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HIV Treatment Strategies - As therapies improve, how to choose what's right for you.

efore 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.

No one knows what kind of side effects might occur after taking antiretroviral therapy for 30 to 40 years or more... [But] The fear of long-term effects, though understandable, is not a reason to avoid treatment.

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.

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.

Too often, we forget that older people are sexually active. In fact, 70% of men and more than 50% of women over the age of 60 are still having sex.

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

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:

The older crowd

It’s beyond the scope of this article to examine every possible reason for prescribing alternative regimens to those recommended above. The expert panel addresses in painstaking detail the pros and cons of various drug combinations in a variety of settings. However, for the first time the guidelines acknowledge a reality of the HIV/AIDS epidemic in the United States and other developed countries: More than a third of people living with HIV/AIDS are older than 50. In another decade, that number will be more than half of all cases. Most trials focus on younger patients. Data for older patients, especially those in the 60- to 80-year-old age group, are limited. In pharmaceutical trials, drug developers control for a number of variables, like gender and race, but they don’t want people in their trials who take medications that may interfere with the drug they’re testing. Their goal is to get their particular drug to market. Diabetics, or people on blood thinners, or those with kidney and liver disease—in short, many elderly individuals—may be excluded from a study because their treatments or disease states may muddy the outcome of the study.

Second, the panelists rightly urge health care providers to take a good sexual history. Too often, we forget that older people are sexually active. In fact, 70% of men and more than 50% of women over the age of 60 are still having sex. Many of these seniors don’t view themselves at high risk for HIV infection. Post-menopausal vaginal dryness, the failure of heterosexual couples to use a condom because pregnancy is no longer an issue, and the availability of drugs for erectile dysfunction all increase the risk of sexually transmitted diseases.

And third, for those individuals over 50 who are taking antiretroviral agents, it’s essential to monitor bone, kidney, cardiovascular, metabolic, and liver health. This is true for younger patients too, but co-morbid conditions and “polypharmacy”—that is, taking medications for other diseases as well as HIV—are more common in the over-50 group.

The cost

What’s also new is that the panel has compiled a list of the Average Wholesale Price (AWP) of individual antiretroviral agents and co-formulations like Atripla, Complera, Truvada, and Epzicom. I’m not sure what purpose this serves except to satisfy our curiosity. Everyone knows that treating HIV is crazy expensive. The wholesale monthly cost of Atripla is $2,080.97; the wholesale monthly cost of Prezista, Norvir, and Truvada is $2,930.25. The difference between generic lamivudine and the brand Epivir is only $48 per month. Most people don’t pay for their medications anyway, although some have substantial co-pays, especially those on multiple drug regimens. I’m not aware that insurers have bothered to look at treatment guidelines to determine what co-pay should be charged to a patient. In my experience, the costs to patients are going up, not down. But as more antiretroviral agents go generic, perhaps those co-pays will go down.

Selecting the optimal treatment may be tricky, but no underlying disease state, except the diagnosis of a terminal illness, should prevent someone from being treated.

Finding the answer

Let’s return to the problem of what a newly diagnosed person should do. I agree with many on the expert panel that most people with HIV should be treated, no matter what their CD4 count is. I’ve seen too many people die to feel otherwise. I’m also concerned about transmission to an uninfected sexual partner. Although this imaginary individual has a normal CD4 count and not a terribly high viral load, he’s not an elite controller (that is, he doesn’t have an undetectable viral load without treatment) and he’s unlikely to be a long-term non-progressor (generally, someone with an average viral load less than 2,000 copies).

After doing a resistance profile (genotype) and determining that this individual did not have underlying resistance to one or more medications in our armament, I would most likely offer a single treatment regimen (Atripla) rather than a multi-drug regimen. That’s a personal preference because of concerns about compliance, not because I feel that the other regimens are inferior.

If this individual were a female of childbearing age, or was pregnant or trying to conceive, a regimen containing Sustiva (efavirenz) should be avoided, especially in the first trimester when toxic effects on the fetus are greatest. In general, a protease inhibitor-based regimen has been proven safer. AZT, no longer a preferred agent for most people, may even be considered as one of the components of therapy because of its proven efficacy in preventing mother-to-child transmission.

Atripla (and possibly Complera, though Complera is new and still considered an alternative to the preferred regimens) could be a good choice for an elderly patient on multiple medications. Drug-drug interactions are fewer than in those on boosted protease inhibitor regimens. However, if that individual suffered from underlying kidney disease, I would not recommend Atripla or Complera since they both contain tenofovir, which can exacerbate kidney disease. In that case, I might recommend Sustiva and Epzicom (abacavir and lamivudine). Abacavir, however, must be used with caution, especially in individuals with a known risk of cardiovascular disease, and a test must be performed to rule out potential hypersensitivity (severe allergy) to that drug. Ah, the complexities of treating HIV! Having so many choices—and taking so many things into consideration—can make one’s head spin.

Once a person begins an antiretroviral regimen, he or she needs to be monitored periodically. The treatment goal is viral suppression to levels of less than 75 or 20 copies/milliliter of blood, depending on the assay used for monitoring. It may take up to 16 weeks for viral levels to fall below detectability, but dramatic drops in viral load are generally seen within two to four weeks of starting therapy. According to the expert guidelines, a viral level should be measured no later than eight weeks after beginning treatment to prevent further resistance to medications if the response to treatment is suboptimal. Thereafter, it should be measured every three to four months. A person is considered to have failed antiretroviral therapy if his or her viral level is persistently greater than 200 copies. Occasionally, after being on therapy for years, a person might experience a “blip”—that is, a rare instance in which the virus is detectable, usually at very low levels (between 76 and 199 copies). It’s not necessary to change therapy or try to perform resistance testing when a blip occurs. The vast majority of the time, viral levels will be undetectable at the next monitoring visit.

In general, a poor CD4 response to therapy is not a reason to change regimens. Those individuals who begin treatment when their CD4 counts are very low (under 200 cells) sometimes do not have as robust a response to therapy as those with higher CD4 counts at the initiation of therapy. The viral load is the best measure of treatment success. The main concern about CD4 counts remaining under 200 is the risk of opportunistic infections, like pneumocystis pneumonia, so it’s necessary to continue prophylaxis (prevention) against these infections until counts rise to safer levels.

Conclusion

To conclude, although HIV is not curable, it’s treatable. And more than that, if started early, the treatment is usually well tolerated and has fewer side effects, especially the newer regimens developed in the past decade. Selecting the optimal treatment may be tricky, depending on the underlying health of the HIV-positive person. Elderly patients, pregnant women, people with a history of substance abuse, and those also infected with hepatitis B or C, or tuberculosis present great challenges to clinicians. But no underlying disease state, except the diagnosis of a terminal illness, should prevent someone from being treated. Treatment means a longer life and better quality of life, perhaps a normal life span. No treatment, when treatment is warranted, means certain death.

 

ROSS SLOTTEN, MD, MPH, is a family practitioner in private practice in Chicago. He has treated people with HIV for 29 years.

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