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Journal of Neuroimmune Pharmacology :... Jun 2018Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50 years of age. Unfortunately, patients are...
Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50 years of age. Unfortunately, patients are required to stay on long-term HAART, which may be causally related to the development of neurological problems such as chronic pain. Little is known about the contribution of HAART or its therapeutic agents to the pathogenesis of pain during aging. In this study, we determined the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on the development of mechanical allodynia and the potential underlying mechanism in aging mice (15.5 months). We found that systemic administration of individual NRTIs, including ddC (2'-3'-dideoxycytidine), ddI (didanosine), AZT (3'-azido-3'-deoxythymidine) and d4T (2', 3'-didehydro-2', 3'-dideoxythymidine), induced allodynia in similar magnitudes and temporal profiles. We used ddC as a representative to investigate cellular and molecular processes induced by NRTIs in the spinal cord that probably underlie the development of allodynia. The results showed that ddC caused evident neuroinflammation in the spinal cord, suggested by the up-regulation of proinflammatory cytokines TNF-α and IL-1β and the reactions of microglia and astrocytes. In addition, we found that Wnt5a, a critical regulator of neuroinflammation, was also up-regulated. Pharmacological inhibition of Wnt5a blocked ddC-induced up-regulation of TNF-α and astrocyte reaction, while activation of Wnt5a signaling potentiated these processes. Furthermore, our data showed that inhibition of Wnt5a significantly reversed ddC-induced mechanical allodynia in aging mice. The results collectively suggest that NRTIs may contribute to the development of chronic pain in aging patients by inducing Wnt5a-regulated neuroinflammation.
Topics: Aging; Animals; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Neuroimmunomodulation; Pain; Reverse Transcriptase Inhibitors; Spinal Cord; Wnt-5a Protein
PubMed: 29429030
DOI: 10.1007/s11481-018-9777-6 -
Journal of the International... 2018The prevalence of non-AIDS-related comorbidities is increasing in HIV-infected patients receiving antiretroviral therapy. In Thailand, data regarding the prevalence of...
OBJECTIVES
The prevalence of non-AIDS-related comorbidities is increasing in HIV-infected patients receiving antiretroviral therapy. In Thailand, data regarding the prevalence of non-AIDS comorbidities and factors associated with metabolic complications in HIV-infected patients have not been well-documented.
METHODS
This cross-sectional study was conducted in 2011 and included 874 HIV-infected patients.
RESULTS
The age of patients was 45(8) years represented as mean (standard deviation [SD]). The current CD4 count was 502(247) cells/mm. In all, 388 (44%) of the included patients had at least 1non-AIDS comorbidity. The most frequently documented comorbidities were hyperlipidemia in 271 (70%) patients. Using multivariate analysis, older age(odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.51-2.19), male sex (OR = 1.55, 95%CI = 1.14-2.11), high current CD4 count(OR = 1.00, 95%CI = 1.00-1.00), and taking abacavir (ABC)-containing(OR = 2.59, 95%CI = 1.16-5.78)and didanosine (ddI)-containing antiretroviral regimens (OR = 4.16, 95%CI = 1.09-15.84)were associated with the presence of metabolic complications (all Ps<.05).
CONCLUSION
The prevalence of comorbidities is substantially high. Clinical monitoring and effective management of these comorbidities and metabolic complications are recommended, especially in HIV-infected patients who present with these associated factors.
Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Comorbidity; Cross-Sectional Studies; Female; HIV Infections; HIV-1; Humans; Hyperlipidemias; Male; Metabolic Diseases; Middle Aged; Prevalence; Referral and Consultation; Thailand
PubMed: 29357771
DOI: 10.1177/2325957417752256 -
PloS One 2018Combined antiretroviral therapy (cART) has improved survival in HIV-patients. While the first antiretrovirals, which became available in particular D-drugs (especially... (Observational Study)
Observational Study
INTRODUCTION
Combined antiretroviral therapy (cART) has improved survival in HIV-patients. While the first antiretrovirals, which became available in particular D-drugs (especially didanosine and stavudine) and unboosted protease inhibitors, may impair liver function, the modern cART seems to decrease liver fibrosis. This study assessed the influence of exposure to previous antiretrovirals on liver fibrosis in HIV-infected patients.
METHODS
This observational cross-sectional single-center study recruited 333 HIV patients and assessed liver fibrosis using transient elastography (TE).
RESULTS
83% were male with a median age of 45, while 131 were co-infected with viral hepatitis. Overall, 18% had significant fibrosis and 7.5% had cirrhosis. 11% of HIV mono-infected patients had significant fibrosis and 2% had cirrhosis. HCV infection (OR:5.3), history of exposure to didanosine (OR:2.7) and HIV load below 40copies/mL (OR:0.5) were independently associated with significant fibrosis, while HCV (OR:5.8), exposure to didanosine (OR:2.9) and azidothymidine (OR:2.8) were independently associated with cirrhosis. Interestingly, in HIV mono-infected patients, a HIV-load below 40copies/mL (OR:0.4) was independently associated with significant fibrosis, and didanosine (OR:20.8) with cirrhosis.
CONCLUSION
In conclusion, history of exposure to didanosine and azidothymidine continues to have an impact on the presence of liver cirrhosis in HIV patients. However, HCV co-infection and ongoing HIV-replication have the strongest effect on development of significant fibrosis in these patients.
Topics: Adult; Anti-HIV Agents; Cross-Sectional Studies; Female; HIV Infections; Hepatitis C; Humans; Liver Cirrhosis; Male; Middle Aged
PubMed: 29346443
DOI: 10.1371/journal.pone.0191118 -
Endocrinology, Diabetes & Metabolism... 2017An 11-year-old male with perinatally acquired human immune deficiency virus (HIV) infection on antiretroviral regimen, which included abacavir plus lamivudine (Epzicom),...
UNLABELLED
An 11-year-old male with perinatally acquired human immune deficiency virus (HIV) infection on antiretroviral regimen, which included abacavir plus lamivudine (Epzicom), didanosine, ritonavir and atazanavir presented with bilateral axillary striae, increased appetite, fatigue, facial swelling and acute weight gain. Two months prior to presentation, the patient had received a diagnostic and therapeutic intra-articular triamcinolone injection in the knee for pain relief and subsequently became progressively swollen in the face, developed striae bilaterally at the axillae, experienced increased appetite, fatigue and an 8 pound weight gain. During the endocrine workup, suspicion for adrenal insufficiency prompted 24-h urine collection for free cortisol, which was found to be undetectable (below LLQ of 1.0 µg/L). This prompted further evaluation of the hypothalamic-pituitary axis (HPA) by standard dose adrenocorticotropic hormone (ACTH) stimulation test. A 250 µg cosyntropin stimulation test was performed and confirmed HPA axis suppression. Baseline cortisol level was <1 µg/dL and stimulated cortisol level at 30 min was 3.8 µg/dL. The patient was diagnosed with iatrogenic Cushing syndrome and suppression of HPA axis secondary to the drug interaction between ritonavir (RTV) and intra-articular triamcinolone injection. Following endocrine evaluation and workup, the patient was admitted for planned orthopaedic procedure including elective left hamstring lengthening, distal femoral osteotomy and patellar tendon advancement. Taking into consideration the diagnosis of iatrogenic Cushing syndrome, at the start of the surgical procedure, 100 mg IV stress dose of hydrocortisone followed by 50 mg hydrocortisone every 8 h for 24 h was administered. Stress dosing was discontinued 24 h after the procedure. Throughout the hospitalization and upon discharge, the patient continued his ART. From initial presentation, patient has remained clinically stable throughout surgery and postoperative period.
LEARNING POINTS
Drug-drug interaction between ritonavir and triamcinolone can cause Cushing syndrome.Although triamcinolone has a half-life of 3 h, an intra-articular injection may be systematically absorbed for 3 weeks after injection, and adrenal suppression may last as long as 30 days.Co-administration of ritonavir and corticosteroids may result in an increase of plasma levels of corticosteroids levels, as they are both eliminated by CYP3A metabolism, and this interaction has the potential to prolong the half-life of triamcinolone several fold.No specific guidelines are available for the management of iatrogenic Cushing syndrome secondary to ritonavir and corticosteroids.One treatment option includes replacing ritonavir with a non-protease inhibitor-based regimen.Initiating hydrocortisone replacement therapy to prevent an adrenal crisis is also an alternate option.
PubMed: 29118985
DOI: 10.1530/EDM-17-0076 -
Journal of Virology Dec 2017Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants...
Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants into the human germ line and are transcriptionally active. In HIV-1 infection and cancer, HK2 genes produce retroviral particles that appear to be infectious, yet the replication capacity of these viruses and potential pathogenicity has been difficult to ascertain. In this report, we screened the efficacy of commercially available reverse transcriptase inhibitors (RTIs) at inhibiting the enzymatic activity of HK2 RT and HK2 genomic replication. Interestingly, only one provirus, K103, was found to encode a functional RT among those examined. Several nucleoside analogue RTIs (NRTIs) blocked K103 RT activity and consistently inhibited the replication of HK2 genomes. The NRTIs zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), and the nucleotide RTI inhibitor tenofovir (TDF), show efficacy in blocking K103 RT. HIV-1-specific nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (IIs) did not affect HK2, except for the NNRTI etravirine (ETV). The inhibition of HK2 infectivity by NRTIs appears to take place at either the reverse transcription step of the viral genome prior to HK2 viral particle formation and/or in the infected cells. Inhibition of HK2 by these drugs will be useful in suppressing HK2 infectivity if these viruses prove to be pathogenic in cancer, neurological disorders, or other diseases associated with HK2. The present studies also elucidate a key aspect of the life cycle of HK2, specifically addressing how they do, and/or did, replicate. Endogenous retroviruses are relics of ancestral virus infections in the human genome. The most recent of these infections was caused by HK2. While HK2 often remains silent in the genome, this group of viruses is activated in HIV-1-infected and cancer cells. Recent evidence suggests that these viruses are infectious, and the potential exists for HK2 to contribute to disease. We show that HK2, and specifically the enzyme that mediates virus replication, can be inhibited by a panel of drugs that are commercially available. We show that several drugs block HK2 with different efficacies. The inhibition of HK2 replication by antiretroviral drugs appears to occur in the virus itself as well as after infection of cells. Therefore, these drugs might prove to be an effective treatment by suppressing HK2 infectivity in diseases where these viruses have been implicated, such as cancer and neurological syndromes.
Topics: Anti-HIV Agents; Cell Line, Tumor; Endogenous Retroviruses; Genome, Viral; Humans; Integrase Inhibitors; Lamivudine; Protease Inhibitors; Reverse Transcriptase Inhibitors; Reverse Transcription; Stavudine; Virus Replication; Zidovudine
PubMed: 28931682
DOI: 10.1128/JVI.01309-17 -
PloS One 2017HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines...
INTRODUCTION
HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve.
METHODS
An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs).
RESULTS
There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required.
CONCLUSIONS
The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.
Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Genotype; HIV-1; Heterocyclic Compounds, 3-Ring; Lamivudine; Lopinavir; Nelfinavir; Oxazines; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine
PubMed: 28753637
DOI: 10.1371/journal.pone.0181357 -
Global Health Action 2017Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector....
BACKGROUND
Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector. However, there have been no published data about the outcomes of such patients until now.
OBJECTIVE
To assess the treatment and programmatic outcomes and factors associated with unfavorable outcomes (treatment failure, death and loss to follow-up from care) among people living with HIV (aged ≥ 10 years) receiving protease inhibitor-based second-line ART under the Integrated HIV Care Program in Myanmar between October 2008 and June 2015.
DESIGN
Retrospective cohort study using routinely collected program data.
RESULTS
Of 824 adults and adolescents on second-line ART, 52 patients received viral load testing and 19 patients were diagnosed with virological failure. However, their treatment was not modified. At the end of a total follow-up duration of 7 years, 88 (11%) patients died, 35 (4%) were lost to follow-up, 21 (2%) were transferred out to other health facilities and 680 (83%) were still under care. The incidence rate of unfavorable outcomes was 7.9 patients per 100 person years follow-up. Patients with a history of injecting drug use, with a history of lost to follow-up, with a higher baseline viral load and who had received didanosine and abacavir had a higher risk of unfavorable outcomes. Patients with higher baseline C4 counts, those having taken first-line ART at a private clinic, receiving ART at decentralized sites and taking zidovudine and lamivudine had a lower risk of unfavorable outcomes.
CONCLUSIONS
Long-term outcomes of patients on second-line ART were relatively good in this cohort. Virological failure was relatively low, possibly because of lack of viral load testing. No patient who failed on second-line ART was switched to third-line treatment. The National HIV/AIDS Program should consider making routine viral load monitoring and third-line ART drugs available after a careful cost-benefit analysis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Cohort Studies; Female; HIV Infections; Humans; Male; Middle Aged; Myanmar; Retrospective Studies; Treatment Failure; Treatment Outcome; Young Adult
PubMed: 28594295
DOI: 10.1080/16549716.2017.1290916 -
Antimicrobial Agents and Chemotherapy Aug 2017We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant...
We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes; Cell Survival; Didanosine; Female; HIV Infections; Humans; Male; Middle Aged; Receptors, CXCR4; Stavudine; T-Lymphocytes, Regulatory; Viral Load; Zalcitabine; Zidovudine
PubMed: 28559274
DOI: 10.1128/AAC.00605-17 -
The Journal of Clinical Endocrinology... Aug 2017HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from...
CONTEXT
HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from birth.
OBJECTIVE
To prospectively evaluate renal and bone health in young adults with lifelong HIV and extensive ARV exposure.
DESIGN
Cross-sectional comparison of bone mineral density (BMD) by dual-energy X-ray absorptiometry, bone turnover, and renal function in young adults infected with HIV in early life (n = 65) to matched healthy controls (n = 23) and longitudinal evaluation (mean follow-up = 4.4 years) within a subset of the HIV cohort (n = 33).
SETTING
Government outpatient research clinic.
RESULTS
Albumin/creatinine ratio, protein/creatinine ratio, anion gap, N-terminal telopeptides, and osteocalcin were significantly increased in persons with HIV compared with controls, whereas whole-body BMD and BMD z scores were lower. Within the HIV group, duration of tenofovir disoproxil fumarate (TDF) correlated with higher anion gap but did not correlate with bone parameters. Longer duration of didanosine and stavudine use correlated with lower BMD and BMD z scores. Longitudinal analyses revealed that BMD and bone metabolism significantly improved over time. No subject had an estimated glomerular filtration rate (eGFR) <60, but decline in eGFR correlated with increasing years of TDF exposure.
CONCLUSIONS
Subclinical markers of renal dysfunction were increased in HIV-infected young adults and associated with TDF exposure, whereas lower bone density was associated with didanosine and stavudine exposure. The tendency for improvement in markers of bone health over time and the availability of less toxic ARV alternatives may herald improvements in renal and bone health for perinatally infected patients in adulthood.
Topics: Absorptiometry, Photon; Acid-Base Equilibrium; Adult; Age of Onset; Albuminuria; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Case-Control Studies; Creatinine; Cross-Sectional Studies; Didanosine; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Function Tests; Longitudinal Studies; Male; Osteocalcin; Prospective Studies; Proteinuria; Renal Insufficiency; Risk Factors; Stavudine; Tenofovir; Time Factors; Young Adult
PubMed: 28531309
DOI: 10.1210/jc.2017-00197 -
Antimicrobial Agents and Chemotherapy Jun 2017HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M...
HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M and four associated mutations, A62V, V75I, F77L, and F116Y, were detected in patients failing therapies with dideoxynucleosides (didanosine [ddI], zalcitabine [ddC]) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we systematically determined the crystal structures of the wild-type RT/double-stranded DNA (dsDNA)/dATP (complex I), wild-type RT/dsDNA/ddATP (complex II), Q151M RT/dsDNA/dATP (complex III), Q151Mc RT/dsDNA/dATP (complex IV), and Q151Mc RT/dsDNA/ddATP (complex V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3'-endo and 3'-exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the deoxynucleoside triphosphate (dNTP)-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed and has a switched conformation for the key conserved residue R72 compared to that in wild-type RT. On the basis of a modeled structure of hepatitis B virus (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.
Topics: Anti-HIV Agents; Crystallography, X-Ray; DNA-Binding Proteins; Didanosine; Drug Resistance, Viral; Gene Products, pol; HIV Reverse Transcriptase; HIV-1; Hepatitis B virus; Humans; Mutation; Protein Conformation; Protein Structure, Quaternary; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine
PubMed: 28396546
DOI: 10.1128/AAC.00224-17