Events In HIV-infected Patients Research Articles

Abstract P368: Risk Factor Interventions are Effective for Preventing Cardiovascular Events in HIV-Infected Patients on Antiretroviral Therapy: A Systematic Review and Meta-analysis

Introduction: The declining rate of HIV-related deaths has become rather slow in recent times, largely because of the rising incidence of cardiovascular events associated with the disease and its long-term treatment with anti-retroviral drugs. While conclusive evidences support the effectiveness of cardiovascular risk factor interventions in the general population, there is a dearth of such evidence of clinical effectiveness in certain high-risk subgroups, particularly HIV-infected patients on antiretroviral treatment. Objective: To evaluate the clinical effectiveness of risk factor interventions in preventing cardiovascular disease in HIV-positive patients on antiretroviral treatment (ART) and summarize the effect size. Design and methods: Systematic review of randomized controlled trials investigating the effects of interventions in modifying ART-associated risk factors for cardiovascular disease. Trials were eligible for inclusion if they were published in the last 12 years [2000 to June 2012] and participants were HIV-positive, on ART and having more than one ART-associated cardiovascular risk factor. Results: In total, 2,071 HIV-positive participants from 10 randomized trials were included in the review. The interventions evaluated comprised lifestyle modification, lipid-lowering treatment and smoking cessation. Overall, the main results showed significant improvements in total cholesterol [P<0.0001], LDL cholesterol [P<0.0001], HDL cholesterol [P<0.002], triglycerides [P<0.001], apolipoprotein B levels [P=0.036], adiposity [<0.001], anthropometry [P<0.001], insulin sensitivity [P<0.05], HbA1c levels [P<0.001], FBG levels [P=0.017], adiponectin levels [P<0.05], dietary intake [P<0.001], smoking abstinence [P<0.0001] and Framingham score [P=0.03]. The results also showed improvements in systolic [from 145.6±14.5 mmHg to 122.8±5.2 mmHg] and diastolic blood pressure [from 84.7±1.7 mmHg to 80.1±3.8 mmHg]; however, there was no improvement in carotid intima-media thickness [P=0.61] or inflammatory biomarkers [P=0.973 to 0.110]. Conclusion: In conclusion, this review presents evidence suggesting that cardiovascular risk factor interventions are effective in HIV-infected persons on ART. However, cardiovascular screening programs targeting people living with HIV and primary studies assessing the effectiveness (clinical and cost) of multiple risk factor interventions in this sub-group are needed.

Free Light Chains and the Risk of Nonmalignant AIDS Events in HIV-Infected Patients Treated With Combination Antiretroviral Therapy

Free Light Chains and the Risk of Nonmalignant AIDS Events in HIV-Infected Patients Treated With Combination Antiretroviral Therapy

In vivo platelet activation and platelet hyperreactivity in abacavir-treated HIV-infected patients

Abacavir (ABC) has been associated with ischaemic cardiovascular events in HIV-infected patients, but the pathogenic mechanisms are unknown. Aim of our study was to assess whether ABC induces in vivo platelet activation and ex vivo platelet hyper-reactivity. In a retrospective, case-control study, in vivo platelet activation markers were measured in 69 HIV-infected patients, before starting therapy and after 6-12 months of either ABC (n=35) or tenofovir (TDF) (n=34), and compared with those from 20 untreated HIV-infected patients. A subgroup of patients was restudied after 28-34 months for ex vivo platelet reactivity. In vivo platelet activation markers were assessed by ELISA or flow cytometry, ex vivo platelet reactivity by light transmission aggregometry (LTA) and PFA-100®. Thein vitro effects of the ABC metabolite, carbovir triphosphate, on aggregation and intra-platelet cGMP were also studied. sPLA2, sPsel and sGPV increased significantly 6-12 months after the beginning of ABC, but not of TDF or of no treatment. Ex vivo platelet function studies showed enhanced LTA, shorter PFA-100® C/ADP closure time and enhanced platelet expression of P-sel and CD40L in the ABC group. The intake of ABC blunted the increase of intraplatelet cGMP induced by nitric oxide (NO) and acutely enhanced collagen-induced aggregation. Preincubation of control platelets with carbovir triphosphate in vitro enhanced platelet aggregation and blunted NO-induced cGMP elevation. In conclusion, treatment with ABC enhances in vivo platelet activation and induces platelet hyperreactivity by blunting the inhibitory effects of NO on platelets. These effects may lead to an increase of ischaemic cardiovascular events.

Predictors of first-line antiretroviral therapy discontinuation due to drug-related adverse events in HIV-infected patients: a retrospective cohort study

BackgroundDrug-related toxicity has been one of the main causes of antiretroviral treatment discontinuation. However, its determinants are not fully understood. Aim of this study was to investigate predictors of first-line antiretroviral therapy discontinuation due to adverse events and their evolution in recent years.MethodsPatients starting first-line antiretroviral therapy were retrospectively selected. Primary end-point was the time to discontinuation of therapy due to adverse events, estimating incidence, fitting Kaplan-Meier and multivariable Cox regression models upon clinical/demographic/chemical baseline patients’ markers.Results1,096 patients were included: 302 discontinuations for adverse events were observed over 1,861 person years of follow-up between 1988 and 2010, corresponding to an incidence (95% CI) of 0.16 (0.14-0.18). By Kaplan-Meier estimation, the probabilities (95% CI) of being free from an adverse event at 90 days, 180 days, one year, two years, and five years were 0.88 (0.86-0.90), 0.85 (0.83-0.87), 0.79 (0.76-0.81), 0.70 (0.67-0.74), 0.55 (0.50-0.61), respectively. The most represented adverse events were gastrointestinal symptoms (28.5%), hematological (13.2%) or metabolic (lipid and glucose metabolism, lipodystrophy) (11.3%) toxicities and hypersensitivity reactions (9.3%). Factors associated with an increased hazard of adverse events were: older age, CDC stage C, female gender, homo/bisexual risk group (vs. heterosexual), HBsAg-positivity. Among drugs, zidovudine, stavudine, zalcitabine, didanosine, full-dose ritonavir, indinavir but also efavirenz (actually recommended for first-line regimens) were associated to an increased hazard of toxicity. Moreover, patients infected by HIV genotype F1 showed a trend for a higher risk of adverse events.ConclusionsAfter starting antiretroviral therapy, the probability of remaining free from adverse events seems to decrease over time. Among drugs associated with increased toxicity, only one is currently recommended for first-line regimens but with improved drug formulation. Older age, CDC stage, MSM risk factor and gender are also associated with an increased hazard of toxicity and should be considered when designing a first-line regimen.

Electrocardiographic Spatial QRS-T Angle and Incident Cardiovascular Disease in HIV-Infected Patients (from the Strategies for the Management of Antiretroviral Therapy [SMART] Study)

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 <0.001). In a model adjusted for study treatment arm, demographics, CVD risk factors, HIV characteristics, inflammatory markers, and other ECG abnormalities, a widened spatial QRS-T angle was associated with a >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.

Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates

AbstractHIV infection is associated with increased risk of cardiovascular complications, the underlying mechanism of which remains unclear. Plasma levels of the coagulation biomarker D-dimer (DD) correlate with increased mortality and cardiovascular events in HIV-infected patients. We compared the incidence of cardiovascular lesions and the levels of the coagulation markers DD and thrombin antithrombin in pathogenic SIV infections of rhesus and pigtailed macaques (PTMs) and in nonpathogenic SIV infection of African green monkeys (AGMs) and sooty mangabeys. Hypercoagulability and cardiovascular pathology were only observed in pathogenic SIV infections. In PTMs infected with SIV from AGMs (SIVagm), DD levels were highly indicative of AIDS progression and increased mortality and were associated with cardiovascular lesions, pointing to SIVagm-infected PTMs as an ideal animal model for the study of HIV-associated cardiovascular disease. In pathogenic SIV infection, DD increased early after infection, was strongly correlated with markers of immune activation/inflammation and microbial translocation (MT), and was only peripherally associated with viral loads. Endotoxin administration to SIVagm-infected AGMs (which lack chronic SIV-induced MT and immune activation) resulted in significant increases of DD. Our results demonstrate that hypercoagulation and cardiovascular pathology are at least in part a consequence of excessive immune activation and MT in SIV infection.

Small Dense Lipoproteins, Apolipoprotein B, and Risk of Coronary Events in HIV-Infected Patients on Antiretroviral Therapy

HIV infection and exposure to certain antiretroviral drugs is associated with dyslipidemia and increased risk for coronary events. Whether this risk is mediated by highly atherogenic lipoproteins is unclear. We investigated the association of highly atherogenic small dense low-density lipoproteins (LDLs) and apolipoprotein B and coronary events in HIV-infected individuals receiving antiretroviral therapy. We conducted a case-control study nested into the Swiss HIV Cohort Study to investigate the association of small dense LDL and apolipoprotein B and coronary events in 98 antiretroviral drug-treated patients with a first coronary event (19 fatal and 79 nonfatal coronary events with 53 definite and 15 possible myocardial infarctions, 11 angioplasties or bypasses) and 393 treated controls matched for age, gender, and smoking status. Lipids were measured by ultracentrifugation. In models including cholesterol, triglycerides, high-density lipoprotein cholesterol, blood pressure, central obesity, diabetes, and family history, there was an independent association between small dense LDL and coronary events [odds ratio (OR) for 1 mg/dL increase: 1.06, 95% confidence interval (CI): 1.00 to 1.11] and apolipoprotein B (OR for 10 mg/dL increase: 1.16, 95% CI: 1.02 to 1.32). When adding HIV and antiretroviral therapy-related variables, ORs were 1.04 (95% CI: 0.99 to 1.10) for small dense LDL and 1.13 (95% CI: 0.99 to 1.30) for apolipoprotein B. In both models, blood pressure and HIV viral load was independently associated with the odds for coronary events. HIV-infected patients receiving antiretroviral therapy with elevate small dense LDL and apolipoprotein B are at increased risk for coronary events as are patients without sustained HIV suppression.

Coronary Events in HIV-Infected Patients

Coronary Events in HIV-Infected Patients

Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy

Cardiovascular events have been reported among HIV-infected patients following antiretroviral therapy. However, the role of HIV itself in determining vascular damage is less described. Chronic inflammatory state might impair some regulatory endothelium properties leading to its activation, apoptosis or erosion. To evaluate the balance between endothelial progenitor cells and microparticles in HIV-infected antiretroviral drug-naive patients. A case-control study comparing HIV-infected patients (n = 35) with sex-matched and age-matched healthy controls (n = 33). Endothelial progenitor cells populations expressing CD34, CD133 and KDR were quantified by flow cytometry. Endothelial-derived microparticles, expressing CD51, and platelet-derived microparticles, expressing CD31/CD42, were also measured. Endothelial function was estimated by flow-mediated dilation. Lower percentages of endothelial progenitor cells (CD34/KDR) were observed in HIV-infected individuals compared with controls (0.02 vs. 0.09%, P = 0.045). In addition, endothelial microparticles concentration was higher in HIV-infected individuals (1963 vs. 436 microparticles/μl platelet-poor plasma, P = 0.003), with similar number of platelet-derived microparticles among groups. Furthermore, flow-mediated dilation was lower among HIV-infected individuals compared with controls [mean (SEM): 10 (1) and 16% (2), respectively; P = 0.03]. Our findings suggest an imbalance between endothelial progenitor cells mobilization and endothelial apoptosis. The alteration in the turnover of endothelial cells may contribute to cardiovascular events in HIV-infected patients.

N-terminal-proB-type natriuretic peptide predicts cardiovascular disease events in HIV-infected patients

Cardiovascular disease (CVD) is increasing in HIV-infected patients. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population. We aimed to quantify the risk of CVD events associated with NT-proBNP at baseline in the Strategies for Management of Anti-Retroviral Therapy study. In a nested case-control study, NT-proBNP was measured at baseline in 186 patients who experienced a CVD event over an average of 2.8 years of follow-up and in 329 matched controls. Odds ratios (ORs) associated with baseline levels of NT-proBNP for CVD were estimated using conditional logistic regression. At baseline median NT-proBNP [interquartile range (IQR)] was 48.1 (18.5, 112.9) pg/ml in patients who developed a CVD event and 25.7 (12.4, 50.2) pg/ml in controls. The unadjusted OR for the highest versus the lowest quartile was 3.7 [95% confidence interval (CI) 2.1-6.5, P < 0.0001]. After adjustment for baseline covariates and CVD risk factors, OR was 2.8 (95% CI 1.4-5.6, P = 0.003); with additional adjustment for IL-6, high-sensitivity C-reactive protein and D-dimer, OR was 2.3 (95% CI 1.1-4.9, P = 0.02). Higher levels of NT-proBNP are associated with increased risk of CVD in HIV patients after considering established CVD risk factors and markers for inflammation and thrombosis.

Association Between Abacavir Exposure and Increased Risk for Cardiovascular Disease in Patients with Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) infection and the receipt of antiretroviral therapy have been associated with the development of cardiovascular disease. The occurrence of cardiovascular events in HIV-infected patients has often been associated with treatment-induced dyslipidemia, insulin resistance, and body composition changes. These treatment-related complications are often the result of exposures to protease inhibitors or thymidine analogs such as stavudine or zidovudine. Recent investigations, however, have suggested an association between exposure to the nucleoside reverse transcriptase inhibitor, abacavir, and the occurrence of cardiovascular disease events. Based on these findings, current guidelines recommend using caution in patients receiving abacavir who are at a high risk for cardiovascular disease. Decisions to replace abacavir in a patient's regimen should be considered on an individual basis and with complete evaluation of the associated benefits and risks. Furthermore, additional studies are necessary to definitively determine the association between abacavir exposure and the occurrence of cardiovascular disease events. Studies are also necessary to definitively identify the contributions of both HIV infection and individual antiretroviral agents on the development of cardiovascular disease.

Aspirin Is Indicated for Primary Prevention of Cardiovascular Events in HIV-Infected Patients

To the Editors: The recommendations on aspirin use for the primary prevention of cardiovascular events,1 based on cardiovascular risk (CVR) calculation according to the Framingham scale, have recently been published.2 Despite the growing interest in CVR among HIV-infected patients,3,4 the use of aspirin in these subjects has received scant attention to date. However, the gradual aging of these patients means that we are reaching a point where aspirin for primary prevention may be indicated according to the above-mentioned recommendations. We have reviewed the indication of aspirin in a group of HIV-infected patients based on the criteria of these recommendations, with calculation of CVR using the Framingham tables. A total of 120 consecutive HIV-infected adults were included in a cross-sectional observational study. Demographic data were recorded, along with information on smoking or diabetes, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and blood glucose. Blood pressure was recorded after the consensus recommendations, with confirmation of the new diagnoses based on Holter blood pressure monitoring to rule out white-coat hypertension. The Framingham tables were used to calculate CVR. The indication of aspirin was based on the published criteria for males >45 years of age and females >55 years of age. Calculation was also made of the variation in percentage indication over the coming years as the patients gradually exceed this age limit without changes in the risk factors. In our experience, primary prevention with aspirin would be indicated in 30.8% of the patients, according to the assessment of the Framingham study, yet only 2 patients were taking the medication. Among the males, the percentage would reach 40%. Without modification of the CVR factors, over the next 5 years the indication would be expanded to another 15% as a result of the aging of the group. Therefore, application of the recently published recommendations on the use of aspirin in HIV-infected patients could help reduce the rise in cardiovascular events described in some studies. Aspirin would be indicated in a large proportion of patients, particularly in males, and this indication moreover may be expected to increase over the coming years. In the management of CVR among HIV-infected patients, it is therefore necessary to also consider aspirin as primary prevention treatment. Carlos Tornero, PhD Ana Ventura, PhD Maricarmen Mafe, PhD Department of Internal Medicine, Hospital Gandia, Spain

Low CD4+T Cell Count Is a Risk Factor for Cardiovascular Disease Events in the HIV Outpatient Study

Traditional cardiovascular disease (CVD) risk factors, human immunodeficiency virus (HIV) infection, and antiretroviral (ARV) agents have been associated with CVD events in HIV-infected patients. We investigated the association of low CD4(+) T lymphocyte cell count with incident CVD in a cohort of outpatients treated in 10 HIV specialty clinics in the United States. We studied patients who were under observation from 1 January 2002 (baseline), categorized them according to National Cholesterol Education Program guidelines into 10-year cardiovascular risk score (10-y CVR) groups , and observed them until CVD event, death, last HIV Outpatient Study contact, or 30 September 2009. We calculated rates of incident CVD events and identified associated baseline risk factors using Cox proportional hazard models. We also performed a nested case-control study to examine the association of latest CD4(+) cell count with CVD events. Among 2005 patients, 148 experienced incident CVD events. CVD incidence increased steadily from 0.4 to 3.0 events per 100 person-years from lowest to highest 10-y CVR group (P < .001). In multivariable Cox analyses adjusted for 10-y CVR, CD4(+) cell count <350 cells/mm(3) was associated with incident CVD events (hazard ratio, 1.58 [95% confidence interval, 1.09-2.30], compared with >500 cells/mm(3)), suggesting an attributable risk of approximately 20%. In the multivariable case-control analyses, traditional CVD risk factors and latest CD4(+) cell count <500 cells/mm(3), but not cumulative use of ARV class or individual drugs, were associated with higher odds of experiencing CVD events. CD4(+) count <500 cells/mm(3) is an independent risk factor for incident CVD, comparable in attributable risk to several traditional CVD risk factors in the HIV Outpatient Study cohort.

Infrequent Replication of Parvovirus B19 and Erythrovirus Genotypes 2 and 3 among HIV‐Infected Patients with Chronic Anemia

We investigated the role that erythroviruses (parvovirus B19 and erythrovirus genotypes 2 and 3) play in the lives of immunosuppressed HIV-infected patients with chronic anemia. We screened the serum samples of 428 patients by specific ultrasensitive real-time polymerase chain reaction assay. Sixteen patients had circulating DNA, with no apparent clinical impact. Erythrovirus-associated anemia is an extremely rare event in HIV-infected patients.

Uncontrolled Viral Replication as a Risk Factor for Non-AIDS Severe Clinical Events in HIV-Infected Patients on Long-Term Antiretroviral Therapy: APROCO/COPILOTE (ANRS CO8) Cohort Study

To determine risk factor for non-AIDS severe clinical events in HIV-infected patients on long-term combination antiretroviral therapy (cART). A validation committee reviewed each severe clinical event that occurred in the APROCO/COPILOTE (ANRS CO8) cohort that enrolled 1281 patients in 1997-1999 at the initiation of cART containing protease inhibitor. Probability of the occurrence of a first non-AIDS, cART-related, and AIDS-defining event was estimated, and potential determinants were studied using Cox regression models. During a median follow-up of 7.3 years, the incidence of non-AIDS events was higher than that of cART-related and AIDS-defining events (10.5, 3.6, and 2.6 per 100 patient-years, respectively). Bacterial (mainly airway) infections were the most frequent non-AIDS events (23.4%) followed by non-AIDS-defining malignancies and cardiovascular events (both 9.5%). Factors independently associated with the occurrence of a first non-AIDS event were age >60 years [hazard ratio (HR) 2.1; 95% confidence interval (CI): 1.3 to 3.2] and CD4 <100 cells per milliliter (HR 2.5; 95% CI: 1.8 to 3.6) but also plasma HIV RNA >4 log10 copies per milliliter at the time of the event (HR 1.9; 95% CI: 1.5 to 2.5). Optimization and permanent continuation of long-term antiretroviral therapy in HIV-infected patients is the best strategy to prevent or reduce the occurrence of non-AIDS severe morbidity.

Intracranial Hemorrhage and Liver-Associated Deaths Associated with Tipranavir/Ritonavir: Review of Cases from the FDA's Adverse Event Reporting System

Tipranavir (TPV), a protease inhibitor, has box warnings for intracranial hemorrhage (ICH) and hepatotoxicity (including hepatic failure and death). A box warning is a labeling statement about serious adverse events leading to significant injury and/or death. A box warning is the most serious warning placed in the labeling of a prescription medication. As a result of the respective morbidity and mortality associated with ICH and hepatic failure, the Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS) was searched for reports of these adverse events in HIV-infected patients receiving a tipranavir/ritonavir (TPV/r)-based regimen. This search comprised part of the FDA's safety analysis for traditional approval. From July 2006 to March 2007, 10 cases of ICH were identified in AERS. From June 2005 to March 2007, 12 cases of liver-associated deaths were identified. One patient experienced liver failure and fatal ICH. Most patients with these events had additional risk factors. Among patients with liver-associated deaths, 3 had HIV-RNA less than 400 copies per milliliter at the time of hepatic failure. Among 10 patients who discontinued TPV/r when hepatic failure developed, median number of days post-TPV/r to death was 23 (range, 2-69 days). Review of AERS did not identify new safety concerns regarding ICH. Among most patients with liver-associated deaths, death appears to occur soon after hepatic failure develops. If considering TPV/r, careful assessment of risk/benefit is suggested for patients at risk for ICH and hepatic failure.

Improvement in HIV-related endothelial dysfunction using the anti-inflammatory agent salsalate: a pilot study

We hypothesized that heightened systemic inflammation contributes to the increased rate of cardiovascular events in HIV-infected patients not receiving combination antiretroviral therapy. We performed a pilot trial to assess the effects of the nuclear factor-kappaB inhibitor salsalate on flow-mediated dilation of the brachial artery, a measure of endothelial function. Flow-mediated dilation significantly improved after 8 weeks of salsalate. However, hepatotoxicity occurred frequently. Research using alternative agents is warranted to examine the role of inflammation in HIV-related cardiovascular disease.

Long-Term Survival and Serious Cardiovascular Events in HIV-Infected Patients Treated With Highly Active Antiretroviral Therapy

There is continuing interest in the longer term effects of highly active antiretroviral therapy (HAART) on the risk of cardiopulmonary events. We assessed this using updated administrative data from an open retrospective cohort of HIV-infected persons receiving care from the US Veterans Affairs (VA). Information on 41,213 HIV-infected patients receiving VA care between January 1993 and December 2003 was included. Patients were followed for an average of 4 years or 168,213 person-years of follow-up. The death rate fell from 20.9 deaths per 100 patient-years of observation in 1995 to 5.2 deaths per 100 patient-years in 2003. In patient-level analysis, adjusted hazard ratios for death dropped precipitously for all races to a low of 0.18 (95% confidence interval: 0.15 to 0.23) at 72 months of exposure to HAART. Hazards for serious cardiovascular events remained near 1.0 for exposure to HAART, and hazards for serious cardiovascular events, stroke, or death were only slightly higher than for death alone. No selection effects or secular trends were found. The benefits of HAART continued to increase in the 8 years after introduction and with 6 years of individual use. The risk of serious cardiovascular events should be factored into individual patient management but does not pose an important public health risk.

Hair Loss Induced by Lopinavir‐Ritonavir

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.

HIV and Cardiovascular Disease: Contribution of HIV-Infected Macrophages to Development of Atherosclerosis

In their Perspective published in PLoS Medicine [1], Carr and Ory provide a fair review of our recent paper in PLoS Biology [2]. However, we believe their commentary puts too much emphasis on the role of low high-density lipoprotein (HDL) cholesterol levels as a cause of atherosclerosis in HIV-infected patients. While HDL cholesterol levels are reduced in untreated HIV infection [3], and defects in reverse cholesterol transport (RCT) that we reported may well be a contributing factor to this abnormality, initiation of antiretroviral therapy restores HDL levels [4]. Although the development of dyslipidemia with prolonged use of anti-HIV drugs again lowers HDL cholesterol and in addition raises very low-density lipoprotein and low-density lipoprotein levels [5], it is unlikely that HIV infection contributes significantly to these effects. Indeed, most HDL comes from the liver and intestine, which are responsible for maintaining plasma HDL levels [6], but neither hepatocytes nor enterocytes are infected by HIV. Also, the number of HIV-infected cells in treated patients is relatively low to account for any general changes in concentration of plasma lipoproteins. We suggest a different model that provides a simple connection between HIV-induced impairment of the cellular step of RCT and pathogenesis of atherosclerosis. We propose that RCT-defective HIV-infected macrophages contribute to development of atherosclerosis in HIV patients by converting into foam cells and initiating plaque formation in the vessel wall. Indeed, specific inactivation of ABCA1 in macrophages has been shown to induce atherosclerosis in a mouse model independently from plasma HDL level [7]. Plaque formation through this mechanism can begin even on the background of normal HDL but would be greatly accelerated by dyslipidemia, a condition observed in HIV patients treated with antiretroviral therapy. Given that even fully suppressive HAART (highly active antiretroviral therapy) does not eliminate long-lived productive reservoirs of the virus and that macrophages are a likely potential component of these reservoirs [8], long-lived HIV-infected macrophages may contribute to atherosclerotic plaque formation long after initiation of HAART. Consistent with this hypothesis, it was found that the majority of cardiovascular events in HIV-infected patients are “one plaque” events [9]. Therefore, several lines of evidence indirectly implicate HIV-infected macrophages in the pathogenesis of atherosclerosis in HIV patients. Future studies will determine the role of HIV-induced RCT impairment in this process and are expected to provide an understanding of the connection between HIV infection and atherosclerosis and to identify novel treatment targets for both diseases.