The purpose of this study is to look at the levels of three HIV medications: atazanavir, darunavir and cobicistat in the blood after drug intake has been stopped, in order to understand how long these drugs persist in the blood. The study will specifically look at blood levels of these three drugs after taking them every day for 10 days. Participants will take Evotaz (atazanavir and cobicistat) on a first stage and Rezolsta (darunavir and cobicistat) on a second stage.

If the participants decide to take part, the duration of the study will be up to 33 days plus a screening visit which will take place up to 28 days prior to the start of the study, and a follow up visit, which takes place 7 to 14 days after the last dose of study medication. This study is not randomised which means that all participants will receive all study medications in the same order.

The participant and the study doctor will know which study medications the participant is taking at all times during the study.

Background: Darunavir and ritonavir (DRV/r) are victims of drug-drug interactions (DDI) with strong cytochrome inducers, such as rifampin (RIF). Recently our group showed that doubling DRV/r dose did not compensate for the RIF-induced decrease in DRV exposure. The impact of similar DDIs within Peripheral Blood Mononuclear Cells (PBMC) is still unknown. Therefore, in the same context, we investigated the intra-PBMC pharmacokinetics of DRV/r, dolutegravir (DTG) and RIF. Methods: People living with HIV were enrolled in a dose-escalation cross-over study (NCT03892161), with treatment periods of 7 days each. Patients started with DRV/r 800/100 mg QD, then RIF (600-750 mg QD) and DTG (50 mg BD) were added, RTV dose was increased to 200 mg, then they received either DRV/r 800/100 BD and then 1600/200 QD or vice versa. Last, RIF was withdrawn. Plasma and intra-PBMC concentrations of each drug were measured through validated LC-MS/MS methods, at the end of each treatment period (steadystate) at the end of dosing interval (Ctrough), and at 2-6 h (start and after DRV/r dose escalations). Seventeen patients were enrolled in this study but, due to high incidence of liver toxicity only 4 patients completed the protocol. Results: Overall plasma and intra-PBMCs Ctrough and AUC0-24 are showed in table 1 for each period. In the patients who completed the protocol, after the addition of RIF, intra-PBMC DRV Ctrough dropped significantly (P = 0.039) from a median starting value of 215 ng/mL (IQR 144-374) to 119 ng/mL (IQR 13-694) and 68 ng/mL (IQR 16-164) for 800/100 BD and 1600/200 QD dosages, respectively. Differences were slighter at 2-6 hours (P = 0.114). RIF addition and dose escalation was associated with a significant increase in the intra-PBMC/ plasma ratio for DRV, from a median starting value of 0.17 (IQR 0.09-0.26) to 0.23 (IQR 0.20-0.26) and 0.28 (IQR 0.21-0.41) for 800/100 BD and 1600/200 QD regimens, respectively. DTG and RIF intra-PBMC concentrations were similar to the ones reported in literature. DTG intra-PBMC/plasma Ctrough ratio showed a slight increase (P = 0.068) between DRV/r BD and QD double doses: median 0.24 (IQR 0.21-0.25) and 0.29 (IQR 0.26-0.32), respectively. Conclusion: The observed data suggest that the relative intracellular disposition of DRV increases with RIF; DTG intra-PBMCs exposure seems similar to what reported in patients not receiving RIF. Considering the intra-PBMCs concentrations may be useful for predicting the clinical relevance of DDIs with strong inducers.

The purpose of the study is to study the effects of switching from an antiretroviral combination that includes two ritonavir boosted protease inhibitors to replacement of these two protease inhibitors with a new protease inhibitor called Darunavir (also boosted with ritonavir).

The study will investigate the effect of the switch on viral load (the levels of the HIV virus in the blood), on immunological parameters (CD4 count) and on other safety parameters and also on quality of life.

In a subgroup of patients the impact of the switch on the body\'s response to the hormone insulin will also be measured (Euglycaemic clamp sub group)

This is a Phase 4, single center, open label, fixed-sequence, multiple dose, 2-way drug-drug interaction study.

The purpose of the study is to examine the effects of switching from antiretroviral combinations that includes efavirenz (Sustiva®), lopinavir/ritonavir (Kaletra®) or atazanavir/ritonavir (Reyataz®/Norvir®) in individuals experiencing side effects from one of these agents, and replacing these with a new HIV medication called Darunavir also given with ritonavir (Norvir®).

The study will primarily investigate the effect of change in medication on the subjects viral load (the levels of the HIV virus in the blood), on immunological parameters (CD4 count) and on other safety parameters (such as cholesterol) and also quality of life.

The management of the side effects caused by the antiretroviral therapy is one of the main problems facing clinicians. The patient's tolerability and safety influence the success of the therapy. This retrospective study assesses the tolerability and impact on metabolic profiles of antiretroviral regimens containing darunavir/ritonavir (DRV/r) versus those containing darunavir/cobicistat (DRV/c), in routine clinical practice. The database of Prof. Dr Matei Bals of the National Institute of Infectious Diseases (INBI MB) was studied for the period 2017-2020, allowing the inclusion in the study of 462 HIV-infected patients who received the current regimen at least three months before evaluation. The following parameters were collected and analyzed: significant medical history, associated diseases, serum levels for profile evaluation: carbohydrate, lipidic, serum level of liver and pancreatic enzymes, serum markers of cardiac function, coagulation, and renal function. DRV/c (800 mg/150 mg, once daily) administrated in combination with other antiretroviral (ARV) in HIV-1 infected subjects proved to be better tolerated and with a lower impact on metabolic profile than DRV/r (600 mg/100 mg, twice daily). Patients in DRV/r group are significantly more at risk of developing, over time, side effects and metabolic impairments than those in DRV/c group, in all body functions studied, with statistically significant differences (p < 0.05) between the two groups. Laboratory data were correlated with patient's demographic and clinical characteristics and statistically significant outcomes have been found, proving that a personalized regimen is needed to minimize the ART side effects and to maximize the success of therapy. The results of the study showed that DRV/c, associated with other antiretroviral drugs in the regimens of Romanian HIV infected subjects, have a more favorable metabolic profile than those containing DRV/r.

Darunavir (DRV) is approved for once-daily use in patients with no DRV resistance-associated mutations (RAMs) and twice-daily use in those with DRV RAMs. Several studies suggest that once-daily DRV retains efficacy in the setting of 1-2 DRV RAMs whereas three or more DRV RAMs are needed for DRV resistance. There are few data to support the long-term use of once-daily DRV in patients with DRV RAMs. This observational study evaluated 48-week clinical outcomes of 22 treatment-experienced patients with ≥1 DRV RAMs switched to once-daily DRV between 2014 and 2017. The primary endpoint was HIV-1 RNA <50 copies/ml at week 48. Safety parameters were analyzed throughout the study. The median age of the sample was 53 years, 18 (82%) had baseline HIV-1 RNA <50 copies/ml, and the median number of historical DRV RAMs was 2. At week 48, 20 (91%) had HIV-1 RNA < 50 copies/ml, and 2 (9%) had HIV-1 RNA of 82 and 59,637 copies/ml and reported non-adherence. No adverse drug reactions were observed through week 48. Once-daily DRV maintained virologic control in patients with ≥1 historical DRV RAMs and was safe and well-tolerated. Further data are needed to validate this as a viable treatment option in this population.

<b>

BACKGROUND:

</b>In previous studies in virologically suppressed patients, protease inhibitor monotherapy has shown trends for more low-level elevations in HIV-1 RNA compared with triple therapy, but no increase in the risk of drug resistance.<b>

METHODS:

</b>A total of 273 patients with HIV-1 RNA less than 50 copies/ml on first-line antiretrovirals switched to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 137) or as triple therapy with two nucleoside analogues (n = 136). Treatment failure was defined as HIV-1 RNA levels 50 copies/ml or above, or discontinuation of study treatment by week 48 (FDA Snapshot algorithm).<b>

RESULTS:

</b>Patients were 83% male and 88% white, with mean age 42 years. In the primary efficacy analysis, HIV-1 RNA less than 50 copies/ml by week 48 [intention-to-treat (ITT)] was 118 of 137 (86%) in the DRV/r monotherapy arm versus 129 of 136 (95%) in the triple therapy arm (difference = -8.7%, 95% confidence interval -15.50, -1.80). In a post-hoc analysis, for patients with nadir CD4 cell count 200 cells/μl or above, rates of HIV-1 RNA suppression were 91 of 96 (95%) in the DRV/r monotherapy arm and 100 of 106 (94%) in the triple therapy arm. There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy. Two patients in the monotherapy arm with CD4 nadir less than 200 cells/μl developed viraemia in both cerebrospinal fluid (CSF) and plasma, with one symptomatic case.<b>

CONCLUSIONS:

</b>In this study for patients with HIV-1 RNA less than 50 copies/ml at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple therapy at week 48 in the primary ITT switch equals failure analysis, with two cases of viraemia in the CSF in the protease inhibitor monotherapy arm.

OBJECTIVES:

Ritonavir-boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir-boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir-induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved.

METHODS:

A 96-week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA < 50 HIV-1 RNA copies/mL and study drug discontinuation because of adverse effects at 24 weeks. Analyses were intent-to-treat.

RESULTS:

One hundred and seventy-eight patients received once-daily treatment with either atazanavir/ritonavir (n = 90) or darunavir/ritonavir (n = 88) plus tenofovir/emtricitabine. At 24 weeks, mean total cholesterol had increased by 7.26 and 11.47 mg/dL in the atazanavir/ritonavir and darunavir/ritonavir arms, respectively [estimated difference -4.21 mg/dL; 95% confidence interval (CI) -12.11 to +3.69 mg/dL; P = 0.75]. However, the ratio of total to high-density lipoprotein (HDL) cholesterol tended to show a greater decrease with atazanavir/ritonavir compared with darunavir/ritonavir (estimated difference -1.02; 95% CI -2.35 to +0.13; P = 0.07). Total bilirubin significantly increased with atazanavir/ritonavir (estimated difference +1.87 mg/dL; 95% CI +1.58 to +2.16 mg/dL; P < 0.01), but bilirubin changes were not associated with lipid changes. Secondary endpoints other than total bilirubin were not significantly different between arms.

CONCLUSIONS:

Atazanavir/ritonavir and darunavir/ritonavir plus tenofovir/emtricitabine did not show significant differences in total cholesterol change or overall tolerability at 24 weeks. However, there was a trend towards a lower total to HDL cholesterol ratio with atazanavir/ritonavir and this effect was unrelated to bilirubin.

Introduction: Monotherapy against HIV has undoubted theoretical advantages and has good scientific fundaments. However, it is still controversial and here we will analyze the efficacy and safety of MT with darunavir with ritonavir (DRV/r) on patients who have received this treatment in our hospitals. Materials and Methods: Observational retrospective study that includes patients from 10 Andalusian hospitals that have received DRV/r in MT and that have been followed over a minimum of 12 months.We carried out a statistical descriptive analysis based on the profile of patients who had been prescribed MT and the efficacy and safety that were observed, paying special attention to treatment failure and virological evolution. Results: DRV/r was prescribed to 604 patients, of which 41.1% had a CD4 nadir B200/mmc. 33.1% had chronic hepatitis caused by HCV, had received an average of five lines of previous treatment and had a history of treatment failure to analogues in 33%, to non-analogues 22 and protease inhibitors (PI) in 19.5%. 76.6% proceeded from a previous treatment with PI. The simplification was the main criteria for the instauration of MT in the 81.5% and the adverse effects in the 18.5%.We managed to maintain MT in 84% of cases, with only 4.8% of virological failure (VF) with viral load (VL)-200 c/mL and 3.6% additional losses due to VF with VL between 50 and 200 copies/mL. Thirty three genotypes were performed after failure without findings of resistance mutations to DRV/r or other IPs. Only 23.7% of patients presented some blips during the period of exposition to MT. Eighty seven percent of all determinations of VL had <50 copies/mL, and only 4.99% had-200 copies/mL. Although up to 14.9% registered at some point an AE, only 2.6% abandoned MT because of AE and 1.2% because of voluntary decision. Although the average of total and LDL cholesterol increases 10 mg/dL after 2 years of follow-up, so (Figure presented) did HDL cholesterol in 3mg/dL and the values of triglycerides (-14 mg/dL) and GPT (-6 UI/mL) decreased. The average count of CD4 lymphocytes increased from 642 to 714/mm3 at 24 weeks. Conclusions: In a very broad series of patients obtained from clinical practice, data from clinical trials was confirmed: MT with DRV as a de-escalation strategy is very safe, it's associated to a negligible rate of adverse effects and maintains a good suppression of HIV replication. VF (with >50 or-200 copies/mL) is always under 10% and in any case without consequences.