Eugenia Vispo

Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir.

Background:Tenofovir (TDF) is the most widely prescribed antiretroviral drug. Kidney abnormalities are the main concern using the drug. As glomerular function is infrequently affected in patients treated with TDF, herein, we report the results of an extensive examination of tubular function. Methods:Cross-sectional study of plasma and 24 h urine markers of kidney tubulopathy (glucosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria and β2-microglobulinuria) could be allocated in three groups: patients under a TDF-containing HAART; patients on HAART never exposed to TDF; and antiretroviral-naive individuals. Significant tubular damage was defined when at least two of these parameters were repeatedly present, being at least one part of the Fanconi syndrome criteria (glucosuria, hyperaminoaciduria and hyperphosphaturia). Glomerular function was assessed using creatinine clearance. Results:A total of 284 consecutive HIV patients were examined, 154 on TDF, 49 on other HAART regimens and 81 drug-naive. No significant differences in creatinine clearance were observed when comparing distinct groups. The proportion of patients with tubular damage in groups 1, 2 and 3 were 22, 6 and 12%, respectively. In a multivariate analysis [odds ratio (OR) {95% confidence interval (CI)} P], the only independent predictors of tubular dysfunction were TDF use (21.6, 4.1–113, <0.001) and older age (1.1 per year, 1.0–1.1, 0.01). Conclusion:Exposure to TDF is associated with an increased risk over time of kidney tubular abnormalities in the absence of significant impaired glomerular function. Although long-term consequences of this tubulopathy are unknown, close monitoring of accelerated bone mineral loss and renal insufficiency are warranted. Periodic screening of tubular function parameters should be recommended to patients receiving TDF.

Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients

Background:Given that peginterferon–ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes. Methods:From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon–ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion. Results:A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6–8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1–21.0; <0.001), serum HCV-RNA less than 600 000 IU/ml (11.9; 3.8–37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4–8.9; 0.009). Conclusion:The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.

Viral hepatitis and HIV co-infection.

Chronic hepatitis B virus (HBV) infection is overall recognised in 10% of HIV+ persons worldwide, with large differences according to geographical region. Chronic hepatitis C virus (HCV) infection affects 25% of HIV+ individuals, with greater rates ( approximately 75%) in intravenous drug users and persons infected through contaminated blood or blood products. HIV-hepatitis co-infected individuals show an accelerated course of liver disease, with faster progression to cirrhosis. The number of anti-HBV drugs has increased in the last few years, and some agents (e.g. lamivudine, emtricitabine, tenofovir) also exert significant activity against HIV. Emergence of drug resistance challenges the long-term benefit of anti-HBV monotherapy, mainly with lamivudine. The results using new more potent anti-HBV drugs (e.g. tenofovir) are very promising, with prospects for stopping or even revert HBV-related liver damage in most cases. With respect to chronic hepatitis C, the combination of pegylated interferon plus ribavirin given for 1 year permits to achieve sustained HCV clearance in no more than 40% of HIV-HCV co-infected patients. Thus, new direct anti-HCV drugs are eagerly awaited for this population. Although being a minority, HIV+ patients with delta hepatitis and those with multiple hepatitis show the worst prognosis. Appropriate diagnosis and monitoring of chronic viral hepatitis, including the use of non-invasive tools for assessing liver fibrosis and measurement of viral load, may allow to confront adequately chronic viral hepatitis in HIV+ patients, preventing the development of end-stage liver disease, for which the only option available is liver transplantation. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations.

Tenofovir (TFV) is a nucleotide analogue active against HIV and hepatitis B virus. Although TFV rarely affects the glomerular function, abnormalities in the kidney tubular function appear to be quite common. The relationship between TFV exposure and kidney tubular dysfunction (KTD) was examined prospectively in 92 HIV-infected individuals. Median TFV plasma trough concentration was higher in patients with KTD than in the rest (182 vs. 106 ng/ml; P = 0.001). This dose-dependent effect further supports an involvement of TFV in KTD.

Directly acting antivirals against hepatitis C virus

The approval of directly acting antivirals (DAA) for the treatment of chronic hepatitis C virus (HCV) infection will represent a major breakthrough for the 180 million persons infected worldwide. Paradoxically, hepatitis C is the only human chronic viral disease that can be cured, as all other pathogenic viruses infecting humans either display self-limited courses or establish non-eradicable persistent infections. Until now, treatment of chronic hepatitis C consisted of the combination of peginterferon-α plus ribavirin, which provided limited rates of cure and was associated with frequent side effects. Several DAA have been identified that inhibit the NS3 protease, the NS5B polymerase or the NS5A replication complex, and have entered the final steps of clinical development. These molecules, coupled with significant progress made in the recognition of more potent and safe interferon forms (e.g. interferon-λ) and host protein targets (e.g. alisporivir), are opening a new era in hepatitis C therapeutics. The expectations are so great that, to some extent, it is reminiscent of what happened in 1996 in the HIV field when the introduction of the first protease inhibitors as part of triple combinations revolutionized antiretroviral therapy. To maximize treatment success and reduce the likelihood of drug resistance selection, a proper individualization of hepatitis C therapy will be required, choosing the most convenient drugs and strategies according to distinct viral and host profiles. The complexity of HCV therapeutics has reached a point that presumably will lead to the birth of a new specialist, the HCV doctor.

Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings.

Background:Liver disease of unknown cause in HIV-infected persons is rare but increasingly being reported. Noncirrhotic portal hypertension is the main feature in a subset of these patients, in whom gastrointestinal bleeding is the most frequent and potentially life-threatening clinical presentation. Methods:We describe the epidemiological, clinical and histological features of 12 HIV-positive individuals presenting with noncirrhotic portal hypertension. Results:An interpretable liver biopsy was available in 11, and cirrhosis was absent in all patients. Three patients had nodular regenerative hyperplasia of the liver, whereas eight showed morphological features previously described as ‘hepatoportal sclerosis’. In four of the later group, a distinctive lesion was noted characterized by massive absence of portal veins along with focal fibrous obliteration of small portal veins. All patients had been treated with didanosine for long periods and inflammatory and thrombotic processes hypothetically triggered by this purine analogue in the hepatic microvasculature might result in this form of obliterative portal venopathy. Conclusion:Noncirrhotic portal hypertension is a rare but unique entity presenting in HIV-positive individuals generally with prior prolonged exposure to didanosine, which shows an obliteration of portal veins as the most distinctive histological finding in the liver.

Risk factors for advanced liver fibrosis in HIV‐infected individuals: role of antiretroviral drugs and insulin resistance

Summary.  Liver damage may result from multiple factors in HIV‐infected patients. The availability of reliable noninvasive tools to measure liver fibrosis has permitted the screening of large patient populations. Cross‐sectional study of all consecutive HIV outpatients who underwent examination by transient elastometry (FibroScan) at one HIV reference clinic during 2007. Advanced liver fibrosis (ALF) was defined as hepatic stiffness >9.5 kilopascals, which corresponds to Metavir stages F3‐F4 in the liver biopsy. A total of 681 consecutive HIV‐infected patients (64% injecting drug users; mean age 43; 78% male; 98% on antiretroviral therapy) had at least one valid FibroScan evaluation. ALF was diagnosed in 215 (32%) of them. In the univariate analysis, ALF was significantly associated with older age, low CD4 counts, chronic hepatitis C, past alcohol abuse, elevated ALT, high triglycerides, low cholesterol, high homeostasis model assessment (HOMA) index and exposure to didanosine and/or stavudine. In a multivariate model (OR, 95% CI), chronic hepatitis C (2.83, 1.57–5.08), past alcohol abuse (2.26, 1.37–3.74), exposure to didanosine and/or stavudine (1.85, 1.14–3.01), high HOMA index (1.25, 1.04–1.51), older age (1.09, 1.05–1.14) and elevated ALT (1.04, 1.03–1.06) remained as independently associated with ALF. Therefore, in addition to chronic hepatitis C and alcohol abuse, insulin resistance and/or exposure to dideoxy‐nucleosides may contribute to ALF in HIV‐infected patients.

Modeling the Probability of Sustained Virological Response to Therapy with Pegylated Interferon plus Ribavirin in Patients Coinfected with Hepatitis C Virus and HIV

BACKGROUND A single-nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) strongly predicts sustained virological response to pegylated interferon plus ribavirin (pegIFN-RBV) treatment for chronic hepatitis C virus (HCV) infection. Given that therapy is poorly tolerated and rates of response are lower in patients coinfected with HCV and human immunodeficiency virus (HIV), the recognition of predictors of response is a high priority in this population. METHODS A baseline noninvasive index was derived on the basis of the probability of achieving sustained virological response in a group of 159 HIV-HCV-coinfected patients treated at one clinic in Spain. The index was then validated using data from a separate cohort of 86 coinfected individuals. Only individuals who had completed a course of pegIFN-RBV therapy and had validated outcomes were considered. RESULTS The final score included 4 variables: 2 host-related variables (IL28B SNP rs12979860 and liver stiffness) and 2 HCV-related variables (genotype and viral load). The area under the receiver operating characteristic curve was 0.89 in the derivation group and 0.85 in the validation group. CONCLUSIONS The probability of achieving sustained virological response with pegIFN-RBV therapy in HIV-HCV-coinfected patients can be reliably estimated prior to initiation of therapy using an index that includes 4 noninvasive parameters.

Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues.

Background:Chronic hepatitis B virus (HBV) infection is common in HIV-positive individuals and increases liver-related mortality. Nucleos(t)ide analogues with activity against both HBV and HIV are widely used in coinfected patients, but its long-term effect on liver disease is unknown. Methods:Clinical outcomes, HBsAg and/or HBeAg clearance, and changes in liver stiffness were longitudinally evaluated retrospectively in all HIV–HBV-coinfected individuals followed at our institution. Results:A total of 92 patients with HIV–HBV coinfection were identified, 19 of them superinfected with hepatitis delta virus. Their median time of follow-up was 35 months. Overall, 94% received lamivudine/emtricitabine and 82% tenofovir. Serum HBV-DNA was undetectable in 89%. Seven patients cleared serum HBsAg (2.6/100 patient-years), in four of them accompanied with anti-HBs seroconversion. Of note, two of them had hepatitis delta. Another 11 out of 42 HBeAg-positive patients cleared HBeAg (9/100 patient-years) and five of them experienced anti-HBe seroconversion. Liver decompensation and death occurred in eight (2.9/100 patient-years) and six (2.2/100 patient-years), respectively.At baseline, liver fibrosis was defined as null-mild (48%), moderate-advanced (28%) or cirrhosis (24%). At last visit, after a median of 40 months in 71 patients, 75% showed no changes, whereas improvement was recognized in 17% and worsening in 8%. Conclusion:Most HIV–HBV-coinfected patients treated with anti-HBV active nucleos(t)ide analogues experience an amelioration of liver fibrosis progression, with low rates of hepatic decompensation and death. Serum HBeAg or HBsAg seroconversion occurs at yearly rates of 9 and 2.6%, respectively, even in patients with delta hepatitis.

Influence of Interleukin-28B Single-Nucleotide Polymorphisms on Progression to Liver Cirrhosis in Human Immunodeficiency Virus–Hepatitis C Virus–Coinfected Patients Receiving Antiretroviral Therapy

BACKGROUND Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV-related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. METHODS All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. RESULTS A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 ± 53 vs 71 ± 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 ± 3.8 years. CONCLUSIONS The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV-HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly.