warfarin and HIV-Infections

To review the literature for information regarding interactions between warfarin and antiretroviral agents and evaluate the clinical significance of these interactions.. Primary literature was identified through a search of MEDLINE (1950-July 2008) and International Pharmaceutical Abstracts (1970-July 2008) using individual antiretroviral drug names and the following key search terms: warfarin, antiretroviral, protease inhibitor, nonnucleoside reverse transcriptase inhibitor, cytochrome P450, 2C9, HIV, and drug interactions. Relevant abstracts from infectious disease and HIV conferences (2005-2008), reference citations from relevant articles, and manufacturers' product information were also reviewed.. All English-language articles identified through the data search were examined. Studies and reports addressing warfarin interactions with antiretrovirals, CYP2C9 polymorphism, and antiretroviral CYP2C9 effects were evaluated. A total of 12 case reports were identified that described interactions between warfarin and either protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs).. The drugs used in the case reports were limited to 6 antiretroviral agents (efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, saquinavir, ritonavir). The mechanism of interaction between antiretroviral agents and warfarin appears to be mediated through alteration in CYP2C9 metabolism. Concurrent use of warfarin with efavirenz or saquinavir was associated with overanticoagulation, identified by increases in international normalized ratio (INR). Use of warfarin with lopinavir/ritonavir, nelfinavir, ritonavir, and nevirapine resulted in subtherapeutic INRs. Interactions with delavirdine, etravirine, and atazanavir are anticipated; however, no published cases have reported these interactions. Interactions between warfarin and nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and CCR5 antagonists are not anticipated.. Interactions between warfarin and antiretrovirals are likely, especially when PIs or NNRTIs are used. Induction or inhibition of warfarin metabolism may occur, depending on the specific antiretroviral agent. When warfarin is used concurrently with antiretrovirals, close monitoring of INR response is recommended in lieu of empiric warfarin dosing adjustments, given the limited information available and the quality of evidence.

Topics: Anti-Retroviral Agents; Aryl Hydrocarbon Hydroxylases; Case-Control Studies; Cytochrome P-450 CYP2C9; Drug Interactions; HIV Infections; Humans; International Normalized Ratio; Protease Inhibitors; Reverse Transcriptase Inhibitors; Warfarin

The array of clinicopathologic factors associated with acquired immune deficiency syndrome (AIDS) patients continues to increase and surprise many physicians. The recent literature contains reports of thrombotic episodes occurring in patients with human immunodeficiency virus (HIV) infection. Various abnormalities predisposing to a hypercoagulable state have also been reported in AIDS patients including the presence of antiphospholipid antibodies and the lupus anticoagulant; deficiencies of protein C, protein S, heparin cofactor II, and antithrombin and increased levels of von Willebrand factor, and d-dimers. These abnormalities correlate with the severity of HIV-associated immunosuppression as measured by the CD4 cell counts and with the presence of concurrent infectious or neoplastic diseases. The authors reviewed the medical literature and describe various abnormalities predisposing to a hypercoagulable state in AIDS patients along with the management of such complications. This issue is important because deep venous thrombosis (DVT), pulmonary embolus (PE), or thrombosis at other sites can develop in patients with AIDS who are ambulatory and have no known risk factors for pathologic thrombus formation, providing another challenge in an already difficult clinical situation. This also provides a strong rationale for careful prospective studies focusing on the prevalence and risk factors involved in the development of thromboembolic complications in patients with AIDS.

Topics: AIDS-Related Opportunistic Infections; Anticoagulants; Coagulation Protein Disorders; Heparin; HIV Infections; Humans; Protease Inhibitors; Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; HIV Infections; Humans; Male; Pyridones; Ritonavir; Rivaroxaban; Stroke; Warfarin

Warfarin remains the most widely prescribed oral anticoagulant in sub-Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine-learning techniques in predicting stable warfarin dose in sub-Saharan Black-African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub-Saharan Africa (War-PATH) clinical dose-initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39-13.76) was the best performing machine-learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75-19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine-learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45-14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine-learning techniques. We have also externally validated our previously developed clinical dose-initiation algorithm, which is being prospectively tested for clinical utility.

Topics: Adult; Africa South of the Sahara; Age Factors; Algorithms; Anticoagulants; Body Weight; Drug Dosage Calculations; Female; HIV Infections; Humans; International Normalized Ratio; Machine Learning; Male; Middle Aged; Models, Biological; Reproducibility of Results; Sex Factors; Simvastatin; Warfarin

Pharmacogenomics is universally relevant for worldwide modern therapeutics and yet needs further development in resource-limited countries. While there is an abundance of genetic association studies in controlled medical settings, there is a paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and under multiple drug treatment regimens. African patients are often burdened with communicable and noncommunicable comorbidities, yet the application of pharmacogenomics in African clinical settings remains limited. Using warfarin as a model, this study aims at minimizing gaps in precision/personalized medicine research in African clinical practice. We present, therefore, pharmacogenomic profiles of a cohort of 503 black Africans (

Topics: Anticoagulants; COVID-19; HIV Infections; Humans; Pandemics; Pharmacogenetics; Polymorphism, Single Nucleotide; Precision Medicine; SARS-CoV-2; Warfarin

Human immunodeficiency virus (HIV) is associated with increased rates of cardiovascular disease and vascular events, and people living with HIV (PLWH) may often have indications for therapeutic anticoagulation. However, the ideal anticoagulant in PLWH remains unknown. This retrospective cohort evaluated the tolerability and effectiveness of oral anticoagulants in PLWH. The primary outcome was tolerability, defined as a composite of bleeding and/or discontinuation rates. The secondary outcomes included recurrent thromboembolism, bleeding, and discontinuations, independently. There were 92 patients included for analysis, 48 in the direct oral anticoagulant (DOAC) arm and 44 in the warfarin arm. There were 35 (38%) PLWH that did not tolerate oral anticoagulation therapy in the total cohort. Among these, 19 received a DOAC and 16 received warfarin. There were 16 (17%) PLWH that experienced a bleeding event: six in the DOAC arm and 10 in the warfarin arm. There were 15 (16%) PLWH that experienced recurrent thromboembolism, with similar rates between DOAC versus warfarin (10, 21% vs 5, 11%, respectively;

Topics: Administration, Oral; Anticoagulants; HIV; HIV Infections; Humans; Retrospective Studies; Warfarin

Warfarin is the most commonly prescribed oral anticoagulant in sub-Saharan Africa and requires ongoing monitoring. The burden of both infectious diseases and non-communicable diseases is high and medicines used to treat comorbidities may interact with warfarin. We describe service provision, patient characteristics, and anticoagulation control at selected anticoagulation clinics in Uganda and South Africa.. We evaluated two outpatient anticoagulation services in Kampala, Uganda and three in Cape Town, South Africa between 1 January and 31 July 2018. We collected information from key staff members about the clinics' service provision and extracted demographic and clinical data from a sample of patients' clinic records. We calculated time in therapeutic range (TTR) over the most recent 3-month period using the Rosendaal interpolation method.. We included three tertiary level, one secondary level and one primary level anticoagulation service, seeing between 30 and 800 patients per month. Care was rendered by nurses, medical officers, and specialists. All healthcare facilities had on-site pharmacies; laboratory INR testing was off-site at two. Three clinics used warfarin dose-adjustment protocols; these were not validated for local use. We reviewed 229 patient clinical records. Most common indications for warfarin were venous thrombo-embolism in 112/229 (49%), atrial fibrillation in 74/229 (32%) and valvular heart disease in 30/229 (13%). Patients were generally followed up monthly. HIV prevalence was 20% and 5% at Ugandan and South African clinics respectively. Cardiovascular comorbidity predominated. Furosemide, paracetamol, enalapril, simvastatin, and tramadol were the most common concomitant drugs. Anticoagulation control was poor at all included clinics with median TTR of 41% (interquartile range 14% to 69%).. TTR was suboptimal at all included sites, despite frequent patient follow-up. Strategies to improve INR control in sub-Saharan patients taking warfarin are needed. Locally validated warfarin dosing algorithms in Uganda and South Africa may improve INR control.

Topics: Adult; Aged; Ambulatory Care; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Drug Monitoring; Female; Heart Valve Diseases; HIV Infections; Humans; International Normalized Ratio; Male; Middle Aged; Secondary Care Centers; South Africa; Tertiary Care Centers; Uganda; Venous Thromboembolism; Warfarin

Topics: Adenine; Alanine; Cobicistat; Emtricitabine; HIV Infections; Humans; International Normalized Ratio; Quinolones; Tenofovir; Warfarin

The prevalence of atrial fibrillation in the HIV-infected population is growing, but the ability of the CHA2DS2-VASc score to predict thromboembolic (TE) risk is unknown in this population.. Within the Veterans Affairs HIV Clinical Case Registry, 914 patients had an atrial fibrillation diagnosis between 1997 and 2011 and no previous TE events.. We compared TE incidence by CHA2DS2-VASc scores and stratified by warfarin use. Using Cox proportional hazards regression with adjustment for competing risks, we modeled associations of CHA2DS2-VASc scores and warfarin use with TE risk.. At baseline, the distribution of CHA2DS2-VASc scores was 0 (n = 208), 1 (n = 285), and 2+ (n = 421); 34 patients developed 38 TE events during a median of 3.8 years follow-up. Event rates by CHA2DS2-VASc scores of 0, 1, and 2+ were 5.4, 9.3, and 8.1 per 1000 person years, respectively; multivariate-adjusted hazards ratios (HRs) were 1.70 (95% confidence interval: 0.65 to 4.45) for CHA2DS2-VASc score 1 (P = 0.28) and HR = 1.34 (0.51, 3.48) for score 2+ versus 0 (P = 0.55). Baseline warfarin use was associated with increased TE risk, although not statistically significant [HR 2.06 (0.86, 4.93), P = 0.11] with similar results when modeled as time-updated use and duration of use.. In this national registry of HIV-infected veterans with atrial fibrillation, CHA2DS2-VASc scores were only weakly associated with TE risk. Furthermore, warfarin did not seem to be effective at preventing TE events. These results should raise concerns about the optimal strategy for TE prevention among HIV-infected persons with atrial fibrillation.

Topics: Adult; Aged; Atrial Fibrillation; Comorbidity; Female; Follow-Up Studies; HIV Infections; Humans; Incidence; Male; Middle Aged; Proportional Hazards Models; Registries; Risk Assessment; Risk Factors; Stroke; Thromboembolism; United States; Veterans; Warfarin

Topics: Aged; Anti-HIV Agents; Anticoagulants; Atazanavir Sulfate; Blood Chemical Analysis; Cobicistat; Darunavir; Drug Interactions; HIV Infections; Humans; International Normalized Ratio; Male; Ritonavir; Warfarin

HIV-infected patients are at an increased risk of developing venous thromboembolism (VTE), and minimal data are available to describe the need for extended treatment.. To evaluate the frequency of and determine predictive risk factors for extended anticoagulation of VTE in HIV-infected patients in rural, western Kenya.. A retrospective chart review was conducted at the Anticoagulation Monitoring Service affiliated with Moi Teaching and Referral Hospital and the Academic Model Providing Access to Healthcare. Data were collected on patients who were HIV-infected and receiving anticoagulation for lower-limb deep vein thrombosis. The need for extended anticoagulation, defined as receiving ≥7 months of warfarin therapy, was established based on patient symptoms or Doppler ultrasound-confirmed diagnosis. Evaluation of the secondary outcomes utilized a univariate analysis to identify risk factors associated with extended anticoagulation.. A total of 71 patients were included in the analysis; 27 patients (38%) required extended anticoagulation. The univariate analysis showed a statistically significant association between the need for extended anticoagulation and achieving a therapeutic international normalized ratio within 21 days in both the unadjusted and adjusted analysis. Patients with a history of opportunistic infections required an extended duration of anticoagulation in the adjusted analysis: odds ratio = 3.42; 95% CI = 1.04-11.32; P = 0.04.. This study shows that there may be a need for increased duration of anticoagulation in HIV-infected patients, with a need to address the issue of long-term management. Guideline recommendations are needed to address the complexity of treatment issues in this population.

Topics: Adult; Anticoagulants; Female; Health Care Rationing; HIV Infections; Humans; International Normalized Ratio; Kenya; Male; Medical Records; Middle Aged; Retrospective Studies; Risk Factors; Rural Population; Time Factors; Ultrasonography, Doppler; Venous Thromboembolism; Venous Thrombosis; Warfarin

People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients.. A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups.. 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups-HIV-uninfected and HIV-infected patients not on ARVs.. There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; CD4 Lymphocyte Count; Female; HIV Infections; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Retrospective Studies; South Africa; Venous Thrombosis; Warfarin; Young Adult

Topics: Anti-HIV Agents; Anticoagulants; Aortic Valve Stenosis; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Middle Aged; Mitral Valve Insufficiency; Oxazines; Piperazines; Pyridones; Ritonavir; Warfarin

The cluster-randomized trial is the methodology of choice for evaluating interventions administered at the group level such as public health and healthcare quality improvement interventions. Because of unique features of this design, it can be difficult to apply standard research ethics guidelines to cluster-randomized trials. The Ottawa Statement on the Ethical Design and Conduct of Cluster-Randomized Trials provides researchers and research ethics committees with comprehensive guidance on the ethical design, conduct and review of cluster-randomized trials. The Ottawa Statement supplements current national and international research ethics guidelines with guidance that is specific to cluster-randomized trials. In a recently published commentary, three examples drawn from the ClinicalTrials.gov registry were used to illustrate challenges associated with the cluster-randomized trial design. The commentary argued that the Ottawa Statement fails to provide comprehensive ethical guidance. In this article, we illustrate the application of the Ottawa Statement to the three trials. We challenge the conclusions reached in the commentary by demonstrating that an ethical analysis requires complete information. We correct some misperceptions about the cluster-randomized trial design.. We collected essential additional information by contacting the authors of trials and by referring to published trial articles. We used the Ottawa Statement to conduct an ethical analysis of each trial and to address a number of substantive concerns raised regarding the identification of study participants, informed consent and harm benefit analysis.. In the two cases in which we were able to obtain detailed study information, we were able to complete the ethical analysis prescribed by the Ottawa Statement.. The Ottawa Statement does provide a useful framework for the ethical design, review and conduct of cluster-randomized trials.

Topics: Anticoagulants; Disease Management; Ethics Committees, Research; Ethics, Research; Family Planning Services; Guidelines as Topic; Health Services; HIV Infections; Humans; Informed Consent; Malaria; Randomized Controlled Trials as Topic; Registries; Research Design; Risk Assessment; Warfarin

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

The purpose of this study was to explore factors associated with venous thromboembolism (VTE) among a cohort of HIV-infected patients and to describe early outcomes of warfarin anticoagulation therapy treated in a pharmacist-based anticoagulation clinic (ACC). A nested case-control study was conducted using the University of Alabama at Birmingham 1917 HIV Clinic Cohort. Conditional logistic regression was used to estimate factors associated with VTE. Among HIV-infected VTE cases, ACC-managed patients were compared to primary care provider (PCP)-managed patients to determine Time within Therapeutic INR Range (TTR). CD4 < 200 cells/µl (OR = 4.50; 95% CI = 1.52, 13.37; p = 0.007) and prior surgical procedures (13.20; 1.56; 111.4; p = 0.018) demonstrated positive associations with VTE, whereas longer HIV duration demonstrated a negative association (0.87; 0.78, 0.98; p = 0.019). TTR was 56.2% among ACC-managed patients compared to 30.5% of PCP-managed patients (p = 0.174). Overall, prior surgical procedures and low CD4 count were associated with an increased risk of VTE among HIV-infected patients. Despite small sample size, patients managed in ACC tend to achieve greater proportion of TTR compared to those managed by PCPs, suggesting that this model of therapy may provide additional benefits to HIV-infected patients.

Topics: Adult; Ambulatory Care Facilities; Anticoagulants; Case-Control Studies; Female; HIV Infections; Humans; International Normalized Ratio; Logistic Models; Male; Middle Aged; Multivariate Analysis; Pharmaceutical Services; Pharmacists; Primary Health Care; Retrospective Studies; Risk Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

Topics: Adult; Anti-HIV Agents; Cobicistat; Drug Interactions; HIV Infections; Humans; Male; Quinolones; Warfarin

This study aimed to describe the contemporary aetiology, clinical characteristics and mortality and its predictors in heart failure (HF) in Tanzania.. Design; Prospective observational study. Setting; Cardiovascular Center of the Muhimbili National Hospital in Dar es Salaam, Tanzania. Patients ≥18 years of age with HF defined by the Framingham criteria.. All-cause mortality.. Among 427 included patients, 217 (51%) were females and the mean (SD) age was 55 (17) years. HF aetiologies included hypertension (45%), cardiomyopathy (28%), rheumatic heart disease (RHD) (12%) and ischaemic heart disease (9%). Concurrent atrial fibrillation (AF), clinically significant anaemia, diabetes, tuberculosis and HIV were found in 16%, 12%, 12%, 3% and 2%, respectively, while warfarin was used in 3% of the patients. The mortality rate, 22.4 per 100 person-years over a median follow-up of 7 months, was independently associated with AF, HR 3.4 (95% CI 1.6 to 7.0); in-patient 3.2 (1.5 to 6.8); anaemia 2.3 (1.2 to 4.5); pulmonary hypertension 2.1 (1.1 to 4.2) creatinine clearance 0.98 (0.97 to 1.00) and lack of education 2.3 (1.3 to 4.2).. In HF in Tanzania, patients are younger than in the developed world, but aetiologies are becoming more similar, with hypertension becoming more and RHD less important. Predictors of mortality possible to intervene against are anaemia, AF and lack of education.

Topics: Anemia; Atrial Fibrillation; Comorbidity; Diabetes Mellitus; Educational Status; Female; Heart Failure; HIV Infections; Humans; Kidney Function Tests; Male; Middle Aged; Mortality; Prognosis; Prospective Studies; Tanzania; Tertiary Care Centers; Tuberculosis; Warfarin

Warfarin, a frequently prescribed anticoagulant with a narrow therapeutic index, is susceptible to drug-drug interactions with antiretroviral therapy (ART). This study compared the warfarin maintenance dose (WMD) between patients receiving and not receiving ART and evaluated predictors of warfarin dosage among those on ART.. This was a case-control (1:2) study. Cases were HIV-infected patients receiving warfarin and protease inhibitor (PI)- and/or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Controls were randomly selected HIV-uninfected patients receiving warfarin. The WMD was compared between cases and controls and between cases on varying ART regimens. Bivariate comparisons were performed and a linear regression model was developed to identify predictors of WMD.. We identified 18 case and 36 control patients eligible for inclusion. Cases were younger than controls (mean age: 45.8 versus 63.1 years, P < 0.01), more often male (72.2% versus 36.1%, P=0.02) and more likely to be African American (50.0% versus 22.2%, P=0.04). ART was classified as PI-based (n=9), NNRTI-based (n=7) and PI + NNRTI-based (n=2). The WMD (mean ± SD) differed between cases and controls (8.6  ±  3.4 mg versus 5.1 ± 1.5 mg, P < 0.01), but not ART regimens (PI: 8.8  ±  4.5 mg; NNRTI: 8.6   ± 1.8 mg; PI + NNRTI: 7.3  ±  3.3 mg; P = 0.86). Race and ritonavir dose were independent predictors of WMD, predicting an increase of 3.9 mg (95% CI: 0.88-6.98, P = 0.02) if a patient was African American or 3.7 mg (95% CI: 0.53-6.89, P = 0.03) if the total daily ritonavir dose was 200 mg.. The required WMD was significantly higher in patients receiving ART. Prompt dose titration to achieve a higher WMD with vigilant monitoring may be required due to these drug-drug interactions.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Black People; Case-Control Studies; Drug Interactions; Female; HIV Infections; Humans; International Normalized Ratio; Linear Models; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Venous Thromboembolism; Warfarin; White People

Topics: Anti-HIV Agents; HIV Infections; Humans; Male; Pyrrolidinones; Warfarin

Venous thrombotic events (VTE) occur at high ratesin HIV/AIDS patients and are likely under-diagnosed in rural sub-Saharan Africa.. To describe clinical presentations and challenges in the management of VTE in patients with advanced HIV/AIDS.. Case series from patients enrolled in a prospective observational cohort study.. A clinical research centre in rural Kericho, Kenya.. Two hundred patients with median age 38 (30-47) years, BMI 16.9 (12.4-20.3) kg/m2, haemoglobin 9.3 (6.8-13.4) g/dL, CD4+ T-cell count 27 (4-77) cells/mm and plasma HIV RNA 5.23 (3.70-5.88) log10 copies/mL.. VTE cases were diagnosed by clinical presentation and Doppler/ radiographic confirmation. Anti-coagulation therapy was managed by a multidisciplinary team; patients were initiated on enoxaparin or heparin followed by warfarin.. Over two years,11patients (5.5%) experienced VTE. All but one (10/11,90.9%) case occurred within six months of starting ART. Nine patients had peripheral VTE (five popliteal, four femoral) and two had cerebral sinus thromboses. VTE was diagnosed 52 (1-469) days after ART initiation, and 81.8% of cases were outpatients at presentation. All patients received at least one concomitant medication that could significantly interact with warfarin (efavirenz, nevirapine, lopinavir/ritonavir, rifampicin, trimethoprim-sulfamethoxazole, and fluconazole). A median of 39 (10-180) days and eight (4-22) additional clinic visits were required to achieve/maintain a therapeutic INR of 2-3. Two minor bleeding complications occurred. No recurrent VTE cases were observed.. Consideration of VTE and preparedness for management in patients with advanced HIV/AIDS starting ART is critical in sub-Saharan Africa. Overcoming challenges in anti-coagulation is possible in rural settings using a multidisciplinary team approach.

Topics: Adult; Anticoagulants; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Disease Management; Drug Interactions; Drug Monitoring; Female; HIV Infections; Humans; International Normalized Ratio; Kenya; Male; Middle Aged; Patient Acuity; Patient Care Team; Rural Population; Ultrasonography, Doppler, Duplex; Venous Thrombosis; Warfarin

To report a probable drug interaction between the antiretroviral TRIO regimen (ritonavir-boosted darunavir, etravirine, and raltegravir) and warfarin in an HIV-infected patient.. In January 2010, a 50-year-old transgender female with HIV infection and recurrent deep vein thrombosis began treatment with the TRIO study regimen. Treatment had been maintained with warfarin for the past 5 years and emtricitabine monotherapy for the preceding 22 months. Emtricitabine was discontinued when the TRIO regimen was started. The mean weekly warfarin dose while the patient was receiving emtricitabine monotherapy was 13.3 mg (95% CI 12.7 to 13.8), with a mean international normalized ratio (INR) of 2.8 (95% CI 2.5 to 3.1). Following the initiation of the TRIO regimen, the mean weekly warfarin dose was increased to 19.3 mg (95% CI 18.5 to 20.1) and was maintained over the ensuing 71 weeks with a mean INR of 2.6 (95% CI 2.2 to 3.0).. Information on the effect of newer antiretrovirals on warfarin metabolism, as well as the collective contribution of combination antiretroviral therapy including multiple agents that may alter warfarin metabolism, is limited. We predicted that warfarin dose requirements would change upon initiation of the TRIO regimen. Given the variability in INR that can occur with chronic warfarin treatment, weekly warfarin doses were averaged during emtricitabine monotherapy (90 weeks) and TRIO regimen (71 weeks) periods. Mean weekly warfarin doses increased by 45% (p < 0.001) following initiation of the TRIO regimen. Mean INR results for the 2 time periods were not significantly different, demonstrating that stable anticoagulation was maintained. The Horn drug interaction probability scale score to assess causation indicated a probable interaction.. An increased weekly warfarin dose requirement is predicted when warfarin is used concurrently with the antiretroviral TRIO regimen. Increased INR monitoring is prudent when the combination is administered.

Topics: Anticoagulants; Darunavir; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; International Normalized Ratio; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Sulfonamides; Venous Thrombosis; Warfarin

Drug co-administration often affects the patient response to warfarin through various mechanisms. We describe here five HIV-1-infected patients on treatment with warfarin in whom the use of raltegravir was associated with a favourable outcome.

Topics: Anti-HIV Agents; Anticoagulants; Drug Interactions; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Warfarin

At the turn of the century, only 300 cases of warfarin-induced skin necrosis (WISN) had been reported. WISN is a rare but potentially fatal complication of warfarin therapy. There are no published reports of WISN occurring in patients with HIV-1 infection or tuberculosis (TB).. We retrospectively reviewed cases of WISN presenting from April 2005 to July 2008 at a referral hospital in Cape Town, South Africa.. Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%). All 6 cases occurred in HIV-1-infected women (median age 30 years, range 27 - 42) with microbiologically confirmed TB and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis 49 cells/microl, interquartile range 23 - 170). Of the 3 patients receiving combination antiretroviral therapy, 2 had TB-IRIS (immune reconstitution inflammatory syndrome). The median interval from initiation of antituberculosis treatment to venous thrombosis was 37 days (range 0 - 150). The median duration of parallel heparin and warfarin therapy was 2 days (range 1 - 6). WISN manifested 6 days (range 4 - 8) after initiation of warfarin therapy. The international normalised ratio (INR) at WISN onset was supra-therapeutic, median 6.2 (range 3.8 - 6.6). Sites of WISN included breasts, buttocks and thighs. Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 days after WISN onset. In 4 patients, the median interval from WISN onset to death was 43 days (range 25 - 45). One of the 2 patients who survived underwent bilateral mastectomies and extensive skin grafting at a specialist centre.. This is one of the largest case series of WISN. We report a novel clinical entity: WISN in HIV-1 infected patients with TB and venous thrombosis. The occurrence of 6 WISN cases in a 40-month period may be attributed to (i) hypercoagulability, secondary to HIV-1 and TB: (ii) short concurrent heparin and warfarin therapy; and (iii) high loading doses of warfarin. Active prevention and appropriate management of WISN are likely to improve the dire morbidity and mortality of this unusual condition.

Topics: Adult; Anticoagulants; Comorbidity; Female; HIV Infections; Humans; Necrosis; Retrospective Studies; Skin; Tuberculosis; Tuberculosis, Pulmonary; Venous Thrombosis; Warfarin

Topics: Adult; Anti-HIV Agents; Anticoagulants; Atrial Fibrillation; Carbamates; Drug Interactions; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Japan; Male; Middle Aged; Organophosphates; Sulfonamides; Treatment Outcome; Warfarin

Nervous system infections by Cryptococcus neoformans may occur not only in congenital or acquired immunodeficiency syndromes, but also in immunocompetent hosts. Neurological manifestations of C. neoformans infection include meningitis and, less commonly, parenchymal CNS granulomatous disease. This paper provides detailed clinical descriptions of highly unusual neurological manifestations of cryptococcal nervous system infections. Medical records and diagnostic data including magnetic resonance imaging, histopathology, serology, and CSF analysis were reviewed. A conus medullaris abscess was found in a patient infected with the human immunodeficiency virus (HIV). A patient with Hodgkin's disease was diagnosed with cryptococcal meningitis and dermatitis mimicking ophthalmic zoster. An immunocompetent patient presented with recurrent cerebral infarctions in the setting of cryptococcal meningitis. Cryptococcal infections of the nervous system can cause severe neurological disability when diagnosis is delayed. Sensitive and specific tests are readily available and should be considered when an unusual clinical presentation is encountered.

Topics: Abscess; Adult; Aged; Amphotericin B; Anticoagulants; Antifungal Agents; Brain; Central Nervous System Fungal Infections; Cryptococcosis; Cryptococcus neoformans; HIV Infections; Hodgkin Disease; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Spinal Diseases; Tomography, X-Ray Computed; Warfarin

The coexistence of human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE) is being increasingly reported and, because of the immunological disturbances demonstrated in HIV-infected patients, diagnostic and therapeutic difficulties may arise when the 2 conditions coexist. Antiphospholipid antibodies are demonstrable in patients with both conditions, but clinical manifestations of the antiphospholipid syndrome (APS) in HIV-infected patients, although reported, are uncommon.. We describe a patient with HIV infection and SLE who manifested 4 episodes of deep vein thrombosis (DVT) complicated by pulmonary embolism. Enzyme-linked immunosorbant assay was used to test for the presence of antiphospholipid antibodies, including anticardiolipin antibodies, anti- beta 2-glycoprotein 1 antibodies, and antiprothrombin antibodies (anti-PT). Additionally, we performed a computer-assisted search of the literature (via the Medline database) to identify all reported cases of HIV infection plus SLE.. We document the case of 35-year-old African woman with HIV infection and SLE who developed recurrent episodes of DVT and pulmonary embolism in the presence of anti-PT and discuss in depth the pathogenic role of these antibodies and the clinical challenges posed to clinicians by the coexistence of HIV and SLE in the same patient.. Immunological reconstitution in HIV-infected patients contributes to the appearance of multiple autoimmune conditions, including SLE and APS. The recognition of the coexistence of these autoimmune disorders in HIV-infected patients has important implications in the treatment of and prognosis for these individuals.

Topics: Adrenal Cortex Hormones; Adult; Anti-HIV Agents; Antibodies; Anticoagulants; Female; HIV Infections; Humans; Lupus Erythematosus, Systemic; Prothrombin; Pulmonary Embolism; Venous Thrombosis; Warfarin

The present study describes a case of pulmonary arterial hypertension (PAH) associated with multicentric Castleman's disease in a patient infected with HIV type 1 and human herpes virus 8. Therapy included highly active antiretroviral therapy, warfarin, diuretics, continuous i.v. epoprostenol and 12-monthly pulses of cyclophosphamide. The patient's condition improved dramatically with complete reversibility of PAH, allowing weaning of continuous i.v. epoprostenol therapy. After 5 yrs, both Castleman's disease and PAH have not relapsed. This supports the hypothesis that control of inflammation and retroviral replication may be of interest in the context of PAH, complicating the course of an inflammatory condition associated with viral infection. In conclusion, further studies should help in characterising the best candidates for anti-inflammatory treatment in the setting of pulmonary arterial hypertension.

Topics: Adult; Anti-Retroviral Agents; Castleman Disease; Cyclophosphamide; Diuretics; Epoprostenol; Female; HIV Infections; HIV-1; Humans; Hypertension, Pulmonary; Treatment Outcome; Warfarin

Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH.. Several significant findings were revealed when examining the possible role of CD40L in PAH. (1) Patients with primary (n=13) and secondary (n=11) PAH but not those with chronic thromboembolic pulmonary hypertension (n=8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n=8). (2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels were higher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6) Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells.. Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.

Topics: Aged; Anticoagulants; Blood Platelets; CD40 Ligand; Cells, Cultured; Chemokine CCL2; Collagen Diseases; Endothelial Cells; Endothelium, Vascular; Epoprostenol; Female; Femoral Artery; Gene Expression Regulation; Heart Defects, Congenital; HIV Infections; Humans; Hypertension, Pulmonary; Interleukin-8; Liver Cirrhosis; Male; Middle Aged; Peptide Fragments; Pulmonary Artery; Recombinant Proteins; Solubility; Thromboembolism; Umbilical Veins; Warfarin

Recent reports suggest that patients infected with human immunodeficiency virus (HIV) may have an increased risk of developing thrombosis, but the etiology, risk factors, and clinical course remain largely undefined, with few descriptive case series.. We identified 30 patients from an HIV outpatient clinic (treatment population, 650 persons) who had had a total of 43 venous or arterial thromboses during 1996-2002. Data pertaining to demographic characteristics, medical history, thrombosis presentation, and clinical outcomes were abstracted from patient medical records.. The median patient age at the time of thrombosis was 43 years. Although the presence of persistent antibody to phospholipids was the most common abnormal finding in the laboratory, evaluation of thrombophilia, cases of low levels of proteins C and S and antithrombin III, and elevated levels of factor VIII and homocysteine were also identified. Seventy-seven percent of the patients smoked cigarettes, 57% had dyslipidemia, and 43% had a malignancy (most commonly Kaposi sarcoma). Although the Centers for Disease Control and Prevention (CDC) classification for 16 patients (53%) was C3, most showed evidence of immune reconstitution (median CD4 cell count, 290 cells/ mu L) and control of the virus (median HIV load, 2290 copies/mL). Lower extremity, deep vein thrombosis and pulmonary emboli accounted for 66% of all thrombotic events. The median time to diagnosis of thrombosis was 1 day (range, 3 h to 3 weeks).. Patients in this series were characterized by a relatively young age at the time of thrombosis, a predominance of elevated levels of lipids, a history of malignancy, and an advanced CDC HIV classification but not by a low CD4 cell count or an elevated HIV load.

Topics: Adult; Aged; Anti-HIV Agents; Anticoagulants; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Heparin, Low-Molecular-Weight; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Thromboembolism; Viral Load; Warfarin

Topics: Adult; Anti-HIV Agents; Anticoagulants; Dose-Response Relationship, Drug; HIV Infections; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Warfarin

Topics: Anti-HIV Agents; Anticoagulants; Drug Antagonism; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Ritonavir; Warfarin

To report an unexpected decrease in warfarin effect following the addition of ritonavir to the medication regimen.. A 27-year-old patient with advanced HIV taking warfarin for an inferior vena cava thrombus was started on ritonavir, clarithromycin, and zidovudine. The international normalized ratio (INR) decreased over a period of weeks after the addition of ritonavir, clarithromycin, and zidovudine to the drug therapy regimen. The warfarin dosage was almost doubled in order to maintain a therapeutic INR. Months later, when ritonavir alone was discontinued, the INR rose rapidly and the warfarin dose requirements decreased significantly.. Potential interactions between warfarin and the protease inhibitors are described in the literature. Ritonavir has been shown to be a potent inhibitor of CYP3A4, an enzyme responsible for warfarin metabolism. Potentiation of warfarin effect and subsequent decrease in the warfarin dosage requirement was anticipated following ritonavir administration; however, the opposite occurred. The mechanism of the potential interaction between warfarin and ritonavir is not known, and may represent a complex, multidrug interaction. The paradoxical decrease in the INR is particularly intriguing.. Frequent, careful monitoring of warfarin is recommended when ritonavir therapy is initiated or discontinued in a patient taking warfarin. The potential for either an increase or decrease in the INR should be anticipated.

Topics: Adult; Anti-HIV Agents; Anticoagulants; Cytochrome P-450 Enzyme System; Drug Interactions; Female; HIV Infections; Humans; International Normalized Ratio; Ritonavir; Vena Cava, Inferior; Venous Thrombosis; Warfarin

Protease inhibitors block HIV by binding with its protease enzyme and it is hoped that they will be more potent and less toxic than nucleoside analogs. The companies Hoffmann-La Roche, Merck, Abbott, Searle, Agouron, Kyoto and Upjohn all have tested protease inhibitors in human trials. The drugs include L-524, ABT-538, AG- 1343, saquinavir, SC-52151, and SC-55389a. The protease inhibitors from Merck, Roche, and Abbott have shown higher anti-viral activity than any previous anti-HIV drug. Vertex, Burroughs Wellcome, and Kissei have conducted animal studies of VX-478, which shows promise in inhibiting the virus, with no toxicity. Other companies developing protease inhibitors include DuPont-Merck, Ciba-Geigy, Hoechst-Bayer, Nippon Mining, Parke-Davis, and Smith-Kline Beecham. Companies increasingly are combining protease inhibitors with nucleoside analogs, mainly AZT, in their large-scale efficacy studies in an effort to produce a strong and sustained anti-HIV effect. Potential cross-resistance to many of these compounds remains a major research issue. It is likely that at least one of the three leading companies in the field -- Merck, Abbott, or Roche -- will file for Food and Drug Administration approval in 1995. The National Drug Development Task Force is expected to announce the creation of a new task force on protease inhibitors.

Topics: Animals; Blood Proteins; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Industry; Drug Resistance; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Isoquinolines; Oligopeptides; Protein Binding; Pyrones; Quinolines; Rats; Saquinavir; Technology, Pharmaceutical; Urea; Warfarin; Zidovudine