Baseline pVL Research Articles

Long-term follow-up of HIV-1 multi-drug-resistant treatment-experienced participants treated with etravirine, raltegravir and boosted darunavir: towards drug-reduced regimen? ANRS CO3 Aquitaine Cohort 2007–2018

To assess the efficacy of raltegravir, etravirine and darunavir/ritonavir (TRIO regimen) in treatment-experienced patients with human immunodeficiency virus-1 (HIV-1) infection by describing the proportion of patients who experienced virological failure (VF) at Week 24. The secondary objectives were to assess the HIV-1 plasma viral load (pVL) after Week 24, the proportion of patients who were receiving dual therapy or monotherapy at the last visit, and the number of deaths. Patients from the ANRS CO3 Aquitaine Cohort who were prescribed the TRIO regimen between February 2007 and September 2018 were classified into two groups based on their pVL at study inclusion: the virological failure group (VFG; pVL >50 copies/mL) and the virologically suppressed group (VSG; pVL <50 copies/mL). The impact of baseline pVL and genotypic susceptibility score (GSS) on VF was analysed. In total, 184 patients were enrolled in this study, with 123 (66.8%) in the VFG and 61 (33.2%) in the VSG. The median length of follow-up was 7.5 (interquartile range 4.1-9.6) years, and 29 (15.8%) patients died. Thirty-seven (25.5%) patients experienced VF at Week 24, including 32/145 (32.7%) in the VFG and 5/47 (10.6%) in the VSG (P<0.01). Resistance-associated mutations were detected in integrase, reverse transcriptase and protease for 7/37 (18.9%), 3/37 (8.1%) and 1/37 (2.7%) patients, respectively. High pVL and GSS at baseline were independently associated with VF. At the last visit, 76/184 (41.3%) patients were still receiving the TRIO regimen, while 55/184 (29.9%) were receiving dual therapy and 1/184 (0.5%) was receiving protease inhibitor monotherapy. Among the 56 patients receiving dual therapy or monotherapy, 51 (96.2%) had pVL <50 copies/mL. Despite a high level of mutation resistance at baseline, long-term virological follow-up was favourable and one-third of patients were eligible for drug-reducing strategies.

Dolutegravir in the long term in children and adolescents: frequent virological failure but rare acquired genotypic resistance.

Although widely recommended, data about dolutegravir efficacy in HIV-1-infected children/adolescents are scarce, limited to short-term follow-up and mainly extrapolated from studies in adults with good adherence to treatment. This study aimed to provide long-term data about the risk of virological failure (VF) and acquired genotypic resistance in children and adolescents receiving dolutegravir. This retrospective monocentric study included 134 paediatric patients who received a dolutegravir-based regimen for ≥12months in 2014-2020. Virological failure was defined as not achieving a plasma viral load (pVL) <50 copies/mL within 3 months of dolutegravir initiation or as experiencing virological rebound ≥50 copies/mL. Most of the subjects were antiretroviral therapy-experienced (90.3%), naïve from integrase inhibitors (90.3%) and displayed virological suppression at baseline (63.4%). Their median (interquartile range, IQR) age was 12.0 (8.0-15.8)years. Genotypic susceptibility score of the new regimen was ≥2 in 96% of cases. Median (IQR) follow-up was 34(22-50) months. Virological failure occurred in 43 people (32.1%), more frequently where the baseline pVL was ≥50 copies/mL (67.4% vs. 22.0%, P<0.01). M184V/I mutations in the reverse transcriptase gene were newly detected in three people with VF. Resistance to dolutegravir (mutations G118R and E138A in the integrase gene) emerged in one adolescent (0.7% of subjects, 2.3% of those with VF). Whereas VF is relatively common on dolutegravir in the paediatric population, regimens associating dolutegravir with more than one fully active drug were associated with a low rate of emergent drug resistance. This result strengthens the recommendation of dolutegravir as part of preferred combinations in children/adolescents.

An observational study of initial HIV RNA decay following initiation of combination antiretroviral treatment during pregnancy

BackgroundIn pregnancy, reduction of HIV plasma viral load (pVL) for the prevention of vertical transmission is time-constrained. The study primary objective is to investigate factors associated with faster initial HIV RNA half-life decay when combination antiretroviral treatment (cART) is initiated in pregnancy.MethodsThis was a multicentre, retrospective, observational study, conducted in south England, United Kingdom, between August 2001 and February 2018. Data were extracted from case notes of eligible women initiating cART during the index pregnancy. Anonymised data were collated and analysed centrally. Regression analyses were conducted to determine factors associated with faster HIV RNA half-life decay in the first 14 days after commencing cART (first-phase), and with achieving an undetectable maternal pVL by 36 weeks’ gestation. We then assessed whether HIV- and obstetric- related parameters differed by antiretroviral third agent class and whether the proportions of women with undetectable pVL at 36 weeks’ gestation and at delivery differed by antiretroviral third agent class.ResultsBaseline pVL was the only independent factor associated with faster first-phase HIV RNA half-life decay on commencing cART. Lower pVL on day 14 after starting cART was associated with an increased likelihood of achieving an undetectable pVL by 36 weeks’ gestation. Integrase inhibitor-based cART was associated with a faster first-phase HIV RNA half-life decay on commencing cART. Overall, 73% and 85% of women had an undetectable pVL at 36 weeks’ gestation and at delivery respectively, with no significant difference by antiretroviral third agent class.ConclusionsOnly high baseline pVL independently contributed to a faster rate of first-phase viral half-life decay. pVL at 14 days after initiating cART allows early identification of treatment failure. In the first 14 days after initiating cART in pregnancy, integrase inhibitor-based cART reduced maternal pVL faster than protease inhibitor- and non-nucleoside reverse transcriptase-based cART. While our study findings support INSTI use when initiated in pregnancy especially when initiated at later gestations and in those with higher baseline pVL, other non-INSTI based cART with more data on safety in pregnancy also performed well.

Long-acting parenteral combination antiretroviral loaded nano-drug delivery system to treat chronic HIV-1 infection: A humanized mouse model study

Human immunodeficiency virus (HIV) patients are often diagnosed in the chronic stage of HIV/AIDS. Combination antiretroviral therapy (cART) has improved quality of life for HIV-infected patients. Present study describes a novel long-acting parenteral formulation of combination antiretroviral (cARV) loaded nano-drugs for treating chronic HIV-1 (cHIV) in a humanized-BLT (hu-BLT) mice model. The cARV (elvitegravir+tenofovir alafenamide+emtricitabine; EVG+TAF+FTC) drugs (mimicking marketed Genvoya® one-pill for HIV-treatment) were encapsulated in poly (lactic-co-glycolic acid) nanoparticles (NPs). To establish cHIV, hu-BLT mice were intravaginally challenged with HIV-1 and maintained for 15 weeks. Plasma viral load (pVL) was monitored by RT-PCR to confirm cHIV. Baseline pVL (week 15) was comparable between treated (n = 10) and control (n = 5) mice groups. Subsequently, treatment hu-BLT mice received 3 subcutaneous doses of cARV NPs (417 mg/kg per dose; n = 10), biweekly, and a fourth/terminal dose a week later. Prior to each treatment and on sacrifice (week 24), pVL was determined. Within three subcutaneous doses of cARV NPs, a non-detectable pVL was established (week 19) and continued until week 22. After the establishment of a non-detectable pVL (week 19–22), 4 treated-mice were sacrificed for tissue drug concentration determination by LC-MS/MS analysis. A considerable amount of cARV was detected at the HIV-infection target and reservoir organs. Subsequently, pVL rebounded comparable to control group by week 24, (7 weeks post-terminal dosage). The present study demonstrated cARV NPs augments sustained ARV efficacy in the cHIV humanized-mouse model. Therefore, cARV NPs could be a novel delivery system to treat cHIV patients, by overcoming drawbacks of conventional cART.

Sociodemographic correlates of HIV drug resistance and access to drug resistance testing in British Columbia, Canada.

Sociodemographic correlates of engagement in human immunodeficiency virus (HIV) care are well studied, however the association with accessing drug resistance testing (DRT) and the development of drug resistance have not been characterized. Between 1996–2014, 11 801 HIV patients accessing therapy in British Columbia were observed longitudinally. A subset of 9456 patients had testable viral load; of these 8398 were linked to census data. Sociodemographic (census tract-level) and clinical (individual-level) correlates of DRT were assessed using multivariable General Estimating Equation logistic regression adjusted odds ratios (aOR). The mean number of tests per patient was 2.1 (Q1-Q3; 0–3). Separately, any drug resistance was determined using IAS-USA (2013) list for 5703 initially treatment naïve patients without baseline resistance; 5175 were census-linked (mean of 1.5 protease-reverse transcriptase sequences/patient, Q1-Q3; 0–2). Correlates of detecting drug resistance in this subset were analyzed using Cox PH regression adjusted hazard ratios (aHR). Our results indicate baseline CD4 <200 cells/μL (aOR: 1.5, 1.3–1.6), nRTI-only baseline regimens (aOR: 1.4, 1.3–1.6), and unknown (therapy initiation before routine pVL in BC) baseline pVL (aOR: 1.8, 1.5–2.1) were among individual-level clinical covariates strongly associated with having accessed DRT; while imperfect adherence (aHR: 2.2, 1.9–2.5), low baseline CD4 count (aHR: 1.9, 1.6–2.3), and high baseline pVL (aHR: 2.0, 1.6–2.6) were associated with a higher likelihood of developing drug resistance. A higher median income (aOR: 0.83, 0.77–0.89) and higher percentage of those with aboriginal ancestry (aOR: 0.85, 0.76–0.95) were census tract-level sociodemographic covariates associated with decreased access to DRT. Similarly, aboriginal ancestry (aHR: 1.2, 1.1–1.5) was associated with development of drug resistance. In conclusion, clinical covariates continue to be the strongest correlates of development of drug resistance and access to DRT for individuals. Regions of high median income and high aboriginal ancestry were weak census-level sociodemographic indicators of reduced DRT uptake, however high aboriginal ancestry was the only sociodemographic indicator for development of drug resistance.

Dolutegravir in HIV-2-Infected Patients With Resistant Virus to First-line Integrase Inhibitors From the French Named Patient Program.

Dolutegravir has shown in vitro activity against human immunodeficiency virus type 2 (HIV-2). We report safety and efficacy data of regimens containing dolutegravir (50 mg twice daily) in antiretroviral-experienced, HIV-2-infected patients. HIV-2-infected patients experiencing virological failure to raltegravir received dolutegravir with optimized background antiretroviral combinations within the French Named Patient Program (NPP). Plasma HIV-2 RNA (pVL) was assessed at time of dolutegravir initiation (baseline), month 3, and month 6. Antiretroviral trough plasma concentrations (C12h) were determined using liquid chromatography coupled with tandem mass spectrometry. Thirteen HIV-2-infected-patients, with a median duration of 15 years' infection and given 16 previous antiretroviral regimens, were included in NPP. Median follow-up was 9 months (min-max, 3-15 months). Median baseline pVL and CD4 cell count were 9544 copies/mL (inter quartile range [IQR], 3096-23 120 copies/mL) and 100 cells/µL (IQR, 77-171 cells/µL), respectively. Available integrase genotypic resistance patterns were Y143C/G/H/R (n = 5), Q148R/K (n = 2), and N155H (n = 4). Optimized background antiretroviral regimens conferring a genotypic sensitivity score ≤2 in 10 patients included nucleoside reverse transcriptase inhibitors associated with darunavir/ritonavir (n = 12), saquinavir/ritonavir (n = 2), and maraviroc (n = 3). At months 3 and 6, pVL was undetectable in 6 of 13 and 4 of 12 patients, respectively, and median CD4 count was 161 (101-188) cells/µL and 167 (135-1353) cells/µL, respectively. Median dolutegravir C12h was 4086 (1756-5717 ng/mL) ng/mL in 9 patients. No serious events were notified except 1 death from progressive multifocal leukoencephalopathy at month 4. Optimized dolutegravir-containing antiretroviral regimens supported by good plasma exposure provide a substantial initial efficacy rate for salvage therapy in heavily antiretroviral-experienced HIV-2-infected patients with virus harboring resistance to first-generation integrase inhibitors. Larger numbers of patients and longer follow-up are needed to confirm these findings.

Predictive Factors of Plasma HIV Suppression during Pregnancy: A Prospective Cohort Study in Benin

ObjectiveTo investigate the factors associated with HIV1 RNA plasma viral load (pVL) below 40 copies/mL at the third trimester of pregnancy, as part of prevention of mother-to-child transmission (PMTCT) in Benin.DesignSub study of the PACOME clinical trial of malaria prophylaxis in HIV-infected pregnant women, conducted before and after the implementation of the WHO 2009 revised guidelines for PMTCT.MethodsHIV-infected women were enrolled in the second trimester of pregnancy. Socio-economic characteristics, HIV history, clinical and biological characteristics were recorded. Malaria prevention and PMTCT involving antiretroviral therapy (ART) for mothers and infants were provided. Logistic regression helped identifying factors associated with virologic suppression at the end of pregnancy.ResultsOverall 217 third trimester pVLs were available, and 71% showed undetectability. Virologic suppression was more frequent in women enrolled after the change in PMTCT recommendations, advising to start ART at 14 weeks instead of 28 weeks of pregnancy. In multivariate analysis, Fon ethnic group (the predominant ethnic group in the study area), regular job, first and second pregnancy, higher baseline pVL and impaired adherence to ART were negative factors whereas higher weight, higher antenatal care attendance and longer ART duration were favorable factors to achieve virologic suppression.ConclusionsThis study provides more evidence that ART has to be initiated before the last trimester of pregnancy to achieve an undetectable pVL before delivery. In Benin, new recommendations supporting early initiation were well implemented and, together with a high antenatal care attendance, led to high rate of virologic control.

Similar virologic response after initiation of triple-class antiretroviral therapy in primary and chronic HIV infection

Similar virologic response after initiation of triple-class antiretroviral therapy in primary and chronic HIV infection

“Dynamic Range” of Inferred Phenotypic HIV Drug Resistance Values in Clinical Practice

Background‘Virtual’ or inferred phenotypes (vPhenotypes) are commonly used to assess resistance to antiretroviral agents in patients failing therapy. In this study, we provide a clinical context for understanding vPhenotype values.MethodsAll HIV-infected persons enrolled in the British Columbia Drug Treatment Program with a baseline plasma viral load (pVL) and follow-up genotypic resistance and pVL results were included up to October 29, 2008 (N = 5,277). Change from baseline pVL was determined as a function of Virco vPhenotype, and the “dynamic range” (defined here by the 10th and 90th percentiles for fold-change in IC50 amongst all patients) was estimated from the distribution of vPhenotye fold-changes across the cohort.ResultsThe distribution of vPhenotypes from a large cohort of HIV patients who have failed therapy are presented for all available antiretroviral agents. A maximum change in IC50 of at least 13-fold was observed for all drugs. The dideoxy drugs, tenofovir and most PIs exhibited small “dynamic ranges” with values of <4-fold change observed in >99% of samples. In contrast, zidovudine, lamivudine, emtricitabine and the non-nucleoside reverse transcriptase inihibitors (excluding etravirine) had large dynamic ranges.ConclusionWe describe the populational distribution of vPhenotypes such that vPhenotype results can be interpreted relative to other patients in a drug-specific manner.

Transient Lowering of the Viral Set Point After Temporary Antiretroviral Therapy of Primary HIV Type 1 Infection

Whether temporary antiretroviral treatment during primary HIV infection (PHI) lowers the viral set point or affects the subsequent CD4 count decline remains unclear. The objectives of this study were to analyze the clinical, viral, and immunological effects of temporary early HAART during PHI. This is a cohort study of patients with laboratory evidence of PHI. Independent predictors of early HAART and the viral set point were analyzed using multiple regression analysis. Plasma HIV-1 RNA (pVL) and CD4 trajectories were analyzed using linear mixed models. A total of 332 patients were included in the analysis. Sixty-four patients started HAART within 180 days of seroconversion. A higher baseline pVL was independently predictive of the start of early HAART (OR: 2.69/log10pVL, p = 0.001). Thirty-two patients who interrupted early HAART were compared with 250 patients who remained untreated for more than 180 days after seroconversion. Temporary early HAART was not significantly associated with a longer AIDS-free survival but did result in an initial, but transient lowering of the viral set point. The viral set point was initially 0.6 log copies/ml lower after interruption of early HAART (p < 0.001) and remained lower during 83 weeks of follow-up. No significant difference in the slopes of CD4 decline was detected between the groups. Temporary HAART in PHI is started more frequently in patients with a higher pVL and can transiently lower the viral set point compared to never treated patients.

Virologic and Immunologic Efficacy of the Tenofovir/Didanosine/Lamivudine Regimen

To the Editor: Antiretroviral regimens combining the nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TDF), lamivudine (3TC), and abacavir or didanosine (ddI) have recently been linked to unexpectedly high rates of virologic failure, raising serious concerns about NRTI-only strategies. The European Agency for Evaluation of Medicinal Products recommended that the TDF/ddI/3TC combination should not be used, particularly as a once-a-day (OAD) regimen.1 This combination is frequently associated with the emergence of the K65R and M184V/I mutations.2 However, there is evidence that thymidine-associated mutations (TAMs) may protect against virologic failure and K65R selection during this treatment.3-6 The combination of TDF, 3TC, and abacavir or ddI therefore appears to provide a low genetic barrier to resistance, especially in previously untreated patients, as suggested by the results of in vitro studies and retrospective cohorts.7-11 Coadministration of TDF and a ddI dose of 400 mg/day appears to have a deleterious effect on the CD4 cell count, despite complete viral suppression. An imbalance in adenosine metabolites resulting from TDF inhibition of purine nucleoside phosphorylase in CD4 cells may explain this phenomenon.12-14 We reviewed the files of all consecutive patients who had been prescribed TDF 300 mg, didanosine 250 mg (reduced dose), and 3TC 300 mg daily, in an OAD schedule, between January 2002 and December 2004 in our center unit. Changes in the CD4 T-cell count and plasma viral load (pVL) were analyzed, together with the results of genotypic testing at baseline and during treatment. The patients were stratified by the baseline pVL (< or >500 copies/mL). Kaplan-Meier analysis was used to compare the outcomes in the 2 strata. Forty-two patients were enrolled, of whom 64% were men. The median age was 39.0 years (range, 24.7-58.2 years). The median duration of previous antiretroviral therapy was 6.3 years (range, 0-14.2 years), and the patients had received a median of 4 lines (range, 0-24 lines) of antiretroviral therapy. Three patients (7%) were antiretroviral-naive. The median duration of the OAD regimen was 16.8 months (range, 10.6-29.8 months). The median baseline CD4 cell count was 429.5 cells/mm3 (range, 9.3-1578 cells/mm3), and the baseline pVL was 3.25 log10 copies/mL (range, 1.7-5.7 log10 copies/mL). Genotyping showed that 31% of the patients had at least 3 TAMs at baseline. None of the antiretroviral-experienced patients developed the K65R mutation during the OAD regimen. In contrast, all 3 antiretroviral-naive patients developed both K65R and M184V mutations and had virologic failure. Overall, the slope of the CD4 cell count during the study period was -18.1/year (range, -594.3-1041.8/year). The median CD4 cell count did not differ significantly between baseline and the end of follow-up (P = 0.56). Overall, 52% of patients had a sustained pVL of less than 500 copies/mL (47.4% <50 copies/mL) after 96 weeks of follow-up. Nineteen patients had a baseline pVL of less than 500 copies/mL. Kaplan-Meier analysis showed a significant difference in pVL kinetics between the 2 strata (Fig. 1), whereas the CD4 cell count kinetics were similar (median, -29/year [range, -362-1042/year], P = 0.32 vs 13/year [range, -170-594], P = 0.47). Overall, the median CD4 cell count did not fall relative to baseline.FIGURE 1: Kaplan-Meier analysis: time on treatment (3TC-ddI-TDF).Experienced patients who switched to the OAD regimen when they already had undetectable plasma viremia continued to have a sustained virologic response, despite the presence of TAMs, such as T215Y, or the 3TC-associated mutation M184V at baseline. No resistance mutations specific for TDF were present at baseline in experienced patients. The results of this observational cohort study show the efficacy of the triple NRTI regimen consisting of TDF, ddI, and 3TC. The results are less worrisome than those of previous studies of triple NRTI regimens in naive patients and/or with ddI standard dosing. Indeed, low-dose ddI plus TDF and 3TC provided sustained virologic control and CD4 cell count stability. Romina Quercia, MD* Corinne Amiel, MD† Elisete Da Silva Marechal, MS* Marie-Gisèle Lebrette, MD* Sandrine Thevenet, CRA* Stéphanie Renaud, PD‡ Veéronique Schneider, MD† Ali Kara, MD† Sabine Guessant, DP‡ Gilles Pialoux, MD, PhD* *Infectious Disease Unit †Virology, ‡Pharmacy Tenon Hospital, Paris, France [email protected]

Viral dynamics after starting first-line HAART in HIV-1-infected children

After starting HAART, the plasma HIV-1 RNA (pVL) declines rapidly to undetectable levels in most treated adults and children. The viral dynamics in children are assumed to differ from those in adults. Therefore viral decay and time to reach a pVL of < 400 copies/ml during the first weeks after starting HAART were studied in a cohort of HIV-1-infected children. Viral decay expressed as half-life and time to reach a pVL of < 400 copies/ml in 39 HIV-1-infected children starting HAART were calculated and correlated with age, pretreatment with antiretroviral mono- or duo-therapy, and baseline pVL. Baseline pVL correlated with age (r, -0.41; P = 0.01). Median half-life of the virus was 2.1 days (interquartile range, 1.8-3.0 days). No correlation was found between the half-life of the virus and the baseline pVL at the start of treatment, antiretroviral pretreatment or age. Eight children did not reach a pVL of < 400 copies/ml with the first allocated medication regimen. These children were significantly younger than those in whom HIV was successfully suppressed (P = 0.009). The remaining 31 children reached a pVL of < 400 copies/ml in a median of 8.1 weeks after the start of therapy; time to reach a pVL of < 400 copies/ml was only correlated with baseline pVL. These results suggest that pVL at baseline correlated with age. HAART was able to suppress pVL below the lower limit of detection in children with a viral decay rate of 2.1 days, similar to adults and irrespective of baseline pVL.

Effectiveness and Safety of Abacavir, Lamivudine, and Zidovudine in Antiretroviral Therapy-Naive HIV-Infected Patients

To analyze the safety and effectiveness of abacavir, lamivudine, and zidovudine (ABC/3TC/ZDV) in antiretroviral therapy (ART)-naive HIV-infected patients. Retrospective observational cohort study. We analyzed all consecutive ART-naive HIV-infected patients who initiated ABC/3TC/ZDV in 71 centers throughout Spain and had a clinical visit and laboratory data at least 16 weeks after initiating this regimen. We assessed safety, mortality, new AIDS-defining conditions (ADCs) and treatment failure, the latter defined by any of the following: (1) reduction in plasma HIV-1 viral load (pVL) <1 log during the first 12 weeks of ART, unless it was less than the lower limit of quantification (LOQ); (2) failure to achieve a pVL <LOQ after 24 weeks of ART; and (3) rebound to 2 consecutive pVLs > or = LOQ after achieving a pVL <LOQ. A total of 730 patients were included, median patient age was 37 years, prior ADCs occurred in 20%, median pVL was 4.76 log, and median CD4 count was 255 cells/mm; 109 (14.9%) patients had <100 CD4 cells/mm. After a median follow-up of 50.5 weeks (interquartile ratio: 28-78), 104 (14.25%) patients discontinued therapy because of adverse events and 36 (4.93%) had a suspected hypersensitivity reaction to ABC. The frequency of treatment failure according to an intention-to-treat (ITT) analysis of observed data was 14.4%. In a more rigorous approach considering losses to follow-up and interruptions or switches of therapy as failures, however, the frequency of treatment failure was 22.92%. Factors independently associated with treatment failure by observed data ITT analysis were adherence <90% (hazard ratio [HR] = 4.248, 95% confidence interval [CI]: 2.640 to 6.833), methadone use (HR = 2.116, 95% CI: 1.180 to 3.797), baseline pVL (HR = 1.651, 95% CI: 1.190 to 2.292 per log), and prior ADC (HR = 1.639, 95% CI: 1.009 to 2.662). The triple-nucleoside regimen of ABC/3TC/ZDV is a reasonable option for ART-naive patients with a pVL <100,000 copies/mL in whom, for any reason, preferred regimens are not advisable, even in patients with a baseline CD4 cell count <100 cells/mm.

Immunologic Response to Antiretroviral Therapy in Hepatitis C Virus–Coinfected Adults in a Population‐Based HIV/AIDS Treatment Program

We sought to characterize the impact that hepatitis C virus (HCV) infection has on CD4 cells during the first 48 weeks of antiretroviral therapy (ART) in previously ART-naive human immunodeficiency virus (HIV)-infected patients. The HIV/AIDS Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS distributes all ART in this Canadian province. Eligible individuals were those whose first-ever ART included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor and who had a documented positive result for HCV antibody testing. Outcomes were binary events (time to an increase of > or = 75 CD4 cells/mm3 or an increase of > or = 10% in the percentage of CD4 cells in the total T cell population [CD4 cell fraction]) and continuous repeated measures. Statistical analyses used parametric and nonparametric methods, including multivariate mixed-effects linear regression analysis and Cox proportional hazards analysis. Of 1186 eligible patients, 606 (51%) were positive and 580 (49%) were negative for HCV antibodies. HCV antibody-positive patients were slower to have an absolute (P<.001) and a fraction (P = .02) CD4 cell event. In adjusted Cox proportional hazards analysis (controlling for age, sex, baseline absolute CD4 cell count, baseline pVL, type of ART initiated, AIDS diagnosis at baseline, adherence to ART regimen, and number of CD4 cell measurements), HCV antibody-positive patients were less likely to have an absolute CD4 cell event (adjusted hazard ratio [AHR], 0.84 [95% confidence interval [CI], 0.72-0.98]) and somewhat less likely to have a CD4 cell fraction event (AHR, 0.89 [95% CI, 0.70-1.14]) than HCV antibody-negative patients. In multivariate mixed-effects linear regression analysis, HCV antibody-negative patients had increases of an average of 75 cells in the absolute CD4 cell count and 4.4% in the CD4 cell fraction, compared with 20 cells and 1.1% in HCV antibody-positive patients, during the first 48 weeks of ART, after adjustment for time-updated pVL, number of CD4 cell measurements, and other factors. HCV antibody-positive HIV-infected patients may have an altered immunologic response to ART.

Foscarnet Salvage Therapy for Patients with Late-Stage HIV Disease and Multiple Drug Resistance

To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance. 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. 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. In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status.

Therapeutic Immunization with Dendritic Cells Loaded with Heat‐Inactivated Autologous HIV‐1 in Patients with Chronic HIV‐1 Infection

Therapeutic immunization with autologous monocyte-derived dendritic cells (DCs) loaded with heat-inactivated autologous human immunodeficiency virus type 1 (HIV-1) in 12 patients with chronic HIV-1 infection who were receiving highly active antiretroviral therapy (HAART) was feasible, safe, and well tolerated. Virus was obtained during an initial interruption of HAART (hereafter, "stop 1") so that DCs could be pulsed. After immunization and a second interruption of HAART (hereafter, "stop 2"), set-point plasma viral load (PVL; 24 weeks after stop 2) decreased > or =0.5 log(10) copies/mL relative to baseline PVL in 4 of 12 patients. We observed a significant lengthening in mean doubling time of PVL rebound and significant decreases in the area under the curve and the mean peak of PVL rebound after stop 2, compared with those after stop 1. This response was associated with changes in HIV-1-specific CD4(+) lymphoproliferative and CD8(+) T cell responses. These changes were not observed in a group of nonimmunized control patients.

Predictors of HIV Drug‐Resistance Mutations in a Large Antiretroviral‐Naive Cohort Initiating Triple Antiretroviral Therapy

The objective of this study was to systematically characterize the incidence and determinants of antiretroviral resistance in the HOMER (Highly Active Antiretroviral Therapy [HAART] Observational Medical Evaluation and Research) cohort of 1191 human immunodeficiency virus-infected, antiretroviral-naive adults initiating HAART in British Columbia, Canada. All plasma samples with plasma virus loads (pVLs) >1000 copies/mL collected during the first 30 months of follow-up were genotyped for drug resistance. The primary outcome measure was time to the first detection of major drug-resistance mutation(s). Cox proportional hazard regression was used to identify factors significantly associated with the detection of drug-resistance mutations. Drug-resistance mutations were detected in 298 subjects (25%). Factors significantly associated with detection of drug-resistance mutations included high baseline pVL (multivariate hazard ratio [HR], 1.59; P<.001) and adherence (estimated using prescription-refill data and/or untimed plasma drug-concentration measurements). When compared with subjects with low (0%-<20%) prescription-refill percentages, subjects at an elevated risk of harboring drug-resistance mutations were those with relatively high but imperfect prescription-refill percentages (80%-<90%; multivariate HR, 4.15; P<.001) and those with essentially perfect (>/=95%) refill percentages but with 2 plasma drug concentrations below the steady-state trough concentration minus 1 standard deviation (multivariate HR, 4.57; P<.001). Initial use of nonnucleoside reverse-transcriptase inhibitor-based HAART was significantly associated with multiclass drug resistance (multivariate HR, 1.84; P=.001). High baseline pVLs and substantial but imperfect levels of adherence were major predictors of antiretroviral resistance.

Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy.

To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based first-line highly active antiretroviral therapy (HAART). A retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive patients initiating either PI-based or NVP-based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason. In total, 920 and 109 patients initiated PI- and NVP-based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/microL in the NVP group) and had higher median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/microL in the PI group and 212 cells/microL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/microL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes. Patients successfully treated with NVP-based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI-based HAART.

Immunological and virological factors at baseline may predict response to structured therapy interruption in early stage chronic HIV-1 infection.

The objective was to analyse which baseline factors could predict a favourable outcome after structured therapy interruption (STI). Data of three Spanish pilot studies of STI in early stage chronic HIV-1-infected patients were analysed. A set of 37 variables at baseline was used. Plasma and tonsillar tissue viral load (VL), lymphocyte immunophenotyping and proliferative responses (LPR) to mitogens and specific antigens, and HIV-1 specific cytotoxic T lymphocyte responses were assessed at baseline. Response was defined as a VL set-point after 6 months off antiretroviral therapy after the last interruption of < 5000 copies/ml and 0.5 log(10) below baseline PVL before any antiretroviral therapy. After STI, the 44 patients were classified as follows: 18 (41%) as responders, 26 (59%) as non-responders. In the univariate analysis patients who responded had a significantly lower baseline level of CD4CD38 (P = 0.0068) and naive CD4 T cells (P = 0.03), and a higher level of memory CD4 T cells (P = 0.03) and proliferative response to tetanus toxoid (TT) (P = 0.01) and HIV-1 p24 (P = 0.03) than non-responders. A model incorporating five qualitative variables transformed according to the median value (CD4CD38, CD4 naive and memory T cells and stimulation index to TT and HIV-1 p24) at baseline could classify 97% of patients correctly (P = 0.0001). A level of memory CD4 T cells and proliferative response to recall antigens above the median may predict a good response to STI, suggesting that preserved memory response in CD4 T cells is important factor.

A Randomized Clinical Trial Comparing Nelfinavir Or Nevirapine Associated to Zidovudine/Lamivudine in HIV-Infected Naive Patients (The Combine Study)

Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed. To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients. Randomized, open-label, multicentre trial. Twelve centres in Spain (9) and Argentina (3). One hundred and forty-two HIV-infected naive patients without AIDS. Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis. At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5-71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65-85) in the zidovudine/lamivudine/nevirapine arm (P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3-61.7) and 65% (95% CI 54.2-76.2), respectively (P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100,000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/nevirapine in 25%, due to toxicity (P>0.2). Our results suggest that zidovudine/lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.