Tag Archives: efavirenz

HIV treatment breaks lead to drug resistance in the female genital tract

Antiretroviral treatment interruptions of 48 hours or more are associated with the emergence of resistant strains of HIV in the female genital tract, investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

The study included 102 women in Kenya who started first-line antiretroviral therapy based on a non-nucleoside reverse transcriptase inhibitor (NNRTI). Drug-resistant virus was detected in the genital tract of five women in the twelve months after treatment was started. Treatment interruptions were the most important risk factor for this outcome.

“We found that ART [antiretroviral therapy] adherence was a key determinant of genital tract resistance and that treatment interruptions of whatever cause lead to a substantial increase in the hazard of detecting genotypic resistance to antiretrovirals in female genital tract secretions,” write the authors. “Efforts to prevent treatment interruptions by improving program effectiveness, promoting adherence and timely refills, and avoiding the use of more toxic antiretroviral agents could therefore play an important role in reducing transmitted drug resistance.”

First-line HIV therapy often comprises two nucleoside reverse transcriptase inhibitors (NRTIs) combined with an NNRTI. This treatment can have a powerful and durable anti-HIV effect. However, it requires high levels of adherence. Drug-resistant strains of HIV can emerge with poorer adherence. Older drugs in the NNRTI class, nevirapine (Viramune) and efavirenz (Sustiva or Stocrin), have a low barrier to resistance.

Little is currently known about the emergence of drug-resistant virus in the genital tract of women treated with NNRTI-based therapy. This is an important gap in knowledge as drug-resistant virus is potentially transmissible.

Investigators therefore designed a prospective study involving women who started first-line HIV treatment in Mombasa between 2005 and 2008. During the first twelve months after starting therapy viral load was monitored at three-monthly intervals in both plasma and the genital tract. Samples with viral load above 1000 copies/ml were sent for resistance testing. The investigators conducted analysis to see which factors were associated with the emergence of drug-resistant virus in the genital tract.

Overall, the women had high levels of adherence to their antiretroviral therapy. Assessed by pill count, median adherence was 97%. However, there were 40 treatment interruptions. Their median duration was four days. Median pill-count adherence following treatment interruptions was just 83%.

Drug-resistant virus was detected in the blood of nine women (incidence, 10 per 100 person-years) and in the genital secretions of five individuals (incidence, 5.5 per 100 person-years). All five women with resistant HIV in their genital secretions also had resistant virus in their blood.

The investigators’ first set of analysis showed that a number of factors were associated with genital tract resistance. These included treatment interruptions (p = 0.006), pill-count adherence (p = 0.001) and a higher baseline viral load (p = 0.04).

But only treatment interruptions remained significant after controlling for potentially confounding factors. Interruptions were associated with a more than 14-fold increase in the risk of genital tract resistance (aHR = 14.2; 95% CI, 1.3-158.4; p = 0.03).

“The reasons for treatment interruption in this study included both unavoidable discontinuations due to drug toxicity or systemic illness and avoidable interruptions due to late refills, when it is likely that consecutive doses were missed,” note the investigators. “Despite a comprehensive program of adherence support including pre-ART counseling, directly administered therapy during the first month of treatment, a support group, pill boxes and transportation reimbursements, we were unable to prevent these events.”

Transport problems and pharmacy stock-outs have emerged as major barriers to adherence in resource-limited settings. The investigators are concerned that “such barriers may lead to the development of genital tract resistance due to treatment interruptions, suggesting an increased risk for transmission of drug-resistant virus”.

The Aids Library of Philadelphia FIGHT has a video on YouTube which explore the subject of HIV which is resistant to anti-HIV medications. Further information can be found on their website.

Original Article via NAM and Philadelphia Fight’s YouTube Channel

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HIV/AIDS: Drug price cuts secured amid growing funding fears

Three international organizations have negotiated reductions on key first- and second-line, and paediatric antiretrovirals (ARVs) that will help countries save at least US$600 million over the next three years.

The Clinton Health Access Initiative (CHAI), the international drug purchasing facility UNITAID and the UK Department for International Development (DFID) made the announcement on 18 May.

The deal expected to affect most of the 70 countries comprising CHAI’s Procurement Consortium, features notable reductions in the prices of tenofovir (TDF), efavirenz, and the second-line ritonavir-boosted atazanavir (ATV/r) used in HIV patients who have failed initial, or “first-line”, regimens.

As part of the deal, the three bodies set price ceilings for more than 40 adult and paediatric ARVs with eight pharmaceutical manufacturers and suppliers, including Cipla Ltd, Matrix Laboratories and Autobindo Pharma.

Together these eight companies account for most ARVs sold in countries with access to generic drugs, according to David Ripin, scientific director of CHAI’s Drug Access Programme.

As a result, the cost of ATV/r is down by two-thirds from just three years ago. Meanwhile, a once-a-day fixed-dose combination (FDC) pill containing TDF and efavirenz will now cost countries less than US$159 per patient per year. In 2008, low-income countries paid about $400 per patient per year for the same pill.

How did they do it?

According to UNITAID and CHAI, this success is a product of increased demand for these drugs and more efficient manufacturing of the active ingredients, which are estimated to account for as much as 75 percent of generic ARV costs.

“When you make an active ingredient, you use a multistep chemical process, to reduce costs, you can look for a less expensive source of raw materials of which there are a few examples, including TDF … or you can tinker with the chemical process used to make the product to make them more efficient.” -Ripin.

But Ripin added that doing either comes at a cost for pharmaceutical companies, for whom a change in raw material suppliers or manufacturing processes means re-applying for approval of the drug with regulatory bodies.

“Any time you change anything with the way you make a drug, you need to get regulatory approval,” he said. “You have to do a fair amount of work to prove that your product works just as well now as it did before. “The pharmaceutical companies and generic manufacturers are fantastic at making these types of improvements… [but] they have a limited set of research and development resources available to them.  They often need to make a decision where they are going to get a higher return on that research and development, and typically that comes from the introduction of new products on the market.”

According to Ripin, the key is providing companies with data on the large and growing markets for ARVs.

“We help companies evaluate for themselves whether it’s a worthwhile business opportunity, the second key factor they have to consider is the competitive marketplace for their drugs, where there is an incentive for lower [production] costs and lower-priced products as they want to maintain their market share.”

CHAI also provides countries with data on best market prices for drugs to help inform national procurement, as was the case with South Africa’s recent ARV tender. Although South Africa is not expected to benefit from the new price cuts, the country has the largest ARV tender in the world, and could secure the drugs at competitive prices. In terms of the CHAI agreement, lower prices are available to members of the Procurement Consortium but are dependant on volumes ordered.

How low can we go?

TDF has become an important drug for many countries, including South Africa, hoping to implement the 2009 World Health Organization (WHO) HIV treatment guidelines, which recommend starting HIV patients on treatment sooner but also a shift away from more toxic ARVs to TDF.

However, the high cost of earlier treatment and better drugs has prohibited many countries from fully implementing the WHO recommendations. According to a recent report released by Médecins Sans Frontières (MSF), both Malawi and Zimbabwe reversed their move to WHO guidelines due to financial constraints.

While new price reductions bring TDF’s price closer to that of the long-time and widely adopted first-line ARV Zidovudine, further drops in TDF’s price will have to be logged to ensure widespread uptake, said Brenda Waning, coordinator of market dynamics for UNITAID.

For Waning and others like MSF, the issue of sustainable funding for the HIV response looms large ahead of the June UN meeting on HIV/AIDS in New York, rumoured to be the last for years to come, according to MSF’s report.

“There has been a lot of attention on commodities and not at other major drivers of cost,” she told IRIN/PlusNews. “We have to look at other places in the health system where we can capture cost-effectiveness.”

In particular, Waning pointed to the potential savings associated with the roll-out of new point-of-care diagnostics, which, although not high on the global agenda, will help countries task shift such testing away from scarce doctors.

Although the cost remains high, introducting FDC would help governments save on ARV shipping, transportation and storage, while improving adherence and patient outcomes.

Source: http://www.plusnews.org/Report.aspx?ReportID=92760
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