We investigated HIV-1 reverse transcriptase (RT) polymorphisms of plasma isolates from 98 HIV-1-infected study subjects with >2 years of antiretroviral therapy who were failing their current protease inhibitor (PI)-containing regimen. In 1 patient, we detected a virus with a heavily mutated beta3-beta4 connecting loop of the HIV-1 RT fingers subdomain, consisting of a single aspartate codon insertion between positions 69 and 70 and five additional variations: 64N, K65, K66, 67G, 68Y, T69, Ins D, 70R, W71, R72, K73, 74I. Mutants with the recently described 2-aa insertions between codons 68 and 70 of RT were detected in another 3 patients. Among the four isolates with the 1- or 2-aa insertions, the novel genotype was the most refractory to therapy and displayed the highest level of phenotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Follow-up samples demonstrated that the novel mutant represents a stable genetic rearrangement and that the amino acid insertions can coexist with nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) mutations resulting in phenotypic resistance to both NRTIs and NNRTIs. An increasing number of HIV-1 isolates containing various insertions in the beta3-beta4 hairpin of the HIV-1 RT fingers subdomain appear to emerge after prolonged therapy with different NRTIs, and these polymorphisms can confer multiple drug resistance against NRTIs.

INTERVENTION:

Trade Name: Atripla Product Name: efavirenz/emtricitabine/tenofovir disoproxil fumarate Product Code: ATR Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

efavirenz CAS Number: 154598‐52‐4 Current Sponsor code: EFV Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐ INN or Proposed

INN:

emtricitabine CAS Number: 143491‐57‐0 Current Sponsor code: FTC Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

tenofovir disoproxil fumarate CAS Number: 52232‐67‐4 Current Sponsor code: TDF Other descriptive name: tenofovir DF Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐ Trade Name: Kivexa Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

abacavir CAS Number: 136470‐78‐5 Current Sponsor code: ABC Other descriptive name: abacavir sulfate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐ INN or Proposed

INN:

lamivudine CAS Number: 134678‐17‐4 Current Sponsor code: 3TC Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐ Trade Name: Sustiva Product Name: efavirenz Product Code: EFV Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

efavirenz CAS Number: 154598‐52‐4 Current Sponsor code: EFV Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐

CONDITION:

Adult, HIV‐1 infected, tenofovir DF‐ and emtricitabine‐naive subjects on a stable HAART regimen of Kivexa (abacavir/lamivudine) and efavirenz, with raised total fasting cholesterol ; MedDRA version: 9.1 Level: LLT Classification code 10020192 Term: HIV‐1

PRIMARY OUTCOME:

Main Objective: To determine if switching from a stable HAART regimen of Kivexa + EFV to once daily Atripla leads to a reduction in total fasting cholesterol at 12 weeks. Primary end point(s): Change from baseline in total fasting cholesterol at Week 12. Secondary Objective: •Evaluation of fasting metabolic parameters (e.g., LDL, HDL, triglycerides, non‐HDL cholesterol and cholesterol ratios).; ; • Evaluation of efficacy and safety by assessing adverse events, clinical laboratory tests, physical examinations and vital signs at every visit.; ; • Evaluation of changes in the 10‐year risk factor for coronary heart disease outcomes as measured by total cholesterol, HDL, blood pressure, smoking status, treatment for hypertension, sex and age.

INCLUSION CRITERIA:

• = 18 years old • Plasma HIV RNA < 50 copies/mL = 12 weeks prior to Screening • Stable HAART regimen of Kivexa + EFV for = 24 weeks prior to Screening • Documented confirmed raised total cholesterol = 5.2 mmol/L for last two consecutive tests (at least 4 weeks apart) with the last result = 4 weeks prior to Screening • Subject willing to continue current unmodified HAART for 12 weeks if randomized to Group 2 • Subjects requiring concomitant lipid regulating therapy must be established on a stable dose/frequency = 12 weeks prior to Screening and be expected to remain stable in dose and frequency throughout the treatment phase of the study • Adequate renal function by calculated creatinine clearance = 60 mL/min according to the Cockcroft Gault formula • Negative serum pregnancy test (females of childbearing potential only i.e., not surgically sterile or at least 2 years post‐menopausal) • Hepatic Total Bilirubin = 22 umol/L • Adequate ha

INTERVENTION:

Product Code: GS‐9883/F/TAF Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

GS‐9883 Current Sponsor code: GS‐9883 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ INN or Proposed

INN:

EMTRICITABINE CAS Number: 143491‐57‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

Tenofovir Alafenamide CAS Number: 379270‐37‐8 Other descriptive name: TENOFOVIR ALAFENAMIDE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐

CONDITION:

Human Immunodeficiency Virus (HIV‐1) Infection ; MedDRA version: 18.1 Level: LLT Classification code 10068341 Term: HIV‐1 infection System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: To evaluate the efficacy of switching to a FDC of GS‐9883/F/TAF versus continuing on a regimen consisting of boosted atazanavir or darunavir plus either FTC/TDF or ABC/3TC in HIV‐1 infected adult subjects who are virologically suppressed as determined by the proportion of subjects with virologic failure (HIV‐1 RNA >= 50 copies/mL) at Week 48 Primary end point(s): The proportion of subjects with virologic failure (HIV‐1 RNA >= 50 copies/mL) at Week 48 as defined by the modified US FDA snapshot algorithm Secondary Objective: To evaluate the safety and tolerability of the two treatment groups through Week 48 Timepoint(s) of evaluation of this end point: Week 48

SECONDARY OUTCOME:

Secondary end point(s): ‐ The proportion of subjects with HIV‐1 RNA < 50 copies/mL at Week 48 as defined by the US FDA snapshot algorithm; ; ‐ The change from baseline in CD4+ cell counts at Week 48 Timepoint(s) of evaluation of this end point: Week 48

INCLUSION CRITERIA:

1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures 2) Aged 18 years or older 3) Currently receiving antiretroviral regimen consisting of ritonavir or cobicistat boosted ATV or DRV plus either FTC/TDF or ABC/3TC for 6 months or more preceding the screening visit 4) HIV RNA < 50 copies/mL at the screening visit 5) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant) 6) Adequate renal function 7) Hepatic transaminases (AST and ALT) <= 5 x upper limit of normal (ULN) 8) Total bilirubin <= 1.5 mg/dL (<= 26 umol/L), or normal direct bilirubin 9) Adequate hematologic function (absolute neutrophil count >= 750/mm3 (>= 0.75 GI/L); platelets >= 50,000/mm3 (>= 50 GI/L); hemoglobin >= 8.5 g/dL (>= 85 g/L)) 10) Serum amylase <= 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if serum lipase is <= 5 × ULN)<br

Background: Dolutegravir is a once‐daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV‐1 infection. Because women are often under‐represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV‐1. Methods: The ARIA study is a randomised, open‐label, multicentre, active‐controlled, parallel‐group, non‐inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV‐1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA‐B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single‐tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three‐tablet combination of ritonavir‐boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV‐1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV‐1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention‐to‐treat exposed population). We used a non‐inferiority margin of ‐12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. Findings: Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV‐1 RNA viral loads of less than 50 copies per mL (mean difference 10.5%, 95% CI 3.1‐17.8, p=0.005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor‐associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug‐related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications. Interpretation: The non‐inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV‐1 infection in treatment‐naive women. Funding: ViiV Healthcare. Copyright © 2017 Elsevier Ltd.

Background. Tenofovir disoproxil fumarate (TDF)-induced nephrotoxicity is a well-recognized complication and one of the reasons for treatment switching in HIVinfected patients. Salvage regimens in renal impairment such as abacavir(ABC)-based regimen or two-drug regimens such as boosted protease inhibitor (PI) plus lamivudine (3TC) are the options for switching. However, ABC is contraindicated in patients with a high risk for cardiovascular disease. In resource-limited setting, only some PIs such as lopinavir and atazanavir are available options. Methods. We conducted a prospective, open-label, randomized controlled trial in a tertiary center in Bangkok. We recruited HIV-infected adults who had viral suppression, with TDF-induced proximal tubulopathy and/or a significant decrease in estimated glomerular filtration rate(eGFR). The patients were randomized to receive ABC/3TC plus efavirenz (ABC-based regimen) or LPV/r+3TC. The primary outcome was the proportion of patients with viral suppression at 24 weeks. The secondary outcomes were the immunologic response, recovery of eGFR, proximal tubular function and change in lipid profile at 24 weeks. Results. Between August 2018 - February 2019, we screened 87 patients and enrolled 24 patients were randomly assigned to the ABC-based regimen and 23 patients to LPV/r+3TC regimen. In the intention-to-treat population, virologic response at 24 weeks was noted in 21 (87.5%) patients assigned to ABC-based regimen and 19 (82.6%) patients assigned to LPV/r+3TC regimen (P = 0.635). There were no differences in the improvement of the percentage change of eGFR, fractional excretion of phosphate, renal tubular reabsorption of phosphate (TmP/GFR), fractional excretion of uric and UPCI at 24 weeks. Triglyceride levels were significantly increased in LPV/r+3TC regimen compared with ABC-based regimen at 24 weeks (91.32% vs. 20.46%; P = 0.001). Conclusion. Our study showed no difference in virologic suppression after switching to ABC-based regimen or LPV/r+3TC regimen in patients with TDFinduced nephrotoxicity. There was no difference in percentage change of eGFR, recovery of proximal tubular function in both arms after discontinuation of TDF. There was a significant change in triglyceride levels in LPV/r +3TC regimen.

INTERVENTION:

Trade Name: KALETRA comprimidos Product Name: KALETRA Pharmaceutical Form: Tablet INN or Proposed

INN:

RITONAVIR CAS Number: 155213675 INN or Proposed

INN:

RITONAVIR CAS Number: 192725170

CONDITION:

Infección por el virus de la inmunodeficiencia humana y lipodistrofia.

INCLUSION CRITERIA:

1. Confirmación de la disposición del paciente a participar en este estudio después de haber sido informados de todos los aspectos del ensayo que puedan influir en su decisión, firmando y fechando el impreso de consentimiento informado aprobado por el Comité Ético. 2. El paciente tiene 18 años de edad o más. 3. Infección por VIH‐1 (documentada). 4. Estar recibiendo tratamiento con ZDV+3TC+ABC (en tratamiento antirretroviral continuado, sin períodos de suspensión, durante los últimos 6 meses). 5. Hay confirmación de que durante los 6 meses previos a la inclusión en el estudio las cargas virales han sido menores de 50 copias/mL, habiéndose realizado la última determinación de carga viral como máximo 30 días antes de iniciar el estudio. 6. No existir historia previa de fallo virológico estando en tratamiento antirretroviral con inhibidores de proteasa (IP). Es decir, nunca han realizado cambio de inhibidor de la proteas

PRIMARY OUTCOME:

Main Objective: Evaluación del cambio absoluto de la masa; grasa en extremidades medido por DEXA a las; 48 semanas respecto a la basal. Primary end point(s): Los pacientes que cumplan criterios de fracaso terapéutico serán retirados; del estudio.; 1. En pacientes que reciben triple terapia (LPV/r+3TC+ABC) a la que se le; aleatorizó en la basal, se considera fracaso terapéutico el fracaso virológico; confirmado, es decir, la presencia de una carga viral mayor de 400; copias/ml en 2 ocasiones separadas 15 días.; 2. Los pacientes asignados al mantenimiento sólo con LPV/r que alcancen el; criterio de fracaso virológico se considerarán fracaso terapéutico si existe; presencia de mutaciones en el gen de la proteasa; 3. Sin embargo, los pacientes asignados al mantenimiento sólo con LPV/r NO; será considerada como fracaso terapéutico ni supondrá discontinuación del; estudio la siguiente situación (a+b+c):; a) Un paciente en la rama de mantenimiento con sólo LPV/r presente; una carga viral mayor de 400 copias/ml en 2 ocasiones separadas; 15días.; b) El test de resistencia genotípicas no muestre resistencias a LPV/r.; c) El paciente sea reinducido con los mismos nucleósidos que; recibía antes de entrar en el estudio y finaliza el período de; seguimiento con CV indetectable. Secondary Objective: 1. Cambio absoluto en masa grasa a nivel de extremidades por; DEXA scan a las 96 s respecto a basal ; 2. Aumento porcentual de grasa en extremidades a las 48 y 96s.; 3. Cambio en la valoración de la lipoatrofia hecha por el propio paciente desde el inicio hasta la semana 48 y 96s.; 4. Cambios en el perfil lipídico a lo largo del estudio (fracciones lipídicas; en ayunas: colesterol total, col‐HDL, triglicéridos y col‐LDL calculado) y; en la glucemia (24, 48, 72 y 96 semanas.); 5. Incidencia de acontecimientos adversos y de toxicidad a lo largo del; estudio.; 6. Incidencia de rebote virológico (dos medidas consecutivas de ARN de; VIH‐1 > 400 copias/ml); 7. Cambio en el recuento de CD4 desde la basal a s24, s48, 72s y s96; 8. Proporción de pacientes que mantienen carga viral indetectable (<50 y; <400 copias/ml) a las 48 y 96 s. ; 9. Incidencia de resistencias a antirretrovirales (inhibidores de proteasa y; análogos de nucleósidos); 10. Calidad de vida de los pacientes.

BACKGROUND:

Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression.

METHODS:

This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm.

RESULTS:

A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively.

CONCLUSIONS:

Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy.

CLINICAL TRIALS REGISTRATION:

NCT02159599.

INTERVENTION:

Product Name: Lamivudina Pharmaceutical Form: Tablet INN or Proposed

INN:

LAMIVUDINE CAS Number: 134678‐17‐4 Trade Name: PREZISTA Product Name: PREZISTA Pharmaceutical Form: Tablet Trade Name: PREZISTA Product Name: PREZISTA Pharmaceutical Form: Tablet Trade Name: NORVIR Product Name: NORVIR Pharmaceutical Form: Tablet Trade Name: NORVIR Product Name: NORVIR Pharmaceutical Form: Tablet Trade Name: TRUVADA Product Name: TRUVADA Pharmaceutical Form: Tablet Trade Name: KIVEXA Product Name: KIVEXA Pharmaceutical Form: Tablet

CONDITION:

HIV chronic infection ; MedDRA version: 17.0 Level: LLT Classification code 10001509 Term: AIDS System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: To compare safety and efficacy of the dual combination DRV/r qd + 3TC qd versus triple therapy with DRV/r qd + TDF/FTC (or ABC/3TC) in HIV‐infected patients who have maintained at least six months of viral suppression while receiving triple therapy with DRV/r qd + TDF/FTC (or ABC/3TC). Primary end point(s): Proportion of patients with HIV‐RNA levels below 50 HIV‐RNA copies/ml by intention to treat analysis (FDA snapshot algorithm) at week 48. Secondary Objective: To evaluate the safety and tolerability of the dual and triple combinations.; To evaluate the incidence and type of resistance mutations in patients suffering virologic failure. Timepoint(s) of evaluation of this end point: 48 weeks

SECONDARY OUTCOME:

Secondary end point(s): 1. Proportion of patients with HIV‐RNA levels below 50 HIV‐RNA copies/ml by intention to treat analysis (FDA snapshot algorithm) at week 24 ; 2. Proportion of patients with HIV‐RNA levels below 200 HIV‐RNA copies/ml by intention to treat analysis (FDA snapshot algorithm) at week 48 ; 3. Proportion of patients with virologic failure at week 48. ; 4. Percentage of patients with resistance development at week 48 ; 5. Median changes in CD4 cell counts ; 6. Incidence of adverse events and incidence of drug discontinuation due to toxicity or intolerance. ; 7. Median changes in triglycerides, total, LDL‐ and HDL‐cholesterol ; 8. Changes in eGFR ; 9. Changes in proportion of patients with renal tubular dysfunction ; 10. Proportion of resistance genotypic mutations in patients showing virologic failure at week 48. ; 11. Description and frequency of resistance genotypic mutations. Timepoint(s) of evaluation of this end point: 24 weeks ; 48 weeks

INCLUSION CRITERIA:

1. Consent to participate in the study, signing and dating the informed consent. 2. HIV patients > 18 years old. 3. Receiving DRV/r qd + TDF/FTC (or ABC/3TC) for at least 4 weeks. 4. Plasma HIV RNA < 50 cop/ml for at least 6 months (2 tests separated at least 6 months with viremia < 50 cop/ml between both determinations). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 256 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 256

Background. Built upon an unboosted integrase-strand transfer inhibitor (INSTI), the FDC of DTG/ABC/3TC offers a complete regimen for HIV-1 infection, with good tolerability and a high barrier to resistance. To gain additional data for women on this regimen, we conducted ARIA, an international, randomized, open-label study to evaluate the safety and efficacy of DTG/ABC/3TC versus ATV/r + FTC/TDF (Clinical- Trials.gov: NCT01910402). Methods. Treatment-naive adult women, with HIV-1 RNA ≥500 copies(c)/mL were randomized 1:1, stratified by plasma HIV-1 RNA and CD4+ count to 48 weeks of treatment with DTG/ABC/3TC or ATV/r + FTC/TDF once daily. The primary endpoint was the proportion of women achieving an HIV-1 RNA <50 c/mL at Week 48 (Snapshot algorithm). Additional analyses were performed to evaluate efficacy based on race subgroups. Results. Four hundred ninety-five women were randomized and treated. Subjects were well matched for demographic and baseline characteristics. Median age was 37 years; 45% of subjects were White and 42% African heritage. DTG/ABC/3TC was superior to ATV/r + FTC/TDF, with 82% and 71%, respectively, achieving HIV-1 RNA <50 c/mL at Week 48 (adjusted difference 10.5%, 95% CI.: 3.1% to 17.8%, p = 0.005). Differences were driven by lower rates of both discontinuations due to adverse events (AEs) and Snapshot virologic failures in the DTG/ABC/3TC group. Higher response rates were observed in the DTG/ABC/3TC arm compared to ATV/r + TDF/FTC across race subgroups, as well as in US subjects (table). The safety profile of DTG/ABC/3TC was favorable compared to ATV/r + TDF/FTC, with fewer drug related AEs in the DTG/ABC/3TC group. There were no treatment-emergent primary INSTI or ABC/ 3TC resistance mutations in the DTG/ABC/3TC group. Conclusion. DTG/ABC/3TC demonstrated superior efficacy and a favorable safety profile compared to ATV/r + FTC/TDF in treatment-naive women, after 48 weeks of treatment. Race subgroup analyses were consistent with overall results. (Table Presented) .

Este artículo no tiene resumen