Biomedical Interventions for HIV Prevention

Kees Rietmeijer, MD, PhD

Department of Community and Behavioral HealthColorado School of Pubic HealthUniversity of Colorado Denver

New York Times December 1, 2008

Recent Developments in “Biomedical” Interventions for

HIV Prevention

• Vaccines

• Circumcision

• Treatment of sexually transmitted infections (STI) as HIV Prevention

• HIV Treatment as HIV Prevention

Vaccines

• Fact: Many viral and bacterial infections result in immunologic protection

• Fact: Many viral and bacterial infections can be prevented through immunization

• Question: Can/will an effective HIV vaccine ever be available?

• Answer: Perhaps, but it doesn’t look good…

Efficacy of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomized, placebo-

controlled, test-of-concept trial.

• 3000 HIV-1-seronegative participants randomly assigned to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506) and followed every six months

• 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]).

• The HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men.

Buchbinder et al. Lancet 2008, November 12 Epub Ahead of Print

Efficacy of a Cell-Mediated Immunity HIV-1 Vaccine (the Step Study): a Double-Blind, Randomized, Placebo-Controlled,

Test-of-Concept Trial

• The HR of HIV-1 infection between vaccine and placebo recipients was higher in:

– Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3])

– Uncircumcised men (3.8 [1.5-9.3])

• Not increased in:

– Ad5 seronegative (1.0 [0.5-1.9])

– Circumcised (1.0 [0.6-1.7]) men.

Buchbinder et al. Lancet 2008, November 12 Epub Ahead of Print

Circumcision

• Fact: Circumcision status is shown to be protective for HIV acquisition among men in HIV prevalence studies

• Question: Can circumcision prevent HIV acquisition prospectively?

• Answer: Yes

Male Circumcision

• 50% reduction in risk for HIV among circumcised men from studies in sub-Saharan Africa

• Circumcision offers even greater protection for men with multiple partners and STD infection–No evidence of benefit for women with HIV

positive partners

Gray et al., Weiss et al., 2000; Westercamp and Bailey 2007

Male Circumcision

• Across nine countries in sub-Saharan Africa, people said they would support circumcision

–65% of uncircumcised men–71% of women (for partners)–81% of parents (for their children)

Weiss et al., 2000; Westercamp and Bailey 2007

Circumcision: Issues

• Sexual disinhibition–None found in the 3 trials

• Early resumption of sexual intercourse after circumcision may increase risk

• Prevention of HIV+ male female transmission–No evidence

• No evidence of prevention effect among MSM

Circumcision: Recommendations

• WHO/UNAIDS:–“Countries with hyperendemic and generalized HIV

epidemics and low prevalence of male circumcision should expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support.”

Circumcision: Challenges

• Acceptability

• Cost

• Increases in high-risk sexual behavior

• Safety–Substitution of surgically safe circumcision

procedures for unsafe, unsterile traditional methods is essential

Diagnosis and Treatment of STI as HIV Prevention

HIV Viral Load and STIs

Acute HIV STI episode STI episode AIDS

Adapted from Cohen and Pilcher, JID 2005

6

5

4

3

2

HIV RNA Log10 Copies/Ml

STI Treatment for HIV Prevention• Fact: STI act as co-factor for the acquisition and

transmission of HIV• Question: Does STI treatment reduce HIV

transmission?• Answer: Yes

– Mwanza trial: Expanding STI diagnostic and treatment services resulted in 42% reduction of HIV incidence• Grosskurth et al. Lancet 1995;346:530-6.

• Answer: No– Rakai study: Mass STI treatment did not result in reduced

HIV incidence • Wawer et al. Lancet 1999:353:525-35

Mwanza Trial

Mwanza Trail (1991 – 1994)

• “… tested the hypothesis that improved treatment services for STDs, integrated within the existing primary health-care system, would reduce HIV-1 transmission in the general population.”

Grosskurth et al. The Lancet 2000;355:1981.

Mwanza Trial - Intervention

• Establishment of STD reference clinic

• Training of existing staff in diagnosis and treatment of STI with syndromic treatment algorithms

• Regular supply of drugs needed to treat STI

• Regular supervisory visits for in-service training

• Periodic visits by team of health educators to villages to provide information on STIs and encourage STI evaluation and treatment

Mwanza Trial - Evaluation

• Randomized, community-level intervention–6 pairs of intervention/control communities

• Randomly selection of cohorts of 1,000 persons/community, 15-54 years of age

• Surveys/HIV testing conducted at baseline and after 2 years

Mwanza Trial - Results

Grosskurth et al. Lancet 1995;346:230-36

Overall: a 42% decrease in HIV incidence in the intervention communities

Rakai Trial

Rakai Trial (1994 – 1998)

“This trial tested the concept that repeated rounds of mass treatment for STDs, delivered to trial participants in their homes would reduce STD rates and HIV-1 transmission.”

Grosskurth et al. The Lancet 2000;355:1981.

Rakai Trial - Intervention

• 3 Rounds @10-month intervals (given over 2 days) of:– Azithromycin 1 gram (all)

• H. ducreyi, C. trachomatis, N. gonorrhoeae (many strains)

• Incubating T. pallidum (?)

– Ciprofloxacin 250 mg (non-pregnant participants)

• N. gonorrhoeae, H. ducreyi

– Cefixime 400mg (pregnant women)

• N. gonorrhoeae,

– Metronidazole (all)• T. vaginalis

– LAB 2.4 Million Units IM • T. only to TRUST-positive inidividuals

Rakai Trial – Control Group

• 3 Rounds @10-month intervals (given over 2 days) of:– Mebendazole 100 mg, two doses

• Anti-helminthic

– Iron Folate

– Single low-dose vitamin

• Participants with STI symptoms or positive syphilis serology referred for free treatment to Rakai Project mobile clinics or government health posts

Rakai – Both Groups

• Identical education on HIV prevention

• Confidential HIV counseling and testing

• Free general health care at Rakai Project mobile clinics, whether or not participating in study

• Free condoms

Rakai - Evaluation

• Multiple study communities aggregated into 10 study clusters and randomization of 5 clusters to intervention and 5 to control conditions

• Study subjects enrolled and consented at baseline and beginning of each intervention/control “round”– 6,000 – 7,000 per round per arm

–Over 80% coverage of all eligible residents

Rakai - Evaluation

• At beginning of each study round (three in total)– Interview: socio-demographics, behavioral, health, treatment

seeking; partner information

– Biological samples:• Venous blood (all): HIV, syphilis, HSV-2 serology

• First-catch urine– N. gonorrhoeae, C. trachomatis (random sample)

– HIV (if no blood available)

– Pregnancy (women)

• Self-obtained vaginal swab (women)– T. vaginalis (culture)

– Bacterial vaginosis (gram stain)

• Multiplex PCR (if reported genital ulcers)– T. pallidum, H. ducreyi, HSV-2

Wawer et al. Lancet 1999;353:525-35

“We found no differences in incidence of HIV-1 infection between the study groups either in the whole HIV-1 negative cohort or in pregnant women. The rate ration was close to unity overall and in all clusters and subgroups.”

Reconciling the Mwanza and Rakai Trials

• Difference in stages of the HIV-1 epidemic influencing:– Risk of exposure

– Distribution of viral load in the infected population

• Potential differences in the prevalence of incurable STDs (e.g., HSV)

• Greater importance of symptomatic vs. asymptomatic STDs in HIV transmission

• Greater effectiveness of continuously available services than intermittent mass treatment

Grosskurth et al. The Lancet 2000;355:1981.

Reconciling the Mwanza and Rakai Trials

• “Population differences in sexual behavior, curable STD rates, and HIV epidemic state can explain most of the contrast in HIV impact observed....”

• “…supports the hypothesis that STD management is an effective HIV prevention strategy in populations with a high prevalence of curable STDs, particularly in an early HIV epidemic.”

White et al. JAIDS 2004;37:1500-13. .

HSV Suppressive Treatment for HIV Prevention

• Fact: Chronic genital HSV infection is an important co-factor in HIV acquisition and transmission

• Question: Can chronic suppressive HSV treatment reduce HIV acquisition?

• Answer: No– Tanzania: no effect of acyclovir 400 mg bid among HSV-2

sero-positive, HIV-negative women after 1.5 years• Watson-Jones et al. N Engl J Med 2008;358:1560-71

• Answer: No– Africa/Peru/USA: no effect of acyclovir 400 mg bid among

HSV-2 sero-positive, HIV-negative women and MSM • Celum et al. Lancet 2008;371:2209-19

HSV Suppressive Treatment for HIV Prevention

• Question: Can chronic suppressive HSV treatment reduce HIV transmission in dually infected individuals?

• Answer: No–Partners in Prevention study: no difference in

transmission among 3,408 African HIV discordant couples in which dually infected individuals were treated with acyclovir

–Suppressive treatment resulted in 73% reduction of genital ulcers due to HSV

HIV Treatment for HIV Prevention

• Post-exposure prophylaxis (PEP)

• Pre-exposure prophylaxis (PrEP)

• Chronic suppressive therapy among those infected to prevent ongoing transmission

Non-OccupationalPost-Exposure Prophylaxis

(nPEP)

Post-Exposure Prophylaxis

• Fact: Post-exposure prophylaxis is used for a number of possible infection exposures:–STIs: Gonorrhea, Chlamydia, and Syphilis

–Hepatitis A and B

–Rabies

–Anthrax

• Question: Would it work for HIV?

nPEP – What’s the Evidence?

• Observational studies– Case-control study of needle stick injuries to health care

workers• Prompt initiation of zidovudine was associated with 81% in

HIV acquisition–Cardo et al. N Engl J Med 1997:337:1485-90

– Sexual assault survivors in Sao Paolo, Brazil• Of 180 women treated with nPEP (zoduvudine,

lamivudine, indiniavir), none sero-converted, compared to 4 serconversions among 145 women not treated.

–Drezett J. 2002

nPEP – What’s the Evidence?

• Observational studies–High-risk MSM in Brazil

• nPEP with zidovudine and lamividune resulted in an initial 6-fold reduction in sero-incidence among men who took nPEP compared to those who did not

• However, long-term follow-up did not reveal a significant decrease in sero-incidence

– Schechter et al. JAIDS 2004;35:519-25.

nPEP – What’s the Evidence?

• Additional evidence–Registries

–Case Reports

nPEP – What’s the Evidence?

• However–No randomized prospective studies

–Sample sizes often too small to yield significant differences

nPEP – What’s the Evidence?

• “Although data from the studies and case reports do not provide definitive evidence of the efficacy of nPEP after sexual, injection drug use, and other non-occupational exposures to HIV, the cumulative data demonstrate that antiretroviral therapy initiated soon after exposure and continued for 28 days might reduce the risk of acquiring HIV.”

CDC. MMWR 2005;54:RR-2.

Recommendation

• “Partners who are contacted within 72 hours of a high-risk sexual or injecting-drug exposure to an HIV-infected partner, which involves exposure to genital secretions and/or blood should be offered PEP with combination antiretroviral therapy to complete a 28-day course.”

CDC. MMWR 2005;54:RR-2

nPEP: Possible Regimens

• Relative low risk exposure–Tenofovir 300 mg plus Emtricitabine 200 mg

(Truvada) once a day

• High risk exposure–Same plus Atazanavir 400 mg once daily

Pre-Exposure Prophylaxis(PrEP)

Pre-Exposure Prophylaxis (PrEP)

• Fact: Medical prophylaxis works for:–Malaria

–AIDS opportunistic infections, such as PCP

–HIV mother-to-child transmission

• Question: Would it work for HIV acquisition among (high-risk) adults?

PrEP: How it Works

• Daily dose of anti-retroviral(s) to prevent acquisition of HIV

• Theoretically any combination of drugs can be used, but Tenofovir alone or in combination with Emtricitabine (Truvada) is most often discussed because:–Once-daily dosing –Good safety profile

PrEP: Advantages

• Gender neutral

• Covert use possible

• Independent of exposure “event”–Sexual intercourse

–Needle sharing

• Intermittent use –Dependent on (anticipated) risk

PrEP: Does it Work?

• Only one study to date– Double-blind, placebo controlled phase-II trial demonstrated

a non-significant 65% reduction in HIV-1 or HIV-2 acquisition among women taking a once daily dose of 300 mg tenofovir

– No increased laboratory or clinical adverse events

– Effectiveness could not be conclusively evaluated because of small number of HIV infections (2 in the treatment group and 6 in the placebo group)

Peterson et al. PLoS Clin Trails 2007;2(5):e27

PrEP Trails in Progress

PrEP: Issues

• Efficacy not established

• Cost –At current pricing: $750 per month (U.S.)

–$298,000 per quality-adjusted life year gained (U.S.)

–Who would pay?

• Who would qualify?

PrEP: Issues

• Resistance

• Side-effects

• Long-term adherence

• Behavioral dis-inhibition

• Would intermittent PrEP work?

Topical Microbicides

Place Holder

Chronic Suppressive Therapy as Prevention of Ongoing Transmission

HIV Suppressive Treatment for HIV Prevention?

• Fact: HIV viral load among HIV-infected is strongly associated with HIV transmission to un-infected partners

Quinn et al, N Engl J Med 2000

HIV Suppressive Treatment for HIV Prevention?

• Question: Can (chronic) HIV suppression prevent transmission?

• Answer: Maybe…– Mathematical modeling using South African data

suggests that annual HIV testing and starting HIV treatment immediately could dramatically reduce HIV incidence within 10 years and drive prevalence <1% in 50 years.• Granich et al. Lancet 2008; Nov 25, epub ahead of print.

HIV Treatment as Prevention

• Dilemmas:–Is (chronic suppressive) treatment for prevention

ethical if there is no clear clinical benefit?

–Will extensive treatment with variable adherence lead to emerging (transmission of) resistant virus?

HIV Treatment as Prevention

• Dilemmas–Can adequate coverage be achieved to make

epidemiologic impact?

–How well are viral loads in plasma and genital secretions correlated?• How well do current treatments penetrate in the genital

tissue compartments?

• Can intercurrent STIs elevate viral load in genital compartment and thus increase transmission risk?