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PRIORITY PRESS - 23rd Annual Canadian Conference on HIV/AIDS Research (CAHR)

St. John’s, Newfoundland and Labrador / May 1-4, 2014

St. John’s - Since the mid 90s, there has been a virtual explosion of novel antiretroviral therapies (ART) targeting HIV replication along multiple pathways. This has led to the development of potent new combinations of ARTs that are capable of driving down HIV RNA levels to unprecedented lows. Indeed, virtually all treatment-naïve patients and even the majority of highly experienced patients can now be treated to “undetectable” levels. Despite major gains in the global management of HIV, efforts are still being directed towards simplifying regimens to improve tolerability and adherence. However, not all patients are candidates for simplification and for those with high viral loads and low CD4 cell counts, more intensive regimens should be maintained.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Globally, the impact of anti-HIV regimens on the HIV epidemic worldwide cannot be overstated. Since 2001, the rate of new HIV infections has fallen by 33%. “AIDS-related deaths have fallen by 30% since their peak in 2005,” added Dr. Catherine Hankins, Deputy Director of Science, Amsterdam Institute for Global Health and Development, the Netherlands. These gains are due in part to greater uptake of anti-retroviral (ART) regimens worldwide.

But a more enlightened approach to the management of HIV infection has also had a major impact on viral transmission—early treatment before CD4 counts fall to current eligibility criteria; treating any positive individual without waiting for them to return for future (and often never fulfilled) visits, and pre-exposure prophylaxis of HIV-negative individuals at high risk for HIV infection due to an HIV-discordant partnership or other high-risk situations including working in the sex trade.

Reducing ART Doses

Long-term suppression of HIV viral load (VL) is now possible but success still rests on the individual patient who needs to stay on ART over a lifetime. To improve adherence, investigators are exploring a number of options, one of which is to reduce standard ART doses. In the ENCORE 1 study group (Lancet 2014;383:1474-82) researchers tested whether efavirenz (EFV), given at a reduced dose of 400 mg, was non-inferior to the standard 600 mg dose when combined with tenofovir (TDF) and emtricitabine (FTC) in treatment-naïve patients with a VL >1000 copies/Ml on study entry.

At 48 weeks, 94.1% of patients in the reduced EFV arm vs 92.2% of those in the standard dose arm had achieved the primary endpoint of a VL <200 copies/mL according to the intent-to-treat (ITT) analysis. “These data are quite compelling to show that EFV at the lower dose of 400 mg is as good as the 600 mg dose in terms of anti-viral efficacy,” said Dr. Jean Michel Molina, Professor of Infectious Diseases, University of Paris Diderot, Paris, He added however, that there was only “limited improvement” in the tolerability of the lower-dose regimen.

The only other drug to have been tested at a reduced dose is darunavir/ritonovir (DRV/r).  In the ODIN trial (AIDS 2011;25:929-39), investigators compared a once-daily reduced dose of the same boosted protease inhibitor (PI) to the standard, twice-daily DRV/r in treatment-experienced patients failing their current regimen. Importantly, patients had no DRV-resistance mutations at entry. At week 48, some 72% of patients receiving the reduced once-daily dose of the boosted PI (800/100 mg) had achieved the primary endpoint of a VL <50 copies/mL (ITT analysis) compared with approximately 71% of those receiving the standard twice-daily dose PI (600/100 mg).   

Clinically relevant improvements in the lipid profile were also seen in patients receiving the reduced once-daily dose PI strategy, Dr. Molina added.

PIs as Monotherapy

“Over the last few years, we have also addressed the issue of using PIs as monotherapy,” Dr. Molina continued. In the MONOI study, for example, patients who had been on previous cART for a minimum of 18 months and had undetectable HIV levels <400 copies/mL were randomized to either a boosted PI monotherapy regimen or to a boosted PI regimen plus 2 nucleoside-reverse transcriptase inhibitors (NRTIs).

At the 48-week endpoint, 99% of patients in the per-protocol population who received DRV/r plus 2 NRTIs had achieved the composite primary endpoint of a VL <50 copies/mL and no change in regimen compared with about 94% of those randomized to the boosted PI monotherapy arm. Analysis of the same MONOI cohort at 96 weeks continued to support DRV/r monotherapy as durable and efficacious (J Antimicrob Chemother 2012;67:691-5) although a higher proportion of patients at 12% in the PI monotherapy arm had intermittent viremia with more extensive follow-up compared to only 2% in the triple-therapy arm.

Not all PI monotherapy studies have been positive. For example, in the PIVOT trial, Paton and colleagues randomized patients with well-controlled HIV disease to continue on their triple regimen or switch to PI monotherapy, the majority of them receiving boosted DRV. As reported at CROI in 2014, nearly one-third of patients in the boosted PI monotherapy arm had virologic rebound at 3 years of follow-up compared to only about 3% in the triple therapy arm. Few absolute numbers of patients in either arm lost further treatment options—the primary endpoint of the study—but the relative difference in the loss of future treatment options was significantly higher for the PI monotherapy arm.

Nuke-Sparing Regimens

In an effort to make ART more tolerable, a number of nucleoside-sparing regimens have been compared to standard ART. In the NEAT study, for example, investigators randomized treatment-naïve patients to a DRV/r–based regimen (800/100 mg once a day) plus either the integrase inhibitor raltegravir, 400 mg twice daily, or standard TDF/FTC, once a day. Importantly, patients had no resistance mutations to any of the study drugs at baseline.

At 96 weeks, 93% of patients in the nucleoside-containing arm achieved a VL <50 copies/mL compared with 89% of those in the non-nucleoside containing arm—“so you could claim non-inferiority of the dual combination compared to the triple combination,” Dr. Molina said. “Full suppression of viral replication should not be compromised,” Dr. Molina cautioned,  “but many options are now available for treatment simplification and the benefits and risk should be assessed and discussed with the patient and decisions made on a case-by-case basis.”

High Viral Loads

Patients for whom a simplification strategy may be less effective are those with a high baseline VLs as well as those with a low baseline CD4 cell count (<200 mm³). In one meta-analysis (HIV Med 2013.14:284-92) cited by Dr. Colin Kovacs, Assistant Professor of Medicine, University of Toronto, the mean percentage of patients achieving a VL <50 copies/mL at week 48 across 21 first-line clinical trials with standard anti-HIV regimens was around 81% for patients with a baseline HIV RNA <100,000 copies/mL compared with around 73% for patients with baseline HIV RNA >100,000 copies/mL (P<0.001).

The difference in efficacy was consistent across trials of different drug treatment classes as well as NRTI backbones, as Dr. Kovacs pointed out. Patients who take longer to suppress to undetectable levels are also less likely to remain suppressed over time. In the MONET study in which boosted PI monotherapy was compared with the same boosted PI plus 2 NRTIs, higher HIV RNA levels were seen in patients with CD4 counts <200 mm³  as well as those with detectable plasma HIV RNA levels, as Dr. Kovacs pointed out.

In the NEAT trial, failure among those with a baseline VL >100,000 copies/mL was seen in 36% of the dual therapy arm and 27% in the triple therapy arm, which was not quite statistically significant. However, failure rates for patients with CD4 <200 mm³ were 39% and 21% for each of the 2 treatment arms, respectively, which was statistically significant. “In all of the simplification trials we’ve looked at, a minority of people do not seem to do as well in terms of virologic failure and the longer we follow these trials out, failure rates don’t really plateau,” Dr. Kovacs said. “So simplification will work in a certain group of people but we don’t have any tools to differentiate those in whom it will and won’t work and if we go ahead and blindly simplify regimens, we need to monitor patients more intensively or we could miss early failure and only diagnose patients late into their virologic rebound.”

Summary

Simplifying ART regimens is an attractive strategy for patients who are well suppressed on maintenance therapy and who have no mutations prior to simplification. However, efficacy of the simplified regimen still depends on the potency of the boosted PI and which PI is chosen is clearly of paramount importance. In contrast, high viral loads and low CD4 cell counts may be a relative contraindication to simplification. Among those for whom more intense regimens are called for, the long-term AE profile of the chosen regimen should guide treatment decisions.