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Author Topic: Improved survival in HIV-infected persons: consequences and perspectives  (Read 4855 times)

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Offline xyahka

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  • Dance together!! aha!! aha!! I like it!!
Hi guys, i think you might enjoy reading this... from Oxford Journal of Antimicrobial Chemotherapy

http://jac.oxfordjournals.org/cgi/content/full/60/3/461

-----------------------------

Improved survival in HIV-infected persons: consequences and perspectives

Journal of Antimicrobial Chemotherapy July 2007 60(3):461-463; doi:10.1093/ jac/dkm241

Nicolai Lohse1,2,*, Ann-Brit Eg Hansen3,4, Jan Gerstoft4 and Niels Obel4

1 Department of Clinical Epidemiology, Århus University Hospital, DK-8000 Århus C, Denmark 2 The Danish HIV Cohort Study, Copenhagen University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark 3 Department of Infectious Diseases, Odense University Hospital and Clinical Institute, University of Southern Denmark, DK-5000 Odense, Denmark 4 Department of Infectious Diseases, Copenhagen University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark

Conclusion
Many HIV-infected persons with access to antiretroviral therapy have a near-normal life expectancy, but mortality among them is still higher than that in the general population. The continuation of the positive trend may be achieved by vaccine development, increased HIV testing, earlier HAART initiation, individually tailored regimens, improved drug adherence, prevention and treatment of HIV-unrelated co-morbidity and collaboration with other medical specialists to treat an ageing co-morbidity- acquiring HIV population.

Abstract
A human immunodeficiency virus (HIV) patient in 2007 has the option to commence an antiretroviral regimen that is extremely efficacious in suppressing the virus and has few side effects. In a recent study, we estimated the median remaining lifetime of a newly diagnosed 25-year-old HIV-infected individual to be 39 years. The prospect of a near-normal life expectancy has implications for the HIV-infected persons as well as for the handling of the disease in the healthcare system. The patients can now on a long-term perspective plan their professional career, join a pension plan and start a family. Further, they may expect to be treated equally with other members of society with respect to access to mortgage, health insurance and life insurance. As the infected population ages, more patients will contract age-related diseases, and the disease burden on some individuals may even come to be dominated by non-HIV-related conditions that may have a worse prognosis and therefore become more important than HIV-related conditions. Despite the improvements in antiretroviral therapy, there is still an excess mortality among HIV patients, which appears to be only partially attributable to immunodeficiency, with lifestyle factors potentially playing a pronounced role. Consequently, an effort to further increase survival must target risk factors for both HIV-related and -unrelated mortality. The continuation of the positive trend may be achieved by increased HIV testing, earlier initiation of antiretroviral therapy, improved drug adherence, prevention and treatment of HIV-unrelated co-morbidity and collaboration with other medical specialists to treat an ageing co-morbidity- acquiring HIV population.

Background
The effectiveness of highly active antiretroviral therapy (HAART) against the human immunodeficiency virus (HIV) has been a medical success story. For those fortunate enough to have access to HAART, an inevitably deadly disease has turned into a chronic condition. In the 1980s, simply finding a drug or drug combination that could delay AIDS or death was the main clinical goal. In the mid-1990s, triple-combination therapy was introduced, leading to substantially prolonged survival. Simultaneously, it was shown that the substrate for the clinical effectiveness was suppression of HIV replication. 1 Many patients experienced the comfort of a rising CD4 cell count and reversal of their AIDS-defining conditions. However, short-term and long-term side effects of the drugs became increasingly concerning, whereas episodes of virological failure led to the development of drug resistance, forcing patients to resort to often less efficacious second- or third-line regimens. Pharmaceutical companies began competing to develop new drugs with fewer side effects, lower pill burden and a better tolerance to non-compliance. Patients and physicians speculated whether controlled treatment interruptions could bring about a clinical success by delaying the potential exhaustion of available drug combinations and reducing the harm due to side effects. The intensive drug development and the massive research into mechanisms of resistance and side effects have paid off. An HIV patient in 2007 has the option to commence a drug combination that is both efficacious in suppressing the virus and has few side effects. Despite HIV's ability to escape antiviral pressure, the rate of resistance to the antiviral drugs-a major problem in the early years when the regimens were suboptimal-is declining in a number of settings and may be <1% annually. Thus, there is growing optimism among HIV experts that a large proportion of their patients will be able to remain on their initial regimens and survive for many years. The big question has been, though, how long?

Survival of HIV-infected persons
Our group has addressed this question in the Danish HIV Cohort Study, using data from a population-based cohort of all HIV-infected persons in Denmark, a country with free tax-supported medical care, including universal, income-independent access to HAART.2 The high quality of the Danish Civil Registration System3 enabled us to compare, with little attrition, the survival of HIV patients with that of a matched cohort from the general population. Life-table methods were used to estimate survival of a 25-year-old HIV-infected person, regardless of whether the person had started HAART. The estimated median remaining lifetime has increased from 8 years in 1995-96 to 23 years in 1997-99 to 33 years in 2000-05. Among persons not co-infected with the hepatitis C virus (HCV), the median remaining lifetime in 2000-05 was 39 years (95% CI: 35-40 years), similar to that of a young person with diabetes.4 In comparison, the median remaining lifetime for a 25-year-old HIV-uninfected person was 51 years. Furthermore, we found that neither time since diagnosis nor duration of HAART was associated with an increased mortality. Importantly, the highest mortality was observed in the first year after the initiation of treatment.

Immediate implications of the improved prognosis
As clinicians know, the prognosis for individual HIV patients depends on many determinants, including immune status at the time of diagnosis, harbouring of a drug-resistant virus strain, adherence to treatment and concomitant infection with HCV. Nevertheless, the overall improved prognosis, with the prospect of a near-normal life, has implications for the HIV-infected persons as well as for their physicians. The patients may now plan their professional career, join a pension plan, start a family-things that just a few years ago seemed to be irrelevant luxuries. They may expect to be treated equally with other members of society and to have easy access to mortgage, health insurance and life insurance. They also expect to receive high-quality healthcare for non-HIV-related conditions, including fertility treatment. As the patients now get older, they will contract age-related diseases, and the disease burden on some individuals may even come to be dominated by non-HIV-related conditions. Some of these diseases may have a worse prognosis and therefore become more important than HIV for some patients. It would be important to know when an HIV-infected person needs a hip replacement, a bypass operation or even a cardiac transplantation. 5 Elements of healthy lifestyle-smoking cessation, weight loss and regular physical exercise-that take 10 years or more to yield full benefits are becoming increasingly relevant for HIV patients. Furthermore, they should be offered prophylactic treatments, such as cholesterol- lowering therapy and antihypertensive treatment, just as their non-HIV-infected counterparts do.

Why do HIV patients still have a higher risk of death?
Even though survival has increased markedly, HIV-infected persons still die at rates that are 3-15 times higher than the general population.2 Cause-specific rates have decreased for both HIV-related and non-HIV-related mortality, but the decreased risk of AIDS has led to a change in patterns of co-morbidity and causes of death, and most deaths (50% to 70% of all deaths) are now non-HIV-related. 2,6-8

Common causes of non-HIV-related death are non-AIDS-defining cancers (10% of all deaths), cardiovascular diseases (about 7%), substance abuse-related death (about 7%), liver-related death (up to 15% reported) and bacterial infections (about 6%).7-9 The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study found mortality rates of non-AIDS-defining cancers to be related to the degree of immunodeficiency. Some cancers are known to be associated with lifestyle-related viral infections, such as hepatitis B virus (hepatocellular carcinoma), HCV (hepatocellular carcinoma and lymphoma) or human papilloma virus (anal, mouth and throat cancer),9 whereas others may be associated with smoking (cancer of lung, mouth and throat).10 Liver-related deaths are mainly seen in hepatitis C or B co-infected patients and the actual risk varies with the prevalence of these co-infections. 11 We have found that a large part of the increased mortality seen in HIV/HCV co-infected individuals is associated with family-related risk behaviours-mainly drug abuse-and to a lesser extent, with the HCV infection itself.12 Behavioural risk factors for disease and death, such as cigarette smoking and excessive alcohol consumption, are common in many HIV-infected populations. 13,14 Thus, the excess mortality among HIV patients appears to be only partially attributable to immunodeficiency, with lifestyle factors potentially playing a pronounced role. Consequently, an effort to further reduce mortality and increase survival must target risk factors for both HIV-related and HIV-unrelated mortality.

How can we provide better care for the patients?
A reduction in HIV-related mortality requires improved virological suppression, and research has shown that adherence to therapy is the key to success.15 The first step is easy and free access to drugs and healthcare, which should be supplemented by a coordinated effort of experienced care teams-physicians, nurses and social workers-in order to adequately address each individual's needs, problems and taboos. Further, and in line with current CDC recommendations, 16 test frequency must be increased for individuals at risk of being HIV-infected, including all adults in healthcare settings. This may help identify HIV-infected patients at an earlier stage of the disease and thereby enable timely therapy initiation. Reducing non-HIV-related mortality calls for a multifaceted approach whose success partly depends on behavioural changes that physicians can merely encourage, but not enforce. In addition, physicians must be aware that the HIV-infected population is getting older and therefore becomes increasingly affected by the diseases common in the general population. Optimal treatment and prevention therefore require the expertise of other medical specialists.

What can be done to stem the epidemic?
In order to optimize the benefit of the highly efficacious antiretroviral drugs that are available today, we must understand how the new treatment strategies may affect the spread of the disease on the population level. The improved survival increases the prevalence of persons who carry HIV and are thus at risk for transmitting the virus to others. In addition, the awareness of improved prognosis may cause people to be less afraid of getting infected and cause them to become less vigilant. Furthermore, increased use of HAART may lead to resurgence of drug resistance. In contrast, a combination of high adherence and efficacious regimens will maintain viral suppression in the population and prevent the development of resistance. In support of the optimistic view, a recent population-based study from our group showed an increase in viral suppression and a decreasing incidence of potential resistance.17 Finally, there are persons who are unaware of their HIV infection; most of them have high viral loads and are more likely to engage in high-risk behaviours than they would if they were aware of being infected. The prevalence of these persons is unknown, and thus the extent of the problem is difficult to estimate.

Hence, the following needs to be considered. First, controlled treatment interruptions have been shown to do more harm than good in the individual,18 nor are they justifiable from a population perspective, because of the increased risk of transmission during periods of interruption. Secondly, initiating HAART at an earlier stage-possibly treating all patients-is an intervention that may restrain the spread of the epidemic. Thirdly, intensified testing will help reduce the prevalence of risk behaviours and improve viral suppression on the population level.

Other research questions are pending: What is the long-term impact of HIV and HAART on the risk of non-HIV diseases? How do antiretroviral drugs interact with other drugs in older individuals? Can we tailor individual regimens based on genetic markers for drug susceptibility and on individual risks for adverse drug reactions? What are the social and economic consequences of a growing population of HIV-infected persons? Some will require intensive medical care and receive financial support from the state, but many will contribute to the economy through work and tax payments. Ultimately, how can we transfer the success in the Western world to resource-poor settings, where poverty may force patients into antiretroviral drug-sharing and treatment interruptions? A requisite, contributory step forward will be the development of a preventive and/or therapeutic HIV vaccine.19

References
1 Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med (1998) 338:853-60.[ Abstract/ Free Full Text]

2 Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med (2007) 146:87-95.[Abstract /Free Full Text]

3 Frank L. Epidemiology. The epidemiologist' s dream: Denmark. Science (2003) 301:163.[Abstract/ Free Full Text]

4 Laing SP, Swerdlow AJ, Slater SD, et al. The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus. Diabet Med (1999) 16:459-65.[CrossRef ][ISI][Medline]

5 Jahangiri B, Haddad H. Cardiac transplantation in HIV-positive patients: are we there yet? J Heart Lung Transplant (2007) 26:103-7.[CrossRef] [ISI][Medline]

6 Pantanowitz L, Schlecht HP, Dezube BJ. The growing problem of non-AIDS-defining malignancies in HIV. Curr Opin Oncol (2006) 18:469-78.[ISI] [Medline]

7 Lewden C, Salmon D, Morlat P, et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol (2005) 34:121-30.[Abstract /Free Full Text]

8 Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med (2006) 166:1632-41. [Abstract/ Free Full Text]

9 Monforte AD, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and risk of fatal AIDS-defining and non-AIDS-defining malignancies: results from the D:A:D study. In: Abstracts of the Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, 2007. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 84.

10 Hessol NA, Pipkin S, Schwarcz S, et al. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol (2007) 165:1143-53. [Abstract/ Free Full Text]

11 Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS (2005) 19:593-601.[ ISI][Medline]

12 Hansen AB, Gerstoft J, Kronborg G, et al. Mortality in siblings of patients coinfected with HIV and hepatitis C virus. J Infect Dis (2007) 195:230-5.[CrossRef ][ISI][Medline]

13 Galvan FH, Bing EG, Fleishman JA, et al. The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV Cost and Services Utilization Study. J Stud Alcohol (2002) 63:179-86.[ISI] [Medline]

14 Saves M, Chene G, Ducimetiere P, et al. Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis (2003) 37:292-8.[CrossRef] [ISI][Medline]

15 Lucas GM. Antiretroviral adherence, drug resistance, viral fitness and HIV disease progression: a tangled web is woven. J Antimicrob Chemother (2005) 55:413-6.[Abstract/ Free Full Text]

16 Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep (2006) 55:1-17.[Medline]

17 Lohse N, Obel N, Kronborg G, et al. Declining prevalence of HIV-infected individuals at risk of transmitting drug-resistant HIV in Denmark during 1997-2004. Antivir Ther (2006) 11:591-600.[ ISI][Medline]

18 El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med (2006) 355:2283-96. [Abstract/ Free Full Text]

19 Titti F, Cafaro A, Ferrantelli F, et al. Problems and emerging approaches in HIV/AIDS vaccine development. Expert Opin Emerg Drugs (2007) 12:23-48.[CrossRef] [Medline]

13/03/07 1er diagnóstico /Peso: 79kg
19/04/07 CD4: 494 /CViral: ?? /Peso: 80kg
19/07/07 CD4: 659 /CViral: ?? /Peso: 79.5kg
06/03/08 CD4: 573 (después de meses muy deprimido) /CViral: ?? /Peso: 79kg
17/09/08 CD4: ?? /CViral: ?? /Peso: 84Kg
06/02/09 CD4: ?? /CViral: ?? /Peso: 85Kg /HCV: Neg /HBV: Neg.
07/03/09 CD4: ?? /CViral: ?? /Peso: 87Kg / Gym 3días/semana y Natación 2días/semana.
12/05/09 CD4: 470 /Cviral: ?? /Peso: 87Kg.
08/07/09 CD4: ? /CViral: ? /Peso: 77Kg.
09/12/09 CD4: 510 /CViral: ? /Peso: 78kg. No medicinas aún
10/01/10 CD4: ? /CViral: ? /Peso: 76Kg.
15/05/10 CD4: 320 /CViral: ? /Peso: 76Kg.
01/02/11 CD4: 291 /CViral: ? /Peso: 78kg.
05/05/11 CD4: 366 /CViral: ? /Peso: 78kg.
27/07/11 CD4: 255 /CViral: 138000 /Peso: 78kg.

Disfrutando y aceptando una nueva vida...

Offline AustinWesley

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  • Posts: 815
    • HIV Discussion Group on Myspace!
Thank You for posting this!    It's encouraging to read this instead of hearing gloom and doom all the time. 

Much appreciated,

Wesley
Diag. 3/06  Infected aprx. 2 mo. Prior
Date        CD4   %      VL
4/6/06     627    32    36,500     NO MEDS YET!
6/7/06     409    27    36,100
8/23/06   408    25     22,300
1/2/07     354    23     28,700
2/9/07     139    30     23,000  Hep A Vaccine same day???
2/21/07   274    26     18,500 
3/3/07    RX of Truvada/Sustiva Started.
4/5/07    321     27      Undectable 1st mo.  
5/16/07  383     28    Undectable 2nd mo.
8/10/07  422     32   UD <48 on new scale!

Offline Jake72

  • Member
  • Posts: 145
It is encouraging to read this.  And it wouldn't surprise me if "near-normal life expectancy" were to turn into "very near-normal life expectancy " or "normal life expectancy" given that this study is based on available treatments.  I'd say that we can expect that treatment options will improve (dramatically, let's hope) for both newbies and treatment-experienced patients over the next 39 years.

Considering that in the '90s, they were saying that we'd have an additional 20 years with HAART, and now, just a decade later, they're saying that we'll have nearly double that, I think that continued progress will be made.

Offline dingowarrior

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  • Posts: 191
i'm surprise there arent more cheers on this post..i for one am VERY ENCOURAGED!  ;D

Offline Esquare

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  • Posts: 237
i'm surprise there arent more cheers on this post..i for one am VERY ENCOURAGED!  ;D

Same here. I never mind reading articles like this.

Offline powerpuff

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  • Posts: 138
It sounds more promising.it's nice to hear good news for once :)
now of course putting all aside are the risks of lymphoma still high? does it matter is a person is duel tropic? or other factors of progression? questions of averages? ::)
Is long term survival a genetic thing or drug enhanced?

Offline Fortitude

  • Member
  • Posts: 4
Re: Improved survival in HIV-infected persons: consequences and perspectives
« Reply #6 on: October 20, 2007, 11:51:34 PM »
I'm very pleased with the post. I've been positive since 2005. (At age 25 in that year.) Here are the things I do to improve my expectancy to the top end of the range, instead of the median. I've been at an undetectable VL with 30's ratio and 500's CD4 for 2 years on ATRIPLA.

A) Gardasil Vaccine (Prevents 4 Strains of HPV)
B) Vaccinated for Hep A and Hep B and no barebacking to prevent Hep C
C) No Smoking
D) Only moderate drinking
E) Exercise 2-4 days a week, weights and cardio
F) Keep Intellectually stimulated (post-graduate education)
G) 100% HAART Adherence (ATRIPLA)
H) Flu shot every year
I) Wash hands before eating
J) No red meat.
K) Low-sugar and low-cholesterol / polysaturated-fat diet
L) Out about HIV status and sexual orientation - not ashamed
M) Very assertive with doctors and medical plan
N) anal physical (to check for cancer) every 6 months and follow-up by proctologist if needed
O) yearly screening for Hep C (even after protected sex)
P) 3-month CD4 monitoring
Q) Drug free.
R) Drink tons of water.
S) Very little soda.
T) Moderate caffeine.
U) Sleep 7.5+ hours per night.
V) Maintain future plans (403B / ROTH/IRA / Pension / Real Estate
W) Check Cholesterol / LDL / HDL every 6 months
X) baby aspirin daily
Y) Pray
Z) Volunteer

Offline NYCguy

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  • Posts: 180
Re: Improved survival in HIV-infected persons: consequences and perspectives
« Reply #7 on: October 23, 2007, 02:51:45 PM »
Hey Fortitude, I love your list! 

Is the no red meat to keep cholesterol down?

One other thought/question - I have read on 'official' websites that Hep C is hard to get through sex and is usually transmitted by IV drugs or transfusion.  However, I often hear people (including my doctor) stating otherwise.  Any ideas?  In terms of barebacking, would topping be safer than bottoming, as in HIV?  My concern with barebacking is mostly HPV (which guardasil should help with - need to to that!) and herpes + the usual STDs. 
11/9/06 = #$%^&!
sometime early Dec 2006:
CD4 530 20%/VL >250,000 (&*$$%!!)
started Reyataz300mg/Norvir/Truvada 12-27-06.
1/30/07 CD4 540 30%/VL <400
4/07 CD4 600+ 33%/VL <50
6/9/07 CD4 720 37%/VL <50
10/15/07 CD4 891 (!) %? VL <50
1/2010 CD4 599 (37%) VL<50 (drop due to acute HCV)
9/2010 - looks like HCV is gone for good! And I'm finally drinking again, thank GOD
2013 - considering a switch to Stribild. but I love my Kidneys (but I hate farting all the time!)...
June 2013 - switched to Stribild.  so far so good...

Offline newt

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  • the one and original newt
Re: Improved survival in HIV-infected persons: consequences and perspectives
« Reply #8 on: October 23, 2007, 03:10:41 PM »
In the UK, most cases of acute HCV in HIV-positive people have been found in gay men. The majority of these cases resulted from sexual exposure rather than IV drug use, even though large studies of straight people show that HCV is not transmitted by sex with ease.

How and why the risk of sexual transmission seems higher for HIV-positive gay men is not exactly clear, but fisting/"rough" sex (whatever that is)/groups are associated factors. Plus stimulant drug use (non IV).

"Ordinary" anal sex and HIV-positive gay men, a moot point, we dunno the complete picture.

Analysis by London and Brighton hospitals reported the following risks for sexual transmission of HCV in gay men:

- Being HIV-positive
- Unprotected anal intercourse
- Sharing sex toys
- Rougher sex (longer fucking or fisting)
- Group sex or sex parties
- Number of partners
- Recreational drug use
- Other sexually transmitted infections (especially syphilis)
- Meeting partners online

HIV is a key factor in these cases of sexual transmission. This is likely to be related to the higher hepatitis C viral load in blood and possibly semen, in people with coinfection.

(I am cribbing liberally & literally in the list above from New hepatitis C infections in HIV-positive gay men from the HIV i-Base guide to hep c coinfection).

- matt
"The object is to be a well patient, not a good patient"

Offline northernguy

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  • Posts: 1,347
Re: Improved survival in HIV-infected persons: consequences and perspectives
« Reply #9 on: October 27, 2007, 02:23:04 AM »
Doesn't rimming put you at risk for Hep C?  Maybe that's why teh rate is higher in gay men.

Its an encouraging article, but as someone living with HPV, it brings home the risk of increased cancers.
Apr 28/06 cd4 600 vl 10,600 cd% 25
Nov 8/09 cd4 510 vl 49,5000 cd% 16
Jan 16/10 cd4 660 vl 54,309 cd% 16
Feb 17/10 Started Atripla
Mar 7/10 cd4 710 vl 1,076 cd% 21
Apr 18/10 cd4 920 vl 268 cd% 28
Jun 19/10 cd4 450 vl 60 cd% 25
Aug 15/10 cd4 680 vl 205 cd% 27
Apr 3/11 cd4 780 vl <40 cd% 30
Jul 17/11 cd4 960 vl <40 cd%33
April 15/12 cd4 1,010 vl <40 cd% 39
April 20/12 Switched to Viramune + Truvada
Aug 2/12 cd4 1040, vl <40, cd% 38
Oct 19 cd4 1,110 vl <40 cd% 41

Offline keyite

  • Member
  • Posts: 514
Re: Improved survival in HIV-infected persons: consequences and perspectives
« Reply #10 on: October 30, 2007, 02:19:12 PM »
Doesn't rimming put you at risk for Hep C?  Maybe that's why teh rate is higher in gay men.

No, you're probably thinking of Hep A or B, both of which can be transmitted via rimming (a good reason to get vaccinated against both A & B).

Hep C requires direct blood contact making rimming a very unlikely transmission scenario.

 


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