Receiving Protease Inhibitors Research Articles

Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study

We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified into tertiles. Factors associated with 25(OH)D levels and associations of 25(OH) levels with subsequent risk of all-cause mortality, AIDS and non-AIDS events were analyzed. Of 1985 persons with 25(OH)D levels available, 23.7% had 25(OH)D below 10, 65.3% between 10 and 30, and 11% above 30 ng/ml. At the time of 25(OH)D measurement, older persons, persons of black ethnic origin, living outside Southern Europe/Argentina, sampled during winter, and infected with HIV through nonhomosexual exposure were at higher odds of having low 25(OH)D levels, whereas persons receiving protease inhibitors were at lower odds. Compared to those in the lowest 25(OH)D tertile (<12 ng/ml), those in the middle (12-20) and higher (>20) tertiles had a significantly lower risk of clinical progression during subsequent follow-up. Adjusted incidence rate ratios for all-cause mortality were 0.68 (95% CI 0.47-0.99, P = 0.045) and 0.56 (95% CI 0.37-0.83, P = 0.0039), and for AIDS events were 0.58 (95% CI 0.39-0.87, P = 0.0086) and 0.61 (95% CI 0.40-0.93, P = 0.020), for the middle and higher tertiles, respectively. There was a similar, nonsignificant reduced incidence of non-AIDS events in the middle and higher tertiles. 25(OH)D deficiency was frequent in HIV-infected persons (83% on combined antiretroviral therapy), and was independently associated with a higher risk of mortality and AIDS events. Causality relationships should be examined, because of potential public health consequences.

Decreased Heart Rate Variability in HIV Positive Patients Receiving Antiretroviral Therapy: Importance of Blood Glucose and Cholesterol

The presence of autonomic dysfunction in HIV patients is largely unknown. Early studies found autonomic dysfunction in patients with AIDS. Antiretroviral combination therapy (ART) has dramatically changed the course of the disease and improved prognosis and decreased morbidity.AimTo evaluate whether autonomic dysfunction is present in an ART treated HIV population and if so to identify factors of importance.MethodsHIV patients receiving ART for at least 12 months (n = 97) and an age-matched control group of healthy volunteers (n = 52) were included. All were non-diabetic and had never received medication for hypertension. Following a 10 min resting period a 15 min ECG recording was performed. Heart-rate variability (HRV) analysis was performed in accordance with current guidelines and data reported as mean [interquartile range].ResultsMean normal-to-normal (NN) and total HRV measured as standard deviation of normal-to-normal (SDNN) was lower in HIV patients compared to controls (905 vs. 982 ms; p<0.001 and 48 vs. 54 ms; p = 0.028, respectively). No differences were found between the groups in parasympathetic activity measured as square root of the mean squared difference of successive NN-intervals (RMSSD) or the percent of differences between adjacent NN intervals greater than 50 ms (pNN50). In the HIV positives, haemoglobin A1c correlated inversely with SDNN, RMSSD and pNN50 (p<0.05). Total cholesterol and LDL-C correlated inversely with RMSSD and pNN50 (p<0.05). Neither HIV duration, HIV-RNA, CD4 cell count nor CD4 nadir correlated with time or phase domain HRV variables.ConclusionsModerate autonomic dysfunction is present in HIV positives patients even with suppressed viral load due to ART. The dysfunction is correlated with HbA1c and hypercholesterolemia but not to duration of HIV or whether the patients were receiving protease inhibitors as part of the ART regime.

Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa.

Data on the development of antiretroviral drug resistance in HIV-1-infected children receiving protease inhibitor (PI)-based antiretroviral therapy (ART) are limited. We examined antiretroviral resistance among a cohort of 323 South African HIV-infected children <2 years old exposed to nevirapine for prevention of mother-to-child transmission. Ritonavir (RTV) was used initially for 138 children who were <6 months old or receiving antimycobacterial therapy; otherwise children received lopinavir/ritonavir (LPV/r)-based ART. HIV-1 population sequencing of the pol gene was conducted on all pretreatment samples and on posttreatment samples for children who did not achieve HIV-1 plasma RNA <400 copies/ml by 52 weeks. Among children in the cohort, 38 died, 22 had <24 weeks follow-up, 209 achieved virologic suppression, and 54 did not. Of 41 children without virologic suppression with posttreatment HIV genotype data available, major resistance mutations were found in 32 (78%): 14 (36%) had PI mutations including V82A, M46I, and L90M; 29 (71%) had M184V/I; and three had NNRTI mutations (K103N, Y181C, and G190A). Among the children who did not achieve virologic suppression, none of the seven children treated exclusively with LPV/r developed PI-related mutations, compared with 14 of 32 (44%) who received RTV-based regimens (p=0.036); PI genotypes were unavailable for two children. Seventy-eight percent of children without virologic suppression developed resistance mutations that impact second-line ART options. Only children who received RTV-based ART developed major PI-related resistance mutations, and use of this regimen should be avoided.

Is Tenofovir-Related Renal Toxicity Incompletely Reversible?

To the Editors: Wever et al1 report “incomplete reversibility of tenofovir (TDF)-related renal toxicity in HIV-infected men”. The authors' report highlights that TDF-related renal toxicity may not always be fully reversible, particularly in those with gradual decline in estimated glomerular filtration rate (eGFR). The study describes 24 patients who ceased TDF for suspected renal toxicity and compared serum creatinine with eGFR (Cockcroft-Gault and Modification of Diet in Renal Disease) before initiating TDF, at the time of stopping TDF, and the most improved value after stopping TDF. The median age of the patients was 56 years, the median duration of TDF exposure 30 months, the median eGFR at TDF initiation 74 ml·min−1·1.73 m−2, and most patients received protease inhibitors and had good virological control. At the time of TDF discontinuation, the eGFR (Modification of Diet in Renal Disease) had declined to 51, with subsequently improvement to 64 ml·min−1·1.73 m−2 (most improved value) and 58 ml·min−1·1.73 m−2 (most recent measurement). The authors conclude that TDF-associated renal toxicity was not fully reversible in 58% of subjects. Although this may be correct, it should be appreciated that many patients with reduced eGFR (<90 or <75 ml·min−1·1.73 m−2) may have underlying chronic kidney disease, the natural history of which may be progressive in nature. Consequently, over a 3-year period (30 months of TDF exposure and 5 months of recovery), eGFR declines that are observed in the setting of drug-induced renal injury may not recover fully after drug discontinuation when the underlying renal disease has progressed during this time. This would be more likely if drug exposure has been prolonged and if drug-induced kidney injury was insidious in onset. We propose that eGFR slopes may provide better insight into the potential reversibility of TDF-associated nephrotoxicity, as they allow estimation of the rate of CKD progression before TDF initiation, during TDF exposure, and after TDF discontinuation. We analyzed renal function using eGFR slopes in 843 patients who initiated TDF-containing cART, and of whom 26 (3.1%) developed CKD (defined as an eGFR <60 ml·min−1·1.73 m−2 for >3 months). Compared with patients who did not develop CKD, those who developed CKD were older (53.6 vs 39.9 years, P < 0.001) and had significantly lower eGFR at TDF initiation (69 vs 102 ml per minute, P < 0.001). In addition, 85% had other risk factors for CKD progression including underlying cardiovascular disease or exposure to other potentially nephrotoxic drugs.2 When changes in renal function over time were examined, patients who developed CKD already experienced modest eGFR decline (−2.3 ml·min−1·year−1) before TDF initiation. Accelerated decline in eGFR (median -8.5 ml·min−1·year−1) was observed during TDF exposure, with subsequent return to the pre-TDF eGFR slope of -2.2 ml·min−1·year−1 after TDF discontinuation. In patients who did not develop CKD, a similar, but much more modest decline in eGFR was observed (Table 1).TABLE 1: eGFR Slopes in Patients With and Without CKD (eGFR <60 mL·min− 1·1.73m−2 for >3 Months)Even though our data suggest that TDF-related renal toxicity may be largely reversible, it clearly is best avoided by monitoring changes in renal function over time. Although the optimal frequency of monitoring is unknown, the modest rate of renal disease progression in patients on TDF would support annual or biannual assessment of renal function. Although we agree with Wever et al1 that an eGFR >60 ml·min−1·1.73 m−2 may lead to consideration of TDF discontinuation, it may be important to identify those at greatest risk of TDF-associated renal toxicity, including those aged >50 (odds ratio: 5.4) and patients who have eGFR <75 ml·min−1·1.73 m−2 at TDF initiation (odds ratio: 17.2),2 and either avoid TDF if suitable alternatives are available, or use TDF with more close monitoring of renal function. Lucy J. Campbell, MSc Lisa Hamzah, MBChB Frank A. Post, MD PhD FCP(SA) Department of Renal Sciences King's College London School of Medicine, London, United Kingdom

Assessment of factors influencing health-related quality of life in HIV-infected patients

Health-related quality of life (HRQL) is used in the assessment of chronic illness. Regarding HIV infection, HRQL assessment is an objective for physicians and institutions since antiretroviral treatment delays HIV clinical progression. The aim of this study was to determine the factors with the most influence on HRQL in HIV-infected people and to create a predictive model. We conducted a cross-sectional study in 150 patients in a tertiary hospital. HRQL data were collected using the Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire. The research team created a specific template with which to gather clinical and sociodemographic data. Adherence was assessed using the Simplified Medication Adherence Questionnaire (SMAQ) and depression data were obtained using the Beck Depression Inventory, Second Edition (BDI-II) inventory. Logistic regression models were used to identify determinants of HRQL. HIV-related symptoms and presence of depression were found to be negatively associated with all the MOS-HIV domains, the Physical Health summary score and the Mental Health summary score. Patients receiving protease inhibitor (PI)-based treatment had lower scores in four of the 11 domains of the MOS-HIV questionnaire. Gender, hospitalization in the year before enrolment, depression and parenthood were independently related to the Physical Health Score; depression and hepatitis C virus coinfection were related to the Mental Health Score. Optimization of HRQL is particularly important now that HIV infection can be considered a chronic disease with the prospect of long-term survival. Quality of life should be monitored in follow-up of HIV-infected patients. The assessment of HRQL in this population can help us to detect problems that may influence the progression of the disease. This investigation highlights the importance of a multidisciplinary approach to HIV infection.

Incidence and Risk Factors for Tenofovir-Associated Renal Function Decline Among Thai HIV-Infected Patients with Low-Body Weight

we aimed at determining the incidence and factors for TDF-associated renal function decline among Thai HIV-infected patients. retrospective and prospective cohort studies were conducted. We enrolled HIV-infected adults who had initiated TDF. Renal function decline that was defined by a decrease of 25% in glomerular filtration rate (GFR) from the baseline. Factors associated with the renal function decline were determined. a total of 405 patients with a median (IQR) body weight of 56.5 (50.5-65.0) kg were enrolled. All but four (99%) were antiretroviral treatment-experience patients. A median (IQR) duration of receiving TDF was 16 (8-21) months. Of these, 78 (19.3%) patients had a 25% decrease in GFR with the incidence rate of 16.2 per 100 person-years. By Kaplan-Meier survival analysis, median time to a 25% decrease in GFR was 28 [95% confidence interval (CI) 25.2-30.8] months. By multiple logistic regression, lower body weight [odds ratio (OR) 1.15 per 5 kg, 95% CI 1.00-1.33], lower body mass index (BMI) (OR 2.26 per 1 kg/m(2), 95% CI 1.74-2.94), baseline GFR (OR 1.62 per 10 ml/min/1.73m(2), 95% CI 1.39-1.88), protease inhibitor (OR 2.12, 95% CI 1.15-3.92), and nephrotoxic drug (OR 3.16, 95% CI 1.44-6.98) were statistically significant factors associated with a 25% decrease in GFR. the study revealed high incidence of TDF-associated renal function decline among patients with low-body weight and BMI. Additional risk factors were baseline GFR, receiving protease inhibitor, and nephrotoxic drugs. Close monitoring of renal function is warranted among patients with these risk factors.

Dyslipidemia in a Cohort of HIV-infected Latin American Children Receiving Highly Active Antiretroviral Therapy

In order to describe the prevalence of hypercholesterolemia and hypertriglyceridemia in a cohort of HIV-infected children and adolescents in Latin America and to determine associations with highly active antiretroviral therapy (HAART), we performed this cross-sectional analysis within the NICHD International Site Development Initiative pediatric cohort study. Eligible children had to be at least 2 years of age and be on HAART. Among the 477 eligible HIV-infected youth, 98 (20.5%) had hypercholesterolemia and 140 (29.4%) had hypertriglyceridemia. In multivariable analyses, children receiving protease inhibitor (PI)-containing HAART were at increased risk for hypercholesterolemia [adjusted odds ratio (AOR) = 2.7, 95% confidence interval (CI) 1.3-5.6] and hypertriglyceridemia (AOR = 3.5, 95% CI 1.9-6.4) compared with children receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing HAART. In conclusion, HIV-infected youth receiving PI-containing HAART in this Latin American cohort were at increased risk for hypercholesterolemia and hypertriglyceridemia compared with those receiving NNRTI-containing HAART.

Long-term follow-up of 11 protease inhibitor (PI)-naïve and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene

Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long-term viro-immunological follow-up of HIV-infected patients harbouring virus with protease insertions. Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected. Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI-naïve patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI-naïve patients were infected with an HIV-1 non-B subtype. Follow-up of these PI-naïve patients showed that the insert-containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI-experienced patients, 63% were infected with HIV-1 subtype B; one had been antiretroviral-free for 5 years and seven were heavily PI-experienced (median duration of follow-up 24 months; range 10-62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI-resistance mutations, and following long-term exposure to PIs. The insert-containing virus persisted for a median of 32 months (range 12-62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity. Our data, obtained during long-term follow-up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI-based regimens, although further work is required to confirm it.

Neither ritonavir nor darunavir affect cell surface expression of tetherin or Vpu-mediated tetherin down-modulation

Neither ritonavir nor darunavir affect cell surface expression of tetherin or Vpu-mediated tetherin down-modulation

Metabolic profile and cardiovascular risk factors among Latin American HIV-infected patients receiving HAART

Determine the prevalence of metabolic abnormalities (MA) and estimate the 10-year risk for cardiovascular disease (CVD) among Latin American HIV-infected patients receiving highly active anti-retroviral therapy (HAART). A cohort study to evaluate MA and treatment practices to reduce CVD has been conducted in seven Latin American countries. Adult HIV-infected patients with at least one month of HAART were enrolled. Baseline data are presented in this analysis. A total of 4,010 patients were enrolled. Mean age (SD) was 41.9 (10) years; median duration of HAART was 35 (IQR: 10-51) months, 44% received protease inhibitors. The prevalence of dyslipidemia and metabolic syndrome was 80.2% and 20.2%, respectively. The overall 10-year risk of CVD, as measured by the Framingham risk score (FRF), was 10.4 (24.7). Longer exposure to HAART was documented in patients with dyslipidemia, metabolic syndrome and type 2 diabetes mellitus. The FRF score increased with duration of HAART. Male patients had more dyslipidemia, high blood pressure, smoking habit and higher 10-year CVD than females. Traditional risk factors for CVD are prevalent in this setting leading to intermediate 10-year risk of CVD. Modification of these risk factors through education and intervention programs are needed to reduce CVD.

Metabolic profile and cardiovascular risk factors among Latin American HIV-infected patients receiving HAART

ObjectiveDetermine the prevalence of metabolic abnormalities (MA) and estimate the 10-year risk for cardiovascular disease (CVD) among Latin American HIV-infected patients receiving highly active anti-retroviral therapy (HAART). MethodsA cohort study to evaluate MA and treatment practices to reduce CVD has been conducted in seven Latin American countries. Adult HIV-infected patients with at least one month of HAART were enrolled. Baseline data are presented in this analysis. ResultsA total of 4,010 patients were enrolled. Mean age (SD) was 41.9 (10) years; median duration of HAART was 35 (IQR: 10-51) months, 44% received protease inhibitors. The prevalence of dyslipidemia and metabolic syndrome was 80.2% and 20.2%, respectively. The overall 10-year risk of CVD, as measured by the Framingham risk score (FRF), was 10.4 (24.7). Longer exposure to HAART was documented in patients with dyslipidemia, metabolic syndrome and type 2 diabetes mellitus. The FRF score increased with duration of HAART. Male patients had more dyslipidemia, high blood pressure, smoking habit and higher 10-year CVD than females. ConclusionsTraditional risk factors for CVD are prevalent in this setting leading to intermediate 10-year risk of CVD. Modification of these risk factors through education and intervention programs are needed to reduce CVD.

The Effects of Protease Inhibitors on Metabolic Complications and Lipodystrophy in Human Immunodeficiency Virus-Infected Patients

Problem statement: Highly Active Antiretroviral Therapy (HAART)-associated metabolic complications include lipoatrophy (loss of Subcutaneous Adipose Tissue (SAT) and insulin resistance. The risk of Diabetes Mellitus (DM) in Human Immunodeficiency Virus (HIV)-infected patients receiving Highly Active Antiretroviral Therapy (HAART) especially protease inhibitors has not been well defined. Approach: We conducted an analysis in the Hospital of Rajeev Gandhi Institute of Medical Sciences (RIMS), Adilabad district of Andhra Pradesh to determine the prevalence and incidence of DM in the cohort of HIV-infected and HIV seronegative men. Prevalence analysis included 1278 men (710 HIV seronegative and 568 HIV infected, 411 receiving protease inhibitors) with fasting glucose concentration determinations at baseline. Results: Fifty-seven (14%) of the 411 HIV-infected men using protease inhibitors at the baseline visit had prevalent DM compared with 33 (5%) of the 711 HIV-seronegative men (prevalence ratio = 4.6; adjusted for age and body mass index). The rate of incident DM was 4.7 cases per 100 person-years among HIV-infected men using protease inhibitors compared with 1.4 cases per 100 person-years among HIV seronegative men (rate ratio = 4.11; adjusted for age and body mass index), during the 4 year observation period, based on a median follow-up of 2.3 years. Conclusion: The incidence of DM in HIV-infected men with exposure of protease inhibitors was greater than 4 times that of HIV-seronegative men, representing a risk that is higher than previous estimates.

Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial

HIV infection and its treatment with protease inhibitors, especially when boosted with ritonavir, can cause lipid disorders. Statins, with the exception of fluvastatin, pravastatin and rosuvastatin, interact with protease inhibitor metabolism via CYP450. Pravastatin is recommended for patients with protease inhibitor-associated dyslipidemia. Rosuvastatin is the statin most effective on low-density lipoprotein cholesterol (LDL-c) in non-HIV patients. HIV-1-infected patients treated with boosted protease inhibitor were randomized to receive either rosuvastatin 10 mg/day or pravastatin 40 mg/day for dyslipidemia (LDL-c >4.1 mmol/l and triglycerides <8.8 mmol/l). The percentage change in LDL-c, triglyceride and high-density lipoprotein-cholesterol levels, measured in a central laboratory, was determined after 45 days of statin treatment. Eighty-eight patients were randomized and 83 took the study drugs, 41 rosuvastatin and 42 pravastatin. The median duration of prior antiretroviral treatment was 9 years. At baseline, the median LDL-c level was 4.93 mmol/l, the triglyceride level 2.29 mmol/l, and the high-density lipoprotein-cholesterol level 1.27 mmol/l. The median percentage changes in the rosuvastatin and pravastatin arms were -37 and -19% for LDL-c (P < 0.001), respectively, and -19 and -7% for triglycerides (P = 0.035), respectively. The change in the high-density lipoprotein-cholesterol level was not significantly different between the two arms. None of the four severe adverse events was attributed to the statins; in particular, there were no renal, hepatic or muscular events. Rosuvastatin 10 mg/day was more effective than pravastatin 40 mg/day on LDL-c and triglyceride levels in HIV-1-infected patients receiving a boosted protease inhibitor.

Plasma Bile Acid Concentrations in Patients with Human Immunodeficiency Virus Infection Receiving Protease Inhibitor Therapy: Possible Implications for Hepatotoxicity

To evaluate whether patients with human immunodeficiency virus (HIV) infection who were receiving protease inhibitor therapy had altered bile acid concentrations compared with noninfected control subjects, and whether bile acid concentrations could predict the onset of hepatotoxicity caused by protease inhibitors. Retrospective sample analysis from a prospectively conducted clinical trial. Academic research center. Eleven adults with advanced HIV disease who were taking protease inhibitor-based antiretroviral therapy, one of whom had developed protease inhibitor-induced hepatotoxicity. Plasma concentrations of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and taurocholic acid (TC) were analyzed by using a novel high-performance liquid chromatography with tandem mass spectrometry detection method. Comparisons of the relative contribution of each bile acid to the total bile acid pool were made with previously published values and with bile acid concentrations contained in two pooled plasma samples from healthy, non-HIV-infected volunteers analyzed in our laboratory. Each pooled plasma sample used for this analysis contained contributions from three non-HIV-infected volunteers. The LCA and TC concentrations in HIV-infected patients were 3-4-fold higher than those previously reported for non-HIV-infected subjects; concentrations of other bile acids were similar to those of previous reports. The relative contribution of CDCA to the total bile acid pool was 9% in HIV-infected patients compared with 30-50% in noninfected subjects. Total and individual bile acid concentrations in the HIV-infected patient who developed hepatotoxicity were similar to the bile acid concentrations from the other study patients who did not develop hepatotoxicity. These data suggest that bile acid concentrations may be altered by HIV infection and/or protease inhibitor therapy. However, further investigations should be performed to assess whether antiretroviral-associated hepatotoxicity can be predicted by alterations in individual bile acid concentrations.

Plasma Bile Acid Concentrations in Patients with Human Immunodeficiency Virus Infection Receiving Protease Inhibitor Therapy: Possible Implications for Hepatotoxicity

Plasma Bile Acid Concentrations in Patients with Human Immunodeficiency Virus Infection Receiving Protease Inhibitor Therapy: Possible Implications for Hepatotoxicity

Estudo da reatividade vascular em portadores de HIV com e sem uso de inibidor de protease

A great number of HIV-infected patients using antiretroviral drugs develop endothelial dysfunction and atherothrombosis, which lead to a high medical and social burden. Thus, it is important to identify pathophysiological mechanisms involved with the endothelial function in these patients, so that early intervention can be made to avoid disease progression.To evaluate endothelial function using endothelium-dependent and independent vasodilation in HIV-positive patients and in a control group.A total of 27 HIV-positive patients and 16 controls were evaluated. Endothelium-dependent (reactive hyperemia) and independent (SL nitroglycerine) vasodilation of the brachial artery was used to evaluate the endothelial function.HIV-positive patients receiving protease inhibitors (PI) showed significantly lower endothelium-independent vasodilation than the HIV-negative (p=0.020) and HIV-positive without PI (p=0.034) subgroups. The change in brachial artery diameter during active hyperemia was not statistically significant in any subgroup. Multiple linear regression analysis showed that only PI was associated with the relative delta of brachial reactivity to vasodilator in HIV-positive patients at 60s and 90s.HIV-positive patients receiving PI presented endothelium-independent dysfunction when compared to HIV-positive patients not receiving PI and to the control group.

Understanding protease inhibitor resistance - aiming for the long term in treatment-experienced patients

The prevalence of antiretroviral drug resistance in patients undergoing routine testing while receiving treatment in the UK is about 50%. Most resistance is against nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, but 25% of patients receiving protease inhibitors (PIs) also have evidence of PI resistance. Although extensive resistance profiles are rare, a proportion of patients present with complex genotypes, which makes treatment selection difficult and vitally important. A resistance profile can be interpreted to provide an indication of the degree of resistance to different drugs and the potential drug options. Factors to bear in mind during treatment selection include phenotypic and genotypic resistance, mutation patterns, numbers and ‘weights’, and the hypersusceptibility and fitness effects of certain mutations. In treatment-experienced patients, physicians should aim for a regimen that combines at least two, preferably three, fully active drugs. In addition to selecting drugs that are predicted to have activity, the relative genetic barrier, cross-resistance potential and support needed to maintain activity in the long term are also key considerations.

Effects of HCV co-infection on apoptosis of CD4+ T-cells in HIV-positive patients

Apoptosis importantly contributes to loss of CD4+ T-cells in HIV infection, and modification of their apoptosis may explain why HIV/HCV (hepatitis C virus)-co-infected patients are more likely to die from liver-related causes, although the effects of HCV on HIV infection remain unclear. In the present study, we studied in a cross-sectional and serial analysis spontaneous ex vivo CD4+ T-cell apoptosis in HIV/HCV-co-infected and HIV-mono-infected patients before and after HAART (highly active antiretroviral therapy). Apoptosis of peripheral blood CD4+ T-cells was measured by both a PARP [poly(ADP-ribose) polymerase] and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay to detect cells with irreversible apoptosis. Although hepatitis C alone did not increase CD4+ T-cell apoptosis, HCV co-infection disproportionately increased elevated rates of apoptosis in CD4+ T-cells from untreated HIV-positive patients. Increased CD4+ T-cell apoptosis was closely correlated with HIV, but not HCV, viral loads. Under HAART, increased rates of CD4+ T-cell apoptosis rapidly decreased both in HIV-mono-infected and HIV/HCV-co-infected patients, without any significant difference in apoptosis rates between the two patient groups after 4 weeks of therapy. Nevertheless residual CD4+ T-cell apoptosis did not reach the normal levels seen in healthy controls and remained higher in HIV patients receiving protease inhibitors than in patients with other antiretroviral regimens. The results of the present study suggest that HCV co-infection sensitizes CD4+ T-cells towards apoptosis in untreated HIV-positive patients. However, this effect is rapidly lost under effective antiretroviral therapy.

Cardiac Diastolic Dysfunction Is Prevalent in HIV-Infected Patients

Combination antiretroviral therapy (ART) has markedly improved survival in HIV-infected patients, but not without significant adverse effects including ART-associated dyslipdemia and insulin resistance, which may in part contribute to an increased risk of cardiovascular events. Other contributing factors to cardiovascular risk may include uncontrolled HIV replication, the effects of HIV and ART on vascular endothelium and inflammatory cytokines. Diastolic dysfunction may be an early sign of cardiovascular disease. Our objective was to determine the prevalence of diastolic dysfunction in HIV-infected patients without cardiovascular symptoms. We enrolled 91 subjects in a cross-sectional study of HIV-infected patients without cardiovascular symptoms between September 2004 and August 2005, to assess whether demographics, HIV-related factors, cardiac risk factors, and ART were associated with diastolic dysfunction. All subjects underwent two-dimensional transthoracic echocardiography with tissue Doppler imaging. Subjects were predominately male with a median age of 38 (interquartile range [IQR]: 33, 42) years and median ART duration 6.15 (IQR: 2.1, 8.4) years. Subjects had low Framingham risk scores. Diastolic dysfunction was observed in 34 patients (37%; 95% confidence interval [CI] 27.4, 48.1). Cardiac risk factors or poor prognostic indicators of AIDS progression were uncommon with no difference between subjects with or without diastolic dysfunction. A nonstatistically significant trend in increased rate of diastolic dysfunction was observed in patients receiving protease inhibitors 1 year or more, 44% versus 28%, respectively (univariate odds ratio 2.02, 95% CI 0.83 to 4.90). This was not observed with prolonged use of either non-nucleoside or nucleoside reverse transcriptase inhibitors. A high prevalence of diastolic dysfunction (37%) in a cohort of HIV-infected patients on ART at low risk for AIDS and cardiovascular disease was demonstrated.

The Expanded Access Program to HAART in Chile: Baseline Characteristics and Primary Outcomes of Patients Receiving Treatment, Evaluated Through the Chilean AIDS Cohort (ChiAC)

Background: Chile, a middle-income country with a population of 16.2 million, has a HIV prevalence of ≈0.3% in adults. Since 2001 there is an expanded access program (EAP) for HAART that reached 100% coverage in 2003; around 13,000 patients are under health care, 85% in the public health system (PHS). 70% of the patients under control required and received treatment, according to the national guidelines. Distribution of therapy is centralized and each request is reviewed and approved on an individual basis. The system provides for free: HAART, CD4, viral load (VL) and genotype tests as well as additional budget for diagnosis and treatment of AIDS related diseases. The outcomes of the EAP in the PHS, have been evaluated by ChiAC, which has enrolled almost 95% of patients on HAART since 2001. Methods: ChiAC database was analyzed for baseline (BL) characteristics and primary outcomes: mortality, maintenance of initial regimen and AIDS free survival. Descriptive statistics was used. Results: In 3649 treatment nave patients (15% female) on HAART, with a follow up (f/u) of 9442 patient-years: BL CDC status: A:23%, B:23.6%, C:53.4%; BL CD4 bellow 200 cells/μL:83.4% (51% < 100). Most common first HAART regimen was Combivir® plus efavirenz. Less than 10% received protease inhibitors initially. Outcomes at 3 years of f/u: 57.5% remained on initial therapy, 20.6% on second HAART, 4.9% had ≥3 HAART regimen. Mortality by BL CD4 count: CD4 0–99: 12.5%, CD4 100–199: 3.5%, CD4>200: 3.1%. Change of HAART due to toxicity: 47%. VL <400 and <80 cps/mL at 3 years were 77.4% and 54.3%, respectively. Overall survival at 3 and 5 years of HAART was 90.5% and 88% respectively; AIDS free survival at 3 and 5 years was 86% and 83% respectively. Conclusions: The EAP to ART in Chile is succeeding in achieving high viral control and survival of HIV patients. These results are comparable to those of high income countries. ChiAC is a useful tool for evaluating the impact of the program. 13th International Congress on Infectious Diseases Abstracts (Oral Presentations)International Journal of Infectious DiseasesVol. 12Preview Full-Text PDF Open Archive