Influence of episodes of intermittent viremia ("blips") on immune responses and viral load rebound in successfully treated HIV-infected patients.
ABSTRACT: Presenting episodes of intermittent viremia (EIV) under combination antiretroviral therapy (cART) is frequent, but there exists some controversy about their consequences. They have been described as inducing changes in immune responses potentially associated with a better control of HIV infection. Conversely, it has been suggested that EIV increases the risk of virological failure. A retrospective analysis of a prospective, randomized double-blinded placebo-controlled study was performed. Twenty-six successfully treated HIV-infected adults were randomized to receive an immunization schedule or placebo, and after 1 year of follow-up cART was discontinued. The influence of EIV on T cell subsets, HIV-1-specific T cell immune responses, and viral load rebound, and the risk of developing genotypic mutations were evaluated, taking into account the immunization received. Patients with EIV above 200 copies/ml under cART had a lower proportion of CD4(+) and CD4(+)CD45RA(+)RO(-) T cells, a higher proportion of CD8(+) and CD4(+)CD38(+)HLADR(+) T cells, and higher HIV-specific CD8(+) T cell responses compared to persistently undetectable patients. After cART interruption, patients with EIV presented a significantly higher viral rebound (p=0.007), associated with greater increases in HIV-specific lymphoproliferative responses and T cell populations with activation markers. When patients with EIV between 20 and 200 copies/ml were included, most of the differences disappeared. Patients who present EIV above 200 copies/ml showed a lower CD4(+) T cell count and higher activation markers under cART. After treatment interruption, they showed greater specific immune responses against HIV, which did not prevent a higher virological rebound. EIV between 20 and 200 copies/ml did not have this deleterious effect.
Project description:BACKGROUND:Many HIV-infected children are diagnosed with tuberculosis (TB), but the effect of TB treatment on virologic and immunologic response to combination antiretroviral therapy (cART) is not well documented. METHODS:Secondary analysis of a prospective cohort of cART-naive HIV-infected South African children aged 0-8 years initiating cART to assess the effect of TB treatment at the time of cART initiation on virologic suppression (HIV RNA < 50 copies/mL), virologic rebound (HIV RNA > 1000 copies/mL after suppression), and CD4 cell percent (CD4%) increase during the first 24 months of cART. RESULTS:Of 199 children (median age 2.1 years), 92 (46%) were receiving TB treatment at cART initiation. Children receiving and not receiving TB treatment at cART initiation had similar median baseline HIV RNA (5.4 vs. 5.6 copies/mL), median time to virologic suppression (6.2 months in each group, adjusted hazard ratio, 1.36, 95% confidence interval: 0.94 to 1.96), and rates of virologic rebound by 24 months (23% vs. 24%, adjusted hazard ratio 1.53, 95% confidence interval: 0.71 to 3.30). Children on TB treatment had significantly lower median CD4% at baseline (15.3% vs. 18.8%, P < 0.01) and during the first 12 months of cART but experienced similar median increases in CD4% at 6 months (9.9% vs. 9.6%), 12 months (14.2% vs. 11.9%), and 24 months of cART (14.5% vs. 14.2%). Exploratory analyses suggest that children receiving lopinavir/ritonavir-based cART and TB treatment may have inferior virologic and immunologic response compared with children receiving efavirenz-based cART. CONCLUSIONS:Receiving TB treatment at the time of cART initiation did not substantially affect virologic or immunologic response to cART in young children.
Project description:The length of time that people with HIV on antiretroviral therapy (ART) with viral load suppression will be able to continue before developing viral rebound is unknown. We aimed to investigate the rate of first viral rebound in people that have achieved initial suppression with ART, to determine factors associated with viral rebound, and to use these estimates to predict long-term durability of viral suppression.The UK Collaborative HIV Cohort (UK CHIC) Study is an ongoing multicentre cohort study that brings together in a standardised format data on people with HIV attending clinics around the UK. We included participants who started ART with three or more drugs and who had achieved viral suppression (≤50 copies per mL) by 9 months after the start of ART (baseline). Viral rebound was defined as the first single viral load of more than 200 copies per mL or treatment interruption (for ≥1 month). We investigated factors associated with viral rebound with Poisson regression. These results were used to calculate the rate of viral rebound according to several key factors, including age, calendar year at start of ART, and time since baseline.Of the 16 101 people included, 4519 had a first viral rebound over 58 038 person-years (7·8 per 100 person-years, 95% CI 7·6-8·0). Of the 4519 viral rebounds, 3105 (69%) were defined by measurement of a single viral load of more than 200 copies per mL, and 1414 (31%) by a documented treatment interruption. The rate of first viral rebound declined substantially over time until 7 years from baseline. The other factors associated with viral rebound were current age at follow-up and calendar year at ART initiation (p<0·0001) and HIV risk group (p<0·0001); higher pre-ART CD4 count (p=0·0008) and pre-ART viral load (p=0·0003) were associated with viral rebound in the multivariate analysis only. For 1322 (29%) of the 3105 people with observed viral rebound, the next viral load value after rebound was 50 copies per mL or less with no regimen change. For HIV-positive men who have sex with men, our estimates suggest that the probability of first viral rebound reaches a plateau of 1·4% per year after 45 years of age, and 1·0% when accounting for the fact that 29% of viral rebounds are temporary elevations.A substantial proportion of people on ART will not have viral rebound over their lifetime, which has implications for people with HIV and the planning of future drug development.UK Medical Research Council.
Project description:The objective of this study is to assess the risk of viral rebound in postpartum women on suppressive combination antiretroviral therapy (cART).Using data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC), women with HIV-RNA 50?copies/ml or less at delivery in 2006-2011, who started life-long cART during pregnancy (n?=?321) or conceived on cART (n?=?618), were matched by age, duration on cART and time period, with at least one control (non-postpartum). The cumulative probability of viral rebound (HIV-RNA >200?copies/ml) was assessed by Kaplan-Meier analysis; adjusted hazard ratios (aHRs) for the 0-3 and 3-12 months postdelivery (cases)/pseudo-delivery (controls) were calculated in Cox proportional hazards models.In postpartum women who conceived on cART, 5.9% [95% confidence interval (95% CI) 4.0-7.7] experienced viral rebound by 3 months, and 2.2% (1.4-3.0%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during the first 3 months [aHR 2.63 (1.58-4.39)] but not during the 3-12 months postdelivery/pseudo-delivery. In postpartum women who started cART during pregnancy, 27% (22-32%) experienced viral rebound by 3 months, and 3.0% (1.6-4.4%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during both postdelivery/pseudo-delivery periods [<3 months: aHR 6.63 (3.58-12.29); 3-12 months: aHR 4.05 (2.03-8.09)].In women on suppressive cART, the risk of viral rebound is increased following delivery, especially in the first 3 months, which may be related to reduced adherence, indicating the need for additional adherence support for postpartum women.
Project description:HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n = 24) (DC-HIV-1) or nonpulsed DCs (n = 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10 to 1.9 copies/10(6) CD4 T cells, P = 0.22) and did increase in controls (mean of 1.8 log10 to 2.1 copies/10(6) CD4 T cells, P = 0.02) (P = 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r [Pearson's correlation coefficient] = -0.69, P = 0.002, and r = -0.82, P < 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.)There is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.
Project description:A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.
Project description:<h4>Background</h4>Long-term benefits of combination antiretroviral therapy (cART) initiation during primary HIV-1 infection are debated.<h4>Methods</h4>The evolution of plasma HIV-RNA (432 measurements) and cell-associated HIV-DNA (325 measurements) after cessation of cART (median exposure 18 months) was described for 33 participants from the Zurich Primary HIV Infection Study using linear regression and compared with 545 measurements from 79 untreated controls with clinically diagnosed primary HIV infection, respectively a known date for seroconversion.<h4>Results</h4>On average, early treated individuals were followed for 37 months (median) after cART cessation; controls had 34 months of pre-cART follow-up. HIV-RNA levels one year after cART interruption were -0.8 log₁₀ copies/mL [95% confidence interval -1.2;-0.4] lower in early treated patients compared with controls, but this difference was no longer statistically significant by year three of follow-up (-0.3 [-0.9; 0.3]). Mean HIV-DNA levels rebounded from 2 log₁₀ copies [1.8; 2.3] on cART to a stable plateau of 2.7 log₁₀ copies [2.5; 3.0] attained 1 year after therapy stop, which was not significantly different from cross-sectional measurements of 9 untreated members of the control group (2.8 log₁₀ copies [2.5; 3.1]).<h4>Conclusions</h4>The rebound dynamics of viral markers after therapy cessation suggest that early cART may indeed limit reservoir size of latently infected cells, but that much of the initial benefits are only transient. Owing to the non-randomized study design the observed treatment effects must be interpreted with caution.
Project description:<h4>Background</h4>HIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized.<h4>Methods</h4>Posttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ?400 copies/mL at two-thirds or more of time points for ?24 weeks. Viral load and CD4+ cell dynamics were compared between posttreatment controllers and noncontrollers.<h4>Results</h4>Of the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection. Posttreatment controllers were more frequently identified in those treated during early versus chronic infection (13% vs 4%, P < .001). In posttreatment controllers with weekly viral load monitoring, 45% had a peak posttreatment interruption viral load of ?1000 copies/mL and 33% had a peak viral load ?10000 copies/mL. Of posttreatment controllers, 55% maintained HIV control for 2 years, with approximately 20% maintaining control for ?5 years.<h4>Conclusions</h4>Posttreatment control was more commonly identified amongst early treated individuals, frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. These results may provide mechanistic insights and have implications for the design of trials aimed at achieving HIV remission.
Project description:INTRODUCTION:Viral remission after analytical treatment interruption (ATI), termed post-treatment control, has been described in a small proportion of HIV-positive patients. This phenomenon has been separately associated to both low levels of HIV-1 proviral DNA as well as cell-associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI). METHODS:We conducted an open single-arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV-1 RNA copies/mL for more than two years, more than 500 CD4 cells/µL for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV-1 DNA (t-DNA) and fewer than 10 copies cell-associated HIV-1 unspliced RNA (US-RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV-1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t-DNA and US-RNA after TI. RESULTS:All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t-DNA and US-RNA increased after TI but returned to pre-ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound. CONCLUSIONS:The combination of low levels of t-DNA and US-RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.
Project description:In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4<sup>+</sup> T-cell responses (<i>P</i> < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8<sup>+</sup> T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (<i>P</i> = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8<sup>+</sup> T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (<i>P</i> = 0.004) and CD27/CD57 (<i>P</i> = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log<sub>10</sub> copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.)<b>IMPORTANCE</b> In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.
Project description:Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl.Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl.