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BACKGROUND: Features of the dyslipidemic pattern reported with the use of antiretroviral therapy predict enhanced postprandial lipemia, which is an emerging cardiovascular disease risk factor. OBJECTIVE: We evaluated the postprandial response to a physiologic, meal-based challenge in HIV-positive subjects without hyperlipidemia. DESIGN: We measured hourly lipid, lipoprotein, glucose, and insulin concentrations during a 13-h period in 25 nonwhite patients (13 women, 12 men): 13 receiving a protease inhibitor (PI)-based regimen (6 nelfinavir and 7 indinavir) and 12 receiving a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen (6 efavirenz and 6 nevirapine). RESULTS: Mean fasting HDL-cholesterol concentrations were lower in HIV patients than in healthy subjects without HIV infection matched for age, sex, and ethnicity (z score: -0.81 +/- 0.9; P = 0.0001). Fasting triacylglycerol concentrations were not significantly different between HIV-infected patients and healthy subjects but were higher in PI-treated than in NNRTI-treated patients [median (interquartile range): 144 (110-191) and 89 (62-135) mg/dL; P = 0.007]. Average daylong triacylglycerol concentrations, but not incremental concentrations, were higher in the PI group than in the NNRTI group [205% (185-248%) and 125% (78-191%); P < 0.05]. For all HIV-positive patients, the fractional triacylglycerol increase was lower after breakfast than after lunch (20 +/- 18% and 42 +/- 40%, respectively; P < 0.04). Insulin concentrations were higher in PI-treated than in NNRTI-treated patients [22.6 (13.1-29.8) and 11.8 (7.1-19.1) microU/mL; P = 0.01] and increased in both groups in response to each meal, whereas glucose concentrations increased only after breakfast. CONCLUSIONS: Despite baseline differences, incremental triacylglycerol and insulin responses to a physiologic caloric load among HIV-positive patients were not significantly affected by differences in the type of antiretroviral therapy.
Along with nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive and important place in the treatment of HIV-1 infections, and are in rapid development. These compounds can be grouped into two classes: the first generation NNRTIs, mainly discovered by random screening, and the second generation NNRTIs, developed as a result of comprehensive strategies involving molecular modelling, rationale-based drug synthesis, biological and pharmacokinetic evaluations. The recent boom of NNRTIs is mainly due to their antiviral potency, high specificity and low toxicity. The rapid emergence of drug-resistant HIV-1 strains induced by the first generation drugs is a disadvantage bypassed, in part, by the broad spectrum second generation NNRTIs. Starting from the first generation, this review will focus on the second generation NNRTIs dealing with the recent and most interesting published results, highlighting the guidelines for the development of a third generation of NNRTIs.
STUDY OBJECTIVE: To assess the risk of acute pancreatitis in patients receiving various combinations of protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of human immunodeficiency virus (HIV) infection. DESIGN: Retrospective cohort study. DATA SOURCE: Ohio Medicaid claims database, January 1997-December 2002. PATIENTS: Four thousand nine hundred seventy-two patients with HIV infection who had received at least one antiretroviral drug. MEASUREMENTS AND MAIN RESULTS: Three combination regimens were evaluated: didanosine plus other antiretroviral agents, protease inhibitors plus NRTIs or NNRTIs, and NRTI combinations (no didanosine) or NRTIs plus NNRTIs. We used Cox proportional hazard regression and Kaplan-Meier plots to examine the risk for acute pancreatitis. We identified 159 (3.2%) cases of acute pancreatitis during the study period. For patients who were newly treated for HIV, the incidence of acute pancreatitis was 1.95/100 person-years. Half of these cases developed within 500 days of the start of drug therapy. Hazard ratios (HRs) for acute pancreatitis were 39-54% higher for nonwhite patients than Caucasians and 240-290% higher for symptomatic versus nonsymptomatic patients. Hazard ratios also were significantly associated with increased age, liver injuries (HR 2.94, 6.73), and cardiovascular diseases (HR 1.68, 2.36), respectively, for both newly treated and previously diagnosed patients with HIV. The risk for patients receiving either protease inhibitors plus an NRTI or an NNRTI, or NRTI plus NNRTI combinations was not significantly different from the risk associated with didanosine combination therapy (p>0.10). CONCLUSION: The risk of acute pancreatitis was significantly associated with age, race, symptomatic HIV infection, and liver and cardiovascular diseases. However, risk did not differ significantly among patients with different antiretroviral regimens. Our results can be used by the medical community to enhance patient safety and minimize costly adverse drug reactions among patients with HIV infection.
In the last years significant advances in the knowledge of all aspects of HIV infection have happened. It is especially important that the new kinds of treatment against the virus have substantially improved the prognosis of the infection. The available antiretrovirals belong to three groups: nucleoside reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors, and protease inhibitors. We review the characteristics of the most recently developed drugs.
OBJECTIVES: The objective of the study was to investigate change in bone mineral density (BMD) over time in HIV-infected women in comparison with healthy control subjects similar in age, race, and body mass index (BMI). DESIGN: This was a prospective cohort study. METHODS: BMD was measured by dual-energy x-ray absorptiometry in 100 HIV-infected females and 100 healthy controls similar in age (41 +/- 1 vs. 41 +/- 1 yr, P = 0.57), BMI (26.1 +/- 0.5 vs. 27.2 +/- 0.4 kg/m(2), P = 0.12), and race (60 vs. 65% non-Caucasian, P = 0.47, HIV-infected vs. controls). Changes in BMD were determined every 6 months over 24 months. RESULTS: At baseline, HIV-infected subjects had lower BMD at the lumbar spine (1.01 +/- 0.01 vs. 1.07 +/- 0.01 g/cm(2), P = 0.001), hip (0.94 +/- 0.01 vs. 0.98 +/- 0.01 g/cm(2), P = 0.02), and femoral neck (0.83 +/- 0.01 vs. 0.87 +/- 0.01 g/cm(2), P = 0.02). Historical low weight, duration of nucleoside reverse transcriptase inhibitor use, and FSH were significantly associated with lumbar BMD, whereas duration of HIV, BMI, historical low weight, smoking pack-years, N-telopeptide of type 1 collagen, viral load, 25 hydroxyvitamin D, and osteocalcin were associated with hip BMD at baseline. In mixed model longitudinal analyses, BMD remained lower in HIV-infected subjects than in controls over 24 months of follow-up (P = 0.001 for the spine, P = 0.04 for the hip, and P = 0.02 for the femoral neck). These differences remained significant controlling for age, race, BMI, and menstrual function. In contrast, rates of change for the spine (P = 0.79), hip (P = 0.44), and femoral neck (P = 0.34) were not different between the HIV and control groups over 2 yr. In the HIV group, longitudinal changes in BMD were not associated with current protease inhibitor, nucleoside reverse transcriptase inhibitor, or non-nucleoside reverse transcriptase inhibitor use but were associated with CD4 count, weight, FSH, N-telopeptide of type 1 collagen, and baseline BMD. CONCLUSIONS: BMD is reduced at the spine, hip, and femoral neck among women with HIV in relationship to low weight, duration of HIV, smoking, and increased bone turnover. Over 2 yr of follow-up, BMD remained stable but lower in HIV-infected women, compared with control subjects.
Clinicians design antiretroviral therapy to prevent HIV-1 replication and resistance, and researchers study antiretroviral concentrations to understand the pharmacokinetics of these drugs. Because drug efficacy and toxicity varies widely between patients receiving the same antiretroviral therapy, there is interest in monitoring individual patient concentrations of antiretroviral drugs. Good science and effective medical care demand inexpensive validated methods with high throughput that are capable of simultaneously analyzing multiple antiretroviral drugs in various matrices. Currently, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and nucleoside reverse transcriptase inhibitors are used to treat HIV-1 infection. This review summarizes published methods for the quantitation of nucleoside reverse transcriptase inhibitors and their metabolites in different matrices using immunoassays, ultraviolet absorption, and mass spectrometry.
BACKGROUND: The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA. METHODS: We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients). Eligible patients were randomly assigned to receive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661. RESULTS: Both L-697,661 and zidovudine were well tolerated. Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine. Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels. However, this response virtually disappeared after six weeks in some patients receiving L-697,661, coincidently with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene. CONCLUSIONS: L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.
Human immunodeficiency virus type 1 (HIV-1) isolates from 50 plasma specimens were analyzed for phenotypic susceptibility to licensed reverse transcriptase inhibitors and protease inhibitors by the Antivirogram and PhenoSense HIV assays. Twenty of these specimens were from recently seroconverted drug-naïve persons, and 30 were from patients who were the sources of occupational exposures to HIV-1; 16 of the specimens in the latter group were from drug-experienced patients. The phenotypic results of the Antivirogram and PhenoSense HIV assays were categorized as sensitive or reduced susceptibility on the basis of the cutoff values established by the manufacturers of each assay. Data for 12 to 15 drugs were available by both assays for 38 specimens and represented a total of 529 pairs of results. The two data sets had a 91.5% concordance by phenotypic category. The discordant results (n = 45) were distributed randomly among 26 specimens and included 28 results (62.2%) which were within a twofold difference of the assay cutoff values. None of the discordant results were associated with primary resistance mutations that predicted high-level (>20-fold) resistance. Discordant results were distributed equally among specimens from drug-experienced and drug-naïve individuals and were slightly higher for protease inhibitors than for nonnucleoside reverse transcriptase inhibitors or nucleoside reverse transcriptase inhibitors. The findings of the present study demonstrate that the results of the Antivirogram and PhenoSense HIV assays correlate well, despite the use of different testing strategies.
Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far.
OBJECTIVE: To assess the antiviral efficacy, safety, and adherence in subjects who switched to Trizivir following long-term HIV-1 RNA suppression. STUDY DESIGN: A randomized, open-label, multicentre, 48-week comparative study in subjects who have received two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or an nonnucleoside reverse transcriptase inhibitor or three nucleoside reverse transcriptase inhibitors for at least 6 months, with a history of undetectable plasma HIV-1 RNA since initiation of therapy and plasma viral load of < 50 HIV-1 RNA copies/mL at screening. METHODS: Subjects were randomized 1:1 to continue their current treatment or to switch to a simplified treatment with Trizivir administered twice daily. Assessments included plasma HIV-1 RNA, lymphocyte counts, clinical laboratory evaluations, adverse events, and adherence to treatment (obtained via subject self-report). Treatment failure was defined as a plasma viral load of >/= 400 HIV-1 RNA copies/mL on two consecutive occasions or premature discontinuation of randomized treatment. RESULTS: At week 48, the proportion of treatment failures in Trizivir arm (23/106, 22%) was noninferior to that observed in continued arm (23/103, 22%) with a treatment difference stratified by prior ART of 1.2%[-10.1; 12.5]. Incidence of adverse events was similar in both treatment groups. The incidence of possible hypersensitivity reaction in the Trizivir trade mark arm was 10%. Significant reductions in cholesterol and triglyceride plasma levels were observed in the Trizivir arm (P < 0.001 and P = 0.006, respectively). CONCLUSION: Switching to Trizivir offers a potent and simplified regimen with equivalent efficacy and significant improvement in lipid abnormalities compared to continued triple therapy.
The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.
(1) First-line antiretroviral combinations generally include, in addition to a protease inhibitor or a non nucleoside reverse transcriptase inhibitor, two nucleoside reverse transcriptase inhibitors, namely zidovudine + didanosine, stavudine + lamivudine, or zidovudine + lamivudine. (2) Tenofovir disoproxil (referred to simply as tenofovir below) is a nucleotide HIV reverse transcriptase inhibitor. Previously recommended for second-line treatment in case of virological failure, it is now approved for first-line therapy in adults. (3) This licence extension is based on a double-blind trial comparing tenofovir + lamivudine + efavirenz with stavudine + lamivudine + efavirenz in 602 patients. After 96 weeks, three-quarters of patients had undetectable viral load (<50 copies/ml), and there was no statistically significant difference among the groups. (4) The number of serious adverse effects was similar in the two groups. Relative to the stavudine combinations, there were fewer reports of lipodystrophy (1% versus 12%), fewer peripheral neuropathies (3% versus 10%) and fewer prescriptions of lipid-lowering therapy (2% versus 10%) among patients taking tenofovir. Tenofovir seemed to have a worse effect on renal function and bone metabolism, however. (5) Tenofovir is taken only once a day, but so are didanosine and lamivudine. (6) In practice, there is not yet enough evidence to support the routine use of tenofovir in first-line antiretroviral combinations. Tenofovir is, however, an interesting alternative when stavudine is poorly tolerated.
We have tested for combined anti-HIV-1 effects of a hammerhead ribozyme and antiretroviral drugs and the possibility of reducing the drug burden of patients on highly active antiretroviral therapy (HAART). The antiretroviral compounds used represent the three groups in HAART: nucleoside analogue reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors. A human T cell line (HUT78), stably expressing a hammerhead ribozyme targeted to nef (hhRz.nef(9016-9029)), was infected with HIV-1(SF2) in the presence of a single drug. The combined effects on HIV-1 replication were measured by p24 antigen determinations over a 2-week period. In the presence of the ribozyme, smaller amounts of antiretroviral drugs were required to reduce the HIV-1 p24 levels equally as much as when only drugs were present. The results support a strategy of combining ribozyme gene therapy with HAART to improve the long-term outcome of anti-HIV-1 therapy.
Resistance testing for treatment-naïve, recently HIV-infected persons is not currently recommended; its clinical value will depend on the prevalence of resistance-associated mutations among recently infected persons. To estimate this prevalence, specimens were collected during 1997-1999 in Seattle and Los Angeles from drug-naïve, recently HIV-infected persons. HIV-1 protease and reverse transcriptase (RT) RNA sequences were amplified from plasma by RT-polymerase chain reaction (RT-PCR), sequenced, and analysed. Of 69 patients, five (7%) had resistance-associated mutations: three (4%) had primary mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI) or non-nucleoside-RTIs, and three patients (4%) had secondary NRTI mutations. No primary mutation associated with resistance to protease inhibitors was observed. Mean age of the five persons with resistance-associated mutations (38 years) was higher than that of the 64 persons without resistance-associated mutations (31 years, P=0.04). The findings suggest that the prevalence of resistance-associated mutations among persons recently infected with HIV in these cities is low.
For AIDS therapy, there are currently a number of compounds available for multiple targets already approved by the FDA and in clinic, e.g. protease inhibitors, reverse transcriptase inhibitors (NRTI, NNRTI), fusion inhibitors, CCR4, CCR5 among others. Some pharmaceuticals act against the virus before the entrance of HIV into the host cells. One of these targets is the glucosidase protein. This novel fusion target has been recently explored because the synthesis of viral glycoproteins depends on the activity of enzymes, such as glucosidase and transferase, for the elaboration of the polysaccharides. In this work we have built an homology model of Saccharomyces cerevisiae glucosidase and superimposed all relevant glucosidase-like enzymes in complex with carbohydrates, and calculated as well molecular interaction fields in our S. cerevisiae active site model. Our results suggest that there are two saccharide binding sites which are the most important for the binding of inhibitors with this family of enzymes which supports the possibility of inhibitors containing only two sugar units. Based on these results, we have proposed a novel pseudo-dissacharide which is a potential pharmaceutical for AIDS treatment.
The beneficial effects of antiretroviral therapy (ART) for the treatment of HIV disease have been accompanied by metabolic changes associated with an increased risk of cardiovascular disease. These changes, which include dyslipidemia, change in body fat distribution, and insulin resistance, resemble the symptoms of metabolic syndrome. Protease inhibitors, nucleoside analogue reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors have all been associated with dyslipidemia to varying degrees. In addition, patients on ART show an increased risk of myocardial infarction and other cardiovascular events. According to the recommendations of the National Cholesterol Education Program and the Adult AIDS Clinical Trial Group, health care providers should assess cardiovascular risk before starting ART and then continue to monitor lipid levels. Treatment of ART-associated dyslipidemia should follow the following sequence: therapeutic lifestyle changes, lipid-lowering drug therapy, and finally, modifying ART if necessary. By providing education, support, and follow-up care, nurse practitioners can help to implement these steps.
BACKGROUND: Patients who are human immunodeficiency virus (HIV) positive are predisposed to the development of infections including tinea pedis and onychomycosis. While smaller studies have been reported, there has been no large study evaluating the prevalence of onychomycosis in HIV-positive individuals, or comparing the development of onychomycosis in a typical temperate area with that in a typical tropical area. METHODS: HIV-positive individuals were evaluated at five clinics: four in Ontario, Canada and one in Sao Paulo, Brazil. The subjects were asked questions to determine the epidemiology of onychomycosis in HIV-positive individuals. The feet were examined and nail material was obtained for mycologic examination to determine the causative organism of onychomycosis. RESULTS: A total of 500 subjects were examined (415 men and 85 women; age (mean +/- SE), 39 +/- 0.4 years; 400 Canadian, 100 Brazilian). The racial origins of the Canadian patients were: Caucasian, 83.8%; Asian, 4.3%; African-American, 8.1%; Hispanic, 3.3%; American Indian, 0.3%. The Brazilian origins were: Caucasian, 68.7%; African, 18.1%; mixed race, 13.3%. Abnormal appearing nails and mycologic evidence of onychomycosis were present in 200 (40.0%) and 116 (23.2%), respectively, of 500 subjects. The prevalence of onychomycosis in the Canadian and Brazilian samples was 24.0% (96 of 400) and 20.0% (20 of 100), respectively. The projected prevalence of onychomycosis in HIV-positive individuals in Canada was 19.9% (95% CI: 16.0-23.9%) after taking into account the age and sex distribution of HIV-positive individuals in the population. When nails appeared clinically abnormal, the prevalence of onychomycosis was 50.5% (Canada, 51.3%; Brazil, 45.5%). For comparison, published data indicate that the prevalence of onychomycosis in immunocompetent individuals living in Canada is 6.9%. The clinical presentation of onychomycosis for the whole sample (n=500) was: distal and lateral subungual onychomycosis (DLSO), 20.0%; white superficial onychomycosis (WSO), 3.6%; proximal subungual onychomycosis (PSO), 1.8% (Canadian and Brazilian samples: DLSO 21.2% vs. 15.0%, WSO 3.3% vs. 5.0%, and PSO 1.5% vs. 3.0%). The distribution of the causative fungal organisms was: dermatophytes: Candida species: nondermatophyte molds, 73:2:2 (Canadian and Brazilian samples: dermatophytes 95.5% vs. 90.9%, Candida species 3.0% vs. 0%, and nondermatophyte molds 1.5% vs. 9.0%). The use of protease inhibitors, reverse transcriptase inhibitors, or oral antifungal agents did not make a significant difference in the prevalence of onychomycosis for both the Canadian and Brazilian groups. Patients with onychomycosis were aware of their abnormal appearing nails (chi2(1)=69.7, P<0.001), embarrassed by the appearance of their nails (chi2(1)=29.7, P<0.001), and took measures to hide their nails from other individuals. A higher proportion of individuals with onychomycosis experienced discomfort compared with those without the disease (chi2(1)=9.0, P=0.003). Also, individuals who experienced pain in the nail unit were more likely to have onychomycosis (risk odds ratio (ROR), 2.2; 95% CI: 1.0-4.7, P=0.05). CONCLUSIONS: The prevalence of onychomycosis in HIV-positive individuals in the sample of 500 patients was 23.2%. In the Canadian (n=400) and Brazilian (n=100) samples, the corresponding figures were 24% and 20%, respectively, with the predominant causative organisms being dermatophytes. The projected prevalence of onychomycosis in HIV-positive Canadians is 19.9%. Predisposing factors include a CD4 count of approximately 370, a positive family history of onychomycosis, a history of tinea pedis, and walking barefoot around pools. Onychomycosis can be symptomatic, a source of embarrassment, and a potential cause of morbidity.