The discriminative ability of the 12-item short form health survey (SF-12) in a sample of persons infected with HIV

BACKGROUND: Self-reported health-related quality of life (HRQOL) assesses constructs that transcend laboratory-based clinical parameters. Corroboration of the hypothesized relationships between the 2 types of health indicators (ie, clinical and HRQOL) could provide evidence of the validity of an HRQOL measurement tool. OBJECTIVE: The purpose of this study was to evaluate the ability of scores on the mental component summary (MCS-12) and physical component summary (PCS-12) of the 12-Item Short Form Health Survey (SF-12) to discriminate between HIV-infected persons in predefined disease-severity groups based on surrogate markers. METHODS: This cross-sectional study involved the collection of clinical data (ie, CD4 cell count, viral load [HIV-1 RNA copies/mL]) from patients' medical records and HRQOL data from the SF-12 at 2 HIV specialty clinics. The ability of SF-12 summary scores to discriminate between patients stratified by disease severity (ie, CD4 cell count <200 vs > or = 200/mm3; HIV-1 RNA >55,000 vs < or = 55,000 copies/mL) was assessed by receiver operating characteristic curve analysis. RESULTS: Data were collected from 478 patients. The scores from the PCS-12 were able to discriminate between groups of patients stratified by disease severity based on CD4 cell count (P < 0.001) and HIV-1 RNA copies/mL (P < 0.01). MCS-12 scores did not discriminate between disease-severity groups. CONCLUSIONS: Although the SF-12 is a brief generic measure of HRQOL, these findings provide further evidence of the validity of the SF-12 and suggest that it may be a practical way to monitor health status from the perspective of the HIV-infected patient.     

Quality of life in patients treated with first-line antiretroviral therapy containing nevirapine and/or efavirenz

OBJECTIVE: To assess whether differences in safety profiles between nevirapine (NVP) and efavirenz (EFV), as observed in the 2NN study, translated into differences in 'health related quality of life' (HRQoL). DESIGN: A sub-study of the 2NN study, with antiretroviral-naive patients randomly allocated to NVP (once or twice daily), EFV or NVP+EFV, in addition to stavudine and lamivudine. METHODS: Comparing differences in changes of HRQoL over 48 weeks as measured with the Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire, using analysis of variance. RESULTS: The 2NN study enrolled 1216 patients. No validated questionnaires were available for 244 patients, and 55 patients had no HRQoL data at all, leaving 917 patients eligible for this sub-study. A total of 471 (51%) had HRQoL measurements both at baseline and week 48. The majority (69%) of patients without HRQoL measurements did, however, complete the study. The change in the physical health score (PHS) was 3.9 for NVP, 3.4 for EFV and 2.4 for NVP+EFV (P=0.712). For the mental health score (MHS) these values were 6.1, 7.0 and 3.9, respectively (P=0.098). A baseline plasma HIV-1 RNA concentration (pVL) > or = 100,000 copies/ml and a decline in pVL (per log10) were independently associated with an increase of PHS. An increase of MHS was only associated with pVL decline. Patients experiencing an adverse event during follow-up had a comparable change in PHS but a significantly smaller change in MHS, compared with those without an adverse event. CONCLUSIONS: First-line ART containing NVP and/or EFV leads to an improvement in HRQoL. The gain in HRQoL was similar for NVP and EFV, but slightly lower for the combination of these drugs.     

Meta-analysis of antiretroviral effects on HIV-1 RNA, CD4 cell count and progression to AIDS or death

There is uncertainty as to how the effects of antiretroviral treatments on human immunodeficiency virus type 1 (HIV-1) RNA levels and CD4 cell counts can predict reductions in clinical progression to AIDS or death. A meta-analysis was conducted for 27 pairwise comparisons of antiretroviral treatments in 15 randomized trials of antiretroviral treatments. For each trial, three measures of treatment effect were used: (i) 16 week change from baseline in HIV-1 RNA; (ii) 16 week change from baseline in CD4 cell count; and (iii) rate of clinical progression. Treatments which caused greater increases in CD4 cell count and greater reductions in HIV-1 RNA were more effective at reducing the rate of clinical progression (P < 0.05 for each comparison). However, there was variability in the consistency of this correlation between different trials and treatments. The results support the use of both CD4 count and HIV-1 RNA levels as the primary markers of the efficacy of antiretroviral treatment.     

The NIQ of lopinavir is predictive of a 48-week virological response in highly treatment-experienced HIV-1-infected subjects treated with a lopinavir/ritonavir-containing regimen

OBJECTIVE: To investigate the normalized inhibitory quotient (NIQ) of lopinavir (LPV) as a predictor of 48-week virological responses to a lopinavir/ritonavir (LPV/RTV)-containing regimen in highly treatment-experienced patients. DESIGN: We calculated the NIQ for 59 patients who completed 48 weeks' treatment and assessed the factors predicting a week-48 virological response. METHODS: The NIQ was calculated by dividing each subject's IQ (LPV Ctrough/fold change in LPV susceptibility, as assessed by VirtualPhenotype) by a reference IQ (mean population LPV Ctrough/fold change in LPV IC50, as assessed by VirtualPhenotype). HIV-1 RNA was assessed by NASBA (quantification limit: 80 copies/ml). The general linear model and multiple logistic regression, respectively, were used to estimate the independent predictors of a change in viral load and HIV-1 RNA <80 copies/ml. RESULTS: The median (interquartile range) baseline levels of CD4+ cells and HIV-1 RNA were 251 (141-385) cells/microl and 4.85 (4.49-5.23) log10 copies/ml, respectively. The median NIQ was 2.2 (0.5-14). At week 48, the median decrease in HIV-1 RNA was 1.4 (0.59-2.79) log10 copies/ml (P<0.0001), with 24 subjects (41%) reaching <80 copies/mi. Baseline HIV-1 RNA (P=0.001), CD4+ cells (P=0.002) and NIQ (P=0.0006) independently predicted the week-48 change in viral load, whereas baseline CD4+ cells (P=0.011) and NIQ (P=0.009) independently predicted a week-48 HIV-1 RNA level of <80 copies/ml. CONCLUSION: The LPV NIQ independently predicts virological responses to an LPV/RTV-containing regimen in highly treatment-experienced HIV-1-infected patients.     

Validation of a quantitative RNA PCR assay for HIV-1 in human plasma

A quantitative human immunodeficiency virus type 1 (HIV-1) RNA polymerase chain reaction assay has been validated analytically and clinically in > 13,000 samples. The assay is highly reproducible with intra- and inter-assay precision of 16% and 19%, respectively. In 1,542 of 1,548 subjects with CD4⁺ counts of 0–500 cells per mm³, viral RNA levels were quantifiable and ranged from ∼ 3,000–52,200,000 copies per milliliter. Median plasma HIV-1 RNA values were inversely proportional to CD4⁺ counts from 0–400 cells per mm³. When patients were off antiretroviral therapies for ∼ 14 days prior to the initial baseline RNA PCR evaluation, the mean variance between the two baseline values was 23% (0.1 log). Of these patients, 95% had a sufficient plasma viral load to quantitate a 10-fold (1 log) diminution in viral load caused by antiviral therapy. In contrast, only 20% and 45% of these subjects had sufficient p24 and ICD p24 levels to detect a 50% diminution in circulating virus. The high precision and reproducibility of this quantitative RNA PCR assay provide an enhanced means of evaluating therapeutic drug regimens for HIV-1. © 1996 Wiley-Liss, Inc.     

Results of the ALBI trial: a randomized comparison of stavudine/didanosine, zidovudine/lamivudine and alternating treatment in antiretroviral-naive patients

In the ALBI trial, 151 antiretroviral-naive patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 10,000 to 100,000 copies/ml and CD4 cell counts > or = 200 cells/mm3 received 24 weeks of treatment with stavudine/didanosine (n=51), zidovudine/lamivudine (n=51) or stavudine/didanosine for 12 weeks followed by zidovudine/lamivudine (n=49). Baseline plasma HIV-1 RNA and CD4 cell counts were comparable in the treatment groups. The mean decrease in plasma HIV-1 RNA at 24 weeks in the stavudine/didanosine group (2.26 log10) was significantly greater than that in either the zidovudine/lamivudine group (1.26 log10) or the alternating treatment group (1.58 log10) (P<0.0001 for both). Proportions of patients with plasma HIV-1 RNA level <500 copies/ml (91% vs 42% and 60%) and <50 copies/ml (47% versus 4% and 9%) were significantly greater in the stavudine/didanosine group (P<0.001 for pairwise comparisons). Stavudine/didanosine was associated with a mean increase in CD4 cell count (124 cells/mm3) significantly greater than that in the zidovudine/lamivudine group (62 cells/mm3, P<0.01) and comparable to that in the alternating group (118 cells/mm3). All study regimens were well tolerated. These findings, indicating superiority of stavudine/didanosine over zidovudine/lamivudine in virological and immunological response over 24 weeks, suggest that the combination should be considered as a basis for highly active antiretroviral therapy.     

Short-term anti-HIV activity of the combination of didanosine and hydroxyurea

The synergistic action of hydroxyurea with some other antiretroviral drugs led us to evaluate the effect of therapy with the combination of didanosine and hydroxyurea in HIV-1-infected patients. We aimed to assess the anti-HIV activity of therapy with this combination by measuring variations in viral load and in CD4 cell counts. We also evaluated the potential side effects of this drug combination in HIV-1-positive patients with advanced disease. A total of 15 HIV-1-seropositive homosexual men with a mean baseline CD4 cell count of 149 cells/mm3 (range: 1-430 cells/mm3) were recruited to the study, and received didanosine (200 mg) plus hydroxyurea (500 mg) twice daily for 12 weeks. Ten patients were didanosine naive and five had previously received didanosine (for > 3 months). The combination therapy was well tolerated, although grade 2-3 alopecia appeared in four patients who had very low CD4 cell counts (< 50 cells/mm3). No significant variation in renal, hepatic and pancreatic functions occurred. A significant reduction in the plasma HIV-1 RNA (> 0.5 logs) was observed in seven of ten patients naive to didanosine after weeks 4 and 12 of the study; five of these patients had a decrease in plasma HIV-1 RNA of > 1.5 logs, with two having a decrease of > 2.0 logs. The viral load became undetectable (below 200 copies/ml) in three patients. The patients whose plasma HIV-1 RNA levels were not significantly reduced by the combination therapy had a higher baseline viral load. CD4 cell counts did not increase significantly in most patients. We observed a better response in those patients who had virus of the non-syncytium-inducing phenotype. In conclusion, hydroxyurea in combination with didanosine was well tolerated and led to a reduction in viral load mainly in patients who were initially naive to didanosine.     

Evaluation of two commercial procedures for quantification of human immunodeficiency virus type 1 RNA with respect to HIV-1 viral subtype and antiviral treatment

To determine the reliability of two commercial assays for quantifying the human immunodeficiency type 1 (HIV-1) RNA levels in patients infected with different HIV-1 subtypes and managed with various drug regimens, blind testing of 127 plasma samples from 57 patients infected with HIV-1 subtypes A, B, C and E was performed using the Amplicor HIV-1 Monitor Test (Roche) and Quantiplex HIV-1 RNA 3.0 Assay (Chiron). Included were time course studies in 7 patients in whom the virus load was correlated with CD4+ cell counts and therapy. Both assays were accurate and precise to measure standardized amounts of viral load and displayed high correlation coefficients that were independent of gender and treatment modality, even though some assay-specific differences may exist in the quantification of viral subtype RNA. Time course studies showed comparable inverse associations between the CD4+ count and viral load measured by the two assays. Hence, both the Amplicor HIV-1 Monitor Test and the Quantiplex HIV-1 RNA 3.0 Assay promise to be useful for the management of HIV-1 infected patients.     

Immunological and virological activity of zalcitabine and zidovudine in combination in HIV-positive people with CD4 cell counts of between 200-500 cells/mm3

We evaluated the effect of combination therapy with zidovudine (AZT) plus zalcitabine (ddC) in human immunodeficiency virus type 1 (HIV-1)-infected patients who had not previously received antiretroviral treatment ('naive' patients). The immunological and virological parameters evaluated were CD4 cell count, syncytium-inducing (SI) viral phenotype and plasma HIV-1 RNA copies/ml (HIV viral load). A total of 75 patients entered the study, with CD4 cell counts between 200 and 500 cells/mm3. All received zidovudine (200 mg) plus zalcitabine (0.75 mg) three times daily for 24 weeks. Treatment was well tolerated. However, four patients presented with anaemia (haemoglobin < 10.0 g/dl) and one patient had both anaemia and neutropenia (0.8 x 10(9) neutrophils/l). Combination therapy with zidovudine plus zalcitabine resulted in a pronounced improvement of virological and immunological markers. Approximately 25% of patients achieved undetectable plasma HIV RNA levels (< 200 copies/ml) at week 24. At the end of the study (24 weeks) a significant reduction (> 0.5 log) of plasma HIV RNA was observed in approximately 70% of patients and in 50% an even greater decrease (> 1 log) was achieved. The most significant decrease in mean plasma HIV RNA levels was observed at week 4, whereas the highest increase in CD4 cell count was found at week 24. Approximately 80% of patients who showed baseline plasma HIV RNA levels below 20000 copies/ml had less than 5000 copies/ml at week 24. The plasma HIV RNA reduction observed at week 4 was significantly maintained at week 24. Therefore, we can rapidly select those who will not respond to therapy and adjust the treatment after a short interval. Our study supports the idea of early therapy because all patients who reached undetectable levels of plasma HIV RNA at week 24 had at baseline a median plasma HIV RNA load of 2560 copies/ml. In conclusion, zidovudine in combination with zalcitabine was well tolerated in the majority of patients and led to a significant reduction in plasma HIV RNA copies in most of the patients with initial viraemia lower than 20000 copies/ml.     

Immunological and virological markers in HIV infection

The use of CD4 lymphocyte counts and plasma RNA levels as markers of HIV infection is examined. Marker candidates for HIV ideally should: 1) have a clear pathophysiological association with HIV; 2) have a role in the natural history of HIV infection; 3) be measurable in the vast majority of affected individuals; 4) change when the patient improves or worsens; and 5) change measurably with successful therapeutic intervention and not change with therapeutic failure. Current immunological and virological markers do not fulfill all of these requirements, and none have been accepted as a primary endpoint in clinical trials by most drug regulatory authorities. Efforts are now underway to validate the use of plasma HIV RNA as a marker. Validation of HIV-1 RNA as a virological marker of clinical efficacy promises faster treatment evaluation and the ability to reach conclusions about a particular drug regimen without having to wait for survival or progression differences. Continued investigation will determine whether HIV-1 RNA quantitation ultimately can help in determining and in evaluating drug responses.     

Mathematical Modeling of the Interrelationship of CD4 Lymphocyte Count and Viral Load Changes Induced by the Protease Inhibitor Indinavir

While CD4 cell counts are widely used to predict disease progression in human immunodeficiency virus (HIV)-infected patients, they are poorly explanatory of the progression to AIDS or death after the introduction of chemotherapy. Changes in HIV load (as measured by RNA PCR) have been shown to be a much better predictor of the risk of disease progression. Since the interrelationship of these markers is of great clinical interest, we modeled the time-averaged return of CD4 cell count and change in viral load subsequent to therapy with the HIV protease inhibitor indinavir. We found that CD4 cell return was significantly related to both the baseline CD4 count (r² = 0.86, P < 0.001) and the decline in HIV RNA PCR-determined viral load (also referred to in this work as the HIV RNA PCR decline) (r² = 0.60, P < 0.01). Simultaneously modeling both influences in a linked nonlinear model (r² = 0.93, P < 0.001) demonstrated that (i) the starting number of CD4 cells accounted for the majority of the change in CD4 cell return and (ii) the return of CD4 cells attributable to viral load decrease was 50% of maximal with only a decrease of approximately 0.2 log of HIV RNA as modeled from the first 12 weeks of therapy. Much greater viral inhibition beyond that necessary for maximal CD4 cell return is possible. Given that HIV RNA PCR decline is more strongly linked to ultimate clinical course in HIV disease, our findings indicate that CD4 return is potentially misleading as an indicator of antiviral effect, since it is determined more by the starting CD4 value than by viral load decline and since near-maximal changes occur with minimal antiviral effect.     

Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects

Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4(+) cell counts of >/=100/mm(3) and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who received randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice-daily (BID) for up to 12 weeks. Plasma abacavir concentrations from sparse sampling were analyzed by standard population pharmacokinetic methods, and the effects of dose, combination therapy, gender, weight, and age on parameter estimates were investigated. Bayesian pharmacokinetic parameter estimates were calculated to determine the peak concentration of abacavir in plasma (C(max)) and the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) for individual subjects. The pharmacokinetics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were observed between the incidence of the five most common adverse events (headache, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC(0-infinity). A significant correlation was observed between C(max) and nausea by categorical analysis (P = 0.019), but this was of borderline significance by logistic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 2.32). The log(10) time-averaged AUC(0-infinity) minus baseline (AAUCMB) values for HIV-1 RNA and CD4(+) cell count correlated significantly with C(max) and AUC(0-infinity), but with better model fits for AUC(0-infinity). The increase in AAUCMB values for CD4(+) cell count plateaued early for drug exposures that were associated with little change in AAUCMB values for plasma HIV-1 RNA. There was less than a 0.4 log(10) difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC(0-infinity) from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.     

Efficacy and safety of once-daily combination therapy with didanosine, lamivudine and nevirapine in antiretroviral-naive HIV-infected patients

BACKGROUND: Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection. METHODS: This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis. RESULTS: Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10log10 copies/ml, and mean CD4 cell count was 262 cells/microl. At month 12, 67% (95% CI: 56-78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/microl. The treatment was more effective in patients with baseline CD4 counts >100 cells/microl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol. CONCLUSION: A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.