1. How do you tell if you are HIV positive?

A positive viral load test appears prior to the emergence of antibodies to HIV as measured by the ELISA test. Individuals who fear that they are recently infected should request an ELISA test and an HIV viral load test. Very early treatment may substantially prolong survival.

2. When do you start treatment with Highly Active Antiretroviral Therapy (HAART)?

• Immediately after infection, before or during seroconversion.
• When the CD4 count drops below 200. -- careful monitoring should begin when the CD4 count drops below 350.
• When the viral load rises above 55,000 -- careful monitoring should begin when the viral load rises above 30,000.

In newly infected patients, Drs. Walker and Rosenberg have shown that early intervention (prior to or during seroconversion) may preserve CD8-positive cytotoxic T-cells which will destroy HIV-infected cells.Nature 2000; 407:523.

Their Strategic Treatment Interruption (STI) Protocol is as follows:

• Treat for 8 - 12 months with 3 - 4 antiviral drugs (complete viral suppression) Then stop all antiretroviral treatment, but re-initiate treatment when viral load rebounds to 50,000 on a single measurement or remains at least 5,000 for three consecutive weeks. IDSA 2001 SIII (not abstracted).

Viremia was successfully controlled in 1/2 of the patients with STI instituted in the first 90 days after infection. ICAAC 2001, I 1908.

3. What drugs do you start with if you are HIV positive?

If you know who infected you, attempt to determine what drugs that individual was taking on the day you were infected.

Obtain a genotype and a phenotype or virtual phenotype to assess if you have been infected with a drug resistant virus. Phenotypic drug testing predicts long-term viral suppression. Journal of Infectious Disease 2001; 183:401.

If you have recently been infected with a resistant virus from someone who is on medication, it will take 20 - 40 weeks for the virus to mutate to a wild strain genotype.

In the absence of this information, this reviewer feels the following data are helpful regarding treatment initiation:

Controversy exists as to whether you should use the strongest possible treatment as first line therapy or use a less powerful treatment and save stronger drugs if the initial drug treatment program fails. This reviewer feels we should treat for success, not for failure. A strong argument can also be made that the partially non-compliant patient will do better with a powerful treatment program rather than a weak treatment program. Recent data suggest that a protease-boosted protease such as Kaletra (for drug names see table below) or Ritonavir boosted Indinavir plus a backbone of two or three nucleoside reverse transcriptase inhibitors would achieve this goal. This reviewer is currently using Kaletra plus Abacavir twice a day.Satellite Presentation; Joseph Eron. ICAAC 2001. Not abstracted

In a long-term study of Indinavir, AZT, and 3TC in 33 patients, 58% have a viral load of 400 at 5 years and a CD4 count rise of 252 (mean). The good news is that there is a durable response to at least 5 years in half of the patients. The bad news is that half of the patients have failed, usually because of non-adherence to the treatment program. 2001(Buenos Aires), Abs 215.

In the Chorus Study (4985 patients) comparing a non-nucleoside reverse transcriptase/reverse transcriptase regimen versus a PI/reverse transcriptase regimen, there was no significant difference between treatment groups. It should be noted that this study did not include a protease-boosted protease, which would probably give a more durable response. ISA 2001(Buenos Aires), Poster 230.

A study of Kaletra ( lopinavir/ritonavir) showed no resistant mutations versus 15 resistant patients out of 40 receiving Nelfinavir at 24 weeks. 3TC resistance was seen in 44% of the Kaletra patients versus 90% of the Nelfinavir patients. It should be noted that Kaletra is a protease-boosted protease whereas Nelfinavir is not. Glasgow 2000, Journal of Infectious Disease 2001; 183:401.

A four-drug combination may promote a faster viral load decline. David Ho, Plenary, ISA 2001(Buenos Aires), Abs Pl 1.

4. How frequently do you follow up with office visits and lab work?

There are no guidelines to follow-up examinations and laboratory evaluations. This reviewer feels that the patient should be seen two weeks after initiation of treatment to assess adherence, side effects, patient questions, and viral load. The viral load should have fallen at least 0.5 log from baseline. If viral load does not fall, treatment should be intensified.

Follow-up should then occur every month for three months, every two months for one year, and then four times a year if the patient is stable on an antiretroviral program.

5. What lab work should be included in the follow-up panel?

Patients should routinely receive:

• CBC with a platelet count
• liver panel including bilirubin and transaminase
• fasting lipid panel fractionated to high density and low density lipoproteins
• serum amylase
• fasting blood sugar
• CD4 count
• Ultra-sensitive viral load

6. How do I deal with "blips?" (Slight rise in viral load)

If the patient's viral load goes from undetectable to measurable, the patient needs to evaluate adherence, drug-drug interactions, and drug absorption. Certain infections, such as influenza or Herpes simplex will cause a transient blip. Viral load should be repeated and the treatment program intensified if the elevation persists.

The current feeling expressed at ICAAC was that with mild elevation of viral load above detection, intensification of the program may be all that is necessary. With a progressive rise in viral load, a genotype and phenotype should be obtained and resistant drugs should be switched out in favor of drugs with demonstrable activity.

Flu vaccines, or other fever-causing injections, may cause temporary increases in the viral load.

7. What is my second drug program choice?

A genotype and phenotype should be done. Resistant drugs should be switched out of the program. Active drugs should be continued and intensified (increased dose and/or frequency) if possible. A protease-boosted protease should be added. If not previously used, boosted Amprenavir may be very effective against common protease-resistant mutations. (Amprenavir 600 mg/ Ritonavir 100 mg twice a day). ICAAC 2001, Abs 1924.

Kaletra and Efavirenz were well tolerated in combination and effective in multiple-PI experienced patients at 72 weeks. ICAAC 2001, Abs 1925. The 184 mutation disappeared after the 180 days off 3TC allowing a switch to Abacavir. ICAAC 2001, I1752.

A new class of drugs (such as Tenofavir DF) should be added if possible. Tenofavir 300 mg once daily was safe and effective at two years in patients with high levels of NRTI resistance.

Forty-eight week data presented in Athens showed that the drug was safe and effective with no drug-drug interactions and very infrequent reverse transcriptase inhibitor mutations. Greece 2000, P 226.

Tenofavir only gives a 0.6 log reduction in the viral load. Using a phenotype, the patient should combine Tenofovir with at least two to three other drugs with demonstrable activity.

8. What is my third drug program choice? (Salvage treatment)

In all probability, if the patient fails therapy three times, it will be almost impossible to suppress the viral load below the level of detection. It has been shown conclusively, however, that continued treatment renders the virus less "fit" by interfering with its ability to reproduce, enter cells, or produce essential proteins. For this reason, treatment with 3-5 drugs should be continued. There appears to be a general agreement that the 184 mutation is an important determinant of viral weakness. 3TC, therefore, should be continued. New England Journal of Medicine 2001, 344:472.

Pegalated interferon may be a useful treatment option in patients with highly resistant virus. ICAAC 2001, I1938.

9. Is there any new information on opportunistic infections and Kaposi's sarcoma?

No new clinically relevant data were reported. The incidences of Kaposi's sarcoma and non-Hodgkin's lymphoma are decreasing. ICAAC I248 and I250.

10. What is new regarding immune restoration?

CD4 depletion is caused by increased cell destruction rather than a block in CD4 production. ISA 2001(Buenos Aires), LB 3.

11. Any new drug-drug interactions reported this year?

St. John's wort prevents the absorption of Indinavir.

Garlic decreases Saquinavir levels by 50%.

Comment: garlic is being taken by numerous patients in an effort to treat cholesterol elevations. CROI 2001, Piscitelli Presentation.

12. What new resistance information was reported?

Doug Richman reported an astonishingly high level of drug resistance in 1999 in 200,000 US AIDS patients.

• 70% showed some resistance to NRTIs
• 42% showed some resistance PIs
• 31% showed some resistance to NNRTIs
• 51% were resistant to 2 or more classes of drugs
• 14% had resistance to all 3 classes of drugs

Fauci and Dybul report no viral rebound and no CD4 decline in patients on a program of seven days on treatment and seven days off treatment at one year. Viral rebound was seen when patients went 10 days off treatment. Blood lipids improved significantly. IDSA 2001, Pl 4 and ICAAC 2001 I 1910.

In patients who are chronically non-adherent, once-a-day treatment in a structured environment may be appropriate. Once-daily treatment was effective in a methadone clinic using Nevirapine/DDI and 3TC. ISA 2001(Buenos Aires), Abs 426 and ICAAC 2001, I 917.

13. Any new useful information on lipodystrophy or other side effects and metabolic complications?

No.

The lipodystrophy syndrome (insuline resistant diabetes, cholesterol elevation, triglyceride elevation, facial lipodystrophy, buffalo hump, abdominal obesity, and peripheral fat loss) remains the major complication of HAART. The cause of this problem and effective treatments remain to be identified. Intensification of HAART regimens caused lipodystrophy to worsen.

Osteopenia and osteoporosis (loss of bone mineralization) was seen in 50% of HIV positive patients with multiple drug regimens. ICAAC, Chicago 2001REF. Osteoporosis is not due to protease inhibitors. ICAAC 2001, I 1328, I 1329.

Dramatic increases in osteonecrosis (bone death) in AIDS patients have been noted. Osteonecrosis is not associated with hyperlipidemia or lipodystrophy. Avascular necrosis of the hip occurs with low CD4 count and presents as hip pain. It is a common side effect, especially in patients receiving steroids. Hip replacement is safe in HIV positive patients. ICAAC 2001, Abs I216 and I218.

Anemia is common in HIV-infected individuals. In one study of 501 patients, 21% were found to have HIV-associated anemia. Anemic patients demonstrate HIV disease progression at a rate 3-8 times faster than non-anemic patients. . ISA 2001(Buenos Aires), Poster 1049.

Procrit (epoetin alpha) administered at a dosage of 40,000 units once-weekly was as effective as 10,000 units administered 3 times a week. ICAAC 2001, Abs I 254.

Myocardial infarction is associated with PI treatment. Patients on protease inhibitors should take drugs to lower their cholesterol, reduce weight and blood pressure, and stop smoking.

Provastatin (Provachol) was safe and effective in lowering cholesterol and triglicerides. IDSA 2001, Abs 18, Abs 730. ICAAC 2001, Abs I 1326.

Lactic acidosis results from mitochondrial toxicity (depletion of mDNA). It occurs more frequently with D4T. Lactic acidosis is characterized by fatigue, gastrointestinal symptoms, elevated lactic acid and XXX in patients on NRTI treatment (eg, D4T). The mortality rate can be 80%. 8 CROI S 64 and Abs 624.

14. What else should I watch out for? (Co-infections and emerging diseases)

Co-infection with hepatitis C appears to be a major problem in HIV-infected patients. Hepatitis C infection slows the rise in CD4 count in treatment-naive HIV-positive patients. ICAAC H 741 and ICAAC 2001, Abstract I205.

Hyperglycemia is more frequent in hepatitis C co-infected HIV-positive patients on HAART. ICAAC 2001 H740.

Hepatitis C pathogenesis appears to be immunologically based whereas hepatitis C plus HIV co-infection hepatic disease appears to be cytokine driven. ICAAC 2001, Poster H456.

Pegalated interferon alpha 2A is emerging as the current treatment for hepatitis C. 180 mcg resulted in less than 100 copies of hepatitis C at 12 weeks. This response was sustained and included genotype 1, which usually does not respond to interferon. ISA 2001(Buenos Aires), 38 and IDSA 2001 Abs 538.

Though most opportunistic infections have decreased in HIV positive patients, tuberculosis appears to be rising in some cities. ICAAC 2001, Abs I244.

Liver toxicity is common with HAART but is usually not severe. Liver toxicity is more frequent with hepatitis C virus co-infection in HIV positive patients. A pre-treatment increase in transaminase levels in hepatitis C infected patients is a predictor of severe liver toxicity. ICAAC 2001, Abs I207.

Liver toxicity occurs occasionally with non-nucleoside reverse transcriptase inhibitors (Nevirapine or Efavirenz). Hepatitis C virus increases the risk of severe liver toxicity with HAART regimens. ISA (Buenos Aires), 2001, Abs 43 and ICAAC 2001, Abs I208 and I209.

Hepatitis C is difficult to treat in HIV co-infected patients because of overlapping toxicity of medications. If possible, Hepatitis C should be treated first. ICAAC 2001, H748.

Ribavirin is antagonistic with AZT, d4T, and 3TC; synergistic with ddI. ICAAC 2001, I 1939.

Pancreatitis was seen in patients treated with Interferon, Ribavirin, D4T and ddI. ICAAC 2001, H 739.

Treatment with a protease inhibitor may slow the rate of disease progression in co-infected patients. Hepatology 2001; 34:283.

End-stage liver disease is a major cause of death in HIV patients co-infected with hepatitis B and/or C. IDSA 2001, S 102.

Patients with hepatitis B and HIV should receive Tenofavir and 3TC, which are effective against both diseases.

Low-dose Adefovir is safe and effective for treatment of hepatitis B. ICAAC 2001, LB 20.

15. What new drugs should I be following?

Tenofovir was approved last month. The dose is 300mg once a day. This is a nonnucleoside reverse transcriptase inhibitor but is a nucleotide and not a nucleoside. It was reported that the drug was significantly effective at 24 weeks in drug-experienced patients. Increases in creatinine and decreases in serum phosphate were seen. ICAAC 2001, Abs I666.

BMS232632 (atazanavir) is a novel once-a-day protease inhibitor. It does not raise cholesterol or triglycerides and was extremely effective in naive patients. Bilirubin is elevated in 2% of patients. ICAAC 2001, P I667. IDSA 2001, Abs 5. ICAAC 2001, LB 16.

TMC125, a second generation nonnucleoside reverse transcriptase inhibitor (NNRTI), is dosed at 900 mg twice a day. In a Phase I study for 7 days, it demonstrated a dramatic 2 log reduction in viral load. It is effective against common NNRTI mutations. Major side effects include headache, fatigue, rash, and diarrhea. ICAAC 2001, I 668.

FTC (emtricitabine), a reverse transcriptase inhibitor, is given one daily, and is as effective as 3TC twice a day. ICAAC I 1931 and I 1932. In a study in African women, FTC was found to be safe and effective. ICAAC 2001, I 1933.

TPV (tipranavir, a new protease inhibitor boosted with ritonavir) was safe and effective. IDSA 2001, Abs 3. ICAAC 2001, LB 15.

DMP 450 Mozenavir is a second generation NRTI. Side effects include diarrhea, nausea, and vomiting. Abnormal EKGs have been seen in some patients. IDSA 2001, Abs 2.

T20 and T1249 in ARV-experienced patients showed a ten-fold drop in viral load. IDSA 2001, Abs. 46.

CCR5 inhibitor (Schering) showed synergy with AZT, 3TC, EFV. IDSA 2001, Abs. 47.

16. Are we winning the War on AIDS? (Epidemiology of HIV/AIDS)

No

• 60 million HIV/AIDS cases worldwide.
• 850,000 HIV/AIDS cases in the United States.
• 450,000 HIV/AIDS cases in the U.S. on treatment.
• 200,000 HIV/AIDS cases failing treatment per year secondary to drug resistance.

17. When will we see an AIDS vaccine?

No major advances were reported.

BGC (a TB vaccine) induces a strong TH1 response in children; BCG with hepatitis B virus vaccine induces a strong TH1 and TH2 response. ICAAC 2001, Abs G 452.

A vaccine with gp 120, nef, Tat, and adjuvant was protective against 5 HIV-infected monkeys one month later (after injection). IDSA 2001, LB 012.

18. What about other sexually transmitted diseases?

Multiple reports from around the US indicate an increase in the incidence of all sexually transmitted diseases. This trend is mirrored by international data:

• From 1995 - 2000, there was a 20% increase in gonorrhea in the UK.
• From 1999 - 2000 there was a 71% increase in gonorrhea and 41% increase in chlamydia in the Netherlands and Belgium.
• From 1999 -- 2000 the incidence of syphilis doubled in the Netherlands and Belgium.

19. Prevention:

Traditional public health prevention methods are not working. If we cannot control the rate of new HIV infections in San Francisco, the best informed, best educated, and most affluent at-risk group in the world, we will not be able to stop the global pandemic.

Patients should be vaccinated for influenza, pneumonia, hepatitis A, and hepatitis B.

Sources for more detailed HIV/AIDS information:

• UCSF AIDS Research Institute: http://ari.ucsf.edu/
• San Francisco AIDS Foundation: http://www.sfaf.org/
• Project Inform: http://www.projectinform.org/

Other favorites:

• UCSF HIV Insite (Info on treatment, prevention, and policy): http://hivinsite.ucsf.edu/InSite
• The Body (AIDS and HIV information): http://www.thebody.com/
• AIDS Treatment News (The most comprehensive list of HIV/AIDS related links): http://www.aidsnews.org/