5.1 Nucleoside Reverse Transcriptase Inhibitors
Two studies have shown no considerable effect on tenofovir disoproxil fumarate (TDF) or emtricitabine exposure post-BS in PLWH [
80,
81]. The first study measured tenofovir concentrations at 1 and 3 months after RYGB and showed no effect on plasma
Ctrough [
80]. Similarly, a case series of eight patients demonstrated no significant decrease in tenofovir or emtricitabine concentrations at 3 months post-SG [
81]. In contrast, data from a case series of individuals with GI disorders (
n = 4; SG, chronic diarrhoea, terminal ileitis and celiac disease) on TDF as a pre-exposure prophylaxis (PrEP) reported a significantly decreased C
trough of tenofovir (but not emtricitabine) [19 ng/mL vs 138 ng/mL in healthy PrEP users] [
82]. None of the four patients seroconverted after > 1 year of follow-up [
82]. The patient that underwent SG had the surgery 2 years before starting PrEP; therefore, other factors may have contributed to the low tenofovir exposure. Nevertheless, the study recommended an increase in TDF dosage or to use an alternative PrEP in individuals with GI disorders, including SG [
82].
As RYGB is essentially a subtotal gastrectomy, results from gastrectomised patients might be extrapolated to those undergoing RYGB [
36]. In this regard, Roelofsen et al. investigated the pharmacokinetics of TDF and emtricitabine as a PrEP in a non-obese patient who had undergone a full gastrectomy ~ 9 years prior to the PK analysis. With the standard dose of TDF/emtricitabine (245/200 mg), the AUC from 0 to 24 hours were 73.2% (tenofovir) and 43.7% (emtricitabine) lower compared with reference values. Trough concentrations were also 2.5-fold and 4-fold lower for emtricitabine and tenofovir compared with reference values (both 0.02 mg/L vs 0.08 and 0.05 mg/L, respectively). After doubling the dose, the AUC from 0 to 24 h increased by 148.9% (15.9 h mg/L) for emtricitabine and by 132.5% for tenofovir (3.7 h mg/L). The authors suggested that with a standard dose of TDF/emtricitabine, patients undergoing a gastrectomy may show a long-term sub-prophylactic exposure, which therefore requires dose doubling [
83].
Abacavir exposure after SG has been investigated in one case report [
84] and two case series [
81,
85]. Trough concentrations of abacavir in one case were reported to be ~ 7-fold and 12-fold-higher at 11 days and 42 days post-SG (58.5 and 103.3 ng/mL), respectively, compared with baseline levels from the same patient (8.7 ng/mL). This patient also had a higher
Ctrough of lamivudine (161 ng/mL, 2.7-fold) and atazanavir (2347 ng/mL, 2.5-fold) at day 42 post-SG compared with pre-surgery concentrations (60 and 919 ng/mL, respectively) [
84]. By contrast,
Ctrough,
Cmax and AUC of abacavir after surgery were within the population range in two cases at 3 and 6 months post-SG [
81,
85]. Furthermore, Badowski et al. showed that in two patients on abacavir-containing regimes, VL was undetectable at 9 months after both RYGB and SG. [
85].
Three cases were reported for lamivudine post-SG [
75,
84] or post-RYGB in a pregnant woman [
86]. Post-SG, twice-daily concentrations of lamivudine 150 mg showed a
Ctrough of 102 ng/mL at 2 months post-SG, but without any control data for comparison [
75]. The second case reported a 2.5-fold increase in concentrations of once-daily lamivudine at 6 weeks post-SG compared with pre-surgery concentrations. The patient was subsequently switched from abacavir/lamivudine/dolutegravir to a dual therapy with dolutegravir/lamivudine for treatment simplification and the VL remained undetectable [
84]. Finally, in the pregnant woman who had RYGB approximately 9 years prior to the analysis, plasma concentrations of twice-daily lamivudine were considerably lower than those published for pregnant controls with HIV (
Cmax of 0.69 µg/mL vs ~ 110 µg/mL). Nonetheless, viral suppression was maintained during the pregnancy and the infant was born HIV negative [
86]. In all cases, the patients maintained viral suppression post-BS.
Amongst commonly used nucleoside reverse transcriptase inhibitors, lamivudine, emtricitabine, and abacavir have favourable pharmacokinetic and pharmacodynamic characteristics post-BS with no considerable changes in exposure concentrations or evidence on viral failure. While TDF has favourable characteristics after SG and RYGB, its use after total gastrectomy should be cautious and under close monitoring. Data are lacking for tenofovir alafenamide post-BS and, therefore, this nucleoside reverse transcriptase inhibitor is not recommended.
5.2 Non-nucleoside Reverse Transcriptase Inhibitors
Published data on nevirapine are limited to one case who underwent SG and showed a
Ctrough of 2545 ng/mL at 12 h post-dosing [
87]. This patient was receiving twice-daily nevirapine 200 mg as part of a combination ARV treatment and was virologically suppressed at > 1-year post-SG. Other than the potential disadvantage of undergoing enterohepatic circulation, nevirapine has in theory favourable properties for patients post-BS (Table
4). Once more clinical data are available, nevirapine could be recommended for patients post-BS. However, it is advised to avoid the prolonged-release formulation of nevirapine for patients post-BS as no PK data exist.
Three and six patients who received efavirenz and etravirine, respectively, as part of their ARV regime maintained viral suppression post-SG [
24,
50,
81]. Data on patients after RYGB are lacking as well as comparative measurement for drug exposure before and after surgery, making it difficult to draw conclusions from the current literature. Caution is advised with oral rilpivirine, as it relies on gastric acidity for solubility and absorption [
88]. In addition, rilpivirine interacts with gastric acid inhibitors [
72], although no study compared its exposure pre-BS and post-BS.
Overall, few data are available for non-nucleoside reverse transcriptase inhibitors use post-BS, thus making it difficult to assess whether these agents are suitable for use post-BS. Rilpivirine should be avoided as it has unfavourable pharmacokinetics and restrictions related to intake (Table
4). The novel non-nucleoside reverse transcriptase inhibitor, doravirine, seems to have favourable drug characteristics, but clinical data post-BS are missing.
5.3 Protease Inhibitors
Darunavir (DRV) is a protease inhibitor that can be boosted either with ritonavir (DRV/r) or cobicistat (DRV/c). Data on DRV/c are limited to one case report showing viral suppression after switching to DRV/c post-SG, with no further PK data [
50]. Ten published cases exist for DRV/r post either SG (
n = 8) or RYGB (
n = 2). After RYGB, DRV/r has been given twice daily at a dose of 600/100 mg with TDF/emtricitabine [
35,
89]. In one case, concentrations of DRV/r experienced a transient reduction after surgery (3 days), while remaining within the therapeutic range (1166 ng/mL), before returning to population plasma concentrations by week 10 and week 48 [
35]. The other case showed also a normal plasma concentration at 12 months post-RYGB (2602 ng/mL) [
89]. Eight cases in the literature underwent SG and were taking DRV/r 800/100 mg once daily [
24,
75,
81]. One case taking DRV/r (plus raltegravir, abacavir and lamivudine) reported a therapeutic plasma concentration of DRV (2270 ng/mL) at 1-month post-SG [
75]. The other seven cases reported no PK data (
n = 6) [
81], or undetectable concentrations for DRV or ritonavir 16 hours post dosing (
n = 1) [
24]. Importantly, virological control was reported in all ten cases on DRV-containing regimes regardless of the surgery type or ARV combinations. Noteworthy, DRV should be taken with food to achieve an optimal exposure, which may be challenging for patients with a reduced stomach pouch. However, a small amount of food consumed with darunavir was shown to be sufficient, which should be achievable post-BS [
90,
91].
Four studies showed subtherapeutic exposure including some cases with subsequent virologic failure both with ritonavir-boosted or unboosted atazanavir post-BS [
24,
76,
81,
85]. A study of 17 PLWH with undetectable VLs who underwent SG showed that 3 months post-SG, the VL of 12 patients remained undetectable while five showed detectable concentrations. Two unsuppressed patients taking ritonavir-boosted atazanavir (ATZ/r) plus abacavir/lamivudine or atazanavir plus raltegravir showed significantly lower
Ctrough post-SG. Subsequently, ARV was changed, and VL became undetectable [
81]. Similar results of suboptimal atazanavir/r exposure were reported in a clinical case post-SG period; however, the VL remained undetectable [
24]. Furthermore, among 23 virologically suppressed individuals undergoing SG or RYGB, two patients receiving atazanavir-containing therapy showed a detectable VL [
76]. Finally, a case series showed that treatment with atazanavir (with raltegravir, emtricitabine and tenofovir) in one patient after gastric banding failed to achieve viral suppression, which was resolved after switching to a dolutegravir-based regime [
85]. One explanation is that for atazanavir, dissolution and absorption are highly dependent on low gastric pH, and at neutral pH, the drug is considered to be insoluble [
92]. Another explanation for the reduced serum concentrations of atazanavir is its high lipophilicity [
80], this factor needs further investigation.
Only two variable cases have been reported for boosted lopinavir after a total gastrectomy with RYGB. In a pregnant patient with HIV who has been gastrectomised 9 years prior,
Ctrough for twice-daily lopinavir and ritonavir (600/100 mg) were within the therapeutic range, thus not requiring dose adjustment [
93]. The other patient was taking lopinavir/ritonavir 400/100 mg twice daily and had also a therapeutic concentration (4864/410 ng/mL) 4 months post-surgery [
94].
To date, DRV boosted with ritonavir is the most suitable protease inhibitor based on both literature and drug considerations provided food intake is guaranteed. In contrast, atazanavir holds the highest risk for lower absorption, DDI and a subsequent viral failure (Table
5).
5.4 INSTIs
Data on the first-line agent, dolutegravir, seem to favour use post-BS, with few cases suggesting the need for a twice-daily dosing in some patients. A case series showed that 9 months post-BS, viral suppression was maintained in 6/6 patients treated with dolutegravir-containing regimes after SG (
n = 2), RYGB (
n = 2) or gastric banding (
n = 2) [
85]. Piso et al. reported that plasma concentrations of dolutegravir were slightly decreased in four subjects directly after RYGB, but remained above therapeutic thresholds [
78]. In two patients, dolutegravir dose was temporarily increased to twice daily during the early 2 months and 7 months post-RYGB to overcome a marginal plasma exposure (0.5 mg/L) or slow viral decay, respectively [
78]. In the studies above, dolutegravir was combined with either, abacavir/lamivudine or tenofovir/emtricitabine and all patients achieved a durable viral inhibition [
78,
85].
However, dolutegravir may be sensitive to a high pH environment post-BS. Given that it is a weak acid (pKa = 8.2), elevated pH in the GI after surgery may increase dolutegravir ionisation [
95]. Thus, dolutegravir solubility in the stomach fluids could increase and consequently its absorption. This hypothesis could explain the outcome of a recent case report in which C
trough of abacavir, lamivudine and dolutegravir were elevated at week 6 post-BS (103, 161 and 2374 ng/mL, respectively) compared with those measured 1-month pre-SG (8.7, 60 and 919 ng/mL, respectively) [
84]. In addition to the potential effect of increased pH, the authors suggest other possible mechanisms for the elevated concentrations post-SG, including alterations in gut microbiota and reduced glucuronidation of abacavir and dolutegravir. However, this assumption requires further evaluation, as PK studies showed no major interaction between dolutegravir and PPIs [
62].
The same study investigated the effect of crushing abacavir/dolutegravir/lamivudine tablet on plasma exposure post-SG and found no substantial effect on abacavir and lamivudine concentrations, but a modest increase in dolutegravir exposure [
84]. A similar effect on dolutegravir exposure (AUC from zero to infinity: +26% and
Cmax: +30%) and approximately no change in lamivudine and abacavir concentrations after crushing abacavir/dolutegravir/lamivudine tablets were detected in an open-label randomised trial on 22 healthy volunteers [
96]. However, higher dolutegravir concentrations after crushing did not exceed those after a three times-daily intake or intake in a fed state and were judged acceptable by the authors.
For raltegravir, Amouyal et al. demonstrated that in PLWH, SG may impair the absorption of raltegravir resulting in viral rebound in some cases [
81]. Seven patients were treated with a raltegravir-containing regime, in whom three showed detectable VL 3 months post-SG, and four remained virally suppressed. The virologic failure was accompanied with a significant reduction in raltegravir plasma exposure. The authors hypothesised that virologic failure is driven by concomitant use of calcium after the surgery. However, one-third of patients with a detectable VL was taking atazanavir/raltegravir and became virologically suppressed after switching to etravirine/raltegravir [
81]. These data suggest that treatment with raltegravir, particularly combined with atazanavir, may increase the risk of virologic failure.
Several mechanisms may contribute to the impaired absorption of raltegravir post-BS. An in vitro study indicated that as pH increases, a charge is introduced at the active site of raltegravir preventing the drug from penetrating across the phospholipid bilayer of the cell membrane [
47]. This mechanism is plausible, as gastric pH is increased after RYGB. Additionally, Roberts et al. reported PLWH taking raltegravir with no detectable VL for 10 months who demonstrated detectable VL 1 month after coadministration of calcium carbonate 1 g plus vitamin D
3 three times a day to prevent osteoporosis [
97]. The HIV-1 phenotype showed resistance to raltegravir and emtricitabine. After switching to abacavir, lamivudine, tenofovir and ritonavir-boosted atazanavir, the VL became rapidly undetectable. Considering that raltegravir resistance is rare in naïve patients and that compliance was good in this case, the authors suggested that viral rebound was likely due to the interaction with calcium, and the subsequent subtherapeutic exposure to raltegravir [
97]. Thus, raltegravir poses several challenges and risks for PLWH post-BS. A comprehensive analysis of raltegravir exposure and virologic response post-BS is essential to determine its suitability in this special population.
Use of elvitegravir boosted with cobicistat (plus emtricitabine and tenofovir) is limited to one case post-SG with no PK data [
50]. Similarly, data on the use of bictegravir post-BS are lacking. Thus, both agents are not recommended post-BS (Table
6).
Amongst INSTIs, dolutegravir is the most suitable agent for use post-BS, particularly if separated from polyvalent-containing agents. Close monitoring of drug exposure is still warranted.