Viral load, in HIV infection

The most recent advance in treating HIV infections has been to simultaneously attack the virus on a second front using a protease inhibitor. Recall from Section 27.10 that proteases are enzymes that catalyze the hydrolysis of proteins at specific points. When HIV uses a cell s DNA to synthesize its own proteins, the initial product is a long polypeptide that contains several different proteins joined together. To be useful, the individual proteins must be separated from the aggregate by protease-catalyzed hydrolysis of peptide bonds. Protease inhibitors prevent this hydrolysis and, in combination with reverse transcriptase inhibitors, slow the reproduction of HIV. Dramatic reductions in the viral load in HIV-infected patients have been achieved with this approach. 

To determine if the high in vitro potents of the anti-HIV compound 30 translates into antiviral efficiency in vivo, Datema et al. investigated the inhibition of HIV-1 production and of depletion of human T cells in HIV-1-infected SCID-hu Thy/Liv mice [37]. Steady levels of 100 ng of 30 or higher per mL in plasma resulted in significant inhibition of HIV p24 protein formation. Daily injection of 30 caused a dose-dependent decrease in viral p24 production, and this inhibition could be potentiated by coadministration of AZT (or DDI). This study suggested that 30 alone or in combination with the licensed anti-HIV agents AZT and DDI may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. 

Chun TW, Carmth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, Kuo YH, Brookmeyer R, Zeiger MA, Barditch-Crovo P, Siliciano RF (1997b) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387 183-188... 

In vitro tests have shown that valproate can increase the viral burden in HIV-infected individuals by potentiating replication of the virus (110). In a retrospective review of 11 HIV-positive patients with behavioral disturbances taking valproate HIV-1 viral load did not increase in six of the nine patients who had measurements between the first week and 3.5 months after the start of valproate treatment no follow-up was available for the other three (111). These data suggest that, contrary to in vitro data, HIV-1 viral load is not adversely affected by valproate in the presence of effective antiretroviral therapy. 

Currently, treatment of DSP and ATN is similar to many other neuropathies that have predominantly painful sensory involvement (Mendell and Sahenk 2003 Gonzalez-Duarte et al. 2007). It is purely symptomatic as there are no proven regenerative therapies to reverse the underlying process. An 8-month prospective pilot study reported an improvement in subjective quantitative sensory testing (QST) in HIV-infected patients who responded to HAART (Martin et al. 2000). The patients who did not respond to HAART did not show any improvements in QST. It is possible that suppression of viral load will slow the progression of DSP. Some studies have found a correlation between viral load and incidence (Childs et al. 1999), or severity (Simpson et al. 2002) of sensory neuropathy. Others, however, did not find any correlation between plasma viral loads and incidence of DSP or ATN (Brew et al. 2003). 

Clinical presentations of primary HIV infection vary, but patients often have a viral syndrome or mononucleosis-like illness with fever, pharyngitis, and adenopathy (Table 40-3). Symptoms may last for 2 weeks. Probability of progression to acquired immune deficiency syndrome (AIDS) is related to RNA viral load in one study, 5-year progression rates to AIDS were 8% and 62% for RNA copies per mElfliter of less than 4,530 and greater than 36,270, respectively. The mortality rates were 5% and 49%, respectively. 

During 2004, two Phase 1 studies and a Phase l/It study of M3 were completed. In the Phase 1 studies, the drug was well tolerated and showed good anti-HIV levels in the body. In the Phase 1/11 study, M3 showed activity in HIV-infected patients and significantly reduced viral blood levels (known as viral load) (122, 123). Another 2004 milestone was that the U.S. Food and Drug Administration (FDA) granted Fast Track Status for M3. 

The Phase Ha study demonstrated the antiviral potency of M3, following once-daUy oral dosing for 10 days in HIV-infected subjects not on other antiretroviral therapy. Viral load was reduced significantly compared with placebo. On day 11, following complete dosing, the median reduction at the 200-mg dose was a 91% decrease. In the Phase Ha trial, M3 was well tolerated, aU adverse experiences were mild or moderate, and no dose-Umiting toxicity was identified (122, 123). 

Abacavir is a guanidine analogue that inhibits HIV reverse transcriptase. In vitro, its potency is similar to that of zidovudine, protease inhibitors, and dual nucleoside combinations. There is evidence that abacavir is effective in reducing viral load and increasing the CD4 count in HIV-infected patients. Viral resistance is not rapidly selected for, but cross-resistance has been shown to other analogues of cytosine and guanidine (didanosine, lamivudine, and zalcitabine). 

The use, benefits, and adverse effects of aldesleukin in HIV-infected patients have been extensively reviewed (8). Aldesleukin significantly increased the CD4+ cell count without an increase in viral load. However, many questions remain unanswered. In particular, it is still not known whether immunological improvements translate into clinical benefit. Regardless of how aldesleukin is administered—intravenously, subcutaneously, or as polyethylene glycol-modified (pegylated) aldesleukin— adverse effects are generally not treatment-limiting. As the duration of adverse effects was shorter with the subcutaneous route, these patients may be treated as outpatients (9). 

Highly active antiretroviral therapy, also known as HAART, refers to a combination of medications to treat HIV infection including protease inhibitors and/or nucleoside analogues. It has been defined as an antiretroviral regimen that can be expected to reduce the viral load to less than 50 copies per milliliter in treatment of naive patients (23). The use of HAART in developed countries commenced in 1995 1996 and it has markedly improved survival in AIDS. The increased CD4+ lymphocyte cell count and the decreased HIV viral load in the peripheral blood secondary to HAART in patients who respond to this therapy, results in a reduction of all opportunistic infections including CMV retinitis (4). Since the introduction of HAART, there has been reduction in the incidence of primary and relapsing CMV disease, CMV viral load and antigenemia (24). The North American incidence of CMV retinitis in the post-HAART era has decreased to approximately one-fourth that of the pre-HAART era (4,24 27). 

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