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Page 5 of 39 Guideline

unusual, however, to see haematological toxicity develop ÿ Dolutegravir has been shown to have greater efficacy
after 6 months. Macrocytosis is usual with AZT therapy and than efavirenz (EFV), driven largely by superior
is of little consequence. Routine measurement of vitamin B12 tolerability.
and folate concentrations is not needed. ÿ Dolutegravir causes a small increase in serum creatinine
° Common pitfall: Discontinuing AZT because of (usually 10 μmol/L – 20 μmol/L) because of interference
macrocytosis. This is of little consequence and does with tubular creatinine secretion; however, this does not
not necessarily portend subsequent anaemia. represent a decline in renal function.
ÿ Although definitive data are still lacking, DTG may be
Pure red cell aplasia, which presents with severe anaemia and teratogenic in a small proportion of patients; thus,
a low reticulocyte production index, has rarely been associated treatment decisions in women of reproductive age should
with 3TC and FTC. A bone marrow examination should be discussed and evaluated carefully (see section 19).
9,10
be performed to confirm the condition. A polymerase chain ÿ Weight gain is a newly recognised side effect of InSTIs,
reaction (PCR) test should be conducted to exclude the presence more so with DTG than with RAL, and more so in black
+
of parvovirus B19 infection. If 3TC and FTC are contraindicated women and in patients with lower baseline CD4 counts
because of pure red cell aplasia, then we suggest contacting an and higher VLs.
expert for advice about alternative regimens.
Overview of integrase strand transfer inhibitors
Hyperlactataemia and lactic acidosis Integrase strand transfer inhibitors – often simply termed
Lactic acidosis is a rare but serious and potentially fatal side ‘integrase inhibitors’ – work by preventing the transfer of
effect of NRTIs, most commonly associated with stavudine proviral DNA strands into the host chromosomal DNA.
(d4T), particularly when combined with didanosine (ddI). Currently, two InSTIs are available in southern Africa: DTG
These drugs are no longer used. It can also occur occasionally and RAL. Dolutegravir is preferred to RAL because of its
with AZT. Symptomatic hyperlactatemia without acidosis is higher barrier to resistance, its availability in FDC formulation
more common and is associated with the same drugs. Neither and the ability to take the drug once daily. The SPRING-2
lactic acidosis nor hyperlactatemia without acidosis is seen trial compared DTG- and RAL-containing first-line regimens
with the newer, safer NRTIs such as TDF, ABC, 3TC or FTC. and found no significant differences in virological
Symptoms are non-specific and include nausea and vomiting, suppression, and adverse effects were similar between
11
abdominal pain, dyspnoea, fatigue and weight loss. A raised treatment groups ; however, although no patients in the
lactate (> 5 mmol/L) together with metabolic acidosis DTG arm were found to have developed resistance, one
confirms the diagnosis of lactic acidosis. Low serum patient in the RAL arm developed InSTI resistance and four
bicarbonate (< 20 mmol/L) is the most sensitive marker of developed NRTI resistance. The high barrier to resistance of
acidosis. Patients receiving AZT who develop hyperlactatemia DTG-containing ART regimens has been replicated in other
should be switched to alternative drugs, and lactate should first-line studies and in a study of ART-experienced patients
be monitored serially until resolution. In severe patients, in which DTG was compared with RAL. 12,13,14 In a meta-
admission may be required. analysis that included clinical trials and observational
studies, the emergence of InSTI resistance was more common
15
Lipoatrophy with RAL than with DTG (3.9% vs. 0.1%). However, the
emergence of InSTI resistance in patients receiving RAL can
The thymidine analogue NRTIs (AZT and especially d4T) are compromise second-generation InSTIs, such as DTG.
associated with subcutaneous fat loss (most noticeable in the
face, limbs and buttocks). Lipoatrophy improves when d4T/ Dolutegravir use has been shown to be superior to EFV-based
AZT are substituted with TDF or ABC, but resolution is very ART in the SINGLE trial. This difference was largely driven
12
slow and often incomplete; therefore, it is important to by the superior tolerability of the DTG arm: 2% in the DTG
recognise lipoatrophy early or, better still, to use NRTIs that arm compared with 10% in the EFV arm had an adverse
are not associated with the condition. Although d4T is no event leading to discontinuation of the study drug.
longer used, patients who received it historically may still Dolutegravir showed superior rates of viral suppression
have lipoatrophy.
compared with EFV (71% vs. 63% at 144 weeks).
3. Integrase strand transfer inhibitor Dolutegravir-based regimens have also been shown to be
class of antiretroviral drugs superior to protease inhibitor (PI)-based regimens. As a first-
Key points line therapy, DTG was superior to darunavir/ritonavir
(DRV/r) in terms of both viral suppression rates and side
13
ÿ Two integrase strand transfer inhibitors (InSTIs) are effect profile. The ARIA trial of ART-naive women
available in southern Africa, namely, DTG and raltegravir demonstrated DTG’s non-inferiority to atazanavir (ATV)/
(RAL). ritonavir (ATV/r), although with a statistically significantly
ÿ Dolutegravir is preferred to RAL because it has a higher higher rate of viral suppression and fewer side effects
16
barrier to resistance, is available in FDC formulation and overall. In the DAWNING trial considering second-line
can be taken once daily. regimens, DTG was found to be superior to lopinavir/

http://www.sajhivmed.org.za 23 Open Access