Mean Baseline Viral Load Research Articles

873. A Retrospective Cohort Study on Treatment Outcomes of Patients on Third-Line Therapy at the HIV Advanced Treatment Centre, University Teaching Hospital, Zambia

BackgroundIn Zambia, third-line regimens consist of a switch to darunavir/ritonavir (DRV/r) and/or raltegravir (RAL) and/or etravirine (ETV), and as of 2017, dolutegravir (DTG), from a failing second-line therapy.5 We assessed virologic suppression (HIV viral load (VL) ≤1000 copies/ml per Zambian national guidelines), immunological response, and patterns of HIV drug resistance mutation among patients on third-line ART at the University Teaching Hospital (UTH) in Lusaka, Zambia.MethodsA retrospective evaluation of adults ≥18 years old on third-line ART regimens at UTH between January 2012 to June 30, 2020 was conducted. Patients were referred for second-line virologic failure defined as HIV RNA VL > 1000 copies/mL on two consecutive measurements after 6 months on second-line ART.5 We assessed virologic suppression VL ≤1000 copies/ml, CD4, mutations, and third-line regimens of this cohort. Patients were excluded if they were on third-line ART < 6 months or received RAL and/or ETV and/or DTG before starting third-line ART. ResultsA total of 539 patients were included; 231 males (42.9%) and 308 (57.1%) females. The mean age of third-line initiation was 29.8 years; mean time from ART initiation to third-line initiation was 9.9 years. Out of 25 combination 349 (64.7%) received DTG, 272 (50.5%) DRV/r, 85(15.8%) ETR, and 49 (9.1%) RAL. There were 215 (39.9%) genotypes; common mutations were to zidovudine (80%), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (78%), and protease inhibitors (PIs) (41%). Patients with at least one viral load and CD4 upon third-line initiation was 296 (54.9%) and 350 (64.9%), respectively. Among patients with sufficient data (21%, n=115), VL suppression increased from 44 (38%) patients at baseline to 53 (46%) at next available follow-up; with mean baseline VL and follow-up VL of log10 3.60 and 3.33, respectively. The immunologic response revealed 49 (56.3%) had CD4 increase with mean increase of 61.1 cells/mm3. (See Table 1.) ConclusionWe found moderate improvements in VL suppression and immunologic response. Nearly all third-line patients had genotypic resistance to first-line NNRTI and nearly half to second-line PI regimens. Quality improvement measures are needed to improve viral load timing following ART changes to better assess regimen efficacy.Disclosures All Authors: No reported disclosures

Immunological and Virological Outcomes among Treatment Experienced HIV-Infected Patients on Dolutegravir Regimen in Tanzania

Introduction The integrase inhibitor dolutegravir (DTG) has recently replaced the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in several Sub-Saharan African countries, including Tanzania. Since this change, there is scarce data on the current treatment outcomes focusing on treatment-experienced HIV-infected patients switched to DTG based regimens in Tanzania. Objectives This study aimed to investigate immunological and virological outcomes among treatment-experienced HIV-infected patients who were switched to DTG based regimen in Tanzania. Results We enrolled 397 patients, majority (65%) were female patients with mean age of 42.7 (95% CI; 40.7 – 44.7) years. The mean baseline CD4+ cell count was 457.1 (95% CI; 426.6 – 489.8) cells/mm3 with 8.3% of patients with CD4+ cell count <200 cells/mm3. The mean baseline viral load (VL) was 169.8 (95% CI; 128.8 – 223.9) copies/ml, whereby 20.6% had VL ≥ 1000 copies/ml. After the use of a new fixed dose combination of Tenofovir (TDF) 300 mg + Lamivudine (3TC) 300 mg + DTG 50 mg (TLD) for at least 24 weeks, the overall rate of virological suppression (<50 copies/ml) was 89.9% (95%CI 86.7% - 92.7%). The significant predictors of virological failure were overall duration on ART use (p = 0.004), duration on TDF + 3TC, and Efavirenz (EFV) (TLE) (p = 0.007), and baseline VL (p < 0.001). Conclusion TLD regimen has provided favorable preliminary results among patients who previously used TLE in HIV/AIDS treatment by showing good virological and immunological outcomes. The long-term treatment outcomes require further investigation.

Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS).

BackgroundWe studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus.MethodsSamples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses.ResultsA total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1−5 years had prolonged viral RNA shedding (±1–2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05–1.12), prior vaccination status (OR, 1.72; CI, 1.22–2.43) and antiviral treatment (OR, 1.74; CI, 1.43–2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39).ConclusionsChildren aged 1−5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment.Clinical Trials RegistrationNCT00884117.

Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1

BackgroundIbalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4.MethodsIn this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (day 7) to day 14.ResultsA total of 31 patients completed the study. The mean baseline viral load was 4.5 log10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (P<0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy.ConclusionsIn patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629.)

Influence of baseline MELD score in the efficacy of treatment of hepatitis C with simeprevir and sofosbuvir

IntroductionThere are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. ObjectiveThe objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. Patients and methodsProspective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Results204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0–1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p=0.042), absence of cirrhosis (p=0.021), baseline albumin ≥4g/dl (p=0.001) and MELD<10 (p<0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score <10 patients had higher SVR12 (p<0.001). ConclusionsThe combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10.

Utility of Mobile Communication Devices as a Tool to Improve Adherence to Antiretroviral Treatment in HIV-infected Children and Young Adults in Argentina.

Optimal adherence is critical to achieve the benefits of antiretroviral treatment (ART). The aim of the study is to evaluate the use of mobile devices as a strategy to improve adherence to ART, measured by viral load (VL) in HIV+ patients less than 25 years of age. A prospective study was conducted in a cohort of HIV+ patients less than 25 years of age. HIV+ patients, on ART, VL >1000 copies/mL, using mobile devices and suboptimal adherence were included. The intervention was based on a mobile generic contact twice a month using text message and Facebook during 32 weeks. Extended communications were generated by the patient. VL was performed before and after the intervention. Twenty-five patients were included. Three were excluded and 22 patients were enrolled. Mean age was 17.2 ± 6.1 years (range: 6-25); 15 (68%) were female; mean baseline VL was 25,100 copies/mL (range: 1020-500,000 copies/mL), mean log was 4.3 (range: 3-5.7 log). Each participant received a total of 16 contacts; 84% (296) were answered by the patient and 54% (189) of the contacts generated extended communications. After the strategy implementation, 20/22 VL results were available: 13/20 (65%) were undetectable, 14/20 (70%) had VL < 1000 copies/mL and 6/20 (30%) VLs had no changes. The use of mobile devices and social networks is a valid tool to improve ART adherence in HIV+ pediatric and young adults, evaluated through VL. The strategy is feasible. The reminder messages trigger additional communications between patients and health provider and better engagement with HIV care. Longer follow-up time is needed.

Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment.

Chronic hepatitis C virus (HCV) infection is characterized by dysregulated natural killer (NK) cell responses. NKs play a critical role in achieving sustained responses to interferon (IFN)‐α‐based therapy. Rapid sustained HCV‐RNA clearance is now achieved with direct‐acting antivirals (DAAs). Studies of patients receiving first‐wave DAAs suggest NK functional restoration. Here, we investigate the effect of mainstream DAA treatment on NKs. We collected a prospective cohort of male HCV genotype 1‐infected patients treated with ledipasvir/sofosbuvir (n = 22). Peripheral blood was obtained at treatment start, week 2 (W2), W4, W8, and W12 of treatment and 12 weeks posttreatment. Flow cytometry was used to characterize NK responses to therapy. Mean baseline viral load was 1.75 million IU/mL. All subjects rapidly cleared virus and remained HCV RNA‐negative posttreatment. No change was seen in total NK levels; however, the frequency of immature NKs (clusters of differentiation [CD]56bright) decreased by W2 and was maintained throughout the study. Phenotypic changes were evident by W2/W4, coincident with rapid viral clearance. At W2, T‐cell immunoglobulin and mucin‐domain containing‐3 and CD161 were significantly increased, returning to pretreatment levels by W12. Some changes were not evident until late (W12 or posttreatment). Down‐regulation of several activation markers, including NKp30 and tumor necrosis factor–related apoptosis‐inducing ligand, was observed at W12 and sustained posttreatment. No difference was observed in IFN‐γ production or cytokine‐mediated killing of NK‐sensitive cell line K562 posttreatment compared to pretreatment. Conclusion: Our phenotype data suggest transient activation followed by dampening of NK cell activity to pretreatment levels. The NK response to ledipasvir/sofosbuvir is not universal in a homogeneous patient cohort. More studies are needed to elucidate the roles of NK cells in IFN‐free regimens, which will have implications for protection from re‐infection and fibrosis progression. (Hepatology Communications 2018;2:364‐375)

Comparison of Time to Viral Suppression Among Treatment-Naïve HIV-Infected Adults Initiating Combination Antiretroviral Therapy by Antiretroviral Regimen Class

BackgroundAntiretroviral therapy (ART) regimens for the treatment of HIV that incorporate the integrase strand inhibitor (INSTI) class of antiretroviral medications have high efficacy and tolerability, and may result in faster time to virologic suppression compared with regimens that contain protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, differences in viral suppression are not well-defined in routine clinical settings.MethodsWe performed a retrospective single-center chart review of treatment-naïve HIV patients initiating ART between 2013 and 2016. Among patients on different ART regimen types, we compared rates of achievement of viral suppression (defined as viral load less than limit of detection or <20 copies/uL) over time and median time to viral suppression using chi-square and independent samples median testing. Patients who were prescribed nonstandard regimens, were nonadherent, or discontinued or changed ART within 6 months were excluded.ResultsOne hundred and fifty-five patients—45 (29.0%) female and 110 (71%) male—met study inclusion criteria. Mean age at ART initiation was 41.3 years (SD 12.5), and mean baseline viral load was 293,974 copies/uL. Twelve (7.7%) patients had an opportunistic infection diagnosed at time of ART initiation. Seventy-one (45.8%) initiated an INSTI-based ART regimen, 58 (37.4%) initiated a NNRTI-based regimen, and 26 (16.8%) initiated a PI-based regimen. Eighty-one (52.3%) patients had documented viral suppression, with median time to viral suppression 105 days (IQR 49–159). Patients on INSTI regimens were more likely to achieve viral suppression by 6 months (93.2% compared with 69.7% on NNRTIs and 30.8% on PIs), and had lower median time to suppression (62.6 days vs. 140.5 days on NNRTI regimens and 154.5 days on PI regimens, P = 0.002).ConclusionIn this cohort, patients on INSTI-based ART regimens experienced higher rates of viral suppression at 6 months and shorter time from ART initiation to viral suppression. In HIV patients on INSTI-based ART regimens, virologic failure should be suspected prior to the current recommendation of 6 months.Disclosures All authors: No reported disclosures.

Influencia de la puntuación MELD basal en la eficacia del tratamiento de la hepatitis C con sofosbuvir y simeprevir

IntroductionThere are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. ObjectiveThe objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. Patients and methodsProspective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Results204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0-1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549 IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p=0.042), absence of cirrhosis (p=0.021), baseline albumin ≥ 4g/dl (p=0.001) and MELD<10 (p<0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score <10 patients had higher SVR12 (p<0.001). ConclusionsThe combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10.

P073 Do financial incentives (FI) and motivational interviewing (MI) promote adherence in vertically infected HIV positive adolescents?

IntroductionFunding was received for 10 patients to participate in a FI &amp; MI scheme aiming to achieve viral load (VL) reduction.MethodsEligibility criteria: 16-25 years, vertically acquired HIV-1 infection, CD4 &lt;350 cells/ul, agrees to ART with treatable virus, poor adherence since diagnosis &amp; failure to achieve VL &lt;40 copies/ml. FIs received for VL reductions ≥ 1 log weeks 2 &amp; 4 and VL &lt;40 week 8, 3/12, 6/12, 9/12 and 1 year. £20 given for VL reduction ≥ 1 log and £50 for VL &lt;40. Adherence support with motivational interviewing (MI) was provided at each visit.Results8 patients enrolled 1/8/12–1/12/15. 5 females, median age 24 years (range 20–26). Mean baseline VL 35750, this reduced to 1390 (mean VL reduction 21842 copies/ml). 5/8 patients achieved VL &lt;40. N=1 had never achieved VL &lt;40, yet during the scheme achieved VL &lt;40 for 8/12. 3 patients were unable to achieve VL &lt;40. Their lowest VL was 71, 883 and 90, representing a 1–2 log VL drop from baseline after 52/12, 4/12 and 1/12, respectively. 1 patient passed away following a Steven-Johnson reaction, never achieving VL &lt;40. Financial incentives given totalled £640.DiscussionDespite widely available treatment options for HIV, preventable deaths still occur each year due to a lack of adherence. Within this cohort, 5 patients were able to achieve periods of VL &lt;40 after years of detectability. These results highlight that FI in conjunction with MI, may have a role in improving adherence for the adolescent HIV infected population.

Sofosbuvir/Ledipasvir Without Ribavirin Achieved High Sustained Virologic Response for Hepatitis C Recurrence After Liver Transplantation: Two-Center Experience.

Current recommended regimens to treat patients with hepatitis C virus (HCV) infection after liver transplantation include the use of ribavirin (RBV). Limited data are available on the efficacy of RBV-free regimens posttransplant, particularly the use of sofosbuvir (SOF)/ledipasvir (LDV) without RBV in this patient population. We aimed to assess the efficacy and safety of SOF/LDV fixed-dose combination without RBV in patients with HCV recurrence posttransplant. This is a retrospective study of 46 patients with HCV recurrence posttransplant. SOF/LDV without RBV was used for 12 weeks in patients with early-stage fibrosis (F0-F2) or for 24 weeks in those with advanced fibrosis (F3-F4) and/or cholestatic hepatitis. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment. Secondary outcomes included relapse after treatment and adverse events. Forty-six patients, with a mean age of 62 ± 8 years, a median duration since time of transplant of 904 days (range, 78-3525 days), an HCV genotype 1, and a mean baseline viral load of 7.79 million IU/mL, were treated. Of these, 32 patients were treated for 12 weeks, and 14 patients were treated for 24 weeks. Twenty-five patients (54%) were treatment experienced (21 with interferon and 4 with SOF). All 46 patients (100%) achieved sustained virological response (SVR) 12. Neither virologic relapses nor serious adverse events were noted. The combination of SOF/LDV without RBV for 12 or 24 weeks produced 100% SVR 12 in patients with HCV recurrence after liver transplantation. The use of RBV may not be necessary to achieve SVR in this patient population.

Evaluating an enhanced adherence intervention among HIV positive adolescents failing atazanavir/ritonavir-based second line antiretroviral treatment at a public health clinic.

Sustaining virological suppression among HIV-infected adolescents is challenging. We evaluated a home-based adherence intervention and characterized self-reported adherence, virological response and drug resistance among adolescents failing atazanavir/ritonavir (ATV/r)-based 2nd line treatment.Methods:HIV-positive adolescents (10–18 years) on ATV/r-based 2nd line treatment with virological failure (viral load (VL) ≥1 000 copies/ml) were randomized to either standard care (SC) or SC with addition of modified directly administered antiretroviral therapy (mDAART) for 90 days. VL was measured and questionnaires were administered at study entry and at 3 months. Genotyping was done for participants with continued failure. Primary outcome was suppression to VL < 1 000 copies/ml.Results:Fifty adolescents aged 10–18 years on 2nd line treatment for >180 days were enrolled, 23(46%) were randomized to mDAART and 27(54%) to SC. Fifty-four percent were female; mean age was 15.8 years; mean baseline VL was 4.8(log10) copies/ml; 40% reported adherence <80% in previous 1 month at baseline; 40% suppressed (VL <1 000 copies/ml) after follow-up. mDAART resulted in significantly increased self-reported adherence (RR= 0.1; 95% CI=0.02–0.8, p=0.023); closely following dosing schedule (RR= 4.8; 95% CI=1.6–13.8, p=0.004); VL decrease (p=0.031) and modest increase in virological suppression to <1 000 copies/ml (p=0.105). Genotyping in 28/30 participants with continued virological failure demonstrated high level atazanavir resistance (I50L, N88S and I84V) in 6(21%); 3(11%) of whom also had high level resistance to lopinavir and darunavir (V32I, I50L, I54V, 147V and V82A).Discussion:The mDAART intervention modestly improved virological suppression among adolescents with ATV/r-based 2nd line treatment failure, significantly increased self-reported adherence and decreased viral load. High level ATV/r resistance was demonstrated.Conclusion:Targeting mDAART to adolescents who are virologically failing PI-based 2nd line treatment decreases viral load and increases self-reported adherence. Early drug-resistance testing could reduce morbidity and mortality.

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

Viral Decay Dynamics and Mathematical Modeling of Treatment Response: Evidence of Lower in vivo Fitness of HIV-1 Subtype C.

Despite the high prevalence of HIV-1 subtype C (HIV-1C) worldwide, information on HIV-1C viral dynamics and response to antiretroviral therapy (ART) is limited. We sought to measure viral load decay dynamics during treatment and estimate the within-host basic reproductive ratio, R0, and the critical efficacy, εc, for successful treatment of HIV-1C infection. Individuals initiated on first-line ART in India and monitored for 6 months of treatment were considered. Viral load, CD4 count, and adherence data were collected at baseline, 4, 12, 16 and 24 weeks after ART initiation. Drug resistance genotyping was performed at baseline. R0 and εc were estimated using a mathematical model. Among 257 patients with complete data, mean baseline viral load was 5.7 log10 copies per milliliter and median CD4 count was 165 cells per cubic millimeter. Primary drug resistance was present in 3.1% at baseline. At 6 months, 87.5% had undetectable viral load, indicating excellent response to ART despite high baseline viremia. After excluding those with transmitted resistance, suboptimal adherence and viral rebound, data from 112 patients were analyzed using a mathematical model. We estimated the median R0 to be 5.3. The corresponding εc was ∼0.8. These estimates of R0 and εc are smaller than current estimates for HIV-1B, suggesting that HIV-1C exhibits lower in vivo fitness compared with HIV-1B, which allows successful treatment despite high baseline viral loads. The lower fitness, and potentially lower virulence, together with high viral loads may underlie the heightened transmission potential of HIV-1C and its growing global spread.

Response of Peg IFN and Ribavarin in HIV-HCV Co-Infection

Background: Hepatitis C infection is one of most common co-infection in HIV. HIV infection influences the natural evolution of chronic hepatitis by higher rate of viral persistence, accelerating fibrosis, cirrhosis progressing to end-stage liver disease. Objective: This retrospective study was conducted in order to see the response to Peg- IFN α-2b with Ribavarin in HIV HCV co-infection. Material and Methods: Alanine aminotransferase and Aspartate Aminotransferase, HCV RNA quantitative and Genotype study, Fibroscan, CD4 were collected from the medical records of ART centre. Results: The mean baseline viral load (log10) was 5.76, 3.00 at 1 st month, 0.44 at 3 rd month, 0 at 6 th month and 12 th month. RVR was observed in 77.7%, EVR in 88.8%, SVR of 100% at 6 th and 12 th month. The mean OT and PT reduction at 3 rd month was 116.11(57.79%) and 132 (61.68%) respectively, at 6 month was 158 (78.65%) and 177.56 (82.97%) respectively, at 12 th month was 159(79.14%) and 176.56 (82.50%). Fibrosis at the start of treatment was 19.0 KPa, 10.00 KPa at 6 th month and 8.20 KPa at 12 th month. Conclusion: Study shows that SVR can be achieved in HCV HIV co infected patients with IFN and Ribavarin therapy which in turn reduces the morbidity and mortality due to liver disease. Inspite of virological response, few patients continue to have deranged AST and ALT and progressive liver fibrosis.

Time Profile of Viral DNA in Aqueous Humor Samples of Patients Treated for Varicella-Zoster Virus Acute Retinal Necrosis by Use of Quantitative Real-Time PCR

The objective of this study was to evaluate the kinetics of varicella-zoster virus (VZV) loads using quantitative PCR (qPCR) in patients treated for acute retinal necrosis (ARN). Six patients (52 ± 13 years old) with ARN syndrome were consecutively studied. Aqueous humor (AH) was sampled from both eyes of all patients for qPCR evaluation. The patients were treated with intravenous acyclovir and intravitreal injections of antiviral drugs. The mean follow-up time was 17.6 ± 16.4 months. Main outcome measures were the numbers of viral genome copies in the AH, assessed using real-time qPCR with hydrolysis probe technology with a threshold of detection of 200 copies/ml. Two main portions of the viral load curves were observed for each patient: a plateau phase (27.8 ± 24.9 days) and a decrease in the number of viral genome copies. The mean baseline viral load was 3.4 × 10(7) ± 4.45 × 10(7) copies/ml (6 × 10(6) to 1.2 × 10(8) copies/ml). The viral load decreased according to a logarithmic model, with a 50% reduction obtained in 3 ± 0.7 days. There was a significant viral load (>102 copies/ml) at 50 days after the onset of treatment, despite antiviral drugs. qPCR use demonstrated reproducible VZV DNA kinetics with a two-phase evolution: a plateau followed by a logarithmic decrease. These data suggest that high-dosage antiviral therapy administered for the conventional 10-day duration is insufficient for most patients. This series of patients responded with a similar decrease in viral load once treatment was initiated, and the data from these patients may be used to predict the responses of future patients.

Four‐drug induction regimen for patients with high baseline viral load

Early virologic changes after treatment have been associated with long‐term virologic success. The objective of this pilot, randomised, prospective study is to evaluate the effect of an induction, 4‐drug HAART regimen in patients with high baseline viral load. Twenty‐one naïve patients with HIV‐RNA&gt;100,000 copies/ml were randomised to TDF+FTC+EFV (1); TDF+FTC+EFV+RAL (2), TDF+FTC+RAL (3). Viral load, CD4 and immune activation markers were evaluated at days 7, 14, 30, 60, 120 from the start of therapy. Mean age was 38.2 years, 19 (90.5%) were male, and the main risk factor for HIV infection was heterosexual contacts in 52.4% of patients. The mean baseline viral load was 265,266 copies/ml and the mean CD4 cell count was 314 cell/mm3. CD8+CD38+HLA‐DR+ cells mean was 38%. No difference was observed among the three groups. Early HIV‐RNA reduction was significantly higher in group 2 at day 7 (P=0.007), 14 (P=0.018), 30 (P=0.046) after HAART start, thereafter HIV‐RNA values were comparable among the groups. No significant differences were observed at any time‐point between group 1 and group 3. The viral decay (delta VL), evaluated as reduction of viral load, was faster and higher in group 2 at any time‐point; the reduction was statistically significant (compared to group 1 and 3) after 7 days (P=0.006), but not thereafter. No differences were observed between group 1 and 3 (Figure, panel A). At the end of follow‐up (120 days) only patients in group 2 reduced HIV‐RNA below&lt;3 copies/ml in 30% of cases. Although not statistically significant (probably because of the small sample) immune recovery, as measured by the increment of CD4 cells, was greater in the two groups receiving RAL (Figure, panel B). At the end of the follow up the mean increment was 142 cells/mm3 in group 1; 258 cells/mm3 in group 2 and 360 cells/mm3 in group 3. No difference was observed as far as the reduction of immune activation is concerned. A 4‐drug regimen in naïve patients with high pre‐therapy viral load improves early virologic response, that has been proved to be a prognostic marker for sustained virologic response. CD4 cell recovery is much higher in patients receiving RAL compared to those treated with EFV. This study highlights the importance of a personalised therapy especially in high‐risk patients. Further studies are necessary to define the best therapeutic regimen in patients with high baseline viral load.image

Time profile of viral DNA in aqueous humor of patients treated for VZV acute retinal necrosis using quantitative real‐time PCR

AbstractPurpose To evaluate the kinetics of varicella zoster virus (VZV) load using quantitative PCR (qPCR) in patients treated for acute retinal necrosis (ARN). Design: Cohort study, evaluation of diagnostic test or technology.Methods Six patients (52±13 years) with ARN syndrome were consecutively studied. Aqueous humor (AH) was sampled from all eyes for qPCR evaluation. The patients were treated with intravenous aciclovir and intravitreal injections of antiviral drugs. The mean follow‐up was 17.6±16.4 months.Results Two main portions of the viral load curves were observed for each patient: a plateau phase (27.8±24.9 days) followed by a decrease in the number of viral genome copies. The mean baseline viral load was 3.4×107±4.45×107copies/ml (6×106 to 1.2×108). The viral load decreased following a logarithmic model, with a 50% reduction obtained in 3±0.7 days. There was a significant viral load (&gt; 102 copies/ml) at 50 days after the onset of treatment, despite antiviral drugs.Conclusion qPCR use demonstrated reproducible VZV DNA kinetics with a two‐phase evolution: plateau followed by logarithmic decrease. These data suggest that high‐dosage antiviral therapy during the conventional 10 days duration is insufficient in most patients. This patient's series responded with a similar decrease in viral load once initiated, this may be used to predict the progression of future patients. The correlation of the viral load threshold with clinical improvement needs to be more clearly defined.

A Randomized, Placebo Controlled, Double Masked Phase IB Study Evaluating the Safety and Antiviral Activity of Aprepitant, a Neurokinin-1 Receptor Antagonist in HIV-1 Infected Adults

BackgroundNeurokinin-1 receptor (NK1R) antagonists have anti-HIV activity in monocyte-derived macrophages, decrease CCR5 expression and improve natural killer cell function ex vivo. Aprepitant is a NK1R antagonist approved by FDA as an antiemetic.MethodsWe conducted a phase IB randomized, placebo controlled, double masked study to evaluate the safety, antiviral activity, pharmacokinetics and immune-modulatory effects of aprepitant in HIV-infected adults not receiving antiretroviral therapy, with CD4+ cell count ≥350 cells/mm3 and plasma viral load ≥2,000 copies/ml. Subjects were stratified by viral load (< vs. ≥20,000 copies/ml) and randomized within each stratum to receive aprepitant at 125 mg QD(Low), or 250 mg QD(High), or placebo(PL) for 14 days, and followed for 42 days.ResultsThirty subjects were randomized and 27 completed treatment (9, 8, 10 subjects in 125 (Low), 250 (High), and PL groups). 63% were male; 37% white; mean (SD) age 43 (9.3) years. Geometric mean baseline viral load (copies/ml) for Low, High, and PL was 15,709, 33,013, and 19,450, respectively. Mean (95%CI) change in log10 viral load at day 14 for Low, High, and PL was −0.02(−0.24,+0.20), −0.05(−0.21,+0.10), and +0.04(−0.08,+0.16), respectively. The number of subjects with AEs was 4(44.4%), 5(62.5%), and 1(10%) for Low, High, and PL. No Grade 4 AEs occurred.ConclusionsAdverse events of aprepitant were more common in the treated groups. At the dose used in this two-week phase IB study, aprepitant showed biological activity, but no significant antiviral activity.Trial RegistrationClinicalTrials.gov NCT00428519

Hepatitis C Virus Sensitivity to Combined Antiviral Therapy in Liver Transplant Versus Immunocompetent Patients

Recurrent hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) frequently causes allograft failure, because viral aggressiveness has been shown to be increased among immunosuppressed patients. Several studies have reported lower efficacy of antiviral therapy after OLT associated with worse tolerability. The aim of this study was to compare the logarithmic falls in viral loads at 4 and 12 weeks of treatment with pegylated interferon alpha and ribavirin among OLT versus immunocompetent patients. OLT patients (group 1) were recruited from 3 Spanish centers. Two age- and sex-matched controls (group 2) were randomly assigned to each case. We excluded coinfection with human immunodeficiency virus or hepatitis B or cholestatic hepatitis. Among group 1 (n = 66) were 72.7% men with an overall mean age of 52.7 +/- 10.1 years; 90.9% were genotype 1. The mean baseline viral load was 6.0 +/- 0.6 log10 IU/mL, and 19% of patients had cirrhosis. Among group 2 (n = 132) were 72.7% men with an overall mean age of 50.1 +/- 10.1 years; 92.4% were genotype 1. The mean baseline viral load was 5.9 +/- 0.5 log10 IU/mL, and 17% of patients had cirrhosis. There were no significant differences in patient characteristics between the 2 groups. The logarithmic falls in viral loads at 4 weeks of treatment were similar in groups 1 and 2: 2.3 +/- 2.1 vs 2.4 +/- 1.9 log10 IU/mL (P = .49); they were also similar at 12 weeks of treatment: 3.9 +/- 1.9 vs 3.7 +/- 2.4 log10 IU/mL (P = .66). In conclusion, in our study HCV sensitivity to combined antiviral therapy was the same among transplant versus immunocompetent patients.