Dual nucleoside reverse transcriptase inhibitors (NRTIs) consist of two coformulated, fixed-dose tablets that prevent HIV viral replication by blocking the activity of HIV reverse transcriptase–an enzyme that converts viral RNA to DNA within an infected cell. Combining NRTIs has a more potent effect and may increase adherence to HIV treatment regimens when compared to the activity of any single NRTI.1,2
According to the U.S. Department of Health and Human Services (DHHS), all currently recommended and alternative regimens for antiretroviral therapy (ART) consist of two NRTIs plus a third active drug. The third active drug can include: an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer. Thus, NRTI backbone therapy remains a key component of anti-retroviral therapy (ART) for most HIV-infected patients.3
Here are 10 things that are essential to know when making treatment decisions about NRTI dual backbone therapy:
1. The two currently recommended dual-nucleoside combinations used in initial therapy are abacavir/lamivudine (ABC/3TC) and tenovir/emtricitabine (TDF/FTC).
The DHHS recommends these two NRTI combinations based on the efficacy and durability of virologic response, toxicities, and ease-of-use.3
2. Virologic efficacy has been shown to be comparable in ABC/3TC and TDF/FTC combinations
The HEAT study demonstrated in 688 patients that virologic efficacy is comparable with both ABC/3TC and TDF/FTC NRTI dual backbone regimens. All patients also received LPV/r (a protease inhibitor, where “r” denotes pharmacokinetic enhancement with ritonavir) as a third medication. In a subgroup analysis in patients with HIV RNA ≥100,000 copies/mL, the proportion of patients who achieved HIV RNA <50 copies/Ml was not significantly different at 96 weeks.4The rate of virologic failure was shown to be similar for both groups (14%).4
3. The ASSERT study showed ABC/3TC to be virologically inferior to TDF/FTC
The ASSERT study was designed to compare ABC/3TC and TDF/FTC NRTI backbone therapies in 385 antiretroviral therapy-naive, HLA B*5701-negative patients. All patients also received efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor. Renal safety, as measured by estimated glomerular filtration rate (eGFR) of both regimens, was assessed.5
While there was no difference in treatment groups in renal function, the results demonstrated that at week 48, the TDF/FTC-treated group had a higher proportion of patients with HIV RNA <50 copies/mL compared with patients treated with ABC/3TC.5
4. ABC/3TC is not recommended when viral RNA is ≥100,00 copies/mL
The ACTG 5202 study was a randomized, controlled trial designed to compare the efficacy and safety of ABC/3TC with TDF/FTC, used with either the NNRTI efavirenz or the protease inhibitor atazanavir (ATV/r).6At screening, randomization was stratified by HIV RNA level: either <100,000 copies per/mL or ≥100,000 copies/mL.6
The study demonstrated that time to protocol-defined virologic failure was significantly shorter in the ABC/3TC arm compared to the TDF/FTC arm in patients with ≥100,000copies/mL. This effect was seen regardless of the third active drug that was used.6,7
There was no difference in time to virologic failure in the group with HIV RNA levels <100,000 copies per/mL.7
5. ABC NRTI backbone therapies should only be considered in patients who are HLA B*5701 negative
Before the use of HLA-B* 5701 testing was standard, 5% to 8% of patients treated with ABC experienced hypersensitivity reactions. Patients who are positive for the HLA-B*5701 allele are at high risk for hypersensitivity reactions, and testing for this allele should precede initiation of ABC-based therapy.8,9
Therefore, current DHHS guidelines recommend that only HLA-B* 5701-negative patients should be initiated with ABC/3TC dual backbone therapy.3
6. Use of ABC as part of dual NRTI therapy should proceed with caution in patients with known cardiovascular risk
The initial report of an association between ABC use and myocardial infarction (MI) came from the D:A:D study. This large, multinational observational study group found that patients who were currently using or had used ABC within the previous 6 months were at increased risk of MI. The risk was increased in patients who had other cardiac risk factors.10
Subsequent to the D:A:D report, there have been conflicting results regarding the association between cardiovascular risk and ABC-based backbone therapy, with only some studies having confirmed CV risk.11–13Other studies have failed to establish an association.14–16
Based on conflicting evidence, the DHHS recommends avoiding ABC/3TC backbone therapy or using it with caution in patients with cardiovascular risk factors.3
7. NRTI dual backbone therapycan be associated with mitochondrial dysfunction, particularly with the “d” NRTIs [didanosone (ddI) and stavudine (d4T)].
Mitochondria have their own DNA with 16,000 bases; the replication, recombination and repair of mitochondrial DNA (mtDNA) is achieved by human gamma-polymerase.17 In addition to impairing HIV replication, NRTIs also inhibit human gamma-polymerase. This results in the decline or depletion of mtDNA, resulting in mitochondrial toxicity and associated mitochondrial disorders.17
MtDNA depletion is both time and dose-dependent, with the “d” NRTIs (ddI, d4T, and zalcitabine [ddC], which are rarely used) having the highest affinity to inhibit gamma-polymerase.
In fact, ddI and d4T are not currently recommended as dual NRTI backbone therapy due to a high incidence of toxicities, in particular peripheral neuropathy, pancreatitis and lactic acidosis. In addition, ddI and TDF are not recommended in combination due to a synergistic increase in ddI concentrations—leading to increased risk of pancreatitis and lactic acidosis.3
NRTI mitochondrial toxicity can accumulate in various tissues and can include the following manifestations:17 hepatotoxicity (increased lipid deposits in the liver, which can be associated with micro or macrovasular steatosis and elevated liver transaminases. In rare cases, steatohepatatitis can progress to liver failure and lactic acidosis); elevation in serum lactate; mitochondrial myopathy (manifested as skeletal weakness); cardiomyopathy; peripheral neuropathy; lipodystrophy (can lead to insulin resistance and hypercholesterolemia); pancreatitis; lymphopenia and anemia; impaired ATP production may elevate serum urate production; renal dysfunction; osteopenia.
8. Use TDF/FTC to treat HIV/hepatitis B (HBV) coinfection
TDF, FTC, and 3TC are active against both HIV and HBV. The use of TDF /FTC or TDF/3TC is recommended wherever possible in patients who are coinfected with HBV and HIV.3
9. FTC and 3TC Have similar resistance profiles and are not recommended as dual NRTI backbone therapy
These two NRTI drugs have been shown to have minimal additive effects and have similar resistance profiles. Therefore, the benefit of decreased risk of resistance with dual therapy is lost with this combination.3
10. Stavudine (d4T) and zidovudine (ZDV) have demonstrated antagonism in combination both in vivo and in vitro
Patients receiving ZDV in combination with d4T showed progressive declines in CD4 cell counts. By 16 weeks, there was a median of 22 cells/mm3. Intracellular levels of d4T-triphosphate in 6 patients were consistent with in vitro studies that demonstrated antagonism between d4T and ZVD.