Wafaa El-Sadr (Columbia University) delivered a plenary talk entitled “HIV and Inflammation: a Paradigm shift”. Despite dramatic decreases in mortality in individuals on HAART, non-AIDS events continue to contribute to high morbidity and mortality in treated individuals. These include renal, hepatic, cardiovascular events and non-AIDS malignancies. During HIV infection, an increase in inflammation and the coagulation cascade, which have been previously described to contribute to various disease conditions (including renal and liver disease, osteoporosis), have been found. Inflammatory and co-agulation markers were measured in the SMART study, including IL-6, C reactive protein (CRP), Amyloid A and P, D dimer and F1.2, and it was found that higher baseline levels were associated with higher mortality. CRP and HIV together were shown to associate with myocardial infarction, and higher levels of CRP are associated with shorter AIDS-free survival. Earlier initiation of treatment may have an impact on decreasing these inflammatory markers and non-AIDS events. Novel interventions such as statins suppressing these inflammatory and co-agulatory markers are being tested.

        Also, Amalio Teleni (University of Lausanne) described the role of host genetics in predicting genetic risk, predicting safe and effective drug levels, optimal treatment choices and the impact of human population differences on HIV disease. In a genome wide scan of human genes, 3 HLA-related genes (HCP5/HLA-B*5701, HLA-C -35, ZNRD1/ HLA-A10) and another host gene, CCR5∆32, could account for 22% of the variation in clinical outcome (disease progression) in HIV disease. Genetic variants of cytochrome metabolizers (CYP2A6, CYP3A4) and transporters were associated with better drug metabolism of selected ARTs. Host genetic determinants were also predictive of dislipidemia and other drug side effects (e.g., hypersensitivity to Efavirenz). However, transcriptome analysis of elite controllers has not revealed new insights on how genetic differences provide protection. Only one gene, OAS1 (Interferon pathway gene), differed in a human transcriptome analysis with various HIV variants. A rare gene analysis (frequency <1%) in human populations may provide new insights on potential therapeutic targets. In such an analysis population origins should be taken into account to distinguish causal variants (population independent) and non-causal variants (population dependent). Overall these genetic analyses may be useful clinically in the determination of how to administer ARVs in the most effective manner.

Reuben Granich of the WHO made the case for the use of antiretroviral therapy to control the HIV epidemic.  In the developing world there are 3 million individuals on antiretroviral therapy (ART) with another 6.7 million in need of therapy.  The rationale to consider universal ART to control the HIV epidemic is derived from many observations, including the correlation of viral load with risk of HIV transmission, the effectiveness of ART to prevent mother-to-child transmission of HIV, and recent cohort data demonstrating a decrease in mortality associated with earlier therapy all provide the rationale to consider the benefit of ART (Granich RM et al.  Lancet 2009;373:48-57). Treating people with CD4 counts <350 results in control of the epidemic at a stable number of infected individuals less than current levels.  Only universal testing and immediate treatment would reduce the size of the epidemic.  Cost estimates of universal treatment are initially $3-4 billion yearly for approximately 10-12 years, but cost savings compared to current HIV treatment patterns are realized by 2030. 

Telenti discussed the utility of genetic profile of an individual in the management of HIV infection, with specific examples of how individual genetic variations predict the risk of HIV infection and the risk of slow or rapid disease progression. Drug metabolism is another area were genetic profile may be useful predicting therapeutic drug levels and toxicities, allowing for the individualized selection and tailoring of antiretroviral therapies.

PMTCT has virtually eliminated vertical transmission in the North, but in resource poor settings decreases vertical transmission only to 8-10%.  Louise Kuhn cited three key interventions to further reduce transmission by breast-feeding (BF): 1) lactation counseling to ensure exclusive BF; 2) HAART for pregnant women, extended throughout BF; and extension of ART prophylaxis throughout BF, i.e 24 weeks and 4 additional weeks for weaning.  Each of these interventions has substantially reduced the fraction of transmission due to BF. Noting that avoiding BF leads to increased child mortality due to non-AIDS mortality such as diarrheal illness and malnutrition, she concluded with an appeal to integrate PMTCT and BF interventions with Child Survival programs.

Non-AIDS related events, i.e. heart, liver, kidney, and neoplastic disease, particularly in patients with higher CD4+ cell counts are a significant cause of morbid-mortality in patients with HIV infection, particularly in those not receiving antiretroviral therapy. Wafaa El-Sadr presented data that suggests that those events and many of the manifestations of HIV disease have inflammation as a key component of their pathogenesis. Therapeutic interventions that decrease inflammation need to be evaluated in prospective clinical trials.

Two plenary presentations focussed on the use of treatment for prevention.

Reuben Granich from WHO, presented the case for a novel approach to HIV prevention based on universal HIV counselling and testing and immediate initiation of antiretroviral therapy (ART). Using mathematical modelling based on data from generalised epidemics in Southern Africa, he argued that the proposed strategy of universal HIV counselling and testing followed by immediate initiation of treatment combined with other interventions could potentially lead to a 95% reduction in new HIV cases within 10 years. This in turn could lead to reductions in HIV prevalence to <1% by 2050, and prevention of 7.35 million deaths. He showed that while this approach might be more expensive initially, it is associated with cost savings in the longer term. Ideally, this approach needs to be evaluated further using randomised controlled trials; consultations are being planned by WHO to take place in November 2009 to discuss this approach further.

Prof Louise Kuhn from Columbia University highlighted the achievements and challenges associated with using treatment to prevent mother-to-child transmission of HIV (PMTCT). She highlighted that while great successes had been achieved in expanding PMTCT across Africa, several challenges still remain. Interventions to prevent HIV transmission during the late post-natal period (i.e. during breast feeding) are a priority. Current options are either to provide HAART to the mother or infant prophylaxis. Dr Kuhn showed that providing maternal HAART to women with CD4+ counts < 350, could prevent 84% transmitted infections, as well as have important health benefits for the mother. The importance of  making breast feeding safer was illustrated by data from the ZEBS study in Malawi  which showed that  no breast feeding or early weaning was associated with worse child outcomes in infants whose mothers were HIV positive.  She concluded that programmes in future would need to expand beyond HIV prevention to focus more broadly on maternal health and child survival.   

Plenary Session

Monday July 20

The issue of treatment as prevention is set to be a major discussion topic at this Conference and it is important one for community to monitor. Dr Reuben Granich from the United States began the plenary with the topic of “HAART as Prevention”. Dr Granich said that a range of biomedical prevention methods was needed as well as antivirals (such as circumcision and prevention of STIs and other infections) but that now it was acknowledged that ART does have a major role to play in reducing HIV transmission and prevalence as well as mortality.

Granich provided evidence from a modelling exercise that if there was universal testing and immediate ART combined with other prevention interventions there would be a 95% reduction in HIV cases in 10 years and the incidence would be reduced from 15-20 000 to 1000 cases per million. Prevalence (or the number of people with HIV) would become less than 1% by 2050. Initial resources would be higher but this approach may provide cost savings.

Amalio Telenti from Switzerland provided an update on the latest research into genomics and HIV. He said that we can now explain 22% of population variance in viral load by genetics, population effects, gender and age. He thought that it won’t be long before there are useful predictive pharmacogenomic strategies to predict toxicities of certain antivirals and to allow for the creation of optimal treatment regimens for individuals.