Adherence to Post-Exposure Prophylaxis (PEP) and Incidence of HIV Seroconversion in a Major North American Cohort.

BACKGROUND: There is limited evidence on the efficacy of post-exposure prophylaxis (PEP) for sexual exposures. We sought to determine the factors associated with adherence to treatment and describe the incidence of PEP failures in a Montreal clinic. METHODS: We prospectively assessed all patients consulting for PEP following sexual exposures from October 2000 to July 2014. Patients were followed at 4 and 16 weeks after starting PEP. Treatment adherence was determined by self-report at week 4. Multivariable logistic regression was used to estimate the factors predicting adherence to treatment. RESULTS: 3547 PEP consults were included. Patients were mainly male (92%), MSM (83%) and sought PEP for anal intercourse (72%). Seventy-eight percent (n = 2772) of patients received a prescription for PEP, consisting of Tenofovir/Emtracitabine (TVD) + Lopinavir/Ritonavir (LPV) in 74% of cases, followed by Zidovudine/Lamivudine (CBV) + LPV (10%) and TVD + Raltegravir (RAL) (8%). Seventy percent of patients were adherent to treatment. Compared to TVD+LPV, patients taking CBV+LPV were less likely to adhere to treatment (OR 0.58, 95% CI 0.44-0.75), while no difference was observed for patients taking TVD+RAL (OR 1.15, 95% CI 0.83-1.59). First-time PEP consults, older and male patients were also more adherent to treatment. Ten treated patients seroconverted (0.37%) during the study period, yet only 1 case can be attributed to PEP failure (failure rate = 0.04%). CONCLUSION: PEP regimen was associated with treatment adherence. Patients were more likely to be adherent to TVD-based regimens. Ten patients seroconverted after taking PEP; however, only 1 case was a PEP failure as the remaining patients continued to engage in high-risk behavior during follow-up. One month PEP is an effective preventive measure to avoid HIV infection.

Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: results from the VERITAS study (TMC114HIV4054).

BACKGROUND: Despite the benefit of maintaining inactive Nucleotide/side reverse transcriptase inhibitors (NRTIs) in salvage regimens, they are associated with increased toxicity and treatment costs. Current evidence suggests that NRTI-sparing regimens in patients failing ART are non-inferior to NRTI-including regimens. This study aimed to evaluate the impact of removing at least one inactive NRTI on virologic, safety, and financial outcomes. METHODS: Drug-resistant, virologically suppressed patients with CD4 >250 cells/ml on a stable regimen of four or more antiretrovirals (ARVs) were enrolled in a 48-week prospective, open-label pilot trial. One inactive NRTI was removed at baseline. Patients taking over five ARVs had a second inactive NRTI removed at 24 weeks. Viral load, CD4 count, and adverse events were assessed at baseline, 24, and 48 weeks. RESULTS: Thirty-one male patients participated. Twenty-nine (94%) patients had lamivudine (3TC) or emtricitabine (FTC) removed and four patients had an additional NRTI removed. One patient was excluded at week 26 for discontinuing an active NRTI. All patients maintained undetectable viral loads at weeks 24 (100%) and 48 [PP = 100%; Intent-to-treat (ITT) = 97%]. At 48 weeks, patients had a median gain of 20 CD4 (IQR: - 50, +133; mean +39) compared to baseline. Three patients exhibited Grade III bilirubin elevation (two Grade II and one Grade III at baseline), which returned to baseline levels. No serious adverse events were observed. Removal of one or two ARVs equated to a mean annual savings of $3319 CDN (11%) and $8630 CDN (24%), respectively. CONCLUSION: Removing inactive NRTIs in patients with a controlled viral load appears to be safe, maintains virological suppression, and reduces treatment costs.

Tolerability is more important than simplicity for treatment durability.

INTRODUCTION: Many studies have shown the superiority of single tablet regimens (STRs) of antiretrovirals for the treatment of HIV in terms of efficacy, adherence and rate of hospitalisation as they offer a low pill burden and once daily dosing. Our objective was to compare the duration of first-line STRs to multi-tablet regimens. METHODS: From our clinical database, we selected patients initiating any of the major first-line regimens between 2007 and 2013. Two STRs, Atripla (ATP) and Complera (CPLR), were compared to three non-STRs: two NRTIs and raltegravir (RAL), atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r). The primary outcome was time to discontinuation of the first-line regimen. The association between regimen type and duration was estimated using Cox proportional hazards models adjusted for age, gender, baseline CD4, baseline viral load, risk factor, site and year of treatment initiation. RESULTS: A total of 743 patients (281 on STRs and 462 on non-STRs) were included. 693 (93%) were male and median age was 43 years. Median length of follow-up was 3.2 years. 56% of patients were MSM, 6% IDU and 6% from endemic countries. Patients on an STR were less likely to be IDU (p<0.024) and have a baseline HIV-RNA ≥100,000 copies/mL (p<0.011). Overall, 321 (43%) patients discontinued their regimen during the study period. The rate of discontinuation one year after starting ARV depends on the regimen: 29% for patients on 2NRTIs+DRV/r, 26% on ATP, 25% on 2NRTIs+ATV/r, 17% on 2NRTIs+RAL and 10% on CPLR (p<0.001). In the adjusted model, durability for STR and non-STR was equivalent (aHR=0.83, p=0.108). Compared to patients on ATP, patients on CPLR were less likely to discontinue (HR=0.58, p=0.070). No difference between ATP and the other regimens was observed: HR for 2NRTIs+RAL=0.92 (p=0.66), 2NRTIs+ DRV/r=1.16 (p=0.36), 2NRTIs+ATV/r=1.11 (p=0.46). CONCLUSIONS: Our findings suggest that STRs do not necessarily result in a more durable treatment. Even with a higher pill burden and/or twice daily dosing, patients initiating therapy with RAL or boosted-PI based regimens were not more likely to discontinue the first-line regimen compared to patients on an STR. Among the STR subgroups, the regimen with better known tolerability conferred more durable treatment. Limitations included our inability to adjust for the patient's adherence to a given regimen.

Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: 96 weeks post VERITAS study.

INTRODUCTION: In HIV+ patients exhibiting multidrug resistance (MDR), NRTIs often have little activity, increased toxicity, drug interactions and add unnecessary treatment costs. The 48 week VERITAS study demonstrated that these patients can have a safe and effective simplification of salvage regimen by removing inactive NRTIs as determined by genotypic data. Virological, immunological, clinical and financial outcomes were evaluated at an additional 96 weeks of follow-up. MATERIALS AND METHODS: MDR patients with an undetectable viral load (VL) on a stable regimen containing at least four ARVs (including one inactive NRTI) were enrolled in an open-label, prospective simplification trial, where one inactive NRTI was removed at baseline (BL). A second NRTI could be removed at week 24 if the regimen contained at least five ARVs at enrolment. RESULTS: 31 male patients participated. The mean length of treatment was 14 years, with a median CD4 count of 525. The BL regimen consisted of 4 ARVs in 22 patients (71%) and 5 ARVs in 9 patients (29%). 3TC or FTC was removed in 29 patients (94%), and either AZT or TDF was interrupted in 2 others. Four patients had a second NRTI stopped. One patient was removed at W26 as an active NRTI was removed for creatinine elevation. 30 well-controlled patients continued follow-up after W48. At W144, six patients had additional changes in their ARV regimen. Half were due to toxicity (jaundice, neuropathy and nephrotoxicity) while the other half were the result of treatment simplification. None of the patients exhibited virologic failure at the time of treatment change and maintained undetectable VLs throughout the entire follow-up. These six patients had a mean gain of 79 CD4 (p=0.17) compared to baseline. 22 of the 24 patients (92%) with no changes in ARV therapy after W48 had undetectable VLs. The other two had confirmed virologic failure, one with genotypic resistance. All 24 had elevated CD4 counts (mean +118 CD4, p<0.0001). No deaths or serious adverse events were observed. One or two ARV removals translated to a mean annual saving of $3319 CDN (11%) and $8630 (24%) respectively. CONCLUSIONS: Final results indicate that removing one or two inactive NRTIs from a regimen in patients taking four or more ARVs with controlled VL appears to be safe, maintains virological suppression through 144 weeks and significantly reduces treatment costs.

Citalopram for the prevention of depression and its consequences in HIV-hepatitis C coinfected individuals initiating pegylated interferon/ribavirin therapy: a multicenter randomized double-blind placebo-controlled trial.

BACKGROUND: Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefit from prevention of depression. OBJECTIVE: The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-α/ribavirin therapy. METHODS: This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-α2b/ribavirin, stratified by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDI- II) score greater than 15, confirmed 2 weeks apart. RESULTS: Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ significantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. CONCLUSIONS: A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it significantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV.

Abacavir/lamivudine fixed-dose combination with ritonavir-boosted darunavir: a safe and efficacious regimen for HIV therapy.

BACKGROUND: Current treatment guidelines recommend the use of tenofovir (TDF) and emtricitabine (FTC) along with a third agent to treat HIV-positive adults. However, other treatment options, including the use of abacavir (ABC) and lamivudine (3TC) when used with ritonavir-boosted darunavir (DRV/r), have rarely been studied. OBJECTIVE: We evaluated the safety and efficacy of the coformulation of ABC/3TC administered with DRV/r in treatment-naïve and treatment-experienced patients. METHODS: HIV-infected adults who received an open-label combination of ABC/3TC/ DRV/r were followed in a community clinic in Montréal. Patients had no resistance to any of the compounds in their regimen. Viral load (VL), CD4 cell count, AST, ALT, and creatinine levels were examined throughout the 48 weeks of follow-up. RESULTS: Sixty-seven patients with a mean age of 45 years were enrolled. Two did not return for follow-up and were excluded. Thirty-five (52%) were treatment- experienced and the remaining were treatment-naïve. HLA-B*5701 test results were available for 56 patients and none were positive. At baseline, mean VL was 4.8 log for treatment-naïve and 2.3 log for experienced patients. Twelve patients discontinued the study regimen prior to reaching the endpoint. At week 48, 79% had a VL <50. Median CD4 cell gain was higher among treatment-naïve patients (273 cells) than among treatment-experienced patients (102 cells) (P = .002). No patient experienced any grade 2 or higher liver enzyme elevation throughout the study. CONCLUSIONS: The new combination of ABC/3TC/DRV/r demonstrates a high rate of antiviral activity with no major toxicity. The drug combination appears to be generally safe and well tolerated.

HAART and progression to high-grade anal intraepithelial neoplasia in men who have sex with men and are infected with HIV.

BACKGROUND: Human immunodeficiency virus (HIV)-seropositive men who have sex with men (MSM) are at risk for anal intraepithelial neoplasia (AIN) and cancer. The goal of this study was to identify risk factors associated with high-grade AIN (AIN-2,3) in HIV-positive MSM, including the receipt of highly active antiretroviral therapy (HAART). METHODS: A cohort study involving 247 HIV-seropositive MSM receiving HAART or initiating HAART was followed up every 6 months for 3 years with human papillomavirus (HPV) testing and high-resolution anoscopy to identify predictors of AIN-2,3 by Cox regression analysis and period prevalence logistic regression. RESULTS: AIN-2,3 was observed during the study in 132 (53%) of 247 participants. The progression rate to AIN-2,3 from a lesser abnormality at baseline was 12.8 cases per 1000 person-months (95% confidence interval [CI], 9.8-16.5 cases per 1000 person-months). The risk of AIN-2,3 increased with age (odds ratio [OR], 3.09 [95% CI, 1.12-8.52] for men 40-49 years of age and 4.78 [95% CI, 1.29-17.73] for men >50 years of age, compared with men <40 years of age) and for men whose CD4+ cell counts were <50 cells/mm(3) before starting HAART (OR, 14.40 [95% CI, 1.45-143.58]). Men who had been receiving their current HAART regimen for >4 years had a marginally significant lower risk of AIN-2,3 after adjustment for HPV (OR, 0.28 [95% CI, 0.07-1.06]) compared with those treated for <4 years. Anal HPV type 16 (HPV16) or type 18 (HPV18) infections (OR, 14.18; [95% CI, 3.51-57.32]) and HPV16 and HPV18 co-infection (OR, 31.03 [ 95% CI, 5.68-169.60]) were strongly associated with progression to AIN-2,3. CONCLUSION: HPV16 and HPV18 infections and a low nadir CD4+ cell count increase the risk of AIN-2,3. Receiving the same HAART regimen for >4 years may contribute some benefit against AIN-2,3.

Episomal and integrated human papillomavirus type 16 loads and anal intraepithelial neoplasia in HIV-seropositive men.

OBJECTIVES: To assess levels of episomal and integrated human papillomavirus type 16 (HPV-16) loads in HIV-seropositive men who have sex with men (MSM) in anal infection and to study the association between episomal and integrated HPV-16 loads and anal intraepithelial neoplasia (AIN). STUDY DESIGN: A cohort study of 247 HIV-positive MSM followed each 6 months for 3 years. Overall, 135 (54.7%) men provided 665 HPV-16-positive anal samples. METHODS: Episomal and integrated HPV-16 loads were measured with quantitative real-time PCR assays. HPV-16 integration was confirmed in samples with a HPV-16 E6/E2 of 1.5 or more with PCR sequencing to demonstrate the presence of viral-cellular junctions. RESULTS: The HPV-16 DNA forms in anal samples were characterized as episomal only in 627 samples (94.3%), mixed in 22 samples (3.3%) and integrated only in nine samples (1.4%). HPV-16 episomal load [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.1], number of HPV types (OR = 1.4, 95% CI 1.1-1.8) and current smoking (OR = 4.8, 95% CI 1.3-18.6) were associated with high-grade AIN (AIN-2,3) after adjusting for age and CD4 cell counts. Integrated HPV-16 load was not associated with AIN-2,3 (OR = 0.7, 95% CI 0.4-1.1). Considering men with AIN-1 at baseline, four (16.7%) of the 24 men who progressed to AIN-2,3 had at least one sample with integrated HPV-16 DNA compared with three (23.1%) of 13 men who did not progress (OR = 0.7, 95% CI 0.2-3.8; P = 0.64). Integration was detected in similar proportions in samples from men without AIN, with AIN-1 or AIN-2,3. CONCLUSION: High episomal HPV-16 load but not HPV-16 integration load measured by real-time PCR was associated with AIN-2,3.

Changes in function of HIV-specific T-cell responses with increasing time from infection.

Recently HIV-infected individuals have virus-specific responses characterized by IFN-gamma/IL-2 secretion and proliferation rarely seen in chronic infection. To investigate the timing of loss of HIV-specific T-cell function, we screened cells from 59 treatment-naïve HIV-infected individuals with known dates of infection for proteome-wide responses secreting IFN-gamma/IL-2 and IFN-gamma alone by ELISPOT. HIV peptide-specific proliferation was assessed by carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution. The contribution of IFN-gamma/IL-2 and IFN-gamma-only secretion to the total HIV-specific response was compared in subjects infected <6, 6-12, and 12-36 mo earlier. The frequency of IFN-gamma/IL-2-secreting cells fell, while that of IFN-gamma-only secretion rose with time from infection. HIV peptide-specific proliferative responses were almost exclusively mediated by CD8(+) T cells, and were significantly lower in cells obtained from the 12-36 mo versus < 6 mo post-infection groups. By the second year of infection there was a significant difference in these functions compared to those assessed within 6 mo.

Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study.

BACKGROUND: Human immunodeficiency virus (HIV)-seropositive men who have sex with men (MSM) are at higher risk of human papillomavirus (HPV) infection. This study was conducted to better understand the natural history of type-specific HPV infection in the anus. METHODS: A cohort study was conducted among HIV-seropositive MSM in Montreal to investigate acquisition and loss of anal HPV infection. Participants were followed up every 6 months for 3 years for risk behaviors, HIV-related parameters, and HPV testing. RESULTS: HPV DNA was detected in 97.9% of the 247 participants at baseline (median, 5 HPV types). The most common types were HPV-16 (38.2%) and HPV-6 (35.3%). Prevalent HPV-16 infections had the lowest clearance rate (12.2 cleared episodes per 1000 person-months [95% confidence interval {CI}, 8.5-17.7]) and a mean retention time of 36 months (95% CI, 32.7-38.8). The highest incidence rates were found for HPV-16 (10.8 new cases per 1000 person-months [95% CI, 8.0-14.7]), HPV-52 (10.8 new cases per 1000 person-months [95% CI, 8.2-14.1]), and HPV-53 (9.8 new cases per 1000 person-months [95% CI, 7.4-13.0]), with cumulative incidences at 36 months of approximately 30%. CONCLUSIONS: Multiple HPV types were common in the anal canals of HIV-seropositive MSM. Incidence and clearance rates were not similar among HPV types. Ongoing surveillance of this cohort will help our understanding of the determinants of HPV persistence and progression to lesions.

Genotyping of human papillomavirus DNA in anal biopsies and anal swabs collected from HIV-seropositive men with anal dysplasia.

BACKGROUND: Human papillomavirus (HPV) causes anal intraepithelial neoplasia (AIN) in HIV-seropositive men. The detection of HPV genotypes in anal biopsies and swabs was compared. METHODS: HPV DNA was detected in anal swabs and biopsies obtained concurrently from 154 HIV-seropositive men [31 without AIN, 60 low-grade AIN (AIN-1), 62 high-grade AIN (AIN-2,3), and 1 indeterminate AIN] under or eligible to highly active antiretroviral therapy. RESULTS: HPV DNA was detected in 24.2% of normal biopsies compared with 93.5% with AIN-2,3 (P < 0.001) and 88.3% with AIN-1 (P < 0.001). The proportion of biopsies containing multiple genotypes was greater in AIN-1 (n = 21, 35.0%; P = 0.002) and AIN-2,3 (n = 38, 58%; P < 0.001) than in normal biopsies (n = 2, 6.5%). The most frequent genotypes in order of frequency were in AIN-2,3 biopsies HPV-16, 18, 58, and 45 and were in AIN-1 biopsies HPV-6, 11, 16, and 39. Controlling for age, CD4 count, and smoking, the presence of high-risk HPV DNA in biopsies [odds ratio (OR) = 50.8, 95% confidence interval (CI): 13.0 to 199.5] but not in swabs (OR = 2.0, 95% CI: 0.6 to 7.0) was associated with AIN-2,3. CONCLUSIONS: AIN-2,3 was associated with high-risk HPV infection detected in biopsies but not in swabs in men under or starting highly active antiretroviral therapy, possibly due to the presence of HPV foci outside of the neoplastic lesion.

Confirmatory real-time PCR assay for human papillomavirus (HPV) type 52 infection in anogenital specimens screened for HPV infection with the linear array HPV genotyping test.

A novel real-time PCR assay for detection of human papillomavirus type 52 (HPV-52) DNA (RT-52) was evaluated on 265 anogenital samples. RT-52 had a sensitivity of 98.4% and a specificity of 100% compared to conventional HPV-52 typing assays, including hybridization of PGMY products with an HPV-52-specific probe and PCR sequencing of HPV-52 E6.

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals.

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.

Enhanced detection and typing of human papillomavirus (HPV) DNA in anogenital samples with PGMY primers and the Linear array HPV genotyping test.

The Roche PGMY primer-based research prototype line blot assay (PGMY-LB) is a convenient tool in epidemiological studies for the detection and typing of human papillomavirus (HPV) DNA. This assay has been optimized and is being commercialized as the Linear Array HPV genotyping test (LA-HPV). We assessed the agreement between LA-HPV and PGMY-LB for detection and typing of 37 HPV genotypes in 528 anogenital samples (236 anal, 146 physician-collected cervical, and 146 self-collected cervicovaginal swabs) obtained from human immunodeficiency virus-seropositive individuals (236 men and 146 women). HPV DNA was detected in 433 (82.0%) and 458 (86.7%) samples with PGMY-LB and LA-HPV (P = 0.047), respectively, for an excellent agreement of 93.8% (kappa = 0.76). Of the 17,094 HPV typing results, 16,562 (1,743 positive and 14,819 negative results) were concordant between tests (agreement = 96.9%; kappa = 0.76). The mean agreement between tests for each type was 96.4% +/- 2.4% (95% confidence interval [CI], 95.6% to 97.2%; range, 86% to 100%), for an excellent mean kappa value of 0.85 +/- 0.10 (95% CI, 0.82 to 0.87). However, detection rates for most HPV types were greater with LA-HPV. The mean number of types per sample detected by LA-HPV (4.2 +/- 3.4; 95% CI, 3.9 to 4.5; median, 3.0) was greater than that for PGMY-LB (3.4 +/- 3.0; 95% CI, 3.1 to 3.6; median, 2.0) (P < 0.001). The number of types detected in excess by LA-HPV in anal samples correlated with the number of types per sample (r = 0.49 +/- 0.06; P = 0.001) but not with patient age (r = 0.03 +/- 0.06; P = 0.57), CD4 cell counts (r = 0.06 +/- 0.06; P = 0.13), or the grade of anal disease (r = -0.11 +/- 0.06; P = 0.07). LA-HPV compared favorably with PGMY-LB but yielded higher detection rates for newer and well-known HPV types.