Dissertation committee:
Χατζηιωάννου Αργυρώ, Αναπλ. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Ρηγόπουλος Δημήτριος, Καθηγητής, Ιατρική, ΕΚΠΑ
Στρατηγός Αλέξανδρος, Καθηγητής, Ιατρική, ΕΚΠΑ
Παπαδαύιδ Ευαγγελία, Αναπλ. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Νικολαΐδου Ηλέκτρα, Αναπλ. Καθηγήτρια, Ιατρική, ΕΚΠΑ
Σταυρόπουλος Παναγιώτης, Ομότιμος Καθηγητής, Ιατρική, ΕΚΠΑ
Κατούλης Αλέξανδρος, Αναπλ. Καθηγητής, Ιατρική, ΕΚΠΑ
Summary:
This is a retrospective study performed in Andreas Syggros Hospital, a tertiary medical center of Athens, Greece. We found that the incidence of drug reactions in our patient population who had initiated ART was highest during the period of introduction of triple therapy in the years 1997–2006 and has subsequently declined over time with the availability of the more recent treatment regimens. Lipodystrophy and maculopapular rashes represented most of drug-related dermatological conditions. Our results are in line with evidence showing a better tolerability of the novel antiretroviral agents introduced since 2007 with a similar or enhanced virological efficacy.108,114 Patients on ART have been described in several studies as showing a higher incidence of adverse drug reactions when compared to HIV-negative individuals. These reactions are estimated to be 100 times more common, and generally occur during the first year of treatment. The reason behind this increased incidence is believed to be multifactorial.48,104
In our study HIV treatment-related dermatological conditions were observed in 352/1329 or 26.48% of ART-treated patients, which is substantially higher than in the general population where it is estimated to be 0–8%.46,49 The number of affected men was 299 out of a total of 1155 (25.9%) who were on ART and 53 women of 174 women (30.4%), with no difference noted between sexes (χ2=1.62, P=0.20) although the total number of affected women was small.
We have divided the distribution of drug reactions into three time periods, which coincided with changes in the main type of ART prescribed. The first peak period is observed in the period 1988–1996, the second in 1997–2006 and the third in 2007–2013 (Graph.5). Table 8 reflects the change of drug-reaction incidence per period. The first period was characterized by maculopapular eruptions, attributed mostly to the administration of TMP-SMX, whereas NVP was the major causative agent for those observed during the second peak period.
Lipodystrophy and maculopapular drug reactions attributed to NVP and other ART medications were mostly observed during the second ART period. TMP-SMX still accounted for some maculopapular rashes, but the majority of them were then linked to NVP use that started in 1998.
According to some studies, the incidence of NVP-related reactions seemed to be double in women compared to men.50 In our study there were 44 cases, of which 13 were in women and 31 in men. When corrected for the total number of men and women receiving NVP, the incidence was 15% in women and 7.5% in men (P=0.03, RR=2077, CI 95% 1135–3799), which is in accordance with previous studies. We believe that the decrease in TMP-SMX-related eruptions observed during the second ART period was a result of the introduction of combination ART, which decreased the need for chemoprophylaxis.
Lipodystrophy peaked during 1998–2006. Combination ART was introduced in Greece in 1996 and recording of lipodystrophy began in 1998. Lipodystrophy is known to be a metabolic evolutionary process and it is hard to determine the exact time of its appearance with stavudine; PI use was considered the most common cause in our study.
During the third ART period, we witnessed the introduction of newer PIs (darunavir, atazanavir) and integrase inhibitors with enhanced efficacy compared to older generation antiretroviral drugs. Furthermore, they seemed to be associated with a lower rate of lipodystrophy.115
It is worth mentioning that in our study, zidovudine does not seem to be the main reason for clinical lipodystrophy despite its wide use for more than 20 years in Greece.
Other well-established studies have shown that thymidine analogues of nucleoside reverse transcriptase inhibitors (NRTIs) such as d4T and AZT are associated with lipodystrophy more often than PIs. NRTIs and PIs interfere with the metabolic process by causing mitochondrial dysfunction and oxidative stress, which in turn alters lipolysis, adipogenesis and glucose transport.116-9
Skin reactions (Maculopapular rashes and Lyell's syndrome) associated with TMP-SMX occurred generally at low CD4 T cell counts (mean 166.5 cells/mm3) and high viral loads (mean 358,698 HIV-1 copies/mL) when the drug was used as chemoprophylaxis in immunocompromised patients. Low CD4 T cell counts and increased interferon-gamma levels may contribute to the development of severe skin reactions like Lyell's syndrome.56,104
During the more recent ART period, the newer regimens seem to cause fewer side effects while maintaining virological efficacy. Our hypothesis was confirmed by the decreased incidence of skin reactions when newer NNRTI-based ART regimens were introduced during the third period of our study. Next generation agents like PIs (atazanavir, darunavir), NNRTIs (rilpivirine, etravirine) and integrase inhibitors (raltegravir) are generally considered to have an improved safety profile.55,107,120
We are aware of the limitations of this study due to the retrospective collection of data from patient files. Furthermore, some conditions may not have been correctly assigned to a drug or not recorded.
In conclusion, the major overall positive impact of ART has been associated over time, as in our study, with dermatological drug reactions including lipodystrophy and maculopapular eruptions. Their incidence since 2007 has been decreasing in association with changes in therapy. We believe that the constant improvement and introduction of new drugs in clinical practice will still require careful monitoring for skin reactions.
