Lack of Effect of Recombinant Human Growth Hormone on the In Vitro Activities of Antiretroviral Drugs against Human Immunodeficiency Virus Type 1

Abstract

We studied the effects of recombinant human growth hormone (r-hGH) on human immunodeficiency virus type 1 replication by growing both wild-type and drug-resistant variants of virus in the presence of various concentrations of eight different antiretroviral drugs. r-hGH had no significant effect on either viral replication or the 50% inhibitory concentrations of these compounds.Although highly active antiretroviral therapy (HAART) has led to declines in the rates of mortality and AIDS-related opportunistic infections in the developed world, there remains a need to prevent the loss of lean body tissue (wasting) in patients with human immunodeficiency virus (HIV) infection and AIDS (12,16). Human growth hormone (hGH) increases lean body mass and muscle nitrogen retention and thus represents a potential approach to the treatment of AIDS-related wasting (9, 13). In randomized double-blind placebo-controlled trials performed in the pre-HAART and HAART eras, recombinant hGH (r-hGH) was shown to increase total body weight and lean body mass and to decrease body fat content (9,15,17,20). These changes are associated with improvements in physical performance and quality of life (15,17,20). Although optimization of nutritional status and exercise may also provide benefits in many cases, treatment with hGH is an excellent option in patients with severe wasting.However, concern exists that r-hGH might stimulate viral replication or inhibit the activities of antiretroviral drugs (ARVs) (4), since one early study actually found that r-hGH increased the levels of p24 antigen released from peripheral blood mononuclear cells (PBMCs) in tissue culture at concentrations of 50 or 100 ng/ml, but not at concentrations of 1, 5, 10, or 250 ng/ml (7). Importantly, r-hGH did not affect the antiviral activity of zidovudine in that study. Subsequent experiments (E. Daar, unpublished data) showed that r-hGH did not increase the level of HIV replication in PBMCs at concentrations of up to 250 ng/ml and had no effect on the antiviral activities of a variety of ARVs used in the pre-HAART era (zidovudine, didanosine, zalcitabine, and stavudine). The present experiments confirm and extend these findings through the use of currently approved ARVs in each of the three major drug classes. Viral isolates. We used two wild-type (wt) and five drugresistant clinical isolates of HIV type 1 (HIV-1), the genotypes of which are shown in Table 1. The wt isolates were from patients who had not received therapy. The concentrations of all approved ARVs that inhibit viral replication by 50% (IC 50 s) for the isolates were confirmed to be the same as those for other wt isolates, and the phenotypes of the isolates were the same as those of other wt isolates. Genotyping for the detection of mutations associated with drug resistance was performed by sequencing analysis with the Tru-Gene system (Bayer Diagnostics Inc., Toronto, Ontario, Canada). The resistant isolates were from patients who had been extensively treated with antiviral agents.In vitro studies. IC 50 s ...