Drug interactions in HIV-infected patients treated for hepatitis C.

INTRODUCTION: The introduction of direct-acting antivirals (DAA) has revolutionized the hepatitis C field. Most hepatitis C patients can now be cured, including those coinfected with HIV. However, drug-drug interactions (DDI) between DAA and antiretrovirals (ARV) should be known to prevent either toxicity due to drug overexposure or treatment failures due to low drug concentrations. Areas covered: Clinically significant DDI may be classified as major (when co-administration should be contraindicated) or minor (when they require close monitoring, changes in drug dosage or in timing). Strategies for preventing and managing DDI influence response rates in HIV/HCV-coinfected patients. Pharmacokinetic evidence of interactions from clinical trials and reports from real-world experience are discussed. Expert opinion: The most frequent DDI between DAA and ARV affect drug metabolism by CYP450 induction/inhibition, leading to abnormal drug exposures. Throughout this mechanism interact HCV and HIV boosted protease inhibitors, and most non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide analogue polymerase inhibitors, most HCV NS5A inhibitors and HIV integrase inhibitors (e.g., dolutegravir), do not or only marginally affect CYP450, and therefore are relatively free of DDI. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (e.g., P-glycoprotein) and requires special attention in patients with renal insufficiency.

Dual antiretroviral therapy for HIV infection.

INTRODUCTION: For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

Prevention and management of treatment failure to new oral hepatitis C drugs.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has become a curable disease. Sustained virologic response rates above 90% have been achieved with recommended direct-acting antiviral (DAA) combinations in most registration trials. However, outcomes in real-world patients are lower. In patients experiencing DAA failure, resistance-associated variants (RAVs) are almost universally selected. At this time it is unclear when and how to re-treat hepatitis C in patients with prior DAA failure. AREAS COVERED: The rate of DAA failure and predictors of lack of treatment response using distinct DAA combinations are analyzed. We discuss the management of HCV treatment failure and the impact of RAVs on re-treatment strategies. EXPERT OPINION: Failure to DAA combinations occurs more often in chronic hepatitis C patients with baseline predictors of poor response, such as those with RAVs, genotypes 3 or 1a, advanced liver cirrhosis, elevated serum HCV-RNA and perhaps HIV coinfection. Impaired antiviral efficacy is more frequent when multiple factors are present. On-treatment predictors of DAA failure are poor drug adherence and development of side effects. Extending the length of therapy, adding ribavirin and/or using DAA from other drug families may allow successful re-treatment of most prior DAA failures.

High serum HCV RNA in chronic hepatitis C patients coinfected with HIV despite successful antiretroviral therapy.

BACKGROUND: Baseline serum HCV RNA predicts treatment success in chronic hepatitis C patients. Thresholds at 0.8, 2, 4 and 6 million IU/ml discriminate treatment outcomes using distinct antiviral regimens. Compared to the general population, immunosuppressed individuals exhibit greater viral load values. This has been confirmed in HIV-HCV-coinfected patients, although little is known about the influence of antiretroviral therapy. METHODS: Serum HCV RNA results recorded from all chronic hepatitis C patients who consecutively attended at our clinic were analysed. RESULTS: A total of 813 patients with detectable HCV RNA were identified. HIV coinfection was present in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 467 (57%), 273 (34%), 170 (21%) and 127 (16%) had HCV RNA >0.8, >2, >4 and >6 million IU/ml, respectively. These high viral load values were found in 60%/36%/23%/18% of HIV-positive versus 47%/25%/11%/6% of HIV-negative individuals (P<0.01), respectively. In multivariate analysis, the greatest HCV RNA values were only significantly associated with HIV coinfection and HCV genotypes-1 or -4. Greater HCV RNA values were paradoxically found in HIV patients on than off antiretroviral therapy. CONCLUSIONS: Serum HCV RNA values above 0.8, 2, 4 and 6 million IU/ml are roughly seen in 47%, 25%, 11% and 6% of chronic hepatitis C monoinfected patients, respectively. Despite being on antiretroviral therapy, the corresponding figures are 1.3- to 3.0-fold greater in HIV-HCV-coinfected patients, who may benefit less frequently from shorter oral HCV treatment lengths.

Hepatitis C cure with antiviral therapy--benefits beyond the liver.

Liver disease is the major complication of chronic HCV infection. However, extrahepatic complications are common (50-75%), including mixed cryoglobulinaemia and B-cell lymphomas. Given that chronic hepatitis C has become curable using expensive oral direct-acting antivirals (DAAs), it seems worth revisiting the whole spectrum and burden of disease in HCV carriers.Herein, we update the most clinically significant medical complications associated with chronic hepatitis C and the evidence of benefits that would derive from a wide use of curative DAA therapies.Chronic HCV infection is associated with a broad spectrum of clinical conditions, including distinct rheumatic disorders (polyarthritis, sicca syndrome), lymphoproliferative conditions (mixed cryoglobulinaemia, monoclonal gammapathies and B-cell lymphomas) and damage at other organs due to persistent systemic inflammation, leading to renal, bone, neurological and/or cardiovascular disease. Eradication of HCV with DAAs is associated with amelioration and/or resolution of most liver-related and extrahepatic complications. Ultimately, gains in quality of life and survival favour treating everyone with hepatitis C regardless of liver fibrosis stage.

New hepatitis C therapies for special patient populations.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has become a curable disease. More than 90% sustained virologic response rates have been obtained with 8-24 weeks of treatment with distinct combinations of direct-acting antivirals (DAA) in most registration trials. However, outcomes in real-world patients tend to be lower and treatment of special patient populations is often challenging. AREAS COVERED: We address the treatment of chronic hepatitis C with DAA in major special patient populations, such as HIV-positive persons, transplant recipients, patients with advanced cirrhosis, renal insufficiency, hepatitis B or D coinfection, injection drug users (IDUs) and prior DAA failures. EXPERT OPINION: Drug interactions between DAA and medications given to persons with HIV infection or transplant recipients can result in treatment failure and adverse events. Severe organ dysfunction as in kidney insufficiency or decompensated cirrhosis may lead to DAA overexposure and toxicities. Dysfunctional social circumstances and behavior are associated to poor drug adherence and increased risk for HCV re-infection in active IDUs. Finally, DAA response might be impaired by viral interference in patients with hepatitis B or D coinfection or drug resistance in HCV either at baseline or after prior DAA failures.

Rate and predictors of serum HCV-RNA >6 million IU/mL in patients with chronic hepatitis C.

BACKGROUND: Baseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values. OBJECTIVES: To estimate the rate and predictors of serum HCV-RNA above 6 millionIU/mL in chronic hepatitis C patients on care outside clinical trials. STUDY DESIGN: Serum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0. RESULTS: A total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6IU/L; mean HCV-RNA 6.02logIU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 127 (15.6%) had serum HCV-RNA values >6 millionIU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p<0.001). In multivariate analysis, serum HCV-RNA >6 millionIU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98-8.19, p<0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05-3.37, p=0.03). CONCLUSIONS: Serum HCV-RNA >6 millionIU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.

Dual antiviral therapy for HIV and hepatitis C - drug interactions and side effects.

INTRODUCTION: Roughly 20% of HIV-positive persons worldwide are coinfected with hepatitis C virus (HCV). The recent advent of direct-acting antivirals (DAA) that cure most hepatitis C patients has attracted much attention. Knowledge on drug interactions between DAA and antiretrovirals (ARV) may allow maximizing antiviral efficacy while minimizing drug-related toxicities. AREAS COVERED: We review the most frequent side effects and clinically significant drug interactions between DAA and ARV. We further discuss how they can be prevented and managed in HIV/HCV-coinfected patients. EXPERT OPINION: The safety profile of current DAA and the most recently approved ARV is quite favorable. Interactions between DAA and ARV could be frequent in clinical practice. The most common drug interactions affect drug metabolism by inducing or inhibiting the cytochrome P450 system, leading to abnormal drug exposures. Throughout this mechanism HCV and HIV protease inhibitors interact, especially when co-formulated with ritonavir as a pharmacoenhancer, and non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide polymerase inhibitors, and most HCV NS5A inhibitors (i.e., ledipasvir) and HIV integrase inhibitors (i.e., dolutegravir), do not or only marginally affect CYP450, and therefore are free of significant drug interactions. Exposure to HIV and HCV nucleos(t)ide analogues (i.e., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (i.e., P-glycoprotein).

Emerging challenges in managing hepatitis B in HIV patients.

Roughly 10 % of HIV-positive individuals worldwide have concomitant chronic hepatitis B virus (HBV) infection, with large differences between geographical regions and/or risk groups. Hepatitis B is a preventable infection with vaccines. However, it cannot be eradicated once acquired, resembling HIV and in contrast with HCV. In developed countries, hepatitis B exhibits particular features in the HIV population. First, HBV infection is less frequently misdiagnosed than in the general population. Second, nucleos(t)ide analogs active against HBV are widely used as part of antiretroviral combinations and are taken by most HIV patients. Lastly, as the HIV population ages given the success of antiretroviral therapy, non-AIDS co-morbidities are becoming a major cause of disease, for which specific drugs are required, increasing the risk of interactions and hepatotoxicity. Furthermore, concern on HBV reactivation is rising as immunosuppressive drug therapies are increasingly been used for cancers and other non-malignant conditions. In this scenario, new challenges are emerging in the management of hepatitis B in HIV-positive individuals. Among them, major interest is focused on failures to suppress HBV replication, HBV breakthroughs and reactivations, the meaning of isolated anti-HBc, screening for liver cancer, and the complexity arising when hepatitis viruses C and/or D are additionally present. This review will focus on these challenges and the major advances in HBV coinfection in HIV.

New update of the DHHS guidelines for adults and children.

On April 2015, the U.S. Department of Health and Human Services (DHHS) released an updated version of its antiretroviral treatment guidelines for adults. The new guidelines include revised recommendations for first-line antiretroviral therapy as well as management of treatment-experienced patients.

Drug interactions with new hepatitis C oral drugs.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has recently become a curable disease with antiviral therapy. The knowledge of drug interactions using direct-acting antivirals (DAA) may permit maximizing antiviral efficacy and avoiding drug-related toxicities. Ageing in the chronic hepatitis C population, along with added co-morbidities that require other medications, has increased the attention on drug interactions using DAA. AREAS COVERED: This review provides an update of the most clinically significant pharmacokinetic and pharmacodynamic drug interactions occurring between currently available DAA and other medications. The review also revisits how drug interactions with DAA can be prevented and managed. EXPERT OPINION: Interactions between DAA and other drugs are frequent in clinical practice. The most frequent drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposures. Through this mechanism HCV protease inhibitors, especially when co-formulated with ritonavir as pharmacoenhancer, and non-nucleoside HCV polymerase inhibitors interact with other medications. In contrast, NS5B nucleos(t)ide analog inhibitors (i.e., sofosbuvir) and some HCV NS5A inhibitors (i.e., ledipasvir), which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions. However, exposure to HCV nucleos(t)ide analogs may be influenced by induction/inhibition of drug transporters (i.e., P-glycoprotein) as well as by pharmacodynamic interference with other nucleos(t)ide analogs used as antivirals or cancer drugs. Drug interactions for some NS5A inhibitors (i.e., daclatasvir) are generally moderate and can be managed with dose adjustments.

Long-term survival and liver-related events after pegylated interferon/ribavirin therapy in HIV-infected patients with chronic hepatitis C.

BACKGROUND: Sustained HCV clearance after hepatitis C therapy is associated with reduced liver-related complications and death. It is unknown if treatment may provide any clinical benefit in patients that fail therapy. This could be particularly relevant in HIV-HCV-coinfected patients, in whom liver disease progresses more rapidly. METHODS: This was a retrospective study of clinical end points in a large cohort of HIV-HCV-coinfected patients with compensated liver disease followed since 2004. Patients were stratified into three groups: treated and cured, treatment failures and non-treated. Follow-up ended at the time of last visit, first liver decompensation event or death. RESULTS: A total of 527 HIV-HCV-coinfected patients were examined, of whom 339 (64.3%) had been treated with pegylated interferon/ribavirin. During a mean follow-up of 70.5 months, hepatic decompensation events or liver-related deaths occurred less frequently in cured patients (4/138; 2.9%) than in treatment failures (28/201; 13.9%) or untreated (25/188; 13.3%) patients (P<0.001). Interestingly, in the subset of patients with baseline advanced liver fibrosis (Metavir F3-F4), those with treatment failure experienced less hepatic decompensation events or deaths than untreated patients (19% versus 42%; P=0.005) and this finding was more pronounced in patients harbouring IL28B-CC alleles (15.8% versus 47.4%; P=0.02). CONCLUSIONS: Sustained HCV clearance following pegylated interferon/ribavirin therapy is associated with a reduced incidence of liver complications and death in HIV-HCV-coinfected patients. In the subset of patients with baseline advanced liver fibrosis, treatment provides clinical benefit despite lack of sustained virological response. The transient antiviral and/or anti-inflammatory effect of interferon, more recognizable in IL28B-CC carriers, could explain this finding.

Misconceptions about HIV infection in Kinshasa (Democratic Republic of Congo): a case-control study on knowledge, attitudes and practices.

OBJECTIVES: To evaluate the prevalence of HIV-related misconceptions in an outpatient centre of Kinshasa (Democratic Republic of Congo) and analyse the association between these beliefs and HIV infection. METHODS: A case-control study was carried out from December 2010 until June 2012. We assessed 1630 participants aged 15-49 attending a primary outpatient centre in Kinshasa: 762 HIV Voluntary Counselling and Testing attendees and 868 blood donors. A 59-item questionnaire about knowledge, attitudes and practice was administered during a face-to-face interview, followed by an HIV test. Cases and controls were respondents with a newly diagnosed HIV-positive or HIV-negative test, respectively. Unconditional logistic regression was used to analyse the association between misconceptions and HIV seropositivity. RESULTS: 274 cases and 1340 controls were recruited. Cases were more likely than controls to have a low socioeconomic status, no education, to be divorced/separated or widowed. An association was found between the following variables and HIV seropositivity: having a poor HIV knowledge (adjusted OR=2.79; 95% CI 1.43 to 5.45), not knowing a virus is the cause of AIDS (adjusted OR=2.03; 95% CI 1.38 to 2.98) and reporting more than three HIV-transmission-related misconceptions (adjusted OR=3.30; 95% CI 1.64 to 6.64), such as thinking an HIV-positive person cannot look healthy and that HIV is transmitted by sorcery, God's punishment, a kiss on the mouth, mosquitoes, coughs/sneezes or undercooked food. CONCLUSIONS: Despite having access to healthcare services, there are still many people in Kinshasa that have HIV-related misconceptions that increase their HIV risk. Our findings underscore the need for a culturally adapted and gender-orientated basic HIV information into Congolese HIV prevention programmes.

Liver fibrosis progression despite HCV cure with antiviral therapy in HIV-HCV-coinfected patients.

BACKGROUND: Accelerated liver fibrosis and more frequent hepatic decompensation events and liver-related deaths are characteristically seen in chronic hepatitis C patients coinfected with HIV compared with HCV-monoinfected individuals. Quantitative estimates of long-term clinical benefits derived from curing HCV with antiviral therapy in coinfected patients are scarce, despite being needed for accurate cost-effectiveness decisions using expensive direct-acting antivirals in this population. METHODS: We retrospectively examined all HIV-HCV-coinfected patients followed at one reference clinic in Madrid since 2004. Liver fibrosis was measured longitudinally using elastometry; changes above 30% in kilopascal units were considered as significant. RESULTS: A total of 568 HIV-HCV-coinfected patients were examined. Pegylated interferon/ribavirin therapy had been given to 396 (69.7%) of whom 138 (34.8%) had achieved sustained virological response (SVR). Mean follow-up was of 6.8 (±1.5) years for hepatic events and 4.4 (±0.8) years for liver fibrosis. Hepatic decompensation events, liver-related deaths and significant liver fibrosis progression occurred less frequently in SVR than in non-treated/treatment failures. Although regression of liver fibrosis occurred in most SVR patients, fibrosis significantly progressed in 7.2% of them, in association with higher plasma HIV RNA (P=0.005) and longer exposure to HIV protease inhibitors (P=0.009). CONCLUSIONS: Achievement of SVR dramatically reduces the risk of hepatic decompensation events and liver-related deaths in HIV-HCV-coinfected patients. Although liver fibrosis generally improves following HCV cure, worsening may occur in association with uncontrolled HIV replication and prolonged exposure to protease inhibitors. Thus, periodic assessment of liver fibrosis is warranted after SVR and screening for liver cancer should continue in coinfected patients with advanced liver fibrosis.

Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients.

BACKGROUND: Hepatitis delta virus (HDV) produces the most severe form of chronic viral hepatitis. We explored whether prolonged tenofovir exposure might be beneficial on hepatitis delta in HIV-infected patients. METHODS: All HIV-infected patients with hepatitis delta followed at our institution since year 2000 were retrospectively examined. Serum HBV-DNA and HDV-RNA were quantified using commercial assays. Liver fibrosis was measured using elastometry. RESULTS: A total of 19 HIV/delta patients were identified. All were viremic for HDV and 11 for HBV. After a median tenofovir exposure of 58 months, all had undetectable HBV-DNA and 10 (53%) had undetectable HDV-RNA. The median drop in HDV-RNA in the remaining nine HDV viremic patients at the end of follow-up was 2.4 log copies/ml. A reduction above 30% in liver stiffness occurred in six out 10 (60%) patients who achieved undetectable HDV-RNA, whereas hepatic stiffness did not change in the remaining HDV viremic patients (P = 0.03). Serum HBsAg concentrations did not decline significantly, although HBsAg seroclearance occurred in three patients, all of whom became negative for HDV-RNA. CONCLUSION: Long-term exposure to tenofovir significantly reduced serum HDV-RNA apart from completely suppressing HBV-DNA in HIV-infected patients with hepatitis delta. This virological benefit is accompanied by significant improvements in liver fibrosis.

Pharmacogenetics of antiretroviral therapy.

INTRODUCTION: Human genetic testing is rapidly entering into most medical disciplines, mainly as a way to predict hereditary conditions including predisposition to cancers or degenerative diseases. Another area of interest for human genomics is to ascertain the therapeutic effect and prevent potential toxicities and/or drug-drug interactions of medication. AREAS COVERED: Several human genotypes have been associated with differences in the metabolism and transport of antiretroviral agents that ultimately affect drug exposure. The accelerated discovery of new gene mutations and polymorphisms that influence the effects of antiretroviral drugs provides a unique opportunity for a personalized medicine approach in the management of lifelong HIV therapy. EXPERT OPINION: Integration of human genomic screening into HIV clinical management will be cost-effective, maximizing the benefit of drugs with the lowest risk of side effects for a given patient.

Progression to advanced liver fibrosis in HIV-HCV-coinfected patients and prioritization of new hepatitis C therapies.

BACKGROUND: Because of their high cost, the use of direct-acting antivirals (DAAs) is being restricted by many governments to chronic HCV-infected individuals with advanced liver fibrosis. However, response rates are lower and toxicities more frequent in this subset of patients. METHODS: All HIV-HCV-coinfected patients followed for at least 3 years at one reference clinic were identified. Liver fibrosis progression (LFP) was defined as a shift from Metavir F0-F2 to F3-F4 estimates (>9.5 KPa) using elastometry. RESULTS: A total of 527 HIV-HCV-coinfected patients were identified, of whom 344 had F0-F2 at baseline. Pegylated interferon/ribavirin therapy was given to 205 patients with null/mild fibrosis, of whom 92 (44.9%) achieved sustained virological response (SVR). After a mean follow-up of 53 months, LFP occurred in 5.4% SVR, 25.7% non-SVR and 18% untreated patients (P=0.005). In multivariate analysis, only achievement of SVR prevented LFP (adjusted hazard ratio 2.1; 95% CI 1.1, 4.1; P=0.01). In 139 untreated patients, only greater baseline elastometry values predicted LFP in multivariate analysis (adjusted hazard ratio 1.84; 95% CI 1.03, 3.3; P=0.03). The area under the receiver operating characteristic (AUROC) curve was 79%. A discriminant threshold of 7.1 kPa gave 68% sensitivity and 82% specificity. CONCLUSIONS: In the absence of successful treatment, more than 20% of HIV-HCV-coinfected patients with null/mild liver fibrosis progress to advanced fibrosis within 5 years. Patients with >7.1 kPa (Metavir F2) display the highest risk. Therefore, all coinfected patients with any significant liver fibrosis should be considered as candidates for new DAA-based therapies.