Primary infection and treatment issues
Simon Collins, for HIV i-Base
Over the last six months the belief held by researchers looking at treatment in early infection was vindicated by the results from Bruce Walkers group at Massachusetts General Hospital.
This showed the possibility that early treatment can generate a sufficient immune response to make intermittent (and possibly no treatment at all) an achievable goal.  Indeed, even the newly revised more conservative US treatment guidelines retain the recommendation to start treatment if early infection is detected. The theoretical rationale for early intervention being stated as:
- To suppress the initial burst of viral replication and decrease the magnitude of virus dissemination throughout the body.
- To decrease the severity of acute disease.
- To potentially alter the initial viral “set point,” which may ultimately affect the rate of disease progression.
- To possibly reduce the rate of viral mutation due to the suppression of viral replication.
- To possibly reduce the risk of viral transmission.
- To preserve immune function.
Such considerations considerably strengthen the importance of early diagnosis and a greater awareness of signs of seroconversion both in GUM/STI and primary care clinics. Over 30 presentations reported on treatment, diagnostics, infectivity, resistance and immunological responses during primary infection.
Primary HIV Infection (PHI) is defined as the period following infection but before seroconversion. This usually takes 2-4 weeks, but can take several months and has been documented in one case to take 10 months. During this asymtomatic period routine HIV tests (ELISA and Western Blot) will generate a negative result although HIV RNA levels are very high (often in the millions/mL), therefore either viral load or p-24 antigen tests can be used to confirm a suspected case of PHI. A combined HIV antibody and p-24 assay developed by Bio Merieux and a combined HIV antibody and antigen assay from Abbott were presented in posters, both with the promise of shortening the period post infection before detection [2, 3].
The practical application for these assays may be more for public health blood screening programmes than individual cases, where a routine viral load assay would generate a positive result in a shorter period. Indeed, Fiebig and colleagues using modelling based on the slope of viral load increase and viral doubling time estimated that a regular RNA viral load test sensitive to 50 copies/ml would already detect primary HIV infection 7 days prior to a p-24 antigen test and 12 days prior to an anti-HIV antibody test. 
Infectivity, transmission and seroconversion symptoms
High levels of viral load in the weeks post infection and the effect of coinfection with other sexually transmitted infections presents a greater risk of infectivity than during chronic infection. Five cases of secondary transmission, prior to symptoms of seroconversion, were reported by Picher and colleagues (one M-M, three M-F and one F-M). The transmission pairs were identified from US and European cohorts and confirmed by phylogenetic analysis of pol sequences.
Transmission to the HIV-negative partner occurred a median of two days prior to seroconversion symptoms occurring in the index case (range – 7 to +7 days). Median peak viral load in the index cases was 6 million copies/ml (range 5.3-7.2 log), other STIs were confirmed in two cases and semen RNA exceeded blood plasma levels in the one case it was measured. A second study from this group looked in further detail at the association between viral load levels in blood and semen during PHI. 
Speed of onset and severity of seroconversion symptoms were both found to be highly predictive of risk of progression to CD4 <200 cells/mm3 (for fever, fatigue and myalgia – but not rash, headache or arthralgia).
Adjusted hazard ratios (CI95%) for progression and incubation and duration cut-offs in this study were as follows:
|Features||ARH (CI95% of progression to AIDS/CD4<200)|
|Fever||Inc <2.5d: ARH 5.8 (1.7-19.1), p=0.004.
Duration >11d: ARH 8.1 (2.4-27.7), p=0.0009
|Fatigue||Inc <21d: ARH 2.7 (0.9-8.3), p=0.06.
Duration >17.5d: ARH 3.1 (1.1-8.9), p=0.03
|Rash||Inc <22d: ARH 1.4 (0.4-4.6), p=0.06.
Duration >10d: ARH 1.7 (0.5-5.4), p=0.3
|Headache||Inc <23.5d: ARH 1.8 (0.6-5.5), p=0.3.
Duration >13d: ARH 4.1 (1.1-14.2), p=0.02
|Myalgia||Inc <25.5d: ARH 3.8 (1.0-14.4), p=0.04.
Duration >11d: ARH 8.0 ((1.6-38.3), p=0.009
|Arthralgia||Inc <19d: ARH 2.8 (0.6-13.6), p=0.2.
Duration >15d: ARH 8.5 (0.8-92.2), p=0.07
Transmission of drug-resistant HIV
Transmission of virus resistant to each and all classes of currently available drugs has already been reported for all methods of transmission (sexual, needle sharing, needlestick,, perinatal). The extent of such transmission are still reported to vary by geographical area.
16/61 newly-infected individuals (1999-2000) from New York (n=55) and Montreal (n=6) treated at the Aaron Diamond Institute showed a prevalence of 26% resistance conferring amino acid substitutions, including 5 cases of multiple class MDR. Phenotypic resistance (from 58 tests using PhenoSense assay) showed an overall prevalence of reduced susceptibility to any drug of 38% (>2.5 to 5-fold: 28%; >10-fold: 7%). Lack of phenotypic susceptibility in these samples was roughly evenly split between NNRTI and PI. Hypersensitivity, (<0.4-fold) to any NNRTI was seen in 10 cases (17%) and to any PI in 4 cases. This represented a statistically significant increase in transmission of drug resistant virus compared to levels of 16% previous years (1995-98), p<0.05. 
A larger US study, looking at phenotype resistance and subsequent response to treatment in over 400 treatment naive subjects with recent infection, found 8% to with >10-fold susceptibility to at least one agent and 4% showing >10-fold reduced susceptibility to at least two classes. Although the importance of referencing separate sensitivity scales for different drugs in now recognised the time to achieve undetectable viral load (<400 copies/ml) was significantly increased in patients with >5- and 10-fold reduced susceptibility to one or more ARV at baseline (p=0.005 an p=0.04). 
Closer to home, genotypic mutations to at least one class of ARV was detected in 10% in three French cohorts (n=108) – 6.5% NRTIs, 3.7% to NNRTIs and 2.8% to PIs. 
A single case study was also shown of a 32-year old man with seroconversion symptoms whose phenotype profile showed >2.5-fold resistance to all RTIS (except ddI and ddC), all NNRTIs and al PIs (except saquinavir). Electing not to take treatment, viral load and CD4 count were monitored and remained constant over the next 4 months (2.9-3.1 log10 copies and 504-629 cell/mm3 respectively). At month 5, co-incident with a log-fold increase in HIV RNA viral genotype showed a reversion to viral type. Although most people expect the resistant strain to remain archived, and likely to return should ARV treatment be initiated in the future the implication of reduced fitness from resistant virus deserves further study. 
Treatment in Primary Infection
One of the most important reports concerning treatment in was presented in a State of the Art lecture on supervised treatment interruption.  Bruce Walker updated results from his cohort of 14 patients that have been treated prior to seroconversion. All patients had been maximally suppressed with antiretroviral regimens for at least eight months prior to the first treatment interruption (mean = 547 days, range 270-1081 days). Mean viral load at diagnosis was 10 million copies/ml.
The study design included restarting treatment if viral load rebounded to >50,000 copies/ml at any time or if it remained >5000 copies/ml for >3 consecutive weeks. Primary endpoints included control of viraemia without therapy, boosting of virus specific immune responses following a regulated exposure to autologous virus and control of viraemia after subsequent interruptions.
Seven patients have so far discontinued treatment once and maintained viral suppression, one of whom has restarted by choice, despite not reaching protocol defined endpoints. This person subsequently stopped treatment for a second time and controlled viral load for almost 300 days before deciding to restart again at a viral load level of only 600 copies/ml. The remaining six of these seven patients all saw their viral load rebound , but not above protocol defined endpoints before they all drove viral levels back down and maintained relative viral control at <5000 copies/ml for between 80-450 days.
The remaining seven patients rebounded above protocol limits following their first interruption and needed to restart therapy after 5-60 days off-treatment (five of whom rebounded to >50,000 copies/ml). All but one of these patients have subsequently controlled viraemia. Time to breakthrough following a second treatment interruption extended considerably in these patients. Mean time to restart was 36 days following the first interruption and 184 days following the second. A highly statistically significant increase in magnitude and breadth of CTL responses was also reported following this second interruption. Only one patient failed to control viraemia (after 4 treatment interruptions) and remains at 7445 copies/ml after 128 days off therapy – and appears likely to restart.
It was clearly acknowledged that this is a small cohort, treated very early after infection, and that neither long term durability nor clinical benefit have been proven. Nevertheless the importance of this study within a PHI as well as STI report is that it demonstrates extremely optimistic results supporting immunological control similar to that seen in long-term slow progressors.
A further ten other posters provided cautions and practical information for treatment in primary infection. Success shown in the Walker study may be the only justification from starting treatment many years before CD4 levels are reached for initiating treatment in chronic infection.
Time to initiation of HAART post infection correlated directly to chance of success in a study from Geise and colleagues from Washington.  All 37 patients starting within 120 days or seroconversion achieved and maintained undetectable viral load and virological failure occurred in only 1/50 people who started treatment within a year. However a closely monitored and supported primary infection cohort in San Diego reported that 29/48 (60%) changed therapy 61 times using a mean of 5 drugs over their first treatment year. Clinical and laboratory toxicity and treatment failure was responsible for 43% of these changes. Suppression to <400 and <50 copies/ml was reported in 52% and 21% patients at week 24 and 46% and 31% respectively at week 48. 
Goujard and colleagues reported on early onset of lipodystrophy in a French cohort of 121 patients treated in primary infection and who had been followed for >6 months. 22 patients (18%) presented with at least one lipodystrophy symptom after a mean 24 months follow-up and a cumulative risk factor was determined as 6% at 12 months, 18% at 24 months and 30% at 36 months.  The decision to initiate therapy early must therefore be sufficiently supported to avoid early development of resistance to drugs, and subsequent interruptions if followed must have some assurance of reversing adverse events.
- Walker B et al, Early antiviral treatment primes the immune system to suppress viral levels without drugs. Nature Oct 2000 (see http://www.i-base.info/htb/3913).
- Erb P. Advantage of Combined HIV Antibody and p24 Antigen Assays to 3rd-Generation HIV Assays in the Diagnosis of HIV Infection. 8th CROI. Abstract 244.
- Chang CD. Combined HIV Antigen and Antibody Assay on a Fully Automated Chemiluminescence Analyzer To Shorten the Seroconversion Window. 8th CROI. Abstract 245.
- Fiebig E. Dynamics of HIV Viraemia Preceding Antibody (Ab) Seroconversion (SC) in Plasma Donors: Implications for Detection of Primary Infection by p24 Antigen (Ag) and Nucleic Acid Amplification (NAT) Screening Assays. 8th CROI. Abstract 415.
- Pilche CD. Sexual Transmission Can Precede Symptoms in Primary HIV-1 Infection. Abstract 411.
- Vanhems P. Incubation and Duration of Specific Symptoms at Acute Retroviral Syndrome (ARS) Are Independent Predictors of Progression to AIDS. 8th CROI. Abstract 414.
- Simon V et al. Prevalence of Drug- Resistant HIV-1 Variants in Newly Infected Individuals during 1999- 2000. 8th CROI. Abstract 423
- Little SJ et al. Antiretroviral drug susceptibility and response to initial therapy among recently infected HIV-infected subjects in North America. 8th CROI. Abstract 756.
- Chaix ML. Prevalence of Genotypic drug resistance among French patients infected during 1999. 8th CROI. Abstract 755.
- Daar E et al. Viral Evolution in an Untreated Patient Who Acquired Multi-Drug-Resistant HIV during Primary Infection. 8th CROI. Abstract 427.
- Walker B. State of the Art Lecture and Summary. Available on webcast. 8th CROI. Session 37.
- Geise R et al. Effects of Therapy Delay on Virologic Failure in Early HIV. 8th CROI. Abstract 400
- Kurup et al. Treatment of Primary HIV Infection: Efficacy, Tolerance, and Predictors of Response. 8th CROI. Abstract 404
- Goujard et al. Early Occurrence of Lipodystrophy in HIV-I-Infected Patients Treated during Primary Infection. 8th CROI. Abstract 403.