2 some data to guide treatment recommendations in resource- poor settings. Given the prevalence of HIV-2 in West Africa, it is imperative that up-to-date recommendations be available for the antiretroviral management of HIV-2 in these clinical settings, characterized by the use of standardized ﬁrst-, and in some cases second-line regimens based on limited formularies, with treatment decisions driven by protocol, that are also highly sensitive to cost. At the time of writing, therapeutic drug monitoring, viral load measurement, and genotypic resistance testing are not routinely available in West Africa, nor are coreceptor tropism assays or HLA typing (to guide the safe use of CCR5 receptor blockers or abacavir, resp.). The monitoring and care of HIV in sub- Saharan Africa has, however, been a litany of barriers brought down, and the “impossible” becomes the standard, so these recommendations seek to strike a balance between optimal and current management trends. Clinical trials of ART in HIV-2 are few compared with HIV-1, primarily because of HIV-2’s lower prevalence and virulence, not to mention its concentration among some of the world’s poorest people. Until there is better evidence from randomized controlled trials, judgment of what consti- tutes good care in HIV-2 management must therefore rely on both in vitro as well as in vivo data from small cohort studies and case series, theoretical assertions, and parallels with HIV- 1 therapeutics. As will be apparent to experienced clinicians and pro- gram oﬃcers, numerous potential factors have been left out of this work that might inﬂuence program-level decisions about ART for HIV-2 in West Africa. This is especially true where such factors aﬀect both HIV-1 and HIV-2 infections in the same way. The current work is not intended as an exhaustive review of all aspects of a public health approach to the use of ART, nor is it intended to function as an ART primer. However, in the absence of universally accepted treatment guidelines for HIV-2, the authors seek to provide their own recommendations, based on the available litera- ture, HIV-2 treatment meetings, discussions with colleagues from major HIV-2 treatment centers in Europe and Africa, and from personal experiences between 2003–2010 at the Genito-Urinary Medicine clinic at the MRC Laboratories in The Gambia, where ART was provided to HIV-2 infected people. 2. Selecting First- and Second-Line ART Regimes in HIV-2 2.1. Natural Polymorphisms and Patterns of Genotypic Resis- tance in HIV-2. The most crucial diﬀerence between HIV-1 and HIV-2 when considering suitable ART regimes is the lack of susceptibility of the latter to what would now be called ﬁrst-generation NNRTIs, nevirapine, and efavirenz [19, 20]. The natural resistance of HIV-2 to these drugs is due to diﬀerences in the amino acid residues that make contact with the NNRTI in the binding pocket of HIV-1 and HIV-2, par- ticularly the Y181I and Y188L natural polymorphisms seen in HIV-2, which signiﬁcantly reduce NNRTI binding [7]. It is worth noting that HIV-1 mutations at these positions AIDS Research and Treatment result in complete resistance to NNRTIs [20, 21]. Although etravirine is reported to have more activity against HIV-2 than previous NNRTIs, the presence of L181 and other structural diﬀerences in the HIV-2 NNRTI-pocket makes HIV-2 naturally resistant to etravirine as well (reviewed in [22, 23]). Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) have a similar potency in both HIV-1 and HIV-2. Earlier in vitro work demonstrating lower potency for zidovudine (AZT) [24] appeared to be an artifact of the assay used, and more recent work demonstrates similar potency in both HIV-2 and HIV-1 [25]. The development of NRTI resistance in HIV-2 shares many parallels with that in HIV-1, although key diﬀerences are worth highlighting that are of clinical relevance. The M184V mutation occurs rapidly, both in vitro [26] and in vivo [27] in approximately 83% of patients failing a lamivudine (3TC)-containing regimen [28, 29]. As in HIV-1, it is associated with high-level phenotypic resistance to 3TC and emtricitabine (FTC) in HIV-2-infected individu- als [30]. Although HIV-1 and HIV-2 share some classic NRTI resistance patterns, the preference for alternative resistance pathways has been noted, in addition to unique resistance patterns in HIV-2. AZT resistance in HIV-1 occurs via two well-documented pathways. The most common and preferred pathway is marked by the accumulation of the six thymidine-associated mutations (TAMs): M41L, D67N, K70R, L210W, T215Y, and K219Q/E [31]. The less common pathway is via the Q151M mutation, which also tends to develop later. The TAM mutations are conspicuously absent in the AZT resistance proﬁles of HIV-2 patients [27, 28, 32–35]. In place of TAMs, AZT resistance in HIV-2 often involves the Q151M mutation, which occurs faster and with a much higher frequency and potency than in HIV-1 [30, 36]. Considering that this mutation causes multi-NRTI resistance in HIV-2, its high frequency raises real concerns [29, 37]. Unlike HIV-1 where K65R leads to TDF, ABC, ddI, and d4T resistance [38], K65R in HIV-2 does not cause phenotypic resistance to TDF, but causes high-level resistance to 3TC and FTC, and low-level resistance to ddI [30]. Current evidence suggests that this mutation rarely occurs in HIV-2 except during suboptimal mono- or dual-therapy with NRTIs that mostly do not include TDF [27, 39, 40], where it is often associated with the Q151M mutation. There is, however, limited experience with widespread use of TDF containing regimes in ﬁrst-line HIV-2 ART, and ﬁrm conclusions on a reduced frequency of K65R in HIV-2 infection cannot be drawn with conﬁdence. Of note, in a recent Senegalese study, two (of 23) patients exhibited K65R mutations at follow-up while on an AZT/3TC/indinavir (IDV) regimen, although in one case the mutation was present at baseline prior to commencing ART [35]. These data together with the phenotypic data by Smith et al. [30] indicate that K65R arises primarily due to 3TC/FTC pressure in HIV-2. The potential fragility of currently available NRTI backbones for use in HIV-2 therapy is highlighted by the ﬁnding that Q151M combined with K65R or M184V results in high- level AZT and 3TC resistance, whereas the presence of all three mutations in combination confers class-wide NRTI resistance, although it should be noted that these mutations