In this cohort of PWH in Liberia on ART during the rollout of InSTI-containing regimens, we found a higher prevalence of virus suppression (81%) than observed in a smaller group after the 2014 Ebola outbreak⁵. In our cohort, a lower percentage on a DTG-based regimen had virologic failure compared with those on EFV/NVP-based ART (5.3% v. 14%, respectively), likely reflecting the higher genetic barrier to resistance of this second generation InSTI compared to NNRTIs¹⁴. Our report, one of the few from West Africa, adds to a growing number suggesting a relatively high prevalence of virus suppression by DTG-containing regimens in sub-Saharan Africa^15,16,17,18.

In our cohort, 7.5% of ART recipients had pVL≥1000 copies/mL at their baseline visit. Younger age, lower CD4 count, longer time on ART, lower hemoglobin, and currently taking EFV, NVP, or AZT were associated with higher virologic failure risk. Lower CD4 count and longer ART duration were associated with virologic failure in a recent review of PWH in sub-Saharan Africa, which also identified sub-optimal adherence and tuberculosis co-infection as risk factors¹⁹. The association between younger age and virologic failure has been attributed to various factors, including reduced adherence and HIVDR related to significant ART experience in perinatally infected adolescents^20,21. Higher virologic failure risk in our participants with lower hemoglobin levels was consistent with the finding that anemia independently predicted increased odds of virologic failure at 72 weeks of ART in a Nigerian cohort²², and published associations between anemia and poor clinical outcomes, including HIV disease progression and increased mortality^23,24. In settings with limited access to pVL monitoring and GDR testing, these routinely measured variables might be useful as initial indicators of virologic failure to prompt closer monitoring and earlier assessment.

HIVDR was highly prevalent in those with virologic failure whose virus was successfully sequenced, with low- to high-level resistance to at least one ARV in 81%. This was mainly composed of resistance to NNRTIs (79%) and NRTIs (61%) or to both NRTIs and NNRTIs (60%). This was similar to the prevalence of drug resistance mutations in those receiving NNRTI-based ART in the only previous study of HIVDR in Liberia⁵, and in adults and children on ART from other countries in sub-Saharan Africa^{25,26,27,28,29,30}. Notably, our study is among the few in sub-Saharan Africa, and the largest to our knowledge in West Africa, to extend previous observations by also investigating resistance to InSTIs and PIs^25,29,30,31. In our participants with virologic failure, the prevalence of any resistance to InSTIs and PIs was low (5.7% and 7.1%, respectively), with much lower rates of resistance to DTG (2.9%) and LPV (5.7%), consistent with recent reports^25,29,30.

The prevalence of intermediate-high resistance to the NRTI backbone that the participants were currently taking was high. All 34 individuals (100%) with virologic failure on an NNRTI-based regimen had intermediate-high resistance to at least one drug in the regimen, and 27/34 (79%) had resistance to one or both NRTIs. A lower percentage of individuals with virologic failure on a DTG-based regimen had resistance (13/32, 41%), but all 13 had intermediate-high resistance to at least one drug in the NRTI backbone.

The prevalence of DTG resistance among participants with virologic failure on a DTG-containing regimen whose virus was successfully sequenced was low (2/32, 6.3%). These two InSTI+2NRTIs recipients had multi-class-resistant HIV with InSTI drug resistance mutations known to be selected by DTG and to impact virus susceptibility to DTG, including G118R, T66A, E138K, and R263K. Although one of these participants may represent a rare case of transmitted InSTI resistance, it is more likely that he did not disclose prior ARV exposure that had selected for resistance, as suggested by the detection of the NRTI and NNRTI drug resistance mutations. Thus, in our cohort, for those who had virologic failure while on DTG-based ART, NRTI resistance probably predated DTG exposure resulting in treatment with DTG + ≤1 NRTI. DTG functional monotherapy has been associated with faster progression to virologic failure, accumulation of more drug resistance mutations, and poor treatment outcome³¹.

In aggregate, our data support the evidence of other studies in sub-Saharan Africa regarding the benefit of fast-tracking the transition from NNRTI-based to DTG-based regimens². Our results also suggest there might be value in performing HIVDR testing in persistently viremic patients receiving failing regimens to inform salvage ARV selection. Even though InSTI-related drug resistance mutations were detected in only 2 of 32 participants who failed a DTG-based regimen in our study, in light of current widespread use of DTG in Liberia, ongoing population-level surveillance for DTG resistance over time will be important to inform future policy on when to perform HIVDR testing at an individual level. The NADIA randomized controlled trial conducted in Africa showed that DTG plus two NRTIs produced durable suppression at 96 weeks, including among subjects with pre-existing NRTI resistance, but DTG was at greater risk of resistance than darunavir in second-line therapy³². Additional studies are needed to assess the ability of InSTI-based regimens to maintain longer-term virus suppression, particularly in those with NRTI- and NNRTI-related drug resistance mutations^15,33, in sub-Saharan Africa.

Although only 7.5% of participants in our study had pVL≥1000 copies/mL, 12% had low-level viremia (pVL 40–999 copies/mL), including 108 DTG recipients. These individuals may be at higher risk of progression to virologic failure and accumulation of drug resistance mutations compared with fully suppressed individuals³⁴. Longitudinal analyses will be needed to determine whether individuals with low-level viremia at enrolment in our study represent cases of persistent low-level viremia, isolated viral blips, early virologic failure, or declining pVL levels after ART initiation or switching proximate to their baseline visit.

We note some important limitations in this study. Sequencing was unsuccessful in 20 (22%) individuals with virologic failure (most likely due to lower pVL levels and/or mismatches between primer and targets sequences), although this failure ratio is comparable to other recent reports^15,26. Secondly, medical records and ARV treatment cards were not consistently available to confirm self-reported ART history. Thirdly, we did not sequence samples from individuals with low-level viremia and do not know if they harbored major HIVDR. Fourthly, we enrolled a heterogeneous population on ART motivated to return for serial study visits who may not be representative of all PWH on ART in Liberia. Lastly, we did not collect medication adherence information during the baseline visit, and therefore could not assess its relationship to virologic failure.

Notwithstanding these limitations, our findings have important implications for the care of Liberian PWH. They provide support for starting PWH on a DTG-based regimen and switching those on NNRTI-based ART to regimens containing DTG, followed by support to ensure optimal adherence. In clinical trials, the majority of patients achieved viral suppression by 12 weeks after starting a DTG-based regimen³⁵. Inability to suppress pVL after three to four months should prompt evaluation for possible drug resistance and other causes of virologic failure, including barriers to adherence, significant drug-drug interactions causing subtherapeutic ARV concentrations, or impaired intestinal absorption⁶. However, current Liberian HIV guidelines recommend pVL testing at six months after initiating or switching ART, which may delay identifying patients with suboptimal treatment response. Routine GDR testing is not currently available in Liberia, but if available, could identify HIVDR in those experiencing virologic failure for early intervention to reduce further DRM accumulation, preserve future treatment options, and improve clinical outcomes. Longer-term pVL surveillance will be important in individuals on DTG-based regimens. As a LMIC with limited options for individuals with InSTI virologic failure and resistance, conducting clinical trials to identify optimal salvage regimens will be critical to inform future treatment guidelines.

In conclusion, we found that 81% of ART recipients were virologically suppressed in the HONOR cohort at enrolment during the rollout of DTG-containing regimens. Higher risk of virologic failure was associated with younger age, lower CD4 count, longer time on ART, lower hemoglobin, and currently taking EFV, NVP, or AZT. There was a high prevalence of resistance to NRTIs and NNRTIs in those with virologic failure whose virus was successfully sequenced, but rare resistance to InSTIs and PIs. Despite improvements in HIV-related services for Liberian PWH, significant work remains if Liberia is to achieve the 95-95-95 UNAIDS targets by 2030⁸.