Challenges in the treatment of HIV and HCV coinfection

HIV and hepatitis C virus (HCV) infections are pandemic illnesses that represent serious global public health problems. It is estimated that there are currently 38 million people infected with HIV and 60–180 million people infected with HCV worldwide. Owing to similar transmission pathways, HIV/HCV coinfection occurs frequently and, indeed, affects approximately a third of all European and North American HIV patients. With the successful introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV in 1996, the morbidity and mortality owing to HIV declined drastically. As the prognosis of HIV infection has improved, liver disease caused by chronic infection with HCV has become increasingly important for mortality and morbidity among HIV/HCV-coinfected patients. Coinfection leads to accelerated progression of liver fibrosis and development of cirrhosis, as well as earlier emergence of hepatocellular carcinomas. Pegylated interferon and ribavirin combination therapy of HCV in coinfected patients showed reasonable sustained virological responses in randomized clinical trials, ranging from 27 to 44%, which, however, is substantially lower than in HCV monoinfected patients. Furthermore, cohort analyses have shown that HAART-induced immune reconstitution can improve the natural course of hepatitis C significantly and delay fibrosis progression. As pharmacokinetic drug–drug interactions and higher rates of hepatotoxicity following HAART initiation must be considered in HIV/HCV coinfection, specific treatment and management guidelines have been developed to optimize care in this clinically challenging group of patients.     

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

Hepatitis C virus (HCV) infection is one of the most frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCV-genotype 1, both for the HCV-monoinfected and HIV/HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.     

The influence of treatment with pegylated interferon-alfa and ribavirin on neutrophil function and death in patients with HIV/HCV coinfection

In patients with human immunodeficiency virus (HIV) as well as in patients with hepatitis C virus (HCV) infection the impairment of neutrophil activity is observed. We decided to analyze how treatment with pegylated interferon-alfa (Peg-IFN-alfa) and ribavirin affects neutrophil function in HIV/HCV coinfected patients. The study group consisted of 18 patients with HIV/HCV coinfection, on combination antiretroviral treatment (cART), aged between 27 and 42?y (mean 33.1±4.5?y). At the beginning of treatment with Peg-IFN-alfa and ribavirin all patients had an undetectable HIV viral load, and CD4 T-cell counts higher than 350?cells/μL. At two time points, before and after 12?wk of treatment with Peg-IFN-alfa and ribavirin, we examined intracellular levels of reactive oxygen species (ROS), and expression of selected adhesion molecules on whole blood neutrophils, along with apoptosis and necrosis of these cells. These analyses were done with flow cytometry. During anti-HCV therapy undetectable HIV levels were maintained in all patients. Treatment with PEG-IFN-alfa and ribavirin resulted in increases in the expression of CD11b and CD18, and decreases of CD16 and CD62L. However, only the change in CD62L expression was statistically significant (p<0.05). Moreover, the treatment resulted in increased apoptosis of neutrophils, while necrosis remained unchanged. After 12 wk of treatment, an increase in ROS production by neutrophils stimulated with PMA was observed (p<0.01). In HIV/HCV coinfected patients on cART, PEG-IFN-alfa and ribavirin treatment caused an activation of neutrophil function, yet it did not affect the suppression of HIV replication.     

Sustained suppression of HCV replication and inflammatory activity after interleukin-2 therapy in patients with HIV/hepatitis C virus coinfection

OBJECTIVE: There is increasing evidence that coinfection of hepatitis C (HCV) with HIV is associated with accelerated progression of liver cirrhosis. The aim of this pilot study was to investigate toxicity and efficacy of interleukin-2 (IL-2) for treatment of affected patients. DESIGN: Because low-dose, daily IL-2 therapy is well tolerated and can elevate CD4 cell counts and improve immune functions, patients were treated with 1-2 million units (MU) IL-2 subcutaneously daily. METHODS: This pilot trial included 7 HIV/HCV-coinfected individuals. During therapy, clinical, virologic, and laboratory parameters were closely monitored. RESULTS: All patients responded to IL-2 therapy with either improvement of either CD4 cell counts or liver function test results. In 2 patients, HCV-RNA in serum became negative 2 and 4 months, respectively, after cessation of therapy. HCV-RNA has remained undetectable in these 2 patients for 18 and 24 months, respectively. Therapy was well tolerated and no grade III or IV toxicities were observed. CONCLUSIONS: Low-dose, daily IL-2 therapy can improve both CD4 cell counts and liver function test results in patients with HIV/HCV coinfection and may in some cases lead to sustained suppression of viremia of HCV.     

Virological and clinical aspects of HBV-HCV coinfection in HIV positive patients

In a long-term follow-up study the clinical and virological presentation of HBV/HCV coinfection in anti-HIV positive patients was evaluated. Plasma HBV-DNA, HCV-RNA, and HIV-RNA were determined by PCR in 5 HBsAg/anti-HCV/anti-HIV positive patients, in 4 HBsAg/anti-HIV positive patients and in 82 anti-HCV/anti-HIV positive patients first observed at a Unit of Infectious Diseases in Naples (Italy) from 1990 to 2000 (follow up 6-16 years). All five hepatitis B and C coinfected patients showed reciprocal inhibition of viral replication on admission and during the follow up. At the end of the follow up a clearance of HBsAg from serum was observed in four patients and a clearance of anti-HCV in one of them. In two patients after clearance of HBsAg, evidence of occult HBV infection was observed, at times associated with a hepatic flare. None of the four patients with HIV/HBV coinfection lost HBsAg and none of the 82 with HIV/HCV coinfection lost anti-HCV during the follow up. In anti-HIV positive patients HBV/HCV coinfection is characterized by reciprocal inhibition of viral replication, more evident in HBV expression in plasma and at times by progression to occult HBV infection.     

Correlates of self-reported nonadherence to antiretroviral therapy in HIV-infected patients: the Swiss HIV Cohort Study

BACKGROUND: Adherence is one of the most crucial issues in the clinical management of HIV-infected patients receiving antiretroviral therapy (ART). METHODS: A 2-item adherence questionnaire was introduced into the Swiss HIV Cohort Study in July 2003. All 3607 eligible patients were on ART for > or =6 months and their current regimen for > or =1 month. Three definitions of nonadherence were considered: missing > or =1 dose, missing > or =2 doses, and taking <95% of doses in the past 4 weeks. RESULTS: Over 30% of patients reported missing > or =1 dose, 14.9% missed > or =2 doses, and 7.1% took <95% of doses in the previous 4 weeks. The rate of drug holidays was 5.8%. Whether using more or less conservative definitions of nonadherence, younger age, living alone, number of previous regimens, and boosted protease inhibitor regimens were independent factors associated with nonadherence. There was a significant association between optimal viral suppression and nonadherence as well as a significant linear trend in optimal viral suppression by missed doses. CONCLUSIONS: Younger age, lack of social support, and complexity of therapy are important factors that are related to nonadherence with ART. Investment in behavioral dimensions of HIV is crucial to improve adherence in ART recipients.     

Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: the fat redistribution and metabolic change in HIV infection (FRAM) study

OBJECTIVE: Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)-infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy. DESIGN: Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression. RESULTS: Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV-infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively. CONCLUSIONS: In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.     

Prevalence of cryoglobulinemia in hepatitis C virus (HCV) positive patients with and without human immunodeficiency virus (HIV) coinfection.

BACKGROUND: Coinfection with human immunodeficiency virus (HIV) has been shown to influence the natural history of hepatitis C infection. OBJECTIVE: Our interest was to determine if HIV coinfection influences the prevalence of cryoglobulinemia in hepatitis C virus (HCV) infected persons. STUDY DESIGN: A total of 384 HCV RNA positive (234 HIV-infected and 150 HIV-uninfected) participants were tested at two visits, 18 months apart, for HCV and HIV RNA, CD4, and liver enzyme levels. Serum cryoglobulin levels were measured at a subsequent visit for a subset of the sample. RESULTS: HIV-infected participants had significantly higher HCV RNA levels (P < 0.0001) and aspartate transaminase (AST) levels (P < 0.0001), but not alanine transaminase (ALT) levels (P > 0.05) as compared with HIV-uninfected participants. These findings were consistent at both visits and no significant changes were observed between visits. Fifty (19%) of the 264 participants tested had detectable cryoglobulins. No difference was observed in HIV seropositivity among participants with or without cryoglobulinemia (68% versus 61%; odds ratio = 1.34, P = 0.37). However, among HIV coinfected participants, elevated AST levels (P = 0.04) and lower CD4 levels (P = 0.02) were associated with cryoglobulinemia. CONCLUSIONS: While previously reported associations were found between HIV and coinfection with HCV in this study, we did not find an association between HIV infection and cryoglobulinemia.     

Investigating the concurrent presence of HCV in serum,oral fluid and urine samples from chronic HCV patients in Faisalabad,Pakistan

Hepatitis C virus (HCV) is normally present in the blood of infected patients; however, it can also be present in some other body fluids. Therefore, in this study, a concurrent presence of HCV-RNA was investigated in oral fluid and urine of 80 Pakistani chronic HCV patients. HCV-RNA was detected in 31 (38.8%) oral fluid and 10 (12.5%) urine samples using RT-PCR in all 80 of the patients whose sera tested positive for HCV-RNA. From this study, it is concluded that, in addition to the blood, HCV RNA can also be found in oral secretions as well as urine of chronic HCV patients.     

Trend in Hip Fracture Incidence and Mortality in Korea: A Prospective Cohort Study from 2002 to 2011

This prospective longitudinal cohort study was to assess the 10-yr hip fracture incidence and mortality trend of person ≥50 yr of age between 2002 and 2011 of eight hospitals in Jeju Island. Sex-specific incidence rate (per 100,000 person-years) were calculated based on that estimated for the population in the United States in 2008. Poisson and logistic regressions were used to examine trends in incidence and mortality. There was a 101% increase in the number of hip fractures from 151 in 2002 to 304 in 2011. The crude incidence of hip fractures in the Jeju population ≥50 yr of age increased from 126.6/100,000 to 183.7/100,000. The fracture incidence in the population standardized to the 2008 population in the United States increased from 100.6/100,000 for men and 194.4/100,000 for women in 2002 to 114.2/100,000 for men and 278.4/100,000 for women in 2011. The annual increasing incidence rate of hip fracture was 4.3% (5.3% in women and 2.2% in men). Poisson regression did not show significant trends in the mortality rates for all age groups or for both genders. The total number of hip fractures increased two-fold and the incidence rate of hip fractures increased markedly during the 10-yr study period.

Graphical Abstract

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Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART

BACKGROUND: Highly active antiretroviral therapy (HAART) is strongly effective in reducing morbidity and mortality in HIV-1-positive individuals. Its main drawback is the potential toxicity. Data on the frequency and determinants of severe hepatotoxicity in a clinical setting are still sparse. METHODS: This is a prospective study of HIV-1-positive individuals with known HBsAg and HCV-Ab serology. The study end point was progression to alanine aminotransferase (ALT) levels > or =200 IU/L after HAART initiation. Cumulative probability of progression to this end point was estimated by the Kaplan-Meier method. Crude and adjusted hazard ratios (HR) were estimated by proportional hazards regression model. RESULTS: One thousand two hundred fifty-five patients were included. HBsAg was found in 91 (7.2%), HCV-Ab in 578 (46.5%) patients; almost all injection drug users (451 of 482; 93.6%) were HCV-Ab positive. Sixty-one individuals progressed to the end point with a probability of 7.9% (95% confidence interval [CI], 5.6-10.0) of progression at 24 months from starting. Independent factors predicting progression to the end point were baseline ALT levels (HR, 5.29; 95% CI, 3.24-8.65; every 10 IU/L higher), HCV-Ab positivity (HR, 4.01; 95% CI, 1.48-10.85) or both HBsAg and HCV Ab positivity (HR, 3.85, 95% CI, 1.01-14.61), and previous non-HAART therapy (HR, 1.84, 95% CI, 1.04-3.42). Patients receiving stavudine-containing regimens had a lower risk than those receiving zidovudine-containing regimens (HR, 0.30, 95% CI, 0.12-0.71). CONCLUSIONS: There was a low risk of ALT > or =200 IU/L in our cohort. Hepatitis C coinfection and elevated ALT levels at HAART initiation are important predictors of progression to ALT > or =200 IU/L; stavudine-containing regimens were associated with a lower risk compared with zidovudine-containing regimens.     

Soluble Fas and Fas ligand in HIV/HCV coinfected patients and impact of HCV therapy

The aim of this study was to evaluate the influence of clinical and epidemiological characteristics of 183 HIV/HCV coinfected patients and HCV clearance after antiviral treatment on serum sFas and sFasL levels. Thirty out of 183 patients underwent HCV antiviral therapy with IFN-???+?RBV for a duration of 48?weeks. HCV genotype 1 and homeostasis model assessment for insulin resistance (HOMA-IR) had a significant positive relationship, and CD4+/??L had a significant negative relationship with sFas (R-square?=?0.582; p?<?0.001) and sFasL (R-square?=?0.216; p?<?0.001) in multivariate linear regression analysis. HCV genotype 1 was the only significant variable associated with the sFas/sFasL ratio (R-square?=?0.201; p?<?0.001). sFas and sFasL levels had positive significant correlations with serum sICAM-1, sVCAM-1, and HOMA levels (p?<?0.05). Among patients on IFN-???+?RBV therapy, 15 patients showed a sustained virologic response (SVR), while 15 patients were non-responders (NR). Patients with SVR had significant decreases in sFas (p?=?0.008) and sFas/sFasL ratio (p?=?0.002), while non-responders had a significant increase in sFasL values (p?=?0.013). In conclusion, HCV genotype 1, high HOMA, and low CD4+/??L were associated with high serum levels of sFas and sFasL, which indicate higher levels of inflammation and, possibly, increased cardiovascular risk. Moreover, response to HCV antiviral therapy is known to reduce inflammation.     

The economic burden to families of HIV and HIV/tuberculosis coinfection in a subsidized HIV treatment program

INTRODUCTION: The high cost of antiretroviral (ARV) drugs has led to the initiation of subsidized HIV treatment programs in developing countries. The care of tuberculosis (TB), a common opportunistic infection, is not built into the subsidized program. The current study was done to evaluate the cost burden of HIV/AIDS, TB, and TB and HIV/AIDS coinfections to the family. SUBJECTS AND METHODS: The study was carried out in the consultant outpatient department of the University of Benin Teaching Hospital in Nigeria. Consecutive families with 21 family member managed for HIV and or TB were recruited into three cohorts of HIV only, TB only and HIV/TB cohorts. The average monthly costs of treatment, transportation family income and percentage of income spent on care were computed for each family. The average monthly man-hours per family spent on clinic visitation were determined. RESULTS: A total of 61 families consisting of 128 family members met the study criteria. The mean cost of treatment per month was significantly higher in families in the HIV/TB cohort than in other cohorts, P = 0.0001. The mean percentage of income spent on treatment was significantly higher in the HIV/TB cohort compared to other cohorts, P = 0.0001. CONCLUSION: The cost of managing TB/HIV coinfection significantly increased the costs to the families in the subsidized HIV treatment program. It is recommended that a comprehensive package of subsidized HIV care that is inclusive of TB treatment and care for other comorbidities be initiated in developing countries.     

Treatment of rheumatic diseases in patients with HCV and HIV infection

A wide variety of rheumatic diseases has been documented in the presence of hepatitis C virus (HCV) infection and in human immunodeficiency virus (HIV) infection. In this conditions, physicians are refrained from using corticosteroids and/or immunosuppressants agents because of the risk of favouring viral replication and the progression of the underlying viral disease. In the present review we have focused our attention on the possible role of cyclosporine A (CsA), anti-Tumour Necrosis Factor (TNF) alpha agents in the treatment of HIV or HCV infected autoimmune patients. The results drown from the literature and from our personal experience confirm the safety of CsA and anti-TNF alpha agents, in terms of viral load and liver toxicity. A limited experience also suggest that both therapies can be given in combination in rheumatoid arthritis patients without increasing the risk of adverse events.     

Reciprocal influence of HIV and HCV infections in co-infected patients and the involvement of HAART

The reciprocal influence of HIV-HCV co-infection was established prior to the era of highly active retroviral therapy (HAART) and continues to be a topic of debate, including the question of which infection to treat first.