Boosted Protease Inhibitor-based Regimens Research Articles

Tenofovir, Lamivudine, and Dolutegravir Among Rural Adolescents in Zimbabwe: A Cautionary Tale.

Tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) as a safe and more effective single daily dose regimen is rolling out in Africa for people living with HIV. Although access to viral load (VL) testing is improving, patients may still be transitioned to TLD with virological failure and potential drug resistance. We reviewed annual VL test results of 390 children and adolescents who had enrolled in a community-based antiretroviral therapy program in rural Zimbabwe between 2018 and 2019. VL testing was done by the near point of care simplified amplification-based assays (Diagnostics for the Real World, Sunnyvale, CA, USA) at Chidamoyo Christian Hospital and rate of virological suppression (VS) on TLD (VL <1,000 copies/mL) was assessed. Overall, 184 children and adolescents on TLD were enrolled in this study. The median [interquartile range (IQR)] age was 15 (11-19) years, above half of the participants were female (57%). Before switching to TLD, rate of VS was 76% (139/184). After a median (IQR) duration of 6.9 (5.5-9.1) months on TLD, VS was observed in 95% (174/184) of the participants. Of the 10 participants with VL ≥1,000 copies/mL on TLD, 90% (9/10) were failing on their previous regimens, 6 of 9 (67%) having been on boosted protease inhibitor-based regimens. A high rate (95%) of VS was observed among children and adolescents on TLD in rural Zimbabwe. TLD may address the problems of virological failure and emergence of resistance in Africa. However, longer follow-up might be needed to ascertain sustained VS in this vulnerable population. Randomized Control Trial NCT03986099.

620. Real-World Insights on HIV Treatment Decision-Making in Federal and Public Healthcare Settings

BackgroundEvidence-based guidelines and novel antiretroviral therapies (ART) for people living with HIV (PLHIV) are quickly evolving. Understanding the practice patterns, gaps, and needs of healthcare professionals (HCPs) who care for PLHIV in specific settings, such as those in the federal and public healthcare sector, can inform education and improvement strategies.MethodsSurveys were administered before and after a series of 1.5 hour continuing education programs (n=20) on HIV treatment conducted live in various US cities between April 2019 and March 2020. These programs were designed for HCPs in federal and public healthcare systems, such as the Veterans Affairs Medical Centers, Military Medical Treatment Facilities, and Federally Qualified Health Centers.ResultsSurvey respondents (n=655) were mostly physicians (35%) or nurse practitioners/physician assistants (25%) practicing in federal healthcare settings (Table 1). Respondents reported a mean patient volume of 1,893 (±240) PLHIV monthly.Before and after the education, only 34% and 61% of HCPs, respectively, correctly identified recommended first-line ART for most PLHIV. Only 19% and 38% of HCPs reported high levels of confidence in selecting ART for rapid ART initiation before and after the education.A case-based survey item showed that 35% (pre-education) and 45% (post-education) of HCPs would recommend switching a virologically suppressed patient over age 50 with comorbidities from a boosted protease inhibitor-based regimen to an integrase inhibitor-based regimen. Only 13% and 33% of HCPs reported high confidence in switching ART for older patients with comorbidities before and after the education, respectively.The biggest challenges identified by HCPs were related to ART selection and patient management (Table 1). After the education, HCPs reported needs and intention to improve their team-based processes to: 1) facilitate rapid ART initiation; 2) optimize ART for patients with comorbidities; 3) optimize treatment for patients with virologic failure. ConclusionThis educational program improved knowledge and competency in evidence-based HIV treatment and supported team-based action planning. The findings also inform persistent challenges and needs among HCPs in federal settings.Disclosures Chad J. Zawitz, MD, Gilead Sciences (Speaker’s Bureau)ViiV (Advisor or Review Panel member) Tamar Sapir, PhD, Gilead Sciences, Inc. (Other Financial or Material Support, Independent medical education grant)ViiV Healthcare (Other Financial or Material Support, Independent medical education grant)

Post-exposure prophylaxis completion and condom use in the context of potential sexual exposure to HIV.

Post-exposure prophylaxis (PEP) care remains a challenge for individuals with potential sexual exposure to HIV in terms of PEP completion and ongoing risk behaviours. A retrospective analysis was carried out on data from the French Dat'AIDS prevention cohort (NCT03795376) for individuals evaluated for PEP between 2004 and 2017. A multivariable analysis was performed of predictors of both PEP completion and condom use [odds ratios (ORs)] and their associated probabilities (P, with P>95% being clinically relevant). Overall, 29060 sexual exposures to HIV were evaluated for PEP [36% in men who have sex with men (MSM) and 64% in heterosexuals]. Overall, 12 different PEP regimens were offered in 19240 cases (46%). Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) was the preferred backbone (n=14304; 74%). We observed a shift from boosted protease inhibitor-based regimens to nonnucleoside reverse transcriptase inhibitor- or integrase inhibitor-based regimens in recent years. Overall, 20% of PEP prescriptions were prematurely discontinued. Older age, MSM, intercourse with a sex worker, rape and intercourse with a known HIV-infected source patient were factors associated with increased rates of PEP completion (OR>1; P>98%). None of the 12 PEP regimens was associated with premature discontinuation. We also found 12774 cases of unprotected sexual intercourse (48%). Condom use decreased (OR<1; P>99%) with the year of exposure, and was lower in MSM and rape victims. Condom use increased (OR>1, P>99%) with age, and was higher in those who had intercourse with a sex worker or with a female partner and in those with knowledge of the partner's HIV status. We provide new insights into how rates of condom use and PEP completion might be improved in those receiving PEP by targeting certain groups of individuals for interventions. In particular, youth and MSM at risk should be linked in a prevention-to-care continuum.

Factors Associated With Nonadherence to Antiretroviral Therapy Among Young People Living With Perinatally Acquired HIV in England.

Young people living with perinatally acquired HIV may be at risk of poor adherence to antiretroviral therapy; identification of predictors, using a conceptual framework approach proposed previously by others, is important to identify those at higher risk. In 261 young people with perinatally acquired HIV in England, 70 (27%) reported 3-day nonadherence, 82 (31%) last month nonadherence, and 106 (41%) nonadherence on either measure. Of those reporting nonadherence on both measures, 52% (23/44) had viral load of <50 copies/ml, compared with 88% (127/145) of those reported being fully adherent. In multivariable analysis, young person and medication theme factors were associated with nonadherence. The main predictors of 3-day nonadherence were antiretroviral therapy containing a boosted protease inhibitor and poorer quality of life. Predictors of last month nonadherence were having told more people about one's HIV status, worse self-perception about having HIV, and boosted protease inhibitor–based regimens. The consistency of individual young person and medication factors in predicting nonadherence gives insight into where interventions may best be targeted to improve adherence.

Is immune recovery different depending on the use of integrase strand transfer inhibitor-, non-nucleoside reverse transcriptase- or boosted protease inhibitor-based regimens in antiretroviral-naive HIV-infected patients?

To analyse whether integrase inhibitor (InSTI)-based regimens achieve better immunological recovery than NNRTI- or boosted PI (bPI)-based regimens as initial ART. In a retrospective analysis, we selected patients who initiated ART with two NRTIs plus an InSTI, an NNRTI or a bPI and maintained both the same 'third drug' and an HIV-RNA <50 copies/mL in ≥95% of determinations once undetectable viral load had been achieved. We compared CD4+ count, %CD4+ and CD4+/CD8+ ratio recovery over 2 years. Data were analysed using mixed-effects regression models for repeated measures. Of the 836 patients included, 208, 481 and 147 initiated with InSTI, NNRTI and bPI, respectively. For CD4+, %CD4+ and CD4+/CD8+ two main slopes were identified: from month 0 to month 6, with the highest increments; and from month 6 to month 24, with smaller increases every semester. Although the patients on InSTI achieved undetectable viral load faster, for CD4+ and %CD4+ there were no differences in the slopes of change according to the third drug either for the first phase (P=0.137 and P=0.393, respectively) or from month 6 onwards (P=0.834 and P=0.159, respectively). The increase in CD4+/CD8+ was slightly higher for bPI compared with InSTI (difference of 0.0119, 95% CI 0.0020-0.0205; P=0.018), but clinically negligible. From month 6 onwards, no differences were found between treatment groups (P=0.176). Immune restoration measured as CD4+ count, %CD4+ and CD4+/CD8+ increases was independent of the third antiretroviral drug class used when given with two NRTIs.

Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand.

To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy. Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration. Infants with perinatal HIV starting cART aged less than 6 months with at least 1 viral load measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last viral load at least 400 and first viral load less than 400 copies/ml. Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3% Thailand; 46 and 54% started a boosted protease inhibitor-based or nonnucleoside reverse transcriptase inhibitor-based regimen, respectively. At cART initiation, the median age, CD4% and viral load were 2.9 [interquartile range (IQR): 1.4-4.1] months, 34 (IQR: 24-45)% and 5.5 (IQR: 4.5-6.0) log10 copies/ml, respectively. Overall, an estimated 89% (95% confidence interval: 86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age [adjusted hazard ratio (aHR): 0.84 per month older; P < 0.001], higher CD4% (aHR: 1.11 per 10% higher; P = 0.010) and lower log10 viral load (aHR: 0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression. We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long-term health.

Persistence of Human Immunodeficiency Virus-1 Drug Resistance Mutations in Proviral Deoxyribonucleic Acid After Virologic Failure of Efavirenz-Containing Antiretroviral Regimens.

BackgroundEfavirenz (EFV)-based regimens select broad drug resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs), limiting the effectiveness of EFV and other NNRTIs. The duration, persistence, and decay of drug resistance mutations (DRMs) in the proviral reservoir is not well defined.MethodsParticipants with virologic failure of EFV-based regimens and drug-resistant viremia with the K103N mutation in plasma ribonucleic acid (RNA) were identified from AIDS Clinical Trials Group (ACTG) studies A364 and A5095. These individuals received a second-line, boosted protease inhibitor-based regimen with suppression of viremia for up to10 years during long-term follow-up (median = 3.6 years; interquartile range, 2.1–6.9 years). Proviral deoxyribonucleic acid (DNA) from cryopreserved peripheral blood mononuclear cells was sequenced to identify the persistence of DRM.ResultsTwenty-eight participants from ACTG 364 and ACTG 5095 were evaluated. Sanger sequencing of proviral DNA detected K103N as well as additional reverse-transcriptase inhibitor (RTI) mutations. Ultradeep sequencing confirmed persistence of K103N in 71% of participants with minimal decay over time. In an adjusted model including years since suppression, persistent proviral K103N was 2.6 times more likely (95% confidence interval, 1.0–6.4) per log10 higher human immunodeficiency virus RNA at EFV failure.ConclusionsPersistence of RTI mutations in proviral DNA after virologic failure has implications for the effectiveness of future drug regimens and the recycling of RTI drugs.

Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial

Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch. In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries. Eligible participants were aged 18 years or older, had an estimated glomerular filtration rate of 50 mL per min or higher, had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 6 months or more before screening, and were on a regimen consisting of boosted atazanavir or darunavir plus either emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated once-daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg), herein known as the bictegravir group, or to remain on their baseline boosted protease inhibitor regimen, herein known as the boosted protease inhibitor group, for 48 weeks. Randomisation was stratified by use of tenofovir disoproxil fumarate or abacavir at screening. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (by US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 4%. Efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting patients and is registered with ClinicalTrials.gov, number NCT02603107. Between Dec 2, 2015, and July 15, 2016, 578 participants were randomly assigned and 577 were treated (290 in the bictegravir group and 287 in the boosted protease inhibitor group). At week 48, five participants (2%) in the bictegravir group and five (2%) in the boosted protease inhibitor group had plasma HIV-1 RNA of 50 copies per mL or higher (difference 0·0%, 95·002% CI -2·5 to 2·5), thus switching to the bictegravir regimen was non-inferior to continued boosted protease inhibitor therapy. The overall incidence and severity of adverse events was similar between groups, although headache occurred more frequently in the bictegravir group than in the boosted protease inhibitor group. 233 (80%) participants in the bictegravir group and 226 (79%) in the boosted protease inhibitor group had an adverse event. Only two (1%) participants in the bictegravir group and one (<1%) in the boosted protease inhibitor group discontinued treatment because of adverse events. 54 participants (19%) in the bictegravir group had drug-related adverse events compared with six (2%) in the protease inhibitor group. Fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide might be a safe and efficacious alternative to continued boosted protease inhibitor therapy in adults with HIV-1 infection. Gilead Sciences.

Durability of Efavirenz Compared With Boosted Protease Inhibitor-Based Regimens in Antiretroviral-Naïve Patients in the Caribbean and Central and South America.

BackgroundEfavirenz (EFV) and boosted protease inhibitors (bPIs) are still the preferred options for firstline antiretroviral regimens (firstline ART) in Latin America and have comparable short-term efficacy. We assessed the long-term durability and outcomes of patients receiving EFV or bPIs as firstline ART in the Caribbean, Central and South America network for HIV epidemiology (CCASAnet).MethodsWe included ART-naïve, HIV-positive adults on EFV or bPIs as firstline ART in CCASAnet between 2000 and 2016. We investigated the time from starting until ending firstline ART according to changes of third component for any reason, including toxicity and treatment failure, death, and/or loss to follow-up. Use of a third-line regimen was a secondary outcome. Kaplan-Meier estimators of composite end points were generated. Crude cumulative incidence of events and adjusted hazard ratios (aHRs) were estimated accounting for competing risk events.ResultsWe included 14 519 patients: 12 898 (89%) started EFV and 1621 (11%) bPIs. The adjusted median years on firstline ART were 4.6 (95% confidence interval [CI], 4.4–4.7) on EFV and 3.8 (95% CI, 3.8–4.0) on bPI (P < .001). Cumulative incidence of firstline ART ending at 10 years of follow-up was 32% (95% CI, 31–33) on EFV and 44% (95% CI, 39–48) on bPI (aHR, 0.88; 95% CI, 0.78–0.97). The cumulative incidence rates of third-line initiation in the bPI-based group were 6% (95% CI, 2.4–9.6) and 2% (95% CI, 1.4–2.2) among the EFV-based group (P < .01).ConclusionsDurability of firstline ART was longer with EFV than with bPIs. EFV-based regimens may continue to be the preferred firstline regimen for our region in the near future due to their high efficacy, relatively low toxicity (especially at lower doses), existence of generic formulations, and affordability for national programs.

Phase 3 Randomized, Controlled Trial of Switching to Fixed-dose Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor-based Regimens in Virologically Suppressed Adults: Week 48 Results

BackgroundBoosted protease inhibitor regimens (bPIs) are effective and often used in HIV-infected individuals with difficulties with adherence, but they can have drug–drug interactions and GI adverse effects. Bictegravir (B), a novel, potent integrase strand transfer inhibitor with a high barrier to resistance and low potential for drug–drug interactions, was coformulated with the recommended nucleoside reverse transcriptase inhibitor backbone emtricitabine (FTC)/tenofovir alafenamide (F/TAF) and demonstrated high efficacy and tolerability in randomized studies in treatment-naïve adults. This randomized Phase 3 study assesses efficacy and safety of switching to B/F/TAF from a multi-tablet regimen containing a bPI.MethodsHIV-infected adults suppressed on regimens of boosted atazanavir (ATV) or darunavir (DRV) + abacavir/lamivudine (ABC/3TC) or FTC/tenofovir disoproxil fumarate (TDF) were randomized 1:1 to continue their current bPI regimen or switch to open-label coformulated B/F/TAF (50/200/25 mg) once daily. Primary endpoint was proportion with HIV-1 RNA ≥50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% confidence intervals (CI) using a margin of 4%. Secondary endpoints included proportion with HIV-1 RNA <50 c/mL and safety measures at W48.ResultsA total of 577 participants were randomized and treated with B/F/TAF (n = 290) or current bPI regimens (n = 287): 17% women, 26% Black, median age 48 years. Most were receiving a bPI with FTC/TDF (85%) at screening. At W48, switching to B/F/TAF was noninferior to continuing bPI with 1.7% in each group having HIV-1 RNA ≥50 c/mL (difference −0.0%; 95.002% CI −2.5% to 2.5%, P = 1.00); the proportion with HIV-1 RNA <50 c/mL was 92.1% in B/F/TAF vs. 88.9% in bPI. No participant on B/F/TAF developed resistance to study drugs. One participant on DRV/ritonavir + ABC/3TC developed a treatment-emergent L74V mutation. Incidence of grade 3 or 4 AEs was similar (B/F/TAF 4%, bPI regimens 6%). No renal discontinuations or tubulopathy cases occurred with B/F/TAF.ConclusionAdults switching to B/F/TAF from a boosted PI maintained high rates of virologic suppression without resistance. B/F/TAF was safe and well tolerated.Disclosures E. Daar, Bristol-Myers Squibb: Consultant, Consulting fee. Gilead Sciences, Inc.: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Janssen: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Teva Pharmaceuticals: Consultant and Scientific Advisor, Consulting fee. ViiV: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. E. DeJesus, Abbott Laboratories; Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann LaRoche, Idenix, Janssen, Merck, Pfizer, Sangamo, Taimed, Tobira, and Vertex: Grant Investigator, Research grant. Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex: Scientific Advisor, Consulting fee. P. Ruane, Gilead: Investigator, Scientific Advisor and Shareholder, Consulting fee and Research support. Merck: Speaker’s Bureau, Speaker honorarium. Boehringer: Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. Janssen: Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. Abbott: Investigator, Scientific Advisor and Speaker’s Bureau, Research support and Speaker honorarium. Idenix: Investigator, Research support. ViiV: Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. BMS: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. G. Crofoot, Gilead: Investigator and Scientific Advisor, Advisory honorarium and Research grant. ViiV: Investigator and Scientific Advisor, Advisory honorarium, Research grant and Research support. C. Creticos, Thera Technologies and ViiV Healthcare: Scientific Advisor, Consulting fee. Gilead sciences, Merck, and ViiV Healthcare: Investigator, Research support. Pfizer: Speaker’s Bureau, Speaker honorarium. J. K. Rockstroh, Abbvie: Consultant and Investigator, Consulting fee and Speaker honorarium. Gilead: Consultant, Investigator and Scientific Advisor, Consulting fee and Speaker honorarium. ViiV: Scientific Advisor, Consulting fee. Janssen: Investigator and Speaker at educational event, Speaker honorarium. J. M. Molina, Gilead, ViiV, Merck, Janssen, BMS and TEVA: Scientific Advisor, Speaker honorarium. Y. P. Liu, Gilead: Employee and Shareholder, Salary and Shareholder. K. Andreatta, Gilead: Employee and Shareholder, Salary and Shareholder. H. Graham, Gilead Sciences: Employee and Shareholder, Salary. A. Cheng, Gilead: Employee and Shareholder, Salary. H. Martin, Gilead Sciences: Employee, Salary. E. Quirk, Gilead: Employee and Shareholder, Salary

Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial.

BackgroundIn Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV-positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy.Methods/designIn order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation.DiscussionGiven the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies.Trial registrationClinicalTrials.gov, NCT02400021

Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden

People with HIV-1 in low-income and middle-income countries increasingly need second-line regimens with boosted protease inhibitors. However, data are scarce for treatment response in patients with HIV-1 subtype C (HIV-1C), which is predominant in these regions. We aimed to examine factors associated with virological failure in patients in a standardised national health-care setting. We analysed data for participants in InfCare HIV, a prospective national cohort that includes more than 99% of people with HIV in Sweden. We extracted data for the cohort from the InfCare HIV database on Jan 14, 2015. Baseline was initiation of antiretroviral therapy. We used logistic regression to assess factors associated with primary virological failure (failure to suppress HIV-1 within 9 months) in patients with HIV-1B and HIV-1C and calculated odds ratios (OR) for failure. We also used Cox regression models to calculate hazard ratios (HR) for time-to-secondary virological failure (detectable viral load after initial virological suppression). We did homology-based molecular modelling to assess docking. We included 1077 patients with HIV-1B and 596 with HIV-1C. In multivariate regression analysis, pre-therapy higher viral load (OR 1·82, 95% CI 1·49-2·21; p<0·0001), subtype C infection (1·75, 1·06-2·88; p=0·028), and boosted protease inhibitor-based regimens (1·55, 1·45-2·11; p=0·004) were associated with increased risk of primary virological failure. Individuals with HIV-1C who were given therapy with boosted protease inhibitors had earlier time-to-secondary virological failure than did those with HIV-1B given similar regimens (adjusted HR 1·92, 95% CI 1·30-2·83; p=0·002). Molecular modelling suggested lower affinity for protease inhibitors to HIV-1C protease than to HIV-1B. Our findings suggest an increased risk of virological failure in patients with HIV-1C, especially in those on boosted protease inhibitor-based regimens. Future studies should further dissect the biochemical and viral mechanisms of resistance to protease inhibitors in patients with non-B subtypes of HIV-1, including clinical studies to assess the efficacy of boosted protease inhibitor-based regimens in low-income and middle income countries. Karolinska Institutet Research Foundation, Swedish Research Council, Stockholm County Council, Swedish Physicians against AIDS, US National Institutes of Health, University of Missouri.

Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: an observational cohort study

Access to combination antiretroviral therapy (ART) is expanding in Latin America (Mexico, Central America, and South America) and the Caribbean. We assessed the incidence of and factors associated with regimen failure and regimen change of initial ART in this region. This observational cohort study included antiretroviral-naive adults starting ART from 2000 to 2014 at sites in seven countries throughout Latin America and the Caribbean. Primary outcomes were time from ART initiation until virological failure, major regimen modification, and a composite endpoint of the first of virological failure or major regimen modification. Cumulative incidence of the primary outcomes was estimated with death considered a competing event. 14,027 patients starting ART were followed up for a median of 3.9 years (2.0-6.5): 8374 (60%) men, median age 37 years (IQR 30-44), median CD4 count 156 cells per μL (61-253), median plasma HIV RNA 5.0 log10 copies per mL (4.4-5.4), and 3567 (28%) had clinical AIDS. 1719 (12%) patients had virological failure and 1955 (14%) had a major regimen change. Excluding the site in Haiti, which did not regularly measure HIV RNA, cumulative incidence of virological failure was 7.8% (95% CI 7.2-8.5) 1 year after ART initiation, 19.2% (18.2-20.2) at 3 years, and 25.8% (24.6-27.0) at 5 years; cumulative incidence of major regimen change was 5.9% (5.3-6.4) at 1 year, 12.7% (11.9-13.5) at 3 years, and 18.2% (17.2-19.2) at 5 years. Incidence of major regimen change at the site in Haiti was 10.7% (95% CI 9.7-11.6) at 5 years. Virological failure was associated with younger age (adjusted hazard ratio [HR] 2.03, 95% CI 1.68-2.44, for 20 years vs 40 years), infection through injection drug use (vs infection through heterosexual sex; 1.60, 1.02-2.52), and initiation in earlier calendar years (1.28, 1.13-1.46, for 2002 vs 2006), but was not significantly associated with boosted protease inhibitor-based regimens (vs non-nucleoside reverse transcriptase inhibitor; 1.17, 1.00-1.36). Incidence of virological failure in Latin America and the Caribbean was generally lower than that reported in North America or Europe. Our results suggest the need to design strategies to reduce failure and major regimen change in young patients and those with a history of injection drug use. US National Institutes of Health.

Patient-Reported Outcomes After a Switch to a Single-Tablet Regimen of Rilpivirine, Emtricitabine, and Tenofovir DF in HIV-1-Positive, Virologically Suppressed Individuals: Additional Findings From a Randomized, Open-Label, 48-Week Trial.

BackgroundPatient-reported outcomes (PROs) can provide important information about treatment tolerability in HIV-1-infected patients.ObjectiveThe aim of this study was to evaluate PROs following switching from a boosted protease inhibitor-based regimen to the single-tablet regimen (STR) of rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in the 48-week open-label Switching Boosted PI to Rilpivirine in Combination with Truvada as a Single-Tablet Regimen (SPIRIT) trial.MethodsIn the open-label SPIRIT trial, patients were randomized to receive an STR of RPV/FTC/TDF (n = 317) for 48 weeks or stay on their baseline regimen of a ritonavir-boosted protease inhibitor and two nucleoside/nucleotide analog reverse transcriptase inhibitors (PI + RTV + 2NRTIs, n = 159) for 24 weeks before switching to RPV/FTC/TDF for another 24 weeks. PRO assessments included the HIV Treatment Satisfaction Questionnaire (TSQ) and the HIV Symptom Index Questionnaire (SIQ).ResultsAt week 24, the mean HIV TSQ improvement from baseline was significantly greater in the RPV/FTC/TDF group than the PI + RTV + 2NRTIs group (p < 0.001). On the HIV SIQ, the percentage of patients reporting a shift from ‘symptom’ to ‘no symptom’ was significantly greater with RPV/FTC/TDF treatment compared with PI + RTV + 2NRTIs for all items (all p ≤ 0.01), with total within-group occurrence of 13/20 symptoms significantly decreasing from baseline for RPV/FTC/TDF patients. In the delayed switch group, significantly fewer patients reported diarrhea and sleep problems at week 48 vs. week 24.ConclusionsThese data suggest that switching to the STR RPV/FTC/TDF from a PI-based multi-pill regimen is associated with greater patient-reported treatment satisfaction and improved tolerability in HIV-1-infected, virologically suppressed individuals.Electronic supplementary materialThe online version of this article (doi:10.1007/s40271-015-0123-2) contains supplementary material, which is available to authorized users.

HIV Tropism and its Relationship with Transmitted Resistance in Naive Patients

Aim: The objective of the present study was to investigate whether patients with transmitted resistance more frequently harbor X4/DM tropic viral strains. Patients &amp; methods: Patients were included from an Italian nationwide database if they were tested for tropism and resistance at the same time. HIV tropism was assessed by the Geno2pheno coreceptor system (false-positive rate: ≤10%) and enhanced-sensitivity Trofile assay. Overall, 299 naive patients, tested between 2009 and 2011, were included: 252 patients tested by Geno2pheno, 116 by enhanced-sensitivity Trofile assay and 80 by both methods. Results &amp; conclusion: Using Geno2pheno, X4/DM tropic virus was detected in 55 patients (21.8%), with an overall mean false-positive rate of 42.3% (standard deviation: ±33.3). Using the enhanced-sensitivity Trofile assay, 29 patients (25.0%) carried X4/DM tropic virus. Resistance mutations were more frequently detected in patients harboring X4/DM tropic virus (mean: 1.18 ± 3.0 vs 0.41 ± 1.2 per patient; p = 0.001) and with both Geno2pheno (0.82 ± 2.6 vs 0.35 ± 0.9; p = 0.034) and enhanced-sensitivity Trofile assay (1.11 ± 1.9 vs 0.46 ± 1.1; p = 0.039). However, significant differences were found for reverse transcriptase-related mutations, but not for transmitted protease resistance, and this might be explained by the low frequency of transmitted protease resistance. Among single mutations, L33F and L90M with regards to protease and K65R, K70E, K219E and V106A/M with regards to reverse transcriptase were found to be significantly associated with X4/DM tropic virus. X4/DM tropism was also associated with lower CD4+cell count, but not with higher HIV RNA levels. X4/DM tropic HIV strains were related to a higher frequency of transmitted reverse transcriptase resistance mutations in this unselected set of naive patients. As a consequence, if a patient harbors a non-CCR5 tropic virus and bears more reverse transcriptase resistance and less protease resistance, a boosted protease inhibitor-based first-line regimen should be preferred.

Endothelial function in HIV-infected patients switching from a boosted protease inhibitor-based regimen to raltegravir: a substudy of the SPIRAL study

Raltegravir has been demonstrated to have a favourable impact on several metabolic parameters, including a lack of changes in lipid and glucose concentrations. We aimed to assess the effect on endothelial function of switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to raltegravir. This is a substudy of the SPIRAL study, a multicentre, randomized, open-label clinical trial including HIV-infected patients on a stable PI/r-based antiretroviral regimen and virologically suppressed for at least the previous 6 months. Endothelial function was prospectively evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline and at weeks 24 and 48. Thirty-five HIV-infected patients were included. Sixteen patients were randomly assigned to continue their current PI/r regimen and 19 to switch the PI/r to raltegravir. Total cholesterol, low-density lipoprotein cholesterol and triglycerides decreased at weeks 16 and 32 in the raltegravir-switch arm, while no changes were observed in the PI/r arm. Triglyceride levels were significantly lower in the raltegravir arm than in the PI/r arm at weeks 16, 32 and 48. No significant changes from baseline occurred in FMD at weeks 24 and 48 within or between the raltegravir and PI/r arms. Adjustment for baseline artery diameter did not have a significant effect on the FMD differences. Switching from a PI/r-based antiretroviral regimen to raltegravir in patients with virological suppression has a beneficial impact on the lipid profile, but it does not seem to have a clear impact on endothelial function after a 1 year follow-up.

Efficacy and safety of a dual boosted protease inhibitor-based regimen, atazanavir and fosamprenavir/ritonavir, against HIV: experience in a pediatric population

BackgroundAlthough dual-boosted protease inhibitors regimen is not recommended in children with HIV infection, such a strategy could be useful in subjects with a complex resistance profile. This study was aimed at assessing the long term efficacy and safety of a double-boosted protease inhibitor combination, fosamprenavir (fAVP) and atazanavir/ritonavir (ATV/r) in a cohort of HIV-infected children and adolescents who had failed with nucleoside reverse transcriptase inhibitors.MethodsSeven vertically infected children and adolescents who had previously failed highly active antiretroviral therapy and were resistant to nucleoside reverse transcriptase inhibitors, received a dual protease inhibitor (PI) regimen including fAVP plus ATV/r for 42 months. The patients were assessed at baseline, every month for the first 24 weeks of therapy and every 3 months until month 32. Physical examination, CD4+ cell count, HIV-RNA viral load, lipid profile and hepatic function were assessed throughout the follow up.ResultsDuring the study no serious adverse events were reported. CD4 absolute number increased over-time in all subjects. At baseline the median HIV-RNA was 6562 cp/mL (ranging 1048 -102772 cp/mL) and rapidly decreased below the limit of detection (50 cp/mL) after 2 months of the new treatment and remained undetectable in all cases through the entire study period. At the beginning of the study all cases showed a normal lipid profile. During the study period, 4/7 subjects showed total cholesterol, low density lipoprotein and triglyceride levels >97th cent.le for the males and 94th cent.le for the females. HDL cholesterol showed protective values. Hepatic enzymes remained stable during the entire observation, whereas total bilirubin showed toxicity II/III grade in 6/7 subjects. No change in fat redistribution and insulin resistance was observed.ConclusionDual-boosted protease inhibitor therapy was virologically and immunologically effective and it could be considered as a possible alternative to a rescue regimen in children and adolescents. However, hypercholesterolemia and hypertriglyceridemia need close follow-up and may limit the use of this therapeutic option.

Second-Line Antiretroviral Treatment Successfully Resuppresses Drug-Resistant HIV-1 After First-Line Failure: Prospective Cohort in Sub-Saharan Africa

Little is known about the effect of human immunodeficiency virus type 1 (HIV-1) resistance mutations present at time of regimen switch on the response to second-line antiretroviral therapy in Africa. In adults who switched to boosted protease inhibitor-based regimens after first-line failure, HIV-RNA and genotypic resistance testing was performed at switch and after 12 months. Factors associated with treatment failure were assessed using logistic regression. Of 243 participants, 53% were predicted to receive partially active second-line regimens due to drug resistance. The risk of treatment failure was, however, not increased in these participants. In this African cohort, boosted protease inhibitors successfully resuppressed drug-resistant HIV after first-line failure.

Second-Line Antiretroviral Therapy for HIV-Infected Children in Resource Limited Settings

Pediatric antiretroviral treatment programs have been rolled out in resource limited settings, providing lifesaving treatment to approximately 300,000 HIV-infected children. The standard first-line antiretroviral regimen is a nonnucleoside reverse transcriptase plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). A meta-analysis showed that 70% of children achieved virologic suppression after 12 months of first line therapy. This article presents the challenges in diagnosis of treatment failure in resource limited settings and reviews the current guidelines for management of HIV-infected children with second-line antiretroviral therapy. The details of antiretroviral drugs recommended for second line regimens are summarized. The current standard second-line regimen is a boostedprotease inhibitor-based regimen plus recycling NRTIs. The potential role of new ARV drug classes for second-line regimen is addressed. Keywords: Pediatric HIV, antiretroviral therapy, resource limited settings

Quantifying the risks and benefits of efavirenz use in HIV-infected women of childbearing age in the USA.

The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz-related teratogenicity) associated with using efavirenz in HIV-infected women of childbearing age in the USA. We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz-based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor-based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100,000 women, we incorporated literature-based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women. Survival for HIV-infected women who received an efavirenz-based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non-efavirenz-based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100,000 exposed women, compared with 72.46/100,000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS-related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz-exposed women. Use of non-efavirenz-based initial ART in HIV-infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision-making regarding efavirenz use presents a trade-off between these two risks; this study can inform discussions between patients and health care providers.