4 basis, TDF may be desirable in ﬁrst-line treatment in spite of its greater cost when compared with AZT (see Table 2), although the low yet measurable risk of renal toxicity with TDF use, particularly in settings where renal monitoring may be limited, is grounds for concern [71]. Tolerability issues should also be considered. If a patient does not tolerate AZT in ﬁrst-line treatment other alternatives (including d4T) could be used, following the same protocols as are used for AZT intolerance in HIV-1-infected individuals; however an equivalent substitute for TDF in the face of resistant virus is not easy to ﬁnd in the event of TDF intolerance. Given that the prevalence of HLA B∗5701 is low in black African individuals [72], with HLA∗B5703 being the only B57 subtype found in populations in Guinea-Bissau [73], the risk of ABC hypersensitivity, if ABC/3TC is used ﬁrst line without the ability to determine HLA type, may not be of great concern in sub-Saharan Africa. As mentioned above, PI options are constrained in HIV-2 as a result of natural polymorphisms that support PI resistance. In addition, unboosted PI regimens should be avoided as they tend to perform poorly [29, 35, 40, 56]. While good clinical outcomes with LPV/r have been observed [34, 65], in vitro data [54] suggests that SQV/r would be a reasonable ﬁrst-line PI [54] too, while IDV/r may also be eﬀective [28]. DRV/r would appear to be reliable based on in vitro data, although at present there is insuﬃcient data to justify its use as the preferred ﬁrst-line PI for HIV-2 given its higher cost (see below). Boosted ATV cannot be recommended in HIV-2 [54, 55], and given the conﬂicting results on the use of boosted TPV [54–56], it also cannot be recommended for use until further studies conﬁrm its eﬃcacy. Second-line therapy should be considered in drafting treatment guidelines for ﬁrst-line ART, as initial regimen choices narrow later treatment options. In the absence of viral load monitoring, resistance should be anticipated at the time of regimen change, and we make the assumption that resistance test results will not generally be available. Two fundamentally diﬀerent strategies in ART are to increase potency up-front in order to minimize failure rates, or to hold potent antiretrovirals in reserve in order to mitigate the impact of failure of the ﬁrst-line. Knowledge of typical mutations selected for during failure allows one to optimize sequential treatment, although HIV-2 is much less well studied in terms of the frequency with which various sequential regimens select for resistance mutations. With regards to NRTIs, extensive resistance should be assumed to include the Q151M, K65R, and M184V, depend- ing on the NRTIs employed in the ﬁrst-line ART. While ABC is probably an option where only the Q151M mutation is present, it would be compromised in the presence of K65R and M184V [30]. Older NRTIs including AZT and ddI are not likely to have much residual potency in the face of these mutations; however TDF and d4T might retain suﬃcient potency in this setting [30]. The argument that the M184V mutation carries a substantial ﬁtness cost has not been demonstrated as clearly in HIV-2 as it has in HIV-1 [75], nonetheless as it occurs in the highly conserved YMDD motif within the reverse transcriptase’s active site [76], we believe AIDS Research and Treatment it is likely to aﬀect ﬁtness similarly, and we recommend continued exposure to 3TC or FTC in order to maintain the M184V. Based on the resistance data described earlier, recom- mended ﬁrst-line boosted PIs for HIV-2 in resource limited settings are LPV/r, SQV/r, and possibly IDV/r. It appears that HIV-2 V47A mutants, selected for by failure on a LPV/r regimen, retain susceptibility to other PIs and are in fact hypersusceptible to ATV and SQV [61]. We ﬁnd that this makes SQV/r an attractive choice for second-line therapy to follow up LPV/r-based ART in HIV-2. Given the more limited range of eﬀective antiretrovi- rals, both biologically and as a consequence of HIV-2’s disproportionate prevalence in the resource-limited settings of West Africa, second-line treatment in HIV-2 becomes markedly challenging. Going back to the broader question of strategy, we support a boosted PI in the ﬁrst regimen because we believe that failure rates on triple NRTI regimens are unacceptable. Nonetheless we recommend TDF be held in reserve to lend potency to second-line treatment. 2.3. HIV-1/HIV-2 Dual Infection. Co-infection with both HIV-1 and HIV-2 occurs in countries where both viruses circulate. Although progression, as implicated by higher viral loads, is driven by HIV-1 in the majority of dually infected individuals [77], this is not always the case [34]. Treatment of dually infected individuals should be carried out using an HIV-2 regimen, to ensure that the drugs used can eﬀectively treat both viruses [34, 78]. Given that the HIV-2 plasma viral load is usually undetectable or low in dual infections, it might seem reasonable to treat and monitor only HIV-1 (discussed in [79]). In our opinion this represents a dangerous strategy, as even with an undetectable baseline HIV-2 VL, the risk exists that as HIV-1 is controlled and CD4+ T-cell targets expand, the potential for HIV- 2 replication will also increase [78]. In addition, we have successfully treated eight dually infected individuals on an HIV-2 regimen of AZT/3TC/LPV/r achieving complete suppression of both viruses for more than three years [34]. Taken together, Tables I(a) and I(b) show possible com- binations that would be likely to optimize control of HIV-2 in mono- and dual-infections, across two regimens, with the authors’ preference given in bold. 2.4. Other Agents. While some newer agents developed for use against HIV-1 show no activity against HIV-2 and other products are currently unrealistic options in resource poor settings, they warrant discussion even if they lie far outside the protocols and budgets of West African treatment programs currently. With potentially increasing numbers of HIV-2 infected patients with ﬁrst-line (and perhaps second- line) regimen failures in West Africa, increasing experience with the use of newer agents in salvage therapy in European settings and, hopefully, the costs of newer agents dropping over time, HIV-2 ART guidelines will require frequent reconsideration and updates. Two types of entry inhibitors, fusion inhibitors (FI) and coreceptor binding inhibitors, have been approved for