Showing papers by "James D. Neaton published in 2013"

Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers.

Abstract: Objective: To investigate the relationship between inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)] and coagulation (D-dimer) biomarkers and cancer risk during HIV infection. Design: A prospective cohort. Methods: HIV-infected patients on continuous antiretroviral therapy (ART) in the control arms of three randomized trials (N = 5023) were included in an analysis of predictors of cancer (any type, infection-related or infection-unrelated). Hazard ratios for IL-6, CRP and D-dimer levels (log-transformed) were calculated using Cox models stratified by trial and adjusted for demographics and CD4 cell counts and adjusted also for all biomarkers simultaneously. To assess the possibility that biomarker levels were elevated at entry due to undiagnosed cancer, analyses were repeated excluding early cancer events (i.e. diagnosed during first 2 years of follow-up). Results: During approximately 24 000 person-years of follow-up (PYFU), 172 patients developed cancer (70 infection-related; 102 infection-unrelated). The risk of developing cancer was associated with higher levels (per doubling) of IL-6 (hazard ratio 1.38, P<0.001), CRP (hazard ratio 1.16, P=0.001) and D-dimer (hazard ratio 1.17, P=0.03). However, only IL-6 (hazard ratio 1.29, P= 0.003) remained associated with cancer risk when all biomarkers were considered simultaneously. Results for infection-related and infection-unrelated cancers were similar to results for any cancer. Hazard ratios excluding 69 early cancer events were 1.31 (P= 0.007), 1.14 (P=0.02) and 1.07 (P = 0.49) for IL-6, CRP and D-dimer, respectively. Conclusion: Activated inflammation and coagulation pathways are associated with increased cancer risk during HIV infection. This association was stronger for IL-6 and persisted after excluding early cancer. Trials of interventions may be warranted to assess whether cancer risk can be reduced by lowering IL-6 levels in HIV-positive individuals.

Increase in 2–Long Terminal Repeat Circles and Decrease in D-dimer After Raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial

Abstract: (See the editorial commentary by Chun and Fauci on pages 1356–8.) One of the major controversies in human immunodeficiency virus (HIV) cure research is whether low-level viral replication persists in otherwise effectively treated HIV-infected individuals. This issue has potential significance not only for ongoing cure strategies, but also for interventions aimed at decreasing the residual immune activation [1–3], immune dysfunction [4, 5], and increased levels of morbidity and mortality [6] that persist in treated HIV-infected individuals. Several recent studies have consistently shown that treatment intensification in HIV-infected patients receiving antiretroviral therapy (ART) does not decrease plasma HIV RNA levels, as measured by ultrasensitive assays [7–12]. However, some studies have suggested that there may be ongoing, low-level viral replication in a proportion of individuals with ART-suppressed plasma HIV RNA levels, as detected by an early increase in the level of 2–long terminal repeat (2-LTR) circles [8], a decrease in immune activation in peripheral blood mononuclear cells (PBMCs) [13], or a decrease in immune activation and levels of cell-associated HIV RNA in gut-associated lymphoid tissue [9]. Moreover, despite relatively effective suppression of HIV replication, ART-treated adults have a higher risk of developing non–AIDS-associated diseases (including cardiovascular disease, liver disease, renal disease, bone disease, and cancer [14–17]), compared with HIV-uninfected adults. Many factors potentially contribute to this excess risk, including a higher prevalence of traditional risk factors, antiretroviral drug toxicity, and chronic inflammation [18]. Compared with age-matched controls, many markers of inflammation (eg, interleukin-6 [IL-6] and T-cell activation) and hypercoagulation (eg, D-dimer level) remain elevated in treated HIV disease [1, 19]. In fact, these biomarkers are strongly predictive of morbidity and all-cause mortality in ART-treated adults [6, 20, 21]. To determine whether HIV replication persists during ART and whether low-level viral replication contributes to persistent immune dysfunction, we conducted a randomized, double-blind, placebo-controlled study of raltegravir intensification in ART-suppressed individuals and assessed whether intensification led to an increase in the level of 2-LTR circles. We also examined whether intensification led to a reduction in biomarkers of inflammation and hypercoagulation in order to assess whether low-level viral replication has any potential clinical consequences and contributes to the increased non–AIDS-related morbidity and mortality observed among treated individuals.

Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study

Abstract: BackgroundUntreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals.PurposeIn this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to asses...

HIV replication alters the composition of extrinsic pathway coagulation factors and increases thrombin generation.

Abstract: Management of Anti-Retroviral Therapy (SMART) trial. Thrombin generation was estimated using validated computational modeling based on factor composition. We characterized the effect of antiretroviral therapy (ART) treatment versus the untreated state (HIV replication) via 3 separate analyses: (1) a cross-sectional comparison of those on and off ART (n=717); (2) a randomized comparison of deferring versus starting ART (n=217); and (3) a randomized comparison of stopping versus continuing ART (n=500). Compared with viral suppression, HIV replication consistently showed short-term increases in some procoagulants (eg, 15% to 23% higher FVIII; P<0.001) and decreases in key anticoagulants (eg, 5% to 9% lower antithrombin [AT] and 6% to 10% lower protein C; P<0.01). The net effect of HIV replication was to increase coagulation potential (eg, 24% to 48% greater thrombin generation from computational models; P<0.01 for all). The pattern of changes from HIV replication was reversed with ART treatment and consistent across all 3 independent comparisons. Conclusions-—HIV replication leads to complex changes in extrinsic pathway factors, with the net effect of increasing coagulation potential to a degree that may be clinically relevant. The key influence of changes in FVIII and AT suggests that HIV-related coagulation abnormalities may involve changes in hepatocyte function in the context of systemic inflammation. Clinical Trial Registration-—URL: ClinicalTrials.gov. Unique identifier: NCT00027352. (J Am Heart Assoc. 2013;2:e000264 doi: 10.1161/JAHA.113.000264)

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

Abstract: Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies

Abstract: BACKGROUND Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies. METHODS Among patients with RT-PCR-confirmed influenza A(H1N1)pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p<0.05) or only in one (p<0.002 after Bonferroni correction) were identified. RESULTS In FLU 002 28/528 (5.3%) outpatients had influenza A(H1N1)pdm09 virus infection that progressed to a study endpoint of complications, hospitalization or death, whereas in FLU 003 28/170 (16.5%) inpatients enrolled from the general ward and 21/39 (53.8%) inpatients enrolled directly from the ICU experienced disease progression. Higher levels of 12 of the 25 markers were significantly associated with subsequent disease progression. Of these, 7 markers (IL-6, CD163, IL-10, LBP, IL-2, MCP-1, and IP-10), all with ORs for the 3(rd) versus 1(st) tertile of 2.5 or greater, were significant (p<0.05) in both outpatients and inpatients. In contrast, five markers (sICAM-1, IL-8, TNF-α, D-dimer, and sVCAM-1), all with ORs for the 3(rd) versus 1(st) tertile greater than 3.2, were significantly (p≤.002) associated with disease progression among hospitalized patients only. CONCLUSIONS In patients presenting with varying severities of influenza A(H1N1)pdm09 virus infection, a baseline elevation in several biomarkers associated with inflammation, coagulation, or immune function strongly predicted a higher risk of disease progression. It is conceivable that interventions designed to abrogate these baseline elevations might affect disease outcome.

When to start antiretroviral therapy: the need for an evidence base during early HIV infection

Abstract: Strategies for use of antiretroviral therapy (ART) have traditionally focused on providing treatment to persons who stand to benefit immediately from initiating the therapy. There is global consensus that any HIV+ person with CD4 counts less than 350 cells/μl should initiate ART. However, it remains controversial whether ART is indicated in asymptomatic HIV-infected persons with CD4 counts above 350 cells/μl, or whether it is more advisable to defer initiation until the CD4 count has dropped to 350 cells/μl. The question of when the best time is to initiate ART during early HIV infection has always been vigorously debated. The lack of an evidence base from randomized trials, in conjunction with varying degrees of therapeutic aggressiveness and optimism tempered by the risks of drug resistance and side effects, has resulted in divided expert opinion and inconsistencies among treatment guidelines. On the basis of recent data showing that early ART initiation reduces heterosexual HIV transmission, some countries are considering adopting a strategy of universal treatment of all HIV+ persons irrespective of their CD4 count and whether ART is of benefit to the individual or not, in order to reduce onward HIV transmission. Since ART has been found to be associated with both short-term and long-term toxicity, defining the benefit:risk ratio is the critical missing link in the discussion on earlier use of ART. For early ART initiation to be justified, this ratio must favor benefit over risk. An unfavorable ratio would argue against using early ART. There is currently no evidence from randomized controlled trials to suggest that a strategy of initiating ART when the CD4 count is above 350 cells/μl (versus deferring initiation to around 350 cells/μl) results in benefit to the HIV+ person and data from observational studies are inconsistent. Large, clinical endpoint-driven randomized studies to determine the individual health benefits versus risks of earlier ART initiation are sorely needed. The counter-argument to this debate topic can be freely accessed here: http://www.biomedcentral.com/1741-7015/11/147 .

Pilot study of vascular health in survivors of osteosarcoma.

Abstract: 300mg/m 2 or more of anthracyclines (N ¼14) or treated with multi-agent chemotherapy (with or without cranial radiation) for ALL (N ¼75) compared to healthy controls [11,12]. The complex mechanisms of cardiovascular injury remain poorly defined and additional study is needed to help guide the testing of therapeutic interventions. The objective of this study was to assess markers of vascular injury among survivors of osteosarcoma, a population with intensive, potentially vascular toxic, chemotherapy exposures, typically without radiation exposure. We previously collected the same biomarkers among survivors of Hodgkin lymphoma and found evidence suggestive of vascular inflammation, dyslipidemia, Background. Cardiovascular-related toxicities have been reported among survivors of osteosarcoma. Methods. Fasting blood samples from 24 osteosarcoma survivors were analyzed for highsensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein-s, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and surface expression of vascular cell adhesion molecule-1 (VCAM-1). Values were compared to subjects in the natural history Coronary Artery Risk Development in Young Adults (CARDIA) cohort study except for CECs and VCAM-1 expression, which were compared to controls studied at the University of Minnesota Lillehei clinical trials unit. Procedure. Survivors (54.2% male), median age 18 years (9–32) at diagnosis,36.5years(20–56)atevaluationweretreatedwithavariety of chemotherapeutic exposures, all but one were exposed to doxorubicin (median dose 450mg/m 2 ; range: 90–645mg/m 2 ), 14 (58.3%) received cisplatin, and 3 (12.5%) were exposed to carboplatin. Two survivors (8.3%) received radiation therapy for disease relapse. Compared to CARDIA subjects, mean hsCRP (3.0mg/L � 2.0 vs. 1.6 � 2.3), triglycerides (151mg/dl � 81.7 vs. 95.4 � 101.3),lipoprotein(a)(34.9mg/dl � 17.7vs.13.8 � 22.0),and fibrinogen (315.0mg/dl � 49.3 vs. 252.4 � 61.7) were significantly elevated. The number of CECs (0.47cells/ml � 2.5 vs. 0.92 � 2.5) did not differ while surface expression of VCAM-1 (86.4% � 34.0 vs. 42.1 � 33.8) was significantly elevated compared to controls. Conclusions. Among survivors of osteosarcoma, assessed a median of 14 years from diagnosis, there is evidence of vascular inflammation, dyslipidemia, and early atherogenesis. Pediatr Blood Cancer 2013;60:1703–1708. # 2013 Wiley Periodicals, Inc.

Biomarkers and Electrocardiographic Evidence of Myocardial Ischemia in Patients With Human Immunodeficiency Virus Infection

Abstract: We assessed the relation of inflammatory and coagulation biomarkers with electrocardiographic (ECG) evidence of myocardial ischemia. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at study entry for 3,085 human immunodeficiency virus-infected participants (mean age 44 years; 26.4% women; 24.6% black) in the Strategies for Management of Antiretroviral Therapy trial. Logistic regression models were used to examine the associations of these biomarkers with prevalent and incident myocardial ischemia. The latter analyses were performed for 1,411 participants who were randomly assigned to receive continuous antiretroviral therapy during follow-up to suppress the human immunodeficiency virus viral load and had ≥1 ECG reading during the follow-up period. The median hsCRP, IL-6, and D-dimer level was 1.65 μg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 μg/ml (interquartile range 0.11 to 0.32), respectively. At baseline, the prevalence of major or minor Q-QS or ST-T ECG abnormalities was 18.6%. The biomarker levels were associated with prevalent major or minor ischemic abnormalities on the univariate analyses; however, adjustment for traditional risk factors attenuated these associations. The adjusted odds ratio for major or minor ischemic abnormalities and 95% confidence intervals for the greatest versus lowest quartiles was 1.3 (95% confidence interval 0.9 to 1.7) for hsCRP, 1.0 (95% confidence interval 0.7 to 1.3) for IL-6, and 1.1 (95% confidence interval 0.9 to 1.5) for D-dimer. During a median follow-up of 2.3 years, new definite or probable ischemic ECG abnormalities developed in 11.7% of participants receiving continuous antiretroviral therapy. Biomarker levels were not associated with incident abnormalities on unadjusted or adjusted analyses. In conclusion, higher levels of hsCRP, IL-6, and D-dimer were not associated with ischemic ECG abnormalities. Elevated biomarker levels and ECG abnormalities indicating myocardial ischemia might reflect different risk pathways for cardiovascular disease.

Electrocardiographic spatial QRS-T angle and incident cardiovascular disease in HIV-infected patients (from the Strategies for the Management of Antiretroviral Therapy [SMART] study).

Abstract: Widening of the electrocardiographic (ECG) spatial QRS-T angle has been predictive of cardiovascular disease (CVD) events in the general population. However, its prognostic significance in human immunodeficiency virus (HIV)-infected patients remains unknown. The spatial QRS-T angle was derived from the baseline resting 12-lead electrocardiogram of 4,453 HIV-infected patients aged 43.5 ± 9.3 years from the Strategies for Management of Antiretroviral Therapy (SMART) trial. CVD events were identified during a median follow-up of 28.7 months. Quartiles of the spatial QRS-T angle was calculated for men and women separately, and values in the upper quartile were considered as a widened angle (values >74° for women and >93° for men). A multivariate Cox proportional hazards analysis was used to examine the association between a widened baseline spatial QRS-T angle and incident CVD events. During 11,965 person-years of follow-up, 152 CVD events occurred at a rate of 1.27 events/100 person-years. The rate of CVD events in those with a widened spatial QRS-T angle was almost double the rate in those with a normal spatial QRS-T angle (rate ratio 1.94, 95% confidence interval 1.40 to 2.69; p 50% increased risk of CVD events compared to a normal spatial QRS-T angle (hazard ratio 1.53, 95% confidence interval 1.07 to 2.17; p = 0.02). No interaction was seen by SMART trial arm (p value for interaction = 0.37) or gender (p value for interaction = 0.84). In conclusion, a widened spatial QRS-T angle was independently predictive of CVD events in HIV-infected patients receiving antiretroviral therapy. This highlights the potential role of routine electrocardiography as a simple noninvasive CVD risk-screening tool in HIV-infected patients.

Protease inhibitors and cardiac autonomic function in hiv-infected patients: A cross-sectional analysis from the strategies for management of antiretroviral therapy (smart) trial

Abstract: Objective To compare cardiac autonomic function as measured by heart rate variability for HIV-infected participants taking protease inhibitors (PIs) with those taking a non-nucleoside reverse transcriptase inhibitor without a PI (NNRTI-no PI) regimen. Design Cross-sectional analysis. Setting Multicentre study. Participants 2998 participants (average age 44 years, 28% females) enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial. Primary outcome measures Heart rate and two heart rate variability measures (the SD of all filtered RR intervals over the length of the recording (SDNN) and the root mean square of successive differences in normal RR intervals (rMSSD)). Results At study entry, 869 participants were taking a boosted PI (PI/r), 579 a non-boosted PI and 1550 an NNRTI-no PI. Median values (IQR) of heart rate, SDNN and rMSSD were: 68 (60–75) beats/min (bpm), 21 (13–33) ms, 22 (13–35) ms in the PI/r group, 68 (60–75) bpm, 21 (13–33) ms and 21 (14–33) ms in the non-boosted PI group and 69 (62–77) bpm, 20 (13–31) ms and 21(13–33) ms in the NNRTI-no PI group. After adjustment for baseline factors, for those given PI/r and non-boosted PI, heart rate was 2.2 and 2.8 bpm, respectively, lower than the NNRTI-no PI group (p Conclusions Compared to an NNRTI-no PI regimen, heart rate was lower for those taking a PI/r or non-boosted PI and heart rate variability was greater, reflecting better cardiac autonomic function, for those taking a non-boosted PI regimen but not PI/r.

HIV and cardiovascular disease: comment on Islam et al.

Abstract: I am writing concerning the paper by Islam et al. [1] titled ‘Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis’, which was published in the September 2012 issue of HIV Medicine. I believe that there are several errors in the paper that require correction. Figure 2(a) and its description on page 458. The subheading for the description is ’RR of CVD for PLHIV not on treatment vs. HIV-uninfected people’. The studies by Triant et al. [2] and Lang et al. [3] should not be cited under this heading or in Figure 2(a). Only the nonsignificant relative risk (RR) for the study by Obel et al. is correct [4]. In the paper by Lang et al. [3] in AIDS they report an overall (for men and women) standardized mortality ratio (SMR) for myocardial infarction (MI) of 1.5 [95% confidence interval (CI) 1.3-1.7] for HIV-infected men and women vs. the general population. This SMR is cited as a RR in Figure 2(a) with the CI. The cases of MI were part of a case–control study described in the Archives of Internal Medicine by the authors (2010; 170: 1228–1238) [5]. From Table 1 of the Archives of Internal Medicine paper, it can be noted that nearly all patients were on treatment at the time of the MI diagnosis. Triant et al. [2] report an adjusted RR of 1.75 for HIVinfected compared with non-HIV-infected patients (95% CI 1.51-2.02). This is the RR cited in Figure 2(a). As noted in Table 1 of their paper in J Clin Endocrinol Metab, nearly all of the HIV-infected participants in the study were on antiretroviral therapy (ART). Figure 3(a) and its description on page 459. Most of the data cited in Figure 3 and under the subheading ‘RR of CVD among those on treatment vs. treatment naïve OLHIV’ are cited incorrectly. There are also errors of omission. The study by Aboud et al. [6] was not a study of cardiovascular disease (CVD) or coronary heart disease (CHD) events. It was a study of predicted CVD or CHD using a Framingham risk formula. This study should not have been included in the meta-analysis. A second problem, but minor by comparison, is that the two estimates cited from Aboud et al. [6] are correlated and cannot simply be pooled. Three estimates from the study by Bozzette et al. [7] are cited. These estimates appear valid but they are also correlated with one another so cannot simply be pooled. The RR cited from the paper by Currier et al. [8] is for those aged 18–33 years (see Table 4 in their JAIDS paper). Estimates for three other age groups are not cited: 1.08 for those aged 34–49 years; 0.79 for those aged 50–65 years; and 1.15 for those 66 years and older. Three RR estimates are cited from the study by Durand et al. [9]. These estimates are all incorrect. They are not RRs of treatment vs. no treatment. The estimates in Durand are RRs of being on a specific treatment vs. not being on that specific treatment. See page 246 of methods and the footnote of Table 4 in the JAIDS paper by Durand et al. [9]. The estimate from the paper by Lang et al. [5] is also incorrectly cited. It is a RR of abacavir vs. no abacavir, not of abacavir vs. no treatment. The estimates cited from the paper by Mary-Krause et al. [10] appear correct. About 90% of the patients in this study were on ART. This probably explains the wide CI for the nucleoside reverse transcriptase inhibitor (NRTI) comparison. The estimates cited from the paper by Obel et al. [11] are not cited correctly. The RR in the paper is abacavir vs. no abacavir, not abacavir vs. no treatment. Likewise, the two estimates from Worm et al. [12] are not cited correctly. They are for recent exposure to abacavir vs. no abacavir and for recent exposure to didanosine vs. no didanosine, respectively (see footnote of Table 3 in the JID paper). Another omission from Figure 3 is that the report from the DAD study in the N Engl J Med (2003; 349:1993–2003) [13] (see Fig. 1) is not cited. I believe that this is the largest study published to date. Figures 3(b)–(d). For reasons given above, most of the RRs cited in Figures 3(b)–(d) are incorrect. The reference group is usually not ‘no treatment’. Page 463. There is an error in the reference to a SMART publication by Phillips et al. [14] The RR cited is reversed. It should be intermittent ART compared with continuous use of ART. Thank you for considering these comments. Correspondence: James D. Neaton, PhD, Division of Biostatistics, School of Public Health, University of Minnesota, 2221 University Ave SE, Room 200, Minneapolis, MN 55414, USA. Tel: (612) 626-9040; fax: (612) 624-2819; e-mail: jim@ccbr.umn.edu DOI: 10.1111/hiv.12043 © 2013 British HIV Association HIV Medicine (2013), 14, 517–518 LETTER TO THE EDITOR