed fewer DALYs averted and higher cost and were therefore dominated.

The researchers say that the findings can be used to inform the development of national policies on dolutegravir use and that the views of people living with HIV on the risks and benefits identified in this analysis should also be sought as part of the national policy development process.