Incidence and risk factors for chronic elevation of alanine aminotransferase levels in HIV-infected persons without hepatitis b or c virus co-infection

BACKGROUND: Chronic liver disease in human immunodeficiency virus (HIV)-infected patients is mostly caused by hepatitis virus co-infection. Other reasons for chronic alanine aminotransferase (ALT) elevation are more difficult to diagnose. METHODS: We studied the incidence of and risk factors for chronic elevation of ALT levels (greater than the upper limit of normal at 2 consecutive semi-annual visits) in participants of the Swiss HIV Cohort Study without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection who were seen during the period 2002-2008. Poisson regression analysis was used. RESULTS: A total of 2365 participants were followed up for 9972 person-years (median age, 38 years; male sex, 66%; median CD4+ cell count, 426/microL; receipt of antiretroviral therapy [ART], 56%). A total of 385 participants (16%) developed chronic elevated ALT levels, with an incidence of 3.9 cases per 100 person-years (95% confidence interval [CI], 3.5-4.3 cases per 100 person-years). In multivariable analysis, chronic elevated ALT levels were associated with HIV RNA level >100,000 copies/mL (incidence rate ratio [IRR], 2.23; 95% CI, 1.45-3.43), increased body mass index (BMI, defined as weight in kilograms divided by the square of height in meters) (BMI of 25-29.9 was associated with an IRR of 1.56 [95% CI, 1.24-1.96]; a BMI 30 was associated with an IRR of 1.70 [95% CI, 1.16-2.51]), severe alcohol use (1.83 [1.19-2.80]), exposure to stavudine (IRR per year exposure, 1.12 [95% CI, 1.07-1.17]) and zidovudine (IRR per years of exposure, 1.04 [95% CI, 1.00-1.08]). Associations with cumulative exposure to combination ART, nucleoside reverse-transcriptase inhibitors, and unboosted protease inhibitors did not remain statistically significant after adjustment for exposure to stavudine. Black ethnicity was inversely correlated (IRR, 0.52 [95% CI, 0.33-0.82]). Treatment outcome and mortality did not differ between groups with and groups without elevated ALT levels. CONCLUSIONS: Among patients without hepatitis virus co-infection, the incidence of chronic elevated ALT levels was 3.9 cases per 100 person-years, which was associated with high HIV RNA levels, increased BMI, severe alcohol use, and prolonged stavudine and zidovudine exposure. Long-term follow-up is needed to assess whether chronic elevation of ALT levels will result in increased morbidity or mortality

Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study

BACKGROUND: It is unclear whether primary prophylaxis against Pneumocystis carinii pneumonia can be discontinued in patients infected with the human immunodeficiency virus (HIV) who are successfully treated with combination antiretroviral therapy. We prospectively studied the safety of stopping prophylaxis among patients in the Swiss HIV Cohort Study. METHODS: Patients were eligible for our study if their CD4 counts had increased to at least 200 cells per cubic millimeter and 14 percent of total lymphocytes while they were receiving combination antiretroviral therapy, with these levels sustained for at least 12 weeks. Prophylaxis was stopped at study entry, and patients were examined every three months thereafter. The development of P. carinii pneumonia was the primary end point, and the development of toxoplasmic encephalitis the secondary end point. RESULTS: Of the 262 patients included in our analysis, 121 (46.2 percent) were positive for IgG antibodies to Toxoplasma gondii at base line. The median CD4 count at study entry was 325 per cubic millimeter (range, 210 to 806); the median nadir CD4 count was 110 per cubic millimeter (range, 0 to 240). During a median follow-up of 11.3 months (range, 3.0 to 18.8), prophylaxis was resumed in nine patients, and two patients died. There were no cases of P. carinii pneumonia or toxoplasmic encephalitis. The one-sided upper 99 percent confidence limit for the incidence of P. carinii pneumonia was 1.9 cases per 100 patient-years (based on 238 patient-years of follow-up). The corresponding figure for toxoplasmic encephalitis was 4.2 per 100 patient-years (based on 110 patient-years of follow-up). CONCLUSIONS: Stopping primary prophylaxis against P. carinii pneumonia appears to be safe in HIV-infected patients who are receiving combination antiretroviral treatment and who have had a sustained increase in their CD4 counts to at least 200 cells per cubic millimeter and to at least 14 percent of total lymphocytes

Hyperlactatemia and Antiretroviral Therapy: The Swiss HIV Cohort Study

The prevalence, clinical presentation, and risk factors for hyperlactatemia among patients receiving antiretroviral therapy was determined during a 1-month period for patients in the Swiss HIV Cohort Study. Overall, 73 (8.3%) of 880 patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine (odds ratio, 2.7; 95% confidence interval, 1.5-4.8), as compared with patients who received zidovudine-based regimens. The risk increased with increasing time receiving stavudine with or without didanosine. The association between hyperlactatemia and stavudine with or without didanosine was not biased by these medications being more recently available and, therefore, being given preferentially to patients who had prolonged use of nucleoside analog reverse-transcriptase inhibitors. Hyperlactatemia was associated with lipoatrophy, hyperlipidemia, and hyperglycemia. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia. Determination of lactate levels may prove useful in the screening for mitochondrial toxicit

Human herpes virus 8 replication during disseminated tuberculosis in a man with human immunodeficiency virus: a case report

INTRODUCTION: Human herpes virus 8 (HHV-8) is mainly responsible for the development of Kaposi's sarcoma and multicentric Castleman's disease in immunocompromised patients with untreated human immunodeficiency virus. Positive viral loads have been described in cases of Kaposi's sarcoma and multicentric Castleman's disease, with higher values found in the latter. We describe the case of a patient with HIV in whom a high level of HHV-8 replication was detected and who contracted an opportunistic disease other than multicentric Castleman's disease or Kaposi's sarcoma. CASE PRESENTATION: A 25-year-old man of West African origin with HIV complained of asthenia, weight loss, fever, and abdominal pain. Physical examination revealed that the patient had adenopathies and hepatosplenomegaly, but no skin or mucosal lesions were seen. Our first presumptive diagnosis was disseminated tuberculosis. However, since the cultures (sputum, bronchoalveolar lavage, blood, urine and lymph node biopsies) for mycobacteria were negative, the diagnosis was expanded to include multicentric Castleman's disease which was supported by high HHV-8 viral loads in the patient's blood: 196,000 copies/ml in whole blood, 39,400 copies/ml in plasma and 260 copies/10E5 in peripheral blood mononuclear cells. However, the histology and positive polymerase chain reaction assay for Mycobacterium tuberculosis complex of a second lymph node biopsy enabled us to conclude that the patient had disseminated tuberculosis and we started the patient on antituberculosis treatment. We analyzed the HHV-8 deoxyribonucleic acid in two other plasma samples (one from six months earlier and the other was 10 days after the positive test) and both yielded negative results. A search for latent and lytic HHV-8 antibodies confirmed that the patient was seropositive for HHV-8 before this episode. CONCLUSION: We describe the case of a patient with HIV who tested positive for asymptomatic HHV-8 replication during an opportunistic disease suggestive of multicentric Castleman's disease. The initial analysis was nullified by the diagnosis of a disease that was unrelated to HHV-8. This case report underlines the need to clarify the full clinical meaning and implication of a positive HHV-8 viral load in patients with AIDS. The diagnosis of multicentric Castleman's disease needs to be studied further to determine its sensitivity and specificity. Finally, when faced with the dilemma of urgently starting chemotherapy on a patient whose condition is deteriorating and whose clinical presentation suggests multicentric Castleman's disease, high HHV-8 viral loads should be interpreted with caution and histological analysis of lymph nodes or liver biopsies should be obtained first

Beneficial effect of the oxygen free radical scavenger amifostine (WR-2721) on spinal cord ischemia/reperfusion injury in rabbits

<p>Abstract</p> <p>Background</p> <p>Paraplegia is the most devastating complication of thoracic or thoraco-abdominal aortic surgery. During these operations, an ischemia-reperfusion process is inevitable and the produced radical oxygen species cause severe oxidative stress for the spinal cord. In this study we examined the influence of Amifostine, a triphosphate free oxygen scavenger, on oxidative stress of spinal cord ischemia-reperfusion in rabbits.</p> <p>Methods</p> <p>Eighteen male, New Zealand white rabbits were anesthetized and spinal cord ischemia was induced by temporary occlusion of the descending thoracic aorta by a coronary artery balloon catheter, advanced through the femoral artery. The animals were randomly divided in 3 groups. Group I functioned as control. In group II the descending aorta was occluded for 30 minutes and then reperfused for 75 min. In group III, 500 mg Amifostine was infused into the distal aorta during the second half-time of ischemia period. At the end of reperfusion all animals were sacrificed and spinal cord specimens were examined for superoxide radicals by an ultra sensitive fluorescent assay.</p> <p>Results</p> <p>Superoxide radical levels ranged, in group I between 1.52 and 1.76 (1.64 ± 0.10), in group II between 1.96 and 2.50 (2.10 ± 0.23), and in group III (amifostine) between 1.21 and 1.60 (1.40 ± 0.19) (p = 0.00), showing a decrease of 43% in the Group of Amifostine. A lipid peroxidation marker measurement ranged, in group I between 0.278 and 0.305 (0.296 ± 0.013), in group II between 0.427 and 0.497 (0.463 ± 0.025), and in group III (amifostine) between 0.343 and 0.357 (0.350 ± 0.007) (p < 0.00), showing a decrease of 38% after Amifostine administration.</p> <p>Conclusion</p> <p>By direct and indirect methods of measuring the oxidative stress of spinal cord after ischemia/reperfusion, it is suggested that intra-aortic Amifostine infusion during spinal cord ischemia phase, significantly attenuated the spinal cord oxidative injury in rabbits.</p

Ambiguous Nucleotide Calls From Population-based Sequencing of HIV-1 are a Marker for Viral Diversity and the Age of Infection

The fraction of ambiguous nucleotide calls in bulk sequencing of human immunodeficiency virus type 1 (HIV-1) carries important information on viral diversity and the age of infection. In particular, a fraction of ambiguous nucleotides of >.5% provides evidence against a recent infection event <1 year ago

Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study

BACKGROUND: Data on the incidence of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected persons are sparse. It is controversial whether and how frequently HCV is transmitted by unprotected sexual intercourse. METHODS: We assessed the HCV seroprevalence and incidence of HCV infection in the Swiss HIV Cohort Study between 1988 and 2004. We investigated the association of HCV seroconversion with mode of HIV acquisition, sex, injection drug use (IDU), and constancy of condom use. Data on condom use or unsafe sexual behavior were prospectively collected between 2000 and 2004. RESULTS: The overall seroprevalence of HCV infection was 33% among a total of 7899 eligible participants and 90% among persons reporting IDU. We observed 104 HCV seroconversions among 3327 participants during a total follow-up time of 16,305 person-years, corresponding to an incidence of 0.64 cases per 100 person-years. The incidence among participants with a history of IDU was 7.4 cases per 100 person-years, compared with 0.23 cases per 100 person-years in patients without such a history (P&lt;.001). In men who had sex with men (MSM) without a history of IDU who reported unsafe sex, the incidence was 0.7 cases per 100 person-years, compared with 0.2 cases per 100 person-years in those not reporting unsafe sex (P=.02), corresponding to an incidence rate ratio of 3.5 (95% confidence interval, 1.2-10.0). The hazard of acquiring HCV infection was elevated among younger participants who were MSM. CONCLUSIONS: HCV infection incidence in the Swiss HIV Cohort Study was mainly associated with IDU. In HIV-infected MSM, HCV infection was associated with unsafe sex

Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside/protease inhibitor-containing regimens

BACKGROUND: Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy. METHODS: A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA ≤ 400 copies/mL after ≥ 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24). RESULTS: Baseline mean HIV-1 RNA was 3.86 log(10 )copies/mL and CD4+ cell count was 345 cells/mm(3). A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (<400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; <50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm(3 )and -63 cells/mm(3 )(P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed. CONCLUSION: ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events

Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders.

BACKGROUND: Single-nucleotide polymorphisms in genes involved in lipoprotein and adipocyte metabolism may explain why dyslipidemia and lipoatrophy occur in some but not all antiretroviral therapy (ART)-treated individuals. METHODS: We evaluated the contribution of APOC3 -482C--&amp;gt;T, -455T--&amp;gt;C, and 3238C--&amp;gt;G; epsilon 2 and epsilon 4 alleles of APOE; and TNF -238G--&amp;gt;A to dyslipidemia and lipoatrophy by longitudinally modeling &amp;gt;2600 lipid determinations and 2328 lipoatrophy assessments in 329 ART-treated patients during a median follow-up period of 3.4 years. RESULTS: In human immunodeficiency virus (HIV)-infected individuals, the effects of variant alleles of APOE on plasma cholesterol and triglyceride levels and of APOC3 on plasma triglyceride levels were comparable to those reported in the general population. However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 and [corrected] APOE were at risk of extreme hypertriglyceridemia. They had median plasma triglyceride levels of 7.33 mmol/L, compared with 3.08 mmol/L in the absence of ART. The net effect of the APOE*APOC3*ritonavir interaction was an increase in plasma triglyceride levels of 2.23 mmol/L. No association between TNF -238G--&amp;gt;A and lipoatrophy was observed. CONCLUSIONS: Variant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV. Interactions between genotypes and ART can lead to severe hyperlipidemia. Genetic analysis may identify patients at high risk for severe ritonavir-associated hypertriglyceridemia