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26th Conference on Retroviruses and
Opportunistic Infections (CROI)
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March 4-7, 2019
Seattle, WA
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 26th Conference on Retroviruses and Opportunistic Infections 2019 (CROI 2019) was an excellent meeting in Seattle that included numerous presentations on HIV pathogenesis, prevention, treatment and comorbidities/coinfections. There were approximately 4000 attendants with 1000 abstracts accepted. The Plenary Session included a presentation by Anthony Fauci summarizing the recently announced government plan, ending the HIV epidemic , which is further outlined in a recent commentary in JAMA (1). I encourage you to review the web site, the recent commentary and Dr. Fauci's presentation during the plenary session where he outlined the focus of the project being on early diagnosis, treatment, prevention with PrEP where appropriate along with rapid identification of emerging clusters. The plan will also exploit the realization that more than 50% of new infections occur in less than 50 of the more 3000 counties across the United States.
This review from CROI 2019 will focus on select studies related to HIV 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." Spoiler alert, the highlight of the meeting was a new strategy for prevention, using tenofovir alafenamide/emtricitabine for PrEP, new therapeutics, including long-acting therapy, a new interest in management of women of childbearing potential based upon 4 cases of neural tube defects in a Botswana cohort reported last summer, and of course the highly publicized case report of sustained remission (not yet cure) in the "London Patient."
HIV CURE
Cure research has been on the agenda for several years, but remains in the very early stages of exploration. At this meeting there were some interesting case reports and gene therapy approaches presented that I thought worth discussing.
Headlines:
• The " London Patient " hit the press throughout the world the day prior to being presented at CROI 2019 and published in Nature . This was a HIV-infected man with nonhodgkins lymphoma treated with chemotherapy and a stem cell transplant from a homozygous CCR5Δ32 donor who has yet to experience viral rebound after an 18-month interruption of antiretroviral therapy (ART). The "Dusseldorf Patient" was similar treated for leukemia and viral suppression was reported to be sustained for 3 months, thus far off ART.
• Zinc finger nuclease (ZFN) gene therapy can modify subset of CD4 cells in HIV-infected patients with very modest impact on viral rebound.
• Ex vivo and in vivo editing of the SIV genome in nonhuman primates by CRISPR-Cas9 can target viral genome in vitro and in vivo.
• Kick and kill strategies remain aspirational but progress is slow with little effect associated with multiple doses romidepsin, a potent histone deacetylase (HDAC) inhibitor.
Study findings/Interpretation:
• For more than a decade the Berlin Patient has been the only person on planet thought to be cured of HIV. There has been a great deal of interest in defining what interventions may account for this success, as well as to determine if this experience can be reproduced. With regards to the latter, most attempts to reproduce his experience have failed because of either breakthrough X4 (CXCR4-using) virus or mortality from underlying disease or its treatment. The London Patient presented at CROI 2019 was the first time since the Berlin Patient that sustained virologic suppression occurred after stem cell transplant with a homozygous, CCR5Δ32 donor (2). This patient was treated for lymphoma with chemotherapy and relatively low level conditioning prior to stem cell transplant. Once stable, ART was stopped and the investigators reported no viral rebound for 18 months, thus far. Investigators were appropriately cautious to not refer to this as a cure, recognizing that in those with very low reservoir it can take a prolonged period of time for viral rebound to occur.
The Dusseldorf Patient was treated for acute myelogenous leukemia in a fashion similar to the London Patient (3). Unlike the Berlin Patient, neither of these newer cases received total body irradiation and they received less intensive conditioning prior to the transplant. In this case the patient was on ART for years after treatment for his leukemia prior to discontinuing therapy with documented continued viral suppression for 3 months at the time of the CROI presentation. Together these cases may provide further insight into the ability of stem cell transplant from homozygous, CCR5Δ32 donor to facilitate long-term viral control or even cure. If viral suppression is sustained, these cases would also provide insight into whether irradiation and intensive conditioning are necessary for this strategy. Nevertheless, it is recognized that such transplants can only be considered in those in which there is a clinical indication, and certainly not for the overwhelming majority living with HIV.
• Ex vivo treatment of CD4+ T cells with CCR5 ZFN has been shown to modify subset of cells so that they have a survival advantage in presence of untreated HIV infection. The current study was designed to see whether engraftment using RNA-based transfection instead of previous Ad5/35 vector, along with single dose cyclophosphamide would result in better outcomes (4). This was a 3 arm, open-label pilot of well controlled HIV-infected individuals. They had CD4+ T cells removed and modified at CCR5 by RNA encoding ZFN SB 728 with or without cyclophosphamide conditioning. They found that after a single infusion of modified cells approximately 25% of CCR5 was disrupted, with greater levels in those who received cyclophosphamide. The treatment was relatively well tolerated and during an analytic treatment interruption there was a suggestion of a modest delay in time to viral rebound when compared to a historical ACTG control group, an effect that did not appear to be influenced by use of cyclophosphamide. While this study is interesting, it remains to be seen whether this type of strategy can impact the ability to withdraw therapy without viral rebound, the goal of such treatment.
• Burdo and colleagues performed ex vivo and in vivo editing of SIV genome in nonhuman primates by CRISPR-Cas9 (5). The goal was to target integrated SIV at Long Terminal Repeats and gag. In fact, the investigators reported that they were able to show cleavage of SIV DNA in vitro. They also demonstrated in samples removed from the animals that there was cleavage in viral DNA from peripheral blood mononuclear cells, lack of outgrowth from these cells, as well as widespread biodistribution of edited SIV genome in tissues, including spleen, lung and lymph nodes. This is a novel strategy in early stages, but one that offers a unique approach for cure research.
• The "kick and kill" strategy for HIV cure has required something to stimulate latently infected cells to express virus, so called latency reversing agents, and an effector function, such as from immune system to kill latently infected cells. HDAC inhibitors have been one of the more aggressively pursued latency reversing agents studied. McMahon and colleagues reported data from ACTG Study A5315 where HIV-infected individuals were treated with increasing doses of romidepsin, an HDAC inhibitor currently approved for treatment of T cell lymphoma, or controls (6). They found that the treatment was well tolerated and safe but that there was no increase in plasma viremia, even when assessed by single copy assay or change in cell-associated HIV RNA or DNA. It is fair to say that this lack of response with what was considered to be one of the more promising HDAC inhibitors being pursued was met with disappointment. Moreover, it raises concerns as to whether more attention should be focused on other classes of latency reversing agents or alternative cure strategies.
HIV PREVENTION
Understanding transmission and ways to prevent HIV spread has resulted in some of the most important advances in clinical research. A key component of the United States plan to control HIV is expanding the use of preexposure prophylaxis (PrEP) amongst those at high risk.
Headlines:
• Tenofovir alafenamide/emtricitabine (TAF/FTC) for PrEP in men who have sex with men (MSM) and transgender women is noninferior to tenofovir disoproxil fumarate (TDF)/FTC and is safer for bone and kidneys.
Study findings/Interpretation:
• The DISCOVER Trial was a randomized-controlled study that enrolled 5387 high risk MSM and transgender women to TDF/FTC or TAF/FTC (7). 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 DISCORVER 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.
Safety data from DISCOVER Trial showed that markers of renal function and proximal tubular protein excretion as well as change in bone mineral density all favored TAF/FTC. Although there will be continued follow-up of those enrolled as well as detailed review by the FDA and eventually publication in peer-reviewed journal, it seems likely that TAF/FTC will become available as a therapeutic option for MSM and transgender women in need of PrEP. It remains to be seen whether it will be approved for those with baseline creatinine clearances of <60 mL/minute, the current cutoff for TDF/FTC. It will also be important to consider pursuing this formulation as an option for high risk women.
ANTIRETROVIRAL THERAPY IN PREGNANCY
If you are going to review a webcast session from CROI 2019 I strongly recommend the symposium on ART and Reproduction which nicely summarized key issues related to treating women of childbearing potential and those pregnant. As you may recall, recent data from a prospective study in Botswana showed a statistically significant increased risk of neural tube defects in those exposed to dolutegravir (DTG) during conception, but not in those exposed later in pregnancy. Although the actual number of events was only 4 in a relatively small number of individuals, the preliminary data has had a profound impact on guidelines, pending further data anticipated to be available in the next several months. In the interim, many groups have mined databases to assess whether other drugs, in particular other integrase strand transfer inhibitors (InSTIs) were associated with neural tube defects. In addition, two studies compared the use of InSTIs and efavirenz (EFV) during pregnancy.
Headlines:
• A review of several databases have failed to demonstrate a relationship between InSTIs and neural tube defects; however, all have limitations and probably cannot be considered definitive.
• InSTI-based therapy with raltegravir (RAL) or DTG in pregnant women results in more rapid virologic suppression than EFV-based regimens.
Study findings/Interpretation:
• There has been a great deal of interest in the recent observations from Botswana Tsepamo cohort showing 4 cases of neural tube defects 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 in cohort, including 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. The challenge associated with this recommendation is, if not DTG, what should be used? While the observed signal has not been reported with other InSTIs, data is limited. With that in mind, several studies analyzed existing data to see what could be learned.
Hill and colleagues looked at FDA, WHO, EMA and UK pharmacovigilance safety data which included data with DTG, RAL, elvitegravir (EVG), bictegravir (BIC), darunavir (DRV), atazanavir (ATV), EFV and nevirapine (NVP) (8). Although there were neural tube defects seen with many of these drugs, there were no strong signals that the rate exceeds that of those unexposed. Notably, there were limitations, including lack of a clear denominator for number exposed, and limited data on timing of exposure during pregnancy. Consequently, the authors emphasized that surveillance studies, such as Tsepamo were needed.
Merck reviewed 1256 pregnancy outcomes in their registries with 295 having periconception exposure (9). There were no neural tube defects seen in a prospectively followed group and 4 in a retrospective cohort, only one of which had periconception exposure. While this analysis does not raise concerns about the current recommendations that RAL be considered the preferred InSTI in women of child-bearing potential, it does not definitively exclude a signal. Another analysis was of the Pregnancy Registry of 20,064 pregnancies from North America, Europe, Africa and South America (10). In this database there were 688 that received InSTIs periconception, 201 on DTG, 207 on EVG and 280 on RAL. Of these, there were no neural tube defects, consistent with the frequency of 0.01 to 0.1% in general population with folate supplementation. Once again, authors concluded that numbers are insufficient to exclude any association.
Although the studies presented at CROI 2019 do not raise new concerns, there remains many unanswered questions. This includes whether the early signal in Tsepamo will hold up with further follow-up, and if it does whether we will be able to exclude a class effect. It is also conceivable that even if there is an effect, it may be mitigated or eliminated with folate supplementation.
• The use of ART during pregnancy has long been known to be a highly effective therapy to reduce vertical transmission. While a major focus has shifted towards potential toxicities, as outlined above, there is also reason to believe that certain treatments may be more effective than others. Study NICHD P1081 is a Phase IV open label study of RAL vs. EFV with zidovudine/lamivudine (ZDV/3TC) in treatment naïve pregnant women presenting at >20 weeks of gestation in Brazil, Tanzania, South Africa, Thailand, Argentina and United States (11). The primary endpoint of the study was plasma HIV RNA <200 copies/mL at delivery, with assessments of tolerability, infant safety and follow-up for 24 weeks post-partum. The study enrolled 334 participants, approximately half being at least 28 weeks pregnant. The investigators reported and showed a significantly greater number being <200 copies/mL at delivery, 94 vs. 84% in RAL versus EFV groups, respectively (p<0.001). The difference was entirely driven by those enrolled at 28 or more weeks of pregnancy. In the 20-27-week group it was 97 and 96% suppressed, whereas for the 28-37-week group it was 93 and 71% suppressed at delivery for RAL vs. EFV-containing regimens, respectively. There was no difference in tolerability, infant safety and there were seven transmissions, six of which occurred in the EFV study arm. Based upon this there appears to be strong evidence supporting RAL over EFV, particularly for those presenting late in pregnancy.
Results were also presented from the DolPHIN-2 study which randomized women at least 28 weeks pregnant to DTG versus EFV, each with two NRTIs (12). The primary endpoint was VL <50 copies/mL at delivery and showed significant advantage for DTG, a difference that was much less prominent for cutoff of <1000 copies/mL and with no differences in safety. This study demonstrated clear benefit of InSTI over nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy, likely related to the known property of the former to get viral load suppressed more quickly, a difference that might be relevant in reducing risk of transmission in general, and particularly in those presenting late in pregnancy.
WEIGHT GAIN WITH InSTIs?
Headlines:
• More data showed that starting or switching to InSTIs may be associated with weight gain.
Study findings/Interpretation:
• Several groups have shown that starting or switching to InSTIs may be associated with weight gain, an observation made in a previous randomized-controlled trial of two NRTIs with RAL vs. boosted ATV or DRV (A5257). Lake and colleagues looked at data from ACTG cohorts that included individuals followed between 2007 and 2017 (13). This analysis included 691 subjects that switched to an InSTI-based regimen. They reported that annual within person weight gain before switch was relatively stable with a significant increase after switching, a finding that was greatest in the 198 who switched to DTG, and to lesser extent with switches to EVG and RAL. It was noted that most of the effect was seen in those switching from NNRTIs, and most prominent in women, blacks and those ≥60 years of age.
Data from the Women's Interagency HIV Study (WIHS) monitored individuals between 2008 and 2017 who switched or added InSTIs to a stable regimen (14). They performed linear regression models comparing 884 that stayed on their current regimen versus 234 that switched/added an InSTI. Those that switched/added an InSTI experienced significant increases in weight, body mass index, percentage body fat and body circumference measurements.
An analysis from 17 of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohorts looked at those who were antiretroviral naïve starting three-drug regimens and performed multivariate linear mixed effects models (15). This included 24,001 patients with approximately 11,000 starting NNRTIs, 7,400 starting protease inhibitors and 4,700 InSTIs. They found weight gain was mostly in first year and was greater in those starting InSTIs. They also noted that the InSTI effect appeared greater with DTG than RAL and EVG. There was no difference by sex and race noted.
Landovitz and colleagues hypothesized that if there was a biologic mechanism for the weight gain associated with InSTI use in cohorts, that an ideal setting to evaluate this would be in HIV-uninfected individuals (16). They analyzed data from HPTN 077 which was designed to evaluate the long-acting InSTI, cabotegravir (CAB) (n=134) versus placebo (n=43) in healthy controls for future use in PrEP studies. They found that there was no difference in weight gain overall or by subgroup analysis.
Studies of weight gain with InSTIs was a hot topic at CROI 2019 and was addressed in a poster discussion section where data was presented and there was open discussion by the authors, session moderators and from the audience. There was general agreement that if the effects seen are real, the increase in weight of 2-3 Kg was potentially clinically relevant. That said, there was extensive discussion as to how difficult it is to control for the many confounders and the challenges in determining how much of this might be a biologic effect versus differences in drug tolerability, an effect related to return to health or other factors. It is also worth noting that if this were a biologic effect, the field would need to consider how this should influence treatment guidelines that now uniformly favor use of InSTIs for first-line therapy.
ANTIRETROVIRALS IN SECOND AND THIRD-LINE THERAPY
Headlines:
• The DAWNING Study demonstrated that DTG with at least one active NRTI was very effective as second-line therapy in those failing first-line NNRTI regimen. A new analysis showed that the advantage of the DTG- over lopinavir/ritonavir (LPV/r), both including a regimen with at least one fully active NRTI persisted regardless of baseline resistance.
• BIC is potentially active in setting of impaired NRTI background regimen and in select individuals failing first generation InSTIs.
Study findings/Interpretation:
• Post-hoc analyses of the DAWNING Study have provided insight into predictors of outcome. At this meeting a detailed analysis was performed to determine how baseline NRTI resistance influenced outcomes (17). The investigators reported that M184V was present in a majority of patients and in isolation in approximately 25%. K65R mutation was present in approximately 30%. Since patients were required to use at least one active NRTI, many of them with K65R received a ZDV-based regimen. They further reported that in those with M184V at baseline, DTG consistently outperformed LPV/r with typically 80-85% suppression. Response rates in those with K65R at baseline were also high and trended to favor DTG over LPV/r, but most did receive ZDV. These analyses provide further insight into how DTG can be used as second-line regimens, even in setting of substantial NRTI resistance.
• There is every reason to believe that BIC has a higher barrier to resistance than first generation InSTIs, e.g. RAL and EVG. This is largely based upon in vitro data and lack of emerging resistance in naïve and switch studies, as previously reported with DTG. In contrast to DTG, which has been studied using it 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 included those with documented underlying resistance to any class except InSTIs (18). 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 CROI 2019 was a planned interim analysis after 12 weeks of follow-up, at which time 99% continued to have plasma HIV RNA <50 copies/mL. The primary endpoint will be at 48 weeks of follow-up and will provide more definitive data as to whether BIC/FTC/TAF is a viable option for switch in those with variable amounts of underlying NRTI resistance.
Unlike with DTG where there are studies defining response in those with underlying InSTI resistance, such data is limited for BIC. There were several studies presented at CROI 2019 that assessed the in vitro susceptibility of BIC, DTG and CAB in InSTI resistant viruses. Santoro and colleagues evaluated 22 resistant isolates and found that most were susceptible to BIC and DTG, with reduced susceptibility for both associated with presence of G140S and Q148H, often with at least one other substitution (19). They concluded from this analysis that BIC given once-daily may be an option in select patients with underlying InSTI resistance. Saladini and colleagues did a similar analysis of 19 primary isolates from patient failing first generation InSTIs (20). They found similar susceptibility pattern for DTG, BIC and CAB with mutations at position 148 plus one other mutation resulting in some decreased susceptibility, acknowledging that the clinical cutoff for resistance to BIC and CAB are unknown. Together these studies provide some information as to how BIC may be used in those experiencing InSTI failure, although none of this was actually clinical data and is completely based on changes in susceptibility relative to wild type.
NEW ANTIRETROVIRALS IN DEVELOPMENT
Headlines:
• Long Acting (LA) CAB and rilpivirine (RPV) maintain viral suppression and are well tolerated in ATLAS and FLAIR Studies.
• MK8591 is a novel nucleoside reverse transcriptase translocation inhibitor that is potent, has activity against NRTI resistant virus and has a long half-life.
• GS-6207 is first-in-class HIV capsid inhibitor with activity against a broad range of isolates and has a very long half-life.
• Trispecific antibodies show potential as anti-HIV agents and may have a role in HIV cure research.
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 (21). The primary endpoint, proportion with plasma HIV RNA >50 copies/mL at 48 weeks with a secondary endpoint of proportion <50 copies/mL at this study visit. 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. The regimen was well tolerated; injection site reactions were relatively low after first weeks of therapy with only 4 stopping because of local reactions. 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 LA CAB plus RPV (22). Endpoints from FLAIR were similar to ATLAS with noninferiority demonstrated for both the primary and key secondary virologic endpoints. Injection site reactions were also unusual after first few weeks with only 2 discontinuing because of them and high rates of patient satisfaction. Virologic failure was rare in both studies with those failing LA CAB plus RPV all carrying subtype A virus, an unexpected observation that will require further analyses in the future.
The next steps for LA CAB plus RPV will be continued follow-up of monthly injections as well as the results from the fully enrolled ATLAS 2M study comparing every 4 to every 8 week injections. There is also ACTG study A5359 which is soon to open at an ACTG site near you. This study will assess the utility of LA CAB plus RPV in those with poor adherence.
• MK8591 (EFdA) is a novel 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. At CROI 2019 they reported data looking at a panel of isolates with well-known mutations and demonstrated potency, despite many being resistant to other available NRTIs (23). It has also been shown to have long half-life with possibility of dosing as infrequently as once weekly. Currently, it is being pursue at low doses as once-daily therapy with the recently approved NNRTI, doravirine. This is one of the more promising new agents on the horizon and could potentially have numerous roles in the treatment of naïve and experienced individuals, depending upon how the company pursues development.
• 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 virus. In addition, its parenteral properties suggest that it can be dosed relatively infrequently. At CROI 2019 investigators reported data on this agent that acts early in the viral life- cycle during capsid disassembly and nuclear transport, as well as during late stages, including viral production and capsid assembly after viral budding from surface of infected cells (24). Data from a Phase 1 study was reported where 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 at 100 mg and above a single dose maintained levels above the protein adjusted EC95 for more than 12 weeks. This would represent a new option for those who need it because of viral resistance, intolerance to existing agents, as well as for novel long-acting regimens for treatment.
Broadly neutralizing antibodies have been studied in early phase studies for their antiviral activity for both treatment and prevention strategies. In fact, several studies have shown the ability of these antibodies to inhibit viral replication. These antibodies also have properties of activating host immune responses that might be important for clearing viral reservoir as part of cure strategy. Single broadly neutralizing antibodies as therapeutics and preventative agents are limited by fact that they do not neutralize 100% of primary viruses and as single agents will select for resistant virus. One strategy to overcome these limitations is to use them as part of a regimen with other antiviral agents. Another path forward is to combine multiple broadly neutralizing antibodies. At CROI 2019 a study was presented using trispecific broadly neutralizing antibodies that act at several different sites with a wide breath of activity against primary isolates. The objective of this study was to recognize viral envelope and mediate antibody dependent cytotoxic cells, activate complement to lyse infected cells and inhibit outgrowth of resistant virus from donor cells as well as suppress viremia in simian HIV-infected non-human primates (25). They found that the trispecific neutralizing antibodies inhibited outgrowth of virus from infected donor cells and in six nonhuman primates challenged with simian HIV was able to reduce viremia by up to 1000-fold after infusion. In addition, this product had potent Fc receptor function. While these agents remain in early stages of development, they do offer unique potential as a part of HIV treatment strategies and cure research.
CONCLUSIONS
CROI 2019 was an excellent meeting with many important studies. 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 http://www.croiconference.org where you can watch videos of presentations and download pdf versions of many of the poster presentations.
NATAP coverage: Conference on Retroviruses and Opportunistic Infections
Seattle, Washington
March 4-7, 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. Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV epidemic: A plan for the United States. JAMA 2019; Epub ahead of print.
2. Gupta RK, Abduljawad S, McCoy L, et al. Sustained HIV-1 remission following homozygous CCR5 delta32 allogenic HSCT. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 29LB.
3. Jensen B-EO, Knops E, Lubke N, et al. Analytic treatment interruption (ATI) after allogeneic CCR5-D32 HSCT for AML in 2013. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 394B.
4. Tebas P, Jadlowsky J, Shaw P, et al. Delayed viral rebound during ATI after infusion of CCR5 ZFN-treated CD4 T cells. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 25.
5. Burdo TH, Manucuso P, Kaminski R, et al. Ex vivo and in vivo editing of the SIV genome in nonhuman primates by CRISPR-CAS9. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 24.
6. McMahon D, Zheng L, Cyktor JC, et al. Multidose IV romidepsin: No increased HIV-1 expression in persons on ART, ACTG A5315. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 26.
7. Hare CB, Coll J, Ruane P, et al. The phase 3 DISCOVER Study: Daily F/TAF or F/TDF for HIV preexposure prophylaxis. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 104LB.
8. Hill A, van de Ven NS, Pozniak A, et al. Reports of neural tube defects for 8 ARTS, in FDA, WHO, EMA, and UK safety databases. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 746.
9. Shamsuddin HH, Raudenbush CL, Sciba BL, et al. Evaluation of neural-tube defects after exposure to raltegravir during pregnancy. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 745.
10. Sibiude J, Le Chenader J, Mandelbrot L, et al. No increase in birth defects in infants exposed to integrase inhibitors at conception. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 744.
11. Mirochnick M, Shapiro DE, Morrison L, et al. Randomized trial of raltegravir-ART vs. efavirenz-ART when initiated during pregnancy. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 39LB.
12. Kintu K, Malaba T, Nakibuka J, Papam C. RCT of dolutegravir vs. efavirenz-based therapy initiated in late pregnancy: DOLPHIN-2. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 40LB
13. Lake JE, Wu K, Erlandson KM, et al. Risk factors for excess weight gain following switch to integrase inhibitor-based ART. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 669.
14. Kerchberger AM, Sheth AN, Angert CD, et al. Integrase strand transfer inhibitors are associated with weight gain in women. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 672.
15. Bourgi K, Jenkins C, Rebeiro PF, et al. Greater weight gain among treatment-naïve persons starting integrase inhibitors. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 670.
16. Landovitz RJ, Zangeneh SZ, Chau G, et al. Cabotegravir is not associated with weight gain in HV-negative individuals: HPTN 077. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 34LB.
17. Brown D, Wang R, Underwood M, et al. DTG vs. LPV/R (DAWNING): Efficacy by baseline NRTI resistance and second-line NRTI use. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 144.
18. Acosta RK, Willkom M, Andreatta K, et al. High level of preexisting NRTI resistance prior to switching to B/F/TAF: Study 4030. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 551.
19. Santoro MM, Fornabaio C, Malena M, et al. Susceptibility to bictegravir in highly ARV-experienced patients after InSTI failure. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 550.
20. Saladini F, Giannini A, Boccuto A, et al. In vitro activity of DTG/BIC/E/CAB on first-generation InSTI-resistant HIV-1. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 549.
21. Swindells S, Andrade-Villanueva J-F, Richmond GJ, et al. Long-acting cabotegravir + rilpivirine as maintenance therapy: ATLAS week 48 results. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 139.
22. Orkin C, Arasten K, Hernandez-Mora G et al. Long-acting cabotegravir + rilpivirine for HIV maintenance: FLAIR week 48 results. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 140LB.
23. Grobler J, Fillgrove K, Hazuda D, et al. MK-8591 potency and PK provide high inhibitory quotients at low doses QD and QW. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 481.
24. Yant SR, Mulato A, Stepan G, et al. GS-6207, a potent and selective first-in-class long-acting HIV-1 capsid inhibitor. 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA 2019, Abstract 480.
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