15/9 Thesis defense by Dawit Assefa Arimide
Dawit Assefa Arimide will defend his thesis: The HIV-1 epidemic in Ethiopia - transmission patterns, antiretroviral drug resistance and treatment outcomes.
Place: Belfrage hall, BMC D15, Klinikgatan 32 i Lund
Opponent: Docent Ujjwal Neogi, Stockholm
The HIV epidemic in Ethiopia –dynamics of viral transmissions and prevalence of transmitted drug resistance — Lund University
A comprehensive understanding of local HIV-1 epidemiology is essential for monitoring transmission, designing, implementing, and evaluating HIV intervention strategies. Although Ethiopia is one of the majorly affected countries by the HIV epidemic in sub-Saharan Africa, no recent comprehensive study has investigated the molecular epidemiology of HIV in Ethiopia. In paper I, we used a total of 1276 Ethiopia HIV-1 subtype C pol sequences and employed state-of-art phylogenetic and phylodynamic tools to describe the dynamics of the HIV-1 epidemic in Ethiopia. Our results showed that the HIV-1 epidemic in Ethiopia resulted from two independent introductions of founder virus from Eastern Africa and southern African countries in the mid-1970s and mid-1980s, respectively. Our phylodynamic analysis also revealed that the HIV-1 epidemic in Ethiopia manifested expanding growth from its introduction until the mid-1990s, followed by a sharp decline in HIV-1 transmissions. The epidemic decline coincided with early behavioral, preventive, and public health awareness campaigns implemented in Ethiopia a decade before the introduction of antiretroviral therapy (ART) in the country. Over the last decades, the rapid expansion of ART has significantly reduced the risk of transmission and improved the survival and quality of life of HIV-infected patients. However, global evidence indicates that the rapid expansion of ART is associated with increase in pretreatment drug resistance (PDR) and acquired drug resistance (ADR), posing threat to both individual outcomes and the prospect of elimination of HIV as a public health threat. Following the increase of PDR to nonnucleoside reverse transcriptase inhibitors (NNRTIs), many countries, including Ethiopia, have switched to the dolutegravir (DTG)-based regimen as first- and second-line therapies. However, differences in naturally occurring polymorphisms (NOPs) have been linked to the development of different mutational pathways, resulting in varying levels of drug resistance against integrase strand transfer inhibitor (INSTIs) among different HIV-1 subtypes. In Ethiopia, there is limited information on HIVDR prevalence (both PDR and ADR) among the general population and risky groups. However, a few studies showed an increase in HIV drug resistance (HIVDR) prevalence with the scale-up of ART in the country. In paper II, we employed the WHO-recommended threshold survey method to assess the transmitted drug resistance (TDR) in Gondar. Our results showed a moderate level of TDR in Gondar, all of which were associated to NNRTI. Our findings also revealed a high rate of HIVDR transmission with the G190A mutation in Gondar. In paper III, we investigated the emergence of ADR among adult patientsreceiving ART in health centers. Our result showed that among 621 individuals included in the study, 83.7% (101/621) had a virological failure (VL≥500 copies/mL) at six and/or twelve months, of which 65.3% had ADR. In paper IV, we assessed the prevalence of virological failure, ADR and PDR among 9 female sex workers (FSWs) who participated in the 2014, Ethiopian biobehavioral survey. PDR was detected in 16.5 % (63/381) of the 381 specimens from ARTnaive FSWs. NNRTI-associated PDR was detected in 14.4%, while nucleoside reverse transcriptase inhibitor (NRTI) and dual-class were detected in 10.5% and 9.2%, respectively. Among the 239 FSWs on-ART 59 (24.7%) had a virological failure. Of these, 39 specimens were successfully genotyped, and 29 (74.4%) had one or more major HIV drug resistance mutations (HIVDRMs). In paper V, we showed that no DTG-associated HIVDRMs were detected among 460 INSTI-naïve, participants in the 2017 Ethiopian national HIVDR surveillance, regardless of previous exposure to ART (NNRTIs, NRTIs and/or protease inhibitors). Furthermore, of the 288 subtype C integrase amino acid positions, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that subtype B and C had similar genetic barriers to DTG resistance at selected amino acid positions, except that subtype C had a higher genetic barrier to G140C and G140S mutations than subtype B, indicating that the Q148H/K/R DTG resistance pathway is less selected in subtype C. Furthermore, dolutegravir docking analysis revealed that NRTI, NNRTI and protease inhibitor (PI)-associated drug resistance mutations did not affect the native structure of the HIV-1 integrase, supporting the implementation of the wide scale-up of DTG-based regimes in Ethiopia. In general, our molecular epidemiology findings provide critical information on the dynamics of the HIV-1 epidemic in Ethiopia and the importance of behavioral interventions along with antiretroviral therapy expansion in preventing and controlling HIV transmission. The HIVDR data from the various study groups will be critical for improving Ethiopia's national ART programme and those of other countries in a similar situation