October 7, 2010

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being female, older age (per 10 y) & women on NNRTI predicted AEs requiring discontinuation (depression 23% of discontinuation due to AE)....older age (per 10 y) also predicted an AE causing a dose modification

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 October 2010

Bhattacharya, Debika MD*; Umbleja, T MS; Carrat, F MD, PhD; Chung, R T MD; Peters, M G MD; Torriani, F MD; Andersen, J PhD; Currier, J S MD, MSc*. From the *University of California, Los Angeles, CA; Harvard School of Public Health, Boston, MA; UMR-S 707, UPMC-Paris 6 and INSERM; Saint-Antoine Hospital, APHP, Paris, France; Massachusetts General Hospital, Harvard University School of Medicine, Boston, MA; University of California, San Francisco, CA; and University of California, San Diego, CA.

"In conclusion, women are more likely to experience AEs, leading to hepatitis C treatment dose modification and discontinuation in the setting of HIV/HCV coinfection. Women on NNRTI regimens were more likely to discontinue therapy, and women on AZT-containing regimens were more likely to require dose modifications, suggesting an important sex-mediated role of ARV regimen on the impact of AEs during hepatitis C therapy. ARV regimen may be an important predictor of treatment discontinuation and modification in women and should be further explored as predictors of AEs in HIV/HCV coinfection trials.

Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM).

Women were more likely to experience an AETD than men, 24% vs. 16% (P = 0.003).....female sex [odds ratio (OR) = 1.63] was a predictor of AETD. .....female sex was a predictor of AEDM (OR = 1.72)......Women were more likely to experience an AEDM than men, 61% vs. 48% (P < 0.0001)......Women discontinued therapy and required dose modification earlier than men......women experience some AEs (depression and anemia) more commonly than men.10,11.....Women on NNRTI-containing regimens were more likely to have an AETD than ARV-naive women or women on other ARV regimens (OR = 2.23), whereas in men, no association between NNRTI-containing regimen and AETD was observed. Of the 69 women with an AETD, depression was responsible for 16 of 69 AETDs (23%); women on NNRTI therapy were more likely to experience depression, 8 of 25 (32%) than those who were on other ARV or not on ARV 8 of 44 (18%); (P = 0.02).

The aim of our study was to investigate whether female sex was associated with an increased incidence and/or more rapid onset of AEs requiring treatment modification or discontinuation. In addition, we examined whether factors such as ARV regimen and BMI were important in predicting AEs in women and men.

We performed a meta-analysis of the AIDS Clinical Trials Group (ACTG) A5071, AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT), and Agence Nationale de Recherches sur le SIDA (ANRS) HCO2-RIBAVIC HCV treatment studies in HIV/HCV coinfection, conducted by different clinical trial networks between 2000 and 2003.

Fifty-three percent of women vs. 67% of men completed study treatment as specified by the respective study protocol; 24% vs. 16% discontinued treatment early due to toxicities, 11% vs. 9% due to nonresponse, 9% vs. 6% due to other known reasons;

Adverse Events Requiring Treatment Discontinuation

Women were more likely to experience an AETD than men, 24% vs. 16% (P = 0.003). Primary etiologies of AETD among the 238 who experienced an AETD included constitutional or other symptoms in 176 (74%) and depression in 44 (18%). Discontinuation due to hematologic abnormalities was not common; anemia, thrombocytopenia, and neutropenia were involved in 5%, 5%, and 3% of the treatment discontinuations, respectively, and there was no difference observed by sex. In a post hoc analysis that examined detailed etiologies of AETD among the 176 subjects with constitutional or other symptoms, 68 (39%) included fever, fatigue, weight loss, or gastrointestinal symptoms; 42 (24%) neurologic or psychiatric side effects, and 15 (9%) elevations in hepatic transaminases or lactic acid. The type of AETD was similar between the 2 sexes.

Our finding that women on NNRTI regimens were more likely to discontinue HCV therapy than men is in agreement with other studies examining ARV regimen discontinuation in HIV infection. Women were more likely to discontinue efavirenz (EFV)-based regimens with 38.8% (95% CI: 28.8% to 48.7%) stopping EFV by 48 weeks of treatment compared with 28.3% of men (95% CI: 23.4% to 33.2%).23 In our analysis, among women with AETD, women receiving NNRTI-based regimens had more depression. This finding, along with the findings that women are more likely to have elevated plasma EFV concentrations24 are more likely to have mood disorders25 and may be more likely to experience depression while on interferon therapy,11 raise the possibility that neuropsychiatric side effects from interferon and EFV-based regimens may be accentuated in women. These findings should be interpreted with caution in this study, however, as we did not have data on type of NNRTI regimen and the number of women on NNRTI regimens who discontinued was small.

The finding that women were more likely to have AEDMs with AZT-containing regimens and a subgroup analysis demonstrating that the majority of AEDM on AZT-containing regimens were hematologic are not unexpected. Women are at an increased risk of developing anemia during ribavirin therapy,10 and our study suggests that AZT may also play a role in hematologic toxicities in women receiving ribavirin. In hepatitis C monoinfection trials, Sulkowski et al10 found that the incidence of reaching a Hgb <10 g/dL was 4-fold higher in women, whereas an analysis of interferon alpha-2a trials also found that women were more likely to have anemia.26 One study demonstrated higher levels of AZT in women,27 suggesting a possible mechanism for the additive toxicity of ribavirin and AZT. Anderson et al found that women had significantly higher intracellular concentrations of AZT with a female to male ratio of 2:3. Interestingly, we did not find a statistically significant sex difference in the rates of anemia leading to treatment discontinuation; the respective rates were small among both men and women, suggesting that these AEs were well managed in this clinical trial setting.

We also found that older age was independently associated with the incidence of AETD and dose modification. This is supported by Sulkowski et al10 who also found that older age was associated with hemoglobin decrease in hepatitis C monoinfection studies. The authors speculated that older age may impact hematopoietic reserves in bone marrow, leading to more bone marrow suppression than in younger subjects.10"

Abstract

Background: In HIV/ hepatitis C virus (HCV) coinfection, adverse events (AEs) during HCV therapy account for 12%-39% of treatment discontinuations. It is unknown whether sex influences complications.

Methods: Meta-analysis to study the effect of sex and other predictors of AEs in 3 randomized trials, ACTG 5071, APRICOT, and ANRSHCO2-RIBAVIC of Interferon (IFN) and Pegylated IFN (PEG), both with and without Ribavirin, in HIV/HCV coinfection. Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM). Multi-covariate stratified logistic regression was used to study predictors and assess interactions with sex.

Results: Twenty-one percent of 1376 subjects were women; 61% had undetectable HIV RNA; 14% were antiretroviral (ARV) therapy naive at entry; median CD4 was 485 cells per cubicmillimeter. Seventeen percent had an AETD and 50% AEDM; women had more AETD than men (24% vs. 16% P = 0.003) and AEDM (61% vs. 48% P < 0.0001). AETD and AEDM occurred earlier in women; but the types of AETD and AEDM were similar between sexes. Seventy-four percent of AETDs and 49% of AEDMs involved constitutional AEs; 18% of AETD depression; and 26% of AEDM neutropenia. We identified interactions with sex and body mass index (BMI) (P = 0.04, continuous) and nonnucleoside reverse transcriptase inhibitor (P = 0.03); more AETDs were seen in men with lower BMI (P = 0.01) and in women on nonnucleoside reverse transcriptase inhibitors (P = 0.009). More AEDMs were seen with PEG [odds ratio (OR) = 2.07]; older age (OR = 1.48 per 10 years); decreasing BMI (OR = 1.04 per kg/m2); HCV genotype 1, 4 (OR = 1.31); Ishak 5, 6 (OR = 1.42); decreasing Hgb (OR = 1.23 per g/dL); and decreasing absolute neutrophil count (1.04 per 500 cells/mm3). Interactions between sex and ARV-naive status (P = 0.001) and zidovudine (P = 0.001) were identified: There were more AEDMs in ARV-naive women (P = 0.06) and ARV-experienced men (P = 0.001) and higher AEDMs in women with zidovudine (P = 0.0002).

Conclusions: Although there was no difference in type of AE, AETD and AEDM were more frequent and occurred earlier in women. In women, ARV regimen may be an important predictor of AETDs during HCV therapy and should be explored as a predictor of AEs in HIV/HCV coinfection trials.

INTRODUCTION

HIV and hepatitis C virus (HCV) coinfection is common, with reported prevalences of 16%-33% in HIV-infected individuals in the United States.1,2 Liver-related mortality is the leading cause of death among HIV-infected persons in the United States in the highly active antiretroviral therapy era.3 When compared with HCV monoinfection, hepatitis C therapy is less effective in HIV- and HCV-coinfected individuals due, in part, to high rates of treatment discontinuation.4-6 In HCV infection without HIV, the percentage of discontinuations secondary to adverse events (AEs) or laboratory abnormalities ranged from 7% to 21%,7-9 whereas in HIV coinfection, treatment discontinuations occurred in 12%-39%.4-6 Understanding the role of factors such as sex and its relationship with the development of adverse drug reactions will be critical to improving treatment outcomes in HIV and HCV coinfection.

In HCV monoinfection, women are more likely to experience anemia with interferon and ribavirin therapy10 and may be more likely to develop depression.11-13 In HIV infection, studies with nucleoside analogue therapy suggested that women were more likely to require dose modifications, to develop severe symptoms, and to experience AEs related to didanosine.14,15 There is little known, however, about the sex differences in AEs during HCV therapy in HIV/HCV coinfection. Additionally, the relationship between female sex, AEs during therapy, and other factors potentially related to AEs such as body mass index (BMI) and antiretroviral (ARV) regimen have not been well described in HIV and HCV coinfection.

The aim of our study was to investigate whether female sex was associated with an increased incidence and/or more rapid onset of AEs requiring treatment modification or discontinuation. In addition, we examined whether factors such as ARV regimen and BMI were important in predicting AEs in women and men.

RESULTS

One thousand three hundred seventy-six subjects were included in the analysis, 288 (21%) of whom were women; 133 (10%), 860 (62%), and 383 (28%) subjects were from A5071, APRICOT, and ANRSHCO2-RIBAVIC, respectively. Subjects from A5071 were more likely to be non-white (52%), older (median age 45 years), overweight, or obese (57%) and have HCV genotype 1 or 4 (80%) than the subjects from APRICOT (21%, 39 years, 39% and 68%) or from ANRSHCO2-RIBAVIC (5%, 39 years, 18% and 61%).

Overall, 67% of subjects were infected with HCV genotype 1 or 4, and 83% had Ishak fibrosis score <4 (Table 1). Treatment regimens included pegylated interferon and ribavirin in 40%, interferon and ribavirin in 39%, and pegylated interferon alone in 21%; 40% of men and 40% of women received pegylated interferon and ribavirin therapy. Seventeen percent of women and 13% of men were ARV naive (P = 0.16); 48% of women and 42% of men were on D4T-containing regimens (P = 0.11); 18% of women and 11% of men were on nucleoside reverse transcriptase inhibitor-only regimens (P = 0.004); 29% of women and 34% of men were on AZT-containing regimens (P = 0.15); and 26% of women and 28% of men were on NNRTI-containing regimens (P = 0.47).

Fifty-three percent of women vs. 67% of men completed study treatment as specified by the respective study protocol; 24% vs. 16% discontinued treatment early due to toxicities, 11% vs. 9% due to nonresponse, 9% vs. 6% due to other known reasons; 1 woman of 288 vs. 1 man of 1088 died, and 3% of both women and men were lost to follow-up (P = 0.002, stratified by study) (not shown in Table 1).

Adverse Events Requiring Treatment Discontinuation

Women were more likely to experience an AETD than men, 24% vs. 16% (P = 0.003). Primary etiologies of AETD among the 238 who experienced an AETD included constitutional or other symptoms in 176 (74%) and depression in 44 (18%). Discontinuation due to hematologic abnormalities was not common; anemia, thrombocytopenia, and neutropenia were involved in 5%, 5%, and 3% of the treatment discontinuations, respectively, and there was no difference observed by sex. In a post hoc analysis that examined detailed etiologies of AETD among the 176 subjects with constitutional or other symptoms, 68 (39%) included fever, fatigue, weight loss, or gastrointestinal symptoms; 42 (24%) neurologic or psychiatric side effects, and 15 (9%) elevations in hepatic transaminases or lactic acid. The type of AETD was similar between the 2 sexes.

Predictors of AETD

In simple stratified analysis, female sex [odds ratio (OR) = 1.63] was a predictor of AETD. In addition, older age and lower baseline hemoglobin were statistically significant and lower baseline BMI was a marginally significant risk factor of AETD (Table 2). There was no evidence of association between AETD and the other factors listed in Methods-Statistical Analysis. In multicovariate analysis, age (P < 0.0001) and interactions between sex and BMI (P = 0.04) and between sex and NNRTI (P = 0.03) were statistically significant (Table 2). Men with higher BMIs were less likely to experience AETD than men with lower BMIs (OR = 0.94). This association was not observed in women. Women on NNRTI-containing regimens were more likely to have an AETD than ARV-naive women or women on other ARV regimens (OR = 2.23), whereas in men, no association between NNRTI-containing regimen and AETD was observed. Of the 69 women with an AETD, depression was responsible for 16 of 69 AETDs (23%); women on NNRTI therapy were more likely to experience depression, 8 of 25 (32%) than those who were on other ARV or not on ARV 8 of 44 (18%); (P = 0.02).

Adverse Events Requiring Treatment Modification

Women were more likely to experience an AEDM than men, 61% vs. 48% (P < 0.0001). Neutropenia and anemia were the primary hematologic etiologies of AEDM, involved in 26% and 17% of the AEDMs, respectively, and 49% of AEDMs involved constitutional AEs, but the type of AEDM was similar in men and women. An analysis that examined only subjects who received pegylated interferon and ribavirin, the standard of care regimen, demonstrated similar results (not shown).

Predictors of AEDM

In simple stratified analysis, female sex was a predictor of AEDM (OR = 1.72). In addition, pegylated interferon-containing regimen; non-white race; older age; lower baseline BMI; HCV genotype 1 or 4; Ishak fibrosis score 5 or 6; CD4 cell count <500; ARV experienced; AZT use; and lower baseline ANC, Hgb, and alanine aminotransferase were statistically significant predictors of AEDM (Table 3). The other factors listed in the Methods-Statistical Analysis were not statistically significantly associated with AEDM. In multicovariate analysis, receipt of pegylated interferon therapy (OR = 2.07, P < 0.0001), increasing age (OR = 1.48 per 10 years), decreasing BMI (OR = 1.04 per kg/m2), HCV genotype 1, 4 (OR = 1.31), Ishak 5, 6 (OR = 1.42), decreasing ANC (OR = 1.04 per 500 cells/mm3), and decreasing Hgb (OR = 1.23 per g/dL) remained statistically significant (Table 3).

We also identified interactions between sex and ARV-naive status (P = 0.001) and between sex and AZT use (P = 0.001). Interestingly, ARV-naive women were more likely to experience AEDMs than ARV-experienced women (OR = 1.96, P = 0.06), but ARV-naive men were less likely to experience AEDMs (OR = 0.51, P = 0.001). In women, more AEDMs were seen with AZT compared with non-AZT regimens or no ARV (OR 3.56, P = 0.0002); but this association was not seen in men (P = 0.59). In a subgroup analysis examining etiologies of dose modifications in 175 women with AEDM, women on AZT-containing therapy were more likely to experience neutropenia and anemia: 20 of 67 (30%) vs. 21 of 108 (19%) (P = 0.12) and 23 of 67 (34%) vs. 13 of 108 (12%) (P = 0.0004), respectively.

Time to AETD and AEDM

Women discontinued therapy and required dose modification earlier than men. The Cox proportional hazards ratio for time to AETD was 1.54 (95% CI: 1.16 to 2.04) for women compared with men (P = 0.003), whereas the Cox proportional hazards ratio for time to AEDM was 1.43 (95% CI: 1.20 to 1.70) for women compared with men (P < 0.0001) (Fig. 1). The median time to AEDM was 24 weeks in women and 48 weeks in men. There was also a trend toward more rapid platelet decline in women; the median time to the lowest platelet level was 15.6 (12.1-18.1) vs. 18.1 (16.1-18.9) weeks (P = 0.05).

DISCUSSION

In a meta-analysis of 3 large HIV/HCV coinfection trials, women were more likely to experience an AETD or AEDM during HCV therapy in HIV infection. However, the observed types of AEs were similar between sexes. Additionally, AETD and AEDM occurred earlier in women. When exploring the effect modification by sex, women on regimens containing an NNRTI without a PI experienced more AETD and women on AZT-containing regimens experienced more AEs requiring interferon or ribavirin dose modification.

This is the first study to demonstrate that HIV-infected women on hepatitis C therapy experience more AETDs. Although similar sex effects on treatment discontinuation were not reported in large trials of HIV-uninfected HCV-infected women receiving interferon and ribavirin therapy,7-9 other hepatitis C monoinfection analyses have demonstrated that women experience some AEs (depression and anemia) more commonly than men.10,11 The relatively lower proportion of women enrolled in the landmark registration trials7-9 may have precluded analysis of sex effects and discontinuation rates.

When examining the HIV literature, our findings of higher treatment discontinuations in women are similar to some17,18 but not all14,19,20 studies in HIV infection. In the CASCADE collaboration, women were more likely to discontinue ARV therapy (HR = 1.61, 95% CI: 1.15 to 2.27),17 whereas in the ICONA study group, women were twice as likely to discontinue treatment secondary to toxicity.18 Conversely, 3 other studies did not find higher overall rates of treatment discontinuations among women.14,19,20

A sex effect on ARV modifications has also been noted in HIV studies; Currier et al14 demonstrated that women were 1.25 times more likely to modify didanosine dosage. In HIV infection, women are also more likely to experience AEs while on therapy with descriptions of increased rates of rash and hepatitis with nevirapine21 and lactic acidosis with nucleoside analogues.22 The reasons for heightened rates of AEs in women are poorly understood. Differences in body weight and composition, renal clearance, cellular kinase activity, and P-glycoprotein activity may all play a role.

Our finding that women on NNRTI regimens were more likely to discontinue HCV therapy than men is in agreement with other studies examining ARV regimen discontinuation in HIV infection. Women were more likely to discontinue efavirenz (EFV)-based regimens with 38.8% (95% CI: 28.8% to 48.7%) stopping EFV by 48 weeks of treatment compared with 28.3% of men (95% CI: 23.4% to 33.2%).23 In our analysis, among women with AETD, women receiving NNRTI-based regimens had more depression. This finding, along with the findings that women are more likely to have elevated plasma EFV concentrations24 are more likely to have mood disorders25 and may be more likely to experience depression while on interferon therapy,11 raise the possibility that neuropsychiatric side effects from interferon and EFV-based regimens may be accentuated in women. These findings should be interpreted with caution in this study, however, as we did not have data on type of NNRTI regimen and the number of women on NNRTI regimens who discontinued was small.

The finding that women were more likely to have AEDMs with AZT-containing regimens and a subgroup analysis demonstrating that the majority of AEDM on AZT-containing regimens were hematologic are not unexpected. Women are at an increased risk of developing anemia during ribavirin therapy,10 and our study suggests that AZT may also play a role in hematologic toxicities in women receiving ribavirin. In hepatitis C monoinfection trials, Sulkowski et al10 found that the incidence of reaching a Hgb <10 g/dL was 4-fold higher in women, whereas an analysis of interferon alpha-2a trials also found that women were more likely to have anemia.26 One study demonstrated higher levels of AZT in women,27 suggesting a possible mechanism for the additive toxicity of ribavirin and AZT. Anderson et al found that women had significantly higher intracellular concentrations of AZT with a female to male ratio of 2:3. Interestingly, we did not find a statistically significant sex difference in the rates of anemia leading to treatment discontinuation; the respective rates were small among both men and women, suggesting that these AEs were well managed in this clinical trial setting.

We also found that older age was independently associated with the incidence of AETD and dose modification. This is supported by Sulkowski et al10 who also found that older age was associated with hemoglobin decrease in hepatitis C monoinfection studies. The authors speculated that older age may impact hematopoietic reserves in bone marrow, leading to more bone marrow suppression than in younger subjects.10

One limitation of our analysis was the heterogeneity of treatment protocols. In ACTG 5071, ribavirin was dose escalated from 600 to 800 mg, and subjects who experienced severe AEs stopped therapy. This dose escalation, however, would only have masked severe AEs. Additionally, the 3 protocols included varying regimens of interferon and ribavirin, with 40% of individuals receiving combination therapy with pegylated interferon and ribavirin. Subgroup analyses on this group with combination therapy, however, demonstrated similar results to that of all regimens. Another limitation of the study included the extensive use of ARVs (AZT and stavudine) that are less common in clinical practice today. Newer more tolerable ARV regimens such as the nuclesos(t)ide transcriptase inhibitor combinations (ie, tenofovir/emtricitabine and abacavir/lamivudine), boosted atazanavir, and raltegravir may lead to a reduced rate of adverse reactions attributable to concomitant ARV and HCV therapy. Analyses of these newer regimens with hepatitis C therapy, and their interactions with sex, are needed. We also acknowledge the presence of competing risks such as LFU, death, nonresponse, and unknown reasons for discontinuation. Therefore, time to AETD and time to first dose modification, respectively, were also analyzed in the competing risks setting, treating death, nonresponse, LFU, and other known reason for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards model, and the conclusions on the effect of sex were the same in both analyses. Competing risks may have also reduced the observed AEs and, if dropout secondary to competing risks was associated with covariates, then confounding may have been introduced. Finally, the overall numbers of women experiencing AETDs and AEDMs were low at 69 and 175, respectively, leading us to interpret the interactions and subgroup analyses, including comparisons of types of AEs between men and women, with caution.
In conclusion, women are more likely to experience AEs, leading to hepatitis C treatment dose modification and discontinuation in the setting of HIV/HCV coinfection. Women on NNRTI regimens were more likely to discontinue therapy, and women on AZT-containing regimens were more likely to require dose modifications, suggesting an important sex-mediated role of ARV regimen on the impact of AEs during hepatitis C therapy. ARV regimen may be an important predictor of treatment discontinuation and modification in women and should be further explored as predictors of AEs in HIV/HCV coinfection trials.

METHODS

We performed a meta-analysis of the AIDS Clinical Trials Group (ACTG) A5071, AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT), and Agence Nationale de Recherches sur le SIDA (ANRS) HCO2-RIBAVIC HCV treatment studies in HIV/HCV coinfection, conducted by different clinical trial networks between 2000 and 2003. Subject-level data were obtained for each study. Only subjects who initiated HCV treatment were included in the analysis. Detailed inclusion criteria, study design, and criteria for treatment discontinuation and dose modifications are described in detail elsewhere.4-6 In A5071, subjects were randomized to receive 180 µg of peginterferon alfa-2a weekly for 48 weeks and dose-escalated ribavirin or 6 million IU of interferon alfa-2a 3 times weekly for 12 weeks followed by 3 million IU 3 times weekly for 36 weeks with dose-escalated ribavirin.5 Ribavirin was administered as 600 milligrams per day for 4 weeks, 800 milligrams per day for 4 weeks, and then 1000 milligrams per day for the remainder of the study. In APRICOT, subjects were randomized to peginterferon alfa-2a (180 µg/wk) plus ribavirin (800 mg/d), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU 3 times a week) plus ribavirin (800 mg/d).6 In RIBAVIC, subjects were randomized to 1.5 µg/kg peginterferon alfa-2b once a week or subcutaneous injections of 3 million units of interferon alfa-2b 3 times a week for 48 weeks. All subjects also received 800 mg of ribavirin daily.4 Laboratory toxicities, signs and symptoms, and clinical events, excluding death, were considered AEs. The primary endpoints were adverse events requiring treatment discontinuation (AETD) or first dose modification (AEDM). The primary endpoints were decided a priori and were selected because identification of factors responsible for treatment discontinuations and drug dose modifications may lead to implications for patient selection and management before and during therapy. Because the present analyses used data on subject level, the overall results are weighted by study, giving the greatest weight to APRICOT (62% of the N = 1376 subjects) followed by ANRSHCO2-RIBAVIC (28%) and A5071 (10%).

Statistical Analysis

Breslow-Day tests were used to ensure that it was appropriate to combine estimates from the 3 studies. Cochran-Mantel-Haenszel tests stratified by study were used to test statistical significance of differences in categorical variables between 2 groups. Stratified Wilcoxon rank-sum tests were used to test the statistical significance of differences between 2 groups in continuous variables. Predictors of AETD and AEDM were examined using simple logistic regression models, stratified by study. In addition to sex, predictors considered in analysis were HCV treatment (pegylated interferon-containing vs. not); race (white vs. non-white); age (continuous); BMI (continuous); HCV genotype (1, 4 vs. other); baseline Ishak fibrosis score (1-4 vs. higher); baseline HCV RNA (<800,000 vs. ≥800,000 IU/mL); baseline HIV-1 RNA (detectable vs. undetectable per definition of each study); baseline CD4 cell count (<500 vs. ≥500 cells/mm3); ARV naive at baseline; stavudine use at baseline; zidovudine (AZT) use at baseline; ARV regimen at baseline, nucleoside reverse transcriptase inhibitors only; containing nonnucleoside reverse transcriptase inhibitors (NNRTI) but no protease inhibitor (PI); containing any PI; baseline absolute neutrophil count (ANC, continuous); baseline platelets (continuous); baseline hemoglobin (continuous); baseline alanine aminotransferase (continuous); and baseline aspartate aminotransferase (continuous). Variables and their interactions with sex that were significant at 0.2 significance level in simple stratified logistic regression were considered in multi-covariate logistic regression models, stratified by study.

Kaplan-Meier estimates were used to summarize time-to-event results. Log-rank tests stratified by study were used to compare times to event between men and women. Stratified Cox proportional hazards model were used to provide an estimate for the magnitude of sex effect. Because AETD and AEDM are competing risks, times to AETD and AEDM were also analyzed using the competing risk methods16 (treating death, nonresponse, loss to follow-up (LFU), and other known reason (primarily administrative) for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards models, and the conclusions on the effect of sex were the same in both analyses. Therefore, the results of standard Kaplan-Meier analysis along with Cox proportional hazards model are provided for simpler interpretation. Results were considered statistically significant if P < 0.05 (2 sided).
 
Source

HIV Positive Muppet Moves To Nigeria's Sesame Street

The first HIV-positive Muppets character joined the existing cast of the "Takalani Sesame", shown here, the South African version of the popular childrens television show.
Reuters/CORBIS

By: Claire McCormack

Elmo, Big Bird and Oscar the Grouch have made some new West African friends who are ready to expand the Sesame Street family.

The Nigerian version of Sesame Street, the latest in a long line of region-specific shows, will be hosted by Kami, a female muppet who is HIV-positive, has golden hair and a zest for adventure; and Kobi, an energetic, furry, blue muppet whose mischievous escapades help others learn from his mistakes.

With a population of over 150 million, nearly half of which are under the age of 14, Sesame Square will address the major challenges facing the young African community today including AIDS, malaria, gender inequality,and religious differences, as well as many positive aspects of Nigerian life. In the case of Zobi, he has a characterized obsession with yams - a traditional food in the Nigerian diet.

"We have a very focused health and hygiene umbrella concept area that we're concentrating on," Naila Farouky, senior director of international projects at Sesame Workshop.

As long as Zobi's love of yams doesn't turn into a love of cookies, NewsFeed welcomes Sesame Streets extended family.

Source
By Carole VanSickle Ellis

DENVER -- October 5, 2010 -- High doses of opioid medication over an extended period of time will increase patient pain sensitivity. It also indicates a set of patient characteristics (depression, hepatitis C) that can be used to predict prescription abuse, researchers reported here October 2 at the American Academy of Family Physicians (AAFP) 2010 Scientific Assembly.

Lead investigator Shannon Essler, a pre-med student at Southwestern University, Georgetown, Texas, and her fellow researchers recommended that clinicians recognise dosages of 50 mg/day or less in morphine equivalence, and reconsider prescribing opioids above 115 mg/day for chronic, non-cancer pain to minimise the risk of addiction and abuse.

The 213 patients in this study had had low back pain for 3 months or longer during 2008; they were followed up in 2009. Patients who were pregnant or had cancer were excluded from the study, leaving a subject group of 204.

The research team used medical records to compile causes for lower back pain, procedural treatment for pain, comorbidities, and body mass index (BMI), reported Essler. A survey on demographic characteristics and other patient characteristics -- including anxiety, depression, and substance abuse -- completed the process and enabled the group to divide the subjects into 3 sections: nonusers of opioid medications (n = 100), moderate users (<=115 mg morphine equivalent per day, n = 94), and high users (>115 mg per day, n = 10).

Seventy percent of the subject group was female, 40% were Hispanic, and 45% were white. The average age was 55 (range: 19-90 years). Half of the subjects used the medication to control back pain, with the average dose for moderate users being 35 mg per day.

When the 3 groups were compared, some distinct differences were apparent. Among the high users, 70% were being treated for depression, while moderate and nonusers being treated for depression measured 44.7% and 26%, respectively (P =.002). Additionally, 30% of the high users had been diagnosed with hepatitis C, with only 10.6% of moderate users and 4% of nonusers receiving this diagnosis (P =.010).

Essler noted that this study was limited by a relatively small sample of high-dose users, but added that the results were significant enough to allow the recommendation that clinicians "reconsider the appropriateness of any opioid prescribing above 115 mg/day for non-cancer pain."

Funding for this study was provided by the Texas Academy of Family Physicians, the South Texas Area Health Education Center, and the Dean's Office, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

[Presentation title: Characteristics of Patients Using Extreme Opioid Dosages in the Treatment of Chronic Low Back Pain. Abstract P052]

Source
American Journal of Medicine
Volume 123, Issue 10, Pages 951-956.e1 (October 2010)

Yusuke Kawamura, MD, Yasuji Arase, MD, Kenji Ikeda, MD, Miharu Hirakawa, MD, Tetsuya Hosaka, MD, Masahiro Kobayashi, MD, Satoshi Saitoh, MD, Hiromi Yatsuji, MD, Hitomi Sezaki, MD, Norio Akuta, MD, Fumitaka Suzuki, MD, Yoshiyuki Suzuki, MD, Hiromitsu Kumada, MD

Abstract

Background
This retrospective cohort study assessed the impact of diabetes mellitus on hepatocarcinogenesis and determined the predictors of hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus infection.

Methods
A total of 2058 hepatitis C virus-positive, noncirrhotic patients treated with interferon were enrolled. The median follow-up period was 6.7 years. The primary end point was the onset of hepatocellular carcinoma. The cumulative rate of new hepatocellular carcinoma cases was computed by the Kaplan–Meier method and Cox proportional hazard analysis according to diabetic state and response to interferon therapy.

Results
The cumulative rates of hepatocellular carcinoma in diabetic patients (3.2% at 4 years, 8.5% at 8 years, and 24.4% at 12 years) were significantly higher than those of nondiabetic patients (1.3% at 4 years, 2.2% at 8 years, and 5.6% at 12 years, P<.001). In patients with a sustained virologic response, diabetes had no significant effect on the rate of hepatocarcinogenesis. In contrast, the rate in patients with a nonsustained virologic response was significantly higher in diabetic than in nondiabetic patients. Multivariate analysis identified lack of sustained virologic response (hazard ratio [HR] 7.28; 95% confidence interval [CI], 3.28-16.15; P<.001) and diabetes as independent risk factors for hepatocarcinogenesis (HR 2.00; 95% CI, 1.05-3.84; P=.036).

Conclusions
Our results highlight the enhancing effect of diabetes mellitus on hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus. The sustained virologic response induced by interferon therapy eliminates the influence of diabetes and markedly reduces the rate of hepatocarcinogenesis in such patients.

Keywords: Diabetes, Hepatocellular carcinoma, Interferon, Sustained virologic response

Department of Hepatology, Toranomon Hospital, Tokyo, Japan

Requests for reprints should be addressed to Yusuke Kawamura, MD, Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470, Japan

Funding: Okinaka Memorial Institute for Medical Research and Japanese Ministry of Health, Labour and Welfare.

Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript.


Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(10)00468-7
doi:10.1016/j.amjmed.2010.05.013
© 2010 Elsevier Inc. All rights reserved

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D. M. Evon 1, K. M. Simpson 1, D. Esserman 2,3, A. Verma 1, S. Smith 4, M. W. Fried 1

Article first published online: 17 SEP 2010
DOI: 10.1111/j.1365-2036.2010.04460.x
Aliment Pharmacol Ther 2010; 32: 1163–1173

Summary

Background Patients with hepatitis C viral (HCV) may perceive barriers to accessing speciality care for HCV, and these barriers may be related to depressive symptoms.

Aim To evaluate the relationship between barriers to care, demographics, and depressive symptoms.

Methods A cross-sectional analysis of 126 patients referred for HCV at two speciality HCV clinics. Barriers to care, depressive symptoms and sociodemographics were measured using standardized instruments. A retrospective chart review was conducted to collect clinical outcome data.

Results Depressive symptoms were reported in 26%. Common barriers included lack of personal financial resources; lack of HCV knowledge in the community; lack of professionals competent in HCV care; stigmatization of HCV; and long distances to clinics offering care. After we controlled for sociodemographics, depression accounted for an additional 7–18% of variability in all barriers (all p values <0.01). Lower depression, marital and employment status were associated with subsequent receipt of HCV treatment in 38% (45/120) of patients; perceived barriers were not.

Conclusions Depression is independently associated with perceived barriers to care. Higher depressive scores, but not perceived barriers, were associated with nontreatment. Healthcare providers who diagnose HCV need to be cognizant of numerous perceived barriers to accessing HCV care, and the impact that depression may have on these perceptions and receipt of treatment.

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By Katie Charles
THE DAILY CHECKUP
Wednesday, October 6th 2010, 4:00 AM

Who's at risk

About 30% of Americans have fatty liver, a condition whose name says it all. "Fatty liver is a condition where there's excess fat accumulation in the liver," says Chang. "A subset of patients who have fat in their liver have fat plus additional damage, which we call nonalcoholic steatohepatitis (NASH)."

If left unmanaged, NASH can lead to cirrhosis, liver transplant or liver cancer. "A liver biopsy is the only way to tell whether someone with fatty liver has the more severe NASH, although sometimes we can make an estimation without having to perform a liver biopsy," says Chang.

Doctors estimate that 2% to 9% of Americans have NASH. "Fatty liver disease is now a common cause of liver abnormalities and the most common cause of abnormal liver tests in the United States," says Chang. "We're seeing more patients for transplant or cancer with the fatty liver disease as the underlying cause."

At this point, fatty liver disease is even more prevalent than hepatitis C, which affects 1.5% of the population.

The main risk factors for fatty liver are obesity and metabolic syndrome. "Fatty liver is the liver manifestation of metabolic syndrome," says Chang. "So it's associated with all the other features of metabolic syndrome: high blood pressure, diabetes, high cholesterol and an increased waistline."

A minority of patients with fatty liver don't have metabolic syndrome. "Some medications can cause fatty liver, and there are genetically inherited disorders of fat metabolism, including a rare condition called congenital lipodystrophy that can be associated with fatty liver," says Chang.

The cause of fatty liver disease is still unclear and is an area of active research. Fatty liver is a condition that increases with age, although young people and kids can be affected. "The prevalence increases with age for a few reasons," says Chang. "Some of it is weight gain over time, and some of it is that the longer you've had fat in the liver, the more years you've had to develop liver damage."

Signs and symptoms

Fatty liver is often a stealth disease. "The early signs and symptoms are often silent," says Chang.

"It's usually an incidental diagnosis picked up by having blood drawn as part of a routine check-up." Most primary-care physicians run liver tests as part of a yearly physical, but it's worth asking to make sure your doctor tests for fatty liver.

Liver damage only begins to show symptoms when it reaches the point of end-stage liver disease. "At this point, the patient progresses to cirrhosis, which can cause symptoms a patient could note on his own — things like fluid retention and jaundice," says Chang.

"Another big concern or end-stage complication is liver cancer," she says. As more patients develop fatty liver disease, doctors are seeing increased amounts of liver cancer that developed in the presence of fatty liver disease. "The goal is to prevent fatty liver from progressing to cirrhosis," says Chang. "Or better yet, preventing it in the first place."

Traditional treatment

The first step for patients diagnosed with fatty liver is to develop a plan with their primary care physician to address obesity and related issues like diabetes and cholesterol. "Losing weight and keeping diabetes under control can improve fatty liver or keep it from causing damage," says Chang.

"I advise patients to limit both saturated fat and high-fructose-containing food products like sodas, both of which are associated with obesity," she says.

About a third of patients who have fatty liver get better, one third stay the same and one third get worse. The focus is on prevention and containment, because doctors don't have many options for patients whose disease worsens to the point of nonalcoholic steatohepatitis (NASH).

"Right now we have no FDA-approved medications to treat NASH," says Chang. "While there has been research using diabetes drugs, weight-loss medications and cholesterol medications to treat NASH, there is not enough evidence at this time to show that these drugs can be used to treat NASH directly."

Patients whose disease continues to progress can develop cirrhosis, an outcome doctors work very hard to prevent. "Once there is cirrhosis in a patient with NASH, there aren't a lot of options to reverse the damage," says Chang.

"Short of a liver transplant, there isn't much we can do besides advise to lose weight and keep diabetes and cholesterol under control," she says. Even liver transplant isn't a perfect cure, because the disease can come back after a transplant.

Research breakthroughs

One recent study had promising results for using vitamin E to fight fatty liver. "Last year, a National Institutes of Health multi-site collaboration called the PIVENS trial published its findings that using vitamin E improved liver tests and reversed scarring in the livers of patients with NASH," says Chang. "We need more supporting studies, but it's worth asking your doctor if vitamin E could help."

Questions for your doctor

Because this disease is usually asymptomatic, it's all the more important for patients to ask, "Could I have fatty liver disease?"

If you've been diagnosed, then the question becomes, "What can I do to keep my fatty liver from progressing?"

Eating a healthy diet and exercising regularly can go a long way toward keep fatty liver disease under control.

Source

A So-So HIV Vaccine May Be a Hard Sell

October 7, 2010

A collection of studies shows that any HIV vaccine, while highly sought by doctors to battle the epidemic, would only be requested by some.

By Brad Wittwer
 
An HIV vaccine — the dream of medical science for a quarter-century — isn’t all that far off. Given that 2.7 million new HIV infections in 2008 alone brought the world total to 33.4 million infected, there is a genuine need.

But rather than a line out the door the first day of availability, new research by Peter Newman and Carmen Logie of the University of Toronto suggests that an HIV vaccine will mostly cause hypochondriacs to rush to their local clinic and others to, at best, scribble an appointment in the weekly planner.

The team gathered 30 original studies, mostly from North America but also from Africa and Southeast Asia, to analyze HIV vaccine acceptability. Selecting 20 studies involving 7,576 participants between 1996 and 2010, the researchers ranked HIV “vaccine acceptability” — how in demand a vaccine would be — on a 100-point scale for each study. Results ranged from 37.2 to 94.0, with the average being 65.3.

Not surprisingly, results varied depending on how effective the putative vaccine would be. Limiting the testing to 11 studies, acceptability was 73.8 for a high-efficacy vaccine (80-95 percent) versus 40.4 for a moderate-efficacy vaccine (50 percent).

The results “raise cause for concern given the likelihood that initial HIV vaccines may be of low to moderate efficacy,” the authors write.

Across studies, acceptance rose alongside vaccination efficacy, duration of protection and perception of being at risk and fell with concerns over side effects, cost, pragmatic obstacles, safety concerns, fear of vaccines and fear of needles. The perception that a vaccine would be very effective drastically increased expectations of use, while the idea that someone wasn’t in the “risk group” for HIV/AIDS infection significantly decreased use.

To overcome this wariness, the researchers propose educating people’s perceptions of susceptibility to be more accurate — most underestimate their current risk of infection by the virus but if educated, people would be more apt to request a vaccine as is warranted. They also propose subsidies to reduce costs — free transportation to clinics for example would be one.

The authors emphasize the need for more research, since roughly 75 percent of the studies were conducted in North America and not Africa, which has the highest rates of HIV infection. In different cultural and socio-economic settings, the factors that most affect vaccine acceptability may be altogether different. Cost and pragmatic factors like remote access will take on a new meaning in less-developed nations.

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