Patricia Echeverría

Early but limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy

BACKGROUND Immune hyperactivation in immunodiscordant patients can induce residual HIV replication and limit CD4 T cell recovery. We assessed the impact of raltegravir intensification on CD4 T cell recovery and viral persistence. METHODS We performed a randomized, controlled, pilot trial. Patients with CD4 T cell counts <350 cells/mm(3) despite suppressive antiretroviral therapy were randomized (2 : 1) to intensify with raltegravir (intensified arm, n = 30) or to continue with the same regimen (control arm, n = 14) for 48 weeks. Then, the control individuals intensified their treatment for 24 weeks (delayed-intensification arm). We analysed changes in CD4 T cell counts, total and episomal HIV DNA in peripheral blood mononuclear cells and predictive factors for response. RESULTS Raltegravir intensification induced a rapid increase in CD4 T cell counts (week 12) (P = 0.007), although this was not sustained over time. Control patients maintained constant but slow increases in CD4 T cell counts (present in the pre-study period), reaching CD4 T cell counts similar to those of patients in the intensification arm at week 48. This effect was confirmed by the analysis of the delayed-intensification arm. Proviral DNA levels remained stable in both arms over time; episomal DNA forms and ultrasensitive plasma viral load were barely detected during the study. Increases in CD4 T cell counts were associated with low baseline CD95 expression in CD4 and CD8 T cells (P = 0.020). CONCLUSIONS Raltegravir intensification modestly impacts viral dynamics and induces a rapid but limited gain in CD4 T cell counts in immunodiscordant patients. Residual viral replication does not seem to be the main cause of unsatisfactory CD4 T cell recovery in these patients.

Improvement in bone mineral density after switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: two-centre randomized pilot study (OsteoTDF study)

BACKGROUND Tenofovir has been associated with a decrease in bone mineral density (BMD). However, data on changes in BMD after discontinuing tenofovir are lacking. METHODS We performed a two-centre randomized pilot study in virologically suppressed HIV-infected patients receiving tenofovir with osteopenia/osteoporosis (OsteoTDF study, ClinicalTrials.gov number NCT 01153217). Fifty-four patients were randomly assigned to switch from tenofovir to abacavir (n = 26) or to continue with tenofovir (n = 28). Changes in lumbar and total hip BMD were evaluated at Week 48 from baseline. RESULTS Five patients discontinued the study (three from the tenofovir group and two from the abacavir group). No significant differences were detected between the groups at Week 48 (P = 0.229 for total hip and P = 0.312 for lumbar spine). However, hip BMD improved by 2.1% (95% CI -0.6 to 4.7) (P = 0.043) in the abacavir group and 0.7% (95% CI -0.9 to 2.4) (P = 0.372) in the tenofovir group. Lumbar spine BMD varied by -0.7% (95% CI -3.8 to 3.3) (P ≤ 0.001) in the abacavir group and -1.2% (95% CI -3.8 to 0.4) (P < 0.001) in the tenofovir group. CONCLUSIONS Switching from tenofovir to abacavir led to a slight improvement in femoral BMD although no differences were detected between groups. Larger studies are necessary before firm recommendations can be made on the discontinuation of tenofovir in patients with a low BMD.

Peak bone mass in young HIV-infected patients compared with healthy controls.

Introduction:Peak bone mass (PBM) is the amount of bone present at the end of skeletal maturation. It is an important determinant of osteoporotic fracture risk. Data on the PBM in the HIV-infected population are lacking. Design and Methods:We performed a multicenter (6 centers in Spain), case–control study to assess PBM using dual-energy x-ray absorptiometry. We studied HIV-infected patients aged 20–30 years and compared them with age- and gender-matched non–HIV-infected controls. We also assessed the predictive factors for a low PBM. Results:We included 307 subjects: 232 HIV-infected patients and 75 non–HIV-infected controls. Bone mineral density was similar in both groups although differences were seen in the total femur T-score (−0.15SD versus +0.50SD, respectively, P = 0.018). The percentage of osteopenia and osteoporosis was higher in the HIV-infected patients (56.5% and 10.7%, respectively) than in the controls (50.7% and 4%, respectively; P = 0.019). Osteoporosis was more frequent in HIV-infected men than in control men and HIV-infected women (12.2% versus 5.5% and 4.8%, P = 0.033). Protease inhibitors and nadir CD4 T-cells were negatively associated with PBM, whereas fat and lean mass were positively associated with PBM. Conclusions:Bone mineral density was similar between HIV-infected patients aged 20–30 years than in age- and gender-matched controls. However, lower femoral T-scores and higher rate of osteopenia and osteoporosis were seen in HIV-infected men. Therapy with protease inhibitors, nadir CD4 counts, and fat and lean mass were predictive factors of PBM. Given that these patients will be living with HIV infection for many years, every effort should be made to modify risk factors.

Pulse wave velocity as index of arterial stiffness in HIV-infected patients compared with a healthy population.

Background:Chronic HIV infection leads to premature atherosclerosis. Arterial stiffness is considered a subclinical marker of cardiovascular disease. Methods:Pulse wave velocity (PWV) was determined in 254 individuals (174 HIV-infected patients and 80 healthy controls, 2:1 matched by age and gender) to compare the prevalence of arterial stiffness and to identify associated factors. PWV was determined using noninvasive automated device (Complior). Factors associated with impaired PWV were assessed among cardiovascular risk factors, HIV infection parameters, and laboratory data. Logistic regression analyses were performed to determine differences between groups and factors associated to arterial stiffness. Results:Overall, 81.4% of participants were male, median age was 46.54 [interquartile range (IQR): 41–52] years. Higher percentages of HIV-infected subjects showed dyslipemia (P = 0.012) and smoking habit (P = 0.002). The median time from HIV diagnosis was 13 (IQR: 6–18) years and the median time on antiretroviral therapy was 11 (IQR: 5–15) years. Nearly, all patients were virologically suppressed (89.7%) at the time of PWV. Arterial stiffness in the global population was 20.5%, 18.9% in HIV-infected group, and 23.8% in controls (P = 0.405). High diastolic blood pressure and high levels of triglycerides at time of PWV were associated with increased PWV (P = 0.009 and P = 0.023, respectively). Conclusions:Virologically suppressed HIV-infected patients showed similar arterial elasticity to non–HIV-infected patients. HIV-related conditions were not associated with arterial stiffness, probably because of the good immunologic and virological status of this group. However, high diastolic pressure at the time of PWV and high levels of triglycerides were associated risk factors.

Switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: changes in bone turnover markers and circulating sclerostin levels

BACKGROUND Tenofovir is involved in accelerated bone mineral density (BMD) loss. METHODS We recently published a hip BMD improvement at week 48 [+2.1% (95% CI: -0.6, 4.7) (P = 0.043)] in HIV-infected patients with osteopenia/osteoporosis randomized to switch from tenofovir to abacavir (n = 26), although without reaching statistical significance compared with those who maintained tenofovir (n = 28). Here, we present changes at week 48 in bone markers [C-terminal telopeptide of collagen type 1 (CTX), osteocalcin and procollagen type 1 N propeptide (P1NP)] as well as in circulating levels of three proteins involved in bone regulation [osteoprotegerin, receptor activator for NF-κB ligand (RANKL) and sclerostin, a selective regulator of bone formation through the Wnt pathway] in 44 of these patients. χ(2) or Fisher and Student t-tests were performed according to the distribution of the variables. RESULTS Bone markers decreased only in the abacavir group [mean (SD) CTX changed from 0.543 (0.495) to 0.301 (0.306) ng/mL; mean (SD) osteocalcin changed from 23.72 (22.20) to 13.95 (12.40) ng/mL; and mean (SD) P1NP changed from 54.68 (54.52) to 28.65 (27.48) ng/mL (P < 0.001 in all cases)], reaching statistical significance between the groups at week 48. Osteoprotegerin did not vary, but sclerostin significantly increased in the abacavir group [from 29.53 (27.91) to 35.56 (34.59) pmol/L, P = 0.002]. No significant differences in osteoprotegerin and sclerostin were detected between the groups at week 48. RANKL values were below the limit of detection in all samples. CONCLUSIONS The switch from tenofovir to abacavir seems to induce a positive effect on bone tissue, since bone turnover markers decreased. In addition, circulating sclerostin levels increased, a change associated with improved bone properties.

Randomised Study to Assess the Efficacy and Safety of Once-Daily Etravirine-Based Regimen as a Switching Strategy in HIV-Infected Patients Receiving a Protease Inhibitor-Containing Regimen. Etraswitch Study

Background Etravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking. Methods HIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water) (ETR group, n = 22) or to continue with the same regimen (control group, n = 21). Percentage of patients with VL≤50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile. Results We included 43 patients [72.9% male, 46.3 (42.2; 50.6) years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure) (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25) and −4 cells/µL in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p = <0.001), and glycemia (p = 0.03) and higher satisfaction (0–10 scale) (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily. Conclusion Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly. Trial Registration ClinicalTrials.gov NCT01034917

Ten-year safety with polyacrylamide gel used to correct facial lipoatrophy in HIV-infected patients

Long-term results (>5 years) for synthetic substances used to repair facial lipoatrophy have not been published. We performed a cross-sectional study to evaluate the 10-year safety of polyacrylamide hydrogel (Aquamid) among the 751 patients from our unit who received facial infiltrations at least 10 years ago. Epidemiological and clinical data such as complications and patient satisfaction were collected. We also identified those patients who presented a facial infection at any time after infiltration. A total of 104 patients had received Aquamid at least 10 years ago. Before infiltrations, 24.0%, 41.3%, and 34.7% presented very severe, severe, and moderate facial lipoatrophy, respectively. After a mean (SD) of 10.3 (0.5) years since the infiltrations, 19.2%, 47.7%, and 31.7% of patients reported moderate, mild, and no signs of facial lipoatrophy. The values reported by physicians for the same categories were 1.9%, 10.6%, and 87.5%. Indurations were detected in 6.7% of patients and nodules in 3.8%. Five patients (4.8%) had a local infection. A further 15 patients with a shorter follow-up (less than 10 years) presented local infections (overall incidence considering the 751 patients who received infiltrations of Aquamid, 2.7%); the product had to be withdrawn in three cases. The majority of patients were highly satisfied (74.8%) or satisfied (23.4%) with the cosmetic results; among patients with severe or very severe lipoatrophy at baseline, 31.4% were satisfied and 65.7% were highly satisfied. Infiltrations with polyacrylamide hydrogel (Aquamid) are a safe strategy for the treatment of facial lipoatrophy in the long term. The rate of severe complications was low, and patient satisfaction with the cosmetic results was high. However, facial infections may appear in the long term. Therefore, HIV-infected patients who received synthetic substances should be carefully monitored over time.

Saquinavir/Ritonavir Monotherapy as a New Nucleoside-Sparing Maintenance Strategy in Long-Term Virologically Suppressed HIVInfected Patients

BACKGROUND The high antiviral potency and low toxicity of saquinavir/ritonavir (SQV/r) prompted us to assess a viable strategy in chronic virologically suppressed HIV-infected patients. METHODS A randomized, multicenter pilot trial. Patients taking triple HAART with (VL <50 copies/mL) and no history of virological failure with a protease inhibitor (PI) or PI-related resistance were assigned in a 2:1 ratio to receive SQV 1000 mg/ritonavir 100 mg BID (SQV/r group) or to continue with their habitual treatment (control group). Comparisons were performed using the Mann-Whitney test for medians, the t test or ANOVA for means, and the χ² or Fishers exact test for proportions. RESULTS 28 patients were randomized: 17 to the SQV/r group and 11 to the control group. Only 1 patient from the SQV/r group experienced virological failure at week 48. A similar mean increase was observed in CD4+ T-cell counts in both groups at week 48. Three patients (17.6%) from the SQV/r group prematurely interrupted the study for reasons other than virological failure. HDL cholesterol increased significantly at week 48 in the SQV/r group (from 41±11 mg/dL to 56±35, P=.026); patients in the control group showed a decrease in LDL cholesterol (from 129±37 mg/dL to 107±17, P=.028). The median (IQR) trough plasma concentrations of SQV were 760 ng/mL (379.5-1332.25 ng/mL). Three patients had saquinavir concentrations lower than 100 ng/mL. CONCLUSION SQV/r as monotherapy has proven to be a valid, safe, and economical option for virologically suppressed HIV-infected patients, especially in those who experience intolerance or toxicity with nucleoside analogs.

Switching from a ritonavir-boosted PI to dolutegravir as an alternative strategy in virologically suppressed HIV-infected individuals.

Background: Switching from PIs to dolutegravir in virologically suppressed HIV-infected individuals has not been assessed. Objectives: The principal aim was to assess the evolution of bone mineral density (BMD) when switching from a ritonavir-boosted PI to dolutegravir in HIV-infected patients with osteopenia or osteoporosis. The secondary objective was to assess the antiviral efficacy and safety of the switch therapy. Methods: This randomized, multicentre study assessed changes in BMD, bone turnover markers, and antiviral efficacy and safety in 73 virologically suppressed patients with osteopenia/osteoporosis taking a ritonavir-boosted PI plus abacavir/lamivudine who were randomized to switch from PI to dolutegravir (DOLU group, n = 37) or continue with a PI (PI group, n = 36). Clinical Trials: NCT02577042. Results: One and three patients from the DOLU and PI groups, respectively, withdrew prematurely (unrelated to treatment). At 48 weeks, 97.3% versus 91.7%, respectively, maintained viral suppression (snapshot analysis, ITT, M = F). No significant differences were seen between the groups in percentage change from baseline to week 48 in femoral (P = 0.56) and lumbar spine (P = 0.29) BMD, although lumbar spine BMD improved by 1.43% (–1.36; 2.92) in the DOLU group [0.12% (–2.83; 2.89) in the PI group]. Bone marker values did not vary significantly. At week 48, triglycerides were lower (P < 0.001) and HDL cholesterol higher (P = 0.027) in the DOLU group. Conclusions: Dolutegravir + Kivexa® was safe and well-tolerated in virologically suppressed patients receiving a PI-based regimen. The lipid profile was better, albeit without significant changes in BMD, probably because of the short follow-up.

Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor–based Regimens for Initial Treatment of HIV Infection: A Systematic Review and Metaanalysis of Randomized Trials

BACKGROUND Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS We searched databases to identify randomized trials that compared NNRTI- vs PI/r-based initial therapy. A metaanalysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were death, progression to AIDS, and treatment discontinuation. We calculated RR of virologic suppression and MD for an increase in CD4 cells at week 48. RESULTS We included 29 trials with 9047 participants. Death or progression to AIDS occurred in 226 participants in the NNRTI arm and in 221 in the PI/r arm (RR, 1.03; 95% confidence interval, .87-1.22; 12 trials; n = 3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04; 0.86-1.25; 22 trials; n = 8311), and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00; 0.80-1.25; 13 trials; n = 4740). Overall treatment discontinuation (1.12; 0.93-1.35; 24 trials; n = 8249) and from toxicity (1.21; 0.87-1.68; 21 trials; n = 6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58; 0.91-2.74; 17 trials; n = 5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR, 1.03; 0.98-1.09) or CD4(+) recovery (MD, -4.7 cells; -14.2 to 4.8). CONCLUSIONS We found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.