HIV care Through a Crystal Ball
Dr V Harindra FRCP, FRCP(Glasg) Consultant Physician St. Mary’s Hospital Portsmouth. UK
Introduction • Viral eradication & cure • Prevention – – – – –
Vaccine Test & treat PrEP HIV testing Circumcision
• Pregnancy & Breast feeding • HIV & Ageing • Treatment - ART
HIV – Where we are 2014 • Deployment of antiretroviral therapy for HIV infection is one of the most extraordinary achievements in recent biomedical history • HIV-infected individuals with access to ART, life expectancy now approximates that of uninfected individuals • Between 1996 and 2012, ART averted an estimated 6.6 million AIDS-related deaths worldwide • These extraordinary successes however are tempered by the necessity of lifelong drug therapy
HIV Cure • Definition of a cure
– Indefinite or permanent absence of disease following the cessation of therapy
• Viral eradication / Sterilising Cure
– All traces of virus are absent, including viral reservoirs
• Approaches to eradicating latent HIV infection
– Intensification of HIV treatment in the acute phase of infection – Gene therapy and stem cell transplantation – Latency reversing agents (help uncover HIV reservoir inhibitors of histone deacetylase (HDAC))
• Functional Cure
– No evidence of measurable viral replication
The Berlin Patient • Diagnosed with acute myelogenous leukaemia and required both extensive pretransplant conditioning therapy and allogeneic hematopoietic stem cell transplantation (HSCT) to cure the malignancy • Donor was homozygous for the CCR5-32 mutation, which confers resistant to infection with HIV • 5 years after transplantation the patient takes no ART and remains free of detectable virus
Tebas P, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901-910
HIV Viral Rebound After Bone Marrow Transplant • Researchers analysed 2 HIV infected men who had received bone marrow transplants for lymphoma with HIV-susceptible donor stem cells • Both men had been receiving ART for at least 2 years before transplant – Had undetectable levels of HIV in blood while receiving ART after transplant
– Patient A stopped ART about 2.5 years after transplant – Patient B stopped ART about 4 years after transplant • HIV rebound at 12 weeks (Patient A) and 32 weeks (Patient B) after stopping ART • Reason for failure
– Less aggressive conditioning regimen – Stem cell transplantation using cells from donors without the homozygous CCR5 gene deletion
• Ongoing research seeks to duplicate the results in the Berlin patient without the need for HSCT T J. Henrich. Ann Intern Med. Published online July 21, 2014. Abstract
Mississippi Baby • The child was born prematurely in a Mississippi clinic in 2010 to an HIV-infected mother who did not receive ART during pregnancy and was not diagnosed with HIV infection until the time of delivery • The infant was started at 30 hours of age on liquid, triple-drug antiretroviral treatment (zidovudine, lamivudine, and nevirapine) – Testing confirmed within several days that the baby had been infected with HIV – ART was continued through age 18 months, at which point the child was lost to follow-up • At age 23 months the child was again seen in clinic and had no detectable virus in the blood, despite not taking ART for the previous 5 months, and had no HIV-specific antibodies • These results persisted for a total of 27 months without therapy – At age 46 months, the child experienced viral rebound & decreased CD4 count
Cancer Drug First to Wake Dormant HIV • One of the strategies used to try to reduce the reservoir in chronically infected patients is kick-and-kill approach
– Expose archived HIV within their DNA out of their resting stage so that it can be killed and eliminated by the immune system
• Romidepsin currently used to treat cancer have been shown to drive enough latent HIV out its reservoir for the virus to become detectable in blood with standard HIV assays • This is the first clear evidence that the latent reservoir can be identified and the hidden virus shocked out of its hiding place • Researchers have launched a study in which well-suppressed HIV-positive patients will receive both romidepsin and a therapeutic HIV vaccine to see if the dual approach can reduce reservoir size
.
20th International AIDS Conference. Abstract TUAA0106LB. Presented July 23, 2014
History of HIV Vaccine Research 1981
HIV was identified as the cause of AIDS.
1987
The first HIV vaccine clinical trial opened at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland. This Phase I trial enrolled 138 healthy, uninfected volunteers. The gp160 subunit vaccine showed no serious adverse effects.
1988
The NIAID AIDS Vaccine Evaluation Group (AVEG), the first U.S. cooperative HIV vaccine clinical trials group, began enrolling volunteers in its first trial.
1992
NIAID launched the first Phase II HIV vaccine clinical trial. This trial included uninfected volunteers with a history of high-risk behavior -- injection drug use, multiple sex partners, or sexually transmitted infections. Participants were counseled repeatedly to avoid any behaviors that put them at risk of HIV infection.
1998
1999
•
First annual HIV Vaccine Awareness Day to honor vaccine study volunteers.
•
First large scale vaccine trial began: VaxGen initiates Phase III trial of AIDSVAX in North America and The Netherlands.
•
NIAID begins first African preventive HIV vaccine trial in Uganda.
•
First large scale vaccine trial in a developing country began: VaxGen initiates Phase III trial of AIDSVAX in Thailand.
•
Dedication of the Dale and Betty Bumpers Vaccine Research Center (VRC).
•
NIAID formed the HIV Vaccine Trials Network (HVTN), a network of clinical sites in the United States and abroad dedicated to developing a preventive HIV vaccine by testing and evaluating candidate vaccines in all phases of clinical trials. The network included more than 25 sites in the United States, Africa, Asia, South America, and the Caribbean
•
First African vaccine trial completed in Uganda.
2000
History of HIV Vaccine Research •
U.S. and Royal Thai governments jointly initiated RV144, a Phase III trial to evaluate a novel HIV vaccine strategy commonly referred to as "prime-boost."
•
Formation of Global HIV Vaccine Enterprise proposed in Science
2003
2004
VaxGen candidate failed in Phase III trials.
2007
NIAID halted the Phase II Step and Phambili studies due to safety concerns.
•
Phase II HVTN 505 study initiated to evaluate a “prime-boost” vaccine regimen developed by the VRC.
•
Results of Phase III Thai Trial (RV144) show vaccine combination is first to demonstrate modest preventive effect in humans. The trial enrolled more than 16,000 volunteers.
•
Two potent antibodies that prevent most strains of HIV identified by the VRC (VRC01 and VRC02).
•
Establishment of Pox-Protein Public-Private Partnership (P5)
2009
2010
2011
HVTN 505 expanded to include protection from HIV as primary endpoint.
2012
Additional analyses of samples from RV144 provide insight about what type of immune response may be needed for an effective vaccine.
2013
HVTN 505 immunizations stopped due to lack of efficacy
Using ART to Prevent HIV Infection: • Treatment as prevention – Immediate treatment of all persons who are infected with HIV so as to achieve virologic suppression – HPTN-052 study (1763 serodiscordant couples) – 96% reduction – PARTNER study (767 serodiscordant couples) – Transmission rate zero
• Pre-exposure Prophylaxis (PrEP) – The PrEP trials demonstrated the biological plausibility that continually bathing the tissues in antiretrovirals will render the tissues less susceptible to HIV acquisition.
• Post-exposure Prophylaxis (PEP) • Intravaginal applications
Large-Scale HIV Test-and-Treat Strategy Viable Door-to-Door Testing Preliminary findings from the ANRS 12249 test-and-treat randomized trial • The study is being carried out in the region of Kwazulu-Natal, subdistrict of Hlabisa, where 228,000 Zulu-speaking people reside. The prevalence rate of HIV in this region is reportedly 24% • Identified 22 groups or clusters of about 1000 residents each - The study team goes door to door offering HIV testing using dried blood spot technology repeated every 6 months • Randomized 11 of these clusters to receive universal antiretrovirals immediately if HIV-positive • Remaining clusters, (control group) will be offered antiretrovirals in accordance with South African guidelines (when CD4 cell counts fall to 350 copies/mL) • During the first attempt at contact, more than 80% agreed to be tested for HIV in the home & 6 months later, 85% of this group again agreed to be tested • Only about one-third of those diagnosed accepted treatment from the outset &In the year that followed, this increased to 48% 20th International AIDS Conference: Abstract WEAC0105LB.
Pre-exposure Prophylaxis Study
Population
Efficacy
Adherence
Partners PrEP (Kenya, Uganda)
Heterosexual couples (4,758)
67% TDF 75% TDF/FTC
82%
TDF 2 (Botswana)
Young men & women (1,219)
62% TDF/FTC
80%
Bangkok TDF
IVDU (2,413)
49% TDF
67%
iPrEX (S American, SA, Thailand, USA)
MSM (2,499)
44% TDF/FTC
51%
FEM-PrEP (Kenya, SA, Tanzania)
Young women (2,210)
6% TDF/FTC
37%
VOICE (SA, Uganda, Zimbabwe)
Young women (5,029)
49% TDF 4% TDF/FTC
30%
Pre-exposure Prophylaxis • Pre-exposure Prophylaxis Initiative (iPrEx) trial found that oncedaily FTC-TDF provided an additional 44% protection against HIV infection in a study population of 2499 high-risk, HIV-negative men or transgender women who have sex with men • • • •
2 dose/week 76% (56%-96%) 4 dose/week 96% (90%-99%) 7 dose/week 99% (96%-9%) If no drug was detected the incidence of HIV was 4.04%
Grant RM, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. Dec 30 2010;363(27):2587-99. Grant RM, et al. Results of the iPrEx open-label extension (iPrEx OLE) in men and transgender women who have sex with men: PrEP uptake, sexual practices, and HIV incidence. Program and abstracts of the 20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia. Abstract TUAC0105LB.
Summary of investigational ARV for PrEP Mechanism
Dosing Route
Frequency
Stage
Oral
Once daily
Rilpivirine-LA
CCR5 antagonist NNRTI
Injectable –IM
Once monthly
Phase 2 enrolling Phase 1 pilot
Dapivirine
NNRTI
Ring
Monthly
Ibalizumab
CD4 attachment Inhibitor Integrase
Injectable –SC
Once weekly
Phase 3 enrolloing Phase 1 pilot
Injectable –IM
Once quarterly
Phase 1 pilot
Maraviroc
744-LAP
PrEP is difficult to implement due to poor adherence & low justification for treating healthy individuals with ART
Pre-exposure Prophylaxis IPERGAY is being conducted in France in sexually active, high-risk men who have sex with men, looking at an on-demand strategy of PrEP using the active drugs tenofovir/FTC and comparing it with placebo • The men are instructed to take 2 tablets 2-24 hours before having sex and 1 tablet daily for the next 2 days for this on-demand strategy • Planning to enrol 2000 men • Pharmacokinetics of the first 129 participants demonstrated that – 86% of the men had detectable tenofovir concentrations in a range that would be protective
Landovitz RJ, Coates TJ. Moving HIV PrEP from research into practice. Lancet Infect Dis. 2014 Jul 22.
Aging and Non-HIV Comorbidities • • • • • • •
Cardiovascular disease Metabolic disorder: DM/ Dyslipidaemia/ Hypogonadism Liver disease Renal disease Osteoporosis HIV-associated dementia (HAD) Malignancies
Concept of multi morbidity • Total is greater than sum of parts (increase lipids & hypertension has more effect in the old) • Frailty phenotype: 3 of 5 ( Weight loss, exhaustion, weakness, slowness & low physical activity) Helleberg M, et al Obel N. Causes of death among Danish HIV patients compared with population controls in the period 1995–2008. Infection 2012; 40:627–634. Helleberg M, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis 2013; 56:727–734
1987: 1st NRTI Approved
1987: Zidovudine 1991: Didanosine 1992: Zalcitabine 1994: Stavudine
1995: 1st PI 1996: 1st NNRTI
1995: Lamivudine, Saquinavir 1996: Nevirapine, Ritonavir, Indinavir 1997: Delavirdine, Nelfinavir 1998: Abacavir, Efavirenz 1999: Amprenavir 2000: Lopinavir/ritonavir 2001: Tenofovir
2003: 1st Fusion Inhibitor
2003: T-20, Atazanavir, Emtricitabine, Fosamprenavir 2005: Tipranavir
2007:
1st
CCR5 Inhibitor
1st Integrase Inhibitor
2006: Darunavir 2007: Maraviroc, Raltegravir 2008: Etravirine 2011: Rilpivirine 2013: Elvitegravir 2014: Dolutegravir
HIV timeline 2013 - 2015 DRV/c Dolutegravir
Dolutegravir NEW LAUNCHES
Rezolsta
PK enhancer
Cobicistat Elvitegravir
Triumeq FDC*
Integrase Inhibitor
= Dolutegravir+Kivexa
Protease Inhibitor NNRTI
Atazanavir / Cobicistat FDC
Stribild (QUAD)
2013
*Triumeq
2014
2015
NRTI
2016
NRTI
Tenofovir Alafenamide (TAF)
NNRTI
INI
GSK1265744
CCRI Fusion I
Long acting parenteral Rilpivirine (IM 4/52 interval)
2017
2018
2019
MK1439 (Doravirine) AIC292 Cinicriviroc (CCR5 & CCR2) BMS663068 (CD4 binding -attachment inhibitor)
GSK1265744 (SC or IM 4/52 interval
Conclusion - Future of HIV care 2020 • Very few patients infected with HIV will be unaware of their diagnosis • Essentially all HIV infected patients will be treated • ARV will be widely used for HIV prevention – both as treatment & PrEP • Overall sexual transmission of HIV will be less common • Maternal transmission will be eliminated • Treatment will be extremely convenient In resource limited countries • More men will be circumcised as an HIV prevention strategy • Vaginal microbicides of moderate potency will have been developed • Antiretroviral drugs will be much more broadly available
Conclusion - Future of HIV care 2020 • HIV eradication will not be achieved • Functional cure may be achievable • HIV prevention will not be supported by an effective vaccine • Health manpower shortage & inadequate infrastructure will result in limited HIV treatment programmes • Antiretroviral access programme will fall far short of the need
THANK YOU