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PubMed2002

Interaction between levothyroxine and indinavir in a patient with HIV infection.

Drug interactions are an important and emerging problem in the treatment of HIV-infected patients. Protease inhibitors, like nonnucleoside reverse transcriptase inhibitors, are metabolized by the cytochrome P-450 enzyme system and each of these antiretroviral agents may interact with other drugs metabolized by this system. Some protease inhibitors may also interact with glucuronosyl transferase activity affecting plasma concentrations of drugs metabolized through this pathway. We describe a case of an HIV-infected patient, taking levothyroxine for hypothyroidism and clinically stable, who, after the introduction of an antiretroviral regimen containing indinavir, developed a pharmacological hyperthyroidism.

Adult↗
PubMed2005

Assessment of the safety and efficacy of poly-L-lactic acid for the treatment of HIV-associated facial lipoatrophy.

BACKGROUND: Lipodystrophy syndrome is uniquely associated with the use of highly active antiretroviral therapy (HAART) containing protease inhibitors or nucleoside reverse transcriptase inhibitors. Between 15% and 80% of patients on HAART develop facial lipoatrophy within 10 months of initiating therapy. At present, no ideal treatment strategies have emerged in spite of the psychosocial stress, resulting in depression and isolation in many HIV-infected patients. Most soft tissue fillers seem to be well tolerated; however, various reactions such as allergic reactions, infection, and inflammatory and allergic granulomatous nodules are possible. Poly-L-lactic acid (PLA; New-Fill, Biotech Industry SA, Luxembourg) is currently being used in Europe and is approved by the Food and Drug Administration (FDA) in the United States for soft tissue augmentation in HIV-associated facial lipoatrophy. OBJECTIVE: To determine the safety and efficacy of PLA for dermal enhancement of facial lipoatrophy in immuncompromised HIV-infected patients with prior use of HAART. METHODS: Sixty-one immunocompromised, HIV-infected male patients (52 whites, 7 African Americans, 1 Latino, and 1 Asian) underwent multiple treatment sessions with PLA over a 5-month period for facial lipoatrophy. The severity of facial lipoatrophy was assessed and photographs were taken at baseline and before each treatment session. Periodic monitoring for adverse reactions and degree of improvement were assessed by the patient, the treating physician, and a non-treating physician. RESULTS: At the 6-month follow-up, all 61 immunocompromised HIV patients had a successful outcome, defined as smoothing of the skin with less concavities or depressions, and improved overall appearance in an average of 3 treatment sessions. Although all patients were very pleased with their results, two patients developed persistent asymptomatic palpable intradermal papules in the infraorbital region as a result of the site of placement and concentration of PLA. On long-term follow-up (18 months), 48 of 61 (79%) required an average of 3 visits to achieve the desired enhancement and 13 of 61 (21%) patients requested additional treatment sessions beyond the initial 3 sessions. Although the patient and the physicians rated the level of improvement as "Excellent," the desire for further dermal enhancement was purely subjective. In general, the procedures were well tolerated without the clinical development of adverse reactions. CONCLUSION: The use of PLA to treat facial lipoatrophy resulted in significant and prolonged improvement in HIV-infected patients. The effect was long lasting, for up to 2 years in some patients, depending on when treatment was initiated. There were no reported cases of infection, allergies, or serious adverse reactions, and the treatment was well tolerated.

Adult↗
PubMed1996

Antiretroviral drugs for AIDS.

Treatment of HIV disease with antiretroviral agents has changed considerably. We now know that monotherapy is not the best strategy in most cases to combat rapid turnover of virus and development of resistance (the exception being mother-to-child transmission) and various combination drug regimens are being explored. Apart from the main drug groups, consisting of nucleoside analogues, proteinase inhibitors, and reverse-transcriptase inhibitors, many new compounds are under development. The timing of therapy may likewise be important, and the indications of benefit from early initiation of treatment need to be confirmed in randomised trials. Overall, there is far more optimism about the use of drugs in HIV infection than there was several years ago.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Biaryl acids: novel non-nucleoside inhibitors of HIV reverse transcriptase types 1 and 2.

A series of biaryl acids has been found to show micromolar inhibition of the HIV reverse transcriptase (RT) from types 1 and 2 with IC50S in the micromolar range. The series was discovered by consideration of the polymerase active site and sub-structure searching of the company compound collection. Synthesis of analogues to investigate the SAR is described. Two of these compounds have shown inhibition of HIV-2 RT only.

Anti-HIV Agents↗
PubMed2001

Long-term changes in adipose tissue in human disease.

Redistribution of white adipose tissue is a long-term symptom of several chronic diseases. Although the roles of adipocytes in acute illness have been thoroughly studied, how or why short-term responses of adipose tissue to disease sometimes produce long-term redistribution, and the causal relationship between the anatomical changes and the associated metabolic syndromes are poorly understood. The present paper reviews explanations for the redistribution of adipose tissue after infection with HIV, and in Crohn's disease; both conditions that share the peculiarity of selective expansion of certain adipose depots while others are depleted. HIV adipose tissue redistribution syndrome (HARS) develops gradually after several months of infection with the HIV both in untreated patients and in those taking protease inhibitors and nucleoside reverse transcriptase inhibitors. Some current theories about the causes of HARS are critically assessed, and reasons presented for implicating local interactions between the immune system and perinodal adipocytes. Some evolutionary aspects of conspicuous long-term changes in the distribution of human adipose tissue are discussed. Adipose tissue acts as a social signal, indicating dietary history and previous exposure to pathogens. A distinctive symptom of Crohn's disease is selective enlargement of the mesenteric adipose tissue near the diseased lymph nodes and intestine. Perinodal adipocytes have site-specific properties not found in adipocytes from nodeless depots, such as perirenal and epididymal, that may equip them to interact locally with lymph-node lymphoid cells, making polyunsaturated fatty acids selectively and rapidly available to activated immune cells. Studies of the time course of activation of perinodal adipocytes via the lymph nodes they enclose indicate that prolonged or frequent stimulation recruits more adipocytes to control by immune cells, which may lead to selective enlargement of node-containing depots. These concepts suggest hypotheses about HARS and the anomalous development of mesenteric adipose tissue in Crohn's disease that could form the basis for further investigations.

Adipose Tissue↗
PubMed2002

Position paper on therapeutic drug monitoring of antiretroviral agents.

Monitoring drug concentrations in humans to optimize efficacy and reduce toxicity is not a new concept in clinical pharmacology. It has been successfully applied to many different classes of drugs. As a result of considerable concentration and response data, the concept of therapeutic drug monitoring (TDM) has been expanded to certain antiretroviral compounds. In particular, protease inhibitors and nonnucleoside reverse transcriptase inhibitors may be viable candidates for TDM, and limited clinical trial data suggest monitoring plasma concentrations of these agents may indeed clinically benefit patients with HIV infection. A primary distinction between TDM of antiretroviral drugs compared with other drugs is that multiple agents are concomitantly used to treat HIV infection. As with all illnesses that require self-administered drug therapy, poor adherence is a major impediment to success. However, in the treatment of HIV infection, inadequate drug concentrations will result in the appearance or evolution of drug resistance mutations that can endanger present and future drug treatment options. Procedures for sample collection, cross-validation of analytical procedures, and interpretation of assay results should be standardized. More clinical data are needed to confirm this approach and methods of implementing TDM should be further explored. This position paper offers guidelines to aid clinicians who choose to incorporate TDM into the routine care of their patients.

Anti-HIV Agents↗
PubMed2002

Lipodystrophy syndrome in human immunodeficiency virus-infected children.

BACKGROUND: Lipodystrophy syndrome in HIV-infected adults is characterized by a variety of physical and/or metabolic abnormalities, including fat redistribution, hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) and peripheral insulin resistance. Many studies suggest that antiretroviral therapy is the underlying cause of the condition. Few data exist for HIV-infected children. METHODS: This is a cross-sectional study evaluating HIV-infected children age 2 to 16 years. Fat redistribution was identified by physical examination and parental questionnaire. Fasting blood analysis included cholesterol, triglycerides, high density lipoprotein, low density lipoprotein, glucose, insulin and C-peptide. RESULTS: Forty HIV-infected children were recruited. Seven children (18%) exhibited physical signs of fat redistribution. Twenty-seven (68%), 11 (28%) and 3 (8%) children exhibited evidence for hypercholesterolemia, hypertriglyceridemia and insulin resistance, respectively. Eleven children (28%) had no physical signs or laboratory evidence of lipodystrophy. Statistical analysis did not reveal any significant association between the presence of lipodystrophic features and patient age, HIV-1 viral load, exposure to specific antiretroviral medications or duration of protease inhibitor or nucleoside reverse transcriptase inhibitor therapy. Drug dosing was significantly associated with the development of lipodystrophy features. Children receiving pediatric dosing regimens vs. adult dosing regimens were less likely to develop lipodystrophy (P = 0.003). CONCLUSIONS: Features associated with lipodystrophy syndrome arise in some HIV-infected children. Subjects receiving pediatric dosing regimens were less likely than those receiving adult regimens to develop lipodystrophy.

Adolescent↗
PubMed2003

Virologic, immunologic, and clinical response to highly active antiretroviral therapy: the gender issue revisited.

BACKGROUND: Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis for patients with HIV. There is ongoing debate over a potential gender effect on patient outcome after HAART. METHODS: Individuals were from the EuroSIDA cohort, naive to protease inhibitors and nonnucleoside reverse transcriptase inhibitors, and had at least one viral load and CD4 measurement prior to starting HAART. Endpoints were virologic (time to <500 copies/mL, time to rebound [first of two consecutive viral loads >500 copies/mL]), immunologic (time to a 100/mm cell rise in CD4 count) and clinical (time to new AIDS and death). Hazard ratios (HR), derived using Cox regression models, compared female to male rates of achieving endpoints. RESULTS: Of 2547 patients, 20% (511) were female. Significantly more females than males were nonwhite (24% vs. 10%, p <.001). Males were older (median age 39 vs. 35 years, p <.0001), had lower CD4 counts (211 vs. 240/mm, p =.03), higher viral loads (4.6 vs. 4.4 log copies/mL, p <.0001), were more likely to have a history of AIDS (26% vs. 18%, p <.001) and were more likely to be treatment-naive (34% vs. 29%, p =.03). Adjusted HR for association between gender (comparing females with males) and the outcomes studied were as follows: for reaching <500 copies/mL 0.91 (0.81-1.03, p =.17), rebound 1.17 (0.95-1.44, p =.15), for 100 cell CD4 count rise 1.02 (0.88-1.14, p =.99), for progression to new AIDS 1.12 (0.73-1.71, p =.59) and for time to death 1.15 (0.69-1.92, p =.57). CONCLUSIONS: We found no significant evidence of a gender difference in virologic, immunologic, or clinical outcomes after starting HAART.

Adult↗
PubMed2006

Antiretroviral therapy and congenital abnormalities in infants born to HIV-1-infected women in the United Kingdom and Ireland, 1990 to 2003.

Antiretroviral therapy (ART) in pregnancy substantially reduces the risk of mother-to-child transmission of HIV, but concerns exist about the potential for teratogenic effects. This analysis was undertaken to explore the relation between ART in pregnancy and birth defects in infants born to HIV-infected women in the United Kingdom and Ireland between 1990 and 2003. Comprehensive obstetric and pediatric HIV surveillance is carried out through the National Study of HIV in Pregnancy and Childhood. Congenital abnormalities were reported in 101 of 3172 infants (100 of 3120 pregnancies). There was no statistically significant association between the prevalence of congenital abnormalities and exposure to ART overall: 3.4% (90 of 2657 pregnancies) in exposed pregnancies and 2.2% (10 of 463 pregnancies) in nonexposed pregnancies (P = 0.166); prevalence was similar whether or not exposure occurred in the first trimester: 3.7% (20 of 541 pregnancies) after early exposure and 3.1% (80 of 2579 pregnancies) without early exposure (P = 0.476). There was also no significant association with type of ART in early pregnancy (ie, highly active antiretroviral therapy [HAART] vs. mono- or dual therapy, HAART with protease inhibitor and/or nonnucleoside reverse transcriptase inhibitor). The lack of association was maintained after adjustment for potential confounding factors. These findings are reassuring, but continued monitoring is essential in view of the increasing number of women on therapy at conception and the likely continuing diversity of drug regimens.

Adolescent↗
PubMed2001

Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi's sarcoma treated with chemotherapy.

PURPOSE: Kaposi's sarcoma (KS) is the most common AIDS-related malignancy. Pulmonary involvement by KS (PKS) has carried a poor prognosis with median reported survival ranging from 3 to 10 months. We studied whether the introduction of highly active antiretroviral therapy (HAART; triple antiretroviral therapy including a protease inhibitor and two reverse transcriptase inhibitors) has been associated with improved survival for AIDS patients with PKS. PATIENTS AND METHODS: A retrospective study was performed of 37 consecutive patients with PKS and human immunodeficiency virus infection in the tumor registry at a large municipal hospital in New York City between 1994 to 1997. There were 16 patients from 1994 to 1995 (pre-HAART period) and 21 patients from 1996 to 1997 (post-HAART period). The primary end point was survival, which was defined as time from start of chemotherapy until death from any cause. RESULTS: Patients were analyzed by the date of diagnosis (pre- v post-HAART period) and whether or not they received HAART. Kaplan-Meier analysis showed significantly better survival in patients diagnosed in the post-HAART period (P =.0025). Additional Kaplan-Meier analysis indicated that patients on HAART had substantially better survival (P <.0001). Cox multivariate analyses showed that HAART therapy was associated with a reduced risk of death (hazard ratio = 0.09; 95% confidence interval, 0.03 to 0.69). CONCLUSION: In patients with AIDS-associated PKS and undergoing chemotherapy, administration of HAART was associated with increased survival.

Acquired Immunodeficiency Syndrome↗
PubMed2001

The metabolic toxicities of antiretroviral therapy.

Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities.

Anti-HIV Agents↗
PubMedDate not supplied

Evaluation of multiple failure time analyses of observational data in patients treated for HIV.

The development of protease inhibitors and nonnucleoside reverse transcriptase inhibitors has substantially increased the number of combinations available for multi-drug therapies in human immunodeficiency virus (HIV) infection. Unfortunately, all antiretroviral therapies lose efficacy over time or induce side effects, thus making secondary and tertiary alternatives necessary. With the multiplicity of multi-drug combination therapies, the challenge is to determine which multi-drug combination to use as initial therapy and which to use as subsequent therapy to maximize survival. No standard methodologic approach has been developed to answer this question within the context of observational clinical HIV data. We demonstrate the use of semi-parametric models employing repeated, multiple failure time analysis to compare the relative efficacy of treatments containing zidovudine, stavudine, or other multi-drug combinations for patients in the CHORUS (Collaborations in HIV Outcomes Research - US) database.

Anti-HIV Agents↗
PubMed1999

Significant interactions with new antiretrovirals and psychotropic drugs.

OBJECTIVE: To provide an update on relevant antiretroviral interactions and psychotropic medications for healthcare practitioners managing complex HIV-related pharmacotherapy. DATA SOURCES: Information was retrieved via a MEDLINE search (January 1966-September 1998) using MeSH headings human immunodeficiency virus, drug interactions, psychiatry, psychotropics, psychiatric illness, and names of medications commonly prescribed for the management of HIV infection. Abstracts of international and national conferences (until February 1999), review articles, textbooks, and references of all articles also were searched. STUDY SELECTION AND DATA EXTRACTION: Literature on pharmacokinetic interactions was considered for inclusion. Pertinent information was selected and summarized for discussion. In the absence of specific data, pharmacokinetic and pharmacodynamic properties were considered in order to predict the likelihood of potential drug interactions. DATA SYNTHESIS: All protease inhibitors and nonnucleoside reverse transcriptase inhibitors are substrates of the cytochrome P450 system and possess enzyme-inhibiting and/or -inducing properties. Psychotropic medications also possess similar metabolic characteristics and may interact with antiretrovirals. Modifications in drug selection, dose, or dosing regimen may be needed to ensure adequate antiretroviral concentrations and thus minimize the risk of incomplete viral suppression and/or development of drug resistance. In the absence of specific data, consideration of metabolic characteristics may assist practitioners in predicting the likelihood of possible interactions. RESULTS: The incidence and implications of antiretroviral drug interactions are reviewed. Practical management strategies are also discussed. Comprehensive tables on clinically significant interactions with antiretroviral combinations and with psychiatric medications are provided. CONCLUSIONS: Given the increasing use of multiple-drug therapy, the potential for drug interactions is extremely high. Drug interactions may lead to undesirable outcomes including subtherapeutic drug concentrations and risk of antiretroviral resistance. Practitioners need to consider pharmacokinetic, pharmacologic, therapeutic, and adherence factors when managing interactions with complex antiretroviral therapy.

Antipsychotic Agents↗
PubMed2002

The changing pattern of bronchoscopy in an HIV-infected population.

STUDY OBJECTIVE: s: Little information exists on the impact of antiretroviral therapies (ARTs) on HIV-related bronchoscopic activity. This study was performed to identify any changes to our pattern of use of bronchoscopy over the last decade, and how this might relate to the introduction of more effective ARTs to our center in 1996. DESIGN: Retrospective data analysis. SETTING: Academic medical center. PATIENTS: HIV-positive patients attending the clinic. METHODS: Basic demographic details and bronchoscopy status were collected and compared for all patients with HIV attending our center between 1989 and 1998. Poisson regression analysis was performed to more formally identify the risk factors for bronchoscopy. Individual case notes and bronchoscopic findings were also examined for all patients undergoing bronchoscopy in 1990, 1995, and 1998. RESULTS: From 1996 to 1998, bronchoscopic rates fell dramatically by 60% (p < 0.0001) despite a linear increase in patients receiving follow-up. Prior use of protease inhibitor (PI)/nonnucleoside reverse transcriptase inhibitor (NNRTI) combinations was significantly associated with a decreased risk of bronchoscopy even after adjusting for CD4 counts. Indications for bronchoscopy and diagnostic yield remained relatively stable in 1990, 1995, and 1998, although rates of pulmonary infection (Pneumocystis carinii pneumonia, bacteria, and virus) requiring bronchoscopy among our HIV population fell significantly from 1990 to 1998. CONCLUSION: Improvements in HIV health care are having a dramatic impact on the rates of certain pulmonary infections requiring bronchoscopy. Of these, the introduction of more effective ARTs to our service in 1996 seems most closely related to the temporal decline in bronchoscopy. PI/NNRTI combinations may have additional protective effects to their recognized action on CD4 counts.

AIDS-Related Opportunistic Infections↗
PubMed2003

Outcomes of dual-protease inhibitor salvage therapy in human immunodeficiency virus-infected patients referred to a telephone consultation service.

OBJECTIVE: To determine the clinical outcomes of dual-protease inhibitor salvage therapy in heavily experienced patients after their providers consulted the National HIV Telephone Consultation Service (Warmline, 800-933-3413). DESIGN: Observational survey study. SETTING: Consultation service for United States health care providers. PATIENTS: Thirty-one human immunodeficiency virus (HIV)-infected patients who had received previous treatment with at least two protease inhibitor--or nonnucleoside reverse transcriptase inhibitor--based regimens and had a viral load of at least 1000 copies/ml. INTERVENTION: Patients whose providers consulted Warmline regarding antiretroviral salvage regimens were identified through a review of telephone calls from January-July 2001. Virologic and immunologic outcomes were determined for patients who had received a regimen containing either ritonavir and indinavir or ritonavir and amprenavir. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were percentages of patients with a viral load less than 500 copies/ml at 3 and 6 months and changes in log10 viral load and CD4+ cell count at 3 and 6 months compared with baseline values. By using intent-to-treat analysis, a viral load less than 500 copies/ml was achieved in 35% of the 31 patients at 3 months and in 32% of them at 6 months. By using as-treated analysis, this outcome was achieved in 48% of 23 patients who continued therapy at 3 months and in 59% of 17 patients who continued therapy at 6 months. At 3 months (23 patients) and 6 months (17 patients), respectively, changes in viral load were -1.7 log10 copies/ml (p<0.001) and -1.4 log10 copies/ml (p<0.001), and changes in CD4+ cell count were +99 cells/mm3 (p<0.001) and +95 mm3 (p=0.012), compared with baseline. CONCLUSION: Significant improvements in virologic and immunologic markers occurred in patients heavily experienced with antiretroviral therapy after starting dual-protease inhibitor treatment regimens. Salvage therapy guided by Warmline consultation appears to be beneficial for this patient population with limited treatment options.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Proteolytic events of HIV-1 replication as targets for therapeutic intervention.

Acquired immunodeficiency syndrome (AIDS) is a worldwide epidemic caused by infection with HIV, a human retrovirus. Proteolysis occurs at many points of the retroviral life-cycle, and these events can be considered as targets for chemotherapy. The most well-known proteolytic action in the retroviral life-cycle is the processing of the Gag and Gag-Pro-Pol polyproteins with the virally encoded protease at the late phase of viral infection. Protease inhibitors, together with reverse transcriptase inhibitors, are important components of the drug combinations currently used to treat HIV patients. The current combination therapy substantially reduced morbidity and mortality in HIV-infected patients. However, these drugs do not allow viral eradication, therefore their long-term use is required, allowing the development of resistance in a large portion of patients. Furthermore, several adverse metabolic side effects have been observed associated with the therapy. Thus, new approaches are required to eradicate HIV infection, which may include targeting of the potential early-phase function of the viral protease, and other crucial proteolytic events of the viral replication, such as the ubiquitin-dependent proteolytic degradation of the unfolded viral proteins as well as the inhibition of envelope protein processing.

Anti-HIV Agents↗