Posts filed under ‘Antirretrovirales’

Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance in a Large U.S. Clinic Population.

Clin Infect Dis. May 28, 2018

Rhee SY1, Clutter D1, Fessel WJ2, Klein D3, Slome S4, Pinsky BA5, Marcus JL6, Hurley L7, Silverberg MJ7, Kosakovsky Pond SL8, Shafer RW1.

Author information

1 Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA.

2 Department of Internal Medicine, Kaiser Permanente Northern California, San Francisco, CA.

3 Department of Infectious Diseases, Kaiser Permanente Northern California, San Leandro, CA.

4 Department of Infectious Diseases, Kaiser Permanente Northern California, Oakland, CA.

5 Department of Pathology, Stanford University, Stanford, CA.

6 Harvard Medical School and Harvard Pilgrim Health Care Institute, Oakland, CA.

7 Division of Research, Kaiser Permanente Northern California, Oakland, CA.

8 Department of Biology, Temple University, Philadelphia, PA.

Abstract

BACKGROUND:

There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the U.S.

METHODS:

HIV-1 RT and protease sequences were obtained from 4,253 antiretroviral therapy (ART)-naïve individuals in a California clinic population from 2003-2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs.

RESULTS:

From 2003-2016, there was a significant increase in overall (odds ratio [OR]=1.05 per year; 95% CI: 1.03 – 1.08; p<0.001) and nonnucleoside RT inhibitor (NNRTI)-associated TDR (OR=1.11 per year; 95% CI: 1.08 – 1.15; p<0.001). Between 2012 and 2016, TDR rates to any drug class ranged from 15.7%-19.2%, and class-specific rates ranged from 10.0%-12.8% for NNRTIs, 4.1%-8.1% for nucleoside RT inhibitors (NRTIs), and 3.6%-5.2% for protease inhibitors. K103N/S, Y181C, Y188L, and G190A mutations accounted for 88.5% of NNRTI-associated TDR. The thymidine analog mutations, M184V/I, and the tenofovir-associated DRMs K65R and K70E/Q/G/N/T accounted for 82.9%, 7.3%, and 1.4% of NRTI-associated TDR, respectively. The proportions of individuals with low-level resistance or higher to boosted atazanavir and darunavir were 2.2% and 0.3%, respectively. 37% of TDR strains clustered with other TDR strains sharing the same DRMs.

CONCLUSIONS:

Although TDR has increased significantly in this large cohort, many TDR strains are unlikely to influence the activity of currently preferred first-line ART regimens. The high proportion of DRMs associated with infrequently used regimens combined with the clustering of TDR strains suggest that some TDR strains are being transmitted between ART-naïve individuals.

FULL TEXT

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciy453/5005024

PDF (CLIC en PDF)

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July 2, 2018 at 6:45 pm

Cancer Risk in Older Persons Living With Human Immunodeficiency Virus Infection in the United States

Clinical Infectious Diseases July 1, 2018 V.67 N.1 P.50–57

Parag Mahale; Eric A Engels; Anna E Coghill; Amy R Kahn; Meredith S Shiels

El riesgo de cáncer en 183.542 personas mayores que vivían con la infección por el virus de la inmunodeficiencia humana se evaluó utilizando datos del estudio de compatibilidad del cáncer de VIH/SIDA. El riesgo relativo de la mayoría de los cánceres disminuyó con la edad, pero los riesgos absolutos fueron más altos para algunos cánceres.

Background

Cancer risk is increased in persons living with human immunodeficiency virus (HIV) (PLWH). Improved survival has led to an aging of PLWH. We evaluated the cancer risk in older PLWH (age ≥50 years).

Methods

We included data from the HIV/AIDS Cancer Match Study (1996–2012) and evaluated risks of Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and cervical, anal, lung, liver, oral cavity/pharyngeal, breast, prostate, and colon cancers in older PLWH with risk in the general population by calculating standardized incidence ratios (SIRs) and excess absolute risks (EARs). Cancer risk by time since HIV diagnosis was estimated using Poisson regression.

Results

We identified 10371 cancers among 183542 older PLWH. Risk was significantly increased for KS (SIR, 103.34), NHL (3.05), Hodgkin lymphoma (7.61), and cervical (2.02), anal (14.00), lung (1.71), liver (2.91), and oral cavity/pharyngeal (1.66) cancers, and reduced for breast (0.61), prostate (0.47), and colon (0.63) cancers. SIRs declined with age for all cancers; however, EARs increased with age for anal, lung, liver, and oral cavity/pharyngeal cancers. Cancer risk was highest for most cancers within 5 years after HIV diagnosis; risk decreased with increasing time since HIV diagnosis for KS, NHL, lung cancer, and Hodgkin lymphoma.

Conclusions

Cancer risk is elevated among older PLWH. Although SIRs decrease with age, EARs are higher for some cancers, reflecting a greater absolute excess in cancer incidence among older PLWH. High risk in the first 5 years after HIV diagnosis for some cancers highlights the need for early HIV diagnosis and rapid treatment initiation.

abstract

https://academic.oup.com/cid/article/67/1/50/4793024

PDF (CLIC en PDF)

June 28, 2018 at 9:09 am

Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study.

Lancet Glob Health. July 2018 V.6 N.7 P.e804-e810.

Zash R1, Jacobson DL2, Diseko M3, Mayondi G3, Mmalane M3, Essex M4, Gaolethe T3, Petlo C5, Lockman S6, Holmes LB7, Makhema J3, Shapiro RL4.

Author information

1 Beth Israel Deaconess Medical Center, Division of Infectious Disease, Boston, MA, USA. Electronic address: rzash@bidmc.harvard.edu.

2 Center for Biostatistics in AIDS Research, Harvard TH Chan School of Public Health, Boston, MA, USA.

3 Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

4 Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA.

5 Botswana Ministry of Health, Gaborone, Botswana.

6 Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA, USA.

7 Medical Genetics Unit, MassGeneral Hospital for Children, Boston, MA, USA.

Abstract

BACKGROUND:

Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana.

METHODS:

In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks’ gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks’ gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs).

FINDINGS:

Our analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88-1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81-1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA.

INTERPRETATION:

Adverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy.

FUNDING: National Institutes of Health.

FULL TEXT

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(18)30218-3/fulltext

PDF

https://www.thelancet.com/pdfs/journals/langlo/PIIS2214-109X(18)30218-3.pdf

June 26, 2018 at 7:58 am

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

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

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