HIV Clinical Trials[JOURNAL]
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200 papers
Renal and metabolic toxicities following initiation of HIV-1 treatment regimen in a diverse, multinational setting: a focused safety analysis of ACTG PEARLS (A5175).
Touzard Romo F, Smeaton LM, Campbell TB … +7 more , Riviere C, Mngqibisa R, Nyirenda M, Supparatpinyo K, Kumarasamy N, Hakim JG, Flanigan TP
HIV Clin Trials · 2014 · PMID 25433664 · Full text
BACKGROUND: Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic...
BACKGROUND: Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. METHODS: This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. RESULTS: Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). CONCLUSIONS: TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study.
Discontinuation of tenofovir disoproxil fumarate for presumed renal adverse events in treatment-naïve HIV-1 patients: meta-analysis of randomized clinical studies.
Winston J, Chonchol M, Gallant J … +7 more , Durr J, Canada RB, Liu H, Martin P, Patel K, Hindman J, Piontkowsky D
HIV Clin Trials · 2014 · PMID 25433663 · Publisher ↗
BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected a...
BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. METHODS: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. RESULTS: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). CONCLUSIONS: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.
Week 144 resistance analysis of elvitegravir/cobicistat/emtricitabine/tenofovir DF versus atazanavir+ritonavir+emtricitabine/tenofovir DF in antiretroviral-naïve patients.
Kulkarni R, Abram ME, McColl DJ … +6 more , Barnes T, Fordyce MW, Szwarcberg J, Cheng AK, Miller MD, White KL
HIV Clin Trials · 2014 · PMID 25350960 · Publisher ↗
OBJECTIVE: To describe baseline and emergent HIV-1 resistance to elvitegravir/ cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) and ritonavir-boosted atazanavir/emtricitabine/tenofovir DF (ATV+RTV+FTC/TDF) in HIV...
OBJECTIVE: To describe baseline and emergent HIV-1 resistance to elvitegravir/ cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) and ritonavir-boosted atazanavir/emtricitabine/tenofovir DF (ATV+RTV+FTC/TDF) in HIV-1-infected, treatment-naïve subjects through 144 weeks. METHOD: This was a randomized, double-blind, phase 3 study. HIV-1 protease (PR) and reverse transcriptase (RT) were sequenced at screening. Genotypic and phenotypic analyses were performed at virologic failure confirmation and retrospectively at baseline for PR, RT, and integrase (IN) for patients with virologic failure through week 144. RESULTS: In the EVG/ COBI/FTC/TDF group through week 144, HIV-1 from 8 patients (2.3%; 8/353 treated patients) developed primary IN strand transfer inhibitor (INSTI) (n = 6) and/or nucleoside RT inhibitor (NRTI) resistance substitutions (n = 7). The emergence of resistance decreased after the first year, with 5 patients developing HIV-1 resistance through week 48, 1 from weeks 48-96, and 2 from weeks 96-144. Emergent substitutions were E92Q, N155H, or Q148R (n = 2 each) and T66I or T97A (n = 1 each) in IN and M184V/I (n = 7) and K65R (n = 1) in RT. All 8 isolates had reduced susceptibility to EVG, FTC, or TDF. Virus with EVG phenotypic resistance showed cross-resistance to raltegravir. In the ATV+RTV+FTC/TDF group, HIV-1 from 2 patients (0.6%; 2/355 treated patients; both at week 144) developed the resistance substitution M184V/I in RT. CONCLUSIONS: Resistance development to EVG/COBI/FTC/TDF was infrequent (2.3%) through 144 weeks of therapy and decreased over time, consistent with durable efficacy.
Efficacy and safety of lersivirine versus etravirine for the treatment of HIV-1 infection in patients with prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance: a randomized phase 2B trial.
DeJesus E, Fätkenheuer G, Orrell C … +5 more , Wang C, Jones J, Craig C, Tawadrous M, Heera J
HIV Clin Trials · 2014 · PMID 25350959 · Publisher ↗
OBJECTIVE: To assess the efficacy and safety of lersivirine versus etravirine in patients with HIV-1 and prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance. METHODS: In this...
OBJECTIVE: To assess the efficacy and safety of lersivirine versus etravirine in patients with HIV-1 and prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance. METHODS: In this 96-week, phase 2b study, 97 patients were randomized and treated with lersivirine 750 mg qd (n = 31), lersivirine 1,000 mg qd (n = 32), and etravirine 200 mg bid (n = 34), plus one optimized nucleoside reverse transcriptase inhibitor and darunavir/ritonavir 600/100 mg bid. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/mL at week 24. RESULTS: At week 24, HIV-1 RNA <50 copies/mL was achieved by fewer patients receiving lersivirine 750 mg (48.4%) and 1,000 mg (43.8%) qd compared with etravirine 200 mg qd (67.7%) (intention to treat [ITT], missing/switch/discontinuation equals failure [MSDF]). At week 48, HIV-1 RNA <50 copies/mL and <400 copies/mL were also achieved by fewer patients receiving lersivirine 750 mg (41.9% and 41.9%, respectively) and 1,000 mg (31.3% and 34.4%, respectively) qd compared with etravirine 200 mg bid (61.8% and 70.6%, respectively) (ITT, MSDF). Least squares means (SE) change from baseline in log transformed HIV-1 RNA at week 48 was -1.42 (0.27) and -0.95 (0.28) copies/mL for lersivirine 750 mg and 1,000 mg qd, respectively, versus -2.02 (0.26) copies/mL for etravirine 200 mg bid (ITT). Lersivirine and etravirine were generally safe and well-tolerated. CONCLUSIONS: Lersivirine 750 mg and 1,000 mg qd was associated with lower rates of viral suppression at week 24 and week 48 versus etravirine in patients with prior NNRTI use and evidence of NNRTI resistance. No new safety signals were detected.
Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients.
Curtis L, Nichols G, Stainsby C … +9 more , Lim J, Aylott A, Wynne B, Clark A, Bloch M, Maechler G, Martin-Carpenter L, Raffi F, Min S
HIV Clin Trials · 2014 · PMID 25350958 · Publisher ↗
BACKGROUND: The efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the lit...
BACKGROUND: The efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the literature. OBJECTIVE: To describe the safety and tolerability profile of DTG in adults based on 5 randomized, controlled trials and comparison with drugs in 3 major antiretroviral (ARV) classes. METHODS: Safety data from phase IIb/III/IIIb trials in ART-naive and ART-experienced, INI-naive adults were integrated. RESULTS: In 4 ART-naive (SPRING-1, SPRING-2, SINGLE, FLAMINGO) and 1 ART-experienced, INI-naive study (SAILING), 1,579 individuals received a DTG-containing regimen. The proportion of individuals from DTG treatment arms who withdrew due to adverse events (AEs) was low (≤2%) compared to raltegravir (RAL; 2% SPRING-2, 4% SAILING), efavirenz (EFV)-containing comparator arm (10% SINGLE), and darunavir + ritonavir (DRV/r; 4% FLAMINGO). The most frequently observed AEs (diarrhea, nausea, headache), typically grade 1 or 2 in severity, did not lead to study discontinuation. Psychiatric and nervous system disorders with DTG were comparable to RAL- and DRV/r-containing regimens and favorable to EFV-containing regimens. In hepatitis B and/or C coinfected ART-naive individuals, the incidence of transaminase elevations was lower with DTG versus RAL and EFV comparators, but was similar to DRV/r. In SAILING, transaminase elevations were more commonly observed with DTG, particularly in the setting of inadequate hepatitis B therapy or immune reconstitution. On DTG treatment, mild creatinine elevations occurred and stabilized early. Few cases of hypersensitivity reaction and/or severe rash were seen. Rates of these events were comparable to or lower than with RAL-, EFV-, and DRV/r-containing regimens. CONCLUSIONS: The safety profile for DTG 50 mg once daily in INI-naive individuals was comparable to RAL- and DRV/r-containing regimens and generally favorable compared with EFV-containing regimens.
The impact of the 2013 WHO antiretroviral therapy guidelines on the feasibility of HIV population prevention trials.
Ross E, Tanser F, Pei P … +9 more , Newell ML, Losina E, Thiebaut R, Weinstein M, Freedberg K, Anglaret X, Scott C, Dabis F, Walensky R
HIV Clin Trials · 2014 · PMID 25350957 · Full text
BACKGROUND: Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization (WHO) guidelines raising the ART init...
BACKGROUND: Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization (WHO) guidelines raising the ART initiation threshold to CD4 <500/µL could attenuate these trials' effect size by increasing ART usage in control clusters. METHODS: We used a computational model to simulate strategies from a hypothetical cluster-randomized HIV prevention trial. The primary model outcome was the relative reduction in 24-month HIV incidence between control (ART offered with CD4 below threshold) and intervention (ART offered to all) strategies. We assessed this incidence reduction using the revised (CD4 <500/µL) and prior (CD4 <350/µL) control ART initiation thresholds. Additionally, we evaluated changes to trial characteristics that could bolster the incidence reduction. RESULTS: With a control ART initiation threshold of CD4 <350/µL, 24-month HIV incidence under control and intervention strategies was 2.46/100 person-years (PY) and 1.96/100 PY, a 21% reduction. Raising the threshold to CD4 <500/µL decreased the incidence reduction by more than one-third, to 12%. Using this higher threshold, moving to a 36-month horizon (vs 24-month), yearly control-strategy HIV screening (vs bian-nual), and intervention-strategy screening every 2 months (vs biannual), resulted in a 31% incidence reduction that was similar to effect size projections for ongoing trials. Alternate assumptions regarding cross-cluster contamination had the greatest influence on the incidence reduction. CONCLUSIONS: Implementing the 2013 WHO HIV treatment threshold could substantially diminish the incidence reduction in HIV population prevention trials. Alternative HIV testing frequencies and trial horizons can bolster this incidence reduction, but they could be logistically and ethically challenging. The feasibility of HIV population prevention trials should be reassessed as the implementation of treatment guidelines evolves.
Relationship between health-related quality of life measures and high HIV viral load in HIV-infected triple-class-experienced patients.
Bucciardini R, Pugliese K, Weimer L … +17 more , Digregorio M, Fragola V, Mancini M, Maroccia Z, Ladisa N, Francisci D, Bellagamba R, Degli Antoni A, Guaraldi G, Cirioni O, Ortu F, Parruti G, Mannazzu M, Libertone R, Donnini S, Floridia M, ISS-NIA Study Group
HIV Clin Trials · 2014 · PMID 25143026 · Publisher ↗
BACKGROUND: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing...
BACKGROUND: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing quality-adjusted survival has become a major target of HIV treatment. Although the association of HIV RNA and CD4 cell count with clinical HIV progression has been well established, the relation between these markers and HRQoL measures is still unclear. METHOD: This cross-sectional study investigated the relationship linking HIV RNA and CD4 to HRQoL measures in 181 triple-class-experienced patients with advanced HIV disease. The instrument used was the ISSQoL, a self-administered and HIV-specific HRQoL questionnaire. RESULTS: Data showed no correlation between HRQoL measures and CD4 counts. Higher HIV RNA levels were, however, associated with poor HRQoL scores in 3 out of 9 scales of social functioning, depression and anxiety, and satisfaction with quality of life. In multivariable analyses, only the satisfaction with quality of life mean score remained significantly lower for the HIV RNA ≯100,000 copies/mL group compared to the HIV RNA 50 to 10,000 copies/mL group. CONCLUSIONS: Although other determinants of HRQoL in people with HIV should also be considered, this finding suggests a negative impact of high viral load on perceived HRQoL that adds to other described determinants of lower quality of life in people with HIV, such as lower social support and self-reported symptoms.
Citalopram for the prevention of depression and its consequences in HIV-hepatitis C coinfected individuals initiating pegylated interferon/ribavirin therapy: a multicenter randomized double-blind placebo-controlled trial.
Klein MB, Lee T, Brouillette MJ … +12 more , Sheehan NL, Walmsley S, Wong DK, Conway B, Hull M, Cooper C, Haidar S, Vezina S, Annable L, Young S, Zubyk W, Singer J
HIV Clin Trials · 2014 · PMID 25143025 · Publisher ↗
BACKGROUND: Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have...
BACKGROUND: Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefit from prevention of depression. OBJECTIVE: The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-α/ribavirin therapy. METHODS: This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-α2b/ribavirin, stratified by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDI- II) score greater than 15, confirmed 2 weeks apart. RESULTS: Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ significantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. CONCLUSIONS: A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it significantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV.
Liver enzyme elevation during darunavir-based antiretroviral treatment in HIV-1-infected patients with or without hepatitis C coinfection: data from the ICONA foundation cohort.
Di Biagio A, Nicolini LA, Lorenzini P … +10 more , Puoti M, Antinori A, Cozzi-Lepri A, Gori A, Vecchiet J, Mussini C, Andreoni M, Viscoli C, d'Arminio Monforte A, For The Icona Foundation Study Group
HIV Clin Trials · 2014 · PMID 25143024 · Publisher ↗
OBJECTIVES: To investigate differences in liver enzyme elevation (LEE) between HIV-infected patients with and without HCV coinfection who start a darunavir/ritonavir-containing regimen. METHODS: HIV-infected patients enr...
OBJECTIVES: To investigate differences in liver enzyme elevation (LEE) between HIV-infected patients with and without HCV coinfection who start a darunavir/ritonavir-containing regimen. METHODS: HIV-infected patients enrolled in the Italian Cohort of Naïve to Antiretrovirals (ICONA) Foundation Study were included if they started darunavir/ritonavir for the first time. Patients were classified as not HCV coinfected, HCV active coinfected (HCV RNA positive), and HCV nonactive coinfected (HCV-Ab positive/HCV RNA negative). Time to LEE endpoint was defined using the ACTG toxicity scale, based on changes relative to baseline. Kaplan-Meier was used to estimate 1-year and 2-year probability of LEE. The incidence rate ratios (IRRs) of LEEs were estimated until the last follow-up (intention-to-treat analysis [ITT]) and up to darunavir/ritonavir discontinuation (on-treatment analysis [OT]). RESULTS: Overall, 703 patients were included. Ninety-one were HCV-Ab positive; of those, 68 (9.7%) had active HCV coinfection. In 879 person-years of follow-up, 101 LEEs occurred (ITT). No severe hepatotoxicity event was registered in active HCV coinfected patients. HCV active coinfection was predictive of LEE in the overall population (OT: adjusted incidence rate ratio (IRR), 2.25; 95% CI, 0.70-7.24; P = .17; ITT: adjusted IRR, 3.62; 95% CI, 1.67-7.83; P < .001) and in naïve patients (OT: adjusted IRR, 6.29; 95% CI, 2.54-15.55; P = .00; ITT: adjusted IRR, 3.87; 95% CI, 0.99-15.16; P = .05). CONCLUSIONS: No grade 3-4 LEEs occurred in HCV active coinfected patients. HCV active coinfected patients experienced low grade LEEs more frequently than HCV-Ab negative patients. Darunavir/ritonavir seems to be safe whatever the HCV status, when liver enzymes are carefully monitored.
Efficacy and safety of darunavir/ritonavir plus etravirine dual regimen in antiretroviral therapy-experienced patients: a multicenter clinical experience.
Gazzola L, Cicconi P, Ripamonti D … +6 more , Di Filippo E, Gustinetti G, Di Biagio A, Marchetti G, Bini T, d'Arminio Monforte A
HIV Clin Trials · 2014 · PMID 25143023 · Publisher ↗
OBJECTIVES: To assess the outcome of a dual regimen combining darunavir/ritonavir plus etravirine in a cohort of antiretroviral therapy (ART)-experienced patients. METHODS: A retrospective analysis was performed on all A...
OBJECTIVES: To assess the outcome of a dual regimen combining darunavir/ritonavir plus etravirine in a cohort of antiretroviral therapy (ART)-experienced patients. METHODS: A retrospective analysis was performed on all ART-experienced patients starting a darunavir/ritonavir plus etravirine regimen at the 3 clinics. Patients were stratified according to HIV RNA detectability (≥ 40 copies/mL) at baseline. Two efficacy endpoints were evaluated by Kaplan-Meier and Cox multivariable models: virological failure (confirmed HIV RNA ≥ 40 copies/mL after 6 months) and therapeutic failure (including virological failure and treatment discontinuation for any reason). RESULTS: Sixty-eight patients were included in the study. They had a median of 10.8 years on ART and 5 previous ART regimens; 61.3% showed primary protease inhibitor (PI) mutations and 70% showed previous non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure. HIV RNA was detectable in 34 (50%) patients. The median observation period was 21 (interquartile range [IQR], 11.9-25.1) months. After 24 months, 75.1% of the patients were still on the study regimen and 88.8% remained free from virological failure. Although a higher therapeutic failure rate was reported in patients with detectable viremia at baseline, only the immunological status revealed an independent predictive role. No differences in virological failure were observed according to HIV RNA detectability at baseline; a higher number of previous ART regimens was the only predictor. Discontinuation due to adverse events occurred in 5.9%. CONCLUSIONS: Darunavir/ritonavir plus etravirine regimen proved virological efficacy and safety in heavily pretreated patients with a high rate of virological success, even in patients who switched during virological failure.
Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164.
Grant PM, Komarow L, Sanchez A … +4 more , Sattler FR, Asmuth DM, Pollard RB, Zolopa AR
HIV Clin Trials · 2014 · PMID 25143022 · Full text
BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the...
BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.
Characteristics of persistent hyponatremia and tolvaptan treatment in nine hospitalized patients with advanced HIV disease.
Wen Y, Zhou Y, Wang W … +4 more , Wang Y, Lu X, Sun C, Liu P
HIV Clin Trials · 2014 · PMID 24947536 · Publisher ↗
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Factors associated with study attrition among HIV-infected risky drinkers in St. Petersburg, Russia.
Kiriazova T, Cheng DM, Coleman SM … +6 more , Blokhina E, Krupitsky E, Lira MC, Bridden C, Raj A, Samet JH
HIV Clin Trials · 2014 · PMID 24947535 · Full text
BACKGROUND: Participant attrition in HIV longitudinal studies may introduce bias and diminish research quality. The identification of participant characteristics that are predictive of attrition might inform retention st...
BACKGROUND: Participant attrition in HIV longitudinal studies may introduce bias and diminish research quality. The identification of participant characteristics that are predictive of attrition might inform retention strategies. OBJECTIVE: The study aimed to identify factors associated with attrition among HIV-infected Russian risky drinkers from the secondary HIV prevention HERMITAGE trial. We examined whether current injection drug use (IDU), binge drinking, depressive symptoms, HIV status nondisclosure, stigma, and lifetime history of incarceration were predictors of study attrition. We also explored effect modification due to gender. METHODS: Complete loss to follow-up (LTFU), defined as no follow-up visits after baseline, was the primary outcome, and time to first missed visit was the secondary outcome. We used multiple logistic regression models for the primary analysis, and Cox proportional hazards models for the secondary analysis. RESULTS: Of 660 participants, 101 (15.3%) did not return after baseline. No significant associations between independent variables and complete LTFU were observed. Current IDU and HIV status nondisclosure were significantly associated with time to first missed visit (adjusted hazard ratio [AHR], 1.39; 95% CI, 1.03-1.87; AHR, 1.38; 95% CI, 1.03-1.86, respectively). Gender stratified analyses suggested a larger impact of binge drinking among men and history of incarceration among women with time to first missed visit. CONCLUSIONS: Although no factors were significantly associated with complete LTFU, current IDU and HIV status nondisclosure were significantly associated with time to first missed visit in HIV-infected Russian risky drinkers. An understanding of these predictors may inform retention efforts in longitudinal studies.
Rate, predictors, and consequences of late antenatal booking in a national cohort study of pregnant women with HIV in Italy.
Floridia M, Pinnetti C, Ravizza M … +12 more , Frisina V, Cetin I, Fiscon M, Sansone M, Antoni AD, Guaraldi G, Vimercati A, Guerra B, Placido G, Dalzero S, Tamburrini E, Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy
HIV Clin Trials · 2014 · PMID 24947534 · Publisher ↗
OBJECTIVE: To evaluate the prevalence and consequences of late antenatal booking (13 or more weeks gestation) in a national observational study of pregnant women with HIV. METHODS: The clinical and demographic characteri...
OBJECTIVE: To evaluate the prevalence and consequences of late antenatal booking (13 or more weeks gestation) in a national observational study of pregnant women with HIV. METHODS: The clinical and demographic characteristics associated with late booking were evaluated in univariate analyses using the Mann-Whitney U test for quantitative data and the chi-square test for categorical data. The associations that were found were re-evaluated in multivariable logistic regression models. Main outcomes were preterm delivery, low birthweight, nonelective cesarean section, birth defects, undetectable (<50 copies/mL) HIV plasma viral load at third trimester, delivery complications, and gender-adjusted and gestational age-adjusted Z scores for birthweight. RESULTS: Rate of late booking among 1,643 pregnancies was 32.9%. This condition was associated with younger age, African provenance, diagnosis of HIV during pregnancy, and less antiretroviral exposure. Undetectable HIV RNA at third trimester and preterm delivery were significantly more prevalent with earlier booking (67.1% vs 46.3%, P < .001, and 23.2% vs 17.6, P = .010, respectively), whereas complications of delivery were more common with late booking (8.2% vs 5.0%, P = .013). Multivariable analyses confirmed an independent role of late booking in predicting detectable HIV RNA at third trimester (adjusted odds ratio [AOR], 1.7; 95% CI, 1.3-2.3; P < .001) and delivery complications (AOR, 1.8; 95% CI, 1.2-2.8; P = .005). CONCLUSIONS: Late antenatal booking was associated with detectable HIV RNA in late pregnancy and with complications of delivery. Measures should be taken to ensure an earlier entry into antenatal care, particularly for African women, and to facilitate access to counselling and antenatal services. These measures can significantly improve pregnancy management and reduce morbidity and complications in pregnant women with HIV.
Virologic and immunologic responses in treatment-naive patients to ritonavir-boosted atazanavir or efavirenz with a common backbone.
Wang Q, Young J, Bernasconi E … +8 more , Vernazza P, Calmy A, Cavassini M, Furrer H, Fehr J, Bucher HC, Battegay M, Swiss HIV Cohort Study
HIV Clin Trials · 2014 · PMID 24947533 · Publisher ↗
BACKGROUND: Atazanavir boosted with ritonavir (ATV/r) and efavirenz (EFV) are both recommended as first-line therapies for HIV-infected patients. We compared the 2 therapies for virologic efficacy and immune recovery. ME...
BACKGROUND: Atazanavir boosted with ritonavir (ATV/r) and efavirenz (EFV) are both recommended as first-line therapies for HIV-infected patients. We compared the 2 therapies for virologic efficacy and immune recovery. METHODS: We included all treatment-naïve patients in the Swiss HIV Cohort Study starting therapy after May 2003 with either ATV/r or EFV and a backbone of tenofovir and either emtricitabine or lamivudine. We used Cox models to assess time to virologic failure and repeated measures models to assess the change in CD4 cell counts over time. All models were fit as marginal structural models using both point of treatment and censoring weights. Intent-to-treat and various as-treated analyses were carried out: In the latter, patients were censored at their last recorded measurement if they changed therapy or if they were no longer adherent to therapy. RESULTS: Patients starting EFV (n = 1,097) and ATV/r (n = 384) were followed for a median of 35 and 37 months, respectively. During follow-up, 51% patients on EFV and 33% patients on ATV/r remained adherent and made no change to their first-line therapy. Although intent-to-treat analyses suggest virologic failure was more likely with ATV/r, there was no evidence for this disadvantage in patients who adhered to first-line therapy. Patients starting ATV/r had a greater increase in CD4 cell count during the first year of therapy, but this advantage disappeared after one year. CONCLUSIONS: In this observational study, there was no good evidence of any intrinsic advantage for one therapy over the other, consistent with earlier clinical trials. Differences between therapies may arise in a clinical setting because of differences in adherence to therapy.
The problem of renal function monitoring in patients treated with the novel antiretroviral drugs.
Maggi P, Montinaro V, Rusconi S … +7 more , Di Biagio A, Bellagamba R, Bonfanti P, Calza L, Corsi P, Montella F, Mussini C
HIV Clin Trials · 2014 · PMID 24947532 · Publisher ↗
Chronic kidney disease (CKD) is currently considered a major comorbidity in patients affected by HIV infection. In addition, new generation antiretroviral drugs that interact with creatinine transporters were recently in...
Chronic kidney disease (CKD) is currently considered a major comorbidity in patients affected by HIV infection. In addition, new generation antiretroviral drugs that interact with creatinine transporters were recently introduced. Rilpivirine, dolutegravir, and cobicistat, with different mechanisms, inhibit the amount of tubular secretion of creatinine causing a slight increase in serum creatinine levels and consensual eGFRcreat reduction. This will require an unprecedented attention to renal issues, because the new drugs can also be associated to old antiretroviral drugs that may exert renal toxic effects. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimating GFR would be desirable. At the moment, methods of direct GFR measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate GFR is still recommended, considering the apparent reduction of eGFRcreat due to these drugs. Tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid. More specific and sensitive markers of tubular damage are still not readily available in all clinical labs. HIV patients treated by the novel drugs need to be monitored on a monthly basis for the first 3 months. Subsequent monitoring should be performed on a quarterly basis or guided by comorbidities.
Is there a higher risk of CNS adverse events for PI monotherapy versus triple therapy? A review of results from randomized clinical trials.
Powderly W, Hill A, Moecklinghoff C
HIV Clin Trials · 2014 · PMID 24947531 · Publisher ↗
BACKGROUND: Protease inhibitor (PI) monotherapy for treatment could avoid the adverse events, drug resistance, and additional costs associated with other antiretrovirals that are normally used, particularly the nucleosid...
BACKGROUND: Protease inhibitor (PI) monotherapy for treatment could avoid the adverse events, drug resistance, and additional costs associated with other antiretrovirals that are normally used, particularly the nucleoside analogues. PI monotherapy has mainly been compared with standard triple therapy in randomized clinical trials of patients who have HIV RNA suppression at screening and no history of virological failure. METHODS: This review included 11 randomized clinical trials of darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r) monotherapy versus triple therapy in 1,267 patients with HIV RNA suppression at baseline who were studied between 48 and 144 weeks. RESULTS: There was no clear difference in the risk of central nervous system (CNS) adverse events between PI monotherapy (either DRV/r or LPV/r) and standard triple drug treatment. There were 2 clinical trials - MONOI (DRV/r) and MOST (LPV/r) - that showed CNS symptoms and detectable HIV RNA levels in the cerebrospinal fluid in a small number of individuals taking PI monotherapy. CONCLUSIONS: There was no consistent evidence from the randomized trials currently available for an additional risk of HIV CNS disease during monotherapy with either LPV/r or DRV/r versus standard triple drug therapy. However, the information on CNS adverse events has not been reported using standardized definitions in the studies. In addition, few randomized studies included detailed analysis of neurocognitive function or detection of HIV RNA in the cerebrospinal fluid.
Aerobic fitness levels and validation of a non exercise VO2max prediction equation for HIV-infected patients on HAART.
Sullivan K, Shikuma CM, Chow D … +6 more , Cornelius E, Romine RK, Lindsey RA, Stickley CD, Kimura IF, Hetzler RK
HIV Clin Trials · 2014 · PMID 24710921 · Full text
BACKGROUND: Non-exercise (N-EX) questionnaires have been developed to determine maximal oxygen consumption (VO2max) in healthy populations. There are limited reliable and validated N-EX questionnaires for the HIV+ popula...
BACKGROUND: Non-exercise (N-EX) questionnaires have been developed to determine maximal oxygen consumption (VO2max) in healthy populations. There are limited reliable and validated N-EX questionnaires for the HIV+ population that provide estimates of habitual physical activity and not VO2max. OBJECTIVES: To determine how well regression equations developed previously on healthy populations, including N-EX prediction equations for VO2max and age-predicted maximal heart rates (APMHR), worked on an HIV+ population; and to develop a specific N-EX prediction equation for VO2max and APMHR for HIV+ individuals. METHODS: Sixty-six HIV+ participants on stable HAART completed 4 N-EX questionnaires and performed a maximal graded exercise test. RESULTS: Sixty males and 6 females were included; mean (SD) age was 49.2 (8.2) years; CD4 count was 516.0 ± 253.0 cells·mm-3; and 92% had undetectable HIV PCR. Mean VO2max was 29.2 ± 7.6 (range, 14.4-49.4) mL·kg-1·min-1 Despite positive correlations with VO2max, previously published N-EX VO2max equations produced results significantly different than actual VO2 scores (P < .0001). An HIV+ specific N-EX equation was developed and produced similar mean VO2max values, R = 0.71, when compared to achieved VO2max (P = .53). CONCLUSION: HIV+ individuals tend to be sedentary and unfit, putting them at increased risk for the development of chronic diseases associated with a sedentary lifestyle. Based on the level of error associated with utilizing APMHR and N-EX VO2max equations with HIV+ individuals, neither should be used in this population for exercise prescription.
Failure to identify HIV-infected individuals in a clinical trial using a single HIV rapid test for screening.
Piwowar-Manning E, Fogel JM, Laeyendecker O … +17 more , Wolf S, Cummings V, Marzinke MA, Clarke W, Breaud A, Wendel S, Wang L, Swanson P, Hackett J, Mannheimer S, Del Rio C, Kuo I, Harawa NT, Koblin BA, Moore R, Blankson JN, Eshleman SH
HIV Clin Trials · 2014 · PMID 24710920 · Full text
BACKGROUND: In the HIV Prevention Trials Network (HPTN) 061 study, 8 (2.3%) of 348 HIV-infected participants identified as HIV uninfected at study enrollment using a single HIV rapid test for screening were found to be H...
BACKGROUND: In the HIV Prevention Trials Network (HPTN) 061 study, 8 (2.3%) of 348 HIV-infected participants identified as HIV uninfected at study enrollment using a single HIV rapid test for screening were found to be HIV infected after additional testing. OBJECTIVES: To evaluate the performance of different HIV assays for detection of HIV infection in HPTN 061 participants with missed infection and individuals with viral suppression. METHODS: Plasma samples from 8 HPTN 061 participants, 17 elite controllers, and 101 individuals on antiretroviral treatment (ART) were tested for HIV with 3 rapid tests, 2 laboratory-based immunoassays, and a Western blot assay. The HPTN 061 samples were also tested with 2 HIV RNA assays and an antiretroviral drug assay. RESULTS: Of the 8 HPTN 061 participants with missed infection, 1 was an elite controller, 1 was taking ART, 2 were missed because of testing or clerical errors, 1 had recent HIV infection (identified using a multi-assay algorithm), and 3 had acute HIV infection. Two (1.7%) of 118 individuals with viral suppression (both taking ART) had at least 1 false-negative test. CONCLUSIONS: In clinical trials, HIV infections can be missed for a variety of reasons. Using more than one assay to screen for HIV infection may reduce the number of missed infections.
Switching to an etravirine-containing regimen due to drug intolerance in clinical practice.
Martín-Carbonero L, Moreno V, Ramírez-Olivenza G … +1 more , Valencia E
HIV Clin Trials · 2014 · PMID 24710919 · Publisher ↗
BACKGROUND: Drug intolerance is one of the main reasons for switching antiretroviral therapy in HIV-infected patients. Etravirine (ETR) has demonstrated good tolerability in clinical trials and may be an option for patie...
BACKGROUND: Drug intolerance is one of the main reasons for switching antiretroviral therapy in HIV-infected patients. Etravirine (ETR) has demonstrated good tolerability in clinical trials and may be an option for patients who switch therapy due to adverse events. METHODS: We retrospectively reviewed all patients who had switched to an ETR-containing regimen in our center due to side effects. Virological suppression, ETR discontinuation, and reasons for discontinuation were studied. RESULTS: A total of 78 patients started treatment with ETR in our center due to previous regimen toxicity. Most of them were men (83.3%), and the median time of infection was 14 years (IQR, 6.5-20 years). HIV RNA was <35 copies/mL in 88.3% of patients, although 33% had archived non-nucleos(t)ide reverse transcriptase inhibitor (NNRTI) mutations that did not compromise ETR efficacy. Efavirenz was the drug most often replaced (38.5%), followed by atazanavir (20.5%) and lopinavir (6.4%). The fixed combination of Trizivir was changed in another 10.3% of patients. After a median follow-up of 14 months (IQR, 6-23), the rate of virologic suppression was 79.5% and 98.4% in intention-to-treat and on-treatment analysis, respectively. Seven patients discontinued treatment due to adverse events (3 gastrointestinal disturbances, 2 rashes, 1 swelling, and 1 neuropathy). ETR was combined with 2 nucleos(t)ide analogues in 75.4% of patients. CONCLUSION: In HIV patients who report drug side effects, switching to an ETR-containing regimen is a safe strategy in terms of virological suppression and toxicity.
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