bluuebunny/crossref_metadata_2025 huggingface dataset:
Heptad-Repeat-2 Mutations Enhance the Stability of the Enfuvirtide-Resistant HIV-1 gp41 Hairpin Structure
Authors: Jenwitheesuk Ekachai , Samudrala Ram
Published: April 2022

Enfuvirtide (T20) is a peptide-based fusion inhibitor derived from the heptad repeat 2 (HR2) region of HIV-1 glycoprotein 41 (gp41). The inhibitor binds to the gp41 heptad repeat 1 (HR1) region, thereby blocking viral HR1/HR2 association. Mutations in HR1 have been reported to cause enfuvirtide resistance and reduce viral fitness. In this study, we first showed that scores obtained by a residue-specific all-atom probability discriminatory function (RAPDF) may be used as a reliable predictor of structural stability of gp41 mutants by comparing it to experimentally determined melting temperatures, and as a reliable indicator of enfuvirtide resistance by comparing it to experimentally determined fusion inhibition and viral fitness levels. We then generated an initial set of 28 theoretical structures of the HR1/HR2 hairpin complex where each structure consists of one mutation on HR1 known to cause enfuvirtide resistance and a wild-type amino acid at the corresponding HR2 residue. Mutations were then introduced in the corresponding HR2 residue of each structure where the wild-type amino acid was changed to each of the other nineteen amino acids. The enfuvirtide-resistant HR1 mutants with compensatory mutations at the corresponding HR2 residues had better RAPDF scores than those HR1 mutants with wild-type HR2. This indicates that mutations in HR2 improve structural stability of the HR1/HR2 hairpin complex and may lead to enhanced enfuvirtide resistance when present with resistant HR1 mutations. Modification of the amino acid side chains that contribute to enfuvirtide resistance using the RAPDF scores as a guide may help design of a second generation of fusion inhibitors against the enfuvirtide-resistant strains.
Efficacy and Safety of Indinavir/Ritonavir 400/100 mg Twice Daily plus Two Nucleoside Analogues in Treatment-Naive HIV-1-Infected Patients with CD4+ T-cell Counts <200 cells/mm3: 96-Week Outcomes
Authors: Mootsikapun Piroon , Chetchotisakd Ploenchan , Anunnatsiri Siriluck , Boonyaprawit Parichat
Published: April 2022

Objective

To evaluate the efficacy and safety of indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily in antiretroviral-therapy-naive Thai HIV-1-infected patients.

Methods

This was an open-label, non-randomized single arm study. Antiretroviral-naive patients ( n=80) with CD4+ cell count <200x106/l were started on stavudine and lamivudine plus indinavir/ritonavir 400/100mg twice daily. CD4+ cell count and HIV RNA were determined at week 0, 12, 24, 48 and 96. HIV RNA was measured to a level of 50 copies/ml by RT-PCR assay. Primary analysis was statistically performed as intent to treat. The primary endpoint was the percentage of patients with plasma HIV RNA below 50 copies/ml at week 96.

Result

Eighty antiretroviral-therapy-naive patients with median CD4+ cell count 19x106/l (range: 2-197x106/l) and median baseline plasma HIV RNA of 174,000 copies/ml (range 16,800–750,000 copies/ml) were enrolled. In the intent-to-treat analysis at week 96, the proportion of patients with HIV RNA of <50 copies/ml was 68.8% (95% confidence interval [CI]: 68.3-69.3), whereas it was 88.7% (95% CI: 88.1-89.3) in the on-treatment analysis at week 96. The regimen was well tolerated. Hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia were found in 8.3, 33.3 and 37.0% of the patients, respectively. Treatment was stopped in 18 patients; two from intolerance, two switched therapy, four as a result of serious adverse event-related death, and ten were lost to follow-up.

Conclusion

Our study demonstrates that indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily, the least expensive boosted protease inhibitor, appears to be effective and safe up to 96 weeks despite high baseline viraemia and low CD4+ cell count in antiretroviral-naive patients.
Nevirapine Plasma Concentrations and Concomitant Use of Rifampin in Patients Coinfected with HIV-1 and Tuberculosis
Authors: Autar Reshma S , Wit Ferdinand WNM , Sankote Jongkol , Mahanontharit Apicha , Anekthananon Thanomsak , Mootsikapun Piroon , Sujaikaew Khanjtta , Cooper David A , Lange Joep MA , Phanuphak Praphan , Ruxrungtham Kiat , Burger David M
Published: April 2022

Objectives

In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels.

Methods

Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations.

Results

We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 ±2.66mg/l, whereas in the control group the mean nevirapine concentration was 8.72 ±3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (<3.1 mg/l), while in the control group two patients had low nevirapine trough concentrations ( P=0.164). In the multivariate linear regression analysis, corrected for time after drug intake, the use of rifampin was significantly ( P<0.001) associated with lower nevirapine plasma concentrations, whereas higher BMI reached borderline significance ( P=0.065).

Conclusion

Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations >3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.
Possible Ways Nucleoside Analogues Can Affect Mitochondrial Dna Content and Gene Expression during HIV Therapy
Authors: Côté Hélène CF
Published: April 2022

In recent years, research into nucleoside reverse transcriptase inhibitor (NRTI)-related mitochondrial (mt) toxicity in HIV therapy has led to conflicting results and many unanswered questions regarding the molecular mechanisms that lead to such toxicity. From the early hypothesis that inhibition of the human mt polymerase γ by NRTIs was responsible for the drugs’ mt toxicity, an increasingly complex picture is emerging that probably involves multiple mt pathways. Results have been presented suggesting that NRTIs affect not only mtDNA but also mtRNA, nucleotide phosphorylation and the mt respiratory chain. Based on the current level of knowledge, this overview addresses some of the potential mechanisms through which NRTIs could affect mitochondria and ultimately cause the toxicity symptoms observed in HIV patients receiving NRTI-containing antiretroviral therapy.
Long-Term Highly Active Antiretroviral Therapy in Chronic HIV-1 Infection: Evidence for Reconstitution of Antiviral Immunity
Authors: Jansen Christine A , Piriou Erwan , De Cuyper Iris M , van Dort Karel , Lange Joep MA , Miedema Frank , van Baarle Debbie
Published: April 2022

In this study we investigated the long-term effect of highly active antiretroviral therapy (HAART) on HIV-specific CD4+ T-cell responses in comparison with virus-specific CD4+ T-cell responses against the persistent herpes viruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). To this end, HIV- and herpes virus-specific cellular immune responses were measured longitudinally in 10 seroconverters with long-term follow-up including 55 months of successful suppression of viral load by HAART. HIV- and CMV-specific CD4+ T cells producing interferon-γ (IFNγ) or interleukin-2 (IL-2) were analysed as well as proliferative capacity. EBV-specific CD4+ T cells were determined using a 12-day ex vivo assay. Initiation of HAART resulted in a transient increase of HIV-specific IL-2+IFNγ+CD4+ T cells and, to a lesser extent, IL-2+CD4+ T cells. Long-term HAART resulted in an increase in HIV-, CMV- and EBV-specific CD4+ T-cell proliferative capacity. The increase in HIV- and herpes-virus-specific CD4+ T-cell proliferative capacity after 55 months of HAART suggests that the improved proliferative response is not specific for HIV, but reflects a more general improvement of antiviral immune responses, which is induced by HAART.
Ritonavir-Boosted Atazanavir-Lopinavir Combination: A Pharmacokinetic Interaction Study of Total, Unbound Plasma and Cellular Exposures
Authors: Colombo Sara , Buclin Thierry , Franc Claudia , Guignard Nicole , Khonkarly Mona , Tarr Philip E , Rochat Bertrand , Biollaz Jérôme , Telenti Amalio , Decosterd Laurent A , Cavassini Matthias
Published: April 2022

Objectives

To assess potential pharmacokinetic (PK) interactions between atazanavir (ATV, 300 mg, once daily) and lopinavir (LPV, 400 mg, twice daily), both boosted by ritonavir (RTV, 100 mg).

Design

Two-parallel groups, addition of LPV in patients receiving ATV ( n=6), and addition of ATV in patients receiving LPV ( n=7), with before/after comparisons.

Methods

Each group had two complete PK profiles before and 2 weeks after the addition of the second protease inhibitor (PI). Total plasma concentrations (Ctot) were analysed by HPLC-UV and unbound plasma concentrations (Cu) and cellular concentrations (Ccell) were analysed by LC-MS/MS. Plasma and cellular PK parameters were also calculated. Unbound and cellular fractions were expressed as Cu/Ctot and Ccell/Ctot ratio. Data were analysed by paired Student t-test on log values; correlations between Ccell, Cu and Ctot were explored by log-log linear regression.

Results

Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV was associated with a decrease in LPV concentrations (by 16% for area under the time-concentration curve, maximum concentration and trough concentration, NS; and by 35% for Cmin, P=0.04). The RTV PK parameters remained unmodified. The Ccell/Ctot and Cu/Ctot ratio was unaffected by the addition of the second PI and remained stable throughout dosing interval. Good correlations were observed between Ccell, Cu and Ctot for each drug. No relevant toxicity was observed.

Conclusions

Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV caused a limited decrease in LPV concentrations. The clinical significance of this decrease is unknown and warrants further investigation to determine the need for tailoring LPV dosage in selected cases.
Evaluation of the HIV Lipodystrophy Case Definition in a Placebo-Controlled, 144-Week Study in Antiretroviral-Naive Adults
Authors: Law Matthew , Puls Rebekah , Cheng Andrew K , Cooper David A , Carr Andrew
Published: April 2022

Objective

To compare three versions of the objective HIV-associated lipodystrophy (HIVLD) case definition (LDCD) and derived severity scale to spontaneous clinical LD assessment in adults initiating antiretroviral therapy. Design and main outcome measures: The LDCD versions were the ‘primary’ LDCD [which includes dual-energy X-ray absorptiometry (DXA) and computerized tomography (CT)], a simpler ‘central’ LDCD that omits CT data, and a simpler but probably less accurate ‘non-imaging’ LDCD. Physician LD assessments were passively reported. Two of the 10 parameters in the primary LDCD were not collected and were imputed.

Setting, participants and interventions

Retrospective analysis of a randomized, placebo-controlled, 144-week study of tenofovir DF or stavudine (d4T) in 600 anti-retroviral-naive adults.

Results

Central LDCD and clinical assessment diagnosed LD in 27% and 19% of d4T recipients at week 144, respectively ( P<0.001), and 3% and 3% of tenofovir DF recipients, respectively ( P=0.248). The central LDCD performed at least as well as the primary LDCD; both were more sensitive than the non-imaging model. There was poor concordance between clinical and LDCD-based diagnosis (kappa 0.02–0.20); most clinical cases did not fulfill any LDCD. Using the central LDCD, most LD was grade 1; 6% of d4T recipients and no tenofovir DF recipient had grade 3–4 LD at week 144 ( P=0.007). Independent risk factors for LD using the central LDCD were d4T, increasing age, female sex and higher baseline triglycerides, whereas clinical assessment consistently identified only d4T. The LDCD score was more sensitive than DXA for assessing LD severity.

Conclusions

In this prospective study of a first antiretroviral regimen, the LDCD was more sensitive for LD diagnosis and identified more lipodystrophy risk factors than spontaneous clinical assessment or DXA, and also objectively quantified LD severity. The central LDCD should make objective LD assessment cheaper and simpler. Spontaneous clinical LD assessment of is of limited value, even in placebo-controlled trials.
Eligibility for and Outcome of Hepatitis C Treatment of HIV-Coinfected Individuals in Clinical Practice: The Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study, Zinkernagel Annelies S , von Wyl Viktor , Ledergerber Bruno , Rickenbach Martin , Furrer Hansjakob , Battegay Manuel , Hirschel Bernard , Tarr Philip E , Opravil Milos , Bernasconi Enos , Schmid Patrick , Weber Rainer
Published: April 2022

Background

Morbidity and mortality of individuals co-infected with HIV and hepatitis C virus (HCV) is often determined by the course of their HCV infection. Only a selected proportion of those in need of HCV treatment are studied in randomized controlled trials (RCTs). We analysed the prevalence of HCV infection in a large cohort, the number of individuals requiring treatment, the eligibility for HCV treatment, and the outcome of the combination therapy with pegylated interferon-α and ribavirin in routine practice.

Methods

We analysed prescription patterns of HCV treatment and treatment outcomes among participants from the Swiss HIV Cohort Study with detectable hepatitis C viraemia (between January 2001 and October 2004). Efficacy was measured by the number of patients with undetectable HCV RNA at the end of therapy (EOTR) and at 6 months after treatment termination (SVR). Intention-to-continue-treatment principles were used.

Results

A total of 2,150 of 7,048 (30.5%) participants were coinfected with HCV; HCV RNA was detected in 60%, and not assessed in 26% of HCV-antibody-positive individuals. One hundred and sixty (12.5%) of HCV-RNA-positive patients started treatment. In patients infected with HCV genotypes 1/4 or 2/3, EOTR was achieved in 43.3% and 81.2% of patients, respectively, and SVR rates were 28.4% and 51.8%, respectively. More than 50% of the HCV-treated patients would have been excluded from two large published RCTs due to demographic, clinical and laboratory criteria.

Conclusions

Despite clinical and psychosocial obstacles encountered in clinical practice, HCV treatment in HIV-coinfected individuals is feasible with results similar to those obtained in RCTs.
The K65R Reverse Transcriptase Mutation in HIV-1 Reverses the Excision Phenotype of Zidovudine Resistance Mutations
Authors: White Kirsten L , Chen James M , Feng Joy Y , Margot Nicolas A , Ly John K , Ray Adrian S , MacArthur Holly L , McDermott Martin J , Swaminathan S , Miller Michael D
Published: April 2022

The HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TFV), abacavir, didanosine and stavudine can select for K65R, whereas zidovudine (AZT) and stavudine can select for thymidine analogue mutations (TAMs) in HIV-1 reverse transcriptase (RT). HIV-1 with TAMs shows reduced susceptibility to all NRTIs, most notably AZT, whereas HIV-1 with K65R shows reduced susceptibility to all NRTIs except AZT. K65R and TAMs rarely occur together in patients. However, when present together, K65R can restore susceptibility to AZT. This study characterizes the underlying mechanisms of resistance of these RT mutants to TFV and AZT. K65R mediated decreased binding/incorporation of TFV and AZT (increased Ki/Km of 7.1- and 4.3-fold, respectively), but also decreased excision of TFV and AZT (0.7- and 0.3-fold, respectively) when compared with wild-type RT. By contrast, TAMs mediated increased TFV and AZT excision (11- and 5.4-fold, respectively), and showed no changes in binding/incorporation. When these mutations were combined, K65R reversed TAM-mediated AZT resistance by strongly reducing AZT excision. Molecular modelling studies suggest that K65R creates additional hydrogen bonds that reduce the conformational mobility of RT, resulting in reduced polymerization and excision. Thus, consistent with clinical HIV-1 genotyping data, there appears to be no net NRTI resistance benefit for TAMs and K65R to develop together in patients taking AZT and TFV disoproxil fumarate, where the TAM pathway alone provides the greatest resistance for both drugs.
Evidence of Differential Selection of HIV-1 Variants Carrying Drug-Resistant Mutations in Seroconverters
Authors: Corvasce Stefano , Violin Michela , Romano Laura , Razzolini Francesca , Vicenti Ilaria , Galli Andrea , Duca Piergiorgio , Caramma Ilaria , Balotta Claudia , Zazzi Maurizio
Published: April 2022

Objectives

To estimate the relative efficiency of transmission of different HIV-1 drug-resistance mutations from patients failing treatment, considered as potential transmitters (PTs), to seroconverters (SCs).

Design

Ecological cross-sectional study.

Methods

HIV-1 protease and reverse transcriptase (RT) sequence data, obtained from 155 SCs and 2,690 PTs at the Department of Molecular Biology of the University of Siena, Italy, in the period 1997–2004 were used. The efficiency of transmission was studied by odds ratio (OR) analysis and evaluation of 95% confidence intervals (95% CIs). For mutations not detected in viruses from SCs, a binomial probability model was used, assuming P-values <0.05 as indicative of a negative selection at transmission.

Results

The overall prevalence of drug mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PIs) was 13.2%, 4.6% and 2.0% in SCs, and 69.9%, 27.6% and 33.7% in PTs, respectively. Among RT mutations present both in PTs and SCs, M184I/V and T215F/Y had the lowest relative efficiency of transmission, whereas V118I, Y181C/I and K219E/Q showed the highest relative efficiency. Of the three major protease mutations that could be evaluated by this approach, M46I/L had a lower rate of transmission than I84V and L90M. Among the mutations not detected in viruses from SCs, the RT E44D, V108I, Q151M and Y188C/H/L, and the protease D30N, G48V and V82A/F/S/T substitutions appeared to be negatively selected.

Conclusions

The transmission rate of drug-resistant HIV-1 variants may be differentially affected by the mutational pattern. The binomial model enabled to evaluate the negative selection against specific substitutions. Given the low prevalence of some resistance mutations in SCs, very large data sets are required to evaluate the potential selection of such mutations.
A Randomized Pilot Study Comparing Combination Therapy plus Enfuvirtide versus a Treatment Interruption followed by Combination Therapy plus Enfuvirtide
Authors: Beatty George , Hunt Peter , Smith Anna , Hoh Rebecca , Huang Wei , Martin Jeff , Deeks Steven G
Published: April 2022

Most individuals with multidrug-resistant HIV who switch to a new therapeutic regimen containing a single fully effective agent experience incomplete viral suppression. We postulated that interruption of antiretroviral therapy prior to the introduction of such a regimen would improve long-term virological outcomes. Thirty, three-class experienced, enfuvirtide-naive individuals with detectable drug-resistant viraemia were randomized to an immediate enfuvirtide/optimized-background treatment regimen or a 16-week treatment interruption followed by enfuvirtide/optimized-background treatment regimen. The median CD4+ T-cell count and viral load at study entry were 39 cells/mm and 4.72 log10 copies RNA/ml, respectively. There was no evidence of any virological or immunological benefit associated with the interruption. In multivariate analysis, only the baseline phenotypic susceptibility score was predictive of treatment response at week 48 ( P=0.009). Only 40% of individuals had evidence of a shift in drug-resistance genotype during the interruption. In summary, interrupting therapy prior to initiating salvage therapy in patients with advanced disease did not result in an improved virological response to enfuvirtide. The collective predictive activity of an enfuvirtide-containing regimen was important in predicting treatment response.
Association of Apolipoproteins C3 and E with Metabolic Changes in HIV-Infected Adults Treated with a Protease-Inhibitor-Containing Antiretroviral Therapy
Authors: Bard Jean-Marie , Lassalle Régis , Capeau Jacqueline , Bach-Ngohou Kalyane , Nazih-Sanderson Françoise , Rémy Gérard , Reynes Jacques , Ecobichon Jean-Luc , Savès Marianne , Raffi François
Published: April 2022

Objective

To examine the relationship between plasma levels of apolipoproteins C3 (APOC3) and E (APOE) and the presence of lipid and carbohydrate metabolism abnormalities or clinical signs of lipodystrophy in HIV-1-infected patients started with a protease-inhibitor-containing antiretroviral therapy.

Methods

The Aproco (Antiproteases Cohort) Study enrolled 1,181 HIV-1-infected adults in 47 French healthcare centres from May 1997 to June 1998. From December 1998 through July 1999, the APROCO-Metabolic Complications (APROCO-MC) cross-sectional study was performed at the month 20 visit for those patients enrolled in 1997 and at the month 12 visit for those enrolled in 1998. The current analysis presents results from a subset of patients who had undergone additional tests to measure APOC3 and APOE in order to study their relationship with metabolic syndrome ( n=157) and abnormal results in an oral glucose tolerance test ( n=135).

Results

Increases in triglycerides and non-high-density lipoprotein (HDL) cholesterol were associated with significantly higher levels of APOC3, in both Lp B (lipoproteins containing apolipoprotein B) and Lp non-B (lipoproteins free of apolipoprotein B), and a significant higher level of APOE Lp B. APOC3 and APOC3 Lp non-B were increased when glucose metabolism abnormalities were more severe. The presence of a metabolic syndrome was associated with increased plasma APOC3, APOC3 Lp B and APOC3 Lp non-B levels. In a multiple regression analysis, high levels of APOC3 in Lp B and APOC3 Lp non-B were associated with the presence of clinical signs of lipodystrophy, even after adjustment for triglycerides and HDL-cholesterol levels.

Conclusions

Lipid and/or glucose metabolism abnormalities in treated HIV-1-infected patients are associated with increased levels of APOC3 and, to a lesser extent, APOE plasma concentrations. Increased values are also related to clinical signs of insulin resistance and lipodystrophy.
Amantadine Inhibits the Function of an Ion Channel Encoded by Gb Virus B, but Fails to Inhibit Virus Replication
Authors: Premkumar Anita , Dong Xuebin , Haqshenas Gholamreza , Gage Peter W , Gowans Eric J
Published: April 2022

A chemically synthesized peptide representing the C-terminal subunit (p13-C) of the p13 protein of GB virus B (GBV-B), the most closely related virus to hepatitis C virus (HCV) showed ion channel activity in artificial lipid bilayers. The channels had a variable conductance and were more permeable to potassium ions than to chloride ions. Amantadine but not hexam-ethylene amiloride (HMA) inhibited the ion channel function of p13-C in the lipid membranes. However, neither agent was able to inhibit the replication and secretion of GBV-B from virus-infected cultured marmoset hepatocytes, which were harvested from a marmoset that was infected in vivo or inhibit replication after in vitro infection of naive hepatocytes. These data suggest that the GBV-B ion channel, contrary to the data derived from the lipid membranes, is either resistant to amantadine or that virus replication and secretion are independent of ion channel function. As the p7 protein of HCV also has ion channel activity that is apparently resistant to amantadine in vivo, the former possibility is most likely. Ion channels are likely to have an important role in the life cycle of many viruses and compounds that block these channels may prove to be useful antiviral agents.
Change in T-Lymphocyte Count after Initiation of Highly Active Antiretroviral Therapy in HIV-Infected Patients with History of Mycobacterium Avium Complex Infection
Authors: Lazaro Estibaliz , Coureau Gaelle , Guedj Jérémie , Blanco Patrick , Pellegrin Isabelle , Commenges Daniel , Dabis François , Moreau Jean-François , Pellegrin Jean-Luc , Thiébaut Rodolphe
Published: April 2022

Objective

To compare changes in CD4+, CD8+ and total lymphocyte counts after initiation of highly active anti-retroviral therapy (HAART) between HIV-infected patients with and without a recent history of Mycobacterium avium complex (MAC) infection.

Method

Matched exposed-non-exposed retrospective cohort study.

Results

Fifty-one patients with a recent history of MAC infection (MAC+) started a combination of at least three antiretroviral drugs. They were individually matched to 145 patients without any history of MAC infection (MAC-) according to CD4+ T-cell count (±30 cells/mm3), previous experience of antiretroviral treatment, AIDS clinical stage at the time of HAART initiation (baseline), age (±10 years) and gender. MAC+ and MAC- patients presented comparable median levels of total lymphocytes (488 vs 688/mm3, P=0.09), CD4+ (11 vs 16/mm3, P=0.15), CD8+ count (359 vs 386/mm3, P=0.39) and plasma HIV RNA (5.3 vs 5.1 log10 copies/ml, P=0.22) at baseline. After 6 months on HAART, the median increase of CD4+ T-cell count was 28 cells/mm3 (interquartile range [IQR]: 1–63) in MAC+ and 72 cells/mm3 (IQR: 34–120) in MAC- patients ( P<0.0001), whereas the percentage of CD4+ T cells was not significantly different between the two groups ( P=0.13). Comparable differences were observed for total lymphocytes and CD8+ T cells ( P<0.001). The 6 months decline of plasma HIV RNA was not significantly different according to MAC exposure (-1.6 in MAC+ vs -1.8 log10 copies/ml in MAC- patients, P=0.65). Results were confirmed after adjustment for other characteristics than the matching variables and after taking into account potential informative bias due to unbalanced number of deaths between the two groups.

Conclusion

MAC infection at the time of HAART initiation is an important deleterious factor for immune reconstitution. A better understanding of the underlying mechanism and an evaluation of additional treatment strategies are necessary to help immune restoration in such circumstances.
The Clinical Impact of Early Detection of the Ymdd Mutant on the Outcomes of Long-Term Lamivudine Therapy in Patients with Chronic Hepatitis B
Authors: Paik Yong-Han , Han Kwang-Hyub , Hong Sun Pyo , Lee Hyun Woong , Lee Kwan Sik , Kim Soo-Ok , Shin Ji Eun , Ahn Sang Hoon , Chon Chae Yoon , Moon Young Myoung
Published: April 2022

The early emergence of lamivudine (3TC)-resistant tyro-sine–methionine–aspartate–aspartate (YMDD) mutants has been reported during 3TC therapy in patients with chronic hepatitis B (CHB) in hepatitis B virus (HBV)-endemic areas; however, its clinical impact during long-term 3TC therapy is unknown. This study was performed to investigate the impact of the early emergence of YMDD mutants 3 months after the initiation of treatment on the outcomes of long-term 3TC therapy in HBV e antigen (HBeAg)-positive CHB. We analysed YMDD genotypes in consecutive samples from 30 patients with HBeAg positive CHB throughout 3TC treatment using both restriction fragment length polymorphism and mass spectrometric assays. Long-term outcome was compared between patients who had YMDD mutations detected at 3 months and those who had no mutations. YMDD mutation was detected in 16 (53.3%) out of 30 patients at 3 months and only the rtM204I mutation was found. Cumulative HBeAg loss rates at 3 years was 12.5% and 57.4% in patients who had the rtM204I mutant and wild-type virus at 3 months, respectively ( P=0.010). Cumulative viral breakthrough rates at 3 years was 75.0% and 14.3% in patients who had the rtM204I mutant and wild-type virus at 3 months, respectively ( P=0.002). Logistic regression revealed that YMDD mutation at 3 months was significantly related to viral breakthrough within 24 months ( P=0.003). In conclusion, early detection for HBV YMDD mutation at 3 months may be useful to predict the long-term outcomes of 3TC therapy in patients with HBeAg-positive CHB in HBV-endemic areas.
Long-Term Lamivudine Treatment is Associated with a Good Maintained Response in Severe Acute Exacerbation of Chronic Hbeag-Negative Hepatitis B
Authors: Chan Henry Lik-Yuen , Wong Vincent Wai-Sun , Hui Alex Yui , Tsang Steven Woon-Choy , Chan Joyce Lai-Yee , Chan Hoi-Yun , Wong Grace Lai-Hung , Sung Joseph Jao-Yiu
Published: April 2022

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B is difficult to treat and there is little long-term data for lamivudine treatment of severe acute exacerbation. We report a prospective, consecutive cohort of severe acute exacerbation of HBeAg-negative chronic hepatitis B patients treated by lamivudine between 1999 and 2004. All patients had respectively increased alanine aminotransferase and serum bilirubin to at least 10 and 2 times the upper limit of laboratory normal. Thirty-two patients were treated with lamivudine for 130 ±58 (range 48–217) weeks. Five patients had evidence of virological breakthrough (HBV DNA >10,000 copies/ml) during lamivudine treatment. The cumulative probability of maintained response without any virological breakthrough was 94% (95% confidence interval [CI], 86–100%) at year 1, 94% (95% CI, 82–100%) at year 2 and 71% (95% CI, 41–100%) at year 3. At the last follow-up visit, 31 (97%) lamivudine patients had HBV DNA <10,000 copies/ml. The prevalence of lamivudine resistance mutation was 1 in 32 patients (3%; 95% CI, 0–9%) at year 1, 1 in 17 patients (6%; 95% CI, 0–17%) at year 2, 1 in 9 patients (11%, 95% CI, 0–32%) at year 3 and 1 in 4 patients (25%; 95% CI, 0–67%) at year 4 of lamivudine treatment. In conclusion, extended lamivudine treatment is associated with a high maintained virological response and a low rate of drug resistance in severe acute exacerbation of HBeAg-negative chronic hepatitis B.
Influence of Hepatitis C Genotypes on Lipid Levels in HIV-Positive Patients during Highly Active Antiretroviral Therapy
Authors: Lapadula Giuseppe , Torti Carlo , Paraninfo Giuseppe , Castelnuovo Filippo , Uccelli Maria Cristina , Costarelli Silvia , Ladisa Nicoletta , Maserati Renato , Pietro Massimo Di , Silvestri Annalisa De , Tinelli Carmine , Puoti Massimo , Carosi Giampiero
Published: April 2022

Background

The independent role of HCV genotype a3 (HCV-3) in dyslipidaemia following highly active anti-retroviral therapy (HAART) is still unexplored.

Methods

Analysis of data from a cohort of 307 HIV/HCV-coinfected patients and 415 HIV-monoin-fected controls was conducted. Patients with available lipid levels at baseline and minimum 3-month follow-up were ranked into three groups by HCV status (HCV-3, other HCV genotypes or HCV negative). Univariate and multivariate GEE models were performed to assess factors correlated with lipid serum levels as coefficient (Coef., defined as mean difference [mg/dl] across the follow-up). Univariate and multivariate logistic regression analyses were performed for prediction of relevant hypertriglyceridaemia (≥500 mg/dl) and relevant hyper-cholesterolaemia (≥240 mg/dl) at 3 months of follow-up.

Results

HCV-3 correlated with lower triglyceridaemia (Coef.=-38.22; P=0.001), independently from the other considered variables, including age, gender and use of stavudine or lopinavir. Even though HCV infection per se appeared to be protective, HCV-3 in particular was also independently associated with lower choles-terolaemia (Coef.=-46.35; P<0.001). At logistic regression analyses, HCV-3, but not HCV-non-3, was associated with lower risk of relevant hypercholestero-laemia (odds ratio [OR] 0.06; P=0.01) and relevant hypertriglyceridaemia (OR 0.11; P=0.05), independently from other considered variables.

Conclusions

Our data confirm that HCV coinfection per se is associated with lower risk of hypercholestero-laemia after HAART. This effect was particularly attributed to HCV-3, which was the only genotype associated with lower triglyceridaemia during HAART.
Virological Responses to Atazanavir–Ritonavir-Based Regimens: Resistance-Substitutions Score and Pharmacokinetic Parameters (Reyaphar Study)
Authors: Pellegrin Isabelle , Breilh Dominique , Ragnaud Jean-Marie , Boucher Sébastien , Neau Didier , Fleury Hervé , Schrive Marie-Hélène , Saux Marie-Claude , Pellegrin Jean-Luc , Lazaro Estibaliz , Vray Muriel
Published: April 2022

Objective

To assess the impact of baseline HIV-1 substitutions, individual pharmacokinetic (PK) parameters (Cmin, Cmax, area under the curve [AUC0→24 h]) and genotype-inhibitory quotient (GIQ) on virological responses (VR) to atazanavir-ritonavir (300 mg/100 mg)-based highly active antiretroviral therapy (HAART) in 71 antiretroviral-experienced, atazanavir-naive patients in virological failure (VF) on HAART.

Methodology

VR was defined as HIV RNA <1.7 log10 copies/ml at week 12 (W12). A clinically relevant genotype-substitutions score for atazanavir-ritonavir was developed and validated (Reyaphar substitutions score). Previously published substitutions scores were also tested.

Results

Patients had a median (Q1; Q3) of 6 (3; 8) previous treatment lines during 9 (7; 11) years. Baseline (W0) values were as follows: 262 (187; 435) CD4+/μl, 3.9 (2.6; 4.9) log10 HIV-1 RNA copies/ml, 4 (2; 6) protease substitutions and 3 (1; 4) NRTI-related substitutions. Respective steady-state Cmin, Cmax and AUC0→24h were 300 (200; 700) ng/ml, 620 (430; 750) ng/ml and 78,000 (61,000; 94,000) ng.h/ml. At W12, 49% of the patients had VR with a median decrease of -1.2 (-0.5; -2.3) log10 HIV-1 RNA copies/ml. The Reyaphar score included 12 baseline protease substitutions from the International AIDS Society USA list that were associated with poorer VR: L10I/F/R/V, K20I/M/R, L24I, M46I/L, I54L/M/T/V, L63P, A71I/L/V/T, G73A/C/F/T, V77I, V82A/F/S/T, I84V, L90M and the polymorphism substitution Q58E. Comparing <5 versus ≥5 Reyaphar substitutions, the W12-W0 HIV-1 RNA decrease was -1.4 (-0.7; -2.3) versus -0.5 (-1.2; +0.5) log10 copies/ml ( P=0.009) with VR in 63% versus 11% ( P<10–4), respectively. This score predicted VF at W12 with 46% sensitivity, compared to 33% and 28% for the ANRS 2004 and 2005 scores. PK parameters alone were not associated with VR, but GIQ was associated with virological outcome ( P=0.04). I50L, known to be correlated with atazanavir-specific resistance, emerged in 2 (8%) of the 24 failing patients with paired genotypes at W0 and VF.

Conclusions

These findings highlight the need to cross-validate genotype-based algorithms to interpret substitution impact on virological outcome using different patient databases before their implementation in routine clinical practice.
Amino Acid Variations in Hepatitis C Virus P7 and Sensitivity to Antiviral Combination Therapy with Amantadine in Chronic Hepatitis C
Authors: Mihm Ulrike , Grigorian Natalia , Welsch Christoph , Herrmann Eva , Kronenberger Bernd , Teuber Gerlinde , von Wagner Michael , Hofmann Wolf-Peter , Albrecht Mario , Lengauer Thomas , Zeuzem Stefan , Sarrazin Christoph
Published: April 2022

Background

Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown.

Methods

HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-α (IFN-α)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed.

Results

No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-α-based therapy with amantadine in HCV genotype 1a/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmem-brane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine ( P=0.015 and P=0.037, respectively), without amantadine ( P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients ( P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine ( P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore.

Conclusion

Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.
Mannose-Binding Lectin in Susceptibility and Progression of HIV-1 Infection in Children
Authors: Dzwonek Agnieszka , Novelli Vas , Bajaj-Elliott Mona , Turner Malcolm , Clapson Margaret , Klein Nigel
Published: April 2022

Background

Mannose-binding lectin (MBL; encoded by MBL-2) is a circulating pattern-recognition molecule that recognizes microbial carbohydrate motifs, leading to complement activation and cell lysis. Mutations in the MBL-2 promoter and of the MBL-2 gene exon 1 result in reduced protein levels and increased susceptibility to infection. We have investigated the effect of MBL-2 polymorphisms on susceptibility and progression of HIV-1 infection in children.

Patients and methods

One-hundred and twenty-eight children, aged 2–16 years were recruited. MBL-2 genotypes were determined by PCR and heteroduplex analyses. Serum MBL levels were measured by ELISA. Comparison of genotypes (A=wild type, 0=variant alleles) and protein levels between groups was performed using χ2, Mann–Whitney U or Kruskal–Wallis tests.

Results

Children were classified according to the Centers for Disease Control and Prevention clinical classification: A, B or C (mildly symptomatic [ n=39], moderately symptomatic [ n=58] or severely symptomatic AIDS [ n=31]) or immune category 1 ( n=77), 2 ( n=46) or 3 ( n=5). Analysis of MBL-2 genotypes with respect to clinical classification yielded minimal differences. However, patients in immunological categories 2 and 3 (<25% CD4+ T cells) were more likely to have MBL-2 variant alleles ( P=0.01). We further explored MBL status with respect to disease progression. Only 1/10 long-term non-progressors (LTNPs) had an MBL-2 mutation (A/D) with a corresponding protein level of 611 ng/ml.

Conclusions

MBL deficiency was more frequent in patients with severe disease as assessed by CD4+ T-cell status. MBL-2 variants may be less frequent in children classified as LTNPs. MBL analysis could be useful in identifying children with slow disease progression and, consequently, may not require immediate antiretroviral treatement.
Foscarnet Salvage Therapy for Patients with Late-Stage HIV Disease and Multiple Drug Resistance
Authors: Canestri Ana , Ghosn Jade , Wirden Marc , Marguet Françoise , Ktorza Nadine , Boubezari Imane , Dominguez Stéphanie , Bossi Philippe , Caumes Eric , Calvez Vincent , Katlama Christine
Published: April 2022

Objective

To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance.

Methods

Three drugs experienced patients with plasma viral load (pVL) >50,000 copies/ml and CD4+ T-cell counts <100/mm3 were eligible for this open-label, single-arm, add-on pilot study. Foscarnet induction therapy consisted of 5 g intravenously twice daily for 6 weeks, in addition to a stable antiretroviral regimen. Patients with at least 1 log10 decrease in pVL at week 6 (W6), were given foscarnet 5 g intravenously twice daily on two consecutive days each week. Primary endpoint was the virological response rate at W6.

Results

Eleven patients were enrolled with a median baseline pVL at 5.16 log10 copies/ml, median CD4+ T-cell count at 10/mm3 and median number of mutations of 9, 2 and 12 associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs and protease inhibitors, respectively. One patient discontinued foscarnet at W2 because of renal toxicity. In an intent-to-treat analysis, the median change in pVL from baseline was -1.99 log10 copies/ml at W2 and -1.79 log10 copies/ml at W6. Eight out of eleven patients had a fall in pVL of at least 1 log10 at W6, and six started maintenance therapy. The median fall in pVL after 12 weeks of maintenance therapy was -0.85 log10 copies/ml in the four patients who reached W12, and the median increase of CD4+ T-cell count was 60/mm3.

Conclusion

In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status.
Does Haart Improve Renal Function? An Association between Serum Cystatin C Concentration, HIV Viral Load and Haart Duration
Authors: Jaroszewicz Jerzy , Wiercinska-Drapalo Alicja , Lapinski Tadeusz W , Prokopowicz Danuta , Rogalska Magdalena , Parfieniuk Anna
Published: April 2022

Aim

The prevalence of renal disease in human HIV-infected individuals varies between 2% and 10%. Many reports have demonstrated the beneficial effect of anti-retroviral (ARV) therapy on slowing the progression of renal diseases. The aim of our cross-sectional study was to determine serum cystatin C concentration in different stages of HIV infection and the relationship between cystatin C concentration and ARV treatment.

Methods

Cystatin C concentration was measured in the sera of 77 HIV-1-infected individuals and 18 HIV-seronegative volunteers. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study formula.

Results

HIV infection resulted in a significant increase in serum cystatin C concentration compared with healthy individuals (933.4±32.1 vs 621.1 ±56.8 ng/ml, P<0.001). There were no significant differences in urea, creatinine and GFR between those groups. On multivariate analyses serum cystatin C was independently associated with highly active antiretroviral therapy (HAART) duration (β=-0.34, P=0.04) and HIV viral load (β=0.33, P=0.04), whereas there were no significant relationships with age, body mass index, HIV duration, CD4+ and CD8+ T-cell counts and serum high sensitivity C-reactive protein concentration.

Conclusions

Our initial observations indicate that serum cystatin C, which may reflect mild renal dysfunction, is increased during HIV-infection and is associated with HIV viral load. Long-lasting HAART seems to decrease cystatin C concentration, thus potentially improves renal function.
Amdoxovir versus Placebo with Enfuvirtide plus Optimized Background Therapy for HIV-1-Infected Subjects Failing Current Therapy (Aactg A5118)
Authors: Gripshover Barbara M , Ribaudo Heather , Santana Jorge , Gerber John G , Campbell Thomas B , Hogg Evelyn , Jarocki Bernadette , Hammer Scott M , Kuritzkes Daniel R
Published: April 2022

Background

Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses.

Methods

ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade ≥3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks.

Results

Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI=-2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI=-1.1, -0.1) in the placebo arm ( P=0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI=1, 115) in the DAPD arm and 60 (95% CI=1, 101) in the placebo arm ( P=0.45). Time to first serious AE did not differ between arms ( P=0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities.

Conclusions

Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.
Declining Prevalence of HIV-Infected Individuals at Risk of Transmitting Drug-Resistant HIV in Denmark during 1997–2004
Authors: Lohse Nicolai , Obel Niels , Kronborg Gitte , Jørgensen Louise Bruun , Pedersen Court , Larsen Carsten Schade , Kvinesdal Birgit , Sørensen Henrik Toft , Gerstoft Jan
Published: April 2022

Background

Transmission of drug-resistant HIV is a potential threat to the substantial clinical benefit of highly active antiretroviral therapy (HAART). To explore the background for the low rates of drug resistance transmission (2–5%) in our population, we estimated acquisition of HIV drug resistance and examined temporal trends in the prevalence of patients at risk of transmitting drug-resistant HIV.

Methods

The study population included all 4,025 patients from The Danish HIV Cohort Study seen during the period 1995–2004. Virological failure to a given drug class was defined as a viral load (VL) >1,000 copies/ml for 120 days while on a HAART regimen including that drug class. In addition, receiving nucleoside reverse transcriptase inhibitors (NRTIs) for 180 days before HAART counted as NRTI failure irrespective of VL. Having experienced failure was considered a proxy for harbouring drug-resistant virus in subsequent observation time. Patients with a current VL >1,000 copies/ml were considered at risk of transmitting HIV.

Results

We found a decrease from 1997 to 2004 in the prevalence of potential transmitters of drug-resistant HIV. The number of these patients with previous NRTI failure decreased from 429 (24% of all patients) in 1998 to 213 (8.0% of all patients) in 2004. Previous protease inhibitor (PI) failure peaked at 279 (14%) in 1999, declining to 142 (5.3%) in 2004. Previous NNRTI failure peaked at 121 patients (4.7%) in 2002, and occurred in 113 patients (4.2%) in 2004. Of all 686 potential transmitters in 2004, 31% had previously experienced NRTI failure, 21% PI failure, and 16% non-NRTI failure.

Conclusion

In the population of HIV-infected individuals in Denmark with complete follow-up, the number at risk of transmitting drug-resistant virus declined over time.