The 14th Conference on Retroviruses and Opportunistic Infections (CROI): Los Angeles, February 25th-28th.
New treatments are being developed to control HIV disease, especially for those who are highly treatment-experienced. Researchers are discovering that some existing drugs used to treat certain diseases and conditions in HIV-negative people are proving useful for those living with HIV. They are also finding solutions for some of the side effects of HIV infection and the drugs used to treat it. Although some of the potential new treatments seem to be less effective than originally thought, research continues. Twenty-five years alter the epidemic began, scientists are learning more and more about improving the lives of people living with HIV and AIDS.
WHAT'S NEW DOC?
There are about 40,000 HIV + people in the US who have developed resistance to available HIV meds. These individuals are running out of treatment options and must rely on a complex and ever-changing combination of approved drugs to keep their HIV under control. Fortunately, the conference brings some very good news. Several drugs in development belong to entirely new classes of HIV drugs: integrase inhibitors and chemokine antagonists. These drugs attack HIV in completely different ways than the traditional ones that have been around for the last 20 years. If these new drugs prove to be effective, they would be the first new classes of HIV reeds to be approved by the US Food and Drug Administration (FDA) since 2003 and would also be the first new classes of oral HIV meds in 10 years. The last HIV med from a new class to be approved was Fuzeon (or T-20), that works by blocking HIV from entering human cells, and needs to be injected twice a day. Given the problems related to treating people who are drug resistant, these new study findings present a new opportunity for hope.
David Cooper, from the University of New South Wales in Australia, presented early results from a study of the integrase inhibitor raltegravir (Abstracts #105aLB and # 105bLB), formerly known as MK-0518, combined with 3 or more existing HIV drugs (optimized background therapy). This drug works by blocking an HIV enzyme called integrase, which is one of the enzymes H IV needs to reproduce in the body. Integrase inhibitors would stop HIV from inserting its genetic material into uninfected cells. All 699 patients who began the study had viral loads between 30,000 to 50,000 copies and T-cell counts between 146 to 163. Alter 16 to 24 weeks of treatment, 77% of the patients taking raltegravir had a viral load below 400 copies (considered undetectable) compared to only 42% of those taking the placebo; 61% of the patients on the new drug had a viral load less than 50 copies. All of these patients had a dramatic decrease in viral load and a much higher increase in T cells compared to the placebo patients and the drug was well-tolerated.
Initial results for another integrase inhibitor known as elvitegravir (previously known as GS-9137) show great promise, although it is still in an early stage of development (Abstract #143LB). According to Anthony Zolopa, from Stantord University, the study involved 278 HIV + people who were highly treatment-experienced and have few treatment choices left. Patients received either 20 mg, 50 mg, or 125 mg of elvitegravir with 100 mg of Norvir or Norvir boosted by a protease inhibitor (either Aptivus [tiptranavir] or Prezista). After 24 weeks of treatment, researchers found that the 125 mg once-daily dose of elvitegravir, taken with Norvir, was the most effective. The drug appears to be very potent and well-tolerated, but it must be taken with at least one other HIV drug. Testing continues on this drug and it probably will not be available before 2009.
A study that tested the chemokine antagonist maraviroc also showed good results (Abstracts #104aLB and #104bLB). This eagerly awaited drug from Pfizer works by blocking HIV from entering cells rather than interfering with it once it is inside cells, which is how the currently available drugs work. Over 1,000 patients took either the new drug with optimized background therapy or a placebo. Almost half of the patients with T-cell counts around 150 and viral loads of 65,000 copies had less than 50 copies after taking the new drug for 24 weeks compared to about one quarter of the patients getting the placebo. For more information on this drug, see the New Drug Profile on p. 9 in this issue.
Anton Pozniak, from London, reported on a Phase 2 study of TMC 278 (Abstract #144LB), the new "non-nuke" still under investigation. TMC 278 seems to have the strength of the HIV med Sustiva (efavirenz), but without some of the central nervous system or psychiatric side effects associated with Sustiva (e.g., dizziness, trouble sleeping, confusion, strange dreams, amnesia, hallucinations). The 368 patients in this study received either 25 mg, 75 mg, or 150 mg of TMC 278 or placebo, combined with either Combivir (Retrovir + Epivir) or Truvada (Viread + Emtriva). Patients taking TMC 278 were less likely to report the above side effects related to Sustiva. Further, the number of patients with a rash was also lower among the TMC 278 patients. Overall, serious side effects occurred in about 10% of both Sustiva and TMC 278 patients.
AWAY ON VACATION
As we reported last year, the international SMART (Strategies for the Management of Anti-Retroviral Therapy) Study was stopped because researchers determined that delayed or interrupted treatment (drug conservation) caused more than twice the risk of AIDS or death than immediate, continuous treatment (viral suppression). At that time, researchers also found that interrupting treatment led to more serious illnesses, including liver, kidney, and heart disease. The original goal of the study was to enroll 6,000 patients and study them for 8 years. Patients were randomized (placed by chance) to either take continuous therapy or to interrupt their therapy when their T-cell count went higher than 350 copies, and then restart HIV therapy only when their T cells dropped below 250 copies.
More research has been done to compare the risk of heart disease between the continuous treatment group and the interrupted treatment group (Abstract #41). There were 48 cases of heart attacks, heart disease, and stroke in the interruption group and 31 cases among the continuous group. This means that in this study, treatment interruption of HIV drugs wits associated with a 50% higher risk for heart disease.
In a different study (Abstract #979) that expanded on the results of the SMART Study, William Burman, from the Denver Department of Public Health, and other researchers found that HIV + individuals who take breaks or vacations from their HIV therapy might be more likely to pass the virus on to their sexual or drug partners. Risk behavior was defined as vaginal or anal sex without a con(lore or needle-sharing. HIV transmission risk was defined its unprotected sex or sharing needles while having an HIV viral load greater then 1,500 copies. In a survey of the 833 patients from the SMART Study, the researchers determined that the risk of transmitting HIV to their partners was similar among patients in both the interrupted and continuous treatment groups. However, viral load levels were higher overall among patients in the interrupted group. This means that if a person on a treatment break has unprotected sex or shares drug-injecting equipment when their viral load is high, the risk of infecting their partners is higher.
SURVIVAL AT ANY COST?
It is well known that HIV + individuals with lower T-cell counts are at increased risk for developing AIDS-related opportunistic infections (OIs). New data presented by Jason Baker and his team of researchers from the University of Minnesota (Abstract #37) indicate that lower T-cell counts create other risks--they raise the risk of serious health conditions not usually associated with HIV or AIDS. The FIRST (Flexible Initial Retrovirus Suppressive Therapies) Study looked at the relationship between fatal and non-fatal OIs in contrast to infections not generally considered opportunistic (not related to HIV/AIDS), taking into account patients' latest T-cell count before any of these events occured.
In this study, almost 1,400 HIV + patients who had never received HIV meds before were assigned to receive 1 of 3 types of standard HIV therapy ("non-nuke" + "nukes", PI + "nukes", or a combination of 3 drugs from 3 different classes). The average baseline (or starting) T-cell count was 163, with an average increase of 238 T cells during follow-up. After 5 years of follow-up, there were 266 new AIDS-defining events and 166 non-AIDS-defining events relating to heart, liver, and kidney disease, in addition to non-AIDS-defining cancers, such as skin, anal, and lung cancers. As expected, OIs occurred more often in subjects with detectable HIV viral loads and lower T-cell counts.
The data suggest that treatment strategies that reduce the amount of time spent with lower T-cell counts will prevent OI events its well as non-AIDS defining illnesses. These FIRST data support the findings of the SMART study (see above), which found that both OIs and non-opportunistic liver, kidney, and heart disease were more common in the group that interrupted therapy and spent more time at lower T-counts compared to those patients receiving continuous therapy.
Although it is well established that people who have low T-cell counts while taking HIV drugs remain at risk of AIDS-defining OIs, the risk of non-AIDS defining illnesses in such people has been unclear. The study raises some interesting questions. Are non-AIDS defining illnesses being caused by the toll that HIV takes on the immune system? Or, are people simply living longer (because of HIV drugs) and suffering from common problems related to older age? Although scientists have thought it was the latter, this thinking might be wrong. Because there was a noticeable drop in risk as T-cell counts rose, researchers now believe that it is not just longer life spans that lead to serious illness. If researchers find out that this is the case, it might be better to start HIV reeds earlier when a person's T-cell count is 350, rather than waiting until it drops further.
Investigators from Europe and North America continue to discuss and investigate the double-edged effect of HIV drugs on kidney toxicity and kidney disease among people with HIV. While HIV drugs can help the kidney function better by reducing the damage that HIV itself does to it, these drugs continue to have their own toxic effects.
Viread (tenofovir) has been associated with kidney failure in certain cases, although the risks have proven to be nearly always mild, rare, and reversible. One presentation (Abstract #832) showed that Viread treatment may be associated with modest declines in the kidney's ability to function properly, especially in treatment-experienced HIV+ patients. Also, exposure to low-dose Norvir may increase the risk of kidney damage in Viread-treated individuals. In a study with over 5,500 patients, researchers at Johns Hopkins University in Baltimore concluded that Viread was associated with a 4% greater decline in the ability of the kidney to work properly compared with alternative "nukes" in treatment-experienced patients.
The Swiss HIV Cohort Study team (Abstract #834) also looked at the effect of Viread on kidney function. They studied 700 people who either had never taken HIV reeds or who had interrupted treatment for at least 12 months and had started combination therapy with or without Viread. The results showed that starting HIV combination therapy was associated with a significant decline in kidney function in all populations studied.
However, the decrease was much more frequent in patients treated with Viread.
HELL NO, THE VIRUS WON'T GO!
New data from the Centers for Disease Control and Prevention (CDC) suggest that 1 in 10 individuals diagnosed with HIV in recent years was infected with HIV strains that are resistant to at least one of the available HIV meds. The US Variant, Atypical, and Resistant HIV Surveillance (VARHS) system, in which blood samples from newly diagnosed individuals are tested for drug-resistant mutations, was created by the CDC to give the clearest picture of the scope and types of resistance in the US. This project involved more than 3,100 HIV+ patients in 11 states (Abstract #648). The system uses standard genotypic resistance testing, which identifies specific HIV mutations associated with drug resistance. Because the patients in this study had not started HIV treatment yet, having HIV drug-resistant mutations in their blood would mean that the resistant virus was transmitted to them at the time of their infection.
Results show that the level of resistance varied depending on the class of drug: resistance to "non-nukes" was the highest (6.9%), then "nukes," at 3.6%, and last were protease inhibitors (2.4%). Only a small minority (1.9%) of individuals newly diagnosed with HIV had evidence of multiple drug resistance. Previous studies have suggested an increase in drug resistance over the last 10 to 15 years, from 5% in the mid-90s to 10% in recent years.
More studies need to be done so that investigators can determine if there are certain characteristics, such as health status before infection with HIV, gender or ethnic differences, sexual practices, or illegal drug use, that make a person more likely to become infected with drug-resistant HIV. This is a growing concern because the number of people with HIV infection who are taking HIV meds for long periods of time has increased. The possibility of infection with a strain of the virus that is harder to treat emphasizes the importance of HIV prevention efforts and the need to identify more effective treatment strategies.
Taking Kaletra (lopinavir/retrovir) once a day may be less effective than taking it twice a day in patients with high viral loads. The AIDS Clinical Trials Group (ACTG) study 5073 (Abstract #138) consisted of over 400 HIV+ people who had a viral load below 200 copies. All patients took Emtriva with either Viread or Zerit (stavudine) in addition to Kaletra.
The patients were placed in 1 of 3 treatment groups. In the first group, patients took standard doses (400 mg lopinavir/100 mg ritonavir) of twice-daily Kaletra. In the second group, patients took standard doses (800 mg lopinavir/200 mg ritonavir) of once-daily Kaletra. In the third group, patients also received once-daily Kaletra, but as a part of "directly observed therapy" for 24 weeks, meaning that they took their daily doses under the direct supervision of health-care workers for the first 6 months of the study (but without supervision for the last 6 months of the trial). Patients in the first two study groups took their medications without supervision.
Overall, both treatment groups were able to achieve viral loads below 200 copies. However, over time, patients taking Kaletra once a day had higher viral loads than the twice-a-day group. For people beginning HIV therapy for the first time, Kaletra-based treatment regimens are a popular option, dosed either once or twice a day. Once-daily dosing requires taking 4 tablets every 24 hours; twice-daily dosing involves taking 2 tablets every 12 hours. A concern with all HIV treatment regimens is that people with high viral loads, usually defined as pre-treatment levels greater than 100,000 copies, may face greater challenges keeping their viral loads undetectable con]pared to those with lower pre-treatment levels. Therefore, as this study showed, the long-term risk of virologic failure is slightly higher for those with high viral loads taking the once-daily Kaletra-based regimen.
THE GOOD, THE BAD, AND THE UGLY
Fosomax for Bone Loss
Bone problems, such as osteopenia, osteoporosis, and osteonecrosis are usually seen in people over the age of 50. Lower levels of estrogen in women and testosterone levels in men may speed up bone loss, which leads to these conditions. As bone loss increases, a person may develop symptoms related to weakened bones, including back pain, loss of height, stooped posture, a curved backbone (dowager's hump), or fractures that may occur with a minor injury, especially of the hip, spine, or wrist.
A study presented at the conference (Abstract #42) examined how well Fosamax, which is approved for the treatment of osteoporosis in HIV-negative individuals, worked in HIV + patients who were doing well on their HIV treatment but who were experiencing bone loss. The AIDS Clinical Trials Group (ACTG) study 5163 was designed to investigate the safety and effectiveness of taking calcium and vitamin D supplements twice daily with or without once-weekly Fosamax for the treatment of bone loss in HIV + people. The 82 patients received either 70 mg of Fosamax plus calcium and vitamin D or calcium and vitamin D plus a placebo. Alter a year of treatment, the patients on Fosamax plus supplements had an improvement in bone strength.
Several studies presented information on drugs that could help reduce lipodystrophy in HIV + individuals. One of these (Abstract #45LB), an experimental drug known as TH9507, stimulates the release of growth hormone, which helps the body develop and grow properly. The drug has the potential to help reduce visceral fat, a buildup of fat around the gut, deep within the body. This condition, which often occurs after beginning certain HIV treatments, is also known as metabolic syndrome and is a common occurrence for HIV + people. But there is a Catch 22. Treatments that reduce visceral fat can also reduce subcutaneous fat (the fatty tissue between skin and muscle). This is bad--it can lead to muscle loss, which is responsible for facial wasting (sunken cheeks) and thinning of the arms and legs.
Stephen Grinspoon, of Harvard Medical School, presented final results for 412 US and Canadian HIV + patients with lipodystrophy-associated visceral fat increases. They received either 2 mg daily subcutaneous (under the skin) injections of TH9507 or placebo injections for 26 weeks. The good news is that patients who received the TH9507 had a 20% reduction in visceral fat compared to patients on placebo but without any significant changes in limb fat. The results also showed that cholesterol and triglyceride levels among those receiving TH9507 improved during the treatment period. No serious side effects were reported.
In the AIDS Clinical Trials Group (ACTG) study 5142 (Abstract #38), which compared 3 HIV drug regimens, researchers found that Kaletra plus 2 "nukes" is less likely to cause limb fat loss than Sustiva plus 2 nukes. Although the 753 patients in the study taking the Sustiva combination had better control of the virus than patients taking the Kaletra combination, they were more likely to have tat loss in the face and limbs. Further, a second study of Kaletra taken alone (Abstract #44LB) also found that when compared to patients treated with Sustiva and Combivir, those who received Kaletra monotherapy were much less likely to lose limb fat after 2 years of treatment. This is not surprising since researchers have known for a long time that AZT, which is part of the Combivir formula (AZT/3TC) can cause fat loss. (NOTE: Monotherapy is not recommended as standard therapy for HIV infection).
Preliminary results from another study (Abstract #39) indicate that Zetia may be a moderately effective cholesterol-lowering option for HIV + patients receiving HIV drugs. A 14-week study conducted by researchers at the University of North Carolina, Chapel Hill, and the University of California, San Francisco, enrolled 48 HIV + patients, all of whom were receiving HIV drugs and who had moderately high "bad" LDL cholesterol levels. In the first phase of the study, patients received 10 mg per clay of Zetia or placebo for 6 weeks. This was followed by a 2-week "washout period" in which no one received treatment. Then, those who originally took the Zetia switched to 6 weeks of placebo treatment, and those originally taking the placebo took 6 weeks of Zetia. After 6 weeks of Zetia treatment, LDL cholesterol decreased by an average of 12% compared to a 3% drop in the placebo group. The researchers concluded that Zetia, used alone, led to significant declines in LDL cholesterol and was well tolerated.
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|Publication:||HIV Treatment: ALERTS!|
|Date:||Jun 1, 2007|
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