The UC San Diego AntiViral Research Center sponsors weekly presentations on infectious diseases research and clinical practices. A presentation on whether widespread HIV treatment can end transmission discussed recent trends showing HIV declining among adolescents and young adults in the US. The presentation reviewed research showing that early HIV treatment dramatically reduces heterosexual transmission but some transmission may still occur through anal sex among men who have sex with men on antiretroviral therapy. Future interventions could focus on optimizing HIV treatment, comparing antiretroviral regimens, and suppressing coinfections like CMV to further reduce HIV transmission.

1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS

2. AIDS Rounds Sept 13, 2013
Is it the End of HIV Transmission
(at the End of the Cascade)?
Sheldon Morris M.D., M.P.H.

3. Introduction
 The test and treat strategy is the highly touted as the
best hope for controlling the HIV epidemic.
1) Is HIV declining?
1) Where are we in the achieving high rates of HIV
treatment and what are the barriers to success?
1) If we get individuals onto durable ART is there still
going to be transmission? How much?

8. Diagnoses of HIV Infection among Adolescents and Young
Adults Aged 13–24 Years, by Transmission Category
2008–2011—United States and 6 Dependent Areas
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been
statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting.
a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection.
b Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or not identified.

9. Diagnoses of HIV Infection among Adolescents and Young
Adults Aged 13–24 Years, by Transmission Category
2008–2011—United States and 6 Dependent Areas
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been
statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting.
a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection.
b Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or not identified.

12. Marks G. AIDS. 2006;20:1447-1450.

13. Marks G. AIDS. 2006;20:1447-1450.

14. Marks G. AIDS. 2006;20:1447-1450.

15. Marks G. AIDS. 2006;20:1447-1450.

16. CCTG 592: a randomized controlled
study of a internet intervention for HIV
infected MSM to reduce STIs
 Enrolled 181 MSM November 2010-July 2012 at UCSD,
USC and Harbor-UCLA
 Final visit of last participant in Aug 2013
 Outcome with be Risk reduction intervention versus
control survey alone for incident STI any site (syphilis,
CT/GC in throat, rectum or urethra)

17. CCTG 592: Baseline Analysis
 Any detectable viral load (>75 copies/ ml) was found in
18%
 High level detectable viral load (>1000 copies/ml) was
found in 9%
 Unprotected anal sex with a potentially serodiscordant
and any detectable viral load occurred in 13%

18. CCTG 592: MSM on Stable ART

19. CCTG 592: HIV-infected MSM on ART
 Complete viral suppression among MSM on ART was
found in only 82%
 Factors associated at risk of transmission of HIV
among MSM on ART based on detectable plasma viral
load were black race, low CD4 count, METH use

20. CNICS: Geospatial Analysis
 891 San Diego CNICS subjects were included if they had
one patient reported outcome (PRO) questionnaire in
2011.
 Geocoding to the census block group (CBG) level
 49% HRTB was defined as any of the following in the
past 6 months: unprotected anal or vaginal sex; sex after
alcohol or drugs; sharing injection drug use equipment;
more than 2 partners; and sex with HIV negative or
unknown partner.
Haubrich CROI 2013

21. CNICS: Geospatial Analysis
Individual characteristics
significantly associated
with an increased risk
(p<0.02) of HRTB included:
CBG rates of HRTB were
significantly higher ( all
p<0.05) in communities
with:
 younger age
 Fewer visits to HIV care
 higher nadir CD4
 No AIDS diagnosis
 current substance use
 higher current CD4
 male gender
 absence of a current
mental health diagnosis
 lower income
 greater percentage males
 higher education
 shorter distance to care and
higher population
 Moran’s global I statistic
indicated significant global
clustering of HRTB (p<0.001)
and cluster ‘hot-spots’ were
identified by Kuldorff’s scan
statistic.
Haubrich CROI 2013

22. Rates of Risk Behaviors HIV-infected Patients in Care by CBG
Bayesian
estimate of
HRTB per
1000
population
Haubrich CROI 2013

23. CCTG 592: What about MSM on ART and Suppressed?
 Among MSM on stable ART and have suppressed virus
in plasma how many are still shedding HIV in their
semen?
 What are the factors associated
with detectable for HIV in semen?

24. 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Status New infections
Aware (ART)
Aware (no ART)
Unaware
Awareness of HIV Serostatus:
Estimates of Transmission
25%
65%
Marks G. AIDS. 2006;20:1447-1450.
20%
??
New
Infections/Year
(~32,000)
People Living
With HIV

25. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
Rates of HIV Shedding in Semen on ART
Trial Pop. HIV shedding Comments
Ghosn 2013 157 MSM on ART
23/304 (7.6%)
5 1st visit
14 2nd visit
2 both visits
2 samples 4 wks apart
74% BPVL ND with
ultrasensitive assay
145 copies (40-1475)
Gianella 2013 114 MSM on ART
11/114 (9.6%)
6/100 (6.0%) when
BPVL ND
1 sample per subject
Semen plasma HIV RNA
2.1 log10 copies (1.7-
2.5)
Politch 2012 101 MSM on ART
30/101 (30%)
detectable HIV RNA
and/or DNA in
semen
Semen HIV RNA or DNA
18% had HIV RNA in
blood - median 560 (80–
650, 000)
Sheth 2009
25 MSM initiating
ART
48% had HIV in
semen at least once
16.4% of all BPVL ND
Blood and semen
were collected at weeks 0,
2, 4, 8, 12, 16, 20 and 24.
Marcellin 2008
145 men on ART in
assisted reproduction
16/264 (6.1%)
7/232 (3.0%) when
BPVL ND
1-6 samples per subject
median HIV-1 RNA in
semen 1770 copies/ml

26. Sheth JAIDS 2009
 After initiation of ART 12/25 (48%) had at least one visit with detectable sVL
 Shedders had higher bVL of 4.65 log10 RNA copies/ml (vs. 4.50; P.0.86) and
lower baseline CD4 T cell count 195 vs. 230/ml (p=0.97)
 Baseline sVL was 10-fold higher in those with isolated semen shedding than in
those without detectable isolated shedding (median 4.42 vs. 3.41 log10 RNA
copies/ml; P.0.03)
 In 13 STI-free, long-term ART-treated men, with an undetectable bVL for
median 82 months (range: 48–216 months), isolated semen HIV RNA shedding
was detected in four of 13 participants (31%; median 564 RNA copies/ml, range:
336–828 copies/ml)
Sheth 2009

27. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Politch AIDS 2012

28. Ghosn IAS 2013
 157x 2 samples 4 wks apart, 74% BPVL ND with ultrasensitive assay
 23/304 (7.6%) – 5 x 1st visit; 14 x 2nd visit; 2 x both visits
 20.5% had an STI (syphilis, gardnerella, ureaplasma, gonorrhea,
mycoplasma, chlamydia, HSV2) but this was not associated with shedding
 Factors associated wth shedding included: CD4 554-735 compared to lower
or higher, presence of PBMC HIV-DNA >318 per 10 x6 PBMCs.

29. Politch AIDS 2013
 Of the 101 men, 18% had HIV RNA in blood [median HIV-RNA copy
number/ml (range): 560 (80–6.4 x 105)], and 30% had HIV RNA and/or DNA in
semen
 Of the 30 men with HIV in semen, 17 had CF HIV-RNA, 17 had CA HIV-RNA
and 5 had CA HIV-DNA
 Detection of HIV in semen was also associated with elevated concentrations of
several other seminal inflammatory markers: TNF-a, IL-6, IL-8, and SLPI.

30.  HIV-infected MSM (n=114)
 CCTG 592
 ON ART (median 882 days, IQR: 406-1725)
 Median CD4+ T-cells: 580 cells/ml
 HIV RNA levels in blood <500copies/ml
 100 subjects HIV RNA <50copiem/ml
Determinants of HIV Shedding in Semen on ART
Gianella CID 2013

31. CCTG 592: MSM on Suppressive ART
Gianella CID 2013

32. CCTG 592: MSM on Suppressive ART
Gianella CID 2013

33. CCTG 592: MSM on Suppressive ART
Gianella CID 2013
** In sub-analysis with HIV RNA in blood <50copies/ml high-level CMV
replication was the only predictor of detectable HIV RNA in semen

34. What could be done to reduce risk of
transmission on ART?

35. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
Heterosexual HIV Transmission After ART
Initiation in Discordant Couples
• Partners for the Prevention of
HSV/HIV Transmission study
– Prospective cohort analysis of
discordant couples (n=3381)
– 7 African countries
• HIV-infected partners starting
HAART (n=349)
– Genetically linked HIV
transmission (n=103)
• Follow-up
– Up to 24 months
Donnell D, et al. Lancet. 2010;375:2092-2098.
HIV Incidence
HIVIncidence
(per100-person-years)
2.24
(1.84-2.72)
0.37
(0.09-2.04)
HIV Partner Had Initiated HAART
No Yes
92% Reduction

36. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
HPTN 052
• Median follow-up: 1.7 years
– HIV RNA <400 copies/mL
• Early ART: 90%
• Delayed ART: 93%
• Linked HIV transmission to HIV-
negative partner (n=39)
– Early therapy (n=1)
• 0.1 per 100 person-years
– Delayed therapy (n=27)
• 1.7 per 100 person-years
• Early ART that suppressed HIV RNA
led to a 96% reduction of sexual
transmission of HIV in serodiscordant
couples
CumulativeProbability
0 1 2 3 4 5
Linked HIV Transmission
Early
ART
Delayed
ART
Cohen M, et al. N Engl J Med. 2011;Jul 18. [Epub ahead of print].
Hosseinipour MC, et al. 6th IAS Conference. Rome, 2011. Abstract MoAX0104.
Years
HR: 0.04
(95% CI 0.01-0.27)
(P<0.001)
*Transmission occurred within 90 days after the index
initiated antiretroviral therapy.

37. Chrakraborty 2001
 Probability of transmission of HIV 3/10000 for semen viral load<1000 copies/ml
Sheth 2009

38. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Attia 2009

39. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Morris 2013
If we estimate a 92% reduction in HIV-transmission during ART to the summary
estimated risk of heterosexual transmission of 0.008 = 0.0007.
If couples had sex on all three days the monthly cumulative probability of
conception would be 0.23 [calculated as 0.084+(1-0.084)*0.086+(1-
0.079)*0.081], while the risk of transmitting HIV would be 0.002.

40. Morris 2013
 average of two unprotected anal sex acts per HIV-infected MSM per month with
serodiscordant partners (CCTG 592)
 probability of transmission of 0.00136 per act (92% reduction from 0.017)
 Estimating 442,000 HIV-infected MSM living in the U.S. (CDC 2009)
 If 59% on ART = 260,000 MSM on ART in the U.S.
 Estimated sexually active MSM at 85%
 approximately 7,000 transmissions in the U.S. related to MSM on ART
Sheth 2009
Estimating HIV Transmissions from MSM on ART

41. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Osborne 2013
Does ART Regimen Matter?

42. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Osborne 2013

43. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Osborne 2013

44. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Future Interventions for Semen Shedding
 Good ART management: Start early, maximize
adherence
 Are some regimens better than others?
 CMV suppression?

45. March 18, 2013
UCSD AVRC

46. Questions