Rapporteur reports
Track A: HIV Basic Science report by Gilda Tachedjian
Wednesdays basic science plenary was presented by Ben Berkhout who gave an
eloquent presentation on HIV-1 evolution and how this drives resistance
to drug therapy.
The reasons underlying HIV-1 evolution include the high error rate of
the HIV-1 reverse transcriptase, mutations introduced by the host RNA
polymerase during transcription of viral RNA transcripts and
recombination. Berkhout proposed that the host cell restriction factor
APOBEC, also has a role in viral evolution by its capacity to introduce G to
A transitions. Berkhout described a general paradigm for the
appearance of drug resistance mutants using resistance to lamivudine as
an example. First the mutation is generated and then it is
selected in the population in the presence of drug. Initial
mutations observed in populations tend to be those that can be
generated easily by the virus i.e. transitions versus transversions.
Whether a mutation is stably maintained in the population will depend
on how fit it is under selective pressure. In this regard, the first
mutation that appears with 3TC therapy is the transient M184I mutation,
which is generated by a single G to A transition that is easy to make.
Because it is less fit, this mutant is competed out of the population
by a second mutant RT expressing Val (GUG), which is harder to make but
results in a more fit virus. Examples of the evolution of HIV-1
protease resistance clearly demonstrate the endless possibilities in
evolution to a resistant and fit virus. Therefore, strategies aimed at
pushing the virus into low fitness and low pathogenicity is highly
unlikely. When presented with siRNAs targeted to
specific sequences on the viral genome, HIV can evolve to evade these
siRNAs with mutations appearing not only in the target sequence but
also at distal sites. Berkhout presented a novel mechanism of
resistance to the fusion inhibitor T-20 where the resistant virus is
dependent on the presence of the drug for viral replication. In the
absence of T-20 the mutant virus, which has mutations in both HR1 and
HR2, is hyperfusogenic and non-infectious. In the presence of T-20 the
inhibitor comes to the rescue and acts like a safety pin preventing the
premature switch that triggers hyperfusogenicity. Berkhout also
presented a study analysing mutations seen in drug treated individuals
in an Amsterdam database and confirmed by the Stanford database.
He found many RT mutations that are not included in the IAS list of
drug mutations considered in genotyping algorithms. Some of these
mutations are likely to directly confer resistance while others may be
compensatory. These studies are consistent with work from other
investigators, including presentations at this conference (Yap et al
MOPEA056 and Santos et al MOPEA059). Berkhout suggested that these
mutations should be considered for inclusion in the IAS list of drug resistance mutations.
Track B: Clinical Research, Treatment and Care report by Helen Byakwaga
Current pediatric treatment issues: Annette Sohn
2.3 million children worldwide are infected with HIV. About 780,000 children are in need of ART, however only 15% of global need is met. Response to treatment is better when ART is started before severe immunodeficiency. Interim analysis results from the CHER study in South Africa show a 75% reduction in mortality in infants receiving ART before 12 weeks of age. More data on threshold to start ART in resource limited settings is required. High rates of early resistance have been reported in children on ART and a combination of social support and clinical interventions is required to delay treatment failure. More pediatric ARV formulations are needed and further research in pediatric HIV is required to obtain better outcomes in children.
Track C: Biomedical Prevention report by Iona Millwood
Synthesizing our options: biomedical prevention technologies in the context of behavioural interventions
This plenary by Nancy Padian (USA) gave an overview of several biomedical prevention methods currently under evaluation in large scale trials, focussing on several methods most relevant to the epidemic in sub-Saharan Africa, HSV-2 suppression, PrEP, microbicides, and female-initiated barrier methods. Some of the issues and challenges faced by large scale prevention trials, involving several components of prevention, were then discussed, with reference to the MIRA phase III trial of diaphragm and lubricant gel for HIV prevention, results of which will be presented in the Late Breaker session WESS3.
With the established association between HIV and HSV-2 infection, suppression of HSV-2 is under evaluation for prevention of HIV transmission in a study of 3,400 discordant couples at 7 sites in sub-Saharan Africa, and for prevention of HIV acquisition in a study of 3,277 MSM and women in the US, Peru and 3 African sites. However, a study of HSV-2 suppression for prevention of HIV acquisition among 821 high risk women in Tanzania, reported by Watson-Jones in session MOAC1, found no effect of aciclovir on HIV incidence, after 12-30 months of treatment, although there was limited evidence for a protective effect in women whose adherence to treatment was highest.
The precedent for use of ARVs for HIV prevention is established with PMTCT and PEP, and a study demonstrating the safety of daily oral tenofovir for pre-exposure prophylaxis among HIV-uninfected women in West Africa was reported at the Toronto AIDS conference 2006. Several further trials of daily oral tenofovir or Truvada for pre-exposure prophylaxis are underway, including trials among MSM in the US and Peru, IDU in Thailand, and young heterosexuals in Botswana. Safety and efficacy results from these trials are expected from 2008-10, with other trials at the planning stages.
Much research interest has focussed on microbicides as an important potential female-controlled method of prevention, and currently four large scale trials are underway, involving several thousand high risk women in sub-Saharan Africa. The microbicide products involved are the buffering agent Buffergel, fusion and entry inhibitors PRO2000 and Carraguard, and the second generation ARV-containing tenofovir gel. Lut Van Damme will provide a comprehensive overview of phase III microbicide trials in session WEBS1, and recent results from phase III trials of cellulose sulfate will be presented in the Late Breaker session WESS3.
Female initiated controlled barrier methods of prevention, the female condom and diaphragm, have received somewhat less attention. Although new designs and formulations of female condoms are becoming available, at present there are no ongoing or planned trials for HIV prevention. Results from two studies of diaphragm use, either with lubricant gel or with cellulose sulfate gel (session TUAC1), have been presented at this conference, and the rest of this plenary focussed on highlighting some of the challenges experienced during the MIRA phase III trial of diaphragm and lubricant gel use for HIV prevention.
There are several recognised challenges from large scale prevention trials, including lower HIV incidence than anticipated, high pregnancy rates, maintaining high retention rates, and suboptimal adherence. It was noted that it will be harder to achieve the high adherence that is required in therapeutic settings, as the perceived risk:benefit ratio is different for people using a preventive intervention.
In the MIRA study, a multi-component prevention strategy was used, with all participants receiving condoms, counselling and diagnosis and treatment of STIs. As the additional component (diaphragm+lubricant gel) may be only partially efficacious, in the background of an effective standard of prevention, studies may be under-powered to detect independent modest levels of protection. With the comprehensive standard of prevention provided in trials difficult to sustain post-study, an additional effect, even partial, can still be of benefit.
Maintaining, and evaluating, adherence to the intervention is another challenge. With a coitally-dependent intervention, DOT (DOP) cannot be used and adherence measures rely on self-report, which may be influenced by several factors, including participants perception of what researchers would like to hear. In an open-label study design, risk behaviour can be influenced by knowledge of treatment group, and again measures are reliant on self-report. In the MIRA study, condom use increased in both study arms from baseline, however, the increase was lower in the group receiving the intervention, which may be due to preventive misconception, partners unwilling to use condoms if diaphragm is used, or participants unwilling to use two barrier products at the same time.
The plenary concluded with a discussion of the need to integrate behavioural and biomedical preventive interventions, a theme also discussed during session TUSY3. In depth and independently conducted behavioural research will be invaluable to evaluate the motivations and context required for adherence and risk reduction, and the role of male partners. Methods for measurement of self-reported behaviours must be studied to find ways to avoid bias in reporting. Run-in studies prior to trials may be used to select for participants either most at risk, or potential good adherers, both which would increase the likelihood of being able to detect an independent effect of the intervention above the standard of prevention. Provision of funding for less “technological” strategies, such as enhancement of gender equity, which may be more easily scaled-up, will in turn be of great support in the success of other components of the overall prevention strategy.
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