Cost-effectiveness and budget impact of dolutegravir/lamivudine for treatment of human immunodeficiency virus (HIV-1) infection in the United States.

BACKGROUND: Dolutegravir(DTG)/lamivudine(3TC) is the first 2-drug regimen recommended as an initial treatment for people living with HIV (PLHIV). OBJECTIVE: To assess the cost-effectiveness and potential budget impact of DTG/3TC in the US healthcare setting. METHODS: A previously published hybrid decision-tree and Markov cohort state transition model was adapted to estimate the incremental costs and health outcome benefits over a patients' lifetime. DTG/3TC was compared with current standard of care in treatment naive and treatment experienced virologically suppressed PLHIV. Health states included in the model were based upon virologic response and CD4 cell count, with death as an absorbing state. Clinical data was informed by the Phase III GEMINI 1 and 2 clinical trials, a published network meta-analysis (NMA) in treatment-naive patients and the Phase III TANGO clinical trial in treatment experienced patients. Costs and utilities were informed by published data and discounted annually at a rate of 3%. A separate 5-year budget impact analysis was conducted assuming 5%-15% uptake in eligible treatment naive and 10%-30% uptake in eligible treatment experienced patients. RESULTS: In the treatment naive analyses based on GEMINI 1 and 2, DTG/3TC dominated, i.e., was less costly and more effective, than all comparators. DTG/3TC resulted in 0.083 incremental quality-adjusted life-years (QALYs) at a cost saving of $199,166 compared with the DTG + tenofovir disoproxil(TDF)/emtricitabine(FTC) comparator arm. The incremental QALY and cost savings for DTG/3TC compared with DTG/abacavir(ABC)/3TC, cobicistat-boosted darunavir(DRV/c)/tenofovir alafenamide(TAF)/FTC, and bictegravir (BIC)/TAF/FTC, based on NMA results were 0.465, 0.142, and 0.698, and $42,948, $122,846, and $44,962, respectively. In the analyses of treatment-experienced virologically suppressed patients based on TANGO, DTG/3TC offered slightly lower QALYs (-0.037) with an estimated savings of $78,730 when compared with continuation of TAF-based regimen (TBR). Sensitivity analyses demonstrated that these conclusions were relatively insensitive to alternative parameter estimates. The budget impact analysis estimated that by 5th year a total of 70,240 treatment naive patients and 1,340,480 treatment experienced patients could be eligible to be prescribed DTG/3TC. The estimated budget savings over 5 years ranged from $1.12b to $3.35b (corresponding to 27,512 to 82,536 on DTG/3TC by year 5) in the lowest and highest uptake scenarios, respectively. CONCLUSION: In conclusion, DTG/3TC with its comparable efficacy and lower drug acquisition costs, has the potential to offer significant cost savings to US healthcare payers for the initial treatment of treatment naive patients and as a treatment switching option for virologically suppressed patients. DISCLOSURES: This study was funded in full by ViiV healthcare, Brentford, UK. Medical writing to support this study was also funded in full by ViiV Healthcare, Brentford, UK. Butler, Hayward, and Jacob are employees of HEOR Ltd, the company performing this study funded by ViiV Healthcare. Anderson is an employee of GlaxoSmithKline and owns shares in the company. Punekar, Evitt, and Oglesby are employees of ViiV Healthcare and own stocks in GlaxoSmithKline.

The Potential Teratogenicity Alert for Women Conceiving on Dolutegravir-Based Regimens: An Assessment of Risk Communication by an Urban HIV Clinic in Uganda and Choices made by Women.

INTRODUCTION AND OBJECTIVE: In May 2018, the World Health Organization and other regulatory authorities released a safety alert for dolutegravir related to a risk of neural tube defects among women exposed to dolutegravir at the time of conception. Models of how drug safety information can be shared effectively in the shortest time are necessary to prevent interruptions of public health programs. We sought to describe an implementation process to inform and support women already on dolutegravir-based regimens at the time of conception to make informed choices following the safety alert of a potential teratogenicity risk. We describe the choices made by women, as well as determine the factors associated with women's choices to switch off dolutegravir. METHODS: A clinic response plan was developed in the first week following the alert and clinic staff were trained on safety guidance. All women aged < 55 years taking dolutegravir were identified from the clinic database and contacted by phone for earlier appointments. Non-menopausal and non-surgically sterilized women were referred for urine pregnancy testing and evaluation of pregnancy intentions in the following 12 months and effective family planning was offered. We describe the coverage of women who received the communication as well as the fidelity to the outlined plan from 21 May to 12 September, 2018. We used modified a Poisson regression analysis to determine factors associated with switching off dolutegravir. RESULTS: Of all active patients in the clinic, 9% (690/7963) were identified as female aged < 55 years taking dolutegravir. Ninety-five percent (656/690) were reviewed by September 2018 and informed of the safety alert, implying a high level of uptake. Fidelity to standard operating procedures was also high at 72%. Twenty-two percent (146/656) of patients were menopausal or surgically sterilized. Five hundred and ten women were of reproductive potential with a median age (interquartile range) of 37 years (30-42 years). Five percent (23/510) were human chorionic gonadotrophin positive and all initial ultrasound reports revealed no deformities. Twenty-one percent (108/510) had intentions to conceive and opted to stop taking dolutegravir with 90% (97/108) switching to efavirenz. Seventy-nine percent (402/510) opted to remain taking dolutegravir. However, only 40% (160/402) chose effective contraceptive methods and 60% (242/402) opted for condoms only/no contraceptive method. CONCLUSIONS: A rapid well-coordinated response ensured prompt communication of the dolutegravir safety warning. The process developed by the clinic can act as a model for response during drug safety alerts. Women made informed decisions with most opting to remain taking dolutegravir; however, effective contraception uptake was low.

Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine.

This single-dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2-drug, fixed-dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single-entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration-time curve (AUC) and maximum concentration (Cmax ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC0-∞ and Cmax ) and lamivudine (AUC0-∞ and AUC0-t ) exposure; however, dolutegravir AUC0-t and lamivudine Cmax were approximately 16% and 32% higher than the reference, respectively. A high-fat meal increased dolutegravir AUC and Cmax by up to 33% and 21%, respectively, and decreased lamivudine Cmax by approximately 30%. Both test and reference formulations were well tolerated. The results support further development of formulation AK as a novel, 2-drug, fixed-dose combination tablet treatment for patients with HIV.

[Analysis of adherence and efficiency when replacing an antiretroviral therapy with efavirenz-emtricitabine-tenofovir in a single daily dose]. / Análisis del cambio en la adherencia y eficiencia del tratamiento antirretroviral con el uso de efavirenz-emtricitabina-tenofovir en dosis única diaria.

OBJECTIVE: To analyse whether the change of antiretroviral therapy to efavirenz/emtricitabine/tenofovir in a single daily dose (EETu) increases adherence and maintains effectiveness, and establish the cost increase caused by the change. METHODS: An observational, retrospective, and intra-subject study, performed in the outpatient dispensing unit. The study period was 1 year (6 months before and 6 months after the change). Computer dispensing records and days of hospitalisation during the study period were reviewed, and the difference in treatment adherence calculated. To determine the effectiveness of treatment, viral load and CD4 lymphocytes data before and after the change were reviewed. The cost before and after treatment for each patient was determined, and therefore the annual cost increase and the incremental cost per patient. RESULTS: The study included 127 patients. The difference in adherence was 0.6%. The percentage of poor adherence was 35.4% and 40.9% before and after the treatment change, respectively. The levels of CD4 lymphocytes and viral load did not change significantly with treatment. The economic analysis revealed an annual increase of 25,374.60 and €199.80 per patient. CONCLUSIONS: The use of EETu did not improve the control of HIV infection in terms of effectiveness and adherence, and resulted in increased economic costs. Therefore, its choice as antiretroviral treatment will have to be based on criteria other than those described above.

Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz.

OBJECTIVES: The Sensio study objectives were to assess the outcome of neuropsychiatric adverse reactions (NPAR) that develop after initiation of efavirenz (EFV) therapy, to ascertain the late NPAR after a 3-month treatment period, to evaluate the impact of NPAR on patients' quality of life (QoL) in a real-life population. METHODS: During a 6-month period, consecutive HIV-infected adult outpatients receiving an ongoing EFV therapy for at least 3 months were asked to fill in a specifically designed self-administered questionnaire addressing sleep disturbances, behavioural changes, mood disturbances, anxiety, cognitive disorders, hallucinations, dizziness and the general impact on patients' QoL. RESULTS: A total of 174 questionnaires were analyzed. The main late emergent NPAR were sleep disorders: abnormal dreams 24.7%, nocturnal waking 19.6%, trouble falling asleep 17.8%; cognitive disorders: memory disorders 23.0%, impaired concentration 18.9%; anxiety 15.5%; mood disorders: sadness 19.3%, suicidal ideations 9.2%. Global neuropsychic discomfort was moderate to severe in 23% of patients after a 3-month treatment period. CONCLUSION: NPAR occur mainly during the first month of EFV therapy but often persist thereafter. A significant percentage of patients reported suicidal ideations at the time of the study. Our results suggest the need for routine screening for NPAR among patients receiving EFV therapy and better management.

Efavirenz's complications.

AIDS: DuPont Merck cautions that efavirenz cuts saquinavir levels in the blood by 60 percent over the course of the day. An exception is the protease inhibitor combination saquinavir/ritonavir, wherein ritonavir appears to reverse efavirenz's effect on saquinavir. No data is available on taking all three drugs. The company intends to present information on the drug interactions at the World AIDS Conference in Geneva. UpJohn is considering selling its HIV drugs or at least finding a partner for further drug development. Delavirdine, the company's FDA-approved NNRTI, has suffered due to the lack of trial data demonstrating a solid anti-HIV effect and due to an inconvenient dosing schedule. The company is now working on an NNRTI designed to work against delavirdine-resistant HIV. While UpJohn is decreasing its presence in HIV drug development, Glaxo is increasing its anti-HIV product line. Glaxo has two new antiretrovirals that will soon reach the market and has also recently bought a family of structurally-related NNRTIs from Hoechst Marion Roussel.^ieng

Efavirenz (Sustiva) receives FDA approval. Food and Drug Administration.

AIDS: The Food and Drug Administration recently approved efavirenz (Sustiva), a non-nucleoside reverse transcriptase inhibitor (NNRTI), for use in treatment of adults and children. When used in combination therapy, efavirenz has shown to be very effective in suppressing viral loads for a minimum of 24 weeks. People taking efavirenz should be aware of potential cross-resistance with the other two approved NNRTIs, Nevirapine and Delavirdine, as well as possible drug interactions. Common side effects and dosing information are described. Because of the high cost, efavirenz may not be covered under some States' AIDS Drug Assistance Programs (ADAPs). The Access Project can provide the numbers of State ADAP coordinators for further information, or individuals may contact Dupont Pharma's Patient Assistance Program at the number provided.^ieng

[Assessment of the genotoxic risk caused by the gyrase inhibitor ofloxacin using sister chromatid exchange rate analysis]. / Zur Beurteilung des genotoxischen Risikos durch den Gyrasehemmer Ofloxacin mittels der Bestimmung von Schwesterchromatidaustauschraten.

Ofloxacin (Tarivid) is a 4-quinolone of the latest generation. Its mechanism of action is the inhibition of the enzyme gyrase which plays a central role in the bacterial DNA-metabolisms. Thus Ofloxacin blocks the reading of the chromosomes and impairs the cell's function and ability to reduplicate leading to eradication of the pathogens. The genotoxicity of Ofloxacin was assessed by analyses of SCE (sister-chromatid-exchange-rates), which is a sensitive and qualitative parameter indicating chromosomal damages. In vitro no change of the SCE-frequencies could be demonstrated in human lymphocytes; in vivo, however, a slight influence not be excluded, which is also true for eventual additive on synergistic effect with other mutagenic factors.