Antiretroviral Therapy Interruption (ATI) in HIV-1 Infected Patients Participating in Therapeutic Vaccine Trials: Surrogate Markers of Virological Response
Abstract
:1. Introduction
2. Utility of Analytical Antiretroviral Treatment Interruption (ATI)
3. Types of ATI: Virological Outcome Measures
4. Potential Adverse Effects
4.1. Clinical Risks
4.2. Effects in Virologic and Immunologic Parameters
4.3. Drug Resistance
4.4. Epidemiological Risks: HIV Transmission
5. Study Design
- (a)
- Active or chronic hepatitis B virus infection and active hepatitis C infection;
- (b)
- Active Mycobacterium tuberculosis infection;
- (c)
- History of cancer (often with exceptions for basal cell or squamous cell carcinoma of the skin or low grade anal or cervical dysplasia);
- (d)
- History of HIV-associated dementia or progressive multifocal leukoencephalopathy;
- (e)
- Resistance to two or more classes of antiretroviral drugs;
- (f)
- History of cardiovascular event or at high risk of an event;
- (g)
- History of AIDS-defining illness/CDC category C events;
- (h)
- History of CD4+ nadir <200 cells/mm3 during chronic stages of infection;
- (i)
- Women who are pregnant or breastfeeding;
- (j)
- Advanced non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis if evidence for substantial fibrosis or evidence of cirrhosis; and
- (k)
- HIV-related kidney disease or moderate-to-severe decrease in estimated glomerular filtration rate (<45–60 mL/min/1.73 m2).
6. Surrogate Markers of Viral Response during ATI
6.1. Host, Viral Load, and CD4+ T Cells Counts Influence Viral Load Rebound
6.2. Immunological Responses Influence Viral Dynamics during ATI
6.2.1. HIV-Specific CD4+ and CD8+ T Cell Responses
6.2.2. HIV Antibodies
6.2.3. Soluble Markers of Inflammation
6.3. Viral Reservoir Size Influence Viral Dynamics during ATI
6.3.1. Quantitative Viral Outgrowth Assay (QVOA)
6.3.2. Total DNA
6.3.3. Proviral DNA
6.3.4. Cell-Associated RNA
6.4. OMICS Data—A New Approach
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Clinical Risks | |
---|---|
Acute Retroviral Syndrome | Ruiz [17] Fagard [16] Tarwater [18] Ortiz [19] |
Thrombocytopenia | Tarwater [18] Ananworanich [20] Piketty [21] |
Cardiovascular, renal, or hepatic disease | SMART study group [6] |
Neurological events | Price [23] |
Opportunistic disease | SMART study group [6] |
Death | SMART study group [6] |
Increase in inflammation markers | Kuller [22] |
Antiretroviral Drug Resistance | |
Antiretroviral drug resistance | Arnedo [30] Lau [10] |
Effects in Virologic and Immunologic Parameters | |
Integrated HIV DNA (viral reservoir) | Clarridge [25] Salantes [26] Strongin [27] Papasavvas [28] Montserrat [29] |
HIV Transmission | |
HIV transmission reported cases | Lelièvre [31] Ugarte [32] |
CD4+ T Cell Count and PreART Viral Load | |
---|---|
Chronic HIV-1 Infected Patients | |
A lower nadir CD4+ T cell count and higher preART viral load had a shorter time to ART resumption | Autran [33] |
CD4+ T cell count and higher preART viral load correlated with time to ART resumption | Huang [34] |
preART viral load correlated with shorter time to viral load rebound | Li [35] |
Patients Treated During Acute HIV-1 Infection | |
No evidence of effect of CD4+ T cell count or preART VL | Colby [36] |
HLA | |
The number of HLA-associated polymorphisms in Gag predicted peak of viremia after ATI. No influence of the presence of protective HLA class I alleles (B*57, B*27 or B*51) or number of HLA footprints in Gag were associated with time to rebound of viral load | Rosas-Umbert [37] |
Participants with neutral HLA alleles had lower median VL 16 weeks after ATI than did vaccinated participants with protective HLA alleles or placebo participants with neutral HLA alleles. Factors independently associated with lower VL 16 weeks after ATI included greater Gag sequence divergence from the vaccine sequence and decreased proportion of HLA-associated polymorphisms in Gag | Li [35] |
Patients Treated in Chronic HIV-1 Infection | |
---|---|
Cell mediated immune responses | |
Slightly higher CD4+ LPR in patients with lower VL No relation in magnitude and breadth of CD8+ T cell responses with VL | Garcia [4] |
Inverse correlation between CD4+ LPR and VL | Kilby [5] |
Positive correlation of both, CD4+ LPR and CD8+ breadth responses, with time off ART | Lévy [6] |
Inverse correlation between CD4+ LPR and CD8+ magnitude and breadth and VL | Andrés [7] |
No association between CD4+ and CD8+ responses and longer TtR | Angel [9] |
No association of CD4+ LPR with time off ART | Pialoux [10] |
No association of T cell responses and VL | Mothe B [11] |
High CD4+ responses but absence of CD8+ responses associated to higher VL and shorter time to restart ART | Papagno [13] |
Patients Treated During Acute HIV-1 Infection | |
No association between CD4+ and CD8+ responses and time off ART | Goujard [8] |
HIV antibodies | |
No association of NAb (pre-ATI) with VL set point | Li [14] |
anti-C5/gp41 increase from week 1-preATI associated with low VL | Huang [15] |
Inflammation markers | |
VL control associated with increase in TNFα and IL-6 from week 1-preATI | Huang [16] |
Higher VL associated with increase in CRP from week 1-preATI | Huang [15] |
Latent Viral Reservoir Measurements | |
---|---|
Patients Treated When Chronically HIV-1 Infected | |
QVOA | |
No evidence of effect on UIPM | Angel [14] |
38% decrease of UIPM after interventions but did not prolong TtR | Leth [15] |
Total (cell-associated) DNA | |
Lower baseline total DNA content was associated with longer time to restart ART | Autran [17] |
Higher baseline level of total DNA correlate with higher pVL set point during ATI | Li [18] |
Reduction of total DNA after interventions but did not prolong TtR | Leth [15] |
Total DNA levels increased during ATI in both study and control group without significant differences Correlation between total DNA levels during ATI and the magnitude of T cell responses during vaccination Correlation between total DNA levels and pVL set point during ATI | Andrés [19] |
No evidence of effect on total DNA | Rosas-Umbert [21] |
No evidence of effect on total DNA—One participant showed a 2-fold reduction during ATI (the only participant carrying HLA alleles associated with natural HIV control) | Mothe [22] |
Proviral (Integrated) DNA | |
Baseline proviral DNA was associated with peak of pVL during rebound Baseline proviral DNA was independently associated to TtR | Rosas-Umbert [21] |
No evidence of effect on proviral DNA after disulfiram but substudy (Rosas-Umbert) | Mothe [26] |
Higher baseline proviral DNA levels trended to correlate with shorter TtR | Thompson [27] |
Correlation between integrated DNA levels during ATI and the magnitude of T cell responses during vaccination Correlation between integrated DNA levels and pVL set point during ATI | Andrés [19] |
Cell-associated RNA (CA-RNA) | |
Higher baseline level of CA-RNA correlate with higher pVL set point during ATI | Li [18] |
No evidence of effect on CA-RNA after disulfiram | Mothe [26] |
Patients Treated During Acute HIV-1 Infection | |
Total (cell-associated) DNA | |
Lower total DNA baseline level was associated with a longer time off ART Low total DNA level at ART interruption was associated with a low peak of pVL | Goujard [20] |
Patients Treated When Chronically HIV-1 Infected | |
QVOA | |
No evidence of effect on UIPM | Angel [14] |
38% decrease of UIPM after interventions but did not prolong TtR | Leth [15] |
Total (cell-associated) DNA | |
Lower baseline total DNA content was associated with longer time to restart ART | Autran [17] |
Higher baseline level of total DNA correlate with higher pVL set point during ATI | Li [18] |
Reduction of total DNA after interventions but did not prolong TtR | Leth [15] |
Total DNA levels increased during ATI in both study and control group without significant differences Correlation between total DNA levels during ATI and the magnitude of T cell responses during vaccination Correlation between total DNA levels and pVL set point during ATI | Andrés [19] |
No evidence of effect on total DNA | Rosas-Umbert [21] |
No evidence of effect on total DNA—One participant showed a 2-fold reduction during ATI (the only participant carrying HLA alleles associated with natural HIV control) | Mothe [22] |
Proviral (Integrated) DNA | |
Baseline proviral DNA was associated with peak of pVL during rebound Baseline proviral DNA was independently associated to TtR | Rosas-Umbert [21] |
No evidence of effect on proviral DNA after disulfiram but substudy (Rosas-Umbert) | Mothe [26] |
Higher baseline proviral DNA levels trended to correlate with shorter TtR | Thompson [27] |
Correlation between integrated DNA levels during ATI and the magnitude of T cell responses during vaccination Correlation between integrated DNA levels and pVL set point during ATI | Andrés [19] |
Cell-associated RNA (CA-RNA) | |
Higher baseline level of CA-RNA correlate with higher pVL set point during ATI | Li [18] |
No evidence of effect on CA-RNA after disulfiram | Mothe [26] |
Patients Treated During Acute HIV-1 Infection | |
Total (cell-associated) DNA | |
Lower total DNA baseline level was associated with a longer time off ART Low total DNA level at ART interruption was associated with a low peak of pVL | Goujard [20] |
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Share and Cite
Leal, L.; Fehér, C.; Richart, V.; Torres, B.; García, F. Antiretroviral Therapy Interruption (ATI) in HIV-1 Infected Patients Participating in Therapeutic Vaccine Trials: Surrogate Markers of Virological Response. Vaccines 2020, 8, 442. https://doi.org/10.3390/vaccines8030442
Leal L, Fehér C, Richart V, Torres B, García F. Antiretroviral Therapy Interruption (ATI) in HIV-1 Infected Patients Participating in Therapeutic Vaccine Trials: Surrogate Markers of Virological Response. Vaccines. 2020; 8(3):442. https://doi.org/10.3390/vaccines8030442
Chicago/Turabian StyleLeal, Lorna, Csaba Fehér, Valèria Richart, Berta Torres, and Felipe García. 2020. "Antiretroviral Therapy Interruption (ATI) in HIV-1 Infected Patients Participating in Therapeutic Vaccine Trials: Surrogate Markers of Virological Response" Vaccines 8, no. 3: 442. https://doi.org/10.3390/vaccines8030442