Therapy-naive Patients Research Articles

Effect of Micronutrient and Probiotic Fortified Yogurt on Immune-Function of Anti-Retroviral Therapy Naive HIV Patients

Background: Micronutrient supplementation has been shown to reduce the progression of HIV but does not have an effect on the intestinal barrier or the intestinal microbiota of HIV patients. Studies have suggested that probiotics could potentially complement micronutrients in preserving the immune-function of HIV patients. Objective: Assess the impact of micronutrient supplemented probiotic yogurt on the immune function of HIV patients. Design:We performed a randomized, double blind, controlled trial with CD4 count as primary outcome among HIV patients naïve to anti-retroviral treatment. Secondary outcomes included hematological parameters, incidence of diarrhea and clinical symptoms. A total of 112 HIV patients were randomized to receive a micronutrient fortified yogurt with (n = 55) or without additional probiotic Lactobacillus rhamnosus GR-1 (n = 57) for four weeks. Results:An average decline in CD4 count of −70 cells/μL (95% CI: −154 to −15) was observed in the micronutrient, probiotic group versus a decrease of −63 cells/μL (95% CI: −157 to −30) in the micronutrient control group (p = 0.9). Additional probiotic supplementation was well tolerated and not associated with adverse events. No difference between groups was detected in incidence of diarrhea or clinical symptoms. An improvement of hemoglobin levels was observed for all subjects, based upon a mean difference from baseline of 1.4 g/L (SD = 6) (p = 0.02). Conclusion:The addition of probiotics to a micronutrient fortified yogurt was well tolerated by HIV patients but was not associated with a further increase in CD4 count after one month.

Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck

Background:Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Methods:In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2–6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity.Results:Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received ⩾4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib.Conclusion:Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Effect of HBV polymerase inhibitors on renal function in patients with chronic hepatitis B

Therapy of chronic hepatitis B with HBV-polymerase inhibitors, in particular tenofovir or adefovir, may affect renal function. To assess renal function more accurately in the normal range, we used the recently validated, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to calculate the estimated glomerular filtration rate (eGFR). Patient subgroups included: patients with HBV-monoinfection treated with lamivudine (n=36), adefovir (n=32), entecavir (n=32), or tenofovir (n=37). HBsAg-positive untreated patients (n=60) served as control. For comparison HIV-monoinfected patients treated with tenofovir (n=120) or zidovudine (n=52) based antiretroviral therapy and antiretroviral naive patients (n=109) were assessed. CKD-EPI equation was used to calculate eGFR. In a more sensitive approach, we modeled the individual change in eGFR over time with linear mixed effects models (LME). Yearly predicted median changes in individual eGFR according to the LME model were: HBV untreated -2.05 ml/min, HBV lamivudine -0.92 ml/min, HBV adefovir -1.02 ml/min, HBV entecavir -1.00 ml/min, and HBV tenofovir -0.92 ml/min (p<0.01 for HBV untreated vs. HBV treated). In HIV-monoinfected patients: HIV untreated -0.62 ml/min, HIV treated with tenofovir -2.64 ml/min, HIV treated with zidovudine -1.0 ml/min (p=0.017 for tenofovir vs. no treatment, p<0.001 for tenofovir vs. zidovudine). Therapy of HBV infection irrespective of medication seems to result in a milder decrease of renal function. In contrast tenofovir as part of HIV combination therapy seems to impair renal function in this Caucasian population.

Molecular Characterization of HIV Type 1 Strains from Newly Diagnosed Patients in Cyprus (2007–2009) Recovers Multiple Clades Including Unique Recombinant Strains and Lack of Transmitted Drug Resistance

HIV-1 evolution generates substantial genetic diversity among isolates, the majority of which are represented in areas where multiple strains cocirculate. A heterogeneous genetic HIV-1 pool has been found in Cyprus, directing us to determine the dynamics of the local HIV-1 infection by characterizing strains isolated from 74 subjects during 2007-2009, representing 88% of the known-living HIV-1-infected population, of whom 53 are newly diagnosed therapy-naive patients and 21 are chronic patients, according to the European HIV Resistance guidelines. Near full-length genome sequences were amplified by RT-nested PCR using diluted RNA from all HIV-1 seropositives and sequenced using a newly designed assay. Resistant mutations were not found among the population of the newly diagnosed therapy-naive patients either to protease, reverse transcriptase, or integrase inhibitors. Phylogenetic analyses indicated subtype B as the main subtype (48.6%), followed by subtype A (18.9%), subtype C (10.8%), CRF02_AG (8.1%), CRF11_cpx (2.7%), and (sub)subtype F1 and CRF37_cpx (1.4% each). Six HIV-1 isolates (8.1%) were not classified in any pure (sub)subtype or circulating recombinant form (CRF). Complete phylogenetic and bootscanning analyses revealed that each isolate had a new, unique recombinant pattern and is distinct from all other CRFs or unique recombinant forms (URFs) reported so far. Two of the six isolates have the same mosaic pattern. Analogous to results of the earlier epidemiological studies, this study expands on the HIV-1 sequence database and reveals the high degree of diversity of HIV-1 infection in Cyprus.

Single-Dose Bioequivalence of a New Fixed-Dose Combination Tablet Containing Tenofovir Disoproxil Fumarate and Lamivudine

Tenofovir Disoproxil Fumarate, CAS 147127-20-6 is a nucleotide reverse transcriptase inhibitor with potent activity against both HIV and hepatitis B infections. Lamivudine, CAS 134678-17-4 is a nucleoside analogue reverse transcriptase inhibitor developed as a treatment for HIV infection and also with activity against hepatitis B virus. The combination of tenofovir and lamivudine associated either with non-nucleoside reverse transcriptase inhibitors or with a ritonavir-boosted or unboosted protease inhibitor are recommended as preferred regimens for antiretroviral therapy-naive patients infected with HIV, and also for the treatment of HIV-HVB coinfected patients. The objective of this study was to compare rate and extent of absorption and to assess the bioequivalence between a new pharmaceutical equivalent tablet formulation containing a fixed-dose combination of tenofovir disoproxil fumarate/ lamivudine 300/300 mg and the innovator products. A randomized, single-center, open-label, single-dose, two-way crossover bioequivalence study in 40 healthy adult subjects was conducted. Dosing was separated by a wash-out period of 14 days. All subjects signed an informed consent form. In each study period, 13 blood samples were collected in Vacutainers containing EDTA over 48 h. Plasma levels of tenofovir and lamivudine were determined by a validated HPLC/fluorescence assay and by a validated HPLC/UV assay, respectively. Rate and extent of absorption were similar between products. The 90% confidence interval(CI) of the ratio of the geometric means for log-transformed C max , AUC last and AUC inf values were used to assess bioequivalence between the two formulations using the equivalence interval of 80 and 125%. In healthy subjects, the point estimate and 90 % C I of the ratios of C max , AUC last and AUC inf values for tenofovir were 100.99%(92.89-109.80%), 96.11%(90.02-102.63%) and 94.73%(88.22-101.73%), respectively; and for lamivudine were 90.37%(83.76-97.50%), 97.02%(93.27-100.93%) and 97.04%(93.41-100.82%), respectively. Both treatments exhibited similar tolerability and safety. It was concluded that the new pharmaceutical formulation was bioequivalent to the innovators.

A Phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC)

Background. Sunitinib induces partial responses in 47% of patients with metastatic renal cell carcinoma (mRCC). However, the achievement of complete responses remains scarce and all patients will eventually develop progressive disease. Recombinant interleukin-21 (rIL-21) is a novel cytokine, which is believed to deliver sustained cellular anti-tumor response and the combination of both agents may work synergistically. Material and method. From July 2007 to July 2008 in this phase I trial nine therapy-naive patients with metastatic RCC in five European centers were enrolled. Patients with either good or intermediate risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) were eligible without restrictions to histology subtype nor measurable disease. Patients were treated with increasing doses of rIL-21 administered subcutaneously (s.c.) in combination with sunitinib 50 mg once daily (OD) orally at the ‘4 weeks on/2 weeks off’ schedule. Dose-escalation was applied by a conventional ‘3+3 design’. Planned dose levels (DL) for rIL-21 were 3, 10, 30 and 100 μg/kg s.c. The primary endpoint was to determine the maximum tolerated dose (MTD) and recommended dose (RD). Secondary objectives included pharmacokinetics of sunitinib and rIL-21, and the induction of rIL-21 antibodies. Results. At 10 μg/kg two dose-limiting toxicities (DLT) occurred in four patients, consisting of grade 4 neutropenia and grade 3 thrombocytopenia. The MTD was 3 μg/kg rIL-21 combined with sunitinib 50 mg OD at the ‘4 weeks on/2 weeks off’ schedule. Frequent occurring adverse events were injection site reaction, stomatitis, fatigue and dysgeusia. Conclusions. The combination of sunitinib 50 mg at the ‘4 weeks on/2 weeks off’ schedule and 10 μg/kg IL-21 was not tolerated due to hematological DLTs. The dose level of 3 μg/kg rIL-21 was considered too low to be therapeutically relevant for further evaluation and therefore the study was discontinued.

The Efficacy of Combination Antiretroviral Therapy in HIV Type 1-Infected Patients Treated in Curaçao Compared with Antillean, Surinam, and Dutch HIV Type 1–Infected Patients Treated in The Netherlands

We compared the efficacy of combination antiretroviral therapy (cART) of Antillean HIV-1-infected patients treated on the Caribbean island of Curaçao (CUR-AN) with Antillean (NL-AN), Surinam (NL-SUR), and Dutch (NL-NL) patients treated in The Netherlands. In total 2118 therapy-naive patients who started cART between January 2005 and August 2008 were included in the comparison. The CUR-AN patients initiated cART at a median CD4 cell count of 141 cells/mm(3) and 63% had counts below 200 cells/mm(3). Within 12 months of the start of cART 76% of the CUR-AN patients achieved viral suppression, defined as HIV-1 RNA plasma levels below 80 copies/ml. The percentage achieving viral suppression was higher in patients treated in The Netherlands (NL-AN = 87%, NL-SUR = 93%, and NL-NL = 96%). Lost to follow-up after 30 months of cART was 10% among CUR-AN patients and was higher than observed among patients treated in The Netherlands (NL-AN = 8%, NL-SUR = 3%, and NL-NL = 2%). A similar pattern was found for progression to AIDS and death (10% of CUR-AN vs. 5%, 6%, and 7% of NL-AN, NL-SUR, and NL-NL patients, respectively). Late start of cART and limited viral suppression after the start of cART determine the higher rate of disease progression to AIDS and death among Antillean patients treated in Curaçao. The high percentage of lost to follow-up may result in an underestimation of AIDS and AIDS-related death among HIV-1-infected Antilleans treated in Curaçao.

LY2784544, a Novel JAK2 Inhibitor, Decreases In Vitro Growth of Hematopoietic Human Progenitors From JAK2 V617F Positive Polycythemia Vera Patients

AbstractAbstract 5054 Introduction:The discovery of JAK2 V617F mutation in patients with myeloproliferative disorders (MPD) has opened new perspectives for the development of targeted therapies. We have studied the efficacy of a novel molecule LY2784544 with JAK2 inhibitory activity in the in vitro growth of myeloid progenitors from JAK2 V617F-positive polycythemia vera (PV) patients. Objectives:To investigate the efficacy of LY2784544 in the inhibition of endogenous(e)BFU-E and CFU-GM growth in PV patients. Methods:In vitro cultures in semisolid media were performed from peripheral blood mononuclear cells (PBMC) of 6 PV patients who had never received cytoreductive treatment (4 patients with homozygous JAK2 V617F and 2 patients with heterozygous JAK2 V617F). PBMC were suspended in methylcellulose (Methocult. StemCell, Vancouver, Canada) without the addition of EPO and containing 0–30.0 μM LY2784544 drug. Concurrent plates containing EPO were plated as control cultures. The medium was distributed in multidishes and they were incubated at 37° with 5% CO2 and 95% humidity. Hemoglobinized colonies and granulomonocytic colonies were counted on day 14 by standard criteria (BFU-E defined by an aggregate of >50 hemoglobinized cells or three or more erythroid subcolonies and CFU-GM was defined by an aggregate of >50 cells). Each in vitro assay was performed in duplicate. DNA was obtained from peripheral blood granulocytes from each patient to quantify the JAK2 V617F allele burden at the time of culture assay. Results:LY2784544, at concentrations ranging from 0.03–30.0 μM, inhibited growth of unselected peripheral blood eBFU-E and CFU-GM from PV patients carrying the JAK2 V617F mutation in a dose-dependent manner, although without achieving complete inhibition of all colonies (fig.1). Conclusions:In vitro studies show that LY2784544 decreases the eBFU-E and CFU-GM growth in therapy-naive JAK2 V617F positive PV patients. Our data suggest that LY2784544 may be a candidate for the treatment of MPD carrying the JAK2 V617F mutation. [Display omitted] Disclosures:Ma:Eli Lilly and Company: Employment. Walgren:Eli Lilly and Company: Employment.

Negative Influence of HIV Infection on Day-Night Blood Pressure Variability

An attenuation of the physiological day-night blood pressure (BP) reduction is an important predictor of cardiovascular (CV) events and death. We compared circadian BP profile in treatment-naive HIV-infected patients and in healthy control subjects. Fifty-two antiretroviral therapy-naive HIV-infected patients (85% men, age 39 ± 11 years, BP 125/78 ± 11/9 mm Hg) and 156 age- and BP-matched HIV-negative controls (85% men, age 39 ± 10 years, BP 125/78 ± 9/7 mm Hg) underwent 24-hour BP monitoring. Subjects with a nocturnal reduction of systolic BP <10% were defined as "nondippers." Nighttime BP was higher in HIV-infected subjects (113/69 ± 11/9 vs 109/67 ± 8/6 mm Hg, P = 0.008/0.005). Nocturnal systolic/diastolic BP reduction was 8.8/13.2% in HIV-positive patients and 11.7/17.2% in HIV negative (P = 0.002/0.001). The prevalence of "nondippers" was 35% and 15%, respectively (P = 0.003). In multivariate analysis, nocturnal systolic BP fall was negatively associated to HIV infection (β = -0.22, P = 0.001). HIV viral load, low CD4 cell count, and AIDS progression risk were all related with a flattened day-night BP profile (P < 0.01). HIV infection per se negatively affects circadian BP rhythm. These findings, obtained in subjects without major CV risk factors and antiretroviral naive, suggest that day-night BP changes may play a role in the HIV-related increase in CV risk.

Population and ultra-deep sequencing for tropism determination are correlated with Trofile ES: genotypic re-analysis of the A4001078 maraviroc study

Background: A4001078 is a study in therapy naive patients of Maraviroc (MVC) plus boosted atazanavir. The Trofile ES (ESTA) was used to determine tropism at Screening. Few re-analyses of genotypic tropism have examined all screened and non-reportable (NR) populations. We aimed to define correlations between methods at screening and evaluate the quantity of X4 using virus in discordant results using ultra-deep sequencing (UDS). Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P128 Cite this article as: Portsmouth et al.: Population and ultra-deep sequencing for tropism determination are correlated with Trofile ES: genotypic re-analysis of the A4001078 maraviroc study. Journal of the International AIDS Society 2010 13(Suppl 4):P128. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112903/

Endothelial progenitor cell trafficking in human immunodeficiency virus-infected persons

Human immunodeficiency virus (HIV)-infected people exhibit a high incidence of vascular diseases. Since in the general population the high cardiovascular risk has been associated with an impaired endothelial cell function, we investigated circulating endothelial progenitor cells in HIV-positive patients. We evaluated circulating colony-forming unit-endothelial cell (CFU-EC) and endothelial colony-forming cell (ECFC) progenitors in 14 antiviral therapy-naive HIV-positive patients, in comparison with 15 normal controls. CFU-EC and ECFC derived from peripheral blood mononuclear cells from HIV-infected and HIV-uninfected individuals were recovered and evaluated for HIV genome presence by PCR. Vascular endothelial growth factor (VEGF) and apolipoprotein B mRNA-editing enzyme catalytic polypeptide like (APOBEC) subunits expression were evaluated in infected colonies by real-time PCR. We found that circulating CFU-EC but not ECFC were significantly reduced in HIV-positive patients and that proviral HIV DNA was detectable only in CFU-EC but not in ECFC. Furthermore, the expression of APOBEC subunits was significantly lower in CFU-EC than in circulating monocytes. Accordingly, the CFU-EC displayed a high content of proviral DNA copies, suggesting that these cells have a high sensitivity to the HIV infection. Although HIV does not affect the 'true endothelial progenitor' compartment, it infects and strongly depletes circulating endothelial progenitors with hematopoietic signature. We unravel a novel pathogenetic mechanism by which HIV infection might cause vascular diseases.

Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients

Treatment simplification strategies involving induction with a ritonavir (RTV)-boosted (/r) protease inhibitor regimen followed by simplification (without RTV) are appealing because they may offer sustained virologic suppression while minimizing potential long-term adverse effects associated with RTV. This open-label, randomized, noninferiority study enrolled 515 antiretroviral therapy-naive patients to receive abacavir/lamivudine plus atazanavir/RTV (ATV/r) followed by randomization at week 36 (N = 419) to maintain or discontinue RTV for an additional 48 weeks. Eligibility for randomization required confirmed HIV RNA level below 50 copies/ml and no virologic failure. Protocol-defined virologic failure after week 36 was confirmed rebound of HIV RNA level at least 400 copies/ml. The primary endpoint was the proportion of patients with HIV RNA level below 50 copies/ml at week 84 (time to loss of virologic response). This study is registered with ClinicalTrials.gov number NCT00440947. At week 84, noninferiority of ATV to ATV/r (95% confidence interval around the treatment difference -1.75 to 12.48%) was demonstrated with 181 of 210 (86%) patients in the ATV group and 169 of 209 (81%) in the ATV/r group maintaining HIV RNA level below 50 copies/ml. During the randomized phase (weeks 36-84), 10 versus 14% of patients in the ATV and ATV/r arms, respectively, experienced a drug-related grades 2-4 adverse event with hyperbilirubinemia being the most frequently reported (4 versus 10%). The overall rate of protocol-defined virologic failure was 2%; no patient had virus that developed a major protease inhibitor mutation. ATV in combination with abacavir/lamivudine is a potent and well tolerated regimen in patients who have achieved initial suppression on an induction regimen and represents a viable treatment simplification strategy.

Sensory neuropathy in patients with cryoglobulin negative hepatitis-C infection

There is growing evidence that hepatitis-C virus (HCV) infection might cause peripheral neuropathy. We aimed to investigate the prevalence, clinical and electrophysiological features of sensory neuropathy in patients with cryoglobulin negative HCV infection. We studied 46 consecutive cryoglobulin negative HCV positive patients (24 of them with and 22 without neuropathic symptoms, NS) and compared to 28 age and gender matched controls. In all patients and controls, clinical neuropathy symptom (NSS) and neuropathy deficit scores (NDS) were assessed and standard nerve conduction velocity (SNCV) and pain related-evoked potentials (PREP) were recorded. Both, SNCV and PREP were abnormal in 13 NS positive patients (13/46, 28%). Abnormal PREP but normal SNCV were found in 5 (5/46, 11%) NS positive and in 2 NS negative patients (2/46, 4%). PREP abnormalities correlated positive with both clinical neuropathy scores (NSS r=0.62; p<0.001; NDS r=0.57; p<0.001), but not with the duration of the disease, current viral load, or the virus subtype. PREP abnormalities were more frequent (16/33, 48.5%) in HCV patients treated with interferon than in therapy naïve patients (4/13, 30.8%); the difference was, however, not significant. In our present study (1) all virus subtypes are capable of inducing neuropathy, (2) no differences were found between interferon therapy and treatment naive patients, (3) the prevalence of peripheral sensory neuropathy including small sensory fibers (20/46, 43.5%) is higher than previously reported and (4) we found that detection of HCV associated neuropathy depends on the evaluation method.

Short Communication: Antiretroviral Therapy Resistance Mutations Present in the HIV Type 1 Subtype CpolandenvRegions from Therapy-Naive Patients in Zambia

The prevalence of antiretroviral therapy (ART) resistance mutations present in HIV-1 subtype C pol and env regions of the proviral DNA was analyzed and compared from therapy-naive individuals before (Cohort A) and after (Cohort B) the availability of free ART in Zambia. Mutations present in sequences published in a previous study from Zambian ART-naive individuals infected with subtype C were analyzed using current parameters for the classification of ART drug resistance and compared with Cohorts A and B. No statistically significant differences were observed when comparing mutations present in the pol and env of these cohorts. However, an increase in the number of minor, borderline, or partial resistance mutations as well as the presence of major resistance mutations were observed in Cohort B. These results suggest there is an increasing trend of drug resistance-associated mutations that could be a result of the availability of free ART in Zambia. Moreover, the high prevalence of resistance mutations observed for maraviroc and vicriviroc in both cohorts may suggest a limited efficacy of entry inhibitors on HIV-1 subtype C.

Maraviroc

Maraviroc (Celsentri; Selzentry) is a CCR5 coreceptor antagonist used in the treatment of CCR5-tropic HIV-1 infection. Administered orally twice daily, maraviroc, in combination with optimized background therapy regimens, showed good virological and immunological efficacy over 48 weeks in antiretroviral treatment-experienced patients aged > or = 16 years with CCR5-tropic HIV-1 infection, in the randomized, double-blind, placebo-controlled, multicentre, MOTIVATE 1 and MOTIVATE 2 studies. Initial data indicate that the efficacy of maraviroc in this patient population is sustained for up to 96 weeks. In the MERIT study in antiretroviral therapy-naive patients aged > or = 16 years with CCR5-tropic HIV-1 infection, maraviroc was noninferior to efavirenz (each in combination with zidovudine/lamivudine) for one primary virological endpoint (HIV-1-RNA levels < 400 copies/mL), but not for the other primary endpoint (HIV-1 RNA levels < 50 copies/mL) in the primary analysis at 48 weeks. However, in a subsequent analysis, which used a more sensitive tropism testing assay than the one originally used and retrospectively excluded patients with non CCR5-tropic HIV-1 infection who were ineligible for inclusion in the study, maraviroc demonstrated noninferiority to efavirenz on both primary virological endpoints. Maraviroc showed sustained virological efficacy in this patient population and improved immunological markers for up to 96 weeks. Maraviroc was generally well tolerated by both treatment-experienced and treatment-naive patients with CCR5-tropic HIV-1 infection. Thus, maraviroc, as a component of antiretroviral combination therapy regimens, is an important option for use in treatment-experienced adults with CCR5-tropic HIV-1 infection. Available data indicate that maraviroc may also have a role in treatment-naive adults with CCR5-tropic HIV-1 infection, a population in whom CCR5-tropic HIV-1 is often the major quasispecies.

Secondary integrase resistance mutations found in HIV-1 minority quasispecies in integrase therapy-naive patients have little or no effect on susceptibility to integrase inhibitors.

The goal of this study was to explore the presence of integrase strand transfer inhibitor (InSTI) resistance mutations in HIV-1 quasispecies present in InSTI-naïve patients and to evaluate their in vitro effects on phenotypic susceptibility to InSTIs and their replication capacities. The RT-RNase H-IN region was PCR amplified from plasma viral RNA obtained from 49 HIV-1 subtype B-infected patients (21 drug naïve and 28 failing highly active antiretroviral therapy [HAART] not containing InSTIs) and recombined with an HXB2-based backbone with RT and IN deleted. Recombinant viruses were tested against raltegravir and elvitegravir and for replication capacity. Three-hundred forty-four recombinant viruses from 49 patients were successfully analyzed both phenotypically and genotypically. The majority of clones were not phenotypically resistant to InSTIs: 0/344 clones showed raltegravir resistance, and only 3 (0.87%) showed low-level elvitegravir resistance. No primary resistance mutations for raltegravir and elvitegravir were found as major or minor species. The majority of secondary mutations were also absent or rarely present. Secondary mutations, such as T97A and G140S, found rarely and only as minority quasispecies, were present in the elvitegravir-resistant clones. A novel mutation, E92G, although rarely found in minority quasispecies, showed elvitegravir resistance. Preexisting genotypic and phenotypic raltegravir resistance was extremely rare in InSTI-naïve patients and confined to only a restricted minority of secondary variants. Overall, these results, together with others based on population and ultradeep sequencing, suggest that at this point IN genotyping in all patients before raltegravir treatment may not be cost-effective and should not be recommended until evidence of transmitted drug resistance to InSTIs or the clinical relevance of IN minor variants/polymorphisms is determined.

Role of Hematological and Alternate Markers in Human Immunodeficiency Virus Disease Progression

Problem statement: The knowledge of HIV infection has expanded tremendously which has led to significant improvement in the treatment , leading to decrease in morbidity and mortality. Considering the limitations in using CD4+T-cell cou nts and HIV RNA viral load as markers in the HIV disease progression, physicians treating the HI V patients now look for alternate markers that predict HIV disease progression and help in initiat ing and monitoring the Antiretroviral Treatment (ART). Approach: Blood samples were collected from 120 HIV sero-positive, antiretroviral therapy naive patients attending the Integrated Counseling and Testing Centre (ICTC) of Kamineni Institute of Medical Sciences, Narketpally, Nalgonda. The study was carried out between January 2007 and June 2008. The CD4+T-cell counts, CD8+T-cell counts were estimated by Flow cytometry.TLC, AEC, HB%, ESR were performed by standard hematological methods. Latex agglutination test was used to measure CRP. Results: The mean CD4+T-cell counts, CD8+T-cell counts and CD4+:CD8+ratio were found to be 308±296.8 (p<0.0001), 976.20±548.61 (p<0.0001) and 0.314±0.198 (p<0.0001) respectively. The hematological parameters estimate d included were Hemoglobin (10.7±204), AEC (391.8±180.1), TLC (8595.8±2146.9) and ESR (75.625±29) Significant positive correlation was observed between CD4+T-cell counts and AEC,TLC, HB% and CD4+:CD8+ratio. ESR and CRP was found to be negatively correlating with CD4+T-cell counts. Conclusion: The study findings reemphasize the importance of alternate markers to assess the stage of the disease, initiate antiretro viral therapy and monitor the response in disease progres sion. The study results also suggested that there i s necessity to evaluate the hematological parameters before initiating antiretroviral therapy.

Is There Any Potential for First-Line Etravirine Use? Analysis From a Large Data Set of Antiretroviral Therapy-Naive HIV-Infected Patients Undergoing Resistance Test

Is There Any Potential for First-Line Etravirine Use? Analysis From a Large Data Set of Antiretroviral Therapy-Naive HIV-Infected Patients Undergoing Resistance Test

Treatment and CD4+T Cell Count Recovery among Antiretroviral Therapy–Naive Patients with HIV/AIDS

Treatment and CD4⁺T Cell Count Recovery among Antiretroviral Therapy–Naive Patients with HIV/AIDS

Sustained Antiretroviral Effect of Raltegravir After 96 Weeks of Combination Therapy in Treatment-Naive Patients With HIV-1 Infection

The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection. Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNA > or =5000 copies per milliliter and CD4 T cells > or =100 cells per microliter. One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA <400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved <50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4 T cells (221 vs 232 cells/uL, respectively). An additional 2 patients (1 in each group) met the protocol definition of virologic failure between weeks 48 and 96; no known resistance mutations were observed in the raltegravir recipient; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations. Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in >10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. Raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir. In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. Raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.