Assessment of the nevirapine safety signal using data from the national antiretroviral dispensing database: a retrospective study

The assumption that the substitution of NVP with a PI (mainly LPV/r) within 24 weeks
of ART was made due to grade III or IV ARs, was substantiated by the following. First:
NVP-related reactions of liver and skin are known to occur mainly within the first
few weeks of ART, but they may also occur as late as 18 weeks and more 4], 16]. Second: Namibia’s 2010 ART guidelines recommended that when a grade III or IV AR
– such as Steven-Johnson’s Syndrome, Toxic Epidermal Necrolysis, and very high alanine
transferase levels in plasma (hepatotoxicity) – occurs, NVP should be substituted
with LPV/r 3]. Third: The replacement of NVP with LPV/r, without any alteration in the nucleoside
backbone, within six months of ART was not judged to be treatment failure. Namibia’s
2008 ART guidelines recommended adherence-counselling for patients with poor virologic
response before, at, or after six months of ART 3]. Therefore, TDF/3TC/LPV/r was considered to be a first line regimen.

During the period before the publication of Namibia’s 2010 ART guidelines, TDF had
been prescribed as part of the nucleoside backbone of first line ART only when zidovudine
or stavudine were contraindicated 20]. Immediately after the publication of these guidelines, there was a substantial increase
in the dispensing of TDF/3TC/NVP, the new preferred first line regimen. This immediate
increase in the dispensing of TDF/3TC/NVP was not surprising, because the coordination
between the Division of Pharmaceutical Services (DPS) and the Directorate of Special
Programs (DSP) allowed the publication of the guidelines only when the medicines were
available at the Central Medical Stores. [The DPS is in charge of the supply chain
management of all pharmaceuticals for the Ministry of Health; and DSP is responsible
for HIV care and treatment.] Therefore, compliance to the ART guidelines on issues
such as the choice of first line ART regimen was facilitated, on the big part, by
availability of the regimen, but also by the training of health care workers (HCW),
who work in health facilities that provide ART.

The publication of the 2010 ART guidelines was followed by the increase in the number
of patients who were newly initiated on ART. The previous guidelines recommended that
one was eligible for ART when one’s CD4 count was 200cells/mm
³
. During that period (2008–Early 2010), an average of 3,414 patients were initiated
on first line ART per quarter (Range?=?613). The 2010 ART guidelines recommended that
one was eligible for ART when one’s CD4 count was ?350cells/mm
³
. After the 2010 ART guidelines were published, in the fourth quarter of 2010, a total
of 5352 were initiated on ART. In the next quarter – Jan-Mar 2011 – almost 6000 patients
were initiated on ART. The average number of patients newly started on ART for these
two quarters – 5,676 – was greater than the average of the previous period by 60 %.
A TIPC report concerning the safety of NVP, showed that HIV infected patients were
initiated on ART when their baseline CD4 cell count was 200cells/mm
³
[“Personal Communications” – Dr. Assegid Mengistu]. Also, the analysis of NVP-related
reaction reports showed that the majority of those who had the baseline CD4 cell counts
recorded on the report (n?=?55), were females (n?=?48). Of these, 60 % had baseline CD4 cell counts 250 cells/mm
³
. It is likely that the increase in the number of patients initiated on ART was a
result of initiating NVP-containing ART in patients with a CD4 cell count 200cells/mm
³
.

The increase in NVP-to-PI substitutions that was observed from the third quarter of
2010 to the third quarter of 2011 started with the use of TDF/3TC/NVP (Fig. 4). Since the new guidelines had lifted the prohibition of the use of NVP in females
with baseline CD4 counts 250cells/mm
³
, plus the fact that female patients were indeed given NVP-containing first line ART
with CD4 counts 250cells/mm
³
, we believed that the increase in NVP-to-PI substitutions was associated with the
high baseline CD4 cell count in females. However, the number of patients for whom
NVP was replaced with a PI was low, despite the statistical significance. We supposed
that the few NVP-to-PI substitutions were because only a handful of female patients
had a baseline CD4 cell count 250cells/mm
³
at the start of TDF/3TC/NVP. This supposition borrowed evidence from the prospective
study that TIPC carried out to assess the safety of first line ART, which showed that
indeed many patients were initiated on ART with a CD4 cell count 250cells/mm
³
[“Personal Communication” – Dr. Assegid Mengistu]. The reduction in the number of
patients newly started on ART, coupled with the decline in the number of NVP-to-PI
substitutions, may be due to reversion of HCW to the previous ART guidelines in regards
to the safety of NVP.

Our findings were limited by the following reasons. First: We eliminated all records
of patients who were changed from NVP to, and remained on EFV. This impacts on the
results, because it is possible that NVP was substituted with EFV following ARs of
any severity level – grades 1 to 4 – without recurrence or escalation of the reaction.
For a sustained, unrelenting grade I reaction, or grade II reaction, the substitution
of NVP with EFV is appropriate 20]. However, for grade III or IV reactions, the change to EFV is not recommended 21]. On the other hand, it was worth eliminating these since a change from NVP to EFV
may have been implemented because of the management of tuberculosis, but this was
not verifiable, by virtue of the data source that was employed. Second: we eliminated
records of patients who were changed from NVP to LPV/r through EFV. We eliminated
these, because we did not know whether the change to LPV/r was due to a reaction associated
with EFV or it was the worsening of NVP’s reaction. Therefore, the elimination of
records may have downplayed the proportion of NVP related reactions. The increase
in the number of NVP-to-PI substitutions could be used to explain the increase in
NVP-related skin and liver AR reports that were shown in the analysis of NVP-related
AR reports 18]. Another limitation to this study was the lack of baseline CD4 count data. This data
would have solidified our argument. Nevertheless, the argument stood the test as the
new ART guidelines reverted back to the former safety measures: to avoid NVP in females
with baseline CD4 counts above 250cells/mm
³
.