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Human Immunodeficiency Virus Infections

There have been dramatic developments in the field of antiretroviral therapies over the past several years. In addition to the availability of many new drugs (including non-nucleoside reverse transcriptase inhibitors and protease inhibitors) knowledge about virus biology has changed the basic approach to treatment and allowed physicians to more accurately and quickly quantitate and monitor response to therapy. Although patients are asymptomatic for years, the virus is always actively replicating. It has been estimated that 10-100 billion HIV particles are produced.

Immune Reconstitution after Institution of HAART

Much work is currently being done to study the nature of the immune reconstitution after highly active antiretroviral treatment (HAART) is started. Our immune system consists of naive and memory T cells. Through T cell receptor (TCR) rearrangements, an extensive repertoire of T cells exist with the ability to recognize a vast number of different foreign antigens complexed with MHC molecules. After encounter with these antigens, these memory T cells are activated and proliferate. These activated cells secrete cytokines that stimulate continued CD4 division.

There are three components of the host-virus interaction that determine if a person can control HIV replication. First, the biology of the virus itself is important. Second, innate host factors such as homozygous deletions in the CCR5 gene (co-receptor for HIV) help the host resist infection. Third, the host's immune responses to HIV determine if infection progresses. Although all HIV-infected people have an initial CD4 response, with recognition of the virus and CD4 proliferation, most infected patients have no HIV-specific CD4 helper cell activity.

The immediate result of HAART, in all patients, is to slow T cell death. This causes an increase in CD4 number but does not necessarily mean that the immune system is qualitatively equivalent to an earlier stage of HIV disease. That is, a person dropping initially to 250 CD4 cells/mm3 is probably less immunosuppressed than a patient being reconstituted from 50 CD4 cells/mm3 to 250 CD4 cells/mm3.

Lymphocyte counts seem to increase in two phases. Initially, there is an increase in the number of CD4 cells that are already present. This is probably due to shut down of cell death and redistribution of cells. This is particularly strong at the onset of therapy, and then plateaus. Many studies have demonstrated that the initial result of HAART therapy.

Viral Load Testing and Significance. The best way to know how actively the virus is replicating is by measuring the viral load. There are two primary assays available to test for HIV RNA.

Viral Resistance. Much is now known about the different mutations associated with resistance to different antiretroviral agents. Knowledge of the mechanisms of resistance will allow us to develop rational plans for the use of therapeutic agents. For example, if resistance to the new protease inhibitor amprenavir doesn't automatically imply resistance to indinavir.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Zidovudine (ZDV, AZT). This is the antiretroviral agent that has been available for the longest period of time and is the most studied. It has minimal effects on viral load and can transiently increase CD4 counts. The usual dosage is 200 mg three times daily or 300 mg twice a day. Adverse effects include anemia, neutropenia, nausea, vomiting, headache, myopathy and hepatitis.

Dideoxyinosine(ddI). ddI was the next major nucleoside analog to become available and is also a reverse transcriptase inhibitor, ddI is useful as an alternative to ZDV in patients who are intolerant to ZDV, have been on monotherapy with ZDV and are being changed to a different regimen or it can be used de novo as part of a multidrug regimen. The use of ddI has been limited

Dideoxycytidine (ddC). Now used infrequently, it is another nucleoside analog that inhibits reverse transcriptase. Although studies showed utility as an agent in combination with ZDV, this is

Stavudine(d4T). Also a nucleoside analog, this is related to ZDV but is effective against many ZDV resistant strains. It also causes peripheral neuropathy, which may respond to dose reduction.

Lamivudine(3TC). Another nucleoside analog that inhibits HIV reverse transcriptase, it has demonstrated synergy to a variety of other available antiretroviral agents. When lamivudine resistance develops via a mutation at residue 184 of the viral reverse transcriptase, this changes ZDV resistant strains to phenotypically sensitive isolates when the two drugs are used together.

Abacavir (1592U89). This is a new nucleoside agent approved in 2006. It is unique among NRTIs because it causes significant drops in HIV-RNA (up to 2 logs). It is well tolerated in most

Adefovir. Adefovir is in a unique class, the nucleotide analogs. It is initially well tolerated, and can be taken once a day. However, its efficacy seems less than the nucleoside analogs in antiretroviral naive patients. Interestingly, 3TC resistance seems to markedly increase it's efficacy. With long term use, it may cause renal toxicity. Evidence is accumulating that on the 120

Hydroxyurea. This drug is a ribonucleotide reductase inhibitor. This drug reduces the amount of adenine, making it more likely that HIV will incorporate the nucleoside analog drugs and cause

Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTIs). Nevirapine and Delavirdine are the prototype drugs, with efavirenz (DMP266, Sustiva) recently FDA-approved. These are highly selective inhibitors of HIV-1 reverse transcriptase. They non-competitively bind directly to the enzyme downstream from the catalytic site. There is extremely rapid development of resistance to these agents when used as monotherapy or in double combination. However, recent trials with triple combination regimens have shown that this resistance can be very much delayed if the viral load is suppressed to low levels and sustained. The main side effect is rash including Stevens-Johnson reaction, and it is recommended that treatment be initiated slowly with dose escalation. The drugs induce their own metabolism, so stepwise institution of the medication prevents excessive dosages early in treatment. Efavirenz is very encouraging because resistance

Protease Inhibitors. This class of drags prevents the cleavage of protein precursors essential for HIV infection of new cells and viral replication. There are four drugs currently available. All are notable for rapid emergence of resistance if used as monotherapy, if dose is reduced inappropriately or if therapy is interrupted for several days i.e. in non-compliant patients.

Saquinavir. Saquinavir was the first drug made available, but its use has been limited by its poor bioavailability, slightly improved by taking the drug with high-fat meals. However, there is a new preparation available, the soft gel capsule. The dose is doubled, and the "area under the curve" is increased eight-fold. It has also been shown that combination with other protease inhibitors,

Ritonavir. Ritonavir has excellent bioavailability and dramatically lowers viral load in limited studies as monotherapy (2 logs at 8 weeks decrease in viral load), or in combination with ZDV and other drugs. It is associated with many adverse effects and drug interactions. The adverse effects include diarrhea, nausea, vomiting, altered cholesterol and triglyceride levels and elevated liver

Indinavir. Indinavir has also been shown to be very efficacious in recent studies. Triple combination of indinavir with ZDV and Lamivudine suppressed HIV RNA below 500 copies/mL in 85% of ZDV experienced subjects and 65% of patients with CD4 counts less than 50 cells/mm3. It has good bioavailability and is generally well tolerated. It is associated with the development of

Nelfinavir. Nelfinavir has a different series of mutations for resistance. The early suggestion that it should be the initial protease inhibitor because it doesn't prevent future efficacy of indinavir or ritonavir has not been confirmed. It is taken with food and given three times a day. Twice a day dosing seems to be equivalent. It also has been shown to have good efficacy. It too has 

Amprenavir (141W94). This is a new protease inhibitor that was approved by the FDA in 2006. The mutation to amprenavir may not cause cross-resistance in the other protease inhibitors. Therefore, initial use of this agent may be warranted. This remains to be verified in clinical practice, however. It is associated with significant gastrointestinal side effects and rashes,

 

Drugs are listed in random order.

Column A                                             Column B

Indinavir                                                 ZDV + ddI

Nelfinavir                                               d4T + ddI

Ritonavir                                                ZDV + ddC

Saquinavir (soft gel)                                ZDV + 3TC

Ritonavir/Saquinavir                                d4T + 3TC

Other double PI therapy

 

Alternative  Unknown if it provides sustained virus suppression equivalent to regimens containing a PI

1 NNRTI + 2NRTIs (column B)


Not generally Strong evidence of clinical benefit but initial virus suppression

recommended is not sustained

2 NRTIs (column B)

Saquinavir (Invirase) + 2 NRTIs (column B)


Not recommended Evidence against use, virologically undersirable, or overlapping

toxicities

All monotherapies

d4T + ZDV

ddC + ddI

ddC + d4T

ddC + 3TC

Prophylaxis of Opportunistic Infections in HIV Seropositive Patients

Introduction

We have known for years that as CD4 counts decline, prophylaxis of common opportunistic infections (OIs) improves the patient's prognosis. In the era of highly active antiretroviral therapy, mortality has significantly declined from 29.4/100 person-years in 1995 to 8.8/100 person-years in 2006. Incidence of the common opportunistic infections (PCP, MAC, CMV) have gone from 21.9/100 person-years in 1994 to 3.7/100 person-years in 2006. Therefore, HIV treatment has had a significant impact on infection. This decrease in OIs has been shown to be true even

Pneumocystis carinii pneumonia (PCP)

It is widely accepted that PCP prophylaxis prolongs survival and delays HIV progression, with safe and inexpensive intervention. Without prophylaxis, up to 40% of patients with CD4 counts below 200 cells/mm3 will develop pneumocystis pneumonia within two years and 80% will eventually get PCP. Therefore the risk of infection is high, and CD4 counts<200 cells/ram3 is a discrete parameter to guide institution of therapy.

Treatments

1. First-line Therapy. Trimethoprim/sulfamethoxazole (Bactrim, Septra) - Has been effective in doses as low as one double strength tablet three times per week, most common dosage is one double strength or single strength tablet daily. Other benefits include prophylaxis against toxoplasma encephalitis, isosporiasis, nocardia, recurrent salmonellosis, pneumococcal and hemophilus

Myeobacterium avium complex (MAC) This infection is frequently seen in HIV patients when their CD4 counts have declined below 50 cells/mm3. Within two years, over 20% of patients will get MAC disease. Rifabutin, which has some activity when given for active MAC infection, was shown to decrease mycobacteremia and improve morbidity when given prophylactically. There was no survival benefit. Rifabutin was the first drug approved for MAC prophylaxis, but currently the macrolides are used most frequently.

Clarithromycin 500 mg BID was associated with a survival advantage, unlike rifabutin, and significant decrease in MAC disease. However, patients with breakthrough disseminated MAC (DMAC) infection had a 58% chance of resistance to clarithromycin, thereby removing one of the most efficacious agents for treatment.

Azithromycin was recently studied as monotherapy and in combination with rifabutin and compared to rifabutin alone. Azithromycin 1200 mg once a week significantly reduced DMAC, and only 11% of breakthrough patients had Azithromycin resistance. The combination was more effective, but less well tolerated and more expensive, making it's additional benefit not great enough to offset these problems. Because it's only given once a week, it is the least expensive treatment for MAC prophylaxis. A new study confirmed the efficacy of azithromycin and again

Cytomegalovirus (CMV) Patients with CD4 counts of less than 100/mm3 have a 21% probability of developing end organ disease within 24 months. After primary infection, there is a very high relapse rate and increasingly poor responses to therapy. This would make CMV an attractive candidate for prophylaxis. Currently, the major medications available for treatment of CMV disease are intravenous, and associated with significant toxicities. Oral ganciclovir, approved for secondary prophylaxis, has been studied. One report showed no benefit with oral ganciclovir in