scholarly journals Genital Shedding of Resistant Human Immunodeficiency Virus-1 Among Women Diagnosed With Treatment Failure by Clinical and Immunologic Monitoring

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Susan M. Graham ◽  
Vrasha Chohan ◽  
Keshet Ronen ◽  
Ruth W. Deya ◽  
Linnet N. Masese ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Treatment Failure ◽  
Genital Tract ◽  
Virologic Failure ◽  
Resistant Virus ◽  
Line Therapy ◽  
Immunodeficiency Virus ◽  
Genital Shedding ◽  
Dual Class ◽  
Hiv 1

Abstract Background.  The accumulation of human immunodeficiency virus (HIV) resistance mutations can compromise treatment outcomes and promote transmission of drug-resistant virus. We conducted a study to determine the duration and evolution of genotypic drug resistance in the female genital tract among HIV-1-infected women failing first-line therapy. Methods.  Treatment failure was diagnosed based on World Health Organization (WHO) clinical or immunologic criteria, and second-line therapy was initiated. Stored plasma and genital samples were tested to determine the presence and timing of virologic failure and emergence of drug resistance. The median duration of genital shedding of genotypically resistant virus prior to regimen switch was estimated. Results.  Nineteen of 184 women were diagnosed with treatment failure, of whom 12 (63.2%) had confirmed virologic failure at the switch date. All 12 women with virologic failure (viral load, 5855–1 086 500 copies/mL) had dual-class resistance in plasma. Seven of the 12 (58.3%) had genital HIV-1 RNA levels high enough to amplify (673–116 494 copies/swab), all with dual-class resistance. The median time from detection of resistance in stored samples to regimen switch was 895 days (95% confidence interval [CI], 130–1414 days) for plasma and 629 days (95% CI, 341–984 days) for genital tract secretions. Conclusions.  Among women diagnosed with treatment failure using WHO clinical or immunologic criteria, over half had virologic failure confirmed in stored samples. Resistant HIV-1 RNA was shed in the genital tract at detectable levels for ≈1.7 years before failure diagnosis, with steady accumulation of mutations. These findings add urgency to the ongoing scale-up of viral load testing in resource-limited settings.

scholarly journals Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity

2003 ◽  
Vol 77 (10) ◽  
pp. 6041-6049 ◽  
Author(s):  
David A. Price ◽  
George Scullard ◽  
Annette Oxenius ◽  
Ruth Braganza ◽  
Simon A. Beddows ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
T Lymphocyte ◽  
Virologic Failure ◽  
Multiple Drug Resistance ◽  
Testable Hypothesis ◽  
Plasma Virus ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Hiv 1

ABSTRACT Many individuals chronically infected with human immunodeficiency virus type 1 (HIV-1) experience a recrudescence of plasma virus during continuous combination antiretroviral therapy (ART) due either to the emergence of drug-resistant viruses or to poor compliance. In most cases, virologic failure on ART is associated with a coincident decline in CD4+ T lymphocyte levels. However, a proportion of discordant individuals retain a stable or even increasing CD4+ T lymphocyte count despite virological failure. In order to address the nature of these different outcomes, we evaluated virologic and immunologic variables in a prospective, single-blinded, nonrandomized cohort of 53 subjects with chronic HIV-1 infection who had been treated with continuous ART and monitored intensively over a period of 19 months. In all individuals with detectable viremia on ART, multiple drug resistance mutations with similar impacts on viral growth kinetics were detected in the pol gene of circulating plasma virus. Further, C2V3 env gene analysis demonstrated sequences indicative of CCR5 coreceptor usage in the majority of those with detectable plasma viremia. In contrast to this homogeneous virologic pattern, comprehensive screening with a range of antigens derived from HIV-1 revealed substantial immunologic differences. Discordant subjects with stable CD4+ T lymphocyte counts in the presence of recrudescent virus demonstrated potent virus-specific CD4+ and CD8+ T lymphocyte responses. In contrast, subjects with virologic failure associated with declining CD4+ T lymphocyte counts had substantially weaker HIV-specific CD4+ T lymphocyte responses and exhibited a trend towards weaker HIV-specific CD8+ T lymphocyte responses. Importantly the CD4+ response was sustained over periods as long as 11 months, confirming the stability of the phenomenon. These correlative data lead to the testable hypothesis that the consequences of viral recrudescence during continuous ART are modulated by the HIV-specific cellular immune response.

scholarly journals Comparisons of Human Immunodeficiency Virus Type 1 Envelope Variants in Blood and Genital Fluids near the Time of Male-to-Female Transmission

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Corey A. Williams-Wietzikoski ◽  
Mary S. Campbell ◽  
Rachel Payant ◽  
Airin Lam ◽  
Hong Zhao ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Genital Tract ◽  
Recent Common Ancestor ◽  
Female Partners ◽  
Immunodeficiency Virus ◽  
Male To Female ◽  
Hiv 1

ABSTRACTTo better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1envgp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples’ sequences demonstrated, with one exception, that the women’s founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women’s founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men’s viruses were found to link to the women’s founders, nor did the women’senvsequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others’ findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters’ blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen.IMPORTANCEMucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males’ genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.

scholarly journals Predictors of Hepatitis C Treatment Failure After Using Direct-Acting Antivirals in People Living With Human Immunodeficiency Virus

2019 ◽  
Vol 6 (3) ◽  
Author(s):  
Edward R Cachay ◽  
Alvaro Mena ◽  
Luis Morano ◽  
Laura Benitez ◽  
Ivana Maida ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mental Illness ◽  
Drug Use ◽  
Treatment Failure ◽  
Illicit Drug ◽  
Virologic Failure ◽  
Illicit Drug Use ◽  
Hcv Treatment ◽  
Immunodeficiency Virus ◽  
Direct Acting

Abstract Background Little is known about the influence of ongoing barriers to care in the persistence of hepatitis C virus (HCV) viremia after treatment with direct-acting antivirals (DAAs) among people living with human immunodeficiency virus (PLWH). Methods We conducted a retrospective cohort analysis of PLWH treated through the standard of care in 3 Western countries, to investigate the predictors of HCV treatment failure (clinical or virologic), defined as having a detectable serum HCV ribonucleic acid within 12 weeks after DAA discontinuation. In addition to HCV and liver-related predictors, we collected data on ongoing illicit drug use, alcohol abuse, mental illness, and unstable housing. Logistic regression analyses were used to identify predictors of HCV treatment failure. Results Between January 2014 and December 2017, 784 PLWH were treated with DAA, 7% (n = 55) of whom failed HCV therapy: 50.9% (n = 28) had a clinical failure (discontinued DAA therapy prematurely, died, or were lost to follow-up), 47.3% (n = 26) had an HCV virologic failure, and 1 (1.8%) was reinfected with HCV. Ongoing drug use (odds ratio [OR] = 2.60) and mental illness (OR = 2.85) were independent predictors of any HCV treatment failure. Having both present explained 20% of the risk of any HCV treatment failure due to their interaction (OR = 7.47; P < .0001). Predictors of HCV virologic failure were ongoing illicit drug use (OR = 2.75) and advanced liver fibrosis (OR = 2.29). Conclusions People living with human immunodeficiency virus with ongoing illicit drug use, mental illness, and advanced liver fibrosis might benefit from enhanced DAA treatment strategies to reduce the risk of HCV treatment failure.

scholarly journals A Human Immunodeficiency Virus (HIV)–Inducing Factor from the Female Genital Tract Activates HIV‐1 Gene Expression through the κB Enhancer

1998 ◽  
Vol 178 (5) ◽  
pp. 1343-1351 ◽  
Author(s):  
Lena Al‐Harthi ◽  
Gregory T. Spear ◽  
Farhad B. Hashemi ◽  
Alan Landay ◽  
Beverly E. Sha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Female Genital

scholarly journals Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates.

1997 ◽  
Vol 41 (4) ◽  
pp. 831-837 ◽  
Author(s):  
R W Buckheit ◽  
M J Snow ◽  
V Fliakas-Boltz ◽  
T L Kinjerski ◽  
J D Russell ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
In Vitro Selection ◽  
Nucleoside Analogs ◽  
Side Chain ◽  
Resistant Virus ◽  
Immunodeficiency Virus ◽  
Virus Isolates ◽  
Hiv 1

The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.

scholarly journals gp340 Promotes Transcytosis of Human Immunodeficiency Virus Type 1 in Genital Tract-Derived Cell Lines and Primary Endocervical Tissue

2009 ◽  
Vol 83 (17) ◽  
pp. 8596-8603 ◽  
Author(s):  
Earl Stoddard ◽  
Houping Ni ◽  
Georgetta Cannon ◽  
Chunhui Zhou ◽  
Neville Kallenbach ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Epithelial Cells ◽  
Cell Lines ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Genital Tract ◽  
Heterosexual Transmission ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human scavenger receptor gp340 has been identified as a binding protein for the human immunodeficiency virus type 1 (HIV-1) envelope that is expressed on the cell surface of female genital tract epithelial cells. This interaction allows such epithelial cells to efficiently transmit infective virus to susceptible targets and maintain viral infectivity for several days. Within the context of vaginal transmission, HIV must first traverse a normally protective mucosa containing a cell barrier to reach the underlying T cells and dendritic cells, which propagate and spread the infection. The mechanism by which HIV-1 can bypass an otherwise healthy cellular barrier remains an important area of study. Here, we demonstrate that genital tract-derived cell lines and primary human endocervical tissue can support direct transcytosis of cell-free virus from the apical to basolateral surfaces. Further, this transport of virus can be blocked through the addition of antibodies or peptides that directly block the interaction of gp340 with the HIV-1 envelope, if added prior to viral pulsing on the apical side of the cell or tissue barrier. Our data support a role for the previously described heparan sulfate moieties in mediating this transcytosis but add gp340 as an important facilitator of HIV-1 transcytosis across genital tract tissue. This study demonstrates that HIV-1 actively traverses the protective barriers of the human genital tract and presents a second mechanism whereby gp340 can promote heterosexual transmission.

scholarly journals Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

2002 ◽  
Vol 76 (14) ◽  
pp. 7000-7009 ◽  
Author(s):  
Gustavo H. Kijak ◽  
Viviana Simon ◽  
Peter Balfe ◽  
Jeroen Vanderhoeven ◽  
Sandra E. Pampuro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Treatment Failure ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Treatment Interruption ◽  
Viral Population ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

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