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antiretroviral therapy
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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/07/23 04:55:47」(JST)
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The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.[1]
HIV treatment has been proven so successful that in many parts of the world HIV has become a chronic condition in which progression to AIDS has become increasingly rare. Anthony Fauci, head of the US National Institute of Allergy and Infectious Diseases has written "With collective and resolute action now and a steadfast commitment for years to come, an AIDS-free generation is indeed within reach." In the same paper he notes that an estimated 700,000 lives were saved in 2010 alone due to antiretroviral therapy.[2] As another commentary in The Lancet noted, "Rather than dealing with acute and potentially life-threatening complications, clinicians are now confronted with managing a chronic disease that in the absence of a cure will persist for many decades"[3]
The US Department of Health and Human Services and other organizations recommend offering antiretroviral treatment to all patients with HIV.[4] Because of the complexity of selecting and following a regimen, the potential for side-effects, and the importance of taking medications regularly to prevent viral resistance, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits.[4]
- 1 History
- 2 Classes of drugs
- 3 Combination therapy
- 3.1 Fixed-dose combinations
- 4 Treatment guidelines
- 4.1 Initiation of antiretroviral therapy
- 4.1.1 Treatment as Prevention
- 4.2 Guideline Sources
- 4.2.1 Current guidelines
- 4.2.2 Baseline resistance
- 4.3 Regimens
- 4.4 Special populations
- 4.4.1 Acute infection
- 4.4.2 Children
- 4.4.3 Pregnant women
- 4.4.4 Older Adults
- 4.1 Initiation of antiretroviral therapy
- 5 Concerns
- 6 Response to therapy
- 6.1 Virologic response
- 6.2 Immunologic response
- 7 Salvage therapy
- 8 Structured treatment interruptions
- 9 Adverse effects
- 9.1 NRTIs
- 9.2 NNRTIs
- 9.3 Protease inhibitors
- 9.4 Integrase inhibitors
- 10 HIV Postexposure Prophylaxis (PEP)
- 11 Pregnancy planning
- 12 Towards a cure
- 12.1 The Berlin Patient
- 12.2 Viral reservoirs
- 12.3 Immune activation
- 13 See also
- 14 References
- 15 External links
The first effective therapy against HIV was the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT). It was approved by the US FDA in 1987.[5] Subsequently several more NRTIs were developed but even in combination were unable to suppress the virus for long periods of time and patients still inevitably died.[6] To distinguish from this early anti-retroviral therapy (ART), the term highly active anti-retroviral therapy (HAART) was introduced. In 1996 by sequential publications in The New England Journal of Medicine by Hammer and colleagues[7] and Gulick and coinvestigators[8] illustrating the substantial benefit of combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir. This concept of 3-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization.[1]
Classes of drugs
There are five classes of drugs, which are usually used in combination, to treat HIV infection. Use of these drugs in combination can be termed anti-retroviral therapy (ART), combination anti-retroviral therapy (cART) or highly active anti-retroviral therapy (HAART). Anti-retroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include 2 NRTIs as a "backbone" along with 1 NNRTI, PI or INSTI as a "base."[4]
- Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug however due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4. In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant.[9] To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.[10]
- Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus and hence unable to become integrated into the DNA in the nucleus of the human cell; it must be "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not done in the mammalian cell it is performed by a viral protein which makes it a selective target for inhibition. NRTIs are chain terminators such that once incorporated, work by preventing other nucleosides from also being incorporated into the DNA chain because of the absence of a 3' OH group. Both act as competitive substrate inhibitors. Examples of currently used NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and tenofovir.[11]
- Non-Nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine.[11] HIV-2 is naturally resistant to NNRTIs.[12]
- Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal binding site of integrase. As of early 2014, two other clinically approved integrase inhibitors are elvitegravir and dolutegravir.[13]
- Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins.[14] Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are Lopinavir, Indinavir, Nelfinavir, Amprenavir and Ritonavir. Darunavir and atazanavir are currently recommended as first line therapy choices.[4] Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, Bevirimat and Vivecon, was halted in 2010.[15] Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.[14]
Combination therapy
The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells.[16] HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made.[17]
When antiretroviral drugs are used improperly, multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.[18]
Antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible, thus reducing the potential pool of spontaneous resistance mutations.[17]
Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs being taken arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs.[4] Combinations usually consist of three drugs from at least two different classes.[4] This three drug combination is commonly known as a triple cocktail.[19] Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.
In recent years, drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed-dose combinations.[20] For instance, there are now several options that combine 3 drugs into one pill taken once daily.[21][22][23] This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (adherence),[24] and thus their effectiveness over the long-term. Not taking anti-retrovirals regularly is a cause of resistance development in people who have started taking them previously.[25] Patients who take medications regularly can stay on one regimen without developing resistance.[25] This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.
Fixed-dose combinations
Fixed dose combinations are multiple antiretroviral drugs combined into a single pill.
|Brand Name
|Drug Names (INN)
|Date of FDA Approval
|lamivudine + zidovudine
|September 26, 1997
|lopinavir + ritonavir
|September 15, 2000
|Abbott Laboratories
|abacavir + lamivudine + zidovudine
|November 15, 2000
|Epzicom (in USA)
Kivexa (in Europe and Russia)
|abacavir + lamivudine
|August 2, 2004
|tenofovir + emtricitabine
|August 2, 2004
|Gilead Sciences
|emtricitabine + tenofovir + efavirenz
|July 12, 2006
|Gilead Sciences and
Bristol-Myers Squibb
|Complera (in USA)
Eviplera (in Europe and Russia)
|emtricitabine + rilpivirine + tenofovir
|August 10, 2011
|Gilead Sciences and
Janssen Therapeutics (formerly Tibotec)
|elvitegravir + cobicistat + emtricitabine + tenofovir
|August 27, 2012
|Gilead Sciences
|abacavir + dolutegravir + lamivudine
|August 22, 2014
|ViiV Healthcare
|atazanavir + cobicistat
|January 29, 2015
|Bristol-Myers Squibb
|darunavir + cobicistat
|January 29, 2015
|Janssen Therapeutics
|lamivudine + raltegravir
|February 6, 2015
|Merck & Co.
Treatment guidelines
Initiation of antiretroviral therapy
Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.[26]
In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs.[8] illustrating the substantial benefit of combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir. Later that year David Ho became an advocate of this "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.[27] Later reviews in the late 90s and early 2000s noted that this approach of "hit hard, hit early" ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned. The only consensus was on treating patients with advanced immunosuppression (CD4 counts less than 350/μL).[28] Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.[29]
The timing of when to initiate therapy has continued to be a core controversy within the medical community. Most recently, the NA-ACCORD study observed patients who started antiretroviral therapy either at a CD4 count of less than 500 versus less than 350 and showed that patients who started ART at lower CD4 counts had a 69% increase in the risk of death.[30]
Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems,[31] and higher CD4 counts are associated with less cancer.[32]
Treatment as Prevention
A separate argument for starting antiretroviral therapy that has gained more prominence is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions.[33][34] This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. In clinical trial HPTN 052, 1763 serodiscordant heterosexual couples in 9 countries were planned to be followed for at least 10 years, with both groups receiving education on preventing HIV transmission and condoms, but only one group getting ART. The study was stopped early for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples where cross-infection had occurred, all but one had taken place in the control group consistent with a 96% reduction in risk of transmission while on ART.[35] The term "treatment as prevention" has been used for the concept of treating patients with HIV to help prevent the spread of HIV.[36] In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention.[37]
In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more efficacious and more affordable than ever before."[38]
There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped. This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited. This allows the drug resistant strains to become dominant. This in turn makes it harder to treat the infected individual as well as anyone else they infect.[4] One trial where ART therapy was periodically stopped had higher rates of opportunistic infections, cancers, heart attacks and death in patients who interrupted their ART.[39][40]
Guideline Sources
There are several treatment guidelines for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests). In the United States there are both the International AIDS Society-USA (IAS-USA) (a 501(c)(3) not-for-profit organization in the USA)[41] as well as the US government's Department of Health and Human Services guidelines.[4] In Europe there are the European AIDS Clinical Society guidelines.[42]
For resource limited countries, most national guidelines closely follow the World Health Organization guidelines.[38]
Current guidelines
The current guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and his or her doctor.
Current US DHHS guidelines (published April 8, 2015) state:
- Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
- ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
- Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.
Alternatively, current World Health Organization guidelines (dated June 30, 2013) state:[38]
- Initiate ART if CD4 cell count ≤500 cells/ml
• As a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤ 350 cells/mm
- Initiate ART regardless of WHO clinical stage or CD4 cell count in
• Active TB disease
• HBV coinfection with severe chronic liver disease
• Pregnant and breastfeeding women with HIV
• HIV-positive individual in a serodiscordant partnership (to reduce HIV transmission risk)
Baseline resistance
Baseline resistance is the presence of resistance mutations in patients who have never been treated before for HIV. In countries with a high rate of baseline resistance, resistance testing is recommended before starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started, which is then modified on the basis of resistance testing.[12] In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine.[43] In the US, 10.8% of one cohort of patients who had never been on ART before had at least one resistance mutation in 2005.[44] Various surveys in different parts of the world have shown increasing or stable rates of baseline resistance as the era of effective HIV therapy continues.[45][46][47][48] With baseline resistance testing, a combination of antiretrovirals that are likely to be effective can be customized for each patient.
Most current HAART regimens consist of three drugs: 2 NRTIs ("backbone")+ a PI/NNRTI/INSTI ("base"). Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.
The US DHHS preferred initial regimens for adults and adolescents in the United States, as of April 2015, are:[4]
- tenofovir/emtricitabine and raltegravir (an integrase inhibitor)
- tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
- abacavir/lamivudine (two NRTIs) and dolutegravir for patients who have been tested negative for the HLA-B*5701 gene allele
- tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat (inhibiting metabolism of the former) in patients with good kidney function (gfr > 70)
- tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors)
In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450 enzymes and "boost" the levels of other protease inhibitors, rather than for its direct antiviral effect. This boosting effect allows them to be taken less frequently throughout the day.[49] Cobicistat is used with elvitegravir for a similar effect but does not have any direct antiviral effect itself.[50]
The WHO preferred initial regimen for adults and adolescents as of June 30, 2013 is:[38]
- tenofovir + lamivudine (or emtricitabine) + efavirenz
Special populations
Acute infection
In the first 6 months after infection HIV viral loads tend to be elevated and people are more often symptomatic than in later latent phases of HIV disease. There may be special benefits to starting antiretroviral therapy early during this acute phase, including lowering the viral "set-point" or baseline viral load, reduce the mutation rate of the virus, and reduce the size of the viral reservoir (See section below on viral reservoirs).[4] The SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no treatment in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below 350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.[51] Since viral loads are usually very high during acute infection, this period carries an estimated 26 times higher risk of transmission.[52] By treating acutely infected patients, it is presumed that it could have a significant impact on decreasing overall HIV transmission rates since lower viral loads are associated with lower risk of transmission (See section on treatment as prevention). However an overall benefit has not been proven and has to be balanced with the risks of HIV treatment. Therapy during acute infection carries a grade BII recommendation from the US DHHS.[4]
HIV can be especially harmful to infants and children, with one study in Africa showing that 52% of untreated children born with HIV had died by age 2.[53] By five years old, the risk of disease and death from HIV starts to approach that of young adults. The WHO recommends treating all children less than 5 years old, and starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml.[38] DHHS guidelines are more complicated but recommend starting all children less than 12 months old and children of any age who have symptoms.[54]
As for which antiretrovirals to use, this is complicated by the fact that many children who are born to mothers with HIV are given a single dose of nevirapine (an NNRTI) at the time of birth to prevent transmission. If this fails it can lead to NNRTI resistance.[55] Also, a large study in Africa and India found that a PI based regimen was superior to an NNRTI based regimen in children less than 3 years who had never been exposed to NNRTIs in the past.[56] Thus the WHO recommends PI based regimens for children less than 3.
The WHO recommends for children less than 3 years:[38]
- abacavir (or zidovudine) + lamivudine + lopinivir + ritonivir
and for children 3 years to less than 10 years and adolescents <35 kilograms:
- abacavir + lamivudine + efavirenz
US DHHS guidelines are similar but include PI based options for children > 3 years old.[54]
Pregnant women
The goals of treatment for pregnant women include the same benefits to the mother as in other infected adults as well as prevention of transmission to her child. The risk of transmission from mother to child is proportional to the plasma viral load of the mother. Untreated mothers with a viral load >100,000 copies/ml have a transmission risk of over 50%.[57] The risk when viral loads are < 1000 copies/ml are less than 1%.[58] ART for mothers both before and during delivery and to mothers and infants after delivery are recommended to substantially reduce the risk of transmission.[59] The mode of delivery is also important, with a planned Caesarian section having a lower risk than vaginal delivery or emergency Caesarian section.[60] HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding.[61] The WHO balances the low risk of transmission through breast feeding from women who are on ART with the benefits of breastfeeding against diarrhea, prneumonia and malnutrition. It also strongly recommends that breastfeeding infants receive prophylactic ART.[38] In the US, the DHHS recommends against women with HIV breastfeeding.[59]
Older Adults
With improvements in HIV therapy, several studies now estimate that patients on treatment in high-income countries can expect a normal life expectancy.[62][63] This means that a higher proportion of people living with HIV are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data that older people with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral levels.[64] However not all studies have seen a difference in response to therapy.[65] Current guidelines do not have separate treatment recommendations for older adults, but it is important to take into account that older patients are more likely to be on multiple non-HIV medications and consider drug interactions with any potential HIV medications.[66] There are also increased rates of HIV associated non-AIDS conditions (HANA) such as heart disease, liver disease and dementia that are multifactorial complications from HIV, associated behaviors, coinfections like Hepatitis B, Hepatitis C, and Human papilloma virus as well as HIV treatment.[66]
There are several concerns about antiretroviral regimens that should be addressed before initiating:
- Intolerance: The drugs can have serious side-effects which can lead to harm as well as keep patients from taking their medications regularly. One recent large cohort of patients had to switch or stop therapy at a rate of 22 per 100 patient-years due to drug toxicity. "The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%)."[67]
- Resistance: Not taking medication consistently can lead to low blood levels that foster drug resistance.[68]
- Cost: The WHO maintains a database of world ART costs[69] which have dropped dramatically in recent years as more first line drugs have gone off-patent.[70] A one pill, once a day combination therapy has been introduced in South Africa for as little as $10 per patient per month.[71] One recent study estimated an overall cost savings to ART therapy in South Africa given reduced transmission.[72] In the United States, new on-patent regimens can cost up to $28,500 per patient, per year.[73][74]
- Public health: Individuals who fail to use antiretrovirals as directed can develop multi-drug resistant strains which can be passed onto others.[75]
Response to therapy
Virologic response
Suppressing the viral load to undetectable levels (<50 copies per ml) is the primary goal of ART.[49] This should happen by 24 weeks after starting combination therapy.[41] Viral load monitoring is the most important predictor of response to treatment with ART.[76] Levels higher than 200 copies per ml is considered virologic failure, and should prompt further testing for potential viral resistance.[4] Lack of viral load suppression on ART is termed virologic failure.
Immunologic response
CD4 cell counts are another key measure of immune status and ART effectiveness.[41] CD4 counts should rise 50 to 100 cells per ml in the first year of therapy.[49] There can be substantial fluctuation in CD4 counts of up to 25% based on the time of day or concominant infections.[77] In one long term study, the majority of increase in CD4 cell counts was in the first two years after starting ART with little increase afterwards. This study also found that patients who began ART at lower CD4 counts continued to have lower CD4 counts than those who started at higher CD4 counts.[78] When viral suppression on ART is achieved but without a corresponding increase in CD4 counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse outcomes, there is no consensus on how to adjust therapy to immunologic failure and whether switching therapy is beneficial. DHHS guidelines do not recommend switching an otherwise suppressive regimen.[4][79]
Salvage therapy
In patients who have persistently detectable viral loads while taking ART, tests can be done to investigate whether there is drug resistance. Most commonly a genotype is sequenced which can be compared with databases of other HIV viral genotypes and resistance profiles to predict response to therapy.[80] If there is extensive resistance a phenotypic test of a patient's virus against a range of drug concentrations can be performed, but is expensive and can take several weeks, so genotypes are generally preferred.[4] Using information from a genotype or phenotype, a regimen of 3 drugs from at least 2 classes is constructed that will have the highest probability of suppressing the virus. If a regimen cannot be constructed from recommended first line agents it is termed salvage therapy, and when 6 or more drugs are needed it is termed mega-HAART.[81]
Structured treatment interruptions
Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment. As mentioned above, randomized controlled studies of structured treatment interruptions have shown higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays.[39][40] With the exception of post exposure prophylaxis, current treatment guidelines do not call for the interruption of drug therapy once it has been initiated.[4][38][41]
Adverse effects
Each class and individual antiretroviral carries unique risks of adverse side effects.
The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and lipoatrophy.[49] Current first line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.[82][83]
NNRTIs are generally safe and well tolerated. The main reason for discontinuation of efavirenz is neuro-psychiatric effects including suicidal ideation. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 counts.[84]
Protease inhibitors
Protease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack.[85]
Integrase inhibitors
Integrase inhibitors (INSTIs) are among the best tolerated of the antiretrovirals with excellent short and medium term outcomes. Given their relatively new development there is less long term safety data. They are associated with an increase in creatinine kinase levels and rarely myopathy.[86]
HIV Postexposure Prophylaxis (PEP)
When people are exposed to HIV-positive infectious bodily fluids either through skin puncture, contact with mucous membranes or contact with damaged skin they are at risk for acquiring HIV. Pooled estimates give a risk of transmission with puncture exposures of 0.3%[87] and mucous membrane exposures 0.63%.[88] United States guidelines state that "feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody."[89] Given the rare nature of these events, rigorous study of the protective abilities of antiretrovirals are limited but do suggest that taking antiretrovirals afterwards can prevent transmission.[90] It is unknown if 3 medications are better than 2. The sooner after exposure that ART is started the better, but after what period they become ineffective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis up to a week after exposure.[89] They also recommend treating for a duration of 4 weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir + raltegravir (an INSTI). The rationale for this regimen is that it is "tolerable, potent, and conveniently administered, and it has been associated with minimal drug interactions."[89] People who are exposed to HIV should have follow up HIV testing at 6, 12, and 24 weeks.
Pregnancy planning
Women with HIV have been shown to have decreased fertility which can affect available reproductive options.[91] In cases where the woman is HIV negative and the man is HIV positive, the primary assisted reproductive method used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man has achieved an undetectable plasma viral load.[92] In the past there have been cases of HIV transmission to an HIV-negative partner through processed artificial insemination,[93] but a large modern series in which followed 741 couples where the man had a stable viral load and semen samples were tested for HIV-1, there were no cases of HIV transmission.[94]
For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination.[92] With appropriate treatment the risk of mother-to-child infection can be reduced to below 1%.[95]
Towards a cure
People living with HIV can currently expect to live a normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However this requires lifelong medication and will still suffer from higher rates of cardiovascular, renal, liver and neurologic disease.[96] This has prompted further research towards a cure for HIV.
The Berlin Patient
So far only one adult (the so-called "Berlin patient") has been potentially cured and gone over six years without treatment with no detectable virus.[97] This was achieved through two bone marrow transplants that replaced his immune system with a donor's that did not have the CCR5 cell surface receptor which is needed for some variants of HIV to enter a cell.[98] Bone marrow transplants carry their own significant risks including potential death and was only attempted because it was necessary to treat a blood cancer he had. Attempts to replicate this have not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is not seen as a mainstream option.[96] It has inspired research into other methods to try to block CCR5 expression through gene therapy. A zinc-finger nuclease has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment.[99]
Viral reservoirs
The main obstacle to conventional antiretroviral therapy eliminating HIV infection is that HIV is able to integrate itself into the DNA of host cells and rest in a latent state, while antiretrovirals only attack actively replicating HIV. The cells in which HIV lays dormant are called the viral reservoir, and one of the main sources is thought to be central memory and transitional memory CD4+ T cells.[100] Recent reports of the cure of HIV in two infants[101] are presumably due to the fact that treatment was initiated within hours of infection, preventing HIV from establishing a deep reservoir.[102] Currently there is work being done to try and activate reservoir cells into replication so that the virus is forced out of latency and can be attacked by antiretrovirals and the host immune system. Targets include histone deacetylase (HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors valproic acid and vorinostat have been used in human trials with only preliminary results so far.[103][104]
Immune activation
Even with all latent virus deactivated, it is thought that a vigorous immune response will need to be induced to clear all the remaining infected cells.[96] Current strategies include using cytokines to restore CD4+ cell counts as well as therapeutic vaccines to prime immune responses.[105]
See also
- Antiviral drug
- Discovery and Development of HIV Protease Inhibitors
- Discovery and Development of Non-Nucleoside Reverse Transcriptase Inhibitors
- Discovery and development of nucleoside and nucleotide reverse transcriptase inhibitors
- ^ a b "Natural history of HIV infection in the era of combination antiretroviral therapy". AIDS 13 (14): 1933–42. October 1, 1999. doi:10.1097/00002030-199910010-00017. PMID 10513653.
- ^ Fauci, AS (25 July 2012). "Toward an AIDS-free generation". JAMA 308 (4): 343. doi:10.1001/jama.2012.8142.
- ^ Deeks, Steven G (8 November 2013). "The end of AIDS: HIV infection as a chronic disease". The Lancet 382 (9903): 1525–1533. doi:10.1016/S0140-6736(13)61809-7.
- ^ a b c d e f g h i j k l m n o "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" (PDF). US Department of Health and Human Services. 2015-04-08.
- ^ "U.S Approves Drug to Prolong Lives of AIDS Patients". New York Times. 1987-03-21.
- ^ "Natural History of Opportunistic Disease in an HIV-Infected Urban Clinical Cohort". Annals of Internal Medicine 124 (7): 633. doi:10.7326/0003-4819-124-7-199604010-00003.
- ^ "A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less.". N. Engl. J. Med. 337 (11): 725–33. Sep 1997. doi:10.1056/NEJM199709113371101. PMID 9287227.
- ^ a b "Treatment with Indinavir, Zidovudine, and Lamivudine in Adults with Human Immunodeficiency Virus Infection and Prior Antiretroviral Therapy". New England Journal of Medicine 337 (11): 734–739. 1997. doi:10.1056/NEJM199709113371102.
- ^ Lieberman-Blum, SS; Fung, HB; Bandres, JC (2008). "Maraviroc: A CCR5-receptor antagonist for the treatment of HIV-1 infection". Clinical Therapeutics 30 (7): 1228–50. doi:10.1016/S0149-2918(08)80048-3. PMID 18691983.
- ^ Bai, Y; Xue, H; Wang, K; Cai, L et al. (2013). "Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket". Amino Acids the Forum for Amino Acid, Peptide and Protein Research 44 (2): 701–13. doi:10.1007/s00726-012-1394-8. PMID 22961335.
- ^ a b Das, K; Arnold, E (2013). "HIV-1 reverse transcriptase and antiviral drug resistance. Part 1". Current Opinion in Virology 3 (2): 111–8. doi:10.1016/j.coviro.2013.03.012. PMID 23602471.
- ^ a b Geretti, ed. (2006). "9". Antiretroviral Resistance in Clinical Practice. Mediscript. ISBN 978-0-955-16690-7.
- ^ "HIV Integrase Inhibitors: 20-Year Landmark and Challenges". Advances in Pharmacology: 75–105. 2013. doi:10.1016/B978-0-12-405880-4.00003-2.
- ^ a b Wensing, AM; van Maarseveen, NM; Nijhuis, M (2010). "Fifteen years of HIV protease inhibitors: Raising the barrier to resistance". Antiviral Research 85 (1): 59–74. doi:10.1016/j.antiviral.2009.10.003. PMID 19853627.
- ^ "Myriad Genetics suspends its HIV maturation inhibitor program". AIDSmeds. 8 June 2012. Retrieved 27 June 2012.
- ^ Perelson, AS; Neumann, AU; Markowitz, M; Leonard, JM et al. (1996). "HIV-1 dynamics in vivo: Virion clearance rate, infected cell life-span, and viral generation time". Science 271 (5255): 1582–6. doi:10.1126/science.271.5255.1582. PMID 8599114.
- ^ a b "The origin of genetic diversity in HIV-1". Virus Research 169 (2): 415–429. November 2012. doi:10.1016/j.virusres.2012.06.015.
- ^ Schmit, JC; Cogniaux, J; Hermans, P; Van Vaeck, C et al. (1996). "Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain" (PDF). The Journal of Infectious Diseases 174 (5): 962–8. doi:10.1093/infdis/174.5.962. PMID 8896496.
- ^ Henkel, J (July–August 1999). "Attacking AIDS with a 'cocktail' therapy". FDA Consumer (Food and Drug Administration, US Dept. of Health and Human Services). Archived from the original on 2009-01-14.
- ^ "Fixed-dose combinations". aidsmap. March 2011. Retrieved 2014-04-09.
- ^ "Atripla Prescribing Information" (PDF).
- ^ "Stribild Prescribing Information". Retrieved 2014-04-09.
- ^ "Complera Prescribing Information". Retrieved 2014-04-09.
- ^ "Fixed-dose combinations improve medication compliance: a meta-analysis". Am. J. Med. 120 (8): 713–9. August 2007. doi:10.1016/j.amjmed.2006.08.033. PMID 17679131.
- ^ a b "Adherence-resistance relationships to combination HIV antiretroviral therapy.". Curr HIV/AIDS Rep 4 (2): 65–72. May 2007. doi:10.1007/s11904-007-0010-0. PMID 17547827.
- ^ Darbyshire, J (1995). "Perspectives in drug therapy of HIV infection". Drugs. 49 Suppl 1 (Supplement 1): 1–3; discussion 38–40. doi:10.2165/00003495-199500491-00003. PMID 7614897.
- ^ Ho, DD (1995). "Time to hit HIV, early and hard". The New England Journal of Medicine 333 (7): 450–1. doi:10.1056/NEJM199508173330710. PMID 7616996.
- ^ Harrington, M; Carpenter, CC (2000). "Hit HIV-1 hard, but only when necessary". The Lancet 355 (9221): 2147–52. doi:10.1016/S0140-6736(00)02388-6. PMID 10902643.
- ^ Sonenklar, C (2011). "Chapter 6: Treatment for HIV and AIDS". AIDS. USA Today Health Reports: Diseases and Disorders. Minneapolis, MN: Twenty-First Century Books. pp. 90–101. ISBN 9780822585817.
- ^ "Effect of early versus deferred antiretroviral therapy for HIV on survival.". New England Journal of Medicine 360 (18): 1815–1826. April 30, 2009. doi:10.1056/NEJMoa0807252.
- ^ "Incomplete Peripheral CD4+ Cell Count Restoration in HIV-Infected Patients Receiving Long-Term Antiretroviral Treatment". Clinical Infectious Diseases 48 (6): 787–794. 2009-03-15. doi:10.1086/597093.
- ^ "HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies". AIDS 22 (16): 2143–2153. Oct 18, 2008. doi:10.1097/QAD.0b013e3283112b77.
- ^ "Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding". AIDS 21 (4): 501–507. Feb 19, 2007. doi:10.1097/QAD.0b013e32801424bd.
- ^ "Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study". AIDS 14 (2): 117–21. Jan 28, 2000. doi:10.1097/00002030-200001280-00006. PMID 10708281.
- ^ "Prevention of HIV-1 infection with early antiretroviral therapy". New England Journal of Medicine 365 (6): 493–505. 2011. doi:10.1056/NEJMoa1105243. PMC 3200068. PMID 21767103.
- ^ "Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here?". Lancet 382 (9903): 1515–1524. Nov 8, 2013. doi:10.1016/S0140-6736(13)61998-4.
- ^ Cohen, J (2011). "Breakthrough of the year. HIV treatment as prevention". Science 334 (6063): 1628. doi:10.1126/science.334.6063.1628. PMID 22194547.
- ^ a b c d e f g h "WHO | Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection". June 30, 2013. p. 38. ISBN 978 92 4 150572 7.
- ^ a b "CD4+ Count–Guided Interruption of Antiretroviral Treatment". New England Journal of Medicine 355 (22): 2283–2296. 2006. doi:10.1056/NEJMoa062360.
- ^ a b "Risk of cancers during interrupted antiretroviral therapy in the SMART study". AIDS 21 (14): 1957–1963. 2007. doi:10.1097/QAD.0b013e3282ed6338.
- ^ a b c d "Antiretroviral treatment of adult hiv infection: 2012 recommendations of the international antiviral society–usa panel". JAMA 308 (4). July 25, 2012. doi:10.1001/jama.2012.7961.
- ^ "EACS Guidelines". European AIDS Clinical Society (EACS). October 2013. Retrieved 2014-04-10.
- ^ UK Group on Transmitted HIV Drug Resistance; Cane, P; Chrystie, I; Dunn, D et al. (2005). "Time trends in primary resistance to HIV drugs in the United Kingdom: Multicentre observational study". BMJ 331 (7529): 1368–71. doi:10.1136/bmj.38665.534595.55. PMC 1309643. PMID 16299012.
- ^ "Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy". Clinical Infectious Diseases 40 (3): 468–74. Feb 1, 2005. doi:10.1086/427212. PMID 15668873.
- ^ "National sentinel surveillance of transmitted drug resistance in antiretroviral-naive chronically HIV-infected patients in France over a decade: 2001-2011". J Antimicrob Chemother 68 (11): 2626–31. Nov 2013. doi:10.1093/jac/dkt238. PMID 23798669.
- ^ "Surveillance of transmitted HIV drug resistance in antiretroviral-naive patients aged less than 25 years, in Bangkok, Thailand.". J Int Assoc Provid AIDS Care 13 (1): 12–4. Jan–Feb 2014. doi:10.1177/2325957413488200. PMID 23708678.
- ^ "A multicenter study of initiation of antiretroviral therapy and transmitted drug resistance in antiretroviral-naive adolescents and young adults with HIV in New York City.". PLoS ONE 58 (6): 865–72. March 2014. doi:10.1093/cid/ciu003. PMID 24429431.
- ^ "Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba". Infect Genet Evol 16: 144–50. June 2013. doi:10.1016/j.meegid.2013.02.002. PMID 23416260.
- ^ a b c d "Antiretroviral Therapy for Human Immunodeficiency Virus Infection". Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th Edition. Churchill Livingstone. 2009. ISBN 978-0-443-06839-3.
- ^ "Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro.". Antimicrob Agents Chemother 56 (10): 5409–13. October 2012. doi:10.1128/AAC.01089-12. PMC 3457391. PMID 22850510. Retrieved 2014-06-06.
- ^ "Short-Course Antiretroviral Therapy in Primary HIV Infection". NEJM 368 (3): 207–217. 2013-1-17. doi:10.1056/NEJMoa1110039. Check date values in:
- ^ "HIV-1 Transmission, by Stage of Infection". J Infect Dis 198 (5): 687–693. 9/1/2008. doi:10.1086/590501. Check date values in:
- ^ "Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis". The Lancet 364 (9441): 1236–1243. October 8, 2004. doi:10.1016/S0140-6736(04)17140-7.
- ^ a b "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection" (PDF). US Department of Health and Human Services. February 12, 2014. pp. 50–61. Retrieved April 11, 2014.
- ^ "Response to Nonnucleoside Reverse Transcriptase Inhibitor-Based Therapy in HIV-Infected Children with Perinatal Exposure to Single-Dose Nevirapine". AIDS Research and Human Retroviruses 25 (10): 989–996. October 2009. doi:10.1089/aid.2009.0054.
- ^ "Nevirapine versus Ritonavir-Boosted Lopinavir for HIV-Infected Children". New England Journal of Medicine 366 (25): 2380–2389. 2012. doi:10.1056/NEJMoa1113249.
- ^ "Maternal Levels of Plasma Human Immunodeficiency Virus Type 1 RNA and the Risk of Perinatal Transmission". NEJM 341 (6): 394–402. 1999. doi:10.1056/NEJM199908053410602.
- ^ "Mother-to-Child Transmission of HIV Infection in the Era of Highly Active Antiretroviral Therapy". Clin Infect Dis. 40 (3): 458–465. 02/01/2005. doi:10.1086/427287. Check date values in:
- ^ a b "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States" (PDF). US DHHS. March 28, 2014. Retrieved 2014-04-11.
- ^ "Mother-to-Child Transmission of HIV Infection in the Era of Highly Active Antiretroviral Therapy". Clin Infect Dis 40 (3): 458–465. 02/01/2005. doi:10.1086/427287. Check date values in:
- ^ "Longitudinal analysis of human immunodeficiency virus type 1 RNA in breast milk and of its relationship to infant infection and maternal disease". The Journal of infectious diseases 187 (5): 741–747. Mar 1, 2003. doi:10.1086/374273.
- ^ "Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy: UK cohort study". AIDS: 1. Feb 19, 2014. doi:10.1097/QAD.0000000000000243.
- ^ "Life expectancy living with HIV: recent estimates and future implications.". Current Opinion in Infectious Diseases 26 (1): 17–25. 2013. doi:10.1097/QCO.0b013e32835ba6b1.
- ^ "Older age and the response to and tolerability of antiretroviral therapy". Arch Intern Med 167 (7): 684. April 9, 2007. doi:10.1001/archinte.167.7.684.
- ^ "Virologic and immunologic response to HAART, by age and regimen class". AIDS 24 (16): 2469–2479. October 2010. doi:10.1097/QAD.0b013e32833e6d14.
- ^ a b "Management of human immunodeficiency virus infection in advanced age". JAMA 309 (13): 1397. April 3, 2013. doi:10.1001/jama.2013.2963.
- ^ "Treatment modification in human immunodeficiency virus–infected individuals starting combination antiretroviral therapy between 2005 and 2008". Arch Intern Med 170 (1): 57. Jan 11, 2010. doi:10.1001/archinternmed.2009.432.
- ^ "Antiretroviral medication adherence and the development of class-specific antiretroviral resistance". AIDS 23 (9): 1035–1046. Jun 1, 2009. doi:10.1097/QAD.0b013e32832ba8ec.
- ^ "Global Price Reporting Mechanism for HIV, tuberculosis and malaria". World Health Organization. Retrieved 2014-04-11.
- ^ "Antiretroviral Drug Prices". Avert. Retrieved 2014-04-12.
- ^ "New one-pill, $10-per-month anti-retroviral AIDS treatment debuts in South Africa". The Raw Story. Agence France-Presse. 4/8/2013. Retrieved 2014-04-14. Check date values in:
- ^ "Cost-Effectiveness of HIV Treatment as Prevention in Serodiscordant Couples". NEJM 369 (18): 1715–1725. 2013. doi:10.1056/NEJMsa1214720.
- ^ Horn, Tim (August 28, 2012). "Activists Protest Stribild's $28,500 Price Tag". AIDSMeds. Retrieved 2014-04-11.
- ^ "Stribild". GoodRx. Retrieved 2014-04-11.
- ^ Beardsley, T (1998). "Coping with HIV's ethical dilemmas". Scientific American 279 (1): 106–7. doi:10.1038/scientificamerican0798-106. PMID 9648307.
- ^ "The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs". AIDS 13 (7): 797–804. May 7, 1999. doi:10.1097/00002030-199905070-00008. PMID 10357378.
- ^ "Within-Subject Variation in CD4 Lymphocyte Count in Asymptomatic Human Immunodeficiency Virus Infection: Implications for Patient Monitoring". J Infect Dis. 169 (1): 28–36. 1994-01-01. doi:10.1093/infdis/169.1.28.
- ^ "Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection". AIDS 24 (12): 1867–1876. Jul 31, 2010. doi:10.1097/QAD.0b013e32833adbcf.
- ^ "The Absence of CD4+ T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological Gaps, and Therapeutic Options". Clin Infect Dis. 48 (3): 328–337. 02/01/2009. doi:10.1086/695852. Check date values in:
- ^ "Stanford University HIV Drug Resistance Database". Retrieved 2014-04-13.
- ^ "HIV drug susceptibility and treatment response to mega-HAART regimen in patients from the Frankfurt HIV cohort.". Antivir Ther 5 (1): 49–55. 2000. PMID 10846593.
- ^ "Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase". J Biol Chem 276 (44): 40847–57. November 2001. doi:10.1074/jbc.M106743200. PMID 11526116.
- ^ "Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors.". Antimicrob Agents Chemother 46 (3): 716–23. March 2002. doi:10.1128/aac.46.3.716-723.2002. PMC 127499. PMID 11850253.
- ^ "Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability". J Int AIDS Soc. 16 (1): 1–14. 2013. doi:10.7448/ias.16.1.18567. PMC 3764307. PMID 24008177.
- ^ "Protease inhibitor-based regimens for HIV therapy: safety and efficacy.". J Acquir Immune Defic Syndr. 45 Suppl 1 (Supplement 1): S5–13; quiz S28–31. June 2007. doi:10.1097/QAI.0b013e3180600709. PMID 17525691.
- ^ "Tolerability of HIV integrase inhibitors". Curr Opin HIV AIDS. 7 (5): 422–8. September 2012. doi:10.1097/COH.0b013e328356682a. PMID 22886031.
- ^ Bell, D M (May 19, 1997). "Occupational risk of human immunodeficiency virus infection in healthcare workers: an overview". Am. J. Med. 102 (5B): 9–15. PMID 9845490.
- ^ "The risk of occupational human immunodeficiency virus infection in health care workers: Italian multicenter study". Arch Intern Med 153 (12): 1451. June 28, 1993. doi:10.1001/archinte.1993.00410120035005.
- ^ a b c "Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis". Infection Control and Hospital Epidemiology 34 (9): 875–92. September 1, 2013. doi:10.1086/672271. PMID 23917901.
- ^ "A Case–Control Study of HIV Seroconversion in Health Care Workers after Percutaneous Exposure". NEJM 337 (21): 1485–90. 1997. doi:10.1056/NEJM199711203372101. PMID 9366579.
- ^ "Decreased fertility among HIV-1-infected women attending antenatal clinics in three African cities". J. Acquir. Immune Defic. Syndr. 25 (4): 345–52. Dec 1, 2000. doi:10.1097/00126334-200012010-00008. PMID 11114835.
- ^ a b Savasi, V; Mandia, L; Laoreti, A; Cetin, I (2012). "Reproductive assistance in HIV serodiscordant couples". Human Reproduction Update 19 (2): 136–50. doi:10.1093/humupd/dms046. PMID 23146867.
- ^ "HIV-1 infection and artificial insemination with processed semen". MMWR 39 (15): 249, 255–6. Apr 20, 1990. PMID 2109169.
- ^ "Safety of sperm washing and ART outcome in 741 HIV-1-serodiscordant couples". Hum. Reprod. 22 (3): 772–777. 03/01/2007. doi:10.1093/humrep/del422. Check date values in:
- ^ Coutsoudis, A; Kwaan, L; Thomson, M (2010). "Prevention of vertical transmission of HIV-1 in resource-limited settings". Expert Review of Anti-infective Therapy 8 (10): 1163–75. doi:10.1586/eri.10.94. PMID 20954881.
- ^ a b c "HIV cure research: Advances and prospects". Virology. 454-455: 340–352. April 2014. doi:10.1016/j.virol.2014.02.021.
- ^ Rosenberg, Tina (May 29, 2011). "The Man Who Had HIV and Now Does Not". New York Magazine. Retrieved 2014-04-12.
- ^ "Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation". NEJM 360 (7): 692–8. 2009. doi:10.1056/NEJMoa0802905. PMID 19213682.
- ^ "Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV". NEJM 370 (10): 901–10. 2014. doi:10.1056/NEJMoa1300662. PMID 24597865.
- ^ "HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation". Nat Med 15 (8): 893–900. August 2009. doi:10.1038/nm.1972.
- ^ McNeil, Donald (3/5/2014). "Early Treatment Is Found to Clear H.I.V. in a 2nd Baby". New York Times. Retrieved 2014-04-14. Check date values in:
- ^ "Absence of Detectable HIV-1 Viremia after Treatment Cessation in an Infant". NEJM 369 (19): 1828–1835. 11/7/2013. doi:10.1056/NEJMoa1302976. Check date values in:
- ^ "Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection". PLoS ONE 5 (2): e9390. 2010-2-23. doi:10.1371/journal.pone.0009390. PMC 2826423. PMID 20186346. Check date values in:
- ^ "Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy". Nature 487 (7408): 482–485. 2012-07-26. doi:10.1038/nature11286.
- ^ "Immune interventions in HIV infection". Immunol Rev 254 (1): 355–371. 7/1/2013. doi:10.1111/imr.12083. Check date values in:
External links
- AIDSinfo - Comprehensive resource for HIV/AIDS treatment and clinical trial information from the U. S. Department of Health and Human Services
- ASHM - Australian Commentary on HHS Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
- Origins of antiretroviral combination therapy
- Viral Load research papers, including effectiveness of HAART on reducing viral load
- Current status of gene therapy strategies to treat HIV/AIDS
UpToDate Contents
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- 1. 未治療HIV感染患者のための抗レトロウイルス療法の選択 selecting antiretroviral regimens for the treatment naive hiv infected patient
- 2. HIV感染症の治療に用いる抗レトロウイルス薬の概要 overview of antiretroviral agents used to treat hiv
- 3. HIV感染患者における抗レトロウイルス療法の開始時期 when to initiate antiretroviral therapy in hiv infected patients
- 4. HIV抗レトロウイルス療法中の患者モニタリング patient monitoring during hiv antiretroviral therapy
- 5. HIV療法に失敗した治療歴のあるHIV感染患者のための抗レトロウイルス療法の選択 selecting an antiretroviral regimen for treatment experienced hiv infected patients who are failing therapy
- Risk and protective factors for internalizing and externalizing outcomes among HIV-affected youth in Haiti.
- Li M1, Betancourt T, Eustache E, Oswald C, Louis E, Mukherjee J, Surkan PJ, Fawzi MC.
- AIDS care.AIDS Care.2015 Aug;27(8):995-9. doi: 10.1080/09540121.2015.1020751.
- The present study aims to: (1) estimate the levels of internalizing symptoms and externalizing behaviors among youth affected by HIV in central Haiti; and (2) examine the risk and protective factors associated with these outcomes to identify potential areas of intervention for HIV-affected youth. Ba
- A novel symptom cluster analysis among ambulatory HIV/AIDS patients in Uganda.
- Namisango E1, Harding R, Katabira ET, Siegert RJ, Powell RA, Atuhaire L, Moens K, Taylor S.
- AIDS care.AIDS Care.2015 Aug;27(8):954-63. doi: 10.1080/09540121.2015.1020749. Epub 2015 Mar 18.
- Symptom clusters are gaining importance given HIV/AIDS patients experience multiple, concurrent symptoms. This study aimed to: determine clusters of patients with similar symptom combinations; describe symptom combinations distinguishing the clusters; and evaluate the clusters regarding patient soci
- Health-related quality of life of HIV-infected adults receiving combination antiretroviral therapy in Addis Ababa.
- Mekuria LA1, Sprangers MA, Prins JM, Yalew AW, Nieuwkerk PT.
- AIDS care.AIDS Care.2015 Aug;27(8):934-45. doi: 10.1080/09540121.2015.1020748. Epub 2015 Mar 18.
- Health-related quality of life (HRQoL) is an important outcome measure among HIV-infected patients receiving combination antiretroviral therapy (cART), but has not been studied extensively in resource-limited settings. Insight in the predictors or correlates of poor HRQoL may be helpful to identify
- Chronic hepatitis B and C co-infection increased all-cause mortality in HAART-naive HIV patients in northern Thailand
- Tsuchiya Naho,Pathipvanich Panita,Rojanawiwat Archawin,Wichukchinda Nuanjun,Koga Ichiro,Koga M.,Auwanit Wattana,Kilgore Paul Evan,Ariyoshi Koya,Sawanpanyalert Pathom
- Epidemiology and Infection 141(9), 1840-1848, 2013-09-00
- … A total of 755 highly active antiretroviral therapy (HAART)-naive HIV-infected patients were enrolled at a government hospital in Thailand from 1 June 2000 to 15 October 2002. …
- No Viral Evolution in the Lymph Nodes of Simian Immunodeficiency Virus-Infected Rhesus Macaques during Combined Antiretroviral Therapy.
- Oue Megu,Sakabe Saori,Horiike Mariko,Yasui Mika,Miura Tomoyuki,Igarashi Tatsuhiko
- Journal of virology 87(8), 4789-4793, 2013-04-00
- … To elucidate the mode of viral persistence in primate lentivirus-infected individuals during combination antiretroviral therapy (cART), four simian immunodeficiency virus 239-infected monkeys were treated with cART for 1 year. … The viral env genes prepared from total RNA extracted from the mesenteric lymph nodes collected at the completion of therapy were assessed by single genome amplification. …
- Changing Burden of HIV/AIDS to Clinical Settings in Northern Thailand over 15 Years
- Pathipvanich Panita,Tsuchiya Naho,Rojanawiwat Archawin,Schmidt Wolf-Peter,Auwanit Wattana,Sawanpanyalert Pathom,Ariyoshi Koya
- Japanese Journal of Infectious Diseases 66(5), 375-378, 2013
- … After the introduction of the national highly active antiretroviral therapy (HAART) program, a profound decline in mortality rates was observed, reaching 2.0 deaths/100 PYO (95% CI, 1.4–2.9) in 2010. … Although HAART has drastically improved the survival of HIV-infected patients, the number of patients receiving therapy at this HIV clinic has substantially increased. …
- Antiretroviral Therapy Antiretroviral therapy is a method of treatment for individuals who have immunodeficiency disorders like HIV. It includes different types of drugs often combined for the best possible treatment. While there is no ...
- Standard antiretroviral therapy (ART) consists of the combination of at least three antiretroviral (ARV) drugs to maximally suppress the HIV virus and stop the progression of HIV disease. Huge reductions have been seen in rates of ...
|「highly-active antiretroviral therapy」「highly active antiretroviral therapy」
- 生殖補助医療 補助生殖医療 生殖補助医療技術 assisted reproductive technology
- 抗レトロウイルス剤療法 antiretroviral therapy、
- acoustic reflex test
「highly-active antiretroviral therapy」
「highly active antiretroviral therapy」
- n.
- 関
- care、cure、curing、practice、psychotherapy、regimen、remediation、remedy、therapeutic、treat、treatment、treatment protocol
WordNet [license wordnet]「(medicine) the act of caring for someone (as by medication or remedial training etc.); "the quarterback is undergoing treatment for a knee injury"; "he tried every treatment the doctors suggested"; "heat therapy gave the best relief"」
PrepTutorEJDIC [license prepejdic]「(病気の)治療,療法 / =psychotherapy」
- adj.
- 抗レトロウイルスの
- n.


text:
Louisiana Department of Wildlife and Fisheries Enforcement Division agents cited three Louisiana men for alleged deer hunting violations on Dec. 10 in Morehouse Parish.
Agents cited Cody Walker, 23, of Mer Rouge, Caleb Harrell, 24, of Bastrop, and Johnathan White, 25, of Bastrop, for taking deer during illegal hours, hunting from a moving vehicle, hunting from a public road, possession of illegally taken deer, intentional litter, discharging a firearm from a public road and taking over the limit of deer. Walker was also cited for intentional concealment or deposit of wildlife.
Agents received a complaint from a confidential source that the men had illegally killed two deer during illegal hours on Dec. 9. The source said the incidents occurred on Viney Woods Road between Mer Rouge and Oak Ridge in southern Morehouse Parish. After an investigation into the matter, agents obtained information and made contact with the three subjects on Dec. 10.
During the interview agents discovered that the men had shot and killed two bucks and two does during illegal hunting hours from a vehicle. Agents seized the four deer from the men.
Hunting deer during illegal hours with an artificial light and intentional concealment of wildlife brings a $900 to $950 fine and up to 120 days in jail for each offense. Possession of illegally taken deer carries a $400 to $950 fine and up to 120 days in jail. Hunting from a moving vehicle, discharging a firearm from a public road and over limit of deer brings a $250 to $500 fine and up to 90 days in jail for each offense. Hunting from a public road carries a $100 to $350 fine and up to 60 days in jail.
Agents participating in the case are Sgt. James Hagan, Lt. Scott Mathews, Sgt. Josh Estis, Senior Agent Justin Lee and Senior Agent Ray Ellerbe.

subset: commoncrawl


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Water's Edge RV & Cabin Resort
Vinita, OK 74301
Water's Edge RV & Cabin Resort in Vinita is nestled on the shoreline of Grand Lake. They offer 11 cabins to suit...Learn More
Water's Edge RV & Cabin Resort in Vinita is nestled on the shoreline of Grand Lake. They offer 11 cabins to suit...Learn More
Two story property....Learn More
This Hampton Inn is one of the only locally owned hotels in town and features spacious rooms with plush king or...Learn More
Recent complete remodeled. A Route 66 boutique hotel. Low rates, truck parking available....Learn More
If you're on historic Route 66 and are looking for a clean and quiet motel room or a well-kept RV site, try out Park...Learn More
Rooms feature free HBO, data ports, in-room coffee, and fridges available. Small pets allowed for a small non-refundable...Learn More
Enjoy our country atmosphere, clean rooms and friendly staff. We offer an indoor heated pool and hot tub, free continental...Learn More
This is a 27 room interior corridor property with nice furnishing. Conveniently located at the corner of I-40 and US 183....Learn More
Looking for a place to stay in Clinton? Check out the Holiday Inn Express & Suites. Conveniently located off I-40, this...Learn More
Days Inn is a full service hotel offering comfortable rooms with one or two queen size beds, as well as executive king...Learn More


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Caribbean States agree on historic roadmap for sustainably managing marine lifeMar 11, 2013
Cartagena, Colombia – Representatives of fisheries and environment ministries of 21 States from the Caribbean region have agreed on a common roadmap towards the sustainable management of their shared living marine resources.
Delegates meeting in Cartagena de Indias last week reached consensus on the content of a 10-year Strategic Action Programme aimed at ensuring the sustainable provision of the goods and benefits derived from the region's marine ecosystems.
The meeting was organized by the Caribbean Large Marine Ecosystem (CLME) Project – which covers almost 4.5 million square kilometres of marine space constituted by the Caribbean and North Brazil Shelf Large Marine Ecosystems. The multi-million dollar project is implemented by the UN Development Programme (UNDP).
The project area is well known for its rich biodiversity as well as for supporting a number of important fisheries such as for the Caribbean spiny lobster and queen conch. However, the region has been suffering from environmental degradation due to overfishing, pollution, invasive species (e.g. lionfish), and climate change.
The agreed upon decade-long programme sets out to reverse this trend by strengthening the cooperation between participating countries, all of which are affected by the transboundary problem of continued marine ecosystem degradation.
The programme outlines the framework and guidelines necessary to ensure coordinated action in the fields of fisheries enhancement, fisheries sustainability, and biodiversity and ecosystem protection within the region.
The Head of UNDP's Water and Ocean Governance Programme, Andrew Hudson, said the marine environment represents a major contribution to the food security, livelihoods and economic development of the Caribbean region.
"The commitment by the 21 countries to sustainably manage their shared marine resources is an historic moment and underscores the tremendous value placed on the goods and services provided by this signficant ecosystem," Mr Hudson said.
Together with the participating United Nations agencies and regional organizations, the Global Environment Facility (GEF) – the entity that co-finances the CLME Project – also applauded this remarkable achievement.


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The "Great California Garage Sale," taking place August 28-29, is selling surplus items from the state government in order to help close a substantial budget deficit.
Items for sale have been deemed non-essential, which raises the question, why did California have some of them in the first place? This includes more than 500 vehicles, a range of confiscated items and other unlikely objects you wouldn't expect to be in government hands. You can also find out more about the auction on our Funny Biz Blog.
Click ahead to see some of the items in this unique garage sale!
By Paul Toscano
Posted 28 Aug 2009


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The One Fund Boston Inc., which has raised more than $30 million to benefit victims of the Boston Marathon bombing, has officially become a tax-exempt nonprofit, according to Dot Joyce, a spokeswoman for Boston Mayor Thomas M. Menino.
The IRS approval clears the way for the fund to collect millions of dollars in pledges that were contingent on the fund becoming a 501(c)3 nonprofit. The fund has received more than $12 million from individuals and more than $17 million in pledges from corporations.
The fund plans to distribute forms for victims to file claims starting Wednesday. Victims and their families will have until June 15 to file the claims, while the money is expected to be distributed by June 30.
Three people died and more than 260 were injured in the blasts at the Marathon finish line on April 15.
IRS spokeswoman Peggy Riley could not immediately confirm whether the fund had received tax-exempt status


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General Comments: Futures closed lower on speculative buying as Florida weather looks to turn colder later this week, but not cold enough to freeze crop. Futures are now trading near the upper end of the Winter trading range. Temperatures are warm in the state, and conditions are dry again, and talk about the potential for more fruit drop and poor development of the crop for next year returned. Forecasts now call for colder weather to hit the state later this week. It is possible that some areas will see freezing temperatures, and crop development is reported to be far enough along that some damage or loss is possible. Harvest in Florida of mid and early oranges is almost over, and the Valencia harvest is underway. Bloom has been reported in groves in all production areas of the state. Weather in Brazil is reported to be good. Brazil is seeing near to above normal temperatures and scattered showers. Harvest is continuing.
Overnight News: Florida weather forecasts call for mostly dry conditions. Temperatures will average below normal.
Chart Trends: Trends in FCOJ are mixed. Support is at 125.50, 123.50, and 122.00 March, with resistance at 131.00, 132.00, and 135.00 March.
General Comments: Futures were higher yesterday, and once again held some support areas. It still seems that New York is trying to form a low in this area. Some support came from news that Colombia Coffee farmers will not deliver as they seek higher prices for crops so they can cover costs and even make a small profit. Reports of rust in Central America and the production cuts that it is causing are getting more attention. For now, it looks like Central America could lose at least 20% of the total crop this year and more next year. Losses next year could be 30% or more of the crop. Current crop development is still good this year in Brazil, and production areas are getting drier weather for the developing crop. There is some talk the drier weather could stress trees. Production ideas remain big there, and also remain big in Vietnam even though producers there talk about the potential for 25% crop losses. Central America crops are mostly harvested. Colombia is reported to have good conditions.
Overnight News: Certified stocks are lower today and are about 2.677 million bags. The ICO composite price is now 132.31 ct/lb. Brazil should get scattered showers through Wednesday, then mostly dry weather. Temperatures will average near to above normal. Colombia should get scattered showers, and Central America and Mexico should get mostly dry conditions. Temperatures should average near to above normal. ICE said that 2 contracts were delivered today against March futures and that total deliveries for the month are 101 contracts.
Chart Trends: Trends in New York are mixed. Support is at 141.00, 137.00, and 134.00 May, and resistance is at 145.00, 147.00, and 149.00 May. Trends in London are mixed to up with objectives of 2110 and 2145 May. Support is at 2070, 2040, and 2010 May, and resistance is at 2110, 2130, and 2140 May. Trends in Sao Paulo are mixed. Support is at 180.00, 178.00, and 177.00 September, and resistance is at 185.00, 187.00, and 189.00 September.
General Comments: Futures closed lower yesterday. Some are looking for a short covering rally in short term as a short squeeze is said to be possible in New York March contracts, and some think that rally is now starting. Supplies appear big around the world, but increasing off take could finally start to offer more stability to the prices. Brazil said it will increase the ethanol in its gasoline blends in May, and this could help work off a lot of the surplus production in Brazil and could tighten world balance sheets. Production has been strong in Brazil so far this year, and reports say that the new crop production looks to be strong as well, so the diversion into more domestic ethanol use will help. However, some Brazil production areas have been too dry in the south, so the production could suffer. Recent rains were beneficial, and more rain is possible in the region this week. Exports from Brazil continue to be very strong. Chart patterns now show that a rally is possible, with London likely to be the leader in any rally attempt.
Overnight News: Mostly dry weather expected in Brazil. Temperatures should be near to below normal.
Chart Trends: Trends in New York are mixed. Support is at 1780, 1760, and 1730 May, and resistance is at 1825, 1850, and 1875 May. Trends in London are mixed to up with objectives of 515.00 and 528.00 May. Support is at 502.50, 499.00, and 494.00 May, and resistance is at 508.00, 512.00, and 517.00 May.


text: Hopkins Pamela is a Partner at Hopkins Architect's, with particular responsibility for interiors, brief development and space planning. She has been involved in major projects across the arts, health and education sectors as well as office and commercial sectors. Pam helped create a "hospital that doesn't feel like a hospital" at Evelina Children's Hospital in London. More recently she has developed the interiors for University College London's Ambulatory Cancer Centre, a new hospital in Italy and a landmark new Civic Centre and Library for Brent Council, due for completion in 2013.


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When I was a kid, there was a guy named Harold Stassen who ran in the Republican presidential primaries every four years. Although his candidacy had become a joke, it was always noted, and he always seemed to attract some votes, sort of like Kucinich this year. In 1964, I think he won a substantial number of votes in a midwest primary (Illinois or Indiana, if memory serves) in which he was the moderate alternative to Barry Goldwater.
At some point, I learned that Stassen had been a serious guy. Indeed, as this biographical sketch shows, he was elected governor of Minnesota at the age of 31, resigned in the middle of his third term to serve in key positions in the Navy during World War II, was a founding delegate to the United Nations and president of the University of Pennsylvania, and held an important post in the Eisenhower administration.
But his defining moment occurred in 1948, when he was the front-runner for the Republican nomination until faltering in one of the key primaries of that day (I think it was a western state, Oregon perhaps). Having come so close, he apparently could never get running for president out of system. His ninth and last "race" was in 1992.
Which brings us to Howard Dean, who clearly is "toast" this year. It would be rash to predict that he will become another Stassen. But considering the extent to which he became intoxicated during this race, and the sudden heartbreak he experienced, I wouldn't be surprised if he runs again. Several times.
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"Arise and take our stand for freedom as in the olden time." Winston Churchill
"Proclaim Liberty throughout All the land unto All the Inhabitants Thereof." Inscription on the Liberty Bell


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Type: Used Year: 2016 Make: BMW Model: 4 SERIES Trim: 2.0TD (184bhp) 420d xDrive M Sport Auto Body: Coupe Trans: Automatic Mileage: 1841 Engine Size: 1995 Ext Color: Mineral Grey Metallic
Automatic air conditioning,Cruise control with brake function,BMW Professional navigation system,Front sport seats,BMW Online services,Headlight wash,Split-folding rear seats,19 inch M Double-spoke 442M Orbit Grey,Aluminium Hexagon interior trim- Blue,Anthracite headlining,Auto headlights with rain sensor,Automatic Dimming Interior Mirror,Black panel display. full,Bluetooth hands-free with USB audio interface,BMW Emergency call,BMW TeleServices,Concierge Service,DAB digital radio,Ext. mirrors- folding with anti-dazzle,Extended interior light package,Front armrest with sliding adjustment,harman kardon loudspeaker system,Heated front seats,High-gloss Shadowline exterior trim,M aerodynamic bodystyling,M Sport braking system,M Sport Plus package,Park Distance Control front and rear,Real time traffic information,Remote Services,Reversing assist camera,Run flat tyres,Sport automatic transmission,Sport model,Sun protection glass,Through load,USB audio interface,xDrive,Xenon headlights,Dakota Leather interior
Halliwell Jones Chester BMW
Chester, CH14LS, Cheshire
United Kingdom
Nov 4, 2016
Apr 18, 2018
Dec 8, 2017


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Groundwater levels declined last year in five wells assessed by UNL's Conservation and Survey Division.
The findings, in a new Conservation and Survey Division report, offer a snapshot of water level changes during the 2012 drought at selected locations in Nebraska.
While the annual reports assess data from about 5,500 wells, only five wells were selected for this special report. The Conservation and Survey Division chose these wells because they are in regions with a high density of irrigation wells and because of their historically significant water-level changes.
The special report's findings are consistent with historical trends, but it is not intended to be a comprehensive study of the impacts of the 2012 drought, said Aaron Young, the groundwater resource coordinator for the Conservation and Survey Division.
All five of the selected sites discussed in the special report experienced a water-level decline from spring 2012 to spring 2013, ranging from 1.85 to 5.5 feet.
Specifically, the Grainton Recorder well in Perkins County fell 1.85 feet; the Alliance Recorder well in Box Butte County fell 3.33 feet; the Elgin Recorder well in Antelope County fell 5.50 feet; the Shickley Recorder well in Fillmore County fell 2.87 feet, and the Aurora Recorder well in Hamilton County fell 5.00 feet.
The Conservation and Survey Division publishes the annual Nebraska Statewide Groundwater-Level Monitoring Reports each fall after the spring water level measurements have been taken and analyzed.
The special spring report is in response to last year's drought and meant to help individuals and organizations prepare for the coming agricultural season.
"Many people are concerned about how much groundwater levels declined due to the 2012 drought," said Young. "This report will give a rough idea of how water levels responded in areas with a high density of irrigation wells."
The annual groundwater-level reports measure the change in Nebraska's water levels and reflect historical trends.
Electronic copies of the spring special report are available free at http://snr.unl.edu/data/download/water/GWMapArchives/GWReports/ESN-9_2012.pdf.
The annual Nebraska Statewide Groundwater-Level Monitoring Reports are available online at go.unl.edu/groundwater. Paper copies of both reports are also available for purchase through the Nebraska Maps and More Store at 101 Hardin Hall.
For more information, go to http://go.unl.edu/6fs, send email to email@example.com or call 402-472-3471.
Special report on groundwater levels released
Groundwater levels declined last year in five wells assessed by UNL's Conservation and Survey Division.


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2010 – 2011: Relationship between metabolic syndrome, low testosterone and male erectile dysfunction (epidemiological study)
2004 – 2005: Efficacy, safety and patient's preference Oral Tadalafil (Cialis®) in men with ED: General Urological practice experience (prospective, non-randomised study).
2000: Assessment of the efficacy and safety of Sildenafil (Viagra®) in general urological practice (prospective, non-randomised study).
1999: Assessment of the efficacy and safety MUSE® in general urological practice (Prospective, non-randomised study).
1998: Assessment the role of spiral CT in the characterization of renal masses (a pilot study).
1995 – 1996: A prospective randomised trial to compare the efficacy, safety and durability of TUVP (Using VaporTrode® electrode) with the conventional TURP for the treatment of symptomatic BPH – 1- 5 year follow-up.
1992 – 1993: Xanthogranulomatous pyelonephritis in children: preoperative diagnosis is possible (Case review).
2000: Assessment of genetic and urogenital anomalies in men with unilateral and bilateral congenital absence of vas deferens (Case review).


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Because of a drought that's affecting nearly all of Minnesota, state officials are telling farmers it's time to consider crop insurance.
The standard deadline is less than one month away. Farmers must finalize a plan with their insurance agent by March 15.
Commerce Commissioner Mike Rothman says crop insurance coverage could be crucial If dry conditions persist in the weeks and months ahead.
Agriculture Commissioner Dave Frederickson says crop insurance is an important tool for managing the risks of farming, so he encourages farmers to review their options carefully.
According to the National Weather Service, more than 96 percent of Minnesota is currently facing moderate to severe drought conditions. It's a turnaround from last year, when farmers and communities across Minnesota were instead bracing for the possibility of severe flooding.


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A Day Out With The Talk's Julie Chen and Sharon Osbourne
Nov 2, 2012 7:00 AM EDT
On paper, Julie Chen and Sharon Osbourne — the queen bees of CBS' girly gabfest The Talk — couldn't be more different. Chen, a pedigreed journalist, spent years rising up the ranks at The Early Show and hosting Big Brother. Osbourne, mean… Read more


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National Rosacea Society Awards New Grants for Rosacea Research
BARRINGTON, Illinois (January 11, 2007) -- The National Rosacea Society (NRS) announced that five new studies have been awarded funding as part of its research grants program to advance scientific knowledge of the potential causes and other key aspects of this chronic and potentially life-disruptive disorder that affects an estimated 14 million Americans.
"We are extremely grateful to the many thousands of rosacea patients whose donations are used to fund this important research grants program," said Dr. Jonathan Wilkin, chairman of the NRS medical advisory board, which reviews and selects the research proposals for funding. "Study results to date are leading to important advances in the understanding of rosacea, and we are hopeful that these findings will result in significant improvements in its effective management and potential prevention or cure."
Dr. Sandra Cremers, assistant professor of ophthalmology at Harvard Medical School, was awarded $25,000 for a study evaluating the role of angiogenesis (new blood vessel formation) in ocular rosacea. Dr. Cremers will investigate the levels of angiogenesis markers, such as vascular endothelial growth factor (VEGF), in the conjunctiva and eyelids of patients with severe ocular rosacea, compared with normal subjects. She postulates that defining the role of angiogenesis in the development of ocular rosacea may bring focus to future research on this common rosacea subtype, and eventually lead to the development of an effective treatment.
Dr. Richard Gallo, chief of the division of dermatology at the University of California - San Diego, and Dr. Kenshi Yamasaki of the Veterans Medical Research Foundation were awarded $25,000 to continue their NRS-funded research of how cathelicidins, one of the body's own natural antibiotics, may play a role in the development of rosacea symptoms.
The investigators most recently determined that an excess of an enzyme in the facial skin of rosacea patients leads to an accumulation of cathelicidins, an antimicrobial peptide that can cause inflammation and increased blood vessel growth. In a new study, they will be investigating the causes of this enzymatic abnormality and testing whether this enzyme may be a key cause of rosacea.
Dr. Richard Granstein, chairman of dermatology at Cornell University, and colleagues were awarded $25,000 to continue their research on the role of adenosine triphosphate (ATP), an agent produced by nerves that earlier NRS-funded studies had shown initiates an inflammatory response in human dermal endothelial cells. The researchers will also expand their study to examine whether three other agents produced by nerves elicit effects similar to ATP, and will test whether therapeutic agents for rosacea work by inhibiting the expression of inflammation-causing molecules by endothelial cells.
Dr. Kent T. Keyser, professor of vision sciences at the University of Alabama at Birmingham, received $25,000 to study the effects of nicotine on rosacea. Because previous research has shown that nicotine can cause new blood vessels to form in the skin, Dr. Keyser plans to investigate which intracellular signaling pathways are affected and which cellular mechanisms may cause a reaction in rosacea. In addition, Dr. Keyser will examine the short- and long-term effects of nicotine on gene expression and transcription as they may relate to the development of rosacea.
Dr. Martin Steinhoff, department of dermatology, University of Muenster, Germany, was awarded $25,000 to study the role of neuroimmune interactions in the pathophysiology of rosacea. In previous NRS-funded studies, Dr. Steinhoff's team found that neuropeptide-positive sensory nerves around blood vessels increase during rosacea's development. In addition, they discovered that a combination of several neuropeptides, neuropeptide receptors and endopeptidases is involved in maintaining homeostasis, but this balance is compromised in rosacea skin. In the new study, the researchers will examine whether the ineffective interaction between neuropeptide receptors and neuropeptide-degrading enzymes results in dysregulation and contributes to the development of rosacea.
Researchers interested in applying for grants can obtain forms and instructions by contacting the National Rosacea Society, 800 South Northwest Highway, Suite 200, Barrington, Illinois 60010, telephone 1-888-662-5874, e-mail firstname.lastname@example.com. The deadline for submitting proposals for research grants in 2007 is September 15. Further information is available on the NRS Web site at www.rosacea.org/grants/.
Because the cause of rosacea is unknown, a high priority in awarding grants is given to studies relating to its pathogenesis, progression, mechanism of action, cell biology and potential genetic factors. Proposals relating to epidemiology, predisposition, quality of life and relationships with environmental and lifestyle factors may also be considered.
Members of the NRS medical advisory board include Dr. Jonathan Wilkin, former director of dermatologic and dental drug products for the U.S. Food and Drug Administration; Dr. Mark Dahl, chairman of dermatology at the Mayo Clinic-Scottsdale and former American Academy of Dermatology (AAD) president; Dr. Michael Detmar, associate professor of dermatology at Harvard Medical School; Dr. Lynn Drake, Harvard Medical School and former AAD president; Dr. David Norris, chairman of dermatology at the University of Colorado and former president of the Society for Investigative Dermatology; Dr. Frank Powell, consultant dermatologist with the Regional Centre of Dermatology, Dublin, Ireland; Dr. Richard Odom, professor of dermatology at the University of California - San Francisco and former AAD president; and Dr. Bryan Sires, clinical associate professor of ophthalmology at the University of Washington.
Rosacea is a chronic disorder primarily of the facial skin, characterized by flare-ups and remissions. According to the standard classification system for rosacea, developed by an NRS consensus committee and review panel of 17 experts worldwide, the primary features of rosacea include flushing, persistent erythema, papules and pustules, and telangiectasia, while secondary features may include ocular manifestations, burning and stinging, plaques, dry appearance, edema, locations beyond the face and phymatous changes. In most cases, some rather than all of these signs and symptoms appear in any given patient.
The NRS is a nonprofit organization dedicated to improving the lives of people with rosacea by raising awareness, providing public health information and supporting research on this common but biologically poorly understood disorder.
Contact Us
- Phone:
- Email:
- firstname.lastname@example.com
196 James St.
Barrington, IL 60010
Our Mission
The National Rosacea Society is a 501(c)(3) nonprofit organization whose mission is to improve the lives of people with rosacea by raising awareness, providing public health information and supporting medical research on this widespread but little-known disorder. The information the Society provides should not be considered medical advice, nor is it intended to replace
consultation with a qualified physician. The Society does not evaluate, endorse or recommend any particular medications, products, equipment or treatments. Rosacea may vary substantially from one patient to another, and treatment must be tailored by a physician for each individual case. For more information, visit About Us.


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Hawaiian law program to provide training to state, county personnelUniversity of Hawaiʻi at Mānoa
Community Outreach Coordinator, Law School
The William S. Richardson School of Law's Ka Huli Ao Center for Excellence in Native Hawaiian Law will provide a free law training course to state and county lawmakers, decision-makers, staff and members of various boards, commissions and councils on Saturday, January 11, 2014, at the Law School campus at UH Mānoa.
The training course is focused on state and county governments' trust obligations, particularly in relation to Native Hawaiian cultural and natural resources. The specific subjects include the public land trust, traditional and customary rights, water and the public trust doctrine, and the law relating to iwi kūpuna or Native Hawaiian ancestral remains.
Explained Associate Professor of Law and Ka Huli Ao Director Melody Kapilialoha MacKenzie, "We offered this training in January 2013 and were encouraged by the number of people and entities that participated – over a hundred people attended. Generally, the feedback was very positive, and attendees found the training invaluable. We're excited to offer this opportunity again."
Due to developments in the law since January 2013, there will be updates to the training course. Law School faculty members will give presentations on each of the subjects. Dr. Davianna McGregor from the Ethnic Studies department will provide an historical overview on land tenure.
The training course has been made possible with funding from the Office of Hawaiian Affairs.


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The Record recently reached an agreement to sponsor The Record Press Club, the area in the Stockton Arena formerly known as the Comcast Club.
The three-year agreement with SMG, the company that operates the Arena, officially begins Feb. 1.
"The goal is for both SMG and The Record to benefit, to have a win-win partnership," Record Publisher Roger Coover said. "For The Record to continue to show its support of the community and obviously to continue to keep our company visible. It's one more venue to increase our marketing."
Record-branded items such as signage and framed front pages will help promote the new sponsorship in the arena and in the club.
Readers will benefit from the agreement too.
"We'll have more contests than we have in the past to give tickets to readers," Coover said. "We'll occasionally offer Record Rewards customers the
opportunity to go into the Press Club even though they don't have a ticket for a seat in that area. We'll continue to look for ways that benefit us and the arena to fill seats and benefit our customers."
Tickets to The Record Press Club will be in a slightly higher tier and will allow patrons access to a private bar, food service and bathrooms.
This sponsorship shows The Record continues to invest in Stockton, Coover said.
"As the community comes out of its low spot in the economic issues of the last few years, … we want to be one of the companies that puts our head up early and says we believe in our community and our future," he said.
Record sponsors Press Club at arena
The Record recently reached an agreement to sponsor The Record Press Club, the area in the Stockton Arena formerly known as the Comcast Club.


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COLUMBUS, Ohio (AP) — A condemned man who fatally shot an adult bookstore security guard at the end of a multistate crime spree "gratuitously brutalized" innocent people who posed no threat to him, the Ohio Parole Board said Friday in rejecting the inmate's plea for mercy.
Frederick Treesh, sentenced to die for killing Henry Dupree in a 1994 robbery, had argued he accepted responsibility for the killing but that it was an unintentional consequence of a struggle for a gun while he was high.
The parole board disagreed, ruling unanimously that the evidence showed Dupree was seated when shot and hadn't shown any sign of being a threat to Treesh. The board also said Treesh's decision to shoot a clerk in the face as he left the store suggests Treesh's "murderous intent" when coming to the store.
Treesh and his co-defendant "gratuitously brutalized, humiliated and killed innocent people, most of whom, like Dupree, posed no real or perceived threat to them," the board said.
The decision came just under a month before Treesh's scheduled March 6 execution. Gov. John Kasich has the final say.
Prosecutors say Treesh, 48, and the co-defendant robbed banks and businesses, committed sexual assaults, stole cars, committed carjackings and shot someone to death in a Michigan robbery during a spree that also took them to Indiana, Iowa, Minnesota and Wisconsin. Treesh was sentenced to die in Ohio for killing Dupree in the town of Eastlake on the shore of Lake Erie.
Attorneys for Treesh argued for clemency last week, while prosecutors presented their case against sparing Treesh for a murder they say was intentional.
Treesh's attorneys described him as a cocaine addict who was high during the robbery and is deeply sorry for what happened.
"Hindsight, regret and remorse cannot turn back the clock and cannot return Mr. Dupree's life," they said in a petition for clemency. "What Fred can do and has tried to do is to help prevent others from making the same mistakes he did" by teaching them to avoid drugs.
His lawyers also alleged Treesh's rights were violated during a prolonged interrogation as he was coming down from a drug high, which contributed to his death sentence. They also say Treesh suffers from health problems, including a seizure disorder, that raise concerns Ohio's lethal injection process would cause him suffering amounting to cruel and unusual punishment.
Treesh attorney Adele Shank said Friday she was disappointed in the decision and hoped Kasich would come to a different decision.
Prosecutors contend Treesh intentionally murdered Dupree and tried to kill others, including police officers in pursuit.
"Treesh has never taken responsibility for his actions," Lake County prosecutor Charles Coulson wrote. "Treesh still claims 'the cocaine made him do it.'"
Coulson also noted that courts previously determined Treesh's constitutional rights weren't violated.
Treesh declined to be interviewed by the parole board.
The parole board cited Treesh's refusal to be interviewed as evidence he has not grown or improved as a person in prison.
Treesh's prison behavior is indicative of "a self-indulgent, petulant and immature individual," the board said.
He was never prosecuted for the crimes in the other states, according to the Ohio Attorney General's office.
Ohio's most recent execution was in November, when the state put to death Brett Hartman for the 1997 stabbing and dismemberment of an Akron woman.
Andrew Welsh-Huggins can be reached on Twitter at https://twitter.com/awhcolumbus.


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Rochester charity hockey game postponed due to possible stormBy JOHN QUINN
Union Leader Correspondent
February 06. 2013 12:19PM
ROCHESTER - As a precaution due to an impending snowstorm, local police and firefighters have postponed their charity hockey game scheduled for Friday.
The 6th annual charity hockey game will now be played Feb. 15 in the Rochester Arena. The arena, located at 63A Lowell St., donates the time on the ice for the event.
Doors are set to open at 6 p.m., and the game should start around 6:45 p.m.
Fire Chief Norm Sanborn said the decision to postpone by a week was prudent to keep everyone safe and to ensure the city is ready for any emergencies as a result of the storm.
"It's definitely the right move to make and people won't want to come out in the snow," Sanborn said. "It's all about having fun."
Spectators will be able to meet and talk to the players from both teams - made up of police, firefighters and their families - according to Detective Steven Gahan.
Local firefighters hope to break the streak, as police are defending their undefeated record.
The entry fee to the game is a nonperishable food item which will be donated to Gerry's Emergency Food Pantry, which provides assistance to Rochester residents and families in need. The pantry - located in the Rochester Community Center at 151 Wakefield St. - assists an average of 300 to 350 people, including families, older residents and couples, each week, according to co-coordinator Anne Ackerman.
Ackerman said the pantry is always in need of donations, especially peanut butter and personal care products such as shampoo, soap, deodorant and shaving cream.
For more information about Gerry's Emergency Food Pantry, visit www.sharefund.org.