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CMAJ : Canadian Medical Association... Jul 2024
Topics: Humans; HIV Infections; Post-Exposure Prophylaxis; Anti-HIV Agents; Canada
PubMed: 38955414
DOI: 10.1503/cmaj.240064 -
MedRxiv : the Preprint Server For... May 2024HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which...
INTRODUCTION
HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the World Health Organization in 2019 for first-, second-, and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.
METHODS AND ANALYSIS
DTG RESIST is a multicentre longitudinal study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virologic failure on dolutegravir-based ART. At the time of virologic failure whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (i) individuals who experienced virologic failure on dolutegravir, and (ii) on those who started or switched to such a regimen and were at risk of virologic failure. For population (i), the outcome will be any InSTI drug resistance mutations, and for population (ii) virologic failure defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virologic failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.
ETHICS AND DISSEMINATION
The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa, and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in IeDEA and have obtained ethics approval from their local ethics committee to conduct the additional data collection.
REGISTRATION
NCT06285110.
STRENGTHS AND LIMITATIONS OF THIS STUDY
- DTG RESIST is a large international study to prospectively examine emergent dolutegravir resistance in diverse settings characterised by different HIV-1 subtypes, provision of ART, and guidelines on resistance testing. - Embedded within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST will benefit from harmonized clinical data across participating sites and expertise in clinical, epidemiological, biological, and computational fields. - Procedures for sequencing and assembling genomes from different HIV-1 strains will be developed at the heart of the HIV epidemic, by the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), in Durban, South Africa. Phenotypic testing, Genome Wide Association Study (GWAS) methods and Bayesian evolutionary models will explore and predict treatment failure genotypes. - A significant limitation is the absence of genotypic resistance data from participants before they started dolutegravir treatment, as collecting and bio-banking pre-treatment samples was not feasible at most IeDEA sites. Consistent and harmonized data on adherence to treatment are also lacking. - The distribution of HIV-1 subtypes across different sites is uncertain, which may limit the statistical power of the study in analysing patterns and risk factors for dolutegravir resistance. The results from GWAS and Bayesian modelling analyses will be preliminary and hypothesis-generating.
PubMed: 38952780
DOI: 10.1101/2024.05.23.24307850 -
BMC Public Health Jun 2024Nitrite inhalants (poppers) are associated with HIV transmission and commonly used among young men who have sex with men (YMSM), a group at increased risk for HIV....
Nitrite inhalants (poppers) are associated with HIV transmission and commonly used among young men who have sex with men (YMSM), a group at increased risk for HIV. Significant research gaps exist in understanding the context in which YMSM use poppers. Qualitative interviews were conducted with 15 YMSM (22-31 years) with HIV to better understand the context in which poppers are used and their impacts on HIV care outcomes, such as care retention and antiretroviral adherence. The Social Ecological Model was applied to understand intrapersonal, interpersonal, community, and system level influences on popper use. Factors influencing popper use included: ubiquity of popper use in sexual settings, introduction to poppers by casual sexual partners, patient-HIV provider communication surrounding poppers, neighborhood, substance use and HIV care systems, and the legal status of poppers. Implications for clinical care, public health, policy, and future research are discussed.
Topics: Humans; Male; HIV Infections; Adult; Homosexuality, Male; Qualitative Research; Young Adult; Nitrites; Interviews as Topic
PubMed: 38951768
DOI: 10.1186/s12889-024-19284-1 -
PloS One 2024Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of...
INTRODUCTION
Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of the reactivation of latent infection. We assessed the prevalence of toxoplasmosis and its associated risk factors in PLWH in the Asia-Pacific region using data from the TREAT Asia Human Immunodeficiency Virus (HIV) Observational Database (TAHOD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA) Asia-Pacific.
METHODS
This study included both retrospective and prospective cases of toxoplasmosis reported between 1997 and 2020. A matched case-control method was employed, where PLWH diagnosed with toxoplasmosis (cases) were each matched to two PLWH without a toxoplasmosis diagnosis (controls) from the same site. Sites without toxoplasmosis were excluded. Risk factors for toxoplasmosis were analyzed using conditional logistic regression.
RESULTS
A total of 269/9576 (2.8%) PLWH were diagnosed with toxoplasmosis in 19 TAHOD sites. Of these, 227 (84%) were reported retrospectively and 42 (16%) were prospective diagnoses after cohort enrollment. At the time of toxoplasmosis diagnosis, the median age was 33 years (interquartile range 28-38), and 80% participants were male, 75% were not on antiretroviral therapy (ART). Excluding 63 out of 269 people without CD4 values, 192 (93.2%) had CD4 ≤200 cells/μL and 162 (78.6%) had CD4 ≤100 cells/μL. By employing 538 matched controls, we found that factors associated with toxoplasmosis included abstaining from ART (odds ratio [OR] 3.62, 95% CI 1.81-7.24), in comparison to receiving nucleoside reverse transcriptase inhibitors plus non-nucleoside reverse transcriptase inhibitors, HIV exposure through injection drug use (OR 2.27, 95% CI 1.15-4.47) as opposed to engaging in heterosexual intercourse and testing positive for hepatitis B virus surface antigen (OR 3.19, 95% CI 1.41-7.21). Toxoplasmosis was less likely with increasing CD4 counts (51-100 cells/μL: OR 0.41, 95% CI 0.18-0.96; 101-200 cells/μL: OR 0.14, 95% CI 0.06-0.34; >200 cells/μL: OR 0.02, 95% CI 0.01-0.06), when compared to CD4 ≤50 cells/μL. Moreover, the use of prophylactic cotrimoxazole was not associated with toxoplasmosis.
CONCLUSIONS
Symptomatic toxoplasmosis is rare but still occurs in PLWH in the Asia-Pacific region, especially in the context of delayed diagnosis, causing advanced HIV disease. Immune reconstitution through early diagnosis and ART administration remains a priority in Asian PLWH.
Topics: Humans; Male; Risk Factors; Adult; Female; Toxoplasmosis; HIV Infections; Asia; Retrospective Studies; Case-Control Studies; Middle Aged; Prevalence; Prospective Studies; Toxoplasma
PubMed: 38950027
DOI: 10.1371/journal.pone.0306245 -
BioRxiv : the Preprint Server For... Jun 2024HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a...
HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1β and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1β and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1β and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14 CD16 intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1β following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.
PubMed: 38948748
DOI: 10.1101/2024.06.14.599106 -
Open Forum Infectious Diseases Jul 2024Dolutegravir resistance is emerging in routine clinical contexts in southern Africa, primarily in patients with prior treatment experience failing dolutegravir-based...
Dolutegravir resistance is emerging in routine clinical contexts in southern Africa, primarily in patients with prior treatment experience failing dolutegravir-based antiretroviral therapy (ART). This potential issue was raised by The Nucleosides and Darunavir/Dolutegravir in Africa trial that compared dolutegravir and boosted protease inhibitor-based therapy as second-line ART, in which new dolutegravir resistance was observed at failure. However, recent data suggest that also at risk are patients who were transitioned to dolutegravir from non-nucleoside reverse transcriptase inhibitor-based ART while viremic. Identifying patients experiencing failure of dolutegravir with resistance will be difficult given current gaps in viral load monitoring and limited capacity for genotypic resistance testing. As a result, in the short term, most patients affected will go unrecognized, with particularly important implications for patients affected who have advanced HIV or who are pregnant/breastfeeding. Prospective research is needed to understand the scope of the problem, identify additional risk factors, and determine best management. In the short term, for most patients with dolutegravir resistance and prior non-nucleoside reverse transcriptase inhibitor exposure, the best option will be a timely switch to a regimen anchored by a boosted protease inhibitor, with a high genetic barrier to resistance.
PubMed: 38947737
DOI: 10.1093/ofid/ofae321 -
Cureus May 2024Histoplasma capsulatum is a dimorphic fungus that grows in nature as a mold or in culture but converts to a small yeast during cellular invasion. While most...
Histoplasma capsulatum is a dimorphic fungus that grows in nature as a mold or in culture but converts to a small yeast during cellular invasion. While most histoplasmosis infections are primarily asymptomatic or mildly symptomatic, disseminated histoplasmosis is a relentlessly progressive granulomatous disease that can mimic other granulomatous diseases, such as tuberculosis, sarcoidosis or coccidioidomycosis, more so in the proper context of immunosuppression. The current global migrant crisis, particularly the United States migrant crisis conversation is mostly socio-political; however, it also has a public health implication as exemplified by the case of a 35-year-old male who migrated from Haiti via Chile and Mexico to the United States. He presented with a four-day history of fever, generalized body aches, and cough. This case underscores the importance of entertaining a myriad of differentials and avoiding the tendency for anchoring, especially when initial therapy yields little clinical response.
PubMed: 38947682
DOI: 10.7759/cureus.61434 -
Cureus May 2024Hodgkin's lymphoma (HL) is a form of cancer that involves abnormal lymphocyte proliferation which affects the lymphatic system. Patients with HIV are at increased risk...
Hodgkin's lymphoma (HL) is a form of cancer that involves abnormal lymphocyte proliferation which affects the lymphatic system. Patients with HIV are at increased risk of developing HL, despite the introduction of combination antiretroviral therapy. The most common presentation of HL is painless lymphadenopathy with classic constitutional symptoms in advanced disease. Here we discuss a 39-year-old female with a history of HIV on emtricitabine/tenofovir and dolutegravir who presented with four days of worsening diarrhea along with fevers and chills. She had a similar presentation at a nearby hospital four months prior. After initial concern for gastrointestinal infection, an extensive infectious workup was conducted and was negative. After complaints of sore throat and increased confusion during the hospital stay, a CT Chest and Neck revealed diffuse lymphadenopathy. Severely elevated ferritin levels raised concern for secondary hemophagocytic lymphohistiocytosis and prompted expedited ultrasound-guided cervical lymph node (LN) core biopsy and bone marrow biopsy. Ultrasound-guided core biopsy of the LN showed classical Hodgkin's lymphoma of mixed cellularity. The patient was started on doxorubicin, vinblastine, and dacarbazine + nivolumab. This is a case of a patient with HIV who presented with chronic diarrhea of unidentifiable origin and was ultimately diagnosed with classical Hodgkin's lymphoma during her hospitalization and highlights the importance of maintaining lymphoproliferative diseases on the differential in patients with HIV and gastrointestinal symptoms.
PubMed: 38947681
DOI: 10.7759/cureus.61361 -
Frontiers in Cellular and Infection... 2024
Topics: Virus Latency; Humans; HIV Infections; HIV-1; Anti-HIV Agents
PubMed: 38947128
DOI: 10.3389/fcimb.2024.1434507 -
MedRxiv : the Preprint Server For... Jun 2024Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by...
BACKGROUND
Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs.
METHODS
We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation.
RESULTS
Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir.
CONCLUSIONS
Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.
PubMed: 38947072
DOI: 10.1101/2024.02.16.24302713