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Short-Term ART in Primary HIV-Infection & Decrease in HIV-DNA...... "....showed that 12 or 48 weeks of ART significantly decreases the cell-associated HIV-DNA. Also that viral load at 'baseline' associates with HIV-DNA levels at baseline and after therapy"
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- HIV-DNA rebounds upon Treatment Interruption
"I'm going to present to you today a detailed analysis of the determinants and implications of cell associated HIV DNA level on clinical outcome in the SPARTAC trial."
J. Williams presented data regarding the SPARTAC trial, which is the largest randomized clinical trial investigating the effect of short-course ART compared to no ART in primary HIV infection (PHI). He showed that 12 or 48 weeks of ART significantly decreases the cell-associated HIV-DNA. Also that viral load at 'baseline' associates with HIV-DNA levels at baseline and after therapy. Also, no evidence was found to suggest that proviral load is associated with time to viral rebound. And finally he showed that total and integrated proviral levels predict primary endpoint of the clinical trial.
HIV-1 DNA levels after antiretroviral therapy in primary infection predict disease progression: the SPARTAC Trial
Presented by James Philip Williams (United Kingdom).
J.P. Williams1,2,3, J. Hurst1,2,3, N. Robinson1,2,3, S. Fidler4, J. Weber4, A. Babiker5, R. Phillips1,2,3, K. Koelsch6, T. Kelleher6, J. Frater1,2,3, SPARTAC Trial Investigators
1University of Oxford, Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom, 2Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom, 3Institute for Emerging Infections, The Oxford Martin School, Oxford, United Kingdom, 4Imperial College London, Division of Medicine, Wright Fleming Institute, London, United Kingdom, 5Medical Research Council Clinical Trials Unit, London, United Kingdom, 6University of New South Wales, Kirby Institute, Sydney, Australia
AUTHOR CONCLUSIONS
· 12 or 48 weeks of ART significantly decreases the cell associated HIV-DNA.
· Viral Load at 'baseline' associates with HIV DNA levels at baseline and after therapy.
· Viral load and HIV DNA levels are not determined by estimated time since seroconversion.
· No evidence to suggest proviral load is associated with time to viral rebound.
· Total and Integrated proviral levels both predict primary endpoint of the clinical trial.
ABSTRACT
Background: The HIV-1 reservoir is the major barrier to HIV eradication. Measuring the reservoir using molecular qPCR techniques reveals associations with HIV-1 plasma viral load and the likelihood of 'post treatment control'. We investigated whether levels of 'total' and 'integrated' HIV-DNA measured by qPCR after 48 weeks of antiretroviral therapy (ART) were associated with surrogate disease markers and clinical progression in the SPARTAC trial, a large randomized RCT investigating short course ART in Primary HIV Infection (PHI).
Methods: 40 HIV+ve participants with PHI recruited to SPARTAC and randomized to receive 48 weeks of ART were investigated. All participants were recruited from the UK and were male. 38/40 (95%) were infected with subtype B HIV-1. Peripheral Blood Mononuclear Cell (PBMC) samples were taken at enrolment and on stopping 48 weeks of ART. Multi-clade compatible qPCR assays were performed on DNA from CD4 T cell enriched PBMCs to measure 'total' and 'integrated' HIV copies per CD4+ T cell. HIV-1 DNA levels were associated with baseline covariates and times to progression using logistic regression, Kaplan-Meier plots, and Cox models.
Results: Baseline plasma viral load levels and CD4 count were significantly associated with the total (p=0.0003 and p=0.0135, respectively) and integrated (p=0.0007 and p=0.0161, respectively) DNA levels after 48 weeks of therapy. There was no association between HIV-1 DNA levels and the estimated time since seroconversion at enrolment. Time to viral load rebound after stopping ART was associated with total (p=0.027) but not integrated HIV-1 DNA. Both total and integrated HIV-1 DNA levels were associated with the SPARTAC trial primary endpoint (HR 8.26; p< 0.0001 and HR 3.08; p=0.014; respectively) which was a composite of reaching either 350 CD4 cells/μl or starting long-term ART. In multivariate cox analyses, total HIV-1 DNA was more strongly associated with clinical progression than other covariates, including plasma viral load at enrolment.
Conclusion: The HIV-1 reservoir level after 48-weeks of treatment strongly predicted disease progression, with total HIV-1 DNA levels being more predictive than integrated HIV-1 DNA levels. These data confirm the significance of the HIV-1 reservoir in circulating CD4 cells and its importance in functional cure strategies.
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"I'm going to present to you today a detailed analysis of the determinants and implications of cell associated HIV DNA level on clinical outcome in the SPARTAC trial."
First of all the effect of ART on total HIV-DNA level was assessed in a cross sectional analysis using participants from the three trial arms. Patients in the ART 12 arm after 12 weeks of therapy, and patients in the ART48 arm after 48 weeks of therapy had significantly lower total HIV DNA levels than SOC untreated patients, by around a log, as seen in other studies. There was no significant further drop after 12 weeks of therapy suggesting that the drop happens early on. We wanted to see if this effect was present longitudinally, so we looked at 7 patients for whom we had sample in the Long arm at wk0 (pre therapy), week 48 (after 48 weeks of therapy) and week 108 (1 year after STI). Again, the trend was for a decrease in HIV total and integrated DNA levels after 48 weeks of therapy, and a subsequent rebound after STI to at or around baseline levels, which is a concern for patients who stop therapy
We were interested in assessing the relationship between HIV RNA and HIV DNA in untreated participants. As seen in other studies, HIV RNA levels in blood plasma and DNA levels from the same timepoint in PBMCs correlate very strongly. We then wanted to see if ART would affect this relationship.
After 12 or 48 weeks of therapy, a high baseline viral load still correlated with a high proviral load as measured by total (black) and integrated assays (red).
This indicates that the scene for proviral reservoir level is set early on.
An unpublished survival analysis of time since STI and rebound probablity demonstrated that longer periods of therapy (red >48wk) led to a later viral rebound, compared to 12 weeks of therapy (blue).
Unpublished, wolfgang stohr at MRC.
1 year - more patients >12 undetectable (14%)
Logistic regression - more likely to remain undetectable 3 months after therapy if >12 weeks therapy.
We addressed the question of whether the reservoir left after 48 weeks of therapy could predict the time for virus to become detectable after STI.
Since submission, we have excluded 7 patients who did not follow protocol and had detectable viremia at wk48. After exclusion of these patients, contrary to what we expected to see there was no longer any evidence to suggest that this was the case, as measured by total and integrated assays. 14% still undetectable 1 year post STI (ART-48) and 4% after 12 weeks.
We finally wanted to investigate associations between proviral HIV DNA level and time taken to reach the primary endpoint of SPARTAC. )
Proviral levels as measured by total and integrated assays were ranked and split by the median into two populations 'low' and 'high'.
After removal of the 7 non-compliant participants, we still find separation between kaplan meier graphs, indicating low total and integrated levels can delay the time taken to reach primary endpoint. but in a univariate analysis, total and integrated HIV DNA levels both significantly predict time to primary endpoint.
Proviral HIV DNA levels also significantly predict time to primary endpoint in a multivariate analysis including baseline viral load and CD4 count at wk48.
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