by Harvey S. Bartnof, MD

Nine abstracts were devoted to the new Abbott Laboratories second-generation protease inhibitor, ABT-378. An anti-HIV effect occurs at very low blood levels of the drug; it is 10 times as potent as ritonavir in vitro. This is due to a low level of binding of the ABT-378 to albumin, a blood protein; in contrast, ritonavir binds albumin avidly. According to Abbott, ABT-378 is more potent than any other protease inhibitor identified to date.

HIV strains resistant to ABT-378 showed "low" levels of cross-resistance to either indinavir or saquinavir. HIV strains resistant to ritonavir are sensitive to ABT-378. The new drug is metabolized by the same liver enzyme that is inhibited by ritonavir. Therefore, co-administering ABT-378 with a low dose of ritonavir (approximately 50 mg) results in even higher blood levels of ABT-378 in laboratory rats. This allows for the possibility of maintaining an adequate blood level with once or twice daily dosing of ABT-378. No data have been presented thus far on using ABT-378 in humans.

Korneyeva M and others. Virological evaluation of ritonavir-resistant HIV to the HIV protease inhibitor ABT-378. Abstract and poster presentation 212.

Kumar GN and others. Increased bioavailability and plasma levels of the HIV-1 protease inhibitor ABT-378 in rats due to inhibition of the in vivo metabolism by ritonavir. Abstract and poster presentation 207.

Sham H and others. Design, synthesis and biological properties of ABT-378, a highly potent HIV protease inhibitor. Abstract and oral presentation 14.

1592U89 plus 141W94: another Promising Combination

• Combination of 1592 and 141 is synergistic in vitro; 141 is also synergistic with AZT and other nucleoside analogs
• Twice daily dosing of each drug is possible, with or without food
• 1592 is a new nucleoside analog drug; 141 is a new protease inhibitor

Several presentations addressed 2 new anti-HIV drugs in the pipeline from Glaxo Wellcome. They are 1592U89, a new nucleoside analog reverse transcriptase inhibitor and 141W94, a new protease inhibitor (formerly known as VX-478). 1592 easily crosses the blood-brain barrier.

Robert Schooley, MD, examined the effects of combining the 2 drugs in a Phase I/II study of 9 patients without prior protease inhibitor therapy. Baseline CD4 counts were between 150-400 cells/mm³ (median 223). Baseline median plasma HIV RNA viral load was 4.19 log copies/mL. After 4 weeks of combination therapy with 141 at a dose of 900 mg twice daily and 1592 at a dose of 300 mg twice daily, an HIV viral load reduction of 2.08 log copies/mL was achieved. Five of 7 (71%) achieved an undetectable viral load (limit of detection 400 copies/mL). A CD4 count increase ranging from 60-125 (mean 79) cells/mm³ also occurred. Adverse events included nausea and vomiting (33%), diarrhea (22%), rash and headache. One patient withdrew from the study because of nausea and 1 because of rash. No blood cell or chemistry adverse effects were noted during the 4 week period. The combination of 1592 plus 141 is attractive, considering the possibility of twice daily dosing with or without food and the absence of immediate blood cell toxicity. Gastrointestinal side effects may be a problem. Further studies are ongoing. See Open Clinical Trials, this issue.

Preliminary data on 42 patients taking 141 as monotherapy for 4 weeks indicated no consistent pattern of resistance mutations for the drug. Twelve week data were also presented on 1592 as monotherapy or in combination with AZT. Combining 1592 and AZT appeared to prevent resistance mutations that developed with 1592 monotherapy.

Bilello JA and others. 1592U89, a novel carbocyclic nucleoside analog with potent anti-HIV activity, is synergistic in combination with 141W94, an HIV protease inhibitor. Abstract and poster presentation 154.

Harrigan R and others. Antiretroviral activity and resistance profile of the carbocyclic nucleoside HIV reverse transcriptase inhibitor 1592U89. Abstract and oral presentation 15.

Schooley RT and others. Preliminary data from a Phase/II study on the safety and antiviral efficacy of the combination of 141W94 plus 1592U89 in HIV-infected patients with 150 to 400 CD4 cells/mm³. Late breaker abstract and oral presentation LB3.

MKC-442: another New Anti-HIV Drug

• MKC-442 is a nucleoside analog that behaves like a non-nucleoside reverse transcriptase inhibitor
• The drug is in Phase IB trials
• Twice daily dosing is possible
• MKC-442 is synergistic with AZT, ddI and saquinavir
• Easily penetrates the central nervous system

Moxham CP and others. Preliminary efficacy and safety of repeated multiple doses of MKC-442 in HIV-infected volunteers. Abstract and late breaker presentation LB1.

Oral Pro-Drug of PMPA Identified: Bis(POC)PMPA

• Greater anti-HIV potency than PMPA
• 30% oral bioavailability
• Human studies to begin in mid-1997

Bischofberger N and others. Bis(POC)PMPA, an orally bioavailable prodrug of the antiretroviral agent PMPA. Abstract and poster presentation 214.

Adefovir Dipivoxil Once Daily Leads to No Resistance at 9 Months

• 16 of 30 patients analyzed
• 75% of participants used prior nucleoside analog therapy
• Oral formulation used as monotherapy for 3 months, then nucleoside analogs were added
• 0.5 log copies/mL HIV viral load reduction
• 125 mg once daily dosing
• Also called bis-POM PMEA, formerly GS 840
• Drug also has activity against HIV, hepatitis B virus and CMV

Cherrington JM and others. Genotypic characterization of HIV-1 variants isolated from AIDS patients treated with adefovir dipivoxil (bis-POM PMEA). Abstract and poster presentation 216.

Update of Triple Therapy for Early HIV Infection

• HIV DNA still present in mononuclear cells from blood and lymph tissue after 18 months
• 36 HIV positive patients treated within a mean of 55 days after acute HIV infection symptoms (Studies 313, 042)
• AZT plus 3TC plus either indinavir or ritonavir used for up to 18 months
• Baseline plasma HIV RNA viral load of 5.5 log copies/mL, decreased by 3.2 log to undetectable levels in all compliant patients (limit 100 copies/mL) after 5 months and continuing up to 17 months
• HIV cultures of blood mononuclear cells reveal no HIV growth, but PCR assay does reveal HIV proviral DNA incorporated into genes
• Mononuclear cells in semen reveal no HIV RNA, yet HIV proviral DNA is still present
• Lymph tissue samples from gut biopsies reveal presence of unspliced, ÒtrappedÓ HIV RNA in some samples by PCR
• HIV Western Blot antibody bands become more faint as levels of antibodies to gp120 (envelope) and p24 (core) have declined
• Absolute CD4 counts increased from a baseline of approx-imately 500 cells/mm³ to the 700-750 cells/mm³ range
• Normalization of the CD4/CD8 count ratio occurred and persisted
• Approximately one-third of ritonavir arm discontinued because of adverse events, noncompliance or drug allergy (one switched to indinavir, one to nevirapine); approximately 15% of the indinavir arm discontinued
• Plan to continue triple therapy for 2 to 2.5 years
• Periodic sampling and analyses of lymph tissues from gut or tonsils will be done
• Cerebrospinal fluid to be examined for presence of HIV
• Will consider stopping triple therapy after 2 or 2.5 years and observing patients for possible recurrence of HIV replication and growth

An update on triple therapy for patients recently infected with HIV (less than 3 months) was presented by Martin Markowitz, MD, and David Ho, MD, both from the Aaron Diamond AIDS Research Center in New York City (see BETA, September 1996, pages 10-11). A total of 36 patients were treated within a mean of 55 days of the appearance of "flu-like" symptoms associated with acute HIV infection. The triple combination included AZT plus 3TC plus either ritonavir or indinavir. For those who were compliant with the therapy, HIV RNA viral loads decreased to undetectable levels (limit of detection 100 copies/mL) after 5 months and remained so through 17 months. CD4 counts increased from the 500 cells/mm³ range to the 700s cells/mm³ range. Almost all of those who started on the indinavir regimen remained on it, compared with approximately two-thirds of those who started on the ritonavir regimen.

New data were presented regarding HIV in lymph tissue. Lymph tissue biopsies were taken from the gut (intestines or rectum) and sampled for HIV. HIV RNA viral loads were decreased dramatically. A few samples tested by PCR revealed unspliced messenger RNA, referred to by both researchers as "trapped" RNA. PCR measurements of HIV DNA (genes) still revealed the presence of the virus. However, such DNA may not be viable, since cultures of lymph tissue and blood mononuclear cells revealed no HIV replication. The significance of these findings is not yet fully known, and the studies will continue for up to 2 or 2.5 years, with periodic lymph tissue and cerebrospinal fluid analyses. Then a decision will be made whether to consider stopping triple therapy to determine whether HIV growth will recur.

Ho discussed the feasibility of HIV eradication. If HIV can be eradicated after 2.5 or 3 years of triple combination therapy, then HIV treatment would be analogous to treatment for acute leukemia, with a resultant cure. However, if HIV cannot be eradicated, then HIV treatment will be analogous to treatment for diabetes or high blood pressure, that is, life-long therapy to keep the virus from replicating.

Markowitz M and others. Recent HIV infection treated with AZT, 3TC and a potent protease inhibitor. Abstract and late breaker presentation LB8.

Ho DD. Can HIV be eradicated from an infected person? Abstract and opening plenary session S1.

Ritonavir plus Saquinavir plus 2 Nucleoside Analogs Effective as "Salvage Therapy"

• Study of 8 patients in Miami, FL, for 3 months
• 6 of 8 patients have mean baseline HIV RNA viral load of 4.65 log (81,750) copies/mL, decreased to undetectable (using RT-PCR assay) after 3 months
• 7 of 8 patients had mean CD4 count increase from a baseline of 52 cells/mm³ to 152 cells/mm³ after 3 months
• All patients were previously unresponsive to nucleoside analog therapy and unable to tolerate ritonavir at the standard dose of 600 mg every 12 hours
• Ritonavir (400 mg every 12 hrs) plus saquinavir (800 mg every 12 hours) plus 2 nucleoside analogs was well-tolerated

Steinhart CR and others. "Salvage therapy" using the combination of ritonavir and saquinavir in patients with advanced HIV infection. Abstract and poster presentation 199.

Ritonavir plus Saquinavir plus 2 Nucleoside Analogs Better than Triple Cocktail Including 1 Protease Inhibitor

Study 1

• Retrospective study of 32 AIDS patients in Palm Springs who failed 4 months of triple combination therapy (HIV disease progression or HIV RNA viral load greater than 10,000 copies/mL)
• A second protease inhibitor was added to the triple combination for an 4 additional months
• Mean baseline plasma HIV RNA after 4 months of triple therapy was 4.86 log (range 3.29-5.82) copies/mL. Viral load decreased to undetectable (limit of detection 400 copies/mL) in 93% (28 of 30 persons) after 4 months of quadruple therapy (initial baseline viral load not stated)
• Mean baseline CD4 count after 4 months of triple therapy was 79 (range 9-236) cells/mm³, and increased to 101 cells/mm³ after 4 months of quadruple therapy (initial baseline CD4 count not stated)
• 2 patients withdrew because of adverse effects of nausea (40%), diarrhea (40%), weakness (27%) and headache (12%)
• Ritonavir dose was 600 mg every 12 hours (full dose); saquinavir dose was 400 mg every 12 hours

Study 2

• Retrospective study in Chicago, IL, of 18 patients for 11 months
• Patients had late stage disease, with a mean of 4.4 years of prior nucleoside analog use; one-third had HIV-related wasting and one-third had CMV disease
• Mean baseline plasma HIV RNA (on dual nucleoside analog therapy) was 5.18 log copies/mL. After using triple cocktail for 5 months, HIV RNA decreased by 0.76 log to 4.42 log copies/mL. After quadruple therapy for 6 months, HIV RNA decreased by an additional 0.69 log to 3.73 log copies/mL (overall 11 month decrease of 1.45 log)
• Mean baseline CD4 count (on dual nucleoside therapy) was 65 cells/mm³. After triple therapy for 5 months, CD4 count increased to 94 cells/mm³. After quadruple therapy for 6 months, CD4 count increased further to 180 cells/mm³ (overall increase of 115 cells/mm³)
• Mean neutrophil counts increased overall by 2,345 cells/µL
• Anemia improved slightly with a mean hematocrit increase of 1.4%
• 1 patient discontinued therapy because of severe diarrhea (excluded from analyses above); the regimen was otherwise well-tolerated
• Ritonavir dose was 800-1,200 mg daily; saquinavir does was 400-800 mg daily (an unstated percentage were taking lower doses of both drug in Study 2, compared with all patients in Study 1 taking the higher doses of both drugs)

The authors did not indicate whether nucleoside analog drugs had been changed prior to adding a new protease inhibitor, as has since been recommended by the International AIDS Society-USA. If this was not done, improvements in HIV surrogate markers and blood parameters might have been even better if it had been. The superior surrogate marker results in Study 1 may have been due to higher doses of both protease inhibitors, or because an apparently greater proportion of patients in Study 2 had later stage HIV disease.

Barbour CO. Efficacy and safety of quadruple combination therapy in treatment experienced HIV/AIDS patients. Abstract and oral presentation 245.

Berger DS and others. Further reduction in plasma HIV load in patients with advanced AIDS when a second protease inhibitor was added to triple drug combination therapy. Abstract and poster presentation 244.

Minority of Patients Taking Ritonavir plus Saquinavir Develop Multiple Resistance Mutations to Both Drugs

• 18 patients with fewer than 50 CD4 cells/mm³
• Dose of each drug was 600 mg every 12 hours
• 1 patient stopped therapy because of active tuberculosis, while another stopped due to elevations in blood triglycerides (fats) and amylase (a pancreas enzyme), leaving 16 evaluable patients
• 5 of 16 (31%) were non-responders; 1 of 16 (6%) transient responders had up to 9 protease gene mutations, most of which were absent at baseline
• 11 of 18 (61%) were responders, and sustained a greater than 1 log decrease in plasma HIV RNA
• 4 of the responders stopped treatment because of side effects of hepatitis (1), numbness (2); 1 patient chose to discontinue
• Lack of benefit after 8 weeks

Hirschel B and others. Escape of viremia and rapid development of protease mutations in advanced HIV infection treated with saquinavir plus ritonavir. Abstract and poster presentation 594.

Ritonavir and Saquinavir Should be Avoided by Those with Active Hepatitis B or C

• Active infection with Hepatitis B or C indicates that 600 mg doses of both ritonavir and saquinavir should be avoided.
• Significant risk of increased liver enzymes and aggravated hepatitis

Mellors J. Combination protease inhibitor therapy. Abstract and oral presentation S55.

Ritonavir plus Saquinavir Leads to Improved Cell-Mediated Immune Responses In Vitro

• Increased responses to tetanus toxoid and phytohemagluttinin (PHA)

Angel JB and others. Rapid improvement in cell-mediated immune function with initiation of ritonavir plus saquinavir in HIV immune deficiency. Abstract and oral presentation 33.

Indinavir Still Beneficial after 96 Weeks of Therapy

• Study 021
• 10 individuals with extensive prior anti-HIV therapy
• Baseline median HIV RNA viral load of 4.9 log (77,455) copies/mL, decreased by 1.34 log copies/mL
• 30% of 10 patients had undetectable HIV viral load (limit of detection 500 copies/mL)
• Baseline median CD4 count of 240 cells/mm³, increased in 10 patients by 140 cells/mm³
• Indinavir taken at standard dose (800 mg every 8 hours) as monotherapy for 12 months, then nucleoside analogs were added

Stein D and others. Two year follow-up of patients treated with indinavir 800 mg every 8 hours. Abstract and poster presentation 195.

Indinavir plus AZT plus 3TC Effective up to 68 Weeks

• Study 035
• Randomized, double-blind study of 97 patients for 52 weeks, extended to 68 weeks
• Subjects had prior experience with AZT but not with 3TC or protease inhibitors
• Baseline median HIV RNA viral load of 43,190 copies/mL, decreased by 2.3 log copies/mL at 52 weeks
• After 68 weeks, 18 of 21 persons (86%) had undetectable HIV RNA (limit of detection 500 copies/mL) and 10 of 14 persons (71%) had undetectable HIV RNA using a more sensitive test (limit of detection 50 copies/mL)
• Baseline median CD4 counts of 142 cells/mm³; increases were not presented
• After 36-52 weeks, 2 of 5 patients had negative groin lymph node cultures for HIV, yet had 50-100 copies of HIV RNA per gram of lymph tissue

Wong JK and others. Reduction of HIV in blood and lymph nodes after potent antiretroviral therapy. Abstract and late breaker presentation LB10.

Interleukin 2

• IL-2 (aldesleukin, Proleukin) dose-escalating study lasting 52 weeks
• 18 patients taking stable double nucleoside therapy
• 60 million international units (MIU) of IL-2 per 28 day cycle (6 MIU daily for 5 days, then off 2 days, then 6 MIU daily for 5 days, then off 16 days) was well tolerated
• 11% developed swelling (angioedema) unrelated to dose
• Modest, sustained rise in CD4 counts; viral load changed little
• Mean HIV RNA viral load at baseline of 30,461 copies/mL, increased to 36,133 copies/mL
• Mean CD4 count at baseline of 332 cells/mm³, increased to 440 cells/mm³
• Of 18 patients, 2 discontinued because of toxicity, 5 by patient request and 1 because of lack of benefit
• Seven of 18 patients (39%) continued treatment during the extension period

Follansbee S and others. Dose ranging study of interleukin 2 (IL-2) in HIV-infected men on antiretroviral therapy. Abstract and poster presentation 419.

d4T plus 3TC Confirmed as a Successful Combination

Altis 1 Study

• Study took place in France, lasted for 24 weeks
• Open pilot study of 42 patients with no prior HIV therapy
• Baseline median plasma HIV RNA viral load of 76,502 copies/mL, decreased by 1.66 log after 24 weeks; HIV RNA undetectable in 57% (limit of detection 5,000 copies/mL) and 21% (limit of detection 200 copies/mL)
• Baseline CD4 count of 258 cells/mm³, increased by 108 cells/mm³
• Severe adverse reactions occured in 13%; none discontinued
• Altis 2 Study
  • Study took place in France, lasted for 24 weeks
  • Open pilot study of 41 patients. All had prior AZT, ddI and/or ddC therapy, but none had prior d4T or 3TC therapy
  • Baseline median plasma HIV RNA viral load of 91,255 copies/mL, decreased by 0.5 log after 24 weeks; HIV RNA undetectable in 22% (limit of detection 5,000 copies/mL) and 5% (limit of detection 200 copies/mL)
  • Baseline CD4 count 172 cells/mm³, increased by 46 cells/mm³
  • Severe adverse reactions in 13%; only 1 discontinued d4T
  • Baseline viral loads were correlated with maximal viral load responses to therapy in both Altis 1 and Altis
  • If baseline viral load was less than 40,000 copies/mL, 79% achieved a viral load reduction of less than 3,000 copies/mL.
  • If baseline viral load was greater than 120,000 copies/mL, only 29% achieved a viral load reduction of less than 3,000 copies/mL.
• Vancouver AIDS Research Study
  • 8 week open pilot study of 48 patients. All either were AZT intolerant or had HIV disease progression while taking AZT; some had prior exposure to d4T or 3TC
  • Baseline median plasma HIV RNA viral load of 4.7 log copies/mL, decreased by 0.97 log after 8 weeks
  • Baseline median CD4 count of 135 cells/mm³, increased by 30 cells/mm³
  • Adverse events in 6%
  • Those without prior exposure to either d4T or 3TC, or with higher baseline CD4 counts had a higher probability of a viral load reduction.
  • Baseline viral load was not predictive of a viral load response

  Retrospective Analysis

  • 330 patients in AmFAR Community Based Clinical Trials Network
  • Those with no prior anti-HIV therapy had greater reductions in HIV RNA viral loads and greater increases in CD4 cell counts than those with prior therapy

  Cohen CJ and others. Lamivudine (3TC) and stavudine (d4T) combination therapy: HIV viral load and CD4 changes in a retrospective study of 330 patients. Abstract and poster presentation 556.

  Katlama C and others. ALTIS: a pilot study of d4T/3TC in antiretroviral naive and experienced patients. Abstract and late breaker presentation LB4.

  Rouleau D and others. Predictors of viral load response in a pilot-open-label study of stavudine (d4T) in combination with lamivudine (3TC). Abstract and poster presentation 557.

  Cerebrospinal Fluid Levels of HIV Become Undetectable after Double Combination Therapy

  • Randomized, open-label 12-week trial of 10 patients with HIV RNA viral loads greater than 10,000 copies/mL and no prior HIV therapy
  • Either d4T plus 3TC or AZT plus 3TC were used
  • Baseline mean cerebrospinal fluid (CSF) HIV RNA viral load of 3.57 log copies/mL, decreased to undetectable in all 10 persons (limit of detection not stated), regardless of combination
  • Baseline mean plasma HIV RNA viral load of 4.2-4.6 log copies/mL, decreased by 1.4 log in both arms
  • Baseline mean CD4 count of 295 cells/mm³, increased by 115 cells/mm³ in both arms; little change in CD8 cell counts
  • Both combinations are equally effective in decreasing viral load in the central nervous system and possibly in preventing HIV-associated dementia
  • Despite a baseline of 3.57 log copies/mL of HIV RNA in CSF, no participants had obvious central nervous system symptoms

  Foudraine N and others. CSF and serum HIV RNA levels during AZT/3TC and d4T/3TC treatment. Abstract and late breaker presentation LB5.

  Nevirapine Penetrates Central Nervous System

  • Nevirapine penetrates central nervous system over 10-fold more than AZT or delavirdine in vitro

  Yazdanian M and others. Nevirapine, a non-nucleoside RT inhibitor, readily permeates the blood brain barrier. Abstract and poster 567.

  Measuring Drug Levels in Blood Cells is Useful in Measuring Benefits of Anti-HIV Drugs

  It has been well recognized that there is great variability in individual patients' responses to anti-HIV drug therapy. Courtney Fletcher, MD, and colleagues, from the University of Minnesota, reported that measuring blood plasma levels of active AZT -- and increasing the dose if levels are subtherapeutic -- resulted in higher intracellular drug levels and better surrogate marker results than those achieved at standard doses of AZT (500 mg daily). After 24 weeks of treatment, 9 of 9 "concentration-controlled" patients (100%) had CD4 cell count increases compared with 4 of 7 of standard dose patients (57%). Similar benefits were observed with regard to HIV viral load reductions among patients enrolled in the concentration-controlled arm. The percent increase in CD4 lymphocyte counts was statistically associated with intracellular but not plasma drug levels of AZT. Measuring and maintaining specific intracellular blood levels of anti-HIV drugs may be helpful in minimizing the variability of patients' responses.

  Fletcher CV and others. Intracellular triphosphate concentrations of antiretroviral nucleosides as a determinant of clinical response in HIV-infected patients. Abstract and oral presentation 13.

  Drug Interactions

  Nevirapine Interactions with Protease Inhibitors

  • When taking nevirapine plus indinavir, consider increasing indinavir dose to 1,000 mg every 8 hours (two 400 mg pills plus one 200 mg pill each dose, which increases indinavir cost by approximately 25%) or consider measuring indinavir blood levels to determine if they are within therapeutic range
  • When taking nevirapine plus ritonavir, no dosage adjustment of either drug is necessary
  • When taking nevirapine plus saquinavir, no dosage adjustment of either drug is necessary

  Murphy R and others. Effect of nevirapine on pharmacokinetics of indinavir and ritonavir in HIV-1 patients. Abstract and oral presentation 374.

  Sahai J and others. Drug interaction study between saquinavir and nevirapine. Abstract and poster presentation 614.

  Delavirdine Interactions with Protease Inhibitors

  • When taking delavirdine (Rescriptor) plus indinavir, decrease indinavir dose to 400-600 every 8 hours (both delavirdine and indinavir should be taken without food on an empty stomach)
  • When taking delavirdine plus ritonavir, no dosage adjustment of either drug is needed
  • When taking delavirdine plus saquinavir, no dosage adjust-ment of either drug is needed (delavirdine is taken 1 hour before or 2 hours after food; saquinavir is taken with food)

  Cox SR and others. Delavirdine and marketed protease inhibitors: pharmacokinetic interaction studies in healthy volunteers. Abstract and oral presentation 372.

  DMP-266 Interactions with Indinavir

  • When taking DMP-266 plus indinavir, consider increasing indinavir dose to 1,000 mg every 8 hours (two 400 mg pills plus one 200 mg pill each dose, which increases indinavir cost by approximately 25%) or consider measuring indinavir blood levels to determine if they are within therapeutic range

  Fiske WD and others. Pharmacokinetics of DMP 266 and indinavir multiple oral doses in HIV-1 infected individuals. Abstract and poster presentation 568.

  Saquinavir Interactions with Indinavir: Hold Off for Now

  • In vivo single dose study
  • Saquinavir plus indinavir leads to 5- to 7-fold increases in levels of saquinavir (either hard gel or soft gel formulation), with indeterminable effects of saquinavir on indinavir
  • In in vitro studies, antagonism with indinavir plus saquinavir (high doses) and synergism at low efficacy doses
  • If AZT-resistant, antagonism occurs at all doses of indinavir plus saquinavir
  • If resistant to multiple reverse transcriptase inhibitors, antagonism occurs at all doses of indinavir plus saquinavir
  • Combination of the 2 drugs is not recommended at this time because of incomplete and somewhat conflicting data

  Manion DJ and others. Combination drug regimens against multi-drug resistant HIV-1 in vitro. Abstract and oral presentation 11.

  McCrea J and others. Indinavir-saquinavir single dose pharmacokinetic study. Abstract and poster presentation 608.

  Merrill DP andothers. Protease inhibitor combination regimens against HIV-1 in vitro. Abstract and poster presentation 158.

  Delavirdine Reverses AZT Resistance

  • Delavirdine plus AZT is a good combination

  In a report by L.K. Wathen from Pharmacia and Upjohn Company, 22 of 24 patients (92%) with AZT resistance had a reversal of resistance and were resensitized to the drug when delavirdine was added for a period of 6 months. A separate analysis was presented of a Phase III trial of 1,200 patients using AZT plus delavirdine at a 3 times daily dose of either 200 mg, 300 mg or 400 mg. In 190 isolates tested after 24 weeks, all of those at the highest dose level were still sensitive to AZT, while 88% were still sensitive to delavirdine. Another antiretroviral drug that has been documented to reverse AZT resistance is 3TC.

  Wathen LK and others. Phenotypic sensitivity of HIV-1 viral isolates during combination delavirdine plus zidovudine therapy. Abstract and oral presentation 12.

  Other Drug Interactions

  • 5-10% of patients taking AZT plus ddI develop resistance to all current nucleoside analogs
  • AZT plus d4T is a bad combination; each drug antagonizes the other and cancels their anti-HIV effect
  • Synergism occurs with either AZT plus 3TC, nevirapine plus AZT, or indinavir plus AZT

  Manion DJ and others. Combination drug regimens against multi-drug resistant HIV-1 in vitro. Abstract and oral presentation 11.

  Clinical Care

  Several AIDS Researchers Declare HIV/AIDS Treatment is Best Handled by "AIDS Specialists"

  Joep Lange, MD, a leading HIV/AIDS clinical researcher from the Academic Medical Center in Amsterdam, asserted that HIV/AIDS is best managed by those with expertise in the field. Leading HIV/AIDS clinical researchers agreed, including Robert Schooley, MD, from the University of Colorado and a member of the Scientific Program Committee for the Conference.

  In the beginning of the HIV/AIDS epidemic in the early to mid-1980s, there was a general consensus that treating HIV/AIDS patients was optimally handled by HIV/AIDS specialists. Later, when the magnitude of the epidemic was better appreciated, guidelines in the Journal of the American Medical Association and elsewhere indicated that HIV care could be handled by any primary care physician, with occasional consultations with an infectious disease or oncology specialist.

  However, HIV care is increasingly complex due to the use of combination therapies comprised of subsets of the 9 FDA-approved drugs for HIV (and many more in the pipeline) and because of drug interactions among the many potential combinations. HIV/AIDS care is changing very rapidly because of the rapid approval of new drugs and the continual generation of new information regarding the various combinations. This makes it very difficult for the primary care practitioner to stay current in the management of patients with HIV infection.

  Patients in suburban, rural and in certain urban locations may not be able to find physicians with expertise in using the new combinations of HIV drugs and in understanding their interactions. There is clearly a need for a mechanism to update HIV/AIDS specialists and other physicians concerning the rapidly expanding field of HIV/AIDS treatment.

  Lange J. Tribulations of trials: where do we go from here? Abstract and oral presentation S54.

  Experienced Providers Prescribe Appropriate Antiretroviral Therapies

  • More likely to prescribe appropriate combination therapy
  • More likely to prescribe appropriate triple combination therapy
  • More likely to treat opportunistic infections according to guidelines
  • Survey of 1,166 physicians in 20 U.S. cities sponsored by San Francisco Community Consortium and the University of California at San Francisco

  Mitchell TF and others. Community patterns of care for HIV disease: does clinical experience make a difference? Abstract and poster presentation 255.

  Cytomegalovirus DNA in Blood Increases Risk of Death

  In a review of cytomegalovirus (CMV) infection and disease, Stephen Spector, MD, from the University of California at San Diego, reported that increasing levels of CMV DNA in the blood are associated with increasing risk of mortality in AIDS. The DNA was quantified by PCR. At baseline evaluation, each log (factor of 10) increase in CMV DNA was associated with a 2.2-fold increased risk of death, regardless of baseline CD4 cell count. The findings help to resolve the controversy regarding whether CMV is an independent co-factor for the risk of HIV disease progression. In the past, some studies demonstrated that CMV antibodies were a co-factor for progression, while others drew the opposite conclusion. If active CMV replication is a true co-factor for increased HIV disease progression or risk of death, then treatment for CMV may lead to decreased disease progression and death. One anti-HIV drug in Phase II/III studies, PMEA (see above), has activity against both HIV and CMV.

  Mellors J. Viral determinants of HIV disease progression. Abstract and oral presentation S38.

  Spector SA. CMV: Advances in pathogenesis and improved approaches for treatment and prevention. Abstract and oral presentation L3.

   

  DHEA Has No Clinical Benefits after 1 Month

  • Placebo-controlled trial of 16 HIV positive men
  • Patients had advanced HIV disease and CD4 counts of fewer than 50 cells/mm³
  • Oral dose of 50 mg twice daily or placebo were taken
  • Blood levels of DHEA and DHEA-sulfate increased in the drug arm
  • No changes in blood interleukin 6 or in acute phase reactants, C-reactive protein or erythrocyte sedimentation rate
  • No measurable clinical benefit after 1 month

  Evans TG and others. Effect of oral dehydroepiandrosterone (DHEA) administration on acute Phase reactants in advanced HIV-1 infected patients. Abstract and poster 433.

  HLA Markers are Better than CKR5 Receptor Phenotype in Predicting HIV Disease Progression

  • Human leukocyte antigen (HLA) also is independent of HIV viral load in predicting progression

  Saah AJ and others. Correlation of HLA and plasma HIV-1 RNA in predicting the course of HIV infection. Abstract and oral presentation 479.

  Keet IPM and others. Consistent associations between HLA and time to AIDS in 3 prospective seroconverters cohorts. Abstract and late breaker oral presentation LB 15.

Harvey S. Bartnof has been a member of the Scientific Advisory Committee at the San Francisco AIDS Foundation since 1987.