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BMC Infectious Diseases Aug 2019Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity,... (Observational Study)
Observational Study
BACKGROUND
Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CT-scan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation.
METHODS
Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome).
RESULTS
prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [- 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]).
CONCLUSIONS
We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH.
Topics: Adiponectin; Adipose Tissue; Adult; Anti-HIV Agents; Biomarkers; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Intra-Abdominal Fat; Longitudinal Studies; Male; Middle Aged; Subcutaneous Fat; Thymidine
PubMed: 31399063
DOI: 10.1186/s12879-019-4347-y -
Expert Opinion on Drug Safety Sep 2019: Efficient antiretroviral-treatment (ART) generally allows control of HIV infection. However, persons-living-with-HIV (PLWH), when aging, present a high prevalence of... (Review)
Review
: Efficient antiretroviral-treatment (ART) generally allows control of HIV infection. However, persons-living-with-HIV (PLWH), when aging, present a high prevalence of metabolic diseases. : Altered adiposity, dyslipidemias, insulin resistance, diabetes, and their consequences are prevalent in PLWH and could be partly related to ART. : At first, personal and lifestyle factors are involved in the onset of these complications. The persistence of HIV in tissue reservoirs could synergize with some ART and enhance metabolic disorders. Altered fat repartition, diagnosed as lipodystrophy, has been related to first-generation nucleoside-reverse-transcriptase-inhibitors (NRTIs) (stavudine zidovudine) and some protease inhibitors (PIs). Recently, use of some integrase-inhibitors (INSTI) resulted in weight/fat gain, which represents a worrisome unresolved situation. Lipid parameters were affected by some first-generation NRTIs, non-NRTIs (efavirenz) but also PIs boosted by ritonavir, with increased total and LDL-cholesterol and triglycerides. Insulin resistance is common associated with abdominal obesity. Diabetes incidence, high with first-generation-ART (zidovudine, stavudine, didanosine, indinavir) has declined with contemporary ART close to that of the general population. Metabolic syndrome, a dysmetabolic situation with central obesity and insulin resistance, and liver steatosis are common in PLWH and could indirectly result from ART-associated fat gain and insulin resistance. All these dysmetabolic situations increase the atherogenic cardiovascular risk.
Topics: Adipose Tissue; Anti-HIV Agents; Dyslipidemias; Glucose; HIV Infections; Humans; Life Style; Lipid Metabolism; Metabolic Diseases; Risk Factors
PubMed: 31304808
DOI: 10.1080/14740338.2019.1644317 -
PharmacoEconomics - Open Mar 2020While dolutegravir has been added by WHO as a preferred second-line option for the treatment of HIV infection, boosted protease inhibitor (bPI)-based regimens are still...
BACKGROUND
While dolutegravir has been added by WHO as a preferred second-line option for the treatment of HIV infection, boosted protease inhibitor (bPI)-based regimens are still needed as alternative second-line options. Identifying optimal bPI-based second-line combinations is essential, given associated high costs and funding constraints in low- and middle-income countries. We assessed the cost-effectiveness of three alternative bPI-based second-line regimens in Burkina Faso, Cameroon and Senegal.
METHODS
We used data collected over 2010-2015 in the 2LADY trial/post-trial cohort. Patients with first-line antiretroviral therapy (ART) failure were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (TDF/FTC LPV/r; arm A), abacavir + didanosine + lopinavir/ritonavir (arm B), or tenofovir/emtricitabine + darunavir/ritonavir (arm C). Costs (US dollars, 2016), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were computed for each country over 24 months of follow-up and extrapolated to 5 years using a simulated patient-level Markov model. We assessed uncertainty using cost-effectiveness acceptability curves, scenarios and prices threshold analysis.
RESULTS
In each country, over 24 months, arm A was significantly less costly than arms B and C (incremental costs ranging from US$410-$US721 and US$468-US$546 for B and C vs A, respectively) and offered similar health benefits (incremental QALY: - 0.138 to 0.023 and - 0.179 to 0.028, respectively). Over 5 years, arm A remained the least costly, health benefits not being significantly different between arms. Compared with arms B and C, in each study country, Arm A had a ≥ 95% probability of being cost-effective for a large range of cost-effectiveness thresholds, irrespective of the scenario considered.
CONCLUSIONS
Using TDF/FTC LPV/r as a bPI-based second-line regimen provided the best economic value in the three study countries.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00928187.
PubMed: 31273686
DOI: 10.1007/s41669-019-0157-9 -
Antimicrobial Agents and Chemotherapy Aug 2019The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens....
The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the screen identified very few ARB hits, which were strain/drug specific. These ARB hits included antimetabolites (zidovudine, floxuridine, didanosine, and gemcitabine), anthracyclines (daunorubicin, mitoxantrone, and epirubicin), and psychoactive drugs (gabapentin, fluspirilene, and oxethazaine). These findings suggest that there are few approved drugs that could be directly repositioned as adjunct antibacterials, and these will need robust testing to validate efficacy.
Topics: Anti-Bacterial Agents; Didanosine; Drug Resistance, Multiple, Bacterial; Ethanolamines; Floxuridine; Gram-Negative Bacteria; Microbial Sensitivity Tests; Mitoxantrone; Zidovudine
PubMed: 31160293
DOI: 10.1128/AAC.00769-19 -
BMC Nephrology May 2019It has been reported that people living with HIV in West Africa exhibited the highest risks for chronic kidney disease (CKD) in the world. Here, we aimed at determining...
BACKGROUND
It has been reported that people living with HIV in West Africa exhibited the highest risks for chronic kidney disease (CKD) in the world. Here, we aimed at determining the CKD frequency and changes in kidney function during antiretroviral treatment (ART) in a large cohort of HIV-patients followed in Burkina Faso.
METHODS
We included ART-naive adults who initiated ART at the Day Care Unit of the Souro Sanou University Hospital between 01/01/2007 and 12/31/2016. We assessed the estimated glomerular filtration rate (eGFR) by serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. Following the K/DOQI recommendations, CKD was defined as eGFR < 60 ml/min/1.73m at two consecutive measurements at least 3 months apart. The factors associated with eGFR decline or CKD were identified by mixed linear regression and Cox regression, respectively.
RESULTS
Three thousand, one hundred and thirty-eight patients (72% women) were followed for a median (IQR) of 4.5(2.2-6.9) years. At baseline, median eGFR (IQR) was 110.7(94.4-128.4) ml/min/1.73m and 93 (3%) patients exhibited eGFR < 60 ml/min/1.73m. The lowest-performing progressions of eGFR during the first year of ART were observed in patients with 40-49 yr. age range (- 8.3[- 11.7;-5.0] ml/min/1.73m, p < 0.001), age ≥ 50 yr. (- 6.2[- 10.7;-1.8] ml/min/1.73m, p = 0.006) and high blood pressure (HBP) (- 28.4[- 46.9;-9.9] ml/min/1.73m, p = 0.003) at ART initiation. Regarding the ART exposure in patients with normal baseline eGFR, zidovudine (AZT) with protease inhibitor (PI) (- 4.7[- 7.7;-1.6] ml/min/1.73m, p = 0.002), tenofovir (TDF) + PI (- 13.1[- 17.4;-8.7] ml/min/1.73m, p < 0.001), TDF without PI (- 3.2[- 5.0;-1.4] ml/min/1.73m, p < 0.001), stavudine (d4T) + PI (- 8.5[- 14.6-2.4] ml/min/1.73m, p = 0.006) and d4T without PI (- 5.0[- 7.6-2.4] ml/min/1.73m, p < 0.001) were associated with poorer eGFR progression. The prevalence of CKD was 0.5% and the incidence was 1.9 [1.3; 2.7] cases/1000 person-years. The risk of CKD was higher in patients with HBP (4.3[1.8;9.9], p = 0.001), 40-49 yr. patients (4.2[1.6;11.2], p = 0.004), ≥50 yr. patients (4.5[1.5;14.1], p = 0.009) and patients exposed to abacavir (ABC) or didanosine (ddI) based ART (13.1[4.0;42.9], p < 0.001).
CONCLUSIONS
Our findings do not confirm the high risk of CKD reported in previous studies of West Africans with HIV, but support the recommendations for early initiation of ART and close kidney function monitoring in patients with HBP or aged ≥40 yr.
Topics: Adult; Age Factors; Anti-HIV Agents; Burkina Faso; Cohort Studies; Creatinine; Didanosine; Dideoxynucleosides; Female; Follow-Up Studies; Glomerular Filtration Rate; HIV Infections; Humans; Hypertension; Incidence; Linear Models; Male; Middle Aged; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Stavudine; Tenofovir; Time Factors; Zidovudine
PubMed: 31064340
DOI: 10.1186/s12882-019-1335-9 -
PloS One 2019Antiretroviral therapy has surely increased the life expectancy of people living with HIV. However, long term complications like HIV associated sensory neuropathy has a...
BACKGROUND
Antiretroviral therapy has surely increased the life expectancy of people living with HIV. However, long term complications like HIV associated sensory neuropathy has a negative impact on quality of life among people living with HIV (PLHIV). In Ethiopia, lack of data on magnitude of the burden and predictors of HIV associated sensory neuropathy in many resource limited setting has led to under diagnosis and eventually under management of HIV-SN. Hence, this study was set out to establish the burden of HIV-associated sensory neuropathy and, its association with demographic, health and clinical characteristics among people living with HIV in Ethiopia.
METHODS
Cross-sectional study was conducted to assess the prevalence of HIV-associated sensory neuropathy and the associated factors among adult HIV patients at University of Gondar Teaching Hospital, Gondar, Ethiopia. Brief Peripheral Neuropathy Screening tool validated by AIDs Clinical trial group was used for screening HIV-associated sensory neuropathy. Data were analyzed descriptively and through uni- and multivariate logistic regression.
RESULTS
In total 359 adult PLHIV with a mean age of 36.5± 9.07 years participated, their median duration of HIV infection was 60 months (IQR 36-84) and their median CD4 count 143cells/μL (IQR 69.5-201.5). Age above 40 years, anti-tuberculosis regimen, tallness, and exposure to didanosine contained antiretroviral therapy were found to be associated with HIV-associated sensory neuropathy (AOR 1.82, 1.84, 1.98 and 4.33 respectively).
CONCLUSIONS
More than half of the HIV patients who attended HIV care clinic at University of Gondar hospital during the study period were found to present with peripheral sensory neuropathy. Higher age, tallness, TB medication, and didanosine in ART were significantly associated with HIV-SN as screened by effective diagnostic (BPNS) tool.
Topics: Adult; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis; Peripheral Nervous System Diseases; Quality of Life
PubMed: 30695060
DOI: 10.1371/journal.pone.0211354 -
AIDS Research and Therapy Apr 2018The prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial...
BACKGROUND
The prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial concern in many low and middle-income countries. The Q151M and T69 insertion (T69i) resistance mutations in the viral reverse transcriptase gene can reduce susceptibility to all nucleoside/tide analogue reverse transcriptase inhibitors, motivating the present study to investigate the risk factors and outcomes associated with these mutations.
METHODS
We considered all data in the UK HIV Drug Resistance Database for blood samples obtained in the period 1997-2014. Where available, treatment history and patient outcomes were obtained through linkage to the UK Collaborative HIV Cohort study. A matched case-control approach was used to assess risk factors associated with the appearance of each of the mutations in ART-experienced patients, and survival analysis was used to investigate factors associated with viral suppression. A further analysis using matched controls was performed to investigate the impact of each mutation on survival.
RESULTS
A total of 180 patients with Q151M mutation and 85 with T69i mutation were identified, almost entirely from before 2006. Occurrence of both the Q151M and T69i mutations was strongly associated with cumulative period of virological failure while on ART, and for Q151M there was a particular positive association with use of stavudine and negative association with use of boosted-protease inhibitors. Subsequent viral suppression was negatively associated with viral load at sequencing for both mutations, and for Q151M we found a negative association with didanosine use but a positive association with boosted-protease inhibitor use. The results obtained in these analyses were also consistent with potentially large associations with other drugs. Analyses were inconclusive regarding associations between the mutations and mortality, but mortality was high for patients with low CD4 at detection.
CONCLUSIONS
The Q151M and T69i resistance mutations are now very rare in the UK. Our results suggest that good outcomes are possible for people with these mutations. However, in this historic sample, viral load and CD4 at detection were important factors in determining prognosis.
Topics: Anti-HIV Agents; Bayes Theorem; Case-Control Studies; Cohort Studies; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Molecular Epidemiology; Mutation; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Survival Analysis; Treatment Outcome; United Kingdom; Viral Load
PubMed: 29661246
DOI: 10.1186/s12981-018-0198-7 -
Drugs in Context 2018A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse... (Review)
Review
A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse effects and antiretroviral therapy is most robust with protease inhibitors, specifically atazanavir and indinavir, and includes reports of crystalluria, leukocyturia, nephritis, nephrolithiasis, nephropathy and urolithiasis. Several case reports describe potential nephropathy (including Fanconi syndrome) secondary to administration of abacavir, didanosine, lamivudine and stavudine. Case reports documented renal events such as acute renal failure, nephritis, proteinuria and renal stones with efavirenz administration. Regarding rilpivirine, a small increase of serum creatinine levels (SCr) was found in clinical trials; however, the clinical significance and impact on actual renal function is unknown. The integrase strand transfer inhibitors and enfuvirtide have a relatively safe renal profile, although studies have shown dolutegravir and raltegravir cause mild elevations in SCr without an impact on actual renal function. This is similar to the reaction observed with cobicistat, the pharmacokinetic enhancer frequently given with elvitegravir.
PubMed: 29623097
DOI: 10.7573/dic.212519 -
PloS One 2018Following widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy...
BACKGROUND
Following widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy (LA) and/or lipohypertrophy (LH). Following phasing-out of stavudine, incidence of newly-diagnosed LA and LH declined dramatically. However, the natural history of existing cases should be explored, particularly with prolonged protease inhibitor exposure.
METHODS
The Collaborative HIV Paediatric Study (CHIPS) is a multicentre cohort study of most HIV-infected children in the United Kingdom and Ireland. Those on ART with a LA/LH assessment recorded in 2003-2011 were included. Assessments were completed annually by consultant physicians. Using the 0-3 grading system, LA or LH was defined as grade 2 or 3. Resolution was defined as return to grade 1 or 0 in all body regions.
RESULTS
Of 1345 children followed for median (IQR) 5.5 (2.9, 8.2) years after ART initiation, 30 developed LA and 27 developed LH, all at least 2 years after ART initiation. Median age at LA diagnosis was 11 (10, 13) years and at LH diagnosis was 13 (11, 15) years. Children with LA were more likely white (p<0.0001); lower height-for-age z-score at ART initiation (p = 0.02); initiated ART earlier (p = 0.04), with longer ART exposure (p = 0.04). Children with LH were similar to those without. Analysis of individual drugs revealed that LA was associated with greater duration of exposure to stavudine and didanosine; while LH was associated with greater duration of exposure to stavudine and ritonavir (given alone or in combination with another protease inhibitor). Median time in follow-up following ART switch was 2.8 (1.9, 4.9) and 2.5 (1.6, 4.7) years respectively. Resolution occurred in 10 (30%) of LA cases (median time to resolution 2.3 [1.8, 3.6] years) and 3 (11%) of LH cases (median time to resolution 2.0 [1.7, 2.1] years).
CONCLUSIONS
Prevalence of LA and LH were low, with some resolution noted, especially for LA. More long-term data are needed.
Topics: Adolescent; Child; Female; HIV Infections; Humans; Incidence; Ireland; Lipodystrophy; Longitudinal Studies; Male; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; United Kingdom
PubMed: 29617438
DOI: 10.1371/journal.pone.0194132 -
AIDS (London, England) Jun 2018Factors affecting kidney function and proteinuria among HIV-positive (HIV+) and HIV-negative (HIV-) persons need better characterization.
BACKGROUND
Factors affecting kidney function and proteinuria among HIV-positive (HIV+) and HIV-negative (HIV-) persons need better characterization.
METHODS
We evaluated estimated glomerular filtration rate (eGFR, ml/min per 1.73 m) changes, proteinuria prevalence (a urine protein-to-creatinine ratio of ≥0.2 at two consecutive visits) and associated factors among HIV+ and HIV- men.
RESULTS
There were 917 HIV+ men receiving HAART, 159 HIV+ men not receiving HAART, and 1305 HIV- men seen from October 2003 to September 2014. Median annual eGFR change was -0.5, -0.8% for HIV+ and -0.3% for HIV- men (P < 0.001). Factors significantly (P < 0.05) associated with more than 3% annual eGFR decline were HAART receipt (but no specific antiretroviral drug), age more than 50, hypertension, diabetes, current smoking. Proteinuria existed in 14.9% of visit-pairs among HAART recipients, 5.8% among non-HAART recipients, and 1.9% among HIV- men, and was associated with subsequent annual more than 3% eGFR decline (odds ratio 1.80, P < 0.001). Proteinuria-associated factors also included HAART use (vs. HIV-), age at least 50 (vs. <40), diabetes, hypertension, current smoking, hepatitis C virus-infection (all P < 0.05) and, among HIV+ men, lower CD4 cell count, didanosine, saquinavir, or nelfinavir use (all P < 0.05). After adjusting for proteinuria, among HAART users, having a detectable HIV RNA, cumulative use of tenofovir disoproxil fumarate, emtricitabine, ritonavir, atazanavir, any protease inhibitor, or fluconazole were associated with more than 3% annual eGFR decline.
CONCLUSION
Longitudinal kidney function decline was associated with HAART use but no individual antiretroviral drug, and traditional kidney disease risks. Proteinuria was nearly seven times more common in HAART-treated men than HIV- men, reflected recent eGFR decline and predicted subsequent eGFR decline.
Topics: Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Glomerular Filtration Rate; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Prevalence; Prospective Studies; Proteinuria; Risk Factors; Young Adult
PubMed: 29561293
DOI: 10.1097/QAD.0000000000001807