25th Anniversary of AIDS
In June, the world commemorated the 25th anniversary of the first published medical reports heralding the beginning of the HIV/AIDS epidemic. The June 5, 1981 issue of Morbidity and Mortality Weekly Report,
published by the Centers for Disease Control and Prevention (CDC), featured an article about five cases of a rare type of pneumonia in gay men in Los Angeles. This was soon followed by reports out of New York City and California about clusters of gay men with Kaposi's sarcoma, an unusual form of skin cancer. According to the CDC, more than one million people are now living with HIV/AIDS in the United States, with some 40,000 new infections annually, increasingly concentrated among African Americans.
The quarter-century commemoration was marked by a flood of ink in the national and international press, a new Joint United Nations Programme on HIV/AIDS (UNAIDS) report on the state of the epidemic, and a United Nations (UN) special session to discuss prevention and treatment efforts. According to the UNAIDS 2006 Report on the Global AIDS Epidemic, an estimated 38.6 million people worldwide were living with HIV/AIDS and nearly three million died from the disease last year. Although the global rate of new infections appears to have leveled off somewhat -- and UNAIDS director Peter Piot, MD, described 2005 as "the least bad year in the history of the AIDS epidemic" -- the number remains staggering.
As the UN special session got underway at the end of May, hundreds of activists protested outside the meeting in New York City. HIV community advocates criticized the failure of wealthy nations to provide adequate funds for HIV/AIDS care in resource-poor countries -- estimated at more than $20 billion by 2010 -- as well as attempts by religious conservatives to limit science-based prevention efforts (such as provision of condoms and clean needles) and thwart initiatives to empower women and girls to have greater control over their own health.
Clearly, there have been dramatic advances in response to the disease over the past two and a half decades, notably the development of increasingly effective combination antiretroviral therapy and a reduction in the rate of mother-to-child HIV transmission
to less than 2% in wealthy countries. A study by Rochelle Walensky, MD, of Harvard Medical School and colleagues, published in the July 1, 2006 Journal of Infectious Diseases,
calculated that these and other improvements in care have saved approximately three million years of life in the U.S.
However, many challenges remain, including the need for new therapies for heavily treatment-experienced patients, an effective HIV vaccine, improved prevention and education efforts, increased voluntary testing and treatment of individuals who currently do not know they are infected, and expanded availability of antiretroviral therapy on a global scale. Indeed, Walensky and colleagues estimated that 740,000 additional years of life might have been saved in the U.S. if all patients had received appropriate therapy starting at the time of HIV/AIDS diagnosis; extending this level of care throughout the world "has the potential to save hundreds of millions of years of life."
Updated HIV Treatment Guidelines
On May 4, the U.S. Department of Health and Human Services (DHHS) once again updated its "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." The new guidelines incorporate the latest data about antiretroviral agents -- including the new formulation of lopinavir/ritonavir (Kaletra) -- and treatment strategies. Among the major changes, the revised guidelines include new information about short- and long-term treatment interruptions (see "Structured Treatment Interruptions: After SMART
"), drug interactions, and coinfection with hepatitis B. No changes were made at this time to recommendations about which preferred or alternative antiretroviral agents to include in a first-line regimen.
The guidelines also recommend that all individuals newly diagnosed with HIV infection should receive genotypic drug-resistance testing before starting antiretroviral therapy to help select appropriate medications; the previous version recommended resistance testing only for treatment-experienced patients. In July, the "Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States" were also updated with recommendations concerning drug-resistance testing in pregnant women. A German study published in the April 15, 2006 Journal of Acquired Immune Deficiency Syndromes found that some 16% of individuals newly diagnosed with HIV in 2002-2003 already harbored drug resistant virus, and that such patients could benefit from resistance testing.
For the latest updated guidelines for HIV treatment in adults, adolescents, children, and pregnant women; post-exposure prophylaxis (PEP) for occupational and non occupational exposure; and opportunistic illness prevention, see www.aidsinfo.nih.gov.
Atripla Approved: First One-Pill, Once-Daily HAART Regimen
On July 12, the Food and Drug Administration (FDA) announced the approval of Atripla, a fixed-dose co formulated tablet containing Gilead Science's tenofovir disoproxil fumarate (Viread; 300 mg) and emtricitabine (Emtriva; 200 mg) -- already available together in the Truvada combination pill -- plus Bristol-Myers Squibb's efavirenz (Sustiva; 600 mg). Atripla is the first-ever one-pill, once-daily complete HAART regimen. It is also the first cooperative venture by two pharmaceutical companies in the HIV field to combine their patented drugs into a single product, and the first multi-class antiretroviral coformulation available in the U.S.
Atripla was approved in less than three months under the FDA's "fast track" expedited review process. Data presented at the 7th Workshop on Clinical Pharmacology of HIV Therapy in April showed that the coformulation is bioequivalent to the three separate drugs used together; that is, it is processed the same in the body and works equally well.
Atripla was approved for treatment-naive and treatment- experienced adults; it may be taken as a stand-alone regimen or in combination with other antiretrovirals. The coformulation will cost $1150 per month -- the same as Truvada and efavirenz purchased separately -- but patients may save money because insurance companies are likely to consider it a single drug requiring one co-payment.
Cautions regarding Atripla are the same as for its component agents: lactic acidosis associated with nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs), kidney impairment due to tenofovir (see conference coverage), and central nervous system side effects related to efavirenz (see news item); pregnant women should not use Atripla because efavirenz may cause birth defects. Discontinuation of Atripla may cause liver inflammation "flares" in people coinfected with hepatitis B. Complete prescribing information is available at www.atripla.com.
In related news, Gilead announced in March that both tenofovir and Truvada had been granted full traditional FDA approval, following earlier conditional accelerated approval in October 2001 and August 2004, respectively. Results from Gilead's Study 934, which showed that Truvada was more effective and better tolerated than Combivir (AZT/3TC) when used with efavirenz, were reported in the January 19, 2006 New England Journal of Medicine.
Darunavir Approved for Treatment-Experienced Patients
On June 23, the FDA announced the accelerated approval of Tibotec's new non peptide protease inhibitor (PI), darunavir, formerly known as TMC114; the drug will be marketed under the brand name Prezista. Darunavir was approved for treatment-experienced adults who do not respond to other potent antiretroviral regimens. To achieve adequate concentrations, darunavir must be co-administered with a boosting dose of ritonavir (Norvir).
The approval was based on evidence from two randomized controlled trials, POWER 1 and 2, showing that boosted darunavir produced superior virological suppression and greater CD4 cell recovery compared with other boosted PIs in treatment-experienced patients with PI resistant HIV. At this year's Conference on Retroviruses and Opportunistic Infections in February, researchers reported that 70% of patients taking darunavir experienced at least a 1-log reduction in HIV RNA and 45% achieved undetectable viral load (below 50 copies/mL) after 24 weeks, compared with 16%-32% and 7%-24%, respectively, in the comparator PI arms (abstract 157). Darunavir appears to work best when used in conjunction with T-20 (enfuvirtide, Fuzeon).
The most common side effects of darunavir were nausea, diarrhea, and headaches, and about 7% of study subjects developed skin rashes of varying severity; it is too soon to know whether darunavir will cause long-term metabolic manifestations (e.g., lipodystrophy) as seen with other PIs. As a condition of the accelerated approval, Tibotec (owned by Johnson & Johnson) must conduct post-marketing trials to assess how well the drug works in children and people with pre-existing liver impairment, as well as drug interaction studies. Complete prescribing information for darunavir is available at www.prezista.com.
"Black Box" Warning About Brain Hemorrhage With Ritonavir-boosted Tipranavir
On June 30, the FDA and manufacturer Boehringer Ingelheim announced that patients taking the PI tipranavir (Aptivus) boosted with ritonavir appear to be at greater risk of developing intracranial hemorrhage (bleeding within the skull). The recent warning follows an analysis of data showing that 13 out of 6840 patients taking ritonavir-boosted tipranavir in clinical trials developed intracranial hemorrhage; one patient experienced two hemorrhages and eight died. Tipranavir was approved in June 2005 for treatment-experienced individuals with multi-drug resistant HIV. In preclinical studies, the drug inhibited human platelet aggregation (clotting) in vitro
and caused impaired coagulation and fatal bleeding in mice, but this was not observed in dogs; in clinical trials, the rate of intracranial hemorrhage among subjects taking tipranavir was 0.2 per 100 person-years (PY) of exposure.
A June 30 "Dear Healthcare Professional" letter from Boehringer Ingelheim urged providers to exercise caution when prescribing tipranavir/ritonavir to patients who may be at risk for bleeding due to head trauma or surgery, who have medical conditions such as hypertension (high blood pressure) or coagulopathy (blood clotting problems), or who are taking drugs such as antiplatelet agents or anticoagulants ("blood thinners") that may increase the risk of bleeding. The revised tipranavir label information advises patients to report any unusual or unexplained bleeding to their physician. Complete, revised tipranavir prescribing information is available at www.aptivus.com.
In related news, Boehringer Ingelheim announced earlier in June that it was discontinuing a study of ritonavir boosted tipranavir in treatment-naive individuals (Study 1182.33) because patients receiving tipranavir plus 200 mg ritonavir (the dose currently approved for treatment-experienced individuals) were more likely to develop elevated liver enzymes compared with patients taking lopinavir/ ritonavir (Kaletra), and those taking tipranavir plus 100 mg ritonavir were less likely to achieve undetectable HIV viral load after 60 weeks.
Triple-NRTI Regimen Associated With Virological Breakthrough
Several studies in recent years have shown that while triple-NRTI regimens are less potent than those containing PIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs), they may be appropriate for some patients, especially those with low HIV viral loads and those starting treatment for the first time. However, a study reported in the July 1, 2006 Journal of Infectious Diseases
found that triple-NRTI combinations containing abacavir (Ziagen) were more likely to lead to eventual loss of virological control than efavirenz-based regimens. Alessandro Cozzi-Lepri and colleagues conducted an observational analysis of data from 744 patients who achieved HIV viral loads of 80 copies/mL or less while taking first-line antiretroviral regimens containing either abacavir or efavirenz plus two other NRTIs (most often AZT/3TC, d4T/3TC, or d4T/ddI). Among individuals taking triple-NRTI regimens, the rates of virological breakthrough and treatment failure were significantly higher than those seen in patients taking efavirenz. The authors concluded that patients who achieved virological suppression while taking triple-NRTI abacavir regimens were more likely to experience eventual virological breakthrough, and should perhaps consider switching to a more potent regimen before treatment failure occurs.
Even "Failing" HAART Reduces Illness
HAART may reduce the risk of disease progression and the incidence of AIDS-related illnesses even if it fails to suppress HIV, according to a study published in the March 15, 2006 issue of Clinical Infectious Diseases.
Tejal Gandhi, MD, and colleagues from the University of Michigan conducted an analysis of the medical records of 302 patients who had CD4 cell nadirs (lowest-ever levels) below 200 cells/mm3
, one of the criteria for an AIDS diagnosis. The researchers found that even patients with HIV viral loads above 100,000 copies/mL and CD4 cell counts below 50 cells/mm3
still had lower rates of opportunistic illnesses (OIs) -- including Mycobacterium avium
pneumonia, and esophageal candidiasis -- compared with individuals who had similar CD4 counts in the pre-HAART era (39 per 100 PY vs. 76 per 100 PY). Among patients with CD4 counts below 100 cells/mm3
, again there were fewer AIDS-related events after the advent of HAART (18 per 100 PY vs. 65 per 100 PY); among subjects with CD4 counts of 200 cells/mm3
or less, the corresponding figures were 8 per 100 PY vs. 35 per 100 PY. "Even in patients with advanced immuno-suppression and inadequate CD4 cell count and viral load responses to HIV therapy," the authors concluded, "continuing HAART may reduce the incidence of new AIDS related events." They suggested that patients on "failing" antiretroviral therapy may harbor less virulent drug-resistant strains of HIV, or that HAART-treated individuals may have higher numbers of memory CD4 cells that attack specific pathogens, even if the overall CD4 count remains low.
Racial Impact on Lipodystrophy
The risk of developing elevated blood fat levels after starting HAART is influenced by race/ethnicity, according to a study in the March 2006 issue of the open-access journal PLoS Medicine.
Andrea Foulkes, ScD, from the University of Massachusetts at Amherst and colleagues conducted a cross-sectional analysis of data from 626 HIV positive individuals taking part in various AIDS Clinical Trials Group (ACTG) studies of antiretroviral therapy. After controlling for other factors, race/ethnicity had a significant impact on the likelihood of blood lipid elevation. On the whole, compared with whites and Latinos, African Americans receiving HAART had lower levels of triglycerides and LDL ("bad") cholesterol, but higher levels of HDL ("good") cholesterol. As expected, PIs as a class -- and in particular, those boosted with ritonavir -- were associated with elevated blood fats. But this also differed based on race/ethnicity: African Americans experienced the greatest triglyceride increases after starting PI-based regimens and -- unlike whites and Latinos -- even after starting unboosted PIs.
The authors further reported that lipid elevations were associated with variant forms of the gene for apolipoprotein C-III (apoC-III), a protein that plays a role in the transport and processing of fats. In Latino patients -- but not whites or African Americans -- certain apoC-III variations were associated with smaller triglyceride increases after starting HAART. The authors emphasized that long-term prospective studies are needed to confirm these observations, tease out the genetic or environmental factors involved, and determine their implications for therapy.
Depression Not Linked to Efavirenz
Efavirenz can cause a variety of central nervous system side effects, including unusual dreams and impaired concentration; some past studies have shown an association with anxiety and depression, and many providers therefore recommend that patients with a history of psychiatric conditions should not receive the drug. A recent study, however, did not find an increased rate of depressive illness among patients taking efavirenz. As reported in the June 15, 2006 issue of Clinical Infectious Diseases,
Valerie Journot, PhD, and colleagues analyzed data from the French ALIZEANRS 099 study, in which 355 HIV positive patients with undetectable HIV viral load were randomly assigned to either continue their current PI-based regimen or switch to a simplified once-daily regimen of efavirenz/ddI/emtricitabine. After 48 weeks, rates of depressive disorders (e.g., depression, suicidal thoughts, suicide attempts) were similar in the efavirenz and PI arms (8% vs. 7%), and no patients discontinued therapy due to depression. Over three years of follow-up, similar numbers in both arms were prescribed antidepressants (7% vs. 4%). The only factors associated with a higher risk of depressive disorders were younger age and a prior history of depression. "Contrary to the idea widely held among HIV-infected patients, physicians, and researchers," the authors concluded, "our data showed no evidence of efavirenz having an effect on the risk of depression or suicide in the first 48 weeks of use -- or even up to 36 months of use." While this study suggests that most patients can safely use efavirenz, caution is still warranted for patients with prior depression, since they are more likely to experience depressive symptoms again.
Smoking Worsens HIV Progression in Women
Tobacco smoking is associated with poorer response to antiretroviral therapy and worse disease progression in women with HIV, according to a report published in the June 2006 American Journal of Public Health.
Joseph Feldman, MD, and colleagues analyzed data from 924 participants starting HAART in the Women's Interagency HIV Study; subjects were followed for periods of up to nearly eight years. After controlling for potentially confounding factors such as age, race, illegal drug use, hepatitis C coinfection, and past AIDS diagnosis, the researchers found that women who smoked cigarettes had poorer virological and immunological response to HAART, lower CD4 cell counts, higher HIV viral loads, a 36% greater likelihood of developing AIDS-defining illnesses, and a 53% higher risk of death compared with nonsmokers; however, the rate of specifically AIDS-related death was similar. The authors concluded that "[s]ome of the benefits provided by HAART are negated in cigarette smokers," and emphasized the need for smoking cessation efforts targeting HIV positive women.
Bone Loss at Menopause
Bone loss, which can lead to disabling fractures, is a concern for all women as they age; a recent study published in the April 1, 2006 issue of Clinical Infectious Diseases
suggests that the problem may be more common among women with HIV. Julia Arnsten, MD, and colleagues with the U.S. Menopause Study analyzed data from 263 HIV positive and 232 HIV negative middle-aged women; the average ages was 44, and most were not yet menopausal. About three-quarters were taking HAART, most were current or former tobacco smokers, 75% had a history of opiate use, and a majority was overweight. The researchers found that, overall, the HIV positive women had lower bone mineral density (BMD) in their hips and lumbar spines than HIV negative women. Among the women with HIV, 27% had low BMD, compared with 19% of HIV negative women; most affected women had osteopenia, or mild bone loss, but a few had osteoporosis, or more severe bone atrophy. After stratifying participants by race (about half were black and half white), the association between HIV and lower BMD was observed among white women but not black women; in the general population, white women are about four times more likely than black women to develop osteoporosis. Past studies have reported decreased BMD in HIV positive individuals, but these included mostly men. Some previous research has also suggested that bone loss may be a side effect of HAART, but this study did not show a link between decreased BMD and use of antiretroviral therapy in general or any specific drugs. The authors recommended that HIV positive women should be screened for osteopenia as they approach menopause, and should consider speaking with their health-care providers about taking calcium and vitamin D supplements.
Liz Highleyman is a freelance medical writer and editor based in San Francisco. firstname.lastname@example.org