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.     

The safety of antiretroviral drugs in pregnancy

Advances in HIV therapy and mother-to-child transmission (MTCT) prophylaxis have led to increasing use of antiretroviral drugs in pregnancy. Highly active antiretroviral therapy in pregnancy has been associated with prematurity, pre-eclampsia and gestational diabetes. Women may be at increased risk of nevirapine-associated hepatotoxicity but whether or not pregnancy is an additional risk is uncertain. Although animal studies suggest a possibility of congenital abnormalities with specific antiretrovirals, such as efavirenz, results from registries and cohort studies do not support an excess of congenital malformations associated with in utero antiretroviral exposure. Concerns regarding the health of uninfected, antiretroviral-exposed children include the potential for cancers, mitochondrial disease and haematological abnormalities. However, the absence of any excess mortality in large observational cohort studies of uninfected, antiretroviral therapy-exposed children born to HIV-infected women is reassuring. Based on current knowledge, the immense benefits of antiretroviral prophylaxis in reducing the risk of MTCT, far outweigh the potential for adverse effects.     

The safety of antiretroviral drugs in pregnancy

Advances in HIV therapy and mother-to-child transmission (MTCT) prophylaxis have led to increasing use of antiretroviral drugs in pregnancy. Highly active antiretroviral therapy in pregnancy has been associated with prematurity, pre-eclampsia and gestational diabetes. Women may be at increased risk of nevirapine-associated hepatotoxicity but whether or not pregnancy is an additional risk is uncertain. Although animal studies suggest a possibility of congenital abnormalities with specific antiretrovirals, such as efavirenz, results from registries and cohort studies do not support an excess of congenital malformations associated with in utero antiretroviral exposure. Concerns regarding the health of uninfected, antiretroviral-exposed children include the potential for cancers, mitochondrial disease and haematological abnormalities. However, the absence of any excess mortality in large observational cohort studies of uninfected, antiretroviral therapy-exposed children born to HIV-infected women is reassuring. Based on current knowledge, the immense benefits of antiretroviral prophylaxis in reducing the risk of MTCT, far outweigh the potential for adverse effects.     

Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz

Introduction: More than 50% of HIV-positive patients experience neuropsychiatric adverse reactions following efavirenz therapy. Discontinuation of efavirenz due to its neuropsychiatric side effects has been reported in 2 – 13% of patients. Dizziness, headache, nightmares, abnormal dreams, mild cognitive difficulty, sleep disturbance (somnolence and insomnia), impaired concentration, depression, hallucination, delusion, paranoia, anxiety, agitation, aggressive behavior, mania, emotional labiality, catatonia, melancholia, psychosis, and fatigue are the most reported efavirenz adverse reactions.

Areas covered: In this review, potential benefits of cyproheptadine in prevention and management of HIV/antiretroviral-associated neuropsychiatric complications are evaluated. The available evidence was collected by searching Scopus, PubMed, Medline, Cochrane central register of controlled trials, and Cochrane database systematic reviews.

Expert opinion: Cyproheptadine is a cheap and safe drug that does not have significant interactions with antiretroviral drugs. Cyproheptadine's common side effects including increasing appetite and weight gain can be useful in HIV-positive individuals with their decreased appetite and weight loss. There is limited evidence regarding the effectiveness of cyproheptadine in neuropsychiatric disorders. It is essential to evaluate cyproheptadine efficacy in the prevention and management of neuropsychiatric complications of HIV/antiretroviral infection in well-designed studies in the future.     

Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen

Introduction: WHO recommends tenofovir, efavirenz, and lamivudine or emtricitabine for first-line antiretroviral therapy (ART) in adults, which replaced more toxic regimens using stavudine, zidovudine or nevirapine.

Areas covered: We searched Pubmed to identify observational studies and randomized controlled trials reporting toxicity of these antiretrovirals published between 2011 and 2016, and hand-searched abstracts presented at major HIV conferences in 2015 and 2016, focusing on data from sub-Saharan Africa. Tenofovir’s nephrotoxicity manifests as mild renal tubular dysfunction (common and of uncertain clinical significance), acute kidney injury (rare), and chronic declining glomerular filtration rate (common). African studies, which include high proportions of patients with renal dysfunction from opportunistic diseases, report population improvement in renal function after starting tenofovir-based ART. Tenofovir modestly decreases bone mineral density, and there is emerging data that this increases fracture risk. Efavirenz commonly causes early self-limiting neuropsychiatric toxicity and hypersensitivity rashes. Recent studies have highlighted its long-term neuropsychiatric effects, notably suicidality and neurocognitive impairment, and metabolic toxicities (dyslipidemia, dysglycemia, and lipoatrophy). We point out the challenges clinicians face in the recognition and attribution of adverse drug reactions.

Expert commentary: Tenofovir and efavirenz are generally well tolerated, but both are associated with potentially serious toxicities. Pharmacovigilance systems in resource-limited settings with high HIV burden should be strengthened.     

Renal disease in patients with HIV infection: epidemiology, pathogenesis and management

With the introduction of highly active antiretroviral therapy, we have witnessed prolonged survival with the potential for normal life expectancy in HIV-infected individuals. With improved survival and increasing age, HIV-infected patients are increasingly likely to experience co-morbidities that affect the general population, including kidney disease. Although HIV-associated nephropathy, the most ominous kidney disease related to the direct effects of HIV, may be prevented and treated with antiretrovirals, kidney disease remains an important issue in this population. In addition to the common risk factors for kidney disease of diabetes mellitus and hypertension, HIV-infected individuals have a high prevalence of other risk factors, including hepatitis C, cigarette smoking and injection drug use. Furthermore, they have exposures unique to this population, including antiretrovirals and other medications. Therefore, the differential diagnosis is vast.Early identification (through efficient screening) and definitive diagnosis (by kidney biopsy when indicated) of kidney disease in HIV-infected individuals are critical to optimal management. Earlier interventions with disease-specific therapy, often with the help of a nephrologist, are likely to lead to better outcomes. In those with chronic kidney disease, interventions, such as aggressive blood pressure control with the use of ACE inhibitors or angiotensin receptor antagonists where tolerated, tight blood glucose control in those with diabetes, and avoidance of potentially nephrotoxic medications, can slow progression and prevent end-stage renal disease. Only with greater awareness of kidney-disease manifestations and their implications in this particularly vulnerable population will we be able to achieve success in confronting this growing problem.     

Elvitegravir: a once-daily inhibitor of HIV-1 integrase

INTRODUCTION: Elvitegravir (EVG) is a potent inhibitor of HIV-1 integrase (IN) undergoing Phase III clinical trials. It blocks the strand-transfer step in a multi-step process that allows double-stranded cDNA to be irreversibly incorporated within the host DNA. It is the second member of the HIV-1 IN inhibitor class, following raltegravir. Co-administration with a CYP3A inhibitor, such as ritonavir or cobicistat, substantially increases EVG plasma exposure and prolongs elimination half-life. AREAS COVERED: A Medline review of Phase II and III trials involving EVG as well as a review of abstracts from major HIV and infectious disease conferences from 2010 to 2011 was conducted. EVG produces rapid and durable virologic suppression when combined with active background therapy. Trials investigating the efficacy of once-daily co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) demonstrate a high rate of virologic suppression with fewer CNS and psychiatric adverse events compared with co-formulated efavirenz/emtricitabine/tenofovir. The resistance profile for EVG is similar to raltegravir. EXPERT OPINION: Co-formulated EVG/COBI/FTC/TDF is an option for the treatment of antiretroviral na?ve and experienced patients. Once-daily dosing offers an advantage over raltegravir, but the requirement for pharmacologic boosting increases regimen complexity. Dolutegravir in development offers a favorable resistance profile and no requirement for pharmacologic boosting.     

Clinical implications of CNS penetration of antiretroviral drugs

The CNS serves as an important sanctuary site for HIV replication. The presence of HIV in this compartment may contribute to neurological complications in individuals infected with HIV. Understanding the CNS penetration capabilities of available antiretroviral agents may help clinicians to design treatment regimens with neuroprotective effects. Although numerous clinical studies and anecdotal reports have examined CSF antiretroviral drug exposure as a marker of CNS penetration, understanding the clinical relevance of these findings is difficult. Challenges with study design and subject recruitment often limit the investigator's ability to collect comprehensive data. Upon review of available data, the antiretroviral agents zidovudine, stavudine, lamivudine, nevirapine, efavirenz and indinavir demonstrate consistent penetration into the CSF. Zidovudine-, stavudine-, lamivudine-, didanosine- and protease inhibitor-based regimens also appear to suppress CSF viraemia or improve HIV neurological disease. These agents may be appropriate candidates for neuroprotective antiretroviral treatment regimens. Despite these data, several unanswered questions about the CSF antiretroviral drug exposure-response relationship still remain. Prospective, controlled studies examining this relationship are needed before absolute clinical recommendations are founded.     

Oxidative stress and mitochondrial impairment after treatment with anti-HIV drugs: clinical implications

Thirty years after the discovery of HIV infection, there are numerous antiretroviral drugs that control the disease when administered in a potent combination referred to as Highly Active Antiretroviral Therapy (HAART). This therapy reduces the viral load and improves immune system reconstitution, leading to a significant reduction of HIV-related morbidity and mortality. However, HAART does not completely eliminate HIV, so treatment must continue throughout the patient's life. Prolonged use of HAART has been related to long-term adverse events that can compromise patient health. These deleterious effects have been reported for the majority of antiretroviral drugs and are the most common causes for therapy discontinuation. In most of these adverse events, such as diabetes, cardiovascular diseases, neurological disorders and metabolic alterations, oxidative stress and mitochondrial impairment play important roles. This review covers the implication of antiretroviral drugs in the overproduction of reactive oxygen species and the reduction of antioxidant defences, and in the consequent mitochondrial dysfunction, focusing on the molecular mechanisms involved and the clinical implications for HIV-infected patients.     

Drug interactions between proton pump inhibitors and antiretroviral drugs

Gastroesophageal reflux disease and other related symptoms are common comorbidities for HIV-infected patients. Therefore, concurrent use of proton pump inhibitors and antiretrovirals is a common practice in the clinical setting. However, this practice may alter antiretroviral pharmacokinetics and lead to treatment failure due to inadequate drug exposure. Clinician awareness of these complex interactions is essential for optimal HIV management. This review summarizes the current knowledge on the interactions between proton pump inhibitors and antiretrovirals, and makes recommendations for the coadministration of proton pump inhibitors.