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1.  Tenofovir-based Antiretroviral Therapy in Hepatitis B Virus/HIV Co-infection: Results from the TREAT Asia HIV Observational Database 
Antiviral therapy  2015;21(1):27-35.
Background
The World Health Organisation recommends Hepatitis B virus (HBV)/HIV co-infected individuals start antiretroviral therapy containing tenofovir. Here we describe first-line tenofovir use and treatment outcomes in co-infected patients in Asia.
Methods
HBV surface antigen positive patients enrolled in the TREAT Asia HIV Observational Database who started first-line antiretroviral therapy were included. Logistic regression adjusted for period of treatment initiation was used to determine factors associated with tenofovir use. Generalised estimating equations were used to evaluate factors associated with alanine transaminase levels and CD4 cell count on treatment.
Results
There were 548 eligible patients, of whom 149 (27.2%) started tenofovir. Patients treated in high/high-middle income countries (odds ratio 4.4 vs. low/low-middle, 95%CI 2.6-7.4, p<0.001) and those with elevated baseline alanine transaminase (odds ratio 4.2 vs. normal, 95%CI 2.4-7.2, p<0.001) were more likely to receive tenofovir. Hepatitis C antibody positive patients (odds ratio 0.4 vs. negative, 95%CI 0.2-0.8, p=0.008) were less likely. In those starting antiretroviral therapy with elevated alanine transaminase, mean reduction after tenofovir initiation was 11.2 IU/L (95%CI 0.9-21.6, p=0.034) lower compared with those using a non-tenofovir-based regimen although this did not significantly increase the chance of alanine transaminase normalization. Tenofovir use was not associated with a superior CD4 response.
Conclusions
HBV/HIV co-infected patients in Asia are most likely to receive tenofovir if they are treated in a high/high-middle income country, have elevated alanine transaminase levels, and are hepatitis C antibody negative. Compared to other antiretroviral therapy, tenofovir-based regimens more effectively reduce liver inflammation in HBV/HIV co-infection but do not result in superior CD4 recovery.
doi:10.3851/IMP2972
PMCID: PMC4757505  PMID: 26069150
2.  Modeling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection 
Antiviral therapy  2015;21(4):297-306.
Modeling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness. Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor and mericitabine, a nucleoside polymerase inhibitor for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data. The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg tid of danoprevir and 500 mg bid of mericitabine and 0.9998 for 600 mg bid of danoprevir and 1000 mg bid of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low SVR rates obtained in more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks. This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.
doi:10.3851/IMP3006
PMCID: PMC4862948  PMID: 26555159
3.  The effect of recombinant human growth hormone with or without rosiglitazone on hepatic fat content in HIV-1 infected individuals; a randomized clinical trial 
Antiviral therapy  2014;21(2):107-116.
Background
Hepatic fat is related to insulin resistance (IR) and visceral adipose tissue (VAT) in HIV+ and uninfected individuals. Growth hormone (GH) reduces VAT but increases IR. We evaluated the effects of recombinant human GH (rhGH) and rosiglitazone (Rosi) on hepatic fat in a substudy of a randomized controlled trial.
Methods
HIV+ subjects with abdominal obesity and IR (QUICKI ≤ 0.33) were randomized to rhGH 3 mg daily, Rosi 4 mg twice daily, the combination, or double placebo. Hepatic fat was measured by magnetic resonance spectroscopy (MRS), visceral fat by MRI, and IR by frequently sampled IV glucose tolerance tests at baseline and week 12.
Results
31 subjects were studied at both time points. Significant correlations between hepatic fat and VAT (r = 0.41, p=0.02) and QUICKI (r = 0.39, p<0.05) were seen at baseline. Insulin resistance rose with rhGH but not Rosi. When rhGH treatment groups were combined, hepatic fat expressed as percent change decreased significantly (p<0.05) but did not change in Rosi (p=0.71). There were no correlations between changes in hepatic fat and VAT (p=0.4) or QUICKI (p=0.6). In a substudy of 21 subjects, a trend was noticed between changes in hepatic fat and serum IGF-1 (p=0.09).
Conclusions
Hepatic fat correlates significantly with both VAT and IR, but changes in hepatic fat do not correlate with changes in VAT and glucose metabolism. Hepatic fat content is reduced by rhGH but Rosi has no effect. These results suggest an independent effect of growth hormone or IGF-1 on hepatic fat. The study was registered at Clinicaltrials.gov (NCT00130286).
doi:10.3851/IMP2927
PMCID: PMC5110034  PMID: 25536669
4.  Bioequivalence of dispersed stavudine: opened versus closed capsule dosing 
Antiviral therapy  2011;16(7):1131-1134.
Background
Stavudine, a nucleoside reverse transcriptase inhibitor, is used commonly to treat HIV-infected children in the developing world. The paediatric liquid formulation presents major logistical difficulties in rural and resource-limited areas, and prescribers are frequently forced to employ off-label ‘opened capsule’ dosing methods using the adult capsule. The South African Department of Health (DoH) has advised that caregivers should be instructed to disperse the contents of an adult capsule in 5 ml water and then withdraw the required dose using a syringe. The bioavailability of stavudine using the opened capsule dosing method has not previously been validated.
Methods
This was a randomized crossover pharmacokinetic study with each subject serving as his/her own control. A total of 28 healthy HIV-negative adult volunteers were randomized on a 1:1 basis to receive one of the two generic preparations. They were then further randomized to receive either intact or opened 30 mg capsules. After 1 week, those who initially received intact capsules, were given opened capsules and vice versa. The capsule dispersion technique used was identical to that prescribed by the DoH. Serial blood samples were collected and plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Stavudine pharmacokinetics were analysed using non-compartmental methods and formulations were compared using ANOVA.
Results
Plasma drug exposure after stavudine administration as a solution using an opened capsule dosing method was found to be bioequivalent to intact capsule administration. This was true for both generics tested. Conclusions: The opened capsule dosing technique is bioequivalent to intact capsule dosing for stavudine in HIV-seronegative adults.
doi:10.3851/IMP1876
PMCID: PMC5054241  PMID: 22024529
5.  IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes 
Antiviral therapy  2015;20(8):805-814.
Background
Lambda interferons (IFNLs) have potent antiviral activity against HCV, and polymorphisms within the IFNL gene cluster near the IFNL3 gene strongly predict spontaneous- and treatment-related HCV infection outcomes. The mechanism(s) linking IFNL polymorphisms and HCV control is currently elusive.
Methods
IFNL induction was studied in primary human hepatocytes (PHH) from 18 human donors, peripheral blood mononuclear cells (PBMCs) from 18 human donors, multiple cell lines and induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-hepatocytes) from 7 human donors. After stimulation with intracellular RNA and infectious HCV, quantitative PCR (qPCR) primers and probes were designed to distinguish and quantify closely related IFNL messenger (m)RNAs from IFNL1, IFNL2 and IFNL3.
Results
PHH demonstrated the most potent induction of IFNLs, although had lower pre-stimulation levels compared to PBMCs, monocytes and cell lines. PHH stimulation with cytoplasmic poly I:C induced >1,000-fold expression of IFNL1, IFNL2 and IFNL3. PHH from donors who were homozygous for the favourable IFNL3 allele (IFNL3-CC) had higher IFNL3 induction compared to PHH from IFNL3-TT donors (P=0.03). Baseline IFNL mRNA expression and induction was also tested in iPSC-hepatocytes: iPSC-hepatocytes had significantly higher baseline expression of IFNLs compared to PHH (P<0.0001), and IFNL3 induction was marginally different in iPSC-hepatocytes by IFNL genotype (P=0.07).
Conclusions
Hepatocytes express IFNLs when stimulated by a synthetic viral RNA that signals the cell through the cytoplasm. IFNL induction may be greater in persons with the favourable IFNL3 allele. These data provide insight into the strong linkage between IFNL3 genetics and control of HCV infection.
doi:10.3851/IMP2974
PMCID: PMC4821403  PMID: 26109548
6.  Preventing and treating secondary bacterial infections with antiviral agents 
Antiviral therapy  2011;16(2):123-135.
Summary
Bacterial super-infections contribute to the significant morbidity and mortality associated with influenza and other respiratory virus infections. There are robust animal model data but only limited clinical information on the effectiveness of licensed antiviral agents for the treatment of bacterial complications of influenza. The association of secondary bacterial pathogens with fatal pneumonia during the recent H1N1 influenza pandemic highlights the need for new development in this area. Basic and clinical research into viral-bacterial interactions over the last decade has revealed several mechanisms that underlie this synergism. By applying these insights to antiviral drug development, the potential exists to improve outcomes by means other than direct inhibition of the virus.
doi:10.3851/IMP1730
PMCID: PMC4907367  PMID: 21447860
7.  Adiponectin and Interleukin-6, But Not Adipose Tissue, Are Associated with Worse Neurocognitive Function in HIV-Infected Men 
Antiviral therapy  2015;20(2):235-244.
Background
Generalized obesity has been associated with cognitive decline, a process potentially mediated by adipocytokines. The effects of regional adipose tissue (AT) on cognition, however, are not well understood. We explored cross-sectional relationships between regional AT, adipocytokines, inflammatory markers and neuropsychological (NP) test scores among HIV+ and HIV− men enrolled in the Multicenter AIDS Cohort Study.
Methods
Visceral, subcutaneous abdominal and subcutaneous thigh AT areas were quantified by computed tomography (CT). NP tests (Trail Making Test parts A and B and Symbol Digit Modalities) obtained within two years of CT screened for psychomotor speed and executive function. Adiponectin, leptin, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were measured.
Results
Of 509 HIV+ and 271 HIV− participants, HIV+ men (98% on ART, 81% HIV-1 RNA <50copies/mL) had lower median subcutaneous AT and adiponectin levels and higher hs-CRP levels, but visceral AT, BMI, IL-6 and NP scores did not vary by HIV serostatus. In multivariable analysis, older age, ≤high school education and African American race, but not AT area or site, were associated with worse NP test scores among all participants. In HIV+ only, higher adiponectin and IL-6 were associated with worse cognitive function independent of AT area. No HIV-specific factors were associated with NP test scores.
Conclusions
Demographic factors were associated with NP test performance, but regional adiposity was not. In HIV+ only, higher adiponectin and IL-6 were associated with worse NP test scores, supporting a role for chronic inflammation and adipocytokine imbalance in neurocognitive decline in HIV+ persons.
doi:10.3851/IMP2952
PMCID: PMC4425574  PMID: 25810377
8.  Liver-to-plasma vaniprevir (MK-7009) concentration ratios in HCV-infected patients 
Antiviral therapy  2015;20(8):843-848.
Background
Some drugs that are actively taken up into the liver exhibit greater than dose proportional increases in plasma exposure, although human liver-to-plasma concentration ratios have rarely been evaluated. Understanding these relationships has implications for drug concentrations at the target site for certain classes of compounds, such as direct-acting antivirals, targeted towards HCV.
Methods
Treatment-experienced, chronic HCV non-cirrhotic patients (n=3) received vaniprevir (600 mg or 300 mg twice daily) on days 1–3 and (600 mg or 300 mg single dose) on day 4. Core needle biopsy was performed at 6 or 12 h post-dose on day 4. Blood samples were collected pre-dose on days 1 and 4, and for 24 h post-dose on day 4. The primary study objective was the hepatic concentration of vaniprevir at 6 and 12 h post-dose.
Results
Vaniprevir plasma pharmacokinetic parameters increased in a greater than dose-proportional manner between the 300 mg and 600 mg doses, with approximately fivefold increases in AUC0–12 and Cmax associated with a twofold increase in dose (AUC0–12, 10.6 µM/h to 59.5 µM/h; Cmax, 2.60 µM to 13.5 µM). In the 300 mg and 600 mg dose groups, mean liver concentrations of vaniprevir were 84.6 µM and 169 µM at 6 h post-dose, and 29.4 µM and 53.7 µM at 12 h post-dose. Liver concentrations were higher than plasma with liver-to-plasma concentration ratios of approximately 20–280.
Conclusions
These data confirm higher vaniprevir concentrations in human liver compared with plasma and demonstrate that measurement of human liver drug concentration using needle biopsy is feasible.
doi:10.3851/IMP2958
PMCID: PMC4714953  PMID: 25849338
9.  Anemia is associated with monocyte activation in HIV-infected adults on antiretroviral therapy 
Antiviral therapy  2015;20(5):521-527.
Background
Anemia has been linked with mortality in HIV infection. The mechanism of anemia in the era of contemporary antiretroviral therapy is not understood. The aim of this study was to describe the association between anemia and markers of immune activation and inflammation in a cohort of HIV-infected adults on stable antiretroviral therapy.
Methods
We performed a cross-sectional study of HIV-infected adults on antiretroviral therapy with HIV-1 RNA < 1000 copies/ml. Soluble and cellular markers of inflammation and immune activation were measured. Relationships between hemoglobin levels, anemia (hemoglobin <13 g/dL for men and <12 g/dL for women) and mild anemia (hemoglobin <14 g/dL for men and <13 g/dL for women) and these markers were explored using multivariable linear regression.
Results
Among the 147 participants, median age was 46 years, 78% were men, 68% were African American and 29% were Caucasian. Median BMI was 26.7 kg/m2, nadir and current CD4+ T cell counts were 179 and 613 cells/mm3, respectively, and 78% had HIV-1 RNA <50 copies/ml (range 20–600 copies/ml). Median (IQR) hemoglobin was 14.3 (13.1–15.1) g/dl; 14% were anemic and 33% had at least mild anemia. In multivariable analyses, mild anemia was independently associated with female sex, older age, shorter duration of ART, lower WBC count, higher platelet count, higher sCD14 and a greater number of CD14dimCD16+ cells or “patrolling” monocytes, which remained significant after further adjusting for race and BMI.
Conclusions
Having hemoglobin <14 g/dL for men and <13 g/dL for women was independently associated with monocyte activation (sCD14 and CD14dimCD16+ cells) in HIV-infected adults on stable antiretroviral therapy.
doi:10.3851/IMP2940
PMCID: PMC4531107  PMID: 25668820
HIV; anemia; systemic inflammation; immune activation; antiretroviral therapy; CD14dimCD16+
10.  Association between First-Year Virologic Response to Raltegravir and Long-Term Outcomes in Treatment-Experienced Patients with HIV-1 Infection 
Antiviral therapy  2014;20(3):307-315.
Background
We explored the relationship between virologic response in the first year of treatment and long-term outcomes in the BENCHMRK studies.
Methods
Patients failing ART with 3-class resistant HIV-1 received double-blinded raltegravir (or placebo) with optimized background therapy (OBT) until week 156, then open-label raltegravir with OBT up to week 240. In this exploratory analysis of patients randomized to raltegravir, virologic response over weeks 16–48 was categorized as�continuous suppression (CS: vRNA always <50 copies/mL), low-level viremia�(LLV: vRNA always < 400 copies/mL; <50 copies/mL at least once), or not suppressed (NS: vRNA <400 copies/mL at least once). The association between these first-year vRNA response categories and baseline factors was analyzed with univariate and multivariate models. Virologic and immunologic outcomes for years 2–5 were assessed by first-year vRNA response category (observed failure approach).
Results
Baseline vRNA, baseline CD4 count, and rapid viral decay (vRNA <50 copies/mL between weeks 2–12) correlated with first-year vRNA response (p<0.001); only rapid viral decay remained significant by multiple regression. Virologic response rates were similar in the LLV and CS groups and lowest in the NS group. CD4 increased through week 240 in the CS and LLV groups. Time to loss of virologic response (confirmed vRNA ≥400 copies/mL) through Week 240 did not support as strong a difference between the LLV and CS groups (log-rank p=0.11) as previously reported through Week 156 and 192 (p<0.05).
Conclusions
Treatment-experienced patients on a raltegravir-based regimen with early LLV may have long-term virologic and immunologic benefit when their therapy is maintained.
doi:10.3851/IMP2912
PMCID: PMC4422784  PMID: 25350973
raltegravir; HIV-1 infection; BENCHMRK studies; low-level viremia
11.  Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy 
Antiviral therapy  2014;20(2):149-155.
Background
HCV kinetic analysis and modeling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease.
Methods
Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to εmax) was fit to viral kinetic data.
Results
Baseline viral load and age were significantly associated with the severity of liver disease (p<0.0001). A biphasic viral decline was observed in most patients with a higher first phase decline patients with less severe liver disease. The maximal effectiveness, εmax, was significantly (p≤0.032) associated with increasing severity of liver disease (εmax[s.e.]=0.86[0.05], εmax=0.69[0.06] and εmax=0.59[0.1]).. The 2nd phase decline slope was not significantly different among groups (mean 1.88±0.15 log10IU/ml/wk, p=0.75) as was the rate of change of SIL effectiveness (k=2.12/day[standard error, s.e.=0.18/day]). HCV-infected cell loss rate (δ[s.e.]=0.62/day[0.05/day]) was high and similar among groups.
Conclusions
The high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.
doi:10.3851/IMP2806
PMCID: PMC4262731  PMID: 24912382
12.  A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV 
Antiviral therapy  2014;20(5):469-477.
Background
Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs).
Methods
We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment.
Results
In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). The second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d−1), whereas the viral decline was slower in the other patients.
Conclusions
Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
doi:10.3851/IMP2879
PMCID: PMC4400215  PMID: 25321394
13.  PHYLOGENETIC EVIDENCE OF HIV-1 SEQUENCE EVOLUTION IN SUBJECTS WITH PERSISTENT LOW-LEVEL VIREMIA 
Antiviral therapy  2014;20(1):73-76.
Background
Persistent low-level viremia (LLV) during the treatment of antiretroviral therapy (ART) is associated with emergent drug resistance mutation (DRM); however insight into its driver is limited. The objectives were to study HIV-1 pol sequence evolution in subjects with persistent LLV and evaluate factors associated with sequence changes.
Methods
HIV-1 pol sequences from 54 treatment-naive subjects undergoing first-line lopinavir-ritonavir- or efavirenz-containing ART were obtained at pre-ART and end of LLV. HIV-1 sequence evolution was evaluated using phylogenetic analysis and hamming distance calculation. DRMs were interpreted based on the International AIDS Society-USA 2011 update.
Results
Subjects with new DRM during LLV had greater HIV-1 evolution across pol from the pre-ART to end of LLV compared to subjects without DRM. Evolution over non-DRM sites was similar between groups. Higher degree of genetic evolution was positively associated with higher HIV-1 RNA levels during LLV, both at DRM and non-DRM sites.
Conclusion
The magnitude of LLV was the primary driver of evolution rate at DRM as well as non-DRM sites. Higher viral load was associated with DRM emergence in these subjects. These findings provide insights that may be applicable to the management of patients with persistent LLV during ART.
doi:10.3851/IMP2772
PMCID: PMC4185268  PMID: 24699164
HIV-1 sequence evolution; drug resistance mutation; low-level viremia; phylogenetic; hamming distance
14.  Loss to follow-up in the Australian HIV Observational Database 
Antiviral therapy  2014;20(7):731-741.
Background
Loss to follow-up (LTFU) in HIV-positive cohorts is an important surrogate for interrupted clinical care which can potentially influence the assessment of HIV disease status and outcomes. After preliminary evaluation of LTFU rates and patient characteristics, we evaluated the risk of mortality by LTFU status in a high resource setting.
Methods
Rates of LTFU were measured in the Australian HIV Observational Database for a range of patient characteristics. Multivariate repeated measures regression methods were used to identify determinants of LTFU. Mortality by LTFU status was ascertained using linkage to the National Death Index. Survival following combination antiretroviral therapy initiation was investigated using the Kaplan-Meier (KM) method and Cox proportional hazards models.
Results
Of 3,413 patients included in this analysis, 1,632 (47.8%) had at least one episode of LTFU after enrolment. Multivariate predictors of LTFU included viral load (VL)>10,000 copies/ml (Rate ratio (RR) 1.63 (95% confidence interval (CI):1.45–1.84) (ref ≤400)), time under follow-up (per year) (RR 1.03 (95% CI: 1.02–1.04)) and prior LTFU (per episode) (RR 1.15 (95% CI: 1.06–1.24)). KM curves for survival were similar by LTFU status (p=0.484). LTFU was not associated with mortality in Cox proportional hazards models (univariate hazard ratio (HR) 0.93 (95% CI: 0.69–1.26) and multivariate HR 1.04 (95% CI: 0.77–1.43)).
Conclusions
Increased risk of LTFU was identified amongst patients with potentially higher infectiousness. We did not find significant mortality risk associated with LTFU. This is consistent with timely re-engagement with treatment, possibly via high levels of unreported linkage to other health care providers.
doi:10.3851/IMP2916
PMCID: PMC4424189  PMID: 25377928
15.  Targeting human papillomavirus genome replication for antiviral drug discovery 
Antiviral therapy  2013;18(3):271-283.
Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agents. This review examines the status of past and ongoing research into the development of HPV antivirals, focused primarily upon approaches targeting the replication of the viral genome. The only HPV enzyme, E1, is a DNA helicase that interfaces with the cellular DNA replication machinery to replicate the HPV genome. To date, searches for small molecule inhibitors of E1 for use as antivirals have met with limited success. The lack of other viral enzymes has meant that the search for antivirals has shifted to a large degree to the modulation of protein–protein interactions. There has been some success in identifying small molecule inhibitors targeting interactions between HPV proteins but with activity against a small subset of viral types only. As noted in this review, it is thought that targeting E1 interactions with cellular replication proteins may provide inhibitors with broader activity against multiple HPV types. Herein, we outline the steps in HPV DNA replication and discuss those that appear to provide the most advantageous targets for the development of anti-HPV therapeutics.
doi:10.3851/IMP2612
PMCID: PMC4658057  PMID: 23615820 CAMSID: cams5351
17.  Recent advances in the search for antiviral agents against human papillomaviruses 
Antiviral therapy  2007;12(4):431-451.
Infection by human papillomavirus (HPV) is extremely common and associated with the development of benign warts or malignant lesions of the skin and mucosa. Infection by a high-risk (oncogenic) anogenital HPV type, most often through sexual contacts, is the starting point of virtually all cases of cervical cancers and the majority of anal cancers. The same viral types are also increasingly being linked with a subset of head-and-neck and non-melanoma skin cancers. Although prophylactic vaccines are now available to protect against the four types most commonly found in cervical and anal cancers (HPV16 and HPV18) and anogenital warts (HPV6 and HPV11), these neither protect against all genital HPVs nor are of therapeutic utility for already infected patients. Thus, the need for antiviral agents to treat HPV-associated diseases remains great, but none currently exist. This article reviews the recent progress made towards the development of antiviral agents to treat HPV infections, from target identification and validation to the discovery of lead compounds with therapeutic potential. Emphasis has been placed on novel low-molecular-weight compounds that antagonize HPV proteins or, alternatively, inhibit cellular proteins which have been usurped by papillomaviruses and are mediating their pathogenic effects.
PMCID: PMC4646640  PMID: 17668552 CAMSID: cams5300
18.  Comparison of cardiovascular disease risk markers in HIV-infected patients receiving abacavir and tenofovir: the nucleoside inflammation, coagulation and endothelial function (NICE) study 
Antiviral therapy  2013;19(2):141-147.
Background
The association between abacavir (ABC) and cardiovascular disease (CVD) risk in HIV-infected individuals is unclear. Putative mechanisms for an effect of ABC on CVD risk including endothelial dysfunction have been proposed; however, a biological mechanism has not been established.
Methods
This was a cross-sectional study of HIV-infected subjects with HIV RNA levels <400 copies/ml, who were randomly assigned to ABC or tenofovir (TDF) as initial therapy during a prior clinical trial. A small cohort of subjects on zidovudine (AZT; not randomly assigned) were studied to explore long-term exposure to this agent. All underwent brachial artery ultrasound for flow-mediated dilation (FMD), and D-dimer, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and fasting lipids were measured. Between-arm differences were evaluated by multivariable linear or logistic regression modelling.
Results
There were 148 subjects (46 on ABC, 72 on TDF and 30 on AZT). Demographic characteristics were balanced across the groups except, as expected, AZT-treated participants were older, had higher CD4+ T-cell counts, and longer antiretroviral therapy duration. After adjusting for age, brachial artery diameter, and treatment duration, FMD was similar in those on ABC (3.9%) and TDF (5.4%; P=0.181). FMD was higher in those on AZT (6.1%; P<0.005). Levels of IL-6, hsCRP and detectable D-dimer were similar between groups.
Conclusions
Among individuals assigned to ABC or TDF in randomized clinical trials there were no significant differences in FMD or markers of inflammation and coagulation. Whether ABC contributes to risk of CVD remains unclear, but our results suggest that endothelial dysfunction, heightened inflammation, and altered coagulation are unlikely to be mechanisms by which the drug could increase CVD risk above that seen with TDF.
doi:10.3851/IMP2681
PMCID: PMC4591920  PMID: 23985706
19.  Prognostic importance of anaemia in HIV-1 infected patients starting antiretroviral therapy: collaborative analysis of prospective cohort studies in industrialized countries 
Antiviral therapy  2008;13(8):959-967.
Background
In HIV-1 infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined.
Methods
We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1120 (9%) had moderate (males: 8.0 to <11.0 g/dl, females 8.0 to <10.0 g/dl) and 2971 (25%) had mild anaemia (males 11.0 to <13.0 g/dl, females 10.0 to <12.0 g/dl). We separately analyzed progression to AIDS or death from baseline and six months using Weibull models, adjusting for CD4 cell count, age, sex, and other variables.
Results
During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17–1.73), for moderate anaemia 2.56 (2.07–3.18) and for severe anaemia 5.26 (3.55–7.81). Corresponding figures for progression to AIDS were 1.60 (1.37–1.86), 2.00 (1.66–2.40) and 2.24 (1.46–3.42). At 6 months the prevalence of anaemia had declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months.
Conclusions
Anaemia at the start of HAART is an important prognostic factor for short and long term prognosis, including in patients whose haemoglobin levels improve or normalize during the first 6 months of HAART.
PMCID: PMC4507810  PMID: 19195321
HIV/AIDS; highly active antiretroviral therapy (HAART); anaemia; prognosis; mortality
20.  Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections 
Antiviral therapy  2014;20(3):257-259.
Sadat et al reported in the 2014 April 24 issue of New England Journal of Medicine that patients genetically deficient in the gene encoding mannosyl-oligosaccharide glucosidase (MOGS), also known as endoplasmic reticulum (ER) glucosidase I, manifested a severe hypogammaglobulinemia without clinical evidence of an infectious diathesis. This paradox phenomenon is, at least in part, because the impaired N-linked glycan processing of the patients compromises their ability to support efficient replication and cellular entry of viruses. This finding unambiguously validates ER glucosidases as valuable targets for antiviral agents against a broad-spectrum of enveloped viruses.
doi:10.3851/IMP2907
PMCID: PMC4446249  PMID: 25318123
21.  Recent trends in early stage response to combination antiretroviral therapy in Australia 
Antiviral therapy  2014;20(2):131-139.
Background
There have been improvements in combination antiretroviral therapy (cART) over the last 15 years. The aim of this analysis was to assess whether improvements in ART have resulted in improvements in surrogates of HIV outcome.
Methods
Patients in the Australian HIV Observational Database who initiated treatment using mono/duo therapy prior to 1996, or using cART from 1996 onwards, were included in the analysis. Patients were stratified by era of ART initiation. Median changes in CD4+ and the proportion of patients with detectable HIV viral load (>400 copies/ml) were calculated over the first 4 years of treatment. Probabilities of treatment switch were estimated using the Kaplan-Meier method.
Results
2,753 patients were included in the analysis: 28% initiated treatment <1996 using mono/duo therapy; and 72% initiated treatment ≥1996 using cART (30% 1996–99; 12% 2000–03; 11% 2004–07; and 19% ≥2008). Overall CD4 response improved by later era of initiation (p<0.001), although 2000–03 CD4 response was less than that for 1996–99 (p=0.007). The average proportion with detectable viral load from 2 to 4 years post treatment commencement by era was: <1996 mono/duo 0.69 (0.67–0.71); 1996–99 cART 0.29 (0.28–0.30); 2000–03 cART 0.22 (0.20–0.24); 2004–07 cART 0.09 (0.07–0.10); ≥2008 cART 0.04 (0.03–0.05). Probability of treatment switch at 4 years after initiation decreased from 53% in 1996–99 to 29% after 2008 (p<0.001).
Conclusions
Across the five time-periods examined, there have been incremental improvements for patients initiated on cART, as measured by overall response (viral load and CD4 count), and also increased durability of first-line ART regimens.
doi:10.3851/IMP2774
PMCID: PMC4185258  PMID: 24704818
22.  Naturally occurring dominant drug resistance mutations occur infrequently in the setting of recently acquired hepatitis C 
Antiviral therapy  2014;20(2):199-208.
Background
Directly Acting Antivirals (DAAs) are predicted to transform hepatitis C (HCV) therapy, yet little is known about the prevalence of naturally occurring resistance mutations in recently acquired HCV. This study aimed to determine the prevalence and frequency of drug resistance mutations in the viral quasispecies among HIV positive and negative individuals with recent HCV.
Methods
The NS3 protease, NS5A and NS5B polymerase genes were amplified from fifty genotype 1a participants of the Australian Trial in Acute Hepatitis C. Amino acid variations at sites known to be associated with possible drug resistance were analysed by ultra-deep pyrosequencing.
Results
Twelve percent of individuals harboured dominant resistance mutations, while 36% demonstrated non dominant resistant variants below that detectable by bulk sequencing (ie < 20%) but above a threshold of 1%. Resistance variants (< 1%) were observed at most sites associated with DAA resistance from all classes, with the exception of sofosbuvir.
Conclusions
Dominant resistant mutations were uncommonly observed in the setting of recent HCV. However, low level mutations to all DAA classes were observed by deep sequencing at the majority of sites, and in most individuals. The significance of these variants and impact on future treatment options remains to be determined.
doi:10.3851/IMP2821
PMCID: PMC4320979  PMID: 25105742
recent hepatitis C; directly acting antivirals; resistance mutations; ultra-deep pyrosequencing; viral quasispecies
23.  “HDL Redox Activity is Increased in HIV-Infected Men in Association with Macrophage Activation and Noncalcified Coronary Atherosclerotic Plaque” 
Antiviral therapy  2014;19(8):805-811.
Background
HIV is associated with atherosclerosis and low HDL. With inflammation, HDL becomes dysfunctional. We previously showed that pro-inflammatory HDL has high HDL redox activity (HRA). In this study, we: 1) compare HRA in HIV-infected versus non-HIV-infected subjects and 2) relate HRA to indices of macrophage activation and cardiovascular disease risk.
Methods
102 HIV-infected subjects and 41 matched non-HIV controls without clinical cardiovascular disease underwent coronary CT angiography (CTA) and testing for immune/inflammatory biomarkers. The effect of purified HDL from each study subject on the oxidation rate of dihydrorhodamine-123(DOR) was normalized to the DOR of pooled HDL from healthy subjects. The normalized ratio DORsubject/DORpooled (nHRA) was used as a measure of HRA, with higher HRA suggesting dysfunctional HDL.
Results
HRA was higher in HIV-infected versus non-HIV subjects (1.4±0.01 versus 1.3±0.01, p=0.03). In multivariate modeling for HRA among all subjects, HIV status remained positively related to HRA (p=0.02), even after controlling for traditional cardiovascular risk factors, comorbid conditions, and immune activation. Among HIV-infected subjects, HRA correlated inversely with HDL (rho=−0.32, p=0.002) and log adiponectin (r=−0.28, p=0.006) and correlated positively with log sCD163 (r=0.24, p=0.02) - a monocyte/macrophage activation marker - and with percent non-calcified coronary atherosclerotic plaque (r=0.29, p=0.03). sCD163 remained significantly associated with HRA in multivariate modeling among HIV-infected subjects (p=0.03).
Conclusions
These data demonstrate increased HRA among HIV-infected subjects versus matched non-HIV subjects with comparable HDL levels. In HIV-infected subjects, HRA relates to macrophage activation and to non-calcified coronary atherosclerotic plaque, which may be rupture prone. Further studies are needed in HIV-infected patients to elucidate the interplay between immune activation, HDL function, and CVD risk.
doi:10.3851/IMP2756
PMCID: PMC4423391  PMID: 24535655
HIV; HDL; atherosclerosis; HDL oxidative potential
24.  Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies 
Antiviral therapy  2008;13(0 2):59-68.
Programmes that monitor local, national and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 drug resistance and has recommended the adoption of a consensus definition of genotypic drug resistance. Such a definition is necessary to accurately compare transmitted drug resistance rates across geographical regions and time periods. HIV-1 diversity and the large number of mutations associated with antiretroviral drug resistance complicate the development of a consensus definition for genotypic drug resistance. This paper reviews the data that must be considered to determine which of the many HIV-1 drug resistance mutations are likely to be both sensitive and specific indicators of transmitted drug resistance. The process used to create a previously published list of drug resistance mutations for HIV-1 surveillance is reviewed and alternative approaches to this process are discussed.
PMCID: PMC4388302  PMID: 18575192
25.  Lack of resistance to integrase inhibitors among antiretroviral-naive subjects with primary HIV-1 infection, 2007–2013 
Antiviral therapy  2014;20(1):77-80.
Background
U.S. guidelines recommend genotyping for persons newly diagnosed with HIV infection to identify transmitted drug resistance mutations associated with decreased susceptibility to NRTIs, NNRTIs, and PIs. To date, testing for integrase strand transfer inhibitor (INSTI) mutations has not been routinely recommended. We aimed to evaluate the prevalence of transmitted INSTI mutations among persons with primary HIV-1 infection in Seattle, WA.
Methods
Persons with primary HIV-1 infection have enrolled in an observational cohort at the University of Washington Primary Infection Clinic since 1992. We performed a retrospective analysis of plasma specimens collected prospectively from the 82 antiretroviral-naive subjects who were enrolled from 2007–13, after FDA-approval of the first INSTI. Resistance testing was performed by consensus sequencing.
Results
Specimens for analysis had been obtained a median of 24 (lQR 18–41, range 8–108) days after the estimated date of HIV-1 infection. All subjects were infected with HIV-1 subtype B except for one subject infected with subtype C. Consensus sequencing identified no subjects with major INSTI mutations (T66I, E92Q, G140S, Y143C/H/R, S147G, Q148H/K/R, N155H). Using exact binomial confidence intervals, the upper bound of the 95% CI was 4.4%.
Conclusions
Although our sample size was small, this study does not support the need at this time to evaluate integrase mutations as part of routine consensus sequencing among persons newly diagnosed with HIV-1 infection. However, it is likely that the prevalence of transmitted INSTI mutations may increase with the recent commercial introduction of additional INSTIs and presumably greater INST1 use among persons living with HIV-1.
doi:10.3851/IMP2780
PMCID: PMC4312242  PMID: 24831260

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