“We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-gamma) production by CD8+ T cells...These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8+ T cells specific for the cytomegalovirus p65 matrix protein.”
Rinaldo CR, et al. Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency . J Virol. 2000 May;74(9):4127-38.

“Results: Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 102 to 105 copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03). ”                                                     
Havlir DV et al. Drug Susceptibility in HIV Infection After Viral Rebound in Patients Receiving Indinavir-Containing Regimens. JAMA. 2000 Jan 12;283(2):229-234.

“These data suggest that a large pool of infectious virus is established soon after infection and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network...The FDC pool of virus is established by the time symptoms associated with primary HIV infection are recognized, based on these data. We observed 7-8 log10 copies of HIV-1 RNA/g of LT sampled within a few days of symptom onset, similar to levels associated with late-stage disease. The fact that this tissue was both axillary and from patients with rectal exposure illustrates the speed at which systemic dissemination occurs after mucosal transmission...This finding was a surprise to us, because it has been reported that accumulation of virus into this pool is gradual. These discrepant results may represent a sampling error, because the number of patients reported by Pantaleo et al. and by us is relatively small...Collectively, these findings on the early accumulation of virus into the FDC pool make it unlikely that antiretroviral therapy initiated as soon as symptoms are recognized will necessarily prevent deposition of large enough quantities of virus in the FDC pool or the FDC network.”   
Shacker T, et al. Rapid Accumulation of Human Immunodeficiency Virus (HIV) in Lymphatic Tissue Reservoirs during Acute and Early HIV Infection: Implications for Timing of Antiretroviral Therapy. JID. 2000 Jan;181(1):354-7.

“ The existence of a reservoir of resting CD4+ T cells harboring latent replication-competent HIV has been demonstrated in patients on prolonged highly active antiretroviral therapy (HAART). Latently infected tissue macrophages may constitute a second HIV reservoir.”                                                                                                 
Lambotte O, et al. Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2000 Feb 1;23(2):114-9.

“Amanda Mocroft (Royal Free Centre for HIV Medicine, London, UK) reported that rates of treatment failure in the EuroSIDA cohort were 50%, 70%, and 80% after first, second, and third courses, respectively. Results from several trials confirmed the poor response (about 30%) to salvage regimens in patients who had already taken a protease inhibitor. Previous use of non-nucleoside reverse-transcriptase inhibitors lowered the response rate further (to about 15%)...Over the past year, the development of several promising drugs has been put on hold or stopped because of toxicity, unfavourable pharmacokinetics, and inadequate potency”    
 Montaner J, et al. Salvage therapy for HIV-1 infection - the challenge grows. LanceT. 2000 Apr 22;335.

“"This virus is a really smart actor," said Dr. Ann Collier, director of the AIDS Clinical Trial Unit at Harborview's Madison Clinic. Collier said about one-third of patients are resistant to the drugs within six months of starting treatment, and the proportion increases over time. Patients are often switched to new combinations of drugs, but their conditions often gradually deteriorate, she said.”     
The Seattle Times. 1999 Nov 10;B1.

“The researchers concluded that, while combination antiretroviral therapies effectively suppress HIV-1 replication in some patients, the benefit to others may not be as great. Considering the half-life of latently infected CD4 lymphocytes, researchers conclude that efficacious antiretroviral therapy may take years to eliminate such sources of HIV-1...The continued replication of HIV-1 in two patients seems to be due to the presence of drug-sensitive viruses within lymphoid tissues. We are unable, however, to explain why drug-sensitive HIV-1 is capable of replicating at low levels during treatment with three or four drugs. But it is essential to the therapeutic effort that the answer, be it pharmacokinetic or cellular in nature, be obtained promptly.”    
Zhang L et al. Quantifying Residual HIV-1 Replication in Patients Receiving Combination Antiretroviral Therapy. NEJM. 1999 May 27;340(21):1605-13.

 “Potent antiretroviral therapy seems unable to eradicate latent HIV-1 reservoirs in CD4+ T cells.”                                                                                                                      
 Furtado M et al. Persistence of HIV-1 Transcription in Peripheral-Blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy. NEJM. 1999 May 27;340(21):1614

“The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status.”                 
Hockett RD et al. Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA. Journal of Experimental Medicine. 1999 May 17;189(10):1545-54.

“As the ADARC group suggested, immediate attention should focus on the reasons why three- and four-drug potent anti-retroviral therapy does not completely suppress virus replication. Based on their data, it is unlikely that anatomical sanctuaries are protecting cells from drugs; instead, the positive cells seem to be readily circulating through the body, as suggested by the presence of many of the HIV-expressing cells in lymphoid sinuses.”                                                                                                                          
Saag MS, Kilby JM. HIV-1 and HAART: A time to cure, a time to kill. Nature Medicine. 1999 June;5(6):609-11.

“our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir”  
Ibanez A et al. Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients. AIDS. 1999 Jun 18;13(9):1045-9..

“According to the study, [published in 7/20/99 Annals of Internal Medicine] 37 percent of the Johns Hopkins patients getting the cocktail treatment had undetectable HIV levels one year after starting therapy. Only 23 percent suppressed the virus in all three time periods studied - 1-90 days, 3-7 months and 7-14 months. Clinical trials using similar drugs show suppression rates twice as high as those numbers.”                                      
Loviglio J. Study looks at HIV ‘Cocktail’. Associated Press. 1999 July 19.

“The proportion of patients who experience virologic suppression during HAART in the clinic setting was substantially lower than that in clinical trials...37% of patients in whom HAART was initiated had undetectable HIV-1 RNA levels 1 year after starting therapy, and only 23% experienced viral suppression in all three time periods”                       
Lucas G et al. Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions. Ann Intern Med. 1999 Jul 24;131:81-7.

“In 3 of the 5 patients, the percentage of productively infected cells increased while on therapy”                                                                                                                    
Patterson BK et al. Monitoring HIV-1 treatment in immune-cell subsets with ultrasensitive fluorescence-in-situ hybridisation. Lancet. 1999 Jan 16;353(9148):211-2.

“The main kinetic difference in the HAART [ritonavir/saquinavar plus one or more nucleoside analogs] group was therefore higher production rates of circulating T cells and shorter (not longer) half lives…This analysis confirms that the rate of removal of CD4+ T cells is indeed elevated and the half-life is indeed shortened in the HAART group”  Hellerstein M et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1 infected humans. Nat Med. 1999 Jan;5(1):83-9.

“As the evanescent blush of success with so-called highly active antiretroviral therapy (HAART) regimens begins to recede into the darkness, we have increasingly come to appreciate the importance of the host immune response. As with pharmacotherapy of other infectious diseases, the drugs are not very effective without substantial help from the immune system. [note that AZT, by damaging or destroying bone marrow, damages the immune system]”                                                                                                 
O’Brien WA. The most potent antiretroviral weapon - cellular immunity. 6th Conference on Retroviruses and Opportunistic Infections. 1999 Feb 2.

“During 7007 person-years of follow-up 2285 (69%) patients started HAART and 318 (10%) developed a new AIDS event. In multivariable analysis controlling for CD4 cell count, viral load and disease stage at baseline, the probability of starting HAART was lower in injection drug users compared with men who have sex with men, hazard ratio 0.63 (95% confidence intervals 0.56-0.70) and in patients with minimum schooling compared with those with vocational training, hazard ratio 0.82 (0.75-0.91). The risk of progression to AIDS was similar among men and women, patients with a history of injecting drug use, and patients with lower educational attainment in both univariable and multivariable analysis.


CONCLUSION: HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression. This observation has important implications for treatment policy and the design of future clinical trials. ”
Junghans C et al. Uniform risk of clinical progression despite differences in utilization of highly active antiretroviral therapy:Swiss HIV Cohort Study. AIDS. 1999 Dec 24;13(18):2547-54.

“our analysis shows that San Francisco would have experienced a significant decline in AIDS cases, due to the decrease in HIV seroconversions, even if combination antiretroviral therapy had not been developed...the treatment [AZT] benefit is temporary and confers no long-term survival advantage”                                                              
Lemp GF et al. Projected incidence of AIDS in San Francisco: the peak and decline of the epidemic. J Acquir Immun Defic Syndr Hum Retro. 1997 Nov;1;16(3):182-189.

“The median prolongation of survival associated with changing therapy was, at best, 3 to 6 months...Mortality within [3.5-4.9 years, depending on starting CD4 cell counts] was 100%, regardless of treatment group or landmark...Overall long-term survival [in a study comparing AZT monotherapy with various combination therapies] was grim, even among patients who changed therapy; this finding indicates the continued need for newer, more active antiretroviral regimens”                                   
Graham NMH et al. Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Ann Intern Med. 1996;124:1031-8.

Excerpts of interview with Dr. Kary Mullis, Nobel Prize winner credited with having invented PCR Polymerase Chain Reaction