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Babafemi Taiwo,
Roy M Matining,
Lu Zheng,
Michael M Lederman,
Charles R Rinaldo,
Peter S Kim,
Baiba I Berzins,
Daniel R Kuritzkes,
Amy Jennings, Joseph J Eron,
Cara C Wilson
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ABSTRACT: OBJECTIVES: One of the goals of antiretroviral therapy (ART) is to attenuate HIV-induced systemic immune activation and inflammation. We determined the dynamics of biomarkers of immune activation, microbial translocation and inflammation during initial ART with a nucleos(t)ide-sparing regimen of darunavir/ritonavir plus raltegravir. We also evaluated associations between these biomarkers and the virological response to the regimen. METHODS: We determined baseline and week 24 and 48 levels of CD4+ and CD8+ T cell activation (% HLA-DR+/CD38+), interleukin-6 (IL-6), interferon-γ-inducible protein-10 (IP-10), soluble CD14 (sCD14), D-dimer and lipopolysaccharide. Associations between the biomarkers at baseline were assessed using Spearman's rank correlation. The Wilcoxon signed rank test analysed changes from baseline. Comparisons between groups were made using the Wilcoxon rank sum test, and Cox proportional hazards models assessed predictors of virological failure (VF). RESULTS: Assays were completed on 107 of 112 subjects after excluding five subjects who had only baseline samples. The subjects included were 94 (88%) men with a median age of 37 years, a median baseline CD4 count of 261.5 cells/mm(3) and a median baseline viral load (VL) of 75 876 copies/mL. Subjects with a baseline VL >100 000 copies/mL had higher baseline T cell activation, IL-6, IP-10, sCD14 and D-dimer. These biomarkers declined during treatment (P < 0.05). Although subjects who experienced VF had higher baseline CD4+ T cell activation (P = 0.035), only baseline VL independently predicted VF (hazard ratio for >100 000 versus ≤100 000 copies/mL was 4.5-5.6, P ≤ 0.002). CONCLUSIONS: Darunavir/ritonavir plus raltegravir attenuated immune activation, inflammation and microbial translocation. T cell activation remained higher in subjects with VF than those without. Baseline VL >100 000 copies/mL remained the primary driver of VF.
Journal of Antimicrobial Chemotherapy 04/2013; · 5.07 Impact Factor
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Julia C Dombrowski,
Mari M Kitahata,
Stephen E Van Rompaey,
Heidi M Crane,
Michael J Mugavero, Joseph J Eron,
Stephen L Boswell,
Benigno Rodriguez,
W Christopher Mathews,
Jeffrey N Martin,
Richard D Moore,
Matthew R Golden
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ABSTRACT: BACKGROUND:: Contemporary data on patterns of antiretroviral therapy (ART) use in the U.S. are needed to inform efforts to improve the HIV care cascade. METHODS:: We conducted a cross-sectional study of patients in the Centers for AIDS Research Network of Integrated Clinical Systems cohort who were in HIV care in 2010 to assess ART use and outcomes, stratified by nadir CD4 count (≤350, 351-500, or >500 cells/mm), demographics, psychiatric diagnoses, substance use, and engagement in continuous care (≥2 visits ≥3 months apart in 2010). RESULTS:: Of 8633 patients at 7 sites who had ≥1 medical visit and ≥1 viral load (VL) in 2010, 94% had ever initiated ART, 89% were on ART, and 70% had an undetectable VL at the end of 2010. Fifty percent of ART-naïve patients had nadir CD4 counts >500 cells/mm, but this group composed just 3% of the total population. Among patients who were ART-naïve at the time of cohort entry (N=4637), both ART initiation and viral suppression were strongly associated with nadir CD4 count. Comparing 2009 and 2010, the percentages of patients with viral suppression among those with nadir CD4 counts 351-500 and >500 cells/mm were 44% vs. 57% and 25% vs. 33%, respectively. Engagement in care was the only factor consistently associated with ART use and viral suppression across nadir CD4 count strata. CONCLUSIONS:: Our findings suggest that ART use and viral suppression among persons in HIV care may be more common than estimated in some prior studies and increased from 2009 to 2010.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2013; · 4.43 Impact Factor
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ABSTRACT: Background: Data on integrase strand transfer inhibitor (InSTI) resistance come primarily from clinical trials and in vitro studies. We examined InSTI resistance among patients in the U.S., using results from genotypic resistance testing (GRT) performed at a referral lab from 2009-2012.
Methods: Sequences of HIV-1 integrase and pol genes were obtained from samples submitted specifically for InSTI GRT; basic demographic data were collected. We analyzed and scored de-identified results using the Stanford HIV Database. InSTI resistance was defined as having ≥1 of T66AIK, E92QV, F121Y, E138AK, G140ACS, Y143CHR, S147G, Q148HKR, or N155H. Select reverse transcriptase and protease inhibitor mutations and scores were recorded.
Results: We analyzed 1905 sequences from InSTI GRT, representing 1764 patients in 39 states; 1168 (66%) had paired pol sequences. The number of tests increased over time, from 73 in 2009 to 1097 in 2011. Mean age was 43.4 years (SD, 10.8); 30% were female. Subtype B predominated (98%), but A, C, CRF01_AE, CRF02_AG, D, F, and G were observed.
InSTI resistance (any level) was detected in 353 patients (20%); 345 (18%) had intermediate or high-level raltegravir resistance. Q148+G140 was present in 137 patients; 135 had N155H. Two specimens harbored F121Y, rarely described in clinical samples. Among 114 patients with sequential samples, 8 had initial mutations fade, 12 had new mutations develop, 7 had no change in mutations over time, and 87 had no mutations seen. Only 1 patient accumulated mutations, adding E138A to G140S+Q148H after 7 months.
InSTI-resistant patients were older (mean 46.3 vs 42.7 years), with more mutations and higher mean resistance scores for NRTIs, NNRTIs, and PIs (all P<0.001). Among those with pol data, four-class resistance was detected in 47 patients (4%); 31 (2.7%) had only InSTI mutations. Sex, geographic region, and year sequenced were not associated with InSTI resistance.
Conclusions: One in five U.S. patients undergoing InSTI GRT for clinical decision-making harbors significant resistance; many appear highly antiretroviral-experienced, based on pol data. N155 and Q148+G140 pathways were equally represented. Dolutegravir is likely to be active against most variants observed. Low numbers of tests relative to pol GRT during the same period (~120,000) suggest pretreatment InSTI resistance is not being routinely assessed. Age and RTI/PI resistance are associated with InSTI resistance.
20th Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta, Georgia; 03/2013
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Elizabeth L Yanik,
Sonia Napravnik,
Patrick Ryscavage, Joseph J Eron,
Susan L Koletar,
Richard D Moore,
Anne Zinski,
Stephen R Cole,
Peter Hunt,
Heidi M Crane,
James Kahn,
W Christopher Mathews,
Kenneth Mayer,
Babafemi Taiwo
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ABSTRACT: We assessed laboratory monitoring following combination antiretroviral therapy (cART) initiation among 3,678 patients in a large US multi-site clinical cohort, censoring participants at last clinic visit, cART change, or three years. Median days (interquartile range) to first hematologic, hepatic, renal and lipid tests were 30 (18-53), 31 (19-56), 33 (20-59) and 350 (96-1106), respectively. At one year, approximately 80% received more than two hematologic, hepatic, and renal tests consistent with guidelines. However, only 40% received one or more lipid tests. Monitoring was more frequent in specific subgroups, likely reflecting better clinic attendance or clinician perception of higher susceptibility to toxicities.
JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2013; · 4.43 Impact Factor
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Babafemi Taiwo,
Elizabeth L Yanik,
Sonia Napravnik,
Patrick Ryscavage,
Susan L Koletar,
Richard Moore,
W Christopher Mathews,
Heidi M Crane,
Kenneth Mayerr,
Anne Zinski,
James S Kahn, Joseph J Eron
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ABSTRACT: OBJECTIVE:: Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000-2010 across the United States. DESIGN:: Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort METHODS:: Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation. RESULTS:: 3,470 individuals contributed 3,639 person-years. Median age, pre-cART CD4 and follow-up duration were 40 years, 206 cells/mm and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post cART initiation were: lipid = 49 (95% Confidence Interval [CI]: 41-58); hematologic = 44 (40-49); hepatic = 24 (20-27); and renal = 9 (7-11), dropping substantially during weeks 17-104 of cART to lipid = 23 (18-29); hematologic = 5 (4-6); hepatic = 6 (5-8); and renal = 2 (1-3) (all p < 0.05). Among patients receiving initial cART with no prior abnormality (N = 1889), strongest associations for hepatic abnormalities after 16 weeks were hepatitis B and C, hazard ratios (HR) = 2.3 (95%CI: 1.2-4.5) and HR = 3.0 (1.9-4.5), respectively. The strongest association for renal abnormalities was hypertension, HR = 2.8 (1.4-5.6). CONCLUSION:: New abnormalities decreased after week 16 of cART. For abnormalities not present by week 16, subsequent monitoring should be guided by co-morbidities.
AIDS (London, England) 02/2013; · 4.91 Impact Factor
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ABSTRACT: Abstract The Southeastern United States (US) has a rapidly growing Latino population, yet little is known about HIV-infected Latinos in the region. To help inform future prevention studies, we compared sociodemographic, clinical, and behavioral characteristics between immigrant and US-born HIV-infected Latinos using face-to-face interviews conducted at three clinics in North Carolina. Questions encompassed HIV testing, acculturation, sexual- and substance-related behaviors, and migration history. Behavioral data were compared with 451 black and white clinic patients. Differences were tested using Pearson's and Kruskal-Wallis tests. Participants (n=127) were primarily male (74%) and immigrants (82%). Most immigrants were Mexican (67%), had low acculturation scores (92%), and were diagnosed a median of 8 years (IQR 0-12) following immigration. Compared with US-born Latinos, immigrants had lower CD4 counts at clinic entry (median 187 vs. 371 cells/mm(3)) and were less likely to have graduated high school (49% vs. 78%) or have insurance (9% vs. 52%; all P <0.05). Most immigrants identified as heterosexual (60%) and reported fewer lifetime partners than US-born Latinos (median 6 vs. 20; P=0.001). Immigrant men were less likely to report sex with men than US-born men (43% vs. 81%; P=0.005). Immigrant men also had similar risk behaviors to black men, and US-born Latino men exhibited behaviors that were more similar to white men in our clinic. At the time of survey, >90% of participants were receiving antiretroviral therapy (ART) and most had achieved HIV RNA <50 copies/mL (62% immigrants vs. 76% US-born; P=0.32). In conclusion, Latino immigrants were more likely to present with advanced disease, identify as heterosexual, and report different risk behaviors than US-born Latinos, yet receipt and response to ART were similar between the two groups. Prevention strategies should prioritize finding innovative methods to reach Latino immigrants for routine early testing regardless of risk stratification and include programs targeted toward the different needs of immigrant and US-born Latinos.
AIDS Care 02/2013; · 1.60 Impact Factor
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ABSTRACT: BACKGROUND: In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viremia and ex vivo recovery of infectious virus from latently-infected CD4 cells is uncertain. METHODS: We measured residual viremia (HIV-1 RNA copies/mL) by single-copy assay (SCA) and the latent reservoir by infectious virus recovery from resting memory CD4 cells (infectious units per million cells [IUPM]) in patients who initiated ART. We assessed immune activation by measuring CD38 expression on T cells. RESULTS: Ten patients who initiated ART and maintained a plasma HIV-1 RNA level <200 copies/mL had residual viremia and IUPM measured every 24 weeks. Five of 10 patients had longitudinal IUPM measured at weeks 24-96; the remainder had IUPM measured 1-3 times over 24-72 weeks. Analyses of 29 paired measurements revealed a positive association between level of residual viremia and IUPM (0.56 higher log(10) HIV-1 RNA copies/mL per 1 log(10) higher IUPM, p=0.005). Residual viremia level was positively associated with CD38 density and percentage on CD8+T-cells in concurrent samples and with pre-ART HIV-1 RNA levels. CONCLUSIONS: In patients with HIV-1 RNA levels <200 copies/mL 24-96 weeks after initiating ART, the level of viremia is positively associated with infectious virus recovery from resting memory CD4 cells. Whether this association persists after longer-term suppressive ART needs to be determined. If additional studies show that residual viremia measured by SCA reflects the size of the latent reservoir in patients who have had virologic suppression for longer periods of time, this could facilitate testing of potentially curative strategies to reduce this important reservoir.
Antiviral therapy 01/2013; · 3.16 Impact Factor
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Kathleen Squires,
Linda-Gail Bekker, Joseph J Eron,
Benjamin Cheng,
Juergen K Rockstroh,
Farid Marquez,
Princy Kumar,
Melanie Thompson,
Rafael Campo,
Karam Mounzer,
Kim M Strohmaier,
Chengxing Lu,
Anthony Rodgers,
Beth E Jackson,
Larissa Wenning,
Michael Robertson,
Bach-Yen T Nguyen,
Peter Sklar
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ABSTRACT: Objectives: The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. Methods: Multicenter, open-label, single-arm observational study in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in US), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naïve patients (limited to ≤20%). All patients received raltegravir 400 mg bid in a combination antiretroviral regimen for up to 48 weeks. Results: 206 patients received study treatment at 34 sites in the US, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in US]. 185 patients were treatment-experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment-naïve. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA <50 copies/mL at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, 17% of non-blacks. At week 48, HIV RNA was <50 copies/mL in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naïve patients. Response rates were similar for men vs women and black vs non-black patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of non-blacks. Conclusion: After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race.
AIDS research and human retroviruses 01/2013; · 2.18 Impact Factor
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ABSTRACT: Initiation of ART during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful ART, and maintained viral suppression through 96 weeks. Pre-therapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and while this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, p=0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2013; · 4.43 Impact Factor
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Alison G Abraham,
Howard D Strickler,
Yuezhou Jing,
Stephen J Gange,
Timothy R Sterling,
Michael Silverberg,
Michael Saag,
Sean Rourke,
Anita Rachlis,
Sonia Napravnik, [......],
James J Goedert,
M John Gill,
Kelly Gebo, Joseph J Eron,
Eric A Engels,
Robert Dubrow,
Heidi M Crane,
John T Brooks,
Ronald Bosch,
Gypsyamber D'Souza
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ABSTRACT: OBJECTIVE:: HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic HPV infection - the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women. METHODS:: Data were obtained from HIV-infected and -uninfected female participants in the NA-ACCORD with no history of ICC at enrollment. Participants were followed from study entry or January, 1996 through ICC, loss-to follow-up or December, 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios (SIR). All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction. RESULTS:: A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years (pys) of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 pys, respectively). HIV-infected women with baseline CD4+ T-cells of ≥350, 200-349 and <200 cells/uL had a 2.3-times, 3.0-times and 7.7-times increase in ICC incidence, respectively, compared with HIV-uninfected women (Ptrend =0.001). Of the 17 HIV-infected cases, medical records for the 5 years prior to diagnosis showed that 6 had no documented screening, 5 had screening with low grade or normal results, and 6 had high-grade results. CONCLUSIONS:: This study found elevated incidence of ICC in HIV-infected compared to -uninfected women, and these rates increased with immunosuppression.
JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2012; · 4.43 Impact Factor
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ABSTRACT: Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this paper, we discuss key design considerations for such single-arm studies.
AIDS research and human retroviruses 12/2012; · 2.18 Impact Factor
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Joseph J Eron,
Bonaventura Clotet,
Jacques Durant,
Christine Katlama,
Princy Kumar,
Adriano Lazzarin,
Isabelle Poizot-Martin,
Gary Richmond,
Vincent Soriano,
Mounir Ait-Khaled,
Tamio Fujiwara,
Jenny Huang,
Sherene Min,
Cindy Vavro,
Jane Yeo
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ABSTRACT: Background. Dolutegravir (DTG; S/GSK1349572), an HIV-1 integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance.Methods. Subjects received DTG 50 mg QD (Cohort I) or 50 mg BID (Cohort II) while continuing failing regimen (without RAL) through Day 10, after which the background regimen was optimized where feasible for Cohort I, at least one fully active drug was mandated for Cohort II. The primary endpoint was the proportion of subjects at Day 11 with ≥0.7 log(10) copies/mL plasma HIV-1 RNA reduction below baseline or <400 copies/mL.Results. A rapid antiviral response was observed. More subjects achieved the primary endpoint in Cohort II (23/24 [96%]) versus Cohort I (21/27 [78%]) at Day 11. At Week 24, 41% and 75% of subjects had HIV-1 RNA <50 copies/mL in Cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen.Conclusion. Dolutegravir 50 mg BID with an optimized background provided greater and more durable benefit versus the QD regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.
The Journal of Infectious Diseases 12/2012; · 6.41 Impact Factor
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ABSTRACT: Data on the effectiveness of second-line combination antiretroviral therapy (cART) are limited. We evaluated virologic outcomes of second cART in a multi-center cohort collaboration. Study population initiated first and second modern cART between 1996 and 2010. Second cART required a switch in at least the anchor agent of first cART. We evaluated time to virologic failure of second cART and factors associated with greater risk of failure using multivariable Cox proportional hazards models. Of 488 patients who switched to second line cART, 67% black were black and 32% were women. Median HIV-1 RNA at second cART initiation was 9,565 copies/mL (interquartile range [IQR]; 123, 94,108). Time to virologic failure of second cART was longer if HIV-1 RNA was undetectable at switch (p = 0.001), although 12% and 17% of patients with undetectable and detectable HIV-1 RNA experienced virologic failure within 6 months of second cART initiation, respectively. A lower CD4 cell count at second cART initiation was associated with a greater risk of virologic failure. Failure rates decreased in more recent calendar years (adjusted relative hazard of 0.40 comparing 2008 to 2010 with 1996 to 1998 [95% confidence interval; 0.15, 1.00]); however, type of anchor agent was not associated with failure. In conclusion, virologic failure of second cART was less likely if patients switched with undetectable HIV-1 RNA, although risk of early failure was similar. Effectiveness of second cART regimens improved over calendar time and was independent of the anchor agent in the regimen.
AIDS research and human retroviruses 10/2012; · 2.18 Impact Factor
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ABSTRACT: BACKGROUND:: HIV infections increased 48% among young, Black men who have sex with men (MSM) in the United States between 2006-2009. Incomplete understanding of this trend undermines prevention strategy development. We investigated a sexual network to characterize the risk environment in which young, Black MSM acquire HIV. METHODS:: Persons reported to the state following diagnosis of HIV or syphilis were included, along with sexual partners. We used network mapping alongside descriptive and bivariate statistics to characterize network connections. Generalized linear models assessed predictors of having untraceable sex partners. RESULTS:: The network included 398 individuals and 419 sexual relationships. Three-quarters were Black (n=299); 94% were MSM. Median age at first network appearance was 26 years and decreased over time (P<0.001). HIV prevalence was at least 29% (n=117); serostatus was unknown for 47% of the network, either because they were untraceable (n=150) or refused HIV testing (n=39). One in 5 network members diagnosed with HIV had a subsequent incident sexually transmitted infection. In multivariable models, one-time encounters increased the risk of having an untraceable partner (risk ratio 4.51, 95% CI, 2.27, 8.97), while being acutely HIV infected at diagnosis reduced it (RR 0.27, 95% CI, 0.08, 0.89). CONCLUSIONS:: HIV prevalence in this sexual network of young, Black MSM rivals that of sub-Saharan Africa, reflecting dramatically increased risk of acquiring HIV from the moment one entered the network. Prevention efforts for this population must consider the effect of sexual networks on HIV risk, and find ways of leveraging network structure to reduce transmission.
JAIDS Journal of Acquired Immune Deficiency Syndromes 09/2012; · 4.43 Impact Factor
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ABSTRACT: Background: Drug-resistant HIV complicates management of HIV infection. Although, an estimated 14% of all HIV-positive persons pass through a prison or jail in the United States are imprisoned, little is known about the overall prevalence of ARV resistance in incarcerated persons. Methods: All genotypic sequence data on HIV positive prisoners in the North Carolina(NC) Department of Corrections(DOC) were obtained from LabCorp. Screening for major resistance mutations in Protease (PI) and Reverse Transcriptase (NRTI and NNRTI) was done using Genosure and the Stanford HIV Database. For subjects with multiple genotype reports, each mutation was counted only once and considered present on all subsequent genotypes. Results: Between October 2006-February 2010, the NC DOC incarcerated 1,911 HIV+ individuals persons of whom 19.2%(n=367) had at least one genotype performed. Overall prevalence of a major resistance mutation was 28.3%(95% CI 23.7, 33.0). Among prisoners ever exposed to an antiretroviral during incarceration (n=329) prevalence of a major resistance mutation was 29.8% (95% CI 24.9, 34.7); resistance by class was: 20.4% (95% CI 16.0, 24.7) for NRTIs, 19.8%( 95% CI 15.5, 24.1) for NNRTIs and 8.8%(95% CI 5.8,11.9) for PIs. Single class drug resistance was most prevalent at 14.2%(10.2,17.7) followed by dual 12.5%(I8.9,16.0) and triple class 3.3%(1.4,5.3) resistance. The three most prevalent mutations were K103N 15.8%(12.0, 20.2), M184V 14.3%(10.7,18.5) and M41L 4.9%(2.8,7.8). Conclusions: In the NC DOC ARV resistance prevalence, dual and triple class drug resistance was moderate over the study period. Resistance to PIs was lower than NNRTIs and NRTIs, likely reflecting higher usage of these two classes or a lower barrier to resistance.
AIDS research and human retroviruses 09/2012; · 2.18 Impact Factor
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ABSTRACT: BACKGROUND: HIV-1-infected individuals with plasma RNA <50 copies/mL on antiretroviral therapy (ART) may have residual, low-level viremia detectable by PCR assays which can detect a single copy of viral RNA (single-copy assay, SCA). The clinical predictors of residual viremia in patients on long-term suppressive ART are incompletely understood. METHODS: We evaluated factors associated with residual viremia in patients on suppressive ART who underwent screening for a raltegravir intensification trial (ACTG A5244). The screened population was HIV-1-infected adults receiving ART for (3)12 months with pre-ART HIV-1 RNA >100,000 copies/mL and on-therapy RNA levels below detection limits of commercial assays for (3)6 months. RESULTS: Of 103 patients eligible for analysis, the median age was 46 years and the median duration of viral suppression was 4.8 years. Sixty-two percent had detectable viremia (>0.2 copies/mL) by SCA (median 0.2 copies/mL; quartile [Q] 1, Q3 [<0.2, 1.8]). Younger patients had lower HIV-1 RNA levels than older individuals (r=0.27, p=0.005). Patients with virologic suppression on ART for 2 years or less had higher residual viremia than those with suppression for more than 2 years (median 2.3 vs. 0.2 copies/mL, p=0.016). CONCLUSIONS: Among HIV-1-infected patients with pre-ART HIV-1 RNA >100,000 copies/mL, residual viremia was detectable in the majority (62%) despite many years of suppressive ART. Higher level viremia was associated with older age and less than 2 years of virologic suppression on ART. These findings should help in selection of candidates for clinical trials of interventions designed to eliminate residual viremia.
Antiviral therapy 08/2012; · 3.16 Impact Factor
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Mehri S McKellar,
Anna B Cope,
Cynthia L Gay,
Kara S McGee,
Joann D Kuruc,
Melissa G Kerkau,
Christopher B Hurt,
Susan A Fiscus,
Guido Ferrari,
David M Margolis, Joseph J Eron,
Charles B Hicks And The Duke-Unc Acute Hiv Infection Consortium
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ABSTRACT: Abstract In 1998 a collaboration between Duke University and the University of North Carolina, Chapel Hill (UNC) was founded to enhance identification of persons with acute HIV-1 infection (AHI). The Duke-UNC AHI Research Consortium Cohort consists of patients ≥18 years old with a positive nucleic acid amplification test (NAAT) and either a negative enzyme immunoassay (EIA) test or a positive EIA with a negative/indeterminate Western blot. Patients were referred to the cohort from acute care settings and state-funded HIV testing sites that use NAAT testing on pooled HIV-1 antibody-negative samples. Between 1998 and 2010, 155 patients with AHI were enrolled: 81 (52%) African-Americans, 63 (41%) white, non-Hispanics, 137 (88%) males, 108 (70%) men who have sex with men (MSM), and 18 (12%) females. The median age was 27 years (IQR 22-38). Most (n=138/155) reported symptoms with a median duration of 17.5 days. The median nadir CD4 count was 408 cells/mm(3) (IQR 289-563); the median observed peak HIV-1 level was 726,859 copies/ml (IQR 167,585-3,565,728). The emergency department was the most frequent site of initial presentation (n=55/152; 3 missing data). AHI diagnosis was made at time of first contact in 62/137 (45%; 18 missing data) patients. This prospectively enrolled cohort is the largest group of patients with AHI reported from the Southeastern United States. The demographics reflect the epidemic of this geographic area with a high proportion of African-Americans, including young black MSM. Highlighting the challenges of diagnosing AHI, less than half of the patients were diagnosed at the first healthcare visit. Women made up a small proportion despite increasing numbers in our clinics.
AIDS research and human retroviruses 07/2012; · 2.18 Impact Factor
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Melanie A Thompson,
Judith A Aberg,
Jennifer F Hoy,
Amalio Telenti,
Constance Benson,
Pedro Cahn, Joseph J Eron,
Huldrych F Günthard,
Scott M Hammer,
Peter Reiss,
Douglas D Richman,
Giuliano Rizzardini,
David L Thomas,
Donna M Jacobsen,
Paul A Volberding
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ABSTRACT: New trial data and drug regimens that have become available in the last 2 years warrant an update to guidelines for antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected adults in resource-rich settings.
To provide current recommendations for the treatment of adult HIV infection with ART and use of laboratory-monitoring tools. Guidelines include when to start therapy and with what drugs, monitoring for response and toxic effects, special considerations in therapy, and managing antiretroviral failure.
Data that had been published or presented in abstract form at scientific conferences in the past 2 years were systematically searched and reviewed by an International Antiviral Society-USA panel. The panel reviewed available evidence and formed recommendations by full panel consensus.
Treatment is recommended for all adults with HIV infection; the strength of the recommendation and the quality of the evidence increase with decreasing CD4 cell count and the presence of certain concurrent conditions. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir). Alternatives in each class are recommended for patients with or at risk of certain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care indicators. Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or intolerance. Confirmed treatment failure should be addressed promptly and multiple factors considered.
New recommendations for HIV patient care include offering ART to all patients regardless of CD4 cell count, changes in therapeutic options, and modifications in the timing and choice of ART in the setting of opportunistic illnesses such as cryptococcal disease and tuberculosis.
JAMA The Journal of the American Medical Association 07/2012; 308(4):387-402. · 30.03 Impact Factor
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Robert C Kalayjian,
Bryan Lau,
Rhoderick N Mechekano,
Heidi M Crane,
Benigno Rodriguez,
Robert A Salata,
Zipporah Krishnasami,
James H Willig,
Jeffrey N Martin,
Richard D Moore, Joseph J Eron,
Mari M Kitahata
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ABSTRACT: : To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.
: Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.
: Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from -2.18 to -1.37 ml/min per 1.73 m per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m: 3.35 (95% confidence interval (CI) = 1.40-8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.
: ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.
AIDS (London, England) 07/2012; 26(15):1907-15. · 4.91 Impact Factor
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ABSTRACT: The p16(INK4a) tumor suppressor gene is a mediator of cellular senescence and has been suggested to be a biomarker of 'molecular' age in several tissues including T cells. To determine the association of both active and suppressed HIV infection with T-cell aging, T-cell p16(INK4a) expression was compared between 60 HIV+ suppressed subjects, 23 HIV+ untreated subjects, and 18 contemporaneously collected HIV-negative controls, as well as 148 HIV-negative historical samples. Expression did not correlate with chronologic age in untreated HIV+ patients, consistent with an effect of active HIV replication on p16(INK4a) expression. In patients on cART with suppressed viral loads, however, p16(INK4a) levels were similar to uninfected controls and correlated with chronologic age, with a trend toward an inverse correlation with CD4 count. These data show that p16(INK4a) is a reliable biomarker of T-cell aging in HIV+ patients with suppressed viral loads and suggest that poor CD4 cell recovery on cART may be associated with increased T-cell expression of p16(INK4a) , a marker of cellular senescence.
Aging cell 06/2012; 11(5):916-918. · 7.55 Impact Factor
