Abstract Objective There is controversy over whether or not chronic HIV infection contributes to atherosclerosis. We investigated the relationship between HIV infection, antiretroviral medication and ...ultrasound evidence of early atherosclerosis in the context of vascular risk factors. Design A case–control design with 292 HIV-positive subjects and 1168 age- and sex-matched controls. Methods We assessed vascular risk factors, blood pressure, serum lipids and carotid intima media thickness (IMT) in cases and controls. With multivariate regression models, we investigated the effects of HIV status and antiretroviral medication on IMT. Results The common carotid artery (CCA) IMT value was 5.70% (95% confidence interval 3.08–8.38%, p < 0.0001) or 0.044 mm 0.021–0.066 mm ( p = 0.0001) higher in HIV-positives, adjusted for multiple risk factors. In the carotid bifurcation (BIF), the IMT values were 24.4% 19.5–29.4% or 0.250 mm 0.198–0.303 mm higher in HIV patients ( p < 0.0001). An investigation of antiretroviral substances revealed higher CCA- and BIF-IMT values in patients receiving combination antiretroviral therapy (HAART). Conclusions HIV infection and HAART are independent risk factors for early carotid atherosclerosis. Assuming a risk ratio similar to that in large population-based cohorts, the observed IMT elevation suggests that vascular risk is 4–14% greater and the “vascular age” 4–5 years higher in HIV-positive subjects. The underlying mechanisms remain to be clarified.
Tenofovir disoproxil fumarate (TDF) was developed for the treatment of human immunodeficiency virus (HIV) infection. However, controlled data are sparse on the long-term renal tolerability of TDF at ...the currently approved daily dose of 300 mg in treatment-naive HIV-infected patients.
Over 144 weeks, this 600 patient, multicentre randomized, placebo-controlled, double-blind trial compared stavudine (301 patients) and TDF (299 patients), both administered in combination with lamivudine and efavirenz, in antiretroviral-naive patients. TDF or placebo and stavudine or placebo were administered in an open-label fashion. All medications were taken orally. At screening, all patients had serum creatinines <1.5 mg/dl, calculated creatinine clearances > or =60 ml/min and a serum phosphorus > or =2.2 mg/dl.
The incidences of grades 1 (> or =0.5 mg/dl increase from baseline), 2 (2.1-3.0 mg/dl) and 3 (3.1-6.0 mg/dl) serum creatinine elevations at week 144 were 4, <1 and 0%, respectively, in the TDF group and 2, 0 and <1% in the stavudine control group (P = NS). There were no grade 4 (>6 mg/dl) serum creatinine elevations. At week 144, there was no change from baseline in the mean (0.83 mg/dl) serum creatinine in the TDF group compared with a 0.1 mg/dl decrease from baseline (0.83 mg/dl) in the stavudine control group. The incidences of grades 1 (2.0-2.2 mg/dl), 2 (1.5-1.9 mg/dl) and 3 (1.0-1.4 mg/dl) hypophosphataemia at week 144 were 4, 3 and <1%, respectively, in the TDF group and 4, 2 and <1% in the control group (P = NS). No patient experienced grade 4 (<1.0 mg/dl) hypophosphataemia. At week 144, the decrease (Delta) of mean serum phosphorus levels from baseline in both groups was similar (Delta 0.2 from 3.6 mg/dl for the TDF group, and 0.1 from 3.5 mg/dl for the stavudine control group). No patient developed Fanconi's syndrome or proximal renal tubular dysfunction during the study.
Through 144 weeks, TDF and stavudine, each administered in combination with efavirenz and lamivudine, had similar renal safety profiles in treatment-naive HIV-infected patients with normal renal function at baseline.
To investigate whether the use of highly active antiretroviral therapy (HAART) is associated with an increased incidence of myocardial infarctions (MI) in HIV infected patients.
Retrospective ...analysis of a cohort of 4993 HIV infected patients treated at our hospital between January, 1 1983 and December, 31 1998. The incidence of myocardial infarctions during 4 observation periods with different antiretroviral treatment strategies are compared. Possible risk factors for MI are evaluated by univariate analysis and using a multiple regression model.
29 patients with MI were diagnosed between 1983 and 1998. The incidence of MI per 1000 patient-years increased from 0.86 (1983-86), 1.14 (1987-90), 0.59 (1991-94) to 3.41 (1995-98) respectively (p = 0.002). Age >40, previous HAART therapy, homo-, or bisexual mode of HIV transmission and previous AIDS diagnosis were significantly associated with MI in univariate analysis. Age >40 and previous HAART therapy remained significantly associated with MI in a multiple regression model.
The incidence of MI in HIV infected patients increased in our cohort after the introduction of HAART.
Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well ...defined.
In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462.
We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 74% EFV, 162 62% NFV, 155 62% EFV/NFV; p=0·004). Mean (95% CI) increases in CD4 count were 316×10
6 cells per L (288–343) for EFV, 289×10
6 cells per L (262–316) for NFV, and 274×10
6 cells per L (231–291) for EFV/NFV (p=0·1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0·005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0·0001) and to a treatment modifying adverse event (p=0·04) than those in the other groups.
Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.
1 From the: Department of Infectious Diseases
2 HIV Center
3 Department of Hematology/Oncoloy
4 Department of Pathology, Hospital of the Johann Wolfgang Goethe University, Frankfurt, Germany
6 HIV ...specialist practice Friedensstraße, Frankfurt, Germany
Corresponding author and requests for reprints: Dr. Timo Wolf, Department of Infectious Diseases, Hospital of the JW Goethe University, Frankfurt, Germany, Timo.wolf{at}kgu.de , Tel.: +49 69 6301 5452 Fax: +49 69 6301 6378
We report on the first successful allogeneic stem cell transplantation (SCT) in an HIV-infected patient with severe aplastic anemia (SAA) performed at a tertiary care institution. Highly active antiretroviral therapy (HAART) was administered until transplantation and restarted 34 days later with sustained virological response. The patient did however develop a rapid rise in HIV load during the interruption of HAART associated with an acute febrile illness. Due to the extended period between the onset of SAA until SCT, the posttransplant course was complicated by bacterial infections. Stage two skin GvHD, but no AIDS-defining opportunistic diseases were experienced. Neutrophils recovered to >0.5/nL on day +18 and the CD4 count reached 250/µL on day +71 and >500/µL on day +182. The patient is in good condition with an ECOG score of 0 twelve months after transplantation. This report demonstrates the feasibility of allogeneic stem cell transplantation in the HIV setting.
Key words: Haematology, HIV, Bone marrow transplantation, Severe aplastic anemia.
Objective. The purpose of the present study was to determine the prevalence and incidence of virological triple drug-class failure (TCF) and to summarize the clinical outcome for patients who started ...receiving highly active antiretroviral therapy (HAART). Methods. The present study is an observational longitudinal study of 3496 treatment-experienced (TE) and treatment-naive (TN) patients monitored from the time they started receiving HAART (baseline) until TCF occurred (as determined on the basis of viral loads), until AIDS was newly diagnosed, or until death. Results. Four hundred forty-five patients (12.7%) had TCF; 370 (16.6%) of 2230 patients were TE, and 75 (5.9%) of 1266 patients were TN. At 6 years after starting HAART, 21.4% of TE and 11.2% of TN patients had TCF (P < .0001). The prevalence of TCF at or after 2002 was 15.5% in TE patients and 4.8% in TN patients. TN patients had a 32% annual increase in the incidence of TCF (95% confidence interval CI, 14%–54%; P < .0001); at 5 years after starting HAART, the rate was comparable for TE and TN patients (3.3 and 3.4 cases/100 person-years of follow-up PYFU, respectively). The incidence of new cases of AIDS or death was 2.7 cases/100 PYFU in patients who did not experience TCF and 5.0 cases/100 PYFU in patients who did experience TCF, an estimated 36% increase with each category of TCF (95% CI, 19%–56%; P < .0001). Conclusion. The prevalence of TCF was low after patients started receiving HAART, particularly among TN patients. Despite the influx of patients who had started receiving HAART more recently, the prevalence of TCF increased over calendar time. Patients with TCF had a higher incidence of newly diagnosed AIDS or death. Treatment of patients with TCF deserves further investigation.
Viral drug susceptibility is associated with virologic response to new treatments. Standardized drug resistance tests are now available, and data from some clinical trials suggest that the use of ...drug resistance testing may be associated with improved virologic outcome. However, drug resistance testing is complex in terms of performance, interpretation and clinical application. HIV-1 drug resistance testing is used across Europe in patient management, but not in a consistent manner. This is due to differences in the national approaches to treatment, treatment management and reimbursement, as well as availability of tests. National guidelines only exist in some countries. In addition, the laboratory quality assurance and quality control standards are not applied uniformly. The EuroGuidelines Group was established to formulate clinical as well as laboratory guidelines for the use of HIV-1 drug resistance testing that are specific for the European setting. The group is comprised of academic clinicians and virologists, scientist from the industry and representatives of the patient community. The panel of experts will review these guidelines and update them on a yearly basis as new scientific evidence becomes available.
Background. With increasing life spans of HIV-infected individuals under highly active antiretroviral therapy, long-term consequences of the chronic infection and antiretroviral treatment are ...becoming more prevalent. Data on prevalence and consequences of hypertension are limited, but recent studies suggest that HIV-infected individuals are at a higher risk of developing hypertension. Methods. In this prospective study, HIV-1-infected patients from the Frankfurt AIDS Cohort Study (FACS) were followed for 1 year to determine the frequency of systemic hypertension and to assess the associated clinical and demographic factors. Results. A total 214 HIV-1-infected patients, predominantly Caucasian males, participated in the study. Prevalence of systemic hypertension was 29%. The groups of hypertensive and normotensive individuals were comparable in terms of ethnic background and duration of infection. As in the general population, hypertensive subjects were older (49.1±11.1 vs 39.0±8.1 years; P<0.0001) and waist-to-hip ratio was higher than in normotensive individuals (0.99±0.07 vs 0.93±0.08; P<0.0001). Hypertension was associated with a much higher frequency of persistent proteinuria (41.1% vs 2.8%; P<0.001), coronary heart disease (16.1% vs 1.3%; P<0.0001) and myocardial infarction (8.1% vs 0.7%; P<0.005), whereas most cardiovascular risk factors were similar in both groups. Conclusions. Our data do not demonstrate any association between the presence of hypertension and antiretroviral therapy or immune status. However, hypertension seems to have a high impact on the existing risk for premature cardiovascular disease. Furthermore, overt proteinuria is frequent in HIV-1 infection with hypertension and might be due to hypertensive nephrosclerosis as well as yet undefined renal disease in these patients.
In most European countries, HIV drug resistance testing has become a routine clinical tool. However, its practical implementation in a clinical context is demanding. The European HIV Drug Resistance ...Panel was established to make recommendations to clinicians and virologists on this topic and to propose quality control measures. The panel recommends resistance testing for the following indications: i) drug-naive patients with acute or recent infection; ii) therapy failure, including suboptimal treatment response, when treatment change is considered; iii) pregnant HIV-1-infected women and paediatric patients with detectable viral load when treatment initiation or change is considered; and iv) genotype source patient when post-exposure prophylaxis is considered. In addition, for drug-naive patients with chronic infection in whom treatment is to be started, the panel suggests that resistance testing should be strongly considered and recommends testing the earliest sample for drug resistance if suspicion of resistance is high or prevalence of resistance in this population exceeds 10%. The panel does not favour genotyping over phenotype, however it is anticipated that genotyping will be used more often because of its greater accessibility, lower cost and faster turnaround time. For the interpretation of resistance data, clinically validated systems should be used to the greatest extent possible. It is mandatory that laboratories performing HIV resistance tests take regular part in quality assurance programs. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and meet regularly to discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. The panel also encourages the timely collection of epidemiological information to estimate the impact of transmission of resistant HIV and the prevalence of HIV-1 non-B subtypes in the different European countries.
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