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EDITORIAL REVIEW

The transition to dolutegravir and other new antiretrovirals in low-income and middle-income countries

what are the issues?

Vitoria, Marcoa,*; Hill, Andrewb,*; Ford, Nathana; Doherty, Mega; Clayden, Pollyc; Venter, Francoisd; Ripin, Davide; Flexner, Charlesf; Domanico, Paul L.e

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doi: 10.1097/QAD.0000000000001845
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Abstract

Introduction

There have been major improvements in antiretroviral therapy (ART) over the past decade. For first-line treatment, nucleoside analogues (NRTIs) with long-term toxicities such as stavudine (d4T) and zidovudine (ZDV) have been replaced by tenofovir disoproxil fumarate (TDF), and the nonnucleoside nevirapine (NVP) has been replaced by efavirenz (EFV) [1]. Randomized trials have shown a slightly improved safety profile for a 400 mg once daily dose of EFV compared with the standard 600 mg dose [2,3]. The pro-drug tenofovir alafenamide (TAF) has a lower daily dose than the original form tenofovir disoproxil fumarate (TDF), which could help to lower costs of mass production of antiretrovirals [2,3].

More recently, the integrase inhibitor dolutegravir (DTG) has been introduced as an alternative for EFV in first-line treatment. Guidelines from high-income countries recommend DTG as the preferred first-line agent [1,4–6], based on favourable results from the Phase 3 clinical trial programme (Table 1). Generic versions of DTG are being introduced into low and middle-income countries (LMICs) [7]. A triple fixed-dose combination of TDF, lamivudine (3TC) and DTG (TDF/3TC/DTG) is becoming available in several LMICs, manufactured by generic producers, at a median price of US$ 75 per person-year. This will make DTG more affordable than first-line EFV-containing regimens [8,9]. Another triple fixed-dose combination tablet of TAF/3TC/DTG was given Food and Drug Administration (FDA) prequalification status in February 2018 [10].

Table 1
Table 1:
Key randomized clinical trials evaluating new antiretrovirals.

As of November 2017, almost 60 LMICs have adopted or are planning to incorporate DTG into their national treatment guidelines: Brazil, Botswana, Kenya and Uganda have already started treating patients with DTG [7]. The Presidents Emergency Plan for AIDS Relief (PEPFAR) has recommended rapid introduction of TDF/3TC/DTG in their priority countries [11]; PEPFAR will soon stop procurement of EFV-based treatment. Forecasts suggest that approximately 15 million people will be taking TDF/3TC/DTG by 2021, progressively replacing first-line EFV-containing regimens [2].

Current WHO treatment guidelines in 2016 still recommended first-line treatment with TDF/3TC/EFV600 as the preferred choice, with DTG as an alternative [1]. TAF is not currently recommended by WHO because of unclear efficacy or safety benefits over TDF, and concerns over limited clinical experience when used in pregnancy or with rifampicin-based TB treatment [12]. Widespread use of TDF/3TC/DTG and other new antiretroviral drugs like TAF and DRV/r could lower unit costs of ART and enhance treatment coverage capacity [7]. To support the use of TDF/FTC/DTG in mass treatment programmes, several clinical trials will assess the pharmacokinetics, efficacy and safety of these new antiretroviral drugs in pregnant/breastfeeding women and TB co-infection, and to compare DTG with EFV, as well as TDF with the newer tenofovir prodrug, tenofovir alafenamide (TAF) in LMICs. However, as shown in Table 1, most of these randomized trials will not generate results until 2019–2020. By then, several million people will already have been started on or switched to DTG and other new antiretrovirals.

There are other, newer antiretrovirals to be approved in North America and Europe in 2018 – for example, bictegravir (BIC), doravirine and ibalizumab [13]. New long-acting formulations of cabotegravir and rilpivirine could also be approved by 2020 [13]. This review article first describes the evidence currently available to guide the transition to TDF/3TC/DTG in LMICs. Given the experience from the roll-out of TDF/3TC/DTG, the implications for development of other, newer antitretrovirals (ARVs) are discussed. These issues were discussed at the Third Conference on Antiretroviral Drug Optimisation (CADO-3) held in Johannesburg in November 2017.

Use of tenofovir/lamivudine/dolutegravir in first-line treatment

The efficacy of DTG has been established in studies of naïve and pretreated patients, compared with EFV in the SINGLE study [14], atazanavir/ritonavir (ATV/r) in the ARIA study [15], darunavir/ritonavir (DRV/r) in the FLAMINGO study [16], raltegravir (RAL) in the SPRING-2 study [17] and BIC in the Gilead 1489 and 1490 studies [18,19]. Summary efficacy and safety results are shown in Table 2. In these studies, DTG showed an improved safety profile compared with EFV and protease inhibitors, with a similar safety profile to RAL and BIC.

Table 2
Table 2:
Phase 3 randomized clinical trials of dolutegravir.

In the clinical development programme for DTG, including over 3000 patients, drug resistance to integrase inhibitors has been observed in only one patient who took DTG as first-line treatment with two nucleoside analogues [20]. This and other data [21] suggests that DTG has a high barrier to the development of drug resistance. However, all of the studies of first-line DTG involved screening tests for genotypic resistance: only the patients with no drug resistance were eligible to receive randomized treatment. In countries where the prevalence of transmitted resistance to nonnucleosides (NNRTIs) is already high, DTG might be a preferable first-line option to EFV [22]. This prediction needs to be validated in prospective randomized trials comparing first-line DTG with EFV in patients with a wider range of HIV sub-types, and who have not been tested for drug resistance before starting treatment. Reductions in HIV RNA might be slower for patients with certain HIV non-B subtypes of HIV [23]; there may be different risks of emergence of resistance to DTG in non-B subtypes [24].

Safety of dolutegravir in clinical trials and cohort studies

Table 2 shows the percentage of patients who discontinued for adverse events on DTG or control treatments in randomized Phase 3 trials. For studies of first-line treatment, rates of discontinuation tended to be lower for DTG compared with either EFV, DRV/r or ATV/r; these rates were similar when comparing DTG to other integrase inhibitors – RAL or BIC.

In a meta-analysis of selected safety endpoints in the Phase 3 trials, there was no significant increase in the risks of cardiovascular events or suicide-related adverse events for DTG-containing regimens compared with other antiretrovirals; however, there was a slight increase in the risk of insomnia associated with DTG [25]. Increased risks of central nervous system (CNS) adverse events for DTG have also been seen in nonrandomized cohort studies [26–28], but these effects might be confounded by channeling or other biases [29].

In observational cohort studies, integrase inhibitors have been associated with higher risks of immune reconstitution syndrome (IRIS) [30,31], but this effect has not been confirmed in randomized trials. For example, in the REALITY trial, 1805 highly immunosuppressed treatment-naive patients in sub-Saharan Africa were randomized to NNRTI-based triple therapy with or without additional 12 weeks of raltegravir. The treatment arm given raltegravir showed more rapid declines in HIV RNA to Week 12, but the percentage of patients developing IRIS was 9.9% in the raltegravir arm versus 9.5% in the control arm. [32].

Key ongoing clinical studies of first-line treatment with DTG are shown in Table 1. The ADVANCE [33] and NAMSAL [34] trials are evaluating the use of first-line ART containing DTG versus EFV in sub-Saharan Africa, including patients with low CD4+ cell counts (Table 1). These studies, and ADVANZ-4 [28] (recruiting treatment-naive patients with low baseline CD4+ counts) could improve our knowledge about the risk of IRIS on DTG at low CD4+ cell counts, the efficacy of first-line DTG in patients with transmitted drug resistance and overall drug safety in an African population. Continued pharmacovigilance is important, with larger safety databases; safety signals are often not detected until several years after drugs have been approved. The pharmacokinetic concentration of DTG can be higher in women and people with low body weight [36], so the safety profile of DTG needs to be evaluated in a wider range of patients, beyond standard Phase 3 studies.

The safety of DTG has been evaluated in several observational studies of pregnant women, with no clear evidence of increases in adverse birth outcomes or congenital anomalies when DTG-containing regimens were started during pregnancy [3,37]. However, information on pregnancy safety in women with preconception exposure to DTG are still limited. The investigator of an independent NIH-funded study has identified a potential safety issue DTG), related to neural tube defects in infants born to women who were taking DTG at the time of conception. The issue has been identified from a preliminary unscheduled analysis of an ongoing observational study in Botswana, which has found 4 cases of neural tube defects out of 426 women who became pregnant while taking DTG. This rate of approximately 0.9% compares to a 0.1% risk of neural tube defects in infants born to women taking other antiretroviral medicines at the time of conception [38]. This potential safety signal has led regulatory authorities in Europe and USA to recommend that women of child-bearing potential avoid the use of dolutegravir unless consistent contraception can be assured. A coordinated review and follow up of this safety issue is in progress, including analysis of birth outcomes for dolutegravir and other integrase inhibitors in randomised trials, other observational studies and pharmacovigilance databases. Results from this integrated analysis are expected in 2Q2019. Guidelines from the United States Department of Health and Human Services (DHHS) were updated in October 2017, to recommend DTG for use in pregnant women, as an alternative to RAL [39]. The VESTED [40] and DOLPHIN [41] studies will provide more evidence for efficacy and safety of DTG in pregnant women by mid-2019 (Table 1).

Dolutegravir in tuberculosis co-infection

The main clinical trials of DTG have excluded people with TB−HIV co-infection requiring rifampicin-based treatment. There is a drug interaction between DTG and rifampicin (RIF), which requires an increase in the dose of DTG to 50 mg twice daily [42]. The complexity of doubling the dose of DTG when using RIF could create programmatic challenges in some countries. In the INSPIRING study [43], DTG 50 mg twice daily was compared with EFV in 113 treatment-naive TB−HIV co-infected patients receiving RIF-based treatment for TB (Table 2). The percentage of patients with HIV RNA suppression less than 50 copies/ml to Week 24 was 81% for DTG versus 89% for EFV. The INSPIRING study is too small to demonstrate noninferior efficacy for DTG and EFV in co-infected patients, and patients with baseline CD4+ counts below 50 cells/μl were excluded. However, there was no increase in the risk of IRIS in the DTG arm. The pharmacokinetics of DTG 50 mg twice daily with RIF in the study were similar to DTG 50 mg once daily without RIF [43].

There are also pharmacokinetic studies in progress to analyse the drug interaction between DTG and other treatments for TB in HIV−TB co-infected patients. Rifabutin lowers DTG Cmin by 30% but does not significantly change the AUC or Cmax. On the basis of these data, rifabutin and DTG can be co-administered at standard doses [42]. There is a potential safety issue when dolutegravir is used with rifapentine – a previous clinical pharmacology study in healthy volunteers had to be stopped early because of serious safety issues [44]. A follow-up study is being set up to investigate this issue further.

Use of tenofovir/lamivudine/dolutegravir as a switching option

Results from two pharmacokinetic studies suggest that people with undetectable HIV RNA levels can be safely switched from EFV to DTG – as pharmacokinetic concentrations of EFV fall, there are gradual rises in DTG concentrations. However, DTG concentrations are slightly below normal levels for the first 2 weeks of dosing [45,46]. This might be an issue for people switching from TDF/XTC/EFV to TDF/XTC/DTG, if they already harbour NRTI drug resistance (XTC = 3TC or FTC).

As shown in Table 2, there have been four large randomized studies evaluating the switch to DTG in patients with undetectable HIV RNA levels – STRIIVING [47], SWORD 1 [48], SWORD 2 [48], and NEAT 022 [49]. In these studies, patients were randomized to switch to DTG (in combination with other antiretrovirals) or remain on their current treatment. Across these studies, there have been more adverse events and more discontinuations for adverse events among the patients who switched to DTG (Table 2). Rate of HIV RNA suppression less than 50 copies/ml have been equivalent for the DTG and control arms. These results suggest that a switch to DTG should maintain HIV RNA suppression. However, the switch to DTG will not necessarily improve overall patient safety.

Notwithstanding this evidence, there might be other programmatic benefits from large-scale switching of patients with undetectable viral load to TDF/3TC/DTG, such as simplicity of supply chains, cost-savings or lower risks of stock-outs. These potential benefits need to be set against increased risks of adverse events for patients who are currently tolerating their existing treatments, switching to DTG.

Dolutegravir and lamivudine as a first-line dual therapy

Results from a pilot study suggest that first-line dual therapy with DTG and 3TC could achieve high levels of HIV RNA suppression for patients with no transmitted drug resistance [50]. The GEMINI 1 and 2 studies [51,52] are comparing first-line treatment with DTG and 3TC and TDF/FTC/DTG in 1400 treatment-naïve patients, with results expected in mid-2018. Even if DTG and 3TC shows similar efficacy to TDF/FTC/DTG in these studies, there would need to be substantial additional research before the DTG and 3TC dual combination could be implemented in LMICs. For example, the GEMINI studies excluded patients with NRTI resistance, pregnant women, rifampicin-based treatment for TB, and hepatitis B virus (HBV) co-infection [51,52].

The GEMINI trials would need to be repeated without resistance testing, as this is rarely used in most LMICs. Patients with transmitted NRTI drug resistance might not show HIV RNA suppression on dual therapy with DTG and 3TC. In addition, the prevalence of HBV infection is high in sub-Saharan Africa, ranging from 6.5% in Zambia to 25% in Zimbabwe [53]. Combinations of DTG and 3TC would not optimally suppress HBV DNA replication and could lead to the development of HBV drug resistance.

In practical terms, the benefits of dual therapy in LMICs must be balanced across several factors where the programmatic complexities and risks associated with this approach could outweigh the potential benefits. DTG and 3TC should be slightly cheaper to produce TAF/3TC/DTG, but only by $10−$20 per person-year in LMICs [2]. This difference is small compared with the overall cost of patient management. A more cost-effective approach might be to optimize treatment monitoring and management of stable patients. Dual therapy may show improved safety over triple therapy. However, in a low-resource setting, if adherence to treatment was only moderate, the simpler regimen may show a lower barrier to development of resistance. Additional training would be required to select the right patients for dual therapy initiation, for managing care and for switching patients off dual therapy after virological failure.

Tenofovir/lamivudine/dolutegravir in second-line treatment

World Health Organization (WHO) currently recommends second-line treatment with two nucleoside analogues (NRTIs) and a boosted protease inhibitor [1]; most international guidelines recommend DRV/r as the preferred boosted protease inhibitor [4–6]. There is evidence for widespread resistance to NRTIs after virological failure of first-line treatment in LMICs, which might be expected to limit future treatment options [54]. However, in several large studies of second-line treatment, patients with no predicted activity from NRTIs still show HIV RNA suppression rates while taking combinations of 2NRTIs with a boosted protease inhibitor (PI/r) [55,56]. Summary results are shown in Table 3. These results suggest that NRTIs retain high levels of efficacy in second-line protease inhibitor-based treatment, despite the predictions of failure from genotypic resistance tests. The results question whether genotypic resistance tests are the most appropriate predictive measure of drug efficacy.

Table 3
Table 3:
HIV RNA suppression rates by genotypic sensitivity score (GSS) for nucleoside reverse transcriptase inhibitors, in four randomized trials of second-line treatment.

The DAWNING study compared the second-line combination of two NRTIs and DTG with two NRTIs with lopinavir/ritonavir (LPV/r) [57]. In DAWNING, patients were genotyped at screening, and only patients with at least one NRTI with predicted sensitivity were included. The DAWNING study was stopped early after the two NRTI and DTG arm showed viral suppression rates higher than the control arm (82 versus 69% at Week 24, P < 0.001). Patients in the DAWNING study treated with one NRTI predicted to be fully active had higher rates of suppression compared with those whose genotypic resistance test results showed full NRTI activity – consistent again with studies of protease inhibitor-based treatment (Table 3).

There are two key unanswered questions relationg to the use of TDF/3TC/DTG in second-line treatment. First, the DAWNING study excluded patients with no active NRTIs at baseline, so it is unknown whether the high efficacy of NRTIs combined with protease inhibitors will be seen when NRTIs are combined with DTG. Second, a high percentage of patients in LMICs will be taking TDF/3TC/EFV first-line, so switching to TDF/3TC/DTG second-line will involve changing only one antiretroviral (i.e. EFV is replaced with DTG), with TDF/XTC remaining constant; the efficacy of NRTIs in this situation is unclear. In the DAWNING study, the majority of patients switched their NRTIs at randomization. Patients who switched their NRTIs at randomization in the DAWNING study showed the highest rates of HIV RNA suppression [58]. So the results from this study do not provide evidence on potential outcomes of a switch from TDF/XTC/EFV to TDF/XTC/DTG.

A recent analysis of observational studies suggested that patients switching their NRTIs at the time of starting second-line protease inhibitor-based treatment had higher HIV RNA suppression rates than patients maintaining the NRTIs used in first-line treatment [59]. These results suggest that patients could switch from TDF to ZDV whenever switching from EFV to DTG. Patients with virological failure on TDF-based treatment are unlikely to have cross-resistance to ZDV, so they are likely to have at least one active NRTI, which is consistent with the inclusion criteria for the DAWNING study. In both the cohort study and DAWNING, patients were not randomized to switch their NRTIs versus remain on their original NRTIs, so there is the potential for bias in the current results. In addition, switching from TDF to ZDV results in a higher risk of adverse events such as anaemia, neutropenia, lipoatrophy; does not protect patients co-infected with HBV co-infection, requires twice daily dosing and higher daily pill counts.

Testing for drug resistance is rarely used in most LMICs and there are many countries in sub-Saharan Africa with little or no access to viral load. So, if we do not know whether patients with detectable viral load can be safely switched from TDF/3TC/EFV to TDF/3TC/DTG, then patients with no viral load results available would be in a similar situation. There are approximately 16 million people taking NNRTI-based treatment in LMICs, of whom only approximately 50% (8 million people) have had a viral load test within the past 12 months [50]. Of the 8 million people with viral load test results, if we assume that 88% of people on NNRTI-based treatment have undetectable levels (consistent with results from clinical trials), then 7 million people in LMICs would have known undetectable levels and so could be switched to TDF/3TC/DTG based on current evidence. However, for the 9 million people with either detectable or unknown HIV RNA levels, follow-up viral load could be used after switching from TDF/3TC/EFV to TDF/3TC/DTG, to monitor long-term suppression of HIV RNA.

Recommended research priorities for dolutegravir

As shown in Table 2, starting patients on first-line TDF/3TC/DTG is supported by results from several randomized Phase 3 trials. Switching patients with viral load suppression from TDF/3TC/EFV to TDF/3TC/DTG can maintain HIV RNA suppression, albeit with no clear evidence for safety benefits. The problem arises with patients who either have known virological failure on TDF/3TC/EFV, or who do not have access to viral load testing. The DAWNING study results only provide partial support for use of TDF/3TC/DTG in second-line treatment: the patients in DAWNING typically switched their NRTIs when starting DTG, and they all had at least one active NRTI predicted by genotypic resistance testing. Many LMICs have little access to routine viral load monitoring, and almost no access to resistance testing.

The two main questions about transition to TDF/3TC/DTG are can people with no predicted sensitivity to NRTIs achieve higher rates of HIV RNA suppression on second-line treatment with DTG, or are boosted protease inhibitors required; and must people with virological failure on TDF-based first-line treatment switch to ZDV, or can they remain on TDF?

To answer these two questions, two randomized clinical trials are being set up, with summary designs shown in Table 1. In the NADIA trial, 440 patients with prior virological failure on NNRTI-based treatment will be randomized to second-line treatment with two NRTIs and either DTG or DRV/r. Patients will also be randomized to either switch their NRTIs at baseline, or to use TDF/FTC. Forty-eight weeks results are expected by 4Q 2020. In the D2EFT trial [60], 1000 patients with prior virological failure on first-line NNRTI-based treatment will be randomized to either TDF/FTC/DTG, DRV/r with DTG or the control arm of two NRTIs with DRV/r. There will be an interim analysis in July 2019, to assess whether the TDF/FTC/DTG arm is showing expected levels of efficacy. Final results are expected in December 2020. In meta-analyses, combinations of protease inhibitors with the integrase inhibitor RAL showed significantly lower efficacy than standard triple combinations of NRTIs with either a protease inhibitor or NNRTI, for first-line and second-line treatment [55,61]. The D2EFT study might show a different result for the combination of DTG with DRV/r.

Countries and donors may decide to switch patients from NNRTI-based treatment to TDF/FTC/DTG before the results from the NADIA and D2EFT studies become available. In the interim, HIV RNA suppression rates should be evaluated for patients switched from TDF/3TC/EFV to TDF/3TC/DTG within country-level treatment programmes, using standardized methods of prospective data collection and statistical analysis,so that results can be compared across settings. HIV RNA suppression rates should be evaluated for at least 800 patients with prior virological failure, switching to TDF/3TC/DTG with an NRTI Genotypic Sensitivity Score (GSS) of 0, 1 and 2.

Implications for other emerging antiretrovirals

As discussed above, there is substantial additional research required to evaluate an antiretroviral for widespread use in LMIC access programmes. This will be important for new antiretroviral treatments in development. For example, results from two clinical pharmacology studies in healthy volunteers suggest that TAF could be dosed at 25 mg once daily with RIF [62,63]. Summary results are shown in Table 4. In both studies, the concentrations of tenofovir diphosphate for TAF used with RIF were higher than a reference group taking standard TDF. These pharmacokinetic results need to be confirmed in new studies of HIV-positive people. A new co-formulated tablet of TAF/3TC/DTG may soon be introduced into LMICs. More data on TAF in pregnancy and with RIF-based treatment for TB is required to support the widespread use of this combination. As shown in Table 5, the data on pregnancy should be available by mid-2019, but plans to evaluate TAF with RIF-based treatment in HIV−TB co-infected patients have not yet been finalized. The integrase inhibitor bictegravir has a strong interaction with RIF, which cannot be reversed adequately by an increase in dose [64]. This limits the usefulness of bictegravir in large-scale HIV treatment programs in LMICs. By contrast, the new 400 mg dose of efavirenz does not show a significant drug interaction with rifampicin (Table 5), and could be given in combination without dose adjustment [67].

Table 4
Table 4:
Availability of data to support use of new antiretrovirals in low-income and middle-income countries.
Table 5
Table 5:
Effects of rifampicin on new antiretrovirals.

Darunavir/ritonavir (DRV/r) holds great promise for second-line treatment in LMIC. A heat stable co-formulation of DRV/r (400 mg/50 mg) is in late-stage product development and should be available in late 2018 [2]. Furthermore, the WHRI 052 study is evaluating a switch from LPV/r to a lower dose of DRV/r 400/100 mg once daily for 300 patients on second-line treatment with HIV RNA suppression [65], with results expected in late 2018. If successful, the results could justify widespread switching to the lower dose of DRV/r for people with HIV RNA suppression. However, it will be important to launch additional studies to evaluate DRV/r (400/100) in people who fail first-line treatment and are not virologically suppressed. Positive results from new studies could make DRV/r price-competitive with generic LPV/r and ATV/r while avoiding their adverse events.

Conclusion

  1. The conventional programmes of phase 3 randomized trials for registration purposes do not provide sufficient evidence to support the widespread use of new antiretrovirals in LMICs, where the HIV epidemic is most prevalent.
  2. For DTG, we urgently need results from new clinical trials to evaluate the transition from TDF/3TC/EFV to TDF/3TC/DTG to ensure safety and efficacy for the nearly 9 million people on NNRTI-based ART in LMICs who have either detectable or unknown HIV RNA levels.
  3. More research is needed on the use of TAF in pregnant women and people with HIV−TB coinfection taking RIF-based treatment to justify widespread use of the new TAF/3TC/DTG combination in LMICs.
  4. Dual therapy with DTG/3TC might show noninferior efficacy to triple therapy in randomized phase 3 GEMINI trials in late 2018, but the overall disadvantages of this approach appear to outweigh the advantages for patients in the setting of LMICs.
  5. Key missing evidence is typically for pregnant women, HIVTB coinfected people and for people who have not been evaluated for drug resistance before starting their antiretroviral treatment. Efforts are needed to design and perform these studies earlier, so that results can support rapid expansion of new treatments in LMICs.

Acknowledgements

We thank the 76 invitees to the third Conference on Antiretroviral Drug Optimization (CADO3) that was held from 29 November to 1 December 2017 in Johannesburg, South Africa. Collectively, they represent broad expertise in the following areas of HIV care: academia, nongovernmental organizations, country program managers, and community representatives and various regulatory agencies around the world. Their comments and feedback formed the basis for this article. We also thank Jacob Levi and Sophie Hughes for help with the preparation of the Tables and Figures.

Conflicts of interest

There are no conflicts of interest.

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    * Marco Vitoria and Andrew Hill contributed equally to this manuscript.

    Keywords:

    dolutegravir; drug resistance; efavirenz; lamivudine; nucleoside analogues; tenofovir; zidovudine

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