Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment

Bratt, Göran; Karlsson, Anders; Leandersson, Ann-Charlotte; Albert, Jan; Wahrén, Britta; Sandström, Eric

doi:10.1097/00002030-199816000-00015

Cited by 52 publications

(41 citation statements)

References 49 publications

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“…Models 2b and 2c shown here correspond to multivariable models 1 and 2 in Table 5. VOL. 76,2002 INFLUENCE OF CHEMOKINE RECEPTOR GENOTYPES ON HIV/AIDS 669 genetic variation on HIV-1 RNA levels is probably more useful than it is on other outcome measures because of the dual impact of viral RNA levels on subsequent disease progression rates (5,28,47,57,66) and HIV-1 transmissibility from infected to uninfected individuals (17,18,56,58,60,65). Our work could not confirm other reported associations of CCR haplotypes and genotypes with clinical outcomes in HIV-1 infection.…”

Section: Discussionmentioning

confidence: 55%

“…The plasma HIV-1 RNA concentration measured in the months after untreated infection accurately reflects the early host-virus equilibrium (10,14,32,38,47,48), which in turn is highly predictive of the rate of later disease progression (5,9,28,47,57,66) as well as HIV-1 transmissibility from infected to uninfected individuals regardless of the transmission mode (17,18,56,58,60,65). Clinical and virological studies of the impact of chemokine receptor-ligand variants on viral dynamics have already suggested a role for ⌬32 and 64I in determining this equilibrium, apparently even in the context of antiretroviral therapy (4,22,31,53).…”

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confidence: 99%

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Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Tang

Shelton²,

Makhatadze

et al. 2002

J Virol

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At the CC (␤) chemokine receptor 2 (CCR2) and CCR5 loci, combinations of common single-nucleotide polymorphisms (SNPs) and a 32-bp deletion (⌬32) form nine stable haplotypes (designated A through G*2).The distribution of these CCR2-CCR5 haplotypes was examined among 703 participants in the Multicenter AIDS Cohort Study (MACS), the District of Columbia Gay (DCG) Study, and the San Francisco Men's Health Study (SFMHS). Highly exposed and persistently seronegative (HEPS; n ‫؍‬ 90) Caucasian men from MACS more frequently carried heterozygous G*2 (⌬32) genotypes (especially A/G*2) and less frequently carried the homozygous E/E genotype compared with 469 Caucasian seroconverters (SCs) from the same cohort (P ‫؍‬ 0.004 to 0.042). Among 341 MACS Caucasian SCs with 6-to 12-month human immunodeficiency virus type 1 (HIV-1) seroconversion intervals and no potent antiretroviral therapy, mean plasma HIV-1 RNA level during the initial 42 months after seroconversion was higher in carriers of the E/E genotype and lower in those with the 64I-bearing haplotype F*2 or the ⌬32-bearing haplotype G*2 (and especially genotypes A/G*2 and F*2/G*2). A multivariable model containing these CCR markers showed significant composite effects on HIV-1 RNA at each of four postconversion intervals (P ‫؍‬ 0.0004 to 0.050). In other models using time to AIDS as the endpoint, the same markers showed more modest contributions (P ‫؍‬ 0.08 to 0.24) to differential outcome during 11.5 years of follow-up. Broadly consistent findings in the larger MACS Caucasian SCs and the smaller groups of MACS African-American SCs and the DCG and SFMHS Caucasian SCs indicate that specific CCR2-CCR5 haplotypes or genotypes mediate initial acquisition of HIV-1 infection, early host-virus equilibration, and subsequent pathogenesis.

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Section: Discussionmentioning

confidence: 55%

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confidence: 99%

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Tang

Shelton²,

Makhatadze

et al. 2002

J Virol

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“…Evaluation of host genetic influence on HIV-1 RNA levels should prove increasingly useful, because early in the course of infection, those levels have profound implications not only for the rate of subsequent progression of both untreated (4,28,43,50,61) and treated (4, 53, 54) disease but also for the transmissibility of HIV-1 from infected to uninfected individuals (12,14,49,51,55,59). If the three consistently favorable HLA markers (Table 7) prove more broadly protective in Zambians and other southern Africans, individuals carrying them should experience a relatively benign course of disease progression without treatment.…”

Section: Discussionmentioning

confidence: 99%

Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1

Tang

Tang²,

Lobashevsky³

et al. 2002

J Virol

133

126

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“…We previously observed that the CCR5 D32 deletion was predictive of a higher immunological and virological response rate to HAART, at 6 and 12 months, in a population of 166 HIV-1-infected patients with advanced disease who were protease inhibitor naïve [23]. A better response in heterozygotes has also been observed in some studies [20,[24][25][26] but not in all [23,[27][28][29].To clarify the impact of the CCR5 D32 deletion on the response to HAART, we analysed here whether the presence of the CCR5 D32 allele affected the immunological and virological outcome after HAART initiation in a larger population of HIV-1-infected patients with a longer followup after HAART initiation; this longer follow-up allowed us to investigate whether D32 heterozygotes also had a better clinical prognosis after HAART initiation. …”

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confidence: 92%

Improved virological response to highly active antiretroviral therapy in HIV‐1‐infected patients carrying the CCR5 Δ32 deletion

et al. 2007

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BackgroundPatients heterozygous for the C-C chemokine receptor 5 (CCR5) D32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 D32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. Patients and methodsWe 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. ResultsThe D32 heterozygous patients (n 5 83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P 5 0.01; and 60 vs 44% at 12 months, P 5 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. ConclusionsCCR5 D32 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 D32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis. Introduction C-C chemokine receptor 5 (CCR5), a receptor for the bchemokine RANTES, macrophage inflammatory protein (MIP)-1a and MIP-1b, is the most important chemokine receptor used by R5 HIV-1 strains for entry into CD4 cells.A 32-bp deletion (CCR5 D32) in the gene encoding the CCR5 coreceptor has been described [1][2][3]. Homozygous CCR5 D32/CCR5 D32 subjects are highly resistant to HIV-1 infection, although a few cases of infection have been reported [4][5][6]. Heterozygotes (CCR5 wt/CCR5 D32) are susceptible to HIV-1 infection, but progress more slowly to AIDS and death than wild-type patients (CCR5 wt/CCR5 wt) [7][8][9][10] 213 expression at the cell surface is diminished in D32 heterozygous patients and early plasma HIV-RNA viral load is lower in these patients than in wild-type patients [11]; this may explain why spontaneous HIV disease progression is slower in heterozygotes [9,10]. Since 1996, the use of highly active antiretroviral therapy (HAART) has provided substantial immunological (in terms of CD4 increase), virological (in terms of decrease in viral load) and clinical benefits to HIV-1-infected patients [12][13][14][15][16][17][18][19][20][21][...

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Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment

Cited by 52 publications

References 49 publications

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Distribution of Chemokine ReceptorCCR2andCCR5Genotypes and Their Relative Contribution to Human Immunodeficiency Virus Type 1 (HIV-1) Seroconversion, Early HIV-1 RNA Concentration in Plasma, and Later Disease Progression

Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1

Improved virological response to highly active antiretroviral therapy in HIV‐1‐infected patients carrying the CCR5 Δ32 deletion

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