Treatment optimisation: technical updates from WHO

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Tucked away before the slog of the International AIDS Conference, the elation of the Olympics and the despair at the appointment of our new health minister, was the release of three technical updates by the World Health Organization (WHO).

These reviews looked at different aspects of the current WHO Treatment 2.0 preferred adult first line regimen of a once-daily fixed dose combination (FDC) of efavirenz/lamivudine/tenofovir (EFV/3TC/TDF).

Efavirenz in pregnancy

Use of EFV in pregnancy has been a cause of confusion, with some programmes switching women to nevirapine (NVP) – frequently after the period of potential risk is passed – due to the belief that its use in early pregnancy could be teratogenic. EFV exposure in pregnancy has sometimes resulted in an increase in abortion and switching to serious NVP-associated hepatic events. Use of efavirenz during pregnancy: a public health perspective reviews the evidence on the safety, tolerability and efficacy of EFV, as well as the clinical and programmatic consequences of complex switching algorithms for this population. The review concludes: “Based on currently available evidence, programmatic considerations and a careful weighing of risks and benefits, EFV should be considered as part of the preferred first-line treatment option, including among women of reproductive age and those in the early stages of pregnancy”. This concurs with the most recent BHIVA guidelines in which, we write: “Based on the emerging prospective data in which no evidence of human teratogenicity has been seen, the Writing Group consider that there are insufficient data to support the former position and furthermore recommend that efavirenz can be both continued and commenced in pregnancy.”

Lamivudine and emtricitabine

3TC and FTC are generally considered to be clinically equivalent (and the figure showing the two molecules side by side on page 5 of the WHO review is a “spot the difference”). But some in vitro studies have suggested there might be pharmacological differences, giving FTC a potential advantage over 3TC.

Pharmacological equivalence and clinical interchangeability of lamivudine and emtricitabine: a review of current literature is a comprehensive survey of all the available data relevant to this comparison, including preclinical studies, efficacy and safety data from clinical trials, comparative data concerning the development of resistance, considerations of patent barriers, comparative cost analysis and the availability of fixed-dose combinations.

The authors note that, although it is based on few direct comparisons, a recent systematic review indicated that the clinical and virological efficacy and safety of 3TC and FTC are comparable. This review also revealed a greater association of the M184V/I mutation with the use of a 3TC- compared to a FTC-containing regimen. But they write, “the clinical and public health implications of this difference are not clear, and seem to depend largely on the presence or absence of other concomitant nucleoside analogue mutations”.

Although the data appear to support the interchangeability of these two antiretrovirals, WHO recommends that population-based monitoring of 3TC- and FTC-associated resistance patterns should be considered.

Tenofovir use in children

The US Food and Drug Administration (FDA) recently approved tenofovir (TDF) for adolescents and children above the age of two years. The recommended dose is 8 mg/kg  (up to a maximum of 300 mg), once daily using either an oral powder formulation or reduced strength tablets.

One of the goals of treatment optimisation is to harmonise paediatric antiretroviral regimens with adult recommendations. Using TDF in children could offer this possibility – although with current options, infants and young children less than three years old need to be considered differently.

That FDA approval, for children aged 2 to 12 (approval for the 12-18 age group was in 2010), took eleven years since its adult approval in 2001 is indicative both of problems developing the formulation and lack of safety data in children.

Use of tenofovir in HIV-infected children and adolescents: a public health perspective reviews the current published and unpublished data on the safety and efficacy of TDF in this population. 

This review found that based on the available data, TDF is efficacious in children and adolescents at current US FDA-approved doses, but further studies are needed to confirm the dose and investigate the side-effects of TDF in combination with EFV in this population.

The main toxicities with TDF are decreased bone mineral density, and glomerular and renal tubular dysfunction. Data in children are very sparse but suggest that the toxicities are similar to those seen in adults.

Bone turnover is higher in young children and adolescents because they are growing. Children’s bone mineral density increases over time whereas in adults it remains constant or decreases with age, so comparisons between adults and children are difficult. Plus children with HIV have lower bone mass than background population for their age and sex.

A correlation between TDF associated decrease in bone mineral density and younger age has been observed as well as with decline in viral load. Other antiretrovirals, such as d4T and protease inhibitors (particularly ritonavir) are also associated with lower bone mineral density. But the authors note that the clinical consequences of low bone mineral density related to HIV or ART are unclear. Unlike adults, increased bone fracture risk has not been seen in children. The impact of lower bone mineral density on longer-term risk of fracture and osteoporosis is not known.

Decreased renal function, phosphaturia and hypophosphataemia occur over time in HIV positive children and adolescents receiving ART. Children on TDF have shown higher rates of hypophosphataemia compared to those treated with other ARVs. Several studies have suggested significant glomerular and renal tubular toxicity in children on TDF, but the role  of other ARVs, such as ddI and ritonavir-boosted lopinavir is unclear.

The authors write: “The benefits of using TDF in children need to be balanced against the potential risk of toxicity… Further research and long-term pharmacovigilance are warranted as TDF is rolled out in treatment programmes for children and adolescents”.

Based on the paediatric approval of TDF, the WHO Paediatric ARV Working Group developed guidance on appropriate future TDF-containing paediatric FDCs and a simplified weight band-based dosing schedule. FDCs with 3TC are priority.

  1. Dual TDF/3TC FDC  – either scored adult tablet if feasible or a child-specific tablet containing TDF 75 mg and 3TC 75 mg (a 1/4 scale down of the adult tablet)
  2. Triple TDF/3TC/EFV FDC  – either scored adult tablet or a child-specific tablet containing TDF 75 mg, 3TC 75 mg and EFV 150 mg (a 1/4 scale down of the adult tablet)
  3. Dual TDF/FTC FDC child-specific tablet containing TDF 75 mg and FTC 60 mg
  4. Triple TDF/FTC/EFV child-specific tablet containing TDF 75 mg, FTC 60 mg and EFV 150 mg.

The feasibility of scoring adult FDC tablets once on one side and twice on the other was considered. The doses delivered by tablets divided into thirds and halves would be acceptable, but there was concern that in practice it may be difficult to manufacture, score and split large, multilayered FDC tablets in this way. So the group noted that if such tablets were possible, it would be important to establish feasibility, PK and bioavailability data to support this dosing strategy.