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April 1998

  1. Initial therapy with d4T or 3TC appears to confer survival benefit
  2. Prophylaxis for common OIs is cost-effective ...
  3. Fine-tuning the treatment of MAC
  4. Help from hydroxyurea
  5. Prophylaxis for cryptosporidiosis
  6. More news from the 5th Conference on Retroviruses and Opportunistic Infections
  7. Nevirapine plus two nucleosides exerts durable effect
  8. New data on workplace exposure to HIV

Initial therapy with d4T or 3TC appears to confer survival benefit

Patients whose earliest nucleoside analog therapy included stavudine or lamivudine seem to live longer

Investigators in British Columbia have performed an interesting analysis of HIV-infected patients based on the initial treatment regimen they received. Since 1986, the Drug Treatment Program has distributed antiretroviral medications to eligible patients in British Columbia at no cost. Hogg et al. performed a retrospective study of 1,178 patients with CD4 counts below 350 cells/mm3 who began taking antiretroviral drugs between October 1992 and June 1996. Patients were stratified to one of two groups: those whose original regimen contained only ZDV, ddI, or ddC (Group 1) and those who received d4T or 3TC as part of their original treatment plan (Group 2). Group 1 included 951 participants who were followed for a median time of 21 months; Group 2 consisted of 227 subjects, followed for a median time of 15 months. No significant differences existed between the groups regarding AIDS diagnosis, use of PCP or MAC prophylaxis, or CD4 level (median, Group 1: 170 cells/mm3; Group 2: 160 cells/mm3).

Patients in Group 1, who did not receive 3TC or d4T as part of their original regimen, were almost twice as likely to die as those in Group 2. A multivariate analysis identified the following characteristics as independent predictors of improved survival: use of a regimen containing 3TC or d4T, absence of an AIDS diagnosis, higher CD4 count, younger age, and use of MAC prophylaxis. A subset analysis of the 690 patients who initially received dual therapy with nucleoside analog drugs reached the same conclusion: subjects in Group 1 were 1.73 times more likely to die as those in Group 2. Furthermore, there was a difference between the groups in progression to AIDS at 15 months: 24% of those in Group 1 progressed to AIDS, compared to 11% of Group 2.

Hogg RS, Heath KV, Yip B, Craib KJP, O'Shaughnessy MV, Schechter MT, Montaner JSG. Improved survival among HIV-infected individuals following initiation of antiretroviral therapy. JAMA 1998; 279: 450-54.

Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:

This study employed an intent-to-treat analysis, which means that patients in Group 1 who were switched to a treatment regimen containing 3TC or d4T were included in Group 1 analyses. Approximately 50% of the original Group 1 participants fall into this category. Keeping in mind the limitations of retrospective studies, this analysis suggests a stark difference in clinical outcome when the initial antiretroviral regimen for patients with CD4 counts below 350 cells/mm3 includes 3TC or d4T. Hogg et al. observe that their findings underscore results from the CAESAR study, which found that 3TC, when added to a regimen containing ZDV, was associated with a 55% reduction in death or progression to AIDS.

Prophylaxis for common OIs is cost-effective ...

... and so is maximally suppressive antiretroviral therapy

In recent years a number of studies have sought to establish the cost-effectiveness of various pharmaceutical agents and treatment strategies -- a trend reflecting the increasing dominance of highly cost-conscious managed-care systems over healthcare delivery in this country. Freedberg and colleagues have made a valuable contribution to this field by evaluating the costs and benefits of the drugs used to prevent common opportunistic infections in patients with HIV infection. Fortunately for all concerned, most of the prophylactic regimens examined by this team were found to be cost-effective.

The authors used a Markov simulation model to compare drug regimens that prevent PCP, toxoplasmosis, MAC, fungal infections, and CMV. The team projected costs per quality-adjusted life-year saved in patients with CD4 counts below 300 cells/mm3. Projections about the natural history of HIV disease were based on data from the Multicenter AIDS Cohort Study; toxicity and efficacy data for drugs evaluated by these researchers were obtained from randomized controlled trials.

The authors conclude that prophylaxis for the following AIDS-related OIs is available at reasonable cost: PCP, toxoplasmosis, MAC, and fungal infections. There has never really been any question that trimethoprim-sulfamethoxazole is the most cost-effective means of preventing PCP and toxoplasmosis, so the team's findings merely reaffirm what is standard practice. However, this group also reports that azithromycin to prevent MAC and fluconazole to prevent disseminated fungal infections are cost-effective treatments.

The median cost per life-year saved for medications to prevent PCP, toxoplasmosis, MAC, and fungal infections is in the same range as median costs for coronary bypass surgery or chemotherapy for breast cancer. Notably, the cost per life-year saved for all these forms of OI prophylaxis is significantly less than the annual cost of renal dialysis or treatment for hypercholesterolemia -- and the costs of those interventions are not generally debated.

Perhaps more importantly, Freedberg et al. also ran a cost-benefit analysis on three-drug combination antiretroviral regimens that contain protease inhibitors. They found that the median annual cost of maximally suppressive antiretroviral therapy falls within the range of other common, broadly accepted medical interventions.

Freedberg KA, Scharfstein JA, Seage GR, Losina E, Weinstein MC, Craven DE, Paltiel AD. The cost-effectiveness of preventing AIDS-related opportunistic infections. JAMA 1998; 279 (2): 130-6.

Fine-tuning the treatment of MAC

Additional confirmation that clarithromycin plus ethambutol is the most efficacious therapy

Determining optimal therapy for Mycobacterium avium complex (MAC) is still a work in progress. Last year we reported a study which demonstrated that there was no benefit to adding clofazimine to a regimen of clarithromycin plus ethambutol (see "Fine tuning the management of MAC," Vol. 3, No. 3). A recent study confirms the efficacy of the two-drug combination of clarithromycin and ethambutol.

Dubé and colleagues recruited 95 patients with active MAC disease at four sites in California. Candidates who had received triple-drug treatment for MAC for more than three days in the month prior to beginning the study were excluded. Those who entered the study were randomized to receive one of two regimens: clarithromycin (1000 mg twice daily) with clofazimine (100 mg daily) plus or minus ethambutol (400 mg twice daily).

Patients were seen monthly throughout the two-year study, and blood was drawn for MAC culture at each visit. The primary endpoint of the study was microbiologic relapse, following demonstration of either negative cultures or a significant decrease in M. avium colony-forming units compared to baseline values. Approximately 70% of both groups experienced microbiologic response, with the median time to response being four weeks in all patients, regardless of treatment arm.

Differences began to emerge at the 16-week mark. At that point, patients assigned to the two-drug arm began to exhibit an increase in colony-forming units and developed positive blood cultures. Comparable changes did not begin to appear in patients receiving the three-drug, ethambutol-containing regimen until 24 weeks into the study. The risk of relapse for two-drug recipients was 22% at 24 weeks and 68% at 36 weeks. Among patients receiving all three drugs, relapse risks were 5% and 12%, respectively, at the same benchmarks. Survival was not increased by the use of three drugs, however.

There was also an advantage observed for patients on the three-drug regimen regarding clinical symptoms: in the period from weeks 4 to 40, significantly fewer of these patients reported fever within one week of their follow-up visit compared to the rest of the cohort. Use of three drugs appears to have delayed the development of resistance to clarithromycin as well. Median time to appearance of resistant organisms was 16 weeks among those on clarithromycin plus clofazimine and 40 weeks among those who also got ethambutol.

The authors point out that another study (ACTG 157), this one of clarithromycin monotherapy, found the median time to development of clarithromycin-resistant M. avium isolates to be 16 weeks, suggesting that clofazimine does not provide an advantage in delaying the development of clarithromycin resistance. It should also be noted that roughly half of all patients in the study required a dose reduction of clarithromycin, to 500 mg twice daily.

This study underscores the utility of clarithromycin and ethambutol as a combination strategy against MAC. It also suggests indirectly that clofazimine does not provide significant benefit when included in an anti-MAC cocktail.

Dubé MP, Sattler FR, Torriani FJ, See D, Havlir DV, Kemper CA, et al. A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. J Infect Dis 1997; 176: 1225-1232.

Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:

As it turns out, the best treatment for disseminated MAC infection may be highly-active antiretroviral therapy. In the newsline section of the last issue of HIV Newsline, my colleague Dr. Judith A. Aberg discussed the impact of maximally suppressive antiretroviral therapy on DMAC in four patients seen at San Francisco General Hospital (see "HAART therapy leads to resolution of MAC infection," Vol. 4, No. 1). As Dr. Aberg, a member of the editorial advisory board of HIV Newsline, reports, these patients were able to discontinue their MAC therapy after a year of maximally suppressive antiretroviral therapy -- and up to a year later these patients still have sterile cultures and no clinical evidence of MAC.

Help from hydroxyurea

Coadministration with ddI increases intracellular concentrations and facilitates activation of this nucleoside

Hydroxyurea has long been used in cancer chemotherapy. Its current indications include melanoma, chronic myelocytic leukemia, and inoperable ovarian carcinoma. More recently, hydroxyurea has become the focus of considerable interest among AIDS researchers, not because the drug has direct anti-HIV activity but because its concomitant administration with certain antiretrovirals seems to increase the intracellular concentration of those agents and to facilitate their activation inside cells. A number of mechanisms have been proposed to explain hydroxyurea's apparent ability to thwart HIV in chronically infected cells: it may induce a state of quiescence; it may deplete pools of nucleoside triphosphates, which the virus needs to reproduce; it may enhance apoptosis in HIV-infected cells.

A number of studies presented at the 5th Conference on Retroviruses and Opportunistic Infections examined the effects of hydroxyurea on traditional antiretroviral cocktails. Galpin et al. administered hydroxyurea (500 mg b.i.d.) to 42 patients as monotherapy, in combination with ddI (200 mg b.i.d.), or with ddI at that dose plus d4T (40 mg b.i.d.). At 28 weeks, a statistically significant increase in CD4 counts was seen in all treated patients, but the best response, in terms of clinical status, virologic markers, and immunologic parameters, was seen in recipients of the three-drug combination.

Galpin and colleagues also examined subsets of lymphocytes, and they were able to document improved CD4 cell diversity at 28 weeks. This finding, they argue, suggests that combining hydroxyurea, ddI, and d4T promotes a certain degree of immune reconstitution. The investigators speculate that, in addition to preventing viral activation in infected cells and acting synergistically with nucleoside analogs, hydroxyurea may retard the emergence of drug-resistant isolates.

In an open-label study of this same three-drug combination, Rossero et al. dispensed hydroxyurea (1000 mg daily) to 31 patients with a median CD4 count of 236 at baseline and HIV RNA levels greater than 40,000 copies/mL. All patients had prior experience with nucleoside analog therapy. After 12 weeks of treatment, mean viral load had decreased 1.3 log, and HIV RNA was undetectable in eight patients. Four patients developed neutropenia; worsening peripheral neuropathy and increased pancreatic enzymes were also observed.

Lori et al. gave hydroxyurea (300 mg t.i.d. to patients weighing less than 60 kg; 400 mg t.i.d. to those weighing more) in combination with ddI (200 mg t.i.d.) and the protease inhibitor indinavir (800 mg t.i.d.) to 20 patients for nine months. Average baseline HIV RNA was approximately 500,000 copies/mL and CD4 count was 448 cells/mm3. Plasma viremia became undetectable in all patients. Interestingly enough, semen viremia was also undetectable as well in all six patients on whom this test was performed. The average CD4 count increase was 166 cells/mm3.

Compared to a control group that received no antiretroviral therapy or hydroxyurea, patients on the triple combination experienced significant and sustained decreases in plasma viremia. This finding is not surprising, but immunologic parameters showed some interesting differences. While absolute levels of immunologic cells were similar in the two groups, the functional ability of lymphocytes from patients treated with the combination was significantly better over the observation period. Parameters examined included lymphocyte proliferation to antigens, levels of naïve CD4 and CD8 cells, and levels of activated CD8 cells. Taken together, the authors report, these findings reflect a measure of immune reconstitution -- a conclusion that echoes the one reached by Galpin and coworkers.

Galpin JE, Lori F , Globe DR, Casciato D. Improvement in CD4 cell diversity during 7-month trial of hydroxyurea in combination with ddI or ddI and d4T. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1998. Abstract 657.

Rossero R, McKinsey D, Green S, Andron L, Pollard R. Open label combination therapy with stavudine, didanosine and hydroxyurea in nucleoside experienced HIV-1 infected patients. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1998. Abstract 653.

Galpin JE, Lori F, Globe DR, Casciato D. Safety, sheltering and synergy of hydroxyurea with ddI or ddI plus d4T in HIV-infected patients. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1998. Abstract 654.

Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:

The potential value of hydroxyurea in the treatment of HIV infection is summed up in the title of the presentation that Dr. Lori and his colleagues made at the 5th Conference on Retroviruses and Opportunistic Infections: "Safety, sheltering and synergy of hydroxyurea with ddI or ddI plus d4T in HIV-infected patients." This chemotherapeutic agent, long familiar to my fellow oncologists, appears to be safe when used at a dose of 500 mg b.i.d. (or 1000 mg per day) in combination with F.D.A.-approved antiretroviral agents. The neutropenia and neuropathy reported by Rossero et al. are a warning to clinicians, however: this drug cannot be used with impunity, and patients who take hydroxyurea as part of an antiretroviral regimen will have to be carefully monitored for side effects.

The other good news about hydroxyurea is that it does indeed appear to act synergistically when used in combination with ddI plus either d4T or indinavir. At least in these short-term studies, the addition of hydroxyurea to a patient's regimen appears to enhance the antiretroviral activity of that regimen. The fact that this synergy also seems to lead to immune reconstitution will make hydroxyurea an appealing addition to current combination therapies, if the results reported here are borne out by larger, longer studies. Finally, the discovery that patients taking hydroxyurea in combination with ddI and indinavir had no detectable HIV RNA in their semen is welcome news to all of us who are concerned about the transmission of HIV infection through unprotected sexual relations.

Useful as hydroxyurea may prove to be, it is no miracle drug. In most of the studies conducted to date -- including a large placebo-controlled clinical trial presented at the 5th Conference on Retroviruses -- the addition of hydroxyurea to a multidrug anti-HIV regimen has resulted in a decline in viral load but produced almost no increase in CD4 count. This poses a dilemma for all of us who treat people with HIV disease: we would like to see a better immunologic response to hydroxyurea before we begin recommending this agent to patients. Studies now underway should help clarify hydroxyurea's role in the treatment of HIV infection, and we should have better information on the efficacy of hydroxyurea-containing antiretroviral regimens after the 12th World AIDS Conference in Geneva. Until then, this drug should probably be reserved for patients who have broken through on maximally suppressive therapy.

Prophylaxis for cryptosporidiosis

Clarithromycin and rifabutin appear to be protective against this OI

The HIV Outpatient Study is a collaborative effort of internists and infectious disease specialists who provide primary care to some 3,000 patients with HIV infection. Participating clinics are scattered across the country. Inspired by a report that clarithromycin might be protective against cryptosporidium, Holmberg and a group of participating clinicians decided to monitor the incidence of this recalcitrant infection among patients receiving prophylaxis for MAC. Starting in 1992, 1,019 patients with CD4 counts below 75 cells/mm3 were recruited for this study. Of this cohort, 535 received prophylaxis for MAC with one of three drugs: 312 received clarithromycin, 214 received rifabutin, and 54 were treated with azithromycin.

In the 312 patients who received clarithromycin, five cases of cryptosporidiosis were diagnosed, while 30 cases occurred among the 707 patients who did not take clarithromycin. A significant difference was also seen when patients who took rifabutin were compared with those who did not (two cases among 214 patients, versus 33 cases among 805 patients). No real difference emerged when recipients of azithromycin were compared with non-treated patients (2/54 versus 33/965, respectively).

Although these results are not from a controlled trial, extensive regression analyses were done to control for confounding variables. Protease inhibitors and triple-drug combination regimens were not generally available until after the period of observation, so the authors exclude these new treatments as potential contributors to the results they obtained. Azithromycin's apparent lack of protective effect was puzzling, since the drug has a structure similar to that of clarithromycin. The investigators point out that the number of participants taking azithromycin was small, and this could account for the equivocal findings.

In summary, Holmberg and colleagues conclude that they found "robust and statistically significant" evidence that clarithromycin and rifabutin protect against development of cryptosporidiosis in HIV-infected patients with low CD4 counts.

Holmberg SD, Moorman AC, VonBargen JC, Palella FJ, Loveless MO, Ward DJ, Navin TR. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. JAMA 1998; 279 (5): 384-6.

More news from the 5th Conference on Retroviruses and Opportunistic Infections

  1. A three-nucleoside combination that offers an alternative to protease inhibitor-containing regimens
  2. Efavirenz plus indinavir dramatically reduces viral load
  3. Further confirmation of the efficacy of triple-combination therapy

1. A three-nucleoside combination that offers an alternative to protease inhibitor-containing regimens

Abacavir is the name Glaxo Wellcome has given to the experimental nucleoside analog formerly known as GW-1592 (see "The Next Generation of Antiretroviral Agents -- An Update," Vol. 3, No. 6). Sixty patients were recruited at European centers for a 24-week dose-ranging study of this compound (100, 300, or 600 mg b.i.d.). All participants had HIV RNA levels greater than 30,000 copies/mL and CD4 counts less than 100 cells/mm3. Forty-six of these patients elected to continue treatment during the open-label portion of the study. They were treated with abacavir (300 mg b.i.d.) plus ZDV and 3TC at standard doses.

Substantial reductions in HIV RNA were observed during the randomized phase of the study. After switching to open-label triple-combination therapy, the proportion of patients with undetectable HIV RNA increased. By 48 weeks, more than 60% of these patients had viral loads below 400 copies/mL and more than 40% had levels lower than 50 copies/mL. CD4 data, presented on 22 patients, showed a median increase of more than 100 cells/mm3 at 32 weeks. The most frequent adverse events were nausea/vomiting (n = 19), malaise/fatigue (11), headache and diarrhea (9 each). This nucleoside combination appears to be a promising treatment option for patients who cannot tolerate, or have developed resistance to, protease inhibitors or non-nucleoside reverse-transcriptase inhibitors.

Staszewski K, Katlama C, Harrer T, Yeni P, Massip P, Cutrell A, et al. Preliminary long-term open-label data from patients using abacavir (1592, ABC)-containing antiretroviral treatment regimens. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1998. Abstract 658.

2. Efavirenz plus indinavir dramatically reduces viral load

Efavirenz is a promising NNRTI that may well win F.D.A. approval this year. One of this investigational drug's appealing features is its long half-life, which makes once-daily dosing a possibility. At this year's Conference on Retroviruses, Kahn et al. reported that this agent, when combined with the protease inhibitor indinavir, produced decreases in viral load of 2.5 logs -- results sustained for 60 weeks. In this study just over 100 patients with asymptomatic or mildly symptomatic HIV infection were randomized to indinavir alone (n = 42) or indinavir plus efavirenz (n = 59). After 12 weeks of treatment, those receiving indinavir alone were allowed to add efavirenz and d4T to their antiretroviral regimen.

In patients originally assigned to combination therapy, CD4 counts increased from a baseline mean of values of 283 cells/mm3 to 550 cells/mm3; the respective figures for the indinavir-monotherapy arm were 284 and 494 cells/mm3. Fully 94% of the patients in the combination-therapy arm had undetectable levels of virus by Week 24 of the study, a statistically significant difference compared to patients who received indinavir monotherapy for the first 12 weeks of the trial. Both treatments were generally well tolerated at 24 weeks.

Kahn J, Mayers D, Riddler S, Stein D, Bach M, Havlir D, Ruiz N, et al. Durable clinical anti-HIV-1 activity (60 weeks) and tolerability for efavirenz (DMP-266) in combination with indinavir (IDV): Suppression to "<1 copy/mL" (OD = background) by Amplicor as a predictor of virologic treatment response (DMP 266-003, cohort IV). 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1998. Abstract 692.

3. Further confirmation of the efficacy of triple-combination therapy

Squires et al. compared two triple-combination regimens: indinavir plus 3TC plus ZDV (Group 1) versus indinavir plus 3TC plus d4T (Group 2). All drugs were given at standard doses. The study recruited treatment-naïve patients with CD4 counts greater than 200 cells/mm3 and baseline viral loads higher than 10,000 copies/mL. In all, 100 patients were randomized to one of the two treatment arms. Both cohorts responded well to treatment, and improvements in viral load and CD4 count did not differ significantly between the groups.

At 12 weeks, Group 1 had a mean decrease in HIV RNA of 1.59 log and a mean increase in CD4 count of 85 cells/mm3; the comparable values for Group 2 were 1.79 log and 150 cells/mm3. At 24 weeks, 80% of Group 1 patients had undetectable levels of virus, while 87% of Group 2 patients were in this category. Both regimens were reasonably well tolerated, with a scattering of patients in each arm experiencing increases in total bilirubin, liver enzymes, and creatine kinase.

Squires K, Santana J, Gulick R, Clark R, Seinhart J, Schoelkopf F, et al. An open-label, randomized, comparative study of stavudine + lamivudine + indinavir versus zidovudine + lamivudine + indinavir in treatment naïve HIV-infected patients. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1998 (poster).

Dr. Harold A. Kessler, the author of "The Next Generation of Antiretroviral Agents -- An Update" (Vol. 3, No. 6) and a member of the editorial advisory board of HIV Newsline, comments:

Experience suggests that most treatment-experienced patients will eventually break through on their original HAART regimen. For those who do -- and for the clinicians who provide their continuing care -- the news that new drugs and new drug combinations are effective in suppressing viral replication, often to undetectable levels, is especially welcome. Efavirenz and abacavir, when used in combination with older, F.D.A.-approved antiretrovirals, appear to offer treatment alternatives to patients who failed their first maximally suppressive regimen.

Clinicians who are considering adding the latter drug to a patient's regimen are cautioned that abacavir causes an allergic reaction in approximately 3% of treated patients -- and individuals who prove to be hypersensitive to the drug should not resume taking it, even if their adverse symptoms resolve promptly and completely.

Nevirapine plus two nucleosides exerts durable effect

Sustained benefits seen after two years of combination therapy

In a previous issue of HIV Newsline we reported the interim data from the INCAS trial, which showed that nevirapine, the first of the non-nucleoside reverse-transcriptase inhibitors, was effective in reducing viral burden and increasing CD4 count when used in conjunction with two nucleoside analogs (see "Combination of ZDV, ddI, and nevirapine produces substantial decrease in viral load," Vol. 2, No. 5, pages 112-114). Analysis of the preliminary data from that trial indicated that the triple combination of ZDV, ddI, and nevirapine produced more substantial and sustained suppression of viral burden than ZDV plus ddI or ZDV plus nevirapine.

The 52-week data from INCAS, presented at last year's Conference on Retroviruses and Opportunistic Infections, reaffirmed that preliminary analysis. After a full year of treatment, viral load measurements remained below 400 copies/mL in half the patients treated with nevirapine plus the two nucleoside analogs, and 45% of the patients in that cohort had viral loads below the 20 copies/mL limit of detection -- a finding that held for only 22% of the patients treated with ZDV + ddI and applied to none of the subjects in the ZDV + nevirapine cohort (see "First of the non-nucleoside analogs exerts durable effect in combination with older agents," Vol. 3, No. 1, pages 16-18).

At this year's conference the INCAS investigators presented data on the results of long-term use of this novel three-drug combination (Figure). At the end of the first year of the study, trial participants who were originally assigned to receive ZDV, ddI, and nevirapine were given the option of continuing this regimen on an open-label basis. Of the 51 patients in this category, 34 elected to do so. These patients were allowed to adjust their nucleoside regimen. Mean duration of follow-up was 128 weeks (range: 86-155 weeks).

After a full year of open-label treatment, 58% (19/33) of these patients had undetectable viral loads by the Amplicor assay (<400 copies/mL). Of the 13 patients who had been followed for two and a half years, nine were still in that category. Immunological parameters also reflected the continuing efficacy of this combination: at 104 weeks, CD4 counts still showed a median increase of 120 cells/mm3 above baseline.

Montaner JC, Reiss P, Cooper D, Vella S, Dohnanyi C, Harris M, et al. Long-term follow-up of patients treated with nevirapine (NVP)-based combination therapy within the INCAS trial. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31-February 5, 1988. Abstract 695.

Patients With
No Detectable
HIV-1 RNA, %
Duration of Treatment, wk

Percentage of patients with undetectable viral load (<20 copies/mL) after one year of treatment with nevirapine plus ZDV (black circles), nevirapine plus ddI (black triangles), and nevirapine plus ZDV and ddI (purple squares). Montaner et al. JAMA 1998, with permission.

Dr. David Hardy, a member of the editorial advisory board of HIV Newsline, comments:

Dr. Julio Montaner, one of the INCAS trial's principal investigators, notes that approximately 80% of his patients who have remained highly compliant with their triple-drug regimen have continued to derive clinically significant benefits from that therapy -- well into the second year of treatment. This heartening finding reminds us how important it is for providers to encourage each patient, at each consultation, to comply fully and faithfully with his or her prescribed antiretroviral regimen.

The long-term data from the INCAS trial do much more than confirm how crucial compliance is to successful suppression of HIV -- they demonstrate that sustained reductions in viral burden can be achieved with combination antiretroviral therapies that do not contain a protease inhibitor.

This finding has implications for those who are just beginning therapy -- and who may want to defer the use of protease inhibitors until their clinical status deteriorates. It also has implications for those patients who have broken through on a protease inhibitor-containing regimen -- because the combination of nevirapine plus two new nucleoside analogs may prove efficacious as salvage therapy in heavily pretreated patients.

New data on workplace exposure to HIV

ZDV prophylaxis reduces risk of infection by 81%

All healthcare professionals who treat HIV-infected patients are concerned about the risk of seroconversion after being exposed to the virus in the workplace (see "Reducing the Risk of Occupational Exposure to HIV," Vol. 1, No, 4, pages 69-73). Cardo et al. gathered data on approximately 700 exposures to HIV in such settings. The study included all persons exposed to HIV occupationally in the United States between 1988 and 1994. In addition, data were collected on 10 health care workers who seroconverted in France, England, and Italy. The study dates varied slightly for the European subjects.

The investigators examined 698 documented incidents of percutaneous exposure to HIV. The vast majority of exposures (91%) resulted from injuries involving hollow-bore needles. The remaining incidents involved other sharp objects such as suture needles. Thirty-three of the exposures resulted in HIV infection while 665 did not. The cohort of workers who did not seroconvert was considered the "control" group.

The following factors were found to be associated with transmission: injury involving a large-diameter needle (<18 gauge), deep injury, visible blood on the device, procedures involving a needle placed in the source patient's vein or artery, emergency procedures, and terminal illness in the source patient. While the diameter of hollow needles emerged as a factor, there was no significant difference in risk between hollow-bore needles and suture needles.

Post-exposure prophylaxis with zidovudine was used by 27% of persons who seroconverted -- and by 36% of those who remained free of infection. However, the authors point out that the figures reflecting crude ZDV use are confounded by the fact that persons who suffered "severe" injuries (i.e. those characterized by one of the factors associated with transmission) were more likely to take ZDV after exposure.

Of those who took ZDV, 67% of patients who seroconverted took their first dose within four hours of exposure; the corresponding figure among controls was 89%, a statistically insignificant difference. Although this study was not designed to estimate the efficacy of ZDV as post-exposure prophylaxis, the authors note that use of the drug did reduce the risk of infection by 81% after controlling for other variables. However, they also point out that this strategy has failed in at least 13 cases. (For San Francisco General Hospital's guidelines for post-exposure zidovudine therapy, see Vol. 1, No. 4, page 72)

Several parameters used in this analysis implicate the volume of blood involved as an important variable in transmission. In addition, the association with late-stage disease suggests that the titer of HIV in the source patient's blood is a factor.

According to these authors, when large quantities of highly viremic blood are involved, the risk of infection following exposure may well be above 0.3%, the figure that is widely accepted as the probable risk of infection following occupational exposure. Their observations are a contribution to the sparse data available on HIV transmission in the workplace.

Cardo DM, Culver DH, Ciesielski CA, Srivastava PU, Marcus R, Abiteboul D, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. New Engl J Med 1997; 337 (21): 1485-90.

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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.