Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) work by acting as nucleotide base analogues. Following incorporation into the DNA chain by HIV’s reverse transcriptase enzyme, they block further chain elongation. A summary of NRTIs is provided in Table 1, and the appropriate baseline investigations and required monitoring in Table 2. NRTIs may be available as single tablets or in fixed dose combinations (FDC). The latter is recommended where possible to decrease overall pill burden. Many NRTIs require dose adjustment in renal failure (see module 21).

Tenofovir is available in two oral prodrug forms: tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Both are converted to the pharmacologically active form, tenofovir diphosphate, intracellularly. Similar to 3TC/FTC, when tenofovir has been part of an initial ART regimen, it may be continued in subsequent regimens even in the face of high-level resistance, as sufficient antiviral activity is maintained if combined with drugs with a high genetic barrier to resistance. ⁴

Both forms of tenofovir offer durable therapy against hepatitis B virus (HBV) as HBV resistance against tenofovir is exceedingly rare. In a minority of patients, tenofovir may cause a tubular wasting syndrome (including wasting of phosphate and potassium). ⁵ If patients receiving tenofovir develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. Tenofovir can also cause acute and chronic renal failure, but this is uncommon. ⁶ Long-term use of TDF together with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal anti-inflammatory agents) should nonetheless be avoided.

TDF also causes a decrease in bone mineral density, but this is generally mild, and most studies have not found an increase in fracture risk.

Of the two forms of tenofovir, we recommend TDF as the drug for use with 3TC or FTC in most instances, as it aligns with public sector programmes, is more widely available as a FDC, and is generally well-tolerated. TDF should not be used if the estimated glomerular filtration rate (eGFR) is < 50 mL/min/1.73m².

TAF has fewer renal and bone side-effects than TDF, although the extent of this has been questioned. ^{7, 8} When coformulated with 3TC/FTC, TAF can be given down to a minimum eGFR of 30 mL/min/1.73m². However, if given as a separate tablet, TAF can be given down to an eGFR of 15 mL/min/1.73m², as well as to patients on chronic haemodialysis. Compared to TDF, TAF is associated with greater weight gain, an adverse lipid profile, and several important drugdrug interactions (see module 17 for more details). ^{9- 11} The TAF 25mg dose currently available in South Africa should not be used with ritonavir-containing PI regimens. Although rifampicin reduces serum TAF levels, intracellular concentrations of the active tenofovir metabolite are in fact higher than achieved with TDF, and thus rifampicin-based TB treatment is safe to co-administer. ¹² TAF/FTC combinations can be considered as an alternative to TDF in patients with eGFR 30-50 mL/min/1.73m² or with osteoporosis, although abacavir (ABC) is also available in these instances as an alternative. TAF is recommended in patients who have one or more of these conditions and hepatitis B.

Tenofovir (either TDF or TAF) should be switched to ABC or an alternative NRTI immediately in patients with acute kidney injury, as it may exacerbate injury even if it is not the primary cause. Consider recommencing tenofovir (either TDF or TAF) with careful monitoring when the eGFR returns to baseline and if an alternative cause of renal failure is established. In patients in whom tenofovir is avoided because of a low eGFR at baseline, it may be possible to switch to tenofovir at a later point if renal function improves. This is often the case where patients had diarrhoea or other opportunistic infections (OIs) at the time of ART initiation.

For monitoring while on TDF see Table 2.

Common pitfall: Permanently discontinuing TDF in patients with a transiently decreased eGFR. Most cases of acute kidney injury (AKI) are not due to TDF, and if another cause of AKI is identified (e.g. severe diarrhoea or pneumonia), then TDF can be re-introduced with monitoring once renal function improves.

Lamivudine (3TC) and emtricitabine (FTC) are welltolerated drugs recommended as part of a firstline regimen. Although there are minor differences between them, 3TC and FTC are considered functionally interchangeable. Their use may be continued in the presence of ‘high-level resistance’ caused by the M184V mutation, since this mutation impairs HIV’s replication ability, causing a ~0.5 log decrease in viral load (VL). Therefore, these drugs are often also recycled in second- and third-line therapy (see the management of patients on second-line ART in module 13). 3TC and FTC are active against hepatitis B, but when used in the absence of a second drug active against hepatitis B, such as TDF, then resistance rates of approximately 50% at 1 year, and 90% at 5 years, are seen. ¹ See module 20.

Pure red cell aplasia (PRCA), which presents with severe anaemia and a low reticulocyte production index, has rarely been associated with 3TC and FTC. ^{2, 3} A bone marrow examination should be performed to confirm the condition. Parvovirus B19 infection should be excluded with a polymerase chain reaction (PCR) test. If 3TC and FTC are contraindicated due to PCRA, then we suggest contacting an expert for advice about alternative regimens (see module 11 for some 3TC/FTC-sparing regimen options).

Abacavir (ABC) does not require dose adjustment in renal failure and is especially useful in patients with chronic renal failure, in whom tenofovir is nephrotoxic and zidovudine (AZT) could aggravate the anaemia of renal failure. A meta-analysis showed that virological suppression is equivalent with ABCand TDF-containing first-line regimens regardless of baseline VL. ¹³

Common pitfall: Avoiding ABC in patients with a high VL. This is a common misconception and is unnecessary, as viral suppression rates are equivalent in meta-analyses.

ABC has been associated with an increased risk of myocardial infarction in some but not other cohort studies, but the association was not confirmed in a meta-analysis of randomised controlled trials (RCTs). ^{13- 15}

ABC hypersensitivity is a systemic reaction occurring within the first 8 weeks of therapy in ~6% of people of European ancestry. ¹⁶ Fatalities may occur on rechallenge. ABC must be discontinued and never reintroduced if hypersensitivity is suspected. The manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. If there is any doubt concerning the diagnosis (e.g. if the patient has a cough with fever), then the patient should be admitted for observation of the next dose: if symptoms progress, hypersensitivity is present. The hypersensitivity reaction has been shown to occur on a genetic basis, with a very strong association with the HLA-B*5701 allele. This allele is very uncommon in people of African descent thus ABC hypersensitivity is less frequent. If testing is affordable and available, then the presence of HLA-B*5701 should be excluded prior to prescribing ABC, especially in patients who are not of African descent.

We recommend reserving zidovudine (AZT) for use only in special circumstances where both tenofovir and ABC are unavailable or contraindicated. In these instances, AZT can be used, provided that the haemoglobin (Hb) is > 8 g/dL. AZT can cause neutropenia and anaemia; platelet counts generally rise with the use of the drug. Monitoring is necessary with AZT (see Table 2). It is unusual, however, to see haematological toxicity develop after 6 months. Macrocytosis is usual with AZT therapy and is of no consequence. Routine measurement of vitamin B12 and folate concentrations is not needed.