Development of HIV with Drug Resistance after CD4 Cell Count—Guided Structured Treatment Interruptions in Patients Treated with Highly Active Antiretroviral Therapy after Dual—Nucleoside Analogue Treatment

Background. For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy. Methods. HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count—guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption. Results. After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n = 2], K70R [n = 2], T215Y [n = 2], and T215I [n = 1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations. Conclusions. Major HIV drug-resistance mutations were not induced through CD4 cell count—guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therap

Transmitted drug resistance in recently infected HIV-positive Individuals from four urban locations across Asia (2007–2010) – TASER-S

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Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen

Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therap

A Novel Immunodominant CD8+ T Cell Response Restricted by a Common HLA-C Allele Targets a Conserved Region of Gag HIV-1 Clade CRF01_AE Infected Thais

Background: CD8+ T cell responses play an important role in the control of HIV-1. The extensive sequence diversity of HIV-1 represents a critical hurdle to developing an effective HIV-1 vaccine, and it is likely that regional-specific vaccine strains will be required to overcome the diversity of the different HIV-1 clades distributed world-wide. Unfortunately, little is known about the CD8+ T cell responses against CRF01_AE, which is responsible for the majority of infections in Southeast Asia. Methodology/Principal Findings: To identify dominant CD8+ T cell responses recognized in HIV-1 clade CRF01_AE infected subjects we drew upon data from an immunological screen of 100 HIV-1 clade CRF01_AE infected subjects using IFN-gamma ELISpot to characterize a novel immunodominant CD8+ T cell response in HIV-1 Gag restricted by HLA-Cw*0102 (p24, 277YSPVSILDI 285, YI9). Over 75% of Cw*0102+ve subjects targeted this epitope, representing the strongest response in more than a third of these individuals. This novel CD8 epitope was located in a highly conserved region of HIV-1 Gag known to contain immunodominant CD8 epitopes, which are restricted by HLA-B*57 and -B*27 in clade B infection. Nonetheless, viral escape in this epitope was frequently observed in Cw*0102+ve subjects, suggestive of strong selection pressure being exerted by this common CD8+ T cell response. Conclusions/Significance: As HLA-Cw*0102 is frequently expressed in the Thai population (allelic frequency of 16.8%), this immunodominant Cw*0102-restricted Gag epitope may represent an attractive candidate for vaccines specific to CRF01_AE and may help facilitate further studies of immunopathogenesis in this understudied HIV-1 clade. © 2011 Buranapraditkun et al

Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance:an individual-patient- and sequence-level meta-analysis

Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.status: publishe

Methamphetamine (MA) use and MA-induced psychosis are associated with increasing aberrations in the compensatory immunoregulatory system, interleukin-1α, and CCL5 levels

Abstract There are only a few studies reporting on the immunological profiles of methamphetamine (MA) use, MA dependency, or MA-induced psychosis (MAP). This study measured M1 macrophage, T helper (Th)-1, Th-2, growth factor, and chemokine profiles, as well as the immune inflammatory response system (IRS) and compensatory immunoregulatory system (CIRS) in peripheral blood samples from patients with MA use (n = 51), MA dependence (n = 47), and MAP (n = 43) in comparison with controls (n = 32). We discovered that persistent MA use had a robust immunosuppressive impact on all immunological profiles. The most reliable biomarker profile of MA use is the combination of substantial CIRS suppression and a rise in selected pro-inflammatory cytokines, namely CCL27 (CTACK), CCL11 (eotaxin), and interleukin (IL)-1α. In addition, MA dependency is associated with increased immunosuppression, as demonstrated by lower stem cell factor levels and higher IL-10 levels. MAP is related to a significant decrease in all immunological profiles, particularly CIRS, and an increase in CCL5 (RANTES), IL-1α, and IL-12p70 signaling. In conclusion, long-term MA use and dependency severely undermine immune homeostasis, whereas MAP may be the consequence of increased IL-1α – CCL5 signaling superimposed on strongly depleted CIRS and Th-1 functions. The widespread immunosuppression established in longstanding MA use may increase the likelihood of infectious and immune illness or exacerbate disorders such as hepatitis and AIDS. Furthermore, elevated levels of CCL5, CCL11, CCL27, IL-1α, and/or IL-12p70 may play a role in the peripheral (atherosclerosis, cutaneous inflammation, immune aberrations, hypospermatogenesis) and central (neuroinflammation, neurotoxic, neurodegenerative, depression, anxiety, and psychosis) side effects of MA use