Adefovir effective in patients resistant to ZDV and 3TC
New safety data and monitoring guidelines clarify role of the lone nucleotide analog
Adefovir is a novel reverse transcriptase inhibitor that is classified as a nucleotide analog. This classification reflects the presence of an additional phosphate group in the compound, one that makes intracellular activation simpler with adefovir than with nucleoside analogs like ZDV and 3TC. Adefovir has a long intracellular half-life, which makes once-daily dosing possible.
Miller et al. have analyzed data from a subset of patients enrolled in an ongoing Phase III study of adefovir (1). This group of 142 patients had genotypic evidence of resistance to ZDV or to both ZDV and 3TC. Interestingly, patients with mutations conferring resistance to both ZDV and 3TC had stronger reductions in viral load after 24 weeks of adefovir therapy than patients who lacked these mutations, although responses were seen in 86% of all patients. By 48 weeks, the antiretroviral effects of adefovir were still evident -- suggesting that both genotypic and phenotypic analyses may be needed to predict which treatment-experienced patients will respond to an adefovir-containing regimen.
Adefovir has also been studied in combination with several other regimens that contained nucleoside analogs (2). In this trial, patients in all of the adefovir-containing arms experienced significant reductions in HIV RNA levels after 20 weeks of combination therapy, confirming earlier indications that this novel compound would prove to be effective when combined with other antiretroviral agents (see "The Next Generation of Antiretroviral Agents," Vol. 3, No. 3).
Because administration of adefovir has been associated with significant nephrotoxicity (specifically, proximal renal tubular dysfunction, or PRTD), clinicians will be particularly interested in the safety data amassed when adefovir was provided to qualified patients under an expanded-access program (3). The study included 5,640 patients who had failed prior therapy with at least two nucleoside analogs and one protease inhibitor. More than 1,500 of these patients were treated for at least 24 weeks. The doses employed were 60 or 120 mg of adefovir once daily. All participants also received L-carnitine 500 mg once daily, because adefovir has been shown to decrease blood levels of this molecule.
Numerous other antiretrovirals were used by the participants in this expanded-access program. Gastrointestinal complaints caused 3% to leave the trial, and 2.5% (141) of treated patients discontinued treatment because they developed nephrotoxicity. At least 30 of these patients had serious renal toxicity that did not completely resolve. In subjects who did develop PRTD, 2% had elevations in creatinine greater than 2.0 mg/dL, but these elevations resolved with dose reduction, interruption, or discontinuation.
Another study, one that randomized 505 patients with CD4 counts less than 200 cells/mm3 to adefovir (120 mg daily) or placebo, revealed a 22% incidence of PRTD at 12 months in the adefovir arm, compared with 0.5% in the placebo arm (4). The first case of PRTD in this trial was seen after four months of treatment. The authors of this study report that 61% of the patients with PRTD experienced resolution of their nephrotoxicity, with a median time to resolution of 17 weeks after adefovir therapy was discontinued.
Dr. Judith A. Aberg, a member of the editorial advisory board of HIV Newsline, comments:
Overall, 2% of patients treated with adefovir develop serious nephrotoxicity. Common electrolyte abnormalities in patients treated with adefovir include decreases in phosphate, bicarbonate, and potassium -- abnormalities that may herald the development of PRTD. For this reason, every patient who is assigned to an adefovir-containing regimen must be scrupulously monitored for changes in kidney function.
The current recommended dose of adefovir is 60 mg daily, as this may reduce the incidence of nephrotoxicity. Electrolytes, BUN, creatinine, phosphate, and urinalysis tests should be conducted monthly on all patients who receive adefovir as part of their antiretroviral regimen. Individuals who experience a rise of more than 0.5 mg/dL in creatinine -- in combination with any two of the following: bicarbonate < 19 mEq/L, proteinuria > 2+, glycosuria > 1+, potassium < 3.0 mEq/L -- should discontinue adefovir therapy for four weeks. (In my own clinical practice, I withhold adefovir if a patient's creatinine rises by more than 0.3 mg/dL.) If laboratory values return to baseline after four weeks, the patient may be rechallenged with adefovir.
The same holds for patients whose creatinine level falls by more than 0.5 mg/dL in combination with a rise in phosphate level of more than 2 mg/dL. If creatinine returns to baseline after four weeks, these patients may also be restarted on adefovir therapy -- but they must be carefully monitored thereafter. The current treatment guidelines call for providers to check the L-caratine levels of all adefovir-treated patients at 16-week intervals, although the clinical significance of low caratine levels is unclear.
In weighing whether to add adefovir to the therapeutic regimen of a heavily pretreated patient, the clinician should take into account that this agent, alone among the antiretrovirals, has activity against a number of herpes viruses as well as HIV. As a result, its use may confer protection against HIV, HHV-6, and CMV as well as against HIV-1 and HIV-2.
Human papilloma virus and anal cancer
Screening programs may save lives and resources
There is a growing literature on the incidence of anal neoplasms and human papilloma virus, or HPV, in HIV-infected gay and bisexual men, and on HPV as the cause of cervical cancer in women. Last year, we covered the former topic in a newsline item that focused on the epidemiology of HPV and anal neoplasms (see "Human papilloma virus and anal cancer: More evidence of an association, especially in HIV-positive men with persistent infection," Vol. 4, No. 4). That study compared the incidence of high-grade squamous intraepithelial anal lesions in HIV-positive and HIV-negative homosexual and bisexual men. HPV can cause benign lesions (such as warts or collections of atypical cells of unknown significance), low-grade squamous intraepithelial lesions (SIL), or high-grade SIL.
The natural history of high-grade SIL is not completely clear, but it is felt that these lesions are very likely to progress to cancer. Cervical neoplasms associated with HPV are widely viewed as a logical model for anal lesions caused by the same group of viruses, and this presumption was reinforced by the report from Palefsky et al. that we covered last year. Those investigators found that HIV-infected men with HPV lesions were significantly more likely than HIV-negative men to develop high-grade SIL.
Motivated by the accumulating evidence that HIV-infected gay and bisexual men are at higher risk of anal HPV infection -- and the presumed sequelae of such infections, high-grade SIL and squamous cell carcinoma of the anus -- Goldie et al. decided to evaluate a proposed screening program for individuals with anal HPV. They employed a mathematical model to calculate lifetime costs, life expectancy, and quality-adjusted life expectancy for no screening program versus screening with Pap smears every three years, every two years, or every six months.
These hypothetical strategies were evaluated in populations of HIV-infected gay and bisexual men with CD4 counts under 200 cells/mm3, between 200 and 500 cells/mm3, and above 500 cells/mm3. The results strongly endorsed the efficacy and cost-effectiveness of a screening program. Screening for SIL in these populations increased quality-adjusted life expectancy at all stages of HIV disease. The authors' calculations suggest that screening every two years or annually would increase quality-adjusted life expectancy in persons with early HIV disease (CD4 counts > 500 cells/mm3) and would be cost-effective. Annual screening was judged to be the most effective strategy in men with CD4 counts less than 500 cells/mm3; increasing the screening frequency to every six months provided little additional benefit.
Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 1999; 281 (19): 1822-29.
Dr. James O. Kahn, a member of the editorial advisory board of HIV Newsline, comments:
Clinicians who treat HIV-infected men are seeing more and more cases of anal cancer among these men, and among men who are at high risk for HIV infection, so it is hardly surprising that there is a heightened interest in diagnosing and treating HPV lesions -- before they lead to high-grade SIL or squamous cell carcinoma. Much of the original work in this area has been done by my colleague Dr. Joel Palefsky at UCSF. The targeted screening program that Goldie et al. have proposed is a natural outgrowth of Dr. Palefsky's initial contributions to our understanding of the sinister relationship between HPV, SIL, and anal cancer.
Goldie's analysis suggests that such a program would be both effective and affordable, saving both lives and health-care dollars. However, this analysis was limited by certain assumptions. For one thing, we don't know the full natural history of high-grade anal SIL, although these lesions are considered likely precursors to squamous cell carcinoma. For another, there are no published figures on the cost of treating anal cancer, so Goldie and coworkers chose to base their estimates on the known cost of treating colorectal cancer. In my experience, this is probably a conservative estimation, given that the treatment for anal cancer, which combines radiation and chemotherapy, is associated with significant clinical toxicities. The authors also acknowledge that the potential effect of maximally suppressive antiretroviral therapy on the incidence of anal neoplasms is difficult to assess at this point.
When it was necessary to make assumptions, however, the authors made it a point to err on the conservative side, so that screening would seem less cost-effective. This decision makes their core finding -- that an annual screening program would save both lives and money -- all the more significant. If history is any guide, the real battle will be to convince third-party payers that it is in their best interests to work with providers, so that they become proficient with the simple and safe procedure, and to work with pathologists, so that they become familiar with the descriptive lesions. And, finally, third-party payers and their care providers need to work with patients -- to educate and empower them, so that they understand that they have a right to insist that this crucial screening tool be a part of their examinations.
Clinical trials vs. the clinic
Viral suppression in the real world
It is easy to get excited by the encouraging data that are routinely presented at major medical conferences these days. Then the care provider goes home and puts those new findings into practice . . . and finds that his or her results fall far short of what the controlled trials achieved. This is the real world of clinical practice. Because the most notable results of these controlled trials get intense media attention, as sensational as it is superficial, the general public knows about the successes being achieved with multidrug antiretroviral therapy . . . but not about the realities of implementing these complex treatment regimens.
What the mainstream media generally fail to report is how infrequently the results of clinical trials are replicated in the clinic itself. Any clinician who treats large numbers of HIV-infected patients is well acquainted with the disparity between glowing media reports about the miraculous effects of combination antiretroviral therapy and clinical reality, which is that a significant percentage of patients do not thrive on these new combinations.
Lucas and colleagues carefully studied a group of patients newly started on combination therapy in an attempt to determine if there are predictable factors associated with lack of optimal response. They enrolled 273 patients, all of whom were protease-inhibitor-naïve, and followed their viral load measurements over 14 months (median length of follow-up: 454 days). These patients were recruited from the Johns Hopkins HIV Clinic in Baltimore, which is an inner-city facility. Sixty-six percent of the patients had no prior exposure to at least two of the drugs started at baseline. The protease inhibitors used were ritonavir, indinavir, and nelfinavir. Mean CD4 count at baseline was 217 cells/mm3. The predominant risk behavior was IV drug use. Most (74%) participants were non-white; within this group, the participants were overwhelmingly African-American. Males constituted 72% of the entire cohort.
In clinical trials, maximally suppressive antiretroviral therapy has reduced HIV RNA to undetectable levels in 60% to 90% of subjects. Lucas et al. report that only 42% of the patients in their cohort had undetectable HIV RNA levels (< 500 copies/mL) within the first 90 days of the study. During months three through seven, this figure was 44%, and it had declined to 37% by 14 months. Only 23% of participants had undetectable levels during all three time periods.
Univariate analysis showed the following parameters to be associated with optimal HIV suppression at all three periods: age greater than 40 years, white ethnicity, and compliance with clinic appointments. On the other hand, a history of injection drug use was linked to poor response. No correlations were found during the observation period between level of viral suppression and sex, education, male-male sexual exposure, history of antiretroviral use, or adverse reaction to protease inhibitors.
The authors also performed a logistic regression analysis. This exercise indicated that only poor clinic attendance was statistically correlated with failure to achieve and maintain an undetectable viral load. The authors therefore view missed appointments as a "surrogate marker" for poor compliance with medication. At the Johns Hopkins HIV Clinic, a rigorous program is now in place to identify and work with patients who miss large numbers of clinic appointments.
Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med 1999; 131: 81-87.
Dr. James O. Kahn, a member of the editorial advisory board of HIV Newsline, comments:
This study provides additional evidence that HIV-infected patients who regularly fail to attend inner-city clinics do not respond as well to combination antiretroviral therapy as do participants in clinical trials or patients who do keep their appointments. Although this may seem to be a painfully obvious observation, the authors have isolated a contributing factor that may respond well to community-based intervention efforts. The notion that patients who chronically miss appointments are also likely to chronically miss taking their assigned medications makes intuitive sense, and Lucas et al. have developed strong evidence of a link. If ways can be found to improve clinic attendance, adherence might be enhanced as well -- to the benefit of the individual patient and the community at large.
Some practical solutions to this problem have been offered by Dr. Margaret Chesney. They include: provisions for day care; providing food, so that patients are assured of a meal whenever they keep a clinic appointment; and providing one-stop care, so that a patient can see a dentist, podiatrist, and social worker -- and can get prescriptions filled in the clinic pharmacy -- on the same day that he or she is seen in the clinic.
Providing patients with some symbol, however nominal, that indicates that they are "part" of the clinic and its team of dedicated care providers, is also important. Patients who feel that they have a place in the healthcare system are more likely to keep scheduled appointments and adhere to their assigned regimens.
Thalidomide for aphthous ulcers
Weight gains seen in treated patients, who find eating easier
Oral and esophageal ulcers not caused by any identifiable organism or other pathology are common in HIV-infected patients. The etiology of these lesions, called aphthous ulcers, is obscure. Over the past few years, researchers have been studying thalidomide as a potential treatment for these ulcers. A cohort of AIDS Clinical Trials Group investigators recently published the results of a double-blind, placebo-controlled trial of thalidomide as treatment for esophageal aphthous ulcers.
Jacobson et al. randomized 24 patients with low CD4 counts (median value < 30 cells/mm3) and biopsy-proven aphthous ulcers involving the esophagus to receive thalidomide (100 mg twice daily) or a look-alike placebo. Originally, investigators had planned to recruit 82 patients. However, poor accrual forced them to analyze data from the 24 subjects who did complete the trial.
Given thalidomide's history of severe teratogenic effects, pre-menopausal women were required to use adequate contraception or to abstain from heterosexual intercourse for a defined period. In addition, these women had pregnancy tests weekly. All patients were closely monitored throughout the study, and they underwent repeat esophagoscopy after four weeks.
Eleven patients were randomized to thalidomide. Of these, eight (73%) had a complete response after four weeks of treatment. By contrast, only three of 13 patients who received placebo (23%) were judged to have had a complete response at the same point. Quality-of-life questionnaires revealed similar differences, with thalidomide recipients reporting greater improvements in symptoms such as pain, trouble eating, and general health.
Furthermore, treated patients experienced an average weight gain of 1.0 kg over the four weeks of the study, compared with an average loss of 1.8 kg in the placebo group. Paradoxically, tumor necrosis factor alpha (TNF-a), TNF receptors, and HIV RNA all increased over baseline values in patients who received thalidomide rather than placebo. None of the differences in these markers were deemed to be significant, however.
Not surprisingly, thalidomide recipients suffered more adverse effects, and five patients required dose reduction or cessation due to toxicity. Three patients developed new peripheral sensory neuropathy or noted a worsening of extant neuropathy. Four patients experienced somnolence, which was not unexpected given that thalidomide was originally developed as a tranquilizer. Additionally, two patients developed rash. No clinically significant neutropenia was seen.
As part of the baseline workup, all lesions were tested for CMV, which was part of the exclusion criteria. Three subjects who tested negative for CMV at entry were diagnosed with cytomegalovirus infection on subsequent biopsy. One of them had been assigned to thalidomide and had not responded to treatment. The other two had been assigned to placebo. All analyses were performed on an intent-to-treat basis.
Jacobson JM, Spritzler J, Fox L, Fahey JL, Jackson JB, Chernoff M, et al. Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. J Infect Dis 1999; 180: 61-67.
Dr. Marc K. Hellerstein, the author of "Update: Treatment of HIV-Associated Body-Composition Abnormalities" in this issue, comments:
This group has previously published data showing that thalidomide helps heal oral ulcers (see "Thalidomide returns," AIDS Care, Vol. 1, No. 4). Here, they augment the evidence that thalidomide is an effective drug for aphthous ulcers of the mouth and esophagus. This is welcome news for providers who treat HIV-infected patients afflicted with these painful lesions -- which can profoundly compromise patients' quality of life, make eating difficult, and thereby contribute to weight loss. Treating aphthous ulcers in these patients should be part of an integrated overall program to combat wasting syndrome in patients with advanced HIV disease.
Update: Treatment of CMV retinitis
Local plus systemic ganciclovir provides potent protection against new lesions
HIV Newsline has covered the treatment of cytomegalovirus infection since our inaugural issue. That issue included a lead article on prophylaxis against CMV retinitis; two Newsline reports on what were then brand-new treatments for this AIDS-related OI, oral ganciclovir and intraocular implants; and a color insert, "CMV Retinitis as Seen Through the Ophthalmoscope," a pull out and save feature designed to help clinicians recognize what was, at the time, the most common viral pathogen seen in patients with advanced HIV infection.
Over the past five years we have provided our readers with frequent updates on the treatment of CMV infection: "Intravitreal cidofovir arrests progression of CMV retinitis" (Vol. 1, No. 3), "F.D.A. approves new and more convenient treatment for CMV retinitis" (Vol. 2, No. 2), "Combination of ganciclovir and foscarnet better than monotherapy for retinitis" (Vol. 2, No. 2), "Update: CMV prophylaxis with oral ganciclovir" (Vol. 2, No. 3), "Cidofovir for CMV retinitis: Therapeutic option for patients who develop resistance to ganciclovir" (Vol. 3, No. 2), "Improved Treatment of CMV Retinitis" (Vol. 4, No. 1), "Withdrawing secondary CMV prophylaxis" (Vol. 4, No. 4), "Better treatment for CMV retinitis: An Update" (Vol. 4, No. 4), and, most recently, "Secondary prophylaxis for CMV retinitis: When is it safe to discontinue maintenance therapy?" (Vol. 5, No. 3). All of these feature articles and news items can be accessed at our Web site, hivnewsline.com.
The widespread use of multidrug antiretroviral therapy has put a palpable dent in the number of new cases of CMV infection, but this once-common OI has not gone away. There are anecdotal reports of patients who have experienced breakthrough infections despite significant immunologic rebound on combination therapy, so it is imperative that care providers perform periodic fundoscopic examination on patients who had low nadir CD4 counts, even those whose counts are now well above 200 cells/mm3.
Ganciclovir, the first-line drug for CMV retinitis, has been available in three forms for some time: intravenous, oral, and as intravitreal inserts. Martin et al. constructed a novel study comparing these different modalities alone or in combination. They enrolled patients who had newly diagnosed CMV retinitis in one eye only and had received no more than six months of prior antiretroviral treatment.
The primary endpoints of the study were development of disease in the contralateral eye or extraocular manifestations of CMV. A total of 337 patients were entered in the study and randomized to one of three arms:
A) GCV implant plus oral placebo
B) GCV implant plus oral GCV at 4500 mg/day (in three divided doses)
C) intravenous GCV (5 mg/kg twice daily for 14-21 days, followed by maintenance therapy at the same dose once daily) with no implant
Patients were followed for one year or until an endpoint was reached, and fundoscopic photographs were taken at each visit. Regimens B and C both proved superior to GCV implants alone in preventing new CMV lesions at six months. The incidence of new CMV disease among patients in arm A was 44.3% halfway through the study, compared with 24.3% and 19.6%, respectively, among patients in arms B and C.
GCV implants also proved to be superior to intravenous therapy in preventing progression of existing lesions (Figure). After 66 days of treatment, half of the patients receiving IV GCV had experienced progression. The median time to progression -- that is, the time by which half of all patients in a given treatment arm had experienced progression of existing lesions -- was never reached among those using implants. Twenty-five percent of those randomized to arm A had experienced progression by 180 days; the comparable figure for arm B was 267 days.
While oral GCV plus implants had the edge in terms of efficacy, there was a statistically higher percentage of patients who developed severe neutropenia among those receiving oral GCV plus an implant. Another significant finding of this study was that the incidence of Kaposi's Sarcoma was lower among patients who received systemic GCV, either orally or intravenously. GCV has demonstrated in vitro activity against human herpes virus type 8, the presumed etiologic agent of KS, which may explain this finding.
Martin DF, Baruch DK, Wolitz RA, Palestine AG, Li H, Robinson CA, et al. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. New Engl J Med 1999;340 (14): 1063-70.
Dr. William G. Powderly, a member of the editorial advisory board of HIV Newsline and the author of "Prophylaxis of OIs in the Age of Protease Inhibitors -- An Update" (Vol. 4, No. 5), comments:
Although the advent of maximally suppressive antiretroviral therapy has resulted in a dramatic decrease in major opportunistic infections like CMV, we still see isolated cases of CMV retinitis -- some of them in patients whose CD4 counts have rebounded well above the theoretical threshold for breakthrough infections. And the grim but inescapable truth is that we will begin to see more and more cases of CMV and other OIs as treatment veterans with few remaining options begin to develop resistance to the regimens they are now on. These individuals will need aggressive treatment when they develop CMV, to prevent the ravages of end-organ retinal disease, and Martin et al. have demonstrated that the combination of local and high-dose systemic anti-CMV treatment is potent protection against new CMV lesions.
They have also shown that this combination is superior to IV GCV in preventing progression of CMV retinitis -- a particularly important finding given how cumbersome, unpleasant, and activity-limiting intravenous therapy can be.
It is worth noting, however, that the progression rate with either therapy was remarkably low when patients also received effective multidrug antiretroviral therapy. This suggests two things: 1) that it may be possible to get away with relatively short courses of IV treatment for CMV retinitis in patients whose HIV RNA levels are suppressed to undetectable levels by combination therapy; and 2) that maximally suppressive antiretroviral therapy should be the standard of care in the management of any opportunistic infection.
Update: Stopping PCP prophylaxis
More evidence that immunologic rebound confers protection against pneumocystis in patients who respond well to maximally suppressive anti-retroviral therapy
In the early, chaotic, catastrophic days of the HIV epidemic, the first ray of hope came with the discovery that PCP could be prevented in susceptible persons with trimethoprim-sulfamethoxazole -- and this prophylaxis regimen became one of the first paradigms in the treatment of people with AIDS. The only controversial aspect of PCP prophylaxis over the years was which drug to use (see "Does PCP Prophylaxis Improve Survival in Patients with HIV Infection?" in Vol. 2, No. 1).
With the advent of maximally suppressive antiretroviral therapy, achieved with drug combinations that usually included two nucleoside analogs and at least one protease inhibitor or one of the potent new NNRTIs, immune reconstitution became possible -- and, with it, the prospect of stopping prophylaxis against the most common HIV-associated OIs. It was only a matter of time before physicians and their better-informed patients began to question the need to continue PCP prophylaxis.
Dr. William G. Powderly, a member of the editorial advisory board of HIV Newsline, has been asking -- and attempting to answer -- that very question in the pages of this publication since June of 1996, when we published his first editorial on the subject, "Prophylaxis of OIs in the Age of Protease Inhibitors" (Vol. 2, No. 3). This same clinical question has been addressed by Dr. Hansjakob Furrer and the Swiss HIV Cohort Study. Their large-scale study included approximately 70% of all patients in Switzerland with advanced HIV disease. From that study population the researchers enrolled 262 patients on combination antiretroviral therapy (which included at least one protease inhibitor for 88% of the subjects). All of the participants had experienced an increase in their CD4 absolute counts to at least 200 cells/mm3 as a result of therapy (or had registered an increase in their CD4 percent to at least 14%). These values had to have been sustained for at least 12 weeks before the patients were eligible for enrollment. The prior median nadir CD4 count for the group was 110 cells/mm3.
None of the participants had suffered a prior episode of PCP. Most (85.5%) had been on TMP/SMX for a median time of 24 months. Over the course of about one year, during which participants stopped taking TMP/SMX, not a single case of PCP occurred in any of the participants.
As a secondary end-point, investigators also monitored the incidence of toxoplasmosis, as TMP/SMX also provides protection against this infection. No cases of toxoplasmosis were observed during the follow-up period, even though 46.2% of the study subjects had positive IgG titers for Toxoplasma gondii. Nine patients resumed PCP prophylaxis during the observation period because their counts fell to a level that put them at theoretical risk for PCP. Their data were censored from the final analysis.
Furrer J, Egger M, Opravil M, Bernasconi E, Hirschel B, Battegay M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. New Engl J Med 1999; 340: 1301-6.
Dr. William G. Powderly, a member of the editorial advisory board of HIV Newsline and the author of "Prophylaxis of OIs in the Age of Protease Inhibitors -- An Update" (Vol. 4, No. 5), comments:
We know that maximally suppressive antiretroviral therapy leads to significant increases in CD4 count in most treated patients. What we do not know, with the same certainty, is how effective these "recovered" lymphocytes are against serious opportunistic infections like P. carinii pneumonia. The data collected by Furrer et al. indicate that combination antiretroviral therapy not only increases CD4 counts but produces a degree of immune reconstitution sufficient to prevent PCP and toxoplasmosis in patients who respond well to multidrug therapy. This observation is supported by recent cohort studies that reached very similar conclusions (1, 2).
These findings are in concordance with the observation that patients on combination antiretroviral therapy have fewer opportunistic infections than would be expected in a similar cohort of HIV-infected patients not taking the new, powerful anti-HIV medications. On the other hand, in vitro studies show that, at least initially, the vast majority of the new CD4 cells generated in patients on multidrug therapy are so-called memory cells, not pluripotent naïve T cells. Naïve cells do begin to appear after three to four months of therapy, however, so while there may be limitations to the protection one can expect from such therapy-induced immune reconstitution, the degree of protection does improve over time.
In the Swiss HIV Cohort Study, a sustained increase in absolute CD4 count (or an increase in the percent of CD4 cells) provided as much primary protection against PCP as TMP/SMX would have, for the year of the study. We do not yet know how durable this protection will prove to be; that answer awaits further data from the Swiss group. But the findings of this study do provide evidence that some degree of immunocompetence is restored in patients who see their CD4 levels rebound on combination antiretroviral therapy. Indeed, this and similar reports have led the U.S. Public Health Service to change its recommendations regarding PCP prophylaxis. Those guidelines now suggest that primary prophylaxis can be discontinued in patients who evidence sustained rises in CD4 counts as a result of maximally suppressive antiretroviral therapy (3).
This revision of the U.S.P.H.S. guidelines is by no means the final answer to this vexing question, however. There are isolated anecdotal reports that pneumocystis is being seen in patients who stop PCP prophylaxis when their CD4 counts rebound, and because primary prophylaxis against PCP is inexpensive, effective, and uncomplicated, clinicians should give careful consideration to terminating this therapy in patients whose nadir CD4 counts were below 50, irrespective of how high they have rebounded.
Nonetheless, the findings of Furrer and his colleagues should provide significant encouragement to patients with advanced HIV disease who have responded well to maximally suppressive antiretroviral therapy. Immunocompetence may not be as complete in these individuals as their most recent CD4 counts would indicate, but that does not mean that significant and sufficient immune reconstitution has not occurred.
Lodenosine study suspended
U.S. Bioscience Inc. recently announced that it had suspended a Phase 2 study of the company's antiretroviral agent, lodenosine, after one patient in the study died and several others showed signs of possible liver and kidney damage. A separate Phase 1 study of the drug, involving about 60 patients and being conducted by the National Cancer Institute, has also been suspended pending review of all trial data. The placebo-controlled U.S. Bioscience trial, which involved 176 patients at 27 clinical centers, was studying three different dosages of lodenosine, a nucleoside analog, in combination with two additional antiretroviral agents. Effective immediately, all patients have been taken off lodenosine, and they are being closely monitored for signs of hepatic or renal damage.