Components Of Highly Active Antiretroviral Therapy Research Articles

Silver Nanoparticles Conjugate Attenuates Highly Active Antiretroviral Therapy-Induced Hippocampal Nissl Substance and Cognitive Deficits in Diabetic Rats.

Background The application of nanomedicine to antiretroviral drug delivery holds promise in reducing the comorbidities related to long-term systemic exposure to highly active antiretroviral therapy (HAART). However, the safety of drugs loaded with silver nanoparticles has been debatable. This study is aimed at evaluating the effects of HAART-loaded silver nanoparticles (HAART-AgNPs) on the behavioural assessment, biochemical indices, morphological, and morphometric of the hippocampus in diabetic Sprague-Dawley rats. Methods Conjugated HAART-AgNPs were characterized using FTIR spectroscopy, UV spectrophotometer, HR-TEM, SEM, and EDX for absorbance peaks, size and morphology, and elemental components. Forty-eight male SD rats (250 ± 13 g) were divided into nondiabetic and diabetic groups. Each group was subdivided into (n = 8) A (nondiabetic+vehicle), B (nondiabetic+HAART), C (nondiabetic+HAART-AgNPs), D (diabetic+vehicle), E (diabetic+HAART), and F (diabetic+HAART-AgNPs). Morris water maze, Y-maze test, and weekly blood glucose levels were carried out. Following the last dose of 8-week treatment, the rats were anaesthetized and euthanized. Brain tissues were carefully removed and postfixed for Nissl staining histology. Results 1.5 M concentration of HAART-AgNPs showed nanoparticle size 20.3 nm with spherical shape. HAART-AgNPs revealed 16.89% of silver and other elemental components of HAART. The diabetic control rats showed a significant increase in blood glucose, reduced spatial learning, positive hippocampal Nissl-stained cells, and a significant decrease in GSH and SOD levels. However, administration of HAART-AgNPs to diabetic rats significantly reduced blood glucose level, improved spatial learning, biochemical indices, and enhanced memory compared to diabetic control. Interestingly, diabetic HAART-AgNP-treated rats showed a significantly improved memory, increased GSH, SOD, and number of positive Nissl-stained neurons compared to diabetic-treated HAART only. Conclusion Administration of HAART to diabetic rats aggravates the complications of diabetes and promotes neurotoxic effects on the experimental rats, while HAART-loaded silver nanoparticle (HAART-AgNP) alleviates diabetes-induced neurotoxicity.

Efavirenz as a psychotropic drug.

Antiretroviral drugs are the mainstay of treatment for human immunodeficiency virus (HIV) infection. Lifelong highly active antiretroviral therapy (HAART) is indicated to prevent disease progression to acquired immunodeficiency syndrome (AIDS). Efavirenz was a first-line component of HAART across the world for many years. The purpose of this article is to review the psychotropic properties of efavirenz, which are the most important adverse events associated with the drug and commonly result in treatment discontinuation. A PubMed search was conducted using efavirenz as a search term, which returned 4655 results. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included in the narrative review. Acute exposure to efavirenz may cause profound perceptual disturbances (delusions and hallucinations) whereas chronic exposure may be associated with abnormal dreams and other sleep disturbances, anxiety, depressed mood and suicidality. It may also be abused as a hallucinogen, especially in individuals with a history of poly-substance abuse. Recent research indicates that efavirenz directly affects monoaminergic neurotransmission and may partially substitute for psychedelic drugs, such as lysergic acid diethylamide (LSD). Efavirenz acts as a serotonin 5-HT2A receptor antagonist, a serotonin-dopamine reuptake inhibitor, an inhibitor of monoamine oxidase (MAO) and a vesicular monoamine transporter 2 (VMAT2) inhibitor, which are mechanisms common with many psychotropic drugs. Efavirenz interacts with many of the same molecular targets as the empathogen methylendioxymethamphetamine (MDMA), but the effects of the 2 drugs may differ. The exact mechanism of action of efavirenz as a psychotropic drug remains unclear and future studies should focus on evaluating whether prolonged exposure could lead to irreversible side effects.

Prevalence of and Risk Factors for Prediabetes in Patients Infected With HIV.

BackgroundThe use of highly active antiretroviral therapy (HAART) has resulted in a dramatic decrease in morbidity and mortality in HIV-infected patients. Components of HAART (e.g., protease inhibitors and nucleoside reverse transcriptase inhibitors), as well as HIV infection itself, can have significant effects on developing new-onset diabetes. The goals of this study were to determine the prevalence of prediabetes and to assess risk factors associated with prediabetes in a cohort of HIV-infected patients.MethodsThis is a retrospective, cross-sectional study of 249 HIV-infected patients in an outpatient multidisciplinary HIV clinic in a university hospital. Patients with prediabetes were identified and compared with patients without prediabetes. The association between the prevalence of prediabetes and risk factors was analyzed.ResultsAmong 249 HIV-infected patients, the mean age was 46.3 years, and 54% were male. Prevalence of prediabetes was approximately 30%, and BMI ≥30 kg/m2 was found to be a significant risk factor for developing prediabetes.ConclusionA high prevalence of prediabetes was observed in this cohort of HIV-infected patients. Interventions targeting HIV-infected patients with increased risk of prediabetes, especially individuals with a high BMI, is needed.

Farnesyltransferase inhibitors prevent HIV protease inhibitor (lopinavir/ritonavir)-induced lipodystrophy and metabolic syndrome in mice.

Highly active antiretroviral therapy (HAART) has successfully reduced the mortality rate of patients with human immune deficiency virus (HIV) and HIV protease inhibitors (HIV PIs) are key components of HAART. Complications of HAART, particularly those associated with HIV PIs including lipodystrophy and metabolic disturbance, have emerged as an important public health issue. No specific treatment is available to prevent and/or treat HIV PI-associated lipodystrophy and metabolic syndrome. The present study demonstrated that a relatively low-dose of farnesyltransferase inhibitor (FTI), tipifarnib (3 mg/kg/day, subcutaneous injection) and lonafarnib (5 mg/kg/day, subcutaneous injection), prevented the onset of lipodystrophy and metabolic syndrome induced by the combination of two HIV PIs, lopinavir (50 mg/kg/day, intraperitoneal injection) and ritonavir (12.5 mg/kg/day, intraperitoneal injection), in mice. Consistent with previous studies, treatment with lopinavir/ritonavir for 2 weeks decreased body weight, adipose tissue mass, levels of plasma adiponectin and leptin, and increased plasma levels of triglycerides, total cholesterol and insulin. Tipifarnib and lonafarnb prevented or ameliorated all of these alterations in the HIV PI-treated mice. These data identify FTIs as a novel potential strategy to prevent or treat HIV PI-associated lipodystrophy and metabolic syndrome in HIV-infected patients on HAART.

Novel Antiretroviral Drugs in Patients with Renal Impairment: Clinical and Pharmacokinetic Considerations.

Highly active antiretroviral therapy (HAART) has dramatically increased the survival of HIV-infected patients from Western countries reducing the incidence of opportunistic infections and AIDS-related malignancies, and improving the patients' quality of life compared with the pre-HAART era. HIV is thus now considered in the West as a chronic disease, with the majority of HIV-infected patients successfully reaching an optimal immune and virological outcome a few months after starting HAART. However, this switch from acute to chronic disease has been accompanied by an increased incidence of chronic kidney disease (CKD), reported in up to 60% of HIV-infected patients. Tenofovir disoproxil fumarate (TDF) is considered to play a significant role in the development of CKD in these patients. It has been proposed that tenofovir alafenamide (TAF), a prodrug formulation able to providing lower systemic and renal drug exposure, could potentially contribute to reduce the development of CKD in HAART-treated patients. On the other hand, the pharmacokinetics of some components of HAART can be significantly altered in HIV-infected patients developing CKD. TDF- or TAF-based antiretroviral regimens should be avoided in patients with a creatinine clearance of less than 50 or 30mL/min, respectively. This review focuses on the pharmacokinetic changes of novel antiretroviral drugs in HIV-infected patients with renal impairment or requiring renal replacement therapy, and provides some suggestions on how to change drug doses in these clinical settings.

Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART) in Resource-Limited Settings.

Highly active antiretroviral therapy (HAART) has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV) and nevirapine (NVP) are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI) of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI) candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL), followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL), Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL), and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL). Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL) on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17) effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the extracts reach the liver, there is a high likelihood of standard doses affecting drug plasma concentrations which could lead to toxicity.

Safety and Effectiveness of Highly Active Antiretroviral Therapy in Treatment-Naïve HIV Patients: Preliminary Findings of a Cohort Event Monitoring Study in Belarus.

Antiretroviral drugs have well-documented evidence-based favorable benefit-risk ratios. Although various studies have investigated and characterized the safety profile of antiretroviral medicines, there are a limited number of studies evaluating the safety of first-line antiretroviral therapy (ART) in patients with a specific co-morbidity. A cohort event monitoring (CEM) study of the safety and effectiveness of antiretroviral medicines in a target population that has a significant level of co-morbidities (chronic infectious diseases, peripheral blood cytopenias) was implemented. The aim was to evaluate the safety profile of the highly active ART (HAART) in the target population and subpopulations with risk factors, to optimize the monitoring and decision-making procedure for subgroups of patients with specific types of co-morbidity, and to implement a more vigilant approach to therapy management in risk groups of patients. Prospective observational CEM was implemented among HAART-naïve HIV-positive patients at four clinical sites from December 2012. Eligible patients were those starting first-line HAART. Close medical supervision of all enrolled patients, with regular clinical and laboratory monitoring, was provided by healthcare professionals within 1 year after commencement of therapy. Standardized forms were used for data collection on initial and subsequent visits. All objective or subjective deviations in condition (events) were assessed for a causal relationship with ART, and for severity, seriousness, reversibility, preventability, and pre-existing risk factors in the case of adverse drug reactions (ADRs). A total of 518 HAART-naïve HIV-positive patients were enrolled in the CEM study. Of these patients, 65% (337) experienced one or several ADRs related to one or more components of HAART. Most of the ADRs reported were non-serious, expected, common (very common), transient (correctable), or reversible. The most common were hematotoxic, hepatotoxic, and neurotoxic adverse reactions. In several cases, some types of toxicities, associated with zidovudine, efavirenz, and nevirapine, had a high level of severity, necessitating hospitalization and drug regimen or single-agent substitution. Severe cases of hematological, hepatobiliary, and psychiatric toxicities were associated with pre-existing risk factors. CEM is an effective tool for safety and effectiveness monitoring and could be successfully implemented for intensive study of important safety issues and for overcoming knowledge gaps regarding safety. In order to achieve a favorable benefit-risk ratio for HAART in the specific sections of the population with pre-existing risk factors for development of ART toxicities, more vigilant consideration and careful assessment before therapy is commenced and further regular monitoring of key laboratory parameters is required.

Viral hepatitis and human immunodeficiency virus co-infections in Asia.

Hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) affect many people in Asian countries, although there are geographic differences. Both HBV and HIV (HBV/HIV) and HCV/HIV co-infections are highly prevalent in Asia. Hetero- and homosexual, injection drug use, and geographic area are strong predictors of HBV, HCV, and HIV serostatus. In HBV endemic regions, the prevalence and genotype distribution of HBV/HIV co-infection is almost comparable with that in the general population. In Japan, where HBV has low endemicity, the prevalence of HBV/HIV co-infection is approximately 10-fold higher than that in the general population, and HBV Ae is the most common subgenotype among HIV infected individuals. Highly active antiretroviral therapy (HAART) is an effective treatment for HIV/Acquired Immune Deficiency Syndrome. Lamivudine, a component of HAART, is an effective treatment for HBV, HIV, and HBV/HIV co-infection; however, cost, emerging drug resistance, antiretroviral-associated liver toxicity and liver-related morbidity due to HCV progression are particular concerns. HCV/HIV co-infection may accelerate the clinical progression of both HCV and HIV. The high prevalence of HBV/HIV and HCV/HIV co-infections in Asia underscores the need to improve prevention and control measures, as fewer evidence-based prevention strategies are available (compared with Western countries). In this review, the most recent publications on the prevalence of HBV/HIV and HCV/HIV co-infections and related issues, such as therapy and problems in Asia, are updated and summarized.

Use of HMG-CoA reductase inhibitors in the HIV population: implications for individualized treatment selection.

The World Health Organization reports that 34 million people are living with human immunodeficiency virus (HIV) worldwide. Several global organizations are making concerted efforts to treat and prevent HIV, centered around providing antiretroviral therapy (ART) to those who are infected and those at risk for infection. The first antiretroviral (ARV), zidovudine, was approved in 1987. Zidovudine belongs to the subclass known as nucleoside reverse transcriptase inhibitors (NRTIs). Since the advent of zidovudine, additional NRTIs and numerous other classes of ARVs have been introduced to the market, including nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, fusion inhibitors, and coreceptor inhibitors. The use of these various classes in combination, known as highly active ART (HAART), provided yet another breakthrough in HIV treatment. In 2008, the Antiretroviral Therapy Cohort Collaboration collected data from several developed countries that showed increased life expectancy for those who began HAART at a CD4+ cell count > 200 per microliter of blood.2 Although HAART benefits people living with HIV, ARVs are not without significant risks. For instance, PIs, a key component of HAART, are associated with insulin resistance, lipodystrophy, dyslipidemia, and hepatoxicity. Notably, it has been estimated that the prevalence of hyperlipidemia in patients receiving PI-based ART may be close to 80%. The Department of Health and Human Services (DHHS) guidelines recommend the use of at least 3 ARVs in combination; of the 4 preferred regimens for nonpregnant, treatment-naive HIV patients, 2 contain PIs. Increased use of PIs and other ARVs, along with an increase in life expectancy, are suggested factors that explain a trend of increased hyperlipidemia diagnoses seen in the HIV-infected population. Statins are a class of medications used to block cholesterol production in the liver. While statins are generally deemed well tolerated, serious side effects such as lethal rhabdomyolysis can occur when concentrations are increased. Recently, a review of drug-drug interactions between statins and PIs, with an emphasis on metabolic pathways, was published. Of the 7 statins currently available (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin), 3 (atorvastatin, lovastatin, and simvastatin) are metabolized through cytochrome P450 (CYP) 3A. All PIs except nelfinavir are coadministered with ritonavir, which is considered a potent COMMENTARY

Cardiac Allograft Vasculopathy in HIV-Infected Patients

Purpose Cardiac transplantation is performed on HIV-infected pts effectively treated with highly active antiretroviral therapy (HAART). Recent data has shown that protease inhibitors, a component of HAART, may contribute to dyslipidemia. This study determines the prevalence of cardiac allograft vasculopathy (CAV) in post-transplant, HIV-infected patients and the role of dyslipidemia in its progression. Methods and Materials A retrospective analysis of all cardiac transplantation in HIV-infected pts was done. Transplant outcome, graft function, angiogram results, and laboratory tests including lipid profile, were obtained from electronic medical records. Results 11 pts (41±12 yo, 72.7% males) underwent heart transplant at a large volume centers. All pts were treated with HAART post-transplant. The median follow up time was 42.5 months. Nine patients (82%) are alive and only 3 patients (27%) were diagnosed with CAV. Graft dysfunction was reported in only 1 patient (9%). Seven patients (63%) experienced cellular rejection, and only 1 patient (9%) experienced humoral rejection. Seven patients (64%) of patients fulfilled at least one criterion of dyslipidemia. Triglyceride levels were elevated in 5 patients (45%), HDL levels were low in 3 patients (27%), and only 1 patient had a borderline-high LDL level; mean values were 167, 50, and 94 mg/dL respectively. Conclusions CAV occurs in patients with HIV who undergo HT and are treated with HAART at a rate that appears similar or lower than those in the greater transplant population. Marked dyslipidemia does not appear to be a plausible explanation as a driving force for CAV. Rejection which also appears to occur somewhat less frequently may be a more likely cause for CAV in this population. [ figure 1 ]

Comparative analysis of genetic toxicity of antiretroviral combinations in somatic cells of Drosophila melanogaster

Nucleoside reverse-transcriptase inhibitor (NRTI) drugs are a major component of highly-active antiretroviral therapy (HAART). NRTI combinations have been demonstrated as producing a sustained reduction in plasma viremia with an increased CD4 count, thereby showing clear clinical benefits. Therefore, the secondary effects caused by the combination of two NRTIs, mainly those related to amplification of genotoxic effects, due to increased risk of DNA damage caused by these drugs, should be carefully examined. We employed the standard version of the wing SMART in Drosophila melanogaster to obtain more detailed knowledge about the genotoxic profile of NRTI combinations of AZT+ddI, AZT+3TC and AZT+d4T. Our results showed that all combinations increased the frequencies of induction of mutant spots. The combinations AZT+ddI and AZT+3TC were shown to induce recombination rates ranging from 86.38% to 98.36% while AZT+d4T showed a large discrepancy between recombination and mutation percentages. The combination index demonstrated that 3TC and d4T produced antagonism while ddI showed synergistic effects in combination with AZT.

Venous and Arterial Thromboembolic Complications Associated with HIV Infection and Highly Active Antiretroviral Therapy

With the advent of highly active antiretroviral therapy (HAART), dramatic improvements have been made in the quality and length of life in people living with HIV/AIDS (PLWA). Complications that are seen with increasing frequency in this group include venous thromboembolism events (VTE) and cardiovascular disease. Recent epidemiologic studies suggest PLWA have a 2-fold to 10-fold greater risk of VTE compared with age-matched controls. Several mechanisms associated with HIV infection, coupled with traditional risk factors, including age, opportunistic infections, and lifestyle choices, may contribute to a heightened risk of VTE and cardiovascular disease. It has been challenging to discern which of these complications are related to HAART. Herein, we review the risk of VTE in the pre-HAART and current HAART era. We call attention to particular instances where components of HAART have been associated with acute myocardial infarction, noncirrhotic portal hypertension and portal vein thrombosis. We also highlight potential drug-drug interactions between HAART and anticoagulant therapy. Additional studies are needed to better understand the mechanisms and risks associated with long-term use of HAART and to what extent HAART contributes to or mitigates the risk of VTE and cardiovascular disease.

CYP2C19 Genetic Variants Affect Nelfinavir Pharmacokinetics and Virologic Response in HIV-1–Infected Children Receiving Highly Active Antiretroviral Therapy

The objective of this research was to identify the impact of genetic variants of P-glycoprotein (ABCB1) and cytochrome P450 (CYP) on nelfinavir pharmacokinetics and response to highly active antiretroviral therapy (HAART) in HIV-1-infected children. HIV-1-infected children (n = 152) from Pediatric AIDS Clinical Trial Group 366 or 377 receiving nelfinavir as a component of HAART were evaluated. Genomic DNA was assayed for ABCB1 and CYP genetic variants using real-time polymerase chain reaction Nelfinavir oral clearance (CL/F), M8 to nelfinavir ratios, CD4 T cells, and HIV-1-RNA were measured during HAART. Nelfinavir CL/F and M8 to nelfinavir ratios were significantly associated with the CYP2C19-G681A genotypes (P < 0.001). Furthermore, the CYP2C19-G681A genotype was related to virologic responses at week 24 (P = 0.01). A multivariate analysis demonstrated that age (P = 0.03), concomitant protease inhibitor use (P < 0.001), and the CYP2C19-G681A genotype (P < 0.001) remained significant covariates associated with nelfinavir CL/F. CYP2C19 genotypes altered nelfinavir pharmacokinetics and the virologic response to HAART in HIV-1-infected children. These findings suggest that CYP2C19 genotypes are important determinants of nelfinavir pharmacokinetics and virologic response in HIV-1-infected children.

Long-Term Ritonavir Exposure Increases Fatty Acid and Glycerol Recycling in 3T3-L1 Adipocytes as Compensatory Mechanisms for Increased Triacylglycerol Hydrolysis

Lipodystrophy with high nonesterified fatty acid (FA) efflux is reported in humans receiving highly active antiretroviral therapy (HAART) to treat HIV infection. Ritonavir, a common component of HAART, alters adipocyte FA efflux, but the mechanism for this effect is not established. To investigate ritonavir-induced changes in FA flux and recycling through acylglycerols, we exposed differentiated murine 3T3-L1 adipocytes to ritonavir for 14 d. FA efflux, uptake, and incorporation into acylglycerols were measured. To identify a mediator of FA efflux, we measured adipocyte triacylglycerol lipase (ATGL) transcript and protein. To determine whether ritonavir-treated adipocytes increased glycerol backbone synthesis for FA reesterification, we measured labeled glycerol and pyruvate incorporation into triacylglycerol (TAG). Ritonavir-treated cells had increased FA efflux, uptake, and incorporation into TAG (all P < 0.01). Ritonavir increased FA efflux without consistently increasing glycerol release or changing TAG mass, suggesting increased partial TAG hydrolysis. Ritonavir-treated adipocytes expressed significantly more ATGL mRNA (P < 0.05) and protein (P < 0.05). Ritonavir increased glycerol (P < 0.01) but not pyruvate (P = 0.41), utilization for TAG backbone synthesis. Consistent with this substrate utilization, glycerol kinase transcript (required for glycerol incorporation into TAG backbone) was up-regulated (P < 0.01), whereas phosphoenolpyruvate carboxykinase transcript (required for pyruvate utilization) was down-regulated (P < 0.001). In 3T3-L1 adipocytes, long-term ritonavir exposure perturbs FA metabolism by increasing ATGL-mediated partial TAG hydrolysis, thus increasing FA efflux, and leads to compensatory increases in FA reesterification with glycerol and acylglycerols. These changes in FA metabolism may, in part, explain the increased FA efflux observed in ritonavir-associated lipodystrophy.

Adverse Effects of Tenofovir Use in HIV-infected Pregnant Women and their Infants

Data regarding use of tenofovir disoproxil fumarate in HIV-infected pregnant women are limited. To identify adverse effects of tenofovir use during pregnancy in HIV-infected women and their infants. In a retrospective case series, the charts of 127 pregnant HIV-infected women who received highly active antiretroviral therapy (HAART) between 2001 and 2005 were reviewed. Those who received tenofovir during pregnancy were selected for this study. Each woman's chart was reviewed for clinical data and adverse events during the pregnancy; each infant's chart was reviewed for growth parameters from birth to 12 months. Fifteen HIV-infected women with limited treatment options were prescribed HAART containing tenofovir during 16 pregnancies. In utero tenofovir exposure was a median of 127 days (range 6-259). Tenofovir was well tolerated by all women throughout pregnancy. There were 15 successful deliveries occurring at a median (range) of 36 weeks (30-40), with a median birth weight of 3255 g (1135-3610). Complications, including 1 spontaneous abortion, occurred in 9 pregnancies and were not attributed to tenofovir. Eleven (73%) women had abnormal laboratory results, including 6 who experienced grade 1 hemoglobin abnormalities; 4 of these women had preexisting anemia. Calculated glomerular filtration rate (calculated by Modification of Diet in Renal Disease equation) remained above 90 mL/min/1.73 m(2) in all women, except one who had a transient decline. Fourteen infants demonstrated normal growth and development for weight and height at birth, as well as during the 12-month follow-up period; no congenital malformations were documented. Mother-to-child transmission of HIV was not observed in this cohort. Tenofovir was found to be a well-tolerated component of HAART in this small cohort. Longer-term assessment of tenofovir effects on childhood growth and larger prospective studies of tenofovir use in pregnant women are warranted.

Bullous Eruption in a Patient Infected With the Human Immunodeficiency Virus

A 30-year-old man diagnosed with human immunodeficiency virus (HIV) infection 10 years earlier, presented with large tense blisters associated with minimal itching of 10 days' duration. He had no history of oral or genital erosions or ulcerations and showed no symptoms of HIV-related illnesses. Highly active antiretroviral therapy (HAART) had been started 6 weeks earlier when his CD4 count was 116/mL. He initially received nevirapine 200 mg once daily; after 2 weeks with no skin eruptions or other adverse reactions, the dose was increased to 200 mg twice daily. Other components of his HAART included lamivudine and stavudine. The patient was not taking any other prescription or alternative medicines. During the past year, he experienced 4 episodes of intensely itchy urticarial lesions that subsided with antihistamines. The present episode of bullous lesions was also preceded by urticarial lesions. On examination, he had multiple, large, tense bullae over relatively normal-looking skin involving all parts of the body (Figure 1). There were a few well-defined erosions. Nikolsky and bullae spread signs were negative, and no oral or genital erosions or ulcerations were noted. Results of a complete blood count, renal and liver function tests, and chest x-ray were within normal limits. Skin biopsy from one of the blisters showed a subepidermal bulla filled with eosinophils and polymorphonuclear leukocytes (Figure 2). The underlying dermis showed perivascular inflammatory infiltrate composed of polymorphonuclear and lymphomononuclear cells. The overall features were suggestive of bullous pemphigoid. A direct immunofluorescence test could not be done because of possible risk of cross-infection to the operator of the cryostat. Workup for herpes simplex virus and cytomegalovirus infection also could not be performed. HAART was discontinued temporarily with the suspicion that it was the causative factor. The patient was started on oral prednisolone 40 mg/d and topical clobetasol propionate (0.05%). Within 1 week of treatment, he had significant improvement with almost complete disappearance of the lesions. A few small, tense vesicles continued to appear between. Once the lesions completely disappeared, the prednisolone was gradually tapered off and all the components of HAART were resumed. The patient did well without any recurrence of lesions, thus virtually excluding HAART as the cause of the bullous pemphigoid-like eruptions. Subsequently, he did not return for follow-up.

Highly Active Antiretroviral Therapy-Induced Liver Injury

With the advent of highly active antiretroviral therapy (HAART), the reduction in overall mortality and morbidity in HIV patients has been accompanied by the emergence of liver disease as a leading cause of death. Elevated liver enzymes may be due to HAART or to other risk factors, including hepatitis co-infection and alcohol use. The different components of HAART are each associated with different risks of liver toxicity. Most drugs are metabolized by cytochrome P450 enzymes in the liver, and this may be affected by liver disease. The mechanisms for drug-induced liver injury include dose-dependent toxicity, hypersensitivity reactions, idiosyncratic reactions, mitochondrial toxicity, and immune reconstitution. The diagnosis of drug-induced liver injury is exclusionary. Once diagnosed, management generally involves discontinuation of the offending drug(s). A number of studies in progress are investigating whether treatment of hepatitis co-infection can improve the tolerability of HAART.

HIV-Therapy Associated Lipodystrophy: Experimental and Clinical Evidence for the Pathogenesis and Treatment

The introduction of highly active antiretroviral therapy (HAART) including nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) has dramatically improved the morbidity and mortality in HIV-infected patients. Unfortunately, HAART has been associated with several side effects among which the development of lipodystrophy syndrome remains a major clinical issue. It is characterized by fat redistribution dominated by peripheral fat loss and complex metabolic alterations including dyslipidemia and insulin resistance. Dissection of the pathogenesis of the lipodystrophy syndrome is hampered by several factors: all HIV-patients receiving HAART have a chronic and often advanced illness with impact on metabolism and energy homeostasis. Secondly, almost all patients are receiving various combinations of drugs that simultaneously reduce viral replication and restore the immune system. Recently, more detailed clinical studies, experiments using animal models and in vitro systems have been successfully used to elucidate important pathogenic aspects. At the same time, partial reversion of fat loss and metabolic disturbances in HIV-patients could be achieved by omitting components of HAART or administration of metabolically active drugs. Here, we will summarize the current knowledge about the molecular alterations that are induced by antiretroviral therapy and possibly contribute to the lipodystrophy syndrome. Specific attention will be given to the role of NRTI and PI on adipocyte development, function, and mitochondrial integrity leading to fat loss, fat accumulation, and increase of serum lipids.

Reasons for discontinuation of nevirapine-containing HAART: results from an unselected population of a large clinical cohort

To evaluate the frequency of and predictive factors for nevirapine-based highly active antiretroviral therapy (HAART) discontinuation. All patients receiving nevirapine as a component of HAART at our centre were retrospectively evaluated for efficacy and tolerability. Logistic regression was used to evaluate the influence of baseline characteristics on the outcome and Kaplan-Meier (KM) estimates to evaluate time-dependent variables. Between January 1999 and June 2006, 582 patients (72% males) received 744 nevirapine-based HAART regimens. Naive patients counted for 83 of these regimens; of the remaining 661 regimens administered to experienced patients, 306 were failing virologically and 355 were undergoing simplification strategies. A once-a-day schedule was used in 136 patients. The likelihood of maintaining the nevirapine-based regimen was statistically (P < 0.0001 in both cases) influenced by the patient's status (mean KM estimate of 812 days for virological failures, 1294 for naive patients and 1657 for treatment simplifications) and by the dosing schedule (once-daily 1315 days; twice-daily 1198 days). The most frequent reason for treatment discontinuation was resistance (17.5%) followed by reduced tolerability (16.3%), patient's decision (14%) and treatment strategies such as structured treatment interruptions (13.8%). During 10.2% of treatments, a grade 3 or greater increase in aminotransferase levels was observed, reflecting an overall incidence rate equal to 5.3 cases per 100 person-years. This lead to treatment discontinuation in 3.9% of cases. Nevirapine, especially when used in simplification strategies, enables doctors to extend the use of HAART over a long period of time. The risk of drug-induced hepatotoxicity is low, but nevirapine should be used with caution in patients co-infected with hepatitis C virus or with elevated liver function tests. As with any decision to prescribe a drug, a careful evaluation of the potential risks and benefits of using nevirapine must be made for each individual.

Long-term effectiveness of highly active antiretroviral therapy (HAART) in perinatally HIV-infected children in Denmark

The long-term impact of highly active antiretroviral therapy (HAART) on HIV-1 infected children is not well known. The Danish Paediatric HIV Cohort Study includes all patients <16 y of age with HIV-1 infection in Denmark. We report the complete follow-up from 1996 to 2005 of 49 perinatally infected children treated with HAART. Initial HAART included 2 nucleoside reverse-transcriptase inhibitors in combination with either a protease inhibitor (n =38) or a non-nucleoside reverse-transcriptase inhibitor (n =12). 19 (39%) patients were previously treated with mono- or dual therapy. Baseline characteristics were median CD4 percentage 14% and HIV-RNA viral load 4.9 log(10). Within the first 12 weeks of therapy approximately 60% achieved HIV-RNA viral load <500 copies/ml, and this remained stable for up to 8 y, although many children changed the components of HAART. The proportion of children with CD4 percentage >25% increased to 60-70% over the y of treatment. For the total cohort, 245 patient-y of observation were available with only 1 death. During our observation period there were no signs of a waning impact. The challenge remains to maintain a high adherence to therapy as the children grow into adolescence and develop more independence from family and health care staff.