Search

Objective: We present findings from a large cohort of individuals treated during primary HIV infection (PHI) and examine the impact of time from HIV-1 acquisition to antiretroviral therapy (ART) initiation on clinical outcomes. We also examine the temporal changes in the demographics of individuals presenting with PHI to inform HIV-1 prevention strategies., Methods: Individuals who fulfilled the criteria of PHI and started ART within 3 months of confirmed HIV-1 diagnosis were enrolled between 2009 and 2020. Baseline demographics of those diagnosed between 2009 and 2015 (before preexposure prophylaxis (PrEP) and universal ART availability) and 2015-2020 (post-PrEP and universal ART availability) were compared. We examined the factors associated with immune recovery and time to viral suppression., Results: Two hundred four individuals enrolled, 144 from 2009 to 2015 and 90 from 2015 to 2020; median follow-up was 33 months. At PHI, the median age was 33 years; 4% were women, 39% were UK-born, and 84% were MSM. The proportion of UK-born individuals was 47% in 2009-2015, compared with 29% in 2015-2020. There was an association between earlier ART initiation after PHI diagnosis and increased immune recovery; each day that ART was delayed was associated with a lower likelihood of achieving a CD4 + cell count more than 900 cells/μl [hazard ratio 0.99 (95% confidence interval, 95% CI 0.98-0.99), P  = 0.02) and CD4/CD8 more than 1.0 (hazard ratio 0.98 (95% CI 0.97-0.99)., Conclusion: Early initiation of ART at PHI diagnosis is associated with enhanced immune recovery, providing further evidence to support immediate ART in the context of PHI. Non-UK-born MSM accounts for an increasing proportion of those with primary infection; UK HIV-1 prevention strategies should better target this group., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Tenofovir DF (TDF) remains one of the preferred backbone agents for naïve HIV patients starting antiretroviral treatment (ART). The impact of TDF on renal function and metabolic parameters may vary by anchor agent. We investigated the impact of TDF in combination with 3 different integrase inhibitors on tubular and glomerular function, and metabolic parameters in ART-naïve patients. Methods: Sixty patients with normal renal function were randomised (20 per arm) to TDF/emtricitabine (FTC) plus either raltegravir (RAL) (400 mg b.d.), dolutegravir (DTG) or elvitegravir/cobicistat (EVG/c) for 48 weeks. Results: 57 patients completed the study. Significant increases in RBP/creatinine ratio at week 24 were seen in all arms [RAL +4.7 μg/mmol (CI 0.43 to 8.98, p  = 0.032); DTG +4.96 μg/mmol (CI 0.77 to 9.15, p  = 0.021); EVG/c +6.95 μg/mmol (CI 2.53 to 11.36, p  = 0.002)], although this was not sustained to week 48 in the RAL arm. Similar changes across the arms were observed for urinary α1microglobulin (RAL +6.20 mg/L, p  = 0.030; DTG +6.30 mg/L, p  = 0.025; EVG/c +8.15 mg/L, p  = 0.003). Urinary β2microglobulin significantly increased at week 24 with DTG and EVG/c but remained unchanged in the RAL arm. Glomerular filtration measured with CKD-EPI creatinine-cystatin C increased significantly in the RAL arm at week 24 through 48 but declined modestly in other two arms. Total and LDL cholesterol decreased in the RAL arm, but increased in the EVG/c arm, with no significant changes in the DTG arm. Weight increased significantly from baseline with DTG but not RAL or EVG/c. Conclusion: INSTIs in combination with TDF/FTC impact differently on tubular microproteinuria, eGFR, metabolic markers and weight. Use of TDF/FTC with RAL had the least tubular effects and the most favorable metabolic profile.

T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial - but not complete - normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes., Competing Interests: WH is an employee of Merck and Company and holds equity in Tango Therapeutics and Arsenal Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martin, Sen, Pace, Robinson, Meyerowitz, Adland, Thornhill, Jones, Ogbe, Parolini, Olejniczak, Zacharopoulou, Brown, Willberg, Nwokolo, Fox, Fidler, Haining and Frater.)

Objectives: Rapid antiretroviral therapy (ART) initiation is recommended in early HIV infection (EHI), even in the absence of baseline viral resistance test result. We analysed time to viral suppression according to ART regimen started in a cohort of patients diagnosed with EHI., Methods: Clinical records of individuals consecutively diagnosed with EHI between July 2016-June 2018 were reviewed. The distribution of clinical, virological and immunological factors was compared in treatment groups using the Mann-Whitney U-test., Results: 262 individuals (97% MSM) were diagnosed with EHI. 58% of patients agreed to start ART within 14 days of diagnosis. Tenofovir-based combinations were prescribed to all patients. DRV/b was the most commonly prescribed third agent (78%), when genotypic resistance testing was not available at time of ART choice. Switching to INSTI was encouraged once VRT became available and 27% switched from DRV/b to INSTI (mainly RAL) within 28 days from ART start. Those receiving INSTI were more likely to have a baseline viral load exceeding 1 million HIV-1 RNA copies/mL compared with those starting with DRV/b. Rapid start with INSTI regimens resulted in quicker viral suppression than when DRV/b was chosen in EHI, even when that was subsequently switched to INSTI. Retention in care following rapid ART start was achieved by all patients at 24 weeks., Conclusions: Starting an INSTI-based ART combination was associated with quicker viral suppression than when a protease inhibitor-based combination was chosen. No differences in the achievement of viral suppression or in retention in care were observed., (© 2020 British HIV Association.)

A fourth-generation HIV test is conventionally performed at baseline for individuals given HIV post-exposure prophylaxis (PEP). However, early HIV infection may be missed by fourth-generation tests especially in settings of high HIV incidence, meaning that recently infected individuals are potentially at risk of transmitting HIV. In 2013, HIV incidence in PEP recipients at the 56 Dean Street clinic was 7.6 per 100 person-years. We therefore wished to see if using a point-of-care PCR HIV test in such individuals would shorten the testing window period and pick up early infections that would be undiagnosed by conventional tests. We compared HIV detection in PEP recipients using the Cepheid GeneXpert® HIV-1 Qual viral load (Qual VL) assay with the standard HIV tests used in our clinical service. Between March 2017 and August 2018, a Qual VL assay was performed in addition to standard baseline HIV tests in consented PEP recipients. Of 494 consented PEP recipients, 476 had valid Qual VL assay results. Of these, 474 (99.6%) had a negative Qual VL result and were also negative on standard baseline HIV tests. Two (0.4%) tested positive for HIV on Qual VL. One of these patients was also HIV-positive on all baseline HIV tests. The other had discordant baseline point-of-care HIV test results. Although no additional HIV infections were diagnosed in PEP recipients using Qual VL, in one individual, it provided confirmation of new HIV infection more quickly than the standard HIV testing pathway.

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3 + CD4 + cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32 low , CD32 + CD14 + , and CD32 high ). Of note, CD4 negative enrichment kits remove the majority of CD4 + CD32 + T cells, potentially skewing subsequent analyses if used. CD32 high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32 low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3 + CD4 + CD32 + phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32 + T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations.

Background: Few data exist on the benefits and acceptability of rapid initiation of antiretroviral treatment in acute HIV infection (AHI). We analysed a large cohort of acutely infected HIV patients starting antiretroviral therapy (ART) to determine uptake, linkage into care and time to achieve viral suppression., Methods: Case notes of all individuals diagnosed with AHI between May 2014 and October 2015 at 56 Dean Street, a sexual health clinic in London, UK were reviewed. AHI was defined through documentation of plasma HIV RNA positivity only, plasma HIV RNA and p24 antigen positivity with a negative HIV enzyme immunoassay (EIA) test or HIV EIA test switching from negative to positive within 6 weeks. Between-group comparisons of time to viral suppression according to ART chosen were performed using the log-rank test., Results: We identified 113 individuals with AHI. Linkage to care was 95%. 77% of patients started ART at first medical appointment: all men who have sex with men, median age 35 years, median viral load (VL) log 10 6.45, median CD4 + T-cell count 483 cells/mm 3 . Median time from diagnosis to ART initiation was 20 days. At 24 weeks, no patients had discontinued ART; 99% of patients achieved viral suppression by 24 weeks, with a median time to documented VL suppression of 74 days. Viral suppression was more rapid with integrase inhibitors compared with other regimens (median 41 versus 88.5 days, P<0.05)., Conclusions: In acute HIV infection, individuals demonstrated high ART uptake and rapid VL suppression suggesting that early treatment with antiretrovirals is acceptable and efficacious.

In the search for a cure for HIV-1 infection, histone deacetylase inhibitors (HDACi) are being investigated as activators of latently infected CD4 T cells to promote their targeting by cytotoxic T-lymphocytes (CTL). However, HDACi may also inhibit CTL function, suggesting different immunotherapy approaches may need to be explored. Here, we study the impact of different HDACi on both Natural Killer (NK) and CTL targeting of HIV-1 infected cells. We found HDACi down-regulated HLA class I expression independently of HIV-1 Nef which, without significantly compromising CTL function, led to enhanced targeting by NK cells. HDACi-treated HIV-1-infected CD4 T cells were also more effectively cleared than untreated controls during NK co-culture. However, HDACi impaired NK function, reducing degranulation and killing capacity. Depending on the HDACi and dose, this impairment could counteract the benefit gained by treating infected target cells. These data suggest that following HDACi-induced HLA class I down-regulation NK cells kill HIV-1-infected cells, although HDACi-mediated NK cell inhibition may negate this effect. Our data emphasize the importance of studying the effects of potential interventions on both targets and effectors.

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.