Background: To inform World Health Organization (WHO) global guidelines, we updated and expanded ... more Background: To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. Methods: We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework. Findings: We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1¢94; 95% credible interval [CrI]: 1¢48À2¢56 at 96 weeks); was protective of drug-resistance (OR: 0¢13; 95%CrI: 0¢04À0¢48); and led to fewer discontinuations (OR: 0¢58; 95%CrI: 0¢48À0¢70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0¢70; 95%CrI: 0¢50À0¢92). Interpretation: The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable. Funding: WHO.
Despite considerable progress in paediatric HIV treatment and timely revision of global policies ... more Despite considerable progress in paediatric HIV treatment and timely revision of global policies recommending the use of more effective and tolerable antiretroviral regimens, optimal antiretroviral formulations for infants, children, and adolescents remain limited. The Paediatric Antiretroviral Drug Optimization group reviews mediumterm and long-term priorities for antiretroviral drug development to guide industry and other stakeholders on formulations most needed for low-income and middle-income countries. The group convened in December, 2018, to assess progress since the previous meeting and update the list of priority formulations. Issues relating to drug optimisation for neonatal prophylaxis and paediatric treatment, and those relating to the investigation of novel antiretrovirals in adolescents and pregnant and lactating women were also discussed. Continued focus on identifying, prioritising, and providing access to optimal antiretroviral formulations suitable for infants, children, and adolescents is key to ensuring that global HIV treatment targets can be met.
, which assessed the probability of switch to second-line ART in children across regions and unde... more , which assessed the probability of switch to second-line ART in children across regions and under different monitoring strategies, using the search terms "child", "children" or "adolescent", "HIV", "antiretroviral therapy", "switch" and "second-line". We identified clinical trials and several cohort studies reporting on the probability of switch that used various different definitions of switch. Very few studies have estimated the incidence of switch to second-line ART in children across multiple countries with varying treatment monitoring strategies. To our knowledge, there is no published global level analysis of switch to second-line ART using a uniform definition of switch.
This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased ... more This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyl-tert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despi...
Lifelong antiretroviral therapy (ART) provision to all pregnant HIV-positive women ("Option ... more Lifelong antiretroviral therapy (ART) provision to all pregnant HIV-positive women ("Option B+") has been recommended by the World Health Organization since 2013, but there remain limited data on the effects of Option B+ on long-term HIV-free survival in breastfeeding HIV-exposed infants. The Kigali Antiretroviral and Breastfeeding Assessment for the Elimination of HIV (Kabeho) study enrolled HIV-positive women from the third trimester of pregnancy to 2 weeks postpartum in 14 heath facilities implementing Option B+ in Kigali, Rwanda. Mother-child pairs in the longitudinal observational cohort were followed until 24 months postpartum, with HIV diagnostic testing at 6 weeks, and 9, 18 and 24 months. The Kaplan-Meier method was used to estimate HIV transmission, survival, and HIV-free survival through 24 months. We enrolled 608 HIV-positive women in 2013-2014; birth outcome data were available for 600 women and 597 live-born infants. By 6 weeks, 11 infants had died and 3 infa...
Early infant diagnosis is an important step in identifying children infected with HIV during the ... more Early infant diagnosis is an important step in identifying children infected with HIV during the perinatal period or in utero. Multiple factors contribute to delayed antiretroviral treatment initiation for HIV-infected children, including delays in the early infant HIV diagnosis cascade. We conducted a retrospective study to evaluate early infant diagnosis turnaround times in Lesotho. Trained staff reviewed records of HIV-exposed infants (aged-6-8 weeks) who received an HIV test during 2011. Study sites were drawn from Highlands, Foothills and Lowlands regions of Lesotho. Central laboratory database data were linked to facility and laboratory register information. Turnaround time geometric means (with 95% CI) were calculated and compared by region using linear mixed models. 1,187 individual infant records from 25 facilities were reviewed. Overall, early infant diagnosis turnaround time was 61.7 days (95%CI: 55.3-68.7). Mean time from specimen collection to district laboratory was 14...
Estimated numbers of children living with HIV determine programmatic and treatment needs. We expl... more Estimated numbers of children living with HIV determine programmatic and treatment needs. We explain the changes made to the UNAIDS estimates between 2015 and 2016, and describe the challenges around these estimates. Estimates of children newly infected, living with HIV, and dying of AIDS are developed by country teams using Spectrum software. Spectrum files are available for 160 countries, which represent 98% of the global population. In 2016, the methods were updated to reflect the latest evidence on mother-to-child HIV transmission and improved assumptions on the age children initiate antiretroviral therapy. We report updated results using the 2016 model and validate these estimates against mother-to-child transmission rates and HIV prevalence from population-based surveys for the survey year. The revised 2016 model estimates 27% fewer children living with HIV in 2014 than the 2015 model, primarily due to changes in the probability of mother-to-child transmission among women with...
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2017
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis ... more International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis (TB) prevention trial conducted among children enrolled from 2004 to 2008 during South Africa's roll-out of combination antiretroviral therapy (ART). To estimate TB incidence and mortality and the effect of ART. Children were pre-screened to exclude TB disease and exposure, actively screened 3-monthly for TB exposure and symptoms, and provided post-exposure isoniazid prophylaxis therapy (IPT). TB diagnoses were definite, probable, or possible, and mortality all-cause. Testing was at the 5% significance level. In 539 children (aged 3-4 months) followed up for a median of 74 weeks (interquartile range [IQR] 48-116), incidence/100 person-years (py) was 10.67 (95%CI 8.47-13.26) for any TB and 2.89 (95%CI 1.85-4.31) for definite/probable TB. Any TB incidence was respectively 9.39, 13.59, and 9.83/100 py before, <180 days after, and 180 days after ART initiation. Adjusted analysis show...
This study of a subset of women and infants participating in National Institutes of Health Pediat... more This study of a subset of women and infants participating in National Institutes of Health Pediatric AIDS Clinical Trials Group protocol 185 evaluated lymphocyte phenotypic markers of immune activation and differentiation to determine their association with the likelihood of human immunodeficiency virus (HIV) transmission from the women to their infants and the potential for early identification and/or prognosis of infection in the infants. Lymphocytes from 215 human immunodeficiency virus type 1 (HIV)-infected women and 192 of their infants were analyzed by flow cytometry with an extended three-color panel of monoclonal antibodies. Women who did not transmit to their infants tended to have higher CD4+ T cells. Most notably, levels of total CD8+ T cells and CD8+ CD38+ cells made significant independent contributions to predicting the risk of mother-to-child transmission. Adjusting for HIV-1 RNA level at entry, a one percentage-point increase in these marker combinations was associat...
HIV-1 RNA response to antiretroviral treatment in 1280 participants in the Delta Trial: an extend... more HIV-1 RNA response to antiretroviral treatment in 1280 participants in the Delta Trial: an extended virology study Delta Coordinating Committee and Delta Virology Committee P.
Very early infant diagnosis (VEID) (testing within two weeks of life), combined with rapid treatm... more Very early infant diagnosis (VEID) (testing within two weeks of life), combined with rapid treatment initiation, could reduce early infant mortality. Our study evaluated turnaround time (TAT) to receipt of infants' HIV test results and ART initiation if HIV-infected, with and without birth testing availability. Data from facility records and national databases were collected for 12 facilities offering VEID, as part of an observational prospective cohort study, and 10 noncohort facilities. HIV-exposed infants born in January-June 2016 and any cohort infant diagnosed as HIV-infected at birth or six weeks were included. The median TAT from blood draw to caregiver result receipt was 76.5 days at birth and 63 and 70 days at six weeks at cohort and noncohort facilities, respectively. HIV-exposed infants tested at birth were approximately one month younger when their caregivers received results versus those tested at six weeks. Infants diagnosed at birth initiated ART about two months ...
Through operations research, Project SOAR will determine how best to address challenges and gaps ... more Through operations research, Project SOAR will determine how best to address challenges and gaps that remain in the delivery of HIV and AIDS care and support, treatment, and prevention services. Project SOAR will produce a large, multifaceted body of high-quality evidence to guide the planning and implementation of HIV and AIDS programs and policies.
Background: To inform World Health Organization (WHO) global guidelines, we updated and expanded ... more Background: To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. Methods: We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework. Findings: We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1¢94; 95% credible interval [CrI]: 1¢48À2¢56 at 96 weeks); was protective of drug-resistance (OR: 0¢13; 95%CrI: 0¢04À0¢48); and led to fewer discontinuations (OR: 0¢58; 95%CrI: 0¢48À0¢70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0¢70; 95%CrI: 0¢50À0¢92). Interpretation: The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable. Funding: WHO.
Despite considerable progress in paediatric HIV treatment and timely revision of global policies ... more Despite considerable progress in paediatric HIV treatment and timely revision of global policies recommending the use of more effective and tolerable antiretroviral regimens, optimal antiretroviral formulations for infants, children, and adolescents remain limited. The Paediatric Antiretroviral Drug Optimization group reviews mediumterm and long-term priorities for antiretroviral drug development to guide industry and other stakeholders on formulations most needed for low-income and middle-income countries. The group convened in December, 2018, to assess progress since the previous meeting and update the list of priority formulations. Issues relating to drug optimisation for neonatal prophylaxis and paediatric treatment, and those relating to the investigation of novel antiretrovirals in adolescents and pregnant and lactating women were also discussed. Continued focus on identifying, prioritising, and providing access to optimal antiretroviral formulations suitable for infants, children, and adolescents is key to ensuring that global HIV treatment targets can be met.
, which assessed the probability of switch to second-line ART in children across regions and unde... more , which assessed the probability of switch to second-line ART in children across regions and under different monitoring strategies, using the search terms "child", "children" or "adolescent", "HIV", "antiretroviral therapy", "switch" and "second-line". We identified clinical trials and several cohort studies reporting on the probability of switch that used various different definitions of switch. Very few studies have estimated the incidence of switch to second-line ART in children across multiple countries with varying treatment monitoring strategies. To our knowledge, there is no published global level analysis of switch to second-line ART using a uniform definition of switch.
This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased ... more This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyl-tert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despi...
Lifelong antiretroviral therapy (ART) provision to all pregnant HIV-positive women ("Option ... more Lifelong antiretroviral therapy (ART) provision to all pregnant HIV-positive women ("Option B+") has been recommended by the World Health Organization since 2013, but there remain limited data on the effects of Option B+ on long-term HIV-free survival in breastfeeding HIV-exposed infants. The Kigali Antiretroviral and Breastfeeding Assessment for the Elimination of HIV (Kabeho) study enrolled HIV-positive women from the third trimester of pregnancy to 2 weeks postpartum in 14 heath facilities implementing Option B+ in Kigali, Rwanda. Mother-child pairs in the longitudinal observational cohort were followed until 24 months postpartum, with HIV diagnostic testing at 6 weeks, and 9, 18 and 24 months. The Kaplan-Meier method was used to estimate HIV transmission, survival, and HIV-free survival through 24 months. We enrolled 608 HIV-positive women in 2013-2014; birth outcome data were available for 600 women and 597 live-born infants. By 6 weeks, 11 infants had died and 3 infa...
Early infant diagnosis is an important step in identifying children infected with HIV during the ... more Early infant diagnosis is an important step in identifying children infected with HIV during the perinatal period or in utero. Multiple factors contribute to delayed antiretroviral treatment initiation for HIV-infected children, including delays in the early infant HIV diagnosis cascade. We conducted a retrospective study to evaluate early infant diagnosis turnaround times in Lesotho. Trained staff reviewed records of HIV-exposed infants (aged-6-8 weeks) who received an HIV test during 2011. Study sites were drawn from Highlands, Foothills and Lowlands regions of Lesotho. Central laboratory database data were linked to facility and laboratory register information. Turnaround time geometric means (with 95% CI) were calculated and compared by region using linear mixed models. 1,187 individual infant records from 25 facilities were reviewed. Overall, early infant diagnosis turnaround time was 61.7 days (95%CI: 55.3-68.7). Mean time from specimen collection to district laboratory was 14...
Estimated numbers of children living with HIV determine programmatic and treatment needs. We expl... more Estimated numbers of children living with HIV determine programmatic and treatment needs. We explain the changes made to the UNAIDS estimates between 2015 and 2016, and describe the challenges around these estimates. Estimates of children newly infected, living with HIV, and dying of AIDS are developed by country teams using Spectrum software. Spectrum files are available for 160 countries, which represent 98% of the global population. In 2016, the methods were updated to reflect the latest evidence on mother-to-child HIV transmission and improved assumptions on the age children initiate antiretroviral therapy. We report updated results using the 2016 model and validate these estimates against mother-to-child transmission rates and HIV prevalence from population-based surveys for the survey year. The revised 2016 model estimates 27% fewer children living with HIV in 2014 than the 2015 model, primarily due to changes in the probability of mother-to-child transmission among women with...
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2017
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis ... more International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis (TB) prevention trial conducted among children enrolled from 2004 to 2008 during South Africa's roll-out of combination antiretroviral therapy (ART). To estimate TB incidence and mortality and the effect of ART. Children were pre-screened to exclude TB disease and exposure, actively screened 3-monthly for TB exposure and symptoms, and provided post-exposure isoniazid prophylaxis therapy (IPT). TB diagnoses were definite, probable, or possible, and mortality all-cause. Testing was at the 5% significance level. In 539 children (aged 3-4 months) followed up for a median of 74 weeks (interquartile range [IQR] 48-116), incidence/100 person-years (py) was 10.67 (95%CI 8.47-13.26) for any TB and 2.89 (95%CI 1.85-4.31) for definite/probable TB. Any TB incidence was respectively 9.39, 13.59, and 9.83/100 py before, <180 days after, and 180 days after ART initiation. Adjusted analysis show...
This study of a subset of women and infants participating in National Institutes of Health Pediat... more This study of a subset of women and infants participating in National Institutes of Health Pediatric AIDS Clinical Trials Group protocol 185 evaluated lymphocyte phenotypic markers of immune activation and differentiation to determine their association with the likelihood of human immunodeficiency virus (HIV) transmission from the women to their infants and the potential for early identification and/or prognosis of infection in the infants. Lymphocytes from 215 human immunodeficiency virus type 1 (HIV)-infected women and 192 of their infants were analyzed by flow cytometry with an extended three-color panel of monoclonal antibodies. Women who did not transmit to their infants tended to have higher CD4+ T cells. Most notably, levels of total CD8+ T cells and CD8+ CD38+ cells made significant independent contributions to predicting the risk of mother-to-child transmission. Adjusting for HIV-1 RNA level at entry, a one percentage-point increase in these marker combinations was associat...
HIV-1 RNA response to antiretroviral treatment in 1280 participants in the Delta Trial: an extend... more HIV-1 RNA response to antiretroviral treatment in 1280 participants in the Delta Trial: an extended virology study Delta Coordinating Committee and Delta Virology Committee P.
Very early infant diagnosis (VEID) (testing within two weeks of life), combined with rapid treatm... more Very early infant diagnosis (VEID) (testing within two weeks of life), combined with rapid treatment initiation, could reduce early infant mortality. Our study evaluated turnaround time (TAT) to receipt of infants' HIV test results and ART initiation if HIV-infected, with and without birth testing availability. Data from facility records and national databases were collected for 12 facilities offering VEID, as part of an observational prospective cohort study, and 10 noncohort facilities. HIV-exposed infants born in January-June 2016 and any cohort infant diagnosed as HIV-infected at birth or six weeks were included. The median TAT from blood draw to caregiver result receipt was 76.5 days at birth and 63 and 70 days at six weeks at cohort and noncohort facilities, respectively. HIV-exposed infants tested at birth were approximately one month younger when their caregivers received results versus those tested at six weeks. Infants diagnosed at birth initiated ART about two months ...
Through operations research, Project SOAR will determine how best to address challenges and gaps ... more Through operations research, Project SOAR will determine how best to address challenges and gaps that remain in the delivery of HIV and AIDS care and support, treatment, and prevention services. Project SOAR will produce a large, multifaceted body of high-quality evidence to guide the planning and implementation of HIV and AIDS programs and policies.
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Papers by Lynne Mofenson