48-week changes in biomarkers in subjects with high cardiovascular risk switching
from ritonavir-boosted protease inhibitors to dolutegravir: the NEAT022 study
(Martinez E, et al; Abst. O113):
Martinez and colleagues presented the 48-week changes in biomarkers in subjects with high cardiovascular risk switching from PI/r to DTG in the NEAT022 study. In 313 evaluable patients, significant decreases in sCD14 (11%, p < 0.001) and adiponectin (11%, p < 0.001) were observed in the switch arm relative to the PI/r group. The decrease in soluble CD14 is a likely predictor of reduced inflammation and reduced CV risk. In contrast, the change in adiponectin was associated with an increase in BMI, and may be associated with an increase in CV risk. The median BMI change (kg/m2) was +0.2 in the PI/r arm and +0.3 in the DTG arm. The investigators suggested that their findings illustrate the complex, multifactorial and competing contributions to CV risk, and noted the need for further evaluation of the role of adiponectin in the observation of weight gain in patients switched to DTG.
Multimorbidity and risk of death differs by gender in people living with HIV in the Netherlands: the ATHENA cohort study (Wit F, et al; Abst. O115):
Wit and colleagues analyzed multi-morbidity and risk of death by gender in PWHIV in the ATHENA cohort. As has been seen in many cohort studies, multi-morbidity was a strong independent predictor of mortality; overall, 1, 2, 3, and 4 co-morbidities increased mortality roughly 2-fold, 4-fold, 10-fold, and 20-fold, respectively. Women with less than three comorbidities had lower mortality than men (RR 0.78 [0.67 to 0.91], p = 0.002). In contrast, women had a higher risk of mortality than men when experiencing three or more comorbidities.
Meta-analysis of the risk of Grade 3/4 or serious clinical adverse events in 12 randomized trials of PrEP (n = 15,678) (Pilkington V, et al; Abst O143):
Over 300,000 people take PrEP worldwide, though this represents a fraction of those at need. Costs are variable, including costs of generics, let alone branded medications. Safety data came originally from the treatment literature and found most of the toxicity in regimens that contained a booster and not in unboosted settings. Pilkington did a meta-analysis of use of TDF that focused on Grade 3/4 adverse events, Grade 3+ creatinine elevations, and bone fractures. 13 RCT included and looked at 15,678 patients and 22,250 PYFU. Meta-analysis showed no increased risk of severe adverse events on PrEP for any of the markers. A wider analysis of PrEP looking at grade 1-4 creatinine elevations showed a slightly increased risk that was significant. No change if regimens were used daily or intermittent, and no sex-based differences. No significant increased risk for high grade creatinine elevations, only for lower range elevations. No other significant risks were noted.
No significant changes to residual viremia after switch to dolutegravir and lamivudine in a randomized trial (Li J, et al; Abst. O145):
There is persistent viremia for the majority of individuals on multiple regimens. This is thought to be present from clonal expansion. Do two drug regimens have a different impact on this persistent viremia, i.e., do fewer drugs leave a higher persistent viremia? Li and colleagues looked at the ASPIRE study, in which suppressed patients were switched to a DTG/3TC-based regimen. Patients had been on regimens an average of 5.7 years at the time of randomization. The rates of suppression were equal between the switch regimen and the subjects who stayed on the original regimen over 48 weeks. A sub-study looked at a single copy assay with a limit of detection of 0.5 HIV-1 RNA cps/mL. The sub-study showed no significant difference in residual viremia at weeks 24 and 48 between the two-drug regimen and the three-drug regimen. Further analysis looked at ART duration > 6 years and CD4 count > 500 and also revealed no difference. This offers some reassurance that in a simplification strategy there is no signal of increased residual viremia with two vs. three drug regimens.
Phase III randomized, controlled clinical trial of bictegravir coformulated with FTC/TAF in a fixed-dose combination (B/F/TAF) versus dolutegravir (DTG) + F/TAF in treatment-naïve HIV-1 positive adults: Week 96 (Stellbrink H, et al; Abst. O211):
Stellbrink and colleagues presented the 96-week outcomes of the randomized controlled comparison of B/F/TAF to DTG + TAF/FTC in 645 treatment naïve adults. At 96 weeks, HIV RNA < 50 c/mL was achieved by 84.1% on B/F/TAF and 86.5% on DTG+F/TAF. These results were non-inferior, and per protocol evaluation were identical. There was a statistically significant improvement in the DTG arm compared to B/F/TAF arm in CD4 improvement (p = 0.008), but the mean CD4/CD8 percentages were identical for both arms (11%). The rates of virologic failure were similar after 96 weeks. There was no treatment-emergent resistance to study drugs in either arm after 96 weeks. Discontinuations due to adverse events were uncommon (2%) and comparable in both arms. The most common AEs were diarrhea and headache, and AEs were reported in 20% of B/F/TAF patients and 28% of DTG + TAF/FTC (p = 0.02). There were lipid increases in both arms that were equivalent. These results provide evidence that both regimens can be excellent options for ART initiation, which was recently confirmed by the inclusion of both these regimens in the current guidelines.
Efficacy and safety of the once-daily, darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen (STR) in antiretroviral treatment (ART)-naïve, HIV-1-infected adults: AMBER Week 96 results (Orkin C, et al; Abst. O212):
Orkin et al presented the 96-week outcomes of the AMBER study of co-formulated DRV/C/TAF/FTC compared to DRV/C + TDF/FTC in 725 treatment-naïve patients with median CD4 of 453 cells/mL. Approximately 15% of patients had NNRTI resistance at baseline and 5% with NRTI baselines and 2% with PI agents. At 48 weeks, viral suppression rates were 91% D/C/F/TAF vs. 88% D/C/F/TDF favoring the TAF arm. At 96 weeks, virologic suppression was seen in 85% of the D/C/F/TAF arm and 84% of the control arm that had switched over to D/C/F/TAF after the first 48 weeks. Subgroup analysis showed a small difference in CD4 < 200 favoring the TDF arm, but this group had only 29 patients. Low VF rates of 6% of VL >50 cps /mL via FDA snapshot were seen in both arms. 2 kilo gain in TAF arm for 96 weeks was seen and 1 kilo in the TDF/TAF switch group, though the significance of this weight gain is unclear. No darunavir, primary PI, or tenofovir resistance mutations occurred during the study, and one subject in each arm had an M184I/V mutation. Improvements in bone and renal markers were observed in the switch arm consistent with previous studies of a switch from TDF to TAF-based ART. No cases of Fanconi syndrome or subclinical PRT were reported through 96 weeks. Most frequent abnormality was elevated LDL cholesterol with increased total cholesterol that was significant when comparing TAF vs. TDF regimens and also associated with slightly more increases in patients initiating lipid lowering therapies. There were improvements in the switch patients from TDF to TAF in urinary markers and GFR as well. D/C/F/TAF is a recommended combination in the EACS 2018 Guidelines, but not the DHHS Guidelines.
Comparable viral decay with dolutegravir plus lamivudine versus dolutegravir-based triple therapy (Taiwo B, et al; Abst. O213):
The potency and durability of two drug regimens is still a subject of debate. The 48-week data of Gemini I and II showed equivalent efficacy of DTG/3TC compared to two different 3-drug regimens. The data on reduction of the viral reservoir size as measured by single copy assay showed no difference between 2- and 3-drug regimens. The concern about the rate of viral decay is based on concerns about the development of resistance if the rate of decay is slower, reflecting more viral replication during drug exposure. ACTG 5353 allowed for the comparison of the virologic decay between this trial of DTG/3TC as an initial regimen and the Single and Spring 1 studies. The evaluation occurred over numerous time points through 24 weeks. There were no differences in the rates of decay between the different drug regimens and the results were non-inferior between 2 and 3 drug regimens, all containing dolutegravir. The rate of the decay in those with VL > 100,000 was faster with the 2-drug regimen and slower with VL < 100,000. Overall, the decay rates were comparable in individuals even with VL > 500,000 cps/mL. The clinical significance of this is unlikely to be relevant. The development of resistance has been equally slow in both integrase and boosted PI based regimens, despite improved decay rates with integrase-based therapies.
The impact of M184V/I mutation on the efficacy of abacavir/lamivudine/dolutegravir regimens prescribed in treatment-experienced patients (Olearo F, et al; Abst. O214):
Olearo and colleagues studied the impact of M184V/I mutation on the efficacy of a switch to DTG/ABC/3TC in an analysis of 1,626 ART-experienced patients from 5 cohort studies in Europe, of whom 137 had an M184I/V. 1:11 (Ratio presence: absence of M184 V/I mutations) patients harbored this mutation, and the rate of additional NRTI mutations was markedly increased as well. Previous data showed that M184V did not confer greater risk of virologic failure with boosted elvitegravir regimens. They looked at a composite endpoint of virologic failure or blips of VL > 50 copies/mL. Patients with an M184I/V were more likely to be older, IDU, and have a longer duration of ART prior to the switch. Virologic failure overall was 15.1/1000 pt-yrs, and higher in patients with M184V/I, though not significantly (29.8/1000 vs 13.6/1000 pt-yrs, p = 0.09). Patients were more likely to have transient low-level viremia (blips) when M184V was present. The composite analysis of blips and M184V suggested increased rate of VF in a univariate analysis, but not in the multivariate. While these data offer some reassurance that an M184V/I does not confer a substantially higher risk of VL failure in the short term in ART-experienced patients switched onto DTG/ABC/3TC, more data over a longer period of time are needed to assess whether these differences may become clinically significant.
STIs among MSM: new challenges in prevention, diagnosis and treatment
(Molina JM; Abst. O131):
STI and MSM
A recent article in Australia tracking condom use shows decreases in use from 2013 of 46% to 31% in 2017. Increases in rates of STI are higher in MSM, with 51% of new syphilis occurring in MSM who represent 3% of the overall population. This is equally significant for chlamydia and lymphogranuloma venereum as well. Increases in bacterial STI were seen at Fenway Health by Mayer et al with the greatest increases seen amongst those on PrEP.
Condoms are key, as are the contribution of sexual partners. There are higher rates of STI with those less than 25, more casual partners, and prior history of STI before the use of PrEP. Vaccines play a role for viral STI, but not bacterial. There is some cross protection against GC with meningococcal vaccine due to homogeneity between protein sequences of the two bacteria. The challenge is that GC can mutate to develop resistance.
The use of doxycycline by Molina et al in IPERGAY showed that doxycycline at approximately 7 pills per month used post sexual exposure demonstrated a significant reduction in bacterial STIs of almost 50%. There were reductions seen in cases of chlamydia and syphilis of almost 70%. No evidence seen of resistance but not enough samples were seen to comment. However, the long-term benefit of PEP for STI is unknown; antibiotic prophylaxis for STIs is not recommended and additional studies will assess benefit/risk ratio.
Test and Treat
Guidelines recommend testing all symptomatic patients and test annually for asymptomatic patients or every 3 months if they have had multiple sex partners or recent bacterial STIs. Testing of asymptomatic MSM for M. genitalium is not recommended. A variety of testing strategies were discussed, such as the cost effectiveness of pooled testing of multiple sites, which was cost effective and offers a way to lower costs with high patient satisfaction. Home based testing in France for 11,000 demonstrated a three-fold increase in testing and showed greater identification of STIs but did not change reinfection rates. Greater rates of testing will detect more STIs, but will they reduce the incidence of STIs? HCV may be different, as more testing and treatment have reduced the incidence of new infections, as evidenced by the Swiss HCVree trial, which showed a 49% decrease in incident infections among HIV-infected MSM.
Should clinicians use ceftriaxone alone or with azithromycin? There are strains of resistance to ceftriaxone that require the addition of azithromycin, but now we see development of strains that are resistant to azithromycin. We are now at the point that we may need new diagnostic tests at point of care (POC) to detect resistance and lead the way to new antimicrobial agents for detection of antibiotic resistance to GC. There are three agents that are in clinical trials today: gepotidacin, zolifloxacin, and solithromycin.
One of the key questions in treating STIs is whether to treat the partners by giving medications to the index patient and having them deliver the medications to their partner or partners, or have them referred for treatment. A study by Golden et al in Seattle had disappointing results with chlamydia but significant improvement with GC. Another study by Clark et al showed improvements of 83% vs. 58% with treatment of STIs, but no impact on reinfection rates. The results of alternative testing strategies and expedited partner treatment are similar with higher cure rates, but no changes in reinfection rates, thus having a limited impact on STIs in the community. In the IPERGAY study, an on-demand strategy for provision of PrEP, partner notification resulted in higher notification for casual partners then for notification of their primary partners. Work is currently underway to establish online registries with an anonymous cohort of individuals with STIs that will allow for automatic partner notification without indicating index partner or any identity for infected individuals.
Phase IIIb, randomized, open-label study to evaluate switching from a tenofovir disoproxil fumarate (TDF)-containing regimen to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in virologically suppressed, HIV-1 infected participants aged ≥ 60 (Maggiolo F, et al; Abst. P145):
Maggiolo and colleagues presented the 48-week results of a 2:1 randomized trial of a switch from a TDF-containing regimen to E/C/F/TAF in suppressed patients who were 60 years or older vs. regimen continuation. The previous regimen was an NNRTI in 78%, INSTI in 12%, and PI/r in 9%. Viral suppression was maintained in 94% of subjects in both arms. Adverse events leading to d/c were rare in both arms. Mean BMD increased in the E/C/F/TAF arm and decreased in the TDF arm at both W24 and W48 in the spine and hip. At W48, 58% of patients who switched to E/C/F/TAF had normal hip T scores compared to 46% of patients remaining on the TDF-containing regimen. These data suggest that significant reductions in osteoporosis and fractures in older HIV+ patients are associated with a switch from a TDF-containing regimen to E/C/F/TAF with similar virologic efficacy and adverse events.
Incidence and risk factors associated with osteoporosis-related fractures (ORF) among PLWHIV in British Columbia (BC), Canada (Barletta J, et al; Abst. P158):
Barletta and colleagues reported the incidence and risk factors associated with osteoporosis-related fractures (ORF) in the hip, wrist, vertebrae, and humerus among 6,846 PLWHIV in British Columbia compared to 514,619 HIV uninfected controls from 1996-2013. Fractures were significantly more common in PLWHIV (6%) than in age-matched HIV negative controls (5.45%, p = 0.02). By multivariate analysis, predictors of ORF included female sex, older age at ART initiation, IDU, previous injuries, and ART initiation prior to 2008. No association was found with PI or NNRTI use, whereas cumulative NRTI use was associated with a lower risk of ORF.
Dolutegravir- versus an efavirenz 400mg-based regimen for the initial treatment of HIV-infected patients in Cameroon: 48-week efficacy results of the NAMSAL ANRS 12313 trial (Delaporte E, et al; Abst. O342):
Delaporte and colleagues reported on a study comparing a lower dose of efavirenz (400 mg, instead of the traditional dose of 600 mg) + TDF/3TC compared to dolutegravir + TDF/3TC. This is relevant because DTG is part of the current WHO guidelines, and EFV was the previous recommended drug, but at the 600-mg dose. The 48-week snapshot analysis showed 74.5% with viral suppression with dolutegravir vs. 69% for efavirenz and this difference was non-inferior (p < 0.001). These differences were similar even in the highest viral strata of > 500,000 cps/mL. Immunologic improvements (CD4 change) at week 48 were statistically similar in both groups: DTG (+178) and EFV (+150) (p < 0.021). All patients in both groups fared worse when their viral loads > 500,000 and this was significantly associated with higher risk of failure, with only 60% reaching < 50 cps/mL. The key distinction between the two regimens was that the EFV arm was associated with greater rates of resistance in the virologic failure patients DTG (3) vs. EFV (16) as well as higher rates of EFV baseline resistance and higher rates of resistance on failure. This study established both the relative efficacy of lower dose efavirenz, but with some cost, relative to the risk of development of resistance compared to dolutegravir. This study supports the current WHO recommendation to make dolutegravir the preferred first-line regimen for initiation of ARV.
Distribution in cerebrospinal fluid (CSF) of cabotegravir (CAB) and rilpivirine (RPV) after intramuscular administration of long-acting (LA) injectable suspensions in HIV-1-infected patients (Letendre S, et al; Abst. O346):
Letendre and colleagues presented the CSF sub-study of the LATTE-2 study of injectable rilpivirine and cabotegravir every 4 or 8 weeks in 18 HIV treatment-naïve patients. The CSF DTG and RPV levels reached a steady state that was consistently above the IC90 for each drug. Additionally, the CSF HIV-1 RNA levels were < 2 c/mL. These data suggest that long-acting injectable cabotegravir and rilpivirine achieve drug levels that are adequate for antiviral activity in the CNS.
Risky Alcohol Consumption and Associated Health Behaviour among HIV-positive and HIV-negative Patients in a UK Sexual Health and HIV Clinic: the HAZAL Study (Suonpera E, et al; Abst. P212) and
Chemsex drugs on the rise among MSM: a longitudinal analysis of the Swiss HIV Cohort Study from 2007-2017 (Hampel B, et al; Abst. P076):
There were numerous reports on the frequency of chemsex and alcohol use amongst HIV-positive patients. Suonpera and colleagues reported on a survey of alcohol use in HIV positive patients. 25% of HIV positive vs. 36% of HIV negative controls reported risky alcohol use that impaired their judgement. Presence of depressive symptoms, smoking and problematic drug use were significantly associated with those who used alcohol. Chemsex participation and poor adherence to ARTs were also significantly correlated with risky alcohol consumption in the univariate analysis, but in the multivariate analysis, only depression and chemsex persisted as impacting ARV adherence. This study may help identify which subpopulations are at more risk for non-adherence and demonstrates the role of alcohol in leading to other recreational drug use with concomitant worse ARV adherence.
A second report, by Hampel et al, reported on prevalence and demographics of chemsex in the Swiss HIV Cohort Study. This cohort is 20,000 HIV-positive individuals with approximately 40% MSM. Among the cohort that recreational drug use were available, rates had increased in the MSM population from 8.8% (2007) to 12.4% (2017). The impact in 1 in 8 MSM may have a significant impact for condom use and adherence and is an additional factor to consider when counselling patients.
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