Soluble urokinase receptor levels in plasma during 5 years of highly active antiretroviral therapy in HIV-1-infected patients

High blood levels of the soluble urokinase receptor (suPAR) strongly predict increased mortality in human immunodeficiency virus-1 (HIV-1)-infected patients. This study investigated the plasma concentration of suPAR in 29 treatment-naive HIV-1-infected patients during 5 years treatment with highly active antiretroviral therapy (HAART). Plasma suPAR decreased after introducing HAART, most pronounced during the first treatment year. The change in plasma suPAR was independent of changes in viral replication and CD4+ cells but it was strongly correlated with plasma levels of the soluble TNF receptor II. Compared with healthy individuals, plasma suPAR and sTN-FrII was increased in untreated patients. After initiating HAART, plasma sTNFrII remained increased whereas plasma suPAR decreased to a level comparable with healthy individuals. The present data indicate that the circulating suPAR level is linked to inflammation in untreated as well as HAART-treated HIV-1-infected patients.     

Prevalence and impact of hepatitis B and C virus co-infections in antiretroviral treatment naïve patients with HIV infection at a major treatment center in Ghana

Data on the effects of the presence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients co‐infected with these viruses and HIV in West Africa are conflicting and little information is available in Ghana. A cohort of 138 treatment naïve individuals infected with HIV was screened for HBV and HCV serologic markers; HBsAg positive patients were tested for HBeAg, anti‐HBe, and anti‐HBc IgM. The viral load of HIV‐1 in the plasma was determined in 81 patients. Eighteen of the 138 patients (13%) and 5 (3.6%) had HBsAg and anti‐HCV, respectively. None of the patients had anti‐HBc IgM, but 10 (55.6%) and 8 (44.4%) of the 18 patients who were HBsAg positive had HBeAg and anti‐HBe, respectively. In patients with measurement of CD4⁺ undertaken within 1 month (n = 83), CD4⁺ count was significantly lower in patients with HBeAg (median [IQR], 81 [22–144]) as compared to those with anti‐HBe (median [IQR], 210 [197–222]) (P = 0.002, CI: ?96.46 to 51.21). However, those with HIV mono‐infection had similar CD4⁺ counts (median [IQR], 57 [14–159]) compared to those with HBeAg (P = 1.0, CI: ?71.75 to 73.66). Similar results were obtained if CD4⁺ count was measured within 2 months prior to initiation of HAART (n = 119). Generally, HBV and anti‐HCV did not affect CD4⁺ and viral loads of HIV‐1 in plasma but patients with HIV and HBV co‐infection who had HBeAg had more severe immune suppression as compared to those with anti‐HBe. This may have implication for initiating HAART in HBV endemic areas. J. Med. Virol. 84:6–10, 2011. © 2011 Wiley Periodicals, Inc.     

Sustained low‐dose growth hormone therapy optimizes bioactive insulin‐like growth factor‐I level and may enhance CD4 T‐cell number in HIV infection

High‐dose recombinant human growth hormone (rhGH) (2–6 mg/day) regimes may facilitate T‐cell restoration in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART). However, high‐dose rhGH regimens increase insulin‐like growth factor‐I (IGF‐I) to supra‐physiological levels associated with severe side effects. The present study investigated whether lower doses of rhGH may improve T‐cell restoration in patients infected with HIV following an expedient response of total and bioactive (i.e., free) IGF‐I. A previous 16‐week pilot‐study included six HIV‐infected patients on stable HAART to receive rhGH 0.7 mg/day, which increased total (+117%, P < 0.01) and free (+155%, P < 0.01) IGF‐I levels. The study was extended to examine whether continuous use of low‐dose rhGH (0.7 mg/day until week 60; 0.4 mg/day from week 60 to week 140) would maintain expedient IGF‐I levels and improve CD4 T‐cell response. Total and free IGF‐I increased at week 36 (+97%, P < 0.01 and +125%, P < 0.01, respectively) and week 60 (+77%, P = 0.01 and +125%, P < 0.01) compared to baseline levels (161 ± 15 and 0.75 ± 0.11 µg/L). CD4 T‐cell number increased at week 36 (+15%, P < 0.05) and week 60 (+31%, P = 0.01) compared to baseline levels (456 ± 55 cells/µL). Following rhGH dose reduction, total IGF‐I and CD4 T‐cell number remained increased at week 88 (+44%, P = 0.01 and +33%, P < 0.01) and week 140 (+46%, P = 0.07 and +36%, P = 0.02) compared to baseline levels. These data support the notion that low‐dose rhGH regimens may increase expediently total and bioactive IGF‐I and improve T‐cell restoration in patients infected with HIV on HAART. J. Med. Virol. 82:197–205, 2010. © 2009 Wiley‐Liss, Inc.     

Association of IL‐4 589 C/T promoter and IL‐4RαI50V receptor polymorphism with susceptibility to HIV‐1 infection in North Indians

The clinical course and outcome of HIV‐1 infection are highly variable among individuals. Interleukin 4 (IL‐4) is a key T helper 2 cytokine with various immune‐modulating functions including induction of immunoglobulin E (IgE) production in B cells, downregulation of CCR5 and upregulation of CXCR4, the main co‐receptors for HIV. Our objective is to investigate whether single‐nucleotide polymorphisms (SNPs) in the IL‐4 promoter 589 C/T and IL‐4 Rα I50V affect the susceptibility to HIV infection and its progression to AIDS in North Indian individuals. The study population consisted of 180 HIV‐1 seropositive (HSP) stratified on the basis of disease severity (stage I, II, III), 50 HIV‐1 exposed seronegative (HES), and 305 HIV‐1 seronegative (HSN) individuals. The subjects were genotyped for IL‐4 589 C/T promoter polymorphism and IL‐4 Rα I50V by polymerase chain reaction restriction fragment length polymorphism. The results showed that IL‐4 589 C/T was not associated with the risk of HIV infection and disease progression. However, the IL‐4Rα I50 allele and genotype was significantly increased in HSP compared to HSN and HSP and was associated with risk of HIV infection. The frequency of IL‐4Rα I50 allele in the HSP group was higher than in HSN (76.11 vs. 64.75%; P = 0.000; OR = 1.734) and HES (76.11% vs. 62.00%; P = 0.007; OR = 1.953). Homozygous IL‐4Rα I50I genotype was significantly increased in HSP group compared with HSN (58.88% vs. 44.26%; P = 0.002; OR = 1.804) and HES (58.88% vs. 42.00%; P = 0.038; OR = 1.978). The present study for the first time suggests an association of IL‐4Rα I50 allele with increased likelihood of HIV‐1 infection in North Indian population. Further studies are required to confirm these findings and understand the effect of IL‐4Rα polymorphism on the outcome of HIV‐1 infection. J. Med. Virol. 81:959–965, 2009. © 2009 Wiley‐Liss, Inc.     

High plasma levels of intact and cleaved soluble urokinase receptor reflect immune activation and are independent predictors of mortality in HIV-1-infected patients

BACKGROUND: High blood levels of soluble urokinase receptor (suPAR) measured by enzyme-linked immunoassay (ELISA) (bulk measurement of 3-domain and 2-domain suPAR [suPAR(I-III), suPAR(II-III)], and suPAR(I-III) ligand complexes) strongly predict mortality in HIV-1-infected patients. This study investigated plasma levels of suPAR(I-III), suPAR(II-III), and 1-domain suPAR [suPAR(I)] and their predictive value for survival in HIV patients. METHODS: Plasma suPAR was measured by ELISA and 3 different time-resolved fluorescence immunoassays detecting suPAR(I-III), suPAR(I-III) plus suPAR(II-III), and suPAR(I) in 99 HIV patients and 59 healthy individuals. RESULTS: Plasma suPAR(I-III), suPAR(II-III), and suPAR(I) were increased in HIV patients and increased with HIV disease progression (P < 0.001 for all). In multivariate linear regression analysis, soluble immune activation markers and hemoglobin were independent predictors of plasma suPAR in HIV patients, whereas the neutrophil concentration was the only independent predictor of plasma suPAR in controls. In univariate Cox analysis, higher levels of suPAR(I-III), suPAR(II-III), and suPAR(I) predicted increased mortality risk (P < 0.001 for all). In multivariate Cox analysis adjusting for CD4+ count, HIV RNA, beta2-microglobulin, hemoglobin and clinical stage, higher levels of suPAR(I-III) and suPAR(II-III) were independent predictors of increased mortality risk (P < 0.05 for both), whereas suPAR(I) was not. CONCLUSIONS: Plasma levels of different suPAR forms are increased and associated with immune activation in HIV patients, and suPAR(I-III) and suPAR(II-III) are independent predictors of mortality in these patients.     

Reduced release of intact and cleaved urokinase receptor in stimulated whole-blood cultures from human immunodeficiency virus-1-infected patients

The blood levels of the soluble forms of the urokinase receptor (suPAR) are increased in human immunodeficiency virus (HIV)-1-infected patients. This study investigated whether the release of urokinase-type plasminogen activator receptor (uPAR) in whole-blood cultures was affected by HIV infection. The release of different uPAR forms in whole-blood cultures incubated 24 h with or without phytohemagglutinin and lipopolysaccharide was analysed in 47 HIV patients and 19 controls. suPAR was measured by enzyme-linked immunosorbent assay (ELISA) (bulk-suPAR) and three different time-resolved fluorescence immunoassays measuring three-domain suPAR [suPAR(I-III)], three- and two-domain suPAR [suPAR(I-III) + suPAR(II-III)] and one-domain suPAR [suPAR(I)]. The uPAR release was correlated to leucocyte subpopulations and plasma levels of suPAR. The stimulated net whole-blood culture release of bulk-uPAR, uPAR(I-III), uPAR(II-III) and uPAR(I) was reduced in HIV patients (all P < 0.01), whereas the spontaneous bulk-uPAR and uPAR(I-III) release was increased in HIV patients (both P < 0.05). The stimulated uPAR release in whole-blood cultures correlated well to leucocytes and circulating suPAR levels in controls, whereas the correlation was weaker to leucocytes and nonexisting to circulating suPAR levels in HIV patients. These findings demonstrate that HIV infection affects stimulated and spontaneous uPAR release in whole-blood cultures. Given that high blood levels of suPAR in HIV patients are linked to immune activation, the perturbations in uPAR release in whole-blood cultures from HIV patients may also reflect immune activation.     

The effect of different combination therapies on oxidative stress markers in HIV infected patients in cameroon

The study assessed the effect of some highly active antiretroviral therapies (HAART), used in the management of HIV/AIDS in Cameroon, on oxidative stress markers such as malondialdehyde (as TBARs), albumin, protein carbonyl content and protein sulfhydryls groups. 85 HIV positive patients (34.8 ± 9.3 years) were on three different highly active antiretroviral therapies (HAART patients). 65 HIV positive patients (32.2 ± 10.9 years) on no treatment (Pre-HAART patients), and 90 non-HIV infected patients (32.6 ± 9.3 years), were the control groups. Plasma TBARs as well as carbonyl levels were significantly higher in HIV patients on HAART compared to pre-HAART patients or non-HIV infected controls. On the other hand, the protein sulfhydryl group content was not different for patients on HAART compared to pre-HAART patients, but both were significantly lower than non-HIV infected controls (P < 0.0001, 0.001). The combination treatment Therapy I [stavudin (80 mg) + Lamivudin (600 mg) + Nevirapin + (400 mg) zidovudin (600 mg)] brought about a significant (p < 0.05) reduction in the plasma concentration of protein sulfhydrl groups as well as TBARs compared to Therapy II [stavudin (80 mg) + Lamivudin (300 mg) + nevirapin (400 mg)] or with combination Therapy III of [zidovudine (600 mg) + lamivudin(300 mg) with efavirenz (600 mg)] (P < 0.05). The content of the antioxidant, Vitamin C was lower in the plasma of patients on Therapy I compared to those on Therapy II (P < 0.01) and Therapy III (P < 0.001).     

Sublingual allergen immunotherapy in HIV‐positive patients

HIV infection is a relative contraindication for allergic immunotherapy (AIT). In the last decade, highly active antiretroviral therapy (HAART) has improved the immune function and life expectancy in HIV‐infected patients whose respiratory allergic incidence is similar to the general population. We evaluated the safety and clinical effectiveness of sublingual immunotherapy in a group of grass pollen‐allergic HAART‐treated HIV‐positive patients. Thirteen patients received sublingual immunotherapy (SLIT) tablet (Oralair, Stallergenes©) and symptomatic therapy and were compared with nine patients receiving symptomatic therapy alone. Clinical benefits were evaluated by the analysis of total combined score (TCS), sum of symptom–medication score, and a quality of life (QoL) questionnaire. HIV viral load and peripheral TCD4 lymphocytes were analyzed at the beginning and at the end of the study. Clinical efficacy data showed a significant improvement in SLIT‐treated patients compared to controls (TCS: P = 0.0001; QoL: P = 0.03). We did not observe any significant alteration of TCD4 cell counts and viral load (VL) in both groups. Our preliminary data showed that SLIT therapy in viro‐immunological controlled HAART treated HIV positive patients was efficacious, safe and well tolerated.     

Occult hepatitis B in persons infected with HIV is associated with low CD4 counts and resolves during antiretroviral therapy

Occult hepatitis B virus (HBV) is defined by the presence of plasma HBV DNA in individuals with HBV core antibodies (anti‐HBc), but without HBV surface antigen (HBsAg). The prevalence of occult HBV in HIV‐infected patients remains controversial, and the risk factors, clinical significance and effect of highly active antiretroviral therapy (HAART) are unknown. The aim of this study was to determine prevalence, risk factors, and clinical significance of occult HBV in HIV‐infected patients and to evaluate the effect of HAART. Plasma HBV DNA levels were determined in 191 HIV positive, antiretroviral naïve patients, who were anti‐HBc positive and HBsAg negative. Quantitative HBV DNA was determined using a Taqman real‐time nested PCR. Additionally, plasma HIV RNA levels, CD4 cell counts, anti‐HBs‐antibodies, anti‐HCV‐antibodies, ALT, AST, and γGT were determined. Occult HBV (a plasma HBV DNA level >50 copies/ml) was detected in 9/191 (4.7%) of the patients. Among 45 anti‐HBs‐negative patients (isolated anti‐HBc positive), the prevalence was 11.1%. Patients with occult HBV had significantly lower CD4 count compared to anti‐HBc‐positive/HBsAg negative/HBV DNA‐negative patients (105 ± 157 (median ± SD) vs. 323 ± 299 cells/mm³, P = 0.019). When HAART (including lamivudine) was initiated in the patients with occult HBV, HBV DNA was no longer detectable in any of the patients during 3 years of follow‐up. In conclusion, occult HBV was associated with low CD4 counts and may be viewed as opportunistic reactivation of HBV that resolves as a consequence of HAART induced immune reconstitution and/or the effect of lamivudine. J. Med. Virol. 81:441–445, 2009. © 2009 Wiley‐Liss, Inc.     

Changes in the levels of some acute-phase proteins in human immunodeficiency virus-1 infected patients, following interleukin-2 treatment

Intermittent interleukin (IL)‐2 administration to human immunodeficiency virus (HIV)‐1 infected patients is well documented and generally used, but there is limited information about the changes of acute‐phase protein (APP) levels in response to this treatment. Fifteen patients undergoing highly active anti‐retroviral therapy (HAART) treatment, with undetectable viral load, but low CD4⁺ cell count (<300/µl), have been treated with 3·6 M IU Proleukine® administered twice daily by subcutaneous injection over 5 days. C‐reactive protein (CRP), d ‐dimer, C3, C9, C1‐inh and alpha‐2HS glycoprotein levels were measured immediately before IL‐2 administration, as well as on day 5 and 2–3 weeks thereafter. After IL‐2 administration, both mean d ‐dimer and CRP levels increased significantly (P < 0·001), but returned (P < 0·001) to baseline within the subsequent 2–3 weeks. Alpha‐2HS glycoprotein decreased immediately after IL‐2 administration. No significant differences were detected in the levels of C3, C9 and C1‐inh. A significant, positive correlation (r = 0·5178, P = 0·0008) was ascertained between the changes of CRP level, measured immediately before as well as 5 days after IL‐2 administration, and changes in CD4 T cell counts measured 2–3 weeks before and after treatment, respectively. IL‐2 administration induces rapid elevation of two major APPs (CRP, d ‐dimer). The positive correlation observed between the changes of CRP levels and CD4⁺ cell counts after IL‐2 administration may indicate that the abrupt, but transitory overproduction of CRP might contribute to the CD4⁺ cell count‐increasing effect of the drug and/ or may be associated with serious side effects.     

T-cell mean telomere lengths changes in treatment naïve HIV-infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART

The effect of highly active antiretroviral therapy (HAART) and granulocyte colony stimulating factor (G‐CSF) on mean telomere restriction fragment (TRF) length of peripheral blood mononuclear cells (PBMC) was examined in 11 treatment naïve human immunodeficiency virus (HIV)‐infected individuals with a CD4⁺ T‐cell count < 350cells/mm³. Patients were randomized to HAART combined with G‐CSF thrice weekly for 12 weeks (n = 6) or placebo (n = 5). An increase in the mean TRF lengths was observed in PBMC of patients on HAART after 24 weeks of treatment mainly owing to increased mean CD8⁺ T‐cell TRF lengths. However, in the group of patients on HAART combined with G‐CSF no changes of PBMC mean TRF length was observed during treatment or during 12 weeks of follow‐up. The mean CD4⁺ T‐cell TRF length did not change in any of the two groups. These results confirm that HAART induces mainly the lengthening of the mean CD8⁺ T‐cell TRF length. However, G‐CSF given simultaneously with HAART induces an inhibition of the expected lengthening in mean TRF length. These results do therefore not support the use of adjuvant G‐CSF treatment simultaneously when initiating HAART and should further be evaluated before use in non‐neutropenic HIV‐infected patients.     

Increased levels of regulatory T cells (Tregs) in human immunodeficiency virus‐infected patients after 5 years of highly active anti‐retroviral therapy may be due to increased thymic production of naive Tregs

This study determines levels of regulatory T cells (T_regs), naive T_regs, immune activation and cytokine patterns in 15 adult human immunodeficiency virus (HIV)‐infected patients receiving prolonged highly active anti‐retroviral therapy (HAART) who have known thymic output, and explores if naive T_regs may represent recent thymic emigrant T_regs. HIV‐infected patients treated with HAART with a median of 1 and 5 years were compared with healthy controls. Percentages of T_regs (CD3⁺CD4⁺CD25⁺CD127^low), naive T_regs (CD3⁺CD4⁺CD25⁺CD45RA⁺) and activation markers (CD38⁺human leucocyte antigen D‐related) were determined by flow cytometry. Forkhead box P3 mRNA expression and T cell receptor excision circles (T_REC) content in CD4⁺ cells were determined by polymerase chain reaction and cytokines analysed with Luminex technology. Levels of T_regs were significantly higher in HIV‐infected patients compared with controls, both after 1 and 5 years of HAART (P < 0·001), despite fully suppressed HIV‐RNA and normalization of both CD4 counts, immune activation and cytokine patterns. Furthermore, levels of naive T_regs were elevated significantly in HIV‐infected patients (P < 0·001) and were associated with thymic output measured as the T_REC frequency in CD4⁺ cells (P = 0·038). In summary, T_reg levels in HIV‐infected patients are elevated even after 5 years of HAART. Increased thymic production of naive T_regs may contribute to higher T_reg levels in HIV‐infection.     

HIV replication is associated with increased severity of liver biopsy changes in HIV-HBV and HIV-HCV co-infection

Histological parameters were assessed in liver biopsies (n = 48) performed in patients co‐infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in order to evaluate factors which were associated with significant liver disease. Necroinflammation and fibrosis was scored by the Ishak classification system, and binary logistic regression analysis was used to assess HIV and antiretroviral‐related determinants of necroinflammation and fibrosis. A total of 46 biopsies were included; 33 were from HIV‐positive patients co‐infected with HCV and 15 biopsies were from HIV‐positive patients co‐infected with HBV. One HIV‐positive patient was co‐infected with HBV and HCV. Median biopsy inflammatory grade for the cohort was 8.5 (IQR 6–10), the median fibrosis Stage 2 (IQR 1.8–4), and the median steatosis score was 1 (IQR 0–2). At the univariate level, HIV‐related variables that were significantly associated with more severe biopsy changes were higher HIV RNA at the time of biopsy (associated with inflammatory Grade 10+; P = 0.018) and any exposure to didanasine (ddI) or stavudine (D4T; associated with fibrosis Stage 3+; P = 0.022). HIV RNA at the time of biopsy remained significant at the multivariate level. Patients with HIV hepatitis co‐infection in this cohort had surprisingly mild changes in liver histology, and there were no statistically significant differences between biopsy results in HBV compared to HCV co‐infection. The association between HIV RNA and necroinflammation supports current recommendations for earlier initiation of HAART in patients with HIV‐hepatitis co‐infection. J. Med. Virol. 84: 993–1001, 2012. © 2012 Wiley Periodicals, Inc.     

Homeostatic chemokines CCL19 and CCL21 promote inflammation in human immunodeficiency virus‐infected patients with ongoing viral replication

CCL19 and CCL21 and their receptor CCR7 are expressed constitutively within lymphoid organs, regulating lymphocyte homing. Recent studies suggest that these chemokines may have inflammatory properties. We hypothesized a role of CCL19/CCL21 in human immunodeficiency virus (HIV) infection by promoting inflammation. We examined the expression of CCL19 and CCL21 in mononuclear cells from peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) in HIV‐infected patients before and during highly active anti‐retroviral therapy (HAART). We also examined the ability of CCL19/CCL21 to promote inflammatory responses in these patients. PBMC from untreated HIV‐infected patients (n = 29) released enhanced levels of CCL19 spontaneously compared with cells from controls (n = 20), particularly in those with symptomatic disease (n = 15, P < 0·01 versus controls). During HAART (n = 9), there was a decrease in the spontaneous CCL19 release and an increase in the phytohaemagglutinin‐stimulated CCL19 release in both PBMC (P < 0·01) and BMMC (P < 0·05). In patients with enhanced HIV replication there was an increased proportion of inflammatory CD8⁺CCR7^‐CD45RA^‐ T cells in peripheral blood [P < 0·01 and P < 0·05 versus controls, untreated (n = 9) and treatment failure (n = 8), respectively]. In vitro, CCL19/CCL21 promoted an inflammatory response in PBMC when accompanied by high viral load, irrespective of HAART. The HIV‐tat protein significantly boosted the inflammatory effect of CCL19/CCL21 in PBMC. These findings link a dysregulated CCL19/CCL21/CCR7 system in HIV‐infected patients to persistent inflammation and HIV replication, not only in untreated HIV infection, but also in treatment failure during HAART.     

Increased oxidative stress condition found in different stages of HIV disease in patients undergoing antiretroviral therapy in Umuahia (Nigeria)

Context: Effective diagnostic tools for management of HIV disease progression in Sub-Saharan Africa is inadequate considering the endemic nature of the infection in the region.

Objective: To elucidate the clinical implication of oxidative stress (measured as Malondialdehyde, MDA) as additional biomarker of HIV disease progression and its implication in HIV clinical management.

Materials and methods: A total of 250 individuals were recruited for the study. FACScan cytometry and spectrophotometric methods were employed in assessing T-lymphocytes (CD3, CD4, CD8) and MDA respectively.

Results: MDA concentration increased significantly (P < 0.05) in highly active antiretroviral therapy (HAART) subjects by 12.72% in category 1, 9.75% in III and in category II (4.63%) on comparison with non-HAART subjects. In subjects taking HAART, 22.2%, 56.3%, and 22.2% were found to be in category I, II and III, respectively, with a corresponding non-HAART values of 15.6%, 45.6% and 38.9%. However, Spearman’s rank correlation (P < 0.001) statistics of MDA and HIV categories showed a negative correlation in all the categories (I, II and III).

Discussion and conclusion: These findings suggest that MDA may be an additional clinical factor in assessing progression of HIV disease; however, necessary fortification of regimen with antioxidant may help reduce the high MDA concentration in the disease progression of the infection.     

The relationship between genotypic sensitivity score and treatment outcomes in late stage HIV disease after supervised HAART

This study investigated the effect of resistance testing quantified through a genotypic sensitivity score (GSS) on virologic, immunologic, and clinical responses among patients with late stage HIV‐1 disease receiving supervised highly active antiretroviral therapy (HAART). Newly admitted patients received drug resistance testing (n = 198) and then HAART supervised by residential health‐care facilities nurses. After initiating a resistance testing‐informed HAART regimen, patients were followed for HIV‐1 RNA suppression (<50 copies/ml), mean change in CD4⁺ T‐cells, new AIDS defining category C opportunistic conditions and death. GSS was constructed using the HAART regimen prescribed after resistance testing and data derived from IAS‐USA consensus mutations table with modification. Regressions with generalized estimating equations for robust estimation of standard errors and Cox proportional hazards regression estimated independent associations between GSS and treatment responses. After adjusting for adherence, initial log₁₀ HIV‐1 RNA levels, and other covariates, patients with a GSS ≥3 had significantly greater HIV‐1 RNA suppression (adjusted odds ratio (AOR) 2.32; 95% CI 1.14, 4.75). HIV‐1 RNA levels were lower among patients with ≥95% adherence, but the effect of GSS on viral suppression was not modified by adherence. Self‐rated health status, and baseline CD4⁺ T‐cell counts independently predicted HIV‐1 RNA suppression. GSS did not predict mean change in CD4⁺ cells/mm³ (236 vs. 233, P = 0.92), occurrence of new AIDS defining category C conditions or death. These data support resistance testing‐guided therapy as an independent predictive factor to improve virologic responses in treatment‐experienced patients. J. Med. Virol. 81:1323–1335, 2009. © 2009 Wiley‐Liss, Inc.     

IL28B polymorphism is not associated with HCV protease diversity in patients co-infected with HIV and HCV treated with pegylated interferon and ribavirin

Recent studies have demonstrated that IL28B polymorphisms predict therapeutic responses in chronic hepatitis C virus (HCV)‐treated patients; however, the effect on HCV viral diversity, particularly on the HCV protease gene, is not clear. This study sought to evaluate the effect of IL28B polymorphisms on HCV diversity at NS3/4 protease region, which may influence therapeutic response to an HCV protease inhibitor based regimen. Twenty‐two patients co‐infected with HIV and HCV genotype 1, treatment‐naïve on stable HIV antiretroviral therapy initiating interferon‐based treatment were evaluated. Plasma HCV NS3 gene diversity was analyzed by clonal analysis at baseline and end of treatment. IL28B (rs12979860) genotypes were tested for associations with virologic outcomes and diversity parameters. There was similar baseline NS3 diversity in patients with CC (favorable) genotype compared to those with CT/TT (unfavorable) genotypes. There was no significant association between IL28B genotype and baseline NS3 nucleotide p‐distance, dS‐dN, amino acid p‐distance, or nucleotide changes. Among patients without a sustained virologic response, between baseline and follow‐up there was a significant trend towards decreased diversity after treatment among patients with favorable genotype, which was not observed in unfavorable genotypes. In patients treated with peginterferon/ribavirin therapy, IL28B polymorphism was not associated with enhanced NS3 diversity at baseline. Among non‐SVR patients with the less favorable genotype, there was no change in diversity after treatment. This suggests that IL28B genotype is unlikely to have a negative impact on subsequent HCV PI efficacy in patients co‐infected with HIV and HCV patients who have previously failed HCV therapy. J. Med. Virol. 84:1522–1527, 2012. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.