Hiv And Aids

New Dangerous Strain Of HIV Discovered

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Researchers have discovered a new, more aggressive strain of the human immunodeficiency virus (HIV) that develops into AIDS much more quickly than other strains, Medical News Today reported.

In a new study published in the Journal of Infectious Diseases, scientists detailed the new strain as a “recombinant” virus – a hybrid of two virus strains. Called A3/02 – a cross between the 02AG and A3 viruses – the strain can develop into AIDS in just five years after first infection – one of the shortest time periods for HIV-1 types.

“Recombinants seem to be more vigorous and more aggressive than the strains from which they developed,” said first author Angelica Palm, a doctoral candidate at Lund University in Sweden.

So far, the A3/02 strain has only been seen in Guinea-Bissau, West Africa, but other studies have shown that recombinants are spreading more quickly across the globe.

“HIV is an extremely dynamic and variable virus. New subtypes and recombinant forms of HIV-1 have been introduced to our part of the world, and it is highly likely that there are a large number of circulating recombinants of which we know little or nothing,” said senior author Patrik Medstran, professor of clinical virology at Lund University. “We therefore need to be aware of how the HIV-1 epidemic changes over time.”

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Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study.

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Abstract

Background

Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study’s finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.

Methods and Findings

We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study’s major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.

Conclusions

Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination.

Discussion

Our study confirms previous reports that an intervention of universal voluntary counseling and testing for individuals aged 15+ y and immediate ART for all HIV-infected individuals (UTT) at 90% coverage will eventually result in the elimination of HIV, even in a highly endemic setting such as South Africa and with realistic assumptions about the efficacy of ART in reducing HIV transmission and enhancing survival. However, the predicted timing of the elimination of HIV (defined as an incidence of below one new infection per 1,000 person-years) differs substantially for the different models in our study, and HIV elimination is likely to take three times longer than the mere 7 y predicted by Granich et al. [9]. In addition, the relative impact of the UTT intervention compared to the baseline differs substantially. Whereas 1,800 infections are averted per 100,000 person-years (range: 1,600; 2,500) in the simplest model, this value is only 100 (range: 83; 150) in the most comprehensive model. In fact, the latter model shows that the current scale-up of ART for patients with CD4 cell counts of ≤350 cells/µl already leads to elimination of HIV without the additional UTT intervention. However, the considerable number of life-years saved makes UTT at 90% coverage still a highly cost-effective intervention, with an incremental cost-effectiveness ratio of US$170/life-year saved (range: 19; 406).

Our sub-model analysis shows that choices in model structure and assumptions have an important impact on the predicted impact of UTT. It makes sense that more up-to-date assumptions on the overall efficacy of ART in reducing infectiousness (90% versus 99.4%) lead to delayed HIV elimination. Also, incorporating high infectiousness during the acute stage results in a less profound impact of UTT, since relatively many transmission events will then occur during this short period of high infectiousness, which is difficult to target in UTT interventions[17],[58]. Adding heterogeneity in sexual behavior and sexual networks to the model also increases the time until elimination—this is because the relative force of infection of HIV is high in certain high-risk groups (e.g., FSWs) and therefore the impact of UTT is less profound in these subgroups. Finally, explicitly modeling male circumcision, condom use, and STI co-factors, and using increases in condom use to quantify the HIV epidemic in South Africa [2],[3], decreases the time until HIV elimination, since the counterfactual of no UTT already shows a substantial decline in incidence, despite the fact that these interventions are not further scaled up in the model after 2012. A model that relies on implicit modeling of these interventions to capture the steady state (e.g., through a prevalence density function, as was used by Granich et al. [9]) will therefore overestimate the impact of UTT. Finally, it appears vital to incorporate the current ART rollout in the counterfactual scenario. The availability of ART in South Africa and many other African countries is now a fact of life, and the rollout that generally started in 2003–2004 is already affecting the epidemics through increased survival and decreased transmission [2].

Given that the stepwise inclusion of model components appeared to change the predicted impact of a UTT intervention, the model that incorporates all these components (model D) gives the most accurate prediction of the impact. In addition, although all models were able to accurately replicate the UNAIDS-reported HIV prevalence in South Africa, model D was the only model that was also able to capture the observed decline in incidence over the past decade [2],[3]. In model D, incidence in the population aged 15–49 y declined from 1.9/100 person-years in 2002 to 1.3/100 person-years in 2008, which is nearly the same as the observed reduction from 2.0/100 person-years in 2002–2005 to 1.3/100 person-years in 2005–2008, as reported by Rehle et al. [3]. Incidence rates in the other models remained constant over the same period (models A to C). In addition, model D was able to replicate data on demographic structure, age-specific HIV prevalence, sexual behavior, STI prevalence, and ART coverage in South Africa (Figure S7; Text S2). Finally, previous studies with STDSIM have shown that the model is capable of reproducing HIV prevalence (overall and age- and sex-specific), incidence, and mortality data from a population-based HIV and demographic surveillance site in KwaZulu-Natal, South Africa [25],[36],[37],[59],[60]. The simulated impact of ART in this highly endemic area of South Africa [25] was very similar to what was recently observed by Tanser et al. [5], providing reassurance that our model predictions are accurate.

To our knowledge, this is the first study that shows that the current rollout of ART for all HIV-infected patients with CD4 cell counts of ≤350 cells/µl will eventually eliminate HIV. This raises questions about the value for money of the additional investments required to implement UTT. Although we show that the UTT intervention proposed by Granich et al. [9] is highly cost-effective, the required number of health workers and financial resources for such a strategy far exceeds the current availability in South Africa [61]. Also, the assumed rates of HIV testing, ART uptake, retention in care, and treatment adherence are rather optimistic [62],[63]. Adherence and retention are likely to decrease when treatment is initiated at higher CD4 cell counts [64], while the number of patients lost to follow-up increases when treatment programs are scaled up[65]. Both these issues are especially important in UTT strategies, where patient numbers increase substantially, and many patients initiate ART at high CD4 cell counts. In addition, maintaining screening coverage levels at 90% for 40+ y seems not very plausible. It is likely that test refusal will be substantially higher than the 10% assumed in our analyses [66], increase over time [67], and be more common among people with HIV [67], resulting in a lower and declining screening coverage over time. Still, our sensitivity analysis shows that UTT would remain a cost-effective strategy, even with coverage rates of only 60%. A recent study on the cost-effectiveness of ART provision in South Africa showed that cost savings will be achieved after just 5 y of UTT at 90% coverage [68], while our modeling indicates that there will be no net savings from this UTT intervention in South Africa. The underlying compartmental transmission model in that study [68] is essentially the same as that previously used by Granich et al. [9],[68], and thus resembles our model A. We show that these types of models, which ignore sexual networks and background prevention interventions underlying the current South African epidemic, predict a far more optimistic impact of UTT compared to the baseline. Cost-effectiveness and economic impact studies based on such models should therefore be interpreted with caution. More research with comprehensive models of the impact of more modest UTT interventions is necessary in order to determine whether universal treatment for HIV really is a cost-effective intervention.

Our study has a number of limitations. We defined elimination as incidence below 1/1,000 person-years. However, real elimination is achieved when both incidence and prevalence reach 0%. Microsimulation allows for such an analysis, and we found that in a model population of about 35,000 people, by 2080, 99% of all model runs predict that HIV prevalence reaches 0% in model A (Figure S5). In model D this point is reached only in year 2116 for the UTT scenario, and in year 2164 for continued scale-up of ART at CD4 count ≤350 cells/µl (Figure S5). In addition, we did not model the development and transmission of drug-resistant strains. Both acquired resistance (development of resistance within an individual on treatment) and transmitted resistance (spread of drug-resistant strains) will have an impact on the effectiveness of treatment programs, and will consequently result in a less profound effect of the current ART scale-up or UTT in South Africa. It is currently unclear, however, to what extent the fears of rapidly spreading drug resistance expressed at the start of the ART scale-up were justified [69]. The prevalence of drug resistance remains low in South Africa after nearly 10 y of scaling up ART [70],[71]. In addition, adherence to treatment is as high as in many high-income countries[72], and survival of patients on treatment in sub-Saharan Africa approaches general life expectancy [73], suggesting that resistance may not become a major problem in South Africa in the near future.

Elimination of HIV in South Africa will have huge implications for public health and socioeconomic development in the country. The current ART rollout is already resulting in a substantial increase in the life expectancy of the general population [74] and in the employment rates of HIV-infected people [75]. Finally, elimination of HIV will also substantially reduce the tuberculosis burden in South Africa, given the close link between the two epidemics [76].

In conclusion, our results from a series of structurally different models support the main message from previous studies that HIV in South Africa can be eliminated through a strategy of annual screening of individuals aged 15+ y and immediate ART for all HIV-infected patients at 90% coverage, but elimination will occur substantially later than previously predicted. Importantly, the most comprehensive model suggests that HIV incidence in South Africa can reach the elimination phase even if the current treatment scale-up of ART at CD4 count ≤350 cells/µl continues without the addition of a UTT intervention. Results from upcoming community randomized trials of treatment as prevention will need to be evaluated with models that allow for sufficient detail in assumptions in order to adequately project the population-level impact and overall cost-effectiveness of the UTT intervention.

SOURCE: PLOS

Modelling the Strategic Use of Antiretroviral Therapy for the Treatment and Prevention of HIV.

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The impact of increased access to antiretroviral therapy (ART) has principally been measured in lives saved, and justifiably so: over the last decade the scale-up of ART has averted over 4 million deaths in low- and middle-income countries [1]. Almost 10 million people in these countries are currently receiving ART, and widespread access to treatment has transformed HIV from a life-threating infection to a chronic disease. Less than 20 years ago, patients presenting at clinics in Africa with an AIDS-defining illness would on average have just 9 months to live [2]. Today, people living with HIV in Africa can, with timely and continuous access to effective ART, have a relatively normal life expectancy [3],[4].

Yet the benefits of ART extend beyond saving lives, and increasingly attention is being given to the potential for ART to prevent new HIV infections. The specific contribution of ART to reducing HIV infection through mother-to-child transmission of HIV is well described—over 800,000 children have avoided infection over the last decade [1]—but the extent to which ART prevents sexual transmission has until recently been less clear. Data from several observational studies have suggested decreased acquisition of HIV among sexual partners of people on ART [5],[6], an association convincingly confirmed by the results of the HPTN 052 trial demonstrating significantly reduced rates of sexual transmission with early ART initiation [7]. At the population level, increased access to ART has been associated with reductions in sexual transmission in ecological studies [8], but the overall proportion of new infections that have been averted by ART is not known. In the absence of such data, mathematical modelling has made an essential contribution.

Models have been used to predict the potential impact of widespread ART on HIV transmission for over two decades [9], but the potential preventive impact of widespread ART access captured international attention only recently, with the landmark publication of what has become known as the “Granich” model in 2009 [10]. Assuming high rates of treatment uptake, coverage, and adherence this model put forward the notion that universal HIV testing and treatment, combined with other interventions, could reduce transmission to low levels such that epidemic would eventually decrease towards elimination. Subsequent models have all pointed in the same direction of reduced incidence with expanded ART access, albeit with varying assumptions and timeframes [11].

In this issue of PLOS Medicine Jan Hontelez and colleagues systematically assessed the universal test and treat intervention suggested by Granich and colleagues by running nine different models with increasing degrees of complexity and realism—including sexual networks, HIV stages with different degrees of infectiousness, and updated treatment effectiveness assumptions—to explore how different scientific approaches to modelling would influence the results [12]. Encouragingly, all models were found to predict that HIV would eventually be eliminated through universal HIV testing and treatment, although timeframes for reaching the elimination phase ranged from 7 to 39 years depending on assumptions about demography, sexual behavior, transmission and natural history, coverage of other prevention interventions (male medical circumcision and condom use), and sexually transmitted infection (STI) co-factors[12]. Of particular note, while previous models have suggested reduced incidence even if treatment is started at a lower CD4 threshold of 350 cells/mm3 [11], this is the first study to predict that the elimination phase will eventually be reached at this threshold, albeit within a longer time horizon and provided very high treatment coverage is attained.

The notion that ART could help curb the HIV epidemic has fundamentally reframed the global HIV response over the past 5 years. For donors, the clinical and public health benefits provided by expanded ART access make a clear case that ART is a good investment [13], while for care providers the possibility that ART could help control or even eliminate the HIV epidemic has provided a renewed impetus to further expand coverage [14].

The latest ART guidelines released by the World Health Organization (WHO) in June 2013 recognize the multiple benefits of ART for both treatment and prevention of HIV, and provide a number of recommendations for expanded eligibility [15]. ART initiation is recommended at CD4 <500 cells/mm3 (with priority given to those with a CD4 <350 cells/mm3) and three new recommendations are made to provide immediate ART initiation based on clinical benefits and programmatic and prevention considerations: pregnant women, people in serodiscordant couples, and children under 5 years of age. Similar to previous guidelines, people co-infected with tuberculosis and hepatitis B infection are also eligible for immediate ART after diagnosis. In order to develop these guidelines WHO commissioned a series of modelling studies done by the HIV Modelling Consortium, which showed that expanding the criterion for ART eligibility to CD4 cell count ≤500 cells/mm3 was highly cost-effective in low- and middle-income settings, in particular if expanded eligibility was coupled with a large increase in HIV testing and linkage to care [16].

With the preventive benefit of ART firmly established in evidence and policy, what could be the future contribution of modelling to treatment scale-up? Rather than continuing to model the magnitude and speed of the preventive impact of ART, modelling efforts could be redirected towards helping programmes make choices about which interventions need to be prioritized in order to achieve the levels of enrolment and retention in care required to achieve optimal prevention benefit. There are three key areas where modelling could help, and encouragingly early work has already started in some of these areas.

First, modelling can help define actions to improve access and retention in care. A positive consequence of the recent focus on universal HIV testing and treatment has been to direct attention on the cascade of care. While much of the modelling work to date has focused on refining the horizons for achieving HIV elimination through ART provision, individuals involved in programme implementation have expressed concern about the feasibility of achieving the high rates of ART uptake, coverage, retention, and adherence upon which these models are based[14]. Recent systematic reviews have highlighted substantial patient attrition at every step from HIV testing to ART initiation to long term retention on treatment [17],[18]. A number of interventions have recently shown promising results in increasing uptake in HIV testing [19], speeding up eligibility assessments for ART [20], and reducing attrition on ART [21]. Modelling work has already been done to help provide a more nuanced understanding of the dynamics of the treatment cascade [22]. Drawing on data from trials underway to assess the impact of ART initiation on HIV transmission [23], future modelling work could assist decision making about where and how to intervene along the treatment cascade to maximize the treatment and prevention benefits of ART.

Second, modelling can help inform country decisions about who should be treated early in priority for maximum prevention benefit. Implementation of the new WHO recommendations for early ART initiation will require countries to make strategic choices around how best to use ART for treatment and prevention according to resource constraints, epidemic dynamics, and societal factors. WHO’s guidelines include a chapter on decision making for programme managers that outlines how modelling can help support costing and planning [15]. Modelling studies have already assessed the preventive impact of immediate ART initiation among pregnant women and serodiscordant couples [24], and key populations [25],[26]. This work will continue to be critical to informing country choices in the strategic use of ART.

Finally, ongoing research will provide further data on the clinical and public health benefits of ART, and future guidelines will likely lead to a continued policy evolution towards earlier initiation. Modelling will make a key contribution to informing future WHO guidance and country decisions about how best to strategically provide ART as a broader package of interventions to save lives, reduce illness, and prevent new infections.

The case for ART impact on HIV transmission is proven. The priority now is to translate this concept into benefits for patients and communities by identifying and implementing approaches that work to maximize early HIV testing and ART uptake and long-term retention in care.

Source:PLOS

 

UGA researcher develops new medicine that attacks HIV before it integrates with human DNA.

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Nair, Vasu-h.env dna model 2013

  • Vasu Nair, Georgia Research Alliance Eminent Scholar and director of the UGA Center for Drug Discovery, has developed a drug that blocks HIV from inserting its genome into the DNA of the host cell.

Athens, Ga. – Thirty-four million people are living with human immunodeficiency virus, or HIV, worldwide and each year some 2.5 million more are infected, according to the World Health Organization.

New medicine developed at the University of Georgia attacks the virus before it integrates with human DNA, understood by researchers as the point of no return.

“In our laboratories, we have discovered a highly potent HIV integrase inhibitor, or blocker, aimed at the ‘point of no return’ in HIV infectivity,” said Nair, who is the Georgia Research Alliance Eminent Scholar in Drug Discovery in the UGA College of Pharmacy. “This inhibitor is highly effective against many variations of HIV.”

According to Nair, HIV integrase is an ideal target for drug therapy because it is essential for viral replication, and there is no human counterpart, which means there is a low risk of side effects.

Cell signaling, the transmission of information by molecules that coordinate and direct cellular actions, plays a key role in HIV cell invasion and the hijacking of cellular biochemistry, allowing the virus to replicate itself.

In the initial stage of HIV infection, the body’s immune system releases antibodies to attack the virus. Helper T-cells, called CD4+ cells, play a central role in the body’s immune response, orchestrating other cells in the immune system to carry out their specific protective functions. In its invasion of CD4+ cells, HIV recognizes and attaches itself to the outer surface of the cell, penetrates it, sheds its outer coat, releases its 15 viral proteins and a ribonucleic acid and proceeds with exploiting the human cellular biochemical machinery to reproduce itself in massive numbers.

“Of all of the steps involved in the replication or reproduction of HIV in its infectivity of the human system, the single most devastating point is the incorporation or integration of viral DNA into human chromosomal DNA,” said Nair.

This insertion of viral DNA into human DNA occurs through a complex biochemical process that is facilitated by HIV integrase, a viral enzyme. Only after this crucial step is the viral invader in a position to exploit human cellular biochemistry to reproduce itself in astonishing numbers to ultimately bring about the destruction of CD4 lymphocytes, the coordinators of the immune response system of the human body.

As the infected T-cells die, the immune system of the infected body is unable to defend itself; opportunistic infections such as pneumonia, meningitis, antibiotic-resistant TB and other bacterial and viral infections become deadly. HIV and, eventually, AIDS and drug-resistant tuberculosis are a particularly deadly liaison, which kill a quarter of a million people a year, according to the WHO.

“A devastating consequence of the integration step is that once viral integration has occurred, it cannot be reversed,” Nair said. “That’s why integration is viewed as the ‘point of no return’ in HIV infection.”
The drug developed in Nair’s lab blocks the viral enzyme from inserting its genome into the DNA of the host cell.

While Nair acknowledges an HIV vaccine that eliminates the virus altogether may not be doable, therapies that allow people to live longer lives while infected are attainable.

“I don’t really think that a single vaccine would be truly effective in providing total immunity against HIV because the virus has multiple forms or subtypes,” he said. “By inhibiting replication while viral counts are still low, however, a drug can render HIV almost entirely impotent.”

Research efforts worldwide on HIV integrase inhibitors have resulted in two Federal Drug Administration-approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to the HIV pandemic, requiring drugs that work well together for antiviral combination therapeutics targeting HIV. Targeting the virus, rather than the human mechanism that allows it to reproduce, prevents interference with enzymes that are key to the natural and required biochemical metabolic processes in the human system.

“The compound displays low toxicity, which is very important,” Nair said. “Its resistance and related drug susceptibility profiles against resistant HIV-1 isolates are favorable. When taken together, the antiviral activity profile and the drug interaction profile of our integrase inhibitor present a compelling case for its further development as an anti-HIV/AIDS therapeutic agent.”

The therapy is now in the pre-clinical testing phase.

“There are potential ramifications of this invention in other therapeutic areas, as well as in co-infection therapeutics,” said Nair. “This is perhaps the most exciting aspect of our discovery.”

The research was funded through the Division of AIDS in the National Institutes of Health’s National Institute of Allergy and Infectious Diseases. Results were recently published in the journal Antiviral Research.