Linfoma de células B primario de mama en una paciente con sida. Presentación de un caso y revisión de la literatura / Primary B-cell lymphoma of the breast in an AIDS patient. Case report and literature review

Los LNH constituyen la segunda neoplasia más frecuente en pacientes con VIH. Estas neoplasias están ligadas a la inmunodeficiencia, suelen ser de período de latencia prolongado y más frecuentes en hombres. Más del 95% de estas neoplasias son de fenotipo B, de alto grado de malignidad, extranodales y representan la causa de muerte en un 12% al 16% de los casos. El linfoma no Hodgkin primitivo de mama (LPM) es una entidad infrecuente, que representa el 2,2% de todos los linfomas extranodales y el 0,5% de todas las neoplasias malignas de la mama. Se presenta una mujer con sida y linfoma primario de mama. (AU)

NHL is the second most common neoplasm in patients with HIV. It is linked to immunodeficiency, tends to have a long latency period and is more common in men. More than 95% of these neoplasms are of phenotype B, high-grade, extranodal and are the cause of death in 12% to 16% of cases. Primitive non-Hodgkin lymphoma of the breast is a rare entity, accounting for 2.2% of all extranodal lymphomas and 0.5% of all breast malignancies. A woman with AIDS and primary breast lymphoma is presented. (AU)

The making of the one pill-Developing single tablet regimens for HIV and for HCV.

A concept of "all or nothing" inspired the innovation of a one-pill-once-daily HIV treatment. Atripla® was the one pill that combined efavirenz, emtricitabine, and tenofovir disoproxil fumarate to become the first daily single tablet regimen that forever simplified HIV treatment to enhance patient compliance and thus, sustained viral suppression. The making of Atripla incorporated dry granulation and bilayer compression technologies to achieve stability and bioequivalence in an optimal pill size. In 2011, there lacked a standard of care for chronic hepatitis C infections that was safe, simple, short, free of interferon and ribavirin, and with high cure rates. A fixed-dose combination of ledipasvir and sofosbuvir was developed and approved in 2014 to be the first complete daily single tablet regimen for CHC genotype 1 infection. A spray-drying process for particle morphology engineering in a polymer matrix was used for improving bioavailability.

Anti-HIV Drugs Cause Mitochondrial Dysfunction in Monocyte-Derived Macrophages.

Combination antiretroviral therapy (cART) dramatically changed the face of the HIV/AIDS pandemic, making it one of the most prominent medical breakthroughs of the past 3 decades. However, as the life span of persons living with HIV (PLWH) continues to approach that of the general population, the same cannot be said regarding their quality of life. PLWH are affected by comorbid conditions such as high blood pressure, diabetes, and neurocognitive impairment at a higher rate and increased severity than their age-matched counterparts. PLWH also have higher levels of inflammation, the drivers of which are not entirely clear. As cART treatment is lifelong, we assessed here the effects of cART, independent of HIV, on primary human monocyte-derived macrophages (MDMs). MDMs were unskewed or skewed to an alternative phenotype and treated with Atripla or Triumeq, two first-line cART treatments. We report that Triumeq skewed alternative MDMs toward an inflammatory nonsenescent phenotype. Both Atripla and Triumeq caused mitochondrial dysfunction, specifically efavirenz and abacavir. Additionally, transcriptome sequencing (RNA-seq) demonstrated that both Atripla and Triumeq caused differential regulation of genes involved in immune regulation and cell cycle and DNA repair. Collectively, our data demonstrate that cART, independent of HIV, alters the MDM phenotype. This suggests that cART may contribute to cell dysregulation in PLWH that subsequently results in increased susceptibility to comorbidities.

PANDAA intentionally violates conventional qPCR design to enable durable, mismatch-agnostic detection of highly polymorphic pathogens.

Sensitive and reproducible diagnostics are fundamental to containing the spread of existing and emerging pathogens. Despite the reliance of clinical virology on qPCR, technical challenges persist that compromise their reliability for sustainable epidemic containment as sequence instability in probe-binding regions produces false-negative results. We systematically violated canonical qPCR design principles to develop a Pan-Degenerate Amplification and Adaptation (PANDAA), a point mutation assay that mitigates the impact of sequence variation on probe-based qPCR performance. Using HIV-1 as a model system, we optimized and validated PANDAA to detect HIV drug resistance mutations (DRMs). Ultra-degenerate primers with 3' termini overlapping the probe-binding site adapt the target through site-directed mutagenesis during qPCR to replace DRM-proximal sequence variation. PANDAA-quantified DRMs present at frequency ≥5% (2 h from nucleic acid to result) with a sensitivity and specificity of 96.9% and 97.5%, respectively. PANDAA is an innovative advancement with applicability to any pathogen where target-proximal genetic variability hinders diagnostic development.

Untimed Efavirenz Drug Levels After Switching From Brand to Generic Formulations: A Short Communication.

BACKGROUND: In British Columbia, antiretrovirals are distributed at no cost to patients via a publicly funded program, using generic formulations if available. A generic efavirenz-emtricitabine-tenofovir DF (EFV-FTC-TDF) combination pill became available in April 2018. The authors compared EFV untimed drug levels in subjects switching from brand to generic EFV-FTC-TDF. METHODS: Archived plasma HIV viral load samples were identified for consenting participants who switched from brand to generic EFV-FTC-TDF; 3 preswitch and 2-3 postswitch samples, collected ≥1 month apart were assessed for each subject. "Untimed" EFV concentrations with unknown dosing and collection time were assessed using a validated liquid chromatography-tandem mass spectrometry method. Participants' mean, minimum, and maximum EFV levels were compared using the Wilcoxon signed rank test. Participants with EFV levels in the range associated with lower risks of virologic failure and central nervous system toxicity (1000-4000 ng/mL), preswitch and postswitch, were enumerated. RESULTS: EFV levels were assessed in 297 preswitch and 249 postswitch samples from 99 participants, having exposure to brand and generic EFV for a median of 103 (Q1-Q3: 87-116) and 10.3 (Q1-Q3: 8.9-11.7) months, respectively. The final brand sample was collected at a median of 98 days preswitch; the first generic sample was collected at a median of 133 days postswitch. No significant differences were observed in participant mean EFV levels before (median 1968 ng/mL; Q1-Q3: 1534-2878 ng/mL) and after (median 1987 ng/mL; Q1-Q3: 1521-2834 ng/mL) switch (P = 0.85). Eighty participants had mean EFV levels within the 1000-4000 ng/mL range on the brand drug, of which 74 remained within this range postswitch. CONCLUSIONS: There were no statistically significant differences between untimed EFV levels in patients switching from the brand to generic EFV combination pill. Given the long elimination half-life of EFV, untimed drug levels may be a convenient way to estimate product bioequivalence.

Human Immunodeficiency Virus Type 1 Vpu Inhibitor, BIT225, in Combination with 3-Drug Antiretroviral Therapy: Inflammation and Immune Cell Modulation.

BIT225 is a first-in-class inhibitor of human immunodeficiency virus (HIV) type 1 Vpu. A phase II trial enrolled 36 HIV-1-infected, treatment-naive participants in Thailand to receive standard-of-care antiretroviral therapy (ART), tenofovir disoproxil fumarate/emtricitabine/efavirenz (Atripla), with 100 or 200 mg of BIT225 or placebo (daily) for 12 weeks. Combined treatment with BIT225 and ART was found to be generally safe and well tolerated, with antiviral efficacy comparable to that of ART alone. The secondary end point-soluble CD163, a marker of monocyte/macrophage inflammation-was noted to be significantly decreased in the BIT225 arm. Plasma-derived activated CD4+ and CD8+ T cells, natural killer cells, and interleukin 21 were increased in those treated with BIT225. These findings are consistent with inhibition of the known effects of HIV Vpu and may reflect clinically important modulation of inflammatory and immune function. Further clinical study is planned to both confirm and extend these important findings in treatment-naive, and treatment-experienced individuals. Clinical Trials Registration. Australian New Zealand Clinical Trials Registry (Universal Trial Number U1111-1191-2194).

Vitamin D and Calcium Supplement Attenuate Bone Loss among HIVInfected Patients Receiving Tenofovir Disoproxil Fumarate/Emtricitabine/ Efavirenz: An Open-Label, Randomized Controlled Trial.

BACKGROUND: Antiretroviral therapy (ART), especially with tenofovir disoproxil fumarate (TDF), has been associated with accelerated bone turnover and leads to significant bone loss. OBJECTIVE: We aimed to determine the effect of vitamin D2 and calcium on bone mineral density (BMD) in HIV-infected patients receiving TDF/emtricitabine (FTC)/efavirenz (EFV). METHODS: A prospective, open-label, randomized controlled study was conducted. Eligible patients were ART naïve HIV individuals who initiated TDF/FTC/EFV. The study group received supplementation with vitamin D2 and calcium carbonate, whereas the control group was administered only ART. The primary outcome was the percentage change in total hip BMD at week 24 compared with baseline. RESULTS: A total of 18 patients were randomized (9 in each group). The mean (standard deviation; SD) total hip BMD significantly decreased from baseline in both groups, from 0.96 (0.14) g/cm2 to 0.93 (0.13) g/cm2 in the study group (p = 0.006) and from 0.87 (0.11) g/cm2 to 0.84 (0.11) g/cm2 in the control group (p = 0.004). The mean (SD) lumbar spine BMD significantly decreased from baseline in both groups, from 1.00 (0.13) g/cm2 to 0.97 (0.13) g/cm2 (p = 0.004) in the study group and from 0.90 (0.09) g/cm3 to 0.86 (0.08) g/cm2 in the control group (p = 0.006). At week 24, the mean (SD) lumbar spine BMD was significantly greater in the study group than in the control group (p = 0.042). However, there were no significant differences in the percentage change of total hip, lumbar spine, and femoral neck BMD between both groups. No adverse events were reported. In conclusion, as early as 24 weeks after TDF initiation, a significant decline in BMD was detected. CONCLUSION: Vitamin D2 and calcium supplements should be considered for HIV-infected patients receiving TDF/FTC/EFV in a resource-limited setting where there are limited ART options (Clinicaltrials. gov NCT0287643).

Multidrug-resistant Klebsiella oxytoca ventriculitis, successfully treated with intraventricular tigecycline: A case report.

A 38-year-old male presented to the hospital with headache, fever, and meningeal signs. He had undergone a surgical review of a ventriculoperitoneal shunt system one month earlier. A head computed tomography scan showed hydrocephalus. His medical history included a human immunodeficiency virus infection identified four years before and resolved cryptococcal meningitis, which had necessitated the implantation of the shunt system. Ventricular cerebrospinal fluid (CSF) was obtained, which showed inflammation and, in culture, grew a Gram-negative bacillus identified as multidrug-resistant Klebsiella oxytoca. The shunt was removed and a ventricular drain was installed. Treatment with meropenem and amikacin was established without a response; the CSF white blood cell count continued to increase, with cultures remaining positive. The patient's clinical condition deteriorated to stupor. With informed consent, intraventricular (ITV) treatment with tigecycline was initiated at a dose of 5 mg every 24 h and, three days later, the CSF cultures were negativized. Tigecycline levels in the CSF were quantified by liquid chromatography with ultraviolet detection and showed peak concentrations achieved at two hours after the dose of between 178 and 310 µg/mL. After 11 days of treatment with ITV tigecycline and eight negative CSF cultures, a new CSF shunt was installed. During follow-up review 10 months later, the patient reported he was working. The dose of tigecycline used in this study produced levels 15 to 20 times the minimum inhibitory concentration of the bacteria for up to six hours with adequate tolerance.

Human immunodeficiency virus-associated giant conjunctival Kaposi's sarcoma: complete remission with antiretroviral therapy and systemic chemotherapy. / Sarcoma de Kaposi conjuntival gigante por el virus de inmunodeficiencia humana: remisión total tras terapia antirretroviral y quimioterapia sistémica.

CASE REPORT: A 35-year-old male patient with a large unilateral haemorrhagic conjunctival tumour lesion and another contralateral haemorrhagic conjunctival flat lesion associated with violaceous cutaneous macules on the extremities and angiomatous lesions in the upper gastrointestinal tract as initial clinical manifestation of HIV-related immunodeficiency. Cutaneous, gastric mucosal and conjunctival biopsy was consistent with Kaposi's sarcoma with complete remission after highly active antiretroviral therapy and systemic chemotherapy. CONCLUSION: HIV-related conjunctival Kaposi's sarcoma, even a large one, can have a good response to antiretroviral therapy and systemic chemotherapy without any additional topical eye treatment.

Acute Kidney Injury After Efavirenz/Tenofovir Disoproxil Fumarate/Emtricitabine (Atripla) Overdose.

We describe a patient with acute renal failure and irreversible kidney damage after an overdose with the fixed dose combination of efavirenz/tenofovir disoproxil fumarate/emtricitabine (Atripla). The acute kidney injury was most probably caused by tenofovir. Efavirenz and emtricitabine seemed relatively safe in overdose. The pharmacokinetics in overdose of all 3 drugs and the effect of hemodialysis on the tenofovir clearance were studied by measuring the plasma concentrations and by the use of clinical pharmacokinetic software.

Short Communication: The Impact of Switching from Atripla to Darunavir/Ritonavir Monotherapy on Neurocognition, Quality of Life, and Sleep: Results from a Randomized Controlled Study.

We investigated whether a treatment switch from Atripla® (tenofovir, emtricitabine, and efavirenz) to DRV/r monotherapy may improve neuropsychological performance, health-related quality of life, and sleep function. Virologically suppressed subjects and asymptomatic on Atripla for ≥6 months were randomized 1:1 to continue Atripla or switch to boosted darunavir (DRV/r) 800/100 mg once daily for 48 weeks. Neurocognitive tests, the International HIV Dementia Scale (IHDS), Medical Outcomes Study HIV Health Survey (MOS-HIV), EQ-5D-3L, and the Hospital Anxiety and Depression Scale (HADS) were completed at baseline and at week 48. Sleep function was evaluated at week 48. Twenty-six patients on DRV/r and 31 on Atripla completed the 48-week study. No significant difference in the change in scores from week 0 to week 48 between the two arms was observed in neurocognitive outcomes, IHDS, health outcomes (EQ-5D-3L and QOL), and HADS score. By contrast, the HADS score and sleep quality were both significantly better in the DRV/r arm. In conclusion, switching to DRV/r monotherapy did not affect neurocognitive function or quality of life but improved anxiety, and sleep quality was significantly better than in continued Atripla.

Improved pregnancy outcomes with increasing antiretroviral coverage in South Africa.

BACKGROUND: Universal multi drug antiretroviral treatment in pregnancy is a global priority in our bid to eliminate paediatric HIV infections although few studies have documented the impact of antiretroviral coverage on overall pregnancy outcomes. METHODS: We conducted a maternity audit at a large regional hospital in South Africa during July-December 2011 and January-June 2014 with an aim to determine an association between pregnancy outcomes and the ARV treatment guidelines implemented during those specific periods. During 2011, women received either Zidovudine/sd Nevirapine or Stavudine/Lamivudine/Nevirapine if CD4+ count was < 350 cells/ml. During 2014, all HIV positive pregnant women were eligible for a fixed dose combination (FDC) of triple ARVs (Tenofovir/Emtracitabine/Efavirenz). RESULTS: In 2011, 622 (35.9%) of 1732 HIV positive pregnant women received triple antiretrovirals (D4T/3TC/NVP) and in 2014, 2104 (94.8%) of 2219 HIV positive pregnant women received the fixed dose combination (TDF/FTC/EFV). We observed a reduction in the proportion of unregistered pregnancies, caesarean delivery rate, still birth rate, very low birth weight rate, and very premature delivery rate in 2014. In a bivariate analysis of all 9,847 deliveries, unregistered pregnancies (2.2%) and HIV infection (37.8%) remained significant risk factors for SB(OR 6.36 and 1.43 respectively), PTD(OR 4.23 and 1.26 respectively),LBW (OR 4.07 and 1.26 respectively) and SGA(OR 2.17 and 1.151 respectively). In a multivariable analysis of HIV positive women only, having received AZT/NVP or D4T/3TC/NVP or EFV/TDF/FTC as opposed to not receiving any ARV was significantly associated with reduced odds of a SB (OR 0.08, 0.21 and 0.18 respectively), PTD (OR 0.52, 0.68 and 0.56 respectively) and LBW(0.37, 0.61 and 0.52 respectively). CONCLUSION: An improvement in birth outcomes is likely associated with the increased coverage of triple antiretroviral treatment for pregnant women. And untreated HIV infected women and women who do not seek antenatal care should be considered most at risk for poor birth outcomes.

Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.

Effects on vitamin D, bone and the kidney of switching from fixed-dose tenofovir disoproxil fumarate/emtricitabine/efavirenz to darunavir/ritonavir monotherapy: a randomized, controlled trial (MIDAS).

BACKGROUND: Efavirenz (EFV) has been associated with reductions in vitamin D (25[OH]D) and tenofovir (TDF) with increased bone turnover, reductions in bone mineral density (BMD) and renal tubular dysfunction. We hypothesized that switching from fixed-dose TDF/emtricitabine (FTC)/EFV to darunavir/ritonavir monotherapy (DRV/r) might increase 25(OH)D and BMD, and improve renal tubular function. METHODS: Subjects with HIV RNA <50 copies/ml on TDF/FTC/EFV for ≥6 months were randomized 1:1 to ongoing TDF/FTC/EFV or DRV/r (800/100 mg once daily) for 48 weeks. The primary end point was change from baseline in 25(OH)D at week 48. Secondary end points included changes in BMD, bone turnover markers and renal tubular function. RESULTS: A total of 64 subjects (86% male, 66% white, mean [sd] CD4(+) T-cell count 537.3 [191.5]/mm(3)) were analysed. After adjustment for baseline 25(OH)D and demographics, at week 48 DRV/r monotherapy was associated with a +3.6 (95% CI 0.6, 6.6) ng/ml increase in 25(OH)D compared to TDF/FTC/EFV (P=0.02). DRV/r monotherapy was associated with an increase in BMD (+2.9% versus -0.003% at the neck of femur and +2.6% versus +0.008% at the lumbar spine for DRV/r versus TDF/FTC/EFV; P<0.05 for all) and reductions in bone biomarkers compared with those remaining on TDF/FTC/EFV. No significant difference in renal tubular function was observed. Reasons for discontinuation in the DRV/r arm included side effects (n=4) and viral load rebound (n=3), all of which resolved with DRV/r discontinuation or regimen intensification. CONCLUSIONS: Switching from TDF/FTC/EFV to DRV/r in patients with suppressed HIV RNA resulted in significant improvements in 25(OH)D and bone biomarkers, and a 2-3% increase in BMD.

Cost-effectiveness of DTG + ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States.

OBJECTIVE: Data from the SINGLE trial demonstrated that 88% of treatment-naïve HIV-1 patients treated with dolutegravir and abacavir/lamivudine (DTG + ABC/3TC) achieved viral suppression at 48 weeks compared with 81% of patients treated with efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). It is unclear how this difference in short-term efficacy impacts long-term cost-effectiveness of these regimens. This study sought to evaluate long-term cost-effectiveness of DTG + ABC/3TC vs EFV/TDF/FTC from a US payer perspective. METHODS: This study is an individual discrete-event simulation which tracked the disease status and treatment pathway of HIV-1 patients. The model simulated treatment over a lifetime horizon by tracking change in patients' CD4 count, clinical events occurrence (opportunistic infections, cancer, and cardiovascular events), treatment switch, and death. The model included up to four lines of treatment. Baseline patient characteristics, efficacy, and safety of DTG + ABC/3TC and EFV/TDF/FTC were informed by data from the SINGLE trial. The efficacy of subsequent treatment lines, clinical event risks, mortality, cost, and utility inputs were based on literature and expert opinion. Outcomes were lifetime discounted medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with EFV/TDF/FTC, DTG + ABC/3TC increased lifetime costs by $19,153 and per person survival by 0.12 QALYs, resulting in an ICER of $158,890/QALY. ICERs comparing DTG + ABC/3TC to EFV/TDF/FTC remained above the traditional, US willingness-to-pay threshold of $50,000/QALY gained in all scenarios, and above $100,000 or $150,000/QALY gained in most scenarios. LIMITATIONS: Due to data limitations, the treatment patterns, CD4 count during viral rebound and treatment switch, viral rebound after trial end, and long-term adverse event-related treatment discontinuation were based on assumptions, presented to and approved by clinical experts. CONCLUSIONS: Compared with EFV/TDF/FTC, DTG + ABC/3TC resulted in higher cost and only slightly increased QALYs over a lifetime, with an ICER that exceeded the standard cost-effectiveness threshold. This indicates that the incremental benefit in effectiveness associated with DTG + ABC/3TC may not be worth the incremental increase in costs.