HIV-2 Therapy Guidelines draft 2017 HIV-2 Working Group ... · LTNPs and HIV controllers were...

HIV-2 Therapy Guidelines draft 2017

HIV-2 Working Group Meeting

04.05.2017 Köln

Dirk Berzow Praxis für Infektiologie und Tropenmedizin

Hamburg

HIV-2 World

HIV-2 epidemiology – world of estimations

Europe (1.000?) HIV-2 Dual HIV-1 Germany (RKI, 05/17) ~100 ~100 ~77.500 reported new in 2016 13 5 France ARNS CO5 1091 (1% of HIV-1) ~0,1% ~140.000 1.8% of new reported HIV infections (-6.500) are due to HIV-2 (120) Portugal 1813 ~34.000 Africa (1 Mio?) Guinea-Bissau (1.4) ~115.000-66.000 ~7.000-50.000 incidence is decreasing 8,3% -4,7% ~1% 0,5%-3,6% The Gambia (2.1) ~5.000 ~20.000 ~0,4% ~1,6%

Differences of HIV-2 (compared to HIV-1)

• Age: patients are older • Viral load: Plasma-RNA is 30-100x lower • Proviral DNA: no difference • CD4: mean CD-4 cell count is higher • Immune system: many patients with only mild alterations (CD4,CD8,nAb, innate immune system) • Mortality: HIV1 =HIV1+HIV2 > HIV-2 > uninfected

progression time to death is longer • AIDS: progression time to AIDS is longer • Ratio progressors /nonprogressors:

more nonproggressors (inhomogenous, depending on time of infection)

• Heterosex. transmission: transmission rate is lower (less virus in genital fluids) • Vertical transmission: MTCT lower

HIV-2 – Clinical Course

HIV-positive Senegalese sex workers 1985 -1993 HIV-1 (32/46) HIV-2(33/103)*) • longer time to develope AIDS/ higher probalility of AIDS free survival • reduced virulence

*) Marlink et al Reduced Rate of Disease Developement After HIV-2 Infection as Compared to HIV-1 Science Sept. 1994

CDC IV disease-free survival

Caio Cohort Guinea-Bissau

prospective study, rural, villagers, 1991-2009 133 HIV-2-positive and 158 HIV-negative • HIV-2+: Age 47 y, VL 347 c/ml CD4 29% • 37% HIV-2 RNA < 100 c/ml , • 17% HIV-2 > 10.000 c/ml • mortality rate HIV-2: 4,5 /100 py, (CI 3.6-5.5 ), compared to 2.1 in HIV-

negative (1.6-2.9) 1. LFU: 6,7% (6,3%) 2. 12,8% became HIV-1 infected

CROI 2017

Statement Joakim Esbjörnsson (University of Oxford): previous literature had suggested that only 15-25% of people with HIV-2 progress to AIDS at all, and only a minority within ten years, but: Guinea-Bissau police cohort • initiated 1990, 4820 members, 13% of them women • 312 HIV+, thereof • HIV-1 (225) • HIV-2 (87) • median follow-up time was 5.9 years • Antiretroviral therapy has been available since 2006

Dirk Berzow PIT Hamburg HIV-2 9

Guinea-Bissau police cohort

Guinea-Bissau Police Cohort

Mean time for progression to AIDS: • 6.2 years with HIV-1 • 14.3 years with HIV-2

Progression time to death: • 8.2 years with HIV-1 • 15.6 years with HIV-2.

Likelihood of progression to AIDS: • 2.84 times greater (HIV-1 - HIV-2) Likelihood of progression to death: • 3.5 times greater (HIV-1 - HIV-2)

Average CD4 decline in cells/mm3: • 22.5 per year in people with HIV-1 • 12.8 per year in people with HIV-2 Progressed to AIDS 20 after 20 years • 90% of people with HIV-1 • 70% of people with HIV-2 Progression to AIDS happened at a higher CD4 count with HIV-2 than HIV-1: Average CD4 count at AIDS diagnosis • 237 cells/mm3 in people with HIV-2 • 137 cells/mm3 in people with HIV-1

Guinea-Bissau Police Cohort

HIV-2 – clinical course, LTNP

342 HIV-2-infected patients of the ANRS CO5 HIV-2 cohort, 2011 LTNPs prevalence 6.1% (95% c.i. 3.9–9.1) “elite-L.” 1,9% HIV-Controllers prevalence 9.1% (6.3– 12.7) “elite-c.” 8,8% 81% LTNPs (81%) were HIV-controllers, 55% of HIV-controllers were LTNPs. LTNPs and HIV controllers were 10–40-fold more frequent among HIV-2-infected p. long-term-nonprogressors (LTNPs) (i.e. asymptomatic for at least 8 years while maintaining CD4 cell count at least 500 cells/ml) HIV controllers (i.e. controlling HIV replication in the absence of antiretroviral treatment for at least 10 years) Thiebaut et al Long-term nonprogressors and elite controllers in the ANRS CO5 HIV-2 cohort, AIDS 2011

HIV-2 therapie Poor CD4-cell recovery after starting ART

ANRS CO5(HIV-2) cohort:

Drylewicz J, Comparision of viro-immunological marker changes between HIV-1 and HIV-2 infec ted patients in France AIDS 2008 Feb 19;22(4): 457-68

CD4-cell recovery after starting ART 2016, IeDEA, n=422 PIT

HIV-2 Therapy Guidelines

HIV-2 working group: Charlotte Charpentier, Ricardo Camacho, Jean Ruelle, Rolf Kaiser, Josef Eberle, Lutz Gürtler, Alejandro Pironti, Martin Stürmer, Françoise Brun-Vézinet, Diane Descamps, Martin Obermeier 2012: HIV-2EU: Supporting Standardized HIV-2 Drug Resistance Interpretation in Europe, published 2013 CID 2015: Update, CID 2016 Meeting Köln: HIV-2 Therapy Guidelines draft (diagnostics & treatment HIV-2) Ricardo Camacho, Jean Ruelle, Ninon Taylor, Rolf Kaiser, Josef Eberle, Lutz Gürtler, Martin Stürmer, Matthias Döring, Martin Obermeier, Dirk Berzow. Draft was sent for revision and editing to Charlotte Charpentier, Sophie Matheron, Jürgen Rockstroh, Hans-Juegen Stellbrink and was sent back with questions and comments. 2017: Meeting Köln: HIV-2 Therapy Guidelines draft (diagnostics & treatment HIV-2) Rolf Kaiser, Josef Eberle, Lutz Gürtler, Matthias Döring, Martin Obermeier, Dirk Berzow, ->

Input: key messages from Ricardo Camacho: • less drugs for treament of HIV-2 (i.e., no NNRTIs, only 3 PI, no T-

20) • only “two shots” • selection of drug-resistance is fast • narrow time window for regimen changement • plasma viral load as tool is limited useful • plasma viral load is almost only detectable in rapid progressors or

end stage disease • immune recovery poorer than in HIV-1

• so we need a good immune system (start)

HIV-2 Therapy Guidelines draft 2016

HIV-2: European Therapy Guidelines, Update 2017


Preface: Patients from high-prevalence countries (West-Africa, Angola, Mozambique, Goa) and patients with high-risk contacts to persons from high-prevalence countries shall be considered for a possible HIV-2 infection.

HIV-2: European Therapy Guidelines, Update 2017 Diagnostics: An infection with HIV-2 should be determined as follows: • standard screening test for HIV-1 and HIV-2 antibodies • samples with a positive result but undetectable HIV-1 viral load should be

analyzed (or re-analyzed in case of older results) by specific antibody-based confirmation assays (immunoblot, IB; Western Blot, WB; antibody differentiation assay), as theses assays can distinguish HIV-1 from HIV-2 infection

• IB or WB assays identifying an untypable HIV infection (HIV-1 and HIV-2 double reactivity) do not confirm the presence of HIV-2, because HIV-1 antibodies may be cross-reactive

• In case of an untypable HIV infection, proviral DNA should be amplified to confirm the presence of either HIV-1, HIV-2, or both. In case of unclear results, the reference laboratory should be contacted

HIV-2: European Therapy Guidelines, Update 2017 Diagnostics (2) Since HIV-2 infection can present without detectable plasma viral load even in the absence of ART, HIV-2 viral load analyses should not be used for verifying the presence of HIV-2 infections but should be performed for monitoring purposes only. Monitoring before start of treatment CD4 cell count and plasma viral load should be monitored regularly at least twice a year depending on the patient’s clinical status, previous CD4 cell count, and the rate at which the CD4 cell count decreases. Any detectable viral load should be confirmed by another measurement on a subsequent sample not more than one month later.

HIV-2: European Therapy Guidelines, Update 2017 Start of therapy (preface) The criteria for starting HIV-2 treatment are more conservative than for HIV-1 because: • only a proportion of HIV-2 infected persons will progress to AIDS • many patients have undetectable plasma viral loads (below 100 copies/mL in

more than 50% of HIV-2 infected patients) • the mean value when detectable is low (< 3 log copies/mL), thus the

treatment indication for prevention of sexual transmission is often not as relevant as for HIV-1.

HIV-2 therapy should not be started too late because immunological recovery after starting treatment is much slower than in HIV-1 infected patients. Limited data from the French cohort suggest that starting therapy early in the course of infection (at ≤500 CD4 cell/µlL) should allow for an efficient recovery of CD4 cell counts.


Recommended therapy start Therapy of HIV-2 infection should be started for patients with any of the following conditions: • symptoms of immunodeficiency • CD4 cell count below 500 CD4 cells per µL of blood • CD4 cell decrease ≥30 cells/year • repeatedly detectable HIV-2 RNA • patient’s age >40 years • comorbidities like chronic HBV, HCV, Tb, etc.

(French Guidelines, Recommendations Conseil National du SIDA, 2016)


Prerequisites to therapy start An initial resistance test (protease, RT, integrase) based on viral RNA or proviral DNA is highly recommended, as the occurrence of primary resistance might dramatically impair the treatment. Unlike in HIV-1 a number of polymorphisms may be present in HIV-2 which impair treatment response. Tropism testing should be performed when the CCR5-coreceptor antagonist maraviroc is considered as a treatment option. Furthermore it can be contemplated as a means of disease staging as X4 viruses occur in advanced stages of the disease. Tropism testing can be performed either phenotypically (e.g. TZM-bl cells) or genotypically with the help of interpretation systems like geno2pheno[coreceptor-hiv2].

First-line treatment The recommended first-line treatment for HIV-2 infection should consist of *still limited data on the efficacy of integrase inhibitors , they are recommended due their in vitro efficiency and tolerability profile. **the dosing of DRV is not clear and a twice daily dosing appears to be favorable. DRV administration should be considered twice daily. Cobicistat can be used alternatively to ritonavir.


Component 1

and

Component 2

2 NRTI: • Tenofovir + FTC or • ABC + 3TC Alternative: Tenofovir + 3TC

1 INSTI* • RAL • EVG/c • DTG or 1 PI • LPV/r • DRV/r, DRV/c** Alternative: SQV


Second-line treatment In case the first line treatment contained a PI, the second line should contain an INSTI and vice versa depending on resistance test results. The recommended drugs for first-line treatments can be combined with AZT, SQV/r, or MVC given that they are effective against HIV-2 according to the results of the resistance-/tropism-testing. NNRTIs and enfuvirtide are not be used because of the natural resistance of HIV-2 against these compounds. All protease inhibitors except for LPV, DRV, and SQV are ineffective against HIV-2 and should not be used for treating HIV-2 infection.


pregnancy + perinatal medicine balance of pros and cons toxicity vs. transmission

cesarean section vs. vaginal delivery

pregnancy: • uncomplicated course of

pregnancy • increased risk ((high) maternal

viral load, low CD4, AIDS-def. illness, vaginal delivery, premature rupture of membranes, preterm infant, multigravidity)

• higly increased risk (amnion infection syndrome, premature rupture of membranes> 4h, incision child, hemorrhagic amniotic fluid ingestion)

drugs: experience pregnancy registries data placental tansfer (maternal p./core)

AZT i.v., AZT + 3TC, full ART,

• unknown status • very late presentation

HIV-2: European Therapy Guidelines, Update 2017 Pregnancy: • Pregnant women fulfilling any of the treatment indication should start

treatment • Pregnant woman is under an antiretroviral treatment should continue • all others: treatment should be started with the recommended drugs

for first-line therapies from the second trimester onwards So far, there is more clinical experience in treating pregnant women with NRTIs and PIs, but cases of NRTI and INSTI combinations are described. If the pregnant woman currently on treatment has a detectable viral load at week 36, the addition of an INSTI should be considered. In case of detectable viral load at delivery, a cesarean section should be considered as in HIV-1. In case of missing viral load determination or late presentation an immediate fully active therapy with additional i.v. AZT therapy and also cesarean section should be considered.


Newborn: • Post-exposure prophylaxis for the newborn is always advised.

• If the mother’s viral load was undetectable at the time of delivery, AZT

monotherapy shall be administered to the newborn for two to four weeks.

• If the mother’s plasma viral load is unknown or detectable at delivery,

a fully active triple therapy (depending on the available formulation of the active drugs) should be administered to the newborn for at least four weeks.


Post-exposure prophylaxis (PEP) In line with the HIV-1 guidelines in Germany and Austria, the same post exposure prophylaxis (TDF/FTC/RAL, alternatively AZT/3TC/LPV/r or DRV/r) shall be offered to exposed persons in case of high-risk contacts. Pre-exposure prohylaxis (PrEP) PrEP is currently discussed in HIV-1 settings. The sexual transmission of HIV-2 is roughly five times less efficient than the sexual transmission of HIV-1. To date, there are no data available for the use of PrEP in HIV-2 settings so that no statement on this topic is currently possible.

The HIV-2 Working Group is now looking westward….


thank you very much for your attention….

HIV-2 working group

back up slides

HIV-2 Guidelines GB, USA, F: British HIV Association (BHIVA) Y Gilleece et al, British HIV Association guidelines for antiretroviral treatment of HIV-2-positive individuals 2010 HIV Medicine (2010), 11, 611–619 Considerations for Antiretroviral Use in Special Patient Populations, HIV-2 Infection Last Updated: April 8, 2015; Last Reviewed: April 8, 2015 aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/24/hiv-2-infection Conseil national du sida et des hépatites virales – Recommendations de groupe d’experts Infection VIH-2 ; Diversité des VIH-1 (septembre 2016) http://cns.sante.fr

HIV-2 Epidemiology – world of estimations

Senegal clinic(n=10.000) 3,2% 1,7% 9,2% HIV+: 50.000 Angola clinic n= 38 3% 18% 79% HIV+: 166.000

Equal Plasma Viral Loads Predict a Similar Rate of CD4+ T Cell Decline in Human Immunodeficiency Virus (HIV) Type 1– and HIV-2–Infected Individuals from Senegal, West Africa Geoffrey S. Gottlieb,1 Papa Salif Sow,7 Stephen E. Hawes,2,5 Ibra Ndoye,8 Mary Redman,4 Awa M. Coll-Seck,7 Mame A. Faye-Niang,7 Aissatou Diop,7 Jane M. Kuypers,2 CathyW. Critchlow,5 Richard Respess,6 James I. Mullins,1,3 and Nancy B. Kiviat1,2 JID 2002;185 (1 April)

HIV-2, CD4-cell decline (compared to HIV-1)

J Acquir Immune Defic Syndr 2005;38:335–341 Baseline Plasma Viral Load and CD4 Cell Percentage

Predict Survival in HIV-1– and HIV-2–Infected Women in a Community-Based Cohort in The Gambia Hansmann, Schim van der Loeff, Whittle et al

HIV-2, mortality, PVL, compared to HIV-1

J Acquir Immune Defic Syndr 2005;38:335–341 Baseline Plasma Viral Load and CD4 Cell Percentage Predict Survival in HIV-1– and HIV-2–Infected Women in a Community-Based Cohort in The Gambia Hansmann, Schim van der Loeff, Whittle et al

HIV-2 Mortality, CD4, PVL, compared to HIV-1

2016, IeDEA, n=422 CD4-cell changes after starting ART

PIT

Transmitted drug resistance?

AIDS 2013, 27:1671–1677 Transmitted drug resistance in French inHIV-2-infected patients Charlotte Charpentier, ANRS CO5 HIV-2 Cohort, France. • The prevalence of transmitted drug resistance was 5.0% (95%

confidence interval, 0.1–9.9) with mutations detected only in protease, not in reverse transcriptase (n=66).

• Protease inhibitor resistance mutations were V47A in two cases and I82F in one case.

• In this series, 10% of patients displayed X4/dual-mixed viruses. • Surveys conducted reported HIV-2 TDR of 5,6% in the Ivory Coast and

3,3% in Portugal

PIT

HIV-2 Therapy Guidelines draft 2017 HIV-2 Working Group ... · LTNPs and HIV controllers were...

Documents

Transcript of HIV-2 Therapy Guidelines draft 2017 HIV-2 Working Group ... · LTNPs and HIV controllers were...