Fit for purpose: antiretroviral treatment optimisation July 2019

9 August 2019. Related: Special reports, Supplements, Fit for purpose.

By Polly Clayden

i-Base’s annual Fit for Purpose summarises key developments in antiretroviral treatment optimisation for low- and middle-income countries.

Download Fit for purpose July 2019 or view below

i-Base produces an annual HIV pipeline review as a companion to Fit for Purpose.

View HIV pipeline report 2019 here

Funded by Unitaid

Thanks to: Meg Doherty, Andrew Hill, Graeme Meintjes, Lynne Mofenson, Michelle Moorhouse, Lloyd Mulenga, Francois Venter, Marco Vitoria and Rebecca Zash

Introduction

Fit for Purpose provides an overview of recent developments in antiretroviral treatment (ART) optimisation for people living with HIV in low- and middle-income countries (LMICs).

Key developments since July 2018 include:

• Week 48 data from ADVANCE and NAMSAL – two key ART optimisation trials of first-line dolutegravir (DTG) vs efavirenz (EFV) showing non-inferiority of DTG regimens in African settings
• Update from Tsepamo study showing a declining rate of neural tube defects in Botswana but still slightly elevated compared to other ART regimens
• World Health Organization (WHO) guidance recommending DTG-based regimens for adults and children (for whom approved DTG dosing is available) as preferred first-and second-line ART

World Health Organization guidelines 2019

New World Health Organization (WHO) recommendations, released on 22 July 2019 at IAS 2019, include dolutegravir (DTG) as the preferred antiretroviral drug in first- and second-line regimens. [1]

This recommendation recognises the declining estimate DTG-associated neural tube defect risk and observed efficacy.

The new policy brief is entitled: Update of recommendations on first- and second-line antiretroviral regimens July 2019. It is a forerunner to the revised 2019 WHO consolidated antiretroviral guidelines to be released later this year.

WHO now recommends tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or emtricitabine (FTC) (XTC)/DTG as the preferred first-and second-line ART regimen for adults, adolescents and children (with approved DTG dosing). Low dose efavirenz (EFV 400 mg) is now recommended for adults and adolescents as the alternative first-line ART.

Tenofovir alafenamide (TAF) is recommended in special circumstances for adults with established osteoporosis and/or impaired kidney function. It is recommended as part of an alternative first-line regimen for children of age and weight groups with approved dosing.

DTG-based first-line ART was previously recommended as an alternative regimen due to evidence gaps for its use in pregnancy, periconception and with rifampicin (RIF)-based tuberculosis (TB) treatment and lack of generic formulations at that time.

Since then, rapidly evolving evidence of safety and efficacy as well as programmatic data has accumulated on the use of DTG and efavirenz (EFV) 400 mg in pregnant women and people coinfected with TB.

Although risk of neural tube defects, associated with DTG, has declined since May 2018 it still remains slightly higher than with other ART exposure groups.

The new recommendations lift any previous restrictions on DTG for women of child-bearing potential. And WHO continues to emphasise the importance of a women-centred approach, providing women with up-to-date information on risks and benefits to make an informed choice.

The recommendations also highlight potential DTG-associated weight gain and the importance of a healthy diet and regular exercise to help manage weight.

See WHO ART recommendations Tables 1, 2 and 3.

Key: AZT, zidovudine; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LPV/r, ritonavir-boosted lopinavir; NVP, nevirapine; PI/r, ritonavir-boosted protease inhibitor; RAL, raltegravir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine

Key: ATV/r, ritonavir-boosted atazanavir; AZT, zidovudine; DTG, dolutegravir; DRV/r, ritonavir-boosted darunavir; EFV, efavirenz; FTC, emtricitabine; LPV/r, ritonavir-boosted lopinavir; NVP, nevirapine; PI/r, ritonavir-boosted protease inhibitor; RAL, raltegravir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine

The ones to watch: what we know and the evidence gaps

Dolutegravir

DTG regimens are now WHO-preferred for first- and second-line, many countries have transitioned and others are planning to transition to DTG.

Week 48 data from two key ART optimisation studies looking at DTG regimens were recently presented.

ADVANCE

Eagerly-awaited results from the ADVANCE study were presented at IAS 2019. [2] In this study, first-line ART regimens tenofovir alafenamide (TAF)/FTC/DTG and TDF/FTC/DTG showed non-inferior efficacy compared with TDF/FTC/EFV at week 48.

Unlike registrational studies, ADVANCE participants reflect the population that will be treated in LMICs.

Among participants who remained on their study ART, TDF/FTC/EFV potency was equivalent to that of the DTG regimens, despite significant reported background resistance in South Africa.

Participants receiving TAF/FTC/DTG had a higher risk of developing obesity.

ADVANCE is a 96-week phase 3, investigator-led, open-label randomised trial, comparing TAF/FTC/ DTG and TDF/FTC/DTG with the local standard-of-care of TDF/FTC/EFV.

The study enrolled ART-naive adults and adolescents ages 12 years and above with viral load greater than 500 copies/mL. The primary endpoint is the proportion with viral load less than 50 copies/mL at 48 weeks.

A total of 1053 participants were randomised between February 2017 and May 2018: 99% black, 59% female, mean age 32 years, and CD4 count approximately 500 cells/mm3.

At week 48, the respective proportions of participants with viral load less than 50 copies/mL were: 84% for TAF/FTC/DTG, 85% for TDF/FTC/DTG, and 79% for TDF/FTC/EFV, confirming non-inferiority.

All three regimens were well tolerated, with slightly greater toxicity and rate of discontinuation in the TDF/FTC/EFV arm. There were no differences in sleep or clinical events between arms, and modest differences in laboratory measures.

TAF/FTC/DTG had less effect on bone density and renal function than other regimens. Weight increase (both lean and fat mass) was greater when DTG and TAF were used together and for women.

Week 96 data from ADVANCE will be presented in 2020.

The investigators are planning to continue the study beyond 96 weeks, particularly to look at weight gain and whether this can be reversed.

NAMSAL

NAMSAL results were presented last year, [3, 4] like ADVANCE, participants reflect the population that will be treated in LMICs. NAMSAL includes a considerable proportion with high baseline viral load who are less likely to achieve a fully suppressed viral load.

Findings from the study were shown at Glasgow 2018: at week 48,
DTG-based first-line ART was non-inferior, but not superior, to that with EFV 400 mg.

Of 613 participants, approximately 70% achieved viral load suppression. But people with high viral load at baseline (greater than 500,000 copies/mL) had poor virological response with less than 60% achieving less than 50 copies/mL in both arms.

Baseline characteristics were similar across both arms: 68% of participants were women, median age was 36 years, CD4 count was 281 cells/mm3, and viral load was 5.3 log copies/mL. A considerable proportion of participants had high viral load at baseline: 66% had greater than 100,000 copies/mL and 30% had greater than 500,000 copies/mL.

At week 48, the proportion of participants with viral load less than 50 copies/mL was 74.5% in the DTG arm and 69.0% in the EFV-400 arm: p=0.13 for the superiority test.

Among participants with baseline viral load less than 100,000 copies/mL, the respective proportions were 91.3% and 83.5%.

And for participants with greater than 100,000 copies/mL at baseline, the respective proportions were 66.2% and 61.5%.

Of participants with greater than 500,000 copies/mL at baseline only 54.8% and 57.9% in the DTG and EFV-400 arms respectively, achieved viral load suppression.

Viral load greater than 100,000 copies, CD4 count less than 200 cells/mm3, and male sex were associated with viral load greater than 50 copies/mL at week 48.

Among participants presenting with high viral load at baseline, the investigators observed persistently low viral replication rates in both arms.

Adherence was good in the study – greater than 80% in both arms.

NAMSAL will continue until 2021 to ensure long-term monitoring of participants who started DTG.

Dolutegravir periconception and pregnancy

On 18 May 2018, WHO issued a statement after a potential safety signal with DTG was identified relating to neural tube defects in infants who had been exposed to this antiretroviral at the time of conception. [5]

The potential safety signal was found at a preliminary, unscheduled analysis of an ongoing observational study in Botswana. The Tsepamo study is a birth surveillance programme, started after the introduction Option B+ (lifelong ART for all pregnant women) in Botswana. When it was designed, there was still some uncertainty about EFV and birth defects.

Tsepamo compares birth outcomes with exposure from conception and/or during pregnancy to the most common ART regimens used in the country since 2014. Surveillance is conducted at eight maternity wards in government hospitals, representing about 45% of all births. Data are extracted from all consecutive births at 24 weeks or more gestational age, using obstetric records. Livebirth and stillbirth outcomes in HIV positive women are also compared to those in HIV negative women.

The study had previously reported reassuring data (similar to that with EFV) with DTG started during pregnancy. [6, 7] The most recent figures, published in Lancet Global Health in June 2018, includes 1729 pregnant women who started DTG-based ART and 4593 EFV-based ART in pregnancy. [8] The risk for any adverse birth outcome among women on DTG versus EFV was similar: 33.2% vs 35.0%. As was the risk of any severe birth outcome: 10.7% vs 11.3%.

But adverse pregnancy outcomes among HIV positive women continue to be elevated compared with HIV negative women, despite ART. When these data were released the Tsepamo investigators emphasised that the findings were reassuring but not the whole story: birth outcomes with DTG exposure from conception still needed to be evaluated.

The periconception analysis revealed four cases of neural tube defects out of 426 births to women who became pregnant while taking DTG.

This rate of approximately 0.9% compared with a 0.1% risk of neural tube defects in infants born to women taking other ARVs at the time of conception.

WHO’s May statement was followed by several others, including from PEPFAR, US FDA, European Medicines Agency (EMA), US Department of Health and Human Services (DHHS), as well as a Dear Doctor letter from ViiV Healthcare. [9, 10, 11, 12] The recommendations advised varying degrees of caution.

Tsepamo data were previously updated on 1 May 2018 to include 596 births to women receiving DTG at conception. No additional neural tube defects were reported in this group, bringing the interim reported rate to 4/596, 0.67%.

The most recent update, presented at IAS 2019 [13], reported 5/1683 neural tube defects among births to women receiving DTG at conception, a rate of 0.30%.

Since 1 May 2018 and as of 31 March 2019 the study accrued data on an additional 29,979 deliveries including 1,257 to women on DTG at conception.

Of the total study population there were 98/119,033 neural tube defects, a rate of 0.08% (95% CI 0.07 to 0.10). For DTG at conception the rate was 0.30% (95% CI 0.13, 0.69) and for non-DTG at conception 15/14792, 0.10% (95% CI 0.06 to 0.17).

The prevalence of neural tube defects with DTG at conception remains higher than all other exposure groups but the estimated difference is small (0.2-0.27%). Compared with all other ART at conception, the 95% CI indicates that this difference is as low as 0.01% and as high as 0.67%.

Tsepamo surveillance continues and DTG at conception exposures continue to accrue without notable decrease (240 since 31 March 2019).

Tsepamo remains the most informative dataset on which to base guidance and policy.

As far as other datasets are concerned, programmes have been looking at this issue for DTG (as well as other integrase inhibitors) and some data from small, and mostly high-income country cohorts were presented at HIV Glasgow 2018 and CROI 2019. [14, 15]

There are data from a few women who became pregnant in DTG phase 3 trials and post marketing but these are not in sufficient numbers to pick up a rare adverse event such as a neural tube defect, nor have a comparator. [16, 17, 18]

Similar programmes to Tsepamo are in place in Uganda and Malawi. [19] But the transition to DTG is only just beginning so neither country has much to report yet.

Brazil has been using DTG in its national programme since early 2017, and has an excellent reporting system and is analysing these data. [20] No neural tube defects among 382 women on DTG at conception were reported in Brazil at IAS 2019. [21]

Data from high-income countries are frequently collected and there has been longer term DTG use – although far fewer women with HIV.

This includes reports to the Antiretroviral Pregnancy Registry (APR). [22] APR is an international (although largely US), voluntary, prospective registry that monitors prenatal antiretroviral exposures to detect potential increases in the risk of birth defects. The APR produces twice-yearly reports.

Antiretroviral exposure is classified by earliest trimester, which means starting ART any time in the first three months. Due to the narrow exposure window of interest for neural tube defects, the current interim reports now include supplementary information on periconception integrase inhibitor exposure.

Data presented at IAS 2019 show one neural tune defect out of 248 periconception DTG exposures, giving a prevalence of 0.40% for DTG and (0.14% for integrase inhibitors overall). [23] This higher than for other drugs/classes classes – but based on one neural tube defect in a relatively small number of exposures.

The overall prevalence of neural tube defects in 8,546 periconception antiretroviral exposures was 0.03%. Most of the reports in the APR come from North America, where there is national food folic acid fortification which has been shown to reduce neural tube defect risk by 36-68% in the general population.

The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) is a network of cohort and surveillance studies conducting epidemiologic research on pregnant women and children with HIV and children exposed to HIV during pregnancy.

Data for 81 infants presented in 2017 reported defects in four infants – these are from any pregnancy exposures (55 mothers ART preconception) and no neural tube defects. [24, 25] EPPICC is analysing preconception exposures to date across participating European countries.

Most European countries have their own surveillance, some like the UK and Ireland NSHPC (National Study of HIV in Pregnancy and Childhood) and the Swiss MoCHiV (Mother and Child HIV Cohort Study) contribute to EPPICC. Others like the French Perinatal Cohort do not (but there are very few pregnancy exposures there because their guidelines were very cautious about the use of DTG in pregnancy).

The presentations at HIV Glasgow 2018 showed data from analyses of DTG use in pregnancy from Canada, Frankfurt and Eastern/Central Europe. [26, 27, 28] Although none of these reports found further neural tube defects, the numbers are small, so at best these findings were faintly reassuring.

Most impenetrable are adverse event reporting systems. Accessing FAERS (AERS) data (data within the FDA’s drug Adverse Event Reporting System) requires the investigative skills of a sleuth (plus US $420 for a drug safety analysis). [29] Obviously, there is no denominator from spontaneous reporting but it is also tricky to work out whether or not events have been reported more than once under different descriptions. A presentation at CROI 2019 looked at the complexities of extracting information from such databases. [30]

So, despite much global commitment to hunting down neural tube risk data – where registries have not yet been established, numbers are too few or data are impossible to interpret – beyond Tsepamo this is proving easier said than done.

But using DTG later in pregnancy appears safe. [31]

And DolPHIN1, the pilot study to DolPHIN2, confirmed that standard dose of DTG should be used in the third trimester. [32]

DolPHIN1 and DolPHIN2 studies suggest there might be some advantages to using DTG late in pregnancy. [33, 34] A significantly greater proportion of women achieved undetectable viral load starting a DTG-based regimen late in pregnancy, compared with one based on EFV. Median time to undetectable viral load with DTG was approximately half of that with EFV.

But HIV positive women who start ART in late pregnancy are a vulnerable group with a higher risk of adverse outcomes and vertical transmission of HIV.

WHO recommends DTG for women of child-bearing potential and recognition of their autonomy and right to make this choice with the relevant information.

And the IAS Forum on the risks of periconceptional dolutegravir exposure published FAQs, [35] also supporting access to DTG for women of child-bearing potential, designed to help provide context and to support public health and clinical decision-making bodies until there are more data available.

Dolutegravir and TB

Treating TB and HIV is complicated by drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). As DTG is poised to become a massively-used antiretroviral worldwide this includes in settings where TB is common.

Week 24 and 48 results from the INSPIRING study – to look at safety and efficacy of DTG in ART naive adults with HIV/TB – suggest that DTG 50 mg twice daily seems effective and well-tolerated in HIV/TB co-infected adults receiving RIF-based TB treatment. [36, 37] This study was not powered to make a comparison with EFV but conducted to obtain some data in people with HIV/TB.

Data from a PK sub-study of the NAMSAL study with DTG 50 mg given twice daily in the presence of RIF also supports this strategy. [38]

The DTG label already recommends twice-daily dosing in the presence of RIF based on a previous drug-drug interaction study in HIV negative participants. [39, 40]

A pharmacokinetic (PK) study in healthy volunteers looked at the effect of RIF on the PK of DTG 100mg once daily. The study was conducted to evaluate whether doubling the DTG dose over 24 hours could offer an easier option than 50mg twice daily to manage the drug interaction. [41]

Whether DTG 100 mg once daily with RIF will be safe and effective in people with HIV/TB coinfection remains unclear from the PK results so far and further studies (including with 50 mg) are planned.

DTG can be given with short-course TB preventive therapy of 12 once-weekly rifapentine/isoniazid (3HP) without dose adjustment, according to data from the DOLPHIN (not to be confused with DolPHIN 1 and 2) trial, presented at CROI 2019. [42]

Dolutegravir and adverse events

DTG was better tolerated than EFV or daunavir/ritonavir (DRV/r) in its registrational studies but there was an increased risk of insomnia. More serious central nervous system (CNS) side effects (depression, suicide ideation) were rare. [43]

A meta-analysis of 6647 patient-years follow up showed no significant effect of DTG on the risk of cardiac, IRIS or suicide-related serious adverse events. [44] There was a higher risk of insomnia with DTG-based ART.

Anecdotes suggest that taking DTG in the morning overcomes difficulties with insomnia in most cases, without causing additional problems during the day. [45]

Another meta-analysis, suggested that treatment with integrase inhibitors appears to lead to greater increases in body weight than with other antiretrovirals. [46] The effect seems to be more pronounced for women and black people. There also might be an additional effect with NRTIs. But it is unclear yet whether these changes are clinically significant.

No clear conclusions emerged from data presented at CROI 2019 on this topic. [47]

But a pooled analysis of the ADVANCE and NAMSAL studies, presented at IAS 2019, found weight gain and clinical obesity for TAF/FTC/DTG and TDF/FTC/DTG compared with TDF/FTC/EFV. [48]

In this analysis, first-line DTG was associated with rises in body weight, clinical obesity, and increased trunk fat. Increased weight gain was higher in women and if used in combination with TAF/FTC. Rises in body weight on TAF/FTC/DTG appear to be progressive in black women.

Longer term follow up and re-analysis of other studies and cohorts – particularly those representative of the global epidemic – are needed to evaluate consequences of weight gain/clinical obesity.

Efavirenz 400 mg

EFV 400 mg with two NRTIs is now the is now recommended by WHO as the alternative first-line – EFV 600 mg is no longer recommended.

The ENCORE 1 study, showed EFV 400 mg to be non-inferior to 600 mg (both plus TDF/FTC) as first-line ART. [49] The lower dose resulted in a reduction in EFV-related side effects 38% versus 48% with the standard dose.

Efavirenz 400 mg and pregnancy

Results from a PK study of EFV 400 mg during pregnancy, showed lower drug concentrations in the third trimester, compared with post-partum. [50] But, these were within adequate ranges achieved with EFV 600 mg during the third trimester and those measured in ART-naive participants receiving EFV 400 mg in ENCORE 1. [51, 52]

All participants in the PK study maintained an undetectable viral load, suggesting that EFV 400 mg can be used in pregnant HIV positive women.

Reassuring real-life data from 271 women in Lusaka, Zambia, presented at IAS 2019, showed EFV 400 mg to be associated with high levels of maternal viral suppression (92%) during pregnancy. [53]

Notably this rate was higher than the previously reported suppression rates of 75% with EFV 600 mg in the same Zambian population, which might be due to the improved tolerability of the lower dose.

Efavirenz and TB

A PK study in HIV positive people without TB found isoniazid (INH)/RIF was associated with limited changes in EFV 400 mg exposure. EFV concentrations were sufficient to maintain virological suppression. [54]

The investigators concluded that EFV 400 mg can be co-administered with anti-TB treatment and this is being confirmed in people with HIV/TB coinfection.

Tenofovir alafenamide

TAF is a nucleotide reverse transcriptase inhibitor. It is being considered as a replacement for TDF – the older prodrug of tenofovir currently recommended first-line.

The first generic TAF-containing FDC was tentatively approved by the US FDA last year: DTG/FTC/TAF. [55, 56] The new FDC might offer several programmatic benefits to LMICs where generics are accessible including lower cost and smaller tablet size (easier to swallow, transport and store). [57]

But, lack of evidence, particularly for use in pregnancy and with TB coinfection, has meant that TAF is only just included (with an honourable mention) in WHO guidelines and is not included in the Essential Medicines List (EML). [58] TAF is also not included in the previous WHO transition document. [59] And participants of the Third Conference on Antiretroviral Drug Optimisation (CADO3), held at the end of 2017, did not consider TAF to be supported by sufficient evidence to inform use in LMICs. [60, 61]

TAF vs TDF

Results from a meta-analysis of TDF vs TAF showed TDF, boosted with ritonavir or cobicistat, led to higher risks of bone and renal adverse events and lower rates of viral load suppression, compared with TAF. [62, 63] But, unboosted, there were no differences between the two versions of tenofovir for efficacy and only slight differences in safety.

Boosting agents significantly increase plasma AUC concentrations of TDF (25-37%). Higher plasma tenofovir levels are linked to higher risks of renal and bone adverse events. The TAF dose is reduced from 25 to 10 mg daily when boosted but TDF remains at 300 mg daily. TDF is most commonly used worldwide in unboosted regimens, combined with 3TC and either EFV or DTG. TAF is expected to replace TDF and likewise will largely be used unboosted.

The meta-analysis evaluated 11 randomised head-to-head trials of TDF vs TAF – including 8110 participants. Those included were largely young to middle aged, with no pre-existing osteoporosis or kidney damage and mostly from high-income countries.

Nine trials compared TDF vs TAF in HIV positive people and two in people with hepatitis B. There were 4,574 participants who received boosting agents (with both TDF and TAF) representing 7,198 person years (p/y) follow up. The remaining 3,537 participants received unboosted regimens, giving 3,595 p/y follow up.

The analysis revealed boosted TDF treated participants had marginally lower viral load suppression rates, more bone fractures, lower bone mineral density and more discontinuation for bone or renal adverse events.

In contrast, there were no significant differences in viral load suppression rates or clinical safety endpoints (except bone mineral density) between unboosted TDF and TAF.

TAF and rifampicin

TAF is a substrate of drug transporters and RIF is a potent inducer and associated with drug-drug interactions and in turn lower drug exposures. Currently TDF is indicated for use with RIF but once-daily TAF is not.

Two PK studies in healthy volunteers suggest that TAF 25 mg could be given once daily with RIF. Both studies found the concentrations of tenofovir-diphosphate (TFV-DP) for TAF with RIF were higher than for people receiving standard TDF 300 mg.

In the first, twice-daily TAF plus RIF provided similar drug exposure to once-daily TAF. [64, 65]

This parallel design PK study showed when twice-daily TAF was given with RIF 600 mg intracellular TFV-DP decreased by 24% and plasma TAF by 15% compared with once-daily TAF alone.

The evaluation found that with twice-daily administration of TAF plus RIF, exposures over 24 hours of TAF total plasma, overall systemic plasma TFV and intracellular PBMC-associated TFV-DP are expected to be reduced by less than 15%, about 20%, and about 24%, respectively, compared with once-daily TAF.

Notably, after twice-daily administration of TAF plus RIF, the mean steady-state trough concentration of TFV-DP was above the historical steady state TFV-DP concentrations achieved with TDF 300 mg.

In the second PK study, plasma concentrations of once-daily TAF AUC were decreased by 55% and intracellular TFV-DP concentrations by 36% when given with RIF. [66, 67, 68]

Although RIF co-administration decreased the plasma TAF by 55% and intracellular TFV-DP AUC by 36%, intracellular TFV-DP AUC were 76% higher with TAF plus RIF than with TDF (300 mg once daily) alone.

These PK data support further evaluation of TAF plus RIF in people with HIV and TB.

TAF and pregnancy

Almost no adequate and well-controlled studies have been conducted on the use of TAF in pregnant women.

In preclinical studies, there was no evidence of adverse developmental outcomes with TAF at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended dose.

The first publicly presented clinical data on TAF in pregnancy are from IMPAACT P1026s – an ongoing, non-randomised, open-label, multi-centre, phase 4 study conducted to characterise antiretroviral pharmacokinetics in HIV positive pregnant women. [69]

TAF exposures during pregnancy were within the typical range of those in non-pregnant adults but higher than expected postpartum when dosed at 25 mg – according to data presented at AIDS 2018.

TAF is manufactured by Gilead, the originator company, as part of a fixed dose combination either with or without the pharmacokinetic booster cobicistat (COBI). TAF is given at a dose of 25 mg unboosted and 10 mg when boosted with 150 mg COBI.

Those eligible to enroll in the TAF arms were receiving the drug as part of routine clinical care at an IMPAACT site.

Steady state PK profiles of TAF were obtained following once-daily dosing of either rilpivirine/emtricitabine/TAF (R/F/TAF) 25/200/25 mg or elvitegravir/COBI/emtricitabine/TAF (E/C/F/TAF) 150/150/200/10 mg during the second and third trimesters and 6-12 weeks postpartum. Maternal plasma and cord blood samples were collected at delivery

Target TAF exposure was assessed relative to the 10th percentile value in non-pregnant adults.

There were 31 participants enrolled in the TAF 25 mg and 27 in the TAF/COBI 10/150 mg arms.

Postpartum sampling was performed at a median of approximately 9 weeks.

Plasma TAF exposures during pregnancy and postpartum were in the range of those observed in non-pregnant adults. TAF exposure with 25 mg was lower during pregnancy compared with postpartum but this difference was driven by higher than expected AUC postpartum.

Congenital anomalies considered possibly related to study drugs included left congenital pseudoarthrosis clavicle in one infant and renal cyst in another.

At the time of analysis 46 infants were HIV negative, 8 indeterminate and 4 pending.

Analyses of all maternal delivery samples, cord blood samples and infant washout samples are not yet complete but TAF was below the limit of quantification (3.95 ng/mL) in all 15 cord blood samples tested to date.

In a further analysis from IMPAACT P1026s, plasma exposures to TAF 25 mg with PK boosters did not differ significantly between third trimester and postpartum, although confidence intervals were wide. [70]

This group plan to look at intracellular levels of TAF in pregnancy and postpartum.

There is an insufficient number of first trimester exposures (minimum of 200) reported to the APR to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems, compared to the population-based rate. [71]

There are 6/162 and 0/62 birth defects reported to APR after first and second/third trimester TAF exposure respectively.

Before TAF can be recommended for use in pregnancy additional safety and outcome data from larger numbers of women and their infants (including preconception exposure) as well as intracellular PK data are needed.

Following the potential periconception safety signal with DTG, programmes are likely to be more cautious about new drugs with limited periconception and pregnancy data.

Darunavir/ritonavir

DRV/r is generally considered to be the most potent and tolerable protease inhibitor but cost has been a barrier to its wide use. Both a heat-stable, co-formulated generic version (hopefully this year) and a recommendation from WHO took their time.

DRV/r remains a potential candidate for dose optimisation. Results from the original dose finding studies and two with 600/100 mg once daily, plus one showing the recommended dose of cobicistat results in a significantly lower DRV Cmin than when it is boosted with ritonavir (in which the investigators say a reduction of up to 50% in Cmin should not make a difference to efficacy), suggest that a dose reduction to DRV/r 400/100 mg might be feasible. [72, 73, 74]

A 400/100 mg once-daily DRV/r dose plus two NRTIs maintained virologic efficacy through 48 weeks in participants previously suppressed with DRV/r 800/100 mg ANRS-165 Darulight study. [75]

A PK sub study of Darulight conducted in 15 men found total and unbound blood and seminal plasma exposure of DRV to be not significantly different between doses, despite 50% dose reduction.

Unexpectedly total blood plasma exposure of ritonavir trended to be higher in 400/100mg once-daily, than in 800/100mg once-daily due to a change in the inducer/inhibitor balance between DRV and ritonavir (RTV). [76]

Data from Johannesburg, presented at AIDS 2018, found stable participants on a twice-daily lopinavir/ritonavir (LPV/r)-based second-line regimen who switched to a once-daily 400/100 mg DRV/r one maintained similar virological suppression to those who remained on LPV/r at 48 weeks. [77]

In this study, 300 participants, stable on 2 NRTI + LPV/r with viral load less than 50 copies/mL, were randomised to 2 NRTI + DRV/r 400/100 mg once daily or to continue on their LPV/r-based regimen. The study defined treatment success as viral load less than 50 copies/mL at week 48.

At baseline participants were 68% women and 99.7% black, with median of age 42 years, and CD4 count greater than 600 cells/mm3.

In the primary efficacy analysis, viral load less than 50 copies/mL by week 48 was 95.3% in the DRV/r arm versus 93.4% in the LPV/r arm.

DRV/r at the lower dose of 400/100 mg once daily showed non-inferior efficacy to LPV/r in this switch study.

These results support further studies with low dose DRV/r, including in PI-naive second-line patients.

Optimised DRV/r 400/100 mg could be cheaper to produce than LPV/r and atazanavir/r.

In the meantime, a heat-stable, formulation of DRV/r is expected to be available this year.

Darunavir/ritonavir in pregnancy

Standard once-daily 800/100 mg dosing of DRV/r leads to reduced trough levels in third trimester – although it has been effective in some reports – 600/100 mg twice daily is recommended. [78, 79]

There are sufficient data for DRV/r to exclude a two-fold increased risk of birth defects. Like other protease inhibitors it crosses the placenta poorly.

Darunavir and TB

Giving DRV/r with RIF is complicated. Double doses of DRV/r with RIF were associated with unacceptable risk of hepatotoxicity and a reduction in DRV trough concentrations in a PK study, in HIV positive people without TB, conducted in South Africa, and presented at CROI 2019. [80]

The study was stopped before completion due to the high rates of hepatotoxicity.

What is planned or ongoing?

First-line

Two African investigator-led studies to look at DTG-based regimens in closer-to-real-life settings are ongoing.

The studies are: ADVANCE, a three-arm randomised comparison of two DTG-based regimens (one with TDF/FTC and the other with TAF/FTC) and EFV 600 mg (with TDF/FTC); and NAMSAL comparing DTG-based to EFV 400 mg based regimens, conducted in South Africa and Cameroon respectively. [81, 82, 83, 84, 85] Both studies have presented 48-week data recently, at IAS 2019 and HIV Glasgow 2018 respectively.

There are a number of ongoing or planned studies to help to address some of the evidence gaps associated with use in pregnant women and people receiving TB treatment.

Key: ART, antiretroviral treatment; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; VL, viral load; Wits RHI, Wits Reproductive Health and HIV Institute; 3TC, lamivudine

Pregnancy

VESTED (IMPAACT P2010) is recruited and ongoing. The study is making the same three-arm comparison as ADVANCE but in pregnant women. [86, 87]

DolPHIN2 is looking at DTG PK, safety and efficacy in pregnant women presenting in the third trimester, postpartum, and during breast feeding until weaning or 18 months. [88, 89] First results with all deliveries were presented at CROI 2019. [90]

These results showed, women living with HIV starting DTG-based ART after presenting in late pregnancy achieved more rapid virological suppression before delivery than those who started with an EFV-based one.

IMPAACT P1026s and PANNA – the respective American and European studies that look at PK of antiretrovirals in pregnancy and post-partum include women receiving DTG and TAF. [91, 92, 93, 94] Data have been presented previously for DTG and TAF.

A ViiV-sponsored study is enrolling ART-naive women only and comparing first-line DTG regimens to boosted atazanavir (ATV/r) ones. [95, 96] Women who become pregnant in the study will remain on their randomly assigned regimen and roll over into a pregnancy study.

Key: ABC, abacavir; ART, antiretroviral treatment; ATV/r, atazanavir/ritonavir; BF, breastfeeding; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; IMPAACT, International Maternal Pediatric Adolescent AIDS Clinical Trials Network; LSTM, Liverpool School of Tropical Medicine; MU, Makerere University; NIH, US National Institutes of health; NRTIs, nucles/tide reverse transcriptase inhibitors; PK, pharmacokinetic; PP, postpartum; PTD, preterm delivery; PW, pregnant women; RU, Raboud University; SGA, small for gestational age; SoC, standard of care; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TM, trimester; UoL University of Liverpool; VL, viral load; 3TC, lamivudine

Key: AIDS 2018, 22nd International AIDS Conference; ART, antiretroviral treatment; BF, breastfeeding; BM, breastmilk; DTG, dolutegravir; EFV, efavirenz; FDC, fixed dose combination; FTC, emtricitabine; IMPAACT, International Maternal Pediatric Adolescent AIDS Clinical Trials Network; NIH, US National Institutes of health; PK, pharmacokinetic; PP, postpartum; PTD, preterm delivery; PW, pregnant women; SGA, small for gestational age; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV-DP, tenofovir diphosphate; TM, trimester; VL, viral load

Tuberculosis

Further PK studies to look at dosing of DTG and TAF with RIF are being planned in people with HIV and TB.

Key: ART, antiretroviral treatment; DTG, dolutegravir; EFV, efavirenz; INH, isoniazid; PK, pharmacokinetics; RIF, rifampicin: RPT, rifapentine; UCT, University of Cape Town; VL, viral load; Wits RHI, The Wits Reproductive Health and HIV Institute

Second-line

For people failing EFV-based first-line treatment – and this population is expected to grow with greater access to viral load testing – there have been discussions about DTG and DRV/r second-line regimens.

The DAWNING study compared DTG + 2 NRTIs to the current standard second-line of LPV/r + 2 NRTIs. [97, 98]

Participants were genotyped at screening and only those with at least one predicted active NRTI were included. The LPV/r arm of the study was stopped early, at 24 weeks, after the DTG arm showed greater viral suppression rates than the LPV/r arm. Week 48 data, where these are available, were shown at AIDS 2018 with similar results. [99]

Whether the results from DAWNING can be duplicated in settings without genotyping, questions about the role and dose of DRV/r, and whether NRTIs can be recycled, drive second-line ART optimisation studies.

These discussions are also important for people currently on EFV-based first-line who will be switched to TDF/3TC/DTG in the absence of viral load monitoring.

Indirect evidence suggests that recycling the TDF/3TC backbone from first- to second-line could be achieved without resistance mutations to DTG.

The ARTIST study, to be conducted in Cape Town, will be a randomised, open-label, controlled trial to determine the virological suppression in participants failing first-line TDF/XTC/EFV who are switched to a DTG based second-line with a recycled TDF/3TC backbone.

It will be in two stages: stage 1 with a supplemental dose of DTG for 14 days to compensate for the enzyme-inducing effect of the discontinued EFV; and stage 2 will compare TDF/3TC/DTG (50 mg) to the WHO-recommended second-line regimen (AZT/3TC/DTG).

VISEND, to be conducted in Zambia and Zimbabwe, will compare short- (24 and 48 weeks) and long-term (72, 96 and 144 weeks) virologic outcomes in ART-treated adults switched from TDF/XTC/EFV or NVP-containing regimens to TDF or TAF/XTC/DTG-containing regimens with and without virologic suppression at time of switch. [100]

Importantly this study will also provide some real-life African data on TAF, including in a regimen with DTG.

ACTG 5381 is an observational cohort, also due to start this year, that will assess efficacy and emergence of resistance following the initiation of TDF/3TC/DTG first- or second-line or with RIF-containing TB treatment. The study is multinational with sites in: Haiti, Kenya, Malawi, South Africa, Uganda, and Zimbabwe.

The D2EFT study is investigating DRV/r 800/100 mg + DTG (which would have no overlapping resistance with EFV + 2 NRTI) vs DTG + 2 predetermined NRTIs vs DRV/r 800/100 mg + 2 NRTIs. [101]

The NADIA study is investigating DTG vs DRV/r once daily with a second factorial with TDF/XTC vs AZT/3TC. [102]

PK data to guide the use of DRV/r with TB treatment are missing and the DARifi PK study compared 1600/200 mg once daily with RIF and DRV/r 800/100 mg 12 hourly with RIF to DRV/r 800/100 mg without RIF. First data was shown at CROI 2019, where the study was stopped for hepatoxicity, and this remains complicated. [103]

And it might be possible to lower the overall dose of DRV (and potentially RTV) needed to achieve therapeutic steady state blood concentrations, using nanoparticles to improve drug absorption – and this work is also ongoing.

The best option for second-line after a DTG-based first-line regimen will be key in the future and the work on DRV/r might also be important here.

More research is needed to determine the best options for optimised second-line ART – but some of the investigations recommended at CADO 3 are already getting started or under discussion.

Key: ACTG, AIDS Clinical Trials Group; ART, antiretroviral treatment; ATV/r, atazanavir/ritonavir; AZT, zidovudine; DTG, dolutegravir; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; IDMC, Independent Data Monitoring Committee; LPV/r, lopinavir/ritonavir; MCC SA, Medicines Control Council South Africa; MSF, Médecins Sans Frontières; MU, Makerere University; NIAID, National Institute of Allergy and Infectious Diseases; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleos/tide reverse transcriptase inhibitor; NVP, nevirapine; PEPFAR, United States President’s Emergency Plan for AIDS Relief; SAHPRA, South African Health Products Regulatory Authority; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; UCT, University of Cape Town; VL, viral load; VS, virological suppression; XTC, lamivudine or emtricitabine; 3TC, lamivudine

Conclusion

As ever, results from ART optimisation studies, as well as observational data, highlight the importance of conducting well-designed trials (with long-term follow up) and having good surveillance systems in LMICs. Data from registrational trials, largely conducted in men, are simply not sufficient to inform widespread use of new drugs in millions of people from different populations.

References

Key: CHAI, Clinton Health Access Initiative; CROI, Conference on Retroviruses and Opportunistic Infections; IAS, International AIDS Society; PEPFAR, Presidents Emergency Programme on AIDS Research; US FDA, US Food and Drug Administration; WHO, World Health Organization

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