139 research outputs found

    Novel therapies based on mechanisms of HIV-1 cell entry

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    Infection with human immunodeficiency virus type 1 (hiv-1), the retrovirus that causes the acquired immunodeficiency syndrome (AIDS), is one of the leading causes of death worldwide. All currently available antiretroviral agents inhibit essential HIV-1 enzymes — either the reverse transcriptase or the protease (Fig. 1). Recent advances have markedly improved the outcome for many patients who receive these classes of antiretroviral drugs. However, the success of current therapy is limited by the emergence of drug-resistant viruses, the necessity of sustained adherence to complex regimens, and the potential for toxic effects. Novel classes of safe and effective agents with a low risk of cross-resistance with other antiretroviral drugs are needed

    US Black Women and Human Immunodeficiency Virus Prevention: Time for New Approaches to Clinical Trials

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    Black women bear the highest burden of human immunodeficiency virus (HIV) infection among US women. Tenofovir/emtricitabine HIV prevention trials among women in Africa have yielded varying results. Ideally, a randomized controlled trial (RCT) among US women would provide data for guidelines for US women's HIV preexposure prophylaxis use. However, even among US black women at high risk for HIV infection, sample size requirements for an RCT with HIV incidence as its outcome are prohibitively high. We propose to circumvent this large sample size requirement by evaluating relationships between HIV incidence and drug concentrations measured among participants in traditional phase 3 trials in high-incidence settings and then applying these observations to drug concentrations measured among at-risk individuals in lower-incidence settings, such as US black women. This strategy could strengthen the evidence base to enable black women to fully benefit from prevention research advances and decrease racial disparities in HIV rates

    Evaluating the Efficacy of Therapies in Patients With Coronavirus Disease 2019

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    There is a proliferation of clinical trials worldwide to find effective therapies for patients diagnosed with coronavirus disease 2019 (COVID-19). The endpoints that are currently used to evaluate the efficacy of therapeutic agents against COVID-19 are focused on clinical status at a particular day or on time to a specific change of clinical status. To provide a full picture of the clinical course of a patient and make complete use of available data, we consider the trajectory of clinical status over the entire follow-up period. We also show how to combine the evidence of treatment effects on the occurrences of various clinical events. We compare the proposed and existing endpoints through extensive simulation studies. Finally, we provide guidelines on establishing the benefits of treatments

    Susceptibility testing by polymerase chain reaction DNA quantitation: A method to measure drug resistance of human immunodeficiency virus type 1 isolates

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    Polymerase chain reaction (PCR) DNA quantitation (PDQ) susceptibility testing rapidly and directly measures nucleoside sensitivity of human immunodeficiency virus type 1 (HIV-1) isolates. PCR is used to quantitate the amount of HIV-1 DNA synthesized after in vitro infection of peripheral blood mononuclear cells. The relative amounts of HIV-1 DNA in cell lysates from cultures maintained at different drug concentrations reflect drug inhibition of virus replication. The rusults of PDQ susceptibility testing of 2- or 3-day cultures are supported by assays measuring HIV-1 p24 antigen production in supernatants of 7- or 10-day cultures. DNA sequence analyses to identify mutations in the reverse transcriptase gene that cause resistance to 3′-azido-3′-deoxythymidine also support the PDQ results. With the PDQ method, both infectivity titration and susceptibility testing can be performed on supernatants from primary cultures of peripheral blood mononuclear cells. PDQ susceptibility testing should facilitate epidemiologic studies of the clinical significance of drug-resistant HIV-1 isolates

    Opioid misuse among persons with HIV engaged in care in the Southeastern US

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    The prevalence of opioid misuse by people living with HIV (PLWH) during the current US opioid epidemic has not been fully described. Among a cohort of persons engaged in HIV care in North Carolina, we examined the prevalence of and risk factors for opioid misuse, defined as self-reported “street” opioid use (e.g., heroin) or nonmedical prescription opioid use on a patient reported outcomes survey. Recent (past three-month) opioid misuse among 1,440 PLWH in care 2012–2017 was 2% (95% CI 2-3%) and lifetime misuse 15% (13-16%). Persons reporting lifetime or recent misuse more commonly had hepatitis C and reported injecting drugs. In multivariable logistic regression models, male-to-male sexual contact was inversely associated with recent or lifetime misuse. White/non-Hispanic race/ethnicity was associated with lifetime misuse and CD4 count and viral load were not associated with opioid misuse. Among 32 persons reporting recent misuse, 81% had a contemporaneous viral load <50 copies/mL. In this cohort of PLWH engaged in care, recent opioid misuse prevalence was similar to general population estimates. Assessments of opioid misuse among PLWH not in care are urgently needed to fully characterize the impact of opioids on all PLWH

    Pretreatment integrase strand transfer inhibitor resistance in North Carolina from 2010-2016

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    Objective: We sought to define the prevalence of pretreatment integrase strand transfer inhibitor (INSTI) resistance and assess the transmission networks of those with pretreatment INSTI resistance. Design: A retrospective cohort study of HIV-positive patients with genotypic resistance testing sent to a single referral laboratory in North Carolina between 2010 and 2016. Methods: We linked genotype and public health data for in-care HIV-positive individuals to determine the prevalence of INSTI resistance among treatment-naive (defined as those with a first genotype ≤3 months after diagnosis) and treatment-experienced (defined as those with a first genotype >3 months after diagnosis) patients. We performed molecular and phylogenetic analyses to assess whether pretreatment INSTI resistance mutations represented clustered HIV transmission. Results: Of 8825 individuals who contributed sequences for protease, reverse transcriptase, or INSTI genotypic resistance testing during the study period, 2784 (31%) contributed at least one sequence for INSTI resistance testing. Of these, 840 were treatment-naive individuals and 20 [2.4%, 95% confidence interval (CI): 1.5, 3.6%] had INSTI mutations; only two (0.2%, 95% CI: 0.02, 0.9%) had major mutations. Of 1944 treatment-experienced individuals, 9.6% (95% CI: 8.3, 11.0%) had any INSTI mutation and 7.0% (95% CI: 5.9, 8.3%) had major mutations; the prevalence of INSTI mutations among treatment-experienced patients decreased overtime (P<0.001). In total 12 of 20 individuals with pretreatment INSTI mutations were part of 10 molecular transmission clusters; only one cluster shared identical minor mutations. Conclusion: The prevalence of major pretreatment INSTI resistance is very low. Pretreatment INSTI mutations do not appear to represent clustered HIV transmission

    Longitudinal opioid use among HIV-infected patients, 2000 to 2014

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    Longitudinal opioid prescription use is unknown among HIV-infected patients. Group-based trajectory modeling followed by multinomial logistic regression was used to identify distinct trajectories and their association with baseline characteristics among 1239 HIV-infected UNC CFAR HIV Clinical Cohort participants, 2000-2014. Three trajectories were identified: (1) 72% never/sporadic opioid use (referent group), (2) 11% episodic use (associated with female sex, depression, drug-related diagnoses, antiretroviral therapy use, and undetectable HIV RNA), and (3) 16% chronic use (associated with older age, female sex, and mental health diagnoses). Overall, opioid prescription decreased substantially with longer time in HIV care among both episodic and chronic users

    Outpatient Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection to Prevent Coronavirus Disease 2019 Progression

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    As of March 2021, coronavirus disease 2019 (COVID-19) had caused more than 123 million infections and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and nonpharmaceutical interventions to stop the spread of infection. However, treatments to stop disease progression are limited. A wide variety of "repurposed"drugs evaluated for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US Food and Drug Administration for emergency use for outpatients with mild to moderate COVID-19 including some active against emerging severe acute respiratory syndrome coronavirus 2 variants of concern. Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19

    Estimating Human Immunodeficiency Virus (HIV) Prevention Effects in Low-incidence Settings

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    Background: Randomized controlled trials (RCTs) for determining efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) infection have not been conducted among US women because their lower HIV incidence requires impractically large studies. Results from higher-incidence settings, like Sub-Saharan Africa, may not apply to US women owing to differences in age, sexual behavior, coinfections, and adherence. Methods: We propose a novel strategy for evaluating PrEP efficacy in the United States using data from both settings to obtain four parameters: (1) intention-to-treat (ITT) and (2) per-protocol effects in the higher-incidence setting, (3) per-protocol effect generalized to the lower-incidence setting, and (4) back-calculated ITT effect using adherence data from the lower-incidence setting. To illustrate, we simulated two RCTs comparing PrEP against placebo: one in 4000 African women and another in 500 US women. We estimated all parameters using g-computation and report risk ratios averaged over 2000 simulations, alongside the 2.5th and 97.5th percentiles of the simulation results. Results: Twelve months after randomization, the African ITT and per-protocol risk ratios were 0.65 (0.47, 0.88) and 0.20 (0.08, 0.34), respectively. The US ITT and per-protocol risk ratios were 0.42 (0.20, 0.62) and 0.17 (0.03, 0.38), respectively. These results matched well the simulated true effects. Conclusions: Our simple demonstration informs the design of future studies seeking to estimate the effectiveness of a treatment (like PrEP) in lower-incidence settings where a traditional RCT would not be feasible. See video abstract at, http://links.lww.com/EDE/B506

    HIV-1 shedding and chlamydial urethritis [1]

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    To the Editor.Drs. Schmid and Fontanarosa thoroughly discussed the causes and management of nongonococcal urethritis. However, they did not emphasize the link between treatment of sexually transmitted diseases and prevention of human immunodeficiency virus (HIV)
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