We reported in this study the virological outcome and HIV drug resistance among patients followed-up in a national HIV treatment centre in Yaoundé – Cameroon, and who stayed under ART for 36±2 months. In the same clinic, we conducted a cross-sectional study in 2006–2007 to assess ART outcome and selection of drug-resistant viruses after 12 or 24 months of ART and found virological failures (VL≥1000 copies/ml) of 16.4% (41/249) and 22.5% (40/178), respectively, at months 12 and 24. We showed in that previous study that at month 24, up to 79% (30/38) of patients who failed, representing 16.9% of all patients recruited at month 24, carried at least one major DRM, while only 32.4% (11/34), 4.4% of all patients at month 12, developed drug resistance, thus illustrating significant adherence issues for these patients, since the majority of those failing treatment after 12 months had no resistant virus [5
]. We did not recruit the same patients for the present study, and the results obtained are promising because we observed no increase of virological failure for patients at M36, as that could be anticipated if we consider observations from months 12 and 24. In fact, we found a failure rate of 17.6% (66/376) in patients with 36 months’ ART experience, which is lower than the result obtained for patients who had 24 months ART (22.5%) [5
]. In addition, the proportion of patients with a resistant virus did not increase significantly, here we reported 81.5% and we previously found 79% for M24 patients. This improvement of ART outcome is either the result of a better management of patients by clinical staff who are gaining more experience over time, and/or a bias due to the cross-sectional design of the study which allows assess only to patients who are still being treated, and therefore unlikely to represent lost to follow up, ART stop and deaths. In addition, this result may indicate that failure due to adherence issues occurs early at treatment initiation and stabilizes over time among long-term treated patients, therefore advocating the need for early introduction of VL testing to identify non-adherent patients.
However, in this study we found that patients failing ART with a resistant virus significantly accumulated DRMs, especially NRTI mutations and TAMs, probably because they stayed longer under failing regimens, correlating with similar studies in Africa [11
]. As already shown, this accumulation of NRTI/TAMs and also NNRTI mutations led to reduced sensitivity to drugs that were not part of the regimen as tenofovir, abacavir and etravirine [13
], but did not significantly compromise currently recommended PI-based second-line regimens. In Cameroon, reference second-line regimens for adults consist of one boosted PI, routinely lopinavir or atazanavir boosted with ritonavir, plus two NRTIs among tenoforvir, lamivudine, zidovudine and emtricitabine, excluding when feasible, NRTIs already prescribed at first-line. In our study, only 7 patients out of the 53 who developed resistance, thus representing 1.9% (7/376) of our total study population, may be at risk of having a suboptimal second-line ART if they receive tenofovir and/or abacavir. However, up to 14% (53/376) of the patients will require a second-line treatment and subsequently third-line ARVs, in a context where access to these drug classes is still extremely challenging, especially for third-lines. In these conditions, there is a risk that patients failing second-lines will stay longer under a failing regimen and may develop additional DRMs that will be transmitted also. That represents a major public health threat for developing countries and thus advocates the need for additional efforts to improve first-line treatment outcome and prevent drug resistance. Although the study was not initially designed to compare gender response to ART treatment or evaluated ART failure according to gender, the analyses we performed did not show any significant difference between males and females. As observed in routine practice, women predominated in our study population, but the proportion of virological failure in both groups was very similar. Detailed assessment of drug resistance mutations showed no specific pattern that can characterise any of the two populations. In addition, for the four women who received ARVs as PMTCT intervention before their ART initiation, we found no specific results since only one failed after 36 months of treatment. However, the limited number of patients did not allow us to draw any conclusion.
We had one patient with a PI mutation, L90M, with an unclear origin since the patient did not receive any PI. Our analysis was limited by the lack of baseline data, including genotypic information before ART initiation, but threshold surveys conducted within the study period in Yaoundé revealed a low (<5%) level of transmitted PI-resistance mutations and low to moderate (5%–15%) rates of transmitted RTI-resistance mutations [15
]. However, it is still likely that the observed L90M mutation resulted from transmitted resistance as we recently published in Cameroon [16
], or from unreported exposure to PIs. Etravirine is currently not recommended in Cameroon as a second-line ARV, but could potentially serve as second- or third-line option, or could be used for patients who initiated ART before implementation of national programmes and who experienced several informal ARV regimens between the 1990s and 2000s. Our study and other reports from African settings [11
] showed that accumulated NNRTI-resistance mutations might impair etravirine efficacy, thus compromising its use in NNRTI-experienced patients.
Contrary to several recent reports assessing failure to stavudine-containing first-line regimens in developing countries, we found no K65R mutation or Q151M complex known as compromising almost all NRTIs [13
]. Several reasons have been suggested to explain the selection of K65R under tenofovir-free regimens, including delay in treatment switch, viral load level and subtype mediated pathway, but the main reasons are still uncertain [13
]. However, some reports have suggested antagonism between K65R and TAMs, indicating that both pathways are unlikely to occur simultaneously. Indeed a large database analysis involving up to 66,000 genotypes found that K65R shows a strong negative association with specific TAMs including M41L, D67N, L210W, T215F/Y, and K219Q/E [21
]. The high frequency of TAMs observed in our study could thus explain the fact that we found no K65R mutation, but other factors cannot be fully excluded.