Viral and immunologic follow up of 4 to 9 years of AIDS treatments by quadruple combinations of virostatics including integrase inhibitors applied in short sequences differing by drug rotation.
OBJECTIVE
To present the 4 to 9 years (median: 6 years) treatment follow up of 10 HIV1-AIDS patients, 9 at AIDS and 1 at A3 stages.


METHODS
We have applied from 1992 to 1994, AZT combined with 2 integrase inhibitors, acriflavine and hydroxy-methyl-ellipticine. We could shift, in 1994, to combinations of 3 drugs including two more retrotranscriptase inhibitors (RTI), ddI and ddC, and, after 1995, to combinations of 4 drugs including also two other RTI, d4T and 3TC, and 3 protease inhibitors (PI), indinavir, ritonavir, and saquinavir. In 1998, as cobalamine was shown by an in vitro test, to act as integrase inhibitor, vitamin B12 was added in cycles of various lengths. Every three weeks, not only the investigations were repeated, but the virostatics were changed.


RESULTS
No grade 2 virostatics toxicity has been registered. The viral loads (VL) decreased according to exponential curves. Their initial parts obeyed first order kinetics. The second parts were and still are asymptotic. The first parts could be rectilinear or sinuous. The sinuosities were associated to cofactors present before treatment (chimerism, UV irradiation, hepatitis C or B and C, brain toxoplasmosis). The asymptotic parts, whose VL were below PCR detectable levels, presented discrete, reversible HIV1 rebounds, associated to other cofactors (such as herpes zoster, herpes 6, CMV, flat condyloma, and influenza). Among immunologic parameters, the monocyte and CTL numbers increased and presented, during the rapidly decreasing part of VL curve, a significant inverse correlation with it. Neither CD4+ nor suppressor T-cell (STC) numbers presented such correlation. Near 100 % of CTL were CD28+. Later, vitamin B12 applications increased monocyte and CD28+ CTL numbers, and appeared to reinforce VL stabilization.


CONCLUSIONS
The combinations of inhibitors affecting 3 retrovirus targets, retrotranscriptase, integrase, and protease have given to 10 out of 10 AIDS patients survivals varying today between 4 to 9 years, in excellent conditions. The UVA-pretreated patient is the only one presenting a not maximally reduced asymptotic VL, while his CD4+ and STC have been absent for 8 years. Other patient VL regressed exponentially to become asymptotic, below PCR detectable levels.
Mathe
Georges
G
Institut de Canc  rologie et d'Immunologie & Hopital Suisse de Paris BP 60-92133 Issy les Moulineaux, France.
Morette
Christian
C
Hallard
Michel
M
Pontiggia
Paulo
P
Blanquet
Denise
D
Hage
Francoise
F
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000167:Acriflavine / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use; D016516:CD4-CD8 Ratio; D016049:Didanosine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004611:Ellipticines / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification*; D006801:Humans; D019429:Integrase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use; D018119:Stavudine / Q000627:therapeutic use; D014805:Vitamin B 12 / Q000627:therapeutic use; D016047:Zalcitabine / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004611:Ellipticines; D019429:Integrase Inhibitors; D011480:Protease Inhibitors; C027767:elliptinium; D000167:Acriflavine; D015215:Zidovudine; D016047:Zalcitabine; D018119:Stavudine; D016049:Didanosine; D014805:Vitamin B 12