Can dolutegravir dual therapy or monotherapy produce and maintain HIV suppression?

The potent integrase inhibitor dolutegravir taken with a single well-tolerated NRTI was able to fully suppress viral load in people initiating antiretroviral treatment for the first time, while dolutegravir alone was able to keep HIV suppressed in most treatment-experienced people who started with undetectable viral load, according to a set of studies presented yesterday at the 15th European AIDS Conference in Barcelona, Spain.

After these presentations, experts offered evidence in favour of and opposed to simplifying treatment by reducing drug burden, disagreeing about whether this strategy is beneficial or too risky.

As people living with HIV continue to face decades on treatment, researchers have attempted to find regimens that are better tolerated, simpler and easier to take. Non-standard antiretroviral therapy (ART) may be especially beneficial for heavily treatment-experienced patients with drug-resistant virus and those who cannot tolerate drug side-effects. Using a single potent drug alone would reduce pill burden and toxicities, but protease inhibitor monotherapy studies to date have yielded conflicting results.

ViiV Healthcare's integrase inhibitor dolutegravir (Tivicay, also in the Triumeq single-tablet regimen) has demonstrated potent antiviral activity – reducing viral load by an impressive 2.5 log₁₀ in an early 10-day monotherapy study – and a high barrier to resistance, making it an attractive prospect for streamlined therapy. It is well-tolerated and does not have the toxicities and drug-drug interactions seen with the protease inhibitor class.

Pedro Cahn of Fundación Huésped in Buenos Aires, Argentina, and fellow investigators with the PADDLE study evaluated a two-drug regimen for initial treatment consisting of dolutegravir plus lamivudine (Epivir or 3TC). Lamivudine is an inexpensive, well-tolerated nucleoside reverse transcriptase inhibitor (NRTI) with minimal side-effects and no known drug interactions, though it has a low barrier to resistance.

This pilot study enrolled 20 treatment-naive participants (people who had not taken treatment before) with low baseline viral load and no NRTI resistance mutations. All but one of the participants were men and the median age was 34 years; people with hepatitis B co-infection were excluded. The median baseline viral load was just over 24,000 copies/ml – though four participants had more than 100,000 copies/ml – and the baseline CD4 count was approximately 400 cells/mm³.

All participants were treated with 50mg dolutegravir plus 300mg lamivudine once daily for 48 weeks. To ensure safety, the first 10 participants were evaluated at 8 weeks before the next 10 started therapy. Stopping rules called for treatment discontinuation if a participant did not achieve at least 1 log₁₀ reduction in viral load by week 8 or had HIV RNA still above 1000 copies/ml at week 12 or above 400 copies/ml at week 24. Cahn presented results from a pre-planned analysis at 24 weeks.

Viral load declined rapidly after starting therapy, falling by a median -2.54 log₁₀ by day 14. All participants – including the four with high baseline viral load – had HIV RNA below 400 copies/ml at week 3 and below 50 copies/ml from week 8 onward. The average CD4 cell gain was approximately 200 cells/mm³. Treatment was well-tolerated with no serious adverse events or grade 3-4 laboratory abnormalities.

"In this pilot, proof-of-concept study, dual therapy with dolutegravir plus lamivudine induced rapid virologic suppression with a favourable safety/tolerability profile in HIV-1 infected, treatment-naive individuals," the researchers concluded.

This dual regimen could offer lower cost, reduced toxicity and smaller pill burden, Cahn said. He noted that follow-up in the pilot study will continue through 96 weeks and a larger randomised clinical trial is currently in preparation. Asked if he agreed that the trial should be limited to people with low baseline viral loads, he said he thought it should take "all comers" given that this regimen appeared to work well even for those with higher levels.

Two studies presented at the same session looked at dolutegravir monotherapy as a maintenance option for people with viral suppression on other regimens. Both studies enrolled heavily treatment-experienced patients, many of whom had extensive drug resistance and were on non-standard regimens.

Esteban Martínez of the University of Barcelona and colleagues evaluated the feasibility of dolutegravir monotherapy for people with limited therapeutic options due to toxicity, drug interactions or drug resistance.

This analysis included 33 participants with sustained viral suppression (<37 copies/ml) on their current ART regimen and no known history of virological failure or evidence of resistance to integrase inhibitors. More than half (55%) were women and the median age was 56 years.

Participants had been diagnosed with HIV for a median of 19 years and nearly 40% had a history of AIDS, but the current median CD4 count was high at about 600 cells/mm³. At baseline, they had been on suppressive ART for a median of 8 years. Two-thirds were taking protease inhibitors – mostly ritonavir-boosted darunavir (Prezista) monotherapy – while about a quarter were on NNRTI-based regimens.

All participants in this pilot study switched from their current regimen to 50mg once-daily dolutegravir monotherapy. Asked why they didn't add lamivudine, Martínez said most participants had the M184V resistance mutation.

Participants were eligible to switch due to any two or more of the following factors: ART-related adverse effects (76%), co-morbidities incompatible with antiretroviral toxicities (97%), risk of drug interactions (85%) or resistance mutations compromising treatment efficacy (48%). Specific reasons included drug interactions (13 people), gastrointestinal symptoms (11), abnormal blood lipids (9), osteoporosis (6), high cardiovascular risk (4) and progressive kidney disease (1).

At 24 weeks, 97% of participants – all but one – maintained viral suppression. One person with extensive treatment experience and multiple resistance mutations had confirmed virological failure after 4 weeks (88 and 155 copies/ml). He was advised to increase his dolutegravir dose to 50mg twice daily, but he opted to continue once-daily therapy and still had low-level detectable viral load at 24 weeks. HIV RNA genotypic testing detected no integrase resistance mutations, but DNA genotyping revealed the 118R mutation in integrated DNA in T-cells.

Treatment was generally well-tolerated with no drug discontinuations, serious adverse events related to dolutegravir or drug interactions. Gastrointestinal symptoms improved, blood lipid levels decreased in all nine people with abnormal levels and three people with high cardiovascular risk saw decreased risk scores.

The researchers concluded that "Dolutegravir monotherapy proved feasible and showed short-term efficacy and tolerability in suppressed patients with limited therapeutic options."

An open-label randomised clinical trial is now in the works that will compare staying on a current ART regimen versus switching to dolutegravir monotherapy or dolutegravir plus lamivudine.

Christine Katlama of Pitié-Salpêtrière Hospital in Paris, France, and colleagues conducted a similar study of once-daily dolutegravir monotherapy in treatment-experienced patients with viral suppression. Her team and the Spanish group did not jointly plan their studies but rather "had the same idea at the same time," she said.

This observational study enrolled 28 people with undetectable viral load (<50 copies/ml) for at least 12 months and no history of prior integrase inhibitor failure. Just over half were men, the median age was 48 years and the media CD4 count was 624 cells/mm³. HIV DNA levels in T-cells were relatively low.

Participants had been diagnosed with HIV for a median of 20 years, on ART for 17 years and virally suppressed for nearly 7 years; 90% had used protease inhibitors and almost half had used integrase inhibitors. At baseline, 36% were on three-drug regimens, 32% were on dual regimens and 32% were on boosted darunavir monotherapy.

At week 24 after switching therapy, 89% of participants (25 out of 28) maintained undetectable viral load <50 copies/ml, and all but one also had <20 copies/ml. One person discontinued dolutegravir monotherapy.

There were three cases of virological failure, with viral loads of 291, 469 and 2220 copies/ml. All regained viral suppression after intensifying therapy by adding tenofovir/emtricitabine. All three had previously taken integrase inhibitors and had various integrase resistance mutations.

The investigators concluded that dolutegravir monotherapy had "a high rate of efficacy over 24 weeks in this particular heavily treated ART-experienced population," but urged caution when considering monotherapy for people with prior exposure to integrase inhibitors.

This strategy showed a high rate of efficacy in a difficult context, was highly acceptable to patients and "deserves further investigation in larger trials," Katlama said.

However, Kimberly Smith from ViiV Healthcare, speaking from the audience, argued that this is "quite a risky strategy given the population."

Following these presentations, Andrea de Luca of Siena University Hospital in Italy and Christoph Wyen of Praxis am Ebertplatz in Germany debated the risks and benefits of lowering drug burden for people with HIV.

De Luca argued that studies of simplification strategies to date, including dual and monotherapy, have produced mixed results. Dual therapy using ritonavir-boosted atazanavir (Reyataz) plus lamivudine has the strongest evidence in its favour, but the dolutegravir dual and monotherapy data presented here are promising. Dropping tenofovir from a regimen can lead to improved kidney function and bone health, he suggested.

Furthermore, it is possible to select patients with a high probability of success (e.g. low baseline viral load using sensitive tests, higher CD4 count) and most people who experience treatment failure are able to regain viral suppression with regimen intensification. Finally, regimens with lower drug burden could save on costs compared to standard three-drug ART.

Wyen succinctly argued that there is still a paucity of data on regimens with lower drug burden, and this strategy may be particularly risky for people with higher viral load, lower CD4 counts, drug resistance and suboptimal adherence. Moreover, with modern antiretroviral options including integrase inhibitors and the forthcoming lower-toxicity tenofovir alafenamide, side-effects and drug burden are already "not such a big issue."

Figueroa M et al. (Cahn P presenting) Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of the PADDLE trial. 15^th European AIDS Conference, abstract LBPS4/1, 2015.

Rojas J et al. (Martínez E presenting) Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: a 24-week pilot study. 15th European AIDS Conference, abstract LBPS4/2, 2015.

Katlama C et al. Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia. 15^th European AIDS Conference, abstract PS4/4, 2015.

De Luca A and Wyen C Should we lower drug burden? 15^th European AIDS Conference, session ML2, 2015.