CROI 2016: Antiretroviral therapy and other interesting observations
Joseph Eron MD Professor
of Medicine University of
North Carolina at Chapel Hill
The success of antiretroviral therapy
In setting where there is widely available and unfettered access to HIV testing, a health infrastructure that facilitates access to antiretroviral therapy and provision of this therapy through well supported system, antiretroviral therapy reaches a large proportion of infected people and suppression rates are remarkably high. In Botswana the Harvard group presented data from a population-based random sample, which suggested that treatment success rates in that country had reached the UNAIDS goal of 90% of HIV-1 infected individual diagnosed, 90% of those diagnosed on antiretroviral therapy and 90% of patients on therapy with HIV RNA below detectable limits (Gaolathe T, et al). Similar results were seen in a developed country health care system in Sweden in a presentaton by Gisslen et al. In that country the authors estimated that 87% of people with HIV infection were diagnosed, linked and retained in care. Of these 95% were on therapy and 95% of those on ART had HIV RNA < 50 c/mL. Overall the authors estimated that 78.5% of all HIV infected patients in the country were suppressed on therapy. (Of note the authors estimate that there are < 8000 HIV infected people in the entire country). Results from these two very different countries are outstanding and provide an opportunity to test the theory behind 90-90-90 which is that both AIDS related deaths should fall substantially and new HIV infections should decrease dramatically. The accuracy of these data is dependent, of course, on the estimated initial denominator - the number of people in the country with HIV-1 infection. If that number is underestimated then the overall percentage of HIV-1 infected patients suppressed on therapy in the country falls accordingly. For example if the HIV-1 prevalence is underestimated by 10% then the proportion of individuals who know their HIV diagnosis drops from 90% to 81% and the proportion of HIV-1 infected individuals in the country who are suppressed on the ART drops from 73% to 65%.
Webcast: Gaolathe T, Botswana 90/90/90 -
Gisslen, Swedish HIV Treatment Cascade -
How are we doing in the US? A presentation from the CDC using data from ART prescription and surveillance data (Bradley H, et al.) demonstrated a statistically significant increase in the percentage of HIV-1 infected patients prescribed ART from 89% in 2009 to 94% in 2013. The proportion of these patients who had at least one HIV RNA < 200 c/mL in the calendar year also increased at a steeper rate from 72% in 2009 to 80% in 2013. The proportion with sustained suppression (all HIV RNA in the calendar year < 200 c/mL) increased the most; 10% over the 5 years though the proportion with sustained suppression in 2013 was only 68%. We presented similar data from our CNICS collaboration (Simoni et al). CNICS is an observational cohort from 8 academic HIV-1 clinics across the US and the analysis was from 31,000 patients. Like with the CDC the proportion of patients on ART increased from approximately 78% in 2009 to just over 90% in 2014 and the proportion suppressed also increased to a somewhat greater extent from 68% to 85% (increasing the proportion on therapy who were suppressed to < 400 c/mL from 87% to 93% over the 6 year period). In CNICS adherence data and substance use data are collected from the participants. Over this 6 year period in which suppression rates increased there was no increase in reported adherence and no decrease in reported substance use. These data, along with the CDC data suggest that our antiretroviral therapies are getting better - meaning despite lack of improvement in adherence or a decrease in substance use patients on therapy are more likely to be suppressed. In the CNICS cohort factors associated with a suppressed HIV RNA include older age, male sex, time in care and notably integrase inhibitor use (OR 2.4 95% CI 2.2 -2.7). Overall the data from Botswana, Sweden and the US are encouraging but there is a long way to go especially in the US. Substantial numbers of infected people remain undiagnosed and linkage and retention in care of those who are diagnosed is substantially behind most other countries. Even in our academic centers, represented by the CNICS, as many as 10% of patient in care are not on treatment. Can improvements in antiretroviral therapy and novel treatment strategies draw people into care, increase the proportion of those in care who are consistently on ART and increase the percentage of patients who have sustained suppression over long periods of time?
Bradley, CDC Viral Suppression - WEBCAST:
Simoni CNICS Viral Suppression -
Is standard oral antiretroviral therapy getting better?
Our current antiretroviral therapy is relatively simple for most patients, very efficacious, well tolerated with minimal serious adverse events, at least over the "short-term" of 5 to 10 years. (Remember a 30 year-old starting on therapy may need to be treated for five decades). However even very good therapy can be improved and alternatives to oral 3-drug therapy developed to safely reach more people. At CROI we saw another tenofovir alafenamide (TAF) randomized, blinded switch study, this time with participants on TDF/FTC 2-NRTI backbone with a third agent undergoing randomization to either continue on the TDF/FTC backbone or switch to TAF/FTC with approximately 330 participants per arm (Gallant et al). Not surprisingly continued suppression of plasma HIV-1 RNA was high in both treatment arms and document HIV RNA > 50 c/mL at 48 weeks was very low in each arm (0.3% with TAF/FTC and 1.5% with TDF/FTC). eGFR actually improved in both groups; modestly but significantly more in the TAF arm (+8.4 versus +2.8 mL/min; P<0.001). Bone mineral density rose, again modestly, on the TAF arm (1.5% for spine and 1.1% for hip) and tubular proteinuria improved. All these findings were very consistent with previous initial and switch studies with TAF in combination with elvitegravir, cobicistat and FTC (Wohl et al, Mills et al). With the approval of TAF/FTC, which is expected in a month or so, we will have multiple TAF-containing potential combinations with much more flexibility for treatment allowing us to side step drug interactions with cobicistat or rilpivirine and be able to use TAF-containing therapy in patients who have resistant virus that preclude elvitegravir or rilpivirine use.
There were also three poster presentations that further examined longer term renal outcomes with TAF-use, each examining E/C/F/TAF either over 96 weeks of follow-up in the single arm study in participants with baseline eGFR between 30 and 70 mL/min (Post et al) or in the head-to-head randomized comparison to E/C/F/TDF in treatment naÏve participants (Wohl et al and Rijnders et al). The results of these studies can be summarized pretty succinctly. In the Post et al presentation eGFR remained stable over 96 weeks whether participants entered with and eGFR in the 30 mL/min range or with eGFR > 50. Five participants had to discontinue the study due to renal adverse events (essentially rises in serum creatinine). All five had hypertension and two also had diabetes. None had evidence of tubulopathy. In the TAF comparison to TDF in treatment naÏve participants over 96 weeks no participant on E/C/F/TAF had acute renal injury, a diagnosis of tubulopathy or required discontinuation due to a renal adverse event. One out of 866 TAF-treated participants met the definition of chronic kidney disease. Favorable outcomes for renal tubular proteinuria and bone mineral density were observed with E/C/F/TAF in both studies. Whether TAF-containing regimens will be completely free of renal toxicity over the longer term will remain unknown for some time however the data available to date remains encouraging. The favorable impact on bone mineral density as measure by DEXA scan seems unequivocal.
CROI: Switching to F/TAF (Tenofovir Alafenamide) from F/TDF (Tenofovir DF) based Regimen Study 311-1089: 48-Week Data - [Gallant] - (02/23/16)
CROI: Longer-Term Renal Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate - [Rijnders] (03/01/16)
CROI: Longer-Term Safety of Tenofovir Alafenamide in Renal Impairment -[Post] (03/01/16)
CROI: Renal Safety of Tenofovir Alafenamide in Patients at High Risk of Kidney Disease - [Wohl] (03/05/16)
Emergence of Resistance
In my plenary talk I presented data from the UK showing how uncommon it is to see resistance emergence to first line therapy when we have viral load monitoring. Looking at almost 9000 patients treated with TDF-containing firstline therapy from 1998 to 2012 Ellen White, David Dunn and colleagues (unpublished) observed that < 5% of these patients developed a major resistance mutation over 5 years of follow-up. I suspect that if we examined more recent data, for example, from 2006 to 2015 (when we have single tablet regimens available) the rate would even be lower.
Data were presented on study participants receiving E/C/F/TAF and resistance emergence (Abram et al). Following over 2200 participants on treatment naÏve or switch studies only 18 (or 0.9%) met criteria for resistance testing and only seven developed resistance mutations.
Antiretroviral Therapy: Where Are We Now? And Where Are We Going? Joe Eron, MD
CROI: Pooled Week-48 Analysis of HIV-1 Drug Resistance in E/C/F/TAF (Genvoya) Phase 3 Studies - (03/05/16)
In British Columbia, Lepik and colleagues looked at emergence of resistance in patients with virologic failure from 2009 to 2015. They used resistance definitions from the Stanford data base and observed that resistance emergence with reverse transcriptase and protease mutations was declining significantly over time. They did demonstrate a significant increase in integrase resistance mutations over the same period but integrase resistance emergence was still very uncommon with only 8 patients (or 6.8 per 1000 treated patients) developing integrase mutations in 2015.
Long acting ART
Perhaps the most groundbreaking treatment data presented at the conference were the data on long-acting agents. We saw the first data from LATTE 2 in which the combination of long-acting cabotegravir (an integrase inhibitor similar to dolutegravir) and long-acting rilpivirine were combined and given either every 4 weeks or every eight weeks in participants who were first suppressed on oral cabotegravir and abacavir/3TC for 20 weeks (Margolis et al). Three hundred and nine individuals with CD4 cell counts > 200 cell/mm3 initiated oral therapy and at 20 weeks 286 were randomized to the maintenance phase with 115 in each of the IM injection LA-arms and 56 randomized to stay on oral therapy. At 8 months or 32 weeks into the maintenance phase 94% of participants on the monthly injections and 95% on every other month injections remained suppressed below 50 c/mL compared to 91% on oral therapy. While one participant and 5 participants on the every 4 week and every 8 week LA therapy met criteria for virologic non-response at 32 weeks no participant in any of the arms developed resistance during the maintenance phase of the study. Despite the fact that participants receive intramuscular injections (typically 2 injections at each treatment) acceptance of the therapy was very high and only 8 participants (3%) withdrew due to adverse events - only 2 of these withdrawals were due to injection site reactions. These reactions were common but decreased over time and were usually mild or moderate.
Opinions vary widely on what the uptake will be when this form of long-acting therapy becomes available. IM injections have to be done carefully, trained practitioners always did the injections in the LATTE 2 study and patients who joined the study were highly motivated to get long acting therapy. On the other hand if it is every 8 week injections that go forward then that is only six treatment per year and perhaps the oral lead-in period (which is necessary to demonstrate safety before the injections which cannot be removed) can be shortened some. Younger patients and patients who are on no other medications may prefer not to take pills and we all have had patients who talk about the daily reminder of their HIV infection that occurs every time they open their antiretroviral medication bottles. Choosing to use long-acting therapy also does not mean someone is committed to that choice for life. Patients may choose long-acting therapy for periods in their life where adherence to oral therapy may be particularly difficult or inconvenient and choose oral therapy at other times.
CROI: Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 32 Results - (02/24/16)
Another potential long-acting therapy, which is earlier in clinical development, was also presented at CROI. MK-8591 (EFdA) is a nucleoside reverse transcriptase inhibitor that also block translocation of the reverse transcriptase enzyme along the HIV RNA template. In vitro this agent has substantially greater potency than any of the NRTI or NtRTI that we currently have available (Grobler et al). In addition the intracellular half-life of the triphosphate form very long and in healthy volunteers, intracellular target concentrations were maintained for 7 days with a single oral dose. A parenteral formulation is being explored and Grobler et al showed that concentrations could be detected over 180 days after a single injection in a rat model. Friedman et al gave a single 10 mg dose to six HIV infected participants and showed that HIV RNA levels fell by over 50-fold (1.78 log10) over 10 days. No resistant virus was detected at the end of the 10 day period and the participants started 3-drug therapy to avoid selection of resistance as MK-8591 levels declined over time.
CROI: Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or Prophylaxis - (02/24/16)
CROI: A Single Monotherapy Dose of MK-8591,a Novel NRTI, Suppresses HIV for Ten Days - (02/24/16)
This agent would obviously need additional antiretrovirals to partner with in the development of long-acting combinations. The data presented raise the possibility of once weekly oral therapy that might be preferable to some patients if appropriate oral partner drugs can be found. Remember that tenofovir-diphosphate has a very long intracellular half-life and some NNRTI (like efavirenz) have long half-lives so development of a once weekly triple therapy might be possible. MK-8591 also looks like it can be delivered in a long-acting formulation. Again for HIV treatment partner agents would need to be explored but having an option that could be dosed once every 3 or 6 months and could be formulated in a removable implant would be a substantial advance.
At CROI we saw additional phase IIB data on doravirine - an NNRTI in development that is once daily, has no specific food requirements, is not impacted by proton pump inhibitors (PPI) and appears to have fewer CNS side effect than efavirenz. The data presented looked at the dose of doravirine that is going forward in phase III studies (100 mg daily) and the results were in comparison to efavirenz 600 mg once daily, both in combination with TDF/FTC, in a blinded randomized assessment (Gatell et al). In total 108 participants were randomized to each treatment and at 48 week 78.7% of participants treated with EFV were < 50 c/mL compared to 77.8% with doravirine with the curves over the 48 week time period virtually overlapping. When the sub-groups of < 100,000 and > 100,000 c/mL at baseline were compared the two arms were very similar in the lower RNA stratum but in the higher stratum the percentages in a NC=F analysis were 83.8% for EFV and 74.3% for doravirine. The difference was due to lower level viremia as when the < 200 c/mL outcome was compared (as opposed to < 50) the two arms were very similar. Discontinuations for adverse events were less for doravirine. Diarrhea, dizziness, and abnormal dreams were all less in the doravirine treated participants. Interestingly insomnia was higher in participants treated with doravirine. We also saw this in the SINGLE study when efavirenz was compared to dolutegravir. One possibility is that efavirenz causes some somnolence and this explains the difference.
CROI: Doravirine 100 mg QD vs Efavirenz +TDF/FTC in ART-NaÏve HIV+ Patients: Week 48 Results - (02/26/16)
In a separate presentation (Lai et al) in vitro resistance selection was compared between doravirine, efavirenz and rilpivirine by passaging virus in the presence of drug concentrations that are achievable in vivo. The experiments started with viruses that were resistant to efavirenz (K103N, Y181C and K103N/Y181C mutants were used). In the selection experiments new mutations were selected for when these viruses were passaged in the lab in the presence of efavirenz and rilpivirine but NOT with doravirine. These results suggest that doravirine has a higher barrier to resistance than rilpivirine and that it will be active against typical transmitted resistant variants that are resistance to efavirenz. However we don't have any clinical data yet to support these laboratory-based results.
The main question is where doravirine will fit in if it meets the non-inferiority bar in the two phase III studies in treatment naÏve patients:
(https://clinicaltrials.gov/ct2/show/NCT02403674?term=MK-1439&rank=3). These studies compared doravirine to either darunavir/ritonavir or to efavirenz. Both studies are fully enrolled so the results should be available in a year or so. But many patients are now being started on integrase inhibitor-based therapy so the studies that are underway won't directly address the question or how doravirine stacks up against our most commonly used initial therapies. As mentioned doravirine appears to have advantages over both efavirenz and rilpivirine and therefore will likely find a role in our treatment paradigm if the phase III studies lead to approval.
CROI: New HIV Drugs (ARTs): prevention/treatment..... - (03/21/16)
Abram M, et al. Pooled Week 48 Analysis of HIV-1 Drug Resistance in E/C/F/TAF Phase 3 Studies. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA.. Abstract 496
Bradley H, et al. Increased HIV Viral Suppression Among US Adults Receiving Medical Care, 2009-2013 Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016. Abstract 53.
Friedman E, et al. A Single Monotherapy Dose of MK-8591, a Novel NRTI, Suppresses HIV for 10 Days. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 437LB
Gallant JE, Daar E, Raffi F, et al. Switching tenofovir DF to tenofovir alafenamide in virologically suppressed adults. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 29.
Gatell JM, et al. Doravirine 100mg QD vs Efavirenz +TDF/FTC in ART-Naive HIV+ Patients: Week 48 Results. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 470.
Gaolathe T, et al. Botswana Is Close to Meeting UNAIDS 2020 Goals of 90-90-90 Coverage. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 111.
Grobler J, et al. Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or ProphylaxisProgram and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 98
Lai MT, et al. Suppress NNRTI-Resistant Mutants by Doravirine at Clinically Relevant Concentrations Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 506.
Lepik K, et al. Prevalence and Incidence of Integrase Drug Resistance in BC, Canada, 2009-2015Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 492LB
Margolis DA, et al. Cabotegravir+Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 32 ResultsProgram and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 31LB
Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis 2016,16:43-52
Post FA, et al. Longer-Term Safety of Tenofovir Alafenamide in Renal Impairment. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 680.
Rijnders BJ, et al. Longer-Term Renal Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 682
Simoni J, et al. Changes in Viral Load Across US Clinics Over Time. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA.. Abstract 1034
Wohl D, Oka S, Clumeck N, Clarke A, Brinson C, Stephens J, et al. A Randomized, Double-Blind comparison of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil fumarate (TDF), each coformulated with Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for initial HIV-1 Treatment: Week 96 results. J Acquir Immune Defic Syndr 2016.
Wohl D, et al. Renal Safety of Tenofovir Alafenamide in Patients at High Risk of Kidney Disease. Program and abstracts from the 23rd Conference on Retroviruses and Opportunistic Infection; February 22-25, 2016; Boston, MA. Abstract 681