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ABSTRACT: We hypothesized that polymorphic mutations exist that are associated with the emergence of the multinucleoside resistance mutations (MNR), 69 insertion and Q151M.
The Swiss HIV Cohort Study was screened, and the frequencies of polymorphic mutations in HIV-1 (subtype B) were compared between patients detected with the 69 insertion (n = 17), Q151M (n = 29), ≥2 thymidine analogue mutations (TAM) 1 (n = 400) or ≥2 TAM 2 (n = 249). Logistic regressions adjusted for the antiretroviral treatment history were performed to analyze the association of the polymorphic mutations with MNR.
The 69 insertion and TAM 1 were strongly associated and occurred in 94.1% (16 of 17) together. The 69 insertion seemed to emerge as a consequence of the TAM 1 pathway (median years until detection: 6.8 compared with 4.4 for ≥2 TAM 1, P Wilcoxon = 0.009). Frequencies of 8 polymorphic mutations (K43E, V60I, S68G, S162C, T165I, I202V, R211K, F214L) were significantly different between groups. Logistic regression showed that F214L and V60I were associated with the emergence of Q151M/TAM 2 opposed to 69 insertion/TAM 1. S68G, T165I, and I202V were associated with Q151M instead of TAM 2.
Besides antiretroviral therapy, polymorphic mutations may contribute to the emergence of specific MNR mutations.
JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2012; 59(2):105-12. · 4.43 Impact Factor
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Alexandra U Scherrer,
Bruno Ledergerber,
Viktor von Wyl,
Jürg Böni,
Sabine Yerly,
Thomas Klimkait,
Cristina Cellerai,
Hansjakob Furrer,
Alexandra Calmy,
Matthias Cavassini,
Luigia Elzi,
Pietro L Vernazza,
Enos Bernasconi,
Huldrych F Günthard
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ABSTRACT: Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential.
To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥ 1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs.
We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥ 4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥ 1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0-1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5-1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome.
The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals.
PLoS ONE 01/2012; 7(6):e37983. · 4.09 Impact Factor
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Alexandra U Scherrer,
Jürg Böni,
Sabine Yerly,
Thomas Klimkait,
Vincent Aubert,
Hansjakob Furrer,
Alexandra Calmy,
Matthias Cavassini,
Luigia Elzi,
Pietro L Vernazza,
Enos Bernasconi,
Bruno Ledergerber,
Huldrych F Günthard
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ABSTRACT: BACKGROUND: The accumulation of mutations after long-lasting exposure to a failing combination antiretroviral therapy (cART) is problematic and severely reduces the options for further successful treatments. METHODS: We studied patients from the Swiss HIV Cohort Study who failed cART with nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The loss of genotypic activity <3, 3-6, >6 months after virological failure was analyzed with Stanford algorithm. Risk factors associated with early emergence of drug resistance mutations (<6 months after failure) were identified with multivariable logistic regression. RESULTS: Ninety-nine genotypic resistance tests from PI/r-treated and 129 from NNRTI-treated patients were analyzed. The risk of losing the activity of ≥1 NRTIs was lower among PI/r- compared to NNRTI-treated individuals <3, 3-6, and >6 months after failure: 8.8% vs. 38.2% (p = 0.009), 7.1% vs. 46.9% (p<0.001) and 18.9% vs. 60.9% (p<0.001). The percentages of patients who have lost PI/r activity were 2.9%, 3.6% and 5.4% <3, 3-6, >6 months after failure compared to 41.2%, 49.0% and 63.0% of those who have lost NNRTI activity (all p<0.001). The risk to accumulate an early NRTI mutation was strongly associated with NNRTI-containing cART (adjusted odds ratio: 13.3 (95% CI: 4.1-42.8), p<0.001). CONCLUSIONS: The loss of activity of PIs and NRTIs was low among patients treated with PI/r, even after long-lasting exposure to a failing cART. Thus, more options remain for second-line therapy. This finding is potentially of high relevance, in particular for settings with poor or lacking virological monitoring.
PLoS ONE 01/2012; 7(11):e50307. · 4.09 Impact Factor
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Philip Rieder,
Beda Joos, Alexandra U Scherrer,
Herbert Kuster,
Dominique Braun,
Christina Grube,
Barbara Niederöst,
Christine Leemann,
Sara Gianella,
Karin J Metzner,
Jürg Böni,
Rainer Weber,
Huldrych F Günthard
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ABSTRACT: In the context of sexual transmission of human immunodeficiency virus type 1 (HIV-1), current findings suggest that the mucosal barrier is the major site of viral selection, transforming the complex inoculum to a small, homogeneous founder virus population. We analyzed HIV-1 transmission in relation to viral and host characteristics within the Zurich primary HIV-1 infection study.
Clonal HIV-1 envelope sequences (on average 16 clones/patient) were isolated from the first available plasma samples during the early phase of infection from 145 patients with primary HIV-1 infection. Phylogenetic and tropism analyses were performed. Differences of viral diversities were investigated in association with several parameters potentially influencing HIV-1 transmission, eg, concomitant sexually transmitted infections (STIs) and mode of transmission.
Median viral diversity within env C2-V3-C3 region was 0.39% (range 0.04%-3.23%). Viral diversity did not correlate with viral load, but it was slightly correlated with the duration of infection. Neither transmission mode, gender, nor STI predicted transmission of more heterogeneous founder virus populations that were found in 16 of 145 patients (11%; diversity >1%). Only 2 patients (1.4%) were assuredly infected with CXCR4-tropic HIV-1 within a R5/X4-tropic--mixed population, as revealed and confirmed using several genotypic prediction algorithms and phenotypic assays.
Our findings suggest that transmission of multiple HIV-1 variants might be a complex process that is not dependent on mucosal factors alone. CXCR4-tropic viruses can be sexually transmitted in rare instances, but their clinical relevance remains to be determined.
Clinical Infectious Diseases 12/2011; 53(12):1271-9. · 9.15 Impact Factor
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Alexandra U Scherrer,
Bruno Ledergerber,
Viktor von Wyl,
Jürg Böni,
Sabine Yerly,
Thomas Klimkait,
Philippe Bürgisser,
Andri Rauch,
Bernard Hirschel,
Matthias Cavassini,
Luigia Elzi,
Pietro L Vernazza,
Enos Bernasconi,
Leonhard Held,
Huldrych F Günthard
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ABSTRACT: Antiretroviral compounds have been predominantly studied in human immunodeficiency virus type 1 (HIV-1) subtype B, but only ~10% of infections worldwide are caused by this subtype. The analysis of the impact of different HIV subtypes on treatment outcome is important.
The effect of HIV-1 subtype B and non-B on the time to virological failure while taking combination antiretroviral therapy (cART) was analyzed. Other studies that have addressed this question were limited by the strong correlation between subtype and ethnicity. Our analysis was restricted to white patients from the Swiss HIV Cohort Study who started cART between 1996 and 2009. Cox regression models were performed; adjusted for age, sex, transmission category, first cART, baseline CD4 cell counts, and HIV RNA levels; and stratified for previous mono/dual nucleoside reverse-transcriptase inhibitor treatment.
Included in our study were 4729 patients infected with subtype B and 539 with non-B subtypes. The most prevalent non-B subtypes were CRF02_AG (23.8%), A (23.4%), C (12.8%), and CRF01_AE (12.6%). The incidence of virological failure was higher in patients with subtype B (4.3 failures/100 person-years; 95% confidence interval [CI], 4.0-4.5]) compared with non-B (1.8 failures/100 person-years; 95% CI, 1.4-2.4). Cox regression models confirmed that patients infected with non-B subtypes had a lower risk of virological failure than those infected with subtype B (univariable hazard ratio [HR], 0.39 [95% CI, .30-.52; P < .001]; multivariable HR, 0.68 [95% CI, .51-.91; P = .009]). In particular, subtypes A and CRF02_AG revealed improved outcomes (multivariable HR, 0.54 [95% CI, .29-.98] and 0.39 [95% CI, .19-.79], respectively).
Improved virological outcomes among patients infected with non-B subtypes invalidate concerns that these individuals are at a disadvantage because drugs have been designed primarily for subtype B infections.
Clinical Infectious Diseases 12/2011; 53(11):1143-52. · 9.15 Impact Factor
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ABSTRACT: The 69 insertion and Q151M mutations are multi-nucleoside/nucleotide resistance mutations (MNR). The prevalence among 4078 antiretroviral therapy (ART)-experienced individuals was <1.3%. Combined ART fully prevented MNR in subtype B infections. Case-control studies were performed to identify risk factors. Control subjects were patients with ≥ 3 thymidine-analogue mutations. The 69 insertion study (27 control subjects, 14 case patients) identified didanosine exposure as a risk (odds ratio, 5.0 per year; P = .019), whereas the Q151M study (which included 44 control subjects and 25 case patients) detected no associations. Following detection, individuals with Q151M tended to have lower suppression rates and higher mortality rates, relative to control subjects. Additional studies are needed to verify these findings in non-subtype B infections.
The Journal of Infectious Diseases 03/2011; 203(6):791-7. · 6.41 Impact Factor
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ABSTRACT: In the Zurich Primary HIV infection study (ZPHI), minority drug-resistant HIV-1 variants were detected in some acutely HIV-1-infected patients prior to initiation of early antiretroviral therapy (ART). Here, we investigated the reappearance of minority K103N and M184V HIV-1 variants in these patients who interrupted efficient early ART after 8-27 months according to the study protocol. These mutations are key mutations conferring drug resistance to reverse transcriptase inhibitors and they belong to the most commonly transmitted drug resistance mutations.
Early ART was offered to acutely HIV-1-infected patients enrolled in the longitudinal prospective ZPHI study. Six patients harboring and eleven patients not harboring drug-resistant viruses at low frequencies prior to ART were included in this substudy. Minority K103N and M184V HIV-1 variants were quantified in longitudinal plasma samples after treatment interruption by allele-specific real-time PCR. All 17 patients were infected with HIV-1 subtype B between 04/2003 and 09/2005 and received LPV/r+AZT+3TC during primary HIV-1 infection (PHI). Minority K103N HIV-1 variants reappeared after cessation of ART in two of four patients harboring this variant during PHI and even persisted in one of those patients at frequencies similar to the frequency observed prior to ART (<1%). The K103N mutation did not appear during treatment interruption in any other patient. Minority M184V HIV-1 variants were detected in two patients after ART interruption, one harboring and one not harboring these variants prior to ART.
Minority K103N HIV-1 variants, present in acutely HIV-1 infected patients prior to early ART, can reappear and persist after interruption of suppressive ART containing two nucleoside/nucleotide analogue reverse transcriptase inhibitors and a ritonavir-boosted protease inhibitor.
Clinicaltrials.gov NCT00537966.
PLoS ONE 01/2011; 6(7):e21734. · 4.09 Impact Factor
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Alexandra U Scherrer,
Viktor von Wyl,
Jürg Böni,
Sabine Yerly,
Thomas Klimkait,
Philippe Bürgisser,
Christian Garzoni,
Bernard Hirschel,
Matthias Cavassini,
Manuel Battegay,
Pietro L Vernazza,
Enos Bernasconi,
Bruno Ledergerber,
Huldrych F Günthard
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ABSTRACT: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs.
The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response.
One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively.
Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2011; 57(1):24-31. · 4.43 Impact Factor
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Adrian Schmid,
Sara Gianella,
Viktor von Wyl,
Karin J Metzner, Alexandra U Scherrer,
Barbara Niederöst,
Claudia F Althaus,
Philip Rieder,
Christina Grube,
Beda Joos,
Rainer Weber,
Marek Fischer,
Huldrych F Günthard
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ABSTRACT: Although combination antiretroviral therapy (cART) initiated in the acute phase of HIV-1 infection may prevent expansion of the latent reservoir, its benefits remain controversial. In the current study, HIV-1 RNA transcription patterns in peripheral blood mononuclear cells (PBMC) were monitored during acute cART to assess the effect of early treatment on cellular viral reservoirs.
Acutely HIV-1 infected patients (n = 24) were treated within 3-15 weeks after infection. Patients elected to cease treatment after ≥1 year of therapy. HIV-1 DNA (vDNA), HIV-1 RNA species expressed both in latently and productively infected cells, unspliced (UsRNA), multiply spliced (MsRNA-tatrev; MsRNA-nef), and PBMC-associated extracellular virion RNA (vRex), expressed specifically by productively infected cells, were quantified in PBMC by patient matched real-time PCR prior, during and post cART. In a matched control-group of patients on successful cART started during chronic infection (n = 15), UsRNA in PBMC and vDNA were measured cross-sectionally. In contrast to previous reports, PBMC-associated HIV-1 RNAs declined to predominantly undetectable levels on cART. After cART cessation, UsRNA, vRex, and MsRNA-tatrev rebounded to levels not significantly different to those at baseline (p>0.1). In contrast, MsRNA-nef remained significantly lower as compared to pretreatment (p = 0.015). UsRNA expressed at the highest levels of all viral RNAs, was detectable on cART in 42% of patients with cART initiated during acute infection as opposed to 87% of patients on cART initiated during chronic infection (Fisher's exact test; p = 0.008). Accordingly, UsRNA levels were 105-fold lower in the acute as compared to the chronic group.
Early intervention resulted in profound depletion of PBMC expressing HIV-1 RNA. This is contrary to chronically infected patients who predominantly showed continuous UsRNA expression on cART. Thus, antiretroviral treatment initiated during the acute phase of infection prevented establishment or expansion of long-lived transcriptionally active viral cellular reservoirs in peripheral blood.
PLoS ONE 01/2010; 5(10):e13310. · 4.09 Impact Factor
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ABSTRACT: Large-scale administration of anthelminthic drugs currently is the most widely used intervention for controlling morbidity due to schistosomiasis and soil-transmitted helminthiasis. An important issue is drug efficacy monitoring. However, the optimal time points post-treatment for assessing the efficacy of praziquantel against Schistosoma mansoni and albendazole against hookworm infections are not known. Forty-nine schoolchildren infected with S. mansoni and 52 infected with hookworm were treated with a single oral dose of praziquantel (40 mg/kg) and albendazole (400 mg), respectively. Stool samples were collected on 19 occasions over a 44-day post-treatment follow-up period, and two Kato-Katz thick smears per sample were examined at each time point. Both the mean egg counts and observed cure rates varied depending on the time point post-treatment. The highest reduction in the geometric mean egg counts (>97%) and the highest observed cure rate (>97%) of S. mansoni infections were found 15–20 days after praziquantel administration. Among the hookworm-infected children, egg counts decreased rapidly within the first week after albendazole administration (>95%), whereas infection rates showed high and heterogeneous (45.0–71.2%) levels at later time points. Both praziquantel and albendazole were highly efficacious in reducing the overall egg burden of S. mansoni and hookworm, respectively. We suggest that 15–20 days post-treatment is the most appropriate time point for efficacy evaluation of praziquantel against S. mansoni. Although no clear conclusion can be drawn for the optimal timing of efficacy evaluation of albendazole against hookworm, a 2–3-week time frame seems a reasonable compromise. This is justified on logistical grounds (i.e. collection of stool samples only once) and growing emphasis on integrating the control of schistosomiasis and soil-transmitted helminthiasis, including drug efficacy monitoring.
Acta tropica 11/2008; · 2.22 Impact Factor
