bluuebunny/crossref_metadata_2025 huggingface dataset:
Enfuvirtide Cerebrospinal Fluid (CSF) Pharmacokinetics and Potential use in Defining CSF HIV-1 Origin
Authors: Price Richard W , Parham Robin , Kroll Jing Lu , Wring Stephen A , Baker Brian , Sailstad Jeff , Hoh Rebecca , Liegler Teri , Spudich Serena , Kuritzkes Daniel R , Deeks Steven G
Published: April 2022

Background

Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analysed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies.

Methods

Enfuvirtide CSF pharmacokinetics were assessed in 18 CSF and plasma sample pairs from four HIV-1-infected individuals. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that included spiked CSF samples from untreated, HIV-negative individuals. A segment of the gp41 coding region encompassing the heptad repeat HR-1 and HR-2 domains was amplified from selected CSF and plasma samples and independent clones sequenced to assess resistance-associated mutations.

Results

CSF and plasma samples obtained between 2 and 20 h after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 SD ±1.828 mg/ml) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 mg/ml. In one individual, who developed a transient increase in CSF HIV-1 RNA, seven of seven CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutations, suggesting that the CSF quasispecies derived from that of blood.

Conclusions

Enfuvirtide penetration into CSF is negligible; thus, in clinical settings, where direct CNS drug exposure is crucial, this drug Is not likely to directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus.
Antiviral Resistance Mutations Potentiate hepatitis B virus Immune Evasion through Disruption of its Surface Antigen a Determinant
Authors: Sloan Richard D , Ijaz Samreen , Moore Penny L , Harrison Tim J , Teo Chong-Gee , Tedder Richard S
Published: April 2022

Background

The hepatitis B virus (HBV) pol gene overlaps the S gene encoding surface antigen (HBsAg). It has been reported previously that drug-induced changes in HBsAg alter its binding to sera from humans immunized against HBV. We investigate here the changes to specific epitopes in the a determinant (the major target of neutralizing antibody) caused by a number of drug-resistant mutations.

Methods

Recombinant HBsAgs, produced by transfection of Chinese hamster ovary cells with S gene plasmids into which lamivudine, adefovir and entecavir resistance and common antibody-escape mutations had been introduced, were probed with monoclonal antibodies to epitopes in the first and second loops of the a determinant.

Results

The mutations rtF166L/sF158Y (lamivudine-associated, compensatory) and rtI169T/sF161L (entecavir-associated, primary) acting alone, and the mutations rtV173L/sE164D (lamivudine-associated, compensatory) and rtSilent/sD144E (antibody escape-associated) each when combined with rtM204V/sI195M (lamivudine-associated, primary) led to decreases in antibody reactivity to epitopes in the first or second loop, or in both loops. The rtM204V/ sI195M+rtV173L/sE164D mutations yielded an epitope–antibody profile similar to the rtR153Q/sG145R vaccine escape mutant. The rtM204V/sI195M mutation combined with the rtF166L/sF158Y or rtR153Q/sG145R mutation restored reactivity to second-loop epitopes previously abrogated by single mutations.

Conclusions

Mutations associated with resistance to nucleos(t)ide analogue therapy, singly or in combination with each other or antibody escape-associated mutations, alter HBsAg immunoreactivity through concomitant amino acid substitutions at codons within and downstream of the a determinant. The findings have implications for understanding the native structure of HBsAg, optimizing treatment of chronic hepatitis B and evaluating the success of immunization programmes.
Evidence of Long-Term Suppression of Hepatitis B virus DNA by Tenofovir as Rescue Treatment in Patients Coinfected by HIV
Authors: Quiros-Roldan Eugenia , Calabresi Alessandra , Lapadula Giuseppe , Tirelli Valeria , Costarelli Silvia , Cologni Giuliana , Zaltron Serena , Puoti Massimo , Carosi Giampiero , Torti Carlo
Published: April 2022

Background

The efficacy of long-term hepatitis B virus (HBV) treatment with tenofovir (TDF) in relation to lamivudine (LMV) resistance in HIV patients failing on LMV deserves further investigations.

Methods

HIV–HBV coinfected patients were selected, provided that LMV was included in the first highly active antiretroviral therapy regimen and TDF was subsequently introduced.

Results

Forty HIV–HBV patients were included, 25 had undetectable HBV DNA on LMV and 15 were failing on LMV treatment. Three cases of triple 173V+180M+ 204V HBV reverse transcriptase (rt) mutants were identified, as well as several mutations or polymorphisms in the surface antigen gene at positions possibly correlating with vaccine escape. A new mutation (rtI233V) was found in one adefovir-naive patient. In 10 patients, uninterrupted TDF treatment led to a sustained treatment response for a median of 160 (interquartile range 111–189) weeks. Two patients underwent intermittent treatment with TDF and LMV, responding any time TDF was reintroduced. In one patient, TDF without LMV provided treatment response. One patient did not respond to TDF because of low treatment adherence. One patient infected with the triple rt mutant did not respond to entecavir, but TDF was successful as rescue.

Conclusions

Combination therapy with TDF was effective against HBV mutant viruses resistant to LMV and provided sustained control of HBV replication over long-term follow-up, even after entecavir failure. Moreover, suppression of HBV vaccine escape variants could provide important benefits from a public health perspective.
Factors Influencing Efavirenz and Nevirapine Plasma Concentration: Effect of Ethnicity, Weight and Co-Medication
Authors: Stöhr Wolfgang , Back David , Dunn David , Sabin Caroline , Winston Alan , Gilson Richard , Pillay Deenan , Hill Teresa , Ainsworth Jonathan , Pozniak Anton , Leen Clifford , Bansi Loveleen , Fisher Martin , Orkin Chloe , Anderson Jane , Johnson Margaret , Easterbrook Phillippa , Gibbons Sara , Khoo Saye
Published: April 2022

Background

The aim of this study was to examine factors influencing plasma concentration of efavirenz and nevirapine.

Methods

Data from the Liverpool Therapeutic Drug Monitoring (TDM) registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. For each patient, the first measurement of efavirenz (600 or 800 mg/day) or nevirapine (400 mg/day) plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifampicin with log-transformed drug concentration, adjusted for time since last intake.

Results

Data from 339 patients on efavirenz (34% black, 17% rifampicin) and 179 on nevirapine (27% black, 6% rifampicin) were included. Multivariable models revealed the following predictors for efavirenz concentration: black ethnicity (59% higher; P<0.001), weight (10% lower per additional 10 kg; P=0.002), 800 mg/day (52% higher; P=0.027), rifampicin (35% lower; P=0.039), and zidovudine (25% lower; P=0.010). Notably, without adjustment for other factors, patients on rifampicin had 48% higher efavirenz concentration, as these patients were mostly black and on 800 mg/day. For nevirapine the predictors were black ethnicity (39% higher; P=0.002), rifampicin (40% lower; P=0.002), protease inhibitor (28% higher; P=0.008) and tenofovir (22% higher; P=0.024).

Conclusions

We observed clear associations between ethnicity and concentrations of nevirapine and efavirenz. Our analyses confirm that concomitant rifampicin substantially decreases concentration of both efavirenz and nevirapine; however, for efavirenz this effect was more than counterbalanced by the effect of ethnicity and increased efavirenz dose. There was also an additional impact of weight, which should be considered when determining optimal dosage. Other associations from our analysis (between tenofovir or protease inhibitor and nevirapine, and zidovudine and efavirenz), require confirmation in formal pharmacokinetic studies.
Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection
Authors: McComsey Grace A , Libutti Daniel E , O'Riordan MaryAnn , Shelton Jessica M , Storer Norma , Ganz Jason , Jasper John , Harrill Danielle , Gerschenson Mariana
Published: April 2022

Background

The aim of this study was to assess the effect of antiretroviral therapy (ART) versus HIV on mitochondria in fat.

Methods

Subcutaneous fat was collected from 45 HIV-infected patients on ART with lipoatrophy, 11 HIV-infected ART-naive patients and nine healthy controls. Three mitochondrial transcripts: NADH dehydrogenase subunit 1 (ND1), cytochrome B (CYTB) and NADH dehydrogenase subunit 6 (ND6) genes were quantitated using TaqMan® probes and normalized to nuclear-encoded ribosomal L13.

Results

ND1/L13 and CYTB/L13 were lower in HIV-positive patients on ART with lipoatrophy versus ART-naive patients (3.4 versus 7.2 [ P=0.017] and 2.5 versus 4.6 [ P=0.006], respectively). No difference was found between ART-naive patients and controls ( P>0.70). ND6/ L13 was similar between all groups. Dual-energy X-ray absorptiometry-measured limb fat and mitochondrial DNA in fat were also lower in HIV-positive patients on ART with lipoatrophy versus HIV-infected, ART-naive patients (4,382 versus 7,662 g [ P=0.02] and 726 versus 1,372 copies/cell [ P=0.03], respectively), but no difference was found between ART-naive and controls. In a multiple regression analysis, limb fat correlated with all three mitochrondrial RNA, whereas mitochondrial DNA did not correlate with mitochondrial RNA or limb fat.

Conclusions

In contrast to ART-naive patients, HIV-positive patients on ART with lipoatrophy had significant depletion in mitochondrial DNA in fat and mitochondrial RNAs. This suggests that mitochondrial toxicity in lipoatrophy could be driven by ART and not by HIV itself. In addition, mitochondrial RNA abnormalities, and not mitochondrial DNA depletion, could be a key driving force behind lipoatrophy.
Same Patient, New Stone Composition: Amprenavir Urinary Stone
Authors: Feicke Antje , Rentsch Katharina M , Oertle Daniel , Strebel Räto T
Published: April 2022

We report here the first case to add amprenavir to the growing list of antiretroviral drugs associated with urinary stones. The first reported case of a nelfinavir urinary stone was reported in 2002 in a 37-year-old HIV-infected woman. In September 2007, the same female patient was referred to our department with recent onset of right flank pain and recurrent urinary tract infections. Abdominal computed tomography revealed three obstructing stones in the distal right ureter, another stone in the right renal pelvis with hydronephrosis and a stone in the left kidney. After stone retrieval, analysis of the stone by liquid chromatography with mass spectrometry revealed a stone composition of 95% unmodified amprenavir and 5% ritonavir.
Effect of tenofovir subtraction on HIV plasma viraemia, CD4+ T-cell count and resistance in a patient with baseline K65R and M184V mutations
Authors: Hsu Ricky , Lanier Ernest R , Rouse Elizabeth G , Oie Katrina L , Pappa Keith A , Ross Lisa L
Published: April 2022

In vitro, the reverse transcriptase mutation K65R can simultaneously reduce drug susceptibility, replicative capacity and restrict HIV-1 replication. Here, we assessed the effect of tenofovir discontinuation for a patient receiving antiretroviral therapy whose HIV-1 had a dominant K65R/M184V genotype. Although limited by the single-case nature, the data support a hypothesis that there is no HIV viral RNA or CD4+ T-cell count benefit of taking tenofovir for experienced patients with genotypic evidence of K65R/M184V.
Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients
Authors: Pea Federico , Tavio Marcello , Pavan Federica , Londero Angela , Bresadola Vittorio , Adani Gian Luigi , Furlanut Mario , Viale Pierluigi
Published: April 2022

Solid organ transplantation in HIV-infected individuals requires concomitant use of immunosuppressants and antiretrovirals that may cause significant drug interactions. Here we report on a peculiar pharmacokinetic interaction between tacrolimus and protease inhibitors (PIs) which occurred in four HIV-infected liver transplant patients who had to shift PI therapy from nelfnavir to fosamprenavir as a consequence of regulatory restrictions. After the switch, tacrolimus trough blood concentrations significantly dropped in all patients (mean ±sd 6.9 ±2.6 versus 3.2 ±2.0 ng/ml before and after the switch, respectively; P=0.01), so that a marked dosage increase was needed (0.29 ±0.14 versus 0.88 ±0.48 mg/day, 1–3 days before and 3 weeks after the switch, respectively; P=0.046) to attain the desired target (8.7 ±2.3 ng/ ml). Consistently, marked changes of the concentration/dose ratio of tacrolimus were observed in all cases (27.2 ±9.7 ng/ml per mg/kg/day versus 9.7 ±4.0 ng/ml per mg/kg/day before and after the switch, respectively; P<0.001). Our findings suggest that fosamprenavir may be less potent than nelfinavir in inhibiting tacrolimus clearance and support the need for higher tacrolimus dosage to avoid insufficient immunosuppression in HIV-infected liver transplant patients when switching from nelfinavir to fosamprenavir or even when directly starting antiretroviral therapy with fosamprenavir.
Estimating Glomerular Filtration Rate in HIV-Infected Adults in Africa: Comparison of Cockcroft–Gault and Modification of Diet in Renal Disease Formulae
Authors: Stöhr Wolfgang , Walker A Sarah , Munderi Paula , Tugume Stefano , Gilks Charles F , Darbyshire Janet H , Hakim James
Published: April 2022

Background

Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae are recommended for glomerular filtration rate (GFR) estimation, but neither has been validated or directly compared longitudinally in HIV-infected patients or in Africa.

Methods

We investigated differences between formulae in baseline GFR, GFR changes and incidence of impaired GFR after initiation of antiretroviral therapy (ART) in 3,316 HIV-infected adults in Africa, considering sex, age, body mass index and baseline laboratory parameters as predictors.

Results

Participants were 65% women, median age 36.8 years, median weight 56.7 kg. Baseline GFR was lower using CG (median 89 ml/min/1.73 m2, 7.4% <60 ml/ min/1.73 m2) versus MDRD (103 ml/min/1.73 m2, 3.1% <60 ml/min/1.73 m2). At 36 weeks, median CG-GFR increased (92 ml/min/1.73 m2), whereas MDRD-GFR decreased (96 ml/min/1.73 m2). Weight (explicitly a factor in CG only) concurrently increased to 62.0 kg. GFR changes from weeks 36–96 (after weight stabilization) were similar across formulae. By 96 weeks, 56 patients developed severe GFR impairment (<30 ml/min/1.73 m2) using one or both formulae (both n=45, CG n=7, MDRD n=4) compared with only 24 by serum creatinine alone. Multivariate models identified different sets of predictors for each formula.

Conclusions

Although severe GFR impairments are similarly classified by different formulae, moderate impairments were more frequently identified using CG-GFR versus MDRD-GFR (with Black ethnicity correction factor 1.21), and creatinine alone had low sensitivity. Given overestimation in underweight patients and sensitivity to weight changes, this MDRD formula might not necessarily be superior for monitoring ART in African HIV-infected adults.
Determinants of Virological Failure after Successful Viral Load Suppression in First-Line Highly Active Antiretroviral Therapy
Authors: Geretti Anna M , Smith Colette , Haberl Annette , Garcia-Diaz Ana , Nebbia Gaia , Johnson Margaret , Phillips Andrew , Staszewski Schlomo
Published: April 2022

Background

We aimed to investigate the long-term virological outcomes of a cohort initially showing good responses to first-line highly active antiretroviral therapy (HAART) with no evidence of virological failure during the first year after achieving viral load (VL) undetectability (<50 copies/ml).

Methods

Virological failure was defined as a confirmed VL>400 copies/ml or a single VL>400 copies/ml followed by a treatment change or end of follow-up. Risk factors for low-level VL rebound (50–400 copies/ml) in the first year after achieving undetectability and for virological failure during subsequent follow-up were investigated by logistic and Poisson regression.

Results

In the first year after achieving VL undetectability, 354/1,386 (25.5%) patients experienced low-level VL rebound, the remaining patients maintained consistent undetectability. Low-level rebound occurred less commonly with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART than with other regimens ( P=0.01). Over median 2.2 (range 0.0–7.4) years of subsequent follow-up, 86 (6.2%) patients experienced virological failure, corresponding to 2.30 failures per 100 person-years (95% confidence interval [CI] 1.82–2.79). Independent predictors of virological failure included low-level rebound during the first year after achieving undetectability relative to consistent undetectability (rate ratio [RR] 2.18, 95% CI 1.15–4.10), female gender (RR 1.79, 95% CI 1.12–2.85) and receiving a ritonavir-boosted protease inhibitor (PI/r) relative to NNRTI-based HAART (RR 1.88, 95% CI 1.02–3.46).

Conclusions

Patients on first-line HAART who maintain consistent VL undetectability for 1 year have a low risk of subsequent virological failure. A subset might benefit from targeted interventions, including women and patients on PI/r-based HAART.
Efficacy and Safety of Adefovir Dipivoxil plus Pegylated Interferon-α2a for the Treatment of Lamivudine-Resistant Hepatitis B virus Infection in HIV-Infected Patients
Authors: Ingiliz Patrick , Valantin Marc-Antoine , Thibault Vincent , Duvivier Claudine , Dominguez Stephanie , Katlama Christine , Poynard Thierry , Benhamou Yves
Published: April 2022

Background

Up to 10% of the HIV-positive population is coinfected with hepatitis B virus (HBV). Generally, combined treatment includes agents against both viruses, such as lamivudine (3TC). However, HBV resistance to 3TC is high. Adefovir dipivoxil (ADV) has shown its efficacy for treating 3TC-resistant (3TC-R) HBV in HIV-coinfected patients. ADV combined with pegylated interferon (PEG-IFN) has never been evaluated in this population.

Methods

HIV-HBV-coinfected patients with positive HBV e antigen (HBeAg), documented 3TC-R HBV mutation and antiretroviral treatment including 3TC were selected and received ADV (10 mg daily) and PEG-IFN-α2a (180 μg weekly) for 48 weeks.

Results

Of 18 eligible patients ( n=16 [89%] male, mean ±sd age 40.45 ±4.82 years), 17 were treated for 48 weeks. One stopped IFN treatment because of adverse events and continued ADV only. The median (interquartile range) HBV DNA at baseline was 8.0 (5.30–8.97) log10 copies/ml and the median (95% confidence interval [CI]) decrease after 48 and 72 weeks was 3.6 (4.9–2.4) and 1.4 (-5.0–2.2) log10 copies/ ml, respectively. None of the patients became HBeAg-negative. Median (95% CI) decrease of serum alanine aminotransferase was 27.8 (-66.2–10.5) IU/ml after 48 weeks and 93.0 (-80.0–26.1) IU/ml after 72 weeks.

Conclusions

ADV and PEG-IFN is safe and effective for treating 3TC-R HBV in HIV patients. However, on-treatment response was not maintained off therapy and did not lead to HBV seroconversion. The combination had no effect on HIV disease progression.
Differences in Virological Response to Pegylated Interferon and Ribavirin between Hepatitis C Virus (Hcv)-Monoinfected and HCV–Hiv-Coinfected Patients
Authors: Tural Cristina , Galeras Josep Antón , Planas Ramon , Coll Susanna , Sirera Guillem , Giménez Dolors , Salas Anna , Rey-Joly Celestino , Cirera Isabel , Márquez Carmen , Tor Jordi , Videla Sebastià , García-Retortillo Montserrat , Clotet Bonaventura , Solà Ricard
Published: April 2022

Background

Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)–HIV-coinfected patients.

Methods

A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients ( n=104) were compared. All patients received PEG-IFN-α2a 180 μg/week plus ribavirin 800–1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000–1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12.

Results

The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV–HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR.

Conclusions

Differences in efficacy of PEG-IFN-α2a plus ribavirin treatment between HCV–HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.
Pharmacokinetics of Lopinavir in HIV Type-1-Infected Children Taking the New Tablet Formulation Once Daily
Authors: van der Flier Michiel , Verweel Gwenda , van der Knaap Linda C , van Jaarsveld Petronette , Driessen Gert-Jan , van der Lee Manon , Hartwig Nico G , Burger David M
Published: April 2022

Background

Recently, a new tablet formulation of the widely used HIV protease inhibitor lopinavir/ritonavir was licensed. Here, we present a pilot study of the pharmaco-kinetics of the new adult tablet formulation taken once daily in children.

Methods

Lopinavir pharmacokinetics of the new adult tablet formulation were evaluated in 15 HIV type-1-infected children between 4 and 15 years of age. A target dose of 460/115 mg/m2 was administered once daily. Plasma concentrations of lopinavir over the course of 24 h were determined with a validated HPLC method.

Results

The median lopinavir dose was 498 mg/m2 (range 424–548). The mean ±sd for lopinavir area under the 24 h curve was 217.9 ±44.9 mg/l•h, the maximum concentration was 14.8 ±2.4 mg/l and the concentration 24 h after intake was 3.1 ±2.6 mg/l. The half-life of lopinavir was 5.8 ±4.5 h and the median time to maximum concentration was 5.8 h (range 1.8-12.2). Overall, the tablet formulation resulted in greater exposure to lopinavir with less variability compared with the soft-gel capsule formulation. All children treated with the new adult tablet formulation had undetectable viral loads (<50 copies/ml) during 24 weeks follow-up.

Conclusions

The tablet formulation could probably result in improved lopinavir dosing and increases the feasibility of once-daily lopinavir/ritonavir-based regimens in children.
World Health Organization/HIVResNet Drug Resistance Laboratory Strategy
Authors: Bertagnolio Silvia , Derdelinckx Inge , Parker Monica , Fitzgibbon Joseph , Fleury Herve , Peeters Martin , Schuurman Rob , Pillay Deenan , Morris Lynn , Tanuri Amilcar , Gershy-Damet Guy-Michel , Nkengasong John , Gilks Charles F , Sutherland Donald , Sandstrom Paul
Published: April 2022

With rapidly increasing access to antiretroviral drugs globally, HIV drug resistance (HIVDR) has become a significant public health issue. This requires a coordinated and collaborative response from country level to international level to assess the extent of HIVDR and the establishment of efficient and evidence-based strategies to minimize its appearance and onward transmission. In parallel with the rollout of universal access to HIV treatment, countries are developing protocols based on the recommendations of the World Health Organization (WHO) to measure, at a population level, both transmitted HIVDR and HIVDR emerging during treatment. The WHO in collaboration with international experts (HIVResNet Laboratory Working Group), has developed a laboratory strategy, which has the overall goal of delivering quality-assured HIV genotypic results on specimens derived from the HIVDR surveys. The results will be used to help control the emergence and spread of drug resistance and to guide decision makers on antiretroviral therapy policy at national, regional and global level. The HIVDR Laboratory Strategy developed by the WHO includes several key aspects: the formation of a global network of national, regional and specialized laboratories accredited to perform HIVDR testing using a common set of WHO standard and performance indicators; recommendations of acceptable methods for collection, handling, shipment and storage of specimens in field conditions; and the provision of laboratory technical support, capacity building and quality assurance for network laboratories. The WHO/HIVResNet HIVDR Laboratory Network has been developed along the lines of other successful laboratory networks coordinated by the WHO. As of August 2007, assessment for accreditation has been conducted in 30 laboratories, covering the WHO‘s African, South-East Asia, Western Pacific, and the Caribbean Regions.
Consensus Drug Resistance Mutations for Epidemiological Surveillance: Basic Principles and Potential Controversies
Authors: Shafer Robert W , Rhee Soo-Yon , Bennett Diane E
Published: April 2022

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.
HIV drug resistance transmission threshold survey in Bangkok, Thailand
Authors: Sirivichayakul Sunee , Phanuphak Praphan , Pankam Tippawan , O-Charoen Rachanee , Sutherland Donald , Ruxrungtham Kiat
Published: April 2022

Background

Antiretroviral therapy (ART) began in Thailand in the Bangkok Metropolitan Area (BMA) in 1988 and scale-up began in 2001. The national first-line regimen is stavudine, lamivudine and nevirapine in fixed-dose combination, which is a regimen with a low genetic barrier for resistance. Because viral load and resistance testing are not widely available, unidentified HIV drug resistance (HIVDR) may occur during treatment and could be transmitted.

Methods

We undertook a threshold survey to assess HIVDR transmission in two subsets of recently infected individuals in the BMA. The first group consisted of returning blood donors tested at the Thai Red Cross National Blood Centre who seroconverted within the past 12 months. The second group comprised recently infected (as defined by BED assay) clients of the Thai Red Cross voluntary counselling and testing centre (VCT).

Results

Genotyping of 50 consecutive specimens each from blood donors and VCT clients during 2005–2006 showed no mutations associated with HIVDR in the reverse transcriptase or protease regions of the HIV pol gene. These results are categorized by the WHO HIV drug resistance threshold survey method as representing a low prevalence (<5%) of transmitted HIV drug resistance.

Conclusions

Every effort should be made to minimize the emergence of resistance in treated individuals and to prevent primary and secondary HIV transmission. To continue to monitor HIVDR transmission, Thailand has planned additional surveys – including longitudinal surveys – in these and additional groups of individuals.
On-Treatment Outcome Prediction and Adjustment during Chronic Hepatitis B Therapy: Now and Future
Authors: Liaw Yun-Fan
Published: April 2022

Studies published to date regarding on-treatment outcome prediction during chronic hepatitis B therapy were reviewed. Studies have shown that initial virological responses in terms of week 24 serum hepatitis B virus (HBV) DNA levels are associated with therapeutic outcomes of 1-year pegylated interferon-α and entecavir therapy, and weeks 52 or 104 of lamivudine and telbuvudine therapy. HBV DNA levels at week 48 are also associated with long-term adefovir therapy outcomes. Conceptual on-treatment adjustment and strategies have been proposed; however, this approach seems only necessary during therapy with nucleos(t)ide analogues with substantial risk of drug resistance. In addition, studies are needed to decide whether switching to or adding on a second drug, and with which drug, is the most cost-effective strategy.
Simplification Strategies to Reduce Antiretroviral drug Exposure: Progress and Prospects
Authors: McKinnon John E , Mellors John W , Swindells Susan
Published: April 2022

Current US guidelines for initial therapy of HIV type-1 (HIV-1) infection recommend daily, lifelong treatment with a combination of three antiretroviral drugs consisting of two nucleoside analogue reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. Although this approach has been successful in reducing morbidity and mortality from HIV-1 infection, concerns remain about adverse events from chronic drug exposure, the requirement for daily medication adherence, the risk of HIV-1 drug resistance and high treatment costs. The availability of antiretrovirals that are coformulated and dosed once daily have reduced pill burden and have simplified dosing schedules, but have not lowered drug exposure or cost. These limitations have stimulated research into drug-sparing strategies including intermittent therapy and simplified maintenance regimens. Randomized clinical trials have shown greater mortality with intermittent therapy compared with continuous therapy leading to rejection of this strategy. Pilot studies of simplified maintenance therapy with a ritonavir-boosted protease inhibitor alone have shown more promise, although concerns remain. This article reviews progress in the simplification of antiretroviral therapy, recent clinical trial results and prospects for the future.
A Phase I study to explore the activity and safety of SCH532706, a small molecule chemokine receptor-5 antagonist in HIV type-1-infected patients
Authors: Pett Sarah L , McCarthy Michael C , Cooper David A , MacRae Karen , Tendolkar Amol , Norris Richard , Strizki Julie M , Williams Kenneth M , Emery Sean
Published: April 2022

Background

SCH532706 is a novel small molecule chemokine receptor-5 (CCR5) antagonist with high in vitro potency (mean 90% inhibitory concentration [IC90] 0.15– 7.0 nM) against diverse HIV type-1 (HIV-1) isolates.

Methods

A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 10 days of SCH532706 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients.

Results

The study enrolled 12 males with CD4+ T-cell count >100 cells/μl. Median (range) CD4+ T-cell count was 327 cells/μl (117–1,008), HIV-1–RNA was 4.6 log10 copies/ml (3.8–5.5) and patients had phenotypically con-firmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1–RNA at days 10 and 15 (4 days off SCH532706) were -1.31 log10 copies/ ml (-1.6– -1.0) and -1.62 log10 copies/ml (-2.0– -1.3), respectively. Day 10 median (range) time to maximum plasma concentration, mean (±sd) effective half-life and mean (±sd) trough concentration were 1.4 h (1.0-4.0), 39.4 h (±14.5) and 178 ng/ml (±34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported ≥1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug.

Conclusions

Overall, SCH532706 with RTV was safe, generally well tolerated and active against HIV-1 over 10 days of dosing. In this setting, SCH532706 trough concentrations exceed the mean in vitro IC (1.1 ng/ml) by >30-fold (after correction for 80% plasma protein binding) and provide a PK rationale for the observed efficacy.
Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors
Authors: Tambuyzer Lotke , Azijn Hilde , Rimsky Laurence T , Vingerhoets Johan , Lecocq Pierre , Kraus Guenter , Picchio Gaston , de Béthune Marie-Pierre
Published: April 2022

Background

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of antiretroviral therapy for HIV type-1 (HIV-1)-infected patients. Development of NNRTI resistance can lead to treatment failure and is conferred by the presence of specific resistance-associated mutations (RAMs) in the reverse transcriptase. In addition to the widely used list of NNRTI RAMs provided by the International AIDS Society-USA HIV-1 Drug Resistance Mutation Group, which were identified on the basis of clinical experience with the approved NNRTIs, a more comprehensive list of NNRTI RAMs is needed to guide the study of baseline and emerging resistance to new NNRTIs.

Methods

We conducted an extensive review of the existing literature on NNRTI resistance, together with several in vitro and in vivo studies on the mechanism of HIV-1 resistance to approved NNRTIs and to NNRTIs formerly or currently in clinical development.

Results

In total, 44 NNRTI RAMs were identified. These included V90I, A98G, L100I, K101E/P/Q, K103H/N/S/T, V106A/I/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/ I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F. These NNRTI RAMs were observed, either alone or in combination with others, ranging in frequency from 0.02% to 56.96% in a panel of 101,679 NNRTI-resistant isolates submitted to Virco BVBA (Mechelen, Belgium) for routine clinical resistance testing. Phenotypical data from site-directed mutants helped to establish the contribution of each mutation to NNRTI resistance.

Conclusions

The list of 44 NNRTI RAMs compiled in this study provides a comprehensive overview of mutations that play a role in HIV-1 NNRTI resistance and can be used to guide further in vitro and in vivo research on the mechanisms of HIV-1 NNRTI resistance.
Advantages of predicted phenotypes and statistical learning models in inferring virological response to antiretroviral therapy from HIV genotype
Authors: Altmann André , Sing Tobias , Vermeiren Hans , Winters Bart , Craenenbroeck Elke Van , Van der Borght Koen , Rhee Soo-Yon , Shafer Robert W , Schülter Eugen , Kaiser Rolf , Peres Yardena , Sönnerborg Anders , Fessel W Jeffrey , Incardona Francesca , Zazzi Maurizio , Bacheler Lee , Vlijmen Herman Van , Lengauer Thomas
Published: April 2022

Background

Inferring response to antiretroviral therapy from the viral genotype alone is challenging. The utility of an intermediate step of predicting in vitro drug susceptibility is currently controversial. Here, we provide a retrospective comparison of approaches using either genotype or predicted phenotypes alone, or in combination.

Methods

Treatment change episodes were extracted from two large databases from the USA (Stanford-California) and Europe (EuResistDB) comprising data from 6,706 and 13,811 patients, respectively. Response to antiretroviral treatment was dichotomized according to two definitions. Using the viral sequence and the treatment regimen as input, three expert algorithms (ANRS, Rega and HIVdb) were used to generate genotype-based encodings and VircoTYPE™ 4.0 (Virco BVBA, Mechelen, Belgium) was used to generate a predicted phenotype-based encoding. Single drug classifications were combined into a treatment score via simple summation and statistical learning using random forests. Classification performance was studied on Stanford- California data using cross-validation and, in addition, on the independent EuResistDB data.

Results

In all experiments, predicted phenotype was among the most sensitive approaches. Combining single drug classifications by statistical learning was significantly superior to unweighted summation ( P<2.2x10-16). Classification performance could be increased further by combining predicted phenotypes and expert encodings but not by combinations of expert encodings alone. These results were confirmed on an independent test set comprising data solely from EuResistDB.

Conclusions

This study demonstrates consistent performance advantages in utilizing predicted phenotype in most scenarios over methods based on genotype alone in inferring virological response. Moreover, all approaches under study benefit significantly from statistical learning for merging single drug classifications into treatment scores.
Clinical usefulness of sequential hepatitis B virus DNA measurement (the roadmap concept) during adefovir treatment in lamivudine-resistant patients
Authors: Shin Jung Woo , Park Neung Hwa , Jung Seok Won , Park Bo Ryung , Kim Chang Jae , Jeong In Du , Bang Sung-Jo , Kim Do Ha
Published: April 2022

Background

Sequential on-treatment monitoring of hepatitis B virus (HBV) DNA levels, known as the roadmap concept, might predict the efficacy of oral therapy with nucleoside/nucleotide analogues among patients naive to this treatment. The goal of this study was to verify the usefulness of the roadmap concept to predict clinical outcomes of adefovir dipivoxil monotherapy in hepatitis B e antigen (HBeAg)-positive patients with lamivudine resistance.

Methods

In 231 patients, serum HBeAg, antibody against HBeAg and HBV DNA levels were measured at weeks 12, 24 and 48 of treatment and every 3 months thereafter.

Results

Complete (HBV DNA<60 IU/ml by PCR), partial (HBV DNA 60–<2,000 IU/ml) and inadequate (HBV DNA≥2,000 IU/ml) virological responses at week 24 were observed in 49 (21.2%), 66 (28.6%) and 116 (50.2%) lamivudine- resistant patients, respectively, who were treated with adefovir dipivoxil monotherapy. At final assessment, rates of complete virological response in these groups were 100%, 71.2%, and 22.4%. Of the total 42 virological breakthroughs, 33 (78.6%) and 8 (19.1%) developed in the inadequate and partial response groups, respectively. Among the 91 patients who had HBV DNA<200 IU/ml at week 48, complete virological response and HBeAg seroconversion were finally achieved in 87 (95.6%) and 39 (42.9%) patients, respectively. Of these 91 patients, virological breakthrough and genotype mutations developed in only 4 (4.4%) and 3 (3.3%) patients. The roadmap concept predicted virological response, HBeAg seroconversion and breakthrough (odds ratios 3.68, 9.67 and 0.15, respectively).

Conclusions

The roadmap concept is useful for choosing between continuation of adefovir dipivoxil monotherapy or early switching to another therapy, or to suggest additional therapy in patients showing lamivudine resistance.
Management of Hepatitis C virus Genotype 2 or 3 Infection: Treatment Optimization on the Basis of Virological Response
Authors: Zeuzem Stefan , Rizzetto Mario , Ferenci Peter , Shiffman Mitchell L
Published: April 2022

Current guidelines recommend a full 24-week regimen for all patients undergoing treatment for genotype 2 or 3 hepatitis C virus (HCV) infection. Recent data from two large randomized studies, one with pegylated interferon-α2a plus ribavirin (RBV) and one with pegylated interferon-α2b plus RBV assessed treatment duration and on-treatment predictors, such as rapid virological response (RVR; HCV RNA <50 IU/ml at week 4) or sustained virological response rates. Overall, these studies have shown that abbreviated regimens are generally less effective than standard 24-week regimens in genotype 2 or 3 patients because of a higher rate of relapse. However, abbreviated treatment might be offered to selected patients with an RVR provided that they have a low baseline viral load and minimal hepatic fibrosis.
Overestimation of liver fibrosis staging using transient elastography in patients with chronic hepatitis C and significant liver inflammation
Authors: Vispo Eugenia , Barreiro Pablo , del Valle José , Maida Ivana , de Ledinghen Victor , Quereda Carmen , Moreno Alberto , Macías Juan , Castera Laurent , Pineda Juan Antonio , Soriano Vincent
Published: April 2022

Background

Transient elastography (TE) is a non-invasive method that allows liver fibrosis staging on the basis of hepatic stiffness measurements. Little is known about the influence of chronic liver inflammation on the stiffness of hepatic tissue.

Methods

A total of 112 patients with chronic hepatitis C underwent a liver biopsy and TE.

Results

Mean values of liver stiffness (in kPa) by inflammation strata were 4.8, 6.4, 9.4 and 12.6 for A0, A1, A2 and A3, respectively, in hepatitis C virus (HCV)-monoinfected individuals ( P=0.018). These figures were 8.0, 10.4, 12.9 and 12.6 for A0, A1, A2 and A3, respectively, in HIV– HCV-coinfected patients ( P=0.35). In HCV-monoinfected patients with fibrosis staging F3-F4, mean liver stiffness was greater if inflammation was ≥A2 versus A0-A1 (14.6 versus 6.2 kPa; P=0.04). By contrast, no differences in liver stiffness according to inflammation were seen in HCV-monoinfected patients with 100 versus <100 IU/l (10.5 versus 8.5 kPa; P=0.04).

Conclusions

The extent of liver inflammation might affect the accuracy of TE for staging liver fibrosis, particularly in HCV-monoinfected patients with advanced fibrosis on liver biopsy and/or increased alanine aminotransferase levels.
Mitochondrial toxicity in HIV type-1-exposed pregnancies in the era of highly active antiretroviral therapy
Authors: Gingelmaier Andrea , Grubert Thomas A , Kost Bernd P , Setzer Bernhard , Lebrecht Dirk , Mylonas Ioannis , Mueller-Hoecker Josef , Jeschke Udo , Hiedl Stephan , Friese Klaus , Walker Ulrich A
Published: April 2022

Background

The aim of this study was to determine the effects of HIV type-1 (HIV-1) infection and antiretroviral therapy (ART) on placental mitochondria.

Methods

HIV-1-infected pregnant women and HIV-1 -uninfected controls were enrolled prospectively. Placental mitochondrial DNA (mtDNA) copy numbers were determined by quantitative PCR, subunits II and IV of cytochrome c oxidase (COX) were quantified by western blot and mitochondrial ultrastructure was evaluated by electron microscopy. Venous blood lactate was measured in newborns.

Results

In total, 45 HIV-1-infected pregnant women on ART and 32 controls were included. Mean ±sd mtDNA copy numbers were significantly reduced in ART and HIV-1-exposed placentas (240 ±118 copies/ cell) in comparison with controls (686 ±842 copies/cell; P<0.001). The mean COX II/IV ratio was 48% lower in the investigational group compared with controls ( P<0.001). There was no evidence of severe ultrastructural damage within mitochondria of HIV-1-infected ART-exposed placentas. Although lactate levels between newborns did not differ, they were negatively correlated with placental mtDNA levels. There was no clear association between mitochondrial parameters and a particular nucleoside reverse transcriptase inhibitor (NRTI), the number of NRTIs or time of NRTI exposure.

Conclusions

Placental tissue of HIV-1-infected ART-exposed pregnancies shows evidence of mtDNA depletion with secondary respiratory chain compromise. The clinical effects of this finding warrant further investigation.
Early initiation of highly active antiretroviral therapy fails to reverse immunovirological abnormalities in gut-associated lymphoid tissue induced by acute HIV infection
Authors: Tincati Camilla , Biasin Mara , Bandera Alessandra , Violin Michela , Marchetti Giulia , Piacentini Luca , Vago Gian Luca , Balotta Claudia , Moroni Mauro , Franzetti Fabio , Clerici Mario , Gori Andrea
Published: April 2022

Background

During the acute phase of HIV infection, large CD4+ T-cell depletion occurs in the gastrointestinal tract. The kinetics of CD4+ T-cell decrease and highly active antiretroviral therapy (HAART)-mediated immune reconstitution were evaluated.

Methods

Rectosigmoid colonic (RSC) biopsies and blood samples of nine patients with acute HIV infection were collected. CD4+ T-cell count, HIV RNA, intracellular HIV DNA and messenger RNA cytokine expression were evaluated before and after 6 months of HAART.

Results

All nine patients presented symptomatic retroviral infection. Early HAART was associated with a sustained and comparable reduction of HIV RNA in plasma, peripheral blood mononuclear cells (PBMCs) and RSC biopsies. HIV DNA decreased in PBMCs, but was only marginally reduced in RSC biopsies. Comparisons between reduction rates of HIV DNA in these two compartments confirmed that HIV DNA clearance was less efficient in RSC biopsies compared with PBMCs. Assessment of immunological profiles in PBMCs and RSC biopsies showed that the T-helper (Th)1-like/Th2-like ratio was sharply decreased in RSC biopsies and increased in PBMCs throughout the study period. A persistent Th2-like profile was detected in RSC biopsies. Efficient clearing of HIV DNA observed in PBMCs correlated with the establishment of a more favourable Th1-like profile.

Conclusions

A less efficient clearance of intracellular HIV DNA following early introduction of HAART is associated with persistent immunological impairment in gut-associated lymphoid tissue (GALT), which is refected by the skewed expression of cytokines in this reservoir. The present study shows that early initiation of HAART, in the short-term, is not effective in containing the establishment of HIV infection and in reversing associated immunological GALT abnormalities.