Human Immunodeficiency Virus (HIV) is a chronic infection attacking the
immune system of the human body, particularly targeting CD4 lymphocytes.
It may cause fatal consequences by leading to the Acquired Immune
Deficiency Syndrome (AIDS), which is characterized by opportunistic
infections as a result of immune suppression. HIV-infected persons
should be begun on antiretroviral therapy (ART) as soon as possible,
both to improve their own survival rate and to reduce the risk of
transmitting the disease to others1. ARTs are known to
exert beneficial effects on the natural course of the HIV infection and
patient survival 2. Combined ARTs (cARTs) are highly
effective in the virological suppression of HIV
infection3. In addition to two nucleoside analog
reverse transcriptase inhibitors (NRTIs), the combined use of a third
active drug is recommended, namely an integrase strand transfer
inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor
(NNRTI), or an amplified protease inhibitor (PI) for the treatment of
HIV-infected persons4.
HIV-positive patients are at risk of both acute kidney injury (AKI) and
chronic kidney disease (CKD) due to drug nephrotoxicity, HIV-associated
nephropathy (HIVAN), and immune complex kidney diseases
(HIVICK)5. Studies have shown that some ARTs have a
greater nephrotoxicity potential6-8. While these drugs
can cause direct kidney injury by tubular dysfunction, acute
interstitial nephritis, and kidney stones, they also cause kidney injury
via drug-drug interactions, drug dosing errors, and ART-induced
rhabdomyolysis, lactic acidosis, and metabolic
complications9. Kidney injury results in increased
serum creatinine and reduced estimated glomerular filtration rate
(eGFR).
ART-associated kidney injury is an important cause of mortality and
morbidity. Hence, it is important to monitor serum creatinine and eGFR
during ART. The aim of our study was to assess the changes in renal
function during a 24-month period in HIV-positive patients who received
cART.Material-methods
The medical records of 140 HIV-positive patients who were followed and
treated between 2017 and 2019 were retrospectively reviewed.
HIV-positive patients older than 18 years were enrolled irrespective of
sex whereas patients younger than 18 years, those who had used antiviral
therapy, those who were receiving nephrotoxic agents, and those who had
a baseline eGFR level below 60 mL/min/1.73m2 were excluded. As a result,
127 patients were enrolled per the study protocol (Figure 1). The study
was approved by the Dicle University Faculty of Medicine local ethics
committee (06.02.2020/146).
The patients were divided into 5 groups:
Group 1 (n=11): Untreated HIV-positive patients.
Group 2 (n=19): HIV-positive patients treated with Dolutegravir (DTG) +
Abacavir (ABC) + Lamivudine (3TC) combination.
Group 3 (n=31): HIV-positive patients treated with Elvitegravir (EVG)/
Cobicistat (COBI)+ Emtricitabine (FTC)+ Tenofovir Alafenamide Fumarate
(TAF) combination.
Group 4 (n=33): HIV-positive patients treated with Emtricitabine (FTC) +
Tenofovir Disoproxil Fumarate (TDF) + Dolutegravir (DTG) combination.
Group 5 (n=33): HIV-positive patients treated with Emtricitabine (FTC) +
Tenofovir Disoproxil Fumarate (TDF) + Raltegravir (RAL) combination.
Age, sex, height, weight, body mass index, pre-treatment HIV RNA level,
CD4, CD8 levels, as well as the pre-treatment and post-treatment 6th,
12th, and 24th-month creatinine and eGFR levels were recorded. eGFR
level was calculated with the 4-variable Modification of Diet in Renal
Disease (MDRD) formula. Then, the eGFR levels of the study groups were
compared.Statistical AnalysisStudy data were statistically analyzed using SPSS (Statistical Package
for Social Sciences) version 24.0 software package (SPSS Inc, Chicago,
IL). The normality of the distribution of the study variables was tested
with visual (histogram and likelihood graphics) and analytic methods
(Kolmogorov – Smirnov / Shapiro – Wilk tests). The results were
reported as number and percentage for categoric variables and mean ±
standard deviation for continuous variables. The effects of treatment
and time on eGFR were evaluated using repeated ANOVA measurements.
Mauchly’s Test of Sphericity was used to check the assumption of
sphericity. If Mauchly’s test statistic was significant, the Greenhouse
– Geisser or Huynh – Feldt correction was used. If the
main/interaction effect was significant, a Bonferroni correction was
applied for multiple comparisons. According to our treatment groups, the
values of eGFR over time are presented with a profile plot (Figure 2).
Inter-group analysis of non-normally distributed variables was performed
with Kruskal – Wallis test, with Mann – Whitney U test being used for
paired group comparisons. A p-value of less than 0.05 was considered
statistically significant.Results The 24-month follow-up data of 127 patients were reviewed and the groups
were compared (Table 1). One hundred and seven (84.3%) patients were
male, and 20 (15.7%) patients were female. The mean age was 29.37± 7.06
years, and the mean BMI was 27.45± 3.65. While there was no significant
difference between the study groups with respect to age, sex, BMI,
pre-treatment CD8 level, creatinine, and eGFR levels, significant
differences were detected regarding pre-treatment HIV-RNA, CD4 level,
CD4/CD8 ratio (p:<0.001 for all comparisons). Pre-treatment
CD4 level and the CD4/CD8 ratio were significantly lower whereas HIV-RNA
level was significantly higher in Groups 2, 3, 4, and 5
(p:<0.001, for all comparisons). Groups 3 and 4 had
significantly higher CD4 levels than Group 2 (p<0.05). Groups
3, 4, and 5 had significantly lower HIV-RNA levels than Group 2
(p<0.05).
The groups’ pre-treatment, 6th month, 12th month, and 24th-month serum
creatinine and eGFR levels were calculated and compared. eGFR levels at
the 6th month of therapy were significantly different between the study
groups (p:0.002). Inter-group comparison of eGFR level showed that it
was significantly lower in Group 4 compared with Groups 1, 2, and 3
(p:0.023, p:0.033, p:0.001, respectively), and also significantly lower
in Group 5 than Group 1 and 3 (p:0.029, p:0.003, respectively). However,
there was no significant difference between Group 4 and Group 5
(p>0.05). Serum creatinine level was significantly higher
in Groups 4 and 5 than in the other groups (p<0.05).
An analysis of eGFR levels at the 12th month of therapy showed a
significant difference between the groups (p:<0.001). Group 4
had a significantly lower eGFR level than Groups 1, 2, and 3 (p:0.002,
p:<0.001, p:0.001, respectively); similarly, Group 5 had a
significantly lower eGFR level compared with Groups 1, 2, and 3
(p:0.002, p:<0.001, p:0.001, respectively). On the other hand,
Group 4 and Group 5 showed no significant difference
(p>0.05). Serum creatinine level was significantly higher
in Groups 4 and 5 compared with the other groups (p<0.001).
The study groups showed significant differences regarding the 24th-month
eGFR levels (p:<0.001). Group 4 had a significantly lower eGFR
than Groups 1, 2, and 3 (p:0.009, p:<0.001,
p:<0.001, respectively); similarly, Group 5 had a
significantly lower eGFR level than Groups 1, 2, and 3 (p:0.005,
p:<0.001, p:<0.001, respectively). However, no
significant difference was found between Group 4 and Group 5
(p>0.05). Serum creatinine level was significantly greater
in Groups 4 and 5 than in the other groups (p<0.001).
Figure 2 shows monthly eGFR changes within treatment groups and
inter-group eGFR comparisons. Temporal eGFR change was not statistically
significant in Groups 1, 2, and 3 (p:0.397, p:0.448, p:0.886,
respectively). A significant decrease in eGFR was observed in Groups 4
and 5 at 6th month (p:<0.001), 12th month
(p:<0.001), and 24th month (p:<0.001) compared to
baseline.DiscussionOur study evaluated the kidney function of HIV-positive patients who
were administered different cART regimens during a 24-month follow-up
period. the cART should be started as soon as possible in HIV-infected
patients to improve quality of life and reduce the transmission
risk1. cARTs are highly effective in the virological
suppression of HIV infection3. Important randomized
clinical trials such as START and TEMPRANO have shown that cART achieves
approximately a 50% reduction in morbidity and
mortality10,11. Although it has been shown that early
initiation of cARTs reduces the incidence of CKD (by reducing the rates
of viral infection, opportunistic infections, immune complex glomerular
injury, and HIVAN), it is known that some antiretroviral drugs have the
potential to induce nephrotoxicity in persons with normal or impaired
eGFR2,6,12. Thus, changes in serum creatinine and eGFR
during treatment should be correctly interpreted and the treatment
should be tailored accordingly.
Tenofovir is a nucleotide reverse transcriptase inhibitor, with both TAF
and TDF being its pro-drugs. Both of them show similar properties by
inhibiting viral replication, which enables them to be used in HIV
therapy. TDF, an important component of the first-line ART regimens
recommended by the World Health Organization13, is
recognized as an ART that is most commonly associated with renal adverse
reactions. Renal toxicity may occur as a result of tubular
dysfunction/injury. Clinical studies performed so far have reported eGFR
decline of variable degree within months after starting TDF. As the
amount of TDF exposure increases, eGFR decline becomes more
pronounced14. In a clinical study performed by Patel
et al. in western India15, kidney dysfunction
developed by an average of 150 days after the initiation of TDF therapy.
Izzedine et al.16 reported that tubular dysfunction or
kidney injury occurred approximately 7 months after the start of TDF. In
a study of patients that had used TDF for 3 years, eGFR declined by 8%
at the end of 2 years and 11% at the end of the third year in
comparison with the baseline level17. In a metanalysis
that involved a total of 17 studies, of which 9 were randomized
controlled studies, it was concluded that ART regimens involving TDF led
to kidney dysfunction more commonly than those that did not involve
TDF18. Similarly, the D: A:D study reported that
5-year TDF exposure nearly doubled the incidence of CKD, with each
additional 1-year exposure to TDF having led to a 23% increase in the
incidence of CKD19. In accordance with the literature
reports, we detected a significant eGFR decline after 24 months of
therapy in Groups 4 and 5 using regimens containing TDF
(p<0.001) (from 107.03± 21.08 to 81.79± 10.4 and from 106.21±
18.35 to 80.97± 9.82, respectively).
Clinical studies have shown that kidney injury risk is less with TAF
than with TDF20,21. The DISCOVER trial, which compared
patients receiving Emtricitabine-TAF combination with patients receiving
Emtricitabine-TDF combination, showed that creatinine clearance
decreased in the TDF group at the end of 48 weeks while it increased in
the TAF group22. In another study that compared TAF
and TDF, although the virological response was more than 90% in 48-week
EVG/COBI/FTC/TAF and EVG/COBI/FTC/TDF combinations, TAF more favorably
affected renal parameters23. Although our study
detected a slight increase in eGFR at the end of 24 months in Group 3
that contained TAF, this increase was not statistically significant
(p:0.886). A comparison of the TDF-containing Groups 4 and 5 and the
TAF-containing Group 3 at 12 and 24 months showed a significant increase
in serum creatinine level (p<0.001) and a significant decrease
in eGFR (p<0.001).
Another preferred regimen in HIV treatment is the DTG/ABC/3TC
combination. This combination can be safely used in patients with
end-stage kidney failure24. DTG may cause a slight
increase in serum creatinine level, depending on its effect on
creatinine’s tubular secretion. However, this increase does not affect
glomerular filtration and renal blood flow25-27.
Long-term exposure to ABC, another drug used in this combination, has
not been linked to increased CKD incidence19. In a
study of 20 patients receiving DTG/ABC/3TC, only one patient had an
increase in serum creatinine level, which was not considered clinically
important28. The SINGLE study also detected a
non-progressive, clinically insignificant increase in serum creatinine
level among patients receiving the DTG/ABC/3TC
combination29. Our study demonstrated a minimal
increase in serum creatinine and a slight reduction in eGFR at the end
of 24 months with the DTG/ABC/3TC combination. In line with the
literature data, however, these changes were not considered
statistically significant (p:0.448). Furthermore, we compared eGFR
levels of Group 2 with those of the other groups at 12 and 24 months.
While no significant difference was observed with Group 3 that received
EVG/COBI/FTC/TAF combination, we found significantly lower eGFR levels
in Group 4 that received FTC/TDF/DTG treatment and Group 5 that received
FTC/TDF/RAL treatment (p<0.001 for both comparisons).
Our study has several limitations. First, it was a retrospective study;
second, it has a small sample size considering the low number of
patients in each study group.ConclusionOur study showed that using regimens involving TDF causes renal
dysfunction. Therefore, we recommend close monitoring of renal
functions, particularly among patients treated with TDF. In our opinion,
periodic monitoring of renal function and early diagnosis of potential
kidney injury may improve outcomes among HIV-infected patients.