Rapporteur reports
Track A: HIV Basic Science report by Gilda Tachedjian
John Rossi took us on a fascinating journey starting from the mechanism
of RNA interference to the development of a triple transgenic
lentiviral vector for use in a HIV gene therapy trial. After the
initial characterisation of RNAi in C elegans it was subsequently found
that double-stranded small interfering RNAs (siRNAs) of 21 nucleotides
in length can mediate sequence specific post-transcriptional gene
silencing (PTGS) in mammalian cells. Due to its sensitivity and
convenience siRNA has become a tool that researchers use to
knock down gene expression in order to understand their function.
RNA interference is active in mammalian cells, forms part of the innate
immune system, and affords protection against RNA viruses. In the cell,
there are around 800 - 1000 microRNAs that regulate gene expression of
over one third of the entire human genome. Rossi described three
mechanisms by which siRNA can inhibit gene expression. These are:
1. Post-transcriptional cleavage of mRNA where a short RNA (of
extensive complementarity) anneals to a target mRNA resulting in
cleavage and destruction of the transcript
2. Translational repression of mRNA where a short complementary RNA
binds to the 3’untranslated region of messages resulting in inhibition
of translation.
3. Transcriptional silencing where RNA interacts with chromosomal DNA, converting active chromatin to silent chromatin.
Rossi described how RNA interference (RNAi) is triggered in mammalian
cells by expression of short hairpin RNA (shRNA), which is processed by
the host cell machinery to produce a siRNA that can act on its mRNA
target. His laboratory is using lentiviral vectors to deliver HIV
targeting siRNA’s into cells. A single vector (Triple construct)
expresses the nucleolar localising TAR decoy to sequester HIV-1 Tat, a
chimeric VA1CCR5 ribozyme that knocks down expression of the CCR5
receptor in the target cell by a catalytic mechanism and an
anti-tat/rev shRNA to directly target and degrade transcripts that
express the HIV Tat and Rev proteins. This combination
approach is aimed at maximizing inhibition of HIV replication. The
target cells are CD34+ cord blood or peripheral stem cells with the
goal of genetically engineering therapeutic genes in all HIV target
cells including macrophages and T cells. Rossi showed that
transduction of hematopoetic stem cells with the triple construct
allowed normal differentiation of cells to monocyte/macrophages and
dendritic cells. Furthermore, the triple construct provided better
protection against HIV infection than individual shRNAs in transduced
CD34+ derived monocyte/macrophages. He also showed that the Triple
vector affords protection to HIV in the SCID-hu mouse model. The Triple
vector also demonstrated lack of immunogenicity, normal thymic T-cell
development and resistance to T-tropic HIV. Rossi described their
proposed clinical protocol for transducing autologous CD34+ stem cells
or T cells (from HIV patients experiencing drug failure) with the
Triple construct. Rossi has obtained FDA approval for an autologous
stem cell trial with the first patient already enrolled in June of this
year. This represents the first human gene therapy trial using
a lentiviral vector that expresses shRNA to transduce hemopoietic stem cells. The outcome of this trial will be of great
interest in ascertaining the feasibility of siRNA based gene therapy for HIV/AIDS.
Track B: Clinical Research, Treatment and Care report by Helen Byakwaga
Joseph J.Eron: Overview of recent and ongoing randomized clinical trials for new ART agents in advanced clinical development. These include the integrase inhibitors raltegravir and elvitegravir, the CCR5 inhibitors maraviroc and vicriviroc, the NNRTI inhibitors etravirine and rilpivirine. The need for well tolerated, highly active and convenient antiretroviral therapy for all individuals who require treatment remains. New agents may improve tolerability and expand target populations: novel combinations that spare nucleoside or ritonavir can be explored. Where available resistance testing guides choice of the new agents, however if more than 2 ‘fully’active new drugs are available, the optimal number is not fully known and therefore combinations of new agents need to be explored. For treatment experienced patients in the developing world, new agents allow alternatives to recycled nucleosides.
Track C: Biomedical Prevention report by Rebecca Guy
This presentation by Professor Robert Bailey reviewed the evidence for the efficacy of male circumcision in reducing HIV acquisition, and discussed some guidelines for the way forward – the road from evidence to practice.
Male circumcision (MC) is not a new intervention: Worldwide about one third of adult men are circumcised - about two-thirds of men in Africa. MC is practiced mainly for religious and cultural reasons.
MC has been found to be protective against many other conditions (other than HIV): i.e. urinary tract infections in infants and chancroid and invasive penile cancer in men. HPV is less prevalent in circumcised men, and partners of circumcised men experience less cervical cancer. The evidence for a protective effect against syphilis and HSV-2 infection is less clear.
Observational evidence for male circumcision and HIV: Four ecological studies, 37 cross-sectional studies, and 15 prospective studies that have found a significant association between HIV acquisition and lack of circumcision (RR ranged from 0.52 to 0.18, 2-8 fold increased risk of infection for uncircumcised men). Meta-analysis of 15 observational studies (Weiss, Quiggley and Hayes) found an adjusted odds of HIV infection for the circumcised men of 0.42. Much of these data were available in 2000-2001 but very few scientists and no policy makers were persuaded due the limitations of observational studies. There were also concerns about safety.
RCT results are now available: All three trials were stopped before completion, because the protective effect of circumcision was found to be so strong, and it would have been unethical to continue. The three trial results were similar: South Africa trial (RR= 0.40, 60% protective effect), trials in Kisumu, Kenya and Rakaio, Uganda (overall RR= 0.43, 57% protective effect). Results are similar to the observational studies from six years ago. Two RCTs have also shown MC has no efficacy against any of the STIs measured. HPV results are not yet available.
Sexual disinhibition, There is no evidence of behavioral disinhibition, instead there was a reduction in risk behaviours and their biological markers during participation in the studies.
Potential impact of circumcision interventions on HIV incidence and prevalence in varying populations: Ecological evidence shows a strong correlation between the prevalence of circumcision in countries and the prevalence of HIV. All the highest HIV prevalence countries are those where circumcision is not highly practiced. No country with nearly universal circumcision coverage has ever had an adult HIV prevalence higher than 8%.
Estimated impact of MC roll out: Modelling approaches by various groups have estimated that after 20 years in Soweto, the HIV prevalence would be reduced from 23% to 14% (based on 50% uptake) and after ten years in Nyanza Province the prevalence would decline from 18% in men to 8%.
Cost effectiveness? The cost-effectiveness of MC, compares well with other HIV prevention interventions. In South Africa (HIV prevalence=25.6%), the cost per HIV infection averted over 20 years was estimated to be $181 (Kahn et al). In a lower prevalence population (e.g. 8%), the cost per infection averted increases to $550. Cost-effectiveness increases the longer circumcision is in place and the faster MC is scaled up, the more infections can be prevented – about 16% more.
Acceptability: Thirteen studies of acceptability in nine sub-Saharan African countries were conducted before the RCT results were available: 65% of uncircumcised men were in favour if it could be done safely and at no or minimal cost, 69% of women were also in favour. Regarding infant MC, high proportions of both men and women were also in favor. Increased cleanliness and reduced chances of having an STI where the main reasons for MC.
Future research: Some questions to be answered include: (1) Is there a protective effect for females? (2) Is there a protective effect for MSM? (3) How long does it take for full healing? (4) How much of the protective effect of MC is attributable to its effect against GUD? (5) What is the impact of MC programs on HIV at the population level? (Phase 4) (6) Will risk behaviours decline?
Advantages of MC: It is a proven effective HIV prevention intervention, it is a one-time treatment, it will save millions of lives, it provides an opportunity to include other reproductive health messages and services and offers an opportunity to gain access to the sex partners of the men. Challenges: Accessing vulnerable young men with linmited contact with health services; providing counselling and services for sexual partners and providing the training and resources to build capacity of health systems.
The road from evidence to practice: MC services should be made available as soon as possible in regions where HIV prevalence is high and most infections occur through heterosexual transmission. MC should be integrated with other HIV/STI prevention strategies, men seeking circumcision services should be encouraged to receive HIV counseling and testing, diagnosis and treatment of STIs should be available, behavioural counseling will be required, systems for monitoring and evaluation of adverse events and behavioural risk compensation will need to be implemented and innovative means to reach the maximum number of males should be considered; e.g. mobile services; medical missions, “circumcision weekends”. Any scale-up program should engage women in plans for consultation and mobilization.
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