Viral Load Decline Research Articles

Antiviral effect of entecavir in chronic hepatitis B: Influence of prior exposure to nucleos(t)ide analogues

Entecavir is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients, but data on the efficacy in NA-experienced subjects are limited. In a multi-center cohort study we investigated 161 chronic hepatitis B patients (34% NA-experienced) treated with entecavir monotherapy. During a median follow-up of 11 (3-23)months, 82 (79%) of 104 NA-naïve patients achieved virologic response (VR), defined as HBV DNA <80IU/ml, and none of the patients (0%) developed genotypic entecavir-resistance. VR was demonstrated in 31 (54%) of 57 NA-experienced patients during a median follow-up of 12 (3-31)months. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving VR compared to lamivudine-naïve patients (HR 0.14; 95% CI 0.04-0.58; p=0.007). Antiviral efficacy was not decreased by prior treatment with lamivudine when lamivudine-resistance had never developed (HR 0.81; 95% CI 0.43-1.52; p=0.52). Prior adefovir therapy without development of adefovir-resistance (HR 0.84; 95% CI 0.43-1.64; p=0.61) and presence of adefovir-resistance (HR 0.86; 95% CI 0.27-2.71; p=0.80) did not influence antiviral response to entecavir. Switching to a tenofovir-containing treatment regimen resulted in viral load decline in patients with entecavir-resistance associated mutations. Entecavir proved to be efficacious in NA-naïve patients. The antiviral efficacy of entecavir was not influenced by prior treatment with adefovir or presence of adefovir-resistance. Entecavir should not be used in patients with previous lamivudine-resistance, yet it may still be an option in lamivudine-experienced patients in case lamivudine-resistance never developed.

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

The relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-naïve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied. Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported. No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of <25 micromol/l. The great majority of treatment-naïve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-naïve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy.

Adenovirus in Solid Organ Transplant Recipients

Adenoviruses are nonenveloped, double-stranded DNAviruses associated with a wide range of clinical syndromesin humans (1). There are 52 immunologically distinct typesof adenoviruses that are further classified into one of7 (A–G) subgroups based on hemagglutinin properties,DNA homology, oncogenic potential in rodents and clin-ical disease (Table 1) (2,3). Adenoviruses typically causeself-limited respiratory, gastrointestinal or conjunctival dis-ease throughout the year without significant seasonal vari-ation. Adenovirus infections are most common amongchildren, people living in close quarters (such as collegestudents and military recruits), and immunocompromisedpatients (1).Adenovirus is the third most important viral infection fol-lowing liver transplantation in children, occurring in 10%of 484 pediatric liver transplant recipients in one series(4). A single series has reported an incidence of 5.8%of 191 adult liver transplant recipients (5). Symptomaticdisease (ranging from self-limited fever, gastroenteritis orcystitis to devastating illness with necrotizing hepatitis orpneumonia) occurred in over 60% of the infected patients.Symptomatic infections typically occurred within the first3 months after transplantation. The frequency of invasiveadenovirus infections after pediatric liver transplantationappeared to decrease with use of tacrolimus-based im-munosuppression(6);similardataarenotavailableforadultliver transplant recipients.Adenovirus infection in other organ recipients is less wellcharacterized. A recent prospective study in adult SOT re-cipients demonstrated measurable adenovirus DNAemiain 7.2% of 263 recipients in the first posttransplant year;nearly 60% of these patients were completely asymp-tomatic with the remaining patients manifesting gastroin-testinal (primarily diarrhea), respiratory or vague, nonspe-cific symptoms (7). In contrast to outcomes found in thisprospective study, case reports and small series identifythe fact that adenoviral infection can be clinically signif-icant in these patients. Severe adenoviral infection hasbeen reported after lung transplantation often leading tofatal disease (8–10). The presence of adenovirus DNA incardiac biopsies after pediatric heart transplantation wassignificantly associated with poor graft survival in one se-ries (11). Adenovirus also has been associated with hemor-rhagiccystitisandgraftdysfunctioninadultrenaltransplantrecipients (12). It has also been found in high rates after pe-diatric intestinal transplantation, though frequently in theabsence of obvious clinical disease or associated pathol-ogy (13). As adenovirus, like cytomegalovirus (CMV), canbe latent and can reactivate asymptomatically, ascribing acausative role in the pathologic process may sometimesbe difficult.Sites and clinical manifestations of adenoviral disease intransplant recipients appear to vary according to the typeof organ transplanted, with frequent involvement of theallograft. In liver transplant recipients, infection with aden-ovirusserotype5typicallyresultsinhepatitiswithamedianonset of 55 days after transplant (4,5), while serotypes 1and 2 are more commonly associated with pneumonia.Adenoviral pneumonia is associated with graft loss, deathor progression to obliterative bronchiolitis for lung trans-plant recipients (8). In one study of pediatric heart trans-plant recipients, detection of adenoviral genome copies inmyocardial biopsy specimens was predictive of adverseclinical events including coronary vasculopathy and graftloss (OR 4.7 compared to adenovirus negative patients;95% confidence interval 1.3–17.1) (11). The strength ofthis association and its pathogenesis remain to be clari-fied. Enterocolitis occurs more commonly in small bowelrecipients and may mimic rejection (7,14). Hemorrhagiccystitis and nephritis are described in renal transplant re-cipients (15). Disease in other organ recipients has beendescribed rarely.

Improving Health Outcomes for Youth Living With the Human Immunodeficiency Virus

To determine if Healthy Choices, a motivational interviewing intervention targeting multiple risk behaviors, improved human immunodeficiency virus (HIV) viral load. A randomized, 2-group repeated measures design with analysis of data from baseline and 6- and 9-month follow-up collected from 2005 to 2007. Five US adolescent medicine HIV clinics. A convenience sample with at least 1 of 3 risk behaviors (nonadherence to HIV medications, substance abuse, and unprotected sex) was enrolled. The sample was aged 16 to 24 years and primarily African American. Of the 205 enrolled, 19 did not complete baseline data collections, for a final sample size of 186. Young people living with HIV were randomized to the intervention plus specialty care (n = 94) or specialty care alone (n = 92). The 3- and 6-month follow-up rates, respectively, were 86% and 82% for the intervention group and 81% and 73% for controls. Intervention Healthy Choices was a 4-session individual clinic-based motivational interviewing intervention delivered during a 10-week period. Motivational interviewing is a method of communication designed to elicit and reinforce intrinsic motivation for change. Outcome Measure Plasma viral load. Youth randomized to Healthy Choices showed a significant decline in viral load at 6 months postintervention compared with youth in the control condition (beta = -0.36, t = -2.15, P = .03), with those prescribed antiretroviral medications showing the lowest viral loads. Differences were no longer significant at 9 months. A motivational interviewing intervention targeting multiple risk behaviors resulted in short-term improvements in viral load for youth living with HIV. Trial Registration clinicaltrials.gov Identifier: NCT00103532.

Effective Treatment of Patients in a Deep Salvage Situation with "Non-Active HAART": Experiences with the Expert Advice System RADATA

Clinical studies suggest expert recommendations as a possibility to optimize highly active antiretroviral therapy (HAART) in patients with multi-drug resistant virus strains. An online system (RADATA) has been developed to provide expert advice for the drug therapy of HIV-infected patients. To evaluate the efficacy of expert-advice-guided HAART switches in patients with triple-class failure. Virological and immunological outcome of patients having undergone at least three prior ART regimens, including nucleoside inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) use, were analyzed. Changes in HIV-RNA and CD4-cell count were evaluated every 3 months. 183 patients with a median baseline viral load of 3.90 log copies/ml (1.88-6.54 log) and a CD4-cell count of 298 c/ll (5-910 c/ll) were eligible for analysis. The patients had a median of seven prior ART regimens and a treatment duration of 83 months. A median of three (range 0-8) NRTI-, two (0-7) thymidine-associated (TA), one (0-4) NNRTI-, and three (0-13) PI-associated resistance mutations were present at baseline. Despite available resistance analyses and expert recommendations, 66% (n = 119) of the patients started a new ART regimen without any active drugs according to the resistance analysis. The HIV-RNA declined by a median of 0.61 log and 0.92 log after 12 and 24 months, respectively, while the CD4-cell count rose by a median of +9 c/microl and +25 c/microl during this period. No significant differences related to number of prior regimens or number of active substances used could be found. Despite extensive pre-treatment and multiple resistances against prescribed HAART, our patients demonstrated a decline in viral load and a stable CD4-cell count over the observation period. We conclude that the activity of antiretroviral regimens is not exclusively explained by the current algorithms used for estimating antiretroviral drug activity.

HD-03/ES: A promising herbal drug for HBV antiviral therapy

Introduction The present study was designed to study the genotypes associated with different groups of chronic liver disease and to see their response to HD-03/ES (an antiviral herbal molecule) on chronic HBV patients. Methods A total of 51 patients of chronic liver disease were recruited in the study and were given HD-03/ES, two capsules twice daily for 6 months. Liver function tests were done every month after initiating treatment. Serum was analyzed for HBsAg, HBeAg and HBV DNA and quantitative estimation of HBV at baseline, 4 and 6 months after therapy. The genotype of all the cases was also determined by PCR-RFLP method. Results After 6 months of therapy with HD-03/ES, a significant reduction of ALT values from 71.2 ± 16.3 to 36.4 ± 6.8 and a significant HBeAg loss (27.4%) and HBV DNA loss (27.4%) was observed. Adverse effects were mild. Genotype D was found in 39 (76.5%) while genotype A was found in 12 (33.5%) cases, respectively. The mean reduction in viral load was observed from log 10 7.1 ± 1.8 copies/ml to log 10 4.4 ± 1.1 copies/ml. However, a sharp decline in viral load was observed in patients infected with genotype A (log 10 6.8 ± 2.5 to log 10 4.9 ± 1.8; P < 0.01) compared to genotype D (log 10 7.0 ± 2.6 to log 10 5.9 ± 3.5; P = 0.074). Conclusion The study had shown that majority of the patients of chronic HBV related liver disease had genotype D. In additional, the molecule HD03/ES had a better therapeutic capability of lowering the HBV viral load in patients with genotype A, which needs to be validated in larger studies.

Clinical performances of two real-time PCR assays and bDNA/TMA to early monitor treatment outcome in patients with chronic hepatitis C

Background Early viral monitoring is essential for the management of treatment outcome in patients with chronic hepatitis C. A variety of commercially available assays are now available to quantify HCV-RNA in routine clinical practice. Objectives Compare the clinical results of 3 commercially available assays to evaluate the positive predictive value (PPV) and the negative predictive value (NPV) of rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12. Study design 287 patients treated with standard care regimen combination therapy were studied. HCV-RNA values measured at baseline, week 4, week 12 with VERSANT ® HCV 3.0 Assay (bDNA), and VERSANT ® HCV-RNA Qualitative Assay (TMA) (bDNA/TMA); COBAS Ampliprep/COBAS/TaqMan (CAP/CTM) and Abbott m2000sp extraction/m2000rt amplification system (ART). RVR was defined as undetectable serum HCV-RNA and EVR as a ≥2 log decline in baseline viral load (BLV). Results Median (range) BVLs were: 5.585(2.585–6.816), 5.189(2.792–7.747) and 4.804(2.380–6.580) log 10 IU/ml, with bDNA/TMA, CAP/CTM and ART, respectively ( p < 0.01); RVR was observed in 22%, 30% and 27% of the patients and PPVs were 97%, 91% and 94% with bDNA/TMA, CAP/CTM and ART, respectively ( p = 0.317). EVR was observed in 76%, 73% and 67% of the patients and NPVs were 93%, 83% and 79% with bDNA/TMA, CAP/CTM and ART, respectively ( p = 0.09). Conclusions Treatment monitoring should include both detection of serum HCV-RNA at week 4 to predict SVR and at week 12 to predict non-SVR. The value of all 3 assays was similar for evaluating RVR or EVR. Because of viral load discrepancies the same assay should be used throughout patient treatment follow-up.

Thrombocytopenia Is Strongly Associated With Simian AIDS in Pigtail Macaques

Simian AIDS has a variable time course and presentation making it difficult to define disease effects of progressive simian immunodeficiency virus (SIV) infection. We commonly observed thrombocytopenia (TCP) associated with progressive SIV infection of pigtail macaques (Macaca nemestrina). We therefore analyzed the relationship between platelet counts, viral load (VL), and CD4 T-cell levels in 44 unselected macaques with chronic SIV infection. Persistent TCP was observed in 70% of pigtail macaques infected with SIVmac251 for up to 77 weeks in the absence of clinically significant bleeding. The presence of TCP correlated with higher SIV plasma VLs and depressed total and memory CD4 T cells. TCP was more common in macaques requiring euthanasia for incipient AIDS than macaques that survived to the end of the studies, although VL and CD4 T-cell decline were stronger independent predictors of AIDS-free survival. There was however no clear correlation between the development of TCP and immune activation as measured by plasma soluble CD14. We conclude that TCP is a useful end point to analyze SIV studies in pigtail macaques.

Rapid HBV DNA decrease (week 12) is an important prognostic factor for first-line treatment with adefovir dipivoxil for chronic hepatitis B

The aim of the study was to estimate the effect of viral factors (HBV genotype, viral load and kinetics) to treatment response in chronic hepatitis B (CHB) and first-line therapy with adefovir dipivoxil (ADV). Sixty-six patients (60% males, 65% HBeAg negative) were treated with 10 mg ADV QD. Quantitative HBV DNA and ALT levels were determined at weeks 4, 12, 24, 48, 72 and 96. Nonresponse or viral resistance to ADV was assessed in patients with either persistent elevated HBV DNA levels (week 24) or with an increase in HBV DNA of at least 1 log after initial decline. Most patients were infected with genotype D (66.7%; genotype A: 27.3%; genotype E: 6%); 86.4% achieved a virological (VR) and 54.5% a biochemical response (BR) in week 48, more often in patients with genotype A (P < 0.01). In week 96, BR increased to 60.5%, whereas a negative HBV DNA was observed in 83.3%. In 3% an ADV-induced viral resistance was detected. As an important predictive parameter for VR, a rapid decline of viral load at week 12 was observed. Of the patients with a negative PCR or drop of viral load of at least 3 log, 96% were still HBV DNA negative at the end of week 96; 77% of patients with a partial response achieved a VR. In contrast, no patient with nonresponse (week 12) reached a negative PCR at week 96 (P < 0.0001). These results underline the importance of early viral kinetics to assess treatment response in CHB. In ADV nonresponders (week 12), an advanced antiviral therapy or switch to another nucleoside analogue should be considered.

597 SERUM/ERITROCYTE RIBAVIRIN X 100 RATIO AS AN INDICATOR OF SVR IN HCV GENOTYPE-1 PATIENTS OBTAINING EVR

ackground. Virologic predictors during treatment with eg-interferon and ribavirin of hepatitis C are useful as hey allow early discontinuation of an unnecessary and xpensive treatment in non-responders. In this setting early irologic response (EVR), defined as viral load decline 2 log10 or undetectable HCV-RNA at week 12 of treatents has emerged as a useful tool to continue treatment. nfortunately, while EVR negative predictive value (NPV) s high, as approximately 2% only of patients not matchng EVR may achieve a sustained virological response SVR), the positive predictive value (PPV), in particular in enotype-1 patients, is low (∼60%). Other indicators may be eeded to predict SVR and in particular in those obtaining VR. im. To evaluate the usefulness of serum and eritrocyte ribvirin levels in predicting SVR in HCV genotype-1 patients ndergoing peginterferon + ribavirin treatment. ethods. 30 HCV genotype-1 patients (22 M/8F mean age 5.2± 13.6 years) undergoing a standard treatment schedle (Peg-IFN 180 mcg weekly + ribavirin 1000 or 1200 mg aily, according to body weight) were included in the study. lasma and eritrocyte ribavirin levels were evaluated in all atients at week 12 and at week 24 in those obtaining EVR nly. Ribavirin concentration was evaluated by high perforance liquid chromatography after solid phase extraction and mploying 3-methyl-cytidine as internal standard. Patients iochemical data were also recorded. esults. There was no difference among EVR and nonVR patients in terms of serum and eritrocyte ribavirin oncentration at week 12. At week 24, EVR patients obtainng SVR exhibited higher levels of ribavirin in serum nd lower in eritrocytes, in comparison with non-SVR atients (serum 14.1± 10.5 M vs. 5.9± 4.1 M; p< 0.02; ritrocyte 1072± 420 M vs. 1793± 903 M; p< 0.02). hen ([serum ribavirin]/[eritrocyte ribavirin]× 100) ratio as compared among these two groups, the difference was nhanced (1.6± 1.5 vs. 0.4± 0.34; p< 0.01). Receiver operting characteristic (ROC) curve analysis identified a cut-off or ([serum ribavirin]/[eritrocyte ribavirin]× 100) ratio in redicting SVR of 0.6, with a NPV of 80% and a PPV f 85%, while those related to EVR were 100% and 63%, espectively. onclusion. ([serum ribavirin]/[eritrocyte ribavirin]× 100) atio at week 24 seems to be an 85% indicator of SVR in a I p n isease 41 (2009) A1–A45 A35

Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort

The efficacy of raltegravir plus optimized background therapy (OBT) has been demonstrated for antiretroviral (ARV)-experienced HIV-1-infected patients in randomized clinical trials. We studied viro-immunological response, pharmacokinetic parameters and genotypic test results in an observational cohort of multiple ARV class-experienced patients starting a raltegravir-based regimen. Already enrolled ANRS CO3 Aquitaine Cohort patients with virological failure were included in this study after starting a raltegravir-based regimen (400 mg twice a day, week 0). Virological success was defined by the plasma HIV-1 RNA level [viral load (VL)] <2.7 log(10) copies/mL at week 12 and <1.7 log(10) copies/mL at week 24. One patient was excluded from further analysis (no follow-up after week 4). Fifty-one patients [male/female = 43/8, median age = 48 (interquartile range = 43, 55) years] were included. At week 0, median CD4 count was 244 (110; 310)/mm(3) and median VL was 4.2 (3.6, 4.7) log(10) copies/mL. At week 24, 39 (78%) patients experienced virological success: 4 (44%), 14 (82%) and 21 (87%) patients with a genotypic sensitivity score <1, > or =1 and <2 and > or =2 (P = 0.02), respectively. Raltegravir-related mutations emerged in 9 of 11 failing patients (82%): Q148H/R (n = 5), N155S/H (n = 3) and S230N (n = 1). Median CD4 increases from week 0 to week 4 and week 24 were 28 (-4, 85) and 57 (0, 156) cells/mm(3), respectively. A poor immune response was independently associated with a lower VL decline (week 0 to week 12) [odds ratio (OR): 3.5, 95% confidence interval (CI): 1.4, 8.4, for 1 log(10) less] and CD4+% at baseline (OR: 2.6, 95% CI: 0.97, 8.3, for 10% lower). Raltegravir plus OBT provided a good virological success rate in highly pre-treated patients under clinical routine conditions.

Preoperative use of raltegravir-containing regimen as induction therapy: very rapid decline of HIV-1 viral load

Known HIV infection and surgery is still a combination that raises dilemmas. Despite safety precautions, occupational blood exposure cannot be completely prevented [1]. To ensure optimal safety for the operating team, we attempt to maximally suppress the viral load before surgery in elective, high-risk surgical interventions (cardiothoracic and orthopedic surgery) [2]. Unfortunately, there are many cases in which surgery is urgent, and there is too little time to achieve complete viral suppression. Faster viral suppression has been observed with newly introduced antiretroviral drugs. Raltegravir is an HIV-1 integrase inhibitor that strongly inhibits viral replication and has been registered recently. As data from phase 2 trials [3,4] and mathematical models [5] have shown very rapid decline in viral load (approximately 2 log10 by week 2), we decided to use raltegravir as a novel addition to the standard regimen to achieve rapid viral suppression before performing surgery. We report two cases in which we applied this strategy in antiretroviral therapy-naive patients who did not have any drug resistance. The first patient is a 46-year-old antiretroviral-naive Hispanic man with an HIV-1 infection since 2004. The patient was admitted with a Streptococcus pneumoniae meningitis and endocarditis, with massive mitral valve and tricuspid valve insufficiency. Despite regular treatment with corticosteroids and high-dose penicillin, a mitral or tricuspid valve replacement, or both, was needed urgently. We started an induction antiretroviral regimen containing tenofovir, emtricitabine and efavirenz combined with raltegravir to maximally suppress the viral load. By day 9, the viral load decreased 3 log10 (from 315 510 to 315 copies/ml). By day 16, the viral load was nearly undetectable (63 copies/ml). Surgery was performed, and the patient recovered speedily. After discharge, raltegravir was discontinued, and tenofovir, emtricitabine and efavirenz were continued as maintenance therapy. The second patient is a 40-year-old antiretroviral-naive white female, with an HIV-1 infection since 2003. She was suffering with progressive dyspnoea caused by a suspected interstitial lung disease. As all diagnostic tests including transbronchial lung biopsy were inconclusive, a surgical lung biopsy was decided for. We treated her with the same regimen as mentioned earlier. By day 14, the viral load had decreased 2.9 log10 (from 418 969 to 499 copies/ml). After surgery, raltegravir was discontinued. Raltegravir was well tolerated in both patients. This is the first report of using raltegravir in this setting. Raltegravir is a very potent inhibitor of HIV replication, with rapid decline of viral load and favourable side-effect profile. We believe it is a valuable addition to antiretroviral therapy in situations in which rapid decline of viral load is desirable. Acknowledgements S.G.P. is the first author. G.E.vdB. reviewed and revised the correspondence. There are no conflicts of interest.

Infants with late breast milk acquisition of HIV-1 generate interferon-gamma responses more rapidly than infants with early peripartum acquisition.

Infants infected with HIV-1 after the first month of life have a lower viral set-point and slower disease progression than infants infected before 1 month. We investigated the kinetics of HIV-1-specific CD8(+) T lymphocyte secretion of interferon (IFN)-gamma in infants infected before 1 month of life compared with those infected between months 1 and 12 (late infection). HIV-1 infection was assessed at birth and at months 1, 3, 6, 9 and 12 and timing of infection was determined by HIV-1 gag DNA from dried blood spots and verified by plasma HIV-1 RNA levels. HIV-1 peptide-specific IFN-gamma responses were measured by enzyme-linked immunospot at months 1, 3, 6, 9 and 12. Timing of development of IFN-gamma responses was compared using the log-rank test and Kaplan-Meier survival curves. Infants infected late developed HIV-1-specific CD8(+) T cell responses 2.8 months sooner than infants infected peripartum: 2.3 versus 5.1 months after HIV-1 infection (n = 52, P = 0.04). Late-infected infants had more focused epitope recognition than early-infected infants (median 1 versus 2 peptides, P = 0.03); however, there were no differences in the strength of IFN-gamma responses. In infants infected with HIV-1 after the first month of life, emergence of HIV-1-specific CD8(+) IFN-gamma responses is coincident with the decline in viral load, nearly identical to what is observed in adults and more rapid than in early-infected infants.

Predictive Value of Pharmacokinetics-Adjusted Phenotypic Susceptibility on Response to Ritonavir-Enhanced Protease Inhibitors (PIs) in Human Immunodeficiency Virus-Infected Subjects Failing Prior PI Therapy

The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC(50)s) to the study PI were high. Median 2-week VL changes were -0.7, -0.1, and -1.0 log(10) for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, -0.39 to -0.50; P < or = 0.029). The strongest correlation with response to FPV/r was the IC(50) FC (r = 0.57; P = 0.001), which improved when only adherent subjects were included (r = 0.68; P = 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P < 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r = -0.72; P < 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed.

Serum/eritrocyte ribavirin×100 ratio as an indicator of SVR in HCV genotype-1 patients obtaining EVR

Background. Virologic predictors during treatment with peg-interferon and ribavirin of hepatitis C are useful as they allow early discontinuation of an unnecessary and expensive treatment in non-responders. In this setting early virologic response (EVR), defined as viral load decline ≥2log10 or undetectable HCV-RNA at week 12 of treatments has emerged as a useful tool to continue treatment. Unfortunately, while EVR negative predictive value (NPV) is high, as approximately 2% only of patients not matching EVR may achieve a sustained virological response (SVR), the positive predictive value (PPV), in particular in genotype-1 patients, is low (∼60%).

The fusion inhibitor enfuvirtide in recent antiretroviral strategies

The purpose of this review is to discuss recent pharmacological, virological, and clinical data that concern enfuvirtide usage in different antiretroviral combinations. Randomized, recent trials in multidrug-experienced patients suggest that antiretroviral combinations with enfuvirtide have excellent virological responses with new antiretroviral compounds, including darunavir, etravirine, raltegravir, vicriviroc, and maraviroc. Trials confirm long-term safety, in spite of moderate injection-site reactions or pain, and lack of significant interactions. Preliminary data suggest that switching from enfuvirtide to raltegravir is effective and using enfuvirtide in prophylaxis of mother-to-child transmission is well tolerated. To administer enfuvirtide in an intensification strategy in antiretroviral-naïve or experienced populations may accelerate virological decline. Dosage adaptations to renal insufficiency are not necessary with enfuvirtide. Spinal fluid concentrations and ombilic cord passage are negligible. Durability of virological responses with enfuvirtide in combinations has been confirmed, in spite of injection-site reactions and twice daily subcutaneous administration. Enfuvirtide should be used with at least one other fully active drug in optimized background therapy in multidrug-experienced populations, a possible exception being with entry inhibitors, which may further benefit from the addition of a third active drug. Data concerning enfuvirtide in antiretroviral combinations show accelerated viral load decline, and the possibility of switching from enfuvirtide to raltegravir without modification of optimized background therapy.

Factors affecting early viral load decline of Asian chronic hepatitis C patients receiving pegylated interferon plus ribavirin therapy

Early viral load decline following pegylated interferon-alpha2a and ribavirin therapy is an important predictor of the treatment responses in chronic hepatitis C (CHC) patients, thus, it is essential to evaluate the influence of host and viral factors on early viral load decline. Clinical and serial virological data were collected from 145 consecutive Asian CHC patients with pegylated interferon-alpha2a plus ribavirin therapy. A dose of pegylated interferon-alpha2a was administered at week 1 and then weekly with daily oral ribavirin for 24 or 48 weeks. Genotyping and quantification of hepatitis C virus (HCV) RNA were done using molecular methods. A total of 81 patients were infected with HCV genotype 1,61 with genotype 2 and 3 with both genotypes 1 and 2. At the end of follow-up, 110 patients attained sustained virological response (SVR). In multivariate analyses, body mass index (BMI) and genotype were related to viral load decline at day 2, baseline viral load and high-density lipoprotein (HDL) cholesterol levels were correlated with viral load decline between days 2 and 28. Genotype, baseline viral load, alanine aminotransferase (ALT) levels and BMI independently predicted rapid virological response, whereas only genotype 2, lower baseline viral load and more substantial viral load decline at day 28 predicted a higher SVR. HCV genotype, baseline viral load, pretreatment BMI, HDL and ALT levels have a significant effect on early viral load decline of Asian CHC patients with interferon-based therapy. Only HCV genotype, baseline viral load and viral load decline at day 28 can independently predict SVR.

SUPPRESSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 VIRAL LOAD DURING ACUTE MEASLES

Acute measles virus infection can result in a transient decrease in plasma human immunodeficiency virus type 1 (HIV-1) RNA loads. We report the kinetics of plasma HIV-1 RNA loads in 2 Zambian children with confirmed and probable measles, and show that the decline in viral load is of similar magnitude to the first-phase decay rate after initiation of antiretroviral therapy.

Bio-mathematical models of viral dynamics to tailor antiviral therapy in chronic viral hepatitis

The simulation of the dynamics of viral infections by mathematical equations has been applied successfully to the study of viral infections during antiviral therapy. Standard models applied to viral hepatitis describe the viral load decline in the first 2-4 wk of antiviral therapy, but do not adequately simulate the dynamics of viral infection for the following period. The hypothesis of a constant clearance rate of the infected cells provides an unrealistic estimation of the time necessary to reach the control or the clearance of hepatitis B virus (HBV)/hepatitis C virus (HCV) infection. To overcome the problem, we have developed a new multiphasic model in which the immune system activity is modulated by a negative feedback caused by the infected cells reduction, and alanine aminotransferase kinetics serve as a surrogate marker of infected-cell clearance. By this approach, we can compute the dynamics of infected cells during the whole treatment course, and find a good correlation between the number of infected cells at the end of therapy and the long-term virological response in patients with chronic hepatitis C. The new model successfully describes the HBV infection dynamics far beyond the third month of antiviral therapy under the assumption that the sum of infected and non-infected cells remains roughly constant during therapy, and both target and infected cells concur in the hepatocyte turnover. In clinical practice, these new models will allow the development of simulators of treatment response that will be used as an "automatic pilot" for tailoring antiviral therapy in chronic hepatitis B as well as chronic hepatitis C patients.