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

Venter, W.D. Francoisa; Serenata, Celiciaa,∗; Vitoria, Marcob; Mkhondwane, Luckyboyc; Sikwese, Kenlyd; Pepperrell, Tobye; Clayden, Pollyf; Qavi, Ambarg; Doherty, Megb; Penazzato, Martinab; Hill, Andrewh

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doi: 10.1097/QAD.0000000000003081
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Abstract

Introduction

The evolution of antiretroviral therapy (ART) is the envy of many other chronic diseases – entire new classes of drugs, often with multiple candidates within each class, appearing since zidovudine's registration in 1987. Some drug regimens are tested in combination from the start, and older drugs fallen into disuse, as safer medication with increasingly robust resistance barriers test boundaries of long-accepted paradigms of ‘triple-therapy’ [1].

Public health approaches to HIV treatment have been remarkably effective in scaling up treatment where HIV is most prevalent, with several low-and-middle-income countries attaining UNAIDS's 90–90–90 targets, and many demonstrating reduced HIV incidence, at least in part because of virally suppressive ART [2].

Aligning strategies using this public health approach reached a high point around 2013 when fixed-dose combination of tenofovir disoproxil fumarate (TDF), lamivudine (or the analogue emtricitabine) was combined with efavirenz (EFV) as the recommended regimen (known as TLE) for most first-line patients, with a simplified pathway to second-line, retrospectively validated by the large EARNEST study [3,4]. The first-line regimen was well tolerated, considered well tolerated in pregnancy, and could be used with tuberculosis drugs. Despite a low barrier to resistance, and side effects, TLE allowed many countries to attain the ‘last 90’ (90% viral suppression) among the tens of millions of people initiated on the regimen.

In the quest for safer drugs with higher resistance profiles, newer nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and integrase inhibitors were introduced in the last decade. Progressive generations of integrase inhibitors emerged and tenofovir alafenamide (TAF) replaced TDF as a preferred NRTI option in richer countries over the last 5 years [1]. The improved tolerability and remarkable resistance barrier of the newer integrase inhibitors led to calls to align WHO public health-oriented guidelines with those of high-income countries.

Fast forward to today, and this alignment has endured many issues, and taught many lessons for future optimized regimens.

Side effects

When antiretrovirals were introduced into large public programmes, side effects unknown during registration studies became apparent, when combinations were tested in the field as well as in independent studies [5]. The demographics of trials for novel antiretrovirals recruited mainly white men (51%), vastly disproportionate to their representation globally (6%) (Table 1). Women, adolescents and people of colour were systemically underrepresented, meaning insufficient safety data at registration are available.

Table 1 - Estimated global racial demographics of people with HIV versus racial demographics in registration trials for dolutegravir, bictegravir, tenofovir alafenamide and doravirine.
% global DTG trials BIC trials TAF trials DOR trials
Black
 Female 42% 530 (7%) 232 (11%) 558 (7%) 35 (3%)
 Male 30% 1151 (15%) 479 (21%) 1299 (17%) 189 (14%)
White
 Female 3% 1062 (14%) 321 (14%) 1233 (16%) 132‘ (9%)
 Male 6% 4048 (53%) 1022 (45%) 3768 (49%) 722 (51%)
Other
 Female 7% 237 (3%) 111 (5%) 301 (4%) 48 (4%)
 Male 12% 639 (8%) 83 (4%) 591 (7%) 264 (19%)
BIC, bictegravir; DOR, doravirine; DTG, dolutegravir; TAF, tenofovir alafenamide.

Examples of side effects emerging in underrecruited populations after registration include stavudine causing lactic acidosis, and nevirapine skin and liver toxicity, more so in women, the greater occurrence of neuropsychiatric effects of EFV in black people, dolutegravir's (DTG) association with neural tube defects, and weight gain seen with newer antiretrovirals in black women [1–4,6].

With integrase inhibitors, now the cornerstone of first-line treatment, one of the most pressing issues is finding alternatives to DTG in those who have preexisting obesity or who are experiencing excessive body weight gain, as well as improve the evidence base for switch options. EFV is the only widely available switch option but we have no data on the impact of switch on the weight trajectory; EFV has its own complex impact on weight, glucose and lipids [7].

Safety in pregnancy

Traditionally, manufacturers, regulators and ethics committees have dealt with women's safety in clinical trials by simply excluding them. This well intentioned policy is now recognized as a major problem – medications are rolled out to women of childbearing age, often with minimal safety data in women or to exposed infants during pregnancy or breastfeeding. The consequence of this has been seen with DTG – women seem more likely to gain weight (itself potentially linked to poorer pregnancy outcomes for mother and infant), than with EFV and have a slightly increased risk of infant neural tube defects when compared with HIV-negative women [8–11].

Consideration regarding tuberculosis and hepatitis B

Rifampicin remains the main drug in all modern first-line TB programmes, and affects many antiretrovirals, including TAF. Previously, compatibility with TB regimens was an obstacle, as TB was such a common presenting feature. Now, the proportion of people initiating and re-initiating ART with TB has decreased in most LMICs, because of earlier HIV diagnosis. Isoniazid and other TB preventive regimens has emerged as a powerful prevention tool. Finally, EFV has a large evidence base, and DTG double-dosing is an effective option, offering temporary solutions for those needing these TB-friendly regimens. It may be that new regimens that cannot be used with rifampicin could be considered, with the EFV or DTG options reserved for the period of TB treatment [12].

Lamivudine is an integral component of almost all ART regimens but needs to be combined with TDF (or TAF) to be effective against chronic hepatitis B, which is common in many settings where HIV is prevalent, limiting appetite for dual regimens. Screening for hepatitis B adds complexity to public health programmes (as does screening for renal dysfunction before using TDF) but as more effective dual ART regimens, including long-acting options become available, this may need re-consideration before commencing ART, if these confer benefits in terms of adherence and quality of life [13].

Regimen alignment between paediatric and adult regimens

Stockout of key paediatric formulations continues to impinge on paediatric programmes in low-and-middle-income countries. A number of challenges affect paediatric development plan and there is little commercial impetus for innovator companies to pursue new paediatric formulations as the number of HIV-positive is globally decreasing with effective scale up of maternal treatment. Alignment between paediatric and adult regimens, and the scoring of breakable adult tablets would assist security of supply [13,14].

In conclusion, working with research institutes and pharmaceutical companies to ensure adequate representation of women and people of colour especially during registration studies would be ideal, as independent studies tend to only follow years after the results of registration studies are published. We are seeing welcome public commitments by pharmaceutical companies, applying recruitment targets for women in their new clinical development programmes but this has yet to be seen in recent registration studies, and regulators may need to issue guidance for future registration studies. Further focus on children living with HIV is paramount to prevent them from being a neglected population. Long-held thinking on restrictions around TB and hepatitis B may need creative approaches, to preserve the gains made with the public health approach while still facilitating access to new ARV regimens. This all will need to be done with input from the most affected communities, who continue to play a critical role in designing programs and assisting in our fight against AIDS.

Acknowledgements

Funding: funding for this AIDS journal supplement was provided by the US Agency for International Development (USAID) through the OPTIMIZE Cooperative Agreement AID-OAA-A-15-00069 to Ezintsha, Wits Reproductive Health & HIV Institute, University of the Witwatersrand. The content of this supplement is solely the responsibility of the authors and does not necessarily represent the official views of USAID, or any other agency.

Author contributions: F.V., and A.H. did the first draft, and all authors contributed to subsequent drafts. All authors have approved the text.

Conflicts of interest

Venter's unit receives funding from the Bill and Melinda Gates Foundation, SA Medical Research Council, National Institutes for Health, AIDS Fonds, Unitaid, Foundation for Innovative New Diagnostics and the Children's Investment Fund Foundation, has recently received funding from USAID, and receives drug donations from ViiV Healthcare, Merck and Gilead Sciences for investigator-led clinical studies. The unit does investigator-led studies with Merck and ViiV providing financial support and is doing commercial drug studies for Merck. The unit performs evaluations of diagnostic devices for multiple biotech companies. Individually, he receives honoraria for educational talks and advisory board membership for Gilead, ViiV, Mylan, Merck, Adcock-Ingram, Aspen, Abbott, Roche, J&J, Sanofi and Virology Education.

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Celicia Serenata deceased.

Keywords:

Treatment optimisation; antiretrovirals; toxicity; potency; dosing

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.