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Antiretroviral Therapy
(Part XXIV)

Update from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication

November 7, 1997

AIDS Information Center VA Medical Center, San Francisco

Protease Inhibitors and Long-Term Viral Suppression

Continued evolution of HIV-1 during combination therapy despite levels of HIV-1 < 500 copies/ml

A group from the NIH performed intensive virological studies on four patients who attained long-term viral suppression on indinavir and IL-2. All four patients achieved undetectable levels of HIV-1 RNA, and remained there for at least two years. The investigators looked at viral genotype, both at baseline and 1.5 years into therapy. Surprisingly, in all 4 patients, the protease gene appeared to evolve over time. This observation, limited by technical difficulties in obtaining sufficient PCR products from patients with low levels of plasma HIV-1 RNA, indicates that viral evolution can occur in the presence of effective protease inhibitor therapy. If true, viral replication must be ongoing [Imanici et al, abstract 63].

Comment: This provocative study may not be generalizable, since patients also received IL-2. However, it does raise concerns about the ability of current regimens to suppress viral replication indefinitely. Other studies presented at the meeting suggest that HIV does not evolve in the presence of potent therapies [Emini et al, abstract 128; Gunthard et al, abstract 66].

Emergence of drug resistance in different tissue compartments after 1 year of potent antiretroviral therapy
Evidence for prevention of new HIV-1 infection cycles in patients treated with indinavir plus zidovudine plus lamivudine

Merck 035 is an important study of 90 patients treated with AZT + 3TC, indinavir monotherapy or AZT + 3TC + indinavir. Approximately 86% of patients receiving the three-drug combination had viral loads of < 500 copies/mL through 68 weeks of therapy. This impressive data set has established AZT + 3TC + indinavir as the standard of care in most clinical studies.

Two groups performed intensive studies on these patients in an attempt to determine if viral replication is completely suppressed. Gunthard and colleagues in San Diego studied the emergence of genotypic resistance to 3TC in 10 patients. Since the M184V mutation typically occurs rapidly in the presence of 3TC, this group assumed that the lack of M184V after prolonged therapy indicates complete, or near complete, viral suppression.

Viral sequences were analyzed using automated dideoxynucleotide (ABI) and high-density oligonucleotide (Affymetrix) sequencing techniques. Plasma HIV-1 RNA and peripheral blood mononuclear cells (RNA, DNA) were obtainedat baseline and after one year of treatment. Samples were also obtained from lymph node biopsies. In subjects with undetectable levels of HIV-1 RNA after one year of therapy, M184V did not evolve in each of the compartments evaluated [Gunthard et al, abstract 66].

The clinical scientists at Merck performed a similar analysis. During the course of Merck 035, several patients receiving AZT, 3TC and indinavir had transient elevations in viral RNA (to > 500 copies/mL) or persistent low levels of viral RNA (using ultrasensitive viral load assays). Genetic analysis from eight such patients revealed no new mutations in the reverse transcriptase or protease genes. One patient did have a new M184V, suggesting loss of viral control [Emini, abstract 128].

Comment: These studies provide evidence that potent combination therapy can fully suppress viral replication. If true, resistance mutations theoretically can not evolve. Long term viralsuppression, and possibly viral eradication, is therefore feasible.

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