News Briefs: Conference Coverage
As the number of antiretroviral drugs has grown, it has become impossible to test all potential combination regimens against each other in clinical trials. In lieu of this, John Bartlett, MD, and colleagues (abstract 586) performed a meta-analysis (an analysis that includes data from multiple trials) of studies looking at three-drug regimens for first-line therapy. This analysis included data from 64 trials with a total of 10,559 subjects. On the whole, regimens containing either a ritonavir (Norvir)-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) performed better than regimens based on unboosted PIs or triple-NRTI regimens (undetectable viral load rates of 64%, 63%, 44%, and 51%, respectively). However, boosted PI regimens produced greater increases in CD4 cell count (209 cells/mm3) than NNRTIs (180 cells/mm3), unboosted PIs (178 cells/mm3), or triple-NRTI regimens (150 cells/mm3).
Triple-NRTI regimens have gotten bad press recently due to several studies showing that they may not be potent enough to durably suppress HIV. However, a combination of AZT/3TC/tenofovir DF (Viread) appears to work well in some individuals. An open-label French study of 36 treatment-naive subjects (abstract 599) found that 90% had viral loads below 50 copies/mL after six months on this regimen, as did 69% after 12 months. During the first year, four subjects (11%) experienced virological failure; two of these stayed on the AZT/3TC/tenofovir regimen and maintained low viral loads. Despite recent recommendations to avoid triple-NRTI regimens, the authors concluded that AZT/3TC/tenofovir "should be further evaluated."
The DART study in Africa (abstract 22) also looked at the same triple-NRTI regimen. In a cohort of 200 symptomatic Ugandan subjects with CD4 cell counts below 200 cells/mm3, 51% achieved viral loads below 50 copies/mL and 68% below 400/copies/mL in an intent-to-treat analysis after 24 weeks; the median CD4 cell increase was 88 cells/mm3. While better outcomes would likely be achieved using PIs or NNRTIs, the researchers concluded that triple-NRTI regimens "are highly relevant in resource-limited settings."
T-20 (enfuvirtide, Fuzeon), one of the few drugs that effectively suppress HIV in people with extensive resistance to the three major antiretroviral drug classes, is itself susceptible to resistance. Cecilia Cabrera and colleagues (abstract 718) studied 15 heavily treatment-experienced subjects. All initially experienced reductions in viral load after starting T-20, but HIV RNA increased soon after week 4 in 13 of the subjects. Mutations in the gp41 envelope protein developed by week 2-4 in all subjects. However, Steven Deeks, MD, and colleagues (abstract 680) reported that after 22 subjects with T-20-resistant HIV stopped taking the drug, they experienced modest viral load increases, leading the authors to conclude that T-20 continues to have "persistent low-level activity" even when resistance mutations are present. Finally, a 30-person study by George Beatty, MD, and colleagues (abstract 581) found that interrupting HAART prior to starting salvage therapy with T-20 did not lead to improved virological response at 24 weeks compared with immediate initiation of T-20, and that baseline susceptibility to T-20 did not predict treatment outcome. [Ed. note: Dr. Beatty is a member of BETA's Scientific Advisory Committee.] Together, these studies indicate that when T-20 failure occurs, it happens relatively early (4-8 weeks), but that individuals who do well on the drug can expect sustained response.
Along with all the study data about specific antiretroviral regimens, researchers presented some "big picture" results. An analysis of more than 6,800 subjects in the EuroSIDA cohort by Christian Holkmann-Olsen and colleagues (abstract 601a) revealed that HAART is effective across the board, regardless of baseline CD4 cell count or viral load. During 22,766 person-years (PY) of follow-up, the researchers recorded 889 instances of new AIDS-defining illness or death (125 deaths). They found that the incidence of AIDS or death for any given CD4 cell count or viral load category was "similar regardless of specific drugs being used." In comparison with indinavir (Crixivan) -- for which clinical endpoint data are available (most newer drugs were approved on the basis of short-term laboratory marker data) -- a wide variety of regimens (two NRTIs plus either an NNRTI or a boosted or unboosted PI, or abacavir plus two other NRTIs) reduced the risk of AIDS-defining illness and death to a similar degree.
In a related study, Wafaa El-Sadr, MD, and colleagues (abstract 42) analyzed how MI risk changes over the course of anti-HIV treatment. Data from the same cohort (median age 39 years; 76% men) were collected through February 2004. During 76,577 PY of observation, 277 first MIs were reported. The MI incidence rate was 1.39 per 1,000 PY among those not exposed HAART, 2.53 per 1,000 PY among those on HAART for less than one year, and 6.07 per 1,000 PY among those on HAART for six or more years. The researchers calculated that for each additional year on HAART, the risk of MI increased by 1.17-fold. A similar association between antiretroviral therapy and MI risk was seen in both sexes and all age groups. Interestingly, the authors noted that elevated blood lipids explained "part but not all" of the association between HAART and increased MI risk.
Importantly, even though the MI risk doubled with HAART, the absolute number of heart attacks was still very small. Lundgren emphasized that the reduction in HIV-related illness and death attributable to the use of antiretroviral therapy greatly outweighs the small additional risk of MI.
Results of this study suggest that a PI-sparing regimen including NRTIs is superior to a regimen that excludes NRTIs, but the side effect profiles of the two regimens tell a somewhat different story. Lipoatrophy (loss of peripheral fat in the face and limbs) presents a particular concern for individuals taking NRTIs, especially d4T. Pablo Tebas, MD, (abstract 40) presented data from 62 subjects in the ACTG-5125s substudy of ACTG 5116. After 48 weeks, limb fat increased significantly in the NRTI-sparing arm, but decreased in those who stayed on NRTIs. Among a subset of 46 subjects followed for a median of 104 weeks, those in the NRTI-sparing arm continued to gain limb fat while those in the NRTI arm continued to lose it. However, triglyceride and total cholesterol levels increased much more in the NRTI-sparing arm. Tebas concluded that the benefits of NRTI-sparing regimens on body fat distribution must be balanced against their inferior virological potency. This study was not powered to detect differences among specific NRTIs (only about one-quarter were taking d4T).
Switching to an NRTI-sparing regimen can reduce lipodystrophy, but it may not be necessary to exclude all drugs in this class; studies suggest that omitting only thymidine analogs (d4T and AZT) may accomplish the same goal. Robert Murphy, MD, (abstract 45LB) reported results from ACTG 5110s. In this study, 101 subjects with lipoatrophy were randomly assigned either to replace a thymidine analog (AZT 24%; d4T 76%) with abacavir, or to switch to an NRTI-sparing regimen of lopinavir plus nevirapine; 77 subjects switched immediately, while 24 controls stayed on their baseline regimen for 24 weeks and then switched. After 24 weeks, based on computed tomography (CT) scans, subjects in both the thymidine-sparing and the all-NRTI-sparing arms experienced significantly increased subcutaneous abdominal fat; visceral abdominal fat decreased in the abacavir group. Thigh fat increased significantly (by 8%) in the all-NRTI-sparing arm but not in the abacavir arm. Subjects in all groups maintained good virological control, but CD4 cell counts increased more in the all-NRTI-sparing arm. Elevated lipids were seen in the lopinavir arm and hypersensitivity reactions were seen in the abacavir arm.
For individuals who wish to stay on an NRTI-containing regimen without thymidine analogs, is it better to switch to abacavir or tenofovir? In the British RAVE study, Graeme Moyle, MD, and colleagues (abstract 44L) randomly assigned 105 subjects with lipoatrophy to switch from a thymidine analog (AZT 33%; d4T 67%) to either abacavir or tenofovir. After 48 weeks, DEXA scans showed that limb fat increased significantly, and by similar amounts, in both the abacavir and tenofovir groups. Subjects in both arms maintained good virological suppression. Looking at lipid profiles, triglycerides, total cholesterol, and LDL "bad" cholesterol decreased more in the tenofovir arm. More subjects discontinued in the abacavir arm due to hypersensitivity reactions; no differences in renal function or bone density were detected. Subjects who switched from AZT showed improvements in anemia. The researchers concluded, "While both agents maintain virological suppression, [tenofovir] is associated with fewer treatment discontinuations and greater improvements in lipid parameters than [abacavir]."
Tenofovir also received support from two Spanish studies. In the LIPOTEST study (abstract 860), 53 subjects with well-controlled HIV and lipoatrophy switched from d4T to tenofovir; other drugs in their regimens did not change. After 18 months, facial fat thickness increased significantly and blood cholesterol decreased slightly. In addition, lactic acid levels decreased significantly and mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells increased slightly; both elevated lactic acid and reduced mtDNA are signs of mitochondrial toxicity. Virological control of HIV was maintained and no serious adverse side effects were reported.
In a study by A. Milinkovic and colleagues (abstract 857), 56 subjects with well-controlled HIV were randomly assigned to continue on d4T, reduce their d4T dose from 40 to 30 mg twice daily, or substitute tenofovir for d4T; other drugs were not changed. After six months, limb fat increased significantly in the dose-reduction and tenofovir arms, but continued to decrease in the full-dose d4T arm. Triglyceride and total cholesterol levels decreased somewhat in the dose-reduction arm and significantly in the tenofovir arm, but increased in the full-dose d4T arm.
Taken together, these studies suggest that substituting tenofovir or abacavir for thymidine analogs can improve lipodystrophy without sacrificing virological control. New fixed-dose combination pills have made tenofovir (in Truvada) and abacavir (in Epzicom) as convenient as Combivir and Trizivir, both of which contain AZT. D4T is clearly the major contributor to lipoatrophy; for this reason, the drug was demoted from "preferred" to "alternative" status in a recent revision of the U.S. federal HIV treatment guidelines. However, AZT also appears to play a role in lipoatrophy, and further studies will show whether it deserves to meet the same fate.
news item below). Another PI in the pipeline, Tibotec's TMC-114, generated perhaps the most excitement at the conference. This and other investigational agents further along in the development process are discussed in "Drug Watch" in this issue.
Data were also presented for several agents further back in the development pipeline. One that generated some excitement was PA-457, the first HIV maturation inhibitor. PA-457 works by interfering with a protein needed to construct functional viral progeny; without it, new viral particles are incomplete and noninfectious. In a placebo-controlled single-dose study (abstract 159), 24 treatment-naive or treatment-experienced HIV positive men received PA-457 at doses of 75, 150, or 250 mg, or placebo. The 250 mg dose reduced HIV viral load by 0.51 logs and PA-457 appeared to suppress HIV for several days. A ten-day study is underway and a Phase II trial should start by the end of the year. (For an explanation of logs, see "About Logs" in this issue.)
Susan Little (abstract 161) presented the first results using Merck's integrase inhibitor, L-870810, in 30 treatment-naive and treatment-experienced HIV positive subjects. Ten-day monotherapy with 200 and 400 mg doses reduced HIV viral load by 1.73 and 1.77 logs, respectively; 20% and 38%, respectively, had viral loads below 400 copies/mL. Although L-870810 was well tolerated in this study and no major toxicities have been detected in humans, development has been halted due to toxicity in dogs; however, research on the related agent L-870812 is continuing. Data were also presented on BioAlliance's candidate integrase inhibitor, FZ41 (abstract 547). GW-873140, a CCR5 coreceptor blocker, was tested in a study of 31 HIV positive and eight HIV negative subjects (abstract 77). Good viral suppression was achieved after 10 days. Researchers also found that GW-873140 appears to continue to block receptors for as long as 10 days after discontinuation, suggesting that infrequent dosing may be possible. This agent is due to enter Phase III trials later this year.
In a seven-day dose-ranging study in 27 treatment-naive subjects (abstract 160), Tibotec's new NNRTI, TMC-278, appeared highly active against HIV that was resistant to approved NNRTIs. The median viral load decrease was about 1.2 logs, which was similar across doses (25, 50, 100, and 150 mg daily). No adverse events were detected and a Phase II trial is now starting (see "Open Clinical Trials" in this issue).
Other experimental agents to keep an eye on include Pfizer's CCR5 antagonist UK-427,857, now named maraviroc (abstracts 96, 663); Tibotec's nucleotide-competing reverse transcriptase inhibitor known as Compound-1 (abstract 156); Takeda's TAK-652, which replaces TAK-779 and TAK-220 (abstracts 541, 542); Boehringer Ingleheim's BILR-335BS (abstracts 557, 558); and NCI UIC-02031, a new nonpeptidic PI (abstract 562).
The announcement set off a flurry of press coverage and discussion among medical professionals and HIV prevention workers. Some criticized New York officials for raising the alarm too soon based on a single case. In a rare move, organizers convened a special symposium to discuss the case at the February Retrovirus conference.
Genetic analysis showed that the man had a strain of subtype B HIV that had not been seen previously. Initial genotypic resistance testing indicated his HIV was resistant to the three major classes of antiretroviral drugs. Drug resistance in newly infected individuals is not uncommon, but resistance to all three classes in treatment-naive individuals is rare (see "Transmission of Drug-Resistant HIV," below). It was later determined that the man's virus was susceptible to efavirenz as well as T-20. The man's HIV strain was also found to be dual-tropic (able to use both CCR5 and CXCR4 coreceptors to enter cells) and syncytium-inducing (causing fusion of cells). Dual-tropic, syncytium-inducing virus, which is associated with rapid disease progression, is not unknown in newly infected individuals, although it is more often seen later in the course of disease. The unusual -- though not singularly unique -- aspect of the New York case is the co-occurrence of multidrug resistance and apparently rapid progression. Details of the genetic analysis were presented at the Retrovirus conference by David Ho, MD (abstract 973B) and published in the March 19, 2005 issue of The Lancet.
Experts emphasized that the New York man's rapid progression did not necessarily herald a "super strain" of HIV. It has long been known that a small proportion of individuals naturally progress rapidly to AIDS, and a variety of factors -- including genetic variations and methamphetamine use -- may have contributed to the early onset of immunosuppression in this case. Since February little new information has come to light. Despite extensive testing of more than a dozen of the New York man's sexual contacts (many of his 100 or more partners were anonymous) and retrospective analysis of stored blood samples, no similar strains have been detected; however, the investigation is ongoing. New York health officials issued a press release on March 29 stating that they were still examining data from several individuals who might be infected with related HIV strains.
A picture of transmission patterns of DR HIV based on geography emerged at the 3rd European HIV Drug Resistance Workshop, held March 30 - April 1 in Athens. Reported rates of DR HIV transmission ranged from 4% (Slovenia, Spain) to 17% (Belgium) -- with 14.5% reported in the U.S. -- in cohorts of newly diagnosed individuals. One retrospective study from Sweden showed a decline in transmission of DR virus between 1992 and 2002, attributed by researcher Jan Albert to the widespread, effective use of HAART in that country. Reports from other countries showed either a steady or increasing rate of DR HIV transmission over time. Geographical differences appeared to be regional as well as national, as two studies from Germany -- one from the western Ruhr region, the other in people mostly from Berlin -- showed different DR HIV transmission rates (12% and 16%, respectively) as well as distinct trends (rising steadily from 8.4% to 14.2% between 2001 and 2004, vs peaking at 20% in 1998/1999 then stabilizing at 16% in 2001). Of note, only a tiny percentage of cases among the various studies involved dual- or triple-class drug resistance.
FDA Approves TipranavirOn June 22 the FDA granted Boehringer Ingelheim's nonpeptidic PI, tipranavir -- which will be marketed under the brand name Aptivus -- accelerated approval for treatment-experienced individuals with HIV. The approved dose is 500 mg tipranavir, which must be taken with 200 mg of ritonavir, twice daily. Studies have shown that tipranavir works against HIV that has developed resistance to other drugs in its class. Data from two large Phase III trials (RESIST-1 and RESIST-2) showed that twice-daily tipranavir boosted with ritonavir worked better than boosted comparator PIs in subjects with PI-resistant HIV. After 24 weeks significantly more subjects in the tipranavir arms achieved undetectable viral loads compared with individuals in the comparator arms. However, subjects receiving tipranavir were more likely to experience severe (grade 3 or 4) ALT (liver enzyme) elevations than those taking other PIs (7% vs 1%, respectively).
At the February Retrovirus conference, David Cooper, MD, (abstract 560) reported that in a study of 1,159 subjects, about twice as many individuals in the tipranavir arm responded to treatment (40% vs 21%) compared with those taking lopinavir after 24 weeks. At the same meeting Jonathan Schapiro, MD, (abstract 104) presented data from genotypic resistance analyses of the same cohort showing that tipranavir worked better than comparator PIs in subsets of subjects with various patterns of PI-resistance mutations. Research suggests that tipranavir may reduce blood levels of other PIs, which could make it unsuitable for use in salvage regimens that combine multiple PIs. The most frequently reported adverse events in people taking tipranavir were gastrointestinal symptoms (e.g., diarrhea, nausea), fatigue, and headache; mild skin rash was seen more often in women than men. The most common severe laboratory abnormalities were elevated liver enzymes and blood lipid levels.
Tipranavir is currently undergoing trials in treatment-naive individuals and in children.
Once-Daily Lopinavir ApprovedOn May 2 Abbott Laboratories announced that the FDA approved a once-daily dosing regimen for lopinavir/ritonavir (Kaletra). A study presented at February's Retrovirus conference (abstract H-570) showed that once-daily and twice-daily lopinavir had similar efficacy when used in combination with FTC (emtricitabine, Emtriva) and tenofovir in treatment-naive individuals. Last October the lopinavir product label was revised to include longer-term data from two trials showing that the drug was still effective after 144 and 204 weeks. Full prescribing information for lopinavir may be viewed at www.kaletra.com.
New Hepatitis B Drug ApprovalsOn March 29 the FDA approved a new antiviral agent, entecavir (Baraclude), for the treatment of adults with chronic hepatitis B virus (HBV) infection. The drug, marketed by Bristol-Myers Squibb, is an NRTI taken orally once daily. Diverging from the typical drug approval path, entecavir was approved simultaneously for use in people with hepatitis B alone and in those with HIV/HBV coinfection. The new drug is indicated for both HBV-monoinfected and HIV/HBV-coinfected individuals who have previously used 3TC (a standard therapy for HBV as well as a common component of anti-HIV regimens), and for first-line therapy in individuals with HBV alone. In clinical trials, after 48 weeks entecavir produced greater reductions in HBV viral load than 3TC in both treatment-naive subjects and those who had previously used 3TC (to which HBV rapidly develops resistance). In a smaller study of 68 subjects, entecavir was shown to be superior to placebo in HIV/HBV-coinfected participants who were taking an antiretroviral regimen containing 3TC. Not all people with chronic hepatitis B require treatment; entecavir was approved for individuals with actively replicating HBV and either elevated liver enzymes (ALT or AST) or histological evidence of liver tissue damage. Based on trials so far, entecavir appears about as safe as 3TC; severe hepatitis "flares" (sudden worsening of symptoms) may occur when either drug is discontinued. Full prescribing information for entecavir may be found at www.baraclude.com.
In May the FDA approved Roche's Pegasys brand of pegylated interferon alfa-2a for the treatment of chronic hepatitis B. In two large multinational Phase III trials of more than 1,500 subjects with HbeAG-negative or HbeAG-positive HBV, significantly more individuals who received Pegasys achieved sustained virological response (continued undetectable HBV viral load 24 weeks after a 48-week course of therapy) compared with subjects taking 3TC. The combination of Pegasys plus 3TC was not shown to be superior to Pegasys alone. These trials did not include HIV positive individuals, and Pegasys was not approved for HIV/HBV coinfection. The drug is already standard therapy for the treatment of chronic hepatitis C (see next item).
Pegasys/Ribavirin for HIV/HCV CoinfectionOn February 25 the FDA approved Pegasys plus ribavirin (Copegus) for the treatment of chronic hepatitis C virus (HCV) infection in people with HIV; this is the first and only hepatitis C therapy approved for HIV/HCV-coinfected individuals. Pegylated interferon (either Pegasys or Schering-Plough's Peg-Intron) plus ribavirin was already standard therapy for HCV-monoinfected individuals. The expanded indication was based on data from the APRICOT study, which showed that 40% of 868 HIV/HCV-coinfected subjects treated with Pegasys/ribavirin achieved sustained virological response (29% for HCV genotype 1; 62% for genotypes 2 and 3); the APRICOT results were published in the July 29, 2004 issue of the New England Journal of Medicine (NEJM). In early February the European Medicines Agency also approved Pegasys/ribavirin for coinfected individuals. Full Pegasys prescribing information may be viewed at www.pegasys.com.
Soft-Gel Saquinavir and ddC to Be DiscontinuedOn March 11 Roche announced that it plans to discontinue two of its antiretroviral medications, ddC (zalcitabine, Hivid) and the soft-gel formulation of saquinavir (Fortovase), due to lack of demand. DdC does not offer any clear benefit over ddI and is associated with a high rate of peripheral neuropathy; it is not included as a component of any of the preferred or alternative antiretroviral regimens recommended in the U.S. federal HIV treatment guidelines. Fortovase has been overshadowed by the older hard-gel formulation of saquinavir (Invirase), which is now used with a boosting dose of ritonavir. Boosted Invirase is better tolerated and more convenient than Fortovase, especially with the recent introduction of a new 500 mg Invirase tablet that allows users to take fewer pills each day. The move comes not long after GlaxoSmithKline (GSK) withdrew its PI amprenavir (Agenerase) from the market at the end of 2004 -- the first drug to be removed from the anti-HIV formulary. Roche said it plans to stop producing ddC and Fortovase around 2006.
Higher Abacavir Hypersensitivity RateThe risk of hypersensitivity reactions associated with abacavir (Ziagen) may be higher than previously believed. Since the drug's introduction, most experts have put the rate of hypersensitivity reactions at around 3-5%. But two new studies suggest that the actual rate may be in the 5-10% range. In an overview of nine recent clinical trials (presented at the February Retrovirus conference, abstract 835), FDA researchers found an overall abacavir hypersensitivity rate of 8% (range 2-9%). The drug's manufacturer, GSK, conducted a similar review that included the same recent studies plus earlier clinical trials (abstract 836); this review found a hypersensitivity rate of 5.4%.
Recent research indicates that 600 mg abacavir once daily is as effective as 300 mg twice daily, but it is not yet clear whether the risk of serious hypersensitivity is greater when using the higher dose. As reported in the April 1, 2005 issue of the Journal of Acquired Immune Deficiency Syndromes (JAIDS), Graeme Moyle, MD, and colleagues found that in study CNA30021 (which included 770 participants) the once-daily and twice-daily arms had similar overall hypersensitivity rates (9% vs 7%, respectively), but the frequency of moderate-to-severe reactions was slightly higher in the once-daily arm. A GSK analysis of data from three large studies totaling more than 900 subjects found no greater risk of hypersensitivity with the higher dose.
Abacavir hypersensitivity may be characterized by symptoms including fever, skin rash, nausea, abdominal pain, cough, sore throat, and/or shortness of breath. Individuals who experience such symptoms while taking abacavir should contact their physicians immediately. Once the drug has been discontinued, it should not be started again. The same caution applies to the fixed-dose combination pills Trizivir and Epzicom, both of which contain abacavir.
More Drug Interaction Warnings for RitonavirIn late March the FDA announced that the product labels for ritonavir (Norvir) and lopinavir/ritonavir (Kaletra) had been revised to include interactions with fluticasone (a synthetic corticosteroid that is the active ingredient in Flonase nasal spray) and trazodone (Desyrel), an antidepressant. Ritonavir interacts with many medications due to its potent inhibitory effect on the CYP450 enzyme system in the liver, which can lead to slower processing of other drugs and thus greater risk for toxicity (see "Drug Interactions" in this issue). In the case of fluticasone, use with ritonavir can lead to decreased blood levels of the hormone cortisol. In addition, the revised label for ritonavir added alfuzosin (Uroxatral), an alpha-blocker drug used to increase the flow of urine in men with benign prostate enlargement, to the drug's contraindications list. The revised package inserts for ritonavir and lopinavir may be viewed at www.norvir.com and www.kaletra.com.
TMC-114 Expanded Access to Start This AutumnTibotec Therapeutics announced June 14 that it plans to start an expanded access program (EAP) this autumn for its experimental protease inhibitor, TMC-114. The company also plans to seek accelerated approval from the FDA for the agent, which has shown promise in Phase II clinical trials (see "Drug Watch" in this issue). The EAP will be open to heavily treatment-experienced HIV positive adults with CD4 cell counts below 100 cells/mm3 and viral loads above 10,000 copies/mL who need TMC-114 to construct a viable HAART regimen. Check the Tibotec web site (www.tibotec.com) for more details and contact information as the launch date approaches. Tibotec recently began an open-label Phase III study of the drug (see "Open Clinical Trials" in this issue); the EAP is for individuals who are not eligible or able to participate in the clinical trial.
Sculptra Physician Locator LaunchedDermik Aesthetics, which manufactures Sculptra (poly-L-lactic acid) -- a recently approved cosmetic treatment for facial lipoatrophy -- has launched a physician locator to help HIV positive people find providers in their area who administer the product. Dermik emphasizes that the inclusion of a physician in the database "is not intended as a recommendation, referral, or endorsement of any particular health-care provider or practice." See www.sculptra.com/US/Locator.do.
Treatment Guidelines Updated for NPEPIn January the U.S. Department of Health and Human Services (DHHS) put forth new recommendations concerning post exposure prophylaxis (PEP) for nonoccupational HIV exposure, referred to as "NPEP" (Morbidity and Mortality Weekly Report, January 21, 2005). Previously the government recommended antiretroviral PEP only for occupational exposures such as accidental needlestick injuries in health-care facilities; in that setting, PEP reduces the risk of HIV infection by about 80%. According to the new guidelines, individuals should be offered a 28-day course of three-drug antiretroviral therapy if they have a "substantial risk" of HIV exposure -- for example, unprotected intercourse or sharing drug injection needles with a person known to be HIV positive; NPEP must be started within 72 hours of the suspected exposure. In the case of lower risk exposures or if the partner's HIV status is unknown, the guidelines recommend weighing the benefits and risks of NPEP on a case-by-case basis. These guidelines are intended to cover accidental or rare exposures (e.g., sexual assault, condom breakage); NPEP should not be considered a "morning after pill" to be used after habitual high-risk behavior.
"Blips" and Spontaneous Undetectable Viral LoadAccording to a study published in the February 16, 2005 issue of the Journal of the American Medical Association (JAMA), transient viral load increases, or "blips," are usually random variations and not a cause for concern. Richard Nettles, MD, and colleagues from Johns Hopkins University collected blood from ten HIV positive subjects and tested their viral loads every 2-3 days for a period of 3-4 months. All subjects were on antiretroviral therapy and had previously had undetectable viral loads for at least six months. Nine subjects (90%) experienced HIV RNA blips of 50 copies/mL or more followed by a return to undetectable levels; the average blip duration was less than three days. Blips were not associated with any demographic or clinical factors and were only marginally associated with intermittent nonadherence. Ultrasensitive genotypic testing showed that blips were not linked to the emergence of drug-resistance mutations. The researchers concluded that transient viral load increases appear to be "random biological and statistical variations" and were not clinically significant. Thus, it is important to obtain confirmatory results and not change antiretroviral therapy based on a single viral load test.
Spontaneous undetectable HIV viral load in individuals not taking antiretroviral medications may be more common than previously believed, according to a study published in the May 1, 2005 issue of Clinical Infectious Diseases (CID). Yoann Madec and colleagues from Paris found that 36 of 426 recently infected individuals (8.5%) with known seroconversion dates had sustained (two readings within 18 months) HIV RNA levels below 400-500 copies/mL with no treatment 4.6-62.8 months after seroconversion. A majority had detectable viral loads during part of the study before achieving undetectable status. According to the researchers, 6.7% of study participants still maintained viral loads below 400-500 copies/mL five years after seroconversion. Women, subjects younger than 26 years of age, individuals with lower baseline viral loads, and subjects with higher baseline CD4 cell counts were more likely to achieve spontaneous HIV clearance. During the period when viral loads were undetectable, the researchers found that subjects experienced slower CD4 cell declines than expected based on past studies of HIV disease progression. As discussed in an editorial by Elizabeth Connick, MD, and colleagues in the same issue, the French study points to the need for further studies of primary HIV infection and its treatment.
Kaletra Maintenance "Monotherapy"In an effort to increase the convenience of antiretroviral therapy and reduce the risk of side effects, researchers have studied a variety of simplified regimens. In the March 4, 2005 issue of AIDS, R.E. Campo and colleagues reported that switching to Kaletra "monotherapy" -- which is really a combination of two drugs, lopinavir plus a boosting dose of ritonavir, in a single pill -- appeared to maintain virological suppression and did not encourage the emergence of resistance in individuals with well-controlled HIV. In this small pilot study, six treatment-naive HIV positive individuals were initially treated with lopinavir plus AZT and 3TC for at least 24 weeks. After virological suppression was achieved (at least three consecutive viral load measurements below 50 copies/mL), the two NRTIs were discontinued. Four individuals (67%) maintained viral loads below 1,000 copies/mL for the duration of the six-month study. The other two subjects, who admitted poor adherence, had at least one viral load above 1,000 copies/mL. When one subject improved his adherence, his viral load fell below 400 copies/mL. No lopinavir-resistance mutations were detected in either individual.
Increase in Drug-Resistant Staph InfectionInfection with methicillin-resistant Staphylococcus aureus (MRSA), once largely confined to health-care facilities such as hospitals and nursing homes, is increasingly being seen in community settings. Drug-resistant staph infection has recently been detected among prisoners, athletes, and children. A study published in the April 7, 2005 issue of NEJM found that between 2001 and 2002, as many as one-fifth of MRSA infections in Atlanta, Baltimore, and Minnesota had no apparent link to health-care settings. "Community-associated MRSA infections are now a common and serious problem," the authors concluded.
Healthy people often carry S. aureus on their skin and in their noses, but the bacteria may be especially likely to cause problems in immunocompromised people. According to a retrospective study reported at the February Retrovirus conference (abstract 142), 94 "clinically significant" cases of drug-resistant S. aureus were detected in a cohort of 3,455 HIV positive subjects between January 2000 and December 2003; 60% of the infections were community-acquired and 40% were potentially linked to hospitals. The incidence of clinically significant MRSA infection increased 6.2-fold from the first six months to the last six months of the study. The risk of MRSA was higher among individuals who acquired HIV through heterosexual sex and those with CD4 cell counts below 50 cells/mm3. Among subjects with CD4 cell counts above 50 cells/mm3, higher HIV viral load was also associated with an increased risk of MRSA infection. According to the researchers, this finding "suggests a direct effect of HIV on anti-staphylococcal defenses."
Adding to the evidence, N.E. Lee and colleagues carried out a case-control study of MRSA skin infections in 35 gay men in Los Angeles; results were published in the May 15, 2005 issue of CID. Most of these cases were community acquired and not associated with hospitals. MRSA skin infections (abscesses, cellulitis, boils) were linked to high-risk sexual behavior (including meeting partners in bathhouses, sex clubs, or over the internet, but not average number of sexual partners), methamphetamine use, nail-biting, close contact with customers at work, and use of a public hot tub or sauna; condoms were found to have a protective effect. In this study MRSA infection was not associated with immunosuppression or use of antiretroviral therapy. The researchers concluded that among this population, MRSA appears to be spread via direct skin-to-skin transmission or indirect transmission related to environmental exposures, and emphasized the need for increased awareness of community-acquired MRSA so that appropriate treatment can be started without delay.
HIV/HCV and HIV/HBV CoinfectionThe problem of HIV and viral hepatitis coinfection has attracted increasing attention over the past few years, and experts have begun to accumulate enough data to make recommendations about optimal management. The May 2005 issue of the Journal of Hepatology featured a summary of recommendations developed at the First European Consensus Conference on Treatment of HBV and HCV in HIV-Coinfected Patients, which took place March 1-2 in Paris. The summary includes guidelines about which coinfected individuals are good candidates for hepatitis B or C treatment, when such therapy should be started, and which anti-HIV medications pose potential risks for individuals with liver disease.
Several researchers presented data on HIV/HCV and HIV/HBV coinfection at the February Retrovirus conference, but coinfection did not grab the headlines as it did at last year's meeting. Mark Sulkowski, MD, and colleagues (abstract 121) presented some of the clearest evidence to date that liver damage can progress faster than expected in HIV/HCV-coinfected individuals. In a cohort of 67 coinfected subjects who received paired liver biopsies an average of two years apart, 28% had fibrosis scores that increased by at least two stages from one biopsy to the next. The researchers suggested that because fibrosis progresses more rapidly in coinfected individuals, the usual recommendation that people with minimal fibrosis can "wait and watch" may not be appropriate for the coinfected population. Sherri Stuver and colleagues (abstract 947) found that having a nadir (lowest ever) CD4 cell count below 200 cells/mm3 -- and especially below 100 cells/mm3 -- was significantly associated with fibrosis progression, but that subjects on HAART who achieved HIV viral loads below 75 copies/mL had a decreased risk of liver disease progression or death.
On the other hand, research continues to turn up contradictory data about whether HCV adversely affects HIV disease progression. A study by R.C. Hershow and colleagues reported in the March 2005 issue of CID looked at 625 HIV positive subjects in the Women's Interagency HIV Study (WIHS), 190 (29%) of whom also had hepatitis C. The researchers found that the coinfected women did not progress to AIDS-defining illnesses or death faster than those with HIV alone. HIV viral load levels were similar in both groups, but CD4 cell percentages were slightly higher among the coinfected women.
In terms of antiretroviral therapy, Barbara McGovern and colleagues (abstract 950) found that HIV/HCV-coinfected individuals who had been exposed to NRTIs -- in particular d4T, ddI, or ddC -- were at higher risk for steatosis (fatty liver), but Alison Uriel and colleagues (abstract 925) did not see a link between specific anti-HIV drugs and this condition. Sulkowski and colleagues reported in the April 8, 2005 issue of AIDS that steatosis was present in 40% of a cohort 112 HIV/HCV-coinfected subjects (99% with HCV genotype 1), most of whom were taking HAART. Steatosis was more common among subjects with advanced liver disease, those with hyperglycemia (high blood sugar), obese individuals, and those receiving d4T; only four subjects had never taken d4T, none of whom had steatosis. Finally, according to a study published in the March 2005 issue of the Journal of Hepatology, HIV/HCV-coinfected individuals taking HAART are more likely to develop fulminant hepatic failure (severe, rapid liver failure) than those with HIV alone. In a retrospective analysis of medical records from 11,678 veterans with HIV monoinfection and 4,761 with HIV/HCV coinfection, R.J. Kramer and colleagues determined that the cumulative incidence of fulminant hepatic failure was 1.1 per 1,000 PY in the HIV-monoinfected group compared with 2.5 per 1,000 PY in the coinfected group. They noted that the risk of fulminant hepatitis was considerably higher since the advent of HAART, suggesting that antiretroviral drug toxicity plays a role. However, the risk of fulminant hepatitis remains low: in this study only 92 total cases were seen between 1991 and 2000.
It remains unclear how often HCV is transmitted sexually among men who have sex with men (studies consistently show very low rates of sexual transmission, in the range of 0-3%, within monogamous heterosexual couples). Marie-Laure Claire and colleagues from Necker Hospital in Paris (abstract 122) presented the latest data on a cluster of 12 HIV positive men diagnosed with acute hepatitis C; ten had the rare genotype 4d, suggesting a common source of infection. The researchers found that male-to-male sex was "the only significant risk factor" for HCV infection in this cohort. In a related study, A. Rauch and colleagues (abstract 943) studied 1,347 HIV positive heterosexual subjects and 1,542 HIV positive gay/bisexual men in the Swiss HIV Cohort. Eight heterosexuals seroconverted to HCV positive (0.2 per 100 PY), compared with 14 gay/bisexual men; among the gay/bisexual men, the rate was the same 0.2 per 100 PY for those who reported only safe sex, but 0.7 per 100 PY for those reporting unprotected sex. However, in a recent study by M. Alary and colleagues published in the March 2005 issue of the American Journal of Public Health, only one new HCV infection was detected among more than 1,000 gay men in Montreal during eight months of follow-up (2,653 PY), even though 63% said they had engaged in unprotected anal sex; the one infection occurred in a man who reported sharing drug injection equipment. Notably, the men in Alary's study were HIV negative while those in the two European studies were HIV positive; research suggests that sexual transmission of HCV may be more likely in people with HIV.
PIs Increase Heart Disease RiskAdding to the evidence from the D:A:D study presented at the Retrovirus conference, a study published in the March 1, 2005 issue of the American Journal of Cardiology also found that elevated blood lipids are linked to increased risk of heart disease in HIV positive people using HAART. Steven Grover, MD, from McGill University and colleagues analyzed data from a trial that compared blood lipid changes in subjects using atazanavir (Reyataz) or nelfinavir for 32 weeks. Using coronary risk equations derived from the Framingham Heart Study (a large, long-term study of cardiovascular risk factors in the general population) and other mathematical models, the researchers estimated that the increases in total cholesterol and LDL "bad" cholesterol seen in subjects taking nelfinavir (24% and 28%, respectively) could be expected to increase the risk of heart disease by 50% over 10 years, regardless of other cardiovascular risk factors. The authors concluded, based on their model, that "minimizing dyslipidemia associated with [HAART] may preserve life expectancy."
In a different type of analysis, U.H. Iloeje from Bristol-Myers Squibb and colleagues looked at a large database of more than 7,500 HIV positive individuals to determine whether cardiovascular events (heart attack, stroke, angina, coronary artery disease, coronary bypass or angioplasty surgery) were associated with antiretroviral therapy. Results were published in the January 2005 issue of HIV Medicine. A total of 127 cardiovascular events occurred during the follow-up period. While 77% of the subjects had taken PIs, 88% of the events occurred in this group. After adjusting for other risk factors, the researchers determined that the rate of cardiovascular disease was 9.8 per 1,000 PY among subjects who used PIs compared with 6.5 per 1,000 PY among the PI-naive participants. Not surprisingly, the researchers found that traditional risk factors -- including smoking, diabetes, and older age -- also contributed to increased heart disease risk. The authors recommended that "clinicians should evaluate the risk of [cardiovascular disease] when making treatment decisions for HIV-infected patients."
Cocaine Also a Cardiac Risk FactorAccording to an article in the March 28, 2005 issue of Archives of Internal Medicine, cocaine use is associated with increased risk of heart disease in people with HIV. Shenghan Lai, MD, and colleagues from Johns Hopkins studied 224 HIV positive and HIV negative African American subjects aged 25-45 years. They found that both individuals with HIV and people who used cocaine were significantly more likely to develop coronary calcification (an early subclinical sign of atherosclerosis) and that the risk was compounded in subjects who were both HIV positive and cocaine users. Using CT scans, the researchers detected coronary calcification in 19% of HIV negative non-cocaine users, 29% of HIV positive non-users, 30% of HIV negative cocaine users, and 38% of HIV positive cocaine users. Among the non-users, however, those with HIV were found to have more and larger areas of calcification. Higher rates of coronary calcification among the nonusers were apparent even among HIV positive individuals who were not taking PIs, which can raise blood lipid levels.
Smoking Cessation Reduces Cardiovascular RiskSome studies have found that HIV positive individuals are more likely to smoke tobacco than the population at large. According to a study published in the April 29, 2005 issue of AIDS, smoking cessation was associated with decreased intima-media thickness (an indicator of atherosclerosis). Rodolphe Thiebaut and colleagues looked at cardiovascular risk-reduction strategies among 233 HIV positive subjects in the French Aquitaine Cohort (median age 44 years; 25% women). After 36 months of follow-up, 17% of the subjects were taking lipid-lowering statin or fibrate drugs (up from 2% at the start of the study), 60% were on PI-sparing antiretroviral regimens (up from 45% at baseline), and 49% were still smoking (down from 59%). Looking at the individual interventions, the researchers found that only smoking cessation was linked to decreased intima-media thickness. They recommended active promotion of smoking cessation to reduce the risk of cardiovascular disease among HIV positive persons.
Alendronate Reduces Bone LossAlendronate (Fosomax) plus vitamin D and calcium increases bone mineral density (BMD) in HIV positive individuals with osteopenia (mild bone loss) or osteoporosis (severe bone loss), according to a study published in the April 1, 2005 issue of JAIDS. Previous research has shown that HIV positive people are at increased risk for bone loss, but it is not yet clear whether this is due to antiretroviral therapy, immunosuppression, or HIV itself. Kristin Mondy, MD, from Washington University in St. Louis and colleagues conducted a prospective study of 31 HIV positive subjects on HAART with low lumbar spine BMD (T-scores less than -1.0); importantly, most of the subjects (87%) were men, and studies in the general population indicate that women are more prone to bone loss. Subjects were randomly assigned to either receive or not receive 70 mg alendronate once weekly; all subjects received daily vitamin D and calcium supplements. After 48 weeks, subjects taking alendronate experienced a 5.2% increase in lumbar spine BMD, compared with a 1.3% increase among those taking supplements alone; no adverse events were seen in either arm. The authors concluded that "alendronate, vitamin D, and calcium are safe and potentially useful in the treatment of osteopenia/osteoporosis associated with HIV infection."
Alendronate also appears to be effective without added supplements. A Spanish study reported in the February 18, 2005 issue of AIDS found that in a 96-week study of 25 HIV positive subjects on HAART with osteoporosis, those receiving 70 mg alendronate once weekly plus dietary counseling experienced increased BMD, compared with no significant improvement in those assigned to receive dietary counseling alone. Increased spine BMD was apparent at 48 weeks, and improved trochanter (near ball of the hip joint) BMD was seen by the end of the study. Although subjects in this study did not receive vitamin D or calcium supplements, dietary counseling helped ensure that their daily diets contained at least 1,200 mg of calcium.
Antidepressants, Medical Marijuana Improve AdherenceDepression is linked to poor adherence, and use of antidepressants can help HIV positive individuals stick to their prescribed HAART regimens, according to a study published in the April 1, 2005 issue of JAIDS. Lourdes Yun, MD, and colleagues from the Denver Public Health Department retrospectively analyzed medical records from 1,713 HIV positive subjects attending public health clinics between 1997 and 2001. Among the 981 subjects (57%) diagnosed with clinical depression, 46% were prescribed antidepressants and 52% were prescribed HAART. About half the subjects with depression refilled their antidepressant prescriptions at least twice. The researchers found that 69% of subjects who took antidepressants regularly adhered well to HAART, compared with 31% of depressed subjects who did not take antidepressants regularly. They also found that while HAART adherence improved over time in all groups, the improvement was greatest in the subjects who took antidepressants regularly. A possible confounding factor in this study is the likelihood that some subjects might have been naturally good adherers who took both their antidepressants and their antiretroviral medications as directed. The authors concluded that "attention to diagnosis and treatment of depressive disorders in this population may improve antiretroviral adherence and ultimate survival."
In related news, a study published in the January 1, 2005 issue of the same journal found that medical cannabis (marijuana) was associated with improved adherence to antiretroviral therapy among HIV positive subjects experiencing nausea. Nausea is a side effect of several anti-HIV drugs and has been shown to interfere with adherence. Bouke de Jong, MD, from Stanford University and colleagues surveyed 252 subjects about their use of cannabis and antiretroviral therapy; 69% were on HAART, 67% provided data on HAART adherence, and 24% reported using cannabis. Among the subjects as a whole, the researchers found no association between marijuana use and HAART adherence. Among a subgroup of subjects with chronic nausea, however, those who used cannabis were about three times more likely to adhere to HAART compared with non-cannabis users. In contrast, among subjects without nausea, marijuana use was associated with decreased adherence. HAART adherence was not associated with sex, race/ethnicity, or age, but was poorer among subjects who used alcohol and illegal drugs other than cannabis. The authors concluded that medical marijuana may "facilitate, rather than impede" HAART adherence for a selected group of individuals.
Benefits of Case ManagementCase management can help newly diagnosed HIV positive people access care, according to a study published in the March 4, 2005 issue of AIDS. Gardner Lytt and colleagues with the Antiretroviral Treatment and Access Study (ARTAS) group looked at 273 participants from Atlanta, Baltimore, Los Angeles, and Miami who had recently been diagnosed with HIV. Half the subjects were randomly assigned to receive case management, while the other half were simply given referrals to treatment providers. The case management group had as many as five contacts with case managers over a 90-day period, during which the case managers helped clients identify and address their needs and barriers to care; case managers also helped clients contact care providers and were available to accompany them to clinic visits. The researchers found that 78% of subjects in the case management arm visited HIV clinics at least once within a period of six months, compared with 60% in the referral-only arm. Looking at those who visited clinics twice within a one-year period, the respective figures were 64% and 49%. The researchers estimated that the case management intervention cost $600-1,200 per client. Since "a relatively modest investment" in case management was associated with "a significantly higher rate of successful linkage to HIV care," they concluded that case management is an "affordable and effective resource" for newly diagnosed individuals.
Greater IRIS Risk With Advanced ImmunosuppressionAn article in the Winter 2005 issue of BETA discussed immune reconstitution inflammatory syndrome (IRIS) in HIV positive people whose immune systems begin to recover with effective antiretroviral therapy. A retrospective analysis published in the March issue of HIV Medicine shed further light on who is most at risk for IRIS. D.J. Jevtovic and colleagues from Belgrade studied 389 subjects who started HAART between 1998 and 2003. Most (87%) had an AIDS diagnosis and 62% had CD4 cell counts below 100 cells/mm3. After 35 months, about three quarters achieved viral loads below 50 copies/mL and 45% reached CD4 cell counts above 400 cells/mm3. The researchers found that 65 subjects (17%) experienced at least one episode of IRIS, including symptoms of herpes zoster (shingles), tuberculosis, cytomegalovirus (CMV), cryptococcosis, toxoplasmosis, hepatitis, and immune recovery vitritis (a type of eye inflammation). The risk of IRIS was highest among individuals who had more advanced immunosuppression (CD4 cell counts below 100 cells/mm3) when they started HAART. Median CD4 cell increases and viral load decreases did not differ between the IRIS and non-IRIS groups, but IRIS risk was very low among those whose CD4 cell counts increased to more than 400 cells/mm3. Previous research has shown that HAART works better when it is started before advanced immune system decline; this study suggests that doing so can also help prevent IRIS.
Liz Highleyman (firstname.lastname@example.org) is a freelance medical writer and editor based in San Francisco.
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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.