Is It Time for Two-Drug Regimens?

The 10th IAS Conference on HIV Science in Mexico City, Mexico, provided a significant amount of new data regarding the efficacy and safety of the innovative paradigm of dual ART. In the first-line setting, we now have long-term data on dual therapy with dolutegravir (DTG)/lamivudine (3TC) from the phase III GEMINI studies. In the switch setting, we now have 48-week efficacy and safety data in individuals switching from a tenofovir alafenamide–based regimen in the phase III TANGO study.

I expect the positive outcomes of these studies will soon affect international guidelines.

Dual Therapy in Current Guidelines
Most international HIV guidelines, such as the DHHS, IAS-USA, and EACS guidelines, currently limit their recommendation for DTG/3TC dual therapy to individuals for whom tenofovir or abacavir (ABC) is not feasible.

Part of the reason for this limitation is the limited amount of long-term data, although new Week 96 data from the GEMINI studies is changing that. In addition, some have pointed to potential lower efficacy in individuals with advanced HIV. And the current WHO guidelines actually exclude DTG/3TC, perhaps because of a higher risk of transmitted 3TC resistance (M184V) and higher prevalence of chronic hepatitis B in developing countries.

Here, I present my thoughts on some of these cases.

Advanced HIV
The GEMINI studies provided strong data regarding the noninferiority of DTG/3TC vs DTG + emtricitabine/tenofovir disoproxil fumarate in individuals with high HIV-1 RNA. However, DTG/3TC efficacy at Week 96 was lower in the subpopulation of individuals with CD4+ cell counts < 200 cells/mm³ at study entry (HIV-1 RNA < 50 copies/mL: 68% vs 87%). Of importance, this difference may have been due to loss of follow-up rather than efficacy issues, as the rates of virologic failure were similar in both study arms.

Chronic Hepatitis B Virus (HBV) Infection
Although universal HBV vaccination programs are having an important impact, the global prevalence of hepatitis B surface antigen (HBsAg) remains high, with prevalence rates exceeding 8% in some regions. And if 3TC is the only HBV active drug administered to individuals with chronic HBV and HIV coinfection, then the risk of resistance reaches 90% at 4 years. Therefore, current guidelines recommend using tenofovir or entecavir in addition to 3TC in these patients—receiving only a single HBV drug as part of dual therapy with DTG/3TC would not be enough. 

Until more information is available, international guidelines continue to recommend assessing HBsAg status before starting treatment with DTG/3TC. Luckily, there is a rapid test for HBsAg that can provide point-of-care results in a few minutes.

3TC Resistance
Some guidelines also recommend performing HIV resistance testing before using dual therapy. In an individual with the M184V mutation and receiving DTG/3TC dual therapy, DTG would be the only active drug—it would effectively act as DTG monotherapy, which we know should be avoided.

However, the global prevalence of M184V is very low and is decreasing in most settings, with values approximately 1% in most countries. Given this very low prevalence, some experts suggest that (as for INSTIs), it may not be cost-effective to routinely screen for 3TC resistance prior to starting DTG/3TC.

Moreover, if the turnaround for resistance testing is short, samples can be obtained at baseline and an initial regimen of DTG/3TC can be switched out later if necessary. For switching suppressed individuals, the TANGO study provides information supporting the use of DTG/3TC if the person has no previous virologic failure or evidence of NRTI or INSTI resistance.

Your Thoughts?
Would you consider two-drug regimens for most patients in your practice or for just a select few? Answer the polling question and add your thoughts to the discussion section.

Then, to hear me and other HIV experts discussing dual ART and other innovative paradigms for ART, see our CME-certified video and read our response to frequently asked questions.