Posts filed under ‘HIV/SIDA’

Clinical and epidemiological features of chronic Trypanosoma cruzi infection in patients with HIV/AIDS in Buenos Aires, Argentina

International Journal of Infectious Diseases February 2018 V.67 P.118–121

Andrés Guillermo Benchetrit, Marisa Fernández, Amadeo Javier Bava, Marcelo Corti, Norma Porteiro, Liliana Martínez Peralta

Highlights

  • Chagas disease reactivation is an AIDS-defining illness with a high mortality rate.
  • Besides the vector-borne route, other means of T. cruzi infection acquisition must be assessed.
  • HIV-infected patients with lower CD4 T-cell counts are at higher risk of Chagas disease reactivation.
  • Severely immunecompromised patients infected with T. cruzi may have negative serological assay results.
  • Direct parasitological techniques should be performed in the diagnosis of patients for whom there is a suspicion of T. cruzi reactivation.

Objectives

Trypanosoma cruzi reactivation in HIV patients is considered an opportunistic infection, usually with a fatal outcome. The aim of this study was to describe the epidemiological and clinical features of T. cruzi infection in HIV patients and to compare these findings between patients with and without Chagas disease reactivation.

Methods

The medical records of T. cruzi–HIV co-infected patients treated at the Muñiz Infectious Diseases Hospital from January 2005 to December 2014 were reviewed retrospectively. Epidemiological and clinical features were assessed and compared between patients with and without Chagas disease reactivation.

Results

The medical records of 80 T. cruzi–HIV co-infected patients were reviewed. The most likely route of T. cruzi infection was vector-borne (32/80 patients), followed by intravenous drug use (12/80). Nine of 80 patients had reactivation. Patients without reactivation had a significantly higher CD4 T-cell count at diagnosis of T. cruzi infection (144 cells/μl vs. 30 cells/μl, p = 0.026). Chagas disease serology was negative in two of nine patients with reactivation.

Conclusions

Serological assays for T. cruzi infection may be negative in severely immunocompromised patients. Direct parasitological techniques should be performed in the diagnosis of patients for whom there is a suspicion of T. cruzi reactivation. HIV patients with a lower CD4 count are at higher risk of reactivation.

abstract

http://www.ijidonline.com/article/S1201-9712(17)30309-0/fulltext

PDF

http://www.ijidonline.com/article/S1201-9712(17)30309-0/pdf

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February 18, 2018 at 4:05 pm

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.

J Acquir Immune Defic Syndr. May 1, V.75 N.1 P.61-66.

Gallant JE1, Thompson M, DeJesus E, Voskuhl GW, Wei X, Zhang H, White K, Cheng A, Quirk E, Martin H.

Author information

1 *Southwest CARE Center, Santa Fe, NM; †AIDS Research Consortium of Atlanta, Atlanta, GA; ‡Orlando Immunology Center, Orlando, FL; §AIDS Arms, Inc., Dallas, TX; and ‖Gilead Sciences, Inc., Foster City, CA.

Abstract

OBJECTIVE:

To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI).

DESIGN:

Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study.

METHODS:

HIV-infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted average change from baseline to day 11 (DAVG11) for plasma HIV-1 RNA. HIV-1 RNA, adverse events (AEs), and laboratory assessments were evaluated through day 17.

RESULTS:

Twenty participants were enrolled (n = 4/group). Mean DAVG11 ranged from -0.92 to -1.61 across BIC doses versus -0.01 for placebo. Significant reductions in plasma HIV-1 RNA from baseline at day 11 were observed for all BIC doses compared with placebo (P < 0.001); mean decreases were 1.45-2.43 log10 copies/mL. Increased BIC exposures correlated with increased reduction in plasma HIV-1 RNA from baseline on day 11. Three participants on BIC (50 or 100 mg) achieved plasma HIV-1 RNA <50 copies/mL by end of study. Median Tmax ranged from 1.0 to 1.8 hours (day 1, postdose) and 1.3-2.7 hours (day 10), with median t1/2 ranging from 15.9 to 20.9 hours. No participant developed primary INSTI-R substitution through day 17. BIC was well tolerated, with no discontinuations because of adverse events.

CONCLUSIONS:

BIC is a novel, potent, unboosted INSTI that demonstrated rapid, dose-dependent declines in HIV-1 RNA after 10 days of monotherapy. BIC was well tolerated, and displayed rapid absorption and a half-life supportive of once-daily therapy in HIV-infected subjects.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389589/pdf/qai-75-61.pdf

February 9, 2018 at 1:13 pm

HIV drug resistance against strand transfer integrase inhibitors.

Retrovirology. June 5, 2017 V.14 N.1 P. 36.

Anstett K1,2, Brenner B2, Mesplede T3, Wainberg MA1,2.

Author information

1 Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, QC, Canada.

2 McGill AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, QC, Canada.

3 McGill AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, QC, Canada. tibo_mes@hotmail.com.

Abstract

Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell’s chromatin.

Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials.

RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance.

Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants.

In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual.

This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays.

While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the “second-generation” drugs of this class.

This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460515/pdf/12977_2017_Article_360.pdf

February 9, 2018 at 1:12 pm

CROI 2017: Advances in Antiretroviral Therapy.

Top Antivir Med. May/June 2017 V.25 N.2 P.51-67.

Jones J1, Taylor BS2, Tieu HV3, Wilkin TJ4.

Author information

1 The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

2 University of Texas Health Science, San Antonio, TX, USA.

3 New York Blood Center and Columbia University Medical Center, New York, NY, USA.

4 Weill Cornell Medicine, New York, NY, USA.

Abstract

The 2017 Conference on Retroviruses and Opportunistic Infections (CROI) featured exciting preclinical data on investigational antiretroviral agents with good in vitro efficacy and long half-lives.

Investigational medications, including bictegravir, demonstrated excellent efficacy and tolerability, as did dual-agent therapy with dolutegravir paired with rilpivirine or with lamivudine. Dolutegravir monotherapy proved inadvisable due to virologic failure and resistance.

The gap between high- and low-income settings along the HIV care continuum is narrowing, with Zimbabwe, Malawi, and Zambia approaching the 90-90-90 targets established by the joint United Nations Programme on HIV/AIDS (UNAIDS), whereas communities in the Southern United States are falling behind.

Innovative strategies to improve outcomes include 2-way text messaging, home-based HIV testing, peer navigation, and New York City’s realignment of services into comprehensive sexual health programs.

A high prevalence of resistance was documented in low- and middle-income settings and policy considerations were modeled to address increasing resistance rates.

Novel resistance mutations to integrase strand transfer inhibitors and nucleoside analogue reserve transcriptase inhibitors were identified, but the clinical implications are unclear and require further investigation.

Several studies provided insights on dosing and safety of antiretroviral therapy to prevent mother-to-child transmission through pharmacokinetic analysis.

A special session devoted to Zika virus included a study of its effects on the central nervous system and a promising animal study of a Zika vaccine.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677043/pdf/tam-25-051.pdf

February 9, 2018 at 1:10 pm

Ceftriaxone versus ceftriaxone plus a macrolide for community-acquired pneumonia in hospitalized patients with HIV/AIDS: a randomized controlled trial

Clinical Microbiology and Infection February 2018 V.24 N.2 p146–151 

Figueiredo-Mello, P. Naucler, M.D. Negra, A.S. Levin

Objectives

To evaluate if treatment with ceftriaxone and a macrolide, improved patient outcome when compared with monotherapy with ceftriaxone, in hospitalized patients with human immunodeficiency virus/acquired immunodeficient syndrome (HIV/AIDS) with community-acquired pneumonia (CAP).

Methods

Adult patients with HIV hospitalized due to suspected CAP were randomized to receive one of two regimens, ceftriaxone plus macrolide or ceftriaxone plus placebo, at a 1:1 proportion (Brazilian Clinical Trials Registry: RBR-8wtq2b). The primary outcome was in-hospital mortality and the secondary outcomes were mortality within 14 days, need for vasoactive drugs, need for mechanical ventilation, time to clinical stability and length of hospitalization.

Results

A total of 227 patients were randomized, two were excluded after randomization; 225 patients were analysed (112 receiving ceftriaxone plus placebo and 113 receiving ceftriaxone plus macrolide). The frequency of the primary outcome, in-hospital mortality, was not statistically different between the regimens: 12/112 (11%) patients who received ceftriaxone plus placebo and 17/113 (15%) who received ceftriaxone plus macrolide died during hospitalization (hazard ratio 1.22, 95% CI 0.57–2.59). We did not find differences between the regimens for any of the secondary outcomes, including mortality within 14 days, which occurred in 5/112 (4%) patients with ceftriaxone plus placebo and in 12/113 (11%) patients with ceftriaxone plus macrolide (relative risk 2.38, 95% CI 0.87–6.53).

Conclusions

Among hospitalized patients with HIV/AIDS with CAP, treatment with ceftriaxone and a macrolide did not improve patient outcomes, when compared with ceftriaxone monotherapy.

abstract

http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30332-4/fulltext

PDF

http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30332-4/pdf

 

January 31, 2018 at 11:25 pm

Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial

Lancet Infectious Diseases January 2018 V.18 N.1 P.47-57

Prof James G Hakim, FRCP, Jennifer Thompson, MSc, Cissy Kityo, MSc, Anne Hoppe, PhD, Andrew Kambugu, MMed, Prof Joep J van Oosterhout, PhD, Abbas Lugemwa, MD, Abraham Siika, MMed, Raymond Mwebaze, MMed, Aggrey Mweemba, MMed, George Abongomera, PhD, Margaret J Thomason, PhD, Philippa Easterbrook, MD, Prof Peter Mugyenyi, FRCP, Prof A Sarah Walker, PhD*, Prof Nicholas I Paton, MD*

Summary

Background

Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.

Methods

We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.

Findings

Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.

Interpretation

Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.

Funding

European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(17)30630-8.pdf

 

Lancet Infectious Diseases January 2018 V.18 N.1 P.3-5

COMMENT

The unexpected success of NRTIs in second-line treatment

Andrew M Hill, Francois Venter

Genotype-defined resistance to antiretrovirals supposedly predicts future virological failure. Findings from clinical studies, including the 144 week results from the EARNEST trial, published in The Lancet Infectious Diseases,1 challenge this decades-long dogma, certainly when it comes to nucleoside analogues.

WHO currently recommends second-line treatment with two nucleoside reverse-transcriptase inhibitors (NRTIs) and a boosted protease inhibitor.2 However, there is evidence for widespread resistance to NRTIs after virological failure of first-line treatment in low-income countries, which might limit future treatment options.3 …

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(17)30631-X.pdf

December 22, 2017 at 8:16 am

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

PLoS Med. November 4, 2017 V.14 N.11 e1002417.     

Henrich TJ1, Hatano H2, Bacon O2,3, Hogan LE1, Rutishauser R1,2, Hill A4, Kearney MF5, Anderson EM5, Buchbinder SP2,3, Cohen SE2,3, Abdel-Mohsen M2,6, Pohlmeyer CW7, Fromentin R8, Hoh R2, Liu AY2,3, McCune JM1, Spindler J5, Metcalf-Pate K7, Hobbs KS1, Thanh C1, Gibson EA1, Kuritzkes DR9,10, Siliciano RF11,12, Price RW13, Richman DD14,15, Chomont N8, Siliciano JD10, Mellors JW16, Yukl SA17,18, Blankson JN7, Liegler T2, Deeks SG2.

Author information

1 Division of Experimental Medicine, University of California, San Francisco, California, United States of America.

2 Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, California, United States of America.

3 San Francisco Department of Public Health, San Francisco, California, United States of America.

4 Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America.

5 HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.

6 The Wistar Institute, Philadelphia, Pennsylvania, United States of America.

7 Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

8 Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.

9 Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America.

10 Harvard Medical School, Boston, Massachusetts, United States of America.

11 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

12 Howard Hughes Medical Institute, Baltimore, Maryland, United States of America.

13 Department of Neurology, University of California, San Francisco, California, United States of America.

14 University of California San Diego, La Jolla, California, United States of America.

15 Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.

16 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

17 San Francisco Veterans Affairs Medical Center, San Francisco, California, United States of America.

18 University of California, San Francisco, California, Unites States of America.

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.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675377/pdf/pmed.1002417.pdf

December 11, 2017 at 8:42 am

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