Determinants of response to first HAART regimen in antiretroviral-naïve patients with an estimated time since HIV seroconversion

Objective

To study the determinants of immunological and virological response to highly active antiretroviral therapy (HAART) in naïve patients, adjusting for time since HIV‐1 seroconversion.

Design

Data from HIV‐cohort studies where dates of seroconversion have been reliably estimated.

Methods

In previously untreated patients, short‐ and long‐term marker responses from HAART initiation (three or more antiretroviral drugs) to the end of follow‐up or any treatment modification were considered using mixed effects models accounting for undetectable HIV viral load and informative dropout.

Results

In total, 943 patients were treated with a first HAART regimen for a median of 29 months. In adjusted analyses, compared with a reference group of homosexual men without AIDS initiating treatment 4 years after seroconversion, injecting drug users (IDUs) were treated at similar CD4 and HIV RNA levels but had poorer short‐term virological response (2.54 vs 2.13 log₁₀ HIV‐1 RNA copies/mL at 1.5 months, P=0.03) and poorer long‐term immunological response (522 vs 631 cells/μL at 24 months, P<0.0001). Although individuals with AIDS at HAART initiation had lower CD4 counts (206 vs 382 cells/μL, P<0.0001), their immunological responses were similar to those of individuals without AIDS. Similarly, individuals further from seroconversion started HAART at lower CD4 counts (e.g. 311 vs 382 cells/μL at vs before 9 years from seroconversion, P<0.0001), but had similar CD4 responses. However, they experienced poorer long‐term virological response (0.67 log₁₀ copies/mL/year smaller decline, P<0.0001) compared to those treated before 9 years from seroconversion.

Conclusion

Taking into account the time elapsed since seroconversion, this study suggests that careful choices of initial treatment should be made and intensive follow‐up carried out in high‐risk subgroups such as IDUs who have poorer responses.

     

Nevirapine- versus efavirenz-based highly active antiretroviral therapy regimens in antiretroviral-naïve patients with advanced HIV infection

Objective

To compare virological and immunological responses to nevirapine (NVP)‐based and efavirenz (EFV)‐based highly active antiretroviral therapy (HAART) regimens in antiretroviral‐naïve patients with advanced HIV infection.

Methods

A retrospective observational cohort study was conducted on antiretroviral‐naïve HIV‐infected patients whose pretreatment CD4 cell counts were less than 100 cells/μL or whose viral loads were greater than 100 000 HIV‐1 RNA copies/mL.

Results

Baseline characteristics of patients in the NVP (n=24) and EFV (n=29) groups were not different. The proportion of patients with viral loads >100 000 copies/mL was higher in the EFV group. The probability of virological success estimated by the Kaplan‐Meier method showed that 3‐ and 6‐month success rates were 30.8% [95% confidence interval (CI): 16.7–52.2%] and 63.1% (95% CI: 44.7–81.3%) for the NVP group. The corresponding values were 41.2% (95% CI: 25.8–61.0%) and 62.9% (95% CI: 45.7–80.1%) for the EFV‐based group. The median success times of the two groups were about 4 and 3 months (P=0.678), respectively, for NVP and EFV. Cox's proportional hazard was used after adjusting for age, previous opportunistic infections (OIs), and viral load at baseline, and showed that patients who received the NVP‐based regimen had about 25% [hazard ratio (HR)=0.75, 95% CI: 0.37–1.51] less chance of virological success than patients who received the EFV‐based regimen (P=0.415). The median times to CD4≥100 cells/μL were 5.6 and 4.4 months for the NVP‐ and EFV‐based regimens, respectively (log‐rank test, P=0.144).

Conclusions

NVP‐ and EFV‐based HAART regimens as initial regimens in patients with advanced HIV infection are effective and comparable, in term of virological and immunological responses. However, further large‐scale randomized controlled clinical trials in this group of patients with advanced HIV infection are needed.

     

Superior virological response to boosted protease inhibitor-based highly active antiretroviral therapy in an observational treatment programme

Background

The use of boosted protease inhibitor (PI)‐based antiretroviral therapy has become increasingly recommended in international HIV treatment consensus guidelines based on the results of randomized clinical trials. However, the impact of this new treatment strategy has not yet been evaluated in community‐treated cohorts.

Methods

We evaluated baseline characteristics and plasma HIV RNA responses to unboosted and boosted PI‐based highly active antiretroviral therapy (HAART) among antiretroviral‐naïve HIV‐infected patients in British Columbia, Canada who initiated HAART between August 1997 and September 2003 and who were followed until September 2004. We evaluated time to HIV‐1 RNA suppression (<500 HIV‐1 RNA copies/mL) and HIV‐1 RNA rebound (≥500 copies/mL), while stratifying patients into those that received boosted and unboosted PI‐based HAART as the initial regimen, using Kaplan–Meier methods and Cox proportional hazards regression.

Results

During the study period, 682 patients initiated therapy with unboosted PI and 320 individuals initiated HAART with a boosted PI. Those who initiated therapy with a boosted PI were more likely to have a CD4 cell count <200 cells/μL and to have a plasma HIV RNA>100 000 copies/mL, and to have AIDS at baseline (all P<0.001). However, when we examined virological response rates, those who initiated HAART with a boosted PI achieved more rapid virological suppression [relative hazard 1.26, 95% confidence interval (CI) 1.06–1.51, P=0.010].

Conclusions

Patients prescribed boosted PIs achieved superior virological response rates despite baseline factors that have been associated with inferior virological responses to HAART. Despite the inherent limitations of observational studies which require this study be interpreted with caution, these findings support the use of boosted PIs for initial HAART therapy.

     

Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months

Objective

To quantify HIV‐RNA in plasma, in lymphoid tissue and proviral DNA in peripheral blood mononuclear cells and to relate these to immunological markers among patients with plasma viral load counts of ≤ 200 HIV‐RNA copies/mL.

Methods

A prospective study of one hundred and three patients was undertaken with an inclusion criteria of plasma viral load of ≤ 200 copies/mL. The patients had advanced HIV infection; 25% had developed AIDS. Patients were seen every 6 months for a period of 2 years.

Results

The median plasma viral load was < 20 copies/mL with no increase during follow‐up. Thirty‐one per cent had plasma viral load of ≤ 20 copies/mL at all visits, 44% had ≥ 1 measurement with 21–200 and 25% had ≥ 1 sample with plasma HIV‐RNA > 200 copies/mL. Lymphoid tissue viral load was low at enrolment and declined further during follow‐up. Baseline HIV‐DNA and immunoglobulin (IgA) differed significantly between the plasma viral load rebound groups (P < 0.05).

Conclusion

In this cohort, selected solely on the basis of having a plasma viral load of ≤ 200 copies/mL, we found stable or declining viral loads in the measured compartments during 2 years of follow‐up. Baseline HIV‐DNA and IgA levels were higher among patients with less complete virological suppression relative to patients with persistently undetectable plasma HIV‐RNA. Hence, a high cellular level of HIV‐DNA and high plasma IgA may predict subsequent development of low‐grade viraemia.

     

CD4 percentage is an independent predictor of survival in patients starting antiretroviral therapy with absolute CD4 cell counts between 200 and 350 cells/microL

Objective

To determine the prognostic value of baseline CD4 percentage in terms of patient survival in comparison to absolute CD4 cell counts for HIV‐positive patients initiating highly active antiretroviral therapy (HAART).

Methods

A population‐based cohort study of 1623 antiretroviral therapy‐naïve HIV‐positive individuals who initiated HAART between 1 August 1996 and 30 June 2002 was conducted. Cumulative mortality rates were estimated using Kaplan–Meier methods. Cox proportional hazards regression was used to model the effect of baseline CD4 strata and CD4 percentage strata and other prognostic variables on survival. A subgroup analysis was conducted on 417 AIDS‐free subjects with baseline CD4 counts between 200 and 350 cells/μL.

Results

In multivariate models, low CD4 percentages were associated with increased risk of death [CD4%<5, relative hazard (RH)=4.46; CD4% 5–14, RH=2.43; P<0.01 for both] when compared with those subjects with an initial CD4 fraction of 15% or greater, but had less predictive value than absolute CD4 counts. In subgroup analyses where absolute CD4 strata were not associated with mortality, a baseline CD4 fraction below 15% [RH=2.71; 95% confidence interval (CI) 1.20–6.10], poor adherence to therapy and baseline viral load >100 000 HIV‐1 RNA copies/mL were associated with an increased risk of death.

Conclusion

CD4 percentages below 15% are independent predictors of mortality in AIDS‐free patients starting HAART, including those with CD4 counts between 200 and 350 cells/μL. CD4 percentage should be considered for inclusion in guidelines used to determine when to start therapy.

     

Effectiveness and tolerability of a once-daily amprenavir/ritonavir-containing highly active antiretroviral therapy regimen in antiretroviral-naïve patients at risk for nonadherence: 48-week results after 24 weeks of directly observed therapy

Objectives

To determine the safety and effectiveness of a once‐daily highly active antiretroviral therapy (HAART) regimen in patients at risk for poor adherence using directly observed therapy (DOT) for 24 weeks followed by weekly phone contact for another 24 weeks.

Methods

A prospective, open‐label pilot study was carried out. Antiretroviral‐naïve patients with advanced HIV disease were treated with once‐daily amprenavir 1200 mg, ritonavir 200 mg, didanosine 400 mg and lamivudine 300 mg. After 24 weeks, DOT was substituted by weekly phone contact. Measurements of viral load and CD4 cell count, and safety laboratory measurements, were taken regularly for 48 weeks.

Results

Twenty‐two patients were enrolled in the study, of whom 19 completed at least 4 weeks of treatment. Seventeen patients completed 24 weeks and 13 completed 48 weeks. None discontinued treatment as a result of adverse events. The median baseline HIV viral load was 5.29 log₁₀ HIV‐1 RNA copies/mL and the median CD4 cell count was 20 cells/μL. At weeks 24 and 48, 74% of the patients had viral loads <400 copies/mL. At 48 weeks, the median decrease in viral load from baseline was 3.06 log₁₀ copies/mL, and the median increase in CD4 cell count was 118 cells/μL. The median trough plasma amprenavir concentrations at weeks 1 and 24 were 1.87 and 1.42 μg/mL, respectively.

Conclusions

This study suggests that DOT followed by weekly patient contact results in good treatment outcome in this challenging population. The median trough plasma amprenavir concentrations were above the effective concentration of drug that resulted in 90% inhibition of viral load in vivo (EC₉₀) for wild‐type HIV.

     

Serum lipid profile in highly active antiretroviral therapy‐naïve HIV‐infected patients in Cameroon: a case–control study

Background

HIV status has commonly been found to affect the serum lipid profile.

Objectives

The aim of this study was to determine the effect of HIV infection on lipid metabolism; such information may be used to improve the management of HIV‐infected patients.

Methods

Samples were collected from December 2005 to May 2006 at Yaounde University Teaching Hospital, Yaounde, Cameroon. Lipid parameters were obtained using colorimetric enzyme assays, while low‐density lipoprotein cholesterol (LDLC) values were calculated using the formula of Friedewald et al. (1972) and atherogenicity index by total cholesterol (TC)/high‐density lipoprotein cholesterol (HDLC) and LDLC/HDLC ratios.

Results

HIV infection was most prevalent in subjects aged 31 to 49 years. Most of the HIV‐positive patients belonged to Centers for Disease Control and Prevention categories B (43.0%) and C (30.23%). Compared with control subjects, patients with CD4 counts<50 cells/μL had significantly lower TC (P<0.0001) and LDLC (P<0.0001) but significantly higher triglyceride (TG) values (P<0.001) and a higher atherogenicity index for TC/HDLC (P<0.01) and HDLC/LDLC (P=0.02); patients with CD4 counts of 50–199 cells/μL had significantly lower TC (P<0.001) and significantly higher TG values (P<0.001); patients with CD4 counts of 200–350 cells/μL had significantly higher TG (P=0.003) and a higher atherogenicity index for TC/HDLC (P<0.0002) and HDLC/LDLC (P=0.04); and those with CD4 counts >350 cells/μL had a higher atherogenicity index for TC/HDLC (P<0.0001) and HDLC/LDLC (P<0.001). HDLC was significantly lower in HIV‐positive patients irrespective of the CD4 cell count. Lipid parameters were also influenced by the presence of opportunistic infections (OIs).

Conclusion

HIV infection is associated with dyslipidaemia, and becomes increasingly debilitating as immunodeficiency progresses. HDLC was found to be lower than in controls in the early stages of HIV infection, while TG and the atherogenicity index increased and TC and LDLC decreased in the advanced stages of immunodeficiency.

     

A randomized placebo-controlled trial of adefovir dipivoxil in advanced HIV infection: the ADHOC trial

Objectives

To assess the efficacy and safety of adefovir dipivoxil (ADV) added to stable background antiretroviral therapy (ART) in HIV‐infected individuals with advanced HIV disease.

Methods

ADHOC was a randomized, double‐blind, placebo‐controlled, international multicentre trial. Three hundred and one individuals with CD4 cell counts < 100 cells/μL or < 200 cells/μL with nadir < 50 cells/μL were allocated to receive either 120 mg ADV (subsequently 60 mg) (n = 161) or matching placebo (n = 140) once daily.

Results

Over a median follow‐up of 76 weeks, 23 (14%) and 18 (13%) participants assigned ADV and placebo, respectively, developed a new AIDS event or died (hazard ratio = 1.23, 95% confidence interval 0.66–2.29, P= 0.51). There was a lower incidence of new or recurrent herpes events in the ADV group (P = 0.009). The mean increase in CD4 cell count from baseline to week 24 was 23.0 and 24.4 cells/µL in ADV and placebo groups, respectively (P = 0.89), and the mean decrease in RNA was 0.32 and 0.35 log₁₀ copies/mL at week 24 (P = 0.87) in a subset of participants. There was greater weight loss in the ADV group during the trial (P = 0.007). One hundred and twenty‐four participants (41%) had stable background ART in the 8 weeks prior to and the 24 weeks after randomization. There was no significant imbalance in background ART regimens between the two treatment groups. Ninety‐seven serious adverse events (SAEs) occurred, 65 and 32 in the ADV and placebo groups, respectively, with significantly shorter time to first SAE in the ADV group (P = 0.002). A total of 33 participants developed proximal renal tubular dysfunction during the trial, all but one in the ADV group.

Conclusions

Due to the early termination of recruitment, ADHOC was unable to assess the original objective of clinical disease progression. Adding ADV to background antiretroviral therapy in advanced HIV disease did not provide immunological or virological improvement compared with placebo. Furthermore, at the doses used in this trial, ADV was associated with a significantly higher incidence of SAEs.

     

HIV-infected long-term nonprogressors display a unique correlative pattern between the interleukin-7/interleukin-7 receptor circuit and T-cell homeostasis

Background

We hypothesized that there may be a correlation between the interleukin‐7 (IL‐7)/IL‐7 receptor (IL‐7R) regulatory system and parameters of T‐cell homeostasis in HIV‐infected long‐term nonprogressors (LTNPs) as compared with patients with disease progression.

Methods

The possibility of a correlation between T‐cell homeostatic parameters and IL‐7/IL‐7R was investigated in 22 LTNPs (CD4 count ≥500 cells/μL for >10 years) vs. HIV‐positive patients at different disease stages [12 early: CD4 count ≥400 cells/μL; 15 late (AIDS‐presenters): CD4 count ≤150 cells/μL].

Results

Compared with early‐stage HIV‐positive patients, LTNPs displayed a higher circulating IL‐7 concentration (P=0.05), which was positively associated with higher IL‐7Rα expression and a higher T‐cell receptor excision circle (TREC) content specifically within CD4 cells (P<0.05). Compared with late‐stage disease patients, early‐stage disease patients displayed a lower IL‐7 concentration (P<0.01) and higher percentages of IL‐7Rα⁺ CD4 and CD8 cells (P=0.05). IL‐7 was positively correlated with the percentage of TREC⁺ CD4 cells (P<0.01), which translated into a higher percentage of naïve CD4 cells in early‐stage disease patients than in late‐stage disease patients; however, the CD4 cells in early‐stage disease patients were less enriched in recent thymic emigrants (RTEs) compared with LTNPs (P<0.05). In late‐stage AIDS‐developing patients, substantially increased IL‐7 was correlated with a decreased percentage of IL‐7Rα⁺ CD4 cells (P=0.01), which resulted in these patients having a significantly lower percentage of naïve T cells (P<0.01) and a significantly lower content of TREC (P<0.01) than the other patients.

Conclusions

The maintenance of high CD4 cell counts in LTNPs was associated with a specific IL‐7/IL‐7R pattern characterized by increased IL‐7 and highest IL‐7Rα‐expressing CD4 cells relative to other patients. Compared with patients with late‐stage disease, LTNPs displayed a phenotypically naïve, less activated CD4 cell pool highly enriched in RTEs, suggesting the existence of a compensatory IL‐7‐mediated pathway specifically sustaining peripheral CD4 counts.

     

Treatment outcomes amongst previously antiretroviral-naïve HIV-infected patients starting lopinavir/ritonavir-containing antiretroviral regimens at the Royal Free Hospital

Objective

To describe outcomes in patients starting first‐line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting.

Methods

Previously naïve patients starting LPV/r‐containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV‐1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan–Meier methods.

Results

A total of 195 individuals had a median follow‐up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50–200 and >200 cells/μL, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow‐up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/μL, respectively.

Conclusions

Few patients experienced virological failure whilst on a LPV/r‐based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r.

     

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

Objectives

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).

Design and methods

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.

Results

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/μL 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/μL in the PI group and 212 cells/μL 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/μL. 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.

Conclusion

Patients successfully treated with NVP‐based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI‐based HAART.

     

Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death

Objectives

The aim of the study was to compare incidence rates (IRs) of AIDS/death in patients with and without treatment interruption (TI) of combination antiretroviral therapy (cART) for periods of 3 months or more for different categories of CD4 cell count and viral load, and to determine risk factors for clinical progression to AIDS/death.

Methods

Patients starting cART with a CD4 cell count and a viral load available within 6 months of starting cART were included in the study. The IR and risk factors of TI were determined. We assessed the incidence rate ratios (IRRs) for TI and AIDS/death events using Poisson regression models.

Results

Of 3811 patients included in the study, 26% were ART‐naïve prior to cART. The median date of starting cART was July 1997, the median CD4 cell count was 226 cells/μL and the median viral load was 4.36 log₁₀ HIV‐1 RNA copies/mL. We observed 1243 interruptions and 403 AIDS‐events/deaths. The IR of AIDS/death was higher in patients with lower CD4 cell counts or higher viral loads, regardless of TI. After adjusting for baseline factors, the IR of AIDS/death was significantly higher in the TI group than in the non‐TI group [IRR 2.63; 95% confidence interval (CI) 2.01–3.44; P<0.0001]; this could be explained by current CD4 cell counts and viral loads, as the CD4 cell count‐ and viral load‐adjusted IRR was 1.14 (95% CI 0.86–1.51; P=0.37). Within the TI group, patients with a current CD4 cell count of <200 cells/μL had a 3‐fold higher risk of AIDS/death than those with a CD4 cell count of 200–350 cells/μL, whereas patients with a current CD4 cell count of >350 cells/μL had a 4‐fold lower risk of disease progression.

Conclusions

TI is common in clinical practice. The risk of AIDS/death increased more than 2‐fold for patients stopping all cART regimen drugs for 3 months or more. Among patients experiencing a TI, those with low CD4 cell counts, high viral loads or prior AIDS had an increased risk of AIDS/death. Hence, TI should be discouraged and closely monitored if it occurs.

     

Mid‐dosing interval concentration of atazanavir and virological outcome in patients treated for HIV‐1 infection

Objectives

We investigated the clinical significance of monitoring the mid‐dosing interval atazanavir (ATV) concentration (measured 12 ± 2 h after intake; C_{12 h}) in patients taking this drug once daily in the evening.

Methods

We retrospectively selected HIV‐infected patients harbouring ATV‐susceptible virus who underwent therapeutic drug monitoring (TDM) of ATV C_{12 h} during routine out‐patient visits, and we correlated C_{12 h} to the 24‐week virological response and toxicity.

Results

A total of 115 plasma samples from 86 patients (76.7% with baseline HIV RNA<50 HIV‐1 RNA copies/mL) were analysed. ATV plasma concentrations showed high inter‐individual variability. ATV plasma levels were higher in samples obtained from patients taking boosted regimens (P<0.001) and not concomitantly receiving acid‐reducing agents (P=0.007). In a multivariate model, ritonavir boosting, use of acid‐reducing agents and liver cirrhosis showed an independent association with ATV level. Virological response at 24 weeks was observed for 94 of the 115 samples (81.7%). We identified a concentration cut‐off of 0.23 mg/L which predicted virological response at 24 weeks: samples with a C_{12 h}≤0.23 mg/L showed virological failure in 41.2% of cases, whereas samples with a C_{12 h}>0.23 mg/L showed virological failure in 14.3% of cases (P=0.021). In multivariate analysis, C_{12 h}>0.23 mg/L was an independent predictor of virological response [odds ratio (OR) 4.23, P=0.031]. ATV levels correlated with concomitant unconjugated bilirubin levels (r=0.223, P=0.037), but a concentration cut‐off predictive of moderate/severe hyperbilirubinaemia could not be identified.

Conclusions

We identified a C_{12 h} efficacy threshold that predicted virological response; this could be useful for morning TDM in selected subjects receiving ATV in the evening. Results must be interpreted with caution given the retrospective design of the study.