Final 192-Week Efficacy and Safety Results of the ADVANCE Trial, Comparing 3 First-line Antiretroviral Regimens.

Background: ADVANCE compared 3 World Health Organization-recommended first-line regimens in participants with HIV who were antiretroviral naive. Methods: This randomized, open-label, noninferiority trial enrolled participants living with HIV with no antiretroviral exposure in the previous 6 months to 1 of the following arms: tenofovir alafenamide (TAF) / emtricitabine (FTC) + dolutegravir (DTG) (2 tablets), tenofovir disoproxil fumarate (TDF) / FTC + DTG (2 tablets), or a fixed-dose combination of TDF / FTC / efavirenz (EFV) (1 tablet). We report the final safety and efficacy data up to 192 weeks. Results: Repeat consent from the original 351 participants randomized to each arm was obtained from 230 participants (66%) in the TAF/FTC + DTG arm, 209 (60%) in the TDF/FTC + DTG arm, and 183 (52%) in the TDF/FTC/EFV arm. At 192 weeks, 213 (61%) of the original 351 participants in the TAF/FTC + DTG arm, 195 (56%) in the TDF/FTC + DTG arm, and 172 (49%) in the TDF/FTC/EFV arm had confirmed RNA <50 copies/mL, with low virologic failure in all groups and no significant integrase inhibitor mutations in any arm. Mean weight gain was 8.9 kg (SD, 7.1) in the TAF/FTC + DTG arm, 5.9 kg (SD, 7.1) in the TDF/FTC + DTG arm, and 3.2 kg (SD, 8.1) in the TDF/FTC/EFV arm at 192 weeks from baseline and was greatest among women, those taking TAF, and those with lower baseline CD4 counts. The weight trajectory slowed after week 96. There were few clinical events and minor laboratory changes and differences among arms after 96 weeks. There were no significant differences in treatment-emergent hypertension or pregnancy outcomes by arm. Conclusions: High viral suppression was seen across arms, with no resistance to DTG. Weight gain continued but slowed after 96 weeks, with few clinical events or laboratory changes.

Clinical and population-based study design considerations to accelerate the investigation of new antiretrovirals during pregnancy.

INTRODUCTION: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies. DISCUSSION: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias. CONCLUSIONS: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.

Accelerating investigation of new HIV drugs in pregnancy: advancing the research agenda from theory to action.

INTRODUCTION: Historical approaches to clinical development of novel therapeutics for treatment and prevention of HIV have led to unacceptable delays in the generation of data to support optimal antiretroviral drug use in pregnancy. Over the last 5 years, multiple stakeholders have voiced their concerns around the exclusion of pregnant women from drug trials, and some progress has been made to consolidate principles and forge consensus. Building on ongoing efforts, the World Health Organization (WHO) and the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) convened a technical consultation designed to move the discussion from theory to practice. DISCUSSION: Accelerating the inclusion of pregnant women in pre-licensure clinical trials, with a goal to have pharmacokinetics (PK) and preliminary safety data for all new HIV agents in pregnancy available at the time of drug approval, requires: (1) performing non-clinical developmental and reproductive toxicology studies early in drug development for all new HIV agents; (2) recognizing and acting on the central role of women of childbearing potential affected by HIV through the research being conducted and the dissemination of associated results; (3) enrolling pregnant women in studies to specifically determine pregnancy PK and preliminary safety, as soon as late non-clinical studies are completed with no negative signals, for all new HIV agents that have demonstrated preliminary evidence of safety and efficacy from phase 2 trials; (4) investigating adverse pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents; and (5) expanding active surveillance of drug safety in pregnancy for rare events, such as birth defects. Strategic actions to pursue include developing tools and resources to support designing and implementing studies among pregnant and breastfeeding women, identifying and promoting modifications of the regulatory framework that are supportive of systematic ethical investigation of new drugs in pregnancy, coordinating surveillance efforts, mobilizing key stakeholders and promoting transparency and accountability for all involved. CONCLUSIONS: With more than 19 million women living with HIV worldwide, ensuring greater inclusion of pregnant women in research on novel therapeutics is a priority to support drug optimization and effective introduction of innovations for treatment and prevention of HIV.

What we have learned from antiretroviral treatment optimization efforts over the last 5 years?

Progression in the development of antiretroviral therapy has been remarkable, with new agents continuing to appear as options for modern regimens, including in low-and-middle income countries where the HIV epidemic is concentrated. Here, we reflect on progress made in guiding regimen changes to public health programmes, and the challenges facing selection of newer agents.

Impact of long-acting therapies on the global HIV epidemic.

Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens may improve dosing convenience, tolerability and cost compared with current daily-based oral therapy. They can also circumvent stigma associated with oral therapy for both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple challenges remain, many specific to low-income and middle-income countries (LMICs), where the epidemic is most concentrated and HIV prevention and treatment options are limited. To optimize the use of long-acting formulations, key outstanding questions must be addressed. Uncertain costing, scale-up manufacturing, complex delivery systems and implementation challenges are potential barriers when considering the scalability of long-acting ARVs for global use.

Weight gain stopping/switch rules for antiretroviral clinical trials.

Obesity develops in a substantial number of people initiating and maintaining modern antiretroviral therapy. The comorbidities associated with obesity make significant weight gain and metabolic changes a major consideration in clinical trials studying different regimens' potency and safety. It is as yet unclear what role individual antiretrovirals or classes play in weight gain but the issue is a complex one for clinical trial design, especially when deciding when "too much" weight has been gained, in a context where we do not yet know if switching to alternative regimens will slow, halt or reverse weight gain or metabolic changes. In addition, clinician and trial participant opinion on acceptable weight gain may differ. We offer preliminary guidance for discussion for future antiretroviral clinical trial design.

Enhanced and Timely Investigation of ARVs for Use in Pregnant Women.

BACKGROUND: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants. SETTING: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10-12, 2018, in Geneva, Switzerland. METHODS: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices. RESULTS: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely-under certain conditions-allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data. CONCLUSION: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy.

Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial.

BACKGROUND: ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study. METHODS: This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262. FINDINGS: Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common. INTERPRETATION: Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study. FUNDING: USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.

Phase 3 trials of new antiretrovirals are not representative of the global HIV epidemic.

INTRODUCTION: People living with HIV (PLWH) are mainly African or Asian, the majority female. In contrast, pharmaceutical companies typically conduct phase 3 regulatory randomised controlled trials (RCTs) in high-income countries (HICs), where PLWH are mainly white males. Regulatory authorities can be conservative about including pregnant women in trials, discouraging female participation. Some adverse events occur more frequently by sex or by race because of differing pharmacokinetics. Most drugs have insufficient safety data in pregnancy and non-white people even after regulatory approval. The present study compared race and sex demographics of phase 3 RCTs of dolutegravir (DTG), bictegravir (BIC) and tenofovir alafenamide (TAF) with global HIV epidemic demography. METHODS: National epidemic sizes by sex were extracted from UNAIDS 2018 data. National demographics were used to estimate prevalence by race. PLWH by national socio-economic status were calculated from World Bank data. Summary race and sex demographic data for 10 phase 3 trials of DTG (n = 7714), four of BIC (n = 2307), eight of TAF (n = 7573) and two of doravirine (DOR) (n = 1407) were extracted from ClinicalTrials.gov. RESULTS: Black females (42%) and black males (30%) have highest prevalence globally. White males comprise 6% of PLWH. Over 60% of PLWH live in low or low-middle-income countries, 68% of whom are black and 23% Asian. Seventy-six per cent of DTG trial centres were in high-income countries (HICs) (5% global burden) and 23% in upper-middle-income countries (UMICs). DTG trials were not representative of PLWH even within the UMIC and HIC setting (49% white male vs 31% income band). White males were overrecruited by 44% to DTG, BIC, TAF and DOR trials in comparison with prevalence. Black females were underrepresented by 35%. CONCLUSION: Phase 3 RCT populations for new antiretrovirals comprised 51% white males, vastly disproportionate to the global HIV epidemic (6%). Females and non-white people are underrepresented. Female safety data are insufficient despite drug approval in Europe and USA. HIV trials should be located in regions representing the global epidemic with no sex-based selection. Trials should aim for at least 50% female and 50% non-white recruitment to properly provide safety information.

Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy.

BACKGROUND: The Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs. METHODS: Four pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class "congenital or familial disorders" were searched for NTDs. RESULTS: NTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators. CONCLUSIONS: Pharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.

Inclusion of pregnant women in antiretroviral drug research: what is needed to move forwards?

INTRODUCTION: To adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure. DISCUSSION: The article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non-pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in non-pregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours. CONCLUSIONS: A formalized step-wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research - the use of newer, more effective drugs in women is at stake (349).

Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities.

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people.

Optimizing responses to drug safety signals in pregnancy: the example of dolutegravir and neural tube defects.

INTRODUCTION: The unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk-benefit messaging when a safety signal is identified. DISCUSSION: The Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll-out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high-quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified. CONCLUSIONS: The response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk-benefit trade-offs in a variety of contexts; guidance to transform this risk-benefit balance into effective and agreed-upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.

Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV.

BACKGROUND: Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. METHODS: We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs - TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) - against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, -10 percentage points). We report the primary (48-week) efficacy and safety data. RESULTS: A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. CONCLUSIONS: Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.).

Risks and benefits of dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study.

BACKGROUND: The integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains. METHODS: We used an existing individual-based model of HIV transmission and progression in adults, which takes into account the effects of drug resistance and differential drug potency in determining viral suppression and clinical outcomes to compare predicted outcomes of alternative ART regimen policies. We calculated disability adjusted life-years (DALYs) for each policy, assuming that a woman having a child with a neural tube defect incurs an extra DALY per year for the remainder of the time horizon and accounting for mother-to-child transmission. We used a 20 year time horizon, a 3% discount rate, and a cost-effectiveness threshold of US$500 per DALY averted. FINDINGS: The greatest number of DALYs is predicted to be averted with use of a policy in which tenofovir, lamivudine, and dolutegravir is used in all people on ART, including switching to tenofovir, lamivudine, and dolutegravir in those currently on ART, regardless of current viral load suppression and intention to have (more) children. This result was consistent in several sensitivity analyses. We predict that this policy would be cost-saving. INTERPRETATION: Using a standard DALY framework to compare health outcomes from a public health perspective, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed the risks. FUNDING: Bill & Melinda Gates Foundation.

The transition to dolutegravir and other new antiretrovirals in low-income and middle-income countries: what are the issues?

: There are currently approximately 16 million people taking NNRTI-based first-line treatment in low-income and middle-income countries. Most of these patients are using the combination of tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV). The integrase inhibitor dolutegravir (DTG) has shown an improved safety profile compared with EFV in randomized studies. DTG also has a high barrier to development of drug resistance. New co-formulated tablets with TDF/3TC/DTG are being introduced into LMICs, for a median price of $75 per person-year. The prodrug of TDF, tenofovir alafenamide (TAF) is cheaper to manufacture than TDF. A combined pill with TAF/3TC/DTG is also being launched in LMICs, at a similar low price. However, the clinical development programmes for DTG and TAF did not include extensive analysis of several key populations: pregnant women, people with HIV-tuberculosis (TB) coinfection taking rifampicin-based treatment, and treatment-naive or pretreated patients with NRTI drug resistance. An observational study in Botswana has shown an increased risk of neural tube defects when dolutegravir is used in early pregnancy. In LMICs, only 50% of patients have access to regular viral load testing, and genotypic resistance testing is rarely performed. There is currently no clinical data to support switching patients from TDF/3TC/EFV directly to TDF/3TC/DTG if their viral load is either detectable or unknown. New clinical trials and observational studies will be needed to better understand the consequences of this switch of treatment in LMICs. Clinical trials of new antiretrovirals in key populations should be conducted earlier in their development. This will ensure that new treatments can be introduced into LMICs soon after their launch in high-income countries.

Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review.

BACKGROUND: The integrase strand transfer inhibitor dolutegravir (DTG) is being introduced into low- and middle-income countries (LMICs) as an alternative to first-line treatment with non-nucleoside reverse transcriptase inhibitors. However, DTG is not yet widely recommended for use in pregnant women. The aim of this systematic review was to analyse all available data on birth outcomes and congenital anomalies in the infants of pregnant women treated with DTG. METHODS: A PubMed and Embase search was conducted using the terms "dolutegravir" or "DTG" and "pregnancy" or "pregnant" from the earliest available date on the database to 26 July 2017. Any reports involving women who were pregnant, HIV positive and taking DTG were included. The percentage of pregnant women with adverse birth outcomes or congenital anomalies in their infants after taking dolutegravir was compared with five historical control databases. RESULTS: There were six databases included in the main analysis of birth outcomes and congenital anomalies, with a total of 1200 pregnant women. The percentage of pregnant women taking DTG with adverse birth outcomes and congenital abnormalities was similar to results from historical control studies of HIV-positive women. However, there was significant heterogeneity among the six databases - the percentage of infants with congenital anomalies ranged from 0.0% in Botswana (0/116 infants) to 13.3% in IMPAACT P1026S (2/15 infants). CONCLUSIONS: Up to 15 million people could be on treatment with DTG in LMICs within the next 5 years, of whom a substantial percentage is likely to be women of child-bearing potential. In many countries with large HIV epidemics, unplanned pregnancies are common and access to antenatal clinic facilities may be limited. Continued pharmacovigilance is essential, but it is reassuring that no clear safety signals have been detected, to date, for pregnant women treated with DTG in terms of birth outcomes or congenital anomalies.