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HIV Treatment Strategies: As Therapies Improve, How to Choose What's Right for You

July/August 2012

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HIV Treatment Strategies: As Therapies Improve, How to Choose What's Right for You

Before the mid-1990s, HIV infection was a death sentence. And almost worse than the prognosis itself was the disease course: suffocation from pneumonia, blindness, dementia, hideous purple skin lesions engulfing limbs and internal organs, and incurable cancers, to name a few. No disease that I can think of is as merciless and mean-spirited as HIV/AIDS.


Treatment Strategy History

Strategies for the treatment of HIV/AIDS have evolved since the introduction of AZT (Retrovir) in the late 1980s. AZT alone was a failure. At most, it extended life by only a few months. Dual therapy with AZT and didanosine (ddI) or lamivudine (3TC), or stavudine (d4T) and ddI or 3TC was better, succeeding in a third of those treated; the other two-thirds died. Real progress came in 1996, with the development of potent triple-drug therapies. In that banner year, the mantra became "hit early and hit hard."

But hitting early and hitting hard had its drawbacks. Some of the side effects -- especially the so-called "Crixivan belly," buffalo hump, wasting of facial and limb fat, and "AZT butt" -- were so alarming that patients and their advocates asked why therapy could not be delayed until absolutely necessary. Those of us who treated people with HIV reluctantly agreed. As a result, until recently, most HIV-infected individuals weren't offered treatment until their CD4 counts approached 250. Now that we have simpler regimens with fewer disturbing side effects, there are once again whispers of "hit early, hit hard."


What to Do

You're newly diagnosed with HIV infection and told that your CD4 count is 510 and your viral load is 7,000. What should you do?

The prospect of treatment still terrifies many people with HIV, sometimes more than the infection itself. For some of us over 40, the disfigurement of body shape changes has been a disturbing experience, whether for ourselves or our friends, partners, or relatives who took early HIV therapies. It's true that those people would not be alive today without those therapies, but the emotional and physical cost has been high. Even changing to newer regimens doesn't reverse the disfigurement. Unfortunately, despite extensive research, the cause remains a mystery and there's no effective solution in sight. Today, we can assure people that if they never take AZT or d4T, they're unlikely to develop the so-called lipodystrophy syndrome. I haven't seen a new case in more than a decade.

Moreover, no one knows what kind of side effects might occur after taking antiretroviral therapy for 30 to 40 years or more. Yes, that's how long most people will be taking these medications, since the treatment of HIV is so successful that many, if not most people in the developed world can expect to live normal life spans, as long as they don't stop their therapy, ever. And a cure is unlikely soon; maybe none will ever be found. A vaccine, if one can be developed, will prevent disease, but it's unlikely to help those already infected. There are potential side effects of anti-HIV medications -- cardiovascular disease, osteoporosis, kidney and liver disease, even cancers. But let's put this disease in perspective: Untreated HIV infection is fatal in more than 95% of those infected. Only rabies is more lethal. No current HIV therapy will ever approach that kind of mortality rate. The fear of long-term effects, though understandable, is not a reason to avoid treatment.


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The Guidelines

Now that we agree that the majority of people with HIV infection should be treated at some point, the question is, when should we start therapy? Since the early part of the last decade, a panel of experts under the auspices of the Department of Health and Human Services has issued a series of guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. These guidelines are based on the latest scientific evidence and the expert opinions of the panelists themselves when that evidence is scanty.

The primary goal of treatment, of course, is to reduce the morbidity and mortality of HIV infection. Morbidity means the development of diseases that are both directly and indirectly related to the AIDS virus. Diseases such as pneumocystis pneumonia, cytomegaloviral retinitis, cryptococcal meningitis, and cryptosporidial diarrhea are direct consequences of advancing disease, when the immune system is so severely impaired that usually harmless organisms cause dreadful illness. Indirect consequences are related to T-cell activation, CD4 cell depletion, and inflammation, all of which increase the risks for heart attacks, cognitive impairment (dementia), and every type of cancer. The panel recommends antiretroviral therapy for all people, regardless of CD4 count, who are pregnant, have a history of an AIDS-defining illness, have HIV-related kidney disease, or are co-infected with hepatitis B. In all four conditions, randomized, controlled studies have proven beyond doubt that the benefits of therapy far outweigh the negatives. Randomized, controlled trials have also proven that treatment is beneficial for those individuals with CD4 counts of less than 350 but who do not have an AIDS-defining illness and appear perfectly healthy.

Non-randomized or observational trials also support the initiation of therapy in people with CD4 counts between 350 and 500. Such trials are considered less scientifically rigorous, since they sometimes lack a control arm and are not randomized, potentially introducing bias into the results. One study, HIV-CAUSAL, a collaborative study between U.S. and European sites, included some 8,300 antiretroviral- naïve (that is, untreated) patients with initial CD4 counts over 500 who then experienced drops below 500 cells. Those individuals whose treatment was delayed until their counts dropped below 350 had a higher risk of an AIDS-defining illness or death than those who started treatment when their counts were greater than 350 but less than 500. Another study from Europe, Australia, and Canada, called CASCADE, showed similar outcomes. As a result, the expert panel recommends therapy for patients with CD4 counts between 350 and 500.

The evidence is weaker for the initiation of therapy in people with CD4 counts greater than 500, in part because it may take a decade or more to know about the benefits (or harms) of early treatment. Because trials are ongoing, are not randomized or controlled, or are observational only, the panel's recommendation for treatment is moderate, rather than strong. Nevertheless, many of the experts would offer treatment to those in the earliest phases of HIV infection. This makes sense -- for no other treatable infectious disease do we opt to delay therapy. If you had syphilis, you wouldn't wait six months to get a shot of penicillin. You'd treat it at the time of diagnosis.

This past year, the panel added a secondary goal of antiretroviral therapy: public health considerations. Although studies long ago demonstrated that treating pregnant women prevented perinatal transmission of HIV, it was not until recently that studies showed a similar benefit in sero-discordant couples. In a multi-continental trial of 1,700 HIV-discordant heterosexual couples, half of the HIV-infected partners were randomized to receive antiretroviral treatment immediately, the other half delayed therapy until their CD4 counts dropped to 250. All were counseled about safe sex practices. In the delayed arm, there were 28 new infections; in the immediate treatment arm, only one infection. There was therefore a 96% reduction in rate of transmission from the HIV-positive partner to the uninfected one. The panel now recommends that the HIV-positive partner in a sero-discordant couple, straight or gay, be treated, regardless of CD4 count or viral load. One can make a case for advising the treatment of any HIV-positive person who has multiple sex partners, some of whom may be HIV-negative.


Which Will It Be?

Once we've decided when to treat, we need to know what treatment to initiate. As of 2012, there are 30 FDA approved antiretroviral agents in six different classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs) CCR5 antagonists, and integrase inhibitors (INSTIs). The decision of which combination of drugs to use is based on at least nine factors:

The presence of cardiovascular disease, chemical dependency, liver or kidney disease, psychiatric illness, or tuberculosis

  • Potential adverse effects
  • Potential interactions with other medications
  • The presence of resistance to one (or more) antiretroviral agent
  • Gender and pre-treatment CD4 count if considering Viramune (nevirapine)
  • The presence of HLA-B*5701 if considering Ziagen (abacavir) or the co-formulation Epzicom
  • Co-receptor tropism if considering Selzentry (maraviroc)
  • Patient adherence issues
  • Pill burden

Assuming that none of those nine factors is a concern, the panel recommends one of four regimens based on the results of randomized, controlled trials:

  • Atripla (efavirenz/tenofovir/emtricitabine)
  • Boosted Reyataz (atazanavir + ritonavir) and Truvada (tenofovir/emtricitabine)
  • Boosted Prezista (darunavir + ritonavir) and Truvada
  • Isentress (raltegravir) and Truvada

That's relatively easy. But what if one or more of those nine factors are concerns?

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This article was provided by Positively Aware. It is a part of the publication Positively Aware. Visit Positively Aware's website to find out more about the publication.
 
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