SEXUAL TRANSMISSION. SEXUAL TRANSMISSION under ART: Biological Considerations

Transcription

1 SEXUAL TRANSMISSION under ART: Biological Considerations Dr Steve Taylor, MB ChB, FRCP, PhD Consultant Physician, HIV/GU Medicine, Lead Consultant HIV Services, Directorate of Sexual Medicine and HIV Birmingham Heartlands Hospital Heart of England NHS Foundation Trust Birmingham UK SEXUAL TRANSMISSION UNDER ART An HIV Infected individual without an additional STD and on anti-retroviral therapy (ART) with completely suppressed viraemia ( effective ART ) is sexually non-infectious,ie he/she does not pass on HIV through sexual contact. EKAF approved English translation from original SWISS Federal commission on AIDS 2008 Bullitin des medecins suisses 2008; 89:5 1

2 as long as the following conditions are fulfilled.. The HIV +ve+ individual complies with ART, and the effects of this treatment are evaluated regularly by the treating physician and The viral load has been non detectable for at least 6 months ( ie viraemia is suppressed ).. and There are no additional sexually transmitted infections (STI) present EKAF approved English translation from original SWISS Federal commission on AIDS 2008 Bullitin des medecins suisses 2008; 89:5 The viral load has been non detectable for at least 6 months ( ie viraemia is suppressed ).. Key assumption: Under ART there are no significant anatomical compartmentalisation effects ie.. Blood plasma viral load (VL) = Male Genital Tract and Semen VL = Female Genital Tract and Cervico-Vaginal VL = Viral load within the Ano-Rectal Mucosa 2

3 There are no additional sexually transmitted infections (STI) present Key assumptions: Asymptomatic STI s such as HSV 1-2, 1 chlamydia,, gonorrhoea, TV etc are routinely tested for OR In the presence of ART asymptomatic STI s cause no increase in genital tract HIV shedding Are the male and female genital tracts separate compartments for viral evolution? 3

4 Compartmental Viral Evolution STI s and Local Immune Activation/ Response Biological / anatomical / physiological barriers R Cell associated DNA TRAFFIC Cell Free RNA Drug 1 Drug 1 Drug 2 Drug 3 Target Cells Genital compartment Blood Compartment Is the genital tract a separate compartment? Evidence For Against Differences in viral load (no ART) Response to ART Drug penetration Local effect of STI s ++ + Viral evolution ++ + Different Resistant genotypes ++ + Cell tropism/types represents the strength of evidence supporting or refuting compartmentalisation 4

5 Compartmentalisation is not an all or nothing phenomenon For the Genital Tract several different patterns exist Viral shedding on and off ART Drug penetration Viral and Resistance Evolution The effect of STI s Male/ Female / Rectal Biology Patterns of Viral Shedding in the Male and Female GT under ART 5

6 Pattern1 Successful plasma ART = Successful Genital ART Plasma Genital Tract Luizzi 99, Vernazza et al 00, Gunthard 01, Leruez Ville 02, Quest 00, Gupta 99, Lowe et al 2006, Goshn et al 2008, Chan et al 2008 CVL HIV-1 1 RNA < 400 copies/ml by therapy % CVL < 400 copie none non-haart HAART Courtesy of Prof Susan Cu-Uvin and Colleagues June 08 Type of Treatment p <

7 Pattern 2: Sub-optimal Plasma ART with ongoing Genital Tract Viraemia +/- resistance Plasma Genital Tract Kalichman et al: 2001, Sadiq et al: 2002, Hart 99, Si Mohamed et al 00 Taylor T et al 2003 Pattern 3: Fully suppressive plasma ART with Viral Escape in GT Plasma Genital tract In semen this is v rare but it can occur.. MGT: Winter et al,1999, Ball et al, 1999, Mayer et al, 1999, : Pilcvher et al 2001, : et al: 2001, Sadiq et al: 2002, Solas et al: 2003, Taylor et al: 2003, Vernazza et al: 2007 FGT: Kovacs et al, 2001 De Pasquale et al, De Fiore et al, 7

8 Successful plasma ART with Viral Escape in the Female Genital tract may be more common than seen in semen.. Determinants of Shedding in the Female Genital Tract 80 *33% 80 (27/83) women with 70plasma RNA <500 c/ml had +ve % Viral shedding Genital tract RNA % 20 on ART 52% 10 on PI +2NAs 6 0 n=268 HIV RNA Culturable Virus Detectable plasma RNA 78 Positive PBMC cultures 33* BPVL< negative PBMC culture Kovacs et al Lancet Nov

9 GT HIV Shedding Among Women with PVL <80 copies/ml Genital Tract HIV-1 RNA Shedding Patterns: 46 women with PVL <80 copies/ml n % Non-shedder 22 48% Shedder 24 52% Intermittent 8 17% Persistent 4 8% Indeterminate 12 26% Courtesy of Prof S Cu-Uvin and Colleagues Results: Non-shedder ID Visit PVL Endocervix Ectocervix Vagina HAART C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP C TC, DDI, d4t, NVP Courtesy of Prof Susan Cu-Uvin and Colleagues June 08 9

10 Results: Intermittent Shedder ID Visit PVL Endocervix Ectocervix Vagina HAART C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV C TDF, FTC, RTV, ATV Courtesy of Prof Susan Cu-Uvin and Colleagues June 08 Results: Indeterminate Shedder ID V is it PVL Endoce r vix Ectoce r vix Vagina HAART C AZT, 3TC, NVP C AZT, 3TC, NVP C AZT, 3TC, NVP C missed visit C AZT, 3TC, NVP C lost to follow up Courtesy of Prof Susan Cu-Uvin and Colleagues June 08 10

11 Results: Persistent Shedder ID Visit PVL Endocervix Ectocervix Vagina HAART C DDI, TDF, NVP C DDI, TDF, NVP C DDI, TDF, NVP C DDI, TDF, NVP C DDI, TDF, NVP C blood draw failed DDI, TDF, NVP C lost specimen DDI, TDF, NVP C DDI, TDF, NVP C DDI, TDF, NVP C DDI, TDF, NVP C off HAART C missed visit Courtesy of Prof Susan Cu-Uvin and Colleagues June 08 Patterns of Drug Penetration into the Genital Tract are both Drug and Gender specific Antiviral drug concentrations in semen of HIV-1 infected men Journal of Sexually Transmitted Infections 2001; 77:4-11. ART to reduce sexual transmission Journal of HIV Therapy 8 (3) August 03,

12 SP:BP Drug concentration ratios at different times post drug ingestion 10 SP:BP Ratio (log scale) RTV SQV IDV JAC: 2001; 48, Time post drug ingestion 600% Cervicovaginal Fluid Exposure (mean percent of blood plasma) N(t)RTIs NNRTI PI Entry Inhibitors 500% 400% 300% 200% 100% 3TC (400%) FTC (375%) ZDV (235%) TDF (110%) IDV (200%) MVC (410%) GT AUC : BP AUC 75% NVP (80%) 50% 25% ddi (21%) ABC (8%) DLV (20%) 0% d4t (5%) EFV (0.4%) Courtesy of Angela Kashuba, ADM, CROI 2008 APV (50%) RTV (26%) ATV (18%) LPV (8%) SQV (ND) Min et al. JAIDS 2005 Dumond et al. AIDS 2007 Dumond et al. CROI

13 FEMALE GENITAL TRACT Cervicovaginal Fluid Exposure MALE GENITAL TRACT Semen plasma exposure 600% 500% 400% 300% 200% GT AUC : BP AUC 3TC (400%) FTC (375%) ZDV (235%) 3TC (660%) TDF (~330%) ZDV (230%) ddi (>100%) GT SP : BP ratio 100% 75% 50% TDF (110%) ABC (~100%) d4t (~100%) 25% 0% Modified from Dummond et al 2007 ddi (21%) ABC (8%) d4t (5%) How do sexually transmitted infections effect genital tract shedding in patients taking ART? 13

14 STI s and Seminal Super Shedders Plasma STI s Genital Tract Taylor et al 00, Hart et al 02, Eron et al 00, Tachet et al 00, Pilcher et al 01, Gupta et al 97, De Pasquale et al 99 Characteristics of 9 HIV-1 Seminal Super Shedders from a cohort of 72 men not taking ART Pt Age STI CD4 BPVL SPVL SP/BP Wk 0 Wk 0 ratio no 480 2,400 14, NSU ,000 >3,000,000 > no , , no , , no , , Chlamydia , , no , , NSU , , no ,724 30, Median SSS 48* 3/9 (30%)* ,990* 460,000* 2.41* N Shedder 35* 2/42 (4.8%)* ,000 9,200* 0.12* Taylor et al 03 CROI Abs

15 STI s appear to increase seminal shedding in patients not on therapy Fluctuations of HIV Seminal DNA with newly acquired STD s (Atkins et al: BMJ 1996) SPVL 8 x higher in men with STD s: Reduced by antibiotic treatment. (Cohen et al: Lancet 1997) 4 x reduction in SPVL post antibiotic treatment of STD s (Dyer et al: JID 1998) Asymptomatic Urethritis independent risk factor for seminal shedding (Winter et al: STI 1999) The effects of urethritis on seminal plasma HIV-1 RNA loads in homosexual men not receiving antiretroviral therapy. (Sadiq et al STI 2005) 94 patient study, 7 patients with Asymptomatic STI s 3 patients on ART had STIs Factor Treated Untreated sig Blood plasma viral load 2.6 ( ) 4.7 ( ) Seminal plasma viral load 2.9 ( ) 3.5 ( ) Detectable semen HIV 6/58 (10%) 21/36 (58%) OR 11.2 p< Among 58 men on ART tested for urethritis those with urethritis were over 8 times more likely to shed HIV in their semen than those without (2/3 with v 4/50 without RR 8.3 p=0.03 by Fishers exact test) AJ Winter, S Taylor, J Workman et al Sexually Transmitted Infections 99 15

16 HIV-RNA load in blood and semen in pts on & off ART & the effect of asymptomatic STI s Cross-sectional sectional cohort of 119 HIV +ve 81 on ART 38 off ART NNRTI n=36 PI n=45 all had BPVL < 50 and SPVL <250 9/119 (8%) subjects had asymptomatic STI s 4/81 on ART had no elevation in SPVL during asymptomatic STI Chan D et al Curr HIV Res Mar;6(2): Semen HIV RNA (log 10 copies/ml) Semen Versus Blood HIV-1 1 RNA in ART treated and 42 untreated individuals & Asymptomatic STI s Untreated Treated Urethritis Blood HIV RNA (log 10 copies/ml) AJ Winter, S Taylor, J Workman et al Sexually Transmitted Infections 99 16

17 ART and STI interactions Semen Log HIV-1 RNA (<1000) 18/24 Antibiotic Treatment (<500) Sadiq, Taylor et al: AIDS ; Blood Log HIV-1 RNA VIRAL LOADS AND RESISTANCE MUTATIONS IN BLOOD PLASMA AND SEMEN PLASMA IN MEN TAKING ANTIVIRALS AT THE TIME OF SYMPTOMATIC URETHRITIS PRE TREATMENT AT TIME OF URETHRITIS POST ANTIBIOTIC TREATMENT Cas e Treatment STI BPVL Visit 1 SPVL Visit 1 Resistance Mutations in blood plasma (BP) and seminal plasma (SP) Visit 1 BPVL Visit 2 SPVL Visit 2 Resistance Mutations BP and SP Visit 2 19 ddi, ABC, NFV,SQV GC 13, RT: M41L, L74V, V118I, M184V, T215Y PR: L10I, K20I, l24i, M36I, M46L, 154V, L63P, A71V,T74S, V82A 11,249 4,012 No change from Visit 1 20 AZT, 3TC, ddc GC 98,882 15,770 RT: M41L, A98G, M184V, L210W/L, T215Y 85,262 23,786 No change from Visit 1 21 AZT, 3TC, ddi GC 85,470 26,422 RT: M41L, E44A, D67N, K70R, M184V, T215Y, K219E, PR:. L10I, L63P, I93L 26,422 21,916 No change except V77I, in SP at Visit 2 22 d4t, ABC, NVP GC 69, ,000 RT: K65R, K103N, Y181C 49,000 4,300 No change from visit 1 SP No Amp 23 d4t,3tc, NFV,SQV GC 713 5,928 No Amp 986 <1000 No Amp 24 d4t, 3TC, NVP NSU <500 1,512 Taylor, Sadiq et al Antiviral therapy 8 (5): No Amp <1000 <1000 No Amp 4/6 patients on Failing ART with STI s had MD-Resistant virus detectable in semen 17

18 Rectal HIV Shedding There is very little data available on the effect of ART and Rectal Viral Shedding (even less with STI s) However ongoing rectal HIV shedding has been reported in the presence of effective plasma ART R Zucker man et al J Infect Dis Jul 1;190(1): Summary 1: ART and Male Genital Tract ART which suppresses blood plasma to undetectable levels will Suppress seminal HIV RNA shedding in the vast majority of men A very small minority will shed HIV despite undetectable BPVL Very limited data suggests ART may protect against increased shedding usually associated with STI s More data is required On the protective effect of ART on seminal HIV shedding in the presence of symptomatic and Asymptomatic STI s including HSV 18

19 Summary 2: ART and the Female Genital Tract ART which suppresses blood plasma to undetectable levels will Suppress female genital tract viral shedding in a significant proportion of women However a significant number of women >30% may continue to shed genital tract HIV RNA on an intermittent basis despite undetectable plasma viral load More data/research is required On the protective effect of ART on Female GT HIV shedding in the presence of symptomatic and asymptomatic sexually transmitted Infections inc HSV Summary 3: ART and Rectal HIV Shedding There is not enough data to comment on the effectiveness of ART to suppress Rectal HIV to undetectable levels in the presence of undetectable blood plasma HIV Limited data suggests that rectal shedding can occur despite the presence of systemic ART More data/research is required on The natural history of rectal HIV shedding The correlation between plasma and rectal HIV shedding in the absence and presence of ART. The penetration and effectiveness of ART on rectal shedding The effect of rectal STI s on rectal HIV shedding 19

20 In Conclusion Based on the biological data or lack of data currently available. To say a a person with completely suppressed viraemia ( effective ART ) ) is sexually non-infectious to their sexual partners Maybe premature 20