Posts filed under ‘Antirretrovirales’

Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype

J Virus Erad April 2019  5:73

Zaunders J et al.

Background

Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3′ long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual.

Methods

PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro.

Results

PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR5.

Conclusions

Subject C135’s early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.

FULL TEXT

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543488/

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543488/pdf/jve-5-73.pdf

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July 16, 2019 at 8:46 am

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice.

Nat Commun. July 2, 2019 V.10 N.1 P.2753.

Dash PK1, Kaminski R2, Bella R2, Su H1, Mathews S1, Ahooyi TM2, Chen C2, Mancuso P2, Sariyer R2, Ferrante P2, Donadoni M2, Robinson JA2, Sillman B1, Lin Z1, Hilaire JR1, Banoub M1, Elango M1, Gautam N3, Mosley RL1, Poluektova LY1, McMillan J1, Bade AN1, Gorantla S1, Sariyer IK2, Burdo TH2, Young WB2, Amini S2, Gordon J2, Jacobson JM2, Edagwa B1, Khalili K4, Gendelman HE5.

Author information

1 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

2 Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19115, USA.

3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

4 Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19115, USA. kamel.khalili@temple.edu.

5 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA. hegendel@unmc.edu.

Abstract

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice.

HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests.

No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus.

In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606613/pdf/41467_2019_Article_10366.pdf

July 9, 2019 at 6:57 pm

Long-term outcomes in a large randomized trial of HIV-1 salvage therapy: 96-week results of AIDS Clinical Trials Group A5241 (OPTIONS).

Journal of Infectious Diseases May 28, 2019  [e-pub].

Gandhi RT et al

Background

Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain.

Methods

Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs.

Results

At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96.

Conclusions

HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression.

Clinical Trials Registration NCT00537394.

FULL TEXT

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz281/5499329

PDF (CLIC en PDF))

July 2, 2019 at 3:11 pm

2011 GUIA MEXICANA – SARCOMA de KAPOSI en pacientes HIV positivos – Guía Práctica Clínica

2011 GUIA MEXICANA – SARCOMA de KAPOSI en pacientes HIV positivos – Guía Práctica Clínica 55p

 Preguntas a responder por esta guía

  1. ¿Cuáles son los factores de riesgo para desarrollar sarcoma de Kaposi?
  2. ¿Qué estudios se deben solicitar al tener sospecha de sarcoma de Kaposi?
  3. ¿Cuál es la tipificación del sarcoma de Kaposi, para toma de decisión de tratamiento?
  4. De acuerdo a la clasificación de riesgo, ¿cuál es la mejor alternativa terapéutica?
  5. ¿Cuál es el papel de la terapia antirretroviral?
  6. ¿Cuál es el beneficio de inicio de terapia sistémica con quimioterapia en pacientes de bajo riesgo?
  7. ¿Cuál es el mejor esquema de tratamiento sistémico con quimioterapia en pacientes con sarcoma de Kaposi de alto riesgo?
  1. ¿Cuáles son las indicaciones de radioterapia en esta neoplasia?
  2. ¿Qué papel tiene el interferón en el manejo del sarcoma de Kaposi?
  3. ¿Cuáles son los criterios para decidir la referencia al tercer nivel?
  4. De los pacientes que requirieron atención en tercer nivel, ¿cuáles son los criterios para su contra referencia a segundo nivel?

http://www.imss.gob.mx/sites/all/statics/guiasclinicas/462GER.pdf

July 1, 2019 at 11:14 am

Successful treatment of HIV eliminates sexual transmission

LANCET June 15, 2019 V.393 N.10189 P.2366-2367

COMMENT

Successful treatment of HIV eliminates sexual transmission

In December, 2011, Science recognised the findings of the HPTN 052 study1 as the scientific breakthrough of the year.2 This study showed a 96% reduction in sexual transmission of HIV in serodifferent couples (one partner HIV positive, the other HIV negative) when the HIV-positive partner was successfully treated with antiretroviral therapy (ART).1

However, the HPTN 052 study included only a small number of men who have sex with men (MSM), for whom HIV acquisition often includes anal exposure, an efficient route of HIV transmission.3

Furthermore, the couples in the HPTN 052 study were counselled to use condoms, so the observed benefits of ART also reflected the contribution of safer sexual behaviours.

Accordingly, other investigators4,  5 have subsequently studied HIV transmission in couples who specifically chose not to use condoms…..

FULL TEXT

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30701-9/fulltext?dgcid=raven_jbs_etoc_email

PDF

https://www.thelancet.com/action/showPdf?pii=S0140-6736%2819%2930701-9

 

LANCET June 15, 2019 V.393 N.10189 P.2428-2438

ARTICLES

Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study

Background

The level of evidence for HIV transmission risk through condomless sex in serodifferent gay couples with the HIV-positive partner taking virally suppressive antiretroviral therapy (ART) is limited compared with the evidence available for transmission risk in heterosexual couples. The aim of the second phase of the PARTNER study (PARTNER2) was to provide precise estimates of transmission risk in gay serodifferent partnerships.

Methods

The PARTNER study was a prospective observational study done at 75 sites in 14 European countries. The first phase of the study (PARTNER1; Sept 15, 2010, to May 31, 2014) recruited and followed up both heterosexual and gay serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex, whereas the PARTNER2 extension (to April 30, 2018) recruited and followed up gay couples only. At study visits, data collection included sexual behaviour questionnaires, HIV testing (HIV-negative partner), and HIV-1 viral load testing (HIV-positive partner). If a seroconversion occurred in the HIV-negative partner, anonymised phylogenetic analysis was done to compare HIV-1 pol and env sequences in both partners to identify linked transmissions. Couple-years of follow-up were eligible for inclusion if condomless sex was reported, use of pre-exposure prophylaxis or post-exposure prophylaxis was not reported by the HIV-negative partner, and the HIV-positive partner was virally suppressed (plasma HIV-1 RNA <200 copies per mL) at the most recent visit (within the past year). Incidence rate of HIV transmission was calculated as the number of phylogenetically linked HIV infections that occurred during eligible couple-years of follow-up divided by eligible couple-years of follow-up. Two-sided 95% CIs for the incidence rate of transmission were calculated using exact Poisson methods.

Findings

Between Sept 15, 2010, and July 31, 2017, 972 gay couples were enrolled, of which 782 provided 1593 eligible couple-years of follow-up with a median follow-up of 2·0 years (IQR 1·1–3·5). At baseline, median age for HIV-positive partners was 40 years (IQR 33–46) and couples reported condomless sex for a median of 1·0 years (IQR 0·4–2·9). During eligible couple-years of follow-up, couples reported condomless anal sex a total of 76 088 times. 288 (37%) of 777 HIV-negative men reported condomless sex with other partners. 15 new HIV infections occurred during eligible couple-years of follow-up, but none were phylogenetically linked within-couple transmissions, resulting in an HIV transmission rate of zero (upper 95% CI 0·23 per 100 couple-years of follow-up).

Interpretation

Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV.

Funding

National Institute for Health Research.

FULL TEXT

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30418-0/fulltext?dgcid=raven_jbs_etoc_email

PDF

https://www.thelancet.com/action/showPdf?pii=S0140-6736%2819%2930418-0

June 14, 2019 at 3:57 pm

Mortality due to Cryptococcus neoformans and Cryptococcus gattiiin low-income settings: an autopsy study

Scientific Reports May 2019       

Cryptococcosis is a major opportunistic infection and is one of the leading causes of death in adults living with HIV in sub-Saharan Africa. Recent estimates indicate that more than 130,000 people may die annually of cryptococcal meningitis in this region.

Although complete diagnostic autopsy (CDA) is considered the gold standard for determining the cause of death, it is seldom performed in low income settings.

In this study, a CDA was performed in 284 deceased patients from Mozambique (n = 223) and Brazil (n = 61). In depth histopathological and microbiological analyses were carried out in all cases dying of cryptococcosis. We determined the cryptococcal species, the molecular and sero-mating types and antifungal susceptibility.

We also described the organs affected and reviewed the clinical presentation and patient management. Among the 284 cases included, 17 fatal cryptococcal infections were diagnosed. Cryptococcus was responsible for 16 deaths among the 163 HIV-positive patients (10%; 95%CI: 6–15%), including four maternal deaths.

One third of the cases corresponded to C. gattii (VGI and VGIV molecular types, Bα and Cα strains) and the remaining infections typed were caused by C. neoformans var. Grubii (all VNI and Aα strains). The level of pre-mortem clinical suspicion was low (7/17, 41%), and 7/17 patients (41%) died within the first 72 hours of admission.

Cryptococcosis was responsible for a significant proportion of AIDS-related mortality. The clinical diagnosis and patient management were inadequate, supporting the need for cryptococcal screening for early detection of the disease.

This is the first report of the presence of C. gattii infection in Mozambique…

FULL TEXT

https://www.nature.com/articles/s41598-019-43941-w.epdf

May 22, 2019 at 7:53 am

Strategies used by gay male HIV serodiscordant couples to reduce the risk of HIV transmission from anal intercourse in three countries

Journal of the International AIDS Society March 2019

Introduction

There are few data about the range of strategies used to prevent sexual HIV transmission within gay male serodiscordant couples. We examined HIV prevention strategies used by such couples and compared differences between countries.

Methods

Opposites Attract was a cohort study of male serodiscordant couples in Australia, Brazil and Thailand, from May 2014 (Australia) or May 2016 (Brazil/Thailand) to December 2016. At visits, HIV‐positive partners had viral load (VL) tested; HIV‐negative partners reported sexual behaviour and perceptions of their HIV‐positive partner’s VL results. Within‐couple acts of condomless anal intercourse (CLAI) were categorized by strategy: condom‐protected, biomedically protected (undetectable VL and/or pre‐exposure prophylaxis [PrEP]), or not protected by either (HIV‐negative partners engaging in insertive CLAI, receptive CLAI with withdrawal, or receptive CLAI with ejaculation).

Results

A total of 343 couples were included in this analysis (153 in Australia, 93 in Brazil and 97 in Thailand). Three‐quarters of HIV‐positive partners were consistently virally suppressed (<200 copies/mL) during follow‐up, and HIV‐negative partners had correct perceptions of their partner’s VL result for 76.5% of tests. One‐third of HIV‐negative partners used daily PrEP during follow‐up. Over follow‐up, 73.8% of couples had CLAI. HIV‐negative partners reported 31,532 acts of anal intercourse with their HIV‐positive partner. Of these, 46.7% were protected by condoms, 48.6% by a biomedical strategy and 4.7% of acts were not protected by these strategies. Australian couples had fewer condom‐protected acts and a higher proportion of biomedically protected acts than Brazilian and Thai couples. Of the 1473 CLAI acts where the perceived VL was detectable/unknown and were not protected by PrEP (4.7% of all acts), two‐thirds (n = 983) were when the HIV‐negative partner was insertive (strategic positioning). Of the 490 acts when the HIV‐negative partner was receptive, 261 involved withdrawal and 280 involved ejaculation. Thus, <1% of acts were in the highest risk category of receptive CLAI with ejaculation.

Conclusions

Couples used condoms, PrEP or perceived undetectable VL for prevention in the majority of anal intercourse acts. Only a very small proportion of events were not protected by these strategies. Variation between countries may reflect differences in access to HIV treatment, education, knowledge and attitudes.

FULL TEXT

https://onlinelibrary.wiley.com/doi/10.1002/jia2.25277

PDF

https://onlinelibrary.wiley.com/doi/epdf/10.1002/jia2.25277

May 14, 2019 at 8:37 am

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