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Antiretroviral Drugs (antiretroviral + drug)
Selected AbstractsAIDS and Antiretroviral Drugs in South Africa: Public Health, Politics, and Individual Suffering: A Review of Brian Tilley's It's My LifeTHE JOURNAL OF LAW, MEDICINE & ETHICS, Issue 1 2003Barbara A. Noah First page of article [source] New drug combinations for the treatment of murine AIDS and macrophage protectionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2001A. Fraternale The failure of highly active antiretroviral therapies (HAART) is mainly due to the existence of latent infected reservoirs, such as macrophages and resting CD4+ T cells. In this paper, we report the results that we obtained in a murine model of AIDS by alternating the administration of the lympholitic drug 2-Fluoro-ara-AMP (Fludarabine) to eliminate the infected cells, with that of Azidothymidine (AZT) plus reduced glutathione (GSH) encapsulated in erythrocytes, to protect lymphocytes and macrophages not yet infected, respectively. Two groups of infected mice were treated as follows: one group was treated by alternating the administration of Fludarabine and AZT (treatment A), while the other group received the same treatment plus GSH-loaded erythrocytes given with AZT (treatment A + L,RBC). Fludarabine was administered intraperitoneally, AZT in the drinking water and GSH was encapsulated in erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. The results obtained show that GSH-loaded erythrocytes provide additive effects in all the parameters examined. Alternation of a lympholitic drug and antiretroviral drug is effective in reducing the progression of murine AIDS. Addition of a system to protect macrophages provides additive effects in almost all the parameters considered, confirming that combination therapies aimed at protecting different infectable cell compartments are better than treatments protecting mainly lymphocytes. [source] Prevalence and risk factors associated with antiretroviral resistance in HIV-1-infected childrenJOURNAL OF MEDICAL VIROLOGY, Issue 9 2007Constance Delaugerre Abstract In the USA and West Europe, nearly 80% of HIV-1-infected adults, experiencing virologic failure, harbored virus strain resistant to at least one antiretroviral drug. Limited data are available on antiretroviral drug resistance in pediatric HIV infection. The aims of this study were to analyze prevalence of HIV-1 drug resistance and to identify risk factors associated with resistance in this population. Prevalence of genotypic resistance was estimated retrospectively in treated children who experienced virologic failure (with HIV-1-RNA,>,500 copies/ml) followed in Necker hospital between 2001 and 2003. Among 119 children with resistance testing, prevalence of resistance to any drug was 82.4%. Resistance ranged from 76.5% to nucleoside reverse transcriptase inhibitor (NRTI), to 48.7% to non-nucleoside reverse transcriptase inhibitor (NNRTI) and 42.9% to protease inhibitor (PI). Resistance to at least one drug of two classes and three classes (triple resistance) was 31.9 and 26.9%, respectively. Resistance was not associated with geographic origin, HIV-1 subtype, and CDC status. In multivariate analysis, resistance to any drug remained associated independently with current low viral load and high lifetime number of past PI. Triple resistance was independently associated with the high lifetime number of past PI and with gender, particularly among children aged 11 years old or more with a prevalence seven times higher in boys than in girls. In conclusion, antiretroviral resistance is common among treated HIV-1-infected children and prevalence was similar with those observed in adult population in the same year period. However, adolescent boys seem to be at greater risk. J. Med. Virol. 79:1261,1269, 2007. © Wiley-Liss, Inc. [source] Therapy of HIV infectionDERMATOLOGIC THERAPY, Issue 6 2004Yuchi C. Chang ABSTRACT:, HIV is a devastating disease caused by the human immunodeficiency virus. Symptoms of illness can manifest in every organ system, including the skin. Although there is no definitive cure, the creation of antiretroviral drugs and aggressive treatment regimens have dramatically altered disease morbidity and mortality. However, the precise drug selection is often difficult and intimidating given the sheer abundance of drug therapies available. In this article, the HIV disease course is reviewed and different classes of antiretroviral medications are presented with emphasis on initial drug regimens, potential adverse effects, particularly those of dermatologic nature, possible drug interactions, patient compliance, and the emergence of drug resistance. [source] Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3,-azido-3,-deoxythymidine and 2,,3,-dideoxyinosine,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2002Quanxin Meng Abstract Combinations of antiretroviral drugs that include nucleoside reverse transcriptase inhibitors (NRTIs) are superior to single-agent regimens in treating or preventing HIV infection, but the potential long-term health hazards of these treatments in humans are uncertain. In earlier studies, our group found that coexposure of TK6 human lymphoblastoid cells to 3,-azido-2,,3,-dideoxythymidine (AZT) and 2,,3,-dideoxyinosine (ddI), the first two NRTIs approved by the FDA as antiretroviral drugs, produced multiplicative synergistic enhancement of DNA incorporation of AZT and mutagenic responses in both the HPRT and TK reporter genes, as compared with single-drug exposures (Meng Q et al. [2000a]: Proc Natl Acad Sci USA 97:12667,12671). The purpose of the current study was to characterize the mutational specificity of equimolar mixtures of 100 ,M or 300 ,M AZT + ddI at the HPRT and TK loci of exposed cells vs. unexposed control cells, and to compare the resulting mutational spectra data to those previously found in cells exposed to AZT alone (Sussman H et al. [1999]: Mutat Res 429:249,259; Meng Q et al. [2000b]: Toxicol Sci 54:322,329). Molecular analyses of HPRT mutant clones were performed by reverse transcription,mediated production of cDNA, PCR amplification, and cDNA sequencing to define small DNA alterations, followed by multiplex PCR amplification of genomic DNA to define the fractions of deletion events. TK mutants with complete gene deletions were distinguished by Southern blot analysis. The observed HPRT mutational categories included point mutations, microinsertions/microdeletions, splicing-error mutations, and macrodeletions including partial and complete gene deletions. The only significant difference or shift in the mutational spectra for NRTI-treated cells vs. control cells was the increase in the frequency of complete TK gene deletions following exposures (for 3 days) to 300 ,M AZT,ddI (P = 0.034, chi-square test of homogeneity); however, statistical analyses comparing the observed mutant fraction values (measured mutant frequency × percent of a class of mutation) between control and NRTI-treated cells for each class of mutation showed that the occurrences of complete gene deletions of both HPRT and TK were significantly elevated over background values (0.34 × 10,6 in HPRT and 6.0 × 10,6 in TK) at exposure levels of 100 ,M AZT,ddI (i.e., 1.94 × 10,6 in HPRT and 18.6 × 10,6 in TK) and 300 ,M AZT,ddI (i.e., 5.6 × 10,6 in HPRT and 34.6 × 10,6 in TK) (P < 0.05, Mann,Whitney U -statistic). These treatment-related increases in complete gene deletions were consistent with the spectra data for AZT alone (ibid.) and with the known mode of action of AZT and ddI as DNA chain terminators. In addition, cotreatments of ddI with AZT led to substantial absolute increases in the mutant fraction of other classes of mutations, unlike cells exposed solely to AZT [e.g., the frequency of point mutations among HPRT mutants was significantly increased by 130 and 323% over the background value (4.25 × 10,6) in cells exposed to 100 and 300 ,M AZT,ddI, respectively]. These results indicate that, at the same time that AZT,ddI potentiates therapeutic or prophylactic efficacy, the use of a second NRTI with AZT may confer a greater cancer risk, characterized by a spectrum of mutations that deviates from that produced solely by AZT. Environ. Mol. Mutagen. 39:282,295, 2002. Published 2002 Wiley-Liss, Inc. [source] Impact of nevirapine or efavirenz co-administration on ritonavir-boosted amprenavir pharmacokinetics in HIV-infected patientsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2008Eric Dailly Abstract The influence of nevirapine or efavirenz co-administration on ritonavir-boosted amprenavir pharmacokinetics was investigated in HIV-infected patients with a population pharmacokinetic approach. The analysis was performed with a population of 61 patients treated with fosamprenavir/ritonavir (700 mg/100 mg twice daily) combined with nucleoside/nucleotide reverse transcriptase inhibitors ± enfuvirtide and no other antiretroviral drugs (group A, n = 46) or nevirapine (group B, n = 10) or efavirenz (group C, n = 5). No significant increase in amprenavir clearance [mean ± standard deviation: 22.49 ± 10.32 (group A) vs. 21.57 ± 9.62 (group B) vs. 20.15 ± 5.18 (group C) L/h] and no significant decrease in trough amprenavir plasma concentrations [1.75 ± 0.95 (group A) vs. 1.82 ± 0.72 (group B) vs. 1.55 ± 0.66 (group C) mg/L] were found in groups B and C in comparison with group A, although nevirapine and efavirenz are inductors of protease inhibitors metabolism. These results suggest that fosamprenavir/ritonavir should be used at standard doses of 700 mg/100 mg twice daily when combined with efavirenz or nevirapine. [source] The implications of P-glycoprotein in HIV: friend or foe?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Andrew Owen Abstract P-glycoprotein (P-gp), coded by the ABCB1 gene, has a wide tissue distribution. The drug transporter is known to limit the bioavailability of a plethora of drugs and xenobiotics including the human immunodeficiency virus (HIV) protease inhibitors. There remains a considerable degree of debate in the literature with respect to the role of ABCB1 polymorphisms in HIV-treatment outcome and some studies have also implicated antiretroviral drugs as inducers of P-gp. Recent evidence indicates a role for P-gp in the inhibition of viral infectivity and/or release and cellular relationships with other infection-related proteins (and cholesterol). It is becoming increasingly clear that future studies on P-gp in HIV should consider both pharmacological and virological issues. [source] Mitochondrial toxicity in HIV-HCV coinfection: It depends on the choice of antiretroviral drugs?HEPATOLOGY, Issue 2 2002Raffaele Bruno M.D. No abstract is available for this article. [source] Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 ,32 deletionHIV MEDICINE, Issue 4 2007JJ Laurichesse Background Patients heterozygous for the C-C chemokine receptor 5 (CCR5) ,32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 ,32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. Patients and methods We included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of serconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan,Meier survival curves, with AIDS and death as outcomes. Results The ,32 heterozygous patients (n=83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P=0.01; and 60 vs 44% at 12 months, P=0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. Conclusions CCR5 ,32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the ,32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis. [source] Determinants of response to first HAART regimen in antiretroviral-naïve patients with an estimated time since HIV seroconversionHIV MEDICINE, Issue 1 2006R Thiébaut Objective To study the determinants of immunological and virological response to highly active antiretroviral therapy (HAART) in naïve patients, adjusting for time since HIV-1 seroconversion. Design Data from HIV-cohort studies where dates of seroconversion have been reliably estimated. Methods In previously untreated patients, short- and long-term marker responses from HAART initiation (three or more antiretroviral drugs) to the end of follow-up or any treatment modification were considered using mixed effects models accounting for undetectable HIV viral load and informative dropout. Results In total, 943 patients were treated with a first HAART regimen for a median of 29 months. In adjusted analyses, compared with a reference group of homosexual men without AIDS initiating treatment 4 years after seroconversion, injecting drug users (IDUs) were treated at similar CD4 and HIV RNA levels but had poorer short-term virological response (2.54 vs 2.13 log10 HIV-1 RNA copies/mL at 1.5 months, P=0.03) and poorer long-term immunological response (522 vs 631 cells/,L at 24 months, P<0.0001). Although individuals with AIDS at HAART initiation had lower CD4 counts (206 vs 382 cells/,L, P<0.0001), their immunological responses were similar to those of individuals without AIDS. Similarly, individuals further from seroconversion started HAART at lower CD4 counts (e.g. 311 vs 382 cells/,L at vs before 9 years from seroconversion, P<0.0001), but had similar CD4 responses. However, they experienced poorer long-term virological response (0.67 log10 copies/mL/year smaller decline, P<0.0001) compared to those treated before 9 years from seroconversion. Conclusion Taking into account the time elapsed since seroconversion, this study suggests that careful choices of initial treatment should be made and intensive follow-up carried out in high-risk subgroups such as IDUs who have poorer responses. [source] Clinical benefit of interventions driven by therapeutic drug monitoringHIV MEDICINE, Issue 5 2005AL Rendón Background Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. Objective To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. Methods All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). Results A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Conclusions Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates. [source] Risk factors and occurrence of rash in HIV-positive patients not receiving nonnucleoside reverse transcriptase inhibitor: data from a randomized study evaluating use of protease inhibitors in nucleoside-experienced patients with very low CD4 levels (<50 cells/m,L)HIV MEDICINE, Issue 1 2004M Floridia Background Most of the studies evaluating rash in HIV-positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI. Methods We evaluated all cases of rash observed during a 48-week randomized multicentre trial in 1251 nucleoside-experienced patients who started treatment with protease inhibitors (ritonavir or indinavir) at CD4 counts below 50 cells/,L. Incidence rates for rash were calculated according to gender, clinical status, age, use of highly active antiretroviral therapy (HAART), Pneumocystis carinii pneumonia (PCP) prophylaxis and use of individual antiretroviral drugs at enrolment. Differences between groups defined according to the above characteristics were tested for statistical significance using the log-rank test in a Kaplan-Meier survival analysis. All factors that gave results in the univariate analyses below the significance level of 0.05 were included in a multivariate analysis using a Cox regression model. Results During a follow-up period of 9690 person-months, 66 patients (5.3%) developed rash (0.68 events/100 person-months). In the univariate analyses, risk of rash did not differ with trial treatment (indinavir or ritonavir), clinical status, PCP prophylaxis, or age. During follow-up, rash was observed in 7.5% of enrolled women and in 4.5% of enrolled men (P=0.03). Serious rash occurred in 4.5% of enrolled women and in 1.6% of enrolled men (P=0.003). Use of HAART (P<0.001) and inclusion of zidovudine and of zalcitabine in the prescribed regimen (P=0.02) appeared to be associated with a lower risk of rash. In the multivariate analysis, the variables that remained significantly predictive of rash were gender (risk for women compared to men: 1.65, 95% confidence interval (CI): 1.00,2.72, P=0.048) and use of a non-HAART regimen (risk for non-HAART patients compared to HAART: 2.73, 95% CI: 1.49,5.02, P=0.001). Conclusions In our study, about 5% of HIV-positive patients who started treatment with protease inhibitors at very low CD4 counts developed rash, generally in the first few weeks after treatment. Risk was significantly higher in women and in patients who did not receive a HAART regimen. Our data indicate that women have a higher risk of rash than men, also with regimens that do not include NNRTI. [source] Genetic characterization of complex inter-recombinant HIV-1 strains circulating in Spain and reliability of distinct rapid subtyping tools,JOURNAL OF MEDICAL VIROLOGY, Issue 3 2008Africa Holguín Abstract Genetic recombination and high rate of mutation increase HIV-1 diversity, allowing viruses to escape more easily from the host immune response or antiretroviral drugs. The recombinant nature of full-length HIV-1 genomic sequences derived from viruses infecting five epidemiologically unlinked individuals carrying HIV-1 non-B variants was investigated. Overlapping PCR amplifications followed by direct sequencing of viral products derived from plasma and phylogenetic analyses were carried out. Four viral sequences clustered with CRF06_cpx and one with CRF02_AG. However, subtyping of separate genes within the same genome revealed that four were recombinant forms involving different subtypes and/or CRFs with distinct breakpoints. Two specimens included CRF02_AG and CRF06_cpx sequences with several fragments from other HIV-1 clades along their genomes. Three rapid subtyping tools (Stanford, NCBI, and REGA) showed discrepant results when interpreting these viral sequences. This is the first description of CRF02_AG/CRF06_ cpx recombinants in Spain. The results highlight the tremendous heterogeneity of HIV-1 recombinant strains currently in circulation. J. Med. Virol. 80:383,391, 2008. © 2008 Wiley-Liss, Inc. [source] Prevalence of X4 tropic HIV-1 variants in patients with differences in disease stage and exposure to antiretroviral therapyJOURNAL OF MEDICAL VIROLOGY, Issue 8 2007Eva Poveda Abstract Viral tropism plays an important role in HIV pathogenesis. However, its correlation with the clinical outcome and following exposure to antiretroviral drugs are still unclear. HIV-1 co-receptor usage was examined in 206 infected individuals: 67 seroconverters, 52 chronically drug-naïve, and 87 antiretroviral-experienced patients. The V3 loop was sequenced from plasma HIV-RNA and co-receptor usage was inferred using a phenotype predictor software (http://genomiac2.ucsd.edu:8080/wetcat/v3.html), which classifies V3 sequences as R5 or X4. The overall prevalence of X4 viruses was 26.2%, with significant differences among groups: 13.4% in seroconverters, 25% in drug-naïve, and 36.8% in antiretroviral- experienced patients (P,=,0.001). The presence of X4 variants in the latter group was associated with higher viral load (P,=,0.002) but not with lower CD4 counts. There was no association between HIV tropism and gender, transmission route or age. Neither with the CCR5 ,32 genotype. Moreover, no association was found between HIV-1 tropism and drug resistance mutations nor with failure to regimens based on either protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Finally, no significant association was found between IL-7 plasma levels with HIV-1 tropism. In summary, X4 viruses are particularly frequent among antiretroviral-experienced patients with high viral loads, irrespective of the CD4 count. Thus, CCR5 antagonists should be used with special caution in this subset of patients. J. Med. Virol. 79: 1040,1046, 2007. © 2007 Wiley-Liss, Inc. [source] Effective program against mother-to-child transmission of HIV at Saint Camille Medical Centre in Burkina FasoJOURNAL OF MEDICAL VIROLOGY, Issue 7 2007J. Simpore Abstract The present research was aimed to prevent mother-to-child transmission of HIV; to use RT-PCR in order to detect, 6 months after birth, infected children; and to test the antiretroviral resistance of both children and mothers in order to offer them a suitable therapy. At the Saint Camille Medical Centre, 3,127 pregnant women (aged 15,44 years) accepted to be enrolled in the mother-to-child transmission prevention protocol that envisages: (i) Voluntary Counselling and Testing for all the pregnant women; (ii) Antiretroviral therapy for HIV positive pregnant women and for their newborns; (iii) either powdered milk feeding or short breast-feeding and RT-PCR test for their children; (iv) finally, pol gene sequencing and antiretroviral resistance identifications among HIV positive mothers and children. Among the patients, 227/3,127 HIV seropositive women were found: 221/227 HIV-1, 4/227 HIV-2, and 2/227 mixed HIV infections. The RT-PCR test allowed the detection of 3/213 (1.4%) HIV infected children: 0/109 (0%) from mothers under ARV therapy and 3/104 (2.8%) from mothers treated with Nevirapine. All children had recombinant HIV-1 strain (CRF06_CPX) with: minor PR mutations (M36I, K20I) and RT mutations (R211K). Among them, two twins had Non-Nucleoside Reverse Transcriptase Inhibitor mutation (Y18CY). Both mothers acquired a major PR mutation (V8IV), investigated 6 months after a single-dose of Nevirapine. Prevention by single-dose of Nevirapine reduced significantly mother-to-child transmission of HIV, but caused many mutations and resistance to antiretroviral drugs. Based on present study the antiretroviral therapy protocol, together with the artificial-feeding, might represent the ideal strategy to avoid transmission of HIV from mother-to-child. J. Med. Virol. 79:873,879, 2007. © 2007 Wiley-Liss, Inc. [source] Impact of unreported HIV-1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non-nucleoside inhibitorsJOURNAL OF MEDICAL VIROLOGY, Issue 1 2006A. Saracino Abstract An extended spectrum of HIV-1 reverse-transcriptase (RT) mutations in HAART-treated patients has been recently described. To verify the possible association of previously unreported RT mutations with a decrease of phenotypic susceptibility to nucleoside (NRTIs) and non-nucleoside (NNRTIs) RT inhibitors, the RT sequence of 328 HIV-1-positive patients (102 naïve and 226 treated with HAART participating in either the PhenGen or Genpherex study) was analyzed. All treated patients were tested at the time of therapeutic failure with both phenotypic (Antivirogram®, Virco) and genotypic analyses (VircoGenÔ); the frequency of RT substitutions (positions 1,240) with respect to consensus B was compared to that of naïve patients using a Chi-square test. Amino acid changes at 13 positions not included in the IAS list of resistance-associated mutations were detected more frequently in treated than in naïve subjects. The mutations involving 10 of these positions were associated with a reduced susceptibility to antiretroviral drugs; K20R, T39A, K43EQN, E203KD, H208Y, and D218E were correlated with NRTI resistance while mutations K101EQP, H221Y, K223EQ, L228HR were associated to NNRTI resistance. A correlation was found between K20R and lamivudine resistance (P,=,0.006) while T39A (P,=,0.005), K43EQN (<0.001), E203KD (P,=,0.010), and H208Y (P,=, <,0.001) seemed to be associated with a previous use of zidovudine and stavudine and with the development of thymidine analog resistance. For H208Y, an association with use/resistance to abacavir (P,=,0.004) was also noted. D218E showed a weak association to didanosine resistance (P,=,0.013). The data confirm that previously unreported mutations are associated with antiretroviral drug experience and, more importantly, with a reduced susceptibility to NRTIs and NNRTIs. J. Med. Virol. 78:9,17, 2006. © 2005 Wiley-Liss, inc. [source] Effect of HIV-1 infection and increasing immunosuppression on menstrual functionJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 5 2010Oliver C. Ezechi Abstract Aim:, The aim of this study was to determine the prevalence, pattern and determinants of menstrual abnormalities in HIV-positive Nigerian women. Methods:, A cross-sectional study was carried out involving 3473 (2549 HIV-seropositive and 924 seronegative) consecutive and consenting women seen at the HIV treatment centers at the Nigerian Institute of Medical Research, Lagos and the Federal Medical Centre, Markurdi. Results:, The sociodemographic characteristics of the two groups were comparable, except for body mass index (BMI): the HIV-negative women (28.1 ± 8.1) had statistically significantly (P < 0.005) higher BMI compared to the HIV-positive women (21.9 ± 7.5). Menstrual abnormalities were significantly more common in women living with HIV/AIDS (29.1%) compared to the HIV-negative (18.9%) women (P < 0.001). The proportions of women in the two groups with intermenstrual bleeding, menorrhagia, hypermenorrhea, and postcoital bleeding were similar (P > 0.005), however amenorrhea, oligomenorrhea, irregular periods and secondary dysmenorrhea were more common in the HIV-positive women (P < 0.02). Primary dysmenorrhea was less common in HIV-positive women (P < 0.03). Among the HIV-positive women, menstrual dysfunction was more common in women living with HIV/AIDS with opportunistic infections, CD4 count < 200, not undertaking therapy, symptomatic disease and BMI < 20. However, after controlling for cofounders, only CD4 < 200 (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.2,9.7), BMI < 20 (OR, 2.4; 95%CI, 1.3,3.5) and not taking antiretroviral drugs (OR, 2.05; CI, 1.7,6.5) were associated with amenorrhea, oligomenorrhea, irregular periods and secondary dysmenorrhea. Conclusion:, HIV-positive women in this study experienced more menstrual abnormalities of amenorrhea, oligomenorrhea, and irregular periods compared to the HIV-negative controls. HIV-positive women with CD4 count < 200, BMI < 20 and who do not take antiretroviral drugs are at the greatest risk. [source] Inhibition of Hematopoietic Progenitor Cell Proliferation by Ethanol in Human Immunodeficiency Virus Type 1 Tat-Expressing Transgenic MiceALCOHOLISM, Issue 3 2001Om Prakash Background: A number of hematological abnormalities are associated with both human immunodeficiency virus type 1 (HIV-1) infection and alcohol abuse. There is little information on how alcohol abuse might further influence the survival and growth of hematopoietic progenitors in HIV-infected individuals in the presence of immune system abnormalities and anti-HIV drugs. Because there is evidence that viral transactivator Tat itself can induce hematopoietic suppression, in this study we examined the role of ethanol as a cofactor in transgenic mice that expressed HIV-1 Tat protein. Methods: Tat transgenic mice and nontransgenic littermates were given ethanol (20% v/v) and the anti-HIV drug 3,-azido-3,-deoxythymidine (AZT; 1 mg/ml) in drinking water. Immunosuppression in mice was induced by weekly intraperitoneal injections of anti-CD4 antibody. Hematopoiesis was examined by erythroid colony forming unit (CFU-E) and granulocyte/macrophage colony-forming unit (CFU-GM) assays of the bone marrow progenitor cells. Results: Administration of ethanol for 7 weeks resulted in a 50% decrease in the proliferative capacity of CFU-E- and CFU-GM-derived progenitors from transgenic mice compared with that of ethanol-treated nontransgenic controls. Similar decreases also were observed in transgenic mice treated with AZT or a combination of AZT and ethanol. Furthermore, ethanol and AZT were significantly more toxic to the granulopoietic progenitors (40,50% inhibition) than to the erythropoietic progenitors (10,20% inhibition) in Tat transgenic mice. Although a 10 day exposure of Tat transgenic and nontransgenic mice to a combination of ethanol and AZT had no suppressive effect on the erythropoietic and granulopoietic progenitor cells, there was a marked decrease (40,60%) in CFU-GM in mice made immunodeficient by CD4+ T-lymphocyte depletion. The ethanol-treated Tat transgenic mice but not the nontransgenic littermates also showed a significant decrease (25%) in CFU-GM. Conclusion: Our in vivo study strongly suggests that ethanol ingestion in HIV-1-infected individuals, particularly those on antiretroviral drugs, might increase bone marrow toxicity and contribute to HIV-1-associated hematopoietic impairment. [source] Humanitarian aid beyond "bare survival": Social movement responses to xenophobic violence in South AfricaAMERICAN ETHNOLOGIST, Issue 4 2009STEVEN ROBINS ABSTRACT In this article, I investigate responses to the humanitarian crisis that emerged following the May 2008 xenophobic violence against South African nonnationals that resulted in 62 deaths and the displacement of well over 30,000 people. I focus specifically on how a South African AIDS activist movement, the Treatment Action Campaign (TAC) and its partners, Médecins Sans Frontières (MSF,Doctors Without Borders) and the AIDS Law Project (ALP), translated a particular style and strategy of AIDS activism into legal, medical, humanitarian, and political responses to the massive population displacement. The TAC provided relief to displaced people in the form of basic needs, such as food, clothes, and blankets, as well as legal aid, and it engaged in activism that promoted the rights of the refugees. I investigate how the ideas and practices of global agencies such as the United Nations High Commission for Refugees (UNHCR) were deployed and reinterpreted by TAC activists. I also examine how TAC activists involved in assisting the refugees drew on a global humanitarian assemblage of categories, legal definitions, norms and standards, and procedures and technologies that went beyond the simple management of "bare life." TAC's shift from fighting for antiretroviral drugs (ARVs) to fighting for refugees' rights reveals a "politics of life" that spans multiple issues, networks, and constituencies. It is also a politics that, at times, strategically deploys standardized bureaucratic logics and biopolitical techniques of humanitarian aid. [source] Assessing teratogenicity of antiretroviral drugs: monitoring and analysis plan of the Antiretroviral Pregnancy Registry,,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 8 2004Deborah L. Covington DrPH Abstract This paper describes the Antiretroviral Pregnancy Registry's (APR) monitoring and analysis plan. APR is overseen by a committee of experts in obstetrics, pediatrics, teratology, infectious diseases, epidemiology and biostatistics from academia, government and the pharmaceutical industry. APR uses a prospective exposure-registration cohort design. Clinicians voluntarily register pregnant women with prenatal exposures to any antiretroviral therapy and provide fetal/neonatal outcomes. A birth defect is any birth outcome ,20 weeks gestation with a structural or chromosomal abnormality as determined by a geneticist. The prevalence is calculated by dividing the number of defects by the total number of live births and is compared to the prevalence in the CDC's population-based surveillance system. Additionally, first trimester exposures, in which organogenesis occurs, are compared with second/third trimester exposures. Statistical inference is based on exact methods for binomial proportions. Overall, a cohort of 200 exposed newborns is required to detect a doubling of risk, with 80% power and a Type I error rate of 5%. APR uses the Rule of Three: immediate review occurs once three specific defects are reported for a specific exposure. The likelihood of finding three specific defects in a cohort of ,600 by chance alone is less than 5% for all but the most common defects. To enhance the assurance of prompt, responsible, and appropriate action in the event of a potential signal, APR employs the strategy of ,threshold'. The threshold for action is determined by the extent of certainty about the cases, driven by statistical considerations and tempered by the specifics of the cases. Copyright © 2004 John Wiley & Sons, Ltd. [source] Gene therapy for HIV/AIDS: the potential for a new therapeutic regimenTHE JOURNAL OF GENE MEDICINE, Issue 8 2003Greg Fanning Abstract Human Immunodeficiency Virus (HIV) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). HIV/AIDS is a disease that, compared with the not so distant past, is now better held in check by current antiretroviral drugs. However, it remains a disease not solved. Highly active antiretroviral therapy (HAART) generally uses two non-nucleoside and one nucleoside reverse transcriptase (RT) inhibitor or two non-nucleoside RT and one protease inhibitor. HAART is far more effective than the mono- or duo-therapy of the past, which used compounds like the nucleoside reverse transcriptase inhibitor AZT or two nucleoside reverse transcriptase inhibitors. However, even with the relatively potent drug cocktails that comprise HAART, there are the issues of (i) HIV escape mutants, (ii) an apparent need to take the drugs in an ongoing manner, and (iii) the drugs' side effects that are often severe. This review speaks to the potential addition to these potent regimens of another regimen, namely the genetic modification of target hematopoietic cells. Such a new treatment paradigm is conceptually attractive as it may yield the constant intracellular expression of an anti-HIV gene that acts to inhibit HIV replication and pathogenicity. A body of preclinical work exists showing the inhibition of HIV replication and decreased HIV pathogenicity by anti-HIV genetic agents. This preclinical work used hematopoietic cell lines and primary cells as the target tissue. More recently, several clinical trials have sought to test this concept in vivo. Copyright © 2003 John Wiley & Sons, Ltd. [source] Structural studies of the catalytic core of the primate foamy virus (PFV-1) integraseACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 8 2010Stéphane Réty Retroviral integrases are vital enzymes in the viral life cycle and thus are important targets for antiretroviral drugs. The structure of the catalytic core domain of the integrase from human foamy virus, which is related to HIV-1, has been solved. The structure of the protein is presented in two different crystal forms, each containing several molecules in the asymmetric unit, with and without the essential manganese or magnesium ion, and the structures are compared in detail. This allows regions of high structural variability to be pinpointed, as well as the effect of divalent cations on the conformation of the catalytic site. [source] Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography,tandem mass spectrometryBIOMEDICAL CHROMATOGRAPHY, Issue 10 2007Byung Hwa Jung Abstract This work describes a sensitive method for the simultaneous determination of 17 antiretroviral drugs including nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors, protease inhibitors and a nucleotide analog reverse transcriptase inhibitor in 50 µL of human plasma. This method employed high-performance liquid chromatography,tandem mass spectrometry with electrospray ionization. The analytes were monitored in multiple reaction monitoring mode and the polarity was switched from positive to negative to positive to detect all compounds after a single injection. A combination of liquid,liquid extraction and protein precipitation was used to extract all compounds, with at least 75% recovery for all analytes. Within- and between-day accuracies were at least 85% for 1,500 ng/mL for nelfinavir, indinavir and abacavir, 10,500 ng/mL for didanosine and stavudine and 5,500 ng/mL for all other compounds. This method is very effective for quantifying and screening antiretroviral drugs in clinical samples with limited (50 µL) volumes. Copyright © 2007 John Wiley & Sons, Ltd. [source] Resampling-Based Multiple Testing Methods with Covariate Adjustment: Application to Investigation of Antiretroviral Drug SusceptibilityBIOMETRICS, Issue 2 2008Yang Yang Summary Identifying genetic mutations that cause clinical resistance to antiretroviral drugs requires adjustment for potential confounders, such as the number of active drugs in a HIV-infected patient's regimen other than the one of interest. Motivated by this problem, we investigated resampling-based methods to test equal mean response across multiple groups defined by HIV genotype, after adjustment for covariates. We consider construction of test statistics and their null distributions under two types of model: parametric and semiparametric. The covariate function is explicitly specified in the parametric but not in the semiparametric approach. The parametric approach is more precise when models are correctly specified, but suffer from bias when they are not; the semiparametric approach is more robust to model misspecification, but may be less efficient. To help preserve type I error while also improving power in both approaches, we propose resampling approaches based on matching of observations with similar covariate values. Matching reduces the impact of model misspecification as well as imprecision in estimation. These methods are evaluated via simulation studies and applied to a data set that combines results from a variety of clinical studies of salvage regimens. Our focus is on relating HIV genotype to viral susceptibility to abacavir after adjustment for the number of active antiretroviral drugs (excluding abacavir) in the patient's regimen. [source] Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Rob Ter Heine WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre-treated for HIV-infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS , We investigated the steady-state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment. AIM To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l,1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK,PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance. [source] Seizures in HIV/AIDS: a southern African perspectiveACTA NEUROLOGICA SCANDINAVICA, Issue 2005A. I. Bhigjee South Africa, with a population of 44.8 million, has over 5 million human immunodeficiency virus (HIV)-infected individuals. Over 70% of HIV-infected patients will present with clinically relevant neurologic disease at some stage during the course of their disease. New onset seizures occur in 3,11% of these patients. The mechanism of seizure production in HIV-positive patients includes incidental association, HIV itself, opportunistic infections (OIs), neoplasia, cerebrovascular disease, drug toxicity, and metabolic derangements. In developing countries, OIs constitute the largest group presenting with seizures. Seizure management in HIV-positive patients presents special problems, especially with respect to drug,disease and drug,drug interactions. The older antiepileptic drugs (AEDs) are protein-bound and largely depend on the cytochrome p450 system for their metabolism. The newer AEDs may be safer in patients on antiretroviral drugs. However, they are expensive, an important consideration in developing countries. [source] Feeding practices of HIV-1-infected mothers: The role of counsellorsACTA PAEDIATRICA, Issue 3 2005Anneka EHRNST Abstract In this issue of Acta Paediatrica, Chopra et al. report that voluntary counselling is central to preparing mothers for making a proper informed choice about adequate feeding practices to prevent their infants from acquiring HIV infection. The recommendations given and the way in which counselling is performed are the most important determinants of a mother's decision about how to feed her infant. In this article, we summarize the main arguments for and against breastfeeding by HIV-infected mothers. Conclusions : Further studies are needed to determine the alternatives to breastfeeding in countries where there is no access to safe formula feeding or to antiretroviral drugs. HIV-positive mothers should be made aware of the available feeding alternatives through adequate counselling from properly trained persons. [source] | |||||||||||||||||||