Page 69 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 4 of 7 Opinion Paper

neuropsychiatric side effects on efavirenz, alternatives are If confirmed, this signal will raise a dilemma regarding the
currently limited. Nevirapine cannot be prescribed for use of dolutegravir in women at risk of falling pregnant.
women initiating ART with CD4+ counts above 250 cells/µL
or men initiating ART with CD4+ counts above 400 cells/µL Dolutegravir in combination with
because of the risk of severe hepatotoxicity. In addition, rilpivirine: A nucleoside-sparing
nevirapine is associated with a higher frequency of severe
adverse events, particularly treatment discontinuations, treatment option
8
than efavirenz. The only other alternative in current Recent data from the SWORD 1 and 2 studies of dolutegravir
guidelines for patients with high CD4+ counts is to initiate in combination with rilpivirine suggest that this dual therapy
ritonavir-boosted lopinavir. As ritonavir-boosted lopinavir is regimen may be effective maintenance regimens in
used in second-line therapy, this limits future treatment virologically suppressed patients. The SWORD studies
46
options. As rilpivirine has better tolerability than efavirenz, randomised virologically suppressed participants with no
14
a rilpivirine-based regimen would be a very useful alternative history of virological failure to continue their current ART
for patients with contraindications to efavirenz or treatment- regimen or switch to dolutegravir and rilpivirine. Switching
limiting toxicity once initiated on efavirenz-based ART.
to the dual therapy regimen was found to be non-inferior to
Role of rilpivirine as programmes continuing the initial regimen over 48 weeks. This is despite
the inherent bias of the switch study design against the drug
move to dolutegravir-containing being studied, where switching may result in adverse events
first-line therapy that could result in virological failure because of non-
adherence. In addition, observational data from several
Dolutegravir is newly included in current WHO guidelines as a cohorts have demonstrated the efficacy of this regimen in
recommendation for first-line ART and is starting to be rolled achieving and maintaining virological suppression in
out across several lower- and middle-income countries. patients with varying degrees of antiretroviral experience. 47,48,49
Dolutegravir has demonstrated robustness with a formidable A fixed-dose combination of rilpivirine and dolutegravir was
barrier to resistance, good tolerability and superiority to both recently approved by the Food and Drug Administration
efavirenz and ritonavir-boosted lopinavir in clinical trials, in (FDA), based on the results of the SWORD studies. However,
50
both antiretroviral-naïve and experienced patients. 33,34 In these the inability to co-administer with rifamycin-containing TB
studies, dolutegravir’s tolerability is likely to have contributed treatment limits the usefulness of this coformulation in
to the superior efficacy demonstrated. The main dolutegravir- lower- and middle-income settings with high TB burdens.
related treatment-emergent adverse event reported in these
studies was insomnia. 33,34 Dolutegravir was found to be Rilpivirine in long-acting injectable
protective of discontinuations because of adverse events in a
network meta-analysis that included 34 032 patients on first-line antiretroviral regimens
ART. Dolutegravir was also shown to have superior efficacy to The combination of long-acting rilpivirine and the integrase
35
both efavirenz and rilpivirine in the network meta-analysis. 35 inhibitor cabotegravir is being studied in an injectable therapy
for the treatment and prevention of HIV-1 infection. The phase
Because of the relatively small number of carefully selected 2b LATTE 2 study randomised patients to oral cabotegravir
participants included in registrational studies of newer plus abacavir plus lamivudine and long-acting cabotegravir
antiretrovirals, more information regarding the safety profile plus rilpivirine injected 4 weekly, and found that the injectable
may emerge only after registration, once the use of the dual therapy regimen was well tolerated and had efficacy
antiretroviral becomes more widespread. Since dolutegravir’s similar to the oral regimen. Further studies, such as first long-
51
approval, observational cohorts have reported neuropsychiatric acting injectable regimen (FLAIR) and ART as long-acting
adverse events, including depression, anxiety and suicidal suppression (ATLAS), are currently underway to evaluate this
ideation in patients receiving dolutegravir. 36,37,38,39 This has dual therapy injectable regimen. However, there is still
been seen with other integrase inhibitors and has been significant research needed before this regimen could be
postulated as a possible class effect. 40,41,42,43 More recently, data considered for programmatic use in lower- and middle-income
44
have suggested that dolutegravir may also be associated with countries. This would need to include data on TB co-infected
weight gain in a number of cohorts as well as clinical studies. and pregnant patients.
Potentially, rilpivirine could be used in people living with HIV
who experience intolerance to dolutegravir as the transition to The role of rilpivirine in HIV
dolutegravir-based first-line ART rolls out. prevention: Pre-exposure prophylaxis

Furthermore, a prospective study was set up in Botswana to Currently the only approved and WHO-recommended pre-
quantify the incidence of neural tube defects with efavirenz exposure prophylaxis (PrEP) option is oral tenofovir-based
30
exposure. This cohort also considers other birth outcomes PrEP, which has demonstrated its efficacy in preventing
and includes a number of patients on dolutegravir. It recently HIV infection in multiple randomised controlled trials and
52
showed a worrying signal of increased incidence of neural demonstration projects in different target populations, with
45
tube defects with periconception use of dolutegravir. more evidence continuing to accumulate. However, there are
http://www.sajhivmed.org.za 62 Open Access