HIV experts unanimously agreed on three aspects of HIV management during the 8th national Conference on Retroviruses and Opportunistic Infections (8th CROI), held in Chicago during Feb 3-5 of this year. The three points of agreement were: promoting voluntary testing, improving access to care, and the need for new approaches to eradicating latent HIV after initiating treatment with HAART.

This article reviews presentations at the conference that were relevant to the management of HIV in corrections, including (1) viral eradication; (2) new aspects of the HHS guidelines for HIV management including management of drug resistance and the application of genotyping in clinical practice, (3) new drugs in the HIV treatment pipeline, and (4) structured treatment interruption.

Viral Eradication: The Elusive Holy Grail?

Bob Siliciano of Johns Hopkins University reviewed the status of HIV eradication in the Monday opening plenary. It is well known that Highly Active Antiretroviral Therapy (HAART) effectively interrupts replication of the virus in activated T cells in the blood, reducing viral loads but not completely eradicating the virus. The identity of the reservoir of latent virus has been debated. Dr. Silicano focused his talk on the population of memory T cells that harbor latent virus in a form that is directly integrated into the T cell DNA. When these cells divide, as they do at a low rate approximately every six months, the viral genes are transferred to daughter T memory cells. Current antiretroviral medications do not have any impact on the perpetuation of this viral reservoir, due to their action on viral proteins (not host and viral gene replication). Thus, no amount of HAART will ever eradicate the virus from the T memory cell reservoir. Newer treatments that attack integrated viral DNA are needed if viral eradication is to be achieved.

There was one bright note in this discussion: new evidence from Dr. Silicano's laboratory appears to confirm that effective HAART can reduce viral replication to zero. Patients with a history of having been adherent to HAART over several years continued to harbor virus that was resistant to previously used drugs, but no new mutations occurred. This data suggests that fully suppressive treatment of HIV creates a viral reservoir that remains "frozen in time," with no genetic evidence for new cycles of virus replication.⁽¹⁾

This finding was relevant in the context of other discussions about drug toxicities and management of patients with HAART at the conference. Several speakers discussed the concept of "substitution" -- substituting triple NRTI or NRTI + NNRTI regimens for the more potent NRTI + PI regimen when patients achieve non-detectable viral loads.⁽²⁾ This observation leads to the next most obvious study: what would be the impact of attacking HIV with highly active drugs (three and four drug regimens including PIs), reducing the replication to zero, and then substituting a new, more tolerable, regimen? This concept was not addressed at the 8th CROI, but studies are sure to follow.

The New Guidelines: Use Tools and Consult Experts

Updated U.S. HHS guidelines⁽³⁾ were made available on the web during the CROI conference; they are now available in PDF format. A yellow-shaded version of the guidelines is also available at this site, highlighting changes from the last document. The most important change in the guidelines is to delay the initiation of HIV treatment until absolute CD4 T cell counts are 350 or lower and/or HIV RNA viral loads are 55,000 or higher (refer to HEPPigram Table 2). Some experts disagreed with this decision, which appears to deemphasize well-known data on the risk of progression to AIDS at higher viral loads (see Table 1, below). Treatment should be initiated by an HIV treatment expert who takes into consideration the "willingness" of the individual to begin therapy, the degree of existing immunodeficiency as determined the CD4 T cell count, the risk of disease progression as determined by the CD4 T cell count and the plasma viral RNA, the potential benefits and risks of therapy, and the likelihood of adherence.

Clinical experts at the CROI meeting cautioned against oversimplification in the rush to delay treatment. Three key components of the guidelines deserve emphasis here: (1) treatment should not be terminated in patients who have already begun treatment based on guidelines distributed prior to this year; (2) careful monitoring of CD4 T cell count and viral load are critical components of HIV treatment and most experts would advise checking these parameters at least every three months because patients often experience sudden declines; (3) use of experts to prescribe and adjust HIV treatment is increasingly important.

CD4 T Cell Count and Viral Load: Tools for HIV Management

The CD4 T cell count (CD4) and the viral load (VL) are the two most important tools in the HIV specialist's armamentarium. RNA-PCR (Roche) is the only FDA approved viral load monitoring tool. These two lab tests provide information on the HIV stage of disease and the likelihood of progression. As can be seen from Table 1, the chance of progressing to AIDS at a CD4 of 350 and VL of 50,000 is 36.4% after three years. Both the CD4 T cell count and the VL should be measured (at least twice, to establish a firm baseline) prior to initiating therapy; the VL should be repeated between two to eight weeks after initiation of therapy so as to establish the rate of decline in response to therapy. There should be a one-log decrease in VL at this point to indicate response to therapy (this emphasis is new). At eight weeks, if the VL is detectable (defined using the ultrasensitive assay as a VL less than 50 copies per ml), adherence should be checked, and the need to intensify or change therapy should be considered.

VL and CD4 are also used to monitor the success of therapy; these tests should be repeated every three to four months. Successful therapy is indicated by VL less than 50 (note the new emphasis on ultra-sensitive viral load testing). A VL increase of three-fold or one log and CD4 T cell decline in absolute numbers more than 30% percent (or more than 3% change in CD4 T cell percentage) should be confirmed, adherence ascertained, and a change of therapy should be considered (see HEPPigram).

Drug-Resistant Viruses Fuel Need for HIV Drug Sequencing

Viral resistance testing (either genotyping or phenotyping) is a new recommendation included in the HHS guidelines this year (see Table 2, below). Genotyping detects mutations in the virus that are linked to changes in drug sensitivity. Genotyping is more rapid than phenotyping, but phenotyping is more precise (some mutations are more or less relevant in vivo). There was no recommendation to use one over the other. Furthermore, expert advice on the interpretation of genotyping results, and a careful history of prior ART exposure are both recommended. In view of reports at the CROI that up to 26% of patients who are recently diagnosed harbor resistant virus, genotyping prior to initiation of therapy may become commonplace, particularly in cases where the patient may have been exposed to a heavily pretreated patient. The value of baseline genotyping in chronically infected treatment-naive patients is less clear, as resistant strains tend to fall to undetectable levels in untreated patients. Interested clinicians should read the HHS guidelines carefully or review the HEPP News on resistance testing (online at http://www.hivcorrections.org/archives/sept00). In short, resistance mutations can be archived and the patient's history of prior exposure to ART, their current ART regimen, and cross-resistance within classes may have an influence on the outcome and interpretation of resistance tests.

Acute HIV Infection

Between 10 and 50% of patients with acute HIV infection present to clinicians with symptoms. Less than 20% of these individuals are correctly identified as having acute HIV. Data presented by Bruce Walker (see STI section, below) suggests that early treatment may lower the "setpoint" of HIV infection, possibly prolonging life and potentially permitting the patient to stop therapy. The duration of therapy of acute HIV infection is completely unknown at this time. Expert consultation should be obtained.

New Approaches and Re-Evaluations of Existing Approaches

Results from 144 weeks of the DPC 006 and DMP 006 studies were presented, showing that the mean time to failure on dual NRTI and NNRTI regimens will be about 6 years. These results supported the inclusion of efavirenz (Sustiva) in the list of "first line" treatments in the new HHS guidelines. Results of studies using Lopinavir/Ritonavir (Kaletra) as initial therapy were also presented at the CROI, showing excellent responses. Ritonavir-boosted PI treatments Lopinavir/Ritonavir and Indinavir/Ritonavir were two new additions to the "recommended therapy" list this year (see HEPPigram Table 1).

Improved formulations of ART medications are permitting researchers to address the topic of once-daily therapy, an innovation in treatment that may improve adherence in correctional settings and methadone programs. Italian researchers and French researchers showed outcomes from treatment with once-daily didanosine (Videx, 300 mg), lamivudine (3TC, Epivir, 300 mg), and efavirenz (Sustiva, 600 mg) in 75 patients naive to antiretroviral therapy.⁽⁴⁾ There is a growing list of ART drugs that can be considered for once-daily therapy, including DDI, 3TC (and newer derivatives), efavirenz, nevirapine (Viramune), abacavir (Ziagen) and amprenavir/ritonavir. This writer believes that these newer, more tolerable regimens will result in yet another revision of the guidelines next year.

New "Entry Blocking" Treatments

Viral entry into the host cell is a new target for HIV drugs. However, compounds that are developed to block entry of virus will be ineffective against virus that spreads by syncitia formation (cell-to-cell) and will not have any effect on non-replicating virus. It is likely that entry blockers will be used in combination with existing antiretroviral agents. Two classes of entry inhibitor are in development -- fusion inhibitors and chemokine receptor blockers. These drugs are probably most effective when used in combination.

• Fusion Inhibitors
  T-20 (made by Trimeris) is the first member of the fusion inhibitor class. T-20 is a very short (39 amino acid) peptide that binds to one of the two helical domains of gp41. Gp41 is a spring-loaded HIV-1 protein that is activated when CD4 binds to HIV gp-120. The fusion action of gp41 is inhibited if its two helical domains cannot fold together. T20 binds to gp41, effectively keeping the protein from functioning. Unfortunately, this drug is a peptide, so it cannot be given orally. It is given as an injection, and more than 10% of patients develop reactions at the injection site. Previous studies of T-20 without HAART showed that resistance is rapid to develop. However, when used in combination with other ART, the drug appears to be effective. In a "late breaker report," Lalezari reported on a Phase I (dose finding) study of 71 patients receiving combination HAART and T20. By week 16, patients participating in the T-20 arms of the study had 0.5 log lower HIV RNA levels than patients in the non T-20 arms.⁽⁵⁾ In the future, due to the need for injections, T20 will probably be used only in the setting of extensive resistance. Trimeris is also developing variant of this drug, called T-1249.

• CCR5 Blockers
  Another key protein involved in HIV entry is CCR5 (chemokine receptor 5). This protein is ubiquitous on immune cell membranes. Blocking this receptor is believed to be safe, and important, since individuals who have homozygous deletion of this gene appear not to have any increased susceptibility to infections and are almost completely resistant to HIV infection. The CCR5 blocking-compound furthest along in development is a Shering Plough drug, SCH-C.⁽⁶⁾

Un-Successful and Un-Structured Treatment Interruptions (STI)

Structured treatment interruptions (STI) were addressed by a number of the speakers at the 8th CROI. The rationale for STI is that CD4 T cell replication is achieved in effective HAART, so providers were interested in whether patients could contain virus (they cannot) and whether "autovaccination" might improve immune responses to the virus (they do not). Furthermore, there is a hope that virus will revert to wild type (it does not, as resistance mutation are archived in latently infected T cells). Finally, STI are viewed by patients as a welcome respite to therapy -- this is probably one of the main motivators for research in this area.

STI may have a role in EARLY (before seroconversion) treatment of HIV, as reported by Bruce Walker.⁽⁷⁾ However, based on the results reported at the 8th CROI, it is too early to know whether STI is viable options, and treatment of acute HIV infection should be supervised by an HIV specialist. At present, no guidelines exist as to whether treatment may be stopped after initial therapy or whether it should be continued indefinitely (which would run counter to the HHS guidelines stating treatment should be delayed until later in the course of disease).

Therapy-Related Adverse Events

Adverse events were one of the major reasons for changes in the HHS guidelines. Details on mitochondrial toxicity and hepatic steatosis, fat maldistribution, rash, and diabetes/pancreatitis are given in the new guidelines. These topics and neuropathy were also covered at the 8th CROI. In short, concern about side effects resulted in changes in the guidelines for the use of antiretroviral therapy this year (see HEPPigram Table 1 and the upcoming HEPP News issue in April on neuropathy).

There's Always More

A special feature for this month, the Rapid Report has further news from the conference. In the upcoming issues we will cover more topics from the 8th CROI such as neuropathy and the CDC's new program on National HIV Prevention. In the meantime, visit the conference website http://www.retroconference.org/2001 or Medscape at http://www.medscape.com.

Funding for this conference coverage was provided by educational grants from Agouron Pharmaceuticals, DuPont Pharmaceuticals Company, Hoffman La Roche, and Boehringer-Ingelheim/Roxane Laboratories.

* Consultant & Speaker's Bureau: Agouron Pharmaceuticals, DuPont, Merck, Roche, Boehringer-Ingelheim/Roxane Laboratories

References

1. Robert Siliciano Viral Reservoirs and Ongoing Virus Replication in Patients on HAART: Implications for Clinical Management. 8th CROI. Abstract L5.

2. Becker S, Rachlis A, Gill J, et al. Successful substitution of protease inhibitors with efavirenz (EFV) in patients with undetectable viral loads -- a prospective, randomized, multicenter, open-label study (DMP-049). 8th CROI. Abstract 20.

3. U.S. Dept of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Washington, DC: US Dept of Health and Human Services; February 2001. Published online at: http://hivatis.org/trtgdlns.html.

4. Maggiolo F, Migliorino M, Maserati R, et al. Once-a-day treatment for HIV infection: final 48-week results. 8th CROI. Abstract 320.

5. J. Lalezari, J. Drucker, R. Demasi, S. Hopkins, and M. SalgoA Controlled Phase II Trial Assessing Three Doses of T-20 in Combination with Abacavir, Amprenavir, Low Dose Ritonavir and Efavirenz in Non-Nucleoside Naive Protease Inhibitor Experienced HIV-1 Infected Adults. 8th CROI. Abstract LB5.

6. Reyes G. Development of CCR5 Antagonists as a New Class of Anti-HIV Therapeutic. 8th CROI. Abstract L11.

7. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000; 407:523-526. 407:523-526., reported by Bruce Walker in his talk: Structured treatment interruption: novel strategy or oxymoron? State-of-the-art lecture and summary. 8th CROI. Abstract 266.

Back to the HEPP News February 2001 contents page.