Use Of Zidovudine Research Articles

Acquired human immunodeficiency virus/ HIV in the neonatal period

Blocking mother-to-child transmission was one of the greatest victories against HIV infection. A reduction in infection rates down to below 2% was achieved by applying strategies such as the recognition of maternal infection (HIV serological testing or rapid test) during the prenatal period or at delivery, use of antiretrovirals, elective route of delivery according to the patient’s viral load, and replacement of breastfeeding by formula. In Brazil, the recommended regimen includes the use of an anti-retroviral scheme composed of three anti-retroviral drugs from two different class es, from the 14th week of pregnancy (after the first trimester), in all pregnant women infected with HIV regardless of their virological or immunological parameters, use of intravenous zidovudine at the time of delivery, and of zidovudine in all children born to HIV infected mothers during the first four weeks of life. In special situations, adding other antiretrovirals, such as lamivudine and nevirapine, has been suggested. The benefits of maternal use of anti-retroviral drugs to prevent HIV transmission to children are unanimous. The safety of these short-term schemes has already been demonstrated, however, the association between maternal use of antiretrovirals drugs and congenital anomalies, prematurity, mitochondrial toxicity, anemia, neutropenia, and increased liver enzymes have been described. Serious effects rarely occur. Long-term follow-up of all children exposed to antiretroviral drugs is still necessary to answer many existing questions.

The Combination Of Arsenic, Interferon-Alpha, and Zidovudine Restores An “Immunocompetent-like” Micro-Environment In Patients With Adult T-Cell Leukemia/Lymphoma

BackgroundHTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN. MethodsHere we assessed Th1/Th2/Treg cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ResultsATL patients at diagnosis displayed a Treg/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4+CD25+ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4+CD25+ cells. ConclusionsThe observed shift from a Treg/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections. Disclosures:Off Label Use:Off label use of arsenic trioxide, zidovudine and interferon-alpha for the treatment of adult T cell leukemia/lymphoma.

Zidovudine Induces Visceral Mitochondrial Toxicity and Intra-Abdominal Fat Gain in a Rodent Model of Lipodystrophy

The use of zidovudine is associated with a loss of subcutaneous adipose tissue (SAT). We assessed if zidovudine treatment also affects visceral adipose tissue (VAT) and if uridine supplementation abrogates the adverse effects of zidovudine on VAT. Rats were fed zidovudine for 21 weeks with or without simultaneous uridine supplementation. Control animals did not receive zidovudine, or were treated with uridine alone. Changes in SAT and VAT were monitored by magnetic resonance imaging. Adipose tissue was examined for structural and molecular signs of mitochondrial toxicity. Zidovudine induced lipoatrophy in SAT and fat hypertrophy in VAT. Compared with controls zidovudine-exposed VAT adipocytes had increased diameters, microvesicular steatosis and enlarged mitochondria with disrupted crystal architecture on electron microscopy. VAT adipocyte mitochondrial DNA (mtDNA) copy numbers were diminished, as were mtDNA-encoded respiratory chain proteins. The 'common' mtDNA deletion was detected in high frequencies in zidovudine treated animals, but not in the controls. Although mtDNA depletion was more profound in SAT compared with VAT, the 'common' deletion tended to be more frequent in the VAT than in the SAT. Uridine coadministration abrogated all effects of zidovudine on VAT and SAT pathology. Zidovudine induces a gain of intra-abdominal fat in association with quantitative and qualitative alterations of the mitochondrial genome and impaired expression of mtDNA-encoded respiratory chain components, indicating that zidovudine may contribute to abdominal fat hypertrophy in HIV-infected patients. In this rodent model, uridine supplementation abrogates both SAT and VAT pathology induced by zidovudine.

Rates and predictors of response to anti‐viral treatment for hepatitis C virus inHIV/HCVco‐infection in a nationwide study of 619 patients

The effectiveness of anti-viral treatment for hepatitis C virus (HCV) in HIV/HCV co-infected patients in 'real world', clinical practice is unclear. To determine the rates and predictors of sustained virological response (SVR) to anti-viral treatment for HCV with pegylated interferon (PEG-IFN) and ribavirin in HIV/HCV co-infected patients. We identified all HIV/HCV co-infected patients who received anti-viral treatment with PEG-IFN and ribavirin in the Veterans Affairs healthcare system nationally between 2002 and 2009 (n = 665). Sustained virological response was achieved in 21.6% overall, 16.7% among patients with genotype 1 HCV (n = 491) and 44% among patients with genotype 2 or 3 HCV (n = 116). Among genotype 1-infected patients, characteristics that were negatively associated with SVR independently included baseline HCV viral load >2 million IU/mL [adjusted odds ratio (AOR) 0.41, 95% CI 0.2-0.7], Black race [AOR 0.56 (0.3-0.96)], diabetes [AOR 0.42 (0.2-0.9)], baseline anaemia [AOR 0.42 (0.2-0.97)], serum aspartate aminotransferase/alanine aminotransferase ratio ≥1.2 [AOR 0.48 (0.2-0.97)] and use of zidovudine [AOR 0.41 (0.2-0.9)]; characteristics positively associated with SVR included a starting dose of ribavirin ≥1000-1200 mg/day [AOR 2.0 (1.1-3.7)] and erythropoietin use during treatment [AOR 2.9 (1.6-5.0)]. Among genotype 2 or 3 infected patients, only erythropoietin use was an independent predictor of SVR [AOR 3.1 (1.2-7.8)], while a starting dose of ribavirin >800 mg/day was not associated with SVR. Sustained virological response rates achieved with PEG-IFN and ribavirin in HIV/HCV co-infected patients are low in clinical practice. The use of erythropoietin was the most important, modifiable factor associated with SVR.

Haemoglobin recovery among HIV-1 infected patients on zidovudine-based antiretroviral therapy and other regimens in north-central Nigeria

We conducted a study to assess trends in haemoglobin recovery among HIV-infected patients initiated on zidovudine-based combination antiretroviral therapy (cART) stratified by baseline haemoglobin level. Haemoglobin data from non-pregnant adult patients initiating cART in rural north-central Nigeria between June 2009 and May 2011 were analysed using a linear mixed effects model to assess the interaction between time, zidovudine-containing regimen and baseline haemoglobin level on the outcome of subsequent haemoglobin level. Best-fit curves were created for baseline haemoglobin in the 10th, 25th, 75th and 90th percentiles. We included 313 patients with 736 measures of haemoglobin in the analysis (239 on zidovudine and 74 on non-zidovudine-containing regimens). Median haemoglobin increased over time in both groups, with differences in haemoglobin response over time related to baseline haemoglobin levels and zidovudine use (p = 0.003). The groups of patients on zidovudine at the 10th and 90th percentiles had downward sloping curves while all other groups had upward trending haemoglobin levels. Although haemoglobin levels increased overall for patients on zidovudine-containing regimens, for those in the 10th and 90th percentiles haemoglobin levels trended downward over time. These results have implications for decisions regarding when to initiate, switch from or avoid the use of zidovudine.

Incidence and predictors of severe anemia in Asian HIV-infected children using first-line antiretroviral therapy

There are limited data on treatment-related anemia in Asian HIV-infected children. Data from Asian HIV-infected children aged <18 years on first-line highly active antiretroviral therapy (HAART) were used. Children who had pre-existing severe anemia at baseline were excluded. Anemia was graded using the United States Division of AIDS (DAIDS) 2004 table. Potential risk factors for severe anemia were assessed by logistic regression. Data from 1648 children (51.9% female, 62.8% World Health Organization (WHO) stage 3/4) were analyzed. Median (interquartile range) age was 6.8 (3.7-9.6) years, CD4% was 9 (3-16)%, and plasma HIV-RNA was 5.2 (4.7-5.6) log10 copies/ml at HAART initiation in those with available testing. The most common regimens were stavudine/lamivudine/nevirapine (42%) and zidovudine/lamivudine/nevirapine (25%). Severe anemia was identified in 47 (2.9%) children after a median time of 6 months after HAART initiation, with an incidence rate of 5.4 per 100 child-years. Mild anemia or moderate anemia at baseline (p = 0.024 and p = 0.005, respectively), previous or current use of zidovudine (p < 0.0001 and p = 0.013, respectively), and male sex (p = 0.008) were associated with severe anemia. Higher weight-for-age z-score (p = 0.004) was protective. The incidence of severe anemia in Asian HIV-infected children after HAART initiation was low and mainly occurred during the first few months after HAART initiation. Mild to moderate anemia at baseline and using zidovudine were independent risk factors for the development of severe anemia.

Anemia among HIV-Infected Patients Initiating Antiretroviral Therapy in South Africa: Improvement in Hemoglobin regardless of Degree of Immunosuppression and the Initiating ART Regimen

Among those with HIV, anemia is a strong risk factor for disease progression and death independent of CD4 count and viral load. Understanding the role of anemia in HIV treatment is critical to developing strategies to reduce morbidity and mortality. We conducted a prospective analysis among 10,259 HIV-infected adults initiating first-line ART between April 2004 and August 2009 in Johannesburg, South Africa. The prevalence of anemia at ART initiation was 25.8%. Mean hemoglobin increased independent of baseline CD4. Females, lower BMI, WHO stage III/IV, lower CD4 count, and zidovudine use were associated with increased risk of developing anemia during follow-up. After initiation of ART, hemoglobin improved, regardless of regimen type and the degree of immunosuppression. Between 0 and 6 months on ART, the magnitude of hemoglobin increase was linearly related to CD4 count. However, between 6 and 24 months on ART, hemoglobin levels showed a sustained overall increase, the magnitude of which was similar regardless of baseline CD4 level. This increase in hemoglobin was seen even among patients on zidovudine containing regimens. Since low hemoglobin is an established adverse prognostic marker, prompt identification of anemia may result in improved morbidity and mortality of patients initiating ART.

Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery

To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Included were 511 patients with a median baseline CD4 count of 57 cells/mm(3) (interquartile range: 22-130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: -22.3 cells/mm(3) (95% confidence interval -43.2 to -1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution.

“Antivirals” in the Treatment of Adult T Cell Leukaemia– Lymphoma (ATLL)

Adult T cell leukaemia / lymphoma (ATLL) is a mature (post thymic) T cell lymphoma caused by the human T-lymphotropic virus type 1 (HTLV-1) infection. Overall survival in the aggressive subtypes (Acute Leukaemia and Lymphomatous) remains poor in part due to chemotherapy resistance. To improve treatment outcome for de novo disease, better induction therapies are required and since the pathogenic agent is known it would seem sensible to target the virus. In a recent meta-analysis the use of zidovudine and interferon alpha (ZDV/IFN) has been associated with improved response rates and prolonged overall survival in leukemic subtypes of ATLL (both acute and Chronic) confirmed in a multivariate analysis. In a more recent UK study the overall response rate for patients with aggressive ATLL treated with chemotherapy alone was 49% compared to 81% with combined first line therapy (chemotherapy with concurrent or sequential ZDV/IFN). Combined first line therapy prolonged median OS in acute (p = 0.0081) and lymphomatous ATLL (p = 0.001).These data support the use of low dose ZDV/IFN with chemotherapy as first line treatment for patients with newly diagnosed aggressive ATLL. Although the mechanisms of action are incompletely understood, some possible explanations for their efficacy will be discussed.

The burden of anaemia and associated factors in HIV positive Nigerian women

Anaemia is the most common complication of pregnancy and a predictor of poor maternal and foetal outcomes. HIV infection is now recognized as one of the major contributors to anaemia in pregnancy. It is therefore important to determine the burden and risk factors of anaemia in maternal HIV infection in others to plan effective prevention strategies as well as optimize management outcomes. To determine the prevalence and risk factors of anaemia in pregnant HIV positive Nigerians. The prevalence and possible risk factors of anaemia were investigated in HIV positive pregnant Nigerian women at a large HIV treatment clinic in southwestern Nigeria using a cross-sectional design between January 2006 and December 2011. Nine hundred and eighty-five (42.5 %) women of 2,318 HIV positive pregnant women seen during the period were anaemic by WHO standard defined by haemoglobin <11 g/dl. Majority were of mild to moderate severity (97.9 %). Short inter birth interval (p = 0.002), presence of opportunistic infections (OIs), (p = 0.001), use of zidovudine containing regimen (p = 0.0005) and CD4 cell count <200 cells/mm(3) (p = 0.001) were found to be independently associated with anaemia in HIV positive pregnant women after controlling for confounding variables. Anaemia was found to be high at 42.5 % among the HIV positive women studied and was found to be independently associated with short inter birth interval, presence of OIs, advanced HIV disease and use of zidovudine containing HAART regimen.

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study

Objective To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom.Design Multicentre observational study.Setting All UK public laboratories...

Evaluation of Different Antiretroviral Drug Protocols on Naturally Infected Feline Immunodeficiency Virus (FIV) Cats in the late Phase of the Asymptomatic Stage of Infection

The aim of this study was to evaluate the efficacy of the antiretrovirals: Zidovudine (ZDV) alone; ZDV + Recombinant Human Interferon-α (rHuIFN-α); ZDV + Lamivudine (3TC) and ZDV + valproic acid (Valp) on naturally feline immunodeficiency virus (FIV)-infected cats, in the late phase of the asymptomatic stage of infection. The follow-up was performed over one year, through clinical evaluation and the determination of viral loads and CD4+/CD8+ ratios. Neurological signs were studied by visual and auditory evoked potentials (VEP, AEP) and the responses were abnormal in 80% of the FIV-infected cats. After one year, an improvement in VEP and AEP was observed in the ZDV + Valp group and a worsening in the group receiving ZDV + rHuIFN-α. The CD4+/CD8+ ratio showed a significant increase (both intra and inter-groups) only in ZDV and ZDV + 3TC, between their pre-treatment and one year values, as well as among the other groups. Viral load only showed a significant decrease in ZDV and ZDV + 3TC groups, when comparing the values at one year of treatment vs. pre-treatment values and when the different groups were compared. In addition, the viral load decrease was significantly more pronounced in the ZDV + 3TC vs. ZDV group. We conclude that ZDV and ZDV + 3TC produce significant reductions in viral load and stimulate a recovery of the CD4+/CD8+ ratio, compared with the other protocols. It is clear that the addition of 3TC resulted in a greater reduction in viral load than use of ZDV as a single drug. Therefore, the combination ZDV + 3TC could be more effective than the sole use of ZDV.

Effectiveness of a Prevention of Mother-to-Child HIV Transmission Programme in an Urban Hospital in Angola

BackgroundAntiretroviral therapy is effective in reducing rates of mother-to child transmission of HIV to low levels in resource-limited contexts but the applicability and efficacy of these programs in the field are scarcely known. In order to explore such issues, we performed a descriptive study on retrospective data from hospital records of HIV-infected pregnant women who accessed in 2007–2010 the Luanda Municipal Hospital service for prevention of mother-to-child transmission (PMTCT). The main outcome measure was infant survival and HIV transmission. Our aim was to evaluate PMTCT programme in a local hospital setting in Africa.ResultsData for 104 pregnancies and 107 infants were analysed. Sixty-eight women (65.4%) had a first visit before or during pregnancy and received combination antiretroviral treatment (ART) in pregnancy. The remaining 36 women (34.6%) presented after delivery and received no ART during pregnancy. Across a median cohort follow-up time of 73 weeks, mortality among women with and without ART in pregnancy was 4.4% and 16.7%, respectively (death hazard ratio: 0.30, 95% CI 0.07–1.20, p = 0.089). The estimated rates of HIV transmission or death in the infants over a median follow up time of 74 weeks were 8.5% with maternal ART during pregnancy and 38.9% without maternal ART during pregnancy. Following adjustment for use of oral zidovudine in the newborn and exposure to maternal milk, no ART in pregnancy remained associated with a 5-fold higher infant risk of HIV transmission or death (adjusted odds ratio: 5.13, 95% CI: 1.31–20.15, p = 0.019).ConclusionsAmong the women and infants adhering to the PMTCT programme, HIV transmission and mortality were low. However, many women presented too late for PMTCT, and about 20% of infants did not complete follow up. This suggests the need of targeted interventions that maintain the access of mothers and infants to prevention and care services for HIV.

Effects of Short-Course Zidovudine on the Selection of Nevirapine-Resistant HIV-1 in Women Taking Single-Dose Nevirapine

Single-dose nevirapine (sdNVP) given to prevent mother-to-child-transmission of HIV-1 selects NVP-resistance. Short-course zidovudine (ZDV) was hypothesized to lower rates of NVP-resistance. HIV-1 infected pregnant women administered sdNVP with or without short-course ZDV were assessed for HIV-1 mutations (K103N, Y181C, G190A, and V106M) prior to delivery and postpartum. Postpartum NVP-resistance was lower among 31 taking ZDV+sdNVP compared to 33 taking only sdNVP (35.5% vs. 72.7%; χ2 P = .003). NVP mutants decayed to <2% in 24/35 (68.6%) at a median 6 months postpartum, with no differences based on ZDV use (logrank P = .99). Short-course ZDV was associated with reduced NVP-resistance mutations among women taking sdNVP.

Successful Treatment of Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PCNS-PTLD) with Zidovudine (AZT), Ganciclovir (GCV), Rituximab and Dexamethasone: A Single-Institution Case Series

Abstract 3067 BACKGROUND:Primary central nervous system post-transplant lymphoproliferative disorder (PCNS PTLD) is a rare complication of solid organ transplantation, with no standard therapy. Most PCNS PTLDs are associated with Epstein-Barr virus (EBV) infection, thus EBV could serve as a potentially attractive therapeutic target. For EBV-targeted antiviral therapy to be effective, antiviral agents must be phosphorylated by lytic-phase EBV kinases BXLF1/vTK and BGLF4. We hypothesized that PCNS-PTLDs would express viral kinases and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based chemotherapy for patients who often have impaired organ function and poor performance status. METHODS:We investigated the safety and efficacy of EBV-targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS PTLD, as well as the relationship of viral protein kinase expression with response to therapy. Patients with biopsy-proven PCNS PTLD following solid organ transplantation were eligible for treatment. Induction therapy consisted of AZT 1500 mg IV, and GCV 5 mg/kg IV, dexamethasone 10 mg IV, twice daily on days 1–14 and 4 weekly doses of rituximab 375 mg/m2 on days 1, 8, 15, and 22. Maintenance therapy was initiated on day 15 with valganciclovir 500 mg twice daily, and AZT 300 mg twice daily until disease progression or intolerable toxicity. Treatment was adjusted for hematologic toxicity and impaired liver and kidney function. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of viral kinases BGLF4 and BXLF1/vTK by in situ hybridization. RESULTS:Eight patients (5 M, 3 F) with a median age of 49 were treated at our institution from 1999–2011. Transplant history included kidney (N=7), and kidney + pancreas (N=1). Pathology data was available for all patients and included diffuse-large B-cell lymphoma (N=4), grade III lymphomatoid granulomatosis (N=2), and B-cell lymphoma, not further classifiable (N=2). EBV positivity (EBER) and CD20 expression was documented in all cases. Evaluation of BXLF1/vTK and BGLF4 was completed in 4 patients and found to be positive. Areas of tumor expressing viral kinases did not express LMP1. Immune suppression was reduced in all patients prior to treatment. All patients completed induction therapy. Median duration of maintenance therapy was 16.6 months. At the time of analysis, 6 patients were still alive and disease free (median duration of follow-up = 19.6 months, inter-quartile range = 10.6 – 28.3). All 8 patients achieved a complete response by MRI criteria with a median duration to response of 2 months (inter-quartile range = 1.5 – 4 months). Two patients died with survival times of 3 and 143 months after diagnosis. No patients had documented disease progression. Thus far, median duration of progression free survival has been 17.1 months (inter-quartile range = 7 – 31 months). Patient 1 was disease-free for 141 months but developed and died from complications of colon cancer. Patient 8 died of multi-organ failure related to pneumonia and septic shock, which was considered non-treatment-related, 3 months after initiation of therapy. At that time, a brain MRI showed evidence of complete response. Grade 3–4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=3), leukopenia (N=5) and neutropenia (N=4). Toxicity in the maintenance phase was generally reversible within 7 days of holding therapy. One patient required discontinuation of AZT during maintenance treatment for persistent, transfusion-dependent anemia. CONCLUSIONS:EBV-targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be safe for the treatment of EBV+ PCNS PTLD, with promising evidence of activity. Responses were generally rapid and durable. Expression of BXLF1/vTK and BGLF4 kinases provides mechanistic rationale for an antiviral approach for this disease. Given the lack of effective standard therapy for these patients, this regimen deserves further investigation. Unanswered questions include the optimum length of maintenance therapy that is still effective while minimizing toxicity, and whether rituximab is necessary to achieve the responses observed. A multi-center phase II trial is in development to further investigate this regimen. Disclosures:Off Label Use: We will discuss the use of zidovudine and ganciclovir to treat primary CNS lymphoma in transplant patients.

Use of Zidovudine and Interferon Alfa With Chemotherapy Improves Survival in Both Acute and Lymphoma Subtypes of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a mature (post-thymic) T-cell lymphoma associated with human T-lymphotropic virus type 1 infection. Survival in aggressive subtypes remains poor, and treatment resistance is frequent. Use of zidovudine (ZDV) and interferon alfa (IFN-α) has been associated with improved response rates in small studies and prolonged overall survival in leukemic ATLL subtypes in a recent meta-analysis. We report the clinicopathologic characteristics, treatment, and outcome of 73 patients with aggressive ATLL (acute ATLL, 29; lymphoma ATLL, 44) diagnosed and treated in England between 1999 and 2009. The impact of ZDV/IFN-α on treatment response and survival was assessed. The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). Median overall survival (OS) was 9 months: 7.5 months for acute ATLL and 10 months for lymphoma ATLL. Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL (hazard ratio, 0.23; 95% CI, 0.09 to 0.60; P = .002). Combined first-line therapy prolonged median OS in acute (P = .0081) and lymphoma ATLL (P = .001) compared with chemotherapy alone. These data support the use of low-dose ZDV/IFN-α with chemotherapy in first-line treatment of acute and lymphoma ATLL.

A Risk-Factor Guided Approach to Reducing Lactic Acidosis and Hyperlactatemia in Patients on Antiretroviral Therapy

BackgroundStavudine continues to be used in antiretroviral treatment (ART) regimens in many resource-limited settings. The use of zidovudine instead of stavudine in higher-risk patients to reduce the likelihood of lactic acidosis and hyperlactatemia (LAHL) has not been examined.MethodsAntiretroviral-naïve, HIV-infected adults initiating ART between 2004 and 2007 were divided into cohorts of those initiated on stavudine- or zidovudine-containing therapy. We evaluated stavudine or zidovudine use, age, sex, body mass index (BMI), baseline CD4 cell count, creatinine, hemoglobin, alanine aminotransferase, and albumin as predictors of time to LAHL with Cox Proportional Hazards (PH) regression models.ResultsAmong 2062 patients contributing 2747 patient years (PY), the combined incidence of LAHL was 3.2/100 PY in those initiating stavudine- and 0.34/100 PY in those initiating zidovudine-containing ART (RR 9.26, 95% CI: 1.28–66.93). In multivariable Cox PH analysis, stavudine exposure (HR 14.31, 95% CI: 5.79–35.30), female sex (HR 3.41, 95% CI: 1.89–6.19), higher BMI (HR 3.21, 95% CI: 2.16–4.77), higher creatinine (1.63, 95% CI: 1.12–2.36), higher albumin (HR 1.04, 95% CI: 1.01–1.07), and lower CD4 cell count (HR 0.96, 95% CI: 0.92–1.0) at baseline were associated with higher LAHL rates. Among participants who started on stavudine, switching to zidovudine was associated with lower LAHL rates (HR 0.15, 95% CI: 0.06–0.35). Subgroup analysis limited to women with higher BMI≥25 kg/m2 initiated on stavudine also showed that switch to zidovudine was protective when controlling for other risk factors (HR 0.21, 95% CI .07–0.64).ConclusionsStavudine exposure, female sex, and higher BMI are strong, independent predictors for developing LAHL. Patients with risk factors for lactic acidosis have less LAHL while on zidovudine- rather than stavudine-containing ART. Switching patients from stavudine to zidovudine is protective. Countries continuing to use stavudine should avoid this drug in women and patients with higher BMI.

Coinfection with Human Immunodeficiency Virus and Hepatitis C Virus: Challenges and Therapeutic Advances

In the United States, approximately 30% of all human immunodeficiency virus (HIV)-positive patients are also infected with hepatitis C virus (HCV). Both viruses share similar routes of transmission. Unlike HIV or hepatitis B virus, HCV is curable if treated and the patient achieves a sustained virologic response. The impact of coinfection includes greater morbidity and mortality, with higher rates of opportunistic disease, development of cirrhosis, and death. The standard of treatment for HIV-HCV coinfection is similar to that for HCV monoinfection and consists of pegylated interferon alpha and ribavirin. As with HCV monoinfection, the best predictor of response to therapy for HIV-HCV coinfection is infection with an HCV genotype other than genotype 1 or 4. Adherence to treatment is critical for improving response to HCV therapy. However, considerable toxicities are associated with pegylated interferon alpha and ribavirin and pose particular problems in the coinfected patient. Coinfected patients are more likely to experience significant weight loss with HCV therapy. Neutropenia and anemia are both common laboratory abnormalities that necessitate dosage reductions and are concerns for development of acquired immunodeficiency syndrome-defining events. The effect of CD4(+) cell count has been evaluated both as a factor in response to HCV therapy and in stratification of risk for infection. Immunosuppression is not a contraindication to HCV therapy, although CD4(+) counts above 350 cells/mm(3) are associated with increased response rates in patients with HCV genotype 1 coinfection. Antiretroviral therapy does need to be adjusted to minimize adverse effects. Concomitant use of zidovudine is contraindicated because of its profound exacerbation of bone marrow suppression. The use of didanosine is also not indicated during HCV therapy because of the risks of hepatic decompensation. Controversy exists regarding the use of abacavir. Newer agents for HCV include the protease inhibitors telaprevir and boceprevir. Although results with the protease inhibitors are highly encouraging, their effects in coinfected patients have not been evaluated. Treatment for HCV in patients with HIV poses potential obstacles to success, but the benefits of viral eradication warrant the challenge of therapy.

Anti-HIV-1 drug toxicity and management strategies

Anti-HIV-1 drug toxicity and management strategies Bechan SharmaDepartment of Biochemistry, University of Allahabad, Allahabad, IndiaAbstract: Antihuman immunodeficiency virus type 1 (anti-HIV-1) medications have helped millions of HIV-1-infected people lead longer and healthier lives. The goal of HIV-1 treatment is to reduce the number of virions in the body of infected individuals and to prevent rapid destruction of CD4+ T-lymphocyte cells, thus protecting the immune system. Most of the anti-HIV-1 drugs in practice are designed using viral reverse transcriptase (HIV-1RT), protease, and integrase as targets. These drugs that inhibit the activities of HIV-1RT, viral protease, and integrase are therefore known as anti-HIV-1RT, antiprotease, and anti-integrase molecules, respectively. The US Food and Drug Administration has approved 22 anti-HIV-1/acquired immunodeficiency syndrome (AIDS) drugs for clinical use by HIV-1-infected individuals and AIDS patients. Among the drugs, most of the nucleoside analogs (excluding two isomers of 3TC, (-)3TC and (+)3TC, which are shown to be less toxic in cell culture) exhibit clinical complications that pose a threat to chemotherapy. The toxicity of these molecules arises due to their negative impact on the activities of human mitochondrial chromosomal DNA polymerases (a, d, &szlig;, and e) in general and DNA polymerase &gamma; in particular. Other anti-HIV-1 regimens are also reported to cause toxicity. The range of toxicity extends from mild to life-threatening levels. The prolonged use of zidovudine (3&prime;-azido-3&prime;-deoxythymidine [AZT] or Retrovir), which was first approved in 1987 as a nucleoside analog reverse transcriptase inhibitor, has been reported to cause severe hematologic toxicity, including severe anemia, granulocytopenia, and symptomatic myopathy. Many other drugs that are often used in combination with AZT have similar toxicities. The newer antiretrovirals (ARVs), such as 2&prime;,3&prime;-dideoxycytidine, 2&prime;,3&prime;-dideoxyinosine, and 2&prime;,3&prime;-dideoxy-2&prime;,3&prime;-didehydrothymidine, which exhibit analogous mechanisms of action and similar toxicities to AZT, have not been studied extensively. Acyclovir and gancyclovir can cause severe nausea and vomiting. Some of these ARVs when taken during pregnancy may generate teratogenic effects. Similarly, use of antiproteases in highly active ARV therapy causes hepatotoxicity, which poses a severe risk to the patients. In addition, application of fusion inhibitors and anti-integrases induces strong side effects in HIV-1-infected or AIDS patients. The present review illustrates a comprehensive analysis of the existing literature on the toxicity of anti-HIV-1/AIDS drugs, their mechanisms of action, and possible management strategies to combat this problem.Keywords: HIV-1, AIDS, anti-HIV-1RT drugs, antiproteases, anti-integrases, fusion inhibitors, dosage, toxicity, management

The incidence, predictors and management of anaemia and its association with virological response in HCV / HIV coinfected persons treated with long-term pegylated interferon alfa 2a and ribavirin

The association of anaemia with outcomes in the HCV/HIV coinfected persons undergoing HCV treatment remains unclear. To study the incidence, predictors and management of anaemia, and its association with outcomes among persons treated with pegylated interferon and weight-based ribavirin. Retrospective analysis of a prospective controlled treatment trial of HCV/HIV coinfection. Among 329 subjects enrolled, 40% developed anaemia during the first 12-18 weeks of treatment (median haemoglobin decrease at week 4: 2.2 g/dL). Among 169 subjects who achieved early virological response and received therapy for 72 weeks, 55% eventually developed anaemia. However, median haemoglobin levels stayed stable after 12-18 weeks of initial therapy. Among these 169 subjects, 45% were prescribed an erythropoiesis stimulating agent (ESA), with 17% receiving it prior to a drop in haemoglobin meeting protocol definition of anaemia. Only 27% completed the study without any ribavirin dose modification. Age >40 years, lower BMI, zidovudine use and lower entry haemoglobin were significant predictors of anaemia in the multi-covariate model. Among all 329, sustained virological response (SVR) rate was similar in those with or without anaemia (23% vs. 30%; P=0.17) with no evidence of association between anaemia or ESA use and treatment response. Anaemia is common in HCV/HIV coinfected persons undergoing HCV treatment, and only a minority of them are able to maintain ribavirin dose. Persons with age >40 years, lower baseline haemoglobin and lower baseline BMI should be monitored carefully. Prescription of erythropoiesis stimulating agent is common, but anaemia or erythropoiesis stimulating agent use is not associated with SVR.