Durable Virologic Suppression Research Articles

The impact of cannabinoids on inflammasome signaling in HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver. Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.

Third-line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource-limited settings: ACTG A5288 strategy trial.

IntroductionACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second‐line protease inhibitor (PI)‐based antiretroviral therapy (ART) from 10 low‐ and middle‐income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third‐line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV‐1 RNA ≤200 copies/ml. We report here long‐term outcomes over 144 weeks.MethodsStudy participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. “Extended Follow‐up” of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow‐up of ≥144 weeks), with HIV‐1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow‐up. Proportion of participants with HIV‐1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow‐up; mean CD4 count changes were estimated using loess regression.Results and DiscussionOf 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm3, and HIV‐1 RNA was 4.6 log10 copies/ml. Median follow‐up was 168 weeks (IQR: 156–204); 15 (6%) participants were lost to follow‐up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV‐1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74–85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm3 (95% CI 247–283).ConclusionsThird‐line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second‐line PI‐based ART prior to the availability of dolutegravir.

Fitting a vaccine into the HIV prevention landscape.

Fitting a vaccine into the HIV prevention landscape.

Rates of Sexually Transmitted Infection Diagnoses Among US Youth With Perinatally and Nonperinatally Acquired HIV.

Of new sexually transmitted infections (STIs) in the United States, 50% occur among youth aged 15 to 24 years. Previous studies among youth with HIV (YHIV) do not distinguish STI trends among individuals with perinatally (YPHIV) and nonperinatally (YNPHIV) acquired HIV. Among 3 Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) studies conducted between 2009 and 2015, we estimated incident diagnoses of trichomonal, bacterial, viral, and overall STIs stratified by sex assigned at birth, mode of HIV acquisition (perinatal [YPHIV] and nonperinatal [YNPHIV]), age (13-17 and 18-24 years), CD4 count (<200, 200-499, and ≥500/μL), and HIV viral load (VL) (<400 and ≥400 copies/mL). Among 3131 YHIV, across the 3 studies, mean (SD) age was 20.6 (2.6) years, 888 (28%) were female, 2498 (80%) had nonperinatal HIV acquisition recorded, and 2298 (73%) were African American/Black. Mean follow-up was 0.9 (0.3) years. Compared with YPHIV, YNPHIV spent less person-time with VL <400 copies/mL (47% vs. 53%) and more time off antiretroviral therapy (49% vs. 15%), and had higher overall STI rates (males, 65.9 vs. 8.5/100 person-years [PY]; females, 54.7 vs. 17.2/100 PY). Among YPHIV, bacterial STIs were higher during person-time spent with VL ≥400 vs. <400 copies/mL (male YPHIV, 10.9 vs. 0.6/100 PY; female YPHIV, 11.2 vs. 2.9/100 PY); no difference was observed among YNPHIV, which may be due to concurrent acquisition of HIV and other STIs and limited follow-up. Compared with YPHIV, YNPHIV spent less time on antiretroviral therapy and virologically suppressed; YNPHIV also had higher STI diagnosis rates. Very high STI diagnosis rates among YHIV, including among those without virologic suppression, highlight the importance of youth-focused efforts to support durable virologic suppression and identify and treat STIs.

116. Antiviral Activity and Safety of Long-acting Cabotegravir (CAB LA) Plus Long-acting Rilpivirine (RPV LA), Administered Every 2 Months (Q2M), in Hiv-positive Subjects: Results from the POLAR Study

BackgroundLong-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) injectable suspensions have demonstrated efficacy in phase III studies. POLAR assessed antiviral activity and safety of CAB LA+RPV LA, administered every 2 mos (Q2M), in HIV-1 infected, antiretroviral therapy–experienced adults who completed LATTE and received once-daily oral CAB30mg+RPV25mg treatment.MethodsPOLAR is a phase IIb, multicenter, open-label, rollover study in 97 virologically suppressed, HIV-infected adults. LATTE participants who completed ≥312 weeks on study, with plasma HIV-1RNA< 50c/mL at screening, were eligible for POLAR and offered the option to switch to CAB LA+RPV LA Q2M or to the oral fixed dose combination of dolutegravir (DTG)/rilpivirine (RPV) once daily, for continued maintenance of HIV-1RNA suppression. 90 participants chose CAB LA+RPV LA and 7 participants chose oral DTG/RPV. The primary outcome measure was proportion of participants with plasma HIV-1RNA≥50c/mL after 12 mos (M12) of therapy. Safety and laboratory measures were assessed throughout the study. Participants selecting LA treatment completed satisfaction and quality-of-life questionnaires at Day 1, M6, and M12.ResultsAt M12, no participant had HIV-1RNA≥50c/mL or protocol defined virologic failure (confirmed plasma HIV-1RNA > 200c/mL). Excluding injection-site reactions (ISRs), nasopharyngitis (11%), upper respiratory tract infection (11%), diarrhea (10%), and pyrexia (10%) were the most commonly reported adverse events (AEs) in the Q2M arm. 10% (9/90) of Q2M participants reported AEs ≥grade 3; 0 were drug related. 2% (2/90) of Q2M participants had AEs leading to withdrawal. 6% (5/90) of participants reported serious AEs (1 considered drug-related). Over 12 mo, 1534 injections were administered; 463 ISRs were reported (30%; all grade 1/2 [84%/16%]); resolution of ISRs occurred after a median of 3 days. Minimal changes in lab parameters were observed in participants across 12 mo. 88% of participants who received LA therapy preferred CAB LA+RPV LA vs oral therapy.Table 1 Table 2 ConclusionCAB LA+RPV LA, administered Q2M, resulted in durable virologic suppression, an acceptable tolerability profile, and high levels of participant satisfaction over the first 12 mo of treatment in POLAR.Disclosures Anthony Mills, MD, Gilead (Grant/Research Support, Advisor or Review Panel member)Janssen Pharmaceutica (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Shionogi (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Gary J. Richmond, MD, FACP, FCCP, Gilead (Scientific Research Study Investigator)TaiMed (Scientific Research Study Investigator)Viv (Scientific Research Study Investigator) Cheryl Newman, MD, Gilead (Grant/Research Support)GlaxoSmithKline (Grant/Research Support, Speaker’s Bureau)ViiV Healthcare (Research Grant or Support, Speaker’s Bureau) Olayemi Osiyemi, M.D, GlaxoSmithKline (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Jerry Cade, MD, Gilead (Consultant, Research Grant or Support, Speaker’s Bureau)Janssen Pharmaceutica (Consultant)Merck (Consultant, Research Grant or Support, Speaker’s Bureau)ViiV Healthcare (Consultant, Research Grant or Support) Cynthia Brinson, MD, Gilead (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Nisha Andany, MD, MPH, FRCPC, Gilead Sciences (Scientific Research Study Investigator)GlaxoSmithKline (Scientific Research Study Investigator)Janssen (Scientific Research Study Investigator) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kenneth Sutton, MA, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Viviana Wilches, HBSc, MBiotech, GlaxoSmithKline (Employee, Shareholder) Jeremy Roberts, MSc, GSK (Employee) Cynthia C. McCoig, MD, ViiV Healthcare (Employee) Kati Vandermeulen, MSC, Janssen Pharmaceutica (Employee, Shareholder) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder)

Despite early Medicaid expansion, decreased durable virologic suppression among publicly insured people with HIV in Washington, DC: a retrospective analysis

BackgroundDespite widely available access to HIV care in Washington, DC, inequities in HIV outcomes persist. We hypothesized that laboratory monitoring and virologic outcomes would not differ significantly based on insurance type.MethodsWe compared HIV monitoring with outcomes among people with HIV (PWH) with private (commercial payer) versus public (Medicare, Medicaid) insurance receiving care at community and hospital clinics. The DC Cohort follows over 8000 PWH from 14 clinics. We included those ≥18 years old enrolled between 2011 and 2015 with stable insurance. Outcomes included frequency of CD4 count and HIV RNA monitoring (> 2 lab measures/year, > 30 days apart) and durable viral suppression (VS; HIV RNA < 50 copies/mL at last visit and receiving antiretroviral therapy (ART) for ≥12 months). Multivariable logistic regression models examined impact of demographic and clinical factors.ResultsAmong 3908 PWH, 67.9% were publicly-insured and 58.9% attended community clinics. Compared with privately insured participants, a higher proportion of publicly insured participants had the following characteristics: female sex, Black race, heterosexual, unemployed, and attending community clinics. Despite less lab monitoring, privately-insured PWH had greater durable VS than publicly-insured PWH (ART-naïve: private 70.0% vs public 53.1%, p = 0.03; ART-experienced: private 80.2% vs public 69.4%, p < 0.0001). Privately-insured PWH had greater durable VS than publicly-insured PWH at hospital clinics (AOR = 1.59, 95% CI: 1.20, 2.12; p = 0.001).ConclusionsParadoxical differences between HIV monitoring and durable VS exist among publicly and privately-insured PWH in Washington, DC. Programs serving PWH must improve efforts to address barriers creating inequity in HIV outcomes.

The role of drug resistance in poor viral suppression in rural South Africa: findings from a population-based study

BackgroundUnderstanding factors driving virological failure, including the contribution of HIV drug resistance mutations (DRM), is critical to ensuring HIV treatment remains effective. We examine the contribution of drug resistance mutations for low viral suppression in HIV-positive participants in a population-based sero-prevalence survey in rural South Africa.MethodsWe conducted HIV drug resistance genotyping and ART analyte testing on dried blood spots (DBS) from HIV-positive adults participating in a 2014 survey in North West Province. Among those with virologic failure (> 5000 copies/mL), we describe frequency of DRM to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI), report association of resistance with antiretroviral therapy (ART) status, and assess resistance to first and second line therapy. Analyses are weighted to account for sampling design.ResultsOverall 170 DBS samples were assayed for viral load and ART analytes; 78.4% of men and 50.0% of women had evidence of virologic failure and were assessed for drug resistance, with successful sequencing of 76/107 samples. We found ≥1 DRM in 22% of participants; 47% were from samples with detectable analyte (efavirenz, nevirapine or lopinavir). Of those with DRM and detectable analyte, 60% showed high–level resistance and reduced predicted virologic response to ≥1 NRTI/NNRTI typically used in first and second-line regimens.ConclusionsDRM and predicted reduced susceptibility to first and second-line regimens were common among adults with ART exposure in a rural South African population-based sample. Results underscore the importance of ongoing virologic monitoring, regimen optimization and adherence counseling to optimize durable virologic suppression.

Genotypic Methods for HIV Drug Resistance Monitoring: The Opportunities and Challenges Faced by China.

AIDS is a globalized infectious disease. In 2014, UNAIDS launched a global project of "90-90-90" to end the HIV epidemic by 2030. The second and third 90 require 90% of HIV-1 infected individuals receiving antiretroviral therapy (ART) and durable virological suppression. However, wide use of ART will greatly increase the emergence and spreading of HIV drug resistance and current HIV drug resistance test (DRT) assays in China are seriously lagging behind, hindering to achieve virological suppression. Therefore, recommending an appropriate HIV DRT method is critical for HIV routine surveillance and prevention in China. In this review, we summarized the current existing HIV drug resistance genotypic testing methods around the world and discussed the advantages and disadvantages of these methods.

1321. Trans Females Receiving Gender-Affirming Surgical Referrals are More Likely to Have Durable Virologic Suppression at Whitman-Walker Health, 2008–2017

BackgroundTrans females bear a disproportionate burden of HIV infection yet little is known about their HIV care continuum participation. We characterized the care continuum among trans female people with HIV (PWH) at Whitman-Walker Health (WWH) in Washington, DC and explored the impact of gender-affirming care on continuum participation.MethodsThis IRB-approved review from 2008 to 2017 analyzed trans female and nontrans PWH cohorts. Trans females were selected via self-identification and chart review, based on hormone prescription or narrative charting. Chi-square analysis was performed to examine associations between gender identity and demographic factors, comorbidities, and achieving steps in the care continuum. Bivariate analysis using chi-square test of independence and point-biserial correlation was performed between predictor and outcome variables in the care continuum. Multivariate logistic regression analysis was performed to identify predictors of poor outcomes in the care continuum.ResultsWe analyzed 219 trans female and 456 nontrans PWH (Figure 1). Trans female PWH were more likely to be Black and/or Hispanic, have unstable housing, and be publically insured when compared with nontrans PWH (Table 1). There was no difference in ART initiation, retention in care (RiC), or durable virologic suppression (DVS) <200 copies/mL based on gender identity (Figure 2). Nontrans PWH had a higher odds of DVS at lower limits of detection (LLOD) than trans female PWH (OR 1.59, 95% CI 1.15–2.20). Hormone prescription did not impact trans female PWH continuum participation (Table 2). Surgical referral was found to impact DVS < 200 (P = 0.036) and DVS < LLOD (P = 0.021), but multivariate modeling could not be performed. Trans female PWH with surgical referrals were more likely to achieve DVS < 200 (OR 3.57, 95% CI 1.02–12.23) and DVS < LLOD (OR 2.85, 95% CI 1.14–7.12).ConclusionThis novel analysis of gender-affirming care and the HIV care continuum shows trans female PWH were less likely than nontrans to achieve durable VS < LLOD. Trans female PWH who received surgical referrals were 3.5 times more likely to achieve durable VS < 200 and almost three times more likely to achieve durable VS < LLOD. Further research is needed to explore this association between surgical referrals and DVS among trans female PWH. Disclosures All authors: No reported disclosures.

A Randomized Trial of Bictegravir or Dolutegravir with Emtricitabine and Tenofovir Alafenamide (F/TAF) Followed by Open Label Switch to Bictegravir/F/TAF Fixed Dose Combination

BackgroundIntegrase strand transfer inhibitors (INSTIs) are widely recommended for initial HIV-1 treatment. Bictegravir (BIC, B) is a novel, once-daily INSTI with potent antiviral activity being developed in coformulation with emtricitabine and tenofovir alafenamide (F/TAF).MethodsIn this Phase 2 study, treatment naïve, HIV-infected adults were randomized 2:1 to receive blinded treatment with BIC or dolutegravir (DTG) coadministered with open label F/TAF (200/25 mg). After all participants completed 48 weeks, they were unblinded and switched to a single fixed-dose combination tablet of B/F/TAF 50/200/25 mg. The proportion of participants with HIV-1 RNA <50 copies/mL (c/mL) was assessed at Week (W) 24 and W48 of the blinded phase and 12 weeks after switching to open label B/F/TAF (W72).ResultsOf 98 participants enrolled in the blinded treatment phase, 65 were randomized to BIC+F/TAF and 33 to DTG+F/TAF. Most were male, had asymptomatic HIV infection, with median HIV-1 RNA 4.4–4.5 log10 c/mL. The proportion of subjects with HIV-1 RNA <50 c/mL at W24 was 97% for the BIC arm and 94% for the DTG arm, and at W48 was 97% and 91%, respectively (Table). All 92 participants who completed the blinded phase were switched to B/F/TAF at W60. At W72 or 12 weeks after switching to open-label B/F/TAF, 99% (91/92) maintained HIV-1 RNA <50 c/mL (98% prior BIC arm [N = 62]; 100% prior DTG arm [N = 30]) and one individual withdrew prior to the analysis. No viral resistance was detected in participants treated with BIC. No participants discontinued open label B/F/TAF due to an adverse event, there were no treatment-related serious adverse events and no deaths. One individual on BIC previously discontinued due to an adverse event of urticaria following the W24 visit.ConclusionAll participants switched from DTG+F/TAF to open-label B/F/TAF maintained virologic suppression, with none discontinuing due to adverse events. During 72 weeks of follow-up, no treatment-emergent resistance to any components was detected in participants taking B/F/TAF. B/F/TAF demonstrated durable virologic suppression in naïve patients through W72 and was safe and effective after switching from DTG + F/TAF, further study in treatment naïve and experienced populations is warranted.Disclosures P. E. Sax, Gilead: Consultant and Investigator, Consulting fee, Research grant and Research support; BMS: Consultant and Investigator, Consulting fee, Research grant and Research support; GlaxoSmithKline/ViiV: Consultant and Investigator, Consulting fee, Research grant and Research support; AbbVie: Consultant, Consulting fee; Janssen: Consultant, Consulting fee; Merck: Consultant, Consulting fee; E. Dejesus, Gilead Sciences: Consultant, Investigator and Speaker’s Bureau, Consulting fee and Speaker honorarium; Janssen: Consultant, Investigator and Speaker’s Bureau, Consulting fee and Speaker honorarium; G. Crofoot, Gilead: Investigator and Scientific Advisor, Advisory honorarium and Research grant; ViiV: Investigator and Scientific Advisor, Advisory honorarium, Research grant and Research support; D. Ward, Gilead: Investigator, Research support; P. Benson, Gilead Sciences: Investigator, Shareholder and Speaker’s Bureau, Research support and Speaker honorarium; ViiV Healthcare: Investigator, Research support; L. Wei, Gilead: Employee and Shareholder, Salary; K. White, Gilead Sciences, Inc.: Employee and Shareholder, Salary; S. Collins, Gilead: Employee and Shareholder, Salary; H. Martin, Gilead Sciences: Employee, Salary; A. Cheng, Gilead: Employee and Shareholder, Salary; E. Quirk, Gilead: Employee and Shareholder, Salary

Treatment interruption in chronically HIV-infected patients with an ultralow HIV reservoir

To investigate the potential for combination antiretroviral therapy (cART)-free remission following analytic treatment interruption (ATI) in chronically HIV-infected patients with ultralow cell-associated DNA. Pilot study of patients (pts) with plasma viral load (pVL) less than 50 copies/ml for more than 2 years on cART, CD4 above 500 cells/μl, CD4/CD8 above 0.9, CD4 nadir above 300 cells/μl and HIV-DNA below 100 copies/10 peripheral blood mononuclear cells (PBMCs), undergoing treatment interruption. Ultrasensitive pVL, CD4 cell count, triplicate HIV-DNA were measured at D0, W2, W4, and every 4 weeks off-ART until W48 and at W4, W12 and W24 after ART resumption (RxR). RxR occurred in case of pVL rebound above 400 copies/ml or CD4 above 400 cells or HIV-related clinical event. The primary endpoint was the percentage of patients who did not reach RxR criteria at W24. Individuals were to be enrolled in three cohorts of five. Enrolment in cohort 2 began if at least one of five patients from cohort 1 remained in success at W8. Cohort 3 did not start. Ten patients were enrolled, with median (range) CD4 1118 cells/μl (608-1494), CD4/CD8 2.1 (1.4-2.6), HIV-DNA 66 copies/10 PBMC (<66-66) at screening, viral suppression of 4.9 years (2.9-8.3), CD4 nadir 495 cells/μl (330-739). One patient remained off-ART up to W48. Viral rebound occurred in nine of 10 patients at W2 (2 patients), W4 (6 patients) and W12 (one patient). pVL was resuppressed on cART at W4 (8 patients) and W12 (one patient). HIV DNA returned to baseline values within a median of 12 weeks following RxR. In a highly selected population of 10 patients with chronic HIV infection, an excellent immune status, durable virological suppression and ultralow reservoir, the success rate of ATI was 10% (95% confidence interval 0.3-44.5%) and nine of 10 patients had prompt rebound of plasma viremia. Resumption of ART led to return to baseline cell-associated total DNA.

Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity

Adoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding. We compared a standard CD4 CAR with CD4-17b CARs where the polypeptide linker between the CD4 and 17b moieties is sufficiently long (CD4-35-17b CAR) versus too short (CD4-10-17b) to permit simultaneous binding of the two moieties to a single gp120 subunit. When transduced into a peripheral blood mononuclear cell (PBMC) or T cells thereof, all three CD4-based CARs displayed specific functional activities against HIV-1 Env-expressing target cells, including stimulation of gamma interferon (IFN-γ) release, specific target cell killing, and suppression of HIV-1 pseudovirus production. In assays of spreading infection of PBMCs with genetically diverse HIV-1 primary isolates, the CD4-10-17b CAR displayed enhanced potency compared to the CD4 CAR whereas the CD4-35-17b CAR displayed diminished potency. Importantly, both CD4-17b CARs were devoid of a major undesired activity observed with the CD4 CAR, namely, rendering the transduced CD8(+) T cells susceptible to HIV-1 infection. Likely mechanisms for the superior potency of the CD4-10-17b CAR over the CD4-35-17b CAR include the greater potential of the former to engage in the serial antigen binding required for efficient T cell activation and the ability of two CD4-10-17b molecules to simultaneously bind a single gp120 subunit. HIV research has been energized by prospects for a cure for HIV infection or, at least, for a "functional cure" whereby antiretroviral therapy can be discontinued without virus rebound. This report describes a novel CD4-based "chimeric antigen receptor" (CAR) which, when genetically engineered into T cells, gives them the capability to selectively respond to and kill HIV-infected cells. This CAR displays enhanced features compared to previously described CD4-based CARs, namely, increased potency and avoidance of the undesired rendering of the genetically modified CD8 T cells susceptible to HIV infection. When adoptively transferred back to the individual, the genetically modified T cells will hopefully provide durable killing of infected cells and sustained virus suppression without continued antiretroviral therapy, i.e., a functional cure.

Treatment as prevention--where next?

Uptake of antiretroviral regimens with associated durable virologic suppression has been shown to reduce the risk of HIV transmission. Expanding antiretroviral therapy (ART) programs at a population level may serve as a vital strategy in the elimination of the AIDS epidemic. The global expansion of ART programs has greatly improved access to life-saving therapies and is likely to achieve the target of 15 million individuals on therapy set by UNAIDS. In addition to the incontrovertible gains in terms of life expectancy, growing evidence demonstrates that durable virologic suppression is associated with significant reductions in HIV transmission amongst heterosexual couples and men who have sex with men. Expansion of successful ART programs, best monitored by a program-level continuum of care cascade to assess progress in diagnosis, retention in care, and virologic suppression, is associated with reductions in HIV incidence at a population level. Expanding and sustaining successful ART delivery at a global level is a key component in a comprehensive approach to combating the HIV epidemic over the next two decades.

True durability: HIV virologic suppression in an urban clinic and implications for timing of intensive adherence efforts and viral load monitoring.

Although the majority of HIV-infected patients who begin potent antiretroviral therapy should expect long-term virologic suppression, the realities in practice are less certain. Durability of viral suppression was examined to define the best timing of targeted adherence strategies and intensive viral load monitoring in an urban clinic population with multiple challenges to ART adherence. We examined the risk of viral rebound for patients who achieved two consecutive viral loads lower than the lower limit of quantification (LLOQ) within 390 days. For 791 patients with two viral loads below the LLOQ, viral rebound >LLOQ from the first viral load was 36.9 % (95 % CI 32.2–41.6) in the first year, 26.9 % (95 % CI 21.7–32.1) in the year following one year of viral suppression, and 24.6 % (95 % CI 18.4–30.9) in the year following 2 years of viral suppression. However, for patients with CD4 ≥300 cells/µl who had 3–6 years of virologic suppression, the risk of viral rebound was very low. At the population level, the risk of viral rebound in a complex urban clinic population is surprisingly high even out to 3 years. Intensified monitoring and adherence efforts should target this high risk period. Thereafter, confidence in truly durable virologic suppression is improved.

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

Long-Term Therapy with Nucleoside/Nucleotide Analogues for Chronic Hepatitis B in Asian Patients

Of the estimated 400 million patients with chronic hepatitis B (CHB) globally, approximately 75% are Asians, representing a clinically important subgroup with a higher risk of cirrhosis and hepatocellular carcinoma than Caucasian patients. This review summarizes recent data from clinical long-term and real-life studies of entecavir and tenofovir, the recommended first-line oral therapies for treating CHB, in nucleoside/nucleotide-naive Asian CHB patients with compensated or decompensated liver disease. Long-term treatment with entecavir or tenofovir achieved profound and durable virological suppression, and led to improved liver histology and function. The data presented in this review will help physicians in making evidence-based decision choices regarding first-line antiviral therapy and long-term management in Asian CHB patients.

Considerations for the long-term treatment of chronic hepatitis B with nucleos(t)ide analogs

Treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogs is often required over a prolonged period to achieve durable virologic suppression. One barrier to the success of long-term therapy is the emergence of drug-resistant mutants. Current guidelines therefore recommend the most potent drugs with optimal resistance profiles, that is, entecavir and tenofovir are used as first-line monotherapies in CHB. Characteristics of the hepatitis B virus, the disease, the patient and the drug can influence the response to antiviral treatment and risk of relapse. This review discusses factors to consider maximizing the chances of successful long-term treatment of CHB, and provides an overview of the long-term efficacy and safety data that have become available over the 4–5 years since entecavir and tenofovir were first approved for the treatment of CHB. Recent findings on whether and under what circumstances long-term therapy of CHB might be stopped are also discussed.

ATV/r‐based regimens: durable virological suppression and good tolerability as switch strategy from NNRTI‐containing regimens in a real‐life cohort

Current therapeutic options for the treatment of HIV provide high rates of virological suppression and good tolerability. However, as long‐term treatment success has become a realistic goal, data evaluating the long‐term efficacy and safety of switching strategies become more needed. The purpose of this sub‐analysis is to describe the long‐term outcomes of ATV/r regimens after switching from combinations containing non‐nucleoside reverse transcriptase inhibitor (NNRTI) in a clinical setting. Non‐comparative, retrospective study including data from 3 European databases (France – DatAids, Germany‐KompNet, Sweden‐InfCare). Data from antiretroviral (ARV)‐experienced adults starting an ATV/r‐regimen between October 2004‐March 2007 were extracted every 6‐months (maximum follow‐up 5 years). Time to virological failure (VF) was analysed by the Kaplan‐Meier method. Reasons for discontinuation and safety data were also collected. Of 1294 patients analysed, 250 switched from a NNRTI‐based regimen. Patients were predominantly male (74%); median age 42 years (min, max: 23, 85); prior ARV exposure: median 5.0 years. At baseline (BL), 56% of patients had HIV‐1 RNA&lt;500 c/mL and 31% had&lt;50 c/mL; median (min, max) CD4 cell count: 388 (6, 1299) cells/mm3. After 3‐year follow‐up, the probability of not having VF was 79% (95% CI 65–88%) and 62% (95% CI 52%–70%) for patients with BL HIV‐1 RNA&lt;or≥50 c/mL, respectively. The most frequent reasons for discontinuation were “unknown” (18%) and adverse events (8%). Hyperbilirubinemia was reported as reason for discontinuation in only 2 patients. In a clinical setting, switching from NNRTI to ATV/r‐based regimen is associated with sustained virological suppression and good tolerability.Time to virological failure (2 consecutive HIV‐1 RNA≥50 c/mL or 1 HIIV‐1 RNA≥50 c/mL followed by discontinuation).image

Long‐term efficacy and safety of atazanavir/ritonavir treatment in a cohort of treatment‐naïve HIV patients: an interim analysis of the REMAIN study

PurposeCombined antiretroviral therapy has dramatically improved HIV‐infected individuals survival. Long‐term strategies are currently needed to achieve the goal of durable virologic suppression. However, long‐term available data for specific antiretrovirals (ARV) are limited. In clinical trials, boosted atazanavir (ATV/r) regimens has shown good efficacy and tolerability in ARV‐naïve patients for up to 4 years. The REMAIN study aimed to evaluate the long‐term outcomes of ATV/r regimens in ARV‐naïve patients in a real life setting.MethodsNon‐comparative, observational study conducted in Germany, Portugal and Spain. Historical and longitudinal follow‐up data was extracted six monthly from the medical record of HIV‐infected, treatment‐naïve patients, who initiated an ATV/r‐regimen between 2008 and 2010. The primary endpoint was the proportion of patients remaining on ATV treatment over time. Secondary endpoints included virologic response (HIV‐1 RNA &lt;50 c/mL and &lt;500 c/mL), reasons for discontinuation and long‐term safety. The duration of treatment and time to virologic failure (VF) were analyzed using the Kaplan‐Meier method. Data from an interim analysis including patients with at least one year of follow‐up are reported here.ResultsA total of 411 patients were included in this interim analysis [median (Q1, Q3) follow‐up: 23.42 (16.25, 32.24) months]: 77% male; median age 40 years [min, max: 19, 78]; 16% IDUs; 18% CDC C; 18% hepatitis C. TDF/FTC was the most common backbone (85%). At baseline, median (Q1, Q3) HIV‐RNA and CD4 cell count were 4.91 (4.34, 5.34) log10 c/mL and 256 (139, 353) cells/mm3, respectively. The probability of remaining on treatment was 0.84 (95% CI: 0.80, 0.87) and 0.72 (95% CI: 0.67, 0.76) for the first and second year, respectively. After 2 years of follow‐up, 84% (95% CI: 0.79, 0.88) of patients were virologically suppressed (&lt;50 c/mL). No major protease inhibitors mutations were observed at VF. Overall, 125 patients (30%) discontinued ATV therapy [median (Q1, Q3) time to discontinuation: 11.14 (6.24, 19.35) months]. Adverse events (AEs) were the main reason for discontinuation (n = 47, 11%). Hyperbilirubinaemia was the most common AE leading to discontinuation (14 patients). No unexpected AEs were reported.ConclusionsIn a real life clinical setting, ATV/r regimens showed durable virologic efficacy with good tolerability in an ARV‐naïve population. Data from longer follow‐up will provide additional valuable information.

Novel clinical trial designs for the development of new antiretroviral agents

We thank Dunn et al.[1] for their comments on our article. The article [2] reports an expert discussion on antiretroviral drug development at a time when the great majority of patients, including most who have experienced virological failure once or more, have licensed treatment options that if, adhered to, will help achieve durable virological suppression. As discussed in the article, traditional large-scale comparative trials like those pivotal for the licensure of raltegravir or etravirine are therefore difficult to conduct. There remains, however, a small group of patients for whom a likely suppressive treatment regimen may not be available, and for whom new agents that are efficacious against viral strains with multiple resistances to existing drugs would be of value. Due to the relative scarcity of patients without remaining treatment options, and to the recognized risk of aggravating drug resistance with incompletely suppressive regimens, drug development in this population is a challenge. As a first point of response to the comment by Dunn et al. [1], we note that the proposed study design discussed at the meeting principally addresses a population that would not be recommended for study in traditional 24–96 week placebo controlled trials according to present European or US regulatory and clinical guidance [3,4]. Dunn et al. [1] question whether the efficacy assessment in the proposed study adds value, over and above that obtained in phase 1/2 dose ranging monotherapy studies. In this context, we note that investigational agents that might be studied according to the proposed design are most likely to be new agents of existing drug classes. Thus, the primary efficacy objective of the randomized phase would be to assess in-vivo antiviral potency against a range of viruses with different genotypic resistance mutation patterns relevant to the drug class, and possibly conferring cross resistance to the new agent. Traditional monotherapy dose-ranging studies are generally performed in treatment-naive patients, and this information would not be obtained in such studies. If ‘functional’ monotherapy (add-on) studies in drug-class experienced patients failing their present regimen were performed in phase 1/2, these might be designed as smaller, pilot-type studies of a similar design as the randomized phase of the proposed pivotal study. Dunn et al. [1] rightly note that the proposed study would not provide randomized evidence of the durability of response. In this context, an assumption of the rationale for the proposed design is that, if an antiretroviral drug showed reasonable short-term potency against a certain viral resistance strain, available experience indicates that it would be highly likely to contribute to the long-term durability of response to a combination regimen, provided that the other agents had different mechanisms of action and did not select for similar drug resistance mutations. The second, nonrandomized phase of the proposed study would provide observational data on the durability of response, to be analyzed in relation to estimated optimized background therapy activity. Furthermore, it would provide information on emerging resistance mutations to the new agent in case of failure. As was discussed at the meeting, in order to generate randomized comparative data on the contribution of the new agent to the durability of response, the agent could be investigated in traditional, reasonably sized studies, which would likely have a noninferiority design. The meeting deliberations, which were prompted by the present treatment landscape, noted that such studies would most readily be conducted in treatment naive or lightly treatment experienced patients. Also, in such studies, rates of emerging drug resistance in case of viral failure would provide valuable information on the barrier to resistance of the agent. Finally, Dunn et al. [1] pose valid questions concerning the lack of randomized evidence on safety with the proposed study design. Neither the meeting nor our report systematically covered the issue of what supporting safety data would be required to bring a drug to market in the context of pivotal trials of the kind proposed. The size of the safety database, as well as the trials in which this may be generated, may differ depending on the range of treatment populations that are targeted in the drug development program. This will need to be further defined by regulatory agencies, if the proposed path is followed. Acknowledgements Conflicts of interest There are no conflicts of interest.