COMPLICATIONS OF HIV AND COVID-19 Oral Abstract Session
Sex may modify the relationship between inflammation and vascular disease in treated HIV.
UCSF 3rd year medical resident Sam Schnittman had an oral presentation with Dr. Peter Hunt that characterized the inflammatory predictors of vascular disease in a case-cohort study of over 1000 PWH within the CFAR Network of Integrated Clinical Systems (CNICS). One important finding was that women had more inflammation than men, particularly after estimated menopause, and that inflammation tended to predict vascular disease more strongly in women than men (with the exception of venous thromboembolism). This may explain the loss of “female advantage” for cardiovascular disease in PWH, and with menopause. It also highlights the importance of enrolling women in clinical trials of immune-based interventions. A fitting message on International Women’s Day!
Plasma proteomic signature predicts mortality in PWH.
UCSF’s own Priscilla Hsue had an oral presentation that identified a plasma proteomic signature (using SomaLogic platform) that predicted increased mortality in PWH in the VACS BC cohort. The identified biomarkers predicted mortality more strongly than and independently from HIV risk factors (CD4/VL) as well as other prognostic indices like the VACS index and even other known inflammatory markers. Future work will try to understand whether novel interventional targets can be identified from the top proteomic hits.
Science Spotlights in the comorbidities section
Predicting optimized treatment duration for MDR treatment patients.
Our own Maria Garcia-Cremades presented a nice science spotlight using a meta-analysis including 7,750 patients. HIV was a key contributor to the risk of treatment failure, which could be attenuated by longer duration of MDR TB
Efficacy of Sofosbuvir in people with HIV (PWH) with HCV Co-infection Getting Liver Transplant.
Dominic Amara, a UCSF 4th year medical student presented a clinical trial of Sofosbuvir-based DAA therapy among PWH after liver transplant. 93% achieved SVR and completed therapy, with excellent survival comparable to people without HIV. These data remove another barrier to liver transplant in PWH in the setting of HCV co-infection.
ISLATRAVIR PK THRESHOLD & DOSE SELECTION FOR MONTHLY ORAL HIV-1 PrEP. In this abstract, data from rhesus macaques, modeling from the clinical trial on islatravir/doravirine, and pharmacokinetic models was put together to determine the appropriate dose to use for islatravir (a novel nucleoside reverse transcriptase translocation inhibitor, NRTTI) as an oral PrEP agent. In conclusion, to provide appropriate exposure for efficacy for PrEP, a 60-mg oral dose of islatravir was selected for the Phase 3 clinical program. This dose will provide islatravir-TP concentrations way above the conservative dose PK threshold 0.05 pmol/106 cells in the event of a delayed or missed monthly dose.
NEXT-GENERATION ISLATRAVIR IMPLANTS PROJECTED TO PROVIDE YEARLY HIV PROPHYLAXIS.
This study shows the ability of a very novel formulation of islatravir (an implant) to last a year for PrEP. Islatravir implants (containing only polymer and islatravir) have demonstrated the potential for yearly administration for PrEP. This study was a double-blind placebo-controlled multicenter Phase 1 trial looking at a single islatravir-eluting (48 mg, 52 mg or 56 mg) or placebo implant placed in participants at low risk of HIV infection for 12 weeks. Safety and tolerability, as well as PK for islatravir parent and islatravir-triphosphate (TP) from plasma and PBMCs, was collected throughout placement and for 8 weeks post removal. Amazingly, data from this trial and from in vitro assessments of the ISL implants suggest that implants of >52 mg will achieve mean ISL-TP concentrations above the PK threshold at 52 weeks in the human body (see slide).
Therefore, next-generation islatravir-eluting implants will provide drug release projected to be sufficient for HIV prophylaxis for at least one year! Also, the implant was well tolerated. A phase 2 trial is being planned.
CLINICAL EVALUATION OF DRUG INTERACTIONS WITH ORAL LENACAPAVIR AND PROBE DRUGS. Lenacapavir is a first-of-its-kind capsid inhibitor being studied both as a PrEP and as an agent for treatment, both in MDR-HIV and naïve patients. In vitro studies had been performed for this agent to examine drug-drug interactions but this study took healthy participants and co-administered lenacapavir with various oral medications to evaluate drug-drug interactions (DDIs) in vivo. Consistent with in vitro data, this study confirmed lenacapavir is a substrate of both CYP3A4 and P-gp. The magnitude of inhibition via cobicistat (COBI), darunavir/COBI, and voriconazole (VORI) is not considered to be clinically relevant, supporting coadministration of LEN with potent inhibitors of CYP3A and P-gp without dose modification. However, potent inducers of either, such as rifampin, should be avoided. Moreover, lenacapavir is not affected by gastric acid reducers so its DDI profile is manageable.
PK OF DOSE-ADJUSTED EMERGENCY CONTRACEPTION WITH EFV-BASED ART IN ACTG 5375. Levonorgestrel (LNG) emergency contraception (EC), when administered as a single dose, prevents pregnancy. However, LNG area under the concentration time curve (AUC) is reduced 57% when coadministered with efavirenz (EFV) in healthy volunteers. Some guidelines recommend dose-adjustment of LNG EC from 1.5mg to 3mg when combined with EFV, but this strategy has not been studied, so the A5375 study examined whether doubling the dose of LNG EC to 3mg would increase LNG exposure in individuals receiving EFV-based ART. The Table summarizes LNG PK parameters. The maximum concentration (Cmax) was 51% higher after LNG 3mg (24.9 ng/mL) compared to 1.5mg (15.1 ng/mL), and the 48h concentration was 133% higher (0.6 vs 0.3 ng/mL, respectively). The AUC over 8 hours was 66% higher in the 3mg group and remained 74-77% higher over 24 and 48 hours post-dose. Therefore, EFV induced LNG metabolism and dose adjustment of LNG EC from 1.5mg to 3mg successfully increased LNG exposure in women receiving EFV-based ART, supporting dose-adjustment of LNG EC to 3mg in women on EFV-based ART.
EMTRICITABINE TRIPHOSPHATE IN DRIED BLOOD SPOTS PREDICTS FUTURE VIREMIA IN PWH (thank you to Matt Spinelli for help with summary). There is increasing interest in using drug-level measurement to measure adherence during routine clinical care and ultimately to predict future HIV viremia. The quantification of emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) is a recent adherence measure of tenofovir (TFV) exposure due to its 35-hour half-life. In this study, FTC-TP DBS assessments and self-reported adherence were collected prospectively at up to 3 routine clinical visits. The investigators found that the interaction of high self-reported 3 day adherence but low FTC-TP levels predicted 6-fold higher odds for future HIV viremia (95%CI: 1.8, 20.3; p=0.001). Given that POC urine TFV and FTC-TP are highly correlated, there is the potential of using POC recent adherence testing (via a point-of-care urine test) to predict future viremia at routine HIV clinical visits.
TENOFOVIR DIPHOSPHATE TO PREDICT FUTURE VIRAEMIA IN POSTPARTUM WOMEN LIVING WITH HIV. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) has been looked at in relationship with concurrent viral load, but there are few studies on predicting future viremia, especially in women. This is a nested case-control study within a trial of differentiated care for postpartum women on ART. Samples for viral loads and TFV-DP assays were taken 3-6 monthly over 24 months, and analyzed how absolute TFV-DP levels during VS predicted subsequent risk of virologic suppression. As shown in the figure, in postpartum women, TFV-DP levels during virologic suppression predict viremia three to six months later, indicating the value of objective adherence markers in high-risk population.
NUCLEOSIDES AND DARUNAVIR/DOLUTEGRAVIR IN AFRICA (NADIA) TRIAL: 48WKS PRIMARY OUTCOME. WHO recommends dolutegravir with two NRTIs for second-line treatment of HIV infection after failure on an NNRTI-based regimen. There is limited evidence for efficacy of this dolutegravir regimen when prescribed NRTIs lack predicted activity due to drug resistance.
So the NADIA trial was an open-label, non-inferiority trial, where participants were randomized from a failing NNRTI/tenofovir/lamivudine first-line regimen with confirmed VL =1000 copies/ml to receive dolutegravir or ritonavir-boosted darunavir; with either tenofovir or zidovudine; all with lamivudine. Viral loads were measured at 24 and 48 weeks; the primary outcome was the % patients with week-48 VL <400 copies/ml using FDA snapshot algorithm (non-inferiority margin 12%). 464 participants at 7 sub-Saharan African sites (61% female, 51% CD4<200, 28% VL=100,000) were enrolled. These were treatment experienced patients: at baseline, 58.5% overall had intermediate-high level resistance to tenofovir and 92% had resistance to lamivudine. Week 48 VL was <400 copies/ml in 90.2% in the dolutegravir group and 91.7% in the darunavir group, indicating non-inferiority of dolutegravir (without superiority). In the subgroup with no predicted-active NRTIs in the prescribed regimen, VL was <400 copies/ml in 92.4% of those in the dolutegravir group and 93.7% of those in the darunavir group. Importantly and consistent with the DAWNING study, 4 with failure have intermediate-high level dolutegravir resistance; 0 have darunavir resistance. In the other randomized comparison, VL was <400 copies/ml in 92.3% in the tenofovir group and 89.6% in the zidovudine group (difference 2.7%; 95% CI, -2.6 to 7.9%; indicating non-inferiority of tenofovir). Grade 3/4 adverse events were uncommon and similar in frequency between groups. This is an important study that shows dolutegravir with two NRTIs gives highly effective viral suppression to 48 weeks, even in a patient population where many have extensive NRTI resistance and no predicted activity in prescribed NRTIs. However, please be aware of the 4 failures with INSTI resistance in those on dolutegravir (compared to no resistance mutations in those on darunavir). Tenofovir can be maintained in second-line therapy without switching to zidovudine, with advantages for patients.
RANDOMIZED TRIAL OF RESISTANCE TESTING FOR VIROLOGIC FAILURE IN SUB-SAHARAN AFRICA. Genotypic resistance testing (GRT) is recommended after virologic failure in high-income settings. By contrast, guidelines in sub-Saharan Africa promote adherence support and repeat virologic monitoring, in the absence of GRT, to guide treatment. The REVAMP study was an open-label, randomized controlled trial to assess whether GRT improved virologic suppression after first-line ART failure. Adults were enrolled from South Africa and Uganda on first-line ART with an HIV-1 RNA VL>1,000 copies/mL and randomized 1:1 to standard-of-care (SOC), with adherence counseling and virologic monitoring to determine management, or immediate GRT. The outcome was achievement of VL<200 copies/mL 9 months after enrollment. 840 participants were enrolled and there was no difference in the proportion in care and achieving a VL<200 copies/mL at 9 months by arm (SOC: 256/423, 61%; RT: 263/417, 63%, OR 1.11, 95%CI 0.83-1.49. Those with a VL>1,000 copies/mL at 9 months in the SOC arm were more likely to have drug resistance detected. Therefore, in public clinics in sub-Saharan Africa, the addition of GRT to routine care did not improve achievement of virologic suppression 9 months after first-line ART failure but did lower the likelihood of drug resistance in those with persistent viremia. Interesting study and cost effectiveness analysis pending.
Live Interactive Session
There was an interactive discussion moderated by our own Peter Hunt on weight gain with HIV and ART, featuring Jane O’Halloran (WUSTL), Grace McComsey (CWRU), Sadaf Farooqi (Cambridge U, UK), and Cissy Kityo (JCRC, Uganda). Dr. O’Halloran highlighted that while weight gain has been observed in INSTI-treated and TAF-treated participants, at least some of the differences observed may be driven by suppression of weight gain by comparator drugs (i.e., EFV and TDF). Ongoing studies, including some featured in the Weight Gain and T2DM Science spotlight sessions continue to probe mechanisms as to why some ART drugs may contribute to weight gain (or blunt it). Dr. McComsey emphasized the fact that even modern NRTIs may have mitochondrial toxicities in adipose tissue, potentially blunting weight gain, though not much is yet known about TAF. Dr. Kityo stressed that there are cultural differences in the perception of weight gain, where weight gain is a sign of affluence and health in some settings like hers in Uganda, but acknowledged that the weight gain observed with TLD switch in LMIC has been associated with a concurrent increase in T2DM. Dr. Farooqi – as a non-HIV expert in the regulation of body weight – highlighted several important aspects of the pathophysiology. For example, when recovering from a catabolic state (i.e. initiating ART), there is not only a reversal of a catabolic state, but there is also a significant increase in hunger that contributes to the weight gain observed (i.e., the body “always overshoots”). She also emphasized the importance of fat fibrosis in contributing to visceral adiposity and insulin resistance and the potential role of inflammation in that process. She also acknowledged that other non-HIV drugs can affect weight gain by affecting the Leptin or melanocortin 4 receptor axes, and that these could be investigated vis-à-vis HIV drugs as well.
Science Spotlights in HIV Cure
Predicting when virus rebounds during a treatment interruption.
Zain Y. Dossani and colleagues from Vitalant and the Gladstone 1, Karla Medina1, Erika Marques de Menezes1, Anna Sellas1, Xutao Deng1, Reuben Thomas2, Katherine Pollard2, Philip Norris1, Clara Di Germanio1, Nadia Roan2, Warner Greene2, Ole Søgaard3, Martin Tolstrup3, Satish Pillai1
Abstract 310: https://ww2.aievolution.com/cro2101/index.cfm?do=abs.viewAbs&abs=2328
Antiretroviral treatment interruptions are often used to determine if an HIV cure strategy worked. As everyone knows, these interruptions are risky to the study participants and their partners, and are often difficult and expensive to conduct. There is hence a massive effort underway to identify predictors of when people rebound. In a fascinating presentation, Zain Dossani, Satish Pillai, and colleagues from Vitalant and the Gladstone found that higher levels of free DNA in the plasma were associated with a longer time to rebound. Why might this be? As DNA is very inflammatory and induces a strong interferon response, the team believes that a non-specific host response is being induced, which in turn delays rebound. This study builds on a rapidly growing literature pointing to interferons playing a key role in what happens soon after ART is interrupted. Devi SenGupta, who recently trained at UCSF and is now leading HIV cure efforts at Gilead, is developing a drug that includes these types or responses (vesotilmod). Intriguingly, this drug was recently shown in a study done at UCSF to cause a delay in time-to-rebound.
Defining the safest way to do an informative antiretroviral treatment interruption.
MATHEMATICAL MODELING OF PREDICTORS OF POSTTREATMENT CONTROL IN HIV CURE TRIALS
Authors: Gesham Magombedze1, Devi SenGupta1, Jonathan Li2, Romas Geleziunas1, Steven G. Deeks3
1Gilead Sciences, Inc, Foster City, CA, USA, 2Brigham and Women's Hospital, Boston, MA, USA, 3University of California San Francisco, San Francisco, CA, USA
Abstract 312: https://ww2.aievolution.com/cro2101/index.cfm?do=abs.viewAbs&abs=1873
As there are no validated biomarkers for the reservoir size, the inconvenient truth of HIV cure studies is that interrupting ART is the gold-standard outcome to determine if an intervention worked. In a collaboration involving the UCSF team, Gilead, and ACTG, multiple treatment interruption studies were mined to determine if early trends predict who during an interruption might do well and who will likely need to start ART soon. An algorithm that includes when the virus first rebounds and when it first goes above 800 copies RNA/mL might inform clinicians if ART will need to be started soon. This would help prevent all of the bad things that might happen during an interruption and give people space to ultimately control their virus if that is their destiny.
Gene deserts and post-treatment control.
LONGITUDINAL DYNAMICS OF INTACT PROVIRAL HIV-1 DNA IN POSTTREATMENT CONTROLLERS
Xiaodong Lian1, Kyra W. Seiger1, Gregory T. Gladkov1, Joshua Chevalier1, Kevin B. Einkauf1, Jane E. Blackmer1, Chenyang Jiang1, Eric S. Rosenberg2, Ce Gao1, Xu Yu1, Tae-Wook Chun3, Mathias Lichterfeld1
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2Massachusetts General Hospital, Boston, MA, USA, 3National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
Abstract 309: https://ww2.aievolution.com/cro2101/index.cfm?do=abs.viewAbs&abs=1789
Xu Yu and her team at the Ragon Institute (Harvard) recently published a paper in Nature that described how elite controllers do what they do. Most of our DNA is transcriptionally silent and lacking in genes. DNA in these so-called gene deserts is hard to activate; accordingly, anything in these areas is essentially dead. Many of the old retroviruses that infected people in the past were deposited in these graveyards. For reasons yet to be defined, she found the virus population in elite controllers – including many enrolled in the UCSF CFAR-funded SCOPE cohort – are enriched in these gene deserts, explaining why there is so little virus being produced. In a related study at CROI, Matthias Lichterfeld's team found that people who control their virus after ART is interrupted ("post-treatment controllers") might be doing the same thing. Most of the intact HIV genomes in these controllers are in these regions. Interestingly, the viruses that live in the genes and hence might be easily induced are rate and seem to be preferentially eliminated by the immune system.
Oral Abstract in HIV Cure
Novel RNA vaccines prevent SHIV infection in macaques
An Env-gag mRNA VACCINE PROTECTS MACAQUES FROM HETEROLOGOUS TIER-2 SHIV INFECTION (starts at 1:36:46)
Peng Zhang1, Elisabeth Narayanan2, Shilei Ding3, Madhu Prabhakaran1, Yaroslav Tsybovsky4, Richard A. Koup1, Malcolm A. Martin5, Johnathan Misamore6, Adrian McDermott5, John R. Mascola1, Andrea Carfi7, Andrés Finzi3, Anthony S. Fauci1, Paolo Lusso1, for the National Institute of Allergy and Infectious Diseases
1National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 2Maasstad Hospital, Rotterdam, Netherlands, 3Université de Montréal, Montreal, Canada, 4National Cancer Institute, Bethesda, MD, USA, 5National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA,6BIOQUAL, Inc, Rockville, MD, USA, 7Aalborg University Hospital, Aalborg, Denmark
Oral Abstract 86: https://ww2.aievolution.com/cro2101/index.cfm?do=abs.viewAbs&abs=2647
The remarkably rapid development of effective vaccines for COVID occurred in large part due to the massive investment in basic and clinical HIV vaccinology. The first COVID vaccines to get emergency approval used the recently developed mRNA technology. In what will likely be a common theme, the knowledge gained in the development of COVID vaccines is now leading to new ways to prevent HIV. In collaboration with Moderna, the NIH Vaccine Research Center (VRC) designed an mRNA vaccine in which monkeys were primed with the genes for the viral gag and envelope proteins and then boosted with the same genes from clades A and C. As we have seen with mRNA vaccine and COVID, the vaccine induced the production of autologous neutralizing antibodies. These antibodies protected animals from becoming infected with a difficult to neutralize variant of SIV. One assumes that this approach will move rapidly toward the clinic.