ABSTRACT
BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials. OBJECTIVE: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents. DESIGN: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394). SETTING: Outpatient HIV clinics. PARTICIPANTS: Treatment-experienced patients with HIV infection and viral resistance. INTERVENTION: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs. MEASUREMENTS: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment. RESULTS: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group. LIMITATION: Unblinded study design, and the study may not be applicable to resource-poor settings. CONCLUSION: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PRIMARY FUNDING SOURCES: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/therapeutic use , Adult , Anti-HIV Agents/adverse effects , CD4 Lymphocyte Count , Drug Resistance, Viral , Drug Therapy, Combination , Female , HIV/genetics , Humans , Male , Middle Aged , RNA, Viral/blood , Reverse Transcriptase Inhibitors/adverse effectsABSTRACT
BACKGROUND: The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear. METHODS: A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests. RESULTS: Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/µL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03). CONCLUSIONS: ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels. CLINICAL TRIALS REGISTRATION: NCT00118898.
Subject(s)
Adipose Tissue/drug effects , Anti-HIV Agents/therapeutic use , DNA, Mitochondrial/drug effects , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/therapeutic use , Adenine/administration & dosage , Adenine/analogs & derivatives , Adenine/therapeutic use , Adipose Tissue/metabolism , Adult , Alkynes , Anti-HIV Agents/administration & dosage , Atazanavir Sulfate , Benzoxazines/administration & dosage , Benzoxazines/therapeutic use , Cyclopropanes , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Dideoxynucleosides/administration & dosage , Dideoxynucleosides/therapeutic use , Drug Combinations , Drug Therapy, Combination , Emtricitabine , Female , HIV-1 , HIV-Associated Lipodystrophy Syndrome/physiopathology , Humans , Lamivudine/administration & dosage , Lamivudine/therapeutic use , Male , Mitochondria/drug effects , Oligopeptides/administration & dosage , Oligopeptides/therapeutic use , Organophosphonates/administration & dosage , Organophosphonates/therapeutic use , Pyridines/administration & dosage , Pyridines/therapeutic use , Reverse Transcriptase Inhibitors/administration & dosage , Ritonavir/administration & dosage , Ritonavir/therapeutic use , Tenofovir , Treatment OutcomeABSTRACT
Low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected subjects. Initiation of antiretroviral therapy is associated with a 2%-6% decrease in BMD over the first 2 years, a decrease that is similar in magnitude to that sustained during the first 2 years of menopause. Recent studies have also described increased fracture rates in the HIV-infected population. The causes of low BMD in individuals with HIV infection appear to be multifactorial and likely represent a complex interaction between HIV infection, traditional osteoporosis risk factors, and antiretroviral-related factors. In this review, we make the point that HIV infection should be considered as a risk factor for bone disease. We recommend screening patients with fragility fractures, all HIV-infected post-menopausal women, and all HIV-infected men ⩾50 years of age. We also discuss the importance of considering secondary causes of osteoporosis. Finally, we discuss treatment of the more severe cases of bone disease, while outlining the caveats and gaps in our knowledge.
Subject(s)
Anti-HIV Agents/adverse effects , Bone Diseases/chemically induced , Bone Diseases/epidemiology , HIV Infections/complications , HIV Infections/drug therapy , Aged , Aged, 80 and over , Anti-HIV Agents/therapeutic use , Bone Density/drug effects , Bone Density/physiology , Female , Fractures, Bone/epidemiology , Humans , Incidence , Male , Middle Aged , Risk AssessmentABSTRACT
During an island-wide PCR-based surveillance study of beta-lactam resistance in multidrug-resistant (MDR) Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter calcoaceticus-baumannii complex isolates obtained from 17 different hospitals, 10 KPC-positive Acinetobacter isolates were identified. DNA sequencing of the bla(KPC) gene identified KPC-2, -3, and -4 and a novel variant, KPC-10. This is the first report of a KPC-type beta-lactamase identified in Acinetobacter species.
Subject(s)
Acinetobacter Infections/epidemiology , Acinetobacter/classification , Acinetobacter/drug effects , beta-Lactam Resistance/genetics , beta-Lactamases/genetics , Acinetobacter/enzymology , Acinetobacter/isolation & purification , Acinetobacter Infections/microbiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Population Surveillance/methods , Puerto Rico/epidemiologyABSTRACT
Antiretroviral (ARV) treatment decisions are difficult for HIV-1-infected patients on complex treatment regimens who have partial suppression of HIV-1 replication and limited treatment options. Information on the ARV activity of the components of a complex regimen would be useful. Sixteen subjects who had received prolonged therapy with zidovudine (ZDV) and lamivudine (3TC), with a median duration of 32.5 months, were discontinuing this dual-nucleoside regimen and volunteered to have plasma HIV-1 RNA levels monitored over the 2 weeks after discontinuation. All subjects experienced an increase in HIV-1 RNA after discontinuation, with a median increase of 0.54 log10 copies/mL over 2 weeks (range: 0.31-1.71; P < 0.001). An inverse correlation existed between the decline in HIV-1 RNA levels over 2 to 3 years on nucleoside analogue therapy and the increase over the 10 to 14 days off therapy (Spearman r = -0.53; P = 0.036). Over the 2-week period, a subset of individuals who had genotype testing at multiple reverse transcriptase codons associated with ZDV and 3TC resistance had no changes in genotype off therapy. Nucleoside analogue reverse transcriptase inhibitors may have continued ARV activity despite long durations of partially suppressive therapy and the presence of resistant HIV-1.
Subject(s)
Anti-HIV Agents/administration & dosage , Lamivudine/administration & dosage , Reverse Transcriptase Inhibitors/administration & dosage , Zidovudine/administration & dosage , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Drug Administration Schedule , Drug Resistance, Viral , Drug Therapy, Combination , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/drug effects , Humans , Lamivudine/pharmacology , Lamivudine/therapeutic use , RNA, Viral/blood , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/therapeutic use , Time Factors , Treatment Outcome , Zidovudine/pharmacology , Zidovudine/therapeutic useABSTRACT
The natural history of HIV infection has been dramatically changed by the highly active antiretroviral therapies, reducing complications, morbidity and mortality of the disease. Approximately 25% of persons infected with HIV are co-infected with hepatitis C, and some high risk populations have a prevalence of HCV of more than 75%. Liver disease has become one of the principal causes of morbidity and mortality in this population. Co-infection increases viremia of hepatitis C, with increase in fibrosis progression, cirrhosis and death related to hepatitis C. The permanent state of chronic immune activation related to the persistent hepatitis C virus favors transcription of HIV in infected cells and causes a more rapid destruction of T4 and absolute lymphocytes. In addition, the immunologic response after the start of highly active antiretroviral therapy for HIV is less than in mono-infected patients. The role of liver biopsy in the management of co-infected patients is controversial. Many of these patients, even with normal transaminases, show fibrosis in liver biopsy. Predictive factors for advanced fibrosis include male sex, alcohol consumption in excess of 50 grams per day, age over 35, and HIV infection of more than 15 years with CD4 lymphocytes less than 400/ mm3. The treatment of hepatitis C is limited and sustained viral response is less than 30% for genotypes 1 and 4. This response is even less in the more advanced stages of HIV and hepatitis C. The determination of when to start treatment and the increased toxicity when combining pegylated interferon plus ribavirin and antiretroviral medications makes the management of these patients more difficult. The development of more potent, safe and tolerated medications is required. Management strategies for patients unresponsive to conventional therapy are geared towards improving liver histology and delaying progression to cirrhosis, hepatocellular cancer and liver transplantation.
Subject(s)
HIV Infections/complications , HIV Infections/therapy , Hepatitis C/complications , Hepatitis C/therapy , Biopsy , Hepatitis C/pathology , HumansSubject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Adenine/analogs & derivatives , HIV-1 , Organophosphonates , Reverse Transcriptase Inhibitors/administration & dosage , Acquired Immunodeficiency Syndrome/virology , Adenine/administration & dosage , Adult , Alkynes , Benzoxazines , Cyclopropanes , Dideoxynucleosides/administration & dosage , Double-Blind Method , Drug Therapy, Combination , Female , Follow-Up Studies , Genotype , HIV-1/drug effects , HIV-1/genetics , Humans , Indinavir/therapeutic use , Male , Nelfinavir/administration & dosage , Oxazines/administration & dosage , Phenotype , Reverse Transcriptase Inhibitors/adverse effects , Treatment FailureABSTRACT
PURPOSE: To compare the efficacy (sustained virologic suppression) and safety/tolerability of a switch to lamivudine 300 mg once daily (QD) versus continued lamivudine 150 mg twice daily (BID) in virologically suppressed patients (HIV-1 RNA <400 copies/mL for > or =3 months) on stable (> or =6 months) therapy with lamivudine 150 mg BID plus stavudine and either indinavir or nelfinavir. METHOD: Eighty-nine suppressed patients > or =18 years old with CD4 counts >50 cells/mm(3) were enrolled in this phase II, open-label, multicenter, randomized, stratified (by pretrial protease inhibitor [PI]), parallel-group clinical trial. Eighty-one patients received either lamivudine 300 mg QD (n = 39) or 150 mg BID (n = 42) with their pretrial stavudine/PI regimens for 24 weeks. RESULTS: A high rate of virologic suppression was sustained with both regimens throughout the trial. At week 24, intent-to-treat:exposed (missing = failure) analyses showed no statistically significant differences in the percentage of patients with HIV-1 RNA <400 copies/mL (95% [QD] vs. 90% [BID]) or <50 copies/mL (82% [QD] vs. 81% [BID]) or in the median change from baseline in CD4 counts (+42 cells/mm(3) [QD] vs. +22 cells/mm(3) [BID]). Both regimens were well tolerated. No patient experienced virologic failure, clinical disease progression, or a drug-related serious adverse event during the trial. Self-reported medication adherence was high in both groups. CONCLUSION: Patients who experience virologic suppression with a regimen of lamivudine 150 mg BID in combination with stavudine/PI can maintain that suppression by continuing their regimen or switching to lamivudine 300 mg QD and continuing the other components. Adverse event profiles were comparable among treatment regimens, and no new safety concerns were raised.
Subject(s)
Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Lamivudine/administration & dosage , Lamivudine/therapeutic use , Stavudine/therapeutic use , Adult , Aged , Anti-HIV Agents/adverse effects , CD4 Lymphocyte Count , Drug Administration Schedule , Drug Therapy, Combination , Female , HIV Infections/virology , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , HIV-1/genetics , HIV-1/isolation & purification , Humans , Indinavir/administration & dosage , Indinavir/adverse effects , Indinavir/therapeutic use , Lamivudine/adverse effects , Male , Middle Aged , Nelfinavir/administration & dosage , Nelfinavir/adverse effects , Nelfinavir/therapeutic use , Patient Compliance , RNA, Viral/analysis , Stavudine/administration & dosage , Stavudine/adverse effectsABSTRACT
El dengue, como entidad clínica, se ha reconocido por más de 200 años y se ha asociado con el desarrollo de desórdenes neurológicos. La distribución geográfica se ha reportado a través de todo el mundo. Las complicaciones neurológicas no pertenecen a una población en específico y se han reportado anteriormente en especial asociadas al espectro clínico de la infección aguda. El dengue se puede presentar clínicamente como una encefalitis viral. Se desconoce en realidad si los signos y síntomas son el resultado de la encefalitis o si existe otro mecanismo patológico. Los cambios patológicos son diversos y varían desde edema cerebral hasta hemorragias focales. Este trabajo presenta la distribución demográfica, manifestaciones clínicas y los serotipos asociados a la infección
Subject(s)
Dengue/complications , Nervous System Diseases/etiology , Encephalitis/etiology , Dengue Virus , Dengue/epidemiology , SerotypingABSTRACT
El síndrome de inmunodeficiencia adquirida (SIDA) es una infección que de alguna forma u otra envuelve todas las áreas de la práctica médica. La condición afecta a ambos sexos en poblaciones selectas. En Puerto Rico se estima que un 2% en poblaciones definidas de mujeres embarazadas está infectada. El manejo de este tipo de paciente es importante por las implicaciones epidemiológicas que representa. El trabajo presenta una serie de guías para el manejo de este tipo de paciente desde la etapa pre-parto hasta el período post-parto. Estas guías no son substituto para las precauciones universales