HIV-associated neurocognitive disorders (HAND) remain prevalent but challenging to diagnose particularly among non-demented individuals. To determine whether a brief computerized battery correlates with formal neurocognitive testing, we identified 46 HIV-infected persons who had undergone both formal neurocognitive testing and a brief computerized battery. Simple detection tests correlated best with formal neuropsychological testing. By multivariable regression model, 53% of the variance in the composite Global Deficit Score was accounted for by elements from the brief computerized tool (p<0.01). These data confirm previous correlation data with the computerized battery, yet illustrate remaining challenges for neurocognitive screening.

(See the editorial commentary by Tossonian and Conway, on pages 10–12.)

Background. The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved.

Methods. A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log10 HIV-1 RNA level at week 72 (both groups) and 36 (DT group).

Results. At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings.

Conclusions. Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment.

Clinical Trials Registration. NCT00090779.

This study examined the association between recent trends in CD4 and viral loads and cognitive test performance with the expectation that recent history could predict cognitive performance. Eighty-three human immunodeficiency virus (HIV)-infected patients with a mean CD4 count of 428 copies/ml were examined in this study (62% with undetectable plasma viral load [PVL]). We investigated the relationships between nadir CD4 cell count, 1-year trends in immunologic function/PVLs, and cognitive performance across several domains using linear regression models. Nadir CD4 cell count was predictive of current executive function (p = .004). One year clinical history for CD4 cell counts and/or PVLs were predictive of executive function, attention/working memory, and learning/memory measures (p < .05). Models that combined recent clinical history trends and nadir CD4 cell counts suggested that recent clinical trends were more important in predicting current cognitive performance for all domains except executive function. This research suggests that recent CD4 and viral load history is an important predictor of current cognitive function across several cognitive domains. If validated, clinical variables and cognitive dysfunction models may improve our understanding of the dynamic relationships between disease evolution and progression and CNS involvement.

(See the editorial commentary by Hull and Montaner, on pages 1154–6.)

Background. AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥105 copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients.

Methods. Primary endpoints were times to virologic failure, regimen modification, and safety event.

Results. In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14).

Conclusions. In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.

Abstract

Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease (CVD) risk, increased HIV disease progression, and death in HIV-infected patients. Use of abacavir has been reported to increase CVD risk. We assessed the effect of virologically suppressive efavirenz (EFV)-based antiretroviral therapy on high sensitivity CRP (hsCRP) levels over a 96-week period with particular attention to the effect of gender and abacavir use. Banked sera from entry and week 96 visits of AIDS Clinical Trials Group A5095 participants were assayed for hsCRP, then analyzed by gender, abacavir randomization, and for correlation with changes in fasting metabolic parameters. Analyses of hsCRP were conducted in two phases and involved a total of 145 men and 51 women. hsCRP did not differ by gender at baseline but higher levels were seen at week 96 in women (median 6 mg/liter; Q1, Q3, 1.8, 13.8) compared to men (median 1.6 mg/liter; Q1, Q3, 0.9, 4.2, p < 0.001), with an estimated shift in hsCRP by gender of 2.5 mg/liter (95% CI 1.0, 5.1). There was no difference in hsCRP levels by abacavir use. Changes in hsCRP did not correlate with changes in insulin resistance or with changes in fasting lipids. Durably virologically suppressive therapy with EFV-based regimens did not decrease hsCRP levels over a 96-week period. hsCRP levels increased significantly only in women. Randomization to abacavir had no effect on changes in hsCRP levels. Changes in hsCRP levels did not correlate with changes in fasting metabolic parameters.

Cytokine disturbances have been linked to brain dysfunction among HIV-infected people. Past studies have not simultaneously examined a large set of cytokine measures and their relationships to HIV-associated neurocognitive deficits. We hypothesized that performance on measures of attention, and executive and psychomotor functions would be associated with plasma cytokine concentrations in HIV-infected individuals. Plasma samples drawn from 30 HIV-infected and 37 HIV seronegative individuals were analyzed via xMAP multiplexed bead array immunoassay to determine concentrations of thirteen cytokines. Performance on Trail Making A/B, Stroop Test, Letter Number Sequencing, Digit Symbol Coding, Symbol Search, and Grooved Pegboard tests was assessed. Statistical analyses were performed to examine group differences in cytokine concentrations, and associations between cytokine and HIV clinical variables and neurocognitive performance. Significant HIV effects were found on seven of the thirteen cytokines, primarily with respect to interleukins. HIV clinical factors (CD4 and HIV RNA levels, duration of illness, antiretroviral treatment) and hepatitis C status were associated with specific plasma cytokine concentrations. Neurocognitive measures were associated with cytokine concentrations, most consistently among the interleukins and IP-10. Generally, cytokine concentrations were among the strongest predictors of neurocognitive function relative to other clinical factors, which reinforces their potential importance in examining the neuropathological processes of HIV. The findings also point to the potential value of simultaneously examining a panel of biomarkers. The current results suggest that a complex relationship likely exists among cytokines [how?], and that these relationships are mediated not only by HIV infection, but also by antiretroviral treatment and other comorbid conditions.

HCV incidence from 1996-2008 among HIV-infected men in U.S. HIV therapeutic trials was 0.51 per 100 person-years. Incident HCV occurred primarily through non-parenteral means; 75% of seroconverters reported no drug injection. At-risk HIV-infected persons should have access to HCV surveillance

Background. Outbreaks of sexually transmitted hepatitis C virus (HCV) infection have been reported among human immunodeficiency virus (HIV)–infected men who have sex with men in Europe, Australia, and New York. Whether this is occurring across the United States is unknown.

Methods. We determined incidence of HCV infection during 1996–2008 among male participants of the AIDS Clinical Trial Group Longitudinal Linked Randomized Trials cohort, a long-term study of HIV-infected persons randomized into selected US-based clinical trials. We evaluated associations with self-reported injection drug use (IDU), time-varying CD4+ cell count, and HIV RNA level with use of multivariate Poisson regression. No sexual or non-IDU risk factor data was available.

Results. A total of 1830 men had an initial negative HCV antibody test result and at least 1 subsequent HCV antibody test result, contributing >7000 person-years. At the time of the initial negative HCV antibody test result, 94% of men were receiving highly active antiretroviral therapy (HAART) and 6% reported current or prior IDU. Thirty-six seroconverted, with overall incidence of .51 cases per 100 person-years (95% confidence interval, .36–.70). Mean age at seroconversion was 46 years. Seroconversion was associated with IDU (25% of seroconverters reported IDU history vs 5% of nonseroconverters; P < .001), whereas 75% (n = 27) of seroconverters reported no IDU (incidence, 2.67 cases per 100 person-years among IDUs, .40 cases per 100 person-years among non-IDUs). Seroconversion was associated with HIV RNA level >400 copies/mL (44% at time of antibody positivity vs 21% at time of last negative antibody test result; P = .02) but not with CD4+ cell count.

Conclusions. Incident HCV infection occurs in HIV-infected men involved in US HIV therapeutic trials, primarily through nonparenteral means, despite engagement in care and HAART. HCV antibody development was not related to immune status but was associated with inadequate HIV suppression. At-risk HIV-infected persons should have access to HCV surveillance.

Abstract

Transmission of HIV-1 drug resistance has important clinical and epidemiological consequences including earlier treatment failure and forward transmission of resistance strains in high-risk groups. To evaluate the prevalence and molecular epidemiology of transmitted drug resistance in Rhode Island, we collected genotypic, demographic, clinical, and laboratory data from treatment-naive individuals presenting to the largest outpatient HIV clinic in the state from January 2007 to November 2007. Sequences from 35 treatment-naive individuals were available, 83% of whom were men who had sex with men (MSM). All sequences were HIV-1 subtype B. Drug resistance mutations were identified in 7/35 [20%; 95% confidence interval (CI), 0.08–0.37] patients, six of whom had K103N. Two phylogenetic transmission clusters were found, involving 17% (6/35) of individuals, three in each cluster. We did not find an association between belonging to a cluster and age, gender, AIDS-defining illness, CD4 cell count, or viral load. Drug resistance mutations were more commonly observed in transmission clusters (p = 0.08). Individuals in one cluster all had K103N and were MSM who had attended local bathhouses. Individuals forming clusters were significantly more likely to have visited a bathhouse compared to nonclusters (p = 0.02). The prevalence of transmitted drug resistance in Rhode Island is high, further justifying genotypic testing on presentation to care and prior to treatment initiation. Molecular epidemiological analysis and association of resistance with phylogenetic networks using data obtained for clinical purposes may serve as useful tools for the prevention of drug resistance transmission and for contact tracing.

Efavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by paired t test. The coefficients of variation in efavirenz plasma AUC0-24 (area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC0-24 ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC0-24 ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration (C24) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC0-24 values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms.

We report a case of cutaneous mucormycosis and Enterobacter infection developing in a 50-year-old diabetic woman following a dog bite that showed delayed development and diagnosis in comparison with typical zygomycotic cutaneous lesions.

HIV is characterized by frontostriatal dysfunction, and is associated with cognitive and psychiatric abnormalities. Several studies have noted impaired facial emotion recognition abilities in patient pollutions that demonstrate frontostriatal dysfunction; however, facial emotion recognition abilities have not been systematically examined in HIV patients. The current study investigated facial emotion recognition in 50 non-demented HIV-seropositive adults and 50 control participants relative to their performance on a non-emotional landscape categorization control task. We examined the relation of HIV-disease factors (nadir and current CD4 levels) to emotion recognition abilities, and assessed the psychosocial impact of emotion recognition abnormalities. Compared to control participants, HIV patients performed normally on the control task but demonstrated significant impairments in facial emotion recognition, specifically for fear. HIV patients reported greater psychosocial impairments, which correlated with increased emotion recognition difficulties. Lower current CD4 counts were associated with poorer anger recognition. In summary, our results indicate that chronic HIV infection may contribute to emotion processing problems among HIV patients. We suggest that disruptions of frontostriatal structures and their connections with cortico-limbic networks may contribute to emotion recognition abnormalities in HIV. Our findings also highlight the significant psychosocial impact that emotion recognition abnormalities have on individuals with HIV.

There have been many studies examining HIV-infection-related alterations of magnetic resonance imaging (MRI) diffusion metrics. However, examining scalar diffusion metrics ignores the orientation aspect of diffusion imaging, which can be captured with tractography. We examined five different tractography metrics obtained from global tractography maps (global tractography FA, average tube length, normalized number of streamtubes, normalized weighted streamtube length, and normalized total number of tubes generated) for differences between HIV positive and negative patients and the association between the metrics and clinical variables of disease severity. We also examined the relationship between these metrics and cognitive performance across a wide range of cognitive domains for the HIV positive and negative patient groups separately. The results demonstrated a significant difference between the groups for global tractography FA (t=2.13, p= 0.04), but not for any of the other tractography metrics examined (p-value range=0.39 to 0.95). There were also several significant associations between the tractography metrics and cognitive performance (i.e., tapping rates, switching 1 and 2, verbal interference, mazes; r≥0.42) for HIV infected patients. In particular, associations were noted between tractography metrics, speed of processing, fine motor control/speed, and executive function for the HIV-infected patients. These findings suggest that tractography metrics capture clinically relevant information regarding cognitive performance among HIV infected patients and suggests the importance of subtle white matter changes in examining cognitive performance.

Aims

To test the efficacy of two smoking cessation interventions in an HIV+ sample: standard care (SC) treatment plus nicotine replacement therapy (NRT) versus more intensive motivationally-enhanced (ME) treatment plus NRT.

Design

randomized controlled trial.

Setting

HIV+ smoker referrals from eight Immunology clinics in the Northeastern US.

Participants

444 participants enrolled in the study (mean age=42 years; 63% male; 52% European-American; mean cigarettes/day=22.8).

Interventions

SC received two brief sessions with a Health Educator. Those setting a quit date received self-help quitting materials and NRT. ME received four sessions of motivational counseling and a quit-day counseling call. All ME intervention materials were tailored to the needs of HIV+ individuals.

Measurements

Biochemically-verified 7-day abstinence rates at 2-month, 4-month, and 6-month follow-ups.

Findings

Intent-to-Treat (ITT) abstinence rates at 2-month, 4-month, and 6-month follow-ups were 12%, 9%, and 9% respectively in the ME condition, and 13%, 10%, and 10% respectively in the SC condition, indicating no between-group differences. Among 412 participants with treatment utilization data, 6-month ITT abstinence rates were positively associated with low nicotine dependence (p=0.02), high motivation to quit (p=0.04), and Hispanic-American race/ethnicity (p=0.02). Adjusting for these variables, each additional NRT contact improved the odds of smoking abstinence by a third (OR=1.32, 95% CI= 0.99–1.75).

Conclusions

Motivationally-enhanced treatment plus NRT did not improve cessation rates over and above standard care treatment plus NRT in this HIV+ sample of smokers. Providers offering brief support and encouraging use of nicotine replacement may be able to help HIV+ patients quit smoking.

Background

Lack of functional CCR5 increases the severity of certain viral infections, including West Nile virus and tickborne encephalitis. In a phase II trial of the investigational CCR5 antagonist vicriviroc (AIDS Clinical Trials Group protocol A5211), 4 lymphomas occurred in study patients who received vicriviroc. Because of the known association between unregulated Epstein-Barr virus (EBV) replication and lymphoma in immunocompromised patients, we evaluated whether vicriviroc exposure was associated with lymphoma EBV antigen positivity and/or had an effect on plasma levels of EBV DNA.

Methods

Clinical findings for all 4 patients enrolled in the A5211 study who developed lymphoma (2 Hodgkin and 2 non-Hodgkin) were reviewed, and tumor specimens were assessed for evidence of ongoing EBV replication. Longitudinal plasma samples from 116 patients in the A5211 study were analyzed, and EBV DNA was quantified by real-time polymerase chain reaction.

Results

Plasma EBV DNA was not detected in the 2 patients with non-Hodgkin lymphoma; both patients with Hodgkin lymphoma who had samples tested had EBV DNA levels <3200 copies/mL. One patient with Hodgkin lymphoma had a lymph node core biopsy specimen that was strongly positive for EBV; the other 3 lymphomas were histochemically EBV negative. None of the 116 patients with available samples experienced sustained increases in plasma EBV levels.

Conclusions

CCR5 antagonism by vicriviroc treatment in treatment-experienced patients was not associated with reactivation of EBV infection.

Objective:

To better characterize smoking in HIV-positive individuals and to identify critical components of a targeted smoking cessation intervention for multiethnic HIV-positive smokers.

Methods:

Differences in baseline characteristics of 444 HIV-positive smokers were examined by race, and a multivariate linear regression model evaluated factors associated with nicotine dependence in an HIV-positive population, with a particular emphasis on race/ethnic differences.

Results:

Low smoking self-efficacy and higher contemplation of quitting were predictive of greater nicotine dependence. An interaction between age and race was noted, with older Hispanic Americans less likely to be nicotine dependent.

Conclusions:

Efforts should be made to tailor smoking cessation intervention content to HIV-positive racial/ethnic minority groups.

Objectives

To examine the efficacy and safety of Prosaptide™ (PRO) for the treatment of painful HIV-associated sensory neuropathies (HIV-SN).

Design

A randomized, double-blind, placebo-controlled, multicenter study in participants with sensory neuropathy. Pain modulating therapy was discontinued prior to baseline. Participants were stratified by sural sensory nerve action potential (SNAP) amplitude. Participants were trained to use an electronic diary (ED) to record pain.

Setting

Peripheral neuropathies are common complications of HIV infection. The pathogenesis is unknown and currently treatments are restricted to symptomatic measures. We examined PRO against placebo (PBO) for treatment of painful HIV-SN and performed a post-hoc evaluation of an electronic diary (ED) to record HIV-associated neuropathic pain.

Participants

Eligible participants included adults with neurologist-confirmed painful HIV-SN.

Interventions

2, 4, 8, or 16 mg/d PRO or PBO administered via subcutaneous (SC) injection for six weeks. Neurotoxic antiretroviral drug usage was held constant.

Outcome Measures

Changes from baseline in the weekly average of evaluable daily random prompts measuring pain using the Gracely pain scale and adverse events.

Results

237 participants were randomized. The study was stopped after a planned futility analysis. There were no between-group differences in the frequency of adverse events or laboratory toxicities. The 6-week mean (sd) Gracely pain scale changes were −0.12 (0.23), −0.24 (0.35), −0.15 (0.32), −0.18 (0.34), and −0.18 (0.32) for the 2, 4, 8, 16 mg, and PBO arms respectively. A similar variability of pain changes recorded using the ED were noted compared to previous trials that used paper collection methods.

Conclusions

6-week treatment with PRO was safe but not effective at reducing HIV-associated neuropathic pain. Use of an ED to record neuropathic pain is novel in HIV-SN, resulted in reasonable compliance in recording pain data, but did not decrease the variability of pain scores compared to historical paper collection methods.

Trial Registration

Current Controlled Trials NCT00286377

Background

Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy.

Methods

A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA ≤ 400 copies/mL after ≥ 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24).

Results

Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (<400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; <50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed.

Conclusion

ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events.