New antiretrovirals and HIV treatment strategies highlighted at ICAAC

Researchers presented findings from several HIV studies at the 55^th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last week in San Diego, USA, including an overview of the START treatment initiation study, an all-women antiretroviral therapy trial, studies of a better tolerated version of tenofovir and news about integrase inhibitors.

ICAAC was once one of the major annual venues for the presentation of HIV and AIDS treatment research, but this has become less of a focus now that antiretroviral therapy (ART) is highly effective and generally well-tolerated. This year's conference, jointly organised by the American Society for Microbiology and the International Society of Chemotherapy, was the last under the ICAAC name; next year it will be incorporated into the new ASM Microbe 2016 meeting.

HIV presentations at ICAAC 2015 included a symposium reviewing 'What’s New in Antiretroviral Therapy', an International AIDS Society-USA interactive session on 'Challenges and Complexities in Managing HIV Infection', a symposium on HIV prevention, and oral slide sessions on new antiretroviral drugs and strategies and HIV-associated comorbidities.

When to start ART?

Professor Jens Lundgren of the University of Copenhagen gave a special lecture on the START study, a large randomised clinical trial that aimed to shed light on the best time to start HIV treatment.

As reported at the summer's International AIDS Society Conference in Vancouver, START enrolled more than 4600 participants with CD4 cell counts above 500 cells/mm³. They were randomly assigned to either start ART immediately or delay therapy until their CD4 count fell below 350 cells/mm³ or they developed AIDS symptoms.

The study showed that people who started treatment early had a significantly lower risk of illness and death compared to those who waited. The immediate treatment group had a 57% reduction in a combined endpoint of serious AIDS-related events, serious non-AIDS events and death. In addition, early starters had an unexpected 72% lower risk when looking at AIDS events alone. There was no apparent rise in adverse events or drug toxicities among people who started treatment promptly.

ART for women with HIV

Sally Hodder of West Virginia University presented findings from the phase 3 WAVES (Women Antiretroviral Efficacy and Safety) study, which compared the Stribild single-tablet regimen containing the integrase inhibitor elvitegravir to a regimen containing ritonavir-boosted atazanavir (Reyataz) in 575 previously untreated women, mostly in the US, Russia and Uganda.

"Historically, there have been maybe 10% women in [HIV treatment] trials," Hodder said during an ASM Live episode discussing the study. "Regulatory agencies have made decisions based on very small populations of women."

The WAVES results (previously presented as a poster at the Vancouver IAS conference) showed that 87% of women taking Stribild had undetectable viral load at 48 weeks of treatment compared with 81% of those taking boosted atazanavir, indicating that Stribild was statistically superior. Hodder noted that in other clinical trials that included mostly men, the two regimens were statistically similar.

Both regimens were generally safe and well-tolerated, with most side-effects being mild. The highest response rates were seen in Uganda and the lowest rates in the US, due to lower drug adherence and more women lost to follow-up. 

Tenofovir: TAF vs TDF

A pair of oral presentations reported results from studies of Gilead Sciences' tenofovir alafenamide or TAF, a new pro-drug formulation of tenofovir that delivers the active agent to HIV-infected cells more efficiently than the current tenofovir disoproxil fumarate or TDF (Viread, also in Truvada, Atripla, Eviplera and Stribild).

TAF produces adequate intracellular drug levels with lower doses, which means lower concentrations in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.

David Shamblaw of La Playa Medical Group and Clinical Research presented findings from a subgroup analysis of Study GS-US-292-0109, in which 376 HIV-positive people who were virally suppressed on Atripla (efavirenz/TDF/emtricitabine) either stayed on the same regimen or switched to a once-daily single-tablet regimen containing elvitegravir, cobicistat (a boosting agent), emtricitabine and TAF – a new coformulation that could replace Stribild. Results from the larger study were presented at the Vancouver IAS conference.

At 48 weeks after randomisation, 96% of people who switched to the TAF-containing regimen maintained undetectable viral load, as did 90% of those who stayed on the TDF-containing regimen – a significant difference.

People taking TAF showed improvements in proteinuria (protein in the urine), but also showed worsening of some kidney function biomarkers, which the researchers attributed to cobicistat.

TAF recipients experienced small gains in hip and spine bone mineral density, while those taking TDF continued to lose bone, resulting in fewer TAF recipients with osteoporosis at 48 weeks. Those on TAF, however, had more detrimental blood lipid changes.

Not surprisingly – given that they stopped taking efavirenz (Sustiva) – people taking the TAF-containing regimen also reported a reduction in central nervous system side-effects.

Samir Gupta of Indiana University and colleagues presented results from another study looking at the elvitegravir/cobicistat/emtricitabine/TAF single-tablet regimen in people with pre-existing kidney impairment – a population advised not to use TDF.

This post-hoc analysis focused on 80 people (mean age 59 years) on suppressive ART who had stable kidney impairment, indicated by an estimated glomerular filtration rate (eGFR) <50 ml/min; another group of 162 patients had eGFR in the 50-69 ml/min range.

There were no significant changes in eGFR at 48 weeks after switching to the TAF-containing coformulation, or in actual GFR at 24 weeks. Other measures of kidney function, including proteinuria and albuminuria, improved; the proportion of people with eGFR <50 who had clinically relevant proteinuria fell from 56% to 25%. Adverse events occurred with about the same frequency in people with eGFR <50 and 50-69 ml/min.

The US Food and Drug Administration is scheduled to make an approval decision on this coformulation by the end of the year.

Dolutegravir

M Aboud from ViiV Healthcare presented findings from a study looking at the most recently approved single-tablet regimen and the only one without TDF: Triumeq, which contains the integrase inhibitor dolutegravir, abacavir and lamivudine.

The open-label STRIVING study included 551 participants (14% women, median age 45 years) with undetectable viral load who were randomly assigned to either stay on their current regimen – consisting of a protease inhibitor, integrase inhibitor or NNRTI plus two nucleoside/nucleotide reverse transcriptase inhibitors – or switch to Triumeq.

After 24 weeks, 85% of people who switched to Triumeq and 88% of those who stayed on their current regimen maintained viral suppression, indicating that Triumeq was non-inferior in effectiveness.

However, Triumeq recipients were more likely to report adverse events overall (65% vs 45%) and to discontinue treatment for this reason (4% vs 0), although only 2% in each group had serious adverse events. Nausea, diarrhoea, headache and fatigue were all more common with Triumeq. Nevertheless, people who took Triumeq showed a significantly larger increase in their treatment satisfaction scores.

"Switching to Triumeq from a variety of regimens was demonstrated to be safe and effective," the researchers concluded. "Greater improvements in treatment satisfaction were demonstrated in subjects switching to Triumeq."

Cabotegravir

Another research team reported on cabotegravir (GSK1265744), an experimental integrase inhibitor related to dolutegravir. Cabotegravir is being developed as both an oral drug and a long-acting injectable, and is being tested for HIV maintenance therapy and pre-exposure prophylaxis (PrEP). Early studies have shown that cabotegravir protected monkeys against infection with an HIV-like virus and it appears an injection every 12 weeks can maintain protective levels in humans.

In the analysis presented at ICAAC, researchers assessed whether cabotegravir is associated with heart rhythm abnormalities, specifically changes in cardiac repolarisation as indicated by the QT interval in the sinus rhythm. Preclinical studies have shown no detrimental effects of cabotegravir on cardiac conduction. This study used the oral formulation of cabotegravir; because a long-acting injectable cannot be discontinued quickly once administered, it is particularly important to rule out adverse events in advance.

This partially blinded, repeat-dose crossover study enrolled 42 adult volunteers without HIV (79% men, mean age 34 years). They were randomised to receive 150mg oral cabotegravir every 12 hours for three doses, placebo every 12 hours for three doses and a single 400mg dose of moxifloxacin as a control drug, with a 21-day washout period between treatments. QT interval data were collected using a continuous Holter monitor for approximately 24 hours before and after dosing.

Cabotegravir was found to have no effect on cardiac repolarisation using a dose higher than needed to have an antiviral effect, with maximum concentrations reaching three times that of the normal 30mg clinical dose. Further, there were no deaths or serious adverse events and almost all reported adverse events were mild.