Lamivudine/Tenofovir Disoproxil Fumarate is an Appropriate PrEP Regimen

Abstract

Oral pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) co-formulated with emtricitabine (FTC) or lamivudine (3TC) is recommended as an additional prevention option for persons at substantial risk of HIV infection by both the World Health Organization (WHO) and the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR). The WHO and PEPFAR consider 3TC clinically interchangeable with FTC for PrEP given comparable pharmacologic equivalence, resistance and toxicity patterns and indirect clinical trial evidence from TDF-containing studies. Globally, FTC/TDF has been widely used in clinical trials, open label extension studies and demonstration projects. Thus, most PrEP efficacy and safety data are based on FTC/TDF use in heterosexual women and men, men who have sex with men and people who inject drugs. However, generic 3TC/TDF is less expensive than FTC/TDF, is already available in supply chains for HIV drugs, and has 60–70% of global adult market share, making it particularly appealing in settings with limited availability or affordability of FTC/TDF. Compelling indirect evidence suggests that scaling up use of 3TC/TDF is potentially cost saving for HIV programmes in settings where restricting drug choice to FTC/TDF would delay PrEP implementation. Guideline committees and public health decision makers in countries should encourage flexibility in PrEP drug selection, support off-label use of 3TC/TDF and approve use of generic formulations to decrease cost of PrEP medications and accelerate PrEP delivery through the public and private sector.

1. Oral PrEP is an effective HIV prevention tool

In 2018, an estimated 1.7 million people were newly infected with HIV, a 16% reduction from 2.1 million infections in 2010 [1]. While any decline in new infections is encouraging, the global community will not achieve its 2020 target of fewer than 500,000 new infections [2]. Delivery of proven HIV prevention tools – including condoms and lubricant, behavioural modification, voluntary male medical circumcision, antiretroviral therapy (ART) to eliminate the infectiousness of people with HIV, harm reduction services, and pre-exposure prophylaxis (PrEP) for HIV negative persons – in combination and at scale – holds the potential to achieve elimination of HIV [2]. PrEP is the use of antiretroviral (ARV) drugs by HIV-negative persons to prevent the acquisition of HIV [3, 4]. There is high-quality evidence that oral tablets containing tenofovir disoproxil fumarate (TDF) with and without emtricitabine (FTC) are an effective HIV prevention method when used consistently, providing an estimated >90% protection in adherent individuals [5–9]. Clinical trials of PrEP containing TDF assessed both TDF co-formulated with emtricitabine (FTC/TDF) as well as TDF alone. A systematic review and meta-analysis of 18 PrEP studies (15 randomized trials and 3 observational studies) involving 19,491 participants in low, middle and high-income settings concluded that oral TDF-based PrEP protects from HIV infection across HIV risk categories – heterosexual women and men, people who inject drugs (PWID), and men who have sex with men (MSM) [10]. There were no significant differences in PrEP effectiveness between sexes and regimens. The review also found that PrEP effectiveness was significantly moderated by adherence, as measured by tenofovir diphosphate blood levels in participants from the included studies.

2. Global PrEP rollout

In January 2011, the United States became the first country to issue recommendations for oral PrEP [3]. In July 2012, the U.S. Food and Drug Administration approved use of FTC/TDF to reduce risk of sexually transmitted HIV in high-risk persons [11], making it the first drug regimen approved to prevent HIV infection. In September 2015, the World Health Organization (WHO) recommended that any person at substantial risk of HIV infection (i.e., populations with ≥3% annual HIV incidence) be offered oral PrEP containing TDF as part of combination HIV prevention approaches [12], based on the meta-analysis by Fonner and colleagues [10]. Following the release of WHO PrEP guidelines, drug regulatory authorities in at least 37 countries have included oral PrEP as FTC/TDF in national guidelines [13]. As of October 2019, generic FTC/TDF was registered in 33 countries and approved as PrEP in India, Lesotho, and Uganda [13]. At least 75 countries worldwide are providing oral PrEP through a variety of delivery models (e.g. fully or partially reimbursed through national programmes, and implementation/demonstration projects) [13]. The 2016 United Nations Political Declaration on Ending AIDS aimed to reach 3 million people with PrEP by 2020 [14], but current global coverage is <20% of this target. In July 2016, the European Medicines Agency granted a marketing authorization in the European Union for use of FTC/TDF as PrEP [15]. Oral PrEP taken as TDF monotherapy or in combination with FTC or lamivudine (3TC) was included on the WHO Essential Medicines List in June 2017; an essential medicine addresses priority health needs and is chosen after consideration of efficacy, safety, cost-effectiveness and public health relevance [16]. As of October 2019, an estimated 380,000–385,000 persons had initiated PrEP globally, of whom 35% were in the United States [13] (Figure 1).

Fig. 1.

Global Oral PrEP Initiations (Q3 2019)

3. 3TC and FTC molecular structure and pharmacokinetic and resistance profiles

The nucleoside reverse transcriptase inhibitors FTC and 3TC are the most widely used antiretroviral medications worldwide [17]. They are structurally similar, anabolized and phosphorylated to their pharmacologically active triphosphates by the same enzymes, accumulate with daily dosing in peripheral blood mononuclear cells (PBMCs). Few prospective studies have performed head-to-head pharmacokinetic comparisons of 3TC and FTC in plasma, PBMCs, and genital fluids. Available data indicate that 3TC has a shorter plasma half-life (6–8 hours) than FTC (8–10 hours) (Table 1) [18–20]. FTC-triphosphate (FTC-TP) and 3TC-triphosphate (3TC-TP) have a relatively similar accumulation half-life in PBMCs (27 and 19 hours, respectively). Elimination half-life (time taken for a drug concentration in blood to decline by half) is longer for FTC-TP than 3TC-TP (37–45 versus 16–32 hours) [18–27]. The terminal half-lives of 3TC (300 mg) and FTC (200 mg) are 7.9 and 7.4 hours, respectively [28]. The FTC half maximal effective concentration (EC₅₀) is lower than 3TC and suggests an 11-fold greater potency for FTC compared with 3TC [29]. Overall, FTC has a longer intracellular half-life than 3TC, but 3TC-TP achieves higher intracellular levels [30]. The intracellular half-life of 3TC is independent of dosing regimen; similar results are obtained with once daily (300mg) and twice daily (150mg) dosing [20, 31]. Both drugs achieve 2–6 fold higher concentrations in the genital tract relative to blood plasma [32–35], and are similarly distributed in cervicovaginal fluid and semen [32–34, 36, 37]. No data are available on 3TC concentrations in human rectal fluid.

Table 1.

Human Pharmacokinetic Properties of emtricitabine (FTC) and lamivudine (3TC)

Pharmacokinetic Parameter	FTC	FTC-TP	3TC	3TC-TP
	N or Median (IQR)
Mean steady-state plasma half-life (t1/2, hours)	11 [34]	39 [19] 19 [34]	5.71 [18] 8.65 [20]
Mean intracellular half-life (t1/2, hours)	8–10 [19]	33 [22]	6.1–7.9 [14]	21 [25] 22 [27]
Median intracellular half-life (t1/2, hours)				16.1 [24] 32 [23]
PBMC accumulation half-life (hours)		19 [36]		27 [21]
PBMC elimination half-life (hours)		37–45 [26]		16–32 [18]
Cervicovaginal fluid [32]  *AUC0–24h (μg*h/ml)		30.8 (25.6, 52.6)		26.3 (1.12, 49.0)
+CT (ng/ml)		596 (537, 644)		1731 (1083, 3265)
Genital tract : blood plasma AUC ratio (%)	75 (37, 645)		395 (187, 671)
Semen *AUC0–12h (h.ng/ml; h.fmol/106 cells) [33]			31084 (28071, 44184)	82068 (64342, 139404)
Semen plasma/blood plasma ratio [33, 35]	2.91 (0.84–10.08)		6.67 (4.10–9.14)	1.0 (0.62–1.30)

^*Area under the curve (AUC) values represen 12 or 24 hour intervals

⁺Genital tract concentrations at end of dosing interval

N number; PBMC peripheral blood mononuclear cell

Despite the differences in some pharmacokinetic properties, both drugs have been shown to be effective with daily dosing for treatment and/or prevention [38–40]. A phase 2 dose-escalation randomized trial of FTC and 3TC monotherapy in HIV-positive individuals showed that significantly greater viral load reduction was observed with FTC [41]; however, 3TC and FTC containing regimens have comparable virologic efficacy [42]. Since the advent of combination ART, 3TC has been a core component of backbone and alternative regimens for first-line and second-line ART for adults, adolescents, and children [43, 44]. Like FTC, 3TC is safe with an excellent toxicity profile, non-teratogenic, effective against hepatitis B virus (HBV), and widely available in fixed-dose combinations in resource-limited settings [45, 14]. Both 3TC and FTC have a low genetic barrier to resistance and resistance quickly occurs in vitro [46] and in vivo [47, 48]; specifically, mutations of codon 184 arise when isoleucine (M184I) or valine (M184V) are substituted for wild-type methionine [46]. The M184V mutation affects the catalytic function of reverse transcriptase resulting in reduced viral replication capacity and low viral fitness [49], but also induces re-sensitization to tenofovir [50] and zidovudine [51]. There are significantly lower levels of tenofovir resistance in viruses carrying thymidine analogue mutations (TAMs) with M184V than with M184M [50]. The synergistic activity of 3TC or FTC and TDF results in sustained antiviral activity and supports the continued use of 3TC in combination with TDF or zidovudine (AZT) even when the M184V mutation is present (e.g., in second-line ART) [52, 44]. Therefore, 3TC is considered an acceptable alternative to FTC [42] and the WHO and U.S. Department of Health and Human Services consider 3TC clinically interchangeable with FTC for HIV treatment and prevention given comparable pharmacologic equivalence, resistance and toxicity patterns and clinical trial effectiveness (Figure 2) [14, 40]. Importantly, 3TC is also less expensive than FTC [53]. Overall, available evidence from pre-clinical, in-vitro, and clinical studies suggests comparative pharmacologic and virological efficacy and clinical equivalence, and supports the interchangeability of 3TC and FTC despite limited data from direct comparisons.

Fig. 2.

Lamivudine (3TC) and emtricitabine (FTC) are clinically interchangable

4. Pharmacokinetics of 3TC in macaques

The mucosal pharmacokinetic (PK) profile in rhesus macaques suggests potential pharmacological equivalence between 3TC and FTC for oral PrEP. A single-dose pharmacokinetic study in rhesus macaques found that 3TC achieves high concentrations in rectal and vaginal fluids [54]. Twelve macaques were provided with a single oral dose of 10, 20 or 30mg/kg of 3TC (4 animals per dose) by gavage under anesthesia based on body weight. Blood and vaginal and rectal secretions were collected at baseline, 2 hours, 6 hours, 24 hours, and 48 hours; vaginal and rectal biopsies were collected at 6 and 24 hours. Validated liquid chromatography-tandem mass spectrometry methods were used to measure 3TC and 3TC-triphosphate (3TC-TP; the active intracellular moiety) concentrations; 3TC-TP was also quantified in vaginal biopsies. The 30mg/kg dose achieved a plasma drug exposure (median AUC_0–24h 16.8 [13.4–28.7] μg*h/mL and median C_max 3.0 [1.8–5.8] μg/mL, respectively) comparable to an oral 3TC dose of 300mg in humans (median AUC_0–24h 16.7 ± 4.1μg*h/mL and median C_max 3.5 ± 0.9 μg/mL, respectively) [28]. Peak 3TC-TP concentrations in PBMCs in macaques were also comparable to humans (1.8 [95% CI: 1.4–1.9] pmols/10⁶ cells versus 1.8 [95% CI: 0.5–1.9] pmols/10⁶ cells, respectively) [21]. Importantly, 24h 3TC-TP concentrations in macaque vaginal biopsies were similar to FTC: 135 (9–208) versus 151 (145–179) fmol/mg of tissue, respectively. These PK data provide indirect evidence supporting the use of 3TC/TDF as PrEP.

5. 3TC/TDF is an appropriate PrEP regimen

Clinical studies of 3TC/TDF for prevention of mother-to-child HIV transmission (PMTCT) provide indirect evidence and serve as proof-of-principle for the use of 3TC/TDF as HIV prophylaxis [55–58]. In the Kesho Bora study (n=805), infants of mothers randomly assigned to the zidovudine/lamivudine/lopinavir-ritonavir group had a 43% lower cumulative rate of HIV acquisition (5.4 vs 9.5%; p=0.029) and a 36% lower cumulative rate of HIV transmission or death (10.2 vs 16.0%; p=0.017) at 12 months compared with the AZT and single-dose nevirapine group [57]. The ANRS 12174 randomized trial (n=1273 infants) found that cumulative HIV infection rates did not differ between the lopinavir-ritonavir and lamivudine groups (HR 0.90; 95% CI: 0.35–2.34; p=0.83) [58]. In the Mitra Study (n=398 infants), vertical transmission of HIV was 62% lower in breastfed infants who received 3TC prophylaxis for 6 months than in those who stopped receiving 3TC after 7 days of age (adjusted relative hazard 2.61; 95% CI: 1.44–4.73; p=0.001) [56]. And in the SIMBA study (n=397 infants), postpartum HIV transmission was observed in 1.1% of infants receiving 3TC prophylaxis compared with 10% of infants on nevirapine [55]. These data suggest that infant HIV prophylaxis with 3TC containing regimens is effective for HIV prevention. In the first study of 3TC/TDF as PrEP (a phase I trial), 40 MSM in Brazil were followed for 4 months and 33 completed study follow up [59]. There were no breakthrough infections reported by the completion of the study. A phase II trial is ongoing [60]. To date, no clinical trial data are available on the use of 3TC/TDF for prevention of HIV acquisition through heterosexual contact or PWID. However, indirect evidence from the Partners PrEP Study, which found no significant differences in the protective effects of FTC/TDF and TDF (hazard ratio 0·67, 95% CI: 0·39–1·17; p=0·16) [61], supports the use of TDF alone as PrEP. An ongoing stepped-wedge cluster randomized trial (n=1,440 couples) is evaluating the effectiveness of delivering an integrated PrEP and ART intervention at public health clinics in Uganda on: a) 3TC/TDF PrEP initiation, b) 3TC/TDF PrEP adherence, c) ART initiation, and d) ART adherence among HIV serodiscordant couples in Uganda (www.ClinicalTrials.gov NCT03586128).

6. Global recommendations for 3TC/TDF

WHO’s existing recommendation for oral PrEP specifies the use of medicines “containing TDF”, i.e., FTC/TDF or 3TC/TDF. Oral PrEP is contraindicated for persons with an estimated creatinine clearance <60ml/min [44]. For the most part, PrEP implementation has used FTC/TDF as the PrEP agent, and regulatory approvals have resulted in the extension of a PrEP indication to FTC/TDF products, both originator and generic. However, TDF is also commonly co-formulated with lamivudine (3TC/TDF) [14], and 3TC is generally considered equivalent to FTC in its mechanism of action and clinical effect when used as ART for HIV treatment as noted above [17]. Yet, no completed clinical trials have evaluated the efficacy or effectiveness of 3TC/TDF as PrEP. The WHO recommends XTC/TDF (i.e., FTC or 3TC) for HIV treatment and for post-exposure prophylaxis (PEP) [44]. This recommendation was based on a systematic review of 12 clinical trials which evaluated the pharmacological equivalence and clinical interchangeability of FTC and 3TC [42]. In studies of HIV treatment, virologic suppression was not significantly different among any of the 12 trials evaluated; the pooled RR for viral suppression comparing 3-drug regimens containing 3TC or FTC was not significantly different (relative risk [RR] 1.00; 95% CI: 0.97–1.02). Three trials that directly compared 3TC and TDF did not find a significant difference in viral suppression (RR 1.03; 95% CI: 0.96–1.10). These compelling data informed the WHO decision in the absence of a head-to-head comparison.

WHO also recommends interchangeability of 3TC/TDF and FTC/TDF as PrEP [44]. Similarly, to enable flexibility in PrEP drug selection, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) Scientific Advisory Board recommended 3TC/TDF as an acceptable alternative to FTC/TDF for PrEP in December 2015. This recommendation was based on the limited availability of TDF alone or co-formulated FTC/TDF, the widespread availability of 3TC/TDF for PMTCT, treatment, and PEP in several PEPFAR countries, and the similar pharmacoavailability of 3TC and FTC in heterosexual populations [62]. The WHO estimates that 3TC/TFC represents 60–70% of global adult market share [14]. This widespread availability also provides the rationale for a public health advantage – inclusion of 3TC/TDF as PrEP in national guidelines.

7. Inclusion of 3TC/TDF as PrEP in national programmes

The WHO’s prequalification programme has ‘approved’ over 10 FTC/TDF and 3TC/TDF products by generic manufacturers [14]. Flexibility in drug selection (i.e., choice of 3TC/TDF, FTC/TDF or TDF alone) is intended to support PrEP implementation in varied settings; generic formulations of 3TC/TDF and FTC/TDF are already in supply chains. European AIDS Society Guidelines suggest use of generic formulations to increase the cost-effectiveness of PrEP [63]. Globally, an estimated 15 million packs (monthly supplies) of FTC/TDF and 3TC/TDF were procured in 2016 and 2017 [53]. At least 21 countries in Africa, Asia and North, Central and South America now recommend use of 3TC/TDF as PrEP in addition to FTC/TDF in accordance with WHO recommendations; Lesotho recommends exclusive use of 3TC/TDF [64]. Six of the 21 countries which recommend use of 3TC/TDF are in sub-Saharan Africa where 3TC/TDF is already procured through supply chains for HIV treatment. In this setting, use of 3TC/TDF saves money and does not require registration which would delay implementation. According to the WHO Global Price Reporting Mechanism, the median cost of 3TC/TDF and FTC/TDF in 2017 was USD $36.76 and $48.83 per person per year, respectively [53]. As of May 2019, use of 3TC/TDF by the estimated 113,750 PrEP initiates in sub-Saharan Africa would result in an estimated annual saving of USD $1,145,463.

8. Conclusion

Rapid scale-up of oral PrEP as part of combination HIV prevention approaches is critical if global targets for HIV elimination are to be met. The nucleoside reverse transcriptase inhibitors FTC and 3TC in combination with TDF are clinically interchangeable when used for PrEP, PEP, and HIV treatment. Ministries of Health should adopt WHO and PEPFAR recommendations for use of 3TC/TDF as an acceptable alternative to FTC/TDF PrEP, as it confers public health advantages. From a supply chain standpoint, 3TF/FTC is already being procured by HIV programmes across Asia, Latin America and sub-Saharan Africa. 3TC/TDF is an acceptable PrEP regimen according to normative international guidelines and may be particularly appealing in settings with limited availability or affordability of FTC/TDF. Most countries recommending the use of 3TC/TDF as PrEP are in sub-Saharan Africa where use of this regimen saves USD $10.07 per person per year. The recent decision by India to recommend 3TC/TDF for PrEP, given its population size, will likely influence other countries in moving towards policy adoption of 3TC/TDF. Furthermore, regulatory authorities should facilitate registration of 3TC/TDF for a PrEP indication. In closing, national-level guideline committees should encourage flexibility in PrEP drug selection by recommending 3TC/TDF, and, where relevant, support off-label use of 3TC/TDF and conduct routine pharmacovigilance monitoring. Public health decision makers in countries should advocate for the use of generic formulations to decrease cost of PrEP programmes, and thereby accelerate PrEP delivery through the public and private sector.

Key Points.

Lamivudine (3TC) and emtricitabine (FTC) are pharmacologically equivalent and clinically interchangeable for HIV prevention and treatment given comparable pharmacologic equivalence, resistance, toxicity patterns and clinical trial effectiveness.

Normative guideline bodies recommend FTC/TDF or 3TC/TDF for HIV treatment, pre-exposure prophylaxis and post-exposure prophylaxis, but few countries are using 3TC/TDF as PrEP.

Public health advantages of using 3TC/TDF as PrEP include widespread availability through supply chains for HIV treatment, lower procurement costs than FTC/TDF and existing registration with drug regulatory bodies.