Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).

Biologic Therapies in HIV/AIDS Patients with Inflammatory Diseases: A Systematic Review of the Literature.

Biologic therapies have been increasingly developed and used for the treatment of severe inflammatory diseases. However, the safety and efficacy profile of biologic drugs in patients with HIV is not well established as this patient population is historically excluded from clinical trials. We review the available evidence of biologic use in people with HIV. We conducted a systematic review of the literature up to June 29, 2022 and included studies that treated patients with HIV who have inflammatory disease using biologic drugs. Clinical data regarding safety and efficacy were abstracted into tables. One hundred twelve studies were included, and 179 patients were included in our study. Nearly all classes of biologics drugs had a favorable safety profile with minimal or minor adverse events. Anti-CD-20 inhibitors and TNF-alpha inhibitors were associated with opportunistic infections. Transient increase in HIV viral load was noted with use of some agents such as TNF-alpha inhibitors. The quality of evidence is low, restricted to case reports and retrospective reviews. However, the safety profile of biologics observed in these patients with HIV was overall favorable.

Ambient particulate matter, a novel factor hindering life spans of HIV/AIDS patients: Evidence from a ten-year cohort study in Hubei, China.

BACKGROUND: The life spans of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients have been extended in the era of antiretroviral therapy. However, few studies have considered the influence of the environment on the life expectancy of people living with HIV/AIDS. Several studies have investigated mortality and air pollution associations, but the evidence for associations between long-term exposure to particulate matter (PM) and mortality among HIV/AIDS patients remains extremely sparse. METHODS: We conceived a dynamic cohort study by enrolling people with HIV/AIDS from 103 counties in Hubei province, China from 2010 to 2019, with 23,809 persons and 78,457.2 person-years of follow-up. The county-level annual concentrations of PM2.5 and PM10 were extracted from the ChinaHighAirPollutants dataset. Cox proportional hazards models with time-varying exposures were conducted to assess the associations between PM and mortality. RESULTS: Per 1 µg/m3 increased in PM2.5 and PM10 would elevate 0.69 % (95 % CIs: 0.39, 1.00) and 0.39 % (95 % CIs: 0.18, 0.59) risk of all-cause deaths (ACD) and 1.65 % (95 % CIs: 1.14, 2.17) and 0.90 % (95 % CIs: 0.56, 1.24) of AIDS-related deaths (ARD), respectively. Significantly stronger associations of PM-ARD were found in patients aged over 60 years old, with corresponding excess risk of 2.66 % (95 % CIs: 1.76, 3.58) for PM2.5 and 1.62 (95 % CIs: 1.01, 2.23) for PM10. CONCLUSIONS: This study added to the existing evidence that long-term exposure to ambient PM adversely affects the life spans of HIV/AIDS patients. Hence, public health departments should take proactive measures to prevent further life loss and promote survival among those living with HIV/AIDS.

A Case of Cerebral Toxoplasmosis and Cryptococcosis Preferred Therapy Associated Adverse Drug Reactions in a Patient Newly Co-diagnosed with Acquired Immune Deficiency Syndrome.

PURPOSE: The simultaneous occurrence of cerebral toxoplasmosis and cryptococcosis is rare. The infections continue to be treated with sulfadiazine and amphotericin-B-based regimens (preferred therapy), respectively. Both these drugs are linked to some serious adverse drug reactions (ADRs). We report such a unique instance of both; the CNS co-infections and adverse drug reactions to the preferred therapy. CASE PRESENTATION: A 44-year-old Asian-Indian female was diagnosed with cerebral toxoplasmosis, impending cryptococcal meningoencephalitis, and acquired immune deficiency syndrome (AIDS). The preferred therapy of opportunistic CNS co-infections commenced. Within a week, she had an occurrence of fall in hemoglobin concentrations (11.3 g/dL to 5.6 g/dL; grade IV), reticulocytosis (1% to 3.2%), and indirect hyperbilirubinemia (0.5 mg/dL to 2.8 mg/dL; grade IV) after sulfadiazine administration. The drug was discontinued and the patient was treated with hematocrit transfusions. After amphotericin-B deoxycholate (AmBd) administration, the patient developed hypokalemia (serum potassium; 4.5 mmol/L to 2.7 mmol/L) and increased serum creatinine (1.0 to 2.2 mg/dL; stage-I) levels. Hence, AmBd was discontinued and potassium correction was given. The patient got diagnosed with sulfadiazine induced hemolytic anemia and AmBd induced acute renal failure. He was switched to alternative therapy regimens for the treatment of cerebral toxoplasmosis and cryptococcosis. Radiological investigations were followed up to confirm the clinical outcomes of alternative therapy. Complete recovery from the ADRs and opportunistic infections was observed. CONCLUSION: The preferred therapy regimens for toxoplasmosis and cryptococcosis are accompanied by potential adverse drug reactions, thus continuous monitoring is vital, especially in the initial phases of therapy. Discontinuation of the treatment should be the preliminary intervention in the management. Having said that, alternative therapy regimens had an optimal clinical response in the present case.

Progressive multifocal leukoencephalopathy in anti-CD20 and other monoclonal antibody (mAb) therapies used in multiple sclerosis: A review.

Progressive multifocal leukoencephalopathy (PML) is a subacute CNS inflammatory disease seen primarily among immunocompromised patients. It is caused by the JC virus (JCV), a polyomavirus that otherwise induces an insidious, latent infection in the general population. This reactivated disease is characterized by cognitive and behavioral changes, language disturbances, motor weakness, or visual deficits. Median survival in patients with AIDS is approximately 2-4 months, and mortality is high (around 4% in untreated AIDS). Recent scientific developments indicate that PML can also be associated with the increased utilization of monoclonal antibody (mAb) immunotherapy. In fact, PML has been witnessed with several mAbs, including natalizumab in multiple sclerosis, rituximab for lymphoma or lupus, efalizumab for psoriasis, and ofatumumab in leukemia; this leads us to the risk reassessment of PML due to treatment-induced immunosuppression. The range of clinical presentations of JCV-related disease has transformed over time and can pose significant challenges to the current diagnostic criteria. Most cases with PML suffer from persistent and irreversible neurological conditions, and some with chronic, low-level viral replication in the CNS. With the expanded use of mAbs for various autoimmune and lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and other recently approved therapies. This article aims to review the relationship between the incidence of PML and all four mAbs used in the treatment of MS. Currently, at least 18 FDA-approved medications carry label warnings for PML;to this date, no treatment has been convincingly effective.

Systemic lupus erythematosus following human papillomavirus vaccination: A case-based review.

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune diseases (AIDs) with many pathogenic factors, ranging from genetic to epigenetic to environmental. The human papillomavirus (HPV), a viral infectious agent, is a common contributor to the onset and exacerbation of SLE. HPV infections are more prevalent among SLE patients than healthy individuals, bringing about a substantial need for treatment. While HPV recombinant gene vaccines are accepted as a universal method for infection prevention, they pose a risk for adverse events such as fever, joint pain, and rashes. In rare cases, they might even trigger AIDs such as SLE, especially in patients with a personal or family history of such diseases. In this article, we provide a report of a case of SLE onset following HPV vaccination and a review of 11 similar cases. An analysis of 12 patients revealed that 7 cases of SLE developed between 3 weeks and 2 months post-vaccination. Symptoms of SLE generally manifest as fatigue, fever, joint pain, and myalgia. Two patients had lupus nephritis, 2 showed central nervous system involvement, including abnormal behavior and epileptic seizures, and 1 had intestinal pseudo-obstruction. All patients showed rapid remission with glucocorticoid and immunosuppressive therapy and remained stable during several months of follow-up.

Safety of immune checkpoint inhibitors in patients with preexisting autoimmune disorders.

In recent years, immune checkpoint inhibitors (ICIs) have been approved for a growing number of cancer types. Approximately a quarter of cancer patients have a concomitant diagnosis of autoimmune disorders (AID). Activation of the immune system with ICIs poses a potential risk of AID worsening, thus, the majority of the ICI clinical trials excluded these patients from the study. There is a paucity of data regarding the benefits and risks of ICIs in cancer patients with AIDs. The primary objectives of this study were to determine the incidence of immunotherapy-related AID worsening and all immunotherapy-related adverse events (irAEs). Secondary outcomes were time to AID worsening and survival difference. All adult patients (age >=18 years) with solid malignancy who received ICIs between Jan 2016 and June 2019 were identified using the University of Louisville pharmacy database. Medical records were reviewed to include all the patients with preexisting AIDs. Descriptive statistics were used to determine the incidence of AID worsening and all irAEs. Baseline characteristics were compared between cancer patients with vs without AID worsening using Pearson chi2 and Student's t-test, where appropriate. Multivariate Cox regression analysis was used to compare survival between the 2 groups. A total of 40 patients with AIDs were identified during the study period. The cancer types were melanoma (57.5%), lung (15%), breast (5%), and others (22.5%). AIDs were rheumatological (52.5%), dermatologic (20%), gastroenterological (12.5%), neurologic (12.5%), and hematological (2.5%). The incidence of all irAEs was 60% (grade >=3 in 20%) and AID worsening was 40% (grade >=3 in 15%). The median time from ICI initiation to AID worsening was 94.5 (range 21-431) days. In multivariate Cox regression analysis, adjusted for demographics, cancer type, and stage, survival was similar for patients who had AID worsening vs those who did not (HR 0.30 (95%CI 0.06-1.40, P = 0.128). In our single-institution study, cancer patients with preexisting AID do have an increased risk of irAEs with high-grade toxicities in 20% compared to historically reported 5% in the general cancer population. About 15% of patients reported grade >=3 worsening of their AIDs. Although the risk of irAEs is numerically higher in patients with AIDs, it may be acceptable to the patients if the potential benefits of ICIs outweigh the risks.

Safety and Tolerability of Carboplatin and Paclitaxel in Cancer Patients with HIV (AMC-078), an AIDS Malignancy Consortium (AMC) Study.

BACKGROUND: Persons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer. METHODS: Eligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles. RESULTS: Sixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/µL) compared with baseline values (median: 389/µL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts. CONCLUSION: Full doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT01249443.

Debut clínico de SIDA: presentación de dos casos / Clinical onset of AIDS: presentation of two cases

Introducción: El debut clínico es un fenómeno particular dentro de la epidemia de VIH/SIDA que se viene observando en todo el mundo. Los cuadros diarreicos son una de las formas de su presentación. Presentación de casos: Se reportan dos pacientes con Virus de Inmunodeficiencia Humana que su debut clínico fueron las diarreas y en los cuales su diagnóstico serológico fue tardío presentándose con estado de inmunodepresión grave. Conclusiones: Luego de ponérseles tratamiento antirretroviral las diarreas desparecieron y hubo una recuperación inmunológica evidente (AU)

Introduction: A clinical onset is a particular phenomenon in HIV / AIDS that has been observed worldwide. Acute diarrhea is one form of their presentation. Case Presentation: We report two patients with Human Immunodeficiency Virus with a clinical onset of diarrhea who had a delayed serological diagnosis and severe immunosuppression. Conclusions: After antiretroviral treatment was begun diarrhea disappeared and there was a clear immunological recovery (AU)

VIH sida y la salud bucodental / HIV AIDS and oral health

El VIH sida es un virus que ataca ala especie humana. Todos los virus son micro organismos que tienen capacidad para multiplicarse por si mismos, por eso tiene que introducirse en las celulas y utilizaralas para reproducirse.

Human herpesvirus 6A accelerates AIDS progression in macaques.

Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the progression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macaca nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD4(+) T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramatically accelerated by coinfection with HHV-6A. Rapid disease development in dually infected animals was heralded by an early depletion of both CD4(+) and CD8(+) T cells. These results provide in vivo evidence that HHV-6A may act as a promoting factor in AIDS progression.

Altered P-glycoprotein expression in AIDS patients with HIV encephalitis.

Penetrance of anti-retroviral drugs into the CNS depends partly on the activity of P-glycoprotein (P-gp), an ATP-dependent efflux pump involved in restricting entry of lipophilic drugs into the brain. The present study characterizes the patterns of P-gp expression in the brains of AIDS patients and examines its relationship with clinical and neuropathological indicators of HIV encephalitis (HIVE). For this purpose, brain tissue collected at autopsy from 26 subjects with a history of HIV (9 without HIVE; 17 with HIVE) was analyzed. Immunocytochemical staining and Western blot analyses for regional P-gp expression were performed and levels were correlated with neuropathological indicators and with HIV RNA. Double labeling experiments were performed with antibodies against astroglial (GFAP), endothelial (CD31), microglial (CD45) and neuronal (MAP2) cell markers. In the HIVE-negative cases, P-gp immunoreactivity was associated primarily with endothelial cells. HIVE-positive cases showed extensive immunolabeling of astroglial and microglial cells, but relatively less endothelial cell immunolabeling. No neuronal P-gp immunostaining was detected in brain tissue from any cases in the study. In the HIVE-positive cases with extensive astroglial labeling, the most intense immunoreactivity was detected in white matter. A subset of HIVE-positive cases displayed intense P-gp immunostaining of astrocytes closely associated with blood vessels in the cortex. Both the immunocytochemical and Western blot analyses showed a significant correlation between P-gp expression and HIV RNA levels. In conclusion, P-gp immunoreactivity was detected largely in glial cells in tissue from HIVE-positive patients. Furthermore, in HIVE-positive patients, brain viral burden and P-gp levels were significantly higher than those in HIVE-negative patients. Taken together, our data suggest that P-gp may be part of a central pathway mediating viral compartmentalization in the brains of HIV-infected individuals and may play a significant part in HIV disease progression in the brain.

Case report. Phaeohyphomycosis caused by Phialophora verrucosa developed in a patient with non-HIV acquired immunodeficiency syndrome.

A 53-year-old woman had asymptomatic multiple nodules on her gluteal region for 6 months. She had a history of systemic corticosteroid treatment for Evans' syndrome. Recently she had developed an immunodeficiency condition with CD4+ cell depletion without an HIV infection and a normal serum gamma globulin level. A smear from the purulent exudate of the nodules revealed many brown-coloured hyphae, spores and few large dark-brown cells. A short, hairy, dark-brown coloured colony was cultivated on Sabouraud glucose agar. Slide culturing revealed only a Phialophora-type conidia formation, and the fungus was diagnosed as Phialophora verrucosa. Severe immunosuppressive condition (non-HIV acquired immunodeficiency syndrome) of this patients after systemic corticosteroid treatment for Evans' syndrome predisposed an opportunistic cutaneous fungal infection due to P. verrucosa. Cases with cutaneous infection due to P. verrucosa reported in Japan are summarized and discussed.

Lymphoepithelial cyst of the parotid gland--a case report.

The lymphoepithelial cyst has been commonly termed branchial cleft cyst or branchial cyst. Although many theories, including the branchial apparatus theory, thymic duct theory, and inclusion theory, have been put forward, the etiology is still controversial. Parotid lymphoepithelial cysts are rare and could be divided into two groups, AIDS-related and non-AIDS related, by the relationship with HIV infection. A non-AIDS related lymphoepithelial cyst of left parotid gland in an 81-year-old man presenting as a parotid tumor is described. A left partial parotidectomy was carried out to remove the lesion. There was no recurrence after 2 years. Lymphoepithelial cysts of the parotid gland are often misdiagnosed as other benign tumors in spite of detailed preoperative investigations. Thus a pathological proof is needed for precise diagnosis. In addition, we also need to take the possibility of HIV infection into consideration, although Taiwan is not an AIDS epidemic area.

[The effect of herbal medicines on the immunodeficient animals by injecting cancer chemotherapeutic agent-special reference to age related recovery of the function].

The acquired immunodeficiency of the host plays an essential role in the occurrence of infections even with low pathogenic bacteria. The increase of cases with MRSA and/or pseudomonas infection is one of the serious problems in hospital management in Japan for the elderly as well as pediatric patients. In the present study, mitomycin C (MMC)-treated hosts were prepared in young, adult and old mice to test the immunopotentiating action of the promising Chinese herbal medicine, Tohki-Rikuoh-Toh (TRT), Hotyu-Ekki-Toh (HET) and Juzen-Taiho-Toh (JTT). The effect of these herbal medicines on organ structure and its function in the MMC-treated hosts is clarified and discussed for medical use. 4-5, 8-10 and over 50 week old male C57BL/6 (Clea Japan Inc.) were injected with MMC at a dosage of 3 to 5 mg/kg to inhibit the bone marrow, thus creating a mouse model with reduced immunopotential. A powder extract of TRT, HET and JTT was administrated orally at a dosage of 500 mg/kg/day for seven consecutive days. The white cell number and the subset analysis were carried out by the FACS method. The bactericidal effect of the host was monitored by NBT reduction test. Peritoneal macrophages were prepared by the adherence technique. The macrophage phagocytic activity was examined by an ACAS system. After the administration of TRT, HET and JTT, the body weights recovered as much as 90%, especially in young animals which had been reduced to 75% of their normal values. After MMC-treatment, with the herbal medicines, HET was good for young mice while JTT was effective for the old ones. As for the effect on B cells, the plaque-forming cells (PFC) of spleen cells were compared among the groups. As a result, PFC in the HET group was 184% and the other two were 80 approximately 95% as compared to 76% in the MMC-treated ones. The number of white blood cells in the MMC-treated mice returned to 80% of their normal value. In addition, the phagocytic activity of macrophages increased to 50% although that of the non-treated group was only 20%. The phagocytic activity also recovered in the JTT and TRT of 131% to 95%, respectively compared to 11% in the MMC-treated control. When TRT, HET and JTT were administered orally to mouse models whose immunopotential had been inhibited, the herbal medicines activated both quantitatively and qualitatively, showing themselves to be effective interstitial medicines. In addition, the data from the animal models showed no side effects, confirming the complete efficacy of the drug. Moreover, there was no direct anti-bactericidal effect from these medicines, suggesting that the immunomodulating action of this medicine is host-mediated. It is interesting that quantitative and qualitative recovery were seen when HET was administered to MMC-treated young hosts while JTT was good for the old. With this investigation, the effective components are still unknown for different generations, and we need to clarify this aspect for better understanding of the efficacy of herbal medicines.