The rationale

Many doctors are now interested in offering three or four antiretroviral drugs to people who have recently contracted HIV, as a means of limiting the spread of HIV in the body and strengthening the body's immune response to HIV. Treatment with antiretroviral drugs during the early weeks of infection may have a significant effect on the course of HIV infection.

Controlled studies have shown that intervention with a range of different drug combinations during primary infection results in significantly lower viral load and significantly less viral infection of lymphoid tissue. However, at the moment we have no idea whether adjusting the viral load at this point in HIV infection affects long-term prognosis, although early treatment does reverse CD4 cell count decline. Research into the impact of treatment during primary infection and all results and recommendations should be treated with caution.

For treatment within 48 hours of exposure to HIV, see Treatment to prevent infection: post-exposure prophylaxis in Anti-HIV therapy: When to start treatment.

Should you start treatment so soon?

There is as yet no definitive answer to the question 'should you treat during the early days of HIV infection?'. It may be the case that the major effect of such early treatment is to use up all available drug options before you develop any symptoms. Alternatively, it may prevent the loss of the bodys own immune response to HIV. Some people may opt for a 'wait and see' approach once infection is established. Waiting may be a good strategy if you have contracted a drug-resistant virus, because treatment may not produce immune benefits until new drugs become available.

Arguments in favour of early treatment should be considered within the context of long-term toxicities of antiretroviral therapy. Lipodystrophy and metabolic disorders have occurred among people treated during primary infection, and the long-term health effects of early treatment are unknown (Miller 2000).

Despite the risks, many people who contract HIV are taking up treatment at a very early stage. British data show that seroconverters are now much more likely to start anti-HIV treatment within six months of infection than in the past. One in five people who contracted HIV in Britain in 1997 and 1998 started early treatment, with an average CD4 cell count of 221 cells/mm³ (Porter 1999).

Early treatment and prevention

While it remains unclear whether treatment during primary infection is best for the individual, there may be a public health case for encouraging treatment during the acute stage of infection. At this time, most people have very high viral loads in blood and sexual fluids which means the risk of transmission is higher than later in the infection. Early treatment has the potential to reduce viral load and the associated risk of HIV transmission (Vernazza 1999).

Immunological response

Preliminary results indicate that treatment with anti-HIV drugs in the first few weeks of HIV infection can sometimes alter the course of the illness and enable the immune system to better respond to HIV infection.

Soon after primary infection, the immune system generates CD4 and CD8 T-cells that are specifically designed to respond to HIV and HIV-infected cells. In most people, HIV simply infects this supply of CD4 T-cells, and the HIV-specific T-CD8 cells are also gradually overwhelmed during the course of the infection. Nevertheless, the body does maintain HIV-specific immune cells in the absence of treatment, albeit at very low levels in most people, and researchers believe that early treatment may strengthen the body's own HIV-specific immune responses. Current research suggests that treatment among people with long-term HIV infection does not lead to the return of HIV-specific CD4 T-cells, but it is hoped that early treatment may (Pitcher 1999).

There is some encouraging evidence that early treatment may stimulate the body's immune response to HIV. Bruce Walker and his team from the Harvard Medical School found that treatment in the first few weeks of infection can protect and sustain HIV-specific CD4 T-cells. Others have found that the magnitude and breadth of HIV-specific CD8 T-cell responses also increase following treatment during primary infection (Ortiz 2002), and this improvement seems to correlate with CD4 T-cell increase. However, despite the preservation of HIV-specific immune responses there is little evidence that early treatment translates into a lower viral load when therapy is stopped. Even the use of therapeutic vaccines or cycles of treatment may not help control HIV when treatment is ceased (Markowitz 2002; Garcia 2002).

A recent study has highlighted the effect of early treatment on the innate immune response. Although primary HIV infection was shown to be associated with dramatic decreases in the antiviral factor type I interferon and the plasmacytoid dendritic cells that produce it, twelve months of HAART started a median of 51 days after infection resulted in a normalisation of type I interferon production. The investigators argue that early initiation of therapy, or possibly artificial interferon therapy with peginterferon alfa, could be of benefit in restoring innate anti-HIV immune responses (Kamga 2005).

Immune recovery seems to be more complete when treatment is started during primary infection. Several teams have found that treatment during primary infection reduces the immune activation that assists the infection of new CD4 T-cells, and increases the number of naive and memory CD4 T-cells (Bart 2000; Bisset 2001; Goh 2001). Compared to starting treatment during the chronic phase of disease, early treatment produces significantly greater CD4 T-cell increases after one year (Kaufmann 2000).

Exactly how quickly a person starts treatment may play a crucial role in immune response. The RIGHT team reported that seven out of eight people treated before full seroconversion developed a vigorous HIV-specific CD4 T-cell response, compared to one of five people treated after seroconversion. Treatment before seroconversion also reduced the reservoir of infected latent cells (Lori 2002).

Reducing the number of target cells which HIV can infect during primary infection may also protect the long-term immune response. Swiss investigators found that adding the immunosuppressant ciclosporin (Neoral / Sandimmun) to highly active antiretroviral therapy (HAART) in primary infection reduced T-lymphocyte activation but paradoxically led to a significantly greater CD4 T-cell increase than seen with HAART alone (Rizzardi 2002). This may be a consequence of the very large number of CD4 T-cells usually activated, and thus infected, during primary infection.

For further discussion of immunological response to early treatment, see Restoring HIV-specific immunity in Anti-HIV therapy: Restoring the immune system.

Virological response

When treatment is taken during primary infection, the proportion of people achieving undetectable viral load is similar to, if not slightly better than, response rates seen during chronic infection. For example, one of the largest studies of treatment during primary infection reported a virological response rates of 82% (Daar 2001). The reason for this strong response rate could be due, in part, to the lack of viral diversity which means drugs and immune responses are more effective.

While treatment during primary infection usually reduces plasma viral load to undetectable levels, viral eradication does not occur. One study that demonstrated the failure of eradication was a small Spanish study which found that most participants had very low levels of viral replication in their blood. Detectable virus was associated with failure to normalise T-cell counts in five of ten participants, even after one to two years of therapy (Garcia 2001). The persistence of HIV DNA and RNA in the cells and lymph nodes of patients who respond well to primary treatment is regarded as evidence of ongoing viral replication despite the apparent suppression of HIV in the blood plasma (Tilling 2002; Yerly 2000a).

Compared to treatment during chronic infection, levels of HIV actually decline more slowly when treatment is given during primary infection (Putter 2000). Experts think this may be because people have not yet developed a strong anti-HIV immune response, which means the body is slower at clearing HIV-infected cells.

Another theory behind treatment during primary infection has been the prevention or disruption of so-called 'viral reservoirs'. The follicular dendritic cells in the lymph nodes are a key site of HIV replication and storage. During primary infection, there are fewer infected cells in the lymph nodes than during chronic infection, suggesting that early intervention may reduce the spread of HIV throughout the body (Tenner-Racz 2000). However, one study has found that very early treatment does not disrupt infection of follicular dendritic cells. Two men treated within four days of seroconversion symptoms underwent lymph tissue biopsies which found viral load between 20,000,000 and 158,000,000 copies/ml (Schacker 2000).

Although treatment during primary infection does not prevent infection, it can limit the size of the pool of latently infected cells. When compared with people who initiated therapy after chronic infection became established, people who began treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen between 60 days and one year after the suspected date of infection had significantly lower levels of HIV DNA and showed similar levels to those of long-term non-progressors (Pires 2004).

Stopping early treatment

Regimens including ddI (didanosine, Videx) and hydroxycarbamide (Hydrea) have been tested in people with primary infection, including a small number of individuals reported to have shown no rebound in viral load after ceasing treatment altogether.

However, these individuals appear to be rare exceptions. A case report from the United States suggests that there is a risk of viral rebound and even of seroconversion illness if treatment ceases. A man who had received triple therapy following identification of acute seroconversion illness was unable to tolerate the regimen after six months, and treatment was stopped. Thirty-five days later he developed an acute illness indistinguishable from HIV seroconversion syndrome and his viral load rebounded above one million copies (Daar 1998).

A few cases have been reported where interruptions to HAART begun very early in infection appear to have resulted in continued viral suppression even after treatment was stopped altogether (Lori 2002; Ortiz 1999). It is hypothesised that a host HIV-specific immune response which has been stimulated through the 'go-stop' therapy is controlling the virus. A common factor amongst these cases is the very early initiation of treatment. See Restoring HIV-specific immunity in Anti-HIV therapy: Restoring the immune system.

A team from Belgium evaluated seven people who began treatment during primary infection and subsequently elected to stop after between twelve and 36 months. Viral load quickly rebounded within two to four weeks in four cases. The remaining three, however, showed no sign of active HIV replication after a year off treatment on average (De Wit 1999).

Whilst doctors have been quick to point out that the most common outcome of 'drug holidays' is a rebound in viral load, perhaps with resistant virus, these cases have naturally created a great deal of interest. A number of research projects are now ongoing worldwide to investigate structured breaks in, and eventual cessation of, antiretroviral treatment. See Anti-HIV therapy: Structured treatment interruption.

Further information about primary infection, its symptoms and prognostic significance can be found in Exposure and primary infection in The immune system and HIV: How HIV damages the immune system.

Research into the effects of treatment during primary infection

Garcia (2002) reviewed data on 44 people treated during primary infection who underwent several cycles of treatment interruption. Six months after ceasing treatment, only 41% had a viral load below 5000 copies/ml or a half a log lower than their pre-treatment viral load. This response was associated with a lower baseline level of CD4CD38 and naive CD4 cells, and a higher level of memory CD4 cells.

David Ho and Martin Markowitz (2002) at the Aaron Diamond AIDS Research Center in New York reported that 16 people treated within 120 days of HIV infection underwent treatment with combination antiretroviral therapy for an average of 3.2 years. 11 also received experimental therapeutic vaccines in an attempt to stimulate HIV-specific immune responses. When treatment was ceased, HIV rebounded in all subjects and then fell to a setpoint above 500 copies/ml. Therapeutic vaccination had no effect on viral setpoint.

Fidler (2002) offered 45 people with confirmed primary HIV a short course of antiretroviral therapy. 37 accepted treatment and all achieved a viral load below 50 copies/ml by week 10. After 64 weeks off therapy, all patients who took short course antiretroviral therapy had sustained HIV-specific CD4 cell responses.

Altfeld (2001) reported that early treatment of HIV infection limits HIV diversity and that HIV-specific CD8 (cytotoxic) responses are accordingly narrow. Early treatment also produces stronger HIV-specific CD4 responses.

Daar reported a non-randomised study of 55 people with acute retroviral syndrome (average baseline CD4 count 485 and viral load 5.34 log HIV RNA). Baseline resistance testing showed 20.5% had NNRTI-resistant virus, 13.6% had PI-resistant virus and 2% had NRTI resistance. 23 people declined treatment, 22 started a PI-based regimen and 10 took a non-PI regimen. At six months, the untreated group had an average CD4 fall of six cells and viral load decline of -0.72 log. In the treated group at six months, CD4 count rose by an average of 101 and viral load fell by -3.25 log; 82.4% had viral loads below 500 and 58.8% were below 50.

Rizzardi and colleagues treated nine patients identified with primary infection with AZT/3TC/ritonavir/saquinavir, plus cyclosporin A (0.6-1.2mg/kg) for the first eight weeks of HAART. HIV RNA and immunological responses were compared with a group of 29 patients who received the same HAART regimen without cyclosporin during primary infection (non-randomised comparison). The cyclosporin recipients had significantly better HIV RNA and CD4 cell outcomes at all time points. 88% of the cyclosporin group vs 52% of the HAART alone group had HIV RNA below 50 copies at week 24. Mean CD4+ cell count increase at 24 weeks was +586 cells in the cyclosporin group vs +198 cells in the HAART group (p=0.017), and at week 64 this difference was sustained (1443 vs 712 cells).

Geise reported 2-year data on 15 people who commenced antiretroviral treatment within 120 days of infection compared to 30 people who deferred therapy. Mean CD4 count was significantly higher in the group who started treatment during PHI (953 vs 701) although the average CD4 increase was similar. Treatment failure (defined as a viral load above 500) was more likely in the group who deferred therapy (0/15 vs 8/30). No difference in clinical endpoints was detected after two years.

The French ANRS 053 study is one of the most significant studies of early treatment published to date. Sixty-four people commenced AZT/3TC/ritonavir between 10-108 days after the first sign of a seroconversion illness during 1996-1997. Only 59% remained on triple therapy by June 1998 and intent-to-treat analysis found that 72% had viral loads below 50 copies after 21 months on treatment. HIV-DNA was detected in the blood cells of 85% of 27 people evaluated after 18 months of treatment, despite undetectable levels of HIV RNA. Eleven of these patients underwent lymph nodes biopsies. HIV RNA and DNA in the lymph nodes was detectable in 6/11 and 8/11 patients after 18 months (Hoen 1999; Garrigue 2000).

Berrey compared treatment with indinavir/AZT/3TC within three months of infection in 20 people, with the effects of no treatment in a control group of 47 recently infected people. All treated individuals suppressed viral load to below 50 copies within 19 weeks, and they achieved an average CD4 increase of 7.4 cells per month. In contrast, the untreated group had an average CD4 decline of 10 cells per month. After 78 weeks of follow-up, six untreated participants had a CD4 count below 200, compared with none in the treatment group, and clinical signs of immune deficiency such as skin conditions, respiratory infections, and opportunistic infections (5% vs. 21.3%, p=0.02) were less common in the treatment group.

Goh (2001) and Tilling (2002) reported on 148 people with HIV primary infection who were recruited into the international QUEST study using a four-drug regimen (amprenavir/abacavir/3TC/AZT) for at least 76 weeks. have shown viral clearance and normalisation of the immune system. Those with viral load below 50 were randomised to continue HAART alone or add ALVAC vCP1452 or ALVAC vCP 1452 plus Remune. At 28 weeks of treatment, 80% of patients had a viral load less than 50 copies/ml. The CD8+CD38++ levels, which had risen to over 60 times normal levels, fell significantly. Normalisation of this activation marker corresponded with suppression of HIV RNA to below 50 copies/ml.

Vernazza found higher levels of HIV in semen samples from 27 people with primary HIV infection, compared to those in 39 untreated people with chronic infection. When 11 of the former group began anti-HIV treatment, viral load in their semen fell nearly 2 logs on average.

A French study of 15 seroconverters treated with triple nucleoside analogue (AZT, 3TC, ddI) therapy has followed participants for over two years. This study found that long-term viral suppression occurred in nine of 15 people treated within a month of seroconversion illness. HIV could not be cultured from the CD4 cells of two people. One participant stopped treatment and viral rebound followed (Poggi 1999).

Of a group of 41 PHI patients on treatment studied over a six month period, where the average duration of therapy was 11.7 months, 22 self-identified fat redistribution, and this was confirmed by their doctor in six cases (Miller).

Hogan reported on responses to primary infection treatment in a cohort of 132 individuals who received PI-containing regimens. 55% remained on treatment or on STI, while 44% had discontinued due to adverse events, lost to follow up or virologic failure. Of 88 individuals who achieved VL < 50 copies/ml, 12 experienced virologic rebound.

Ortiz (2002) compared 31 people treatment during primary infection and 23 treated during chronic infection. People treated during the early phase of infection who subsequently have transient detectable virus have higher levels of HIV-specific CD8 cell responses.

Yerly (2000) compared 10 people who began treatment during chronic infection with CD4 above 500, 21 people with CD4 below 500, and 10 people treated during primary infection. 55% of those treated during primary infection had persistently very low viral load (below 3 copies/ml) compared with none of the chronically infected patients.

Carcelain (1999) reported that 8 people treated with triple nucleoside therapy during primary HIV infection had an average viral load reduction of -2.1 log and a CD4 cell increase of 158 at week 4.

Research into PHI treatment options

The Spanish Earth-1 Study has found that early treatment with three drugs including a protease inhibitor produces better results than dual nucleoside therapy. At one year, 29 of 33 people in the ritonavir arm had viral loads below 20 copies compared with 8 of 94 on the various two-drug arms. After one year, those not on treatment were seven times more likely to experience disease progression, defined as development of symptoms or loss of CD4 cells, compared with those on treatment (Garcia). The two drug control arm has now been abandoned.

Kahn reported a comparative study of patients with primary infection randomised to combination therapy with or without IL-2. IL-2 increased CD4 levels but made no difference to HIV-specific CD8 responses, expansion of the immune repertoire or viral control.

A Swiss study of AZT monotherapy for people who had experienced seroconversion illness showed a net gain in CD4 cells amongst the AZT treated group over 15 months of follow-up, compared with a net loss in CD4 cells amongst the placebo group (Kinloch-de Loes).

A Swedish study comparing treated and untreated people with symptomatic primary infection suggested that antiretroviral treatment was more likely to result in suppression below the limit of detection (50 copies) if it was initiated within days of the onset of symptoms and if it consisted of three drugs rather than two (Gaines). In untreated patients viraemia peaked at a level above 500,000 copies just after the onset of symptoms and declined by 2 log over the following four months. However, long-term follow-up found that AZT during primary infection did not delay HIV disease progression or death (Lindback).

Italian research among people with primary HIV infection has found that early treatment with AZT had little effect on CD4 count and viral load, whereas combination therapy significantly reduced viral load and restored CD4 counts. Three people on HAART had not fully seroconverted after 12 months of treatment (Lillo 1999).

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