Christina Diong

The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening.

Objective:To assess anal oncogenic human papillomavirus (HPV) and anal cytology as screening tests for detecting high-grade anal intraepithelial neoplasia (AIN 2+), as this is an immediate anal cancer precursor. Design:Cross-sectional study of 401 HIV-positive men who have sex with men (MSM). The endpoint was histologically confirmed AIN 2+ obtained by high-resolution anoscopy. Cytology and biopsy specimens were assigned random numbers and independently assessed by two pathologists. Methods:We did concomitant anal cytology, anal HPV testing and HRA with directed biopsies without knowing the results of each intervention. The main outcome measures were the sensitivity, specificity, negative predictive value and positive predictive value of anal cytology and oncogenic HPV for the detection of AIN 2+. Results:Cytology was abnormal in 67% of patients: high-grade squamous intraepithelial lesion, 12%; low-grade squamous intraepithelial lesion, 43% and atypical squamous cells of undetermined significance, 12%. Biopsies were abnormal in 68% of patients: AIN 2+, 25% and AIN 1, 43%. HPV was detected in 93% with multiple HPV types in 92% and oncogenic HPV types in 88%. Test performance characteristics for the detection of AIN 2+ using any abnormality on anal cytology were: sensitivity 84%, specificity 39%, negative predictive value 88% and positive predictive value 31%; using oncogenic HPV: sensitivity 100%, specificity 16%, negative predictive value 100% and positive predictive value 28%. Conclusion:Anal cytology and HPV detection have high sensitivity but low specificity for detecting AIN 2+. HIV-positive men who have sex with men have a high prevalence of AIN 2+ and require high-resolution anoscopy for optimal detection of high-grade anal dysplasia.

Screening for HIV-Associated Anal Cancer: Correlation of HPV Genotypes, p16, and E6 Transcripts with Anal Pathology

Background: HIV-positive men with a history of anal-receptive intercourse are at risk for anal cancer. We determined whether human papilloma virus (HPV) biomarkers were correlated with anal pathology in these men. Methods: HPV genotype was determined by PCR/line blot assay. Real-time PCR assays were done for viral load, E6 transcripts for HPV genotypes 16, 18, and 31, and p16 transcripts. Results: The most common oncogenic HPV types were HPV 16 (38%), 18 (19%), 45 (22%), and 52 (19%). HPV types 16, 18, 31, 52, 59, and 68 were associated with high-grade histology. The number of HPV genotypes per anal swab was higher for anal intraepithelial neoplasia (AIN) 2/3 than for normal or AIN 1 histology [median, 5 types (interquartile range) (IQR), 3-7 versus 3.5 (IQR), 2-6; P = 0.0005]. HPV 16 viral load was also associated with AIN 2/3 histology. There was no difference in p16 or E6 transcripts between histologic grades. In the multivariable logistic regression model, HPV genotypes 16 [odds ratio, 2.58; 95% confidence interval (95% CI), 1.31-5.08; P = 0.006] and 31 (odds ratio, 4.74; 95% CI, 2.00-11.22; P = 0.0004), baseline CD4 count < 400 cells/mm3 (odds ratio, 2.96; 95% CI, 1.46-5.99; P = 0.0025), and Acquired Immunodeficiency Syndrome (AIDS)-defining illness (odds ratio, 2.42; 95% CI, 1.22-4.82; P = 0.01) were associated with high-grade histology after adjusting for age. Conclusions: The presence of high-grade anal pathology (AIN 2/3) in HIV-positive men was associated with multiple HPV genotypes, HPV genotypes 16 and 31, and HPV 16 viral load. (Cancer Epidemiol Biomarkers Prev 2009;18(7):1986–92)

High prevalence of unintended pregnancies in HIV-positive women of reproductive age in Ontario, Canada: a retrospective study.

There is speculation, but there are few data, on the high rates of unintended pregnancies in HIV‐positive women. We investigated rates and correlates of unintended pregnancies among HIV‐positive women of reproductive age.

A Meta-Analysis of Six Placebo-Controlled Trials of Thiazolidinedione Therapy for HIV Lipoatrophy

Abstract Objective: To determine the impact of thiazolidinediones (TZD) on changes in limb fat mass in HIV-infected individuals, particularly in those not receiving a thymidine analogue.Methods: Individual patient data from placebo-controlled, randomized trials of rosiglitazone (n = 5) or pioglitazone (n = 1) were combined. Generalized estimating equation (GEE) models were used to estimate the treatment effect on changes in limb fat mass.Results: In the combined dataset of 427 patients, the baseline median age was 45 years, 86% were male, 80% were Caucasian, 63% were receiving stavudine (d4T) or zidovudine (AZT), 66% were on protease inhibitors, and median body mass index was 23 kg/m2. In a univariate GEE model, TZD was associated with an increase in limb fat mass (coeff = 0.14 kg vs placebo,P = .04). In a multivariable GEE model, patients receiving pioglitazone had significantly higher limb fat mass gains (coeff = 0.35 kg,P δ .01) compared to patients receiving placebo, while patients on rosiglitazone did not (coeff = 0.05 kg,P = .48). Interactions between thymidine analogue use and rosiglitazone and pioglitazone were not significant.Conclusions: In this meta-analysis, pioglitazone therapy was more effective than placebo to increase limb fat mass whereas rosiglitazone was not significantly better than placebo. The effectiveness of these drugs did not vary according to whether the patients were receiving thymidine analogues.

Ethnicity and gender differences in lipodystrophy of HIV-positive individuals taking antiretroviral therapy in Ontario, Canada.

Abstract Purpose: This study assessed ethnicity and gender differences in prevalence, type, and severity of antiretroviral-associated lipodystrophy in HIV-positive individuals in Ontario. Methods: This was a cross-sectional analysis of the Ontario Cohort Study (OCS), a prospective study of HIV-positive patients in Ontario. Lipodystrophy was defined as at least 1 major or 2 minor self-reported changes of peripheral lipoatrophy and/or central lipohypertrophy. Prevalence, type, and severity were compared by ethnicity (Black, White, or Other) and gender. Univariate and multivariate logistic regression analyses identified predictors of lipodystrophy. Results: Data were available for 778 participants (659 men, 119 women). There were 517 Whites, 121 Blacks, and 140 patients of Other ethnicities. In univariate analyses, Whites reported more peripheral lipoatrophy (P = .004) and abdominal lipohypertrophy (P = .04); these ethnic differences were observed in males (P = .05 and P = .03, respectively) but not females. Males reported more peripheral lipoatrophy (P = .01), whereas females had more central lipohypertrophy (P < .0001) and mixed fat redistribution (P < .0001). Multivariable regression analyses revealed Black women to be most vulnerable to lipodystrophy (P = .02), particularly lipohypertrophy (P < .0001). Conclusions: Ethnicity and gender are important factors influencing lipodystrophy. Combining lipoatrophy and lipohypertrophy into a single entity is not appropriate. Black women were most vulnerable to lipohypertrophy, which has important implications for antiretroviral therapy roll-out in Africa.

Long-term efficacy and safety of polyalkylimide gel for the treatment of HIV-associated lipoatrophy.

Abstract The long-term safety and efficacy of products used in the correction of HIV-associated facial lipoatrophy (FLA) are largely unknown. The purpose of this study was to describe the long-term efficacy and safety of polyalkylimide gel (PAIG) in the treatment of HIV-associated FLA. In this open-label, randomized, single-center study, 31 HIV-positive individuals (median age 48 years (interquartile ranges (IQR) 45, 55, 97% male) with FLA were randomized to immediate (week 0 and six) or delayed (week 12 and 18) PAIG injections. Week 96 endpoints included change in FLA severity scores (FLSS) (five-point scale), proportion of patients with adverse events, and changes in quality of life, depression and anxiety using validated surveys. Results at week 96 were available for 28 patients. Adverse events, including swelling, redness, bruising and pain, were mild, and resolved after a median of three days following the injection. At week 96, median changes in physician and patient FLSS scores were −2 (IQR −3, −1; p<0.001 vs. baseline) and −2 (IQR −2, −1; p<0.001 vs. baseline), respectively. Physician and patient FLSS scores were not significantly different between the groups at week 96. Significant improvements in patients anxiety (p<0.001), depression (p<0.001) and mental health (p=0.01) were observed from baseline to week 96. In conclusion, treatment with PAIG was associated with sustained improvements in both the physical and psychological components of FLA through 96 weeks of follow-up.

A Prospective Study of Body Fat Redistribution, Lipid, and Glucose Parameters in HIV-Infected Patients Initiating Combination Antiretroviral Therapy

Abstract Purpose: To prospectively determine incidence, prevalence, and extent of lipodystrophy (LD) and associated metabolic changes. Method: This was a prospective cohort study. Body habitus changes were determined by anthropometrics, photography, and regional dual-energy X-ray absorptiometry (DXA) scan. Metabolic parameters included triglyceride (TG), total (TC), LDL and HDL cholesterol, glucose, and insulin. Results: 68 patients were included. 51 (75%) received protease inhibitor (PI)-based and 17 (25%) non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ARV) and 90% a thymidine analogue. Statistically significant increases in TC, TG, LDL, and HDL by 12 months developed on PI but only in TC for NNRTI. At 24 months, on DXA scanning, there were no statistically significant changes in median limb or total body fat on NNRTI but a statistically significant decrease in limb fat on PI (p = .01). There was considerable individual variation with overall 3 (7%) patients having >20% increases and 16 (36%) with >20% decreases in limb fat and 6 (14%) having >20% increases and 7 (16%) with >20% decreases in total body fat. Conclusions: Lipid changes occurred early and progressed. Median changes in body fat were minor and more common on PI, but individual variation in change was large, challenging the use of medians or threshold changes to predict impact of different ARV agents.

HIV/hepatitis C virus and HIV/hepatitis B virus coinfections protect against antiretroviral‐related hyperlipidaemia

Hyperlipidaemia is a recognized complication of HIV antiretroviral therapy. The interactions among HIV, viral hepatitis, antiretroviral therapies and lipids are poorly understood.

Virologic and Immunologic Impact and Durability of Enfuvirtide-Based Antiretroviral Therapy in HIV-Infected Treatment-Experienced Patients in a Clinical Setting

Abstract Objective: To evaluate the effectiveness and safety of enfuvirtide–based therapy in treatment–experienced patients in a clinical setting. Method: Retrospective study of treatment–experienced patients receiving enfuvirtide-based therapy for a minimum of 2 months. Endpoints included virologic suppression, virologic rebound, immunologic response, and adverse events. Results: Sixty-four patients were eligible for inclusion in the analysis. Median baseline viral load and CD4+ count were 4.7 log10 copies/mL (interquartile range [IQR], 4.0–5.2) and 150 cells/mm3 (IQR, 60–250), respectively. At month 12, viral load declined by a median of 2.53 log10 copies/mL (IQR, 0.97–3.12). The unadjusted median time to virologic suppression was 7.7 months (95% CI 4.1–10.4 months). Baseline viral load and number of protease inhibitors in the current regimen were significantly associated with virologic suppression following multivariate analysis (hazard ratio [HR] 0.45, 95% CI 0.31–0.63,p<.0001, and HR 0.51, 95% CI 0.27–0.94, p = .03, respectively). Among the 42 patients who attained sustained virologic suppression, 10 experienced virologic rebound during a median follow–up of 13.3 months (IQR, 7.0–19.1). Injection site reactions were reported in 33 (52%) patients, resulting in treatment discontinuation in nine patients. Conclusion: Enfuvirtide-based therapy provides durable antiretroviral activity for treatment–experienced patients in a clinical setting.

Impact of CMV therapy with valganciclovir on immune activation and the HIV viral load in semen and blood: an observational clinical study.

Background:The HIV RNA viral load (VL) in vaginal secretions and semen is an independent predictor of HIV transmission. Blood VL is associated with semen VL, and local mucosal factors, such as semen cytomegalovirus (CMV) reactivation, may play an important role. Methods:Twenty-one HIV-CMV–coinfected, antiretroviral-naive men received 900 mg of oral valganciclovir once daily for 2 weeks in an open-label study. Blood and semen were collected at baseline, after 2 weeks of valganciclovir, and 2 months after therapy completion. The primary end point was change in semen HIV levels at 2 weeks, and the secondary end points were change in semen HIV VL at 2 months and change in semen CMV levels. Results:The HIV VLs fell significantly at 2 weeks in semen (median 3.44−3.02 log10 copies/mL, P = 0.02) and blood (median 3.61−3.10 log10 copies/mL, P < 0.01) and returned to baseline after therapy completion (median 3.24 and 3.71 log10 copies/mL in semen and blood, respectively). Semen CMV levels also fell on treatment (median 2.13−1.62 log10 copies/mL, P < 0.01) and continued to fall after therapy completion (median 0.91 log10 copies/mL at week 8, P < 0.001 vs. baseline). The reduced semen CMV VL was associated with decreased semen T-cell activation and enhanced CMV-specific T-cell responses in blood; changes in the semen HIV VL were not associated with immune parameters. Conclusions:Although valganciclovir therapy was associated with reduced HIV and semen CMV levels, these results suggest that the reduced HIV VL was a direct drug effect rather than a CMV antiviral effect or CMV-associated immune alterations.