Initial Therapy for Human Immunodeficiency Virus: Broadening the Options

Abstract

The goal of investigation into new therapeutic options for HIV/AIDS is to further the achievements of highly active antiretroviral therapy by developing new drugs with improved efficacy. Although several therapies are currently available for initial therapy in HIV-infected patients, ongoing research focuses on additions to existing and novel drug classes that might have improved pharmacokinetic and tolerability profiles, as well as on new therapeutic combinations that might result in synergistic activity. To retain activity against resistant strains, novel drugs need to target the numerous critical points in the life cycle of HIV, inhibiting different enzyme subsites than those affected by antiretroviral agents currently in use. An improvement in patient adherence to therapy is another key objective of efforts in HIV treatment, as suboptimal drug levels are a main determinant of antiretroviral regimen failure. This article reviews the current classes of antiretroviral agents in development, describing the clinical data obtained to date. These agents may have potential use as initial therapy in HIV patients.     

Initial therapy for human immunodeficiency virus: broadening the options

The goal of investigation into new therapeutic options for HIV/AIDS is to further the achievements of highly active antiretroviral therapy by developing new drugs with improved efficacy. Although several therapies are currently available for initial therapy in HIV-infected patients, ongoing research focuses on additions to existing and novel drug classes that might have improved pharmacokinetic and tolerability profiles, as well as on new therapeutic combinations that might result in synergistic activity. To retain activity against resistant strains, novel drugs need to target the numerous critical points in the life cycle of HIV, inhibiting different enzyme subsites than those affected by antiretroviral agents currently in use. An improvement in patient adherence to therapy is another key objective of efforts in HIV treatment, as suboptimal drug levels are a main determinant of antiretroviral regimen failure. This article reviews the current classes of antiretroviral agents in development, describing the clinical data obtained to date. These agents may have potential use as initial therapy in HIV patients.     

Frequency of medical history items,drug interactions,and lifestyle characteristics that may interfere with antiretroviral medications

Abstract

PURPOSE: There were two study questions: How often do HIV-infected patients present with a medical history or concurrent medication use that might contraindicate the use of one or more antiretroviral drugs? What is the frequency of patients having lifestyle behaviors that might preclude them from successfully following an antiretroviral drug regimen? METHOD: One hundred patients were given a 52-item questionnaire that asked about their medical histories, concurrent use of non-HAART drugs, and lifestyle. The results were analyzed to determine the frequency of potential side effects, drug interactions, or lifestyle behaviors that could interfere with the patient being able to successfully adhere to antiretroviral drug regimens. RESULTS: 96% of the patients had at least one medical history item or were taking at least one medication that could potentially create a serious side effect to one or more of the 14 antiretroviral drugs that were studied. All of the patients had at least one lifestyle behavior that would have interfered with successful adherence to one or more of the drugs. CONCLUSION: The questionnaire utilized in the study identified potential factors that could cause medical problems or that could interfere with the successful use of various antiretroviral drugs. The frequency of occurrence of these factors was unexpectedly high.     

Antiretroviral treatment 2010: progress and controversies

Effective antiretroviral therapy (ART) changes the clinical course of HIV infection. There are 25 antiretroviral drugs approved for the treatment of HIV infection, and current antiretroviral drug regimens are highly effective, convenient, and relatively nontoxic. ART regimens should be chosen in consideration of a patient's particular clinical situation. Successful treatment is associated with durable suppression of HIV viremia over years, and consequently, ART reduces the risk of clinical progression. In fact, current models estimate that an HIV-infected individual appropriately treated with antiretroviral drugs has a life expectancy that approaches that of the general HIV-uninfected population, although some patient groups such as injection drug users do less well. Despite these advances, continued questions about ART persist: What is the optimal time to start ART? What is the best regimen to start? When is the optimal time to change ART? What is the best regimen to change to? In addition, newer antiretroviral agents are in development, both in existing classes and in new classes such as the CD4 receptor attachment inhibitors and the maturation inhibitors. Further research will help optimize current antiretroviral treatments and strategies.     

Therapeutic drug monitoring of antiretroviral agents

HIV+ patients fail antiretroviral therapy due to inadequate drug concentrations reaching the site of viral replication and/or the development of viral resistance to the antiretroviral agents. Adequate drug concentrations may not be reaching the virus due to poor compliance, poor absorption, or other pharmacokinetic factors such as metabolism, elimination, and drug interactions. The most important and most common pharmacokinetic drug interactions involve inhibition of metabolism, induction of metabolism, altered drug absorption, inhibition of renal excretion, and displacement from plasma protein binding sites. If a patient is failing antiretroviral therapy, TDM of antiretroviral agents could help in determining both adequacy of drug concentrations and patients' adherence. Ongoing studies will determine whether total drug concentration or free drug concentration of the protease inhibitors is the best predictor of response. Trough concentrations could prove to be the most important predictor of response, but additional studies are needed to compare trough, peak, and AUC concentrations with response to treatment. Finally, if some patients fail therapy due to inadequate drug concentrations, then increasing the dose could benefit patients' outcome and increase longevity. Clinical trials are needed that compare patients who receive a fixed-dosage regimen with patients who have adjusted dose regimens. Such a study is the best way to determine the true value of TDM of the antiretrovirals.     

Therapeutic drug monitoring: Pharmacologic considerations for antiretroviral drugs

Therapeutic drug monitoring (TDM) is the process by which a patient’s dosing regimen is guided by repeated measures of plasma drug concentrations. An enormous challenge with regard to TDM of antiretroviral drugs (ARV) is that the concentration goals can be moving targets. Well-designed prospective studies demonstrating that prospectively altering ARV doses based on TDM leads to virologic success and increased tolerability are needed. Nevertheless, there are specific clinical instances where this experimental intervention should be considered to potentially reduce toxicity and improve therapeutic outcomes.     

Abnormal pharmacokinetics: the need for monitoring

Optimal use of a drug depends on rational dosing and subsequent therapeutic drug monitoring for effectiveness and toxicity. Drug monitoring is not relevant for all drugs, but is indicated in the case of drugs which have a narrow therapeutic range or show a large inter-individual variation. If the response is not satisfactory or toxic side effects are observed, the regimen has to be adjusted or another drug used. Methods have been developed to establish rational dosing schedules for the individual patient. In previous methods, the patient's specific data such as age, length, weight and serum creatinine are integrated with population pharmacokinetic parameters for a drug. This approach is subject to an appreciable margin of error, particularly in patients whose physiology is far from normal. Therapeutic drug monitoring via blood level determination makes it possible to evaluate the patient's individual pharmacokinetic parameters on which a rational dosage regimen can be based.     

Antiretroviral therapy. Immune restoration disease in HIV-infected patients on HAART

Inflammatory diseases related to a preexistent or subclinical infection with an opportunistic pathogen in patients with HIV infection who respond to HAART may be caused by the restoration of an immune response against the pathogen. One danger can be misinterpreting the patient's condition as evidence of treatment failure and then stopping the drug regimen. Instead, measurement of pathogen-specific immune responses may help in the diagnosis of immune restoration diseases. The next step may be to continue HAART and therapy for the related infection and add anti-inflammatory drugs, such as corticosteroids. Generally, antiretroviral therapy should only be stopped, even temporarily, if that approach fails.     

Initial therapy of HIV infection.

BACKGROUND: The use of antiretroviral therapy has improved the quality of life and has increased the survival of HIV-infected individuals. However, the rapid rate of virus mutation and subsequent emergence of drug-resistant HIV variants threaten the longer-term efficacy of HIV treatment. The initial regimen provides the greatest chance for lasting suppression of viral load. AIMS: Appropriate selection of the initial antiretroviral regimen is critical. The growing number of drug classes allows healthcare providers to individualize treatment regimens. Factors influencing the selection of first-line therapy include baseline viral load and CD4 count, drug pharmacokinetics, potency, tolerability, safety, resistance and salvageability. Characteristics likely to affect adherence, such as regimen complexity and pill burden, must also be considered, as poor adherence is the most common cause of treatment failure. CONCLUSION: The selection of the initial regimen requires consideration of several factors. Drugs from new classes as well as new drugs from existing classes with favorable resistance and side effect profiles are in various stages of development. Many of these drugs will enhance available options for initial therapy.     

Approach to the Treatment-experienced patient

Failure of antiretroviral therapy can occur for a variety of reasons, but is often caused by or accompanied by drug resistance, which increases with continued time on nonsuppressive, failing regimens. Response to early virologic failure on an initial regimen may be associated with minimal or no resistance and can sometimes be managed simply by reinforcing adherence or by intensifying therapy. Resistance testing is an important tool for managing patients who are failing therapy; it should be used in most cases to guide selection of the next regimen. For patients with extensive treatment experience and drug resistance, there are a variety of approaches that have been suggested when fully suppressive options are not available. Clinicians caring for such patients must balance the benefit of slower progression associated with continued therapy against the risk of increasing drug resistance and loss of future treatment options.     

Effect of therapeutic drug monitoring on outcome in antiretroviral experienced HIV-infected individuals.

BACKGROUND: The role of therapeutic drug monitoring (TDM) in the routine management of HIV-infected individuals is still unclear, largely due to a lack of basic data regarding specific drug concentrations and how they correlate with maximal effect and minimal toxicity within given populations. Nevertheless, it has a potentially important role to play in the management of HIV-infected patients, with the aim of limiting toxicity, optimising antiviral effect and decreasing virological failure and emergence of viral resistance. OBJECTIVES: To measure serum concentrations of specific antiretroviral drugs in individuals changing antiretroviral therapy and assess relationship to virological response. STUDY DESIGN: A prospective, non-randomised, 24-week study of 40 antiretroviral experienced HIV-infected patients. Subjects had failed their previous antiretroviral regimen and were beginning new regimens based on genotypic testing. Serum antiretroviral concentrations and virological response was measured after initiation of treatment. RESULTS: There was a significant correlation between higher concentrations of lopinavir and efavirenz and better virological outcome. This was not seen with amprenavir. CONCLUSIONS: Use of TDM in this setting helps predict virological response to therapy. Optimal use of TDM would require dose adjustment on the basis of a TDM level. Further research is necessary to enable this practice to become routine in the management of HIV-infected patients.     

International perspectives on antiretroviral resistance. Clinical utility of resistance testing: retrospective and prospective data supporting use and current recommendations

Data from retrospective and prospective studies support use of genotypic and phenotypic resistance assays to guide treatment changes when initial or subsequent antiretroviral regimens fail. Several retrospective studies have shown that response to antiretroviral therapy can be predicted based on genotypic analysis of HIV, with baseline genotypic evidence of resistance predicting virologic failure. Other retrospective analyses demonstrated that phenotypic drug sensitivity correlates with increased viral load suppression, particularly when virus remains sensitive to two or three drugs at initiation of the regimen. Furthermore, prospective studies such as VIRADAPT and Genotype-Assisted Antiretroviral Resistance Testing (GART) have substantiated that drug selection based on genotypic assay results yield superior viral suppression compared with empiric treatment assignment. One additional study suggested significant improvement in short-term virologic outcome when phenotypic testing was used to guide treatment selection. Based on these findings, resistance testing is currently recommended for patients with acute HIV infection, those who have failed one or more antiretroviral regimens, and pregnant women. Although these tests move toward becoming a standard of care, several research questions remain: the long-term benefit of resistance testing is not yet certain, the interpretation of specific genotypic resistance patterns needs to be better defined, and clinical cut-off points for phenotypic resistance need to be established. As these issues continue to be studied, resistance testing likely will prove a reliable tool to help plan successful ART strategies.     

The Problem of Renal Function Monitoring in Patients Treated With the Novel Antiretroviral Drugs

Chronic kidney disease (CKD) is currently considered a major comorbidity in patients affected by HIV infection. In addition, new generation antiretroviral drugs that interact with creatinine transporters were recently introduced. Rilpivirine, dolutegravir, and cobicistat, with different mechanisms, inhibit the amount of tubular secretion of creatinine causing a slight increase in serum creatinine levels and consensual eGFR_creatreduction. This will require an unprecedented attention to renal issues, because the new drugs can also be associated to old antiretroviral drugs that may exert renal toxic effects. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimating GFR would be desirable. At the moment, methods of direct GFR measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate GFR is still recommended, considering the apparent reduction of eGFR_creat due to these drugs. Tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid. More specific and sensitive markers of tubular damage are still not readily available in all clinical labs. HIV patients treated by the novel drugs need to be monitored on a monthly basis for the first 3 months. Subsequent monitoring should be performed on a quarterly basis or guided by comorbidities.     

US Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States,February 25, 2000, by the Perinatal

Abstract

These recommendations update the 1994 guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report provides health care providers with information for discussion with HIV-1 infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy. Various circumstances that commonly occur in clinical practice are presented as scenarios and the factors influencing treatment considerations are highlighted in this report. It is recognized that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving. The Perinatal HIV Guidelines Working Group will review new data on an ongoing basis and provide regular updates to the guidelines; the most recent information is available on the HIV/AIDS Treatment Information Service (ATIS) website (http://www.hivatis.org).

In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1-infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy, pregnancy is not a reason to defer standard therapy. The use of antiretroviral drugs in pregnancy requires unique considerations, including the potential need to alter dosing as a result of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily to treat HIV-1 infection, to reduce perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy for infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen. Information included in these guidelines may not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. Specifically, the terms “safe” and “effective” may not be synonymous with the FDA-defined legal standards for product approval.     

Novel Methodology for Antiretroviral Quantitation in the Female Genital Tract

Abstract

A constant and nearly absolute adherence is required to ensure a successful long-lasting outcome of highly active antiretroviral therapy (HAART). Pill burden and regimen complexity are important contributors to adherence problems. The most significant treatment-related strategy to improve adherence may be the reduction in the number and frequency of pills to be taken every day. If one accepts the concept that once-daily therapy is likely to benefit patients, then the issue turns to whether we have adequate drugs to implement once-daily HAART. There is quite a difference between using a once-a-day drug within an HAART regimen and designing an HAART regimen that is dosed once daily. To date, studies that explore the feasibility of once-a-day HAART regimens are still few, mostly exploratory, not controlled, and performed in a limited number of patients. However, most data are consistent one with the other, and evidence on the utility of such regimens is growing. Once-daily therapy cannot be the answer to all the questions that complex and life-long therapies give rise to, but it could be a further choice that can meet the needs of many patients. The range of once-daily options is expanding rapidly, and the patients' request for easier therapies that are respectful of their lifestyle could be fulfilled.     

Hepatotoxicity of antiretroviral therapy

Hepatotoxicity is a serious complication in patients taking HAART. Coinfection with hepatitis viruses increases the risk of liver toxicity while taking antiretroviral therapy. Baseline transaminases should be checked before beginning antiretorviral therapy and all patients should be screened for pre-existing liver disease, most notably hepatitis B and C infections. Regular monitoring of transaminases is mandatory when commencing antiretroviral therapy. In patients with normal liver function, transaminases may be checked monthly after commencing HAART for the first 3 months. If stable this can be broadened to 3 month intervals. In patients with pre-existing liver disease monitoring should be performed more frequently (every 2 weeks) when initiating therapy. Once stable liver enzymes should be checked monthly. The less hepatotoxic drugs such as lamivudine and abacavir should be preferred in patients at high risk for hepatotoxicity. Risks include co-infection with hepatitis B and C viruses, a previous record of hepatotoxicity, cirrhosis, obesity and female gender. Minor enzyme elevations (< 5-fold upper normal limit) are generally safe to tolerate and usually resolve. Patients must be closely observed with regular liver function tests and a hypersensitivity type drug reaction should be excluded. The onset of clinical symptoms, elevated serum lactate or evidence of severe hepatic dysfunction (coagulopathy or elevation of ammonia levels) are suggestive of severe toxicity and HAART should be withheld. Treatment of suspected HAART related hepatotoxicity should first involve withdrawal of therapy. Hypersensitivity reactions may be treated with corticosteroids. Nucleoside-induced mitochondrial damage may improve with riboflavin or thiamine therapy.     

When paradigms fall: the demise of "hit hard, hit early"

Based on information presented at the World AIDS Conference in 1996, doctors and researchers presumed benefits of early treatment for HIV infection with antiretroviral drugs. The assumptions that highly active antiretroviral therapy (HAART) will cure HIV, safeguard the immune system, postpone possible drug resistance, and increase drug tolerance may be false. Selected data dispute the advantages of early HAART therapy. Although the decrease in AIDS-related deaths are correlated to the introduction of HAART, this decline most often related it to patients with late stage disease. Recent feedback cautions implementing HAART too early, and without adequate clinical data.     

Current management challenges in HIV: antiretroviral resistance

Emergence of drug-resistant viral variants is a major reason why HIV-infected patients experience viral rebound during antiretroviral therapy. Although combination antiretroviral therapy substantially inhibits viral replication, replication-competent mutant virus remains. In addition, it is now clear that virologic failure is not necessarily caused by failure of all drugs in a regimen. The use of resistance-testing data can assist in understanding the reasons for failure of antiretroviral therapy. However, there is a need for additional trials to better define the role resistance testing may play in developing management approaches to mitigate or minimize emergence of resistant HIV.     

Can HIV infection be treated successfully with a once-daily regimen?

Although once-daily dosing might not be appropriate for all patients, this schedule provides patients with a regimen that can fit more easily into their established routines, thereby increasing treatment adherence. Maintaining strict adherence is especially important in the treatment of HIV infection, because drug-resistant variants of HIV can emerge in suboptimal treatment environments. Didanosine, tenofovir, efavirenz, and lamivudine are the 4 single-agent antiretroviral drugs currently approved for once-daily administration. The combination of amprenavir boosted with ritonavir was FDA-approved for once-daily use in February 2002. Other new antiretroviral drugs are currently in development, as are new dosing schedules for existing antiretroviral drugs. Combinations of antiretroviral drugs, especially protease inhibitors boosted with ritonavir, are also being studied.