AIDS Research and Treatment result only in low level resistance (4-5 fold) to d4T and TDF [30]. Lastly, the L74V mutation is rarely documented in HIV-2 [41], with one report of L74I in an HIV-2-infected patient on dual therapy (which included ddI) [40]. HIV-1 and HIV-2 proteases have an amino acid sequence similarity of about 50%, substantially less than that observed in their reverse transcriptase enzymes. These sequence diﬀer- ences are reﬂected in very distinct natural polymorphisms in the HIV-1 and HIV-2 proteases, most of which occur outside the functionally relevant areas [42]. Several HIV-2 natural polymorphisms correspond to drug resistance mutations in HIV-1. These include the major drug resistance mutation M46I, conferring resistance to indinavir (IDV), and several minor mutations, L10V, V32I, M36I, I47V, A71V, and G73A, that may decrease the activity of nelﬁnavir (NFV) and amprenavir (APV) [32, 43–46]. Several in vitro cultural and cell-free assays using individual PIs have suggested that while IDV, saquinavir (SQV), lopinavir (LPV), darunavir (DRV), and tipranavir (TPV) may exert full activity against wild-type HIV-2 [47–52], NFV and APV show a signiﬁcant reduction in activity [46, 53]. A more in-depth study (kinetic inhibition assays) has shown that LPV, SQV, TPV, and DRV exhibit the highest potency in this order and that atazanavir (ATV), NFV, and APV show the lowest potency, respectively [54]. The data on TPV are however controversial, with other studies showing several fold lower potency when compared to LPV, SQV, and DRV [55, 56]. Once protease inhibitor- (PI-) based ART starts, this background of minor mutations may result in rapid acquisition of a multi-PI resistance phenotype [45, 46]. In HIV-1, PI resistance is associated with the accu- mulation of four or more resistance mutations in the protease gene, though major mutations can cause substantial resistance on their own [57]. HIV-1 and HIV-2 have similar PI resistance mutations [33, 43, 45, 46, 53], with a few muta- tions unique to HIV-2 [20, 45, 46]. The presence of certain natural polymorphisms in HIV-2 can reduce the time to resistance in some cases [34, 46]. For instance, I47A and V32I are associated with high-level resistance to LPV/ritonavir (LPV/r) in HIV-1 [58–60], and V47A is associated with phenotypic resistance to LPV/r in HIV-2 [61]. In HIV-1, the emergence of the LPV/r mutation I47A is a two-step process (I → V → A), whereas in HIV-2 it can occur in a single step from V → A [61]. In addition, V321 is present naturally in HIV-2. Therefore while LPV/r resistance in HIV-1 requires the acquisition of V32I and a two-step process to acquire I47A, only a one-step change in HIV-2 is required, making the development of this mutation easier and faster in HIV-2 [34]. 2.2. Potential Options for Standardized First- and Second- Line Regimes in Resource Poor Settings. Until recently, most studies reporting antiretroviral use in HIV-2 patients were from European cohorts, and often involved mono- or dual- therapy and multiple heterogeneous regimens [28, 32, 33, 40, 62]. Due to the recent availability of ART in West Africa, data from the use of standardized ﬁrst-line ART regimens in these cohorts are now appearing [34, 35, 63], although the numbers are still relatively small when compared to 3 the HIV-1 literature. Given the lack of utility of NNRTIs in HIV-2, a key issue in choosing ﬁrst-line ART regimes in HIV-2 infection is the question of whether triple NRTI regimens are a viable, safe, and eﬃcacious option. The appeal of this approach lies in its lower pill burdens and reservation of PIs for second-line therapy, maintaining parallels with HIV-1 protocols. Prior to the development of a heat stable formulation of ritonavir, and in settings where this is not yet available, cold chain requirements also argue for a PI- sparing regimen. Unfortunately studies to date suggest that these regimes, including those with TDF, perform poorly in HIV-2 [28, 62, 64] and in our opinion should be avoided, although in certain speciﬁc circumstances they may represent the best balance of risk and beneﬁt (see special populations, below). One case of a patient achieving viral suppression on a quadruple NRTI regimen (d4T/3TC/ABC/TDF) has been reported [62], although clearly more evidence is needed to conclude that such a regimen is superior to using triple NRTIs in HIV-2. The principal challenge of the PI-sparing nucleoside regimens in HIV-2 is the rapid development of the Q151M pan-NRTI resistance mutation [36]. Unlike the case in HIV-1 where this typically arises only after multiple other resistance mutations have developed, in HIV-2 it is one of the earliest and most common NRTI mutations (after those at the M184 locus), especially after mono-/dual- /triple-NRTI treatment [28, 32, 33, 40, 62] and compromises the entire regimen [36]. Triple nucleotide regimes containing ABC (in the absence of TDF) have also been shown to rapidly select for K65R in HIV-2 patients [64]. Our experience at the MRC Gambia [34] and that of others [62, 65] suggest that the combination regimen of AZT/3TC and LPV/r has a reasonable chance of success as a ﬁrst-line regime for HIV-2 infection [34, 62, 65]. The use of an AZT/3TC backbone with unboosted IDV, however, has been shown to result in a high proportion of ART failures and accumulation of resistance mutations in a Senegalese cohort [35, 56]. ABC/3TC, TDF/FTC, and ddI-based regimens have the advantage of daily dosing and show potential for success, although in our opinion there is currently insuﬃcient experience with those combinations in HIV-2 to draw ﬁrm conclusions. Moreover the inclusion of appropriate PIs in HIV-2 regimes will necessitate twice daily dosing in most circumstances, reducing the beneﬁt of once-daily nucleoside analogue dosing. Didanosine also has a rather unique set of advantages and disadvantages as part of ART regimes. It should generally be taken on an empty stomach while other antiretrovirals, in particular TDF, should be taken with food, adding to regimen complexity. We believe ddI is less well tolerated than ABC, AZT, TDF, or 3TC and that this could threaten patient adherence to the overall regimen. Its use with TDF is relatively contraindicated because of the negative impact this combination has on CD4 cell counts and the increased risk of viral failure [66], even at the appropriate 250 mg dose [64]. Although no head-to-head comparisons have been performed in HIV-2-infected individuals, the HIV-1 literature suggests that an NRTI backbone of TDF/FTC (or 3TC) may, on the grounds of eﬃcacy and tolerability, be a better choice than AZT/3TC [67, 68] or ABC/3TC [69, 70]. On that