HTB

Antiretroviral treatment optimisation for adults and children

Fit for purpose: Antiretroviral treatment optimisation for adults and children. HIV i-Base. July 2017Polly Clayden, HIV i-Base

Adults

WHO 2016 Consolidated Guidelines

The preferred and alternative first-line ART regimens recommended in the 2016 World Health Organisation (WHO) Consolidated Guidelines are shown in Table 1. [2]

A fixed dose combination (FDC) of EFV 600 mg plus tenofovir disoproxil fumarate (TDF) and XTC – meaning either emtricitabine (FTC) or lamivudine (3TC) remains the preferred first-line regimen for adults and adolescents. The alternatives include EFV 400 mg and DTG based regimens.

Table 1: WHO 2015 preferred and alternative first-line adult ART regimens
First line ART Preferred regimens Alternative regimens
Adult TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP)orTDF + 3TC (or FTC) + DTG

or

TDF + 3TC (or FTC) + EFV400

or

TDF + 3TC (or FTC) + NVP

Pregnant /
breastfeeding
women
TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP)or

TDF + 3TC (or FTC) + NVP.

Key: ABC, abacavir; AZT, zidovudine; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; NVP, nevirapine; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.

Recommendations for second-line ART are shown in Table 2. Those include DRV/r or raltegravir (RAL) as alternatives to boosted lopinavir (LPV/r).

Third-line includes new drugs (if available) with the least risk of cross-resistance to those used already.

Table 2: WHO 2016 preferred and alternative second- and third-line adult ART regimens
First line ART Preferred regimens 2nd-line regimens 3rd-line regimens
Adults 2 NRTIs + EFV 2 NRTIs +ATV/r or LPV/r DRV/r + DTG (or RAL) + 1-2 NRTIs
2 NRTIs + DRV/r
2 NRTIs + DTG 2 NRTIs +ATV/r or LPV/r DRV/r + 2 NRTIs + NNRTI
2 NRTIs + DRV/r Optimise regimen using genotype profile.
Pregnant /breastfeeding
women
2 NRTIs + EFV 2 NRTIs +ATV/r or LPV/r DRV/r + DTG (or RAL) + 1-2 NRTIs.
2 NRTIs + DRV/r

Key: ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; LPV/r, lopinavir/ritonavir; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; RAL, raltegravir.

Early adopters

EFV 400 mg, DTG and tenofovir alafenamide (TAF) (the later not yet recommended by WHO but studies in LMICs are on the way) are expected to make up a large slice of the adult first-line market over the next five years, and contribute to ART cost reductions, according to projections by The Clinton Health Access Initiative (CHAI). [3]

Although several countries have changed or are in the process of making the transition to DTG-based first-line (and in fewer countries EFV 400 mg) more information is needed on how they are likely to perform in real world, low- and middle-income country (LMIC) settings for these drugs to be recommended in WHO guidelines without restriction. [4, 5]

To date at least 15 LMICs have recommended DTG first-line in their national guidelines. [6] And five countries have already began providing DTG in their programmes: Botswana, Brazil, Kenya, Nigeria and Uganda. The countries have taken different approaches to the transition, use in pregnancy and with TB treatment.

Several countries are also considering EFV 400 mg first-line: China, Cambodia, Kenya, Nigeria and Zimbabwe, among others.

Kenya was the first country to start providing generic DTG in its national programme – launched 28 June 2017. [7] Single DTG was tentatively approved by the FDA in September 2016 – and is now being rolled out. [8] DTG-based FDCs with TDF and FTC/3TC should be approved later this year.

EFV 400 mg based products will also be available in the not-too-distant future.

CHAI and Unitaid are working on a three-year large-scale initiative to speed up the introduction and access to optimal ARVs. [9]

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

Dolutegravir

With a low 50 mg once daily dose that does not require boosting, a high barrier to resistance, good efficacy, minimal toxicity, [10, 11, 12, 13] and the potential to be low-cost and coformulated, DTG looks like it will be an important potential option for use in LMICs. It is beginning to replace EFV first-line.

DTG studies have not yet included significant numbers of people who would be treated in LMICs – although several are now underway as is its use in early adopter countries. The registrational trials for DTG comprised approximately 80% men and few non-white participants and hardly anyone co-infected with other diseases (a few with hepatitis B and none with TB or malaria). People with baseline NRTI resistance were not included.

Partly because of insufficient data in pregnancy and with TB co-treatment, WHO 2016 guidelines recommend DTG as an alternative rather than preferred first-line option.

Dolutegravir and pregnancy

Pharmacokinetic (PK) data from women enrolled in IMPAACT P1026s and PANNA studies suggest DTG exposures in pregnancy are similar to that in non-pregnant adults but lower compared with postpartum. [14, 15, 16]

In IMPAACT P1026s DTG infant elimination half-life was more than twice that of the mothers in the study and historical non-pregnant adult controls.

Both studies reported good viral suppression in mothers and all evaluable infants were HIV negative.

Pre-clinical studies did not show any toxicities. [17] In the DTG registrational trials and compassionate use programmes, congenital anomalies were seen in six of 97 births. [18] But reports from postmarketing surveillance could be subject to reporting bias, as clinicians are more likely to report infants with anomalies.

Five of 15 DTG-exposed babies in IMPAACT P1026 were reported to have congenital anomalies (and two babies with findings considered to be “normal variants”).

The investigators deemed that, based on the nature of the anomalies and the timing of first exposure in pregnancy, the association with DTG can be ruled out for all but two of the five anomalies (renal cysts). Because of the gestational age at which DTG was started and the nature of the renal cysts, the investigators also consider it unlikely that they are related to DTG-exposure.

The most recent (to 31 January 2017) Antiretroviral Pregnancy Registry (APR) reported two birth defects out of 77 pregnancies with first trimester exposure to DTG (2.7%) and two out of 56 pregnancies with second trimester exposure. [19, 20] This is consistent with rates reported for other ARVs to the APR (2.8%) but the denominator of 200 or more live births with first trimester exposure, needed to rule out a two-fold increase in the rate of birth defects, has not been reached.

The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) analyses outcomes from observational studies of HIV positive pregnant women and their infants in Europe.

EPPICC reported two congenital anomalies out of 29 (6.9%) pregnancies with first trimester DTG exposure and one out of 32 (3.1%) with second/third trimester exposure. [21] The preterm delivery rate was 7% and 27% for infants with first and second/third trimester exposure respectively.

Small numbers preclude firm conclusions and no patterns of anomalies have been observed across these data sets reporting safety of DTG in pregnancy.

Observational data from Botswana – which changed from EFV-based to DTG-based first-line ART in 2016 including for pregnant women – reported similar adverse birth outcomes for the two regimens when started during pregnancy. [22] There were 845 pregnancies among women receiving DTG of which 116 were first trimester exposures. There were no major congenital anomalies among DTG exposed infants.

Dolutegravir and TB

Information about treating HIV/TB coinfection with a DTG-based regimen is limited. A phase I study has been conducted in healthy volunteers of DTG given with rifampicin and with rifabutin. [23] The study suggested that 50 mg twice daily dosing is likely to be required when it is co-administered with rifampicin to overcome UGT1A/CYP3A induction by this drug, which is used in standard first-line TB treatment.

Studies to look at DTG and TB treatment are ongoing or planned.

Dolutegravir and adverse events

DTG was better tolerated than EFV or 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. [24] Some recent observational studies have reported increased risk of CNS side effects with DTG.

Immune Reconstitution Inflammatory Syndrome (IRIS) could be a risk for people with low CD4 counts starting DTG as integrase inhibitors suppress viral load faster than other classes of ARVs. [25, 26]

Efavirenz 400 mg

EFV 600 mg – the currently approved and recommended dose – fulfils many of the desirable characteristics profile as part of an ideal ART regimen. For those who tolerate the drug, it is safe and effective, can be used in pregnancy and in people also receiving TB treatment and needs minimal laboratory monitoring.

But it has a low genetic barrier to resistance. It is also associated with CNS side effects, which can lead to drug discontinuation. [27] And there is an interaction between EFV and some hormonal contraceptives that can reduce their efficacy. [28]

The ENCORE 1 study, showed EFV 400 mg to be non-inferior to 600 mg (both plus TDF/FTC) as first-line ART. [29] The lower dose resulted in a reduction in EFV-related side effects 38% versus 48% with the standard dose.

But questions about whether or not 400 mg would be robust in the third trimester of pregnancy and with TB treatment have delayed recommendations from WHO and national guidelines.

Efavirenz 400 mg and pregnancy

PK modelling, conducted to simulate EFV exposure using 600 mg and 400 mg during the third trimester of pregnancy, suggested that although pregnancy decreases total exposure of EFV the unbound fraction is predicted to be unchanged. This study indicates that a dose reduction to 400 mg might be feasible in pregnancy. [30]

Preliminary results from the SSAT063 study, in progress to look at EFV 400 mg PK in pregnancy, suggest that the lower dose can be used in pregnant women. [31, 32]

Efavirenz and TB

For rifampicin, there have been seven short-term PK studies with EFV 600 mg (less than two weeks) showing reduction in plasma concentrations. It is unclear how useful these results are when EFV has not reached steady state. Five longer-term studies in HIV positive people have shown increased Cmin or no effect. [33]

A study in progress in London and Kampala is looking at the PK of EFV 400 mg in the presence of rifampicin and isoniazid. [34]

Efavirenz expected to remain an option

EFV is likely to remain a recommended first-line antiretroviral for a while. In countries where generics are not accessible until a drug is off patent this is likely to be for some time. The EFV/TDF/3TC regimen will be generic in most countries worldwide by 2017, but DTG and TAF patents extend for at least another 10 years. This will mean many middle-income countries that do not qualify for minimum prices – including swathes of South America, South East Asia, and Eastern Europe, where countries can pay four times as much for antiretrovirals than African ones with similar Gross National Incomes – will encounter significantly higher (likely prohibitive) ones. [35]

While it does remain an option, it is important that the lower dose is recommended without restriction as soon as results from the PK studies support this, to ensure that people who need it receive the most optimised version.

Tenofovir alafenamide

TAF’s low milligram dose and potential to be low cost and coformulated could offer benefits to generic accessible LMICs.

TAF is a novel prodrug of tenofovir. It is being considered as a replacement for TDF – the older prodrug of tenofovir currently recommended first-line. TAF doses are one tenth or less than that of TDF and give intracellular levels of the active metabolite, tenofovir diphosphate, which are four to seven times higher and plasma concentrations that are 90% lower than those with TDF. [36] It is dosed at 25 mg unboosted and 10 mg in a boosted regimen.

The reduction in plasma concentrations with TAF could mean less tenofovir accumulation in bone and kidneys and, in turn, fewer bone and kidney associated toxicities compared with TDF.

There were no significant differences in efficacy or clinical side effects between TAF and TDF across phase 2 and 3 studies at 48 and 96 weeks. At 48 weeks, participants receiving TAF had statistically significant less renal toxicity and reduced bone mineral density compared to those receiving TDF. But TAF was also associated with increases in low-density lipoprotein (LDL) cholesterol and total cholesterol plasma levels. It is unclear whether or not these differences will have clinical significance long-term.

A recent meta-analysis conducted to compare TAF versus TDF, that included 10 trials, did not reveal statistically significant differences in virological outcomes, adverse events, lab abnormalities or deaths. [37] But the analysis reported significantly less detrimental effects from TAF on bone and renal markers. The trials included were largely conducted in white, male participants around 40 years old with baseline CD4 count greater than 50 cells/mm3.

The authors concluded that the use of TAF in LMICs requires more data on pregnancy, TB and in people with advanced HIV.

TAF is notable for its absence in the WHO transition document. [38]

Tenofovir alafenamide and pregnancy

The APR reports only one defect among eight pregnancies with first trimester exposure and no defects with 10 second and third trimester exposures. [39] Obviously falling short of the 200 pregnancies threshold.

Tenofovir alafenamide and TB

TAF is a minor CYP3A4 substrate and a substrate of p-glycoprotein, both of which are induced by rifampicin, so there is likely to be an interaction with rifampicin. Use of TAF-based products and rifampicin together are currently contraindicated. Gilead has not yet conducted any interaction studies with TAF and rifampicin – although these are now planned. Co-administration with carbamazepine leads to a 55% decrease in TAF in plasma; results from modelling to predict the interaction with rifampicin predict this reduction will be 73% in plasma. [40] The intracellular concentrations of tenofovir-diphosphate when TAF is co-administered with rifampicin need to be investigated clinically.

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, coformulated version 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. [41, 42, 43]

Darunavir 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. [44, 45] There is 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

There have been no drug interaction studies with DRV/r and rifampicin; one is now planned.

What is planned or ongoing?

First-line

A DTG-based preferred first-line regimen is the current goal for first-line ART. As well as offering clinical advantages, in combination with TAF and FTC the total daily dose would be 275 mg (375 mg with 3TC) compared to 1200 mg with the current WHO preferred first-line: EFV 600 mg/TDF/3TC.

For people who cannot access (or tolerate) DTG, EFV 400 mg based regimens should be an alternative first-line.

Table 3: New first-line regimen studies
Study Sponsor (collaborators) Design Status Purpose
ADVANCE. WRHI 060. NCT03122262. Wits RHI (USAID, Unitaid) DTG/FTC/TAF vsDTG/FTC/TDF vsEFV 600/FTC/TDF non-inferiority, open label. 1110 treatment naive adult participants (370 per arm). Of these 60–90 treatment naive 12–15 year olds weighing > 40 kg (20 per arm analysed separately). Johannesburg, South Africa. Phase 3. Started January 2017. 48-week data available Q1 2019. Completion Q4 2019. Establish non-inferior efficacy for DTG/FTC/TAF compared to other study arms. Primary outcome number of participants with VL <50 copies/mL at 48 weeks. Secondary outcomes include: VL <50 copies/mL at 96 weeks, CD4 changes, tolerability, safety and efficacy.
NAMSAL (Efficacy and safety of a dolutegravir-based regimen for the initial management of HIV infected adults in resource-limited settings). ANRS 12313. NCT02777229. Inserm-ANRS (Institute de Recherche pour le development (Unitaid) DTG/3TC/TDF vs EFV 400 /3TC/TDF non-inferiority, open label. 606 treatment naive participants (303 per arm). Yaoundé, Cameroon. Phase 3. Started June 2016. 48-week data available October 2018. Establish non-inferior efficacy for DTG/3TC/TDF compared to EFV 400mg/3TC/TDF. Primary outcome number of participants with VL <50 copies/mL at 48 weeks. Secondary outcomes include: VL <50 copies/mL at 24 weeks, CD4 changes, tolerability, safety and efficacy
ADVANZ-4 dolutegravir. NCT02337322. Hospital Clinic of Barcelona DTG/ABC/3TC vsDRV/r + ABC/3TC, randomised, open label. 108 treatment naive participants with less than 100 CD4 cells/mm3. Barcelona, Spain. Phase 4. Completion Q4 2017. Compare immunological reconstitution and virological efficacy during 96 weeks in people with advanced HIV. Primary endpoint is the median increase in CD4 cell count at 48 weeks.

Key: DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; Inserm-ANRS, French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis; NIH, United States National Institutes of Health; NRTI, nucleos(t)ide reverse transcriptase inhibitor; PK, pharmacokinetic; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; VL, viral load; XTC, lamivudine or emtricitabine; 3TC, lamivudine

Two African investigator-led studies to look at these regimens in closer-to-real-life settings are in progress. The studies are: ADVANCE, a three-arm randomised comparison between 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. [46, 47, 48]

Although not conducted in an African setting, ADVANZ-4, a study currently underway in Spain will also provide information on DTG use in people with less than 100 CD4 cells/mm3. [49]

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.

Pregnancy

Table 4: First-line pregnancy studies
Trial Sponsor (collaborators) Design Status Purpose
Dolutegravir
DolPHIN1. NCT02245022. University of Liverpool (University of Cape Town, University of Makerere) Pilot study of DTG PK in pregnant women in third trimester and post-partum during 2 weeks breastfeeding. 60 late presenting women (28 to 36 weeks gestation). Women randomised 1:1 to receive DTG (50 mg once daily) or standard of care (EFV) plus two NRTIs. South Africa and Uganda. Phase 2. Started March 2017. Primary completion December 2017. Primary endpoint: PK 3rd trimester. Secondary endpoints: safety and tolerability of DTG up to 2 weeks post-partum and VL at delivery.
PK and safety study in pregnant women with HIV. ING200336. NCT02075593. ViiV Healthcare PK and safety single arm study of women with unintended pregnancies while participating in ARIA study of DTG/ABC/3TC FDC vs ATV/ r +TDF/FTC in 474 treatment naive women.(NCT01910402) to be completed in 2018. Estimated enrolment 25 women (approx 237 receive study drug in ARIA). Multicountry (US, Russian Federation, Spain, UK). Phase 3. Started Jan 2015 (recruiting). Primary completion. February 2019 Primary endpoints: PK 2nd /3rd trimester. Secondary endpoints: PK in neonates, maternal:cord blood ratio, maternal and infant AEs; adverse pregnancy outcomes.
DolPHIN2. Dolutegravir in Pregnant HIV Mothers and Neonates. University of Liverpool (University of Cape Town, University of Makerere). DTG PK, safety and efficacy in pregnant women in 3rd trimester and post-partum during breastfeeding until weaning or 18 months. 250 late presenting women (28 weeks gestation to delivery). Women randomised 1:1 to receive DTG (50 mg once daily) or standard of care (EFV) plus two NRTIs. South Africa and Uganda. Phase 3.Planned to start Q3 2017. Primary completion Q1 2021. Primary endpoints: PK third trimester. Secondary endpoints: VL at delivery, safety, tolerabilty and breast milk sterilisation.
Tenofovir alafenamide
WAVES (OLE). Women’s AntiretroViral Efficacy and Safety (Open Label Extension). NCT01705574. Gilead Sciences EVG/COBI/FTC/TDF vsTDF/FTC + ATV/r in treatment naive women with OLE in ATV/r arm re-randomised to remain or switch to EVG/COBI/FTC/TAF. 583 women total, those that become pregnant can remain on study regimen. Multicountry (US, Belgium, Dominican Republic, France, Italy, Mexico, Portugal, Puerto Rico, Russian Federation, Thailand, Uganda, UK). Phase 3.Started February 2016 (ongoing). Primary completion March 2017. Safety, efficacy and tolerability in naive PW. Safety and efficacy of EVG/COBI/FTC/TAF vs TDF/FTC + ATV/r.
Dolutegravir and tenofovir alafenamide
VESTED. IMPAACT P2010. NCT01302847. NIH (NIAID) DTG/TAF/FTC vsDTG/TDF/FTC vsEFV/TDF/FTC in 549 mother/infant pairs.Treatment-naive women starting ART at 14 to 28 weeks gestation. Randomised 1:1:1 open label. Only study that evaluates DTG/TAF/FTC in pregnancy. Multicountry: IMPAACT sites (US, Botswana, Brazil, Haiti, India, Malawi, South Africa, Tanzania,Thailand, Uganda, Zambia, Zimbabwe). Phase 3. Planned to start August 2017. Primary completion December 2019. Comparative data on safety and virologic efficacy during pregnancy and through 50 weeks of maternal and infant follow-up postpartum. Superiority (virologic endpoint); comparison by arm for difference (adverse pregnancy outcome, toxicity endpoints). Primary endpoints: VL <200 copies/mL at delivery; adverse pregnancy outcomes (SAB, foetal death, PTD or SGA); maternal toxicity; infant toxicity. Main secondary endpoints: VL <50 at delivery; VL <200 at 50 weeks postpartum; renal toxicity (mothers and infants); bone toxicity by DXA (subset of mothers and infants); adverse pregnancy outcomes including congenital anomaly; resistance (among women with VF, and among HIV-infected infants).
IMPAACT P1026s. NCT00042289. IMPAACT network, NIH (NIAID) PK properties of antiretroviral and related drugs during pregnancy and postpartum.Each study arm 12–25 (target) women with evaluable 3rd trimester PK data. Pregnant women > 20 weeks gestation receiving DTG (1 arm) and TAF (3 arms – within FDCs) as part of clinical care. Washout PK in drug exposed infants. Multicountry: IMPAACT sites (US, Argentina, Botswana, Brazil, Puerto Rico, South Africa, Thailand, Uganda). Phase 4. Started in September 2014 (enrolment completed in DTG arm, recruiting for TAF arms). Primary completion June 2017 (DTG) and June 2018 (TAF). Primary endpoint: PK 2nd /3rd trimester. Secondary endpoints: PK in neonate, maternal:cord blood ratio, maternal and infant adverse events; adverse pregnancy outcomes.
PANNA study. NCT00825929. Radboud University (PENTA Foundation, ViiV Healthcare) Pregnant women <33-week gestation receiving DTG as part of clinical care. Each study arm 16 with evaluable 33-week data. Multicountry: PANNA sites (Belgium, Germany, Ireland, Italy, Netherlands, Spain, UK). Phase 4. Started in July 2015 (recruiting). Primary completion December 2020. Primary endpoint: PK at 33 weeks and 4-6 weeks after delivery. Secondary endpints: PK in neonates, safety, VL and transmission.
Efavirenz 400 mg
SSAT063.PK of EFV 400 mg. Once daily during
pregnancy in HIV
positive women. NCT02499874.
SSAT (Mylan Inc.) PK single arm 25 women stable on 2 NRTI plus EFV 600 mg for >12 weeks, switch to EFV 400 mg at gestational age 28 weeks. UK and Uganda. Phase 1. Started September 2016 (ongoing). Primary completion October 2017. Primary endpoint: PK (AUC 24h and Ctrough) EFV 400 mg. 3rd trimester pregnancy and post part. Secondary endpoints: Safety and tolerability, genetic influences on EFV PK.

Key: AE, adverse event; ABC, abacavir; ATV/r, atazanavir/ritonavir; BF, breast feeding; COBI, cobicistat; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; IMPAACT, International Maternal Pediatric Adolescent AIDS Trials Network; NAID, NIH, United States National Institutes of Health; NRTI, nucleos(t)ide reverse transcriptase inhibitor; OLE, open label extension; PANNA, Study on Pharmacokinetics of Newly Developed ANtiretroviral Agents in HIV-infected pregNAnt Women; PK, pharmacokinetic; PTD, preterm delivery; SGA, small for gestational age; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; VL, viral load; XTC, lamivudine or emtricitabine; 3TC, lamivudine

A ViiV-sponsored study is enrolling ART-naive women only and comparing first-line DTG regimens to boosted atazanavir (ATV/r) ones. [50, 51] Women who become pregnant in the study will remain on their randomly assigned regimen and roll over into a pregnancy study.

DolPHIN 1 and 2 will look at DTG PK, safety and efficacy in pregnancy and post-partum, the pilot study is ongoing and the larger one is now supported by the Unitaid programme. [52, 53]

The women-only Gilead study WAVES includes an open label extension in which women are re-randomised to remain on a boosted atazanavir-based regimen or switch to one that includes TAF. [54] Women who become pregnant in the study can stay on their ART regimen.

IMPAACT P1026s and PANNA (both have presented preliminary data for DTG described earlier) – the respective American and European studies that look at PK of antiretrovirals in pregnancy and post-partum include women receiving DTG and TAF. [55, 56, 57, 58]

VESTED (IMPAACT P2010) will make the same three-arm comparison as ADVANCE but in pregnant women. [59]

ADVANCE will give women who become pregnant during the study the option to continue on their study drugs. [60]

And for EFV 400 mg, the safety concerns in pregnancy were resolved with wide use of EFV 600 mg, and we can expect results from the ongoing SSAT063 pregnancy PK study later this year. [61]

Tuberculosis

Table 5: First-line HIV/TB co-treatment studies
Trial Sponsor (collaborators) Design Status Purpose
Dolutegravir
INSPIRING. Open label study of DTG vs EFV for HIV/TB confection. NG117175. NCT02178592. ViiV Healthcare 50 mg DTG twice daily vs 600 mg EFV (open label, randomised 3:2 ratio) during TB treatment (rifampicin, isoniazid, pyrazinamide and ethambutol) 125 treatment naive participants. Multicountry (Argentina, Brazil, Mexico, Peru, Russian Federation, South Africa, Thailand). Phase 3. Start Jan 2015 (ongoing). Primary completion December 2017. Establish antiviral activity of DTG or EFV containing regimens with TB treatment. Primary outcome number of participants with VL <50 copies/ mL at 48 weeks. Secondary outcomes include: VL <50 copies/mL at 24 weeks, CD4 changes, tolerability, safety and efficacy.
RADIO. PK DTG 50 mg and 100 mg once daily with rifampicin. NCT03199690. SSAT (Wits RHI) DTG 50 mg once daily with food for 1 week, PK on day 7. Then DTG 100 mg once daily for 1 week, PK on day 14. Then 7-day wash out period. Start RIF on day 22 for 35 days and add DTG 50 mg on day 44, PK day on day 44. Then increase DTG to 100 mg OD for another 7 days, PK day on day 5720 HIV negative participants. UK. Phase 1. Planned start September 2017. Primary completion January 2018. Primary objective: investigate the PK of rifampicin 600 mg once daily and DTG 50 or 100 mg once daily in HIV negative participants. Secondary objective: investigate the safety and tolerability of rifampicin 600 mg once daily and DTG 50 or 100 mg once daily in HIV negative participants. Results will inform a bigger study that will be conducted in South Africa in people with HIV and TB who will be given rifampicin-containing regimens and DTG, ideally once daily.
Efavirenz 400 mg
Steady state PK of efavirenz in the presence of rifampicin and isoniazid. SSAT062. NCT02832778. SSAT (Mylan Inc) Sequential: 98 days (stage 1) and 28 days (stage 2) open label PK study. Stage 1 (London) PK in 25 HIV positive participants on established EFV 600 mg containing ART switch to EFV 400 mg plus rifampicin and isoniazid for 12 weeks (2 weeks after reduced EFV dose). Stage 2 (Kampala) PK in 10 participants with HIV and TB on established EFV 600 mg containing ART switch to EFV 400 mg plus rifampicin and isoniazid for 28 weeks (2 weeks after reduced EFV dose). UK and Uganda. Phase 1. Start September 2016 (recruiting). Primary completion October 2017. Evaluate steady state PK of EFV 400 mg during co-administration with rifampicin and isoniazid. Secondary endpoints: safety and tolerability. Relationship between genetic polymorphisms and EFV exposure.
Tenofovir alafenamide fumarate
RIFT. The effect of rifampicin on the plasma pharmacokinetics of emtricitabine (FTC) and tenofovir alafenamide fumarate (TAF) and intracellular tenofovir-diphosphate (TFV-DP) and FTC triphosphate (FTC-TP). SSCR101. NCT03186482. SSAT (Wits RHI, Gilead Sciences) Stage A 20 participants. Phase 1
: TAF/FTC 25/200 mg once daily for 28 days (days 1-28). Phase 2
: TAF/FTC 25/200 mg once daily plus rifampicin 600 mg once daily for 28 days (days 29-56). Phase 3: 
TDF 245 mg once daily for 28 days (days 57-84). If Stage A is only partially informative, Stage B will follow where a similar study will be undertaken with modified doses of TAF (eg 50 mg once daily or 25 mg twice daily with double dose of FTC too) and/or potential P-gp inhibitors (eg cobicistat). Stage B will be submitted as a protocol amendment. UK. Phase 1. Started June 2017. Primary completion October 2017. Primary
 objective: PK of TAF, plasma tenofovir, Intracellular TFV-DP, FTC, and FTC-TP, during co-administration of TAF/FTC or TDF with rifampicin in HIV negative participants. Secondary
 objective: safety and tolerability of the co-administered drugs in HIV negative participants.

Key: DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; FTC-TP, FTC triphosphate; PK, pharmacokinetic; SSAT, St Stephens AIDS Trust; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV-DP, tenofovir diphosphate; Wits RHI, Wits Reproductive Health and HIV Institute

ViiV is sponsoring INSPIRING, an open label study of regimens containing 50 mg DTG twice daily or EFV 600 mg once daily during first-line TB treatment, which begun enrolling early 2015. [62]

As it would be better to be able to take DTG once daily, the RADIO study will look at the drug concentrations in the presence of rifampicin at doses of 50 mg and 100 mg in HIV negative people. [63] This will inform a study in people with HIV/TB coinfection.

SSAT062 is in progress to investigate the PK of EFV 400 mg in HIV positive people in the presence of rifampicin and isoniazid in London and in HIV and TB coinfected participants receiving full anti-TB treatment in Kampala. [64]

For TAF the key PK parameter is intracellular tenofovir diphosphate in plasma and peripheral blood mononuclear cells. The RIFT study will measure this in the presence of rifampicin in HIV negative people. [65] Once this has been established then studies can be conducted in HIV/TB coinfected people.

It might be that EFV/TDF/3TC remains the recommended regimen during TB co-treatment if studies suggest that adjusting the dose of DTG (and possibly TAF) is necessary, as this can get a bit too complicated.

Two drugs first-line

There is currently interest, including from the AIDS Clinical Trial Group (ACTG) in looking at DTG/3TC dual therapy, as a potential new strategy to reduce ART cost and toxicity (discussed in detail in the adult pipeline section).

The main problems with two-drug treatment in LMIC are coinfection with Hepatitis B, underlying resistance to 3TC, reduced concentrations of DTG in third trimester of pregnancy and with TB treatment. [66]

It would be hard to extrapolate the results of the studies to date to routine LMIC programme settings where viral load data may be less available, and where resistance tests are unlikely.

In order for this strategy to be considered for LMICs there would need to be robust data from large pragmatic studies in unselected African populations, including TB and pregnancy. Both TB and pregnancy occur at incidence rates around 5% on ART in Southern Africa, so it is critical that the preferred first-line regimen is effective in these populations.

Although preliminary data from IMPAACT P1026s and PANNA suggest DTG exposures in pregnancy will be sufficient to suppress maternal viral load and prevent transmission in three drug regimens, some PK parameters are reduced in the third trimester. There is also considerable reduction in DTG exposure with rifampicin. Using it with only 3TC would likely scupper the possibility that DTG might still be effective at the standard dose with TB co-treatment, despite this reduction, which will be investigated further along the line.

Although every rand, pound or dollar saved in ART programmes is important at scale, the projected annual difference adding TAF to the regimen is about US $10–15 per person, which would have to be considered against the cost impact of potential first-line failure.

At the moment, it seems that the potential risks outweigh the potential benefits. The studies would need to be designed to make sure these potential risks could be ruled out, before this regimen could be considered for global guidelines.

Second-line

Table 6: Second-line DTG and DRV/r studies
Trial Sponsor (collaborators) Design Status Purpose
DAWNING ViiV 612 participants who failed 1st line (NNRTI + 2 NRTI) randomised to DTG + 2 NRTI vs LPV/r + 2 NRTIs. 2nd line NRTIs genotype guided. 48 weeks. Multicountry: Argentina, Brazil, Chile, China, Colombia, Kenya, Mexico, Peru, Romania, Russian Federation, South Africa, Thailand, Ukraine. Phase 3b. Ongoing 24-week results July 2017. Primary completion August 2017. Primary endpoint VL <50 copies/mL at 48 weeks. Secondary endpoints include VL <50 copies/mL at 48 weeks; time to virological failure; AEs and laboratory markers.
DRV/r 400/100 mg vs LPV/r. WRHI052. Wits RHI (USAID, MRC SA). 300 participants stable on LPV/r + 2 NRTI twice daily randomised to stay or switch to DRV/r 400/100 mg once daily. 48 weeks. South Africa. Phase 3. Ongoing. Primary completion September 2017. Primary endpoint VL <50 copies/mL at 48 weeks, AEs. Secondary endpoints time to virological failure.
D2EFT UNSW (Unitaid, National Health and Medical Research Council, Australia). ViiV, Janssen. 610 participants who failed 1st line regimen randomised to DRV/r + DTG vs DRV/r + 2–3 NRTIs.96 weeks. Multicountry: Argentina, Chile, Colombia, India, Indonesia, Malaysia, Mexico, Peru, South Africa, Thailand, Zimbabwe. Phase 4. Starting September 2017. Primary endpoint VL <50 at 48 weeks. Secondary endpoints differences in VL using different thresholds, time to VL <50 copies, changes in baseline CD4 count
Low dose DRV/r pilot SSAT 120 treatment-naive participants randomised to DRV/r 800/100 mg vs 600/100 mg vs 400/100 mg + TDF/FTCUK and Uganda. Phase 2 pilot. Funding application stage. PK and VL
Low dose DRV/r SSAT 600 1st line treatment- experienced participants randomised to DRV/r 800/100 mg vs 600/100 mg vs 400/100 mg + TDF/FTC. 96 weeks. UK and Uganda. Phase 3. Funding application stage. PK and VL

Key: AEs, adverse events; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir, MRC SA, Medical Research Council South Africa; NRTI, nucleoside/tide reverse transcriptase inhibitor; PK, pharmacokinetic; SSAT, St Stephens AIDS Trust; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; UNSW, University of New South Wales, VL, viral load; Wits RHI, University of Witwatersrand

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 is comparing DTG plus 2 NRTIs to LPV/r plus 2 NRTIs and 24-week data looks promising for DTG. [67, 68] Choice of NRTIs in DAWNING is genotype guided, so in order to consider this second-line strategy more information will be needed about taking this approach without resistance testing.

A regimen of DRV/r plus DTG has the potential to be a second-line option with no cross-resistance to an EFV/TDF/3TC first-line. Although with the current DRV/r mg dose of 800/100 mg a single pill daily regimen is less likely than two 400/50 mg ones. The D2EFT study will compare this regimen to DRV/r plus NRTIs. [69]

There is also the potential for a dose reduction of DRV/r to 400/100 mg and one study is underway and others are planned. [70]

PK data to guide the use of DRV/r with TB treatment are missing and plans to look at this are underway. The best option for second-line after a DTG-based first-line regimen will also be important. More research is needed to determine the best options for optimised second-line ART.

Paediatrics

The development of new antiretroviral drugs and appropriate formulations for children continues to be far too slow. Scale up of access for children is no better: in 2015, only 51% of children with HIV received ART; only half of those who did received optimal regimens. [71]

Few optimal regimens mean limited options for newborns, few appropriate FDCs, and paediatric regimens that cannot harmonise with those recommended for adults.

Treating paediatric HIV requires different regimens for different age groups. As children grow and the mechanisms by which they metabolise drugs mature, doses and often regimens must be changed. Such complexities have led to poor uptake and slow revision of recommendations as better ARVs become available for LMICs.

For manufacturers, there is scant incentive to develop appropriate ARVs for children. The vast success of maternal treatment and prevention of vertical transmission – although in every way a global victory – has led to an ever-shrinking market for paediatric ARVs.

There is still some way to go with formulations and regimens appropriate to children. Despite some advances in the last few years, innovation and access in antiretrovirals for children still lags behind that for adults.

Recent recommendations from the Paediatric Antiretroviral Working Group (PAWG) of the WHO suggest ways in which research can speed up the availability of new drugs and formulations. [72]

These include: the simultaneous enrolling of different age cohorts (rather than taking a de-escalated staggered approach see the paediatric pipeline section), the investigation of WHO weight bands in any paediatric development plan, the assessment of acceptability and feasibility while products are developed, and the use of PK modelling to inform dosing, as well as more efficient study designs. Prioritising optimal drugs and formulations needs to happen early and take programmatic constraints into account.

WHO 2015 guidelines

Recommendations for adolescents are the same as those for adults, guidance for younger children and infants is determined by age group. See tables 7 and 8.

But, as with the 2013 recommendations, there are no suitable generic formulations yet to support this guidance (except for adolescents who will be able to take DTG and EFV 400 mg based FDCs on the way for adults).

Only one regimen (that is not preferred), zidovudine (AZT) plus lamivudine (3TC) plus nevirapine (NVP) is currently available as an FDC.

Table 7: WHO recommended first-line ART for children and adolescents
First line ART Preferred regimens Alternative regimens
Adolescents TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP). TDF (or ABC) + 3TC (or FTC) + DTGTDF (or ABC) + 3TC (or FTC) + EFV 400 mg. TDF (or ABC) + 3TC (or FTC) + NVP.
Children 3 years to less than 10 years ABC + 3TC + EFV ABC + 3TC + NVPAZT + 3TC + EFV (or NVP). TDF + 3TC (or FTC) + EFV (or NVP).
Children less than 3 years ABC (or AZT) + 3TC + LPV/r ABC (or AZT) + 3TC + NVP

Key: ABC, abacavir; AZT, zidovudine; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LVP/r, lopinavir/ritonavir; NVP, nevirapine; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine

Table 8. WHO recommended second- and third-line ART for children and adolescents
First line ART Preferred regimens 2nd-line regimens 3rd-line regimens
Children 2 NRTIs + LPV/r Less than 3 years:
2 NRTIs + RAL
DTG + 2 NRTIs. DRV/r + 2 NRTIs. DRV/r + DTG + 1-2 NRTIs
Older than 3 years:
2 NRTIs + EFV or RAL
2 NRTIs + EFV 2 NRTIs + ATV/r or LPV/r

Key: ATV/r, atazanavir/ritonavir; DTG, dolutegravir; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ ritonavir; NVP, nevirapine; NRTI, nucleos(t)ide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; RAL, raltegravir

Missing paediatric formulations

Several gaps remain in available products for children that need to be filled before longstanding recommendations from the 2013 WHO guidelines (you read that right) can be implemented in most LMICs. [73]

Where possible these should be reduced strength tablets, and dispersible tablets for young children and infants. For compounds that cannot be formulated in this way (large and/or insoluble molecules like LPV/r) pellets are preferable to liquids.

Two priority formulations still needed to treat children according to the guidelines remain in slowly advancing development: abacavir/lamivudine/efavirenz (ABC/3TC/EFV) (150/75/150 mg), and lopinavir/ritonavir (LPV/r) 4-in-1 (30/15/40/10 mg).

Currently ABC/3TC/EFV can only be given by using ABC/3TC coformulated tablets with EFV tablets. A one-pill, once-daily regimen for children aged three to 10 years (less than 35 kg) would be useful.

LPV/r-based formulations are still in development and are needed to make it possible to give FDCs to children younger than three.

In May 2015, the big news for paediatric HIV was that finally heat-stable oral pellets of LPV/r (a finite number of LPV/r 40/10 mg pellets in a capsule, which is opened and sprinkled on soft food) suitable for infants and young children less than three years old were approved by the FDA. [74] These became available for country procurement mid-2016.

Less good news is that there is concern that currently forecasted demand for the pellets might exceed the production capacity for the manufacturer (though efforts are being made to increase capacity in the near future). [75]

The LIVING study is an implementation study using the LPV/r pellets ongoing in Kenya and starting soon in several other sub-Saharan African countries. [76]

The 4-in-1 granule formulation (finer than the 0.8mm pellets and more sand-like in texture) [77] has an anticipated approval date in early 2019.

Newborns

LPV/r is not suitable for neonates. [78] This age group is the least well-served by current options, meanwhile evidence for treating as early as possible continues to grow.

From birth to less than four weeks, there is currently no alternative to nevirapine (NVP) plus 3TC plus AZT. Although very early treatment is being explored for infants, data for this very young age group are scarce. Data from population modelling can help to predict dosing regimens in this age group.

IMPAACT have presented population modelling and PK simulations predicting dosing regimens to achieve target NVP treatment concentrations in term and late preterm infants. [79]

NVP clearance is low in term neonates, and lower still in preterm ones, because of immaturity in CYP2B6 and CYP3A4 activity. Clearance is also autoinduced in proportion to the size of the NVP dose in the first years of life.

PK data are available to guide NVP dosing for treatment of HIV in infants after one month of life: trough concentration target 3.0 ug/mL (target). Less than one month old evaluations of dosing regimens are limited to prophylaxis for HIV-exposed: trough concentration target 0.1 ug/mL.

The model revealed that typical NVP clearance in term infants increased by nearly 6-fold from birth to 6 months due to maturation and by an additional 79% due to induction. Simulated doses of 6 mg/kg twice daily for term and 4mg/kg twice daily for one week followed by 6 mg/kg twice daily for late preterm infants achieved NVP targets.

The dosing regimens supported by these simulations and NVP PK in preterm infants are being studied in the IMPAACT 1115 and 1106 protocols.

More missing data for priority antiretrovirals will be provided by ongoing IMPAACT trials:

  • P1026s – phase 4, prospective, PK study in pregnancy and post partum that obtains infant antiretroviral washout data. [80]
  • P1093 – phase 1/2, open label, non-comparative, intensive pharmacokinetics and safety study of DTG down to four weeks. [81]
  • P1097 – washout pharmacokinetic study of RAL including in low birth weight (<2500 g) infants. [82]
  • P1106 – phase 4 prospective pharmacokinetic study in low birth weight infants receiving NVP prophylaxis, tuberculosis (TB) prophylaxis or treatment and/or LPV/r-containing ART. [83]
  • P1110 – phase 1 open label, non-comparative pharmacokinetic dose-finding study of RAL in high risk, HIV-exposed neonates. [84]
  • P1115 – phase 1/2 proof of concept study of very early intensive ART in infants to achieve HIV remission. [85]
Table 9: Newborn treatment options (or lack of options to date): including ongoing and planned IMPACT trials
Compound Preterm Term 2 weeks
Nucleos(t)ide Reverse Transcriptase Inhibitor
ABC P1106 < 2500 g
AZT
ddI
d4T P1106 < 2500 g
FTC
TAF P1026s washout P1026s washout
3TC P1106 < 2500 g
Non-nucleoside Reverse Transcriptase Inhibitor
Doravirine P1026s washout P1026s washout
EFV P1026s washout P1026s washout
ETR P1026s washout P1026s washout
NVP P1106 < 2500 g P1115 >34 weeks GA
RPV
Protease Inhibitors
ATV
DRV P1026s washout P1026s washout
LPV P1026s washoutP1106 <2500 g P1026s washout
Integrase Inhibitors
DTG P1026s washout P1026s washout. P1093 dosing (in development). P1093 dosing (in development).
EVG P1026s washout P1026s washout
RAL P1097 washout P1097 washout. P1110 dosing.
CCR5 Receptor Antagonist
Maraviroc In development

Updated from Ruel T. IMPAACT 2015.

Key: ABC, abacavir; ATV, atazanavir; AZT, zidovudine; ddI, didanosine; DTG, dolutegravir; d4T, stavudine: EFV, efavirenz; FTC, emtricitabine; ETR, etravirine; LPV/r, lopinavir/ritonavir; NVP, nevirapine; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; 3TC, lamivudine. GA, gestational age.

Recommendations from PADO 3

WHO has led several consultations, to advance the discussion on drug and formulation development for children, resulting in a more collaborative and coordinated response among key stakeholders. A third WHO meeting on Paediatric ARV Drug Optimisation (PADO 3) took place on 6–7 December 2016. [86, 87]

As with adults, DTG and DTG FDCs are a big priority for paediatric use and future first-line regimens in treatment-naive children and second-line for ART-experienced children are likely to be DTG-based. (See table 10 for PADO 3 priorities; for more details and references on drugs and formulations currently in development for children see the paediatric pipeline section)

Table 10: PADO 3 priorities
Advance development Mid-term priority (3–5 years) Long-term priority (5–10 years)
Lopinavir/ritonavir (LPV/r) 4-in-1. 30/15/40/10 mg. Nevirapine/zidovudine (NVP/AZT) neonates Dolutegravir/lamivudine (DTG/3TC)
Abacavir/lamivudine/
efavirenz (ABC/3TC/EFV).
150/75/150 mg.
Darunavir/ritonavir (DRV/r) (120/20 mg)
Raltegravir (RAL) 50 mg scored Long acting oral/ injectable
Dolutegravir (DTG) 5 mg
DTG/3TC/ABC
(5/30/60 mg)
F/TAF Neutralising antibodies
DTG/FTC or 3TC/TAF
DTG/DRV/r

Source: WHO. PADO 3 meeting report. December 2016.

DTG is under investigation in IMPAACT 1093 and is also being evaluated in children and adolescents the PENTA trial ODYSSEY. [88, 89]

IMPAACT 1093 is now enrolling younger children and infants and children aged 4 weeks to <2 years (and also assessing WHO weight band dosing), and preliminary results are anticipated later in 2017.

ODYSSEY is a multi-centre randomised trial of DTG-based regimens versus standard of care for first- and second-line. It includes a PK sub-study to validate weight band dosing and will also look at PK in TB co-treatment. 100 participants are now recruited in ODYSSEY and results are expected in 2020.

RAL could be a useful drug to fill a gap for infants and children until DTG development for children is completed and it becomes available. It is the only integrase inhibitor recommended down to 4 weeks of age and is being investigated for neonates.

PADO 3 participants also discussed TAF and its potential for future use in paediatrics – including the issue of taste-masking. A first-line regimen with DTG and TAF (plus XTC) has the potential to harmonise across age and weight bands and with adults.

A reduced strength version of the boosted PI DRV/r is another priority.

The group also looked at two-drug regimens, such as DTG/3TC, for which adult phase 3 trials are ongoing. There was also concern with this regimen, particularly in the setting with high levels of NRTI resistance; with hepatitis B, during the third trimester of pregnancy and with TB treatment.

Longer term still there was also interest in the potential for long-acting formulations for infants, children and adolescents.

What needs to be done?

  • Upgrade the new first-line adult regimen. Sufficient evidence to change WHO guidelines to recommend DTG (which is now starting to be provided in national programmes) and TAF as part of the preferred first-line regimen needs to be generated. A recommendation from WHO is the strongest signal to generic manufacturers to take the risk and produce new FDCs. Such WHO recommendations will require results from the studies discussed here.
  • Originators donate drugs to strategy studies for LMICs. Originator manufacturers must take responsibility and supply prioritised antiretrovirals to key investigator-led studies (as well as the supporting substudies) to generate evidence to support their use in LMICs. And not after several years of deliberation. The lack of information on use of new drugs and doses in pregnancy and with TB treatment – that is critical to treating populations in LMICs – will continue to be a barrier to the recommendation and of any new regimen, however impressive the results from the phase 3 trials are.
  • Countries get ready to switch. Countries with high volume ART programmes, need their guideline committees briefed as results are generated (even before they are publicly released), so that they can make new recommendations, hopefully before final WHO decisions.
  • Donors must support switch to new drugs and regimens. Donors can play a huge part in changing standard of care in countries. Unitaid bought large volumes of TDF and helped to bring down the price and speed up the switch from d4T – so called market dynamics.
  • Timely approval. Regulatory agencies in LMICs, need to register new originator and generic formulations for adults and children, as swiftly as possible. The Indian regulatory agency needs to waiver the request for Indian trials before prioritised ARV products can be exported. Ideally this should happen before new WHO and national recommendations.
  • Generic companies need time to plan for high volume manufacture. Generic manufacturers need to be briefed on when data from key studies are expected to be released, guideline changes, and tender timing in countries, so that they can start planning to compete to supply the newly recommended regimens.
  • Pre-empt possible chaos. Before introducing new drugs, issues such as stockpiling (and stock outs) need to be discussed and planned, so that hitches with switching from old to new regimens are kept to a minimum.
  • Adult second-line needs more consideration. Although there is consensus on the likely best optimised first-line regimen, second-line is not quite there yet and requires more discussion and research and development to ensure best regimens and formulations.
  • Speed up development for children. The gap needs to be narrowed between approval of new drugs for adults, children, and neonates. Simultaneous enrolling of different age cohorts, use of PK data and modelling and the consideration of weight bands. Speeding up research and in turn availability will require building on existing partnerships and research networks and collaboration between the research community, pharmaceutical companies, regulators and policy makers.
  • Speed up approval for children. Harmonisation of regulatory requirements (including age categories and weight bands) between stringent authorities, WHO prequalification, and national authorities is also needed to help speed up availability.
  • Implement WHO recommendations. As simpler formulations identified to implement the paediatric guidelines become available (most topically LPV/r pellets), countries must ensure that they are swiftly approved and distributed, with appropriate training for health workers. And manufacturers need to ensure availability meets demand.
  • Coordinate paediatric procurement. Guidance on optimal formulations for children needs to be easily available to countries and updated as better ones become available. Companies need to be informed of the priority formulations. Plans need to be in place to phase out suboptimal paediatric formulations and phase in new ones. Donors need to ensure the availability of low volume products in a diminishing market.

References

Key: CROI, Conference on Retroviruses and Opportunistic Infections; IAS, International AIDS Society

  1. HIV pipeline 2017: new drugs in development. 14 July 2017.
    http://i-base.info/pipeline-2017
  2. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach – Second edition. June 2016.
    http://www.who.int/hiv/pub/arv/arv-2016/en/
  3. Clinton Health Access Initiative. ARV market report: the state of the antiretroviral drug market in low- and middle-income countries, 2015–2020. Issue 7, October 2016.
    http://www.clintonhealthaccess.org/content/uploads/2016/10/CHAI-ARV-Market-Report-2016-.pdf
  4. Vitoria M et al. Choice of antiretroviral drugs for continued treatment scale-up in a public health approach: what more do we need to know? JIAS 2016, 19:20504.
    http://www.jiasociety.org/index.php/jias/article/view/20504
  5. Vitoria M et al. When could new antiretrovirals be recommended for national treatment programmes in low-income and middle-income countries: results of a WHO Think Tank. Current Opinion in HIV & AIDS . 12(4):414-422, July 2017.
    http://journals.lww.com/co-hivandaids/Citation/2017/07000/When_could_new_antiretrovirals_be_recommended_for.18.aspx
  6. WHO technical update. Transition to new antiretroviral drugs in HIV programmes: clinical and programmatic considerations. July 2017.
  7. Africanews. Kenyans are first in Africa to get generic of latest AIDS drug. 28 June 2017.
    http://www.africanews.com/2017/06/28/kenyans-are-first-in-africa-to-get-generic-of-latest-aids-drug/
  8. CHAI press release. Aurobindo Pharma receives US FDA tentative approval for dolutegravir. 22 September 2016.
    http://www.clintonhealthaccess.org/usfda-tentative-approval-dolutegravir/
  9. Unitaid press release. New Unitaid and CHAI initiative to speed introduction and access to critical HIV drugs. 30 November 2016.
    http://unitaid.org/en/press-releases/1619-new-unitaid-and-chai-initiative-to-speed-introduction-and-access-to-critical-hiv-drugs
  10. Walmsley SL et al. Dolutegravir plus abacavir–lamivudine for the treatment of HIV-1 Infection. N Engl J Med 2013; 369:1807-1818. 7 November 2013.
    http://www.nejm.org/doi/full/10.1056/NEJMoa1215541.
  11. Walmsley S et al. Dolutegravir regimen statistically superior to efavirenz/tenofovir/emtricitabine: 96-week results from the SINGLE study (ING114467). CROI 2014. Boston, MA. Poster abstract 543.
    http://www.croiconference.org/sessions/dolutegravir-regimen-statistically-superior-tenofoviremtricitabineefavirenz-96-wk-data
  12. Cahn P et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013 August. (382) 9893:700–708.
    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61221-0/abstract.
  13. Castagna A et al. Dolutegravir in antiretroviral experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014 Aug 1;210(3):354-62.
    http://jid.oxfordjournals.org/content/210/3/354.long
  14. Mulligan N et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women. Conference on Retroviruses and Opportunistic Infections (CROI) 2016. 22-25 February 2016. Boston, Massachusetts. Poster abstract 438.
    http://www.croiconference.org/sessions/dolutegravir-pharmacokinetics-hiv-infected-pregnant-and-postpartum-women-0
  15. VESTED/IMPAACT 2010 protocol. Final version 1.0. 1 December 2016.
    http://www.impaactnetwork.org/DocFiles/IMPAACT2010/IMPAACT2010_FINALv1.0_01DEC2016.pdf
  16. Bollen P et al. A comparison of the pharmacokinetics of dolutegravir in pregnancy and postpartum. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy. 14-16 June 2017. Chicago. Oral abstract 0_7.
    http://regist2.virology-education.com/2017/18AntiviralPK/10_Bollen.pdf
  17. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2017.
    http://www.apregistry.com/forms/interim_report.pdf
  18. Vitoria M et al. When could new antiretrovirals be recommended for national treatment programmes in low-income and middle-income countries: results of a WHO Think Tank. Current Opinion in HIV & AIDS . 12(4):414-422, July 2017.
    http://journals.lww.com/co-hivandaids/Citation/2017/07000/When_could_new_antiretrovirals_be_recommended_for.18.aspx
  19. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2017.
    http://www.apregistry.com/forms/interim_report.pdf
  20. Vannappagari V et al. Dolutegravir use during pregnancy and birth outcomes: data from the Antiretroviral Pregnancy Registry (APR). IAS 2017. 23–26 July 2017. Paris. Poster abstract MOPEBO283.
  21. Thorne C. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. IAS 2017. 23–26 July 2017. Paris. Poster abstract MOPEC0609.
  22. Zash R et al. Dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC) started in pregnancy is as safe as efavirenz / tenofovir / emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. IAS 2017. 23–26 July 2017. Paris. Oral abstract MOAX0202LB.
  23. Dooley KE et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr 2013,62:21-27.
    journals.lww.com/jaids/Fulltext/2013/01010/Safety,_Tolerability,_and_Pharmacokinetics_of_the.4.aspx.
  24. WHO technical update. Transition to new antiretroviral drugs in HIV programmes: clinical and programmatic considerations. July 2017.
  25. Wijting I et al. Integrase inhibitors are an independent risk factor for IRIS: an ATHENA cohort study. CROI 2017. February 13-16, 2017. Seattle. Poster abstract 731.
    http://www.croiconference.org/sessions/integrase-inhibitors-are-independent-risk-factor-iris-athena-cohort-study
  26. Dutertre M et al. Initiation of art based on integrase inhibitors increases the risk of IRIS.
 CROI 2017. February 13-16, 2017. Seattle. Poster abstract 732.
    http://www.croiconference.org/sessions/initiation-art-based-integrase-inhibitors-increases-risk-iris
  27. Ford N et al. Comparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line antiretroviral therapy: a systematic review and meta-analysis of randomised trials. J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):422-9.
    http://journals.lww.com/jaids/Abstract/2015/08010/Comparative_Safety_and_Neuropsychiatric_Adverse.5.aspx
  28. Scarsi KK et al. Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks. Clin Infect Dis. 2016 Mar 15;62(6):675-682.
  29. ENCORE1 Study Group. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, doubleblind, placebo-controlled, non-inferiority trial. Lancet. April 2014. 383(9927):1474–82.
  30. Schalkwjik S et al. Is pregnancy a barrier to the proposed lower dose of efavirenz? 17th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington DC, USA. 8–10 June 2016. Poster abstract P_26.
  31. US National Institutes of Health. SSAT063- Pharmacokinetics of efavirenz 400 mg once daily during pregnancy in HIV-1 infected women.
    https://clinicaltrials.gov/ct2/show/NCT02499874
  32. Boffito M et al. Pharmacokinetics, pharmacodynamics and pharmacogenomics of efavirenz 400mg once-daily during pregnancy and postpartum. IAS 2017. 23–26 July 2017. Paris. Poster abstract TUPDB0203LB.
  33. Hill A et al. The drug interaction between rifampicin and efavirenz is time-dependent: systematic review of 12 pharmacokinetic studies. IAS 2014. Melbourne, Australia. 20-24 July 2014. Poster abstract MOPE040.
    http://pag.aids2014.org/EPosterHandler.axd?aid=7933.
  34. US National Institutes of Health. Pharmacokinetics of efavirenz in the presence of rifampicin and isoniazid.
    https://clinicaltrials.gov/ct2/show/NCT02832778
  35. Ford N et al. Is the pricing of antiretrovirals equitable? Analysis of antiretroviral drug prices in 20 low- and middle-income countries. 7th IAS Conference on HIV Pathogenesis Treatment and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia. Oral abstract WELBDO.
    http://pag.ias2013.org/flash.aspx?pid=596.
    http://pag.ias2013.org/Abstracts.aspx?SID=72&AID=3102.
  36. Sax PE et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 27 Jun 2015;385(9987):2606-15.
  37. Gotham D et al. Candidates for inclusion in a universal antiretroviral regimen: tenofovir alafenamide. Current Opinion in HIV & AIDS . 12(4):324-333, July 2017.
    http://journals.lww.com/co-hivandaids/Fulltext/2017/07000/Candidates_for_inclusion_in_a_universal.4.aspx
  38. WHO technical update – Transition to new antiretroviral drugs in HIV programmes: clinical and programmatic considerations. July 2017. Forthcoming.
  39. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2017.
    http://www.apregistry.com/forms/interim_report.pdf
  40. Personal communication. Gilead Sciences.
  41. Molto J et al. Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomised clinical trial. J Antimicrob Chemother. 2015 Apr;70(4):1139-45
  42. Lanzafame M et al. Efficacy of a reduced dose of darunavir/ritonavir in a cohort of antiretroviral naive and experienced HIV-infected patients: a medium-term follow-up. J. Antimicrob. Chemother. 2015 Feb;70(2):627-30.
  43. Kakuda TN et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers. J Clin Pharmacol. 2014 Aug;54(8):949-57.
  44. Khoo S et al. Pharmacokinetics and Safety of darunavir/Ritonavir in HIV-Infected Pregnant Women. AIDS Rev 2017 Jan-Mar;19(1):16-23.
  45. Slogrove AL et al. Toward a universal antiretroviral regimen: special considerations of pregnancy and breast feeding. Current Opinion in HIV & AIDS. 12(4):359-368, July 2017.
    http://journals.lww.com/co-hivandaids/Fulltext/2017/07000/Toward_a_universal_antiretroviral_regimen__.10.aspx
  46. US National Institutes of Health. ADVANCE Study of DTG + TAF + FTC vs DTG + TDF + FTC and EFV + TDF+FTC in first-line antiretroviral therapy (ADVANCE)
    https://clinicaltrials.gov/ct2/show/NCT03122262
  47. Venter WDF et al. The ADVANCE study: a groundbreaking trial to evaluate a candidate universal antiretroviral regimen. Current Opinion in HIV & AIDS. 12(4):351-354, July 2017.
    http://journals.lww.com/co-hivandaids/Fulltext/2017/07000/The_ADVANCE_study___a_groundbreaking_trial_to.8.aspx
  48. US National Institutes of Health. Efficacy and safety of a dolutegravir-based regimen for the initial management of HIV infected adults in resource-limited settings (NAMSAL)
    https://clinicaltrials.gov/ct2/show/NCT02777229
  49. US National Institutes of Health. Immune reconstitution in severely immunosuppressed antiretroviral-naive HIV-1-infected patients (<100 CD4+ T Cells/μL) taking antiretroviral regimens based on dolutegravir or ritonavir-boosted darunavir (the Advanz-4 Trial).
    https://clinicaltrials.gov/ct2/show/NCT02337322
  50. US National Institutes of Health. A study to determine safety and efficacy of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) in human immunodeficiency virus (HIV)-1 infected antiretroviral therapy (ART) naive women (ARIA).
    https://clinicaltrials.gov/ct2/show/NCT01910402
  51. Clayden P. Dolutegravir is superior to boosted atazanavir in women in the ARIA study. HTB. 1 August 2016.
    http://i-base.info/htb/30376
  52. US National Institutes of Health. Safety and pharmacokinetics of dolutegravir in pregnant HIV mothers and their neonates: a pilot study (DolPHIN1).
    https://clinicaltrials.gov/ct2/show/NCT02245022
  53. Unitaid. Dolutegravir in pregnant mothers and neonates (DolPHIN2 trial).
    https://unitaid.eu/project/dolutegravir-pregnancy-dolphin2-trial/
  54. US National Institutes of Health. Safety and efficacy of E/C/F/TDF (Stribild) versus RTV-boosted ATV plus FTC/TDF (Truvada) in HIV-1 infected, antiretroviral treatment-naive women (WAVES)
    https://clinicaltrials.gov/ct2/show/NCT01705574
  55. US National Institutes of Health. Pharmacokinetic study of antiretroviral drugs and related drugs during and after pregnancy.
    https://clinicaltrials.gov/ct2/show/NCT00042289
  56. Mulligan N et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women. Conference on Retroviruses and Opportunistic Infections (CROI) 2016. 22–25 February 2016. Boston, Massachusetts. Poster abstract 438.
    http://www.croiconference.org/sessions/dolutegravir-pharmacokinetics-hiv-infected-pregnant-and-postpartum-women-0
  57. US National Institutes of Health. Pharmacokinetics of antiretroviral agents in HIV-infected pregnant women. (PANNA).
    https://clinicaltrials.gov/ct2/show/NCT00825929
  58. Bollen P et al. A comparison of the pharmacokinetics of dolutegravir in pregnancy and postpartum. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy. 14-16 June 2017. Chicago. Oral abstract 0_7.
    http://regist2.virology-education.com/2017/18AntiviralPK/10_Bollen.pdf
  59. VESTED/IMPAACT 2010 protocol. Final version 1.0. 1 December 2016.
    http://www.impaactnetwork.org/DocFiles/IMPAACT2010/IMPAACT2010_FINALv1.0_01DEC2016.pdf
  60. US National Institutes of Health. ADVANCE Study of DTG + TAF + FTC vs DTG + TDF + FTC and EFV + TDF+FTC in first-line antiretroviral therapy (ADVANCE)
    https://clinicaltrials.gov/ct2/show/NCT03122262
  61. US National Institutes of Health. SSAT063- Pharmacokinetics of efavirenz 400 mg once daily during pregnancy in HIV-1 infected women.
    https://clinicaltrials.gov/ct2/show/NCT02499874.
  62. US National Institutes of Health. Open-label study of dolutegravir (DTG) or efavirenz (EFV) for Human Immunodeficiency Virus (HIV) – tuberculosis (TB) coinfection.
    http://clinicaltrials.gov/show/NCT02178592
  63. US National Institutes of Health. A clinical study investigating rifampicin and dolutegravir in combination in healthy volunteers (RADIO).
    https://clinicaltrials.gov/ct2/show/NCT03199690
  64. US National Institutes of Health. Pharmacokinetics of efavirenz in the presence of rifampicin and isoniazid.
    https://clinicaltrials.gov/ct2/show/NCT02832778
  65. US National Institutes of Health. RIFT: Effect of rifampicin on plasma PK of FTC, TAF and intracellular TFV-DP & FTC-TP (RIFT).
    https://clinicaltrials.gov/ct2/show/NCT03186482
  66. WHO Think Tank on HIV treatment optimization: implications for 2015 WHO ARV guidelines and future updates. Summary meeting report 21 February 2016.
    http://www.who.int/hiv/pub/arv/think-tank-tx-optimization-2016/en/index8.html
  67. US National Institutes of Health. Comparative efficacy and safety study of dolutegravir and lopinavir/ritonavir in second-line treatment.
    https://clinicaltrials.gov/ct2/show/NCT02227238
  68. Aboud M et al. Superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment: interim data from the DAWNING study. IAS 2017. 23–26 July 2017. Paris. Oral abstract TUAB0105LB.
  69. US National Institutes of Health. Dolutegravir and darunavir evaluation in adults failing therapy (D²EFT).
    https://clinicaltrials.gov/ct2/show/NCT03017872
  70. US National Institutes of Health. Evaluation of low-dose darunavir in a switch study (DRV).
    https://clinicaltrials.gov/ct2/show/NCT02671383
  71. Joint United Nations programme on HIV/AIDS. On the fast-track to an AIDS-free generation. Geneva: Joint United Nations Programme on HIV/AIDS 2016.
    http://www.unaids.org/sites/default/files/media_asset/GlobalPlan2016_en.pdf.
  72. Penazzato M et al. Optimizing research to speed up availability of pediatric antiretroviral drugs and formulations. Clin Infect Dis (2017) 64 (11): 1597-1603.
    https://academic.oup.com/cid/article-abstract/64/11/1597/3065486/Optimizing-Research-to-Speed-Up-Availability-of
  73. World Health Organization. March 2014 Supplement to the 2013 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach.
    http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_march2014/en/
  74. US Food and Drug Administration. Tentative approval letter. 21 May 2015.
    http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.pdf
  75. ARV procurement working group memorandum. 11 April, 2017.
  76. National Institutes of Health (US). Prospective study of Lopinavir based ART for HIV Infected childreN Globally (LIVING Study).
    https://clinicaltrials.gov/ct2/show/NCT02346487
  77. Drugs for Neglected Diseases initiative. Press Release. DNDi is awarded USD 17.3 million from Unitaid to bolster development and delivery of child-adapted antiretroviral (ARV) formulation.
    http://www.dndi.org/media-centre/press-releases/1514-grant-unitaid-arv.html
  78. US Food and Drug Administration. FDA Drug Safety Communication: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution.
    8 March 2011.
    https://www.fda.gov/Drugs/DrugSafety/ucm246002.htm
  79. Mirochnick M et al. Nevirapine dosing for treatment in the first month of life. CROI 2016. 22-26 February 2016. Boston. Poster abstract 440.
    http://www.croiconference.org/sessions/nevirapine-dosing-treatment-first-month-life-0
  80. US National Institutes of Health. Pharmacokinetic study of antiretroviral drugs and related drugs during and after pregnancy.
    https://clinicaltrials.gov/ct2/show/NCT00042289
  81. US National Institutes of Health. Safety of and immune response to dolutegravir (GSK1349572) in HIV-1 infected infants, children, and adolescents.
    https://clinicaltrials.gov/ct2/show/NCT01302847
  82. US National Institutes of Health. Evaluating the safety and pharmacokinetics of raltegravir in infants.
    https://clinicaltrials.gov/ct2/show/NCT01828073
  83. US National Institutes of Health. IMPAACT P1106: Pharmacokinetic characteristics of antiretrovirals and tuberculosis medicines in low birth weight infants.
    https://clinicaltrials.gov/ct2/show/NCT02383849
  84. US National Institutes of Health. Safety and pharmacokinetics of raltegravir in HIV-1-exposed newborn infants at high risk of acquiring HIV-1 infection.
    https://clinicaltrials.gov/ct2/show/NCT01780831
  85. US National Institutes of Health. IMPAACT P1115: Very early intensive treatment of HIV-infected infants to achieve HIV remission.
    https://clinicaltrials.gov/ct2/show/NCT02140255
  86. WHO. Paediatric Antiretroviral Drug Optimization (PADO) Meeting 3. Meeting report. 6–7 December 2016. Geneva, Switzerland.
    http://www.who.int/hiv/pub/meetingreports/paediatric-arv-optimization-pado3/en/
  87. Penazzato M et al. Prioritizing the most needed formulations to accelerate paediatric antiretroviral scale-up. Current Opinion in HIV & AIDS. 12(4):369-376, July 2017.
    http://journals.lww.com/co-hivandaids/Fulltext/2017/07000/Prioritizing_the_most_needed_formulations_to.11.aspx
  88. US National Institutes of Health. Safety of and immune response to dolutegravir in HIV-1 infected infants, children, and adolescents
    https://clinicaltrials.gov/ct2/show/NCT01302847
  89. US National Institutes of Health. A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care (SOC) in children with HIV infection starting first-line or switching to second-line ART.
    https://clinicaltrials.gov/ct2/show/NCT02259127

 

Links to other websites are current at date of posting but not maintained.