A better first line?

A new study is being planned for South Africa. The results from the study could change first-line treatment here and in other low- and middle-income countries.

What are the new drugs that will be studied?
For first-line HIV treatment, South African, World Health Organisation (WHO) and many other national guidelines currently recommend a fixed dose combination (FDC) of efavirenz (EFV) plus tenofovir diphosphate fumarate (TDF) plus emtricitabine (FTC).

Dolutegravir
Dolutegravir (DTG) is a new drug from the integrase inhibitor class. It has a low 50 mg once-daily dose, a very high barrier to resistance, good efficacy, minimal toxicity, and the potential to be low-cost and co-formulated. DTG could replace EFV as preferred first-line in South Africa, as it has in some high-income countries. In previous studies, DTG was superior to EFV at 48 weeks in people taking first-line ART (and remained so at 96 weeks). At 48 weeks fewer people stopped treatment due to side effects in the DTG group than the EFV group (2 percent vs 10 percent). Rash and central nervous system side effects, frequently associated with EFV, were more common in the EFV group.

Data from this comparison and from studies comparing DTG to raltegravir (RAL) and in people with resistance to other integrase inhibitors, were used to gain approval in adults and adolescents aged 12 and above in the US and Europe. DTG studies have not yet included significant numbers of people who would be treated in low-and middle-income countries. The registrational studies for DTG had approximately 80 percent men and few non-white participants. Hardly anyone in the studies was co-infected with other diseases (a few with hepatitis B and none with TB or malaria). There is not much information about treating HIV/TB coinfection with a DTG-based regimen. It is likely that 50 mg twice-daily dosing of DTG will be required when it is given with TB treatment to overcome drug-drug interactions. As yet information about DTG in pregnant women is scarce. For DTG to be recommended in South Africa, more information is needed on how it is likely to perform in real world, low- or middle-income settings.

Integrase inhibitors

During the HIV life cycle, its RNA is converted into DNA by the reverse transcriptase enzyme (and nucleoside/nucleotide reverse transcriptase inhibitors, or NRTIs, work by blocking this process). Once reverse transcription of RNA into DNA is done, HIV DNA must be integrated into the CD4 cell’s DNA. Integrase inhibitors work by blocking integration. Perhaps viral lifecycle picture? We have one here: http://i-base.info/hiv-life-cycle/
Raltegravir is the only integrase inhibitor that is available in the South African public health system at the moment. It is only recommended for third-line treatment. It is expensive and needs to be taken twice a day.

Tenofovir alafenamide fumarate
Tenofovir disoproxil fumarate (TDF) – the current formulation of tenofovir – is recommended globally as part of first-line treatment and used widely in high-, low- and middle-income settings. The downside of TDF is its potential for kidney and bone toxicity. There are limits to the lowest possible price of TDF with the current formulation, due to its high milligram dose (300 mg). Gilead Sciences (the originator manufacturer) has developed a new version of tenofovir: tenofovir alafenamide fumarate (TAF).

TAF is not yet approved but it has been submitted to the FDA and EMA as part of an FDC (with a different integrase inhibitor to DTG) and co-formulated with FTC.
Both TDF and TAF are prodrugs of tenofovir. TAF doses are one tenth or less than that of TDF and give levels of tenofovir in cells, which are four to seven times higher and blood plasma concentrations that are 90 percent lower than those with TDF.

It is possible that the reduction in blood plasma concentrations with TAF could mean less tenofovir accumulation in bone and kidneys and, in turn, fewer bone and kidney associated toxicities compared with TDF. The studies that the originator company has conducted to gain approval for TAF (and that are ongoing) will not give sufficient information to recommend TAF with DTG in a setting such as South Africa. That is why independent investigators in South Africa plan to establish this evidence.

What is the design of the study?
In order to justify widespread use of TAF 25mg/FTC/DTG as first-line treatment for millions of people worldwide, the efficacy and safety of this combination will be compared with a recognised standard of care. A TDF/FTC/ DTG regimen is a preferred regimen in the US Department of Health and Human Services (DHHS), International Antiviral Society-USA and European AIDS Society guidelines.

The study will randomise 600 HIV-positive, treatment-naive people to a 96-week, non-inferiority comparison. The treatment arms will be:
Arm 1 (Experimental): TAF25mg/FTC/DTG
Arm 2 (Control) TDF/FTC/DTG

The study will compare the proportion of people in each arm with viral load less than 200 copies/mL at week 96. If this is similar (the margin is specified before the study starts), then the experimental arm is considered to be non-inferior to the control arm.

The study will also look at the results at 48 weeks and at viral load less than 50 copies/mL.
The study will enrol a substantial number of women – who will not be excluded if they become pregnant during the study – and include people on TB treatment.

Why is there no EFV arm?
As the current standard of care is TDF/XTC (either FTC or 3TC)/EFV 600 mg, why does the study not compare the new regimens to this one?
Other studies have shown that DTG is better than 600 mg EFV. The study is designed in the context of studies that are ongoing or in the planning stage. Another study is looking at DTG/TDF/XTC vs 400 mg EFV/TDF/XTC. This study is focused on demonstrating TAF versus TDF.

Will the trial use FDCs?
There are not yet FDCs of the new regimens. The study will use dual formulations – TAF/FTC and TDF/FTC – and a single DTG. Both arms will have the same number of pills – two, once daily. Generic companies are planning to develop FDCs.

Will the new FDC be cheaper?
The reduced dose overall means potentially considerable reductions in generic prices. It will also mean smaller tablet sizes.
DTG 50 mg /TAF 25 mg /FTC 200 mg gives a total daily dose of only 275 mg, which is a considerable reduction from EFV 600 mg/TDF 300 mg/ FTC 200 mg with a total of 1 100 mg.