Posts filed under ‘HIV/SIDA’

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

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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

Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial.

PLoS Med. 2017 Jul 25;14(7):e1002357.

Koenig SP1,2, Dorvil N1, Dévieux JG3, Hedt-Gauthier BL4, Riviere C1, Faustin M1, Lavoile K1, Perodin C1, Apollon A1, Duverger L1, McNairy ML5,6, Hennessey KA1, Souroutzidis A7, Cremieux PY7, Severe P1, Pape JW1,5.

Author information

1 Haitian Study Group for Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti.

2 Division of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America.

3 AIDS Prevention Program, Florida International University, Miami, Florida, United States of America.

4 Department of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, United States of America.

5 Center for Global Health, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America.

6 Division of General Internal Medicine, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America.

7 Analysis Group, Boston, Massachusetts, United States of America.

Abstract

BACKGROUND:

Attrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.

METHODS AND FINDINGS:

We conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.

CONCLUSIONS:

Same-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.

TRIAL REGISTRATION:

This study is registered with ClinicalTrials.gov number NCT01900080.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526526/pdf/pmed.1002357.pdf

September 7, 2017 at 8:15 am

Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa

N Engl J Med July 20, 2017 V.377 P.233-245.

James Hakim, F.R.C.P., Victor Musiime, Ph.D., Alex J. Szubert, M.Sc., Jane Mallewa, M.D., Abraham Siika, M.Med., Clara Agutu, M.B., Ch.B., M.P.H., Simon Walker, M.Sc., Sarah L. Pett, Ph.D., Mutsa Bwakura-Dangarembizi, M.Med., Abbas Lugemwa, M.D., Symon Kaunda, M.B., Ch.B., Mercy Karoney, M.Sc., Godfrey Musoro, M.Sc., Sheila Kabahenda, M.B., Ch.B., Kusum Nathoo, M.B., Ch.B., Kathryn Maitland, Ph.D., Anna Griffiths, Ph.D., Margaret J. Thomason, Ph.D., Cissy Kityo, M.Sc., Peter Mugyenyi, Ph.D., Andrew J. Prendergast, D.Phil., A. Sarah Walker, Ph.D., and Diana M. Gibb, M.D., for the REALITY Trial Team*

BACKGROUND

In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%.

METHODS

In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim–sulfamethoxazole plus at least 12 weeks of isoniazid–pyridoxine (coformulated with trimethoprim–sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim–sulfamethoxazole alone). The primary end point was 24-week mortality.

RESULTS

A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan–Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups.

CONCLUSIONS

Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374.)

abstract

http://www.nejm.org/doi/10.1056/NEJMoa1615822

PDF

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1615822

 

N Engl J Med  July 20, 2017 V.377 P.283-284

EDITORIAL – The enduring challenge of advanced HIV infection.

Nathan Ford, M.P.H., Ph.D., and Meg Doherty, M.D., Ph.D.

Until recently, progress in the fight against human immunodeficiency virus (HIV) infection was primarily measured in terms of the number of patients who were started on antiretroviral therapy (ART). Major efforts to increase access to ART in the low- and middle-income countries that are most affected by HIV infection began in 2000, and over the following 15 years, an estimated 8 million HIV-related deaths were averted. In countries with a high burden of disease, this decline translated into important increases in life expectancy.1

Notwithstanding these gains, the decrease in HIV-associated deaths appears to have plateaued in recent years. HIV still causes more than 1 million deaths per year worldwide and remains a leading cause of death and complications in sub-Saharan Africa.1 A key explanation for this enduring high mortality is that despite an evolution toward offering treatment earlier in the course of the disease,2 HIV continues to be identified in a substantial number of patients with advanced infection (which is defined by the World Health Organization [WHO] as a CD4+ count of fewer than 200 cells per cubic millimeter). A recent study of trends across 55 countries showed that more than a third (37%) of the patients who initiated ART in 2015 already had advanced HIV infection.3 Such patients are at high risk for death, even after starting ART (which can increase the inflammatory response), and the risk increases with a decreasing CD4+ count.3 A worrisome new trend that has been observed in countries with long-standing HIV treatment programs is an increase in the number of patients who present for care with advanced HIV infection after a period of treatment interruption…..

abstract

http://www.nejm.org/doi/10.1056/NEJMe1707598

PDF

http://www.nejm.org/doi/pdf/10.1056/NEJMe1707598

 

August 11, 2017 at 8:27 am

2017-07 Guidelines for the managing advanced HIV disease and rapid initiation of antiretroviral therapy. WHO 56 pags

Overview

The objectives of these guidelines are to provide recommendations outlining a public health approach to managing people presenting with advanced HIV disease, and to provide guidance on the timing of initiation of antiretroviral therapy (ART) for all people living with HIV.

The first set of recommendations addresses the specific needs of people with advanced HIV disease and defines a package of interventions aimed at reducing HIV-associated morbidity and mortality. WHO recommends that a package of screening, prophylaxis, rapid ART initiation and intensified adherence interventions be offered to everyone living with HIV presenting with advanced disease. This is a strong recommendation that applies to all populations and age groups. The guidelines also include an algorithm to support decision making for providing care for people with advanced HIV disease.

The second set of recommendations defines how rapidly ART should be initiated within the context of the “treat all” policy, especially when coinfections are present. WHO strongly recommends that rapid ART initiation should be offered to people living with HIV following confirmed diagnosis and clinical assessment. Rapid initiation of ART is defined as within seven days of HIV diagnosis. WHO further strongly recommends ART initiation on the same day as HIV diagnosis based on the person’s willingness and readiness to start ART immediately, unless there are clinical reasons to delay treatment. Both of these recommendations apply to all populations and age groups. People with advanced HIV disease should be given priority for clinical assessment and treatment initiation.

PDF

http://apps.who.int/iris/bitstream/10665/255884/1/9789241550062-eng.pdf?ua=1

August 7, 2017 at 9:56 am

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