This report includes highlights from the 3rd International Workshop on Salvage Therapy for HIV Infection held April 12-14, 2000, in Chicago, and the 10th International Symposium on Viral Hepatitis and Liver Disease held April 9-13, 2000, in Atlanta. The Atlanta conference featured a few reports about coinfection with HIV and hepatitis C virus (HCV), an increasingly important issue in the HIV/AIDS pandemic.
What Is Salvage Therapy?
Experienced HIV researchers and clinicians at the Salvage Workshop discussed what salvage therapy means. Some believed it referred to a second-line regimen of therapy after having HIV viral rebound or never achieving viral undetectability with the first anti-HIV regimen. Others believed it referred to HIV positive persons who had detectable HIV RNA after several regimens that collectively represented all three anti-HIV drug classes. No consensus was reached, and salvage therapy is currently a nonspecific term. When seeing salvage therapy in connection with treatment for HIV, it is important to ascertain the specific anti-HIV drug history of the HIV positive persons in the study.
On the second day, the issue was extended to a discussion about the title of the workshop. John Mellors, MD, of the University of Pittsburgh and conference co-chair, led the discussion. A few community representatives were present. Some people felt that the term salvage has a negative connotation and that the title of the workshop should be changed. Some expressed the opinion that potentially negative terms, such as salvage, rescue (therapy), and (drug) failure, should not be used in the title. Dr. Mellors said that the organizing committee would attempt to resolve the issue after the workshop had concluded. It is possible that the title of next year's workshop will be different.
Why Is Salvage Therapy Important?
Unfortunately, only half of HIV positive persons achieve and maintain an undetectable HIV RNA viral load with their first regimen. (The exception to this would be higher rates of undetectability in a few more recent studies, such as combination regimens based on lopinavir/ritonavir [ABT-378/Norvir; the combination of the two drugs is now called Kaletra] or efavirenz [Sustiva].) As a general rule, the likelihood of achieving undetectability decreases with each successive anti-HIV regimen. Thus, finding a salvage regimen that will be successful in achieving and maintaining an undetectable viral load is important. The best combination and strategy will not necessarily be the same for every person with HIV.
How Successful Are Salvage Therapy Regimens?
Several speakers reported results of studies with second-, third-, or even fourth-line treatment regimens. Some results were discouraging, some more promising.
Five-drug salvage regimen leads to 78% viral undetectability after 60 weeks
- For induction therapy, all 92 participants were hospitalized
- One-half never reached undetectability or had viral rebound at week 76
Michael Youle, MBChB, of the Royal Free Centre for HIV Medicine in London, UK, presented the results of a study that had one of the better virologic success rates. The 92 people (13% women) who participated in the study had had previous virologic failure (at least 1,000 copies/mL of HIV RNA) with at least one regimen that contained a protease inhibitor (PI). All were hospitalized as a part of induction (initiation) therapy with a mean of five anti-HIV drugs. Even though 17% had previously taken nevirapine (Viramune), none had taken efavirenz. Both drugs are non-nucleoside reverse transcriptase inhibitors (NNRTIs).
The median CD4 cell count was 112 cells/mm3, with a median baseline HIV viral load of 5.5 log (309,000) copies/mL. AIDS was previously diagnosed in 58%. The previous number of anti-HIV drugs taken was a mean of 5.1, including 3 NRTIs (nucleoside reverse transcriptase inhibitors) and 1.7 PI drugs.
All study subjects were hospitalized during treatment induction. A specially designated health-care team included some who closely communicated with subjects to maximize adherence of doses and to help manage side effects. The number of physicians prescribing medications was strictly limited, to limit the number of therapeutic approaches and variability in prescribing.
The most common five-drug combination was efavirenz/ritonavir (Norvir)/indinavir (Crixivan)/ddI (Videx)/hydroxyurea (Hydrea). Hydroxyurea is an anticancer drug also used to treat sickle cell anemia. It was common for the physician and subject to agree to stop an intolerable drug in the regimen. The most commonly discontinued drug among the five was hydroxyurea.
The percentage of people who started each anti-HIV drug was as follows: efavirenz (100%), ddI (80%), ritonavir (75%), hydroxyurea (75%), indinavir (73%), d4T (Zerit) (36%), 3TC (Epivir) (26%), saquinavir soft gel (Fortovase) (16%), nelfinavir (Viracept) (12%), AZT (Retrovir) (5%), and abacavir (Ziagen) (5%). Doses of indinavir/ritonavir were either 800/200 or 800/400 mg, respectively, twice daily. Interestingly, some participants also received intravenous (IV) foscarnet (Foscavir) as an additional anti-HIV drug, even though it is FDA-approved to treat cytomegalovirus (CMV) infection (a common cause of blindness) and not HIV. The median time of follow-up in this observational trial was 41 weeks. The median frequency of viral load testing was once every 6.7 weeks. Some had periods of treatment interruption, but specifics were not reported.
Using a strict intent-to-treat analysis (all enrolled subjects included), the results showed that HIV viral undetectability occurred in 85% (limit of 400 copies/mL) by 30 weeks, with a plateau thereafter. Using an ultrasensitive test (limit of 50 copies/mL), 78% achieved undetectability by 60 weeks. Yet, by using a definition of two consecutive HIV RNA results greater than 400 copies/mL, approximately one-third who achieved undetectability (limit of 400 copies/mL) had viral rebound up to 76 weeks. If virologic failure were defined as two consecutive viral load results greater than 400 copies/mL or never achieving a level less than that, approximately half of all enrolled participants had failure by 60 weeks. Not surprisingly, those who had previously taken nevirapine fared worse virologically than those without previous NNRTI drug experience. Among those without previous nevirapine experience, approximately 25% had virologic failure at 32 weeks, compared to approximately 50% for those with previous nevirapine experience. After 64 weeks of follow-up, approximately 66% had achieved a CD4 cell count increase of at least 100 cells/mm3.
Discontinuation of at least one drug due to adverse events occurred in 37%. Dr. Youle did not mention the various types of adverse events. Ten subjects (11%) did develop new AIDS-defining conditions during the study.
The initial results in this study were impressive, although with a strong trend toward viral rebound. However, the regimen and strategy might be used to buy time until newer medications or strategies are available. Dr. Youle believes that the favorable outcomes were due to several specific factors: hospitalization for induction therapy; the initial inclusion of hydroxyurea; higher doses of indinavir/ritonavir; a specially devoted staff who were constantly in communication with study subjects to optimize adherence and manage side effects; treatment interruptions; intensification with 3TC, if appropriate; and a limited number of physicians prescribing medications.
There were some limitations in the study as it was presented. Dr. Youle was not specific about several factors that would have been helpful to know. Examples are the average number of drugs discontinued and when they were discontinued, the rate of dose reductions, the rate and duration of treatment interruptions, types of adverse events, and whether those who had CD4 cell count increases maintained or had additional increases or even decreases. Some measurement of adherence would have been useful. Also, baseline drug resistance testing, if it had been performed, would have been relevant, including its relationship to virologic outcome.
As was emphasized later at this workshop, the potential for adverse drug concentrations increases with increasingly complex anti-HIV regimens. It is quite possible that virologic failure in this study was associated with blood levels of anti-HIV drugs that were subtherapeutic (too low). In addition, in an era of managed care in the U.S. and elsewhere, access to hospitalization for induction therapy and specially dedicated staff for constant communication are unlikely luxuries. The additional costs of those components will surely increase the overall cost of care for persons with HIV. Lastly, quality-of-life measurements of participants would have been helpful.
Youle, M. and others. Prolonged viral suppression after introduction of a post HAART salvage regimen. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 23.
W. David Hardy, MD, from Pacific Oaks Research in Beverly Hills, CA, reviewed the results of Study ICC-605. This small study enrolled 25 subjects who had a detectable HIV RNA viral load (at least 2,000 copies/mL) while taking a PI-based regimen for at least six months. Study subjects also must have never taken an NNRTI or any of the drugs in the regimen of this study. The median baseline viral load was 4.6 log (39,810) copies/mL, with a CD4 cell count of 178 cells/mm3. The new four-drug regimen was abacavir 300 mg twice daily, amprenavir (Agenerase) 1,200 mg twice daily, efavirenz 600 mg once daily, and adefovir (formerly called Preveon) 60 mg once daily. This represents one drug from each of the FDA-approved anti-HIV drug classes plus the experimental nucleotide reverse transcriptase inhibitor drug called adefovir. (Gilead Sciences has discontinued development of adefovir for HIV, although they are pursuing development as an anti-HBV [hepatitis B virus] drug at a much lower dose.) There was only one, open-label arm in the study.
The results, using a strict intent-to-treat analysis, were that 32% had an undetectable viral load (limit of 500 copies/mL) at 24 weeks. However, eleven (44%) discontinued early. Four discontinued due to detectable virus, three due to adverse events, three due to nonadherence, and one due to "other." In an as-treated analysis (discontinuing subjects excluded), 62% of 13 subjects had an undetectable viral load (limit of 500 copies/mL) at 24 weeks and 54% did so with a lower limit of 50 copies/mL. The median CD4 cell increase at that time was 44 cells/mm3. Eleven subjects added ritonavir 100 mg twice daily to increase blood levels of amprenavir. This option was added to the protocol after the study was started. The most frequent adverse events were gastrointestinal (stomach-colon) or neurological (e.g., dizziness, sleep problems). A few had severe (grade 3) or life-threatening (grade 4) abnormal laboratory values. Unfortunately, the overall results of the study were somewhat disappointing.
Hardy, W.D. and others. ICC-605: a pilot study of abacavir + amprenavir + efavirenz + adefovir in PI- and NRTI-experienced HIV-infected subjects. 3rd International Workshop on Salvage Therapy in HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 20.
AIDS Clinical Trials Group 359
This complex study, presented by Roy M. Gulick, MD, of Cornell University, included six study arms. (ACTG stands for AIDS Clinical Trials Group.) A factorial design (a particular type of statistical analysis) was used to compare different combinations of drugs. The 277 HIV positive persons had at least 2,000 copies/mL of HIV RNA after more than six months of indinavir combination therapy. None had taken NNRTIs. The six arms of the study were
- Saquinavir (Fortovase) 400 mg twice daily, ritonavir 400 mg twice daily, and delavirdine (Rescriptor) 600 mg twice daily;
- Saquinavir (same dose), ritonavir (same dose), and adefovir 120 mg once daily;
- Saquinavir (same dose), ritonavir (same dose), adefovir (same dose), and delavirdine (same dose as in arm number one);
- Saquinavir 800 mg 3-times daily, nelfinavir (Viracept) 750 mg 3 times daily, and delavirdine (same dose);
- Saquinavir (same dose as in number 4), nelfinavir (same dose as in number 4), and adefovir (same dose);
- Saquinavir (same dose as in number 4), nelfinavir (same dose as in number 4), adefovir (same dose), and delavirdine (same dose).
The median baseline HIV RNA viral load was 4.5 log (31,746) copies/mL, with a median CD4 cell count that was not reported in the abstract. At 16 weeks, only 30% had an undetectable viral load (limit of 500 copies/mL). The percentages with an undetectable viral load were (1) 33%, (2) 20%, (3) 31%, (4) 47%, (5) 16%, and (6) 38%. Statistical analyses showed a significantly greater proportion with undetectable virus in the delavirdine-containing arms than in the adefovir-containing arms. However, no significant difference appeared when comparing the three ritonavir-containing arms with the three nelfinavir-containing arms. Also, there was no significant difference when comparing the delavirdine-containing (without adefovir) arms with the delavirdine plus adefovir-containing arms. Among the 30% who had an undetectable viral load at 16 weeks, only 55% of them (17% of the total) still were undetectable at week 48. CD4 cell count changes were not reported in the abstract.
Gulick, R.M. and others. Salvage therapy with saquinavir in combination with ritonavir or nelfinavir plus delavirdine, adefovir, or both -- ACTG 359. 3rd International Workshop on Salvage Therapy in HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 19.
AIDS Clinical Trials Group 398
The results of this study were presented by John Mellors, MD, of the University of Pittsburgh. ACTG 398 was designed to determine whether a second PI would be helpful when added to a salvage regimen that included standard doses of amprenavir (1,200 mg twice daily), abacavir (300 mg twice daily), efavirenz (600 mg once daily), and adefovir (60 mg once daily with L-carnitine daily).
A total of 481 HIV positive persons were enrolled. All had treatment experience with one to three PIs, and all had an HIV RNA viral load of at least 1,000 copies/mL. Participants were randomized to one of four treatment arms, depending upon their PI drug history. The four arms all took the above-mentioned four anti-HIV medications. The second PI in the four arms was (1) saquinavir 1,600 mg twice daily; (2) indinavir 1,200 mg twice daily; (3) nelfinavir 1,250 mg twice daily; and (4) placebo, or inactive drug. Enrollment also was stratified by experience with any NNRTI. The median baseline HIV RNA was 4.7 log (51,601) copies/mL, with a median CD4 cell count of 202 cells/mm3. Forty-four percent had previously taken an NNRTI.
After 24 weeks, 31% had an undetectable viral load (limit of 200 copies/mL), with rates in the four arms that were (1) 34%, (2) 36%, (3) 34%, and (4) 23%. A strict intent-to-treat analysis was used. When comparing the placebo arm (4) to all three of the double PI drug arms, the results were statistically significant. Also, a significantly greater percentage achieved undetectability if there had been no previous NNRTI experience (43%) than among those with previous NNRTI experience (16%). There also was a trend toward a higher undetectability rate among those with one PI drug experience than among those with multiple PI drug experience. At 24 weeks, 7% of enrollees had discontinued from the study, 33% were off drugs due to toxicity, and 19% were off study due to detectable viral load. CD4 cell count changes were not reported in the abstract.
Dr. Mellors concluded that HIV undetectability at 24 weeks was only 31%, despite four to five new anti-HIV drugs. Also, the dual PI drugs arms performed better than the placebo or single PI drug arm. In addition, prior experience with NNRTI drug(s) was significantly associated with inability to achieve viral undetectability, while prior PI experience (at least two PIs) was marginally associated with a poorer virologic outcome than experience with only one PI drug. Lastly, the off-treatment rates were high, indicating that "more effective and better tolerated salvage regimens are needed."
Mellors, J. and others. A randomized-placebo-controlled trial of saquinavir soft gel, indinavir, or nelfinavir in combination with amprenavir, abacavir, efavirenz, and adefovir in people with protease inhibitor failure. 3rd International Workshop on Salvage Therapy in HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 21.
Multi-drug Rescue Therapy
Julio Montaner, MD, from the British Columbia Centre for Excellence in HIV/AIDS in Canada, presented an update of his multi-drug rescue therapy (MDRT) among heavily pre-treated individuals with HIV. This group had more treatment experience than in the studies described above. The MDRT protocol called for using up to nine "recycled" anti-HIV drugs as a part of the new regimen. This included up to four NRTIs, two PIs, and two NNRTIs, with or without hydroxyurea. The 245 persons enrolled in the study were divided into three different time periods. Group I was enrolled before June 1998, Group II between July and December of 1998, and Group III between January and May of 1999. All three groups had an approximate median baseline viral load of 4.8 log (56,500-63,700) copies/mL. The median number of anti-HIV drugs that was started for each group was (I) five, (II) seven, and (III) six.
After 47 to 57 weeks, 40% of Group I achieved viral load undetectability (limit of 400 copies/mL) using a strict intent-to-treat analysis. After 25 to 35 weeks, 44% of Group II and 34% of Group III had an undetectable viral load (same limit). However, toxicity was very high, and many participants had to stop part or all of their therapy for varying durations. For Group I, baseline phenotype drug resistance testing revealed that sensitivity (not resistance) to 3TC, d4T, ddI, and saquinavir (Fortovase) was significantly correlated with a favorable virologic response. (Phenotypic drug resistance testing measures HIV growth of a person's dominant strain when each of the FDA-approved drugs is added. To do this, the reverse transcriptase and protease genes are removed from the person's HIV strain and subsequently inserted into a laboratory HIV strain.)
Montaner, J.S.G. and others. Multi-drug rescue therapy (MDRT) in three cohorts of HIV-positive individuals. 3rd International Workshop on Salvage Therapy in HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 24.
Indinavir plus Ritonavir Four-drug Combination
One salvage study with better results than most was presented by Howard Grossman, MD, from New York City. In order to achieve a higher level of indinavir with fewer side effects, 800 mg of the drug were combined with 200 mg of ritonavir, each twice daily in combination with a median of two NRTIs, with or without an NNRTI. The twice-daily dosing with 800 mg indinavir plus 200 mg ritonavir achieves even better drug concentrations than occurs with the previously popular dose of 400 mg of each, twice daily. The pharmacokinetics (drug concentration, metabolism, and distribution within the body) of these dual PI regimens are significantly improved with increased minimum (trough) and area-under-the-curve (AUC, or total drug exposure) concentrations and a mild decrease in the maximum, or peak concentration (compared with indinavir monotherapy with standard dosing). Also, there are no food restrictions, fluid requirements, or reported kidney stone complications with either dual-PI drug combination regimen.
This small study with 41 participants (no women, 27% non-White) was open-label and was analyzed retrospectively by chart review. The study took place at three clinics. The regimen was second-line, or salvage therapy. Included were those who had taken the newer indinavir/ritonavir dosing above, in combination with a median of two NRTIs (with or without an NNRTI) for at least eight weeks after having had a detectable viral load previously with at least one PI drug combination. Before entry into the current study, all enrollees had taken a mean of six anti-HIV regimens. Seventy-three percent had previously taken an NNRTI.
The median baseline CD4 cell count was 258 cells/mm3, with a median HIV RNA viral load of 4.5 log (30,015) copies/mL. An NNRTI was included in 71% of enrollees' regimens, including 24% who had never taken one. At the time of the chart analysis, the mean duration of the new regimen was seven months.
After 12 weeks, 51% achieved an undetectable viral load (limit of 400 copies/mL). For the 30 participants who completed 24 weeks, 57% had an undetectable viral load. Only 10 enrollees completed 36 weeks: their viral load undetectability rate was 63%. The CD4 cell count increase for the 40 subjects who completed 12 weeks with a level in the chart was approximately 35 cells/mm3. The CD4 cell count increase was approximately 80 cells/mm3 for the 28 subjects who completed 24 weeks and who had a level in the chart. The discontinuation rate was only 5% (2 subjects) and was due to hair loss in one and nausea/vomiting in the other. Other side effects were paresthesias (numbness/tingling), rash, dry skin, diarrhea, and bloody urine in 5% of enrollees. However, there were no reports of kidney stones or flank/groin pain that can occur with standard indinavir dosing without ritonavir.
Using the twice-daily dosing of both indinavir 800 mg and ritonavir 200 mg with NRTI drug(s), with or without an NNRTI, in a highly therapy-experienced group, appeared to be promising based on this retrospective and small study. The rates of viral undetectability were good, and were similar to those in treatment-naive persons.
Unfortunately, the authors did not report their results when controlling for those who had taken an NNRTI in their new regimen and for those who had had prior experience with that drug class. It is quite possible that adding an NNRTI into the regimen of those without experience to that drug class might have represented a major proportion of those who had HIV RNA undetectability. However, such subsets would have had only small numbers of subjects, limiting statistical analysis. Another limitation was the small size of the study and short follow-up. Also, the study is retrospective (after the fact), which carries less weight than a prospective and preferably randomized study. Lastly, drug resistance tests were not reported and possibly not performed. Baseline drug resistance tests might have added predictive value as to which persons would respond. Additional follow-up is expected, since the study is ongoing. The authors anticipate that more people will be enrolled.
Campo, R.E. and others. Efficacy of indinavir/ritonavir-based regimens among patients with prior protease inhibitor failure. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and poster presentation 7.
Condra, J.H. and others. Resistance to HIV-1 protease inhibitors and predicted responses to therapy. 3rd Salvage Therapy Workshop. Abstract and oral/poster presentation 2.
Grossman H.A. and others. Salvage therapy with twice-daily indinavir (Crixivan) 800 mg plus ritonavir (Norvir) 200 mg regimen in clinical practice. 3rd Salvage Therapy Workshop. Abstract and poster presentation 27.
Drug Treatment Interruptions: More from the Frankfurt Cohort
Veronica Miller, PhD, of J.W. Goethe Universität in Frankfurt, Germany, first presented her group's observations about drug treatment interruptions in 39 persons from her institution (known as the Frankfurt cohort) at the 2nd International Workshop on Salvage Therapy for HIV Infection held one year ago in Toronto.
To review briefly last year's report, the 39 people had multi-drug resistant HIV and at least two months of a treatment interruption. During the interruption, Dr. Miller measured a median decrease in the CD4 cell count of 89 cells/mm3, with an approximate viral load increase of 0.7 log (5-fold) copies/mL. That CD4 cell count decrease placed many of them at risk for life-threatening AIDS-related opportunistic illnesses, or OIs. Quite surprisingly, Dr. Miller reported that 66% of those 39 subjects had a shift in their dominant HIV strain from multi-drug resistant to wild type (without mutations). The other 34% maintained the same pattern of drug resistance and did not have a shift during the treatment interruption. She found that those who shifted to wild type had a much higher CD4 cell count (approximate mean of 150 cells/mm3) at the start of the interruption than those whose HIV did not shift (approximately 50 cells/mm3). After a new regimen was started, those whose dominant HIV shifted to wild type during the interruption were more likely to achieve viral load undetectability, a greater decrease in the viral load, and a higher CD4 cell count increase than those whose dominant HIV strain did not shift to wild type.
This year Dr. Miller presented additional information about the original group of 39 participants. Thirty-three had a virologic response to a new anti-HIV regimen after the interruption. The mean follow-up time after responding was 385 days. Among the responders, 24 (73%) did have subsequent viral rebound within a median of 78 days. There was a nonsignificant trend toward a more durable virologic response with the new regimen among the "shifters" (25% maintained viral undetectability) than among "nonshifters" (none maintained undetectability). Immunologically, 74% did achieve a return of CD4 cell count to within 90% of the preinterruption level after a new regimen was started. However, a median duration of 251 days (more than eight months) was required to reach that endpoint.
Then, Dr. Miller reported observations during a treatment interruption of at least two months among a larger, expanded group of 165 participants (21% women) using the entire Frankfurt cohort of persons with HIV infection. Another requirement for being included in this new group was a history of a viral rebound to at least 5,000 copies/mL during the interruption, after having taken a regimen of at least three anti-HIV drugs.
The mean duration of the treatment interruption in this larger group was 126 days. There was a mean CD4 cell count decrease of 31 cells/mm3, with a mean viral load increase of 0.48 log copies/mL. The mean lowest (nadir) CD4 cell count during the interruption was 66 cells/mm3, placing many at risk for an AIDS-defining OI. Note that these changes are milder than those in the original smaller group.
After the CD4 cell nadir, the mean follow-up time was 408 days. In this larger group of 165 subjects, 64% did respond to a new regimen after the treatment interruption. However, 86% of them subsequently had HIV viral rebound. Dr. Miller then presented correlates of those findings. Those with higher CD4 cell counts at the start of the interruption were significantly less likely to have viral rebound; in contrast, those with a lower CD4 cell nadir were significantly more likely to have rebound. Unfortunately, drug resistance results were not included in the analyses. Therefore, the results of the current multivariate analyses might be misleading, since they could be different after the resistance information is included.
In this expanded group of participants, 75% did have a recovery of CD4 cell count to within 90% of the pre-interruption level after starting a new regimen. However, the median time was three months, compared with eight months for the original smaller cohort. During the treatment interruptions, 17 documented new AIDS-defining conditions occurred in 15 different participants. Those included five different types of opportunistic infections (OIs), wasting syndrome, encephalopathy (brain disease), and Kaposi's sarcoma (KS, a cancer primarily due to human herpesvirus type 8 [HHV8]).
Much is still unknown about treatment interruptions, but several ongoing studies will help to clarify the potential benefits and related risks with this very experimental approach to treating persons with HIV infection. In her next round of analysis, Dr. Miller will be able to include the resistance data of the expanded group that is being analyzed.
WARNING: Drug treatment interruptions are risky. For most people, the HIV RNA viral load increases and the CD4 cell count decreases. The decreased CD4 cell count might place many at risk for AIDS-defining, life-threatening OIs. Note that this happened to some of Dr. Miller's study subjects. Another risk is that HIV might be able to seed previously uninfected cells or reseed different types of immune cells and various body compartments. Theoretically, this might make HIV eradication in the future more difficult, when and if a cure is discovered. Do not start a treatment interruption without discussing the issue fully with a physician.
Miller, V. and others. Antiretroviral treatment interruptions in patients with treatment failure: analyses from the Frankfurt HIV Cohort. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 25.
Miller, V. and others. Abstract and oral presentation at the 2nd International Workshop on Salvage Therapy for HIV Infection. May 19-21, 1999.
New Drug Resistance at a Low Viral Load May Predict Viral Rebound
Neil T. Parkin, PhD, of ViroLogic in South San Francisco, CA, presented the results of a small, 16-person study about predicting virologic failure with a new regimen. In ten people who experienced viral rebound, new drug resistance mutations at a low viral load (fewer than 1,000 copies/mL) were detected. In six other people, who did not experience rebound after at least 24 weeks, new drug resistance mutations were not detected.
The study was a retrospective analysis using the PhenoSense HIV phenotype drug resistance test. Genotypic resistance testing also was performed for additional correlations. (Genotypic drug resistance testing evaluates the presence or absence of gene mutations in a person's dominant HIV strain that previously have been associated with resistance to the drug being tested or the class of the drug being tested.)
The 16 study subjects originally had a detectable viral load with their first PI-containing regimen. Then, they were switched to a four-drug regimen: (1) nelfinavir (1,250 mg twice daily, PI drug); (2) saquinavir soft gel (1,200 mg twice daily, PI drug); (3) abacavir (NRTI drug); and (4) either one other NRTI drug or nevirapine (NNRTI drug). Blood samples were evaluated periodically for drug resistance.
Dr. Parkin's results were that drug resistance could be measured at a level as low as 260 copies/mL. In the ten participants who had drug failure, all had HIV that was susceptible to one to three drugs at baseline. Yet, at the time of their drug failure, 100% developed resistance to one to three drugs in their respective regimens. The duration until new drug resistance developed ranged from 4 to 36 weeks. Also, the time to drug failure was 4 to 26 weeks. Drug resistance was detected before drug failure in 70% and simultaneously in the other 30%. (Several weeks elapsed between blood samplings. Therefore, drug resistance might have developed prior to drug failure in this 30%; however, there was no blood sample for proof.) Eleven weeks was the longest interval between detecting drug resistance and drug failure. No new mutations were detected in the six people who maintained viral undetectability (limit of 50 copies/mL). Detecting new resistance at a low viral load might allow for intervening with drug intensification or a change of the regimen with the goal of potentially avoiding continued rebound in the future.
This small study was a retrospective analysis, which carries less statistical weight than a prospective analysis. A larger, prospective study is therefore needed to establish the implications of this trial. If finding resistance at a low viral load and intensifying or changing the regimen led to long-term viral undetectability, then more frequent viral load testing might significantly benefit people with HIV infection. A separate cost analysis would help to determine whether more frequent testing would fall into a range of comparable cost-effective interventions in health-care delivery. Notwithstanding these limitations, Dr. Parkin's results are provocative and might have tremendous implications for persons with HIV.
Parkin, N.T. and others. Detection of reduced drug susceptibility at low viral loads (
Negative Drug Interaction with Amprenavir and Efavirenz Is Avoided by Adding Ritonavir
Jean-Louis Vilde, MD, of the Hôpital Bichat in Paris presented the results of a study indicating that the triple combination of amprenavir/efavirenz/ritonavir avoids the negative interaction when the first two are used alone. In that situation, amprenavir levels in blood are reduced significantly by efavirenz. However, adding low-dose ritonavir and also reducing the amprenavir dose leads to an even higher amprenavir blood level than with amprenavir monotherapy using the FDA-approved dose of 1,200 mg twice daily. The doses of the three drugs in Dr. Vilde's presentation were amprenavir 450 mg twice daily, ritonavir 100 mg twice daily, and efavirenz 600 mg once daily. The example used the three drugs in combination with two NRTI drugs.
After two weeks in the current study, seven persons had a steady-state (stable) minimum concentration of amprenavir that was 1,380 nanograms/mL, approximately five-fold higher than what is achieved with standard dosing of amprenavir without ritonavir. That level in the current study is ten-fold higher than the IC50 (concentration that will inhibit 50% of HIV growth in the laboratory) of drug resistant HIV and thirty-fold higher than the IC50 of wild-type HIV. Also, the variability of the minimum concentration among study subjects was significantly less than it was during the first two weeks. Dr. Vilde did not present AUC concentration results. However, in the few studies to date that have examined this issue for PI drugs, the minimum concentration was a better determinant of anti-HIV benefits than the AUC concentration. Increasingly, physicians have been starting people on a double PI drug regimen (rather than a single PI drug in combination) in which one drug is ritonavir, or adding it to an existing single PI drug-based regimen.
Dr. Vilde also presented short-term virologic and immunologic benefits of the five-drug regimen in a small study. Seven persons with HIV had had significant anti-HIV drug exposure, including a PI drug(s). The mean baseline viral load was 5.3 log (194,984) copies/mL, while the CD4 cell count was 186 cells/mm3. After four weeks, the mean viral load was reduced to 3.2 log (1,584) copies/mL, with 86% achieving a viral load below 3 log (1,000) copies/mL. Forty-three percent had an undetectable viral load (limit of 500 copies/mL). The mean CD4 cell count increase was 69 cells/mm3. Possible side effects from the higher minimum blood concentration of amprenavir were not discussed.
Duvall, X. and others. Addition of ritonavir to amprenavir counteracts the negative effect of efavirenz on amprenavir concentrations. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 15.
Piscitelli, S. and others. The addition of a second protease inhibitor eliminates amprenavir-efavirenz drug interactions and increases plasma amprenavir concentrations. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30-February 2, 2000. Abstract and poster presentation 78.
Two NNRTI Drugs in the Same Regimen?
One presentation at the Salvage Therapy Workshop, by Alicia Tesiorowski, MD, of the University of British Columbia, Canada, addressed using two NNRTI drugs in the same regimen. The 7th Conference on Retroviruses and Opportunistic Infections (CROI), held January 30-February 2, 2000, in San Francisco featured a few presentations about the pharmacokinetics of dual NNRTI therapy.
Dr. Tesiorowski discussed drug concentrations among HIV positive persons taking nevirapine with either efavirenz or delavirdine. With either of the two combinations, the mean minimum blood serum concentrations of nevirapine were not changed significantly, with levels that were approximately 80% of historical control measurements with nevirapine monotherapy. However, in either combination, the level of the other NNRTI drug was significantly reduced. Delavirdine's mean minimum serum level was reduced to 23% of the level in historical controls. And, when combined with nevirapine, the mean minimum serum level of efavirenz was reduced to 33% of the level in historical controls. However, Dr. Tesiorowski commented that either of those reduced concentrations still were significantly greater than the IC90 (inhibitory concentration that will block 90% of wild-type HIV growth in the laboratory) for each. For example, the reduced concentration of efavirenz was still at least 74 times greater than the IC90 of wild-type HIV, while that for delavirdine was still at least 35-fold greater than the IC90 of wild type. Therefore, Dr. Tesiorowski indicated that an increased dose of either efavirenz or delavirdine would not be required. The people in her study were taking up to nine anti-HIV drugs in multidrug rescue therapy. Thus, they were also taking PI drugs that might have altered blood levels of the NNRTI drugs that could have confounded her results.
Somewhat different results were presented in a report at the 7th CROI. A.I. Veldkamp, MD, and colleagues from Slotervaart Hospital in the Netherlands examined drug interactions with two NNRTI drugs. They tested a standard lead-in dose of once-daily nevirapine in combination with efavirenz in 12 persons with HIV. Efavirenz levels were significantly decreased by 36% (minimum concentration), and the AUC concentration was decreased by 22%. Blood levels of nevirapine were not changed significantly. The researchers concluded that when nevirapine is combined with efavirenz, "it may be appropriate to increase the dose of EFV [efavirenz] to 800 mg qd [daily]."
Harris, M. and others. Evaluation of the pharmacokinetics of the concurrent administration of two nNRTIs, nevirapine/delavirdine and nevirapine/efavirenz, in patients receiving multi-drug rescue therapy. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 14.
Veldkamp, A.I. and others. DONUT: the pharmacokinetics (PK) of once-daily nevirapine (NVP) and efavirenz (EFV) when used in combination. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30-February 2, 2000. Abstract and poster presentation 80.
Oral L-Acetyl Carnitine Improves HIV-related Peripheral Neuropathy
Michael Youle, MBChB, presented a very interesting report about treatment for peripheral neuropathy (tingling/numbness/burning in the feet and sometimes hands). This condition is present in 33% of persons with HIV infection. It is also a common side effect of the "d" drugs in the NRTI drug class -- ddC (Hivid), ddI, and d4T.
Other causes include diabetes, the antibiotics isoniazid (Nydrazid) and dapsone (Avlosulfon), the cancer chemotherapy drug vincristine (Oncovin), vitamin B12 deficiency, and chronic alcoholism. In persons with HIV infection, peripheral neuropathy is associated with toxicity to mitochondria (energy-producing component of cells) that may be caused to varying degrees by drugs within the NRTI class (see the detailed report about this topic in this issue of BETA).
The treatment for mild peripheral neuropathy (i.e., that does not interfere with everyday functioning) in people taking any of the "d" NRTI drugs is to stop that medication(s). Other treatments help to ease the symptoms, including amitriptyline (Elavil, an antidepressant drug), lamotrigine (Lamictal, an anti-seizure drug), topical lidocaine (Lidoderm), or pain relievers (acetaminophen or Tylenol, NSAIDs [non-steroidal anti-inflammatory drugs, including Motrin and Aleve]) that might include narcotics. Recombinant (manufactured) human nerve growth factor is an experimental treatment. Acupuncture may also help.
Dr. Youle's small observational study treated HIV-related peripheral neuropathy with oral L-acetyl carnitine (LAC). He found that 1,500 mg twice daily of the supplement orally led to improved symptoms after several months. The improvement in symptoms was associated with an increase in nerve tissue staining on biopsy samples from four subjects. This was accomplished using immunohistochemical (IHC) staining of nerve tissue. IHC uses a dye that is tagged with antibodies directed against nerve tissue. A previous study showed abnormally decreased IHC staining of nerve tissue even before numbness and tingling symptoms occurred in HIV negative diabetics who subsequently were diagnosed with peripheral neuropathy.
LAC naturally occurs in the body and is derived from the amino acid carnitine. It facilitates the normal oxidation and movement of free fatty acids into mitochondria within cells. LAC also helps to maintain living nerve cells in tissue culture in the laboratory. In a diabetes animal model of peripheral neuropathy, supplementing the diet with LAC improved the neuropathy. In a separate study, LAC improved nerve regeneration. Interestingly, in those who are HIV positive with peripheral neuropathy due to d4T, ddI, or ddC, blood serum (liquid portion without cells) shows abnormally low levels of LAC. Previously, one small study showed that LAC supplements in persons with HIV-related peripheral neuropathy improved symptoms.
In the current study, three HIV positive persons with peripheral neuropathy continued the same regimen without stopping their NRTI drug(s). Skin biopsies with nerve tissue were taken from the lower leg at baseline and six months after starting LAC therapy. The biopsies were stained by IHC for "innervation" by three types of nerve fibers: (1) small sensory C and A-delta fibers (CGRP), (2) pan-neuronal fibers (PGP 9.5), and (3) cholinergic efferent sympathetic fibers (VIP). The area of staining for each biopsy was measured by computer using quantitative image analysis.
Dr. Youle showed pictures of representative biopsy samples that were stained by IHC and measured. Tissues examined included sweat glands in the skin that normally have nerve tissue attachments (innervation), the epidermis (top skin layer), and dermis (lower skin layer). Comparisons of the stained biopsies from his study participants before and after LAC showed an increase in staining, both in percentage of area stained and in intensity of staining. The changes in the biopsy samples were accompanied by improvements in participants' symptoms of peripheral neuropathy, particularly dysaesthetic ("phantom") pain. Several months of LAC therapy were required before symptoms improved. Dr. Youle said that one of his participants had required narcotic pain medication before LAC and no longer needed it several months after LAC therapy.
In his clinic, Dr. Youle has about 60 to 70 people taking LAC for HIV-related peripheral neuropathy. The only adverse symptom reported is mild diarrhea. Dr. Youle did not say whether participants had any changes in standard blood or urine tests or in viral load. He did not know whether LAC entered the cerebrospinal fluid (CSF) around the brain and spinal cord or whether it might benefit AIDS-related dementia (loss of brain function). He emphasized, however, that L-acetyl carnitine is not the same as carnitine that is commonly available in many vitamin stores as a dietary supplement.
As this article goes to press, long-term larger studies using LAC have not been reported. The exact dose is unknown, as are potential toxicities that would be revealed only in larger studies. Also, adverse drug interactions, particularly with anti-HIV medications, are unknown. Persons with HIV should always discuss with their physicians before taking any medication or supplement.
De Simone, C. and others. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS 8(5):655-60. May 1994
Famularo, G. and others. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS 11(2):185-90. February 1997
Famularo, G. and others. Carnitine stands on its own in HIV infection treatment. Archives of Internal Medicine 159(10):1143-4. May 24, 1999
Hart, A.M. and others. Immunohistochemical quantification of cutaneous innervation in HIV-associated peripheral neuropathy: a study of L-acetyl carnitine therapy. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral presentation 36.
Virmani, M.A. and others. Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacologic Research 32(6):383-9. December 1995
Poor Adherence Associated with Increased AIDS Progression and Death
Poor adherence to dosing of anti-HIV therapy is associated with a decreased rate of achieving or maintaining viral load undetectability. In one study of incarcerated subjects, 100% adherence to dosing for one year was associated with an 85-100% rate of viral undetectability (see conference notes from 7th CROI in the Spring 2000 issue of BETA). In a new study, researchers from the British Columbia Centre for Excellence in HIV/AIDS report for the first time that not adhering to dosing of anti-HIV therapy accompanies a significant increase in progression to AIDS and death. The presenting author was Julio S.G. Montaner, MD.
Study entry required starting highly active antiretroviral therapy (HAART) between August 1996 and December 1998 in British Columbia. HAART meant two NRTI drugs and either a PI or an NNRTI drug. Drug adherence was defined by the following percentage: dividing the number of months that anti-HIV drugs were dispensed by the pharmacy during the first year of HAART by the total number of months of follow-up in the first year of HAART. Nonadherence was measured for each 10% decline in drug adherence. Participants had had no previous treatment.
A total of 950 people (15% women) met the study criteria and were included in the analysis. Median HAART duration was 13 months. During that time, 64 participants died and 11 were diagnosed with primary AIDS.
The researchers used a multivariate statistical model to obtain their results. Death was independently associated with being nonadherent to anti-HIV dosing. The statistical "adjusted relative risk" of death with not being adherent was 1.16 (i.e., 16% increased risk). Also, the risk of death was associated with a lower baseline CD4 cell count. The results of nonadherence were the same when an AIDS diagnosis was used as an endpoint. All of these results reached statistical significance, and they indicate the importance of strictly adhering to all doses of anti-HIV therapy.
One limitation of the study is the fact that receiving medications from the pharmacy does not necessarily mean that participants took all doses. Yet people are less likely to request a medication refill if they do not plan to use it.
Montessori, V. and others. Non-adherence to triple combination therapy is predictive of AIDS progression and death in HIV positive men and women. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral/poster presentation 28.
HIV Deaths in the U.S. Are Increasingly Associated with Liver Disease
A growing percentage of deaths in persons with HIV infection in the U.S. have at least one form of liver disease as a cofactor. In 1997, the rate was 10%. The vast majority appear to be associated with HBV, HCV, HAART, or a combination of those factors. However, hepatitis virus coinfection was not proven to be the cause. Even though other HAART drugs were not excluded, researchers from the Centers for Disease Control and Prevention (CDC) believe that PI drug therapy was the most likely causative component. Death certificate information from 1987 to 1997 -- the last year for which complete information is available -- from all 50 states and the District of Columbia was used. The report was presented at the 10th International Symposium on Viral Hepatitis and Liver Disease. The lead author was Richard M. Selik, MD.
Recent reports have shown that coinfection with HCV has been present in an increasing percentage of persons with HIV infection in the U.S. That rate currently is approximately 33%, although it closely tracks with the percentage who acquired HIV by injection drug usage. Also, a few reports have concluded that in persons with HIV infection, coinfection with HBV or HCV represented a risk factor for liver enzyme increases after HAART was started.
Death certificates were examined using the U.S. National Vital Statistics System. The National Center for Health Statistics maintains that database using standardized ICD-9 diagnosis codes. Each person who dies in the U.S. must have a death certificate signed by that person's physician, a coroner, or a medical examiner. Certificates list the cause(s) of death, including contributory causes (such as HIV infection) and secondary causes (such as AIDS-related OIs).
Among deaths in persons with HIV, the percentage who had liver disease listed on their death certificates had increased between 1987 and 1997 from approximately 3% to 10%. The increases were greater after 1995, compared with the years between 1987 and 1995. Note that the PI drugs were widely introduced in the U.S. after 1995.
In persons with HIV, the percentage that had any one of several liver-related diagnoses increased from 1987 to 1997. Those categories included chronic liver disease, non-A/non-B hepatitis, HBV, nonalcoholic-related cirrhosis (scarring), and unspecified disorders of the liver. (Other studies have indicated that most non-A/non-B hepatitis during that time period would be due to HCV, although there was no FDA-approved blood test for HCV until 1990.) Adding up the percentages from all of those liver conditions, the totals come to approximately 3% in 1985, 5% in 1987, and 10% in 1997.
Dr. Selik commented, "The surge in the percentage of deaths with liver disease after 1995 coincides with the introduction and increased use of protease inhibitors to treat HIV infection, possibly reflecting a hepatotoxic [liver toxicity] effect of these drugs." He continued, "Such toxicity may be insufficient to cause fatal liver disease by itself, but it may aggravate the severity of liver diseases due to other causes, such as [viral] hepatitis." Also, it should be emphasized that association does not necessarily mean causation.
The researchers acknowledged a few limitations in their report. First, the increase in reported liver disease on death certificates among persons with HIV might be due to an increased use of HCV tests that were first approved in 1990. Second, the increasing percentage of persons with HIV who were dying with liver disease might be due to a decrease in the number of deaths due to AIDS-related OIs. Reasons could be improved immunity due to HAART, effects from antibiotic prophylaxis (prevention) therapy, or both. Third, liver toxicity might be due to other drugs that are part of HAART regimens or possibly antibiotic prophylaxis. However, this is less likely, since antibiotic prophylaxis and NRTI usage was common before the 1995-1997 period when the rate of liver disease on death certificates in persons with HIV rose significantly. Lastly, the results could be caused by a cohort effect -- if a significant proportion of persons with HIV infection became infected with HBV or HCV in the late 1970s, then an increased proportion of deaths associated with liver disease might be due to a delay of 15 years or longer until liver complications begin to appear.
Selik, R.M. and others. Increases in the percentage with liver disease among deaths with HIV infection. 10th International Symposium on Viral Hepatitis and Liver Disease. Atlanta. April 9-14, 2000. Abstract and poster presentation F006.
In Persons with HIV, Coinfection with HBV or HCV Might Be Missed Due to False Negative Tests
- 6% false negative rate of HCV antibody test, yet HCV RNA positive
- 4% false negative rate of HBV surface antigen test, yet HBV DNA positive
Researchers from the University of Iowa have found a significant rate of false results from screening tests for HCV and HBV infection in their cohort of persons with HIV infection. The findings suggest that when the standard screening tests for hepatitis virus infection are negative in persons with HIV infection, supplemental gene tests are indicated. The reports were presented at the 10th International Symposium on Viral Hepatitis and Liver Disease.
A total of 381 persons with HIV infection were evaluated in the first report that was authored by Dr. S. George and colleagues. Excluding 106 participants (28%) who were HCV antibody positive, 17 (6%) had a positive HCV RNA test on more than one occasion. (The Abbott enzyme immunoassay [EIA] version 2.0 was the antibody test used, while an "in-house" RT-PCR, or reverse transcriptase-polymerase chain reaction test, was used to detect HCV RNA.) Using the Roche Monitor HCV RNA test, three of the nine who tested positive by the RT-PCR test also tested positive with the commercial assay. There was no relationship between HCV RNA positivity/HCV antibody negativity and any of the following: CD4 cell count, HIV RNA level, age, gender, or alanine aminotransferase (ALT) liver enzyme level. However, more than twice the number in this group had a history of injection drug use (18%) than did the HCV RNA negative group (7%).
One limitation was that some of the people with HIV and a false negative antibody test for HCV could have been recently infected with HCV (during the "window" period) and subsequently would have developed a positive antibody test result. Another limitation is that an in-house HCV RNA test was used. It is possible that this test would not be as reliable as a test kit from a commercial manufacturer. Lastly, a history of or concurrent anti-HIV therapy was not mentioned as a potential confounding cofactor.
People with HIV infection normally have a screening test for HBV infection, usually HBV surface antigen. If negative, most clinicians would not perform any other tests for HBV. In a second study from the University of Iowa, authored by Dr. J. Xiang and colleagues, some persons with HIV and a negative HBV surface antigen test had detectable HBV DNA. This indicates active HBV infection.
A total of 491 persons with HIV infection were tested for HBV DNA in blood serum and plasma by using polymerase chain reaction (PCR). Seventy (14%) had HBV DNA that was detectable on multiple samples, indicating active HBV infection. Only 48 of those 70 persons had results in their chart of three HBV tests including surface antigen, core antibody, and HBV DNA. Among those 48 people, 19 (40%) had a negative test for HBV surface antigen. Moreover, nine out of those 19 were negative for both HBV surface antigen and HBV core antibody.
Factors that were not associated with so-called serosilent (i.e., positive HBV DNA with negative tests for surface antigen and core antibody) HBV coinfection were gender, race/ethnicity, and HIV transmission category. However, those with serosilent HBV infection had a higher mean aspartate aminotransferase (AST) level (53 international units per liter, or IU/L) compared with those who were seropositive (41 IU/L). Also, HBV serosilent people had a lower CD4 cell count (244 cells/mm3) than HBV seropositive people (320 cells/mm3).
There were several limitations in this report. First, the mean HBV DNA results were not presented. It is possible that those coinfected subjects with serosilent HBV infection had lower (or higher) HBV DNA levels than those with seropositive HBV infection. This might help to explain the findings, but would not necessarily change the conclusions. Second, anti-HIV therapy as a cofactor was not mentioned. While the number of persons was small, it is possible that a higher percentage of HIV/HBV coinfected persons with more typical HBV seropositive tests were more likely to be taking anti-HIV therapy than those with serosilent HBV infection. This could have been one reason why HBV seropositive people had a higher mean CD4 cell count than those who were serosilent. Third, the authors did not indicate whether HIV viral load was a potential cofactor. Fourth, age as a potential cofactor was not mentioned.
The results of these two studies need confirmation in a larger number of people. If still present, the findings are significant for HIV positive persons. The conclusions suggest that in persons with HIV infection: (1) HBV DNA testing should be performed on HIV positive persons with negative tests for HBV surface antigen and core antibody, and (2) HCV RNA testing should be performed if the HCV antibody test is negative. In addition, the findings have potential implications for possible hepatitis virus transmission (HBV and/or HCV) through sharing needles and sexual partners, when the source person might have been told that he or she was negative.
George, S. and others. Antibody negative HCV infection in HIV-positive individuals. 10th International Symposium on Viral Hepatitis and Liver Disease. Atlanta. April 9-14, 2000. Abstract 127.
Xiang, J. and others. HBV viremia in HIV-positive individuals. 10th International Symposium on Viral Hepatitis and Liver Disease. Atlanta. April 9-13, 2000. Abstract B033.
In Two ACTG Studies of Persons with HIV, 33% Were HCV Positive
In a retrospective study, researchers at the University of Cincinnati measured the rate of HCV infection among HIV positive enrollees in two studies sponsored by the ACTG. The report was presented by Kenneth Sherman, MD, at the 10th International Symposium on Viral Hepatitis and Liver Disease.
Using the HCV EIA antibody test from Abbott, investigators tested participants' blood plasma. A total of 213 people (18% women) were analyzed before they started anti-HIV therapy. The median age was 38 years. Seventy-six (36%) were positive by EIA for antibodies to HCV. Among those 76, 89% also were positive for HCV RNA, indicating active infection. The standard PCR test from Roche was used. Compared with other age groups, those aged 40 to 49 were significantly more likely to have HIV/HCV coinfection. Yet neither gender nor race was associated with HCV infection. The median CD4 cell count among those who were HIV/HCV positive was 377 cells/mm3 compared with 423 cells/mm3 among the HIV positive, HCV negative subjects. Interestingly, all of those with a CD4 cell count below 100 cells/mm3 were HCV positive, compared with only 24% of those with a CD4 cell count greater than 500 cells/mm3. In coinfected people, the mean HCV RNA was 12 million copies/mL. HCV genotype 1, the most difficult to treat, was present in 88%. In people with HIV infection, HCV coinfection is most common among injection drug users and those who received a blood transfusion before 1990.
Sherman, K.E. and others. Hepatitis C prevalence in HIV-infected patients: a cross-sectional analysis of the US Adult Clinical Trials Group. 10th International Symposium on Viral Hepatitis and Liver Disease. Atlanta. April 9-13, 2000. Abstract and oral presentation 116.
Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee of the San Francisco AIDS Foundation since 1987.
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