New Briefs: Conference Coverage
The XV International AIDS Conference, held July 11-16 in Bangkok, Thailand, drew some 20,000 participants. The conference was opened by United Nations Secretary-General Kofi Annan, and former South African president Nelson Mandela gave the closing address. As has become typical of the huge biannual conference, this year's event focused on political issues, including treatment access for developing countries (and the need for wealthy countries to contribute more to such efforts), gender inequality, epidemiology, and prevention issues (including vaccine and microbicide development).
Although access to treatment still lags in many developing countries, evidence continues to accumulate that antiretroviral therapy can be effective in such settings if the drugs are available. For example, the humanitarian group Médecins Sans Frontières (Doctors Without Borders) presented data from an analysis of more than 30 free antiretroviral treatment programs in Africa, Asia, and Latin America, which serve a total of more than 12,000 people. Use of antiretroviral therapy improved immune function and survival, even among individuals who started with low CD4 cell counts and advanced (WHO stage 4) HIV disease. Médecins Sans Frontières also reported that generic fixed-dose combination pills were as effective as the original brand-name drugs (although several generic drugs from India have since been taken off the WHO list of approved agents due to manufacturing irregularities). Other studies presented at the conference suggested that with appropriate support and education, people in resource-poor settings can adhere to anti-HIV therapy as well as those in the West.
The 44th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held October 30 - November 3 in Washington, DC, drew a smaller crowd than the Bangkok conference and was more focused on basic and clinical science.
Treatment Regimens and Strategies
Many of the HIV presentations at ICAAC addressed specific antiretroviral regimens and treatment strategies.
Some HIV positive people and their physicians have sought to use regimens without protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) in an attempt to avoid the side effects associated with these drug classes. Several past studies have suggested that regimens containing three nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are not sufficiently potent to suppress HIV, especially in people with high viral loads. But a study by Graham Moyle, MD, and colleagues (abstract H-1131) found that a regimen of four NRTIs -- once-daily tenofovir DF (Viread) plus twice-daily Trizivir (AZT [zidovudine]/3TC [lamivudine]/abacavir combination pill) -- was as effective and well tolerated as the NNRTI-based efavirenz (Sustiva, Stocrin) plus Combivir (AZT/3TC combination pill) regimen in treatment-naive subjects. Edwin DeJesus, MD, and colleagues (abstract H-564) looked at an even simpler all-NRTI regimen -- once-daily tenofovir plus once-daily Trizivir -- but virological response was less impressive than that seen in Moyle's study, with several subjects developing resistance mutations after 24 weeks. Another presentation (abstract H-563) revealed that the tenofovir/Trizivir combination appeared effective in people who had experienced treatment failure with a prior NNRTI- or PI-based regimen.
In another attempt to avoid antiretroviral toxicity, many clinicians have come to favor NNRTIs over PIs for first-line therapy (see "In Their Own Words" in this issue). But according to a presentation by Pablo Barriero, MD (abstract H-576), individuals who interrupt or restart NNRTI-based regimens are more likely to develop drug resistance than those discontinuing PI-based therapy. It is well known that combination antiretroviral therapy generally produces the best outcomes, but two small studies add to the evidence that individuals on so-called Kaletra (lopinavir/ritonavir) monotherapy (in reality, two drugs) can maintain good viral control without developing resistance mutations (abstract H-183). While undetectable HIV RNA (viral load) remains the "holy grail" of antiretroviral therapy, transient increases in viral load -- often called blips -- are common and do not appear to lead to the development of resistant virus, according to a presentation by Richard Nettles, MD (abstract H-1134).
Antiretroviral Side Effects
As has been the case at all recent HIV/AIDS conferences, side effects of antiretroviral therapy were a key topic at ICAAC. At the 11th Conference on Retroviruses and Opportunistic Infections in February 2004, researchers had reported that African Americans were more likely to experience side effects due to a genetic variation that slows clearance of efavirenz, leading to higher blood concentrations of the drug. A presentation at ICAAC showed that greater benefits accompany the increased risk. In a study by J. Guest and colleagues (abstract H-579), African Americans were less likely than white individuals to experience immunological failure (indicated by CD4 cell count increases of less than 50 cells/mm3) while taking efavirenz, although the risk of virological failure (indicated by continued detectable HIV viral load) did not differ among racial groups.
Research continues to accumulate that some PIs are better than others when it comes to metabolic side effects. A study by Mustafa Noor, MD, and colleagues (abstract H-162) confirmed past research showing that the newer PI atazanavir (Reyataz) was associated with fewer metabolic abnormalities than older drugs in its class. And the most recently approved PI, fosamprenavir (Lexiva), was linked to increased levels of HDL "good" cholesterol. According to a presentation (abstract H-156) by Jeffrey Nadler, MD, in the NEAT study, subjects receiving fosamprenavir experienced mean HDL increases of 37%, compared with 22% in those taking nelfinavir (Viracept); however, the ratio of total cholesterol to HDL was little changed.
Individuals who experience altered lipid profiles while taking HAART are often prescribed lipid-lowering drugs in an effort to reduce their cardiovascular risk. But according to a study by J. Bhalodia and colleagues (abstract H-155), such medications are not completely effective in reversing blood lipid changes associated with antiretroviral therapy.
Bone loss is another metabolic complication that has been linked to antiretroviral therapy and/or HIV infection itself. In a study of 267 HIV positive individuals (85% male, 61% African American, average age 41 years) Naomi Aronson, MD, and colleagues observed osteopenia (mild bone loss) in 40% and osteoporosis (more severe bone loss) in 6% of the subjects (abstract H-166). However, no significant association was detected between bone loss and use of d4T (stavudine, Zerit), tenofovir, or any PI.
New Anti-HIV Drugs
Like most major HIV/AIDS conferences, the 2004 ICAAC also featured several presentations on experimental antiretroviral agents. Robert Murphy, MD, presented final ten-week data (abstract H-1130) from a study of an investigational NRTI known as D-D4FC, or Reverset (for more on this agent, see "Drug Watch," BETA, Summer 2004). In ten treatment-experienced subjects with various resistance mutations, HIV viral load decreased by a mean of 0.8 logs; in treatment-naive individuals, the corresponding decrease was 1.77 logs. (Log changes in viral load are used as scientific shorthand. A 0.3 log change is a two-fold change; a 0.5 log change, 66.6%; a 1 log change, 90%; and a 2 log change, 99%.)
In another study of 39 subjects, a new experimental NNRTI, GW695634, was well tolerated with no serious adverse side effects (abstract A-23). This compound, which has shown impressive anti-HIV activity in the laboratory, is now entering clinical trials to determine its efficacy in humans. Looking at a new class of anti-HIV drugs, Jay Lalezari, MD, presented data from a Phase I study of 837140, a new CCR5 antagonist entry inhibitor being developed by GlaxoSmithKline (abstract H-1137b). During treatment with 837140, subjects experienced viral suppression in a dose-dependent manner, and no significant adverse side effects were reported.
Revised Federal Treatment Guidelines
On October 29 the U.S. Department of Health and Human Services (DHHS) issued the latest revision of its Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. The new version was rewritten to improve readability and contains a number of important changes, but no radical shifts in treatment philosophy. The DHHS panel of experts made changes concerning the role of HIV viral load in guiding treatment decisions. In a continuation of the trend away from the "hit hard, hit early" strategy and toward later therapy, the viral load cut-off for initiating HAART in asymptomatic, treatment-naive individuals was raised from 55,000 to 100,000 copies/mL (having previously been increased from 20,000 copies). The panel recommended that people with HIV RNA levels above 100,000 copies/mL should begin HAART even if their CD4 cell counts remain above 350 cells/mm3. Conversely, individuals with CD4 counts below 200 cells/mm3 are advised to begin treatment even if they have low viral loads.
The revised guidelines include an extended discussion of which antiretroviral regimens to use for first-line therapy, as well as interruption or discontinuation of treatment. Given the side effects associated with d4T, including lipoatrophy (fat loss in the face and limbs) and possible mitochondrial toxicity, this NRTI was demoted from a "preferred" to an "alternative" medication. Tenofovir and the recently approved FTC (emtricitabine, Emtriva) were included as components of a dual-NRTI "backbone" for use with either NNRTI- or PI-based regimens. Hydroxyurea (Hydrea) was deleted from the guidelines, since it is not an antiretroviral medication indicated for the treatment of HIV. The latest revision also adds information about treatment of special populations, including HIV positive adolescents, injection drug users, and HIV positive individuals coinfected with hepatitis B or C, and/or tuberculosis. The revised DHHS guidelines can be viewed at www.aidsinfo.nih.gov/guidelines.
FDA Approves Two Fixed-Dose Combos
On August 2 the U.S. Food and Drug Administration (FDA) approved two new NRTI fixed-dose combination pills. Truvada, manufactured by Gilead Sciences, contains 200 mg FTC plus 300 mg tenofovir. For full prescribing information, see www.truvada.com. The new product was approved in just four months under the FDA's recently implemented priority review process for fixed-dose combinations. Epzicom, produced by GlaxoSmithKline (GSK), combines 300 mg 3TC plus 600 mg abacavir. For full prescribing information, see www.epzicom.com. GSK also manufactures the two previously available fixed-dose anti-HIV combination pills, Combivir (AZT/3TC) and Trizivir (AZT/3TC/abacavir).
Fixed-dose combinations allow individuals to take fewer pills per day, potentially improving adherence. Truvada and Epzicom are the first once-daily fixed-dose combination pills. Combining the new pills with atazanavir or efavirenz allows for a complete once-daily regimen. To construct an effective anti-HIV regimen, Truvada and Epzicom should be used with a PI or an NNRTI, not alone or only with other NRTIs.
Truvada was approved largely on the basis of study data for a similar agent, 3TC. Soon after the combination pill was approved, Gilead released preliminary 24-week data from Study 934, a multicenter trial of 509 participants, showing that tenofovir/FTC works better than AZT/3TC when used in combination with efavirenz (these results were also presented as a late-breaker at ICAAC, abstract H-1137c). In this study, 88% in the tenofovir/FTC arm achieved viral loads below 400 copies/mL, compared with 80% in the AZT/3TC arm; discontinuation rates were 3% and 9%, respectively.
Truvada appears safe based on studies to date, but the tenofovir component has been associated with kidney problems in a small number of individuals. The abacavir in Epzicom can cause a potentially life-threatening allergic reaction in about 5-8% of people who use it. Anyone with known hypersensitivity to abacavir should not take Epzicom (or Trizivir). If such a reaction is suspected (symptoms may include skin rash, fever, nausea, abdominal pain, sore throat, cough, and/or shortness of breath), the drug should be stopped immediately and not restarted.
Both Epzicom and Truvada will sell for a wholesale price of about $800 per month. GSK announced that it would issue a limited supply of vouchers for a free two-month supply of Epzicom to people who are starting anti-HIV treatment or who need to change their regimens; it will also provide the combination pill at a much lower noprofit price in developing countries. Gilead will offer Truvada to HIV positive people in the U.S. who are unable to afford or obtain reimbursement for the product; this company, too, will provide its new combination pill to 68 developing countries (mostly in Africa) at the no-profit price of about $30 per month.
FDA Gives Final OK to Sculptra
The FDA announced in early August that it had granted approval for Sculptra (poly-L-lactic acid), a synthetic injectable polymer used to fill in sunken cheeks in people with HIV-related facial wasting, or lipoatrophy. Sculptra, manufactured by Dermik Laboratories, causes the body to produce collagen (a fibrous protein) to replace lost fat. As reported in the previous issue of BETA, an FDA advisory group recommended approval of Sculptra in March 2004. In four studies including a total of more than 250 participants (mostly white men), treated individuals reported good results, including improved appearance, reduced depression, and improved quality of life. As a condition of approval, the company agreed to conduct a postmarketing study that will include more women and people of color. Common side effects of Sculptra include pain, temporary bruising or swelling, and small nodules (lumps) under the skin; for optimal results, the product should be administered only by a trained practitioner. Because the substance is biodegradable, the therapy is not permanent and repeated injections may be necessary. Poly-L-lactic acid has been available for cosmetic use in Europe since 1999 under the name New-Fill. The recent U.S. approval covers only HIV-related facial fat loss, but the advisory panel expressed concern that once approved, the product could be used off-label for cosmetic purposes such as wrinkle reduction.
FDA Reviewing Once-Daily Kaletra, Approves New Invirase Pill
In July Abbott Laboratories submitted a supplemental new drug application (NDA) for a once-daily indication for its PI Kaletra (lopinavir boosted with ritonavir). The request is based on study data showing that once-daily and twice-daily Kaletra had similar efficacy when used in combination with FTC and tenofovir in treatment-naive people (ICAAC abstract H-570). In October the Kaletra product label was revised to include new longer-term data from two trials showing that the drug was still effective after 144 and 204 weeks. The revision also included a caution regarding increased blood concentrations of the drug in people with liver impairment due to hepatitis C, as well as some additional drug interactions. The revised label may be viewed at www.kaletra.com.
In related news, the FDA announced in December that it had approved Roche's new 500 mg tablet of hard-gel saquinavir (Invirase). The new formulation is smaller than the existing 200 mg pill, and only two are taken at a time (previously, the approved dose was five 200 mg tablets twice daily). Invirase should be used only if boosted with ritonavir (Norvir), which is necessary to enable optimal absorption (ICAAC abstract A-453).
Tipranavir Approval Requested
In late October Boehringer Ingelheim requested U.S. and European approval for tipranavir, its investigational nonpeptidic PI. The drug has been studied in treatment-experienced individuals as past research shows it works against HIV that has developed resistance to other drugs in its class. The NDA for tipranavir is based on data from two large Phase III trials, RESIST-1 and RESIST-2. At the 2004 ICAAC Charles Hicks, MD, presented interim data from RESIST-1 showing that twice-daily tipranavir boosted with ritonavir worked better than other ritonavir-boosted PIs (Kaletra, amprenavir [Agenerase], indinavir [Crixivan], or saquinavir [Invirase or Fortovase]) in subjects with PI-resistant HIV (late-breaker abstract H-1137). After 24 weeks, about 42% of subjects receiving tipranavir achieved at least a 90% decrease in viral load, compared with about 22% of those taking other PIs; in addition, about twice as many in the tipranavir arm achieved undetectable viral loads (below 400 copies/mL). Subjects receiving tipranavir were significantly more likely to experience severe (grade 3 or 4) ALT (liver enzyme) elevations than those taking other PIs (7% vs. 1%, respectively). Some research suggests that tipranavir reduces blood levels of other PIs, which could make it unsuitable for use in salvage regimens that combine multiple PIs. Boehringer is seeking accelerated approval from the FDA, and asked for a priority six-month review; if granted, the company expects that the drug may be available as soon as the spring of 2005.
Meanwhile, a new expanded access program (EAP) for tipranavir started on November 30. The drug will be available through physicians for people with limited treatment options who need tipranavir to construct a viable anti-HIV regimen. Eligible individuals will have previously used at least two PI-based regimens and have documented PI resistance. There are no viral load or CD4 cell count restrictions. Individuals enrolled in ongoing clinical trials of tipranavir are not eligible for the EAP. Physicians may register to participate in the program at www.tpv-eap.com. For more information about the program, visit the web site or call 888-524-8675.
In response to the pending commercial availability of tipranavir, which requires a high 400 mg boosting dose of ritonavir, the latter drug's manufacturer, Abbott Laboratories, announced that it would expand its Patient Assistance Program to provide high-dose ritonavir for free. Abbott came under fire in December 2003 when it increased the price of ritonavir by 400%. Under the new expansion, everyone is eligible for free high-dose ritonavir, including people obtaining their medications through private insurance, Medicaid/Medicare, or an AIDS Drug Assistance Program (ADAP). Physicians must request ritonavir for their patients. A lower dose of ritonavir (typically 100 mg) is used to boost several other PIs; people with private insurance or public benefits that cover the drug remain ineligible for free low-dose ritonavir. For more information, call 800-222-6885.
Priority Review for HIV/HCV Coinfection Treatment
The FDA announced in October that it would grant priority review status for Roche's Pegasys brand of pegylated interferon-alpha-2a plus ribavirin (Copegus) for the treatment of chronic hepatitis C virus (HCV) infection in individuals coinfected with HIV. The combination, which is already standard therapy for people with hepatitis C alone, could be approved for coinfected individuals by April 2005. The European Medicines Agency recommended approval of the regimen for this population this past December. As presented at the 2004 Retrovirus conference and reported in the previous issue of BETA, treatment with this combination in the APRICOT study yielded a sustained virological response (SVR) rate of 40% in coinfected subjects (62% for HCV genotypes 2 or 3; 29% for genotype 1, which is most common in the U.S. and is most difficult to treat). SVR refers to continued undetectable HCV viral load six months after the end of treatment. In the ACTG A5071 study, presented at the same conference, the SVR rate for Pegasys plus ribavirin was 27% (73% for genotypes 2 or 3; 14% for genotype 1). Both studies were published in the July 29, 2004 issue of the New England Journal of Medicine (NEJM).
First Generic Antiretroviral Approved
On December 3 the FDA announced the approval of a generic formulation of delayed-release ddI (didanosine), which is sold by Bristol-Myers Squibb under the brand name Videx EC. This is the first time a generic anti-HIV medication has received approval in the U.S., although several generic antiretroviral drugs and fixed-dose combinations are available in other countries. The new generic ddI, manufactured by Barr Laboratories, will be available in 200 mg, 250 mg, and 400 mg capsules, and has the same indications as the brand-name version of the drug.
Amprenavir to Be Withdrawn From Market
GlaxoSmithKline announced in September that it would discontinue the sale of its PI amprenavir (Agenerase) by the end of 2004 -- the first approved antiretroviral drug to be taken off the market. The move is due to decreased demand for amprenavir following the approval of fosamprenavir (Lexiva), a prodrug of amprenavir that reaches higher concentrations in the blood and allows users to take fewer pills. The latest revision of the federal HIV treatment guidelines includes fosamprenavir, but no longer amprenavir, as a preferred component of antiretroviral therapy.
Product Label Revisions
In July the FDA approved a new dosing regimen for atazanavir (Reyataz). For treatment-experienced individuals, the new recommended dose is 300 mg atazanavir (two 150 mg capsules) plus 100 mg ritonavir taken once daily with food. For treatment-naive people, the dose is still 400 mg (two 200 mg capsules) atazanavir once daily with food. The revised recommendation is based on data from Study AI424-045 showing that the new atazanavir/ritonavir dosing regimen worked as well as twice-daily Kaletra. After 48 weeks of treatment, 55% in the atazanavir arm and 57% in the Kaletra arm had HIV viral loads below 400 copies/mL (38% and 45%, respectively, below 50 copies/mL). The revised product label, which also includes new information about the use of atazanavir in first-line regimens, is available at www.reyataz.com.
The following month, the product label for efavirenz (Sustiva, or Stocrin outside the U.S.) was revised to expand the indication to include long-term therapy. The change is based on new clinical trial data from Study 006 showing that efavirenz remains effective after more than three years. After 168 weeks, 48% of subjects receiving efavirenz/AZT/3TC, 40% of those taking efavirenz/indinavir, and 29% of those taking indinavir/AZT/3TC achieved viral loads below 400 copies/mL (43%, 31%, and 23%, respectively, below 50 copies/mL). The revised label, which also includes new information on psychiatric side effects, hepatotoxicity, and drug interactions, can be viewed at www.sustiva.com.
Finally, product labels for several antiretroviral drugs were revised to include information on immune reconstitution syndrome (IRIS). This condition occurs when effective antiretroviral therapy improves immune function enough to cause the immune system to mount an inflammatory response to indolent (subclinical) or residual (low-level) opportunistic pathogens such as Mycobacterium avium, Mycobacterium tuberculosis, Pneumocystis carinii (now called P. jiroveci), or cytomegalovirus (CMV). When this happens, opportunistic illness symptoms may temporarily arise or worsen, since some such symptoms are caused by the immune system's response to a pathogen, rather than as a direct effect of the pathogen itself. For more information on IRIS, see "Immune Reconstitution Syndrome" in this issue.
Tenofovir in HIV/HBV-Coinfected Individuals
In July the tenofovir DF (Viread) product label was revised to add a "black box" warning that the drug is not indicated for the treatment of chronic hepatitis B virus (HBV) infection, and that it has not been shown to be safe or effective in HIV/HBV-coinfected individuals. Severe worsening of hepatitis B symptoms ("flares") have been reported in coinfected individuals who have stopped tenofovir. Such flares may also occur when stopping 3TC or FTC. It is recommended that HIV positive people be tested for HBV before starting antiretroviral therapy and have their liver function monitored for several months following discontinuation of tenofovir. Several studies have shown that tenofovir reduces HBV replication in coinfected individuals, but this use is still considered experimental and research is ongoing. The revised label, which also includes new information about drug interactions with atazanavir and Kaletra, is available at www.viread.com.
According to a report by Michael Lim, PharmD, and colleagues published in the August 15, 2004 issue of the Journal of Acquired Immune Deficiency Syndromes (JAIDS), the anticonvulsant drug phenytoin (Dilantin) may reduce blood concentrations of Kaletra, while Kaletra appears to increase phenytoin levels. This occurs because both drugs are metabolized by the same cytochrome P450 (CYP450) enzymes in the liver. The combination should be avoided or used with caution, including drug level monitoring, to avoid subtherapeutic Kaletra levels and/or intensified phenytoin side effects.
Erythromycin/PI Coadministration Increases Heart Risk
The common oral antibiotic erythromycin can increase the risk of sudden cardiac death when administered concurrently with PIs and other medications metabolized by the same CYP450 system of liver enzymes, researchers reported in the September 9, 2004 issue of NEJM. Erythromycin can prolong heart repolarization, causing potentially fatal heart rhythm disturbances. In people taking other drugs metabolized by the same CYP3A liver enzyme, blood concentrations of erythromycin may be higher, thus increasing the risk of adverse cardiac events. Wayne Ray and colleagues examined the medical records of Tennessee Medicaid recipients covering 5,305 total person-years (PY) of erythromycin use; during this time there were ten cases of sudden cardiac death with no known cause, for a rate of 1.2 per 1,000 PY. However, three such deaths occurred in people using erythromycin plus drugs metabolized by the CYP3A enzyme, for a sudden cardiac death rate of 15.5 per 1,000 PY in this subgroup. In a multivariate analysis, the adjusted rate of sudden cardiac death was twice as high among subjects using erythromycin, and five times as high among those using both erythromycin and CYP3A-inhibiting drugs. Although HIV positive individuals were not included in this analysis, PIs are known to be potent inhibitors of CYP3A activity. The researchers recommended that erythromycin not be used at the same time as CYP3A inhibitors.
Caution Regarding Tenofovir/ddI Combination
On November 12 Bristol-Myers Squibb issued a letter to health-care providers concerning data from two studies showing that use of tenofovir plus delayed-release ddI (Videx EC) plus either efavirenz or nevirapine (Viramune) led to virological failure in an unexpectedly high proportion of individuals. In one open-label study, six of 14 subjects using tenofovir/ddI/efavirenz experienced treatment failure, and a retrospective database analysis found that five of ten subjects on this regimen did not achieve HIV suppression. In another retrospective database analysis, two of four subjects receiving tenofovir/ddI/nevirapine experienced treatment failure. Virological failure tended to occur early and was most pronounced in people with high baseline viral loads. In October Gilead issued a warning letter regarding the high failure rate of tenofovir/ddI/3TC. While several triple-NRTI regimens have proven insufficiently potent, there has been concern about the tenofovir/ddI combination in particular. However, tenofovir/ddI has been shown to be effective in other studies, including one that found tenofovir/ddI to be a superior NRTI backbone in regimens containing boosted PIs. The company advised clinicians to exercise caution when administering tenofovir/ddI plus either efavirenz or nevirapine, and stated that further investigation is underway.
Viral Load and CD4 Cell Count
Several recent studies have examined anti-HIV treatment strategies and their relation to viral load and CD4 cell count.
Stephen Raffanti, MD, and colleagues with the Collaborations in HIV Outcomes Research/U.S. study reported in the September 1, 2004 issue of JAIDS that people with persistent, detectable but low-to-moderate viral load levels may continue to do well and are not necessarily at increased risk of HIV disease progression. The researchers, following more than 3,000 subjects for up to 4.3 years, found that people with viral loads between 400 and 20,000 copies/mL were no more likely to develop AIDS-defining illnesses or to die than people with HIV RNA levels below the 400 copies/mL limit of detection. Those with viral loads above 20,000 copies/mL, however, had a significantly higher risk of disease progression and death. Although clinical outcomes were similar for people with 400-20,000 copies/mL and those with fewer than 400 copies/mL, the subjects who maintained lower viral loads experienced greater CD4 cell increases (75 vs. 13 cells/mm3, respectively); subjects with more than 20,000 copies/mL lost an average of 23 cells/mm3. "These data suggest that maintenance of moderate viremia may confer clinical benefit not seen when viremia exceeds 20,000 copies/mL," the authors concluded. "[T]his should be taken into account when considering the risks and benefits of continuing failing therapy." These results do not change the optimal goal of achieving undetectable viral load; if it is possible to construct a more effective regimen, this should be done. However, the study does suggest that treatment-experienced individuals with limited remaining therapeutic options may benefit from staying on a "failing" regimen.
In the same issue, Colette Smith, MSc, and colleagues reported that viral load after four weeks of antiretroviral therapy could predict longer-term response. In their study, subjects who achieved a good early virological response were more likely to have undetectable HIV RNA at 24 weeks; 84% of subjects with fewer than 1,000 copies/mL, 61% of those with 1,001-10,000 copies/mL, 37% of those with 10,001-100,000 copies/mL, and 24% of those with more than 100,000 copies/mL at four weeks had HIV RNA levels below 50 copies/mL at week 24. The researchers calculated that for every 1 log change in viral load at four weeks, the odds of achieving an undetectable viral load at 24 weeks decreased by 65%. If treatment response after one month can be used to predict outcomes at six months, the four-week viral load measurement could help clinicians adjust therapy at an early stage in people who do not appear to be responding optimally, thus helping prevent the emergence of drug-resistant virus.
Finally, in the November 1, 2004 issue of the same journal, Daniel Skiest, MD, and colleagues reported that treatment interruptions appear safe for people who had nadir (lowest ever) CD4 cell counts above 350 cells/mm3 before starting antiretroviral therapy. The latest DHHS HIV treatment guidelines (see previous news item) recommend starting therapy when the CD4 cell count falls below 350 cells/mm3, but progression to AIDS is uncommon in people with counts above 200 CD4 cells/mm3. What to do if the CD4 count falls within the 200-350 cells/mm3 range remains uncertain. In Skiest's study of 107 subjects, the median CD4 cell count before starting therapy was 463 cells/mm3. After stopping HAART, CD4 counts declined by 8 cells/mm3 per month; viral load increased by about 2.54 log copies/mL during the first two months off therapy, but thereafter remained stable for the duration of the study. Subjects remained off therapy for a median of 8.9 months, and responded favorably when they restarted treatment. No AIDS-defining events were observed during ten months of follow-up. The results of this study suggest that people with nadir CD4 cell counts above 350 cells/mm3 may have started treatment "too soon," and thus can safely stop therapy; it does not, however, imply that structured treatment interruptions in general are safe.
Should Injection Drug Users Start Treatment Earlier?
Injection drug users (IDUs) may benefit from earlier treatment than other people with HIV, suggests a study published in the September 15, 2004 issue of the Journal of Infectious Diseases (JID). C. Cun-lin Wang and colleagues from the Baltimore-based AIDS Linked to Intravenous Experience (ALIVE) study analyzed data from 583 HIV positive and 920 HIV negative IDUs (about 75% male, 90% African American, median age about 42 years) between 1997 and 2000. The researchers found that during follow-up, the mortality rate from any cause was lowest among HIV negative IDUs (19.9 per 1,000 PY). Among HIV positive subjects, the all-cause mortality rate was 24.1 per 1,000 PY for those who started HAART with CD4 cell counts above 350 cells/mm3 (not significantly different from the rate in the HIV negative group), but 50.5 per 1,000 PY for those who started HAART with CD4 cell counts of 200-350 cells/mm3, and 86.7 per 1,000 PY for those who began treatment with CD4 cell counts below 200 cells/mm3.
Only IDUs who started therapy at CD4 cell levels above 350 cells/mm3 gained the full survival benefit from HAART. Looking at just AIDS-related mortality, the rates in HAART-treated and untreated IDUs were similar in those with more than 350 cells/mm3 or 200-350 cells/mm3; among those with fewer than 200 cells/mm3, however, HAART still conferred a significant survival benefit. Also, among individuals with 200-350 cells/mm3, higher viral loads were associated with poorer survival. The current DHHS guidelines (see previous news item) recommend initiating treatment when the CD4 cell count falls below 350 cells/mm3, although research suggests that most asymptomatic HIV positive people can safely wait until their CD4 cell counts approach 200 cells/mm3. But in IDUs, according to the authors, "to optimize survival ... initiation of HAART at CD4 cell levels higher than the current treatment guidelines indicate might be considered."
Anti-HIV Effect of Statins
According to a study in the August 16, 2004 issue of the Journal of Experimental Medicine, drugs in the statin class (e.g., pravastatin [Pravachol], atorvastatin [Lipitor]), which are used to reduce elevated cholesterol levels, appear to have activity against HIV both in the laboratory and in humans. Gustavo del Real and colleagues from the Spanish Council for Scientific Research found that statins inhibited HIV infection of cells both in vitro and in mice, apparently by preventing the virus from crossing host cell membranes, a process that requires adequate cholesterol levels. Further, administration of the drug lovastatin (Mevacor) was associated with modestly decreased HIV viral loads and increased CD4 cell counts in a small study of six treatment-naive HIV positive individuals (three of whom were coinfected with hepatitis C); after the statin was discontinued, viral load rebound occurred. Although this research is only at the proof-of-concept stage, it suggests that the low-cost statins could potentially be used as a component of anti-HIV therapy.
Further Risks of Smoking
According to a study presented at the Bangkok AIDS conference and the 70th annual meeting of the American College of Chest Physicians, HIV positive smokers are more likely to develop chronic obstructive pulmonary disease (COPD) than their HIV negative counterparts. Kristina Crothers, MD, of Yale University School of Medicine and colleagues studied 895 HIV positive and 653 HIV negative veterans. In this cohort, HIV positive individuals with a total of 40 pack-years of smoking had 5.5 times the risk of COPD as HIV negative people who smoked the same amount. After adjusting for various risk factors such as age and smoking history, subjects with HIV were 59% more likely to develop COPD. Crothers did not have a clear explanation for the findings, but suggested that "HAART therapy or HIV itself may be factors promoting COPD." She also found that HIV positive smokers tended to have higher viral loads than HIV positive nonsmokers, even though a similar percentage in both groups (90%) were on HAART. The smokers also reported lower quality of life scores and had a higher overall mortality rate. COPD is a progressive condition that is seen more often as people age; as people with HIV live longer, they are prone to this and other chronic problems associated with aging (see "Mortality Trends" in this issue). Clinicians should assess respiratory function in their HIV positive patients who exhibit persistent respiratory symptoms.
Uncommon Infection Seen in San Francisco, Europe
In late December the San Francisco Department of Public Health (SFDPH) announced that a rare sexually transmitted infection (STI), lymphogranuloma venereum (LGV), had been detected in four men who have sex with men in the city. LGV is caused by a strain of Chlamydia trachomatis, bacteria associated with the common STI chlamydiasis (chlamydia). While chlamydia often causes no symptoms or only mild genital discharge and/or pain, LGV may lead to genital and rectal ulcers, proctitis (rectal inflammation), constipation, flu-like symptoms, potentially severe gastrointestinal distress, and swollen lymph nodes (especially in the groin area). Although Dr. Sam Mitchell of the SFDPH said that HIV positive individuals are not known to be at higher risk for LGV, any STIs that cause open ulcers can increase the risk of HIV transmission.
LGV made the news earlier in 2004 when officials reported an outbreak of nearly 100 cases among gay and bisexual men in the Netherlands (an early cluster of 15 cases was reported in the October 1, 2004 issue of Clinical Infectious Diseases). Other isolated cases were detected in Britain, France, Belgium, and Sweden -- countries where the disease is also rare. LGV is more typically seen in tropical developing countries in Africa, Latin America, the Caribbean, and Asia. None of the San Francisco men with LGV reported having recently visited the Netherlands, suggesting the possibility of multiple independent outbreaks. LGV can be treated and cured with a three-week course of doxycycline, although eradication is more likely with an early diagnosis. The SFDPH recommends that all cases of rectal chlamydia be presumptively treated as if they were LGV. The risk of LGV transmission can be reduced by using condoms for anal sex.
Syphilis and HIV
Researchers and public health officials have expressed increasing concern in recent years about high rates of syphilis in certain groups of men infected with or at risk for HIV. Research shows that syphilis increases the likelihood of HIV acquisition and transmission, and the disease is an indicator of unprotected sexual activity. According to a Chicago Department of Public Health (CDPH) study published in the October 22, 2004 issue of Morbidity and Mortality Weekly Report, the incidence of syphilis is on the rise, and the disease can be spread through oral as well as anal or vaginal sex. In the 1998-2002 period, the CDPH recorded 1,582 cases of primary or secondary syphilis, or 11-12 cases per 100,000 persons. During this interval, the majority of cases shifted from heterosexuals throughout most of the 1990s to men who have sex with men (MSM) since 2001. Case rates declined dramatically among women (from 9.2 to 2.9 per 100,000), but increased among men (from 14.7 to 22.1 per 100,000). While 90% of heterosexual cases occurred in black individuals, the racial breakdown among MSM was 54% white, 26% black, and 13% Latino. Less than 10% of the heterosexual cases, but about half the cases among MSM, were in HIV positive people. Based on interviews and surveillance data, Carol Ciesielski, MD, and colleagues estimated that nearly 14% of Chicago syphilis cases are attributable to oral sex -- a rate that increases to just over 20% for gay and bisexual men. Use of barrier methods (condoms, dental dams) can protect against syphilis.
In related news, Kate Buchacz, PhD, from the Centers for Disease Control and Prevention (CDC) and colleagues reported in the October 21, 2004 issue of AIDS that syphilis is associated with higher HIV viral loads and lower CD4 cell counts. This retrospective review included data on 17 cases of primary and 35 cases of secondary syphilis in HIV positive men in San Francisco between 2001 and 2003. Among the 36 subjects with viral load results available before and during syphilis infection, HIV RNA levels increased during infection by a mean of 0.21 logs overall, and by 0.33 logs in the men with secondary syphilis. However, results varied by viral load at the time of syphilis infection; men on HAART and/or with undetectable HIV RNA were less likely to experience viral load spikes during syphilis infection than untreated men and/or those with detectable viral load. Although HIV viral load decreased after syphilis treatment, it remained above the presyphilis level. Among the 31 men with available CD4 cell measurements before and after syphilis, CD4 cell counts declined by a mean of 62 cells/mm3 during syphilis infection, with greater decreases among men with secondary syphilis and those not taking HAART.
These results indicate that syphilis likely increases HIV infectivity due to higher blood viral loads (the virus is more easily transmitted when an HIV positive person has a high viral load), as well as the presence of open sores, which allow the virus to gain entry to the body. This study underlines the importance of syphilis prevention initiatives for gay and bisexual men such as the San Francisco Department of Public Health's "Healthy Penis" campaign.
High HIV Levels in Rectal Secretions
Levels of HIV in rectal secretions are much higher than blood or semen HIV viral loads, according to a study in the July 1, 2004 issue of JID. Richard Zuckerman, MD, from the University of Washington in Seattle and colleagues studied 64 HIV positive MSM in Seattle and Lima, Peru. The researchers measured significantly higher HIV levels in rectal mucosa secretions than in semen or blood. The median HIV concentrations in the semen, blood, and rectal secretions were 3,550, 17,400, and 91,200 copies/mL, respectively. Higher HIV concentrations in rectal secretions were observed even in men taking HAART (42% of the study population), and antiretroviral therapy had less impact on rectal secretion viral load than on semen or blood viral load. Among the men on HAART, the median semen, blood, and rectal secretion viral loads were 1,000, 200, and 3,980 copies/mL, respectively; among the untreated men, the corresponding HIV RNA levels were 12,600, 63,100, and 316,000 copies/mL. In some cases, HIV was present in rectal secretions even when the virus was undetectable in the blood. However, rectal, semen, and blood viral loads were correlated; individuals who had higher HIV RNA in their blood also tended to have higher levels in their semen and rectal secretions. These results suggest that the "top" in anal sex may be at greater risk of HIV infection than previously believed, and reinforces the recommendation to use condoms for anal sex even if only the "bottom" is HIV positive.
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.