Treatment in primary HIV infection

25 March 2006. Related: Conference reports, Treatment strategies, CROI 13 (Retrovirus) 2006.

Simon Collins, HIV i-Base

Several posters at the conference looked at the effect of a short course of treatment in primary infection. The main rationale for very early treatment were the early findings from Bruce Walker and colleagues at Massachusetts General Hospital that showed CD4-specific immunity is retained in people treated within six month of infection, but lost in everyone else except long-term slow progressors. It has not been clear how long HIV-specific immune is retained, however, after treatment is stopped, or more importantly, whether this translates into a clinical benefit of slower disease progression.

Julie Fox presented results from a non-randomised pilot study at St Mary’s Hospital in London, which allowed patients diagnosed within 6 months of infection (using a de-tuned antibody test) to choose whether to use a three-month period of immediate treatment.

Three-year follow-up after stopping the initial three-month treatment showed that HIV-specific CD4+ interferon-gamma (INF-g) cellular immune responses were maintained in 5 out of 11 patients (45%). However, this did not have any clear impact on disease progression in terms of reducing CD4 decline or reducing viral load increases.

Similar results were presented by Henrick Streeck from a group of German researchers, who were also working with Bruce Walker, and who randomised 20 patients diagnosed in early infection (ELISA at baseline, <3 positive bands Western blot, and a positive HIV RNA), to either receive treatment for 6 months (n=12), or remain off therapy for the 12-month study period (n=8). Baseline characteristic were similar, and, as expected, CD4 and viral load were significantly different at 6 months: 895 vs 548 cells/mm³ (p=0.007) and <50 copies/mL vs 131,000 copies/mL (p = 0.006), in the treated and untreated groups respectively.

However, there were no differences at week 48, six months after stopping therapy, with median CD4 and viral load of 596 vs 456 cells/mm³ (p=0.15) and 32,300 vs 38,300 copies/mL (p=0.41) respectively; although there were significantly higher HIV-1-specific interferon-gamma responses in the treated group compared with the untreated group (p=0.06).

Several other studies in primary infection were also worth reporting.

Stekler and colleagues from University of Washington, Seattle, reported on dynamics of viral load in semen in 110 men treated during primary infection, from 326 semen specimens (median 2, range 1 to 11), collected from 1993-2005.

Subjects were evaluated median 59 days (range 3 to 199) after the estimated date of HIV infection; median day of initial semen specimen was day 108 (range 11 to 868). In untreated men (n=89), initial median semen RNA level was 3.6 log copies/mL (range 2.3 to 6.1) and was highest among 9 samples within 1 month of infection (5.0, range 2.5 to 5.9); initial levels in semen were moderately correlated with blood levels (r = 0.45, p <.0001).

Semen and blood plasma RNA levels did not maintain a linear relationship, but having detectable levels in blood was associated with detectable semen levels (p =0.003). Levels in semen were >1 log above blood levels in 35 samples from 26 men (10 while untreated, 15 on ART, and 1 both while treated and not).

In the first year, 122 (77%) of 158 semen samples from untreated men had detectable RNA compared to 2/9 (22%) on only RTI-, 0/11 on NNRTI-, and 2/20 (10%) on PI-containing regimens. Two sample tests of proportions among regimen types were not significant.

Corinne Amiel and colleagues from Hospital Tenon in Paris reported responses to treatment in primary infection in patients with high initial viral load levels. [4]

In this group 43/67 (64%) had initial viral load >500,000 copies/mL. Plasma dilution performed in 34 of 43 of these patients showed median levels of 6.58 log (range 5.8-7.6 log; 3.8 million – 42.3 million copies/mL). Median initial plasma viral load in the 24 patients in the lower group was 5 log (2.7 to 5.7). Time to sampling was related to viral load. The median time from HIV infection in the high group was 27 days (12 to 37) compared with 37 days (24 to 46) for the low group.

HAART was used by 54 patients (37 from the high and 17 from the low group). Change in viral load was greater in the group with higher viral load at baseline (approximated 1 log greater at month 1 and 3, and 2 logs greater by month 6. Importantly, viral load reached the same in both groups at month 3 and 6, and a higher percentage of patients from the high viral load group were <50 copies/mL at month 6 (83% vs 50%).

PI-based therapy was used more frequently (15 high, 6 low;) than efavirenz-based (11 high, 10 low) for patients starting with very high viral load levels.

Finally, Susan Morpeth and colleagues from Dukes University looked at time from seroconversion to positive ELISA and documented the case of one patient who took over a year to produce a positive antibody test result. [5]

This prospective cohort includes 46 patients enrolled from 1998 to 2004 who were diagnosed within 30 years of seroconversion, At the time of acute HIV-1 diagnosis, 25 of 46 patients had a negative ELISA. Median time (IQR) from symptom onset to first ELISA test:  negative ELISA = 7 (4-15) days; reactive ELISA = 29 (18-42) days, p <0.0001. Median initial viral load was higher among negative than reactive ELISA patients (5,649,238 vs 303, 318 copies/mL, p <0.0001). Patients with a negative ELISA were more likely to be non-Caucasian (p = 0.0186). Nadir CD4 count was comparable (median, 413 vs 471, p = ns) as was time to first positive ELISA (median, 26 days vs 29 days, p = ns).

The patient with the delayed response was a 22-year-old man who presented with viral load >10 million copies/mL and had repeatedly negative HIV-1 ELISA tests over the ensuing year, rapidly clinically progressed, with PCP during the year. He seroconverted only after initiation of effective antiretroviral therapy. Antibody responses to non-HIV antigens including prior tetanus and diphtheria immunization were normal.

This patients’ HLA type was not one associated with abnormal responses (HLA-B72). Plasma-derived virus (at initial diagnosis) used both CCR5 and CXCR4 co-receptors and the researchers concluded that perhaps targeting of HIV-1-specific T cells that augment specific B cell responses might explain their observations.

Comment

HIV-specific immunity remains a very important piece of the larger puzzle. The goal of generating and maintaining an immune response to HIV that limits the need for antiretroviral treatment is currently the aim of strategies aimed at inducing and/or preserving antiviral immune responses. Assessment of described potential correlates of protective immunity should be monitored. IFN-gamma responses do not fall into this category, as the presence of IFN-gamma producing HIV-specific CD4 T cells does not independently correlate with viral control in studies conducted so far.

While these initial reports are disappointing, further research has important potential, and should be supported in patients who tolerate early treatment without a serious impact on their daily quality of life.

A larger randomised study is currently ongoing at St Mary’s. Referral to this study for patients diagnosed very early after infection who are interested in early treatment.is recommended.

The results from Amiel and colleagues caution that early treatment does not produce undetectable viral load for all patients at month 6, although very high levels of initial viraemia, was not an obstacle in itself, and suggested that perhaps PI-based therapy may be more appropriate in this group.

References:

Unless stated otherwise, all references are to the Programme and Abstracts from the 13th Conference on Retroviruses and Opportunistic Infections, 5-8 February 2006, Denver, Colorado.

1. Fox J, Scriba T, Fidler S et al. HIV-specific immune responses fail to predict CD4 decline or clinical outcome following treatment at primary HIV-1 infection. Abstract 394.
2. Streeck H, Jessen H, Rockstroh et al. Clinical and immunological effect of HAART during acute HIV infection. Abstract 398.
3. Stekler J, Sycks B, Holter S et al. Semen HIV dynamics and effect of ART following primary HIV infection. Abstract 396.
4. Amiel C, Kara A, Schneider V et al. Primary HIV-1 infection: plasma dilution for peak viremia level and response to treatment. Abstract 402.
5. Morpeth S, Thielman N, Giner J et al. Time to HIV-1 seroconversion is similar among patients with acute HIV-1 infection, but there are exceptions. Abstract 389.