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Infectious diseases (ID) physicians play a crucial role in public health in a variety of settings. Unfortunately, much of this work is undercompensated despite the proven efficacy of public health interventions such as hospital acquired infection prevention, antimicrobial stewardship, disease surveillance, and outbreak response. The lack of compensation makes it difficult to attract the best and the brightest to the field of ID, threatening the future of the ID workforce. Here, we examine compensation data for ID physicians compared to their value in population and public health settings and suggest policy recommendations to address the pay disparities that exist between cognitive and procedural specialties that prevent more medical students and residents from entering the field. All ID physicians should take an active role in promoting the value of the subspecialty to policymakers and influencers as well as trainees.
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Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/terapia , Gerenciamento Clínico , Controle de Infecções/organização & administração , Médicos , Salários e Benefícios/estatística & dados numéricos , Especialização , HumanosRESUMO
BACKGROUND: Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS: We searched databases to identify randomized trials that compared NNRTI- vs PI/r-based initial therapy. A metaanalysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were death, progression to AIDS, and treatment discontinuation. We calculated RR of virologic suppression and MD for an increase in CD4 cells at week 48. RESULTS: We included 29 trials with 9047 participants. Death or progression to AIDS occurred in 226 participants in the NNRTI arm and in 221 in the PI/r arm (RR, 1.03; 95% confidence interval, .87-1.22; 12 trials; n = 3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04; 0.86-1.25; 22 trials; n = 8311), and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00; 0.80-1.25; 13 trials; n = 4740). Overall treatment discontinuation (1.12; 0.93-1.35; 24 trials; n = 8249) and from toxicity (1.21; 0.87-1.68; 21 trials; n = 6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58; 0.91-2.74; 17 trials; n = 5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR, 1.03; 0.98-1.09) or CD4(+) recovery (MD, -4.7 cells; -14.2 to 4.8). CONCLUSIONS: We found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Quimioterapia Combinada , HumanosRESUMO
Climate change is a phenomenon that has had, and will continue to have, wide-ranging effects on the world in both the near and distant future. With regards to human health, research has demonstrated the impact of climate change on heat-related illness, mental health, and vector-borne infectious diseases. Through a review of the literature, this paper aims to elucidate both current and future consequences of climate change on cellulitis, a type of skin infection that is associated with significant morbidity, mortality, and cost. Factors such as elevated temperature, pollution, rising sea levels, and the increased frequency of natural disasters pose an alarming risk for the increased proliferation of infections such as cellulitis. Lastly, in light of these trends, this paper will address potential strategies individuals can implement to reduce the effects of climate change on cellulitis.
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Combination antiretroviral therapy (cART) has markedly increased life expectancy in people with HIV (PWH) but has also resulted in an increased prevalence of cardiometabolic disorders, whose etiopathology remains ill-defined. Notably, the respective contribution of cART and HIV-derived proteins to obesity and vascular alterations remain poorly understood. Therefore, we investigated the individual and combined effects of HIV-proteins and of the integrase strand transfer inhibitor Dolutegravir (DTG) on body composition and vascular reactivity. Male wildtype (WT) and HIV transgenic (Tg26) mice, received DTG or vehicle for 12 weeks. Viral proteins expression in Tg26 mice lowered fat mass, increased heat production, and induced a 2-fold increase in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression. DTG increased the expression of markers of adipogenesis in adipocytes in culture, but also reduced heat production and BAT UCP1 and UCP3 expression in Tg26 mice. DTG increased food intake, fat percentage and protected from lean mass reduction in Tg26 mice only. However, DTG did not increase body weight in either WT or Tg26 mice. Viral protein expression reduced acetylcholine (endothelium)-mediated relaxation by 14% in mesenteric arteries preconstricted with phenylephrine. However, DTG did not impair nor improve endothelium-dependent relaxation. Together, these data indicate that DTG's effects on food intake, adipogenesis and energy expenditure are insufficient to increase body weight, even in the presence of HIV-proteins, suggesting that body weight gain in PWH involves additional factors likely including other cART components and pre-existing comorbidities. Moreover, these data rule out DTG as a source of vascular disorders in PWH.
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Modelos Animais de Doenças , Metabolismo Energético , Infecções por HIV , Inibidores de Integrase de HIV , Compostos Heterocíclicos com 3 Anéis , Camundongos Transgênicos , Oxazinas , Piperazinas , Piridonas , Animais , Metabolismo Energético/efeitos dos fármacos , Masculino , Piperazinas/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Oxazinas/farmacologia , Piridonas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inibidores de Integrase de HIV/farmacologia , Camundongos , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Vasodilatação/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/virologia , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options. OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo. CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.
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Canais de Cloreto/antagonistas & inibidores , Diarreia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infecções por HIV/complicações , Proantocianidinas/uso terapêutico , Adulto , Diarreia/etiologia , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Proantocianidinas/efeitos adversosRESUMO
Diarrhea remains a common problem for patients with human immunodeficiency virus (HIV) infection despite highly active antiretroviral therapies (HAART) and can negatively affect patient quality of life and lead to discontinuation or switching of HAART regimens. In the era of HAART, diarrhea from opportunistic infections is uncommon, and HIV-associated diarrhea often has noninfectious causes, including HAART-related adverse events and HIV enteropathy. Diarrhea associated with HAART is typically caused by protease inhibitors (eg, ritonavir), which may damage the intestinal epithelial barrier (leaky-flux diarrhea) and/or alter chloride ion secretion (secretory diarrhea). HIV enteropathy may result from direct effects of HIV on gastrointestinal tract cells and on the gastrointestinal immune system and gut-associated lymphoid tissue, which may be active sites of HIV infection and ongoing inflammation and mucosal damage. New therapies targeting the pathogenic mechanisms of noninfectious diarrheas are needed.
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Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Diarreia/induzido quimicamente , Diarreia/terapia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , HIV/patogenicidade , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , HumanosRESUMO
BACKGROUND: Limited data are available regarding asymptomatic COVID-19 among people with HIV (PWH). Data on a representative subset of PWH enrolled in Randomized Trial to Prevent Vascular Events in HIV, a global clinical trial, are presented here. METHODS: Randomized Trial to Prevent Vascular Events in HIV is an atherosclerotic cardiovascular disease prevention trial among 7770 PWH on antiretroviral therapy. Beginning April 2020, targeted data on coronavirus disease 2019 (COVID-19) diagnosis and symptoms were collected during routine trial visits. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was defined as either COVID-19 clinical diagnosis or presence of SARS-CoV-2 Immunoglobulin G (IgG) or Immunoglobulin A (IgA) receptor binding domain protein (antispike) antibodies in the absence of prior COVID-19 vaccine. RESULTS: The group (N = 2464) had a median age 53 years, 35% female sex, 47% Black or African American race, median CD4 count 649 c/mm 3 , and 97% with HIV VL <400 cp/m. SARS-CoV-2 infection occurred in 318 persons (13%): 58 with clinical diagnosis and 260 with detectable antibodies. Of these PWH, 304 completed symptom questionnaires: 121 (40%) reported symptoms, but 183 (60%) were asymptomatic. PWH with asymptomatic SARS-CoV-2 infection were more likely to be from low-income or middle-income regions, of Black or African American race, older in age, and with higher atherosclerotic cardiovascular disease risk score. Symptomatic COVID was more common with obesity, metabolic syndrome, and low HDL levels. CD4 counts and HIV viral suppression rates were similar among PWH with symptomatic vs. asymptomatic COVID. CONCLUSIONS: Asymptomatic SARS-CoV-2 infection is common among antiretroviral therapy-treated PWH globally. We determined that 60% of infections in PWH were asymptomatic. HIV clinicians must remain vigilant about COVID-19 testing among PWH to identify asymptomatic cases.
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COVID-19 , Doenças Cardiovasculares , Infecções por HIV , COVID-19/complicações , Teste para COVID-19 , Vacinas contra COVID-19 , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2RESUMO
PURPOSE: This study assessed ethnicity and gender differences in prevalence, type, and severity of antiretroviral-associated lipodystrophy in HIV-positive individuals in Ontario. METHODS: This was a cross-sectional analysis of the Ontario Cohort Study (OCS), a prospective study of HIV-positive patients in Ontario. Lipodystrophy was defined as at least 1 major or 2 minor self-reported changes of peripheral lipoatrophy and/or central lipohypertrophy. Prevalence, type, and severity were compared by ethnicity (Black, White, or Other) and gender. Univariate and multivariate logistic regression analyses identified predictors of lipodystrophy. RESULTS: Data were available for 778 participants (659 men, 119 women). There were 517 Whites, 121 Blacks, and 140 patients of Other ethnicities. In univariate analyses, Whites reported more peripheral lipoatrophy (P = .004) and abdominal lipohypertrophy (P = .04); these ethnic differences were observed in males (P = .05 and P = .03, respectively) but not females. Males reported more peripheral lipoatrophy (P = .01), whereas females had more central lipohypertrophy (P < .0001) and mixed fat redistribution (P < .0001). Multivariable regression analyses revealed Black women to be most vulnerable to lipodystrophy (P = .02), particularly lipohypertrophy (P < .0001). CONCLUSIONS: Ethnicity and gender are important factors influencing lipodystrophy. Combining lipoatrophy and lipohypertrophy into a single entity is not appropriate. Black women were most vulnerable to lipohypertrophy, which has important implications for antiretroviral therapy roll-out in Africa.
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Fármacos Anti-HIV/efeitos adversos , Soropositividade para HIV/tratamento farmacológico , Lipodistrofia/induzido quimicamente , Caracteres Sexuais , Adulto , População Negra , Canadá , Estudos Transversais , Feminino , Humanos , Lipodistrofia/etnologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , População BrancaRESUMO
The Medical College of Georgia (MCG) responded to the COVID-19 pandemic's challenges to medical education with a novel, comprehensive curriculum. The Pandemic Medicine Elective was an effective solution with a safe, virtual alternative to traditional clinical experiences. As the elective evolved to include pre-clinical students and service initiatives across Georgia, students and faculty navigated online platforms to execute critical community-based projects. This curricular development utilized an interdisciplinary approach by faculty across each of MCG's regional campuses. We describe the curriculum of the electives, the student initiatives, and lessons learned while quickly adapting curriculum during the COVID-19 pandemic.
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BACKGROUND After initial infection with HIV, loss of CD4+ T cells progresses along a predictable timeline. The clinical latency stage lasts an average of 10 years, until the CD4+ T cell count falls below 200 cells/uL or the patient develops an AIDS-defining opportunistic infection/cancer. This report describes an unusual opportunistic infection in a young patient with no prior clinical evidence of HIV infection. CASE REPORT An 18-year-old man presented with fever, abdominal pain, and dyspnea for the previous 2 weeks and was symptomatically treated for gastroenteritis. He presented 2 weeks later with extreme fatigue, and a CT scan revealed diffuse lymphadenopathy. He was transferred to a regional hospital, but upon arrival and prior to detailed investigative work-up, he developed cardiac arrest. Despite maximal resuscitative efforts, he died approximately 8 h after admission. At autopsy, diffuse lymphadenopathy, splenomegaly, and pulmonary congestion were noted. Disseminated cryptococcal infection involving almost every organ system was identified at autopsy. A postmortem HIV-1 antibody test was positive. The cause of death was severe immunodeficiency as a result of advanced HIV infection resulting in disseminated cryptococcal infection, with cerebral edema, herniation, and respiratory failure. CONCLUSIONS This patient's non-specific symptoms in conjunction with his rapid decline made arriving at a correct diagnosis challenging. Only during autopsy was the disseminated fungal infection discovered, leading to suspicion of HIV infection. HIV autopsies are not uncommon, but the clinical history is usually known beforehand. This case report highlights the importance of considering HIV-related conditions in patients presenting with this array of symptoms, as well as to alert healthcare providers and staff to the need for increased biosafety precautions.
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Criptococose , Infecções por HIV , Edema Pulmonar , Adolescente , Autopsia , Criptococose/complicações , Criptococose/diagnóstico , HIV , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , MasculinoRESUMO
Maraviroc is the first US Food and Drug Administration-approved drug from a new class of antiretroviral agents that targets a host protein, the chemokine receptor CCR5, rather than a viral target. Binding of maraviroc to this cell-surface protein results in blocking human immunodeficiency virus type 1 (HIV-1) attachment to the coreceptor and prevents the virus from entering CD4+ cells. In this review, we include the details of the discoveries that led to the development of this drug. The drug's pharmacology, including pharmacokinetics and drug interactions, is discussed, as are the clinical efficacy studies that led to licensure. HIV-1 mechanisms of resistance to maraviroc, assays to determine viral coreceptor use (tropism), drug safety, and clinical use of maraviroc are discussed at length.
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Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Cicloexanos/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Triazóis/farmacologia , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Bioensaio , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Ensaios Clínicos como Assunto , Cicloexanos/efeitos adversos , Cicloexanos/uso terapêutico , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Farmacorresistência Viral/fisiologia , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Maraviroc , Receptores CCR5/metabolismo , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Tropismo , Internalização do VírusRESUMO
Symptoms and quality of life were assessed among human immunodeficiency virus (HIV)-infected individuals initiating their first course of antiretroviral therapy. Symptoms, which were mostly mild or moderate, were common in the first year and significantly affected the patients' quality of life. Quality of life was inversely related to the number of symptoms and in the change in the number of symptoms from baseline.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , HIV-1 , Qualidade de Vida , Inibidores da Transcriptase Reversa , Adulto , Fármacos Anti-HIV/efeitos adversos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
PURPOSE: To compare long-term virologic, immunologic, and clinical outcomes in antiretroviral-naïve persons starting efavirenz (EFV)- versus nevirapine (NVP)-based regimens. METHOD: The FIRST study randomized patients into three strategy arms: PI+NRTI, NNRTI+NRTI, and PI+NNRTI+NRTI. NNRTI was determined by optional randomization (NVP or EFV) or by choice. For this randomized substudy, the primary endpoint was HIV RNA >50 copies/mL after 8 months or death. Genotypic resistance testing was done at virologic failure (VF; HIV RNA >1,000 copies/mL at or after 4 months). RESULTS: 228 persons (111 randomized to EFV, 117 to NVP) were followed for median 5 years. Rates per 100 person years for the primary endpoint were 41.2 (EFV) and 42.8 (NVP; p = .59). The percent of persons with HIV RNA <50 copies/mL was similar throughout follow-up (p = .24), as were average increases in CD4+ cells (p = .30). 423 persons declining the substudy chose EFV; 264 chose NVP. There were 915 persons in the combined cohort (randomized and choice). In the combined cohort, the risk of VF and VF with any NNRTI or NRTI resistance or resistance of any class was significantly less for EFV compared to NVP. CONCLUSIONS: EFV-based regimens as initial therapy resulted in a lower risk of VF and VF with resistance than did NVP-based regimens, although immunologic and clinical outcomes were similar.
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Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Nevirapina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Alcinos , Contagem de Linfócito CD4 , Estudos de Coortes , Ciclopropanos , Farmacorresistência Viral , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Carga ViralRESUMO
BACKGROUND: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. METHODS: Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922. FINDINGS: 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001). INTERPRETATION: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.
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Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Análise de Variância , Contagem de Linfócito CD4 , Esquema de Medicação , Feminino , Seguimentos , Infecções por HIV/sangue , Infecções por HIV/mortalidade , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Estados Unidos , Carga ViralRESUMO
BACKGROUND: Treatment-naïve participants were randomized to three antiretroviral strategies (all with nucleoside reverse transcriptase inhibitor [NRTI] background): protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or PI+NNRTI. The strategies were compared for drug resistance at first virologic failure (VF; HIV RNA >1000 copies/mL). The impact of resistance on AIDS or death was determined. METHOD: Drug resistance was determined by genotype. Cox models were used to compare the strategies for VF with resistance and to determine the impact of resistance on AIDS or death. RESULTS: Of 1,360 participants, 866 experienced VF; 226 experienced AIDS or death (median follow-up 5 years). Rates (per 100 personyears) for VF with resistance were 14.9 (PI), 10.8 (NNRTI), and 11.5 (PI+NNRTI); hazard ratio (HR) was 0.78 (95% CI 0.61-0.99) for NNRTI versus PI. Compared to those with no VF, there was a significantly increased risk of AIDS or death for participants with solitary NNRTI resistance (HR 2.31, 95% CI 1.46-3.66) and for those failing with no known resistance (HR 1.78, 95% CI 1.18-2.68). Participants failing with solitary NNRTI resistance and with no resistance had the lowest percent of time on antiretroviral treatment (ART) and the lowest cumulative mean adherence scores. CONCLUSION: For treatment-naïve participants, the risk of AIDS or death is increased for those who failed virologically with solitary NNRTI resistance and those who failed with no known drug resistance compared to those with no virologic failure. Both the lack of ART exposure in nonadherent participants and the development of NNRTI resistance among those who take and fail their ART regimen predict poor clinical outcomes.
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Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV/genética , Terapia Antirretroviral de Alta Atividade , Progressão da Doença , Infecções por HIV/mortalidade , Humanos , Incidência , Cooperação do Paciente , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
The U.S. Department of Health and Human Services Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) treatment guidelines are modified several times per year to reflect the rapid evolution of the field (e.g., emergence of new antiretroviral drugs). As such, a treatment-decision support system that is capable of self-learning is highly desirable. Based on the fuzzy discrete event system (FDES) theory that we recently created, we have developed a self-learning HIV/AIDS regimen selection system for the initial round of combination antiretroviral therapy, one of the most complex therapies in medicine. The system consisted of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. Supervised learning was achieved through automatically adjusting the parameters of the models by the optimizer. We focused on the four historically popular regimens with 32 associated treatment objectives involving the four most important clinical variables (potency, adherence, adverse effects, and future drug options). The learning targets for the objectives were produced by two expert AIDS physicians on the project, and their averaged overall agreement rate was 70.6%. The system's learning ability and new regimen suitability prediction capability were tested under various conditions of clinical importance. The prediction accuracy was found between 84.4% and 100%. Finally, we retrospectively evaluated the system using 23 patients treated by 11 experienced nonexpert faculty physicians and 12 patients treated by the two experts at our AIDS Clinical Center in 2001. The overall exact agreement between the 13 physicians' selections and the system's choices was 82.9% with the agreement for the two experts being both 100%. For the seven mismatched cases, the system actually chose more appropriate regimens in four cases and equivalent regimens in another two cases. It made a mistake in one case. These (preliminary) results show that 1) the System outperformed the nonexpert physicians and 2) it performed as well as the expert physicians did. This learning and prediction approach, as well as our original FDESs theory, is general purpose and can be applied to other medical or nonmedical problems.
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Síndrome da Imunodeficiência Adquirida/terapia , Algoritmos , Antirretrovirais/administração & dosagem , Inteligência Artificial , Sistemas de Apoio a Decisões Clínicas , Quimioterapia Assistida por Computador/métodos , Lógica Fuzzy , Síndrome da Imunodeficiência Adquirida/diagnóstico , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: HIV-1 protease gene mutations at codon 33 have been associated with resistance to some but not all protease inhibitors (PIs). Little is known about the difference in prevalence of codon 33 mutations and polymorphisms between treatment-naive and treatment-experienced patients, and the effect of codon 33F on PI phenotypic resistance patterns. METHODS: Baseline genotypes (TRUGENE) from 772 patients participating in two different randomized clinical trials [504 antiretroviral treatment-naive patients and 268 antiretroviral treatment-experienced patients] were evaluated for the presence of protease codon 33 mutations and polymorphisms. Baseline phenotypes (Antivirogram), including fold-change in resistance for 16 antiretroviral drugs, were available for the 268 treatment-experienced patients. Multivariate linear regression models were used to determine factors associated with phenotypic fold-change for PIs. RESULTS: The prevalence of codon 33 mutations and polymorphisms was 5.2% in the naive cohort (0.2% 33F, 2.5% 33V, 2.5% 331) and 34.7% in the experienced cohort (30.2% 33F, 1.5% 33V, 3.0% 331). In the antiretroviral-experienced cohort (mean = 4.2 prior PIs, 10.6 prior antiretroviral drugs overall), a model adjusting for the presence of specific major protease and multi-PI resistance conferring mutations, the number of other minor PI mutations, prior PI drug exposure (current, prior only, never), and HIV transmission risk factor was used to estimate the phenotypic fold-change in resistance for those with and without mutation 33F. Those with 33F had a significantly higher fold-change for amprenavir (33 vs 19, P<0.0001), ritonavir (162 vs 82, P<0.0001), lopinavir (49 vs 38, P=0.04), and saquinavir (47 vs 41, P=0.02). The presence of the 33F was not a significant predictor of fold change in susceptibility for indinavir or nelfinavir. CONCLUSIONS: At protease codon 33, the prevalences of polymorphisms 33V and 331 were similar for PI-naive and PI-experienced patients (<3.0%), but the prevalence of 33F was significantly different (0.2% versus 30.2%). In the treatment-experienced cohort, the differences in phenotypic fold-change for amprenavir, lopinavir, saquinavir, and ritonavir between those with and without 33F persist after adjustment for the presence of other major PI mutations and PI drug exposure history. Given the availability of newer PIs that may select for 33F, monitoring for the presence of this mutation should be ongoing for both treatment-naive and treatment-experienced patients.
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Fármacos Anti-HIV/uso terapêutico , Códon/genética , Infecções por HIV/tratamento farmacológico , Protease de HIV/genética , Mutação , Polimorfismo Genético , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/virologia , HIV-1/enzimologia , HIV-1/genética , Humanos , Masculino , Prevalência , Resultado do TratamentoRESUMO
Treatment decision-making is complex and involves many factors. A systematic decision-making and optimization technology capable of handling variations and uncertainties of patient characteristics and physician's subjectivity is currently unavailable. We recently developed a novel general-purpose fuzzy discrete event systems theory for optimal decision-making. We now apply it to develop an innovative system for medical treatment, specifically for the first round of highly active antiretroviral therapy of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients involving three historically widely used regimens. The objective is to develop such a system whose regimen choice for any given patient will exactly match expert AIDS physician's selection to produce the (anticipated) optimal treatment outcome. Our regimen selection system consists of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. The optimizer enables the system to either emulate an individual doctor's decision-making or generate a regimen that simultaneously satisfies diverse treatment preferences of multiple physicians to the maximum extent. We used the optimizer to automatically learn the values of 26 parameters of the models. The learning was based on the consensus of AIDS specialists A and B on this project, whose exact agreement was only 35%. The performance of the resulting models was first assessed. We then carried out a retrospective study of the entire system using all the qualifying patients treated in our institution's AIDS Clinical Center in 2001. A total of 35 patients were treated by 13 specialists using the regimens (four and eight patients were treated by specialists A and B, respectively). We compared the actually prescribed regimens with those selected by the system using the same available information. The overall exact agreement was 82.9% (29 out of 35), with the exact agreement with specialists A and B both at 100%. The exact agreement for the remaining 11 physicians not involved in the system training was 73.9% (17 out of 23), an impressive result given the fact that expert opinion can be quite divergent for treatment decisions of such complexity. Our specialists also carefully examined the six mismatched cases and deemed that the system actually chose a more appropriate regimen for four of them. In the other two cases, either would be reasonable choices. Our approach has the capabilities of generalizing, learning, and representing knowledge even in the face of weak consensus, and being readily upgradeable to new medical knowledge. These are practically important features to medical applications in general, and HIV/AIDS treatment in particular, as national HIV/AIDS treatment guidelines are modified several times per year.