Adverse Effects and Contraindications of Lamivudine, Dolutegravir, and Tenofovir

Introduction to Adverse Effects

The combination of dolutegravir with lamivudine and tenofovir is generally well-tolerated with minimal toxicity, but requires specific monitoring for renal effects with tenofovir, potential neural tube defects with dolutegravir in early pregnancy, and viral resistance with lamivudine in hepatitis B co-infection 1, 2

Insomnia and headache are the most common adverse effects reported in comparative studies, although they are generally mild 1
These neuropsychiatric symptoms were more frequent with dolutegravir than with some comparators in clinical trials 1
There is a risk of neural tube defects: initially, a small but statistically significant increase in neural tube defects was observed in Botswana among infants conceived while mothers were receiving dolutegravir 1, 2
Updated data show that this risk has decreased over time and the difference is no longer statistically significant compared to other antiretroviral regimens 2
Dolutegravir plus tenofovir/emtricitabine is recommended as a safe option when initiated during pregnancy 2
Elevated serum creatinine due to inhibition of creatinine tubular secretion (does not represent real renal damage) 3

Critical contraindication: co-infection with hepatitis B, as lamivudine monotherapy can select for hepatitis B virus resistance 1, 2, 4, 5, 6
This is an absolute contraindication that requires verification before initiating the regimen 2
Lamivudine is generally well-tolerated with minimal toxicity 1

Tenofovir disoproxil fumarate (TDF) is associated with proximal renal tubular toxicity, the most significant adverse effect 4, 6
TDF is also associated with reduced bone mineral density 4, 6
These effects are more pronounced when TDF is used with pharmacological boosters (ritonavir or cobicistat) that increase tenofovir levels 4, 6
Tenofovir alafenamide (TAF) has fewer adverse effects associated with tenofovir (renal toxicity and bone loss) compared to TDF 4, 6
TAF is associated with greater weight gain than TDF 4, 5, 6
TAF has higher lipid levels than TDF 4, 5, 6

CD4 <200 cells/μL: numerically lower response rate with dolutegravir/lamivudine (79%) vs 3-drug regimen (93%), although not related to higher virologic failure rate 1, 4, 5, 6
Viral load >500,000 copies/mL: efficacy of the 2-drug regimen (dolutegravir/lamivudine) is unknown in this population 1, 4, 5, 6
The American College of Physicians recommends confirming the absence of resistance through genotypic testing before initiating dolutegravir/lamivudine 1, 4, 5, 6
The World Health Organization recommends against using dolutegravir/lamivudine in co-infection with hepatitis B without additional coverage for hepatitis B 1, 2, 4, 5, 6