bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Dna Depletion and Respiratory Chain Enzyme Deficiencies are Present in Peripheral Blood Mononuclear Cells of HIV-Infected Patients with Haart-Related Lipodystrophy
Authors: Miró Òscar , López Sònia , Pedrol Enric , Rodríguez-Santiago Benjamín , Martínez Esteban , Soler Anna , Milinkovic Ana , Casademont Jordi , Nunes Virginia , Gatell Josep M , Cardellach Francesc
Published: April 2022

The main objective of the present study was to ascertain if mitochondrial DNA (mtDNA) depletion as reported in HIV-infected patients with highly active antiretroviral therapy (HAART)-related lipodystrophy (LD) implies any degree of mitochondrial respiratory chain (MRC) dysfunction. For this purpose, we evaluated HIV patients on different HAART schedules with LD (group A; n=12) and on HAART but without LD (group B; n=12), and untreated HIV-infected patients as controls (group C; n=24). mtDNA content was determined on peripheral blood mononuclear cells (PBMCs) with a real-time PCR method. Complex II, III and IV activities of the MRC were simultaneously measured spectrophotometrically, as were spontaneous and stimulated oxygen consumption by PBMCs. Compared to controls (group C, 100%), patients with LD (group A) showed a decreased mtDNA content (54%, P<0.001), which was associated with a decline in complex III (62%, P<0.05) and IV activity (69%, P<0.05) (both complexes partially encoded by mtDNA), but not in complex II activity (exclusively encoded by nuclear DNA). Patients in group B showed a similar pattern of mitochondrial dysfunction but to a lesser extent and without statistical significance. Respiratory activities in both treated groups (A and B) did not differ in comparison with controls. We conclude that mtDNA depletion occurring during HAART is associated with deficiencies in MRC complexes partially encoded by mtDNA, which are detectable by PBMCs. Presented in ‘Late Breakers and Hot Topics’ session at 6th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 17–21 November 2002.
Protection from HIV-1 Infection of Primary Cd4 T Cells by Ccr5 Silencing is Effective for the Full Spectrum of Ccr5 Expression
Authors: Butticaz Christophe , Ciuffi Angela , Muñoz Miguel , Thomas Jérôme , Bridge Alan , Pebernard Stephanie , Iggo Richard , Meylan Pascal , Telenti Amalio
Published: April 2022

Stable gene silencing by RNA interference (RNAi) can be achieved by expression of small hairpin RNAs (shRNAs) from RNA polymerase III promoters. We have tested lentiviral vectors expressing shRNAs targetting CCR5 in primary CD4 T cells from donors representing various CCR5 and CCR2 genetic backgrounds covering the full spectrum of CCR5 expression levels and permissiveness for HIV-1 infection. A linear decrease in CCR5 expression resulted in a logarithmic decrease in cellular infection, giving up to three logs protection from HIV-1 infection in vitro. Protection was maintained at very high multiplicity of infection. This and other recent reports on RNAi should open a debate about the use of RNAi gene therapy for HIV infection.
Total Lymphocyte Count as a Possible Surrogate of Cd4 Cell Count to Prioritize Eligibility for Antiretroviral Therapy among HIV-Infected Individuals in Resource-Limited Settings
Authors: Bedell Richard , Heath Katherine V , Hogg Robert S , Wood Evan , Press Natasha , Yip Benita , O'Shaughnessy Michael V , Montaner Julio SG
Published: April 2022

Objective

To characterize the value of total lymphocyte counts in predicting risk of death among patients initiating triple combination antiretroviral therapy.

Methods

Study subjects included antiretroviral-naive persons aged 18 years or older who initiated treatment with triple combination therapy between August 1 1996 and September 30 1999 in a population-based observational cohort of HIV-infected individuals. Total lymphocyte counts as well as CD4 count and plasma viral load were assessed at baseline. Separate Cox proportional hazards models were devised to evaluate the effect on survival of total lymphocyte count in lieu of or with CD4 count after adjustment for other prognostic factors including plasma viral load.

Results

A total of 733 antiretroviral-naive persons initiated triple drug combination antiretroviral therapy over the study period with a median follow-up of 29.5 months. In the first analysis, only baseline CD4 cell counts of 50–199 cells/μl or less than 50 μl were associated with an increased risk of mortality [adjusted relative risk (ARR) 2.90; 95% CI: 1.40, 5.98] and (ARR 6.30; 95% CI: 2.93, 13.54), respectively. When CD4 counts were excluded from the analysis as if unavailable, total lymphocyte count of between 0.8 and 1.4 G/l, and less than 0.8 G/l were both significantly associated with an increased risk of mortality (ARR 2.36; 95% CI: 1.16, 4.78) and (ARR 6.17; 95% CI: 2.93, 13.01), respectively.

Conclusion

Total lymphocyte count may provide a simple and cost-effective alternative for prioritizing therapy initiation in resource-limited settings. Our results suggest that, if appropriately validated, judicious application of total lymphocyte counts could overcome one of the practical obstacles to more widespread provision of antiretroviral therapy in resource-poor settings.
Medium-Term Survival, Morbidity and Immunovirological Evolution in HIV-Infected Adults Receiving Antiretroviral Therapy, Abidjan, Côte D'Ivoire
Authors: Seyler Catherine , Anglaret Xavier , Dakoury-Dogbo Nicole , Messou Eugène , Touré Siaka , Danel Christine , Diakité Nafissa , Daudié Alain , Inwoley André , Maurice Chantal , Tonwe-Gold Besigin , Rouet François , N'Dri-Yoman Thérèse , Salamon Roger ,   for the ANRS 1203 Study Group
Published: April 2022

Objectives

To evaluate survival, morbidity, and CD4 and viral load (VL) evolution in HIV-infected adults receiving antiretroviral therapy (ART) in Côte d'Ivoire.

Methods

Since 1996, 723 HIV-infected adults have been followed up in the ANRS 1203 cohort study in Abidjan. For those patients who received ART, we describe data between ART initiation and August 2002.

Results

One-hundred-and-one adults (61% women) were followed up under ART for a median of 17 months. At ART initiation, median age, CD4 count and VL were 36 years, 135/mm3 and 5.3 log10 copies/ml, respectively. Initial ART regimens were two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor in 74 patients, two NRTIs plus one non-nucleoside reverse transcriptase inhibitor in 16, and two NRTIs in 11. No patient was lost to follow-up. The most frequent causes of severe morbidity were bacterial infections [11.6/100 person-years (PY), 95% CI: 7.2–18.7], drug-related events (6.5/100 PY, 3.5–12.0), tuberculosis (3.1/100 PY, 1.3–7.4) and malaria (3.1/100 PY, 1.3–7.4). The incidence of death was 3.0/100 PY (1.1–8.0) in patients with baseline CD4 ≥50/mm3 and 16.1/100 PY (7.2–35.9) in patients with CD4 <50/mm3. Fifty percent of causes of death were active infections pre-existing ART initiation, mainly atypical mycobacteriosis. After 1 year, 51% of patients had undetectable VL, 28% had detectable VL reduced by more than 0.5 log10 copies/ml since ART initiation, and the median gain in CD4 was +115/mm3.

Conclusion

Medium-term survival under ART may be as good in Africa as in industrialized countries, provided that patients benefit from access to care for opportunistic infections, including bacterial diseases, tuberculosis and malaria.
Drug-Resistant HIV-1 in the Semen of Men Receiving Antiretroviral Therapy with Acute Sexually Transmitted Infections
Authors: Taylor Stephen , Sadiq S Tariq , Weller Ian , Kaye Steve , Workman Judith , Cane Patricia A , Bennett Julie , Copas Andrew J , Drake Susan M , Pillay Deenan
Published: April 2022

Sexually transmitted infections may enhance the sexual transmission of HIV-1. It is possible that loss of virological control in patients with such infections receiving antiretroviral therapy (ART) may even facilitate the transmission of drug-resistant HIV. We have recently demonstrated that in those on maximally suppressive ART this effect is reduced. We have examined the virus obtained from the blood plasma and seminal plasma of six HIV-1-infected men receiving poorly suppressive ART with acute urethritis for the presence of drug resistance-associated mutations. In four men with gonorrhoea the blood and seminal plasma HIV-1 had mutations conferring reduced susceptibility to one or more available drugs. In one of these men the viral load of drug-resistant virus in seminal plasma was 20fold higher during gonorrhoea than following antibiotic treatment, with no change in blood plasma viral load. We conclude that in the presence of suboptimal ART, sexually transmitted infections may enhance the spread of drug-resistant HIV-1.
Impact of Early versus Late Adherence to Highly Active Antiretroviral Therapy on Immuno-Virological Response: A 3-Year Follow-Up Study
Authors: Carrieri Maria Patrizia , Raffi François , Lewden Charlotte , Sobel Alain , Michelet Christian , Cailleton Valérie , Chêne Geneviève , Leport Catherine , Moatti Jean-Paul , Spire Bruno ,   the APROCO study group,   Scientific Committee, Leport C , Raffi F , Chêne G , Salamon R , Moatti J-P , Pierret J , Brun-Vézinet F , Fleury H , Peytavin G , Garraffo R ,   Other members, Costagliola D , Dellamonica P , Katlama C , Meyer L , Morin M , Sicard D , Sobel A , Ballereau F ,   Observers, Bach M-A , Bourdillon F , Choutet P , Delfraissy J-F , Dormont J , Souteyrand Y , Vildé J-L ,   Events Validation Committee, Dupon M , Le Moing V , Marchou B , May T , Morlat P , Waldner-Combernoux A ,   Monitoring and statistical analysis, Alfaro C , Boucherit S , Cailleton V , Charlois C , Droz C , Duran S , Ecobichon JL , Egouy C , Journot V , Lassalle R , Latour L , Le Moing V , Lewden C , Masquelier B , Nouioua W , Palmer G , Petit C , Préau M , Roloff S , Savès M , Spire B , Winum R ,   Sponsorship,   Other supports,   Scientific Committee,   Clinical centres (coordinators)
Published: April 2022

Objective

To assess the impact of different patterns of adherence to highly active antiretroviral therapy (HAART), in particular, the relative impact of early and late adherence, on long-term immuno-virological response in HIV-infected individuals started on a protease inhibitor-containing regimen.

Design

Clinical, immuno-virological and self-reported adherence data were collected at 4 (M4), 12 (M12), 20 (M20), 28 (M28) and 36 (M36) months after HAART initiation in the French APROCO cohort.

Methods

A standardized self-administered questionnaire classified patients as non-adherent, moderately or highly adherent at each visit. Stable viral suppression at both M28 to M36, and a CD4 cell increase >200 between M0 and M36 were used as outcome measures.

Results

Of the 582 patients followed regularly through M36, 360 patients had complete adherence data. Although 59.2% were highly adherent at M4, only 25.8% maintained consistent high adherence throughout the follow-up. High adherence at M4 was independently associated with both stable viral suppression at M28–M36 [OR (95% CI): 2.8 (1.4–5.5)] and a CD4 cell increase >200 during the same period [OR (95% CI): 3.9 (1.7–9.7)]. However, ‘moderately adherent’ patients between M12 and M36 had the same likelihood [OR (95% CI): 1.9 (1.1–3.2)] as patients who were always high adherent [OR (95% CI): 1.9 (1.1–3.2)] of achieving stable viral load suppression, relative to those who reported non-adherence episodes.

Conclusion

Optimizing adherence in the early months of treatment is crucial to ensure long-term immuno-virological success. Moderate deviations from high adherence during follow-up have a less negative impact. Priority should be given to interventions aimed to improve adherence in the early months of HAART.
Antiviral Efficacy of Abacavir in Antiretroviral Therapy-Experienced Adults Harbouring HIV-1 with Specific Patterns of Resistance to Nucleoside Reverse Transcriptase Inhibitors
Authors: Lanier E Randall , Ait-Khaled Mounir , Scott Janna , Stone Chris , Melby Thomas , Sturge Glenn , Clair Marty St , Steel Helen , Hetherington Seth , Pearce Gillian , Spreen William , Lafon Stephen
Published: April 2022

Objective

To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy.

Design

The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults.

Methods

Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed.

Results

Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1–2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with ≥3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus ( P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), ≥4 mutations were required to diminish virological response significantly ( P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense™ HIV assay and the Antivirogram™ assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/μl by weeks 12-28.

Conclusions

Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.
High Rate of Didanosine-Related Mitochondrial Toxicity in HIV/HCV-Coinfected Patients Receiving Ribavirin
Authors: Moreno Ana , Quereda Carmen , Moreno Leonor , Perez-Elías María J , Muriel Alfonso , Casado Jose L , Antela Antonio , Dronda Fernando , Navas Enrique , Bárcena Rafael , Moreno Santiago
Published: April 2022

Background

Nucleoside analogues may induce mitochondrial toxicity, particularly didanosine. Ribavirin increases didanosine exposure, which might be clinically relevant when coadministered in HIV/HCV-coinfected patients.

Objective

To evaluate, among 89 patients receiving highly active antiretroviral therapy (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial toxicity in those treated with concomitant ribavirin and didanosine ( n=35, 39%).

Methods

From January 2000 to July 2002 longitudinal analysis of the incidence and clinical course of didanosine-related hyperamylasaemia, pancreatitis, hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using univariate and multivariate Cox's proportional hazards model.

Results

Among 35 patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (≥10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18 patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients, respectively. Two patients (6%) with pancreatitis and severe lactic acidosis died; the other patients recovered uneventfully despite continuation of anti-HCV therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher baseline amylase levels (HR: 1.04, 95% CI: 1.02–1.06, P=0.001) and three nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73–16.24, P=0.003) were significantly associated to toxicity.

Conclusions

The coadministration of didanosine and ribavirin should be avoided in HIV/HCV-coinfected patients, due to a high rate of clinically significant toxicity, particularly in triple nucleoside-based HAART. Amylase levels should be strictly monitored, especially if elevated at baseline.
Enhanced T-Cell Maturation, Differentiation and Function in HIV-1-Infected Individuals after Growth Hormone and Highly Active Antiretroviral Therapy
Authors: Pires Antonio , Pido-Lopez Jeffrey , Moyle Graeme , Gazzard Brian , Gotch Frances , Imami Nesrina
Published: April 2022

Background

Strong virus-specific helper and cytotoxic T-cell responses correlate with non-progression during HIV-1 infection. Administration of antiretroviral therapy (ART) during the chronic phases of HIV-1 infection fails to restore these responses in most patients.

Design and methods

We assessed the changes in immune function of 12 HIV-1-positive individuals treated with ART for over 4 years, who received 4 mg/day of recombinant human growth hormone (rhGH) for 12 weeks and were then randomized into groups receiving either placebo, twice weekly or alternate day dosing of rhGH. Peripheral blood was drawn for phenotypic analysis and functional assays at time points 0, 12 and 24 weeks.

Results

At week 12, we observed significant increases in naive CD4 T cells ( P<0.01) and effector CD8 T cells based on CD45RA and CCR7 expression ( P<0.02). In addition, we observed a rise in HIV-1 antigen-specific CD4 ( P<0.005) and CD8 ( P<0.05) T-cell responses. Twelve weeks post-randomization into placebo, alternate day or twice weekly dosing (24 weeks post-baseline), the phenotype and function of the virus-specific effector CD8 T cells seen at week 12 was maintained in most patients regardless of randomization arm and despite the disappearance of HIV-1-specific CD4 T-cell responses.

Conclusions

Concomitant administration of rhGH at 4 mg/day with highly active ART appears to partially reverse some of the defects exerted on the immune system by HIV-1. This combination may represent a valuable immunotherapeutic intervention aiding in the treatment of chronic HIV-1 infection.
Antiretroviral Drug Resistance in Non-Subtype B HIV-1, HIV-2 and Siv
Authors: Parkin Neil T , Schapiro Jonathan M
Published: April 2022

Patients infected with HIV-1 of subtype other than B (‘non-subtype B’) or with HIV-2 are being treated with antiretroviral drugs in increasing numbers. In addition, healthcare providers and laboratory workers working with clinical specimens or animals infected with HIV, SIV or SHIV are at risk of being exposed to the virus and might require post-exposure prophylactic treatment. Thus, it is important to understand the inherent antiviral susceptibility of non-subtype B HIV-1, HIV-2 and SIV to currently available antiretroviral drugs, which have been developed with subtype B HIV-1-infected patients as the primary target population. In addition, knowledge about the consequences of treatment failure in non-subtype B HIV-1- and HIV-2-infected patients, with respect to the development of drug resistance, is crucial for designing optimal treatment strategies. This review summarizes the current state of knowledge in these areas. Non-subtype B group M HIV-1 appears to be susceptible to available agents, but follows several unique pathways to resistance to some drugs that have important clinical implications. Group O HIV-1 is naturally resistant to the non-nucleoside reverse transcriptase inhibitors (NNRTIs). HIV-2 and SIVsm are also naturally resistant to the NNRTIs as well as the protease inhibitor amprenavir. More research into the clinical responses to existing drugs and interpretation of genotypic information is needed, as well as development of diagnostic assays specific for non-subtype B HIV-1 and HIV-2.
Strategies to Decrease Viral Load Rebound, and Prevent Loss of Cd4 and Onset of Resistance during Structured Treatment Interruptions
Authors: Foli Andrea , Maserati Renato , Barasolo Gabriele , Castelli Francesco , Tomasoni Lina , Migliorino Marco , Maggiolo Franco , Pan Angelo , Paolucci Stefania , Scudeller Luigia , Tinelli Carmine , D'Aquila Richard , Lisziewicz Julianna , Lori Franco
Published: April 2022

Background

Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured treatment interruptions (STIs) may limit VL rebound, maintain CD4 counts and minimize resistance.

Methods

We conducted a clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic HIV infection (CD4 >300, VL >10000) randomized to receive didanosine-stavudine-indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12 weeks. Subsequently, all patients were randomized again to start STI (short induction) or to continue the therapy for an additional 24 weeks before starting STI (long induction). Both groups underwent four STI cycles and then stopped therapy as long as viraemia remained below 10000 copies/ml before reinitiating another four cycles of STI.

Results

During continuous therapy VLs were suppressed at similar rates in both the HU and IDV groups, while a blunted CD4 count was documented in the HU group. Following the first stop median VL rebounded close to baseline values in both groups, however, during the following STI median VL rebound decreased in the HU group, while in the IDV group VL continued to rebound to values close to baseline, and the difference between the two groups was statistically significant. Moreover, patients treated with HU had a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in the IDV group, with sharp falls during treatment interruptions and partial CD4 recovery following treatment restart. Even in the presence of IDV resistance predisposing mutations at baseline, no genotypic change in the protease sequence was observed during STI. A relevant mutation in the reverse transcriptase sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of continuous therapy and in one patient after four STI cycles. Side effects (no major events) were similar among groups.

Conclusions

An appropriate choice of STI schedule and regimens containing drugs less prone to resistance and/or able to prevent CD4 fluctuation may contribute to optimizing STI for chronically infected patients with respect to limiting viral rebound, improving CD4 counts and maintaining a resistance profile comparable to continuous highly active antiretroviral therapy.
Comparisons of the Hbv and HIV Polymerase, and Antiviral Resistance Mutations
Authors: Bartholomeusz Angeline , Tehan Benjamin G , Chalmers David K
Published: April 2022

The antiviral treatment of chronic hepatitis B is limited by the selection of antiviral resistance mutations. Primary resistance to lamivudine occurs at rtM204I/V in the C Domain of the polymerase. Recently, resistance to adefovir has also been described in the D Domain at rtN236T. The treatment of patients with resistant virus without complete suppression can lead to the further selection of compensatory mutations. Thus, to gain an understanding of the hepatitis B virus (HBV) polymerase and also mutations associated with resistance, a three-dimensional model of the HBV reverse transcriptase core region based on homology with human immunodeficiency virus (HIV) was created. A comparative analysis of the HIV polymerase and the model of HBV polymerase was performed. In addition, the antiviral resistance mutations including potential compensatory mutations were mapped to determine their effect on the HBV polymerase model, especially in the nucleotide binding site.
Asymptomatic Hyperlactataemia: Predictive Value, Natural History and Correlates
Authors: McComsey Grace A , Yau Linda
Published: April 2022

Background

The significance of asymptomatic hyperlactataemia is unknown.

Methods

We measured serial lactate levels in a group of HIV-infected subjects. Objectives were to identify covariates associated with hyperlactataemia, and to explore the natural history of hyperlactataemia.

Results

Overall, 1487 lactate measurements were performed on 396 subjects; 299 subjects had serial lactate testing, with a median of four performed per patient (range: 2–16). At study entry, lactate was >2.4 mmol/l in 6% of subjects and >3.6 mmol/l in 1%. A multiple logistic regression analysis revealed that cholesterol and current stavudine were the only predictors of hyperlactataemia. Lactate levels were highly reproducible both for short-term (within 3 months) and long-term (>1 year) follow-up. During the study period, 16 subjects were identified with sustained hyperlactataemia; 12/16 remained asymptomatic after a median of 210 days (30–585), and four developed symptoms suggestive of lactic acidosis syndrome. In three of the four, asymptomatic hyperlactataemia had preceded the onset of symptoms by 18–122 days. A longitudinal model showed a rapid rise of lactate levels from 0 to 12 months on nucleoside reverse transcriptase inhibitor (NRTI) and then stabilization. Lactate levels did not correlate with baseline or on-study development of lipoatrophy.

Conclusions

Even when optimal methods of collection are used, asymptomatic hyperlactataemia does exist and could be sustained in a subset of NRTI-treated subjects for as long as 585 days. A subset of these subjects became symptomatic, after as long as 122 days of asymptomatic hyperlactataemia. Asymptomatic hyperlactataemia is not predictive of lipoatrophy. This work was partly presented at the 9th Conference on Retroviruses & Opportunistic Infections. Seattle, Wash., USA, February 2002.
Influence of Mother and Infant Zidovudine Treatment Duration on the Age at Which HIV Infection Can be Detected by Polymerase Chain Reaction in Infants
Authors: Prasitwattanaseree Sukon , Lallemant Marc , Costagliola Dominique , Jourdain Gonzague , Mary Jean-Yves
Published: April 2022

Objective

To investigate the influence of zidovudine (ZDV) prophylaxis duration in mothers and infants on the age at which infection becomes detectable by DNA polymerase chain reaction (PCR) in non-breastfed infants.

Methods

Blood samples were collected sequentially from birth to 6 months in a Thailand perinatal HIV prevention trial in which 98 transmissions occurred. The proportions of infections detectable at birth and the Turnbull distributions of age at which infection became detectable after birth were compared according to actual ZDV treatment duration (mothers: no more than 7.5 weeks versus more; infants: 3 days versus at least 4 weeks), provided an adherence greater than 75%.

Results

Detectable infection at birth was less frequent in children whose mothers received a long treatment as compared to a short treatment (27 vs 50%, P=0.04). When mothers received a long treatment, infant ZDV treatment duration did not influence the distribution of age at which infection became detectable after birth (median 24 days). However, when mothers received a short treatment, this distribution was shifted to the right when infants received a long treatment (median 43 days, P<0.0001), and to the left when infants received a short treatment (median 11 days, P<0.0001).

Conclusions

When mothers receive a short treatment, the proportion of infections detectable at birth is higher and the time at which infection becomes detectable after birth depends on the infant treatment duration. In the study conditions, a PCR result after 2 months could be used to define infection status.
In Vitro Susceptibility of Lamivudine-Resistant Hepatitis B Virus to Adefovir and Tenofovir
Authors: Lada Olivier , Benhamou Yves , Cahour Annie , Katlama Christine , Poynard Thierry , Thibault Vincent
Published: April 2022

Emergence of lamivudine-resistant hepatitis B virus (HBV) is a major concern in human immunodeficiency virus (HIV) and HBV coinfected patients. Following selection of resistant mutants, hepatitis flare or rapid progression to cirrhosis may occur. Treatment of patients with new nucleotide analogues such as adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF) has shown good efficacy in controlling wild-type or lamivudine-resistant HBV replication. The purpose of this study was to assess the in vitro efficacy of new nucleotide analogues on HBV strains isolated from lamivudine-treated patients.

After purification of HBV DNA from patient sera, the whole HBV genome was PCR-amplified and cloned. Drug sensitivity was measured after transfection of the isolated full genomes into HepG2 cells and measurement of HBeAg, HBsAg and viral replication in the culture media under increasing drug concentrations. A wild-type strain isolated from an untreated patient served as control. In a clinical study of ADV (Gilead 460i study), seven of the 35 patients carried HBV strains with the triple lamivudine resistance-associated amino-acid changes rtV173L/L180M/M204V at baseline. Although all patients responded to ADV in this clinical study, the serum HBV reduction was lower in the seven patients with the triple mutation (median –3.3 log copies/ml) compared to the patients who had only the rtL180M/M204V mutations (median –4.1 log copies/ml) at week 48 ( P=0.04, Mann-Whitney test).

In our in vitro system, lamivudine IC50 on lamivudine-resistant HBV carrying amino-acid substitutions rtL180M and rtM204V within the polymerase encoding region increased by more than 16000-fold (from 6 nM to over 100 μM) when compared to wild-type HBV. For ADV and TDF, comparison of wild-type and lamivudine-resistant HBV IC50 (rtL180M-M204V) showed, respectively, 2.85fold (from 0.07 to 0.2 μM) and 3.3-fold (from 0.06 to 0.2 μM) increases, indicating a mild decrease of both drug activities, in vitro. At the ADV concentration of 0.1 μM, presence of the V173L mutation reduced the inhibition of HBsAg production from 50 to 30% ( P<0.01) and the viral replication from 45 to 32% ( P<0.01, Mann-Whitney). Conversely, tenofovir had similar potency on both HBV mutation profiles with 60% inhibition of HBsAg production and 45% inhibition of viral replication at 0.1 μM.

Our study supports the high efficacy of ADV and TDF seen in patients after lamivudine breakthrough. The excellent activity of TDF on lamivudine-resistant virus independently of the resistance mutation profile offers an interesting treatment alternative to HIV–HBV coinfected patients.
Psychosocial Determinants of Adherence to Highly Active Antiretroviral Therapy among Injection Drug Users in Vancouver
Authors: Kerr Thomas , Palepu Anita , Barnes Gordon , Walsh John , Hogg Robert , Montaner Julio , Tyndall Mark , Wood Evan
Published: April 2022

Background

Sub-optimal adherence to highly active antiretroviral therapy (HAART) among injection drug users (IDUs) is a significant concern. As such, there is an urgent need to identify psychosocial determinants of adherence that can be incorporated into interventions designed to promote optimal adherence.

Objective

To identify psychosocial determinants of adherence to HAART, as well as self-reported reasons for missing doses of HAART among HIV-infected IDUs.

Methods

We developed an eight-item adherence self-efficacy scale comprised of two sub-scales: adherence efficacy and self-regulatory efficacy. We examined correlates between adherence self-efficacy, outcome expectations, socio-demographic characteristics, drug use and risk behaviours, social support and HAART adherence among 108 HIV-infected participants in the Vancouver Injection Drug Users Study (VIDUS). Pharmacy-based adherence to HAART was obtained through a confidential record linkage to the province of British Columbia's HIV/AIDS Drug Treatment Program. Participants were defined as adherent if they picked-up 95% of their HAART prescriptions. Participants were also asked to indicate reasons for missing doses of HAART. Logistic regression was used to identify the factors independently associated with adherence to HAART.

Results

Seventy-one (66%) HIV-infected IDUs were less than 95% adherent. Forgetting was the most frequently cited reason (27%) for missing doses of HAART. Factors independently associated with adherence to HAART included adherence efficacy expectations [OR=1.8 (95% CI: 1.0–3.1); P=0.039] and negative outcome expectations [OR=0.8 (95% CI: 0.7–0.9); P=0.027].

Conclusions

We found low rates of adherence to HAART among IDUs. Psychological constructs derived from self-efficacy theory are highly germane to the understanding of adherence behaviour, and interventions that address these constructs should be developed and tested among HIV-infected drug users.
HIV Drug Resistance Testing: Is the Evidence Really There?
Authors: Dunn David T , Gibb Diana M , Babiker Abdel G , Green Hannah , Darbyshire Janet H , Weller Ian VD
Published: April 2022

Objectives

To assess the strength of evidence supporting the routine use of HIV drug resistance testing.

Design

A critical review of all studies relating to the clinical utility of HIV resistance testing, with a focus on randomized trials.

Results

Two cohort studies found no evidence of a difference in virological response in patients who had resistance testing compared with matched controls. We identified nine published randomized trials that were specifically designed to assess the clinical utility of drug resistance testing. In a meta-analysis of these trials, resistance testing increased the proportion of patients who achieved undetectable viral load by an average of 7% (95% confidence interval: 3–11%). However, this may be an over-estimate of the impact of resistance testing in clinical practice because of the idealized design and analytical approaches used in most of the studies.

Conclusions

The available evidence does not clearly demonstrate that HIV drug resistance testing is clinically effective. To optimize their value for health decision-making, future trials of HIV resistance testing should be carefully designed to mimic the circumstances of routine clinical practice.
Current Patterns in the Epidemiology of Primary HIV Drug Resistance in North America and Europe
Authors: Pillay Deenan
Published: April 2022

Despite numerous studies in recent years, it is still difficult to draw general conclusions about the extent to which drug-resistant HIV-1 is transmitted. In addition to the highly stratified nature of primary resistance itself, true epidemiological surveillance has been rare and studies to date have suffered from wide variability in their designs, definitions and datasets. In the absence of consensus standards, this has resulted in a large number of isolated ‘snapshots’ with little scope for data-pooling and comparison.

This brief review examines some of the major confounding factors that restrict the utility of individual studies and prevent the combination of studies to increase statistical power. Despite these limitations, data from North America and Europe lead to the tentative conclusion that transmission rates in these areas have generally fallen or remained stable in the past 2–3 years. However, data for the UK seem to indicate an ongoing rise in the transmission of drug resistance mutations, currently present in up to 20% of new infections.

Transmission of resistant HIV represents a clinically important phenomenon, although the scale and relevance are being obscured by methodological variations and non-clinical definitions of resistance. Those of us with an interest in the epidemiology of drug resistance, whether in primary transmission or on-treatment, must learn to speak the same language if we are to establish meaningful correlations between survey datasets and the HIV-infected population as a whole.
Comparison of Dual-Energy X-Ray Absorptiometry Machines for Measuring Fat Distribution Changes of HIV-Associated Lipodystrophy
Authors: Yang Yong , Zhu WD Jason , Paton Nicholas I
Published: April 2022

Background

Dual-energy X-ray absorptiometry (DXA) is regarded as a useful objective method for diagnosis of HIV-associated lipodystrophy (LD).

Objective

To determine whether the use of different DXA machines may affect the diagnosis of LD.

Methods

Body composition in 24 HIV-infected patients, 12 of whom had clinically diagnosed LD, was measured on two DXA machines (Lunar and Hologic).

Results

Hologic gave significantly higher values than Lunar DXA for total body fat percent (22.9 vs 20.5%, P<0.001), arm fat percent (27.9 vs 14.5%, P<0.001) and leg fat percent (23.4 vs 17.5%, P<0.001), and significantly lower values than Lunar for trunk fat percent (22.3 vs 24.7%, P<0.001) and trunk-to-limb fat percent ratio (0.89 vs 1.62, P<0.001). When measured by Lunar, patients with LD had significantly lower leg fat percent (13.5 vs 21.6%, P=0.04) and higher trunk-to-limb fat percent ratio (1.85 vs 1.38; P=0.012) than those without LD. When measured by Hologic, patients with LD had values of leg fat percent (20.1 vs 26.8%, P=0.11) and trunk-to-limb fat percent ratio (0.95 vs 0.85, P=0.43) that did not differ significantly from those without LD. There was a significant difference in the contribution to a composite LD score between Lunar and Hologic measurements.

Conclusion

DXA machines from different manufacturers give major differences in measurements of body fat content and distribution, and this may affect the ability to distinguish patients with LD from those without LD. Further standardization of DXA technology is needed before widespread application in the clinical diagnosis of LD.
Pkr Gene Expression and Response to Pegylated Interferon plus Ribavirin Therapy in Chronic Hepatitis C
Authors: Gerotto Martina , Pero Francesca Dal , Bortoletto Gladis , Realdon Stefano , Ferrari Alessia , Boccato Silvia , Alberti Alfredo
Published: April 2022

Pegylated interferon (PEG-IFN) alpha combined with ribavirin is the current standard treatment for hepatitis C, but around 50% of patients do not respond for reasons that are not fully understood. To explore the regulation of IFN-inducible protein kinase (PKR), we have measured PKR mRNA levels in peripheral blood mononuclear cells (PBMCs) and in liver biopsies from patients with chronic hepatitis C. PBMCs were also analysed after in vitro incubation with IFN and during antiviral therapy. Non-responders to PEG-IFN plus ribavirin had pre-treatment PKR mRNA levels in PBMCs (0.1 ±0.0074) and in liver (0.102 ±0.051) that were significantly higher than those of responders (PBMCs: 0.023 ±0.014, P=0.0005; liver: 0.034 ±0.020; P=0.0002). On the other hand, PKR mRNA levels in PBMCs were similar in non-responders and in responders after in vitro exposure to IFN (0.434 ±0.301 vs 0.403 ±0.222; P=NS) and during therapy (0.31 ±0.10 vs 0.30 ±0.12; P=NS). These results indicate that in hepatitis C, non–responsiveness to IFN-alpha is associated with pre-treatment up-regulation of the PKR gene, evidence that the infecting hepatitis C virus is able to stimulate endogenous IFN production, being resistant to its antiviral effect. On the other hand, the PKR gene response to exogenous IFN was similar in responders and non-responders, at least in PBMCs, suggesting that variations in its activation are not major determinants of the outcome of antiviral treatment.
Partial Splenic Embolization for the Treatment of Hypersplenism in Cirrhotic HIV/HCV Patients Prior to Pegylated Interferon and Ribavirin
Authors: Moreno Ana , Bárcena Rafael , Blázquez Javier , Quereda Carmen , Gil-Grande Luis , Sánchez Juan , Moreno Leonor , Perez-Elías María J , Antela Antonio , Moreno Javier , del Campo Santos , Moreno Santiago
Published: April 2022

Partial splenic embolization (PSE), a non-surgical treatment for hypersplenism, has also been reported to improve hepatic function. As severe thrombocytopaenia or leukopaenia contraindicate the use of combined therapy with pegylated interferons (PEG-IFNs) and ribavirin (RBV) in HCV-related cirrhosis, we evaluated, from July 2002 to October 2003, the safety and effectiveness of PSE as a procedure to allow therapy for HCV in three Child-Pugh class B cirrhotic patients with hypersplenism and HIV co-infection. HCV genotypes were 1b ( n=2) and 3a ( n=1). Severe thrombocytopaenia (in all) and leukopaenia (in two) precluded therapy for HCV. PSE was successfully performed in all with a mean infarcted area of 80%, leading to a significant increase in platelet and leukocyte counts that allowed therapy with weight-adjusted RBV and PEG-IFN-α-2b (patients 1 and 3) or 180 μg of PEG-IFN-α-2a (patient 2) 8 weeks after the procedure. Moderate pain, well controlled with conservative measures, followed PSE in 100% of cases, but during follow-up (mean 422 days) there were no infectious complications or liver decompensation episodes. Although preliminary, these results suggest the potential role of PSE in HIV/HCV-cirrhotic subjects with hypersplenism as a procedure to allow the use of combined PEG-IFN and RBV.
Tubular Cell Apoptosis and Cidofovir-Induced Acute Renal Failure
Authors: Ortiz Alberto , Justo Pilar , Sanz Ana , Melero Rosa , Caramelo Carlos , Guerrero Manuel Fernández , Strutz Frank , Müller Gerhard , Barat Antonio , Egido Jesús
Published: April 2022

Cidofovir is an antiviral drug with activity against a wide array of DNA viruses including poxvirus. The therapeutic use of cidofovir is marred by a dose-limiting side effect, nephrotoxicity, leading to proximal tubular cell injury and acute renal failure. Treatment with cidofovir requires the routine use of prophylactic measures. A correct knowledge of the cellular and molecular mechanisms of cidofovir toxicity may lead to the development of alternative prophylactic strategies.

We recently cared for a patient with irreversible acute renal failure due to cidofovir. Renal biopsy showed tubular cell apoptosis. Cidofovir induced apoptosis in primary cultures of human proximal tubular cells in a temporal (peak apoptosis at 7 days) and concentration (10–40 μg/ml) pattern consistent with that of clinical toxicity. Apoptosis was identified by the presence of hypodiploid cells, by the exposure of annexin V binding sites and by morphological features and was associated with the appearance of active caspase-3 fragments. Cell death was specific as it was also present in a human proximal tubular epithelial cell line (HK-2), but not in a human kidney fibroblast cell line, and was prevented by probenecid. An inhibitor of caspase-3 (DEVD) prevented cidofovir apoptosis. The survival factors present in serum, insulin-like growth factor-1 and hepatocyte growth factor, were also protective.

The present data suggest that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity. The prophylactic administration of factors with survival activity for tubular epithelium should be further explored in cidofovir renal injury.
Nevirapine and Efavirenz Pharmacokinetics and Covariate Analysis in the 2Nn Study
Authors:   for the 2NN study group, Kappelhoff Bregt S , van Leth Frank , MacGregor Thomas R , Lange Joep MA , Beijnen Jos H , Huitema Alwin DR
Published: April 2022

Objective

The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz.

Methods

Treatment-naive, HIV-1-infected patients received nevirapine (once or twice daily), efavirenz or a combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Using non-linear mixed effects modelling, pharmacokinetics of nevirapine and efavirenz and factors involved in the inter-individual variability were investigated.

Results

Clearance of nevirapine in the induction phase (<14 days) and at steady state (>28 days) were 2.02 l/h and 2.81 l/h, respectively. Volume of distribution and absorption rate constant were 77.0 l and 1.66 h-1, respectively. Clearance of nevirapine was lower in females (13.8%) and in patients with hepatitis B (19.5%). Patients from South America and Western countries had higher clearance of nevirapine compared with Thai and South African patients. The clearances of efavirenz in the induction phase and at steady state were 7.95 l/h and 8.82 l/h, respectively. The volume of distribution and absorption rate constant were 418 l and 0.287 h-1, respectively. Concomitant use of nevirapine increased clearance of efavirenz (43%). Patients from Thailand had lower clearance than the rest of the population.

Conclusions

The population pharmacokinetics of nevirapine and efavirenz were assessed in the 2NN trial. For both drugs, an induction phase was distinguished from the steady-state phase. Gender, hepatitis B and geographical region were involved in the variability of the pharmacokinetics of nevirapine. Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz.
Prediction of HIV-1 Protease Inhibitor Resistance using a Protein–Inhibitor Flexible Docking Approach
Authors: Jenwitheesuk Ekachai , Samudrala Ram
Published: April 2022

Emergence of drug resistance remains one of the most challenging issues in the treatment of HIV-1 infection. Here we focus on resistance to HIV-1 protease inhibitors (PIs) at a molecular level, which can be analysed genotypically or phenotypically. Genotypic assays are based on the analysis of mutations associated with reduced drug susceptibility, but are problematic because of the numerous mutations and mutational patterns that confer drug resistance. Phenotypic resistance or susceptibility can be experimentally evaluated by measuring the amount of free drug bound to HIV-1 protease molecules, but this procedure is expensive and time-consuming. To overcome these problems, we have developed a docking protocol that takes protein–inhibitor flexibility into account to predict phenotypic drug resistance. For six FDA-approved PIs and a total of 1792 HIV-1 protease sequence mutants, we used a combination of inhibitor flexible docking and molecular dynamics (MD) simulations to calculate protein–inhibitor binding energies. Prediction results were expressed as fold changes of the calculated inhibitory constant ( Ki), and the samples predicted to have fold-increase in calculated Ki above the fixed cut-off were defined as drug resistant. Our combined docking and MD protocol achieved accuracies ranging from 72–83% in predicting resistance/susceptibility for five of the six drugs evaluated. Evaluating the method only on samples where our predictions concurred with established knowledge-based methods resulted in increased accuracies of 83–94% for the six drugs. The results suggest that a physics-based approach, which is readily applicable to any novel PI and/or mutant, can be used judiciously with knowledge-based approaches that require experimental training data to devise accurate models of HIV-1 PI resistance prediction.