Posts filed under ‘Antirretrovirales’

HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study.

PLoS Med November 7, 2017 V.14 P.e1002417.

Henrich TJ et al.

Abstract

Background

It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.

Methods and findings

Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.

Conclusions

We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

FULL TEXT

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002417

PDF

http://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1002417&type=printable

 

 

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November 21, 2017 at 7:27 am

HIV Drug Resistance — An Emerging Threat to Epidemic Control

N Engl J of Med October 2017 V.377 P.1605-1607

Perspective

Chris Beyrer, M.D., M.P.H., and Anton Pozniak, M.D.

There are now an estimated 19.5 million people worldwide living with HIV and receiving antiretroviral therapy (ART). That’s approximately half of all people thought to be living with the virus in 2017 — an extraordinary achievement in global health and human solidarity. The United Nations agencies, led by the Joint United Nations Program on HIV/AIDS (UNAIDS) and the World Health Organization (WHO), have committed to the goals of ending the AIDS pandemic as a public health threat by 2030 and ensuring that by 2020, 90% of people with HIV infection know they have it, 90% of those infected are receiving ART, and sustained viral suppression is achieved in 90% of those receiving treatment.1 This last goal is critically important both to individual health and survival and to epidemic control of HIV, since data continue to mount showing that viral suppression greatly reduces the risk of continued transmission — whether sexual or perinatal — of the virus…..

FULL TEXT

http://www.nejm.org/doi/full/10.1056/NEJMp1710608?query=infectious-disease

PDF

http://www.nejm.org/doi/pdf/10.1056/NEJMp1710608

November 7, 2017 at 7:17 am

HIV Drug Resistance — An Emerging Threat to Epidemic Control

N Engl J of Med Oct 2017 V.377 P.1605-1607

Perspective

Chris Beyrer, M.D., M.P.H., and Anton Pozniak, M.D

There are now an estimated 19.5 million people worldwide living with HIV and receiving antiretroviral therapy (ART). That’s approximately half of all people thought to be living with the virus in 2017 — an extraordinary achievement in global health and human solidarity. The United Nations agencies, led by the Joint United Nations Program on HIV/AIDS (UNAIDS) and the World Health Organization (WHO), have committed to the goals of ending the AIDS pandemic as a public health threat by 2030 and ensuring that by 2020, 90% of people with HIV infection know they have it, 90% of those infected are receiving ART, and sustained viral suppression is achieved in 90% of those receiving treatment.1 This last goal is critically important both to individual health and survival and to epidemic control of HIV, since data continue to mount showing that viral suppression greatly reduces the risk of continued transmission — whether sexual or perinatal — of the virus…..

PDF

http://www.nejm.org/doi/pdf/10.1056/NEJMp1710608

October 26, 2017 at 7:53 am

Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): A double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.

Lancet August 31, 2017    

Joel Gallant, MD, Prof Adriano Lazzarin, MD, Anthony Mills, MD, Chloe Orkin, MD, Daniel Podzamczer, MD, Pablo Tebas, MD, Prof Pierre-Marie Girard, MD, Indira Brar, MD, Eric S Daar, MD, David Wohl, MD, Prof Jürgen Rockstroh, MD, Xuelian Wei, PhD, Joseph Custodio, PhD, Kirsten White, PhD, Dr Hal Martin, MD, Andrew Cheng, MD, Erin Quirk, MD

Background

Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug–drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine.

Methods

We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50–199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of −12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930.

Findings

Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference −0·6%, 95·002% CI −4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001).

Interpretation

At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting.

Funding

Gilead Sciences.

FULL TEXT

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32299-7/fulltext

PDF

http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)32299-7.pdf

October 11, 2017 at 7:53 am

Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): A randomised, double-blind, multicentre, phase 3, non-inferiority trial.

Lancet August 31, 2017     

Prof Paul E Sax, MD, Anton Pozniak, MD, M Luisa Montes, MD, Ellen Koenig, MD, Edwin DeJesus, MD, Hans-Jürgen Stellbrink, MD, Andrea Antinori, MD, Prof Kimberly Workowski, MD, Jihad Slim, MD, Jacques Reynes, MD, Will Garner, PhD, Joseph Custodio, PhD, Kirsten White, PhD, Dr Devi SenGupta, MD, Andrew Cheng, MD, Erin Quirk, MD

Background

Integrase strand transfer inhibitors (INSTIs) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are recommended as first-line treatment for HIV, and coformulated fixed-dose combinations are preferred to facilitate adherence. We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir—a novel INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug interactions—coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide.

Methods

In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia, Europe, Latin America, and North America. Participants were previously untreated adults (HIV-1 RNA ≥500 copies per mL) with estimated glomerular filtration rate of at least 30 mL/min. Chronic hepatitis B virus or hepatitis C co-infection was allowed. We randomly assigned participants (1:1) to receive oral fixed-dose combination bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg, with matching placebo, once a day for 144 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of −12%. This study is registered with ClinicalTrials.gov, number NCT02607956.

Findings

Between Nov 11, 2015, and July 15, 2016, 742 participants were screened for eligibility, of whom 657 were randomly assigned to treatment (327 with bictegravir, emtricitabine, and tenofovir alafenamide fixed-dose combination [bictegravir group] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [dolutegravir group]). 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses. At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference −3·5%, 95·002% CI −7·9 to 1·0, p=0·12), showing non-inferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p=0·022).

Interpretation

At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen.

Funding

Gilead Sciences Inc.

FULL TEXT

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32340-1/fulltext

PDF

http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)32340-1.pdf

October 11, 2017 at 7:52 am

The triumph of HIV treatment: Another new antiretroviral.

Lancet August 31, 2017   

Comment

Boffito M and Venter F.

Since the approval of the first integrase strand inhibitor (INSTI) raltegravir for the treatment of HIV 10 years ago, INSTIs have become agents of choice in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in many international guidelines.1, 2 This was driven by the sound real-world experience of this antiretroviral class, especially following the introduction of the most recently licensed INSTI, dolutegravir.

Dolutegravir has shown superiority to other major alternative third agents belonging to the classes of protease inhibitors and non-NRTIs, and it has become the gold standard against which other drugs need to prove their efficacy. It is dosed once daily in most patients, and it is coformulated with either abacavir and lamivudine or tenofovir disoproxil fumarate and lamivudine. Importantly, dolutegravir does not require the coadministration of a pharmacoenhancer and is characterised by a low potential for drug–drug interactions, unlike elvitegravir. The high barrier to the development of resistance3 might go some way to address the recent concern over rising resistance to efavirenz (the current primary recommendation for low-income and middle-income countries), resulting in WHO looking for alternative treatments, with dolutegravir appearing to be the current leading cost-effective candidate.4, 5, 6 The tide is changing and middle-income countries like Brazil, Botswana, and South Africa are starting to adopt INSTIs for first-line treatment.5 …

FULL TEXT

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32297-3/fulltext

PDF

http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)32297-3.pdf

October 11, 2017 at 7:52 am

Antiretroviral therapy in pregnant women living with HIV: A clinical practice guideline.

BMJ 2017 Sep 11; 358:j3961.

Siemieniuk RAC et al.

Approximately 1.4 million women living with HIV become pregnant every year. Most women use antiretroviral therapy, to reduce the risk of vertical transmission or for personal health reasons. Using the GRADE framework according to the BMJ Rapid Recommendation process, we make recommendations for optimal choice of combination antiretroviral regimen considering patient values and preferences, the balance of desirable and undesirable outcomes, their uncertainty, and practical issues. We suggest a zidovudine and lamivudine-based regimen over one that includes tenofovir or emtricitabine (weak recommendation). We recommend alternatives over the combination of tenofovir, emtricitabine, and lopinavir/ritonavir (strong recommendation).

FULL TEXT

http://www.bmj.com/content/358/bmj.j3961

PDF

http://www.bmj.com/content/bmj/358/bmj.j3961.full.pdf

October 5, 2017 at 9:52 am

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