HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir.

OBJECTIVE: PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy. METHODS: Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response ('successes'). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag-protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain. RESULTS: Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001). CONCLUSIONS: We report an association between reduced PI susceptibility (using full-length Gag-protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure.

Virologically suppressed patients with asymptomatic and symptomatic HIV-associated neurocognitive disorders do not display the same pattern of immune activation.

OBJECTIVES: Inversion of the CD4:CD8 ratio is a marker of immune activation and age-associated disease. We measured the CD4:CD8 ratio as a marker of cognitive impairment in HIV-infected patients and explored differences according to clinical severity. METHODS: Post hoc analysis of data from two prospective cohorts of HIV-infected patients randomly selected to undergo neuropsychological tests was performed. Test scores were adjusted for age, gender and education. Inclusion criteria were undetectable viral load and stable treatment for at least 6 months. Subjects with HIV-associated dementia were excluded. Patients were divided into an unimpaired group, a group with asymptomatic neurocognitive disorder (ANI) and a group with symptomatic HIV-associated neurocognitive disorder (sHAND), represented by mild neurocognitive disorder (MND). Demographic and background parameters, immune activation markers and the CD4:CD8 ratio were recorded. RESULTS: Two hundred patients were included in the study. The mean age was 52 years, 78% were male, the mean CD4 count was 624 cells/µL, the mean nadir CD4 count was 240 cells/µL, 27% were hepatitis C virus (HCV)-coinfected, the mean duration of HIV infection was 16 years, and the mean time on current combination antiretroviral therapy (cART) was 2.9 years. Twenty-nine per cent of subjects had HAND (21% had ANI and 8% had MND). In multivariate analysis, a CD4:CD8 ratio < 1 was associated with a nadir CD4 count < 200 cells/µL [odds ratio (OR) 3.68] and with the presence of CD4(+) CD38(+) HLA(+) cells (OR 1.23). Multinominal logistic regression showed that, in comparison with the unimpaired group, diagnosis of sHAND was associated with a CD4:CD8 ratio < 1 (OR 10.62), longer HIV infection (OR 1.15) and longer current cART (OR 1.34), while the ANI group differed from the unimpaired group only for education level. CONCLUSIONS: Aviraemic patients with sHAND did not display the same pattern of immune activation as subjects with ANI, suggesting that the underlying pathophysiological mechanisms could be different.

Long-term (96-week) follow-up of antiretroviral-naïve HIV-infected patients treated with first-line lopinavir/ritonavir monotherapy in the MONARK trial.

BACKGROUND: The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral-naïve patients. METHODS: A total of 136 antiretroviral-naïve patients, with a CD4 cell count above 100 cells/microL and a plasma HIV RNA below 100,000 HIV-1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n = 83) or lopinavir/ritonavir + zidovudine/lamivudine (n = 53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent-to-treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n = 83), and then focused on patients who had an HIV RNA < 50 copies/mL at week 48 (n = 56). RESULTS: At week 96, 39 of 83 patients (47%) had HIV RNA < 50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA > 400 copies/mL. Focusing on the 56 patients with an HIV RNA < 50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA < 50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI-associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96. CONCLUSION: By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA < 50 copies/mL at week 96. The occurrence in some patients of low-level viraemia (50-500 copies/mL) may increase the risk of drug resistance. First-line lopinavir/ritonavir monotherapy cannot be systematically recommended.

Simplification and first validation of a short battery of patient questionnaires for clinical management of HIV-infected patients: The HIV-SQUAD (Symptom Quality of life Adherence) Questionnaire.

PURPOSE: Questionnaires assessing patient-reported outcomes in HIV are either too long or not HIV-specific. Our aim was to develop and validate a simplified HIV patient questionnaire. METHOD: 607 HIV patients treated with a combination of antiretroviral (ARV) drugs were enrolled in an observational, longitudinal study. Questionnaires covering health-related quality of life (HRQoL), satisfaction, tolerability, and adherence were administered at baseline (BL) and Month 3 (M3). The items were selected according to their content and discriminant properties. The simplified questionnaire was then administered at Month 12 (M12). Psychometric properties of physical wellbeing, psychological well-being, and global HRQoL scores were assessed. RESULTS: The simplified questionnaire included 12 HRQoL items, 13 side-effects items, and one visual analog scale (VAS) measuring adherence. The principal component analysis (PCA) confirmed the validity of the global HRQoL score. The multivariate analysis showed acceptable-to-good internal consistency of the three scores. Convergent and discriminant validity were excellent for the physical score. The global score showed significant differences according to time since diagnosis, hepatitis coinfection, CD4 count, and viral load. CONCLUSION: This questionnaire deals with the major aspects of HIV patient perceptions. The global HRQoL score is well correlated to the surrogate markers of HIV. Such a questionnaire may represent a new tool for the therapeutic management of HIV-infected patients. Further steps are required to complete these results.

Prospective one-year bone loss in treatment-naïve HIV+ men and women on single or multiple drug HIV therapies.

Antiretroviral therapy has decreased the rate of HIV-related mortality and extended the life span of HIV patients. Current guidelines recommend the use of a 3-drug regimen, such as two nucleoside reverse transcriptase inhibitors and a protease inhibitor, boosted by ritonavir. Osteoporosis can be associated with the HIV disease itself or with antiretroviral therapy. Many trials have been conducted employing a single drug regimen to simplify antiretroviral therapy but few studies assessed the effect of the single drug regimen on bone mineral density (BMD). The objectives of the study were to assess and compare the relative (%) changes in lumbar spine and hip BMD over 48 weeks in HIV patients treated with mono or triple antiretroviral regimens The study was conducted using data from a randomized trial (MONARK) conducted in 136 antiretroviral-naïve HIV patients (89 men and 47 women) comparing the antiviral efficacy of a single-drug protease inhibitor regimen of lopinavir/ritonavir (LPV/r) versus LPV/r in combination with zidovudine (ZDV) and lamivudine (3TC). Lumbar spine and total hip BMD were assessed in 100 patients by dual-energy X-ray absorptiometry at baseline and 48 weeks. 48 week-BMD data were available for 43 patients (mean age 37years) with a mean baseline lumbar spine Z-score of -0.1 in the LPV/r monotherapy group and for 25 patients (mean age 35.8years) with a mean baseline lumbar spine Z-score of -0.2 in the LPV/r+ZDV+3TC group. After 48weeks, lumbar spine BMD significantly decreased by 4.4% (-5.1% to -2.1%, P≤0.001) in the LPV/r group and by 4.0% (-5.0% to -1.7%, P≤0.0001) in the LPV/r+ZDV+3TC group. There was no significant difference in BMD changes between the two groups. These results suggest that bone loss is observed 48 weeks after the initiation of antiretroviral therapy, whether the patients receive a single- or triple-drug antiretroviral regimen.