A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

OBJECTIVE: To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy. DESIGN: A collaborative analysis of data from 12 cohorts in Europe and North America on 20,379 adults who started HAART between 1995 and 2003. METHODS: Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. RESULTS: During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/microl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone. CONCLUSION: On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org.

Discordant responses to potent antiretroviral treatment in previously naive HIV-1-infected adults initiating treatment in resource-constrained countries: the antiretroviral therapy in low-income countries (ART-LINC) collaboration

OBJECTIVES: To assess the frequency of and risk factors for discordant responses at 6 months on highly active antiretroviral therapy (HAART) in previously treatment-naive HIV patients from resource-limited countries. METHODS: The Antiretroviral Therapy in Low-Income Countries Collaboration is a network of clinics providing care and treatment to HIV-infected patients in Africa, Latin America, and Asia. Patients who initiated therapy between 1996 and 2004, were aged 16 years or older, and had a baseline CD4 cell count were included in this analysis. Responses were defined based on plasma viral load (PVL) and CD4 cell count at 6 months as complete virologic and immunologic (VR(+)IR(+)), virologic only (VR(+)IR(-)), immunologic only (VR(-)IR(+)), and nonresponse (VR(-)IR(-)). Multinomial logistic regression was used to assess the association between therapy responses and clinical and demographic variables. RESULTS: Of the 3111 patients eligible for analysis, 1914 had available information at 6 months of therapy: 1074 (56.1%) were VR(+)IR(+), 364 (19.0%) were VR(+)IR(-), 283 (14.8%) were (VR(-)IR(+)), and 193 (10.1%) were VR(-)IR(-). OF THE 3111 patients eligible for analysis, 1914 had available information at 6 months of therapy: 1074 (56.1%) were VRIR, 364 (19.0%) were VRIR, 283 (14.8%) were (VRIR), and 193 (10.1%) were VRIR. Compared with complete responders, virologic-only responders were older, had a higher baseline CD4 cell count, had a lower baseline PVL, and were more likely to have received a nonstandard HAART regimen; immunologic-only responders were younger, had a lower baseline CD4 cell count, had a higher baseline PVL, and were more likely to have received a protease inhibitor-based regimen. CONCLUSIONS: The frequency of and risk factors for discordant responses were comparable to those observed in developed countries. Longer follow-up is needed to assess the long-term impact of discordant responses on mortality in these resource-limited settings.

HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Assessment of recent HIV-1 infection by a line immunoassay for HIV-1/2 confirmation

BACKGROUND: Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this "recency" information can also be gained from an HIV confirmatory assay. METHODS AND FINDINGS: The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (< or = 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%-46%). CONCLUSIONS: Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation.

Inhibition of HIV-1 multiplication by a modified U7 snRNA inducing Tat and Rev exon skipping

The HIV-1 regulatory proteins Tat and Rev are encoded by multiply spliced mRNAs that differ by the use of alternative 3' splice sites at the beginning of the internal exon. If these internal exons are skipped, the expression of these genes, and hence HIV-1 multiplication, should be inhibited. We have previously developed a strategy, based on antisense derivatives of U7 small nuclear RNA, that allows us to induce the skipping of an internal exon in virtually any gene. Here, we have successfully applied this approach to induce a partial skipping of the Tat, Rev (and Nef) internal exons. Three functional U7 constructs were subcloned into a lentiviral vector. Two of them strongly reduced the efficiency of lentiviral particle production compared to vectors carrying either no U7 insert or unrelated U7 cassettes. This defect could be partly or fully compensated by coexpressing Rev from an unspliced mRNA in the producing cell line. Upon stable transduction into CEM-SS or CEM T-lymphocytes, the most efficient of these constructs inhibits HIV-1 multiplication. Although the inhibition is not complete, it is more efficient in combination with another mechanism inhibiting HIV multiplication. Therefore, this new approach targeting HIV-1 regulatory genes at the level of pre-mRNA splicing, in combination with other antiviral strategies, may be a useful new tool in the fight against HIV/AIDS. Copyright (c) 2007 John Wiley & Sons, Ltd

CD4+ T-cell count increase in HIV-1-infected patients with suppressed viral load within 1 year after start of antiretroviral therapy

BACKGROUND: CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). METHODS: Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included (n=1816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2-3 and years 4-5 of suppression. Multiple median regression adjusted for repeated CD4+ T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. RESULTS: Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/microl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell <650 cells/microl at start of the period and low CD4+ T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+ T-cell increases compared with stavudine. CONCLUSIONS: In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.

Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types

BACKGROUND: Standard first-line combination antiretroviral treatment (cART) against human immunodeficiency virus 1 (HIV-1) contains either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Differences between these regimen types in the extent of the emergence of drug resistance on virological failure and the implications for further treatment options have rarely been assessed. METHODS: We investigated virological outcomes in patients from the Swiss HIV Cohort Study initiating cART between January 1, 1999, and December 31, 2005, with an unboosted PI, a PI/r, or an NNRTI and compared genotypic drug resistance patterns among these groups at treatment failure. RESULTS: A total of 489 patients started cART with a PI, 518 with a PI/r, and 805 with an NNRTI. A total of 177 virological failures were observed (108 [22%] PI failures, 24 [5%] PI/r failures, and 45 [6%] NNRTI failures). The failure rate was highest in the PI group (10.3 per 100 person-years; 95% confidence interval [CI], 8.5-12.4). No difference was seen between patients taking a PI/r (2.7; 95% CI, 1.8-4.0) and those taking an NNRTI (2.4; 95% CI, 1.8-3.3). Genotypic test results were available for 142 (80%) of the patients with a virological treatment failure. Resistance mutations were found in 84% (95% CI, 75%-92%) of patients taking a PI, 30% (95% CI, 12%-54%) of patients taking a PI/r, and 66% (95% CI, 49%-80%) of patients taking an NNRTI (P < .001). Multidrug resistance occurred almost exclusively as resistance against lamivudine-emtricitabine and the group-specific third drug and was observed in 17% (95% CI, 9%-26%) of patients taking a PI, 10% (95% CI, 0.1%-32%) of patients taking a PI/r, and 50% (95% CI, 33%-67%) of patients taking an NNRTI (P < .001). CONCLUSIONS: Regimens that contained a PI/r or an NNRTI exhibited similar potency as first-line regimens. However, the use of a PI/r led to less resistance in case of virological failure, preserving more drug options for the future.

Hypogonadism in HIV-1-infected men is common and does not resolve during antiretroviral therapy

OBJECTIVES: To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART). DESIGN: Multicentre cohort of HIV-infected adults. METHODS: We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated. RESULTS: At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+ T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART. CONCLUSIONS: Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.

HIV-1 p24 may persist during long-term highly active antiretroviral therapy, increases little during short treatment breaks, and its rebound after treatment stop correlates with CD4(+) T cell loss

The dynamics of HIV-1 RNA during structured treatment interruptions (STIs) are well established, but little is known about viral proteins like p24. We studied 65 participants of an STI trial. Before the trial, continuous highly active antiretroviral therapy (HAART) had suppressed their viral load to <50 copies/mL during 6 months. They then interrupted HAART during weeks 1 through 2, 11 through 12, 21 through 22, 31 through 32, and 41 through 52. The p24 was measured by boosted enzyme-linked immunosorbent assay of plasma pretreated by efficient virus disruption and heat denaturation. At time point 0, p24 was measurable in 22 patients (34%), who had maintained a viral load <50 copies/mL for 25.4 months (median, range: 6.2-38.9 months) under HAART. Viral rebounds during 2-week STIs led to a mean p24 increase of only 0.08 to 0.19 log10 (ie, 20%-60%). Pre-HAART viral load and p24 at time 0 independently predicted p24 rebounds during the 4 2-week STIs. The p24 at time 0 and HIV-1 RNA rebound during weeks 41 through 52 independently determined the concomitant p24 rebound. An increase of p24 but not viral load during the first 8 weeks of the long STI correlated significantly with concomitant CD4(+) T cell loss. Persisting p24 despite successful HAART may reflect virus replication in reservoirs not represented by plasma viral load and has implications for the concept of therapeutic vaccination.

Androgen and gonadotropin patterns differ in HIV-1-infected men who develop lipoatrophy during antiretroviral therapy: a case-control study

OBJECTIVES: We compared androgen and gonadotropin values in HIV-infected men who did and did not develop lipoatrophy on combination antiretroviral therapy (cART). METHODS: From a population of 136 treatment-naïve male Caucasians under successful zidovudine/lamivudine-based cART, the 10 patients developing lipoatrophy (cases) were compared with 87 randomly chosen controls. Plasma levels of free testosterone (fT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone and luteinizing hormone (LH) were measured at baseline and after 2 years of cART. RESULTS: At baseline, 60% of the cases and 71% of the controls showed abnormally low fT values. LH levels were normal or low in 67 and 94% of the patients, respectively, indicating a disturbance of the hypothalamic-pituitary-gonadal axis. fT levels did not significantly change after 2 years of cART. Cases showed a significant increase in LH levels, while controls showed a significant increase in DHEA levels. In a multivariate logistic regression model, lipoatrophy was associated with higher baseline DHEA levels (P=0.04), an increase in LH levels during cART (P=0.001), a lower body mass index and greater age. CONCLUSIONS: Hypogonadism is present in the majority of HIV-infected patients. The development of cART-related lipoatrophy is associated with an increase in LH and a lack of increase in DHEA levels.

Factors associated with the emergence of K65R in patients with HIV-1 infection treated with combination antiretroviral therapy containing tenofovir

BACKGROUND: The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study. METHODS: A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed. RESULTS: In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%). CONCLUSIONS: In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor-induced mutations.

Effects of cognitive behavioral stress management on HIV-1 RNA, CD4 cell counts and psychosocial parameters of HIV-infected persons

OBJECTIVE: To determine the effects of cognitive-behavioral stress management (CBSM) training on clinical and psychosocial markers in HIV-infected persons. METHODS: A randomized controlled trial in four HIV outpatient clinics of 104 HIV-infected persons taking combination antiretroviral therapy (cART), measuring HIV-1 surrogate markers, adherence to therapy and well-being 12 months after 12 group sessions of 2 h CBSM training. RESULTS: Intent-to-treat analyses showed no effects on HIV-1 surrogate markers in the CBSM group compared with the control group: HIV-1 RNA < 50 copies/ml in 81.1% [95% confidence interval (CI), 68.0-90.6] and 74.5% (95% CI, 60.4-85.7), respectively (P = 0.34), and mean CD4 cell change from baseline of 53.0 cells/microl (95% CI, 4.1-101.8) and 15.5 cells/microl (95% CI, -34.3 to 65.4), respectively (P = 0.29). Self-reported adherence to therapy did not differ between groups at baseline (P = 0.53) or at 12 month's post-intervention (P = 0.47). Significant benefits of CBSM over no intervention were observed in mean change of quality of life scores: physical health 2.9 (95% CI, 0.7-5.1) and -0.2 (95% CI, -2.1 to 1.8), respectively (P = 0.05); mental health 4.8 (95% CI, 1.8-7.3) and -0.5 (95% CI, -3.3 to 2.2) (P = 0.02); anxiety -2.1 (95% CI, -3.6 to -1.0) and 0.3 (95% CI, -0.7 to 1.4), respectively (P = 0.002); and depression -2.1 (95% CI, -3.2 to -0.9) and 0.02 (95% CI, -1.0 to 1.1), respectively (P = 0.001). Alleviation of depression and anxiety symptoms were most pronounced among participants with high psychological distress at baseline. CONCLUSION: CBSM training of HIV-infected persons taking on cART does not improve clinical outcome but has lasting effects on quality of life and psychological well-being.