High Prevalence of NRTI and NNRTI Drug Resistance Among ART-Experienced, Hospitalized Inpatients.

BACKGROUND: Patients hospitalized with advanced HIV have a high mortality risk. We assessed viremia and drug resistance among differentiated care services and explored whether expediting the switching of failing treatments may be justified. SETTING: Hospitals in the Democratic Republic of (DRC) Congo (HIV hospital) and Kenya (general hospital including HIV care). METHODS: Viral load (VL) testing and drug resistance (DR) genotyping were conducted for HIV inpatients ≥15 years, on first-line antiretroviral therapy (ART) for ≥6 months, and CD4 ≤350 cells/µL. Dual-class DR was defined as low-, intermediate-, or high-level DR to at least 1 nucleoside reverse transcriptase inhibitor and 1 non-nucleoside reverse transcriptase inhibitor. ART regimens were considered ineffective if dual-class DR was detected at viral failure (VL ≥1000 copies/mL). RESULTS: Among 305 inpatients, 36.7% (Kenya) and 71.2% (DRC) had VL ≥1000 copies/mL, of which 72.9% and 73.7% had dual-class DR. Among viral failures on tenofovir disoproxil fumarate (TDF)-based regimens, 56.1% had TDF-DR and 29.8% zidovudine (AZT)-DR; on AZT regimens, 71.4% had AZT-DR and 61.9% TDF-DR, respectively. Treatment interruptions (≥48 hours during past 6 months) were reported by 41.7% (Kenya) and 56.7% (DRC). Approximately 56.2% (Kenya) and 47.4% (DRC) on TDF regimens had tenofovir diphosphate concentrations <1250 fmol/punch (suboptimal adherence). Among viral failures with CD4 <100 cells/µL, 76.0% (Kenya) and 84.6% (DRC) were on ineffective regimens. CONCLUSIONS: Many hospitalized, ART-experienced patients with advanced HIV were on an ineffective first-line regimen. Addressing ART failure promptly should be integrated into advanced disease care packages for this group. Switching to effective second-line medications should be considered after a single high VL on non-nucleoside reverse transcriptase inhibitor-based first-line if CD4 ≤350 cells/µL or, when VL is unavailable, among patients with CD4 ≤100 cells/µL.

CNS Neurotoxicity of Antiretrovirals.

The development of novel antiretroviral treatments has led to a significant turning point in the fight against HIV. Although therapy leads to virologic suppression and prolonged life expectancies, HIV-associated neurocognitive disorder (HAND) remains prevalent. While various hypotheses have been proposed to explain this phenomenon, a growing body of literature explores the neurotoxic effects of antiretroviral therapy. Research to date brings into question the potential role of such medications in neurocognitive and neuropsychiatric impairment seen in HIV-positive patients. This review highlights recent findings and controversies in cellular, molecular, and clinical neurotoxicity of antiretrovirals. It explores the pathogenesis of such toxicity and relates it to clinical manifestations in each medication class. The concept of accelerated aging in persons living with HIV (PLWH) as well as potential treatments for HAND are also discussed. Ultimately, this article hopes to educate clinicians and basic scientists about the neurotoxic effects of antiretrovirals and spur future scientific investigation into this important topic. Graphical Abstract.

Polypharmacy and potential drug-drug interactions for people with HIV in the UK from the Climate-HIV database.

OBJECTIVES: People with HIV (PWHIV) are likely to need therapies for comorbidities as they age. We assessed risk of drug-drug interactions (DDIs) in PWHIV. METHODS: The Climate-HIV electronic recording system was used to cross-sectionally analyse records from PWHIV aged ≥ 18 years attending four UK HIV units with a current antiretroviral (ARV) prescription in February 2018. Antiretroviral and non-ARV medications were categorized by clinical significance of DDIs (University of Liverpool DDI tool). Potential DDIs were predicted using treatment guidelines for commonly recorded comorbidities. RESULTS: Among 4630 PWHIV (44% female), 41% were ≥ 50 years old. The average number of non-ARV comedications increased from < 1 for patients aged ≤ 24 years to > 5 for patients aged ≥ 75 years; 65% were taking one or more non-ARV comedications. The median (interquartile range) number of non-ARVs was 1 (0-2) and 2 (1-5) for those aged < 50 and ≥ 50 years, respectively. Common comorbidities/concurrent health conditions occurred more frequently in patients aged ≥ 50 years vs. < 50 (53% vs. 34%). Boosted protease inhibitors were associated with the highest proportion of contraindicated comedications; dolutegravir and raltegravir had the fewest. For non-ARVs, sildenafil and quetiapine were most likely to result in DDIs. Guideline-recommended treatments for hepatitis C, hepatitis B, and tuberculosis had the highest proportions of contraindications when combined with ARV regimens, while treatments for hepatitis C, malignancy, and mental health conditions had the highest proportion of combinations potentially causing DDIs requiring dose monitoring or adjustment. CONCLUSIONS: Non-ARV use by PWHIV is high and increases with age. Treatment decisions for ageing PWHIV should consider guideline recommendations for comorbidities.

A Review and Clinical Understanding of Tenofovir: Tenofovir Disoproxil Fumarate versus Tenofovir Alafenamide.

HIV is a serious chronic medical condition. Significant improvements in antiretroviral therapy have led to a transformation in its management. No curative treatment is available for HIV, and lifelong therapy is required with a combination of agents to control viral replication and prevent complications. Some of the older agents are notorious for many side effects, making patient compliance difficult, which is critical to preventing HIV resistance. Tenofovir is one of the newer, more tolerable, nucleotide reverse transcriptase inhibitors on the market; is a mainstay of many antiretroviral therapy combinations; and is now available in 2 different formulations, tenofovir disoproxil fumarate (TDF) and, the more recent, tenofovir alafenamide (TAF). These 2 formulations have very different pharmacokinetics, which seem to affect their efficacy and safety. This manuscript provides insight into the history of TDF and TAF development, their unique pharmacokinetics and pharmacology, clinically important adverse effects, monitoring, interactions, resistance, review of clinical studies, and guideline recommendations and clinical applications for tenofovir's various indications.

Antiretroviral drug class and anaemia risk in the current treatment era among people living with HIV in the USA: a clinical cohort study.

OBJECTIVE: Anaemia is common among people living with HIV (PLWH) and has been associated with certain, often older, antiretroviral medications. Information on current antiretroviral therapy (ART) and anaemia is limited. The objective was to compare the associations between anaemia incidence or haemoglobin change with core ART classes in the current ART era. DESIGN: Retrospective cohort study. SETTING: USA-based prospective clinical cohort of PLWH aged 18 and above receiving care at eight sites between January 2010 and March 2018. PARTICIPANTS: 16 505 PLWH were included in this study. MAIN OUTCOME MEASURES: Anaemia risk and haemoglobin change were estimated among PLWH for person-time on a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI)-based regimen, relative to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based reference. We also examined PLWH on regimens containing multiple core classes. Cox proportional hazards regression analyses were conducted to measure the associations between time-updated ART classes and incident anaemia or severe anaemia. Linear mixed effects models were used to examine the relationships between ART classes and haemoglobin change. RESULTS: During a median of 4.9 years of follow-up, 1040 developed anaemia and 488 developed severe anaemia. Compared with NNRTI use, INSTI-based regimens were associated with an increased risk of anaemia (adjusted HR (aHR) 1.26, 95% CI 1.00 to 1.58) and severe anaemia (aHR 1.51, 95% CI 1.07 to 2.11) and a decrease in haemoglobin level. Time on multiple core classes was also associated with increased anaemia risk (aHR 1.39, 95% CI 1.13 to 1.70), while no associations were found for PI use. CONCLUSION: These findings suggest INSTI use may increase the risk of anaemia. If confirmed, screening for anaemia development in users of INSTIs may be beneficial. Further research into the underlying mechanisms is warranted.

Comparative efficacy and safety of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: a systematic review and network meta-analysis.

BACKGROUND: Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents. METHODS: A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4+ cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4+ ≤/>200cells/µL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses). RESULTS: The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78-2.59) and NNRTIs (ORs 1.51-1.86), and similar but numerically higher than other INSTIs. CD4+ count increase was significantly greater with DTG than PIs (difference: 23.63-31.47 cells/µL) and efavirenz (difference: 34.54 cells/µL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76-100%) and NNRTIs (probability: 50-100%), and a greater CD4+ count increase versus PIs (probability: 72-100%) and NNRTIs (probability: 60-100%). DTG was more likely to result in patients achieving VS (probability: 94-100%), and a greater CD4+ count increase (probability: 53-100%) versus other core agents, including INSTIs (probability: 94-97% and 53-93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents. CONCLUSION: INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL, who can be difficult to treat.

Prevalence of arterial hypertension and risk factors among people with acquired immunodeficiency syndrome.

OBJECTIVES: to verify the prevalence of arterial hypertension and its risk factors among people with acquired immunodeficiency syndrome under antiretroviral therapy. METHOD: cross-sectional study with 208 patients. Data collection was conducted through interviews using a form containing data on sociodemographic, clinical and epidemiological aspects, hypertension risk factors, blood pressure, weight, height, body mass index and abdominal circumference. Mean, standard deviation, odds ratio and confidence interval were calculated, t-test and Chi-square test were used, considering P < 0.05 as statistically significant. Hypertension associated variables were selected for logistic regression. RESULTS: patients were male (70.7%), self-reported as mixed-race (68.2%), had schooling between 9 and 12 years of study (46.6%), had no children (47.6%), were single (44.2%), in the sexual exposure category (72.1%) and heterosexual (60.6%). The prevalence of people with acquired immunodeficiency syndrome and arterial hypertension was 17.3%. Logistic regression confirmed the influence of age greater than 45 years, family history of hypertension, being overweight and antiretroviral therapy for more than 36 months for hypertension to occur. CONCLUSION: the prevalence of hypertension was 17.3%. Patients with acquired immunodeficiency syndrome and hypertension were older than 45 years, had family history of hypertension, were overweight and under antiretroviral therapy for more than 36 months.

Evolution of transmitted HIV-1 drug resistance and viral subtypes circulation in Italy from 2006 to 2016.

OBJECTIVES: The aim was to evaluate the evolution of transmitted HIV-1 drug resistance (TDR) prevalence in antiretroviral therapy (ART)-naïve patients from 2006 to 2016. METHODS: HIV-1 sequences were retrieved from the Antiviral Response Cohort Analysis (ARCA) database and TDR was defined as detection of at least one mutation from the World Health Organization (WHO) surveillance list. RESULTS: We included protease/reverse transcriptase sequences from 3573 patients; 455 had also integrase sequences. Overall, 68.1% of the patients were Italian, the median CD4 count was 348 cells/µL [interquartile range (IQR) 169-521 cells/µL], and the median viral load was 4.7 log10 HIV-1 RNA copies/mL (IQR 4.1-5.3 log10 copies/mL). TDR was detected in 10.3% of patients: 6% carried mutations to nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 4.4% to nonnucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 2.3% to protease inhibitors (PIs), 0.2% to integrase strand transfer inhibitors (INSTIs) and 2.1% to at least two drug classes. TDR declined from 14.5% in 2006 to 7.3% in 2016 (P = 0.003): TDR to NRTIs from 9.9 to 2.9% (P = 0.003) and TDR to NNRTIs from 5.1 to 3.7% (P = 0.028); PI TDR remained stable. The proportion carrying subtype B virus declined from 76.5 to 50% (P < 0.001). The prevalence of TDR was higher in subtype B vs. non-B (12.6 vs. 4.9%, respectively; P < 0.001) and declined significantly in subtype B (from 17.1 to 8.8%; P = 0.04) but not in non-B subtypes (from 6.1 to 5.8%; P = 0.44). Adjusting for country of origin, predictors of TDR were subtype B [adjusted odds ratio (AOR) for subtype B vs. non-B 2.91; 95% confidence interval (CI) 1.93-4.39; P < 0.001], lower viral load (per log10 higher: AOR 0.86; 95% CI 0.75-0.99; P = 0.03), site in northern Italy (AOR for southern Italy/island vs. northern Italy, 0.61; 95% CI 0.40-0.91; P = 0.01), and earlier calendar year (per 1 year more recent: AOR 0.95; 95% CI 0.91-0.99; P = 0.02). CONCLUSIONS: The prevalence of HIV-1 TDR has declined during the last 10 years in Italy.

Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother-Infant Pairs Enrolled in a Large Perinatal Study.

Background: The presence of antiretroviral drug-associated resistance mutations (DRMs) may be particularly problematic in human immunodeficiency virus (HIV)-infected pregnant women as it can lead to mother-to-child transmission (MTCT) of resistant HIV strains. This study evaluated the prevalence and the effect of antiretroviral DRMs in previously untreated mother-infant pairs. Methods: A case-control design of 1:4 (1 transmitter to 4 nontransmitters) was utilized to evaluate DRMs as a predictor of HIV MTCT in specimens obtained from mother-infant pairs. ViroSeq HIV-1 genotyping was performed on mother-infant specimens to assess for clinically relevant DRMs. Results: One hundred forty infants acquired HIV infection; of these, 123 mother-infant pairs (88%) had specimens successfully amplified using ViroSeq and assessed for drug resistance genotyping. Additionally, 483 of 560 (86%) women who did not transmit HIV to infants also had samples evaluated for DRMs. Sixty-three of 606 (10%) women had clinically relevant DRMs; 12 (2%) had DRMs against >1 drug class. Among 123 HIV-infected infants, 13 (11%) had clinically relevant DRMs, with 3 (2%) harboring DRMs against >1 drug class. In univariate and multivariate analyses, DRMs in mothers were not associated with increased HIV MTCT (adjusted odds ratio, 0.8 [95% confidence interval, .4-1.5]). Presence of DRMs in transmitting mothers was strongly associated with DRM presence in their infants (P < .001). Conclusions: Preexisting DRMs were common in untreated HIV-infected pregnant women, but did not increase the risk of HIV MTCT. However, if women with DRMs are not virologically suppressed, they may transmit resistant mutations, thus complicating infant management.

Prevalence of arterial hypertension and risk factors among people with acquired immunodeficiency syndrome / Prevalência de hipertensão arterial e fatores de risco entre pessoas com síndrome da imunodeficiência adquirida / Prevalencia de hipertensión arterial y factores de riesgo entre personas con síndrome de inmunodeficiencia adquirida

ABSTRACT Objectives: to verify the prevalence of arterial hypertension and its risk factors among people with acquired immunodeficiency syndrome under antiretroviral therapy. Method: cross-sectional study with 208 patients. Data collection was conducted through interviews using a form containing data on sociodemographic, clinical and epidemiological aspects, hypertension risk factors, blood pressure, weight, height, body mass index and abdominal circumference. Mean, standard deviation, odds ratio and confidence interval were calculated, t-test and Chi-square test were used, considering P < 0.05 as statistically significant. Hypertension associated variables were selected for logistic regression. Results: patients were male (70.7%), self-reported as mixed-race (68.2%), had schooling between 9 and 12 years of study (46.6%), had no children (47.6%), were single (44.2%), in the sexual exposure category (72.1%) and heterosexual (60.6%). The prevalence of people with acquired immunodeficiency syndrome and arterial hypertension was 17.3%. Logistic regression confirmed the influence of age greater than 45 years, family history of hypertension, being overweight and antiretroviral therapy for more than 36 months for hypertension to occur. Conclusion: the prevalence of hypertension was 17.3%. Patients with acquired immunodeficiency syndrome and hypertension were older than 45 years, had family history of hypertension, were overweight and under antiretroviral therapy for more than 36 months.

RESUMO Objetivos: verificar a prevalência de hipertensão arterial e seus fatores de risco entre pessoas com síndrome da imunodeficiência adquirida em terapia antirretroviral. Método: estudo transversal, com amostra de 208 pacientes. Coleta de dados realizada por meio de entrevista, com formulário envolvendo dados sociodemográficos, clínicos, epidemiológicos, fatores de risco para hipertensão, verificação da pressão arterial, peso, altura, índice de massa corporal e circunferência abdominal. Foram calculadas média, desvio padrão, odds ratio e intervalo de confiança e utilizados testet e teste do qui-quadrado, considerando-se estatisticamente significante P < 0,05. Variáveis associadas à hipertensão foram selecionadas para regressão logística. Resultados: destacaram-se pacientes do sexo masculino (70,7%), cor parda (68,2%), escolaridade entre nove e 12 anos de estudo (46,6%), sem filhos (47,6%), solteiros (44,2%), categoria de exposição sexual (72,1%) e heterossexuais (60,6%). A prevalência de pessoas com síndrome da imunodeficiência adquirida e hipertensão foi de 17,3%. Regressão logística confirmou influência da idade maior que 45 anos, história familiar de hipertensão, sobrepeso e terapia antirretroviral acima de 36 meses para ocorrer hipertensão. Conclusão: a prevalência de hipertensão foi de 17,3%. Pacientes com síndrome da imunodeficiência adquirida e hipertensão tinham mais de 45 anos, história familiar de hipertensão, sobrepeso e terapia antirretroviral por mais de 36 meses.

RESUMEN Objetivos: verificar la prevalencia de hipertensión arterial y sus factores de riesgo entre personas con síndrome de inmunodeficiencia adquirida en terapia antirretroviral. Método: estudio transversal, con muestra de 208 pacientes. La recolección de datos se realizó a través de entrevistas con formulario de datos sociodemográficos, clínicos, epidemiológicos, factores de riesgo para la hipertensión arterial, verificación de la presión arterial, peso, altura, índice de masa corporal y la circunferencia abdominal. Se calcularon la media, la desviación estándar, la razón de probabilidades (odds ratio)y el intervalo de confianza, y se utilizaron la prueba t y la prueba del chi-cuadrado, considerándose estadísticamente significante P <0,05. Las variables asociadas a la hipertensión fueron seleccionadas para la regresión logística. Resultados: se destacaron pacientes del género masculino (70,7%), color parda (68,2%), escolaridad entre nueve y 12 años de estudio (46,6%), sin hijos (47,6% ), solteros (44,2%), categoría de exposición sexual (72,1%) y heterosexuales (60,6%). La prevalencia de personas con síndrome de inmunodeficiencia adquirida e hipertensión fue del 17,3%. La regresión logística confirmó que hay influencia de la edad mayor de 45 años, del historial familiar de hipertensión, del sobrepeso y de la terapia antirretroviral por más de 36 meses para ocurrir la enfermedad. Conclusión: la prevalencia de hipertensión fue del 17,3%. Los pacientes con el síndrome de inmunodeficiencia adquirida y hipertensión tenían más de 45 años, historial familiar de hipertensión, sobrepeso y terapia antirretroviral por más de 36 meses.

Antiretroviral changes during the first year of therapy.

INTRODUCTION: The Brazilian HIV/AIDS management and treatment guideline (PCDT), published in 2013, recommends and standardizes the use of highly active antiretroviral therapy (HAART) in all adult patients, in spite of LTCD4 count. This study aimed to analyze the first year of HAART use in patients from a reference center on HIV/AIDS management in Fortaleza, Ceará. METHOD: This descriptive study reviewed all prescription forms of antiretroviral regimens initiation and changes from January to July 2014. All antiretroviral regimen changes that occurred during the first year of therapy were evaluated. Data were analyzed with SPSS version 20. Mean, standard deviation and frequency, Student's t and Mann-Whitney tests calculations were used, with significance at p<0.05. RESULTS: From 527 patients initiating HAART, 16.5% (n=87) had a regimen change in the first year. These patients were mostly male (59.8%; n=52), aged 20 to 39 years, with only one HAART change (72.4%; n=63). Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir. Mean time of HAART changes was 120 days, with adverse reactions as the most prevalent cause. HAART was effective in decreasing viral load since second month of treatment (p=0.003) and increasing LTCD4 lymphocytes since fifth month (p<0.001). CONCLUSION: The main cause of initial HAART changes was adverse reaction and most patients had only one change in the HAART regimen. HAART prescription was in accordance to the PCDT from 2013.

Antiretroviral changes during the first year of therapy / Mudanças de terapia antirretroviral durante o primeiro ano de tratamento

Summary Introduction: The Brazilian HIV/AIDS management and treatment guideline (PCDT), published in 2013, recommends and standardizes the use of highly active antiretroviral therapy (HAART) in all adult patients, in spite of LTCD4 count. This study aimed to analyze the first year of HAART use in patients from a reference center on HIV/AIDS management in Fortaleza, Ceará. Method: This descriptive study reviewed all prescription forms of antiretroviral regimens initiation and changes from January to July 2014. All antiretroviral regimen changes that occurred during the first year of therapy were evaluated. Data were analyzed with SPSS version 20. Mean, standard deviation and frequency, Student's t and Mann-Whitney tests calculations were used, with significance at p<0.05. Results: From 527 patients initiating HAART, 16.5% (n=87) had a regimen change in the first year. These patients were mostly male (59.8%; n=52), aged 20 to 39 years, with only one HAART change (72.4%; n=63). Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir. Mean time of HAART changes was 120 days, with adverse reactions as the most prevalent cause. HAART was effective in decreasing viral load since second month of treatment (p=0.003) and increasing LTCD4 lymphocytes since fifth month (p<0.001). Conclusion: The main cause of initial HAART changes was adverse reaction and most patients had only one change in the HAART regimen. HAART prescription was in accordance to the PCDT from 2013.

Resumo Introdução: O Protocolo Clínico e Diretrizes Terapêuticas para manejo da infecção pelo HIV em adultos (PCDT) de 2013 recomenda e normatiza início de terapia antirretroviral (TARV) em pacientes com qualquer contagem de LTCD4. O objetivo do estudo foi analisar o primeiro ano de TARV de pacientes em acompanhamento em um centro de referência em HIV/AIDS de Fortaleza, Ceará. Método: O estudo descritivo revisou formulários de solicitação de início e modificação de TARV em pacientes que iniciaram tratamento entre janeiro e julho de 2014. Foram avaliadas todas as mudanças que ocorreram durante o primeiro ano de terapia. Os dados foram analisados no programa Statistical Package for the Social Sciences (SPSS) versão 20. Foram calculados médias, desvios padrão, frequências, testes t Student e Mann-Whitney, com significância de p<0,05. Resultados: Dos 527 pacientes que iniciaram TARV, 16,5% (n=87) realizaram troca no primeiro ano. A maioria era do sexo masculino (59,8%; n=52), de 20 a 39 anos, com apenas uma mudança da TARV (72,4%; n=63). Efavirenz foi o fármaco mais substituído, seguido por tenofovir, zidovudina e lopinavir/ritonavir. O tempo médio de ocorrência das modificações da TARV foi de 120 dias, tendo reações adversas como causas principais. TARV foi efetiva na queda da carga viral desde o 2ºmês de tratamento (p=0,003) e na elevação de LTCD4 desde o 5º mês (p<0,001). Conclusão: Os principais fatores envolvidos em modificações de TARV inicial foram reações adversas, com apenas uma mudança de esquema na maioria dos pacientes. O manejo da TARV estava de acordo com o PCDT de 2013.

HIV and its relationship to insulin resistance and lipid abnormalities.

Antiretroviral therapy has revolutionized the care of people with human immunodeficiency virus (HIV) by reducing morbidity and mortality from acquired immunodeficiency syndrome-related conditions. Despite longer life expectancy, however, HIV-infected individuals continue to have a higher risk of death compared with the general population. This has been attributed to the increasing incidence of noncommunicable diseases, in particular, atherosclerotic cardiovascular diseases. This is driven, in part, by the emergence of metabolic disorders, particularly dyslipidemia, insulin resistance, and lipodystrophy, in those on antiretroviral therapy. The pathogenesis of these metabolic derangements is complex and multifactorial, and could be a consequence of an interplay between traditional age-related risk factors, HIV infection, antiretroviral therapy effects, and the inflammatory state and immune activation in this population. Understanding the contributions of each of these factors could not just impact the current management of these individuals and help mitigate the risk for premature cardiovascular disease, but also shape the future direction of research in HIV.

Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients.

INTRODUCTION: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial. Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English. Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations.

Characterizing Class-Specific Exposure-Viral Load Suppression Response of HIV Antiretrovirals Using A Model-Based Meta-Analysis.

We applied model-based meta-analysis of viral suppression as a function of drug exposure and in vitro potency for short-term monotherapy in human immunodeficiency virus type 1 (HIV-1)-infected treatment-naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class-specific models relating viral load kinetics from monotherapy studies to potency normalized steady-state trough plasma concentrations. These models were integrated with a literature assessment of doses which demonstrated to have long-term efficacy in combination therapy, in order to set steady-state trough concentration targets of 6.17- and 2.15-fold above potency for NNRTIs and InSTIs, respectively. Both the models developed and the pharmacokinetic targets derived can be used to guide compound selection during preclinical development and to predict the dose-response of new antiretrovirals to inform early clinical trial design.

Dynamics of an HIV Model with Multiple Infection Stages and Treatment with Different Drug Classes.

Highly active antiretroviral therapy can effectively control HIV replication in infected individuals. Some clinical and modeling studies suggested that viral decay dynamics may depend on the inhibited stages of the viral replication cycle. In this paper, we develop a general mathematical model incorporating multiple infection stages and various drug classes that can interfere with specific stages of the viral life cycle. We derive the basic reproductive number and obtain the global stability results of steady states. Using several simple cases of the general model, we study the effect of various drug classes on the dynamics of HIV decay. When drugs are assumed to be 100% effective, drugs acting later in the viral life cycle lead to a faster or more rapid decay in viremia. This is consistent with some patient and experimental data, and also agrees with previous modeling results. When drugs are not 100% effective, the viral decay dynamics are more complicated. Without a second population of long-lived infected cells, the viral load decline can have two phases if drugs act at an intermediate stage of the viral replication cycle. The slopes of viral load decline depend on the drug effectiveness, the death rate of infected cells at different stages, and the transition rate of infected cells from one to the next stage. With a second population of long-lived infected cells, the viral load decline can have three distinct phases, consistent with the observation in patients receiving antiretroviral therapy containing the integrase inhibitor raltegravir. We also fit modeling prediction to patient data under efavirenz (a nonnucleoside reverse-transcriptase inhibitor) and raltegravir treatment. The first-phase viral load decline under raltegravir therapy is longer than that under efavirenz, resulting in a lower viral load at initiation of the second-phase decline in patients taking raltegravir. This explains why patients taking a raltegravir-based therapy were faster to achieve viral suppression than those taking an efavirenz-based therapy. Taken together, this work provides a quantitative and systematic comparison of the effect of different drug classes on HIV decay dynamics and can explain the viral load decline in HIV patients treated with raltegravir-containing regimens.

Dual Raltegravir-Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/Nucleotide Reverse Transcriptase Inhibitors.

BACKGROUND: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class. METHODS: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks. RESULTS: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (-85.2 mg/dL), in the prevalence of tubular proteinuria (-56%) and in the mean level of interleukin-6 (-0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events. CONCLUSION: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.

HIV-1 functional cure: will the dream come true?

The reservoir of human immunodeficiency virus type 1 (HIV-1), a long-lived pool of latently infected cells harboring replication-competent viruses, is the major obstacle to curing acquired immune deficiency syndrome (AIDS). Although the combination antiretroviral therapy (cART) can successfully suppress HIV-1 viremia and significantly delay the progression of the disease, it cannot eliminate the viral reservoir and the patient must continue to take anti-viral medicines for life. Currently, the appearance of the 'Berlin patient', the 'Boston patients', and the 'Mississippi baby' have inspired many therapeutic strategies for HIV-1 aimed at curing efforts. However, the specific eradication of viral latency and the recovery and optimization of the HIV-1-specific immune surveillance are major challenges to achieving such a cure. Here, we summarize recent studies addressing the mechanisms underlying the viral latency and define two categories of viral reservoir: 'shallow' and 'deep'. We also present the current strategies and recent advances in the development of a functional cure for HIV-1, focusing on full/partial replacement of the immune system, 'shock and kill', and 'permanent silencing' approaches.