News Briefs
For the latest updated guidelines for HIV treatment in adults, adolescents, children, and pregnant women; postexposure prophylaxis (PEP) for occupational and non-occupational exposure; and opportunistic illness (OI) prevention, visit www.aidsinfo.nih.gov.
Reports From the 11th Retrovirus Conference
Nearly 4,000 participants gathered February 8-11, 2004, for the 11th Conference on Retroviruses and Opportunistic Infections, the major annual U.S. scientific meeting on HIV. The conference opened with Stephen Lewis, United Nations Special Envoy for HIV/AIDS in Africa, calling on the developed world to devote more funding to AIDS relief efforts in poor countries. Some new epidemiological information was presented -- including a report of an unexpected HIV outbreak among college men in North Carolina -- but the Retrovirus conference was primarily devoted to basic science and treatment.
For the 2004 Retrovirus conference program and abstracts, see www.retroconference.org. For more complete conference coverage, see:
www.hivandhepatitis.com/2004icr/11croi/main.html
www.thebody.com/confs/retro2004/retro2004.html
www.natap.org/2004/CROI/croi.htm.
Nevirapine Resistance After a Single Dose
HIV can develop resistance to nevirapine (Viramune) after just one dose, which has important implications for the use of single-dose nevirapine monotherapy to prevent mother-to-child HIV transmission in resource-poor settings.
Gonzague Jourdain, M.D., from Harvard School of Public Health (abstract 41LB) reported results from a Thai study of more than 1,800 HIV-positive pregnant women who received AZT (zidovudine, Retrovir) with or without single-dose nevirapine. Women and infants who received the combined regimen had a vertical transmission rate of just 2%, comparable to rates seen in the U.S. and Europe. Following delivery, about 25% of the women began taking triple-drug regimens containing nevirapine. A random subset of 90 women received genotypic resistance tests 10 days after giving birth; resistance mutations (e.g., K103N, Y181C, G190A) were detectable in 18%. After six months of treatment, only 34% of women who had taken nevirapine monotherapy during delivery and had resistance mutations had viral loads below 50 copies/mL, compared with 53% of women who had taken intrapartum nevirapine but did not have resistance mutations, and 75% who did not receive nevirapine during delivery. In a second study of more than 600 HIV-positive mothers in South Africa, presented by Neil Martinson from Johannesburg (abstract 38), about 39% of HIV-positive mothers and about 42% of infants who were infected despite use of nevirapine developed resistance to the drug.
HIV easily develops cross-resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), and nevirapine resistance can also limit future use of efavirenz (Sustiva) and possibly other NNRTIs yet to be developed. Some research suggests that nevirapine resistance may be short-lived. In the Thai study, mothers who started a nevirapine-based regimen more than six months after delivery responded better than those who started therapy sooner; however, in the South African study, nevirapine-resistant HIV persisted for at least nine months. Because the single-dose nevirapine regimen is inexpensive, convenient, and effective in reducing mother-to-child transmission, experts are not calling for an end to its use in areas with limited resources. "Single-drug therapy should not be withheld if no other alternative exists," said Elaine Abrams, M.D., from Columbia University in the session's concluding remarks. Wherever possible, however, HIV-positive pregnant women should receive combination antiretroviral therapy as appropriate for their viral load and CD4 cell count.
Atazanavir Still Looks Good at 48 Weeks
Following up on 24-week data presented at last summer's International AIDS Society meeting showing that atazanavir (Reyataz) boosted with ritonavir (Norvir) is nearly as effective as lopinavir/ritonavir (Kaletra), Margaret Johnson, M.D., from the Royal Free Hospital in London (abstract 547) reported that boosted atazanavir continued to suppress HIV at 48 weeks. The BMS 045 study included 358 treatment-experienced participants with resistant virus randomly assigned to receive boosted atazanavir, atazanavir plus saquinavir (Invirase or Fortovase), or lopinavir, along with tenofovir DF (Viread) plus a nucleoside reverse transcriptase inhibitor (NRTI). After 48 weeks, 46% of subjects receiving lopinavir had viral loads below 50 copies/mL, compared with 38% receiving boosted atazanavir and 26% receiving atazanavir/saquinavir. Participants in the boosted atazanavir and lopinavir/atazanavir arms had CD4 cell increases of about 11 5 cells/mm3, while the third arm saw of gain of 72 cells/mm3. While lopinavir appears slightly more effective, atazanavir is less likely to cause gastrointestinal problems or blood lipid (fat) abnormalities.
In related news, recent small studies have shown that atazanavir can be used to boost blood levels of amprenavir (Agenerase) and saquinavir -- a potential benefit for individuals who cannot tolerate ritonavir. Also, a case report series published in the April 9, 2004 issue of AIDS suggests that beyond causing fewer lipid abnormalities itself, atazanavir may help reverse dyslipidemia (blood lipid abnormalities) and lipodystrophy (body shape changes) associated with use of other protease inhibitors (PIs). Within 12 weeks of switching to atazanavir, two individuals experienced reduced dorsocervical fat pad ("buffalo hump") size and one experienced decreased waist size; lipid levels declined in all three, and the subjects maintained viral loads below 50 copies/mL. "We propose that in patients with lipodystrophy syndrome, switching to atazanavir from established [PIs] could lead to a reversal of the metabolic alterations and ... rapid regression of pre-existing body fat accumulations," the authors concluded.
Treatment During Acute Infection
There appears to be little benefit to starting antiretroviral therapy in the months immediately following HIV infection, according to a presentation by Bruce Walker, M.D., from Harvard Medical School (abstract 24). Walker presented final data from a small cohort of individuals who began therapy during acute, or primary HIV infection (PHI) followed by supervised treatment interruptions (STIs). Researchers have hypothesized that such interruptions might help spur the immune system to fight HIV. Earlier data from the study looked promising, with all eight initial subjects demonstrating continued viral suppression after one or two STIs. (Subjects were restarted on therapy if their viral loads stayed above 5,000 copies/mL for three weeks, or ever increased above 50,000 copies/mL.) With 14 subjects now enrolled and after an average of five years of follow-up, however, it appears that the ability to control HIV without treatment is short-lived. While 11 subjects maintained virological control for at least 90 days, that figure dropped to six subjects after one year, and to three subjects after three years. Most participants experienced gradual increases in viral load and declines in CD4 cell count. HIV-specific CD8 cell responses increased three-fold during the first STI, less during the second and third interruptions, and not at all after subsequent breaks; however, increased CD8 response did not correlate with improved virological control. In addition, two reports based on data from the French PRIMO study (abstracts 396 and 397) also failed to demonstrate benefits from early therapy and STIs. In an editorial review in the March 26, 2004 issue of AIDS, Walker and coauthors concluded, "Based on the currently published data, there is no clear evidence that patients with access to antiretroviral therapy have any greater clinical benefit if therapy is introduced immediately during or prior to their seroconversion illness. ... [T]here is currently no evidence from these studies to suggest that therapy during PHI results in a reduction in clinical progression compared with use of effective therapy in later disease."
Promising HIV/HCV Coinfection Data
Coinfection with HIV and hepatitis C virus (HCV) received considerable attention at the Retrovirus conference. Douglas Dieterich, M.D., from Mt. Sinai School of Medicine presented eagerly awaited results from the Roche APRICOT study of 868 coinfected subjects in 19 countries (abstract 112). Participants were randomly assigned to receive standard interferon plus ribavirin, Pegasys brand pegylated interferon plus placebo, or Pegasys plus ribavirin, all for 48 weeks. Most participants were white men on HAART with well-controlled HIV. Overall, 40% of the participants treated with Pegasys/ribavirin achieved a sustained virological response (SVR; undetectable HCV viral load at the end of a 24-week post-treatment follow-up period) -- the highest SVR rate yet seen in a coinfected population -- compared with just 12% of those receiving standard interferon/ribavirin. Among those with genotype 1 HCV (which is harder to treat), the corresponding SVR rates were 29% and 7%; among those with genotypes 2 or 3, the SVR rates were 62% and 20%, respectively.
At the same session, Raymond Chung, M.D., from Massachusetts General Hospital (MGH) presented final results from ACTG A5071 (abstract 110). In this trial, 133 participants received either standard interferon or Pegasys for 48 weeks; both groups also received daily ribavirin, starting with lower than normal doses to reduce side effects. Most participants were men and about half were African American. After 72 weeks (48 weeks of therapy plus 24 weeks of follow-up), 27% in the Pegasys/ribavirin arm and 12% in the standard interferon/ribavirin arm had undetectable HCV viral load. Among those with genotype 1, the corresponding SVR rates were 14% and 6%; among those with genotypes 2 or 3, the SVR rates were 73% and 33%, respectively. Notably, while the end-of-treatment and SVR rates were similar in the standard interferon arm, the response rate declined dramatically from week 48 to week 72 in the Pegasys arm. Chung suggested that the lower initial dose of ribavirin may have contributed to the higher relapse rate.
Finally, Christian Perronne, M.D., presented results from the French RIBAVIC trial (abstract 117LB). This study compared Peg-Intron brand pegylated interferon to standard interferon, both with ribavirin. Most participants were men and 40% had advanced liver disease. Overall, 27% of participants receiving Peg-Intron/ribavirin had sustained undetectable HCV viral load after 72 weeks, compared with 19% of those taking standard interferon/ribavirin. Among those with genotype 1 HCV, the SVR rates were 15% and 5%; in those with genotypes 2 or 3, the corresponding rates were 45% and 40%. About 40% of subjects in both groups stopped treatment prematurely, and about 30% experienced severe side effects.
It is unclear why the SVR rates were so much higher in APRICOT compared with the other two trials, but there were some important differences in the study populations. Subjects in all three trials had well controlled HIV with median CD4 cell counts of 400-500 cells/mm3; at least 80% were on HAART. However, ACTG 5071 included more African Americans, a group that responds less well to interferon therapy. RIBAVIC included more participants with advanced liver disease, another "hard to treat" population, and drop-out rates were higher than in the other two trials.
Efavirenz Side Effects in People of Color
Data from substudy A5097s of the ACTG 5095 trial presented by Heather Ribaudo of Harvard School of Public Health (abstract 132) revealed that people of color clear efavirenz more slowly than whites. The substudy included about 200 participants (53% white, 32% black, 12% Hispanic); about 80% were men. Black and Hispanic subjects cleared the drug about 30% slower than whites. Similarly, Stephen Taylor, M.D., from the University of Birmingham in the U.K. (abstract 131) presented data from the STOP study showing that efavirenz reaches higher concentrations and persists longer after drug discontinuation in black women compared with white men.
Helping to explain this effect, David Haas of Vanderbilt University (abstract 133) reported data from another ACTG 5095 substudy showing that a gene variant seen most often in blacks is associated with slower efavirenz clearance and thus higher drug concentrations in the body. The gene controls expression of the CYP2B6 enzyme in the liver, which plays a role in drug processing. Each individual has one of three genotypes: T/T, G/T, or G/G. The T/T genotype (indicating two copies of the variant gene) was seen in 20% of blacks and just 3% of whites. Efavirenz concentrations were nearly three times as high in people with the T/T genotype, and slightly higher in those with the G/T combination, than in those with the G/G pairing. In this study, the T/T genotype was associated with adverse central nervous system side effects (e.g., bizarre dreams, depression). In related news, Lucia Gallego and colleagues from Madrid reported in the February 1, 2004 issue of Clinical Infectious Diseases that higher blood concentrations of efavirenz are associated with sleep disturbances such as insomnia and waking during the night. Together, these studies suggest that therapeutic drug monitoring may help physicians determine appropriate individualized levels of efavirenz.
Treatment Complications
Metabolic side effects associated with HAART remain a major cause for concern, but studies of long-term complications continue to yield frustratingly inconsistent data. On the cardiovascular front, the latest analysis of data from the D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) trial, collected from more than 23,000 HIV-positive individuals, revealed a cardiovascular event rate of 5.5 per 1,000 person years (PY), including 121 heart attacks and 30 strokes (abstract 737). The heart attack rate among subjects on HAART was only slightly higher than that seen in the Framingham Heart Study, a long-term study of cardiovascular risk factors in the HIV-negative population. However, risk increased with longer duration of antiretroviral therapy. In the D:A:D study, HAART was not associated with hypertension (high blood pressure) (abstract 75), but in the Women's Interagency HIV Study (WIHS) use of HAART -- and increased duration of therapy -- were independently associated with new-onset hypertension (abstract 741). Uchenna Iloeje, M.D., from Bristol-Myers Squibb (abstract 736) reported that in a subset of the HIV Outpatient Study (HOPS) cohort, PI use was associated with an increased risk of cardiovascular disease (9.8 per 1,000 PY in the PI group vs. 6.5 per 1,000 PY in the non-PI group), along with traditional risk factors such as older age, tobacco use, hypertension, and hyperlipidemia (elevated blood lipids). With PIs looking problematic, it is reassuring that T-20 (enfuvirtide, Fuzeon) was not associated with metabolic abnormalities or body fat changes after 48 weeks (abstract 715); this is not surprising, since T-20 works by a different mechanism than other antiretroviral drugs and does not interfere as much with normal cellular functioning.
Todd Brown, M.D., from Johns Hopkins (abstract 73) presented data from the ongoing prospective MACS study showing that HIV-positive men using HAART had higher rates of hyperglycemia (high blood sugar; fasting glucose 110 mg/dL or higher) and diabetes (fasting glucose 126 mg/dL or higher) compared with HIV-negative men. The study included 5,622 gay or bisexual men, about 85% white. Overall, the risk of prevalent (existing) and incident (new onset) fasting hyperglycemia was 2-3 times greater, and the risk of prevalent and incident diabetes was 4-5 times greater, in HIV-positive men on HAART compared with HIV-negative men. In an incidence analysis of 765 subjects (after excluding those with hyperglycemia at study entry), about 19% of HIV-positive men on HAART developed new-onset hyperglycemia, compared with about 9% of HIV-positive men not on HAART, and about 11% of HIV-negative men; the corresponding incidence rates for frank diabetes were about 11%, 5%, and 3%. Use of any PI, d4T (stavudine, Zerit), or efavirenz was associated with an increased risk of hyperglycemia. In addition, men with lower nadir (lowest ever) CD4 cell counts were more likely to develop blood glucose abnormalities.
Deaths Due to Non-AIDS-Defining Illnesses
With HAART causing dramatically lower rates of opportunistic illnesses (OIs), an increasing proportion of deaths in people with HIV are now due to non-AIDS-defining illnesses. Frank Palella, M.D., of Northwestern University (abstract 872) presented the latest analysis of data from the HOPS cohort, showing that while the rate of death due to OIs fell from 23 per 100 PY in 1996 to 6 per 100 PY in 2002, mortality due to nonopportunistic causes rose during the same period by 45% among individuals on HAART for two years, and by 70% among those on HAART for seven years. "If someone takes [antiretroviral therapy], they will live longer and when death occurs, it will not be due to an AIDS-related condition," Palella concluded.
One area where this shift is evident is the increased rate of nonopportunistic cancers in people with HIV. AIDS-defining malignancies such as Kaposi's sarcoma (KS) and invasive cervical cancer have declined in the HAART era. For example, in the May 10, 2004 online edition of Cancer, researchers with the EuroSIDA trial reported that in a study of nearly 10,000 HIV-positive subjects, the rate of KS declined 39% from 1994 to 2003; the decrease was especially marked in participants with higher CD4 cell counts and those with a longer duration of HAART use. But rates of some other types of cancer are on the rise. Based on a retrospective analysis of data from more than 12,000 HOPS participants collected between 1992 and 2000, Pragna Patel, Ph.D., from the Centers for Disease Control and Prevention (CDC) (abstract 81) found that rates of lung, head/neck, and anorectal cancer, Hodgkin's lymphoma, and malignant melanoma were higher in people with HIV than in the general population. The incidence of other common cancers (e.g., breast, colon, prostate) was not significantly different in the HIV-positive and HIV-negative populations. The likelihood of developing a nonopportunistic cancer was correlated with nadir CD4 cell count. This suggests that immune suppression plays a role in the development of cancer, for example by allowing oncogenic (cancer-causing) viruses such as human papillomavirus (HPV) and Epstein-Barr virus (EBV) to proliferate.
Back to the Drawing Board for HIV Vaccines
After several HIV vaccine studies have shown little or no benefit, Ronald Desrosiers, M.D., from Harvard Medical School (presentation 109) suggested that it might be time to go back to the laboratory to learn more about how the immune system responds to the virus. According to Desrosiers, none of the dozen or so current HIV vaccine candidates have much likelihood of success, due to the present "inability to solve some fundamental scientific questions." At the same session, Dennis Burton, M.D., from the Scripps Research Institute (presentation 108) said that the standard vaccine strategy of mimicking the human immune system -- for example, encouraging heightened immune cell activity and/or antibody production -- is not the best approach, since the immune system itself is not very good at controlling HIV. Desrosiers suggested that more research on basic immunology is indicated before spending more time and money on large human trials of current vaccine candidates.
Superinfection Rate 5%
In a small study of men who have sex with men in San Diego and Los Angeles, researchers observed an HIV superinfection rate of 5% per year, higher than previously assumed. (Superinfection refers to subsequent infection with a new strain of the virus in a person who is already HIV positive.) Davey Smith, M.D., from the University of California at San Diego (UCSD) (abstract 21) detected three cases of superinfection out of a total of 78 men by matching HIV pol gene sequences. All three men were exposed to their second strain through sexual activity. None were on antiretroviral therapy; two men were initially infected with drug-resistant strains and then superinfected with a wild-type (nonmutated) strain, while the third was superinfected with drug-resistant virus. Studies have shown that infection with more than one strain of HIV can lead to more rapid disease progression; indeed, in this study the men experienced viral load increases and CD4 cell decreases after becoming superinfected. The results suggest that even two individuals who are already HIV positive should consider safer-sex precautions.
More Conference News in Brief
Michael Kozal, M.D., from Yale University (abstract 35LB) reported that a small proportion of HIV-positive men who have sex with men (about 7% in his study) may be responsible for a large proportion of sexual transmissions. Peter Chin-Hong, M.D., from the University of California at San Francisco (UCSF) (abstract 845) reported that individuals with drug-resistant HIV were at least as likely as those with susceptible virus to have unprotected sex; factors associated with unprotected sex included younger age, less education, use of sildenafil (Viagra), and depression. John Mellors, M.D., from the University of Pittsburgh (abstract 39) reported that low-level resistance due to "minority variants" (those that comprise less than 25% or so of the HIV in the body) may not be detected by standard genotypic resistance tests. Finally, Cheryl Jay, M.D., from UCSF (abstract 496) reported results from a small study showing that smoked marijuana relieves pain due to peripheral neuropathy, a possible side effect of certain NRTIs. After smoking three marijuana cigarettes per day for seven days, 10 out of 16 subjects reported that their average daily neuropathy pain decreased by 30% or more.
Sculptra Recommended for Facial Wasting
A Food and Drug Administration (FDA) advisory group voted unanimously on March 25 to recommend conditional approval of a new treatment for facial wasting (lipoatrophy) in people with HIV. Sculptra, manufactured by the French company Aventis and marketed by Dermik Laboratories, is an injected substance (polylactic acid) that causes the body to produce collagen (a fibrous protein) to fill in areas of lost fat. Results from studies to date (mostly in white men) have been impressive, with most treated individuals reporting a high degree of satisfaction. The therapy is not permanent, however, and repeated injections may be needed. Common side effects include pain at the injection site, temporary bruising, swelling, and small nodules (lumps) under the skin. To reduce the risk of adverse outcomes, Sculptra should be administered only by trained practitioners. Polylactic acid -- under the name New-Fill -- has been approved in Europe since 1999 for cosmetic use. The pending U.S. approval would be only for HIV-related facial fat loss; advisory panel members expressed concern that once approved, Sculptra could be used off-label for other cosmetic purposes such as reducing wrinkles.
Rapid Oral HIV Test Approved
Also in late March the FDA approved the first rapid oral HIV antibody test. The new version of the OraQuick test, manufactured by OraSure Technologies of Bethlehem, PA, uses a sample of oral fluid taken with a swab from around the gums. Results can be read in about 20 minutes. The rapid OraQuick test was previously approved only for use with blood samples. The new test is more than 99% accurate; a positive result should be confirmed with a Western blot test. The rapid oral test will allow individuals to receive their results during a single session. When using older antibody tests, many people never returned to obtain their results, which typically took about two weeks. The test, expected to cost $12 to $15, will be available at some 40,000 approved medical laboratories, and federal officials have approved a waiver to use the test in other settings such as doctors offices, community clinics, and mobile vans. The rapid oral HIV test is not approved for home use.
Generic Ribavirin
In welcome news for the 30-40% of HIV-positive people coinfected with HCV, the FDA in early April approved two generic versions of ribavirin, an antiretroviral drug used in combination with standard or pegylated interferon to treat chronic hepatitis C. The generic drugs will be marketed by Sandoz (a subsidiary of Novartis) and Three Rivers Pharmaceuticals in partnership with Pharmaceutical Resources, Inc. Patient advocates have long called for the approval of generic ribavirin, which has been held up for years by patent lawsuits. But many were disappointed at the announced cost of the new versions. Generic drugs are typically priced at a fraction of the cost of their brand-name equivalents. Both Sandoz and Three Rivers, however, set prices for their generic ribavirin at about $10 per capsule -- in between the average wholesale prices for Schering-Plough's Rebetol (about $11) and Roche's Copegus (about $6). Schering countered by announcing its own generic version of ribavirin, priced to undercut the two newcomers. The first manufacturer(s) of new generic drugs receive exclusive marketing rights for six months, but more companies are expected to enter the generic ribavirin market by the end of the year, thus driving down prices.
T-1249 Development Halted
As mentioned briefly in the Winter 2004 edition of BETA, Roche and Trimeris announced in January that they have halted clinical trials of T-1249, a fusion inhibitor that was touted as a more potent second-generation successor to T-20. Like T-20, T-1249 must be administered by injection. The two companies said they remain committed to developing new fusion inhibitors that are more effective and easier to administer -- a process expected to take years, according David Reddy, Ph.D., Roche's head of HIV research. T-1249 (again like T-20) is a peptide that has proven difficult to manufacture; Roche said it was not confident it could produce T-1249 on a large scale. Advocates speculate that Roche abandoned T-1249 in part because sales of T-20 have not met expectations, largely due to its inconvenient twice-daily administration and exceedingly high price (about $20,000 per year). In related news, Roche announced that as of late April, T- 20 would be available through retail and specialty pharmacies. Previously, due to supply limitations, the drug had to be ordered thr