IAS 2013 Wrap Up – Dolutegravir and the New State of the ART

IAS 2013 Wrap Up – Dolutegravir and the New State of the ART
[learn_more caption=”By Elizabeth Boskey”]
Elizabeth_Boskey_ViroChannelElizabeth Boskey, Ph.D. is a Certified Health Education Specialist and A.A.S.E.C.T. Certified Sexuality Educator as well as an independent scholar, writer, and teacher focusing on sexual health.

Although she is best known as the Guide to Sexually Transmitted Diseases at About.com, where she writes a consumer-focused site about sexual health, she has been enjoying writing more in depth content for health professionals at ViroChannel.

A researcher herself, Elizabeth has published several peer-reviewed papers on topics in women’s reproductive health and is on the editorial boards of the American Journal of Sex Education and Contemporary Sexuality – the journal of the American Association of Sexuality Educators, Counselors, and Therapists.

She has also written or contributed to a number of popular science books including America Debates Genetic DNA Testing, The Truth About Rape, and The Invision Guide to Sexual Health.

As always, one of the highlights of any HIV conference is newly released information about the next generation of antiretroviral therapy (ART). The 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS2013) has been no exception. Unsurprisingly, one drug that has received a lot of focus is the next-generation integrase inhibitor dolutegravir (DTG) that is currently under development. It was the subject of six presentations – three comparing its efficacy to raltegravir (RAL), two discussing resistance profiles, and one examining its effects on the kidneys.

A late-breaker presentation shared the 48 week results from the SAILING trial, a double-blind, Phase III trial comparing RAL and DTG in treatment experienced, but integrase inhibitor naïve, patients. The results showed that DTG was significantly more effective than RAL at helping patients achieve a viral load of

The second DTG efficacy study presented at IAS2013 shared the 96 week results of the SPRING-2 trial, a multi-center, Phase III non-inferiority trial comparing the effect of the drug to RAL, each in combination with an NRTI backbone. It found that not only was DTG non-inferior to RAL, there were no resistant mutations. The two drugs also had similar safety profiles. Creatinine increases were seen, once again, in the DTG patients in the early phases of the trial, but they did not progress after 48 weeks.

A third study examined the efficacy of DTG in patients who weren’t treatment naïve but instead were known to have drug resistant virus. The VIKING-3 study was a single arm, open-label study to look at safety and efficacy of DTG through 24 weeks. Most of the patients with integrase resistance mutations had sustained viral responses to DTG, although susceptibility to the drug did vary by the type and number of mutations.

In light of those results, the resistance studies of DTG presented at IAS2013 were particularly interesting. The two studies, both by scientists at McGill, examined why no integrase-inhibitor naïve patients have ever developed resistance to the drug. In the first long-term, in vitro experiment designed to induce viral resistance, the scientists were able to identify two common integrase resistance mutations induced by DTG use – R263K and H51Y. However, although R263K led to increased DTG resistance, it also decreased integrase activity in the mutated virus, causing it to replicate and integrate less efficiently. No secondary mutations seemed able to mitigate the effect. When the mutation H51Y, which alone affected neither resistance nor enzyme activity, was present alongside R263K, both changes were magnified. The virus became further resistant to DTG, but it also lost approximately 70 percent of its replication capability.

The second study examined the effects of the secondary mutations M50I and E138K in combination with R263K. As with H51Y, the presence of these secondary mutations failed to restore integrase function. However, they affected the enzyme differently. M501 altered integrase interaction with viral DNA, while E138K affected the structure of catalytic site. Both also increase DTG resistance to different levels, but that may not be particularly dangerous. If these results can be confirmed in animal models, they may explain why no resistance to DTG has yet been seen in human studies. The mutations that increase resistance to the drug decrease viral fitness even more.

Finally, scientists from GlaxoSmithKline and ViiV Healthcare reviewed the renal safety results from two Phase III trials of DTG – SPRING-2 and SINGLE. The first compared DTG containing regimens to regimens containing RAL. The second compared DTG combined with abacavir/lamivudine (ABC/3TC) to a tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) regimen. There were few renal adverse events in either study. Elevated creatinine levels were seen in the DTG groups of both studies, but it did not affect the albumin/creatinine ratios or lead to kidney toxicity. Therefore, the observed effects on estimated glomerular filtration rate (GFR) were thought to be an artifact of the use of creatinine levels in its calculation.

Dolutegravir wasn’t the only investigational drug making news at IAS2013. Scientists were also discussing another exciting development in ART – the possibility that long acting parenteral drugs could make therapy substantially more convenient for patients. An early safety and tolerability study of monthly or quarterly intramuscular injections of a combination of the investigational integrase inhibitor GSK1265744 (GSK744) and the NNRTI TMC278 LA found that the long-acting nanosuspensions were well tolerated in patients. Both dosing regimens achieved clinically relevant concentrations of the drugs, with few adverse events aside from injection site tenderness.

All in all, the successful results seen for the investigational treatments were an exciting conclusion to a satisfying conference focusing on innovations in HIV care. Looking at them in combination with the multiple presentations highlighting the potential for early initiation of ART to limit, or even prevent, the formation of the viral reservoir, raises hopes for an AIDS-free future. Add in the other exciting, closing day late-breakers – including strong, early adherence results from a PrEP trial in Thailand; good follow-up interest in PreP from the continuing participants in iPrEx; and a positive report about the minimally-invasive Shang Ring circumcision device – and it’s easy to see why people are already looking forward to AIDS 2014 in Melbourne.