High prevalence of the integrase resistance associated accessory mutation L74I in the Russian Federation

17TH EUROPEAN MEETING ON HIV & HEPATITIS22 May 2019, Rome, Italy

Alina Kirichenko1, Jeroen van Kampen2, Charles Boucher2, David van de Vijver2, Dmitry Kireev1

1Central Research Institute of Epidemiology, Moscow, Russian Federation2 Viroscience department, Erasmus Medical Centre, Rotterdam, the Netherlands

Characteristics of HIV infection in the Russian Federation

o At the end of 2018, 1 007 369 citizens with HIV-1 were living in Russia(0.7% of the total population in Russia)

Routes of HIV transmission, 1987-2018

HIV care cascade in Russia, 2018

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

HIV diagnosed Linked to care On ART HIV RNA < 500copies/ml

Nu

mb

er

of

pe

op

le

100 %

75 %

44 %34 %

Loss 25% Loss 41%

Characteristics of HIV infection in the Russian Federation

Loss 22%

by A. Pokrovskaya, Central Research Institute of Epidemiology of Rospotrebnadzor

UNAIDS 90-90-90 An ambitious treatment target to help end the AIDS epidemic 2014

The number of patients on ART is constantly increasing

Since the 2016 year according to the Russian National recommendations for dispensary observation and treatment of HIV patients, the indication for initiating therapy is the presence of HIV infection.

Pokrovsky V.V., Yurin O.G., Kravchenko A.V. et al. National guidelines for dispensary observation and treatment of patients with HIV infection. Epidemiology and Infectious Diseases. Topical Issue, 2016, No. 3

Russian guidelines for treatment of HIV-infected people(First-line ART regimens)

Gradation of drugs Nucleoside basis Third drug

Preferred Tenofovir or Abacavir+ Emtricitabine or Lamivudine

NNRTI: Elsulfavirine* or Rilpivirine* or Nevirapine* PI: Atazanavir/r* orDarunavir/r* or Lopinavir/r*INSTI: Dolutegravir* or Raltegravir*

Alternative Phosphazide or Zidovudine+Emtricitabine or Lamivudine

PI: Atazanavir or Fosamprenavir/r or Saquinavir/r

Acceptable Stavudine or Didanosine+Emtricitabine or Lamivudine

PI: Indinavir

* For special patient groups

Source: Pokrovsky V.V., Yurin O.G., Kravchenko A.V. et al. National guidelines for dispensary observation and treatment of patients with HIV infection. Epidemiology and Infectious Diseases. Topical Issue, 2018, No. 4

Integrase strand transfer inhibitors (INSTIs)

* RAL and DTG are registered in Russia since 2008 and 2014 respectivelyRAL and DTG are included in Vital and Essential Drugs, are entered the first line of therapy

Approved in Russia*

FDAapproved

Raltegravir RAL + +

Dolutegravir DTG + +

Elvitegravir EVG +

Bictegravir BIC +

Cabotegravir CAB in phase III of clinical trials

Source: Orkin C., et al. CROI 2019; Seattle, WA, Abstract 3947

FLAIR: week 48 results of long-acting Cabotegravir+Rilpivirine for HIV maintenance

LA regimen of CAB and RPV is non-inferior for HIV maintenance therapy as compared to an oral regimen of DTG, ABC and 3TC.

Mutation L74IAccording to the Stanford HIV drug resistance database L74I is polymorphic mutation commonly selected by each of the INSTIs. Alone has minimal, if any, effect on INSTI susceptibility. However, they contribute reduced susceptibility to each of the INSTIs when is occurs with major INSTI-resistance mutations.

Prevalence of L74I

Subtype A B C D F GCRF01_

AECRF02_

AG

Number of sequences of this

subtype1034 644 2517 335 244 203 1824 843

Prevalence of L74I among this

subtype21% 4% 6% 2% 4% 12% 1% 16%

Subtype A A1 A6

Number of sequences of this subtype

57 266 338

Prevalence of L74I among this subtype

12.3% 9.5% 91.9%

Stanford database

Los-Alamos database

In vitro studies

Resistance profiles to CAB Article

L74F+G140S+Q148H Hachiya A., Kirby K.A., Ido Y., Shigemi U., Matsuda M., Okazaki R., Imamura J., Sarafianos S.G., Yokomaku Y., Iwatani Y.

Impact of HIV-1 Integrase L74F and V75I Mutations in a Clinical Isolate on Resistance to Second-Generation Integrase Strand Transfer Inhibitors.

Antimicrob Agents Chemother. 2017, 25;61(8)

L74F+ V75I+N155

L74F+ V75I+G140S+Q148H

L74M+G140A+Q148R Steven J. Smith,Xue Zhi Zhao,Terrence R. BurkeJr. andStephen H. HughesEfficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase

mutants. Retrovirology. 2018;15(1):37.

L74M+G140S+S147G+Q148K Oliveira M., Ibanescu R.I., Anstett K., Mésplède T., Routy J.P., Robbins M.A., Brenner B.G. Selective resistance profiles emerging in patient-derived clinical

isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir.Retrovirology. 2018;15(1):56.

L74M+E138K+G148R+R263K

L74I+E138L+G140S+Q148R

L74M+Q148R+E138K+Q148R Yoshinaga T., Seki T., Miki S., Miyamoto T., Suyama-Kagitani A., Kawauchi-Miki S., Kobayashi M., Sato A., Stewart E., Underwood M., Fujiwara T. Novel secondary

mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors. Antiviral Res. 2018;152:1-9.L74M+V75A+G140S+Q148R

Baseline characteristic

Treated patientswithout INSTIs with virological failure

(n=185)

Treatment-naïve patients (n=227)

HIV-infected INSTI- naïve patients from Russia*(n=412)

Median age (range): 33 (0,1-73) yearMale: 236 (57%)

17.2%

1%

4.9%

5.8%

25%

46.1%

Unknown

Outbreak

Mother-to-child

Homosexual

Intravenous drug user

Heterosexual

Route of transmission

assess the prevalence of mutation L74I in INSTI-naïve sequences from Russia.

Aim:

A6

A/G

Subtype

7.3%0.7% 4.1% 1.7%

86.2%

A*

B

G

CRF 02_AG

CRF 63_02A1

Viral subtypes (protease and reverse transcriptase sequences) were determined using the HIVdb Program v.8.8. and phylogenetic analysis (Maximum Likelihood method)

* A6 (Foley B.T., Leitner T., Paraskevis D., Peeter M. Primate immunodeficiency virus classification and nomenclature. Infect. Genet. Evol., 2016, pp. 150-158.)

227 treatment-naïve patients

Subtype Prevalence of L74INumber of sequences of

this subtypePrevalence of L74I among this

subtype

A6 190 194 97.9%

B 1 16 6.25%

G 0 3 0%

CRF02_AG 4 9 44.4%

CRF63_02A1 1 5 20%

Correlation of mutation L74I in subtypes

Prevalence of mutation L74I

196 sequences (86.3%) from 227 treatment-naïve patients contained the mutation L74I

Correlation of mutation L74I in subtypes

Prevalence of mutation L74I

157 sequences (84.9%) from 185 treatment-naïve patients contained the mutation L74I

185 treated patientswithout INSTIs with virological failure

Subtype Prevalence of L74INumber of sequences of

this subtypePrevalence of L74I among this

subtype

A6 154 161 95.7%

B 1 14 7.1%

G 0 0 NA

CRF02_AG 2 8 25%

CRF63_02A1 0 2 0%

Number ofpatients

Country Prevalence L74I in

subtype A6

Article

21 Russia 100% Kazennova E., Lapovok I., Laga V., Vasilyev A., Bobkova M. Natural polymorphisms of HIV-1 IDU-A variant pol gene. HIV Infection and

Immunosuppressive Disorders, 2012, Vol. 4, No. 4, pp. 44-51 (In Russ)

61 Russia, Ukraine

100% Lapovok I., Laga V., Vasilyev A., Salamov G., Kazennova E., Matkovsky I., Mokhniy G., Melnik T., Bobkova M. Molecular genetic analysis of pol gene region coding for HIV-1 integrase in patients from Russia and

Ukraine. HIV Infection and Immunosuppressive Disorders, 2012, Vol. 4, No. 2, , pp. 73-81 (In Russ)

55 Russia 100% Gashnikova N., Totmenin A., Ivlev V., Zyryanova D., Astahova E., Gashnikova M., Ismailova T., Chernov A., Mikheev V.

Investigation of HIV-1 diversity in the integrase coding region. Far Eastern Journal of Infectious Pathology, 2015, Vol. 28, pp. 58-61 (In

Russ.)

258 Russia, Ukraine, Armenia,

Kyrgyzstan, Kazakhstan,Uzbekistan,

Belarus, Georgia

93.1% Lapovok I., Laga V., Kazennova E., Bobkova M. HIV type 1 integrase natural polymorphisms in viral variants circulating in FSU countries.

Current HIV Research, 2017, 15, pp. 1-9

Prevalence of L74I in Russia and FSU countries in articles published previously

Conclusion

o Our results and results of previous studies demonstrate that the prevalence of mutation L74I among patients from Russia is extremely high, L74I was present in almost all subsubtype A6 sequences, and in a large proportion of CRF02_AG sequences. This high prevalence of L74I should be considered when introducing cabotegravir in Russia and FSU countries.

o Mutation L74I is distributed unevenly among subsubtypes of subtype A. Therefore, the quality / accuracy of existing algorithms for genotyping is becoming added importance.

o The role of natural polymorphisms for the development of drug resistance and for treatment failure remains disputed and should be clarified in further research.

Thank you for attention