Economic evaluation of differentiated service delivery models for HIV treatment in Lesotho: costs to providers and patients.

INTRODUCTION: Lesotho, the country with the second-highest HIV/AIDS prevalence (23.6%) in the world, has made considerable progress towards achieving the "95-95-95" UNAIDS targets, but recent success in improving treatment access to all known HIV positive individuals has severely strained existing healthcare infrastructure, financial and human resources. Lesotho also faces the challenge of a largely rural population who incur a significant time and financial burden to visit healthcare facilities. Using data from a cluster-randomized non-inferiority trial conducted between August 2017 and July 2019, we evaluated costs to providers and costs to patients of community-based differentiated models of multi-month delivery of antiretroviral therapy (ART) in Lesotho. METHODS: The trial of multi-month dispensing compared 12-month retention in care among three arms: conventional care, which required quarterly facility visits and ART dispensation (3MF); three-month community adherence groups (CAGs) (3MC) and six-month community ART distribution (6MCD). We first estimated the average total annual cost of providing HIV care and treatment followed by the total cost per patient retained 12 months after entry for each arm, using resource utilization data from the trial and local unit costs. We then estimated the average annual cost to patients in each arm with self-reported questionnaire data. RESULTS: The average total annual cost of providing HIV care and treatment per patient was the highest in the 3MF arm ($122.28, standard deviation [SD] $23.91), followed by 3MC ($114.20, SD $23.03) and the 6MCD arm ($112.58, SD $21.44). Per patient retained in care, the average provider cost was $125.99 (SD $24.64) in the 3MF arm and 6% to 8% less for the other two arms ($118.38, SD $23.87 and $118.83, SD $22.63 for the 3MC and 6MCD respectively). There was a large reduction in patient costs for both differentiated service delivery arms: from $44.42 (SD $12.06) annually in the 3MF arm to $16.34 (SD $5.11) annually in the 3MC (63% reduction) and $18.77 (SD $8.31) annually in 6MCD arm (58% reduction). CONCLUSIONS: Community-based, multi-month models of ART in Lesotho are likely to produce small cost savings to treatment providers and large savings to patients in Lesotho. Patient cost savings may support long-term adherence and retention in care.

Economic vulnerability and non-initiation of antiretroviral therapy in India: a qualitative study.

In India, many people living with HIV (PLHIV) do not successfully initiate antiretroviral therapy (ART) after diagnosis. We conducted a clinic-based qualitative study at the Y.R. Gaitonde Centre for AIDS Research in Chennai, Tamil Nadu to explore factors that influence ART non-initiation. We interviewed 22 men and 15 women; median age was 42 (IQR, 36-48) and median CD4+ was 395 (IQR, 227-601). Participants were distrustful of HIV care freely available at nearby government facilities. Faced with the perceived need to access the private sector and therefore pay for medications and transportation costs, non-initiators with high CD4+ counts often decided to postpone ART until they experienced symptoms whereas non-initiators with low CD4+ counts often started ART but defaulted quickly after experiencing financial stressors or side effects. Improving perceptions of quality of care in the public sector, encouraging safe serostatus disclosure to facilitate stronger social support, and alleviating economic hardship may be important in encouraging ART initiation in India.

COVID-19 pandemic and antiretrovirals (ARV) availability in Nigeria: recommendations to prevent shortages.

HIV/AIDS is an infectious disease that has claimed the lives of millions of people worldwide. Currently, there is no vaccine that has been developed in a bid to fight this deadly infection, however, antiretrovirals (ARVs), which are drugs used in the treatment of HIV infection are routinely prescribed to infected persons. They act via several mechanisms of action to reduce the severity of infection and rate of infectivity of the virus by decreasing the viral load while increasing CD4 counts. COVID-19 pandemic has resulted in unprecedented events affecting almost all areas of humans' life including availability of medicines and other consumables. This paper analyses the availability of ARVs during COVID-19 era and offered recommendations to be adopted in order to prevent shortages.

The impact of socioeconomic factors on the healthcare costs of people living with HIV in Turkey.

BACKGROUND: This study addresses an important field within HIV research, the impact of socioeconomic factors on the healthcare costs of people living with HIV/AIDS (PLHIV). We aimed to understand how different socioeconomic factors could create diverse healthcare costs for PLHIV in Turkey. METHODS: Data were collected between January 2017 and December 2017. HIV-positive people attending the clinic who had been referred to the national ART programme from January 1992 until December 2017 were surveyed. The questionnaire collected socioeconomic data. The cost data for the same patients was taken from the electronic database Probel Hospital Information Management System (PHIMS) for the same period. The PHIMS data include costs for medication (highly active antiretroviral therapy or HAART), laboratory, pathology, radiology, polyclinic, examination and consultation, hospitalisation, surgery and intervention, blood and blood products, supplies and other costs. Data were analysed using STATA 14.2 to estimate the generalised linear model (GLM). RESULTS: The findings of our GLM indicate that age, gender, marital and parental status, time since diagnosis, employment, wealth status, illicit drug use and CD4 cell count are the factors significantly related to the healthcare cost of patients. We found that compared with people who have AIDS (CD4 cells < 200 cells/mm3), people who have a normal range of CD4 cells (≥ 500 cells/mm3) have $1046 less in expenditures on average. Compared to younger people (19-39 years), older people (≥ 55) have $1934 higher expenditures on average. Costs are $644 higher on average for married people and $401 higher on average for people who have children. Healthcare costs are $518 and $651 higher on average for patients who are addicted to drugs and who use psychiatric drug(s), respectively. Compared to people who were recently diagnosed with HIV, people who were diagnosed ≥10 years ago have $743 lower expenditures on average. CONCLUSION: Our results suggest that in addition to immunological status, socioeconomic factors play a substantial role in the healthcare costs of PLHIV. The key factors influencing the healthcare costs of PLHIV are also critical for public policy makers, healthcare workers, health ministries and employment community programs.

Integrated care experiences and out-of-pocket expenditures: a cross-sectional survey of adults receiving treatment for HIV and hypertension in Malawi.

OBJECTIVES: As HIV-positive individuals' life expectancy extends, there is an urgent need to manage other chronic conditions during HIV care. We assessed the care-seeking experiences and costs of adults receiving treatment for both HIV and hypertension in Malawi. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional survey was conducted with HIV-positive adults with hypertension at a health facility in Lilongwe that offers free HIV care and free hypertension screening, with antihypertensives available for purchase (n=199). Questions included locations and costs of all medication refills and preferences for these refill locations. Respondents were classified as using 'integrated care' if they refilled HIV and antihypertensive medications simultaneously. Data were collected between June and December 2017. RESULTS: Only half of respondents reported using the integrated care offered at the study site. Among individuals using different locations for antihypertensive medication refills, the most frequent locations were drug stores and public sector health facilities which were commonly selected due to greater convenience and lower medication costs. Although the number of antihypertensive medications was equivalent between the integrated and non-integrated care groups, the annual total cost of care differed substantially (approximately US$21 in integrated care vs US$90 for non-integrated care)-mainly attributable to differences in other visit costs for non-integrated care (transportation, lost wages, childcare). One-third of those in the non-integrated care group reported no expenditure for antihypertensive medication, and six people in each group reported no annual hypertension care-seeking costs at all. CONCLUSIONS: Individuals using integrated care saw efficiencies because, although they were more likely to pay for antihypertensive medications, they did not incur additional costs. These results suggest that preferences and experiences must be better understood to design effective policies and programmes for integrated care among adults on antiretroviral therapy.

The short-term effects of the implementation of the "Treat All" guidelines on ART service delivery costs in Namibia.

The introduction of "Treat All" (TA) has been promoted to increase the effectiveness of HIV/AIDS treatment by having patients initiate antiretroviral therapy at an earlier stage of their illness. The impact of introducing TA on the unit cost of treatment has been less clear. The following study evaluated how costs changed after Namibia's introduction of TA in April 2017. A two-year analysis assessed the costs of antiretroviral therapy (ART) during the 12 months before TA (Phase I-April 1, 2016 to March 31, 2017) and the 12 months following (Phase II-April 1, 2017 to March 31, 2018). The analysis involved interviewing staff at ten facilities throughout Namibia, collecting data on resources utilized in the treatment of ART patients and analyzing how costs changed before and after the introduction of TA. An analysis of treatment costs indicated that the unit cost of treatment declined from USD360 per patient per year in Phase I to USD301 per patient per year in Phase II, a reduction of 16%. This decline in unit costs was driven by 3 factors: 1) shifts in antiretroviral (ARV) regimens that resulted in lower costs for drugs and consumables, 2) negotiated reductions in the cost of viral load tests and 3) declines in personnel costs. It is unlikely that the first two of these factors were significantly influenced by the introduction of TA. It is unclear if TA might have had an influence on personnel costs. The reduction in personnel costs may have either represented a positive development (fewer personnel costs associated with increased numbers of healthier patients and fewer visits required) or alternatively may reflect constraints in Namibia's staffing. Prior to this study, it was expected that the introduction of TA would lead to a significant increase in the number of ART patients. However, there was less than a 4% increase in the number of adult patients at the 10 studied facilities. From a financial point of view, TA did not significantly increase the resources required in the ten sampled facilities, either by raising unit costs or significantly increasing the number of ART patients.

Neighborhood Poverty and Control of HIV, Hypertension, and Diabetes in the Women's Interagency HIV Study.

Neighborhoods with high poverty rates have limited resources to support residents' health. Using census data, we calculated the proportion of each Women's Interagency HIV Study participant's census tract (neighborhood) living below the poverty line. We assessed associations between neighborhood poverty and (1) unsuppressed viral load [VL] in HIV-seropositive women, (2) uncontrolled blood pressure among HIV-seropositive and HIV-seronegative hypertensive women, and (3) uncontrolled diabetes among HIV-seropositive and HIV-seronegative diabetic women using modified Poisson regression models. Neighborhood poverty was associated with unsuppressed VL in HIV-seropositive women (> 40% versus ≤ 20% poverty adjusted prevalence ratio (PR), 1.42; 95% confidence interval (CI) 1.04-1.92). In HIV-seronegative diabetic women, moderate neighborhood poverty was associated with uncontrolled diabetes (20-40% versus ≤ 20% poverty adjusted PR, 1.75; 95% CI 1.02-2.98). Neighborhood poverty was associated with neither uncontrolled diabetes among HIV-seropositive diabetic women, nor uncontrolled hypertension in hypertensive women, regardless of HIV status. Women living in areas with concentrated poverty may need additional resources to control health conditions effectively.

The Impact of Mental Health Conditions on Public Insurance Costs of Treating HIV/AIDS.

Medicare and Medicaid insurance claims data for Californians living with HIV are analyzed in order to determine: (1)The prevalence of treatment for particular mental health diagnoses among people living with HIV (PLWH) with Medicare or Medicaid insurance in 2010; (2)The relationship between individual mental health conditions and total medical care expenditures; (3)The impact of individual mental health diagnoses on the cost of treating non-mental health conditions; and (4)The implications of the cost of mental health diagnoses for setting managed care capitation payments. We find that the prevalence of mental health conditions among PLWH is high (23% among Medicare and 28% among Medicaid enrollees). PLWH with mental health conditions have significantly higher treatment costs for both mental health and non-mental health conditions. Setting managed care capitations that account for these greater expenditures is necessary to preserve access to both mental health and physical health services for PLWH and mental health conditions.

Updated direct costs of medical care for HIV-infected patients within a regional population from 2006 to 2017.

OBJECTIVES: The aim of the study was to reappraise the precise costs of HIV care and cost drivers, to determine the optimal tools for modelling costs for HIV care, and to understand the implications of changing medical management of HIV-infected patients for both subsequent outcomes and health care budgets. METHODS: We obtained all drug, laboratory, out-patient and in-patient care costs for all HIV-infected patients followed between 1 January 2006 and 31 December 2017 (2017 Cdn$). Mean cost per patient per month (PPPM) was used as the standard comparator value. Patients were stratified based on CD4 count: (1) ≤ 75, (2) 76-200, (3) 201-500 and (4) > 500 cells/µL. We determined the cost for only HIV-related expenses. We compared current costs with costs previously reported for the same population. RESULTS: The number of HIV-infected patients in care doubled from 2006 to 2017; total costs increased from $12.4 to $30.1 million, with antiretroviral (ARV) drugs accounting for 78.8% of costs by 2017. Out-patient/laboratory costs declined from 12% to 8.5%, while in-patient costs exhibited more annual variation. Mean PPPM costs increased from $1316 in 2006 to $1712 in 2014, declining to $1446 in 2017. Higher PPPM costs were associated with CD4 counts < 200 cells/µL. Costs have shifted. While the cost of ARV drugs increased by 32%, the costs of out-patient and in-patient services decreased by 80% and 71%, respectively. Most of the decrease for in-patient costs was attributable to a substantial decrease in HIV-related hospitalizations. CONCLUSIONS: Although antiretroviral therapy (ART) provides immense benefits, it is not inexpensive. ARV drugs remain the largest cost driver. Hospital costs have remained low. Substantial costs of lifelong ART necessitate innovative, locally applicable strategies for ARV selection and use.

Association of HIV-syphilis coinfection with optimal antiretroviral adherence: a nation-wide claims study.

Condomless sex is not totally discouraged after achieving undetectable human immunodeficiency virus (HIV) load, but the prevalence of sexually transmitted diseases (STDs) in the group is unknown. This study was retrospective in nature, using the claims database of the National Health Insurance system from 2008 to 2016. The clinical characteristics of people living with HIV with or without syphilis coinfection were analyzed. People with HIV and syphilis coinfection were divided into two groups according to antiretroviral therapy adherence, as optimal and suboptimal adherence groups by a medication possession ratio of 95%. Of the 9393 people living with HIV, 4536 (48.3%) were diagnosed with syphilis coinfection. Optimal adherence was associated with syphilis coinfection (odds ratio [OR] 1.18; 95% confidence interval [95CI] 1.08-1.30; p = .001). This suggests that unsafe sex occurs regardless of medication adherence. Being male, bacterial/protozoa STDs, and genital herpes virus infection were also risk factors for HIV-syphilis coinfection. Although HIV is unlikely to be transmittable when viral load is controlled, consistent use of condoms is necessary to prevent infection with syphilis.

Do challenges still exist amongst HIV/AIDS patients in managing their condition? A cross-sectional study of 297 participants in the Ethekwini Metro of KwaZulu-Natal, South Africa.

Background: South Africa has the largest HIV/AIDS epidemic globally and the largest anti-retroviral treatment (ART) programme in the world, yet HIV incidence is still chronically high in South Africa, especially in KwaZulu-Natal province (KZN). In light of this, a study was conducted to investigate the extent of challenges making the management of HIV/AIDS difficult in people living with HIV (PLWH) in KZN, South Africa. Methods: A cross-sectional study was carried out with 297 study participants living with HIV and receiving ART from three selected clinics in the Ethekwini Metro of KZN. A self-administered questionnaire assessed the challenges experienced by PLWH, their knowledge of their condition and their management thereof. One-way frequency tables were used to descriptively assess participant responses. Associations between certain demographic characteristics and responses to HIV treatment management challenges were assessed using chi-square tests, with statistical significance set at p < 0.05. Results: One-fifth of the participants (n = 60; 20.1%) were within the 18-23 age group, with over 53% (n = 158) having secondary level education. Some of the challenges cited included: difficulty in obtaining medication, mainly due to cost; side effects resulting in non-adherence; shame for taking medication in public (younger patients were more likely to feel ashamed for taking their medication in public [χ2 = 20.3, p = 0.009]); and non-disclosure of HIV-positive status to partners. We found a significant association between education and financial status and management of their condition [χ2 = 11.2, p = 0.011]. Conclusion: These findings that challenges still exist have implications for more robust programmes on education and counselling to address such challenges.

Cost implications of HIV retesting for verification in Africa.

INTRODUCTION: HIV misdiagnosis leads to severe individual and public health consequences. Retesting for verification of all HIV-positive cases prior to antiretroviral therapy initiation can reduce HIV misdiagnosis, yet this practice has not been not widely implemented. METHODS: We evaluated and compared the cost of retesting for verification of HIV seropositivity (retesting) to the cost of antiretroviral treatment (ART) for misdiagnosed cases in the absence of retesting (no retesting), from the perspective of the health care system. We estimated the number of misdiagnosed cases based on a review of misdiagnosis rates, and the number of positives persons needing ART initiation by 2020. We presented the total and per person costs of retesting as compared to no retesting, over a ten-year horizon, across 50 countries in Africa grouped by income level. We conducted univariate sensitivity analysis on all model input parameters, and threshold analysis to evaluate the parameter values where the total costs of retesting and the costs no retesting are equivalent. Cost data were adjusted to 2017 United States Dollars. RESULTS AND DISCUSSION: The estimated number of misdiagnoses, in the absence of retesting was 156,117, 52,720 and 29,884 for lower-income countries (LICs), lower-middle income countries (LMICs), and upper middle-income countries (UMICs), respectively, totaling 240,463 for Africa. Under the retesting scenario, costs per person initially diagnosed were: $40, $21, and $42, for LICs, LMICs, and UMICs, respectively. When retesting for verification is implemented, the savings in unnecessary ART were $125, $43, and $75 per person initially diagnosed, for LICs, LMICs, and UMICs, respectively. Over the ten-year horizon, the total costs under the retesting scenario, over all country income levels, was $475 million, and was $1.192 billion under the no retesting scenario, representing total estimated savings of $717 million in HIV treatment costs averted. CONCLUSIONS: Results show that to reduce HIV misdiagnosis, countries in Africa should implement the WHO's recommendation of retesting for verification prior to ART initiation, as part of a comprehensive quality assurance program for HIV testing services.

Reasons for noncompliance with the national guidelines for initial antiretroviral therapy of HIV-infected patients in Spain, 2010-2015.

INTRODUCTION: Our aims were to investigate the adherence to national guidelines of initial antiretroviral therapy (ART) in the Spanish multicenter CoRIS cohort during the years 2010-2015, to identify the reasons for the prescription of nonrecommended treatments, and to explore the role of institutional constraints to guideline compliance. METHODS: ART regimens were classified as recommended, alternative or nonrecommended according to the guidelines. Physicians were asked the reasons for prescribing nonrecommended regimens. Factors associated with the prescription of non recommended regimens were assessed using multivariable logistic regression. RESULTS: During the study period, 586 (10.7%) of 5479 patients who started ART were given a regimen not recommended in the guidelines. The most frequent reasons for prescribing nonrecommended regimens were: enrolment in clinical trials (43.3%), comorbidities and/or interactions (10.2%), pregnancy (8.7%), and cost (7.7%). Among 37 participating centers, 16 (43%), treating 3561 patients, reported limitations related with the cost of ART, and 20 (54%), treating 1365 patients, reported restrictions for prescribing at least one recommended antiretroviral. In multivariable analysis, a higher risk of receiving nonrecommended regimens was associated with male gender, HIV acquisition by heterosexual transmission, low viral loads, initiation of treatment during the years 2011 to 2015, and initiation of treatment in a center with restricted access to at least one antiretroviral drug. CONCLUSIONS: Compliance to clinical guidelines was high. A high proportion of centres reported cost limitations for ART or restricted access to at least one recommended antiretroviral drug, with a significant impact on the choice of initial regimens.

Patient costs incurred by people living with HIV/AIDS prior to ART initiation in primary healthcare facilities in Gauteng, South Africa.

PURPOSE: To quantify costs to patients of accessing HIV care prior to ART initiation. MATERIALS AND METHODS: Using a cross-sectional study design, costs incurred by HIV-positive patients prior to ART initiation were estimated at urban primary healthcare facilities in South Africa. Costs included direct costs, indirect (productivity) costs, carer and coping costs (value of assets sold and money borrowed). The percentage of individual income spent on healthcare was calculated and compared by patient income tertiles and CD4 count strata. RESULTS: 289 patients (69% female, mean age 37 (SD: 10) years, median CD4 317 (IQR: 138-494) cells/mm3) were interviewed. The total mean monthly cost of pre-ART care was US$15.71. Indirect costs accounted for $2.59 (16.49%) of this when time was valued using the patient's reported income. The mean monthly patient costs were $31.61, $12.78, $12.65 and $11.93 for those with a CD4 count <100, 101-350, 351-500 and >500 cells/mm3 respectively. The percentage of individual income spent on healthcare was 7.25% for those with a CD4 count <100 cells/mm3 and 4.05% for those with a CD4 count >500 cells/mm3. CONCLUSIONS: Despite the provision of charge-free services at public clinics, care prior to ART initiation can be costly, particularly for the poor and unemployed. Our study adds to the growing body of evidence that highlights the need to consider policies to reduce the economic barriers to HIV service access, particularly for low income or unwell patient groups, such as improving access to disability grants.

The per-patient costs of HIV services in South Africa: Systematic review and application in the South African HIV Investment Case.

BACKGROUND: In economic analyses of HIV interventions, South Africa is often used as a case in point, due to the availability of good epidemiological and programme data and the global relevance of its epidemic. Few analyses however use locally relevant cost data. We reviewed available cost data as part of the South African HIV Investment Case, a modelling exercise to inform the optimal use of financial resources for the country's HIV programme. METHODS: We systematically reviewed publication databases for published cost data covering a large range of HIV interventions and summarised relevant unit costs (cost per person receiving a service) for each. Where no data was found in the literature, we constructed unit costs either based on available information regarding ingredients and relevant public-sector prices, or based on expenditure records. RESULTS: Only 42 (5%) of 1,047 records included in our full-text review reported primary cost data on HIV interventions in South Africa, with 71% of included papers covering ART. Other papers detailed the costs of HCT, MMC, palliative and inpatient care; no papers were found on the costs of PrEP, social and behaviour change communication, and PMTCT. The results informed unit costs for 5 of 11 intervention categories included in the Investment Case, with the remainder costed based on ingredients (35%) and expenditure data (10%). CONCLUSIONS: A large number of modelled economic analyses of HIV interventions in South Africa use as inputs the same, often outdated, cost analyses, without reference to additional literature review. More primary cost analyses of non-ART interventions are needed.

Desimplification of Single Tablet Antiretroviral (ART) Regimens-A Practical Cost-Savings Strategy?

INTRODUCTION: The use of lifelong antiretroviral therapy (ART) results in increased costs of care; the ability to finance and control sustained costs of ART needs to be discussed. APPROACH: The Southern Alberta Clinic initiated a practical cost savings approach that switched select patients from a branded ART to a less expensive generic variation. Our approach surveyed physicians and patients on their acceptance of switching and then launched a program asking patients if they would switch to generic variations for cost control purposes. RESULTS: Our early findings found >50% of patients approached agreed to switch. We found no evidence of increased risk of viral breakthrough, resistance, side effects, or displeasure with generic drugs. Measured cost savings in the first year were >$1.1 million with annual projected savings of between $4.3 million and $2.6 million (in 2017 Cdn$). CONCLUSION: Our approach can provide an option for controlling costs of HIV care without compromising quality.

Impact of three decades of antiretroviral therapy in a longitudinal population cohort study.

BACKGROUND: We have used a comprehensive HIV population to characterize antiretroviral therapy (ART), drug class selection, pill burden, drug costs and health outcomes over the entire span of the HIV epidemic. METHODS: Antiretroviral (ARV) use (drugs, classes, formulations) and both the laboratory and clinical outcomes (HIV-1 RNA, CD4+ T-cell count and mortality) were determined for all patients in Southern Alberta, Canada, at each year-end between 1986 and 2017. Pill burden, cumulative drug exposure and costs were calculated for each year. RESULTS: The number of ARV-treated patients increased from 29.6% (77/260) in 1989 to 93.4% (1,814/1,943) in 2017. Regimen selection showed continuous adjustments for toxicity, resistance, pill burden and adherence. Dramatic improvements in outcomes were seen. In 1997, 22.4% of treated patients had an undetectable viral load, this has been consistently around 90% since 2010 (92.7% in 2017). While HIV-related annual mortality rate declined from 11.0% in 1994 to 0.1% in 2017, all-cause mortality remained relatively stable from 1997 onwards. ART pill burden escalated in 1997 (12.4/day), then decreased to 2.1/day in 2016. Mean ART cost increased in 1997 (CAN$905/month/regimen in 1997, $1,223 in 2016). Mean cumulative lifetime exposure to protease inhibitors is 5.98 ±4.9 and to nucleoside reverse transcriptase inhibitors 8.8 ±6.2 years. CONCLUSIONS: Our findings demonstrate not only the immense burden that HIV has imposed on both patients and society, but also the substantial benefit of ART on patient outcomes. They show that research, patient engagement and programme support can with time minimize the harmful long-term effects of HIV-infection.

Alternative switching strategies based on regimens with a low genetic barrier: do clinicians have a choice nowadays?

Clinicians sometimes use switching strategies based on regimens such as RAL + ABC/3TC or RPV + ABC/3TC in order to resolve tolerability or safety issues associated with conventional recommended first-line strategies. Despite the low genetic barrier of these regimens, high safety and efficacy rates have been reported in retrospective studies.