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IAS 2017 Summary Report, Eric Daar, MD, Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA
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9th International AIDS Society Conference on HIV Sciences
July 23-26, 2017
Paris, France
Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
The 9th International AIDS Society Conference on HIV Science 2017 (IAS 2017) was an excellent meeting in Paris that included broad discussions about the global epidemic along with numerous presentations on HIV epidemiology, pathogenesis, prevention and treatment. A major focus included discussion related to the progress towards 90-90-90 around the world, i.e. goal of 90% of people living with HIV knowing their status, 90% of these on antiretroviral therapy (ART) and 90% of these virally suppressed. Much of the new data discussed was recently reported in the very comprehensive Global AIDS Update 2017. The data shows progress in many countries towards 90-90-90 as well as getting to goal of 30 million on treatment by 2020 [estimated 33 million have HIV globally]. In select countries progress towards 90-90-90 is promising and in others much less so, with particularly disappointing statistics for Eastern Europe and Central Asia. Globally, recent data suggests that just under 20 million people are on treatment, which is good but demonstrates that there remains a long way to go between now and 2020.
This review will focus on select studies related to cure research, prevention and treatment. I will touch on the presentations that I thought were particularly interesting, providing a summary that includes what I considered the "headlines" followed by "study findings/Interpretation."
HIV CURE
Cure research has been on the agenda for several years, but remains in the very early stages of exploration. Timothy Ray Brown remains the best characterized and most likely to be truly cured individual. At this meeting an excellent overview of progress and research was provided by Anthony Fauci from NIAID and there were several other reports of work in this area.
Headlines:
⋅ Fauci's presentation defined types of "cure" and new avenues of research, including presentation of a negative [demonstrated no efficacy] therapeutic vaccine trial in participants previously treated during acute infection.
⋅ An African child was described to not have viral rebound for 8.5 years after treatment interruption.
⋅ Use of a broadly neutralizing antibody in those treated during acute infection demonstrated no clear evidence of delaying viral rebound.
Study findings/Interpretation:
⋅ Anthony Fauci provided an excellent overview on the topic of cure research entitled "Sustained ART-free HIV Remission: Opportunities and Obstacles." He defined classic cure as eradication of replication-competent HIV, versus control of viral rebound without eradication as "sustained virologic remission." He presented data from a study using a therapeutic HIV vaccine with multiple primes with DNA and boosts with rVSV with multiple gene inserts of gag, pol, env, nef, tat and vif along with adjuvant IL-12 in participants treated during acute infection. Despite a fairly aggressive approach toward remission in participants with a relatively small viral reservoir resulting from early treatment there was no difference between the treated and placebo group in time to viral rebound or impact on size of the viral reservoir. With time and further appreciation of the challenges of cure or remission, Dr. Fauci concluded that "Eradication of the HIV reservoir is an aspirational goal that is highly unlikely to succeed on a large scale." He further noted that a more realistic goal might be "The preservation of natural immunity without additional immune enhancing approaches will prove effective in controlling HIV rebound following analytic treatment interruption for varying durations of time in a subset of individuals."
⋅ A South African child treated with ART during infancy as part of CHER Trial of early therapy was presented. Initial plasma HIV RNA was 150,000 copies/mL at 8.5 weeks of life and then after 40 weeks of treatment with undetectable viral load had treatment interrupted with no viral rebound for 8.5 years thus far (1). This is somewhat reminiscent of the "Mississippi Baby," only in that case the virus rebounded after approximately 28 months. A hypothesis in these cases is that if the viral reservoir is markedly reduced with early treatment it might dramatically delay the time to viral rebound upon withdrawal of therapy, which is typically a matter of weeks. This experience is similar to select other cases of early therapy with sustained suppression off treatment, such as a French teenager suppressed off therapy for approximately 11 years and several in the VISCONTI cohort. Whether this patient is truly cured, i.e. without virus in the body or simply in long-term remission is not known. Similarly, only time will tell whether viral rebound will occur in the future.
⋅ A group of 24 patients treated during very early stages of acute infection had been on therapy with viral suppression for approximately 3 years when they were randomized to either VRCO1, a broadly neutralizing antibody versus placebo with subsequent treatment interruption. The primary objective was to maintain viral suppression at 24 weeks (2). The hypothesis was that those treated during acute infection would have a smaller reservoir to be managed off therapy and that VRC01 would be able to control virus better than what would be seen with treatment interruption alone. The study showed that while VRC01 was well tolerated there was only a trend towards delayed virologic rebound and it was not sufficient to maintain viral suppression even in this idealized study population.
HIV PREVENTION
The greatest advances in prevention have been related to use ART in HIV-infected or uninfected people at risk. There were several studies addressing these issues.
Headlines:
⋅ A large cohort of serodiscordant men who have sex with men (MSM) were followed with over 12,000 condomless sex acts while the infected partner had undetectable viral loads on treatment and PrEP was not being used by the uninfected partner without a single case of HIV transmission.
⋅ On demand PrEP was effective in the less sexually active participants in the ipergay study.
⋅ Injectable long-acting cabotegravir (CAB LA) demonstrated adequate levels for PrEP with every 8-week dosing.
⋅ Weekly oral MK-8591 protects macaques from infection.
Study findings/Interpretation:
⋅ The Opposites Attract Serodiscordant Cohort followed serodiscordant MSM in Australia, Rio De Janeiro and Bangkok (3). The average follow-up was 1.5 years with a subset of the 359 having been virologically suppressed with the partner not using PrEP while engaging in condomless sex. There were approximately 12,000 condomless sex acts with no transmission events, an estimated risk of 0 with 95% CI of 0, 1.56%. this experience complements data from the PARTNER study which included a relatively small number of MSM with similarly no linked transmission events, estimated risk of 0 with slightly broader 95% CI of 0, 2.7%. This is another data set that supports the concept that those stably suppressed are highly unlikely to transmit to their partner, with an increasing number of MSM being analyzed. This adds further evidence for the concept that undetectable equals untransmittable.
⋅ The ipergay study was an important attempt to determine if on-demand PrEP would be effective. The study design targeted high risk, HIV-uninfected MSM who took two tablets of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) between 2 and 24 hours before sex then one tablet 24 hours and again 48 hours after sex. Those who had another exposure within 48 hours of previous event they continued the daily dosing at 24 and again 48 hours after the last sex act. During an interim review it was found that the treatment was very effective and the study was stopped after approximately 400 individuals were enrolled. An important limitation of the study was that the enrolled subjects had a high frequency of exposures translating into the average person taking a median of more than 15 doses per month. Because of this it was difficult to know whether the results could be applied to those who were less sexually active. At this meeting a post-hoc analysis was performed on 269 participants with 134 patient-years of follow-up that took below the median pill taking, a median in this group being 9.5 pills/month with 5 sexual encounters/month, 25% being <2 per month. There were a total of 6 infections in this group, all in the placebo arm with 0 in the treatment arm with estimated reduction in risk being 100% with 95% CI of 39, 100. This was fairly compelling evidence for this strategy in MSM, recognizing the CI were very wide. It is unclear whether this post-hoc analysis would be sufficient to support a recommendation for this strategy in MSM and currently the only approved dosing schedule for PrEP remains daily.
⋅ HPTN 077 is a safety and pharmacokinetic study of long-acting cabotegravir (CAB LA), a novel integrase strand transfer inhibitor (INSTI) moving forward in clinical trials for treatment and prevention. An important first step for PrEP was to determine at what dosing frequency it would need to be given. HPTN 077 was a study to assess the safety, tolerability and pharmacokinetics of this agent in low-risk, HIV-uninfected women and men (5). The study assessed these factors giving CAB LA injections at a dose of 800 mg every 12 weeks or 600 mg every 8 weeks with detailed pharmacokinetics with specific pharmacokinetic specific drug level targets. The study demonstrated the drug to be well tolerated overall with pharmacokinetic targets being met consistently with every 8-week dosing, which is the dose advanced in large efficacy trials that are underway.
⋅MK-8591, known as EFdA is a novel agent with a long half-live that inhibits reverse transcriptase by preventing translocation. This study included 8 male macaques who were given 3.9 mg/kg of MK-8591 or placebo on days 0, 7 and weekly thereafter for maximum of 14 doses or until simian HIV infection was confirmed after serial challenges (6). All were challenged intrarectally on day 6 and weekly thereafter for a maximum of 12 challenges or until infection was confirmed. The placebo-treated macaques became infected after 1-4 challenges, median 1 with all treated animals remaining uninfected throughout. This data suggests that this agent is highly effective in this animal model and shows great promise as a long-acting agent for PrEP.
ANTIRETROVIRAL THERAPY
This meeting was particularly rich with important presentations related to treatment. This included new drugs and new treatment strategies for first-line therapy, maintenance therapy in those suppressed and second-line treatment. Many of these studies are likely to impact treatment in the not too distant future. I have taken the liberty to describe a select group of studies that for a variety of reasons I believe are likely to be most impactful over next few years.
Headlines:
⋅ First-line therapy
⋅ Raltegravir (RAL) given as a new formulation of two 600 mg tablets once per day with two NRTIs demonstrated similar safety and efficacy at 96 weeks as the previously approved 400 mg twice daily dosing.
⋅ Darunavir (DRV)/ritonavir (RTV) plus lamivudine (3TC) had similar efficacy as DRV/RTV plus 3TC and another nucleoside reverse transcriptase inhibitor (NRTI) at 24 weeks of follow-up.
⋅ Fixed-dose combination Doravirine (DOR), a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) combined with 3TC/TDF was similarly efficacious and better tolerated than efavirenz (EFV)/FTC/TDF at 48 weeks.
⋅ Bictegravir (BIC), a novel integrase strand transfer inhibitor (INSTI) combined with FTC/Tenofovir alafenamide (FTC/TAF) as a single tablet regimen demonstrated similar efficacy as Dolutegravir (DTG) with the same NRTIs. Notably, no emergent resistance mutations were seen in either study arm.
⋅ BIC combined with FTC/TAF in single tablet regimen demonstrated similar efficacy as single tablet DTG/abacavir (ABC)/3TC. Once again, there were no emergent drug resistance mutations seen in either study arm.
⋅ DTG plus 3TC demonstrated high rates of viral suppression in two single-arm pilot studies.
⋅ Maintenance therapy
⋅ CAB LA plus long-acting rilpivirine (RPV LA) demonstrated sustained suppression at 96 weeks as part of a maintenance strategy.
⋅ Second-line therapy
⋅ DTG with two NRTIs, where at least one of the latter being fully active, was equally efficacious as lopinavir/ritonavir (LPV/r) plus two NRTIs in those with first-line failure on two NRTI plus a NNRTI regimen.
⋅ New agents in early stage development
⋅ MK-8592 (EFdA) is a potent, long-acting nucleoside reverse transcriptase translocation inhibitor that suppressed viral load to more than 1.5 log10 copies/mL after a single dose of drug.
Study findings and interpretation:
⋅ The ONCEMRK Study was the registrational trial for a new formulation of RAL that can be given once-daily (7). Previous reports from this study demonstrated excellent tolerability and similar potency as first-line regimen when two NRTIs were given with previously approved dose of RAL 400 mg twice daily compared to the new form with once-daily dosing. This study enrolled treatment-naïve patient into double-blind, double-dummy with 2:1 randomization to either 1200 mg RAL once-daily (n=500) or 400 mg RAL twice daily (n=250), both combined with TDF/FTC. The virologic outcome reported at this meeting was suppression to <40 copies/mL at 96 weeks which was approximately 81% in both groups and met criteria for noninferiority. There was no difference in protocol-defined viral failure and emergent resistance was rare (∼1%), but did occur to both NRTIs and INSTIs in both study groups. The safety profile was very similar between groups. This study provides further follow-up of a new and recently FDA approved formulation of RAL, arguably one of the best tolerated antiretrovirals that is associate with minimal drug-drug interactions and can be given once-daily. Based upon the available data, the current indications for this formulation of RAL is for those starting therapy for the first time with two NRTIs or in those stably suppressed on twice-daily RAL.
⋅ The ANDES Study assessed the safety and efficacy of open-label RTV (100 mg)-boosted DRV (800 mg) in fixed dose combination plus 3TC compared to with 3TC/TDF (8). This presentation was of the Phase 1 portion of the study which included 145 treatment-naïve patients randomized 1:1 to the dual versus triple drug regimen. The investigators reported the interim results assessing the proportion with viral loads <400 copies/mL at 24 weeks. The study population included approximately 25% of subjects with baseline plasma HIV RNA >100,000 copies/mL. The Interim results showed similar efficacy between groups with 97% versus 95% meeting this criterion for suppression in the triple and dual therapy arms, respectively. All subjects in both arms with baseline viral loads of >100,000 copies/mL achieved this level of suppression. There were less grade 2 and 3 adverse events in the dual therapy arm, mostly driven by lower frequency of mild gastrointestinal complaints. The study will move on to assess the primary endpoint of <50 copies/mL at 48 weeks and enter Phase 2 portion that will enroll an additional 190 participants to be fully powered to assess noninferiority for this endpoint at 48 weeks. Prior to this study the only contemporary, fully-powered studies to look at a tenofovir and abacavir-sparing first-line regimen was LPV/r plus 3TC and DRV plus RTV plus RAL. Both of these studies had limitations with the former using a protease inhibitor (PI) with inferior tolerability and the latter demonstrating reduced antiviral activity in those with high plasma HIV RNA and low CD4 cell counts. Once fully enrolled, the ANDES Study will provide data using a better tolerated more commonly used PI option.
⋅ The DRIVE AHEAD Study was one of two registrational trials of DOR, a new NNRTI that was developed to be potent, well-tolerated and be active against some viruses resistant to first generation NNRTIs (9). The first study in treatment-naïve patients compared DOR with two NRTIs to DRV plus RTV with two NRTIs and demonstrated good tolerability and efficacy. This study compared DOR (100mg/d) as a single tablet regimen combined with 3TC and TDF, which is the formulation that they plan to move forward with once approved, compared to Efavirenz (EFV)/TDF/FTC. The primary endpoint was to show noninferiority for proportion with HIV RNA <50 copies/mL at week 48. A second primary endpoint was superiority to EFV/FTC/TDF as assessed by the proportion of participants with neuropsychiatric adverse events by week 48 in categories of dizziness, sleep disorders and disturbances, and altered sensorium. The study included 85% males with 20-23% having baseline plasma HIV RNA >100,000 copies/mL and 12-13% with CD4 cell count <200 cells/uL. The study demonstrated noninferiority for the primary endpoint with proportion <50 copies/mL at 48 weeks being 84 and 81% for the DOR versus EFV, respectively. This held true across subgroups, including those with plasma HIV RNA >100,000 copies/mL and CD4 counts <200 cells/uL at baseline. Protocol-defined virologic failure occurred in 5% of DOR and 3.8% of EFV patients with NNRTI and NRTI resistance being selected for in a subset of both groups. The DOR-containing regimen proved to be superior for prespecified neuropsychiatric adverse event endpoint with significant differences in dizziness, sleep disorders and disturbances and altered sensorium. The investigational regimen was also more lipid neutral with less of an effect on LDL and non-HDL cholesterol. Overall this study demonstrated that DOR was as effective and better tolerated than EFV. Moreover, unlike what was seen in some studies of RPV, efficacy was similar regardless of baseline characteristics. While this represents a new drug in an existing class that could impact guidelines, one interesting aspect is that it will be moving forward as a fixed-dose combination with 3TC which is generic, and TDF which will soon be generic, potentially being available at a substantially reduced price.
⋅ Bictegravir (BIC) is a new INSTI that is dosed at 50 mg/d, has limited drug-drug or drug-food interactions and does not require boosting. The drug is being developed as a single tablet regimen combined with FTC/TAF. The primary analysis of two registrational trials in treatment naïve patients were presented at this meeting. The first study compared BIC/FTC/TAF to DTG plus FTC/TAF in placebo-controlled trial with a primary endpoint of noninferiority for proportion with viral loads <50 copies/mL at 48 weeks (10). For the primary efficacy endpoint noninferiority was shown with proportion <50 copies/mL being 89 and 93% for the BIC and DTG arms, respectively. True virologic failure was extremely rare in both arms with the biggest difference seen in those discontinuing for reasons other than adverse events/death who happened to have last HIV RNA greater than or equal to 50 copies/mL. There was no hint that this difference was related to study drug with 6 participants in the BIC study arm having their last measured viral load done at baseline prior to the study participant leaving for a variety of nonstudy, or study drug-related reasons. Only 12 total patients met criteria for resistance testing across the entire study with none demonstrating emergence of NRTI or INSTI resistance mutations. From a tolerability perspective, there were no obvious differences in frequency of all grade adverse event or adverse events leading to study drug discontinuation. There was a very modest, but significantly greater decline in estimated glomerular filtration in those on DTG than BIC which is of unknown clinical relevance. Changes in lipids were comparable between study groups. In conclusion, this study demonstrated that BIC appears to have similar potency and as well tolerated as DTG. As seen with DTG, there has been no emergent resistance to any study drugs in those treated with BIC. This latter observation is a factor that has made DTG a standout amongst currently approve INSTIs, which has now been a consistent finding across 4 fully powered studies presented prior to this conference and two more at this conference in the head-to-head comparisons with BIC. It is promising that in the two studies at this conference BIC has shown similar properties, although more follow-up will be necessary to fully define the barrier to resistance of BIC.
The second registration trial compared BIC/FTC/TAF to DTG/ABC/3TC in treatment naïve participants (11). This was another fully-powered noninferiority trial that enrolled over 600 patients randomized to either drug or placebo once-daily with primary endpoint being proportion with plasma HIV RNA <50 copies/mL at 48 weeks. The study enrolled approximately 10% women with baseline characteristics for the study having 16-17% with viral loads >100,000 copies/mL and 10-11% with CD4 cells <200 cells/uL. Noninferiority for the primary endpoint was shown with an extraordinarily high suppression rate of 92.4 and 93% for the BIC and DTG arms, respectively. Virologic failure was extremely low with only 5 participants meeting criteria for resistance testing, 4 in DTG and 1 in BIC arms with no emergent NRTI or INSTI resistance identified. From a tolerability perspective, frequency of adverse events was similar across groups except for significantly higher rate of mild nausea in the DTG/ABC/3TC (22.9%) compared to BIC/FTC/TAF study arm (10.2%). Presumably this difference was driven by the NRTI component of the regimen since it was not seen in the DTG vs. BIC comparison using the same NRTI backbone. Other safety assessments from this trial showed similar results for minimal change in estimated creatinine clearance, change in proteinuria and rental tubular protein excretion, bone mineral density and lipids. There was preliminary data from HIV Symptom Distress Module and Pittsburgh Sleep Quality Index that appeared to favor BIC for several parameters at select times of follow-up, e.g. nausea/vomiting, loss of appetite, trouble remembering, headache, fever/chills, difficulty sleeping, pain in hands/feet, skin problems and cough. On the Pittsburgh Sleep Quality Index, it also favored BIC over DTG for sleep disturbances. Although these later findings will be important, presented data was limited and probably will be more thoroughly described at a future meeting.
Conclusion from these two studies is that BIC is a highly efficacious and well tolerated INSTI. Like DTG, it can be given at low doses resulting in small single tablet regimen, has limited drug-drug interactions and will offer a new single tablet INSTI option that includes TAF/FTC as the NRTI backbone. The initial data is also very promising with regards to barrier to resistance. That said, the two studies with 48-week follow-up does not yet provide the assurances that have emerged with DTG. The latter having demonstrated this characteristic in now 6 large first-line therapy studies, several with extended follow-up, years of clinical practice, and emerging data showing potency in those with only one other fully active agent included in the regimen.
⋅ Extended follow-up of the PADDLE Trial and first presentation of ACTG Study A5353 provided additional data showing the potential safety and efficacy of DTG plus 3TC in treatment naïve patients. The PADDLE Trial was a pilot of 20 patients who were treatment naïve with screening plasma HIV RNA <100,000 copies/mL and CD4 count >200 cells/uL (12). The 48-week data had been previously presented and showed 18 of 20 were undetectable at this interval with one having committed suicide, which was not thought to be study drug related and the other to have low level viremia at 48 weeks that suppressed with change in treatment. At this meeting they showed the 96-week data, at which time 17 of the 18 suppressed at 48 weeks remained so with the other participant having a viral load of 70 copies/mL which upon repeat testing was <50 copies/mL without a change in regimen. This data was very promising for a novel tenofovir and abacavir-sparing regimen that will be coformulated into single tablet regimen. However, the study was limited by the small sample size and exclusion of those with relatively high plasma HIV RNA and low CD4 cell counts.
A5353 was another single arm pilot study of DTG plus 3TC in treatment naïve patients (13). Unlike PADDLE, the study enrolled approximately 120 participants and targeted at least 25% to have baseline plasma HIV RNA between 100,000 and 500,000 copies/mL. Participants needed to have no resistance to NRTIs, INSTIs or PIs and all received once-daily DTG plus 3TC with primary endpoint being suppression at 24 weeks of follow-up. Overall, 90% of subjects were suppressed at 24 weeks with no difference in efficacy between those with baseline plasma HIV <100,000 or between 100,000 and 500,000 copies/mL. There were three with protocol-defined virologic failure, all of whom had DTG levels suggesting suboptimal adherence. One of these individuals did have emergent M184V and R263R/K mixture, the latter of which confers some level of resistance to DTG. Although this remains a small, single-arm study, it does expand the experience to larger numbers of participants and included those with higher viral loads. The GEMINI Studies are fully powered, registrational trials of this regimen that will definitively show the safety and efficacy of this novel two drug, tenofovir and abacavir (ABC)-sparing regimen.
⋅ The LATTE 2 study is a phase 2 trial to assess the ability of CAB LA plus RPV LA given as intramuscular injections to maintain viral suppression (14). The study enrolled approximately 300 treatment naïve participants who were initiated on abacavir/lamivudine plus oral CAB (30 mg/day) for 20 weeks. Those virologically suppressed had oral RPV added for four weeks to assure tolerability and then if still suppressed, which was the case for the overwhelming majority, they were randomized 2:2:1 to either every month or every two month injections of CAB LA (400 or 600 mg) and RPV LA (600 or 900 mg) or continued ABC/3TC plus oral CAB as a control. The LA drugs were given at the once monthly and every two month intervals as either two 2-mL or two 3-mL intragluteal injections, respectively. After 32 weeks of follow-up on LA therapy plasma HIV RNA levels were less than 50 copies/mL in greater than 90% in all groups with only 2 protocol-defined virologic failures. There were no major adverse events noted other than injection site reactions, mostly being pain that lasted only a few days and became less frequent with time. At this meeting data was shown for 96-week follow-up which continues to suggest that this is a highly promising combination, potentially give at once monthly or even every other month dosing. In fact, the virologic response at 96 weeks was 94% for every 8-week dosing, 87% for every 4 week dosing and 84% for those continued on two NRTIs plus short acting CAB once daily. There were 2 with protocol-defined virologic failure in the every 4-week arm compared to non in every 4 weeks and one in the oral regimen. For those on every 8 week LA regimen 1 had no emergent resistance and another had both INSTI and NNRTI mutations present at 48 weeks. This included K103N, E138G and K238T in reverse transcriptase and Q148R in integrase gene. The regimen was well tolerated and found to be highly acceptable to those who chose to participate in this phase 2 study. The ATLAS Studies are ongoing registrational trials looking at this regimen given every 4 weeks for maintenance therapy in virologically suppressed individuals and will better define the overall safety, efficacy and acceptability of this regimen. There is also ongoing discussion regarding the initiation of an every 8-week trial in the near future.
⋅ The DAWNING Study was one of the most important studies presented at the meeting with the potential to impact on the care of many patients in resource limited and rich countries. This was a large randomized phase III study in those experiencing virologic failure on two NRTI plus a NNRTI-based regimen. 968 were screened and 624 randomized (15). Participants underwent drug resistance testing and were randomized to open label DTG or LPV/r plus 2 NRTI of investigators choice. Importantly, unlike earlier studies of first-line NNRTI failures where resistance testing was not routinely performed and many enrolled with extensive NRTI resistance, this study required that at least one NRTI in the regimen be fully active based upon resistance testing. At baseline, the overwhelming majority of study participants received a study regimen including <2 fully active NRTIs The NRTI selection was approximately 40% zidovudine (ZDV)/3TC, 40% TDF with 3TC or FTC, 12% TDF plus ZDV and 2% ABC plus 3TC. At the time of an interim analysis at 24 weeks the Data Safety Monitoring Board recommended the LPV/r arm be stopped due to superior suppression of plasma HIV RNA in the DTG group. By the time of the interim analysis there were a substantial number of participants who had gotten to 36 and 48 weeks of follow-up, with these individuals continuing to show superior efficacy with DTG. These findings were consistent regardless of baseline plasma HIV RNA, CD4 cell count and whether they had 2 or <2 active NRTIs in the regimen. There was no data presented regarding baseline drug resistance above and beyond how many active NRTIs were in the study regimen. However, one could likely assume that for those who received <2 active NRTIs the overwhelming majority must have had the M184V mutation. If this proves to be true, this study is by far the largest to demonstrate that DTG can be highly active when combined with one active NRTI, even when that NRTI is not 3TC or FTC.
Based upon the DAWNING data, DTG with at least one active NRTI would be superior to LPV/r in those who are INSTI and PI-naïve and experiencing virologic failure. Unfortunately, one could not extrapolate this data to those in which resistance testing in not available to verify the availability of an active NRTI, a common situation in select resource limited settings. In contrast, when resistance testing is available this represents strong data showing that those with virologic failure can be effectively managed with a regimen that does not include a boosted PI, which is distinct from current treatment guidelines. The study also complements emerging data in first-line and maintenance therapy regimens that include DTG with a single active NRTI. Most of the existing data in this area included 3TC or FTC as the active NRTI. Results from DAWNING suggests that the same would be true with TDF and possibly other NRTIs. Unfortunately, there were very few that used ABC as an active NRTI in this study so one could not be as confident using this drug in this setting. Extrapolating from this data may also profoundly impact recommendations for switching in virologically suppressed patients. The current teaching has been that one should not switch from a boosted PI to a non-boosted PI-based regimen unless confident that the background agents, typically NRTIs were fully active. Now we have data showing DTG may be an alternative to a boosted PI in the setting where only one of the NRTIs is active, opening up new options for these patients.
⋅ MK-8591, known as EFdA which inhibits reverse transcriptase by preventing translocation. Preliminary data presented at this meeting showed that a single dose dramatically reduced plasma HIV RNA for extended periods of time. The drug was dosed at 0.5, 1, 2, 10 and 30 mg to 6 individuals per dose. All groups exhibited a decline in plasma HIV RNA ranging from approximately 1.2 to 1.6 log10 copies/mL with no evidence of rebound during the 10 days of follow-up. All doses were well tolerated and no drug resistance mutations were noted to emerge after the single dose (16).
CONCLUSIONS
IAS 2017 was a superb meeting with many important studies of pathogenesis, cure, prevention, treatment and complications. I have chosen to focus on a select group of studies in the Cure, Prevention and Treatment arena that are likely to impact the field and HIV management moving forward. I strongly encourage readers to go to Conference website for additional presentations that might be of great interest.
Conflicts: In the last year Eric Daar has received research support from Gilead, Merck, ViiV and was a consultant for Bristol Myers Squibb, Gilead, Janssen, Merck, Theratechnologies and ViiV.
REFERENCES
1. Vilari A, Cotton M, Kuhn L, et al. Viral and host characteristics of a child with perinatal HIV-1 following a prolonged period after ART cessation in the CHER trial. IAS 2017, Abstract TUPDB0106LB.
http://programme.ias2017.org/Abstract/Abstract/5836
2. Crowell TA, Colby DJ, Pinyakorn S, et al. HIV-specific broadly-neutralizing monoclonal antibody, VRC01, minimally impacts time to viral rebound following treatment interruption in virologically-suppressed, HIV-infected participants who initiated antiretroviral therapy during acute HIV infection. IAS 2017, Abstract TUAB0106LB.
http://programme.ias2017.org/Abstract/Abstract/5527
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4. Antoni G, Tremblay C, Charreau I, et al. On-demand PrEP with TDF/FTC remains highly effective among MSM with infrequent sexual intercourse: a sub-study of the ANRS IPERGAY trial. IAS 2017, Abstract TUAC0102.
http://programme.ias2017.org/Abstract/Abstract/3629
5. Landovitz R, Li S, Grinsztejn B, et al. Safety, tolerability and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected women and men: HPTN 077. IAS 2017, Abstract TUAC0106LB.
http://programme.ias2017.org/Abstract/Abstract/5481
6. Markowitz M, Gettie A, St. Bernard L, et al. Weekly oral MK-8591 protects male rhesus macaques against repeated low dose intrarectal challenge with SHIVC109P3. IAS 2017, Abstract MOAX0203.
http://programme.ias2017.org/Abstract/Abstract/5533
7. Cahn P, Kaplan R, Sax P, et al. Raltegravir (RAL) 1200 mg once daily (QD) versus RAL 400 mg twice daily (BID), in combination with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), in previously untreated HIV-1 infection through week 96. IAS 2017, Abstract TULBPEB20.
http://programme.ias2017.org/Abstract/Abstract/5493 TULBPEB20
8. Sued O, Figueroa MI, Gun A, et al. Dual therapy with darunavir/ritonavir plus lamivudine for HIV-1 treatment initiation: week 24 results of the randomized ANDES study. IAS 2017, Abstract MOAB0106LB.
http://programme.ias2017.org/Abstract/Abstract/5615
9. Squires KE, Molina J-M Sax PE, et al. Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study. IAS 2017, Abstract TUAB0104LB.
http://programme.ias2017.org/Abstract/Abstract/5585
10. Sax PE, Pozniak A, Arribas J, et al. Phase 3 randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-dose combination (B/F/TAF) vs dolutegravir (DTG) + F/TAF in treatment-naïve HIV-1 positive adults: week 48 results. IAS 2017, Abstract TUPDB0201LB.
http://programme.ias2017.org/Abstract/Abstract/5793
11. Gallant J, Lazzarin A, Mills A, et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, vs ABC/DTG/3TC in treatment-naïve adults at week 48. IAS 2017, Abstract MOAB0105LB.
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12. Figueroa MI, Rolon MJ, Patterson P, et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naïve patients: 96 week results of the PADDLE trial. IAS 2017, Abstract MOPEB0287.
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13. Taiwo BO, Zheng L, Nyaku AN, et al. ACTG A5353: a pilot study of dolutegravir (DTG) + lamivudine (3TC) for initial treatment of HIV-1-infected participants with HIV-1 RNA < 500,000 copies/mL. IAS 2017, Abstract MOAB0107LB.
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14. Eron J, Margolis D, Gonzalez-Garcia J, et al. Safety and efficacy of long-acting CAB and RPV as two drug IM maintenance therapy: LATTE-2 week 96 results IAS 2017, Abstract MOAX0205LB.
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15. Aboud M, Kaplan R, Lombaard J, et al. Superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment: interim data from the DAWNING study. IAS 2017, Abstract TUAB0105LB.
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16. Matthews RP, Schurmann D, Rudd DJ, et al. Single doses as low as 0.5 mg of the novel NRTTI MK-8591 suppress HIV for at least seven days. IAS 2017, Abstract TUPDB0202LB.
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