PD-1 Predicts CD4 Loss Rate in Chronic HIV-1 Infection Better Than HIV RNA and CD38 But Not in Cryopreserved Samples

AbstractObjectiveTo evaluate the effects of four drug (quadruple) versus three drug (triple) combination antiretroviral therapies in treatment naive people with HIV, and explore the implications of existing trials for clinical practice and research.DesignSystematic review and meta-analysis of randomised controlled trials.Data sourcesPubMed, EMBASE, CENTRAL, Web of Science, and the Cumulative Index to Nursing and Allied Health Literature from March 2001 to December 2016 (updated search in PubMed and EMBASE up to June 2018); and reference lists of eligible studies and related reviews.Study selectionRandomised controlled trials comparing quadruple with triple combination antiretroviral therapies in treatment naive people with HIV and evaluating at least one effectiveness or safety outcome.Review methodsOutcomes of interest included undetectable HIV-1 RNA, CD4 T cell count, virological failure, new AIDS defining events, death, and severe adverse effects. Random effects meta-analyses were conducted.ResultsTwelve trials (including 4251 people with HIV) were eligible. Quadruple and triple combination antiretroviral therapies had similar effects on all relevant effectiveness and safety outcomes, with no point estimates favouring quadruple therapy. With the triple therapy as the reference group, the risk ratio was 0.99 (95% confidence interval 0.93 to 1.05) for undetectable HIV-1 RNA, 1.00 (0.90 to 1.11) for virological failure, 1.17 (0.84 to 1.63) for new AIDS defining events, 1.23 (0.74 to 2.05) for death, and 1.09 (0.89 to 1.33) for severe adverse effects. The mean difference in CD4 T cell count increase between the two groups was −19.55 cells/μL (−43.02 to 3.92). In general, the results were similar, regardless of the specific regimens of combination antiretroviral therapies, and were robust in all subgroup and sensitivity analyses.ConclusionIn this study, effects of quadruple combination antiretroviral therapy were not better than triple combination antiretroviral therapy in treatment naive people with HIV. This finding lends support to current guidelines recommending the triple regimen as first line treatment. Further trials on this topic should be conducted only when new research is justified by adequate systematic reviews of the existing evidence. However, this study cannot exclude the possibility that quadruple cART would be better than triple cART when new classes of antiretroviral drugs are made available.

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Time-Updated CD4+ T Lymphocyte Count and HIV RNA as Major Markers of Disease Progression in Naive HIV-1-Infected Patients Treated With a Highly Active Antiretroviral Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/00126334-200307010-00013 ◽

2003 ◽

Vol 33 (3) ◽

pp. 380-386 ◽

Cited By ~ 12

Author(s):

Rodolphe Thiébaut ◽

Geneviève Chêne ◽

Hélène Jacqmin-Gadda ◽

Philippe Morlat ◽

Patrick Mercié ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Disease Progression ◽

T Lymphocyte ◽

Highly Active Antiretroviral Therapy ◽

Lymphocyte Count ◽

Hiv Rna ◽

Highly Active ◽

Hiv 1

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Defective HIV-1 proviruses produce viral proteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1917876117 ◽

2020 ◽

Vol 117 (7) ◽

pp. 3704-3710 ◽

Cited By ~ 18

Author(s):

Hiromi Imamichi ◽

Mindy Smith ◽

Joseph W. Adelsberger ◽

Taisuke Izumi ◽

Francesca Scrimieri ◽

...

Keyword(s):

T Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Viral Proteins ◽

Open Reading Frames ◽

Peripheral Blood Mononuclear ◽

Hiv Rna ◽

Rna Transcripts ◽

Extracellular Virus ◽

Hiv 1

HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as “defective” by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant “graveyard” of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cell–cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.

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Safety and Efficacy of Starting Antiretroviral Therapy in the First Week of Life

Clinical Infectious Diseases ◽

10.1093/cid/ciaa028 ◽

2020 ◽

Author(s):

Kenneth Maswabi ◽

Gbolahan Ajibola ◽

Kara Bennett ◽

Edmund V Capparelli ◽

Patrick Jean-Philippe ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

Viral Suppression ◽

Safety And Efficacy ◽

Hiv Rna ◽

Early Infant ◽

Immunodeficiency Virus ◽

Trough Concentrations ◽

Hiv Exposed ◽

Hiv 1

Abstract Background Early antiretroviral therapy (ART) is recommended for infants with human immunodeficiency virus (HIV) infection. However, few antiretroviral options are available for neonates. Methods The Early Infant Treatment Study in Botswana tested HIV-exposed infants within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6 mg/kg twice daily, zidovudine (ZDV), and lamivudine (3TC) at age < 7 days. NVP trough concentrations were tested at 1 and 2 weeks. NVP was switched to ritonavir-boosted lopinavir (LPV/r) at week 2, 3, 4, or 5 according to delivery gestational age. Results Forty HIV-infected infants started ART at median age 2 days (range, 1–5 days). NVP trough concentrations were highly variable and below therapeutic target (3000 ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only 1 unscheduled treatment modification was required. Within 4 weeks of transition to LPV/r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV/r palatability. At 12 weeks, 22 (55%) of 40 were <40 copies/mL (93% <400 copies/mL); by 24 weeks, 27 of 38 (71%) were < 40 copies/mL (84% < 400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA or other factors. Conclusions NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV/r, but by 12 and 24 weeks most children achieved and maintained viral suppression. Clinical Trials Registration U01AII4235.

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