Researchers at CROI 2012 Report an Increase of ARV Drug Resistance in the U.S.

via Aidsmeds.com, by Tim Horn

New surveillance data from the U.S. Centers for Disease Control and Prevention (CDC) suggest that about two in 10 individuals infected with HIV in recent years involved strains of the virus harboring mutations conferring at least partial resistance to one ore more available antiretroviral (ARV). The report was presented Wednesday, March 7, at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle.

The U.S. Variant, Atypical, and Resistant HIV Surveillance (VARHS) system, in which HIV specimens from newly diagnosed individuals are tested for drug-resistance mutations, was established by the CDC to provide the clearest picture to date of the scope and type of resistance in the United States.

The analysis reported at CROI included a total of 10,338 resistance profiles from eight U.S. regions; this consisted of 2,339 profiles from individuals with recent infections (confirmed using a specialized antibody test or a negative HIV test results within six months before diagnosis) and 7,999 profiles from individuals with confirmed long-standing HIV infection (individuals diagnosed with AIDS within six months of testing positive for the virus). Regions represented in the analysis were Seattle, Los Angeles, Chicago, Colorado, Michigan, Louisiana, New York and South Carolina.

The system uses standard genotypic resistance testing, which identifies specific viral mutations associated with drug resistance. Because neither the recently infected individuals nor the subjects with established infection included in the analysis had yet started treatment, the presence of any HIV drug resistance mutations in their blood would indicate that the resistant virus was transmitted to them at the time of their infection.
Overall, 15.2 percent of all samples included in the analysis had evidence of at least one transmitted drug resistance mutation.

Among the recently infected individuals, 19.1 percent had evidence of at least partial resistance to at least one drug in a particular ARV class, compared with 14.7 percent of the individuals with long-standing HIV infection. This difference was found to be statistically significant, meaning it was too great to have occurred by chance.

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Poor adherence usually cause of second-line treatment failure in resource-poor settings

via Aidsmap, by Carole Leach-Lemens

Poor adherence rather than drug resistance appears more likely to be the cause of virological failure among patients on second-line ART in resource-poor settings, according to a systematic review and meta-analysis published in the advance online edition of AIDS.

The cumulative pooled proportion of the 2035 adults comprising the 19 studies from eight countries in sub-Saharan Africa and Asia failing virologically was 21.8%, 23.1%, 26.7% and 38.0% at six, 12, 24 and 36 months, respectively.

The authors note caution should be taken when reviewing these estimates as there were considerable differences between the studies as well as substantial statistical differences.

While most of the studies did not provide enough information to be able to distinguish conclusively between poor adherence and drug resistance as reasons for virological failure, in those that did poor adherence was the primary cause.

Nonetheless these findings highlight the limited options available after second line in resource-poor settings, notably where drug resistance is the cause of virological failure.

The researchers also stress the importance of improved access to greater virological monitoring as well as more intensive adherence counselling before resistance mutations develop.

The scale-up of ART in resource-poor settings has had a considerable effect on reducing death and disease. Standardised regimens notably simple, affordable fixed-dose combination therapies have facilitated adherence with rates comparable to those in resource-rich settings.

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[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]

New Approach to Phase 3 Clinical Drug Trials

viaThe Sacremento Bee, by the Forum for Collaborative HIV Research

As the war on HIV/AIDS begins its fourth decade, medical researchers, pharmaceutical manufacturers, patient advocates and government regulators face a new and unexpected scientific challenge: how to demonstrate the safety and efficacy of promising new antiretroviral drugs when the two traditional study designs – the superiority trial and the non-inferiority trial – are no longer useful in showing improvements in both "treatment experienced" patients and those who have never received drug therapy (treatment-naive patients).

Because this challenge could have a dampening effect on what is now a robust drug development pipeline for HIV, the Forum for Collaborative HIV Research has just released a new scientific paper that lays out a substantially different approach for conducting Phase 3 HIV clinical trials. 

Published in the journal AIDS, the paper summarizes the insights of specialists from the Food and Drug Administration, European Medicines Agency, academia, the patient advocacy community and industry that overcoming the current difficulties in conducting new HIV drug trials requires moving from the large-scale study model to a new approach where clinical improvements are demonstrated through a sequence of short, step-wise efficacy and safety studies.

"Despite the many valuable antiretroviral drugs now available to treat HIV, new antiretrovirals can bring important benefits, such as fewer side effects, less frequent dosing and a lower risk of drug resistance. That is why overcoming the barriers to innovation in HIV drug development is so critical," said Veronica Miller, Ph.D., Director of the Forum and one of the authors of the paper. "Our paper offers a new pathway for regulatory approval of promising new HIV drugs and reflects the best thinking of the top experts in the field."
The new pathway described in the paper calls for a multi-phased study design, which includes:

•A short study (10-14 days) comparing the investigational compound versus placebo, with the patient's current failing regimen as background, to evaluate short-term efficacy in viral load reduction
•A follow-on study where all participants receive the investigational drug (at a single or different doses) and are assessed at 24 weeks to evaluate dose response, safety, durability of initial response and development of resistance
•The possibility of a second comparative safety trial in patients with a minimum of two active drugs available where participants are randomized to the investigational agent plus a new optimized background regimen of antiretroviral drugs versus patients on a new optimized background regimen plus placebo

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Successes of Second Line Treatment in Sub-Saharan Africa

via aidsmap, by Carole Leach-Lemens

"The authors conclude, “in ART programmes [in sub-Saharan Africa] switching patients to second-line regimens based on WHO immunological failure criteria appears to reduce mortality, with the greatest benefit in patients switching immediately after failure is diagnosed.”"

Mortality was reduced by about 75% among adults experiencing immunological failure according to the World Health Organization (WHO) criteria who switched to a second-line regimen compared to those who remained on a failing regimen in two public sector ART programmes without access to routine viral load monitoring in Zambia and Malawi, researchers report in the advance online edition of AIDS.

Additionally in this collaborative analysis Thomas Gsponer and colleagues on behalf of the Southern African region of the International epidemiological databases to evaluate AIDS (IeDEA-SA) showed the less time spent on a failing regimen the lower the risk of death, HR:0.70 (95%  credible intervals (CI): 0.44-1.09), p=0.11 for each six months of shorter exposure.

An estimated 6.6 million people are now getting ART in resource-poor settings. As access to treatment increases so does the number of people experiencing treatment failure with a corresponding increase in the use of second-line treatment regimens.

Cost and the absence of the necessary laboratory infrastructure preclude the regular use of viral load monitoring in resource-poor settings, especially in rural areas.

Without viral load monitoring immunological (CD4 cell counts) and clinical criteria are used to determine treatment failure. However, the accuracy of such criteria to detect virological failure is poor. This may lead to unnecessary switching with many health care providers reluctant to switch using these criteria. So people are switched later and at lower CD4 cell counts compared to programmes where viral load monitoring is available, note the authors.

The authors chose to examine further the effect of switching to second-line ART on mortality in settings without viral load monitoring.

All adult patients experiencing treatment failure according to WHO immunological criteria from two public sector ART programmes in Lusaka, Zambia and Lilongwe, Malawi were included in the analysis. Clinical and immunological monitoring was done every three to six months. In both sites viral load testing is limited because of cost and operational difficulties.

Criteria for inclusion: all patients 16 years of age and over with immunological failure after January 1, 2004 based on any of the three WHO criteria: 1) CD4 cell counts staying persistently under 100 cells/mm3 2) a fall of CD4 cell counts below the baseline count and 3) a fall greater than 50% from the peak value.

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Activists Urge a Change in Patent Laws in South Africa

via PlusNews Global

Ten years ago, the Doha Declaration allowed countries to circumvent patent rights to access life-saving medicines, particularly those used to treat HIV/AIDS, tuberculosis and malaria. However, the South African government has failed to take advantage of these provisions, and increasingly important TB medication and second- and third-line antiretrovirals (ARVs) remain out of reach, activists warn.

"Pre-Doha, treating [HIV] without generics... meant HIV was a death sentence," said Gilles van Cutsem, medical coordinator for Médecins Sans Frontières (MSF).

In South Africa, with the world's highest HIV infection rate, the availability of generic first-line ARVs meant a drop from an annual cost of more than US$10,000 per patient to $60. Now, with more than one million people on treatment, the country will need to put more HIV-positive people on second- and third-line regimens.

Right to health

The Doha Declaration, or the Declaration on the TRIPS Agreement (Agreement on Trade-related Aspects of Intellectual Property Rights), was signed by members of the World Trade Organization (WTO) in response to concerns that patent protection granted by the TRIPS Agreement would undermine the ability of countries to protect their right to health and access to medicines.

The 1995 TRIPS Agreement made all WTO members beholden to a pharmaceutical patent period of 20 years, during which time no generic could be produced. Before TRIPS, countries such as Brazil and India did not respect patent periods at all, and many other nations observed shorter time-spans (16 years in South Africa).

With the 2001 Doha Declaration, provisions within the TRIPS agreement to protect public health were reaffirmed, as were the rights of member countries to "use, to the full, the provisions in the TRIPS Agreement, which provide flexibility for this purpose".

This included the granting of compulsory licences, which allow a government to formulate or import generic versions of medicines essential to public health but still under the 20-year patent period.

To take advantage of public health flexibilities such as compulsory licensing, however, it must be enacted into national legislation. Unfortunately, few countries, including South Africa, have taken advantage of their rights.

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Integrating ART in Patients with TB

via The New England Journal of Medicine, by Salim S. Abdool Karim, M.B., Ch.B., Ph.D., Kogieleum Naidoo, M.B., Ch.B., Anneke Grobler, M.Sc., Nesri Padayatchi, M.B., Ch.B., Cheryl Baxter, M.Sc., Andrew L. Gray, M.Sc.(Pharm.), Tanuja Gengiah, M.Clin.Pharm., M.S.(Epi.), Santhanalakshmi Gengiah, M.A.(Res.Psych.), Anushka Naidoo, M.Med.Sci.(Pharm.), Niraksha Jithoo, M.B., Ch.B., Gonasagrie Nair, M.B., Ch.B., M.P.H., Wafaa M. El-Sadr, M.D., M.P.H., Gerald Friedland, M.D., and Quarraisha Abdool Karim, Ph.D.

Background

We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved.

Methods

We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here.

Results

At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006).

Conclusions

Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.)

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HIV Drug Resistance Reduced by Availability of New Drugs

via The Lancet, by The Pursuing Later Treatment Option II (PLATO II) project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Group

Background

Limited treatment options have been available for people with HIV who have had virological failure of the three original classes of HIV antiretroviral drugs—so-called triple-class virological failure (TCVF). However, introduction of new drugs and drug classes might have improved outcomes. We aimed to assess trends in virological and clinical outcomes for individuals with TCVF in 2000—09.

Methods

In our cohort study, we analysed data for adults starting antiretroviral therapy from 1998 in cohorts participating in the PLATO II project, which is part of COHERE, a collaboration of European cohorts. TCVF was defined as virological failure to at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse-transcriptase inhibitor, and one ritonavir-boosted protease inhibitor, with virological failure of a drug defined as one viral-load measurement of greater than 500 copies per mL after at least 4 months of continuous use. We used multivariable generalised estimating equation logistic models and Poisson regression models to study trends in virological suppression and incidence of AIDS or death after TCVF. We adjusted for sex, transmission group, age, AIDS status, CD4 cell count, plasma viral loads at TCVF, achievement of virological response (<50 copies per mL), and number of drug failures before TCVF.

Findings

28 of 33 cohorts in COHERE contributed data to the PLATO II project, of which four had no participants eligible for inclusion in this study. 2476 (3%) of 91 764 participants from the remaining 24 cohorts had TCVF and at least one viral load measurement in 2000—09. The proportion of patients with virological response after TCVF increased from 19·5% in 2000 to 57·9% in 2009 (adjusted p<0·0001). Incidence of AIDS decreased from 7·7 per 100 person-years in 2000—02 to 2·3 in 2008 and 1·2 in 2009 (adjusted p<0·0001). Mortality decreased from 4·0 per 100 person-years between 2000 and 2002 to 1·9 in 2007 and 1·4 in 2008 (unadjusted p=0·023), but the trend was not significant after adjustment (p=0·22).

Interpretation

A substantial improvement in viral load suppression and accompanying decrease in the rates of AIDS in people after extensive failure to drugs from the three original antiretroviral classes during 2000—09 was probably mainly driven by availability of newer drugs with better tolerability and ease of use and small cross-resistance profiles, suggesting the public health benefit of the introduction of new drugs.


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The Inevitability of Antibiotic Resistance

via The Atlantic, by Megan Mcardle

On Christmas Eve 1947, George Orwell was admitted to a Scottish hospital with a case of galloping consumption. Orwell had first been diagnosed with tuberculosis almost 10 years earlier, but nonetheless, in what a biographer called “one of the many ill-judged decisions in a life littered with misjudgements,” he had recently moved to a remote and primitive Scottish cottage, where he began work on Nineteen Eighty-Four. There, he developed the night sweats, fever, and weight loss that are hallmarks of active TB. By the time he was admitted to the hospital, Mycobacterium tuberculosis had husked nearly 30 pounds off his already slender frame.

When I was younger and more romantic, I imagined that tuberculosis made you a good writer. After all, so many great ones, from Keats to Chekhov to all three Brontës, seemed to have died of it. Indeed, in 19th-century Europe, the “White Plague” may have caused as many as a quarter of all deaths. Though that proportion had fallen by Orwell’s time, writers from Camus to Bukowski were still contracting tuberculosis, as were millions of their less famous countrymen. Only antibiotics finally conquered the disease.

Victory arrived just barely too late for Orwell. His friends actually managed to obtain a supply of streptomycin, the brand-new anti-TB drug, from America, but it caused such a violent reaction that every morning when he woke, blood from the ulcers in his mouth had glued his lips shut. It had to be soaked off before he could speak. After several weeks, his doctors had to give up. A less powerful new drug called PAS, which he tried in 1949, didn’t make him so sick, but apparently didn’t much bother the tuberculosis bacilli, either. In January of 1950, an artery burst in his lungs, and at the age of 46, George Orwell drowned in his own blood.

It seems a medieval end for a very modern man. But we are not as far from TB as we like to think. It remains endemic in the developing world and is coming back in richer countries, thanks to travel and immigration, but also to a phenomenon that Alexander Fleming, the discoverer of penicillin, warned of in the 1940s: antibiotic resistance.

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[Content that is linked from other sources is for informational purposes and should not construe a Mapping Pathways position.]