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10th International AIDS Society Conference on HIV Science
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July 21-24, 2019
Mexico City, Mexico
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 10th International AIDS Society Conference on HIV Science 2019 (IAS 2019) was an excellent meeting in Mexico City that included numerous presentations on HIV prevention and treatment. This review will focus on select studies in these areas of research. 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." Notably, there were several presentations from this meeting that have, or will have substantial impact on treatment around the world.
HIV PREVENTION
HIV prevention represents one of the pillars that will need to be exploited in order to curb the spread of HIV infection. There were important updates on previous studies, as well as novel approaches in development in the arena of preexposure prophylaxis (PrEP) that I will describe below.
Headlines:
• The Prevenir study was updated showing the high level of effectiveness of on-demand PrEP amongst primarily MSM in Paris.
• In DISCOVER Trial, tenofovir alafenamide/emtricitabine (TAF/FTC) for PrEP in men who have sex with men (MSM) and transgender women is associated with rapid accumulation of active form of drug intracellularly compared to tenofovir disoproxil fumarate/FTC (TDF/FTC).
• MK-8591 (Islatravir) is a potent antiretroviral agent that demonstrates favorable pharmacokinetics when used as long-acting implant.
Study findings/Interpretation:
• The Prevenir Studywas an open-label study conducted in Paris where primarily MSM at high risk for acquiring HIV were offered either once-daily TDF/FTC or on-demand TDF/FTC dosed as used in iPergay study, as 2 tablets 2-24 hours prior to sex and then 24 and 48 hours after the pre-sex dose, so called 2-1-1 regimen. The primary end point of the study was to reduce the number of new HIV diagnoses among MSM in Paris. At this meeting they reported the results from 3145 enrolled individuals, approximately half of which chose the on-demand strategy. They reported a very low incidence of infection in both groups, 0 in the daily dosing and 2 in the on-demand group, both of the latter having stopped PrEP 7-10 weeks before there date of infection (1). While the iPergay study had limitations because it was stopped early with only approximately 200 people in the investigational study arm and had very high risk groups that were dosing at a high frequency, this open-label study included approximately 1500 participants receiving on-demand strategy. The high rate of success is supportive of several guidelines panels recommending this as an optional strategy, particularly for those engaging in relatively infrequent sex. A few caveats are worth noting. First, this was not a randomized study. Second, there will be further follow-up likely reported at future meetings. Third, the regimen is not currently approved or endorsed as a strategy by the United States FDA or CDC and finally, it is not clear this approach can be extrapolated to high risk women.
• The DISCOVER Trial was a randomized-controlled study that enrolled 5387 high risk MSM and transgender women to TDF/FTC or TAF/FTC. The primary endpoint was specified to be assessed when all participants had at least 48 weeks of follow-up and 50% had reached 96 weeks. The primary endpoint was presented at CROI 2019 and was noted to have a much lower event rate than expected based upon results from previous PrEP trials in this patient population. In fact, the sample size for DISCOVER was determined based upon an expected incidence rate per 100 patient years of 1.44. What was see was an incident rate for TDF/FTC and TAF/FTC of 0.34 and 0.16, respectively, with upper 95% confidence interval of 1.15, which met the pre-specified noninferiority criteria. There were a total of 22 transmission events, the overwhelming majority of which occurred in those with low drug levels. A low incident rate in a non-placebo controlled trial could reflect high levels of drug adherence and efficacy in both study arms, which could explain the TDF control group having lower infection rates than seen in previous PrEP studies. Alternatively, these results could be explained by the study group being at very low risk for acquiring HIV infection, even without an active intervention. If the latter were true, one could find that the noninferiority results were driven by the low risk for HIV acquisition in the study groups rather than the activity of either drug. This concern was largely mitigated by the data showing a high incident rate of sexually transmitted diseases in both study arms throughout the course of the study.
At IAS 2019 investigators reported data on the pharmacokinetics of intracellular tenofovir-triphosphate, the active form of drug and showed that there was considerably quicker accumulation and possibly persistence of active drug with TAF/FTC (2). They determined the percent with a level above the 90% effective concentration by 20-28 hours post dose which was observed in 98% of those on TAF/FTC versus 68% in TDF/FTC group. They also found that steady state intracellular levels were more than 6-times higher in the TAF/FTC than TDF/FTC-treated individuals. Another observation of interest related to modeled data showing that concentrations would remain greater than 90% effective concentration for 16 days after final dose with TAF/FTC compared to 10 days for TDF/FTC. Although the available data cannot prove that these findings are clinically relevant or could explain the findings in DISCOVER, they do represent potential advantages, above and beyond• safety signals, of using TAF instead of TDF as part of PrEP regimen. The new formulation for PrEP is under FDA review and if approved further consideration will need to be given as to whether the potential difference in cost, especially once TDF/FTC becomes generic is outweighed by the potential advantages of TAF/FTC.
• Islatravir is a potent and novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) antiretroviral agent that has high level of activity and a long half-life when given at relatively small doses. These properties allow for consideration of novel dosing strategies for treatment and possibly prevention. At IAS 2019 data was presented on the safety and pharmacokinetics of an Islatravir implant for potential PrEP indication (3). This was a double-blind, placebo-controlled trial in healthy individuals with objectives being safety, tolerability and pharmacokinetics. Implants were 4 cm x 2 mm of either placebo (n=4), 54 mg (n=12) or 62 mg (n=12) that were placed subdermally in upper arm for 12 weeks followed by 4 weeks post-removal with plasma and periphaerl blood mononuclear cell levels assessed for drug levels. There were no discontinuations due to adverse events and no laboratory or other signs of systemic reactions. Local tolerability with erythema, induration, pruritus and tenderness were reported as generally mild. The intracellular islatravir triphosphate level target was to exceed threshold of 0.05 pmol/106 cells throughout the 12-week period the implant was in place, which was achieved in both groups. It is clear that one of the limitations of current PrEP is the importance of adherence with increasing focus on potential novel long-acting strategies. The possibility of an implant is potentially promising although it is worth noting that this data is limited to pharmacokinetics and future studies will need to assess concentrations in mucosa and ultimately efficacy in preventing infection.
ANTIRETROVIRAL THERAPY IN PREGNANCY
Recent data from a prospective study in Botswana showed a statistically significant increased risk of neural tube defects (NTDs) in those exposed to dolutegravir (DTG) during conception, but not in those exposed later in pregnancy. Although the preliminary data reported only 4 events in a relatively small number of individuals, the initial data had a profound impact on guidelines and challenged the plan to widely recommend DTG as preferred first and second line option for all individuals in resource-limited settings.
Headlines:
• The Tsepamo study update markedly expanded the number of sites prospectively evaluating the incidence of NTDs and demonstrated that while the rate of defects declined, it remained significantly higher for those receiving DTG during conception than those who received it later in pregnancy or alternative agents at time of conception.
• Botswana data was reported from sites not included in Tsepamo where numbers of exposed was much smaller and failed to demonstrate a NTD signal in those exposed to DTG during conception.
• Brazil had expanded use of DTG for some time and reported in relatively small, compared to Tsepamo data, number of women exposed at conception, without demonstrating a significant signal NTD risk.
• At the time of the meeting, and with advanced access to updated data the WHO guidelines announced that women should be informed of the small but significantly greater risk of NTD observed in Tsepamo, but still consider DTG a preferred first and second-line antiretroviral option for all men and women in resource-limited settings.
Study findings/Interpretation:
• There has been a great deal of interest in recent observations from Botswana Tsepamo cohort initially showing 4 cases of NTD in those exposed to DTG at time of conception. This was a significantly higher rate than observed in HIV-uninfected individuals, those exposed to other drugs, including efavirenz (EFV), and those exposed to DTG after conception. The initial observation led to most guidelines recommending that pending more data, DTG should not be used in those who might become pregnant or are in the first trimester of pregnancy. When this data was first reported approximately one year ago, it was announced that the cohort would be expanded to include approximately 70% of pregnant women in Botswana with expansion of the number exposed to approximately four-times that initially reported. At IAS 2019 this was presented with an increase in the denominator to approximately 1600 women exposed to DTG during conception and a single additional NTD case, bringing the total number to five (4, 5). This represented a decrease in the incidence from the original report of approximately 0.9, which was then reduced to 0.67 and now 0.3, although still significantly higher than the approximately 0.1 seen in other populations. The conclusion being that while the absolute risk is low it is approximately 3-times higher and significantly greater than those exposed to other drugs, primarily EFV or no drugs at the time of conception.
• Prospective birth outcomes surveillance assess outcome among Botswanan women in study commissioned by Ministry of Health and Wellness in response to Tsepamo findings. It included 22 facilities not covered by Tsepamo expanded cohort. From this group there were 157 DTG exposures, 381 non-DTG exposures and 261 exposed to EFV with only 1 NTD which was seen in the DTG group, but not significantly different than other groups in light of very broad confidence intervals associated with small sample size (6).
• Brazil reported retrospective data from 1452 birth outcomes of possible DTG-exposures at conception (n=384) and unexposed (n=1068) pregnant women. From this group there were no cases of NTD reported (7). The only significant difference noted was a relatively low, but significantly greater risk of stillbirth amongst those not exposed to DTG. This study has many limitations, including fact that it was relatively small, retrospective and less reliable for both assessing timing of drug exposure during pregnancy and case finding. Nevertheless, it is one additional piece of data available for counseling women about overall risks.
• WHO Guidelines were updated at time of the meeting based upon new data presented at IAS 2019 (8). It is likely that the guidelines were further influenced by consideration of the benefits associated with DTG use relative to alternative agents, such as EFV, namely better tolerability, potential increased antiviral efficacy and higher barrier to resistance, all of which have benefits for the women, which can translate into improved outcomes for them and decreased risk of transmission, in event of virologic failure, to the newborn.
CURRENT ANTIRETROVIRALS IN TREATMENT NAïVE INDIVIDUALS
Headlines:
• GEMINI 1 and 2 shows sustained noninferiority of DTG + 3TC compared with DTG plus TDF/FTC for 96 weeks without any emergent resistance.
• ADVANCE demonstrated in South African study group that there was similar efficacy when using DTG/FTC/TAF vs DTG/FTC/TDF vs EFV/FTC/TDF, although increased weight gains with DTG-based therapy and more resistance with EFV-based regimen was observed.
• Weight gain in NAMSAL ANRS 12313 a Cameroon study which showed similar virologic efficacy in treatment naïve patients given DTG (50 mg/d) versus low dose EFV (400 mg/d) with TDF and 3TC, at IAS 2019 presentation showed significantly greater increase in weight for the DTG-treated study group.
Study findings/Interpretation:
• The GEMINI 1 and 2 studies randomized 1433 treatment-naïve HIV-infected individuals with no transmitted resistance, without chronic hepatitis B infection and screening plasma HIV RNA of <500,000 copies/mL to either DTG plus TDF/FTC or DTG plus 3TC. The primary endpoint was proportion <50 copies/mL at 48 weeks and was previously reported to have met noninferiority criteria. Another important observation was that there was no emergent resistance to any component of the regimen in either study arm. These studies led to the FDA approval of DTG/3TC as a single tablet regimen for treatment-naïve patients. Interestingly, the approval was for naïve patients regardless of baseline HIV RNA, despite the fact that the study excluded those with screening levels >500,000 copies/mL. At IAS 2019 the 96-week data was presented with proportion <50 copies/mL in the DTG plus TDF/FTC versus plus 3TC being 89.5 and 86%, respectively, with no emergent resistance (9). It was also noted that there were renal and bone biomarkers that favored the two versus three drug regimen, recognizing that the three drug regimen was TDF-based. Review of this extended follow-up will occur by various guidelines panels to determine whether this data justifies consideration of this regimen as a preferred option for most patients. In addition, it remains to be seen whether guidelines will comment on whether this regimen should be considered for all, regardless of baseline viral load per FDA guidelines, or with caveats recognizing that very few had HIV RNA >500,000 copies/mL at baseline in these studies.
• The ADVANCE study was conducted in South Africa and randomized treatment-naïve patients to efavirenz (EFV)/TDF/FTC, DTG/TDF/FTC or DTG/TAF/FTC. This study was relevant to this setting where there has been a push to transition people to DTG-based regimens and where TDF may still be a commonly used option. The study demonstrated similar efficacy between the groups with proportion <50 copies/mL in the EFV/TDF/TDF, DTG/TDF/FTC and DTG/TAF/TAF being 79, 85 and 84%, respectively. Emergent resistance occurred in 4 EFV group patients to NRTIs and NNRTIs, compared to 0 in DTG/TAF/FTC arm and 4 in DTG/TDF/FTC, all of which was limited to NRTIs (10, 11). An observation of great interest related to the data on weight change during the course of this study. There have now been numerous observational studies attempting to define whether InSTIs in general, and DTG in particular may be associated with increased weight gain over comparator regimens. Several of these studies have also suggested that TAF may be associated with weight gain. Unlike the data thus far, this study allowed direct comparison in a randomized study of DTG versus EFV, as well as TAF versus TDF. The outcomes were quite strong in showing that both DTG and TAF were associated with increased weight gain, with greatest impact being on those receiving them in combination, and particularly in women. When considering the clinical relevance of this increase, it is worth noting that the magnitude of the change in weight at 96 weeks between the EFV/TDF/FTC, DTG/TDF/FTC and DTG/TAF/FTC was +1 Kg, +4 Kg and +5 Kg, respectively, with both DTG study arms being significantly greater than that with EFV. Of note, amongst women the mean increase in weight across these three groups was +3 Kg, +5 Kg and +10 Kg, respectively with suggestion that increasing weight may still have been going up at the time of the last visit.
• An analysis of weight change in ADVANCE and NAMSAL ANRS 12313 study was also conducted. As noted, the NAMSAL study was recently published and evaluated treatment-naïve individuals in Cameroon that were randomized to low dose EFV (400 mg/d) versus DTG (50 mg/d), both with TDF and 3TC, regimens that are recommended in resource-limited settings. The study enrolled 613 patients that included 66% with viral load >100,000 copies/mL and 65% women. They found similar rates of virologic suppression at 74.5 versus 69% for the DTG versus the EFV study groups, respectively, at 48 weeks (12). At IAS 2019 there was an additional analysis that looked at change in weight in both ADVANCE and NAMSAL which provided further insights into the impact treatment choice has on weight gain as well as the magnitude of the change (13). This analysis is particularly important in light of several reports suggesting that starting or switching to InSTIs in general, and DTG in particular may be associated with increases in weight gain. As noted above, there were significantly greater weight gain in the DTG arms compared to EFV. There were also greater increases in weight amongst those given DTG with TAF/FTC than DTG with TDF/FTC. The same was seen at 48 weeks in NAMSAL where the DTG mean increase was 5 Kg compared to an average increase of 3 Kg in the EFV group (P<0.001). In NAMSAL at 48 weeks there was a significantly greater frequency of incident obesity (BMI becoming >30 kg/m2) of 12 versus 5 % (p<0.01). The same was seen in ADVANCE for DTG/TAF/FTC where at 48 and 96 weeks, emergent obesity was seen in 14 and 19%, respectively. In contrast, at 48 and 96 weeks for DTG/FTC/TDF it was only 7 and 8%, and for EFV/TDF/FTC it was 6 and 4%. Collectively, this represents perhaps the strongest data thus far showing a relationship between DTG, especially with TAF being associated with not just significantly greater increases in weight, but weight changes that are probably clinically relevant. Further data is needed to know how these findings relate to other InSTIs, e.g. bictegravir (BIC) and raltegravir (RAL), as well as to how these findings should impact clinical care moving forward. In addition, if determined to be a clinically relevant finding whether the affect is reversible when regimen is changed.
ANTIRETROVIRALS IN SUPPRESSED PATIENTS
Headlines:
• The TANGO study demonstrated that virologically suppressed individuals without underlying resistance can be safely switched to DTG plus 3TC.
• GS 380-4030 showed that BIC/FTC/TAF is a switch option for those suppressed on DTG plus two NRTIs even when there is underlying NRTI resistance.
Study findings/Interpretation:
• The TANGO study was a fully powered study to determine whether those without underlying resistance who are suppressed on a stable regimen can be switched to DTG plus 3TC. Although in light of the GEMINI studies it was certainly expected that this strategy would work, this was first large study to demonstrate that it does and is associated with select safety advantages (14). The study included 741 subjects on TAF-based regimen that did not have evidence of underlying resistance and no evidence of chronic hepatitis B virus infection. The primary endpoint, proportion with VL >50 copies/mL, as well as key secondary endpoint of proportion with VL <50 copies/mL at 48 weeks both demonstrated noninfereiority to continuing current regimen, 93.2 versus 93% remaining <50 copies/mL. Of those rare individuals with viral failure in either study arm, none selected for resistance. While the findings are not surprising, they certainly provide strong evidence that this is a viable strategy. They also raise the issue for clinicians to start grappling with whether those without underlying resistance to DTG or 3TC and do not have chronic hepatitis B virus infection should routinely be switched to this option to reduce cost and even minor toxicity associated with the second NRTI. Of course this consideration may be influenced by increasing data showing a relationship between weight gain and DTG, although it does avoid TAF which also seems to be associated with increased weight gain.
• There is every reason to believe that BIC has a higher barrier to resistance than first generation InSTIs, e.g. RAL and elvitegravir. This is assumption is largely based upon in vitro data and lack of emerging resistance in naïve and switch studies. In contrast to DTG which has been studied with only one other active agent in first-line and second-line therapy, most BIC use was in naïve or stably suppressed patients without underlying resistance. Study GS 4030 enrolled virologically suppressed patients that at times had documented underlying resistance to any class except InSTIs (15). The subjects were randomized to stay on a DTG plus TDF or TAF/FTC regimen or switch to BIC/FTC/TAF. The study enrolled 565 participants with baseline NRTI resistance classified as no documented resistance (∼75%), high level resistance with K65R or >2 thymidine analogue mutations (5%), or low resistance (∼20%), not meeting criteria for either of the other groups. The presentation at IAS 2019 was of the primary endpoint at 48 weeks of follow-up and showed noninferiority for primary and key secondary endpoints with 93% on the switch versus 91% on those on continued therapy study arm maintaining plasma HIV RNA <50 copies/mL. In addition, there were no individuals with emerging resistance and no safety differences. This is perhaps the strongest and most direct evidence to date that BIC can be considered as a switch option in those stably suppressed on an alternative regimen, although in this study it was exclusively DTG, even when there is underlying NRTI resistance.
NEW ANTIRETROVIRALS IN DEVELOPMENT
Headlines:
• Long Acting (LA) cabotegravir (CAB) and rilpivirine (RPV) maintain viral suppression and are well tolerated in pooled analysis of ATLAS and FLAIR Studies.
• DRIVE2: MK8591 is a novel nucleoside reverse transcriptase translocation inhibitor that is potent, has activity against NRTI resistant virus and has a long half-life and was shown in DRIVE2 to achieve viral suppression when used with 3TC and doravirine (DOR) and maintain suppression when used with DOR alone.
• GS-6207 is first-in-class HIV capsid inhibitor with activity against a broad range of isolates, has a very long half-life and was shown to have potent anti-HIV activity after single subcutaneous dose.
• Fostemsavir is a gp120 binding small molecule that has been shown to have antiviral activity in those with multidrug resistant HIV in the BRIGHTE Study.
Study findings/Interpretation:
• The much anticipated ATLAS and FLAIR studies were presented at CROI 2019 addressing the safety and efficacy of monthly intramuscular LA CAB plus RPV in virologically suppressed patients. ATLAS enrolled 616 virologically suppressed individuals on PI, NNRTI or InSTI-based regimens and randomized them to remain on current regimen or to switch to short-acting CAB plus RPV for 4 weeks and then LA CAB plus RPV for 48 weeks. The primary endpoint was the proportion with plasma HIV RNA >50 copies/mL at 48 weeks, and a key secondary endpoint was proportion <50 copies/mL at this time point. Rates of HIV detectability were very low and met pre-specified criteria for noninferiority, with very high rates of continued suppression in both study arms.
FLAIR had a slightly different study design as it enrolled 566 treatment naïve individuals, started them on DTG/ABC/3TC and those undetectable at 20 weeks were randomized to continue regimen or switch to 4 weeks of short-acting CAB plus RPV and then monthly LA CAB plus RPV. Endpoints from FLAIR were similar to ATLAS with noninferiority demonstrated for both the primary and key secondary virologic endpoints. At IAS 2019 they analyzed pooled data from the two studies with a total of 1245 individuals and further verified the high rates of sustained virologic suppression, 93.1% in LA group compared to 94.4% in continued therapy study arm maintaining viral load <50 copies/mL at 48 weeks with good tolerance (16). In addition, as previously reported in the primary analyses for each study, injection site reactions were relatively unusual after first few weeks with quality of life and acceptability being high amongst study subjects.
We are now anticipating the results of the FDA review of ATLAS and FLAIR as well as the presentation of the fully enrolled ATLAS 2M study comparing every 4 to every 8 week injections. In fact, on August 22, 2019 there was a press release from ViiV reporting that this study met primary endpoint with complete data to be presented in near future. There is also an ACTG study, A5359 which is currently enrolling those with detectable viral load and poor adherence to see whether with financial incentives they can be suppressed on a standard of care regimen prior to then being randomly assigned to either remain on current oral regimen or switch to open-label monthly LA CAB plus RPV.
• The DRIVE2 Study evaluated islatravir as part of a three drug regimen for treatment and then maintenance of virologic suppression as part of a novel two drug regimen (17, 18). Islatravir is a nucleoside with a unique mechanism of action, acting both as a reverse transcriptase and translocation inhibitor which inhibits HIV through multiple mechanisms. It also has chemical properties that may allow for infrequent dosing. It has been shown to be potent against multiple strains, including those that have underlying resistance. It has also been shown to have long half-life with possibility of dosing as infrequently as once weekly. DRIVE2 was a phase IIB study with three parts; Part 1 treated naïve individuals with islatravir at 0.25, 0.75 or 2.25 mg/d plus daily 3TC and DOR for 20 weeks versus DOR/TDF/3TC control with approximately 30 individuals per group. They demonstrated high rates of suppression across the 4 groups at 20 weeks with 83.9, 90.0, 88.9 and 96.4% having viral load less than 50 copies/mL, respectively.
Suppressed individuals were then moved on to Part 2 where the control group of DOR/TDF/3TC was unchanged and the other groups stopped the 3TC and remained on two-drug regimen of islatravir plus DOR. At 24-weeks in Part 2, viral suppression at <50 copies/mL were maintained in 89.7, 90.0, 77.4 and 83.9% for the islatravir 0.25, 0.75, 2.25 and DOR/TDF/3TC groups, respectively. It was noted that all with protocol defined virologic failure had viral loads <80 copies/mL and none were eligible for resistance testing. In addition, there were no early safety signals. Part 3 will ultimately continue all of the islatravir groups on a to be selected dose with an additional 48 weeks of follow-up.
• GS-6207 is a first-in-class HIV capsid inhibitor, representing a new class that should be active even in those with extensive multiclass resistant HIV. In addition, its parenteral properties suggest that it can be dosed relatively infrequently. At CROI 2019 investigators reported data from a Phase 1 study with four cohorts received single subcutaneous infection of 30, 100, 300 and 450 mg of drug. Exposure was monitored during extensive pharmacokinetic sampling and showed that doses of 100 mg and above maintained levels above the protein adjusted EC95 for more than 12 weeks. At IAS 2019 the first data was presented showing in vivo antiviral activity with this agent (19). The study enrolled those who were capsid and InSTI naïve with 6 individuals receiving single subcutaneous doses at 50, 150 and 450 mg or placebo with serial plasma HIV RNA levels measured over 10 days. The results showed good tolerability and approximately 1.5 to 2.0 log10 copies/mL decrease after single dose at 10 days. This agent could represent a new option for those who need it because of viral resistance or intolerance to existing agents, as well as for novel long-acting regimens for treatment.
• Fostemsavir is a gp120 binding small molecule that has been shown to have antiviral activity in those with multidrug resistant virus. The BRIGHTE Study is a phase III, registrational trial that enrolled those with multidrug resistant HIV and virologic failure on a stable regimen. There was 272 who had at least one active drug to include in a new regimen that were randomized to add either twice-daily fostemsavir (n=203) or placebo (n=69). The primary endpoint was change in viral load over 8 days after randomization phase which has previously been shown to demonstrate significantly greater decline in log10 copies/mL viral suppression in the fostemsavir (-0.79) than placebo (-0.17) group. After this 8-day period, all were given optimized background regimen with fostemsivir. At IAS 2019 they reported the proportion with plasma HIV RNA <40 copies/mL at 96 weeks to be 60% in these highly drug resistant study subjects (20). The study also enrolled 99 individuals that did not have an active agent to include in a new regimen to a nonrandomized arm where they were simply given open-label optimized regimen with fostemsivir. In this extremely difficult to treat group, the proportion less than 40 copies/mL at 96 weeks was 37%. This study demonstrates that fostemsivir was well tolerated and has the potential to have considerable impact in those in need of new drugs in new classes.
LINKAGE AND RETENTION IN CARE
Headlines:
• HPTN 078 was a study of enhanced case management in a highly challenged population that did not demonstrate significant improvement in the proportion with viral suppression after 12 months.
Study findings/Interpretation:
• HPTN 078 represents another attempt to impact one of the most challenging deficits observed in the treatment cascade, targeting those infected but not retained in care or virologically suppressed. The study utilized an enhanced case management strategy with outreach to MSM who were not engaged in care and had detectable viral load (21). The study enrolled 72 participants into a control and 72 into an intervention group. The study population was 84% black, with >90% having high school education, 65% having annual incomes of <$20,000 per year and 86% being antiretroviral naïve. Ultimately, despite an expanded case management component there was no significant difference in proportion with plasma HIV RNA <200 copies/mL at 3, 6, 9 and 12 months, with 42% of control and 54% of intervention group meeting this endpoint at 12 months. Although it is great to see these types of studies implemented to enhance retention into care and virologic suppression, this represents yet another attempt without obvious impact of an intervention in this very challenged group of high risk individuals.
CONCLUSIONS
IAS 2019 was an excellent meeting with many important studies. I have focused on a select group of studies in the prevention and treatment arena that are likely to impact the field and HIV management in the near future. I strongly encourage readers to go to https://programme.ias2019.org/ where you can review some of the data presented at the meeting.
NATAP IAS 2019 Coverage includes full slide poster presentations of those discussed in this review.
IAS 2019: Conference on HIV Pathogenesis Treatment and Prevention
Mexico City
July 21-24 2019
Conflicts: In the last year Eric Daar has received research support from Gilead, Merck, ViiV and has been a consultant for Gilead.
REFERENCES
1. Molina JM, Ghosn J, Algarte-Genin M, et al. Incidence of HIV-infection with daily or on demand Prep with TDF/FTC in Paris area. Update from the ANRS Prevenir Study. International AIDS Society 2019, abstract TUAC0202.
2. Spinner CD, Brunetta J, Shalit P, et al. DISCOVER study for HIV pre-exposure prophylaxis (PrEP): F/TAF has a more rapid onset and longer sustained duration of HIV protection compared with F/TDF. International AIDS Society 2019, Abstract TUAC0403LB.
3. Matthews RP, Barrett SE, Patel M, et al. First-in-human trial of MK-8591-eluting implants demonstrates concentrations suitable for HIV prophylaxis for at least one year. International AID Society 2019, Abstract TUAC0401LB.
4. Zash R, Holmes L, Diseko M, et al. Neural tube defects by antiretroviral and HIV exposure in the Tsepamo Study, Botswana. International AIDS Society 2019, Abstract MOAx0105LB.
5. Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med 2019, Epub ahead of print.
6. Raesima MM, Forhan S, Thomas V, et al. Addressing the safety signal with dolutegravir use at conception: Additional surveillance data from Botswana. International AIDS Society 2019, Abstract MOAx0106LB.
7. Pereira G, Kim A, Jalil E, et al. No occurrences of neural tube defects among 382 women on dolutegravir at pregnancy conception in Brazil. International AIDS Society 2019, Abstract MOAx0104LB.
8. WHO ARV Policy Update. July 2019
9. Cahn P, Sierra Madero J, Arribas J, et al. Durable efficacy of dolutegravir (DTG) plus lamivudine (3TC) in antiretroviral treatment-naïve adults with HIV-1 infection- 96-week results from the GEMINI studies. International AIDS Society 2019, Abstract WEAB0404LB.
10. Venter WF, Moorhouse M, Sokhela S, et al. The ADVANCE trial: Phase 3, randomized comparison of TAF/FTC/DTG, TDF/FTC/DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection. International AIDS Society 2019, Abstract WEAB0405LB.
11. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different products of tenofovir to treat HIV. N Engl J Med 2019, Epub ahead of print.
12. The Namsal ANRS 12313 Study group. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1. N Engl J Med 2019, Epub ahead of print.
13. Hill A, Venter WF, Delaporte E, et al. Progressive rises in weight and clinical obesity for TAF/FTC/DTG and TDF/FTC/DTG versus TDF/FTC/EFV: ADVANCE and NAMSAL trials. International AIDS Society 2019, Abstract MOAx0102LB.
14. Van Wyk J, Ajana F, Bisshop F, et al. Switching to DTG + 3TC fixed dose combination (FDC) is non-inferior to continuing a TAF-based regimen (TBR) in maintaining virologic suppression through 24 weeks (TANGO Study). International AIDS Society 2019, Abstract WEAB0403LB.
15. Acosta R, Willkom M, Andreatta K, et al. Keeping the pressure on archived NRTI resistance: Switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) triple therapy in study 4030. International AIDS Society 2019, Abstract MOPEB241.
16. Overton ET, Orkin C, Swindells S, et al. Monthly long-acting cabotegravir and rilpivirine is non-inferior to oral ART as maintenance therapy for HIV-1 infection: Week 48 pooled analysis from the Phase 3 ATLAS and FLAIR studies. International AIDS Society 2019, Abstract MOPEB257.
17. Molina JM, Yazdanpanah Y, Sfani Saud A, et al. Tolerability, safety and efficacy of MK-8591 at doses of 0.25 to 2.25 mg QD, in combination with doravirine and lamivudine through 24 weeks in treatment-naïve adults with HIV-1 infection. International AIDS Society 2019, Abstract LBPED46.
18. Molina JM, Yazdanpanah Y, Afani Saud A, et al. MK-8591 at doses of 0.25 to 2.25 mg QD, in combination with doravirine establishes and maintains viral suppression through 48 weeks in treatment-naïve adults with HIV-1 infection. International AIDS Society 2019, Abstract WEAB0402LB.
19. Daar ES, McDonald C, Crofoot G, et al. Safety and antiviral activity over 10 days following a single dose of subcutaneous GS-6207, a first-in-class, long-acting HIV capsid inhibitor in people living with HIV. International AIDS Society 2019, Abstract LBPEB13.
20. Lataillade M, Lalezari J, Aberg J, et al. Week 96 safety and efficacy of the novel HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced participants infected with multi-drug resistant HIV-1 (BRIGHTE study). International AIDS Society 2019, Abstract MOAB0102.
21. Remien RH, Gamble T, Farley JE, et al. HPTN 078: primary results of a randomized study to engage men who have sex with men (MSM) living with HIV who are virally unsuppressed in the US. International AIDS Society 2019, Abstract MOAx0101LB.
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