Table 2.
Description of the findings reported in eligible studies
| References | Country/year | Review type | Study population | Articles included | Type of ART | Implications for drug resistance | Virologic Failure risk factors | Main findings |
|---|---|---|---|---|---|---|---|---|
| [30] | USA/2023 | Critical review | NR | 94 |
-PI -NNRTIs - INSTIs -Fusion inhibitors -CCR5 inhibitors -post attachment inhibitors -attachment inhibitors |
A substantial risk of resistance selection may accompany treatment regimens combining long-acting injectable medications and conventional oral medications | – | |
| [31] | Ethiopia/2022 | Systematic Review and Meta‐Analysis | 6638 | 18 | NR | – |
-Lower ART adherence -Longer ART duration -Lower CD4 count -Co-infection with TB |
– |
| [32] | Brazil/2018 | Systematic Review and Meta‐Analysis | 18,010 | 38 | NR | – | – | Self-report measures of adherence can predict virologic failure as well as or better than objective measures like pharmacy refills, electronic monitoring, physician assessment, and pill count. Combining different metrics did not improve the predictive value, comparatively to any single measure |
| [33] | South Africa/2020 | literature review | N = NR (adolescents with PHIV) | 34 | NR | As ART was continued longer, the risk of resistance increased. In both high-income and low- and middle-income nations, there is a high occurrence of multi-drug resistance |
-Higher viral load (> 1 million copies/ml) at ART initiation -lower CD4 percentage at ART initiation -lower current CD4 levels -lower CDC staging -pre-adolescent viral failure -prior exposure to PMTCT regimens -prior non-combination ART -increased number of prior ART regimens -receiving second-line regimens -use of nevirapine versus lopinavir with ritonavir -use of nevirapine versus efavirenz -use of ritonavir as a single PI |
- 90% of children whose first-line ART had failed showed mutations related to resistance |
| [34] | South Africa/2022 | Systematic Review and Meta‐Analysis | 14189 | 36 | NR | – | – | In Sub-Saharan Africa, the CD4 cell count at the time of virologic failure identification and at second-line ART switch has not significantly changed over the course of more than ten years. Besides, the time between virologic failure and second-line ART initiation is about 530 days, far longer than what is recommended by international standards |
| [35] | Switzerland/2020 | Systematic Review and Meta‐Analysis | 31441 | 32 | NNRTIs | NNRTI-based first-line ART with PDR was associated with new resistance mutations | - NNRTI-based first-line ART with PDR | The incidence of virological failure was tripled in those with PDR, and the clinical impact was considerably greater in those with NNRTI-PDR |
| [36] | Australia/2016 | Systematic Review and Meta‐Analysis | 27905 | 43 |
-NNRTI -Boosted-PIs -Unboosted-PIs |
– | −Suboptimal drug adherence | Optimal adherence to ART is related to favorable clinical outcomes, regardless of the threshold for such adherence. Adherence levels for adequate virologic outcomes appear to be lower than the conventionally accepted cut-off point (95% adherence) |
| [37] | Spain/ 2018 | literature review | NR | 8 | DTG | DTG monotherapy is associated with the occurrence of drug resistance | – | DTG's robustness, defined as the absence of resistance selection following virological failure, is undisputed when combined with other active drugs in triple or even dual therapy |
| [38] | Denmark/2016 | Systematic Review and Meta‐Analysis | 9047 | 39 |
- NNRTI - PI/r |
– | - NNRTI regimens specifically those based on NVP | PI/r poses a lesser probability of viral resistance emerging than NNRTI and according to analyses limited to trials with EFV as the third medication, NNRTI-based combination ART appeared to be linked with a slenderly decreased risk of discontinuation due to virologic failure |
| [39] | UK/2020 | A Review of Published Cases | NR (INSTI-Naïve Patients on First-line or Second-line ART) | 8 | DTG | Emergent drug resistance can occur even in highly resistant regimens like those containing DTG due to reasons such as poor medication adherence and HIV disease factors particularly high baseline viral load and active co-infections | – | – |
| [40] | Italy/2019 | Systematic Review and Meta‐Analysis | 6407 | 7 | DTG and non- DTG containing ART, in combination with 2 NRTIs | Prolonged exposure to RAL or EVG in the case of treatment failure, can lead to cross-resistance to DTG and BIC | – | Compared to RAL and EVG, DTG and BIC have a stronger barrier to resistance. NRTIs in combination with DTG or BIC in the initial triple-drug ART regimen did not accompany drug resistance, and only rarely has Dolutegravir resistance been observed in patients who have previously received treatment |
| [41] | Brazil/2015 | literature review | N = NR (adolescents with PHIV) | 64 | NR | The difficulty in maintaining treatment compliance throughout childhood contributes to the establishment of resistance-associated mutations in the HIV virus | – | In 42% of the sexually active adolescents with PHIV, the viral load exceeded 5000 copies/mL, and practically all of these patients had mutations linked to resistance |
| [42] | Brazil/2023 | Systematic Review | N = NR (adolescents and young adults living with HIV) | 31 | NR | - |
-low CD4 levels -substance misuse -alcohol use -low education level -poor adherence to medications -missing doses of ART due to forgetfulness |
– |
| [43] | South Africa/ 2018 | literature review | NR | NR | NR | DTG as monotherapy is related to high risk of developing drug resistance | DTG monotherapy | Due to the high prevalence of pretreatment NNRTIs resistance mutations in sub-Saharan Africa, Dolutegravir-based first-line ART has been implemented and it appears to be particularly effective in both ART-naïve and ART-experienced patients if it is coupled with a strong NRTIs foundation |
| [44] | Canada/2020 | Systematic Review | 18985 | 28 |
- NNRTIs - NRTIs - PIs |
The most common resistance mutations included the M1841/V for the NRTIs and K103N, and Y181 for the NNRTIs |
-pre-ART CD4 < 200 cell/μl -low adherence |
It is recommended that alternate ART regimens be taken into consideration given the rise of NRTIs and NNRTIs resistance mutations |
| [45] | Ethiopia/ 2019 | Systematic Review and Meta‐Analysis | 18550 (participants receiving second-line HIV treatment) | 33 | - PIs with or without ritonavir boost | – |
- Poor adherence -higher baseline viral load -lower CD4 cell counts -more advanced WHO clinical stages |
Failure rates were higher among children, in the southern area of sub-Saharan Africa, and between 12 and 18 months after treatment started |
| [46] | China/2019 | Systematic Review and Meta‐Analysis | 4251 | 12 | quadruple and triple cART | Adding a fourth drug to first-line treatment might lead to lower adherence to treatment and consequently drug resistance and treatment failure | – | The effects of quadruple cART were not better than standard triple cART for first-line treatment of PWH |
| [47] | UK/2023 | Systematic Review | 369 | 5 |
- BIC/FTC/TAF - DTG/3TC - DTG/RPV |
The dual ART regiments showed less drug resistance occurrence than triple therapy | – | The regimen based on dual antiviral drugs is less toxic than triple therapy and has more adherence to treatment, effectiveness in achieving or maintaining viral suppression, and as a result, it has less drug resistance than TT |
| [48] | China/2021 | Systematic Review and Meta‐Analysis | 3558 | 12 |
- NNRTIs - INIs |
Prevalence of drug resistance to NNRTIs is the highest, while the drug resistance to INIs is the lowest. This may guide the selection of clinical antiretroviral drugs |
– | The prevalence of drug resistance in naive people with acute HIV infection, primary HIV infection and early HIV infection is moderate and it is necessary to identify the drug resistance in developing and advanced countries before starting retroviral drugs |
| [49] | UK/2001–2016 | Systematic review and meta-regression analysis | 56044 | 358 datasets |
- NNRTIs - NRTIs |
Drug resistance in NNRTI regimen was significantly higher than NRTI regimen | – | Pre-treatment drug resistance is increasing significantly in low- and middle-income countries, specifically resistance to NNRTIs has approached the 10% WHO threshold for first-line switching |
| [50] | Switzerland/ 2022 | Systematic Review | 2690 | 19 |
- NNRTIs - NRTIs |
The K65N/R gene mutation rise as a result of adding TDF to NRTI after two years, increasing drug resistance to NRTIs | – | NRTI/NNRTI drug resistance mutations are common in patients failing first-line ART in South Africa. These patients may be switched to a DTG-based regimen with compromised NRTIs, which can impair the long-term efficacy of ART |
| [51] | China/2018 | Systematic Review and Meta‐Analysis | 3773 | 9 | LPV/r-based second-line ART | LPV/r-based regimen significantly induces viral suppression and decreases drug resistance in patients with first-line virologic failure and drug resistance | – | The use of LPV/r therapy has significant efficacy in patients who have failed first-line antiretroviral therapy |
| [52] | Lebanon/2015 | literature review | NR | NR | -Complera (RPV/FTC/TDF) | drug resistance was higher with RPV, especially in patients with baseline viral load > 100,000 copies/mL | viral load > 100,000 copies/mL | Complera is a recommended alternative treatment in ART naïve patients who have a pre-ART plasma HIV RNA < 100,000 copies/mL and CD4 count > 200 cells/mm3 |
| [53] | Canada/2015 | literature review | NR | NR | DTG | In patients who used DTG as a first-line drug, no cases of drug resistance and virological failure were observed | – | DTG is an effective antiretroviral agent for both treatment-naïve and treatment-experienced patients infected with HIV |
| [54] | India/2018 | Systematic Review | 3353 | 23 |
- NNRTIs -NRTIs |
K65R and 103N were the only NRTI and NNRTI mutations, respectively | – | Complications of resistance against drugs in the first-line regimen remained steady over the 10-year period. However, periodic monitoring is required |
| [55] | Ethiopia /2018 | Systematic Review and Meta‐Analysis | 28149 | 17 |
-TDF based-Regimens - ZDV based-Regimens |
– | Virologic failure was significantly observed in patients treated with ZDV compared to those treated with TDF | Regimens based on ZDV are more effective in preventing death and suppressing viral load in infected patients. However, TDF-based regimens were better in terms of safety and tolerance |
| [56] | Spain/2018 | Systematic Review | 6175 | 14 |
- NNRTIs - NRTIs -PI -INSTIs |
The increase of K65N/R gene mutation was observed as a result of drug resistance | – | Because standard definitions of virologic failure and resistance testing criteria do not exist in pivotal phase III RCTs of first-line ART, there is a possibility of underreporting of resistance mutations, particularly when genotyping is performed only at higher viral load cutoffs |
| [57] | Canada/2016 | Systematic Review and Meta‐Analysis | 3278 | 12 |
-NVP -EFV |
Development of drug resistance is probably less in the EFV than NVP | – | EFV- and NVP-based regimens are both equally effective in viral suppression, preventing disease progression, and reducing mortality. EFV affects the mental performance of patients more. While NVP causes more liver damage, decreased white blood cells and rashes |
| [58] | Switzerland/2020 | Systematic Review | 1148 | 92 |
-NNRTIs -NRTIs -PIs -INSTIs |
The relevance of drug resistance will depend on the prevalence of transmitted INSTI resistance, which remains low but may increase in the future; and the overall genetic barrier of INSTI regimens | – | There is a considerable range in the lower limit of detection of low-abundance drug-resistant human immunodeficiency virus-1 variants for different assays, from < 0.01% as seen with AS-PCR to 1%–5% for ultradeep sequencing assays and other methods |
| [59] | USA/2022 | literature review | NR | 2 | DTG | The DTG-containing regimens have low resistance and virologic failure |
-poor adherence -PDR |
– |
| [60] | India/2021 | Systematic Review | NR | 46 |
-NNRTIs -NRTIs -PIs -INIs -fusion and CCR5 inhibitors |
A combinatorial drug delivery approach using nanocarriers has the potential to reduce the emergence of drug-induced resistance | – | The combinational medication delivery method for HIV infection may provide a more effective therapeutic response compared to traditional HAART therapy and single drug-loaded nanoformulation |
| [61] | Italy/2015 | State-of-the-art review | NR | NR | Dual therapy | – |
- HIV/RNA levels > 100,000 copies/ml -CD4 levels < 200/mmc. |
Dual ART is typically less effective than suggested triple regimens. As a result, this strategy should only be used cautiously in individuals who are ARV-naive and not openly recommended |
| [62] | UK/2021 | Systematic Review | 5017 | 73 | DTG + 3TC | Dual therapy of DTG plus 3TC has long-lasting efficacy and a high barrier to resistance | – | DTG + 3TC was effective at achieving and maintaining virologic suppression in a range of people with HIV, including those who were switching from three-drug regimens to two-drug regimens |
| [63] | Nigeria/2015 | literature review | 5541 | 99 |
- NNRTIs -NRTIs -PIs |
- HIV subtype diversity, patient adherence, drug stock-outs, counterfeit drugs, and lack of monitoring are specific risk factors related to drug resistance in resource-limited settings | – | HIV drug resistance prevalence in Africa is relatively high. Changing patterns of drug resistance over time, regular surveillance of ART resistance, and collecting drug resistance data for informed policies must be considered |
| [64] | Spain/2017 | literature review | NR | NR |
-NNRTIs -INSTIs -PIs |
As DRMVs impact treatment efficacy, particularly for drugs with a low genetic barrier to resistance like NNRTIs, DRMVs detection through sensitive techniques is essential | NNRTI-resistant DRMVs | The impact of DRMVs on INSTIs and PIs is less certain and requires further research |
| [65] | Romania/2023 | literature review | NR | NR |
- FTR -IBA -PRO 140 - ISL -LEN |
-Resistance to IBA is conferred by decreased viral expression of specific binding sites in the HIV gp120 envelope protein | – | - FTR as a long-acting CCR5 inhibitor is being considered as a life-saving option for patients with drug-resistant HIV |
| [66] | USA/2019 | Systematic Review | > 100,000 | 127 |
- NNRTIs - NRTIs |
The risk of 3TC- or RPV-resistant mutations in treatment-naive, HIV-1-infected individuals is low | – | The use of two-drug regimens such as DTG and 3TC (in treatment-naïve people) and DTG and RPV (in people who are virally suppressed in the 3-drug regimen and change to 2DR) is highly effective |
| [67] | South Africa/2017 | literature review | 614 | 5 | NNRTI | PDR, the timing of treatment onset, HIV subtype, antiretrovirals used in first- and second-line ART, viral load monitoring, and medication adherence are associated with the emergence of drug resistance | – | – |
| [68] | China/2022 | literature review | NR | NR | NR | -Higher CD4 T cell counts are associated with lower drug resistance and reduced viral loads | – | The mortality rate of patients developing drug-resistant HIV within 1 year after starting ART was 1.9 times higher than the mortality rate of those developing drug resistance at a later time point |
| [69] | China/2020 | Systematic Review and Meta‐Analysis | 21,451 ART-naïve and 30,475 ART-treated individuals with HIV-1 infection | 170 | 3TC and/or EFV or NVP | As NRTI-associated mutations (M184V/I) and NNRTI-associated mutations (K103N/S, Y181C/I and G190A/S) were responsible for most cases of acquired and transmitted drug resistance, the currently available first-line ART regimens containing 3TC and/or EFV or NVP should be urgently amended, or promptly switched to the second-line regimens | – | -Drug Resistance was rapidly rising in China in recent years (typically since 2012), and this rise was mainly driven by NNRTI resistance |
Antiretroviral therapy (ART), combination antiretroviral therapy (cART), Not reported (NR), people with HIV (PWH), Protease inhibitors (PIs), ritonavir-boosted protease inhibitors (PI/r), Non-nucleoside reverse transcriptase inhibitor (NNRTIs), Nucleoside reverse transcriptase inhibitor (NRTIs), Integrase strand transfer inhibitors (INSTIs), C–C motif chemokine receptor (CCR5), perinatally HIV-infected (PHIV), prevention of mother-to-child transmission (PMTCT), pretreatment human immunodeficiency virus drug resistance (PDR), Dolutegravir (DTG), Efavirenz (EFV), Nevirapine (NVP), raltegravir (RAL), elvitegravir (EVG), bictegravir (BIC), emtricitabine (FTC), tenofovir alafenamide (TAF), lamivudine (3TC), abacavir (ABC), tenofovir disoproxil fumarate (TDF), Rilvipirine (RPV), integrase inhibitors (INIs), Ritonavir-boosted lopinavir (LPV/r), Zidovudine (ZDV), allele-specific polymerase chain reaction (AS-PCR), drug-resistant minority variants (DRMVs), Fostemsavir (FTR), Ibalizumab (IBA), Leronlimab (PRO 140), Islatravir (ISL), Lenacapavir (LEN)