Nephrotoxicity associated with antiretroviral therapy in HIV-infected patients

Background: With the success of modern antiretroviral therapies in increasing longevity of patients with HIV infection, chronic conditions including renal disease have assumed a greater importance in patient management. Some antiretroviral therapies have themselves been identified to have clinically significant nephrotoxicity. Objective: To review the risk factors and mechanisms for renal toxicity of antiretroviral drugs, and their impact on the clinical management of patients with HIV. Methods: Current literature and HIV treatment guidelines are reviewed. Results/conclusions: Background rates of renal disease and associated risk factors are significant in the HIV clinic population, and renal function should be assessed in all HIV-infected patients. Modern HIV treatment regimens have a relatively low but clinically significant nephrotoxic potential; therefore, renal function should be evaluated on an ongoing basis in patients receiving antiretroviral therapy.     

Interactions between antifungal and antiretroviral agents

Importance of the field: Since the advent of combination antiretroviral therapy, the incidence of opportunistic infections has declined and the life expectancy of HIV-infected people has significantly increased. However, opportunistic infections, including fungal diseases, remain a leading cause of hospitalizations and mortality in HIV-infected people. With the availability of several new antiretroviral and antifungal agents, drug–drug interactions emerge as a potential safety concern.

Areas covered in this review: Relevant literature was identified using a Medline search of articles published up to March 2010 and a review of conference abstracts. Search terms included HIV, antifungal agents and drug interactions. Original papers and relevant citations were considered for this review.

What the reader will gain: Readers will gain an understanding of the pharmacokinetic properties of antiretroviral and antifungal agents, and insight into significant drug–drug interactions which may require dosage adjustments or a change in therapy.

Take home message: Azole antifungal drugs, with the exception of fluconazole, pose the greatest risk of two-way interactions with antiretroviral drugs through CYP450 enzymes effects. Limited studies suggest the risk of interactions between antiretroviral drugs and echinocandins is much lower. The combination of tenofovir and amphotericin B should be used with caution and close monitoring of renal function is required.     

Pharmacokinetics and dosage adjustment in patients with renal dysfunction

Introduction  Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment. Methods  Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft–Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required. Discussion  According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics. Conclusion  In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.     

Pediatric HIV: new opportunities to treat children

Background: Treating HIV-infected children remains a challenge due to a lack of treatment options, appropriate drug formulations and, in countries with limited resources, insufficient access to diagnostic tests and treatment. Objective: To summarize current data concerning new opportunities to improve the treatment of HIV-infected children. Methods: This review includes data from the most recently published peer-reviewed publications, guidelines or presentations at international meetings concerning new ways to treat HIV-infected children. Results/conclusions: New WHO guidelines recommend starting combination antiretroviral treatment in all infants aged < 1 year. Although this is common practice in some high-income countries, implementation of these recommendations in countries with limited resources is still a challenge. There is still an important gap between the availability of licensed drugs in children compared with adults. There remains a need for further pharmacokinetic studies, and for more pediatric formulations of antiretroviral drugs with improved palatability.     

Impaired maraviroc and raltegravir clearance in a human immunodeficiency virus-infected patient with end-stage liver disease and renal impairment: a management dilemma

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189?hours for maraviroc and 61?hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18?hours and 9-12?hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48?hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population.     

A HAART‐Breaking Review of Alternative Antiretroviral Administration: Practical Considerations with Crushing and Enteral Tube Scenarios

Selection of an appropriate antiretroviral regimen for the patient infected with human immunodeficiency virus can be challenging, as various considerations must be taken into account including viral resistance mutations, patient comorbidities, drug interactions, and the potential for drug‐related adverse effects and toxicities. Treatment is further complicated when a clinical scenario arises requiring an alteration in the dosage form. Factors ranging from dysphagia to administration through an enteral feeding tube can affect decisions regarding antiretroviral dosage forms. Limited pharmacokinetic data exist regarding the alteration of antiretroviral medications from their original form. Bioavailability may vary substantially between dosage forms, which can lead to unpredictable drug concentrations. Supratherapeutic or subtherapeutic antiretroviral drug concentrations can result in increased toxicity, virologic failure, or the emergence of drug resistance. We performed a systematic literature search to review the available antiretroviral literature on the modification of solid dosage forms as well as alternative routes of administration of oral antiretroviral agents and their application to clinical practice.     

Pharmacologic consideration for the use of antiretroviral agents in the elderly

The prevalence of human immunodeficiency virus (HIV) infection among people older than 50 years is increasing. HIV-infected patients require lifelong treatment with antiretroviral agents to suppress viral replication and maintain immune function. The use of antiretroviral agents in the elderly can be complicated by multiple chronic comorbidities and coadministered non-HIV medications. The pharmacokinetics of antiretroviral agents may be altered due to age-related decrements in hepatic and renal function. The elderly may be more sensitive than younger people to antiretroviral drug toxicity. A better understanding of the pharmacokinetics of antiretroviral agents in the elderly is of importance for the successful management of complex antiretroviral regimens in this population.     

Safety and pharmacokinetics of antiretroviral therapy during pregnancy

Combined antiretroviral therapy can reduce the transmission of human immunodeficiency virus (HIV) to an unborn child to less than two percent. An HIV-infected woman of childbearing age and her medical provider are in the unique position of making treatment decisions that not only will impact the woman's health but also that of her child. Treatment recommendations for pregnant women infected with HIV state that therapies of known benefit to women should not be withheld during pregnancy, unless there are known adverse effects for the mother and fetus, and these adverse effects outweigh the benefit for the women. However, the recommendations of antiretroviral drugs for the treatment of HIV-infected pregnant women are subject to unique considerations, including potential changes in dosing requirement resulting from physiologic changes associated with pregnancy, and potential adverse effects on the development of the fetus and/or newborn. Currently there is a general lack of pharmacokinetic data in pregnant HIV-infected women. The limited available information suggests that pregnant women may be exposed to subtherapeutic drug levels of certain antiretroviral agents during the later stages of pregnancy, which can lead to the failure of virologic suppression, development of resistance and increased risk of vertical transmission of HIV infection. The available pharmacokinetic data regarding the use of antiretroviral therapy in pregnancy is reviewed.     

Pitfalls of pharmacokinetic dosage guidelines in renal insufficiency

As the renal elimination of most drugs is closely correlated with the endogenous creatinine clearance, it is possible to use this parameter of kidney function to adjust drug dosage in renal failure. However, this simple procedure neglects possible changes in the volume of distribution, plasma protein binding, drug metabolism, intestinal absorption, and pharmacodynamics in renal insufficiency, as well as the occurrence of biologically active drug metabolites. Because of these uncertainties in critical cases the validity of the dosage calculated using the creatinine clearance should be checked by clinical surveillance and measurements of drug blood concentrations. Further, pharmacokinetic dosage guidelines based on the individual creatinine clearance may not be applicable to diuretics and drugs which have markedly differing kinetics of pharmacodynamic effects and blood levels.     

Pharmacokinetic considerations in the treatment of tuberculosis in patients with renal failure

Tuberculosis is re-emerging in patients with altered immune status, such as those with chronic renal failure. Clinicians should thus be aware of the pharmacokinetics and dosage adjustment of antitubercular drugs in patients with renal insufficiency. Among patients with renal insufficiency, those who are dialysed should be treated with special care. Indeed, dosage should always be closely adjusted in these patients and potential removal by dialysis must be taken into account. However reliable the dosage adjustment recommendations are for these drugs in patients with renal failure, further pharmacokinetic investigations need to be performed, especially in dialysis patients in whom the influence of haemodialysis and continuous ambulatory peritoneal dialysis on drug pharmacokinetics needs to be detailed. In the meantime, it could be generally advised to administer all antitubercular drugs after the haemodialysis session, even though some drugs are known to be non-dialysable.     

Pharmacokinetic predictions for patients with renal impairment: focus on peptides and protein drugs

AIM

Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived.

METHODS

Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid E_max model was applied and fitted to the data and the prediction error was analyzed.

RESULTS

Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life).

CONCLUSION

An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients.     

Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment

Hepatic and renal insufficiency due to co-infection, alcoholism, diabetes mellitus, family history, adverse effects of antiretrovirals and other factors are commonly seen in HIV-infected patients. Therefore, the use of antiretrovirals in this patient setting requires attention to the pharmacokinetic issues that clinicians must consider when prescribing highly active antiretroviral therapy for these patients. This review summarizes the current knowledge of the use of antiretrovirals in patients with hepatic or renal impairment, and makes dosing recommendations for this subpopulation of HIV-infected patients.     

Effect of haemodialysis on the pharmacokinetics of antineoplastic drugs

Since renal failure itself creates an immunocompromised situation, malignant tumours in haemodialysis patients are increasing due to the prolonged lifespan of these patients. In treating these patients with anticancer agents, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs with extensive renal excretion. On the other hand, if an anticancer drug is removed significantly by haemodialysis, dosage increase would be required to ensure adequate therapeutic efficacy. We address in this review the clinical pharmacokinetic aspects of antineoplastic therapy, and the application of pharmacokinetic principles to the adjustment of dosage of anticancer agents in haemodialysis patients.