Estimating the individualized HIV-1 genetic barrier to resistance using a nelfinavir fitness landscape

<p>Abstract</p> <p>Background</p> <p>Failure on Highly Active Anti-Retroviral Treatment is often accompanied with development of antiviral resistance to one or more drugs included in the treatment. In general, the virus is more likely to develop resistance to drugs with a lower genetic barrier. Previously, we developed a method to reverse engineer, from clinical sequence data, a fitness landscape experienced by HIV-1 under nelfinavir (NFV) treatment. By simulation of evolution over this landscape, the individualized genetic barrier to NFV resistance may be estimated for an isolate.</p> <p>Results</p> <p>We investigated the association of estimated genetic barrier with risk of development of NFV resistance at virological failure, in 201 patients that were predicted fully susceptible to NFV at baseline, and found that a higher estimated genetic barrier was indeed associated with lower odds for development of resistance at failure (OR 0.62 (0.45 - 0.94), per additional mutation needed, p = .02).</p> <p>Conclusions</p> <p>Thus, variation in individualized genetic barrier to NFV resistance may impact effective treatment options available after treatment failure. If similar results apply for other drugs, then estimated genetic barrier may be a new clinical tool for choice of treatment regimen, which allows consideration of available treatment options after virological failure.</p

Personalizing HIV therapy, mission impossible?

Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naïve patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance. This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Chronic hepatitis B (CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma (HCC). Liver transplantation (LT) is considered gold standard for treatment of hepatitis B virus (HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival. The combination of lamivudine (LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA (cccDNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy

Evolution of Interferon-Based Therapy for Chronic Hepatitis C

Since 1986, interferon-alfa (IFN-α) monotherapy has been administered for patients with chronic hepatitis C (CHC). However, sustained response rate is only about 8% to 9%. Subsequent introduction of ribavirin in combination with IFN-α was a major breakthrough in the treatment of CHC. Sustained virological responses (SVRs) rate is about 30% in hepatitis C virus genotype 1 (HCV-1) patients, and is about 65% in HCV-2 or -3 patients. After 2000, pegylated interferon (PegIFN) much improved the rates of SVR. Presently, PegIFN-α-ribavirin combination therapy has been current standard of care for patients infected with HCV. In patients with HCV-1, treatment for 48 weeks is optimal, but 24 weeks of treatment is sufficient in HCV-2 or -3 infected patients. Clinical factors have been identified as predictors for the efficacy of the IFN-based therapy. The baseline factor most strongly predictive of an SVR is the presence of HCV-2 or -3 infections. Rapid virological response (RVR) is the single best predictor of an SVR to PegIFN-ribavirin therapy. If patients can't achieve a RVR but achieve a complete early virological response (cEVR), treatment with current standard of care can provide more than 90% SVR rate. HCV-1 patients who do not achieve an EVR should discontinue the therapy. Recent advances of protease inhibitor may contribute the development of a novel triple combination therapy

Reconsidering first-line antiretroviral therapy in the pregnant population

Too many children are still being newly infected with HIV. The Global Plan is to eliminate new HIV infections among children by 2015 and keep their mothers alive. The rate of MTCT of HIV-1 has fallen to less than 2% in countries with the implementation of recommendations. The best documented factor that correlates to higher rates of transmission is the maternal level of plasma viremia. Therefore it is important to maximally inhibit HIV replication in order to prevent HIV-associated morbidity and mortality and to prevent MTCT. Durable viral suppression prolongs life by improving immune function and overall quality of life, lowering the risk of both AIDs-defining and non-AIDS-defining complications. Clinical data are more limited on antiretroviral drugs in pregnant women than in non-pregnant individuals due to concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. However there are sufficient data to base recommendations for drug choice for many of the available antiretroviral drugs. Preferred drugs must show durable viral suppression, increased CD4 cell count, and a favorable safety profile. In addition to the aforementioned characteristics of a preferred drug, preferred antiretroviral drugs for pregnant individuals must pay special attention to maternal toxicity, potential teratogenicity, and fetal safety, efficacy of reducing perinatal transmission, and pharmacokinetics data during the perinatal transmission of HIV. Currently the optimal initial antiretroviral regimens to treat antiretroviral-naïve patients in high resource regions consist of two nucleoside/tide reverse transcription inhibitors in combination with either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with RTV. Continually re-evaluation is recommended to challenge current paradigms. Treatment advances may lead to safer and even superior alternatives to current first-line therapy. The WHO current first-line therapy in less developed or developing regions includes the nonnucleoside reverse transcriptase inhibitor, EFV and considerations of poorer overall efficacy compared to newer drugs, toxicity, resistance, and adverse effects suggest that EFV should be reconsidered for use in first-line therapy. Although preferred protease inhibitors are as effective as EFV with fewer adverse effects, serious issues arise when patients are on concomitant medications with drug interactions. Currently raltegravir is the only integrase strand transfer inhibitor drug (INSTI) with data during pregnancy. Raltegravir is an attractive alternative or additional drug for pregnant women requiring medications with resistance, incomplete virologic response, or significant interactions with current first-line regimen drugs. Furthermore, based on recent data, raltegravir could provide pre-exposure prophylaxis in the fetus. DTG is a newer generation INSTI with clinical trials data showing safety and efficacy in nonpregnant adults. These studies suggest great promise for DTG and justify its role as first-line therapy for the nonpregnant population with relatively few drug interactions; in addition, it offers the only single tablet regimen for patient with or at risk for renal dysfunction. Although more data must be collected to ensure the safety and efficacy of INSTI as a first-line therapy in pregnant women, current studies show promise and with increasing experience INSTI agents may become part of the recommended first-line regimen for pregnant women

Estimating the dynamics and dependencies of accumulating mutations with applications to HIV drug resistance

We introduce a new model called the observed time conjunctive Bayesian network (OT-CBN) that describes the accumulation of genetic events (mutations) under partial temporal ordering constraints. Unlike other CBN models, the OT-CBN model uses sampling time points of genotypes in addition to genotypes themselves to estimate model parameters. We developed an expectation-maximization algorithm to obtain approximate maximum likelihood estimates by accounting for this additional information. In a simulation study, we show that the OT-CBN model outperforms the continuous time CBN (CT-CBN) (Beerenwinkel and Sullivant, 2009. Markov models for accumulating mutations. Biometrika 96(3), 645-661), which does not take into account individual sampling times for parameter estimation. We also show superiority of the OT-CBN model on several datasets of HIV drug resistance mutations extracted from the Swiss HIV Cohort Study databas

Individualized hepatocellular carcinoma risk : the challenges for designing successful chemoprevention strategies

Hepatocellular carcinoma (HCC) develops in the context of environmental risk factors like chronic viral hepatitis, diabetes and alcohol exposure, often associated to an increased risk of cirrhosis. Antiviral treatments that are effective to counteract hepatitis B and C may also attenuate the risk of tumor development. However, since hepatitis B-related carcinogenesis is promoted independently of the onset of cirrhosis, such antiviral treatments as nucleo(t)side analogs can promote regression of cirrhosis, prevent clinical decompensation and variceal bleeding but not HCC. This means that in successfully treated patients with cirrhosis, HCC is often the consequence of their extended survival. In hepatitis C patients, a sustained virological response to interferon-based therapies can reduce the rate of HCC development, even in patients with cirrhosis who experience histological regression of their liver disease. Future therapies aimed at this endpoint in at risk populations should take into consideration pretreatment patient stratification for host, viral and environmental risk factors. In this context the recent discovery of single nucleotide polymorphisms involved in the immune system function and tumorigenesis, might permit enrollment of populations of patients enriched with HCC risk factors for targeted chemopreventive therapies. This could finally pave the way to personalized algorithms, as already seen in the diagnosis and treatment schemes for chemoprevention