Current Issue : April - June Volume : 2014 Issue Number : 2 Articles : 7 Articles
The nucleoside(tide) reverse transcriptase inhibitors (NRTIs) have traditionally been an important ââ?¬Ë?back-boneââ?¬â?¢ of an\r\nantiretroviral therapy (ART) regimen. However all agents have been associated with both short- and long-term toxicity.\r\nThere have also been concerns regarding the efficacy and safety of a treatment sequencing strategy in which those\r\nwith past exposure and/or resistance to one or more NRTIs are re-exposed to ââ?¬Ë?recycledââ?¬â?¢ NRTIs in subsequent\r\nART regimens. Newer, potent and possible safer, agents from various ART classes continue to become available.\r\nThere has therefore been growing interest in evaluating NRTI-sparing regimens. In this review, we examined studies of\r\nNRTI-sparing regimens in adult HIV-positive patients with varying degrees of ART experience. We found that in\r\ntreatment experienced patients currently on a failing regimen with detectable viral load, there now exists a\r\nrobust evidence for the use of NRTI-sparing regimens including raltegravir with a boosted-protease inhibitor\r\nwith or without a third agent. In those on a virologically suppressive regimen switching to a NRTI-sparing\r\nregimen or in those ART-naÃ?¯ve patients initiating an NRTI-sparing regimen, evidence is sparse and largely\r\ncomes from small exploratory trials or observational studies. Overall, these studies suggest that caution needs to be\r\nexercised in carefully selecting the right candidate and agents, especially in the context of a dual-therapy regimen, to\r\nminimise the risks of virological failure. There is residual toxicity conferred by the ritonavir boost in protease-inhibitor\r\ncontaining NRTI-sparing regimens. Fully-powered studies are needed to explore the place of N (t)RTI-sparing regimens\r\nin the sequencing of ART. Additionally research is required to explore how to minimise the adverse effects associated\r\nwith ritonavir-based pharmacoenhancement....
Background: CCR5-delta32 heterozygous individuals are susceptible to HIV-1. However, it is not clear if there is a\r\nrelevant protective effect against transmission and a beneficial effect in terms of HIV progression which cannot be\r\nattributed to CCR5 surface density alone. Therefore we investigated HIV-1 dependency factors (HDF) which might\r\nbe differently regulated in CCR5 wild type (WT) and CCR5-delta32 heterozygous individuals.\r\nMethods: We examined CD34+ hematopoietic progenitor cells derived from bone marrow samples from 19\r\nhealthy volunteers, 12 individuals with CCR5 WT and 7 with heterozygous CCR5-delta32 deletion. Samples were\r\nanalyzed using a global gene expression oligonucleotide microarray (HG-U133plus 2.0, Affymetrix Inc.).\r\nResults: A total of 205 genes were found with altered expression (3fold difference, present call rate of 75%,\r\np < 0.05) and 7 of these had a connection to HIV-1 pathogenesis. In 4 genes: TOP1, CXCR2, SREBF2, and TAP we\r\nfound a different regulation which was consistent with a supposed beneficial effect for CCR5-delta32 heterozygotes.\r\nConclusion: The CCR5-delta32 deletion is associated with other HDFs in HIV-1 pathogenesis as a possible\r\nexplanation for beneficial effects regarding the deletion leading to a variant expression profile in heterozygous\r\ncarriers of this mutation....
Background: Early recognition of antiretroviral therapy (ART) failure in resource limited settings is a challenge given\r\nthe limited laboratory facilities and trained personnel. This study aimed at describing the incidence, risk factors and\r\nthe resistance associated mutations (RAMs) of first line treatment failure among HIV-1-infected children attending\r\nthe Joint Clinical Research Centre (JCRC), Kampala, Uganda.\r\nMethods: A retrospective cohort of 701 children who had been initiated on ART between January 2004 and\r\nSeptember 2009 at the JCRC was studied. Data of children aged 6 months up to 18 years who had been started on\r\nART for at least 6 months was extracted from the clinic charts. The children who failed the first-line ART were taken\r\nas cases and those who did not fail as the controls. Data was analysed using STATA version10.\r\nResults: Of 701 children, 240(34%) failed on first line ART (cases) and 461(66%) did not fail (controls). The overall\r\nmedian time (IQR) to first line ART failure was 26.4 (18.9 ââ?¬â?? 39.1) months. The factors associated with treatment\r\nfailure were poor adherence [(OR = 10, 95 CI: 6.4 ââ?¬â?? 16.7) p < 0.001], exposure to single dose nevirapine (sdNVP)\r\n[(OR = 4.2, 95% CI:1.8-9.4), p = 0.005] and a NVP containing regimen [(OR = 2.2,95% CI:1.4-3.6), p < 0.001]. Of 109\r\ngenotypic resistance profiles analyzed, the commonest non nucleoside reverse transcriptase inhibitor (NNRTI) resistance\r\nassociated mutations (RAM) were: K103N (59; 54%)), Y181C (36; 27%)) and G190A (26; 24%)) while the commonest\r\nnucleoside reverse transcriptase inhibitor (NRTI) RAM was the M184V (89; 81%). Thymidine analogue- mutations\r\n(TAMs) were detected in 20% of patients.\r\nConclusions: One in three children on first-line ART are likely to develop virological treatment failure after the first\r\n24 months of therapy. Poor adherence to ART, a NVP based first-line regimen, prior exposure to sdNVP were\r\nassociated with treatment failure....
The success of highly active antiretroviral therapy (HAART) has determined a dramatic decline in AIDS- and\r\nimmunodeficiency-related causes of death in the HIV-infected population. As life-expectancy increases, such individuals\r\nhave become gradually exposed not only to the effects of aging itself, but also to the influence of environmental risk\r\nfactors, which are known to act in the general population. These features can lead to obesity, diabetes mellitus and\r\nultimately cardiovascular diseases (CVD). Metabolic complications and abnormal fat distribution were frequently\r\nobserved after a few years of antiretroviral therapy and, as the array of antiretroviral drugs became broader, long term\r\nmetabolic alterations are becoming far more common worldwide. Nevertheless, the risk of not being on HAART\r\nis overwhelmingly greater than the metabolic adverse events in terms of morbidity and mortality events. HIV/\r\nHAART-induced metabolic unbalances overlap in some extent the components of Metabolic Syndrome (MetS) and\r\nits high rates in the HIV population place infected individuals in an elevated CVD risk category. MetS can explain at\r\nleast in part the emergence of CVD as the major morbidity and mortality conditions in the HIV population. In this\r\nreview we convey information on the underlying aspects of MetS during HIV infection, highlighting some\r\nphysiopathological and epidemiological features of this comorbidity along with the role played by HIV itself and\r\nthe synergy action of some antiretroviral drugs. Considerations on MetS management in the HIV population are\r\nalso depicted....
Like most cellular mRNAs, the 5' end of HIV mRNAs is capped and the 3' end matured by the process of\r\npolyadenylation. There are, however, several rather unique and interesting aspects of these post-transcriptional\r\nprocesses on HIV transcripts. Capping of the highly structured 5' end of HIV mRNAs is influenced by the viral TAT\r\nprotein and a population of HIV mRNAs contains a trimethyl-G cap reminiscent of U snRNAs involved in splicing.\r\nHIV polyadenylation involves active repression of a promoter-proximal polyadenylation signal, auxiliary upstream\r\nregulatory elements and moonlighting polyadenylation factors that have additional impacts on HIV biology outside\r\nof the constraints of classical mRNA 3� end formation. This review describes these post-transcriptional novelties of\r\nHIV gene expression as well as their implications in viral biology and as possible targets for therapeutic intervention....
Despite the major advances in the management of HIV infection, HIV-infected patients still have greater morbidity\r\nand mortality than the general population. Serious non-AIDS events (SNAEs), including non-AIDS malignancies,\r\ncardiovascular events, renal and hepatic disease, bone disorders and neurocognitive impairment, have become the\r\nmajor causes of morbidity and mortality in the antiretroviral therapy (ART) era. SNAEs occur at the rate of 1 to 2 per\r\n100 person-years of follow-up. The pathogenesis of SNAEs is multifactorial and includes the direct effect of HIV and\r\nassociated immunodeficiency, underlying co-infections and co-morbidities, immune activation with associated\r\ninflammation and coagulopathy as well as ART toxicities. A number of novel strategies such as ART intensification,\r\ntreatment of co-infection, the use of anti-inflammatory drugs and agents that reduce microbial translocation are\r\ncurrently being examined for their potential effects in reducing immune activation and SNAEs. However, currently,\r\ninitiation of ART before advanced immunodeficiency, smoking cessation, optimisation of cardiovascular risk factors\r\nand treatment of HCV infection are most strongly linked with reduced risk of SNAEs or mortality. Clinicians should\r\ntherefore focus their attention on addressing these issues prior to the availability of further data...
Thirty years since the discovery of HIV, the HIV pandemic in sub-Saharan Africa accounts for more than two thirds\r\nof the world�s HIV infections. Southern Africa remains the region most severely affected by the epidemic. Women\r\ncontinue to bear the brunt of the epidemic with young women infected almost ten years earlier compared to their\r\nmale counterparts. Epidemiological evidence suggests unacceptably high HIV prevalence and incidence rates\r\namong women. A multitude of factors increase women�s vulnerability to HIV acquisition, including, biological,\r\nbehavioral, socioeconomic, cultural and structural risks. There is no magic bullet and behavior alone is unlikely to\r\nchange the course of the epidemic. Considerable progress has been made in biomedical, behavioral and structural\r\nstrategies for HIV prevention with attendant challenges of developing appropriate HIV prevention packages which\r\ntake into consideration the socioeconomic and cultural context of women in society at large....
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